Fishman's Pulmonary Diseases and Disorders - PART 05-08 by HD Derma

PART

V Occupational and Environmental Disorders

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SECTION ELEVEN

Occupational Disorders

54 CHAPTER

Occupational Lung Disorders: General Principles and Approaches Mridu Gulati

Carrie A. Redlich

I. CLASSIFICATION OF OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASE II. BASIC PRINCIPLES OF OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASE III. IMPORTANCE OF OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASES IV. ESTABLISHING A CAUSE Diagnostic Criteria Determination of Causal Relationship

Hazardous exposures in the workplace and elsewhere in the environment continue to contribute to the burden of lung disease. With increasing concerns regarding the health effects of environmental and occupational exposures, such as exposures following the World Trade Center collapse, clinicians must be prepared to recognize, diagnose, and manage occupational and environmental lung diseases. As patient access to sources of information regarding such exposures expands, health care providers must also be prepared to provide preventive advice and to address patientsâ&#x20AC;&#x2122; concerns regarding such exposures. Most respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease, and lung cancer may be caused or exacerbated

V. CLINICAL APPROACH TO THE PATIENT General Approach The Occupational and Environmental History Diagnostic Tests Exposure Assessment VI. PREVENTION Social, Economic, and Public Health Considerations Prevention Regulatory Issues Respirators

by factors in the workplace, but rarely are such disorders distinguishable pathologically or clinically from idiopathic or nonoccupational causes. Thus a high level of suspicion and knowledge of the basic approaches used in the diagnosis and management of occupational and environmental disorders is essential for all practitioners. This chapter provides an overview to these approaches. Since the last edition, a growing body of literature has expanded our understanding of several aspects of occupational and environmental lung diseases, including a substantial contribution of workplace exposures to the development of COPD and asthma, adverse health effects related to indoor and outdoor air pollution, and greater recognition that work-exacerbated asthma can be as disabling

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as primary occupational asthma. Additional information can be obtained from several excellent recent texts on this topic.

CLASSIFICATION OF OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASE Environmentally induced lung diseases can be classified according to several schemes. One useful approach is to classify them by clinical presentation or disease, as shown in Table 54-1. A given exposure (asbestos, cobalt, etc.) can cause more than a single disorder. When one is examining a patient, it can also be helpful to consider occupational lung diseases by types of exposures that can cause lung disease, such as mineral dusts (asbestos, silica, coal), biologic factors (animal exposures, microbial agents), metals (beryllium, cobalt, aluminum), or inorganic gases (carbon monoxide, chlorine,

nitrogen oxides), or by the type of industry associated with selected respiratory problems, such as mining, agriculture, forestry, or welding. For patients presenting with interstitial lung disease, a classification scheme based on histological pattern, as shown in Table 54-2, may facilitate diagnosis and management. Occupational and environmental exposures play an important role in many lung disorders. However, accurate estimates of the contribution of such factors to specific lung diseases can be difficult to find. It is generally believed that under recognition and under reporting of occupational lung diseases are widespread. Although historically the pneumoconioses have been the most commonly diagnosed occupational lung diseases, occupational airways diseases have become the most prevalent occupational lung disorder in developed countries. Worldwide, silicosis remains the most common occupational lung disease. In a few instances, such as the rare tumor mesothelioma, most cases can be attributed to occupational exposure to asbestos. However, the contribution of

Table 54-1 Classification of Occupational Lung Disorders Major Disease Category

Representative Causative Agents

Upper respiratory tract irritation

Irritant gases, fumes, dusts

Airway disorders Occupational asthma Sensitization Low molecular weight High molecular weight Irritant-induced, RADS Byssinosis Grain dust effects Chronic bronchitis/COPD

Diisocyanates, anhydrides, wood dusts Animal-derived allergens, latex Irritant gases, smoke Cotton dust Grain Mineral dusts, coal, fumes, dusts

Acute inhalation injury Toxic pneumonitis Metal fume fever Polymer fume fever Smoke inhalation

Irritant gases, metals Metal oxides: zinc, copper Plastics Combustion products

Hypersensitivity pneumonitis

Bacteria, fungi, animal proteins

Infectious disorders

Tuberculosis, viruses, bacteria

Pneumoconioses

Asbestos, silica, coal, beryllium, cobalt

Malignancies Sinonasal cancer Lung cancer Mesothelioma

Wood dust Asbestos, radon Asbestos

Note: Abbreviations: RADS = reactive airway dysfunction syndrome; COPD = chronic obstructive pulmonary disease.

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Occupational Lung Disorders: General Principles and Approaches

Table 54-2 Histologic Classification Lung Disorders Selected Histologic—Clinical Descriptions

Selected Associated Occupational Exposures

Usual interstitial pneumonitis/idiopathic pulmonary fibrosis

Asbestos, radiation

Nonspecific interstitial pneumonitis

Organic antigens

Acute interstitial pneumonitis (diffuse alveolar damage)

Irritant inhalational injury—NOx , SOx

Hypersensitivity pneumonitis

Organic antigens (i.e. farmer’s lung, wood worker’s lung), Animal antigens (birds), Metal working fluids Chemicals—isocyanates, anhydrides

Sarcoid-like granulomatous lesions

Beryllium, organic antigens, aluminum

Giant interstitial pneumonitis

Cobalt (hard metal)

Bronchiolitis obliterans

Toxic fumes (nitrogen dioxide, sulfur dioxide, diacetyl-popcorn lung), painting textiles

Alveolar proteinosis

High level exposure to silica

Diffuse alveolar hemorrhage

Acid anhydrides

occupational and environmental factors to most other lung diseases is much harder to determine. For example, estimates of the proportion of lung cancers attributable to occupational exposures have ranged from 1 to over 40 percent. Occupational factors are estimated to account for 10 to 20 percent of cases of asthma in adults. A growing literature supports the conclusion that occupational exposures account for about 15 percent of COPD, and a higher proportion of COPD in nonsmokers. However, clinicians rarely diagnose occupational asthma, COPD, or lung cancer, especially in patients who smoke.

BASIC PRINCIPLES OF OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASE

Certain principles apply broadly to the full range of respiratory disorders caused by inhalation exposure to agents in the workplace or environment: 1. While a few environmental and occupational lung diseases may present with pathognomonic features, such as mesothelioma, most are difficult to distinguish from disorders of nonenvironmental origin. In addition, most lung disorders can be caused or ex-

acerbated by environmental or occupational exposures. Thus, environmental and occupational triggers must be constantly sought in the evaluation and management of pulmonary disorders. A given substance in the workplace or environment can cause more than one clinical or pathologic entity. For example, cobalt exposure can cause interstitial lung disease and airway disease. The etiology of many lung diseases may be multifactorial, and occupational factors may interact with other factors. For example, the risk of developing lung cancer in asbestos-exposed workers who smoke is much greater than in those exposed to either asbestos or cigarettes alone. The dose of exposure typically is an important determinant of the proportion of people affected and the severity of disease. Higher doses of exposure usually result in more affected individuals or greater disease severity. Dose generally correlates with severity in patients experiencing nonimmunologic direct toxicity, such as chemical toxic pneumonitis, asbestosis, or silicosis. In those with cancer or immune-mediated disorders, dose more commonly affects incidence than severity. Individual differences in susceptibility to exposures exist. Adverse effects occur in some persons,

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while others with similar exposure are spared. Host factors that determine susceptibility to environmental agents are poorly understood but probably include, genetic factors and also acquired factors such as diet, and the presence of other lung diseases and exposures. Occupational diseases, especially immune-mediated processes such as chronic beryllium disease or occupational asthma, can occur or progress at low levels of exposure, below government-set exposure standards. 6. The effects of a given exposure occur after the exposure with a predictable latency interval. For acute diseases such as toxic pneumonitis, there is a short and usually predictable period between exposure and resultant clinical manifestations, which facilitates recognition of a causal relationship between exposure and disease. When symptoms or signs are recurrent with repeated exposures, as with occupational asthma, this temporal relationship can help establish the diagnosis. For chronic diseases such as cancer or most pneumoconioses, long latency periods between the first exposure and subsequent clinical manifestations are common. Consequently, the patient’s exposure to the offending agent(s) may have ceased long before the onset of disease, making the diagnosis of such diseases particularly challenging.

IMPORTANCE OF OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASES There are several compelling reasons to search for an occupational or environmental cause in all cases of pulmonary disease. First, knowledge of cause may affect patient management and prognosis, and may prevent further disease progression in the affected person. Second, establishment of cause may have significant legal, financial, and social implications for the patient. Third, the recognition of occupational and environmental risk factors can also have important public health and policy consequences. For example, a larger population at risk may benefit from the initiation of preventive measures. In addition, new associations between exposure and disease may be identified, such as the growing recognition that occupational exposures contribute to COPD. Last, occupational and environmental lung diseases can also serve as important disease models. For example, chronic beryllium disease may serve as a model for sarcoidosis.

ESTABLISHING A CAUSE Diagnostic Criteria To establish whether a lung disease has an occupational or environmental origin, the disease should first be defined and characterized, and then the degree to which occupational

or environmental exposures are causative or contributory should be determined. The following criteria are used to determine whether a disease is caused or exacerbated by agents in the workplace or environment: 1. The clinical presentation and work-up are consistent with the diagnosis. 2. A causal relationship between the exposure and the diagnosed condition has been previously established or strongly suggested in the medical, epidemiological, or toxicological literature (see below). 3. There is sufficient exposure to cause the disease (see below). 4. The details of the particular case, such as the temporal relationship between exposure and disease, are consistent with known information about the exposure-disease association. 5. There is no other, more likely diagnosis. In addition, for acute diseases such as occupational asthma, improvement away from the exposure or reproduction of the disease manifestations by re-exposure to the suspected agent can provide additional evidence to support the diagnosis. The degree of uncertainty in diagnosing occupational illnesses is generally substantially greater than in other medical settings—a source of uneasiness for clinicians. For example, in the United States, for most workers’ compensation systems, a disease is considered occupational if “more probably than not” (greater than 50 percent chance) it is work related.

Determination of Causal Relationship Three main types of information have been used to support a causal relationship between an exposure and a respiratory condition: case series or reports, epidemiological studies, and toxicology animal studies. Clinical studies of similarly exposed patients have identified potential occupational causes of lung disease, which have then undergone further epidemiological investigation. The clinical practice of occupational and environmental lung disease relies heavily on the field of epidemiology, as well as toxicology to provide databases for diagnostic decision making. Epidemiology and Toxicology Epidemiology focuses on the causes of disease in populations. Occupational and environmental epidemiological studies (e.g., cohort or case-control studies) can demonstrate associations between certain exposures or jobs and adverse effects, using industrial hygiene (exposure) records and data such as medical surveillance. Occupational and environmental epidemiological studies may also provide useful information about the magnitude of the risk, the amount of exposure that can cause or exacerbate disease, and the latency between exposure and disease, and whether control measures are effective in reducing the risk of disease. There are three basic study designs of epidemiological studies: (1) cross-sectional observation of a population at one point in time; (2) longitudinal observation of a group (or cohort) over time; and (3)

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case control studies comparing cases with the disease to controls. All give some measure of the relative risk of disease in the exposed group compared to the nonexposed group. A relative risk or odds ratio greater than 2 implies that, more probably than not, the abnormality observed can be attributed to the exposure in question. Toxicology studies are especially relevant for the thousands of new chemicals introduced into production each year, in which human data are often limited. Toxicology studies use animal and in vitro data to characterize the toxicity of individual chemicals. Such studies elucidate dose-response relationships, and the primary organ of toxicity for a given exposure. Serious limitations include potential differences between species, and the use of single or high-dose exposures that do not simulate the long-term, chronic, lower-level mixed exposures seen with humans.

CLINICAL APPROACH TO THE PATIENT General Approach There are two important phases in the work-up of any patient with a potential occupational or environmental lung disease. First, as with any patient presenting with a potential disorder of the respiratory tract, its nature and extent should be defined and characterized, regardless of the suspected origin. Although knowledge of exposures may guide the order of the diagnostic work-up, it is important to establish the basic disorder before proceeding to investigate the etiology of the process. Second, the extent to which the disease or symptom complex is caused or exacerbated by exposure(s) at work or in the environment must be determined. The initial approach to such patients includes a detailed history, physical examination, appropriate laboratory testing, chest radiograph, and spirometry. Initial exposure information can be used to direct the sequence of the work-up and obviate unnecessary procedures when the diagnosis is fairly straightforward. If the initial evaluation does not fully explain the patient’s symptoms, other tests are available to better characterize the nature and extent of the respiratory disorder, including additional physiological testing, computed chest tomography, cardiopulmonary exercise studies, bronchoscopy, open lung biopsy, and immunological studies. However, few are specific for any given occupational or environmental diagnosis. Prior medical records can be extremely helpful in the evaluation of a patient with a potential occupational or environmental lung disease. Such records can establish the patient’s complaints at earlier points in time, may provide objective data such as prior pulmonary function testing or chest radiographs for comparison, and may clarify temporal relationships between exposure and effect and rate of progression of disease; factors which may help establish cause. Medical and spirometry surveillance records, if available, can be quite informative in the diagnostic work-up of occupational diseases.

Occupational Lung Disorders: General Principles and Approaches

The Occupational and Environmental History The occupational and environmental history is the single most important tool to determine whether a respiratory problem may be related to an occupational or environmental exposure. A detailed occupational history includes a chronological list of all jobs, including job title, a description of job activities, potential exposures at each job, and an assessment of the extent and duration of exposure (Table 54-3). Given clinicians’ time constraints, the history should focus on the jobs and exposures of greatest concern, which vary given the nature of the problem (i.e., cancer with latency vs. acute inhalation injury). The occupational history can provide essential information on whether exposure to one or more environmental agents has occurred, the magnitude and extent of the exposure, and the timing of the exposure in relationship to symptoms or the disease (Table 54-3). A thorough description of the job process or work done is imperative. The length of time (hours to years) of exposure to the agent, the nature and use of personal protective equipment such as respirators, and a description of the ventilation and overall hygiene are all helpful in estimating exposure from the patient’s history. Patients should be asked whether they think their problem is related to anything in their home or work environments, and temporal relationships between exposures and symptoms, such as whether or not symptoms improve away from work. Historical and current exposure data in the form of material safety data sheets (MSDS) and industrial hygiene databases often kept for administrative purposes can further characterize an individual’s exposure. Whether co-workers have similar symptoms should be clarified. Information about potential exposures outside the workplace, such as in the home or hobbies, should also be obtained. Physical Examination With occupational lung diseases, the physical examination is generally unrevealing about specific cause. It is most helpful in ruling out nonoccupational causes of respiratory symptoms or diseases such as cardiac problems or connective-tissue diseases.

Diagnostic Tests A number of tests can be helpful in the diagnosis of occupational lung disorders, such as chest radiography and pulmonary function tests (PFTs). The use of these diagnostic tests in the occupational setting is discussed below. Chest Radiography The chest radiography is the most important diagnostic test for occupational pneumoconioses. It is critical that radiographs of high technical quality be obtained. Under certain circumstances, the chest radiograph can be unique or highly suggestive of an occupational disorder and may be sufficient, along with an appropriate exposure history, to establish a diagnosis. For example, silicosis, coal workers’ pneumoconiosis, and asbestosis with pleural disease all have characteristic radiographic findings strongly suggestive of the specific

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Table 54-3 Taking an Occupational and Environmental History General health history Does the patient think symptoms/problem is related to anything at work? When was the onset of symptoms, and how are they related to work? Has patient missed days of work, and why? Prior pulmonary problems Medications Cigarette use Current or most relevant employment Job/process: title and description Type of industry and specific work Name of employer Years employed Exposure information General description of job process and overall hygiene Materials by worker used Ventilation/exhaust system Use of respiratory protection Are other workers affected? Industrial hygiene samples/OSHA data Environmental nonoccupational factors Cigarettes Diet Hobbies Pets

Figure 54-1 Posteroanterior chest radiograph of a patient with silicosis. Multiple small nodular densities are seen throughout both lungs. Bilateral conglomerate masses of progressive massive fibrosis are also seen. International Labour Office classification of the film is category 3/3 showing category C large opacities.

occupational diagnosis. The finding of small rounded opacities, progressive massive fibrotic lesions in the upper zones, and â&#x20AC;&#x153;eggshellâ&#x20AC;? calcification is highly suggestive of silicosis (Fig. 54-1). Similarly, the finding of bilateral pleural plaques and diffuse small irregular linear opacities in the lower lung zones is highly suggestive of asbestosis (Fig. 54-2). However, the chest radiography findings can also be nonspecific, as with asbestosis without pleural plaques where linear shadows in the lower lobes and honeycombing resemble the findings

Specific workplace exposures Fumes/dusts/fibers Gases Metals Solvents Other chemicals: plastics, pesticides, corrosive agents Infectious agents Organic dusts: cotton, wood Physical factors Noise Repetitive trauma Radiation Emotional factors, stress Past employment List jobs in chronologic order Job title Exposures Military service

Figure 54-2 Posteroanterior chest radiograph of a patient with asbestosis and pleural plaques. Calcified pleural plaques are seen on the diaphragms bilaterally, en face in the left thorax, and on the right medial pleural surface. Increased reticular markings greatest at the lung bases are also seen. International Labour Office classification of the film is category 1/1 small irregular opacities predominantly in the lower lung fields.

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of idiopathic pulmonary fibrosis, or the hilar adenopathy or diffuse nodules found in beryllium disease are identical to the features of sarcoidosis. Chest radiographs can also be normal in patients with symptomatic pneumoconiosis. Under the auspices of the International Labour Office (ILO) in Geneva, Switzerland, a uniform classification system has evolved to evaluate chest radiographs for epidemiological studies, clinical evaluation, and screening. The system requires a posteroanterior radiograph and comparison to a standard set of radiographs. Parenchymal opacities are classified according to size, shape (rounded or irregular), extent, and profusion (concentration). Examples of ILO readings are shown in Figs. 54-1 and 54-2. Pleural changes are also graded according to site, pleural thickening, and pleural calcification. Computed Tomography There is a growing literature addressing the role of computed tomography (CT) scanning in the evaluation of patients with occupational interstitial lung disease, primarily asbestosis and hypersensitivity pneumonitis. Similar to the nonoccupational setting, conventional CT scanning (8- to 10-mm thick slices) and high-resolution computed tomographic (HRCT) scanning (1- to 3-mm thick slices) can be used to better evaluate pleural and parenchymal abnormalities (see Chapter 30). The use of CT scans for screening for lung cancer is also under investigation. Conventional CT scanning is more sensitive than chest radiography for the diagnosis of pleural disease and is helpful in distinguishing subpleural fat from pleural fibrosis. HRCT scanning allows improved visualization of the lung parenchyma and is used in the evaluation of patients with suspected asbestosis and other occupational interstitial diseases. HRCT scanning is especially informative in patients with unrevealing chest radiographs and unexplained respiratory symptoms or abnormal physiology (restrictive lung function, abnormal gas exchange, or abnormal response to exercise). CT scan features have been shown to correlate with physiological and histological changes. For example, interlobular septal thickening represents interstitial fibrosis, as seen in asbestosis, and ground-glass opacities likely represent active alveolar inflammation, as seen in hypersensitivity pneumonitis. The specific features and distribution of HRCT changes may be suggestive of a specific cause and narrow the differential diagnosis. For example, centrilobular nodules, groundglass opacities, and air trapping may suggest hypersensitivity pneumonitis. Additional imaging techniques may also be useful. Inspiratory and expiratory imaging may demonstrate air trapping seen in hypersensitivity pneumonitis, and prone imaging may distinguish lower lung zone reticulations seen in asbestosis from dependent changes. Although less commonly used, classification systems such as the ILO chest radiograph system have been proposed for CT scans. Physiological Methods PFTsâ&#x20AC;&#x201D;including spirometry, lung volumes, and diffusing capacityâ&#x20AC;&#x201D;are the most important tools to assess functional

Occupational Lung Disorders: General Principles and Approaches

respiratory status in patients with occupational lung disease, as with nonoccupational diseases (see Chapter 34). PFT findings are generally not specific for a particular cause but are important for evaluating dyspnea, differentiating obstructive from restrictive airway defects, and assessing the degree of pulmonary impairment. Although in clinical practice obstructive lung disease may be treated before objective physiological documentation, it is especially important to clarify the diagnosis in settings where work exposures may be causative or contributing factors, and management decisions may involve a workerâ&#x20AC;&#x2122;s job. Spirometry with bronchodilator response can document airflow obstruction and reversibility (see Chapter 34). However, the increased use of inhaled steroids, which are effective at reducing airway inflammation, can make reversible airflow obstruction more difficult to confirm, especially in milder asthmatics. Testing can be repeated off inhaled steroids. Forced expiratory flow rates between 25 percent and 75 percent (FEFR 25 to 75) have also been used to determine the presence of small airways disease; however, caution must be used in relying upon FEFR 25 to 75 given the significant variability in the general population. When spirometry is normal, nonspecific bronchial hyperresponsiveness (NSBH) such as methacholine challenge testing can be helpful in demonstrating the presence of hyperreactive airways. NSBH can also be used to estimate severity as well as to follow improvement away from work. Peak expiratory flow rate (PEFR) diaries can be particularly useful in the diagnosis of occupational asthma. Use of a peak flow meter and diary for at least 2 to 3 weeks including periods at work and away from work, such as vacation or weekends away from work, can document work-related changes in lung function. The confounding effects of bronchodilator therapy, respiratory protection and patient effort may influence results, and should be noted on the diary. Specific inhalation challenge with the suspected agent(s) is considered the gold standard for diagnosing sensitizer-induced occupational asthma. However, such testing requires specialized facilities and expertise, carries certain risks, is not widely available, and false-negatives can occur. With occupational interstitial lung diseases, restrictive ventilatory impairments and reductions in the diffusing capacity of carbon monoxide (DlCO ) are highly suggestive of disease. Hence, obtaining full pulmonary function testing are important since screening spirometry and plain chest radiographs may not be sufficiently sensitive to explain the presence of respiratory symptoms. Reductions in DlCO may often be the first sign of disease and present as an isolated abnormality. Longitudinal testing may be particularly informative given the variation in testing in the population and is often available in working populations undergoing routine medical surveillance. Careful attention must also be paid to several factors that may affect the quality of the testing; these include that spirometry is performed according to ATS guidelines and that the equipment is routinely calibrated. Changes in

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technicians and in the equipment can also affect spirometry results. Cardiopulmonary Exercise Testing Cardiopulmonary exercise testing can be used to assess functional impairment and disease progression in selected patients with occupational respiratory disorders (see Chapter 35). Exercise testing can help distinguish among cardiac, pulmonary, and deconditioning causes of dyspnea. In patients with significant interstitial lung disease, exercise results in an increase in the alveolar-arterial oxygen gradient and arterial hypoxemia. Cardiopulmonary exercise testing is helpful in evaluating a select group of patients with dyspnea and normal pulmonary function tests or dyspnea that appears out of proportion to the changes in lung function. However, cardiopulmonary exercise testing is not helpful in determining the specific origin of the pulmonary disease. Bronchoscopy The diagnosis of major pneumoconioses such as asbestosis, silicosis, or coal workersâ&#x20AC;&#x2122; pneumoconiosis usually can be made on the basis of the occupational history, chest radiograph, and PFTs, as noted. Under certain circumstances, such as the evaluation of chronic beryllium disease, bronchoscopy with transbronchial biopsy and bronchoalveolar lavage (BAL) may be helpful diagnostically (see Chapter 56). Transbronchial biopsies yield small tissue samples that are most helpful in identifying granulomatous interstitial processes such as sarcoidosis, beryllium disease, and hypersensitivity pneumonitis, or diffuse malignant processes. Sufficient tissue is usually not obtained for analyses for dust or metal content. Under certain circumstances, BAL can be diagnostically helpful. A predominance of lymphocytes suggests certain diagnoses such as sarcoidosis, hypersensitivity pneumonitis, or chronic beryllium disease, but is not by itself diagnostic. The diagnosis of chronic beryllium disease can be established with the finding of a positive beryllium lymphocyte proliferation test (BeLPT) using BAL cells. Characteristic multinucleated giant cells may be seen in the BAL cells of patients with hardmetal lung disease. BAL cells may contain dust or mineral particles, such as asbestos, which can reflect current and past exposures. For example, asbestos bodies (asbestos particles coated with iron) have been quantitated in BAL, and have correlated variably with disease and symptoms. Pathologic Examination of Tissues Open lung biopsy techniques are usually not needed to make a diagnosis of the more common occupational interstitial lung diseases, as noted. However, when there is no clear cause, limited exposure history, atypical features, more than one causative agent, or potentially a newly recognized agent, lung biopsies can be very helpful. Certain histopathologic findings can suggest a specific disease such as hypersensitivity pneumonitis, asbestosis, or hard metal disease. Lung biopsies can also rule in or out certain nonoccupational causes of lung disease, such as pulmonary vascular disease or infection. Open

lung biopsy enables sufficient amounts of tissue for histological and mineralogical (qualitative and quantitative) analysis. Several methods have been used to analyze the dust content of lung tissue. Light microscopic evaluation with polarization is widely available and can provide a qualitative assessment of the presence of dust particles and ferruginous bodies. It does not, however, identify the specific dust particles or enable quantification. Bulk and microanalytic techniques that allow more definitive identification and quantification of minerals and dusts are also available. They include radiographic fluorescence scanning electron microscopy and energy dispersion radiographic spectroscopy. These methods can be used to identify and quantify specific minerals in sections or tissue digests. In a patient with interstitial lung disease of unclear origin in whom an occupational or environmental etiology is being considered, more extensive particle analysis should be considered if light microscopic histological examination is not diagnostic. There are limitations that should be remembered. Only substances that are insoluble and retained in tissue at sufficient concentration will be detected. More soluble agents, such as cobalt, can be underestimated with these techniques. The analytic methods can be tedious and standards to compare findings are limited. Most important, a positive finding documents biologically detectable exposure but does not demonstrate disease or establish a causal relationship. Other Laboratory Tests As noted, few laboratory tests exist that diagnose specific occupational lung diseases. Skin tests and detection of specific IgE to a suspected agent, such as large-molecular-weight antigens (i.e., animal or plant proteins) can demonstrate exposure and a specific immunological reaction, but does not confirm a clinical disease, and a negative finding does not rule out either exposure or disease. The BeLPT is quite sensitive and specific for beryllium sensitization, but does not distinguish asymptomatic sensitization from chronic beryllium disease.

Exposure Assessment A careful occupational and environmental history is the single best way to evaluate a patientâ&#x20AC;&#x2122;s exposures, as noted. Substantial information regarding work and home exposures can usually be obtained directly from the patient. Other Sources of Exposure Information There are a several other sources for additional workplace exposure information. In the United States, employers are required by federal law to provide employees with information about the potential toxicity of all materials used in the workplace, called Material Safety Data Sheets (MSDS). Patients should obtain an MSDS on any substances of concern. For recent or current exposures, a site visit is usually most helpful in providing information about the nature and extent of potential exposures and other exposed workers. A number of methods and sampling strategies exist to measure

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particular exposures in either the work or home environment. They include personal and area sampling devices, and direct monitoring devices. It should be remembered that sampling variability and analytic errors can occur, and that the exposure information obtained usually reflects a narrow window of time during which monitoring was performed. Another potential source of information is the results of inspections by health and regulatory agencies such as the Occupational Safety and Health Administration (OSHA). Unions, insurance groups, and community groups may also provide exposure information. In addition, epidemiological data on coworkers or workers with similar types of jobs can be used to assess the nature and extent of exposure for a given patient. Compliance with established occupational exposure limits does not exclude the possibility of disease. Low levels of exposure can induce disease in susceptible individuals. Also exposures are often variable and high levels of brief exposure may not be noted in industrial hygiene records. There has been great interest in developing biologic markers that attempt to more accurately identify and quantify exposure(s), or an early effect of the exposure, such as sensitization to a specific antigen. Such markers can be measured in the target organ, such as the lung or BAL fluid, or in blood or urine. In general, although of great research interest, most markers have relatively limited use in the clinical practice of occupational and environmental medicine and associations between these markers of exposure and disease is not always clear. Once the available information is obtained, the clinician has to make a final determination about whether occupational or environmental exposures are causing or contributing to the patient’s disease process. As noted, there are several criteria to determine whether work or environmental exposures are causative, including a consistent clinical picture, sufficient exposure, and appropriate temporal relationships. The diagnosis of an occupational lung disease frequently entails a greater degree of diagnostic uncertainty than physicians are generally used to in other settings. In most workers’ compensation cases in the United States, the standard of certainty is greater than 50 percent likelihood that the disorder is related to an occupational or environmental exposure. Thus, occupational or environmental diseases are diagnosed even in the presence of a significant degree of uncertainty.

PREVENTION Social, Economic, and Public Health Considerations It is important for the clinician to remember that making the diagnosis of an occupational or environmental respiratory disease almost invariably has important social, economic, legal, and public health considerations. Many countries and selected states in the United States require reporting of occupational illnesses and injuries. For the individual patient,

Occupational Lung Disorders: General Principles and Approaches

such a diagnosis can have a profound impact on the patient’s work, income, and social situation. Many countries, including the United States, have a workers’ compensation no-fault system of insurance to provide medical, lost work time and other benefits for workers with injury or illness caused by work. Physicians are obligated to diagnose and treat work-related illness, inform the patient of such an illness, and assist with documentation to obtain benefits. Physicians are asked to determine the presence and severity of respiratory impairment, a loss of physical or physiological function (see Chapter 39). Disability refers to the impact of the impairment on the person’s life and is determined by administrators based on the information provided by physicians, requirements of the job and other factors, discussed in Chapter 39.

Prevention Prevention is central to the practice of occupational and environmental medicine. There are two main strategies for prevention: primary prevention, which entails removal or modification of the hazardous risk or exposure before disease has occurred, such as product substitution or engineering controls to reduce exposures. Secondary prevention depends on early detection, and prompt treatment after some adverse effect of the exposure has occurred. The physician can play an important role in both primary and secondary prevention. The physician should also consider the relevant public health issues when a patient is diagnosed with an occupational or environmental lung disease, such as whether others are currently or in the future similarly exposed and at risk of disease. Reporting of occupational illnesses is critical in identifying problem areas that need further investigation and improved preventive strategies. Physicians are essential for secondary prevention. With knowledge of workplace hazards and appropriate monitoring of patients, early abnormalities can be detected, and treatment instituted, typically with removal from further exposures. Reporting of occupational illnesses is critical in identifying problem areas that need further investigation and improved preventive strategies.

Regulatory Issues In the United States, several federal and state laws and agencies regulate hazardous substances in the environment and workplace, including the Environmental Protection Agency and OSHA, which was established in 1970 by the Occupational Safety and Health Act to reduce the risk of injury and illness to workers. The National Institute for Occupational Safety and Health (NIOSH), also established in 1970, is charged with performing research and teaching, and evaluating occupational hazards. Several organizations recommend occupational exposure limits. OSHA establishes enforceable permissible exposure limits (PELs). In addition, the American Conference of Governmental Industrial Hygienists (ACGIH) and NIOSH recommend threshold limit values (TLVs) and recommended exposure limits (RELs), respectively.

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Respirators The best strategy for reducing inhalation exposures is to prevent or contain the exposure or substitute a less harmful material for a toxic one. Respiratory protective devices (respirators) are used to provide protection from exposure by inhalation when adequate engineering control of airborne contaminants is not feasible, or in an emergency or temporary situation. There are two main types of respirators: air-purifying respirators, which remove contaminants from the air using filters or chemical absorbents, and atmosphere supply respirators, which supply breathable air from another source, such as an air cylinder. Types of air-purifying respirators include dust masks, cartridge respirators, and highefficiency particulate air (HEPA) filters. Physicians may be asked to determine a worker’s fitness for respirator use. OSHA regulations require that a worker not be assigned to a job requiring use of a respirator unless the worker is able to perform the work with a respirator. It should first be determined whether appropriate engineering controls and an appropriate respiratory protection program are in place. No spirometry or other specific criteria exist to determine respirator fitness. The physician must use clinical judgment in determining whether a given worker will be able to use a respirator. Respirators can increase the work of breathing, and they can interfere with the worker’s ability to perform the job (by reducing vision, range of motion, and hearings). Factors that can limit respirator use include facial hair, inability to tolerate the respirator, claustrophobic reactions, and particular medical conditions, such as pulmonary or cardiovascular disease. Reassessment after a brief trial of respirator use is indicated if the patient is having problems or concerns.

SUGGESTED READING Akira M, Yamamoto S, Inoue Y, et al: High-resolution CT of asbestosis and idiopathic pulmonary fibrosis. AJR Am J Roentgenol 181:163–169, 2003. Balmes J, Becklake M, Blanc P, et al: American Thoracic Society Statement: Occupational contribution to the burden of airway disease. Am J Respir Crit Care Med 167:787–797, 2003. Bernstein IL, Chan-Yeung M, Malo JL, et al, eds. Asthma in the Workplace and Related Conditions, 3d ed. New York, Taylor & Francis, 2006. Churg A, Green FHY, eds. Pathology of Occupational Lung Disease. Baltimore, Williams & Wilkins, 1998. Crapo RO, Casaburi R, Coates AL, et al: Guidelines for methacholine and exercise challenge testing. Am J Respir Crit Care Med 161:309–329, 2000. Doll R, Peto R: The causes of cancer: Quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst 66:1191–1308, 1981.

Glazer CS, Newman LS: Occupational interstitial lung disease. Clin Chest Med 25:467–78, 2004. Guidelines for the Use of ILO International Classification of Radiographs of Pneumoconioses, in Occupational Safety and Health Series. Geneva, International Labour Office, 1980. Hendrick DJ, Burge PS, Beckett WS, et al, eds: Occupational Disorders of the Lung: Recognition, Management and Prevention. London, WB Saunders, 2002. Lynch DA, Rose CS, Way D, et al: Hypersensitivity pneumonitis: Sensitivity of high-resolution CT in a population-based study. AJR Am J Roentgenol 159:469–472, 1992. Maier LA: Clinical approach to chronic beryllium disease and other nonpneumoconiotic interstitial lung diseases. J Thorac Imaging 17:273–284, 2002. Mapp CE, Boschetto P, Maestrelli P, et al: Occupational asthma. Am J Respir Crit Care Med 172:280–305, 2005. Mulshine JL, Sullivan DC: Clinical practice. Lung cancer screening. N Engl J Med 352:2714–2720, 2005. Nicholson PJ, Cullinan P, Taylor AJ, et al: Evidence based guidelines for the prevention, identification, and management of occupational asthma. Occup Environ Med 62:290– 299, 2005. Rosenstock L, Cullen MR, Brodkin CA, et al, eds: Textbook of Clinical Occupational and Environmental Medicine, 2d ed., Philadelphia, Elsevier Saunders, 2005. Sette A, Neder JA, Nery LE, et al: Thin-section CT abnormalities and pulmonary gas exchange impairment in workers exposed to asbestos. Radiology 232:66–74, 2004. Sood A, Redlich CA: Pulmonary function tests at work. Clin Chest Med 22:783–793, 2001. Sue DY: Exercise testing in the evaluation of impairment and disability. Clin Chest Med 15:369–387, 1994. Townsend MC: ACOEM position statement. Spirometry in the occupational setting. American College of Occupational and Environmental Medicine. J Occup Environ Med 42:228–2245, 2000. Townsend MC: Evaluating pulmonary function change over time in the occupational setting. J Occup Environ Med 47:1307–1316, 2005. Vandenplas O, Toren K, Blanc PD: Health and socioeconomic impact of work-related asthma. Eur Respir J 22:689–697, 2003. Vathesatogkit P, Harkin TJ, Addrizzo-Harris DJ, et al: Clinical correlation of asbestos bodies in BAL fluid. Chest 126:966– 971, 2004. Vedal S: Update on the health effects of outdoor air pollution. Clin Chest Med 23:763–775, 2002. Zhang J, Smith KR: Indoor air pollution: A global health concern. Br Med Bull 68:209–225, 2003.

55 Asbestos-Related Lung Disease William N. Rom

I. EFFORTS AT ASBESTOS CONTROL II. TYPES OF EXPOSURE III. NONMALIGNANT PLEURAL MANIFESTATIONS Pleural Plaques Diffuse Pleural Thickening Rounded Atelectasis Acute Benign Pleural Effusions IV. ASBESTOSIS Pathology Pathogenesis Epidemiology Natural History Clinical and Physiological Features Radiographic Features Diagnosis Treatment and Prognosis

EFFORTS AT ASBESTOS CONTROL Asbestos is a fibrous hydrated magnesium silicate with more than 3000 commercial uses due to its indestructible nature, fire resistance, and spinnability. It has been used for centuries: the ancient Greeks called asbestos amiantos, and the Greek biographer Plutarch (a.d. 46–120) commented on its use in wicks for oil lamps and napkins that could be cleansed in a fire. Mining and milling that began in the late nineteenth century used asbestos in textiles and insulation materials. Cooke described the first case of asbestosis in 1924 in a 33-yearold textile worker with 25 years of exposure to asbestos and extensive pulmonary fibrosis. Approximately 98 percent of the asbestos used in the United States has been chrysotile, a serpentine form of asbestos. Other asbestos types are the amphiboles—notably amosite, mined in South Africa, and crocidolite, mined in

V. MALIGNANT MESOTHELIOMA Pathology Epidemiology Pathogenesis Clinical and Radiographic Features Diagnosis Treatment and Prognosis VI. LUNG CANCER Epidemiology Pathology Pathogenesis Clinical Features Radiographic Features Diagnosis Treatment and Prognosis VII. EFFORTS AT ASBESTOS CONTROL

the Cape Province of South Africa and in Western Australia. Anthophyllite in minimal amounts has been used commercially in Finland. These asbestos fiber types have strikingly different physical characteristics: chrysotile tends to be wavy and long, and occurs in bundles; crocidolite is needle-shaped with many long fibers; and amosite is similar to crocidolite but generally thicker. Initially, asbestos was widely used in fireproof textiles and later as insulation for boilers and pipes. Thereafter, asbestos was used in yarn, felt, paper, millboard, shingles, paints, cloth, tape, filters, and wire insulation. More recently, asbestos has been used in cement pipes for potable water, in gaskets, and in friction materials, including brake linings, and roofing and floor products. Asbestos was extensively used for ship construction during World War II. World consumption of asbestos declined in the 1990s to approximately 50 percent of the peak in 1973. In 1994, approximately 2.7 million tons

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were produced, with the United States consuming less than 27,000 metric tons. Worldwide production by mining in 1994 was led, in order, by Russia, Canada, Kazakhstan, China, and Brazil.

posure in the pleural space include circumscribed pleural plaques, diffuse pleural thickening, rounded atelectasis, and asbestos-related pleural effusions.

Pleural Plaques TYPES OF EXPOSURE Asbestos exposure has occurred in a variety of settings. Primary exposures occurred in miners and millers. Secondary exposures occurred in manufacturing plants using asbestos in the production of textiles, friction materials, tiles, and insulation materials. Epidemiological studies focused on cohorts in these plants, since asbestos fiber type was often specified and dust measurements were obtained. These studies demonstrated that intensity and duration of exposure play an important role in the prevalence of asbestos-related disease. In a study of 1584 insulation workers and 1330 sheet-metal workers, 83.5 percent of the insulators had abnormal chest radiographs (55 percent with parenchymal opacities), whereas 42 percent of the sheet-metal workers had abnormal chest radiographs (17 percent with parenchymal opacities). Although measurements of airborne asbestos fibers were seldom made, the most significant exposures appear to have occurred in the construction trades. These trades included asbestos insulators (called “laggers” in the United Kingdom), who mixed asbestos cement on site to insulate joints and elbows on pipes; boilermakers and sheet-metal workers, who worked adjacent to the asbestos workers; and electricians, carpenters, plumbers, and others who worked in the vicinity of work requiring asbestos exposure. These exposures were mainly to chrysotile asbestos, since practically no crocidolite was imported into the United States, and only small amounts of amosite were admixed. Asbestos workers and other construction workers wore their asbestos-covered clothes home, so their wives and children were exposed either upon greeting them or while washing their garments. These household contact exposures are often referred to as indirect exposures, and those exposed while working near asbestos workers are called bystander exposures. In the United States, approximately 14 million persons who were exposed to asbestos in the workplace between 1940 and 1979 were alive in 1980. From this cohort, estimates have been projected for the late 1990s of a peak incidence of approximately 3000 mesothelioma deaths and 5000 asbestos-related lung cancer deaths. Pleural fibrosis remains a relatively common finding among asbestos-exposed blue-collar workers, whereas asbestosis is becoming increasingly uncommon.

NONMALIGNANT PLEURAL MANIFESTATIONS Pleural disease is the most common manifestation of asbestos exposure. The nonmalignant manifestations of asbestos ex-

Pathology Pleural plaques are the most common manifestation of asbestos exposure. They are focal, irregular, raised white lesions found on the parietal and, rarely, the visceral pleura. The plaques may be small or extensive; commonly they occur in the lateral and posterior midlung zones, where they may follow rib contours and the diaphragm. They commonly enter lobar fissures and can invade the mediastinum or pericardium; rarely do they invade the apices or costophrenic sulci. Histologically, asbestos-related pleural plaques are characterized by a paucity of cells, extensive collagen fibrils arranged in a basket-weave pattern, and a thin covering of mesothelial cells. The parietal pleura is uniformly involved, with minimal thickening of the visceral pleura. The two pleural surfaces are free of adhesions. Pleural calcifications frequently develop in these fibrohyaline lesions as the length of time from exposure increases. Exposure to asbestos is the most frequent cause of pleural plaques. These plaques, although typical of asbestos, are not specific for asbestos exposure. Pathogenesis Two theories have been proposed for the pathogenesis of pleural plaques. The most plausible is based on the direct effects of fibers that reach the pleural space. Asbestos fibers—the short, thin ones in particular—have been shown to be transported by subpleural lymphatics to the pleural space. In the pleural space, it is believed that they scratch, injure, and irritate the pleural surface, leading to hemorrhage, inflammation, and eventually fibrosis. The plaques are submesothelial. Cell-cell interactions appear to play an important role in this response. In the absence of macrophages, pleural reactions tend to be disorganized and widespread. Mesothelial cells also appear to play an important role in the pathogenesis of these lesions: they internalize asbestos fibers via an integrin receptor that recognizes vitronectin; in vitro pleural mesothelial cells also can synthesize collagens (types I, III, and IV), elastin, laminin, and fibronectin. In keeping with the submesothelial location of the plaques, cultured mesothelial cells can organize these macromolecular connective-tissue components into an assemblage of extracellular matrix that is limited to the base of the cell. Epidemiology and Natural History In the 1960s, hyaline and calcified pleural plaques were noted to be an index of exposure to asbestos. In shipyard workers, the frequency of pleural abnormalities was approximately 10 times that of parenchymal disease. The greater the exposure, the more likely the worker was to have extensive calcified pleural plaques as well as parenchymal fibrosis. The intensity of the exposure has been noted to be an important

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determinant of the prevalence of these abnormalities. For example, among British shipyard workers, 36 percent of those with continuous exposure as “laggers” developed pleural plaques, while extensive pleural thickening and pulmonary fibrosis were seen in 5 and 7 percent, respectively. In contrast, those with intermittent exposure had a 6 percent prevalence of plaques and no pulmonary fibrosis. On average, the latency time for the appearance of plaques is 30 years, but the time can vary greatly. This variation can also be appreciated from studies of British shipyard workers in whom the prevalence of pleural plaques increased from 17 percent at 10 years after the first exposure to 70 percent at 30 years among those with continuous exposure; for those with intermittent exposures, the prevalence increased from 1 percent at 10 years to 16 percent at 30 years. All asbestos fibers are equally capable of inducing pleural plaques: pleural plaques are found in US insulators or shipyard workers exposed to chrysotile or amosite, as well as miners in Western Australia who were exposed to crocidolite. Circumscribed pleural plaques are not associated with pleural effusions. They increase in size slowly, usually over decades, and rarely, if ever, give rise to diffuse malignant mesothelioma. In addition to occupational exposures, domestic and residential exposures have, on rare occasions, been implicated in the production of pleural plaques. Evidence for the latter is the remarkably high rates of pleural calcification (up to 30 percent) in some rural areas of Greece, Bulgaria, and Turkey. Clinical and Physiological Features In the absence of concomitant asbestosis or obliteration of the costophrenic angle, pleural plaques are usually asymptomatic. Most often they are incidental findings on chest radiographs. In addition, they do not cause significant abnormalities such as pleural rubs, rales, or rhonchi on auscultation of the chest. Pleural disease has been recognized as a cause of reduced pulmonary function since the 1970s. Among 998 shipyard workers in Groton, Connecticut, who had 15 or more years of asbestos exposure, 17 percent of those with pleural changes had a forced vital capacity (FVC) under 80 percent of predicted; for those with normal chest radiographs, 9 percent had decreased vital capacities ( p > 0.05). In those with normal chest radiographs, the values were significantly reduced only among smokers and ex-smokers. Recent studies that have applied stepwise regression analysis to data from insulation workers have disclosed a significant inverse relationship between FVC and an integrative pleural index for patients with circumscribed pleural plaques. Even among those with pleuroparenchymal abnormalities, the pleural index was found to make a significant contribution to decrements in FVC, independent of that due to parenchymal abnormalities. In nonsmoking asbestos workers with circumscribed or diaphragmatic pleural plaques, flow rates (FEV1 , FEF25–75% , and FEF75–85% ) have been reported to be reduced. In an epidemiological study of 1211 sheet-metal workers, pleural fibrosis was detected in 334 and was related to age, duration of

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exposure, more pack-years of smoking, and the presence and degree of interstitial fibrosis. After controlling for these confounders, multivariate regression analysis found that both plaques and diffuse thickening were independently associated with decrements in FVC, but not with decrements in the FEV1 / FVC ratio. Furthermore, diffuse pleural thickening was associated with a decrement in FVC twice as great as that seen with circumscribed pleural plaques. After confounding variables such as age, height, smoking status, and the presence of parenchymal abnormality as assessed by chest radiography and gallium scintography were taken into account, there was a significant decrease in FEV1 and FVC (222 and 402 ml, respectively) among workers who had pleural plaques or diffuse pleural fibrosis. Radiographic Features The visualization of plaques on routine chest radiography depends on their thickness, location, and the orientation of the radiographic beam. As a result, they can be viewed in profile along the lateral chest wall or on en face with a rolled or holly-leaf pattern, especially if calcified (Fig. 55-1). Only a modest proportion of plaques detected at autopsy can be seen on standard posteroanterior (PA) chest radiograph. Oblique views and computed tomographic (CT) scanning increase plaque detection.

Figure 55-1 Posteroanterior (PA) chest radiograph of a 75-yearold man who worked in a shipyard during World War II insulating ships. The radiograph shows bilateral calcified pleural plaques en face and on top of the diaphragm. The pleura is diffusely thickened bilaterally and the costophrenic angles are blunted. Mediastinal pleural calcification is present on the right. (Courtesy of Dr. Timothy Harkin.)

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The CT scan can recognize plaques at a much earlier and less well-defined state than the conventional chest radiograph. The CT scan is particularly useful for perivertebral and pericardiac plaques, and high-resolution CT scanning (HRCT) helps to establish the presence of diaphragmatic lesions. In all cases, the CT scan can help to differentiate plaques from extrapleural fat pads and can detect concomitant parenchymal abnormalities that may be difficult or impossible to see on the PA chest radiograph. Diagnosis Pleural plaques due to asbestos exposure are usually bilateral (80 percent of the time), whereas unilateral pleural plaques may be due to trauma, previous tuberculosis, or, rarely, other causes, such as collagen vascular disease. The lesions are usually stable and will remain the same size for months. This helps to differentiate plaques from pleural tumors. Histological tissue examination is not necessary for diagnosis the vast majority of the time. Treatment No specific treatment is required for asbestos pleural plaques. Since they are markers of asbestos exposure and identify patients at risk for other asbestos-related disorders, medical surveillance, including periodic chest radiographs, is recommended.

Diffuse Pleural Thickening Pathology Pleural fibrosis in persons who have been exposed to asbestos has been well described. The fibrotic responses can be localized or diffuse and either unilateral or bilateral. Macroscopically, the lesions vary in thickness from a whitish discoloration of the lung surface to a thick white peel that can encase significant pulmonary structures. Diffuse pulmonary thickening is most often seen as a continuous sheet that is 5 to 10 cm in craniocaudal extent, and in 90 percent of patients it affects the costophrenic angle. Interlobar and interlobular fissures are commonly involved. Whereas pleural plaques predominantly affect the parietal pleura, diffuse pleural thickening or fibrosis is a disease of the visceral pleura. Diffuse pleural fibrosis occurs most commonly as part of a fibrotic process of the visceral pleura and subadjacent interstitium. It may occur, however, and be quite severe, in patients with minimal pulmonary parenchymal fibrosis. Asbestos bodies or fibers are often found in the visceral pleura, the underlying parenchyma, or both. Pathogenesis Diffuse pleural thickening has been proposed to result from three different mechanisms. The first is the confluence of large pleural plaques. This is believed to account for 10 to 20 percent of the cases. The second is the extension of subpleural fibrosis to the visceral pleura. This probably accounts for 10 to 30 percent of cases. The most common pathogenic mech-

anism is thought to be the fibrotic resolution of a benign pleural effusion, producing diffuse pleural thickening. The importance of this mechanism is highlighted by the finding that about one-third of patients with diffuse pleural thickening have had a prior benign asbestos-related pleural effusion diagnosed by thoracentesis or on serial chest radiographs. The pathogenic mechanisms differentiating diffuse pleural thickening from circumscribed pleural plaques are not well defined. However, the fundamental irritative mechanism of asbestos fibers is likely to be important in both. In the case of diffuse pleural responses, these fibers are deposited mainly in the parenchymal subpleural areas of the lung. Clinical and Physiological Manifestations Diffuse pleural fibrosis most often occurs long after shortterm heavy exposure to asbestos. When mild, diffuse pulmonary fibrosis can be asymptomatic and discovered as an incidental finding on a chest radiograph obtained for another reason. The diffuse nature of the lesion, however, often leads to pulmonary symptoms, including dyspnea on exertion, chronic dry cough, and chest pain. As noted above, diffuse pleural thickening can cause a restrictive physiological abnormality. The degree of physiological abnormality varies with the degree of fibrotic response. On rare occasions, in patients with severe bilateral disease, respiratory insufficiency and death have occurred. Diffuse pleural fibrosis can increase in severity over time. In miners heavily exposed to crocidolite asbestos, however, progression of diffuse pleural thickening has been noted to level off as much as 15 years after the initial exposure. Radiographic Features On the routine chest radiograph, diffuse pleural fibrosis presents as a continuous pleural opacity extending over more than 25 percent of the pleural surface of a lung, often blunting the costophrenic angle. It can be unilateral or bilateral and seen in the presence or absence of concomitant asbestosis and pleural calcifications. Rarely, the pleural fibrosis will produce a fibrotic pseudotumor with a pleural basis (rounded atelectasis) (see below). CT scanning is particularly useful in delineating the relationship between diffuse fibrosis and other pleural abnormalities and differentiating pleural fibrosis from fat deposits. Diagnosis The diagnosis of diffuse pleural fibrosis is usually based on the clinical presentation and chest radiograph. In more than 30 percent of cases, a history of asbestos-related pleuritis can be obtained. The lesions of diffuse pleural fibrosis are not unique to asbestos-exposed persons and can represent old inflammatory reactions from tuberculosis, thoracic surgery, hemorrhagic chest trauma, or drug reactions. Differentiation among these causes is frequently based on a careful clinical history. Radiographic patterns are also helpful, since bilateral interstitial changes in the lower lung zones in association with

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pleural plaques or calcifications strongly support a diagnosis of asbestos exposure. A biopsy may be required when the thoracic lesion is progressing or when malignancy is in the differential. Treatment As seen with circumscribed pleural plaques, there are no specific therapies for asbestos-related diffuse pleural fibrosis. Medical surveillance is required to detect disease progression and observe for other asbestos-related disorders. In the rare extremely severe case, pleurectomy may be required.

Rounded Atelectasis Rounded atelectasis is a rare complication of asbestosinduced pleural disease. It is caused by scarring of the visceral and parietal pleura and the adjacent lung, with the pleural reaction folding over on itself. The pleural surfaces then fuse to one another, trapping the underlying lung and leading to atelectasis. As a result of this alteration, a mass lesion that mimics lung cancer can be seen on the PA chest radiograph (Fig. 55-2). This lesion is most easily appreciated to be a pseudotumor with use of CT scanning. HRCT can noninvasively demonstrate continuity to areas of diffuse pleural thickening, evidence of volume loss in the adjacent lung, or a characteristic comet tail of vessels and bronchi sweeping into a wedge-shaped mass (Fig. 55-2). CT scanning can also demonstrate stability over time (from months to years), which supports the diagnosis of a benign lesion, and pleural plaques or parenchymal changes, which support a diagnosis of asbestos exposure. In one clinical series of 74 patients with rounded atelectasis, 64 had significant asbestos exposure, and the lingula or right middle lobe was affected in 49 of the patients. HRCT scans localized most cases of rounded atelectasis to the lower, posterior portion of the lung (Fig. 55-2); moreover, in one-third of the patients, the lesions were multiple. In most patients, rounded atelectasis occurs suddenly on a background of only plaques or a normal chest radiograph. In others, a slowly increasing pleural effusion may precede its appearance. If the benign nature of the lesion cannot be assured by chest radiography, the patient may require fiberoptic bronchoscopy with a transbronchial biopsy or transthoracic needle aspiration to rule out a malignant process.

Figure 55-2 Rounded atelectasis and other pleural abnormalities in an asbestos worker. The chest radiograph (A) shows a left-sided pleural effusion, bilateral pleural thickening, greater on the left than on the right, and a mass in the left midlung field. HRCT (B ) demonstrates the mass to be rounded atelectasis, with bronchovascular structures entering the trapped lung. It also reveals the pleural effusion, bilateral pleural thickening, and pleural plaques, one of which is on the right hemidiaphragm. (Chest radiograph and HRCT courtesy of Dr. Coralie Shaw.)

Acute Benign Pleural Effusions Acute benign pleural effusions are common pleural manifestations in asbestos-exposed persons between 20 and 40 years of age. The latency period for these effusions is shorter than for pleural plaques, malignant mesotheliomas, or pulmonary malignancies. Benign pleural effusions generally occur earlier after exposure than do other asbestos-related processesâ&#x20AC;&#x201D;12 to 15 years after the first asbestos exposure. However, benign effusions can also occur as long as 30 years after first exposure. The effusions may be small to moderate in size or may

be manifested as an increase in the extent or severity of an existing pleural reaction. About 50 percent of the patients with acute benign pleural effusions are asymptomatic. When patients are symptomatic, the manifestations may be those of a pleurisy (chest pain, chest tightness, dyspnea, cough, and fever). Physical examination reveals the signs of a pleural effusion; a pleural friction rub may be heard. The effusions are exudative and often bloody; glucose concentrations are normal. Mesothelial

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cells are found in about 50 percent of patients. In about 25 percent of patients, the fluid is eosinophilic. Rarely are asbestos bodies found even though they may be present in underlying lung tissue. The designation â&#x20AC;&#x153;benignâ&#x20AC;? refers to the lack of evidence of malignancy. The collections may persist for 6 months or more. They frequently clear spontaneously, only to recur on the contralateral side. Benign asbestos pleural effusions do not presage the development of malignant mesotheliomas. Moreover, patients with effusions have the same risk of developing asbestosis as do patients with chronic pleural fibrosis. However, a benign asbestos pleural effusion is a risk factor for the development of pleural thickening, especially diffuse pleural fibrosis. The diagnosis of acute benign pleural effusions is one of exclusion. Thoracentesis is essential. Pleural biopsy is frequently required to rule out other causes of pleural effusions, including mesothelioma. The usual pathological findings are a chronic fibrous pleurisy with minimal cellularity. Long-term follow-up is also a diagnostic requirement, since the diagnosis of a benign pleural effusion cannot be fully established until a tumor-free interval of 3 years has elapsed.

Figure 55-3 Lung tissue from a 64-year-old asbestos insulator with 46 years of exposure to asbestos while insulating pipes. His chest radiograph revealed extensive irregular opacities and bilateral pleural thickening. The figure illustrates peribronchiolar fibrosis, interstitial chronic inflammation, accumulation of macrophages in the airspaces, and proliferation of type II pneumocyte. (Based on data from Rom WN, Travis WD, Brody AR: Cellular and molecular basis of the asbestos-related diseases: State of the art. Am Rev Respir Dis 143:408â&#x20AC;&#x201C;422, 1991, with permission.)

ASBESTOSIS Pathology Asbestosis is the interstitial pneumonitis and fibrosis caused by exposure to asbestos fibers. Early lesions are characterized by discrete areas of fibrosis in the walls of respiratory bronchioles. The septi adjacent to the respiratory bronchioles are often thickened, and the fibrosis sometimes appears to spread outward from the bronchioles. In addition to the peribronchiolar fibrosis, there is an intense peribronchiolar cellular reaction that may narrow and obstruct the airway lumen. Macrophage accumulation is a prominent feature of this cellularity. Proliferation of type II alveolar epithelial cells is enhanced. The interstitium may contain collections of lymphocytes; smooth-muscle proliferation may be prominent in areas of remodeling; and buds of loose connective tissue may be seen within the alveoli (Fig. 55-3). Initially, the disease usually involves first-order bronchioles; subsequently, secondand third-order bronchioles are affected. As the disease progresses, the fibrosis becomes diffuse, the architecture of the lung undergoes extensive remodeling, and honeycombing supervenes. In contrast to other pneumoconioses, lymph node enlargement and progressive massive fibrosis do not occur. Pathologically, the alterations seen in asbestosis cannot be differentiated from many other interstitial fibrotic disorders except for the presence of asbestos bodies and uncoated asbestos fibers.

Pathogenesis Asbestos fibers are deposited at airway bifurcations and in respiratory bronchioles and alveoli by impaction, sedimenta-

tion, and interception. Fibers then migrate into the interstitium, in part via an uptake process involving type I alveolar epithelial cells. This causes alveolar macrophages to accumulate in the alveolar ducts, peribronchiolar interstitium, and alveolar spaces, constituting an alveolar macrophage alveolitis. Following this initial macrophage alveolitis, most fibers are cleared, leaving the lungs unscarred. If clearance is incomplete, fibrosis can ensue. The degree of fibrosis in asbestosis relates, in general, to the lung dust burden. If the dust load is small, the tissue reaction may be limited and the disease may be mild and not progress. If the retained dust load is great, tissue reaction and macrophage alveolitis are proportionately more intense, greater injury occurs, and chronic and progressive lung disease can develop. The macrophage alveolitis that is seen in early stages of asbestosis results from monocyte recruitment from the blood and in situ macrophage replication. These cells appear to play an important role in the pathogenesis of the inflammation and fibrosis seen in this disorder. Morphologically, they express an activated phenotype characterized by cellular multinucleation and a striking increase in membrane ruffling, surface blebbing, and lysosomes and phagolysosomes. These macrophages are presumably attempting to engulf and clear the asbestos fibers. This process is not uniformly successful, however. First, the fibers induce apoptosis in the cells. Although the coating of asbestos fibers to form asbestos bodies makes them less toxic, the vast majority of fibers in the lung remain uncoated. Second, the long fibers cannot be completely phagocytosed. Finally, chrysotile asbestos fibers tend to split longitudinally. This generates additional fibers that can multiply the asbestos effect even after exposure has ceased. As

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a result, asbestos has a prolonged residence and surprising mobility and penetrates the interstition of the distal lung. These characteristics probably contribute to the pathogenesis of the disease, since—in contrast to inert particles, which can be ingested by macrophages and cleared without generating a significant response—asbestos fibers stimulate macrophages to produce a variety of important moieties. These include cytokines, such as platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), interleukin-1β (IL-1β), tumor necrosis factor (TNF), and IL8, the matrix molecule fibronectin, oxygen free radicals, and plasminogen activators. The oxygen radicals contribute to tissue injury via direct cell cytotoxicity and lipid peroxidation of membrane components. The IL-8 recruits granulocytes to sites of disease activity. The PDGF, IGF-1, IL-1, TNF, and fibronectin contribute to tissue fibrosis by stimulating fibroblast proliferation and chemotaxis and collagen biosynthesis. Bronchoalveolar lavage (BAL) in asbestosis has demonstrated an alveolar macrophage alveolitis with a modest increase in neutrophils. This neutrophilia correlates with the finding of rales on physical examination and oxygenation parameters and is apt to be more pronounced in patients with advanced disease. In patients with asbestosis, 67gallium lung scans may also be positive. Clinically apparent asbestosis occurs only after a significant latent period. However, studies using BAL, CT scanning, and 67gallium scanning have demonstrated that inflammatory events occur well before the onset of clinical disease. Thus, it is likely that the initial exposure induces inflammation and injury that persist through the latent or subclinical phase and develops into the clinical disease diagnosed by classic radiography and other techniques. Current concepts of the pathogenesis of the disease link inflammation and fibrosis in a causal fashion.

Epidemiology The prevalence of parenchymal asbestosis among asbestos workers increases as the length of employment increases. This is illustrated in an early report in which investigators analyzed the chest radiographs of 1117 New York and New Jersey asbestos insulation workers. They found asbestosis in 10 percent of the workers who had been employed for 10 to 19 years, in 73 percent of those who had worked for 20 to 29 years, and in 92 percent of those who had worked 40 or more years. A similar dose-response relationship was found in the asbestos cement industry. Among “bystanders” (i.e., among sheet-metal workers who worked in close proximity to insulation workers) the overall prevalence of asbestos-related changes was 31 percent, including 9 percent who had only pleural abnormalities and 12 percent who had parenchymal abnormalities. Among those who had been in the trade for 40 years or more, 41.5 percent had radiographic signs of asbestos-related disease. Cigarette smoking can affect the expression of asbestosis. Smokers without dust exposure may have a few irregular radiographic opacities, probably representing acute or chronic bronchitis or bronchiectatic changes in the lung

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parenchyma. Both smokers and ex-smokers have a higher frequency of asbestos-related irregular opacities on their chest radiographs than do their nonsmoking colleagues. Among asbestos insulation workers, lower grades of radiographic small opacities predominated. Smoking does not alter the expression of asbestos-induced pleural fibrosis. The effects of smoking on asbestosis may be clinically important, since the mortality from asbestosis is higher in asbestos workers who have smoked than in their nonsmoking coworkers. This risk declines if the worker quits smoking. The mechanism of interaction of asbestos and cigarette smoking is poorly understood. However, cigarette smoking may interfere with the clearance of inhaled asbestos, thereby potentiating the effects of the dust in the lung.

Natural History Following asbestos exposure, asbestosis becomes evident only after an appreciable latent period. The duration of exposure and its intensity influence the prevalence of radiographically evident parenchymal pulmonary fibrosis. Because work sites around the world increasingly meet recommended control levels, high-level exposure to asbestos is now uncommon and clinical asbestosis is becoming a less severe disease that manifests after a longer latent interval. In Western Australian crocidolite workers, a median of 14 years elapsed before asbestosis was detectable radiographically (range, 2 to 34 years). In retired Quebec chrysotile miners and millers, the frequency of pleuroparenchymal lesions was 31 percent, and progression of parenchymal opacities occurred in 9.3 percent; progression was confined to the more heavily exposed group. One approach to the study of low-level exposure is to evaluate the outcome from short-term exposure. In such a study in an amosite asbestos factory, employment for even as little as 1 month resulted in a 20 percent prevalence of parenchymal opacities: one-third of the participants had pleural abnormalities after 20 years of follow-up; it is significant that both “first attacks” and progression of established radiographic abnormalities occurred 20 and more years after exposure had ceased. Radiographic asbestosis, once established, may remain static or progress. Rarely has regression been recorded. The factors that determine the outcome are poorly understood. The level and duration of exposure (i.e., cumulative exposure) appear to be prognostic factors. Progression is also considerably more common in persons who already have radiographic abnormalities. This fact provides the basis for the advice that further exposure is to be avoided once the diagnosis of parenchymal asbestosis has been made.

Clinical and Physiological Features Dyspnea on exertion is the earliest, most consistently reported, and frequently the most distressing symptom of asbestosis. Often dyspnea is accompanied by a persistent cough, which can be spasmodic, and sputum production. Chest tightness is not uncommon, and wheezing also can occur.

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In a cross-sectional survey of 816 asbestos-exposed workers using the respiratory symptom questionnaire of the American Thoracic Society, cough, phlegm, wheeze, and dyspnea were inversely related to pulmonary function. Cough, phlegm, and chronic bronchitis were associated with a 2 to 8 percent reduction in FVC and FEV1 ; the reduction in these measurements was more significant with wheeze and dyspnea, which caused an 11 to 17 percent reduction. Similarly, based on the British Medical Research Council questionnaire for dyspnea, the prevalence of grade 3 dyspnea among asbestos insulators increased in stepwise fashion from 19.4 percent in patients with category 1 chest radiographic abnormalities (1/0 to 1/2 abnormalities by International Labor Organization [ILO] classification) to 34.5 percent in patients with category 2 chest radiographs and to 49.4 percent in patients with category 3 radiographic abnormalities. Rales are a distinctive feature of asbestosis. They are usually bilateral, late to paninspiratory in timing, heard best at the posterior lung bases, and not cleared by coughing. They differ in quality and timing from the crackles of bronchitis, which tend to be fewer and earlier. The crackles of asbestosis appear first at the bases in the midaxillary line and tend to spread toward the posterior bases. In prevalence surveys, approximately 83 percent of patients with higher radiographic categories of asbestosis have bilateral rales. In a study of 42 patients with a clinical diagnosis of asbestosis, in 40 the chest radiograph showed at least 1/0 profusion of irregular opacities, 36 had rales, 36 had dyspnea, and 22 had digital clubbing. Rales and clubbing were almost as common among those with less as those with more advanced categories of asbestosis. In years past, asbestosis-induced respiratory failure was a frequent cause of death in patients with this disorder. In recent years, as the severity of asbestosis appears to have attenuated, cancer has become an increasingly common terminal event. It is important to appreciate that the clinical features of asbestosis and the findings on physical examination are not unique to this disorder and resemble those of a variety of other diffuse interstitial inflammatory and fibrotic processes. The characteristic pulmonary function changes of asbestosis are a restrictive impairment with a reduction in lung volumes (especially FVC and total lung capacity), decreased lung diffusing capacity (DlCO ), and arterial hypoxemia. Large-airway function, as reflected in the FEV1 /FVC ratio, is generally well preserved. In one of the earliest studies, approximately 50 percent of asbestos workers had a reduced FVC and the vital capacity was decreased, on average, by 18 percent as predicted over the next 10 years. Among the 1117 asbestos insulators in New York and New Jersey, the frequency of an abnormal FVC increased to more than 50 percent as follow-up was prolonged. In a larger cohort of 2611 asbestos insulators, the FVC percent predicted decreased as the profusion of irregular opacities on the chest radiograph increased; pleural thickening exaggerated the decrease for each category of profusion. For each category of profusion, diffuse pleural thickening caused a further decrease (at least 10 percent) in FVC percent predicted compared to circumscribed plaques.

Mild airway obstruction can also be seen in nonsmokers with asbestosis. These patients usually have a restrictive pattern of lung function, increased isoflow volume, and increased upstream resistance at low lung volumes. Open lung biopsies from a limited number of these patients suggest that these obstructive findings may be due to peribronchiolar fibrosis, since they revealed peribronchiolar infiltrates with macrophages and fibrosis that extended into the adjacent interstitium. Therefore, it is not surprising that lesser grades of asbestosis can show a mixed restrictive and obstructive abnormality. Long-term medical surveillance is recommended for all asbestos-exposed persons, especially those with radiographic abnormalities. Periodic physiological assessments play an important role in these evaluations. Although complex physiological abnormalities can be seen in these patients, for prospective assessments of asbestosis carried out in the clinical context, simple measurements of lung volume, such as the FVC, seem to be the most useful.

Radiographic Features In asbestosis, the standard PA chest radiograph reveals bilateral diffuse reticulonodular opacities, predominantly in the lower lung zones. In 2000, the International Labor Organization (ILO) revised the International Classification of the Radiographs of the Pneumoconioses to make provisions for reading the radiographic features of asbestosis. It used the term small irregular opacities to describe the irregular linear shadows that develop in the lung parenchyma and obscure the normal bronchovascular branching pattern seen in diseasefree lungs. This schema categorized the irregular rounded opacities found on PA chest radiographs according to size and expressed them on a 12-point scale. Category 0 was defined as a normal radiograph and category 1 as mild asbestosis. Typically, a profusion of irregular opacities at the level of 1/0 is taken as the break point between normal and abnormal. Moderate asbestosis and advanced asbestosis were defined as category 2 and 3 chest radiographs, respectively. As duration from onset and intensity of exposure increase, there is an increase in prevalence and severity of asbestosis as reflected in the chest radiograph. CT scanning has improved the sensitivity for detecting asbestos-related lesions (Fig. 55-4). It eliminates a common problem with PA chest radiographsâ&#x20AC;&#x201D;i.e. the superimposition of pleural abnormalities over parenchymal lesions. It also enhances the attenuation discrimination for parenchymal opacities. As a result of more than 300 HRCT evaluations of persons with asbestos exposure, five HRCT features of asbestosis have been identified: (1) curvilinear subpleural lines, (2) increased intralobular septa, (3) dependent opacities, (4) parenchymal bands and interlobular core structures, and (5) honeycombing. These changes have recently been corroborated by histological examination. This spectrum of radiographic findings stands in contrast to the fine irregular opacities that are so prominent on the PA chest radiographs of these persons. In asbestos-exposed workers, abnormal HRCT

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Figure 55-4 HRCT scan with irregular opacities of the lung parenchyma and interlobar structure. The PA chest radiograph was graded 2/1 on the ILO International Classification of the Radiographs of the Pneumoconioses. (Courtesy of Dr. David Naidich.)

has been shown to correlate with restrictive physiological abnormalities and abnormal diffusing capacities. HRCT is also extremely sensitive in documenting the asbestos-related pleural abnormalities discussed above. The presence of pleural plaques (particularly if they are bilateral) provides useful evidence that the parenchymal process is asbestos related. Hilar node enlargement is not a feature of asbestosis, and progressive massive fibrosis is also uncommon.

Diagnosis Asbestosis is defined as parenchymal fibrosis, with or without pleural thickening, usually associated with dyspnea, bibasilar rales, and pulmonary function changes. To diagnose this disorder, one must establish the presence of pulmonary fibrosis and determine whether exposure has occurred of a duration and intensity sufficient to put the person at risk for developing this syndrome. The PA chest radiograph and its interpretation are the most important factors. As noted above, a profusion of irregular opacities at the level of 1/0 is used as the break point between normal and abnormal in the evaluation of lung fields on the chest radiographs of asbestos-exposed persons. When radiographic or lung function changes are marginal, CT scanning often reveals characteristic parenchymal abnormalities as well as pleural plaques and/or pleural fibrosis. These

Asbestos-Related Lung Disease

lesions, particularly when bilateral, are strongly suggestive of asbestos exposure. The diagnosis of asbestosis must always be based on an appropriate exposure history. The features of the history that need to be defined include the duration, onset, type, and intensity of exposure experienced by the patient. Convincing occupational exposures include manufacture of asbestos products, asbestos mining and milling, construction trade worker (insulator, sheet-metal worker, electrician, plumber, pipe fitter, carpenter), power plant worker, boilermaker, and shipyard worker. In performing this evaluation, it is important to keep in mind that intensity of exposure can be heavy even if duration of exposure is short. For example, heavy exposures were experienced by shipyard workers engaged in insulation application or removal in contained areas for brief periods aboard ship and by asbestos insulators during their apprenticeship when they unloaded asbestos sacks into troughs and mixed asbestos cement. Short, intense exposures of this sort, which lasted from several months to 1 or 2 years, can be sufficient to cause asbestosis. Exposures over 10 to 20 years are, however, usually necessary. The timing of the exposure is also relevant. Industrial hygiene controls in the 1950s and 1960s, especially in the construction trades, were not widely applied or enforced. Thus, workers exposed during these periods may have received a heavy asbestos load. Time since onset of exposure is also crucial. Cohort studies have identified latency to be an important factor, with the prevalence of asbestosis increasing with time since the onset of exposure. The specificity of the diagnosis of asbestosis increases as the number of clinical criteria (symptoms, signs, chest radiograph, pulmonary function) increase. In addition, as the accuracy of the diagnosis increases, the more significant the asbestos exposure. The more trivial the asbestos exposure, the less likely it is to be causal. Misclassification and diagnostic difficulty occur in patients with a heavy cigarette-smoking history and concurrent emphysema (which also reduces the diffusing capacity). Patients with idiopathic pulmonary fibrosis (IPF) may have a history of asbestos exposure. These patients tend to be younger, however, and their asbestos exposure is usually casual, brief, and recent and can often be discounted. Since patients with IPF require a lung biopsy for confirmatory diagnosis, an asbestos fiber count per milligram of dry lung can be helpful (see below). An open lung biopsy is not required in most cases when a significant exposure history can be identified. In the absence of an adequate exposure history or in the presence of a confusing clinical presentation, biopsy material may be helpful in identifying the nature of the disease. It allows the pulmonary interstitial process to be compared to the known features of asbestosis and other interstitial disorders. It also allows the pathologist to look for the presence of asbestos materials. Asbestos fibers exist in the lung in two forms: uncoated or bare fibers, which, for practical purposes, are visible only on electron microscopy, and coated fibers, which are also called asbestos bodies. The latter are visible by light microscopy (Fig. 55-5). Uncoated fibers are much

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lioma or lung cancer, 8 asbestos bodies per milliliter of lavage fluid. Of 49 patients with more than 100 asbestos bodies per milliliter of lavage fluid, 30 had asbestosis, 8 had pleural disease, 13 had mesothelioma or lung cancer, and 3 had an exposure history only. Others have estimated that one asbestos body per milliliter of BAL fluid correlates with 1000 to 3000 asbestos bodies per gram of dry lung tissue. The problems inherent in counting asbestos bodies in an attempt to establish a diagnosis of asbestosis were noted above. Thus, the utility of BAL asbestos body counts in diagnosing asbestos awaits further definition.

Treatment and Prognosis Major causes of morbidity and mortality in patients with asbestosis include the progression of the underlying lung disease and the development of lung cancers and malignant mesotheliomas. Longitudinal observations of asbestosexposed trade workers have demonstrated accelerated declines in pulmonary function. In a study of 77 workers with a mean of 31 ± 1 years of occupational exposure, linear regression demonstrated a mean annual decline of 92 ± 28 ml per year in FVC, 66 ± 22 ml per year in FEV1 , and 14 ± 53 ml per year in total lung capacity. Although corticosteroids and colchicine have been used for the treatment of IPF, they have not been demonstrated to be beneficial in asbestosis. At present, there is no established treatment for this disorder. Because of the risk of lung cancer and mesothelioma, however, medical surveillance is recommended. Figure 55-5 Light microscopic appearance of an asbestos body in a cytocentrifuged preparation of alveolar macrophages lavaged from a nonsmoking asbestos insulator (Wright-Giemsa stain, ×400). (Courtesy of Dr. T. Takemura and Dr. V. Ferrans.)

more common, exceeding the frequency of coated fibers by anything from 5- to 10,000-fold. Although other inhaled particles may also become coated, most coated fibers found in human lungs have an asbestos core. Thus, the presence of asbestos bodies or asbestos fibers is considered the hallmark of exposure, past or current. The presence of more than one coated fiber has been cited as a necessary criterion for the pathological diagnosis of asbestosis, even in a subject with an obvious exposure history. This may be inappropriate, however, since asbestos bodies may not be able to be detected even after heavy exposure. Cases have been described in which the load of uncoated fibers was high in the absence of asbestos bodies, and asbestos bodies have been noted in the tissues of people without significant asbestos exposure. Thus, although asbestos bodies probably reflect exposure, their absence by no means excludes it. Asbestos bodies can also be detected in BAL samples. In some studies, these asbestos bodies correlate with heavy exposure and asbestosis. This is illustrated in a large series of 563 patients: those with asbestosis had a mean of 120 asbestos bodies per milliliter; those with pleural disease, 5 asbestos bodies per milliliter; and those with malignant mesothe-

MALIGNANT MESOTHELIOMA Pathology Most instances of mesothelioma occur in persons who have been exposed to asbestos fibers. In its early stage, the mesothelioma appears as multiple, small, grayish nodules on the visceral and parietal pleura that evolve to coalesce and form larger masses of tumors. These tumors then invade thoracic and other structures by direct extension, causing the morbidity and mortality of disease. Fewer than 25 percent of malignant mesotheliomas are peritoneal in origin. Mesotheliomas are conventionally classified into three histological patterns: epithelial, sarcomatous, and mixed or biphasic; these patterns account for 50, 20, and 30 percent, respectively. The epithelial variant—in which neoplastic cells are arranged in papillary, tubular, or solid nest configurations—is most easily confused with metastatic adenocarcinoma. The sarcomatous variant has spindle-shaped cells that may be pleomorphic, with considerable mitotic activity. The pathological diagnosis of malignant mesothelioma may be difficult. In particular, the differentiation of malignant mesotheliomas, adenocarcinomas, and other tumors may be problematic. Histochemistry and immunohistochemistry

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may be helpful in making the distinction. Thus, in contrast to mesotheliomas, adenocarcinomas contain neutral mucin that stains positive with the periodic acid–Schiff stain and is often resistant to diastase. Hyaluronic acid, the major acid mucopolysaccharide in mesotheliomas, can be identified with the Alcian blue or colloidal iron stain. Removal by prior digestion with hyaluronidase increases the specificity of the reaction. In contrast, adenocarcinomas are negative for Alcian blue and colloidal iron. Mesothelial cells contain cytoskeletal filaments, including cytokeratin and vimentin; staining for these structures is not specific, since other tumor types are also positive. Carcinoembryonic antigen is absent in malignant mesothelioma but is present in up to 90 percent of adenocarcinomas. Similarly, the monoclonal antibody B72.3, generated against a membrane fraction of human metastatic breast cancer, was positive in 19 of 22 pulmonary adenocarcinomas but none of 20 mesotheliomas. Monoclonal antibody Leu MI is frequently positive in lung carcinomas and nonreactive with mesotheliomas. The ultrastructural features of malignant mesotheliomas are also noteworthy. Malignant mesotheliomas contain abundant tonofilaments, often organized into perinuclear bundles, and long, sinuous, slender surface microvilli. The microvilli sometimes show secondary and tertiary branching and may interdigitate with stromal collagen. Malignant mesothelial cells produce collagen, a prominent feature of the sarcomatous variant. Malignant mesotheliomas are locally invasive, spreading along the pleural wall and invading the lung, mediastinal lymph nodes, and other thoracic and nearby structures. At autopsy, tumor may be found in the diaphragm, heart, liver, spleen, adrenals, gastrointestinal tract serosa, bone, pancreas, and kidneys. Between 50 and 80 percent of patients also have metastases. About 10 percent of patients with a malignant mesothelioma are alive at 24 months. Survival is significantly longer for patients with an epithelial subtype or with a pleural rather than a peritoneal mesothelioma, and for those under 65 years of age. The incidence of mesothelioma is increasing because of the cohort exposed to asbestos between 1940 and 1970. Incidence rates vary from a low of 11 to 13 per million per year in the United States to 33 per million per year in South Africa and to 66 per million per year in Western Australia. These rates reflect mining and manufacturing industries and the location of crocidolite mines. Although the peak incidence in the United States may have passed since imports decreased after 1945, imports of asbestos in the United Kingdom reached their peak in the 1960s to 1970s. Thus, the peak of mesothelioma deaths in the United Kingdom is expected to occur in 2020, when up to 1 percent of men may die of the disease. Chrysotile was the major asbestos import to the United Kingdom, and half of this material went into the construction industry. Amosite was the leading amphibole import, and most of it went into insulation board. Thus, workers in the construction industry in the United Kingdom seem to be at greatest risk.

Asbestos-Related Lung Disease

Epidemiology In 1960, Wagner and colleagues published a landmark paper demonstrating an association between malignant mesothelioma and asbestos exposure. They reported on 33 patients from South Africa, 28 of whom were exposed in the crocidolite mining region and 4 of whom were exposed in asbestos factories. They observed that mesotheliomas occurred 20 to 40 years after exposure to asbestos dust and found asbestos bodies in lung tissue from 8 of 10 patients from whom lung tissue was available for study. Subsequently, the importance of direct asbestos exposure was confirmed and the potential importance of indirect exposure to asbestos was recognized. Evaluations of asbestos fiber content have shown a clear association between asbestos exposure and the occurrence of mesothelioma.Epidemiological studies have shown that crocidolite may be the more potent fiber type among asbestos miners. Most mesotheliomas have occurred from chrysotileamphibole mixtures, since chrysotile is the most common fiber in commercial use. Few controversies in medicine are as intense as the disagreements concerning the relation between asbestos fiber type and carcinogenic risk. Nonetheless, associations between malignant mesothelioma and other (noncrocidolite) fiber types have been reported. For example, the incidence of malignant mesotheliomas among chrysotile workers who came before the Workers’ Compensation Board of Quebec was similar to that in Western Australian crocidolite miners. Studies of Canadian cohorts have also indicated that high concentrations of chrysotile, or an amphibole contaminant, are required to cause mesothelioma, suggesting that chrysotile has weaker biopersistence than does tremolite, which is merely a contaminant in most ores. In the United States, amosite is the predominant amphibole found in lung tissue: in one study it was identified in 81 percent of 90 patients with mesothelioma; in this population, it accounted for 58 percent of all fibers at least 5 µm in length. Cigarette smoking is a confounding variable in studies that relate asbestos-exposed persons to cancer risk. The contribution that cigarettes make to the risk of lung cancer is impressive (see below). It is universally accepted, however, that mesothelioma is not associated with cigarette smoke per se.

Pathogenesis Insight into the pathogenesis of malignant mesothelioma has come from experiments in which asbestos fibers were introduced into the pleural space of animals. These studies have demonstrated that amosite, anthophyllite, crocidolite, and Canadian chrysotile can all cause these pleural malignancies. Studies of fiber size have shown that the most carcinogenic fibers in the pleural space are 1.5 µm or less in diameter and more than 8 µm in length. Inspection of electron micrographs of asbestos fibers has shown that crocidolite and amosite possess needlelike characteristics, whereas anthophyllite has a more boxlike appearance and chrysotile has a long, curly appearance. These variations in size are also consistent with epidemiological studies indicating that crocidolite and amosite

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may have greater risk for mesothelioma than do other types of asbestos, although these studies are often confounded by intense exposures to these amphibole types. One theory concerning the mechanism of asbestosinduced carcinogenesis focuses on the observation that asbestos fibers become entangled in the mitotic spindle during interphase, thereby causing chromosomal abnormalities. Electron microscopic evaluations have shown fibers penetrating between multiple lobes of the nucleus and associating, along their length, with the outer surface of the nuclear envelope. Structural chromosomal abnormalities in mesothelioma are clonal and complex, and include both chromosomal gains (chromosome 22) and losses (chromosome 7). Deletions of the short arm of chromosome 3, the break point 1p11 to p22, chromosome 17, and structural and numeric changes in chromosome 7 have been described. The last is quite interesting, since the tumor suppressor gene p53 is located in the region of 17p13. In asbestos insulators, sister chromatid exchanges in circulating lymphocytes are increased: larger chromosomes are more susceptible, and in the largest chromosome group, there is a significant interactive effect between asbestos exposure and cigarette smoking. Cell lines established from malignant mesotheliomas have been shown to constitutively up-regulate the PDGF B-chain gene and, to a lesser extent, the PDGF A-chain gene. High levels of transforming growth factor-β1 (TGFβ1 ), TGF-β2 , and TGF-β3 mRNA and bioactivity have been reported for cell lines derived from malignant mesotheliomas. These TGF-β moieties may be involved in the considerable matrix formation that accompanies mesothelial tumors. Mesothelioma cell lines also release IGF-1 and express mRNA for the IGF-1 receptor. This is consistent with an IGF-1–based autocrine loop for mesothelioma cell proliferation.

Figure 55-6 Large pleural effusion in an asbestos-exposed worker with an underlying malignant mesothelioma. (Courtesy of Dr. J. Elias.)

along the lateral chest wall that can extend to the apex with an irregular nodular surface, multiple pleural nodules or masses, plaquelike opacities, and pleural effusion(s). As the disease progresses, the lung parenchyma may be involved, the affected hemithorax may decrease in size, and the mediastinum or hilar may be invaded. Pericardial thickening or effusion, abdominal extension, and chest wall invasion are common. The HRCT can help in differentiating pleural effusion from tumor and in determining the extent of tumor progression. The presence of asbestosis or of pleural plaques on the opposite side can assist in establishing the diagnosis of malignant mesothelioma.

Clinical and Radiographic Features

Diagnosis

Pleural mesotheliomas are found mainly in males (ratio, between 3 and 4 to 1) and are most commonly diagnosed in patients between 50 and 70 years of age. Chest pain is the most common symptom experienced by patients with mesotheliomas. Dyspnea is next in frequency. Less common symptoms are cough, weight loss, and fever. A pleural effusion is usually present and can be massive. The effusion is an exudate, can be hemorrhagic, and may have high levels of hyaluronic acid (Fig. 55-6). Malignant mesothelioma is locally invasive, spreading along the pleural wall and invading the lung and nearby structures. Metastases are less common but can give rise to symptoms due to tumor in the diaphragm, heart, liver, spleen, adrenals, gastrointestinal tract, bone, pancreas, and kidneys. The syndrome of inappropriate antidiuretic hormone secretion, clubbing, or hypoglycemia is rare. Thrombocytosis is common—in 90 percent of cases in one series—and thromboembolic complications can occur. Ascites and weight loss are characteristic features of peritoneal mesothelioma. A variety of radiographic abnormalities are found in malignant mesothelioma. They include a thick pleural peel

The diagnosis of malignant mesothelioma requires cytological or histological validation. Obtaining a cytological diagnosis from the pleural exudate is difficult because reactive mesothelial cells and malignant cells are not easy to distinguish. Biopsy is required. Because mesothelioma has been shown to invade the track of the needle on about 20 percent of patients in whom biopsy was performed by transthoracic needle, open biopsy is preferable. Thoracoscopy is probably the procedure of choice in establishing the diagnosis of mesothelioma. Its diagnostic rates are greater than 80 percent—a value similar to that of open pleural biopsy. Local radiation after biopsy significantly reduces spread in needle tracks or incisions.

Treatment and Prognosis Median survival time is approximately 8 to 12 months for all patients with malignant mesothelioma. Overall, fewer than 20 percent of patients are alive at 2 years. Pleurectomy or pneumonectomy, combined with radiation therapy, has failed to significantly influence survival rates. Chemotherapy

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with doxorubicin (Adriamycin) has shown variable responses without prolonging survival. Interventions, such as gene therapy or the use of cytokines, for the treatment of malignant mesothelioma are currently being investigated. Thus, in 89 patients, the intrapleural instillation of γ-interferon twice weekly for 8 weeks resulted in eight histologically confirmed complete responses and nine partial responses, with at least a 50 percent reduction in tumor size. The overall response rate was 20 percent, increasing to 45 percent in stage I disease. In 15 patients, a phase I clinical trial of continuous infusion into the pleural space of recombinant IL-2 for 5 days, when evaluated at 36 days after infusion, revealed one complete remission and six partial remissions. The main side effect was fluid retention, no greater than 10 percent, in one-third of the patients. In mice with severe combined immune-deficiency, gene therapy, using a replication-defective adenovirus carrying the herpes simplex–thymidine kinase gene followed by the antiviral drug ganciclovir, was used successfully to treat malignant mesothelioma. A significant antitumor effect occurred with clinically achievable dose ranges, even in bulky tumors. The virus did not spread from the serosal cavity following instillation. In mice with subcutaneously implanted mesothelioma, tumor regression occurred when only 10 percent of cells were infected—a result consistent with a bystander effect. A phase I clinical trial has shown this therapy to be safe. However, humoral and cell-mediated immune responses that developed against viral surface proteins compromised the therapeutic effectiveness of this approach. Also, the thymidine kinase gene in vivo had no effect on promoting regression of the tumor. These promising areas of research need further development before they can be applied as standard therapy.

LUNG CANCER Epidemiology The association between asbestos exposure and the development of lung cancer is based on a number of successive epidemiological investigations. Case reports of lung cancer and asbestos deaths occurred as early as 1935. Series of patients with asbestosis who went to autopsy were reported by 1947. In 1955, an epidemiological cohort study of 113 men exposed to asbestos for 20 years disclosed 11 deaths due to cancer (compared with 0.8 expected), all of which had evidence of asbestosis. In 1965, a retrospective cohort study in two asbestos insulator unions in the United States reported that deaths from lung cancer were 6.8 times the expected rate and that the incidence of lung cancer increased with time after exposure. In 1968, a follow-up of men in this cohort demonstrated an important synergy between asbestos exposure and cigarette smoking, since the risk of lung cancer was almost entirely borne by those who had a history of cigarette smoking. The largest survey of asbestos-related deaths looked at a North American asbestos insulator cohort. This study

Asbestos-Related Lung Disease

demonstrated a threefold excess of cancer deaths that were due primarily to pulmonary malignancies. Comparatively few of these excess deaths were observed among those less than 25 years after the start of exposure. Lung cancer peaked at 40 years from exposure and mesothelioma at 45 years. In contrast, death rates from asbestosis increased progressively with time. This study confirmed the multiplicative effect of smoking plus asbestos exposure on the risk of lung cancer. Moreover, it showed that deaths from lung cancer dropped by almost two-thirds for asbestos insulators who subsequently stopped smoking. Additional insights were provided by a study of amosite workers who were exposed to concentrations of 50 fibers per milliliter. These patients experienced a fivefold increase in lung cancer. Long-term follow-up showed: (1) a latency period of about 20 years before the increase in cancer occurred; (2) the greater the dose or the longer the exposure, the greater risk of developing lung cancer; and (3) the greater the dose or exposure time, the shorter the latency period before the tumor developed. Malignancies were also noted in the wives and children of these workers who were exposed to asbestos in the household, primarily on work clothes. In addition, men employed for less than 1 month between 1941 and 1945 developed lung cancer at an increased rate. Studies of a variety of other cohorts have confirmed the increased incidence of lung cancer in asbestos-exposed populations. They have also demonstrated an increased frequency of digestive cancers and cancer of the larynx; in the latter, asbestos has been found in laryngeal tissue. As in the case of cancer of the lung, cigarette smoking has a strong association with the occurrence of these laryngeal malignancies. Epidemiological studies have also provided information about dose-response relationships and about the importance of asbestos-processing techniques and fiber type in the pathogenesis of pulmonary malignancies. A number of investigators have observed linear dose-response relationships for lung cancer. Different dose-response relationships have, however, been found in other studies. These differences may be the result of differences in processing techniques. For example, studies in a South Carolina plant demonstrated that the steeper dose-response relationship of miners vs. textile weavers was probably due to the manufacturing process, which resulted in high levels of brief exposure during the opening of asbestos bags and the sudden separation of the asbestos fibers. Similarly, differences in lung cancer mortality in asbestos cement product plants in Louisiana were found to be associated with the addition, in one of these plants, of crocidolite to the asbestos cement pipe mixture. Other risk factors in the work place— such as concomitant metals, ionizing radiation, and other chemicals—may also contribute to the differences that have been noted. It has been argued that there is a difference in lung cancer risk for different asbestos fiber types; however, the risk of lung cancer increases most clearly with cumulative asbestos exposure. Despite these uncertainties, however, it is clear that each of the asbestos fiber types causes lung cancer.

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Pathology Asbestos-related lung cancers are not distinct from lung cancers that occur in cigarette smokers and otherwise normal persons in type, nature, or location. All histological types of lung cancer occur with increased frequency, but adenocarcinoma has the highest incidence. In the vast majority of patients, there is histological evidence of asbestosis and asbestos bodies are frequently found. Asbestos-related lung cancer can occur in the absence of asbestosis.

Pathogenesis Animal experiments using several types of asbestos have succeeded in reproducing pulmonary malignancies. In one study, approximately one-third of rats exposed by inhalation to asbestos (amosite, anthophyllite, crocidolite, Canadian chrysotile, or Rhodesian chrysotile) for periods ranging from 1 day to 24 months developed adenocarcinomas or squamous cell carcinomas of the lung. In these experiments, a clear dose-response relationship existed between asbestos dose and the occurrence of tumors. The mechanisms responsible for the induction of these malignancies are poorly understood. However, DNA injury and activation of nuclear transcription factors may play an important role. The former appears to relate to the physical properties of the asbestos fibers, which enable DNA, RNA, and chromatin to bind to asbestos. Reactive oxygen species may also play an important role in this process, since chrysotile asbestos, along with cigarette smoke, synergistically increases the number of breaks in DNA strands, and oxidant scavengers—such as mannitol, catalase, iron chelators, and dimethylsulfoxide—prevent this DNA damage. Asbestos also induces nuclear factor-κB (NF-κB) DNA binding in tracheal epithelial cells in vitro. NF-κB is an important transcription factor for cytokines, growth factors, and protooncogenes that could contribute in a variety of ways to malignant transformation.

In addition, in amphibole miners from South Africa with carcinoma of the lung who were evaluated by stepwise regression analysis for exposure variables, asbestosis was by far the most striking variable. Moreover, a dose-response relationship was found between the severity of asbestosis and the frequency of lung cancer. However, in keeping with the high frequency of asbestosis that cannot be seen on the chest radiograph (i.e., asbestosis that can be detected only in vivo by HRCT or biopsy) it is clear that radiographic evidence of asbestosis cannot be detected in all patients with asbestosrelated lung cancer. Thus, in the North American insulator cohort, 18 percent of the patients who died of lung cancer did not have radiographic evidence of parenchymal fibrosis. Similarly, in a case control study of 271 patients with lung cancer, a small but definite increase in cancer risk was noted in patients whose chest radiographs were not definitely abnormal (0/1 or less by ILO classification). This study indicated that asbestos exposures that do not cause small opacities on the chest radiograph may nevertheless increase the risk of lung cancer.

Radiographic Features The radiographic manifestations of asbestos-induced lung cancers do not differ, per se, from those of lung cancers associated with other carcinogens. Mass lesions, atelectasis, postobstructive pneumonia, and pleural effusions are all seen. As noted above, these lesions are frequently superimposed on a background of asbestosis or asbestos-induced pleural abnormalities. Confusion with lung cancer may arise from en face pleural plaques or rounded atelectasis. In contrast to lung cancer, however, these abnormalities are stable over time. Newer techniques, such as the helical CT scan, which can evaluate the chest in a single breath, may increase the early detection rate of lung cancer in this high-risk patient population.

Diagnosis Clinical Features The patterns of presentation of lung cancer among asbestos workers are similar to those of high-risk patient populations: cough, chest pain, dyspnea, hemoptysis, recurrent bouts of pneumonia, and localized wheezing are major symptoms that frequently bring patients to medical attention. However, patients can also be asymptomatic at the time of initial discovery, the abnormality being noted on a routine or screening chest radiograph. Other manifestations of carcinoma—such as rib invasion, shoulder-arm pain, and paraneoplastic syndromes—can also occur in asbestosrelated malignancies. One of the most vexing questions in asbestos-related lung cancers is the relationship between the lung cancer and asbestosis. Asbestosis can be detected radiographically or histologically in the vast majority of patients with asbestosrelated lung cancer. Most, but not all, patients with lung cancer in the Quebec asbestos mining district had small parenchymal opacities on the chest radiograph before death.

The principles employed in the diagnosis of lung cancer in asbestos workers are identical to those in the diagnosis of pulmonary malignancies in patients exposed to other carcinogenic agents. Appropriate cytological or histological specimens are required. This can be accomplished by sputum analysis or by bronchoscopy with brushings, biopsy, or lavage. Transthoracic needle aspirates, thoracoscopic parenchymal biopsies, or open lung biopsies may be required for definitive diagnosis.

Treatment and Prognosis The therapeutic approaches utilized for asbestos-related lung cancers are similar to those employed for lung cancers induced under other circumstances. When one is dealing with non– small-cell malignancies, patient operability and resectability need to be evaluated and, if appropriate, surgical extirpation undertaken. The impact of other asbestos-related pulmonary processes must always be taken into account. For

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example, severe asbestosis may limit operability, and diffuse pleural thickening may make surgical intervention problematic. Overall, however, lung cancer has a poor prognosis— 15 percent survival at 5 years.

EFFORTS AT ASBESTOS CONTROL In order to control the risk of exposure to asbestos, the US Occupational Safety and Health Administration regulates the usage of all types of asbestos fibers. Industrial hygiene efforts to control exposure have focused on engineering controls, including enclosure of the process lines, especially all sites where asbestos is introduced into a system, increasing ventilation, and the use of wet manufacturing methods. Personal respirators are used as a last resort in achieving control of exposure in the workplace. Most of the insulation-manufacturing industry has switched to alternative materials, especially fibrous glass, rock and slag wool, and refractory ceramic fibers. Animal experiments have generally shown these asbestos substitutes to be safe, except that refractory ceramic fibers were able to produce mesotheliomas in hamsters. Asbestosis and asbestos-related cancers may occur at increased rates in the future, owing to the increased use of asbestos in developing countries.

SUGGESTED READING American Thoracic Society: Diagnosis and initial management of nonmalignant diseases related to asbestos. Am J Respir Crit Care Med 170:691–715, 2004. Appel JD, Fasy TM, Kohtz DS, et al: Asbestos fibers mediate transformation of monkey cells by exogenous plasmid DNA. Proc Natl Acad Sci USA 85:7670–7674, 1988. Becklake M: Fiber burden and asbestos-related lung disease: Determinants of dose-response relationships. Am J Respir Crit Care Med 150:1488–1492, 1994. B´egin R, Cantin A, Berthiaume Y, et al: Airway function in lifetime-nonsmoking older asbestos workers. Am J Med 75:631–638, 1983. B´egin R, Guntier JJ, Desmeules M, et al: Work-related mesothelioma in Quebec, 1967–1990. Am J Ind Med 22:531–542, 1992. Brodkin CA, Barnhart S, Anderson G, et al: Correlation between respiratory symptoms and pulmonary function in asbestos-exposed workers. Am Rev Respir Dis 148:32–37, 1993. Brody AR, Hill LH, Adler KB: Actin-containing microfilaments of pulmonary epithelial cells provide a mechanism for translocation asbestos to the interstitium. Chest 83(Suppl):11–12, 1983. Churg A, Vedal S: Fiber burden and patterns of asbestosrelated disease in workers with heavy mixed amosite and

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chrysotile exposure. Am J Respir Crit Care Med 150:663– 669, 1994. Cullen MR, Barnett MJ, Balmes JR, et al: Prediction of lung cancer among asbestos-exposed men in the beta-carotine and retimal efficacy Trial. Am J Epidemiol 161:260–270, 2005. Dement JM, Harris RL, Symons MJ, et al: Exposures and mortality among chrysotile asbestos workers: Part II. Mortality. Am J Ind Med 4:421–433, 1983. de Vuyst P, Dumortier P, Moulin E, et al: Diagnostic value of asbestos bodies in bronchoalveolar lavage fluid. Am Rev Respir Dis 136:1219–1224, 1987. Doll R: Mortality from lung cancer in asbestos workers. Br J Ind Med 12:81–86, 1955. Ehrlich R, Lilis R, Chan E, et al: Long-term radiological effects of short-term exposure to amosite asbestos among factory workers. Br J Ind Med 49:268–275, 1992. Finkelstein MM: Mortality among employees of an Ontario asbestos cement factory. Am Rev Respir Dis 129:754–761, 1984. Gamsu G, Salmon CJ, Warnock ML, et al: CT quantification of interstitial fibrosis in patients with asbestosis: A comparison of two methods. AJR Am J Roentgenol 164:63–68, 1995. Hillerdal G: Pleural plaques and risk for bronchial carcinoma and mesothelioma. Chest 105:144–150, 1994. Hillerdal G: Rounded atelectasis. Chest 95:836–841, 1989. Hillerdal G, Ozesmi M: Benign asbestos pleural effusion: 73 exudates in 60 patients. Eur J Respir Dis 71:113–121, 1987. Hughes JM, Weill H, Hammad YY: Mortality of workers employed in the asbestos cement manufacturing plants. Br J Ind Med 44:161–174, 1987. Kipen HM, Lilis R, Suzuki Y, et al: Pulmonary fibrosis in asbestos insulation workers with lung cancer: A radiological and histopathological evaluation. Br J Ind Med 44:96–100, 1987. Lilis R, Miller A, Godbold J, et al: Comparative quantitative evaluation of pleural fibrosis and its effects on pulmonary function in two large asbestos-exposed occupational groups—insulators and sheet metal workers. Environ Res 59:49–66, 1992. Lilis R, Miller A, Godbold J, et al: Pulmonary function and pleural fibrosis: Quantitative relationships with an integrative index of pleural abnormalities. Am J Ind Med 20:145– 161, 1991. Lilis R, Miller A, Godbold J, et al: Radiographic abnormalities in asbestos insulators: Effects of duration from onset of exposure and smoking: Relationships of dyspnea with parenchymal and pleural fibrosis. Am J Ind Med 20:1–15, 1991. Lilis R, Selikoff IJ, Lerman Y, et al: Asbestosis: Interstitial pulmonary fibrosis and pleural fibrosis in a cohort of asbestos insulation workers: Influence of cigarette smoking. Am J Ind Med 10: 459–470, 1986. Markowity SB, Marabia A, Lilis R, et al: Clinical prediction of mortality from asbestoses in the North American insulator

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cohort 1981–1991 Am J Respir Crit Care Med 156:101–108, 1997. Miller A, Lilis R, Godbold J, et al: Relationship of pulmonary function to radiographic interstitial fibrosis in 2611 long-term asbestos insulators. Am Rev Respir Dis 145:263–270, 1992. Newhouse ML, Berry G, Wagner JC: Mortality of factory workers in east London, 1933–80. Br J Ind Med 42:4–11, 1980. Ohar J, Sterling DA, Bleecker E. et al: Changing patterns in asbesto-induced lung disease. Chest 125:744–753, 2004. Peto J, Hodgson JT, Matthews FE, et al: Continuing increase in mesothelioma mortality in Britain. Lancet 345:535–539, 1995. Picado C, Rodriguez-Roisin R, Sala H, et al: Diagnosis of asbestosis: Clinical, radiological and lung function data in 42 patients. Lung 162:325–335, 1984. Roggli V, Pratt PC, Brody AR: Asbestos fiber type in malignant mesothelioma: An analytical scanning electron microscopic study of 94 cases. Am J Ind Med 23:605–614, 1993. Rom WN: Accelerated loss of lung function and alveolitis in a longitudinal study of non-smoking individuals with occupational exposure to asbestos. Am J Ind Med 21:835– 844, 1992. Rom WN, Basset P, Fells G, et al: Alveolar macrophages release an insulin-like growth factor I–type molecule. J Clin Invest 82:1685–1693, 1988. Rom WN, Bitterman PB, Rennard SI, et al: Characterization of the lower respiratory tract inflammation of nonsmoking individuals with interstitial lung disease associated with chronic inhalation of inorganic dusts. Am Rev Respir Dis 136:1429–1434, 1987. Rom WN, Travis WD, Brody AR: Cellular and molecular basis of the asbestos-related diseases: State of the art. Am Rev Respir Dis 143:408–422, 1991. Rosenstock L, Barnhart S, Heyer NJ, et al: The relation among pulmonary function, chest roentgenographic abnormalities, and smoking status in an asbestos-exposed cohort. Am Rev Respir Dis 138:272–277, 1988. Schwartz DA, Galvin JR, Yagla SJ, et al: Restrictive lung func-

tion and asbestos-induced pleural fibrosis. J Clin Invest 91:2685–2692, 1993. Sebasti´en P, Armstrong B, Monchaux G, et al: Asbestos bodies in bronchoalveolar lavage fluid and in lung parenchyma. Am Rev Respir Dis 137:75–78, 1988. Seidman H, Selikoff IJ, Gelb SK: Mortality experience of amosite asbestos factory workers: Dose-response relationships 5 to 40 years after onset of short-term work exposure. Am J Ind Med 10:479–514, 1986. Selikoff IJ, Churg J, Hammond EC: Asbestos exposure and neoplasia. JAMA 188:22–26, 1964. Selikoff IJ, Lee DH: Asbestos and its distribution: Historical background, in Selikoff IJ, Lee DH (eds), Asbestos and Disease (Environmental Science Series). New York, Academic Press, 1978, pp 3–32. Selikoff IJ, Seidman H: Asbestos-associated deaths among workers in the United States and Canada, 1967–1987. Ann NY Acad Sci 643:1–14, 1991. Sheers G, Templeton AR: Effect of asbestos on dockyard workers. Br Med J 3:574–579, 1968. Staples CA, Gamsu G, Ray CS, et al: High resolution computed tomography and lung function in asbestos-exposed workers with normal chest radiographs. Am Rev Respir Dis 139:1502–1508, 1989. Takemura T, Rom WN, Ferrans VJ, et al: Morphological characterization of alveolar macrophages from individuals with occupational exposure to inorganic particles. Am Rev Respir Dis 140:1674–1685, 1989. Wagner JC, Sleggs CA, Marchand P: Diffuse pleural mesothelioma and asbestos exposure in the northwestern Cape Province. Br J Ind Med 17:260–271, 1960. Welch LS, Haile E, Dement J, Michael D: Change in prevalence of asbestos-related disease among sheet metal workers 1986 to 2004. Chest 131:863–869, 2007. Wilkinson P, Hansell DM, Janssens J, et al: Is lung cancer associated with asbestos exposure when there are no small opacities on the chest radiograph? Lancet 345:1074–1078, 1995. Xaubet A, Rodriguez-Roisin R, Bombi JA, et al: Correlation of bronchoalveolar lavage and clinical and functional findings in asbestosis. Am Rev Respir Dis 133:848–854, 1986.

56 Chronic Beryllium Disease and Hard-Metal Lung Diseases Mary Elizabeth Kreider Milton D. Rossman

I. CHRONIC BERYLLIUM DISEASE History Clinical Presentation Radiography Immunopath ogenesis Diagnosis Differential Diagnosis Treatment Beryllium and Lung Cancer

CHRONIC BERYLLIUM DISEASE History Beryllium is the lightest weight metal and has an atomic number of 4. Gem stones, such as aquamarine, emerald, and beryl, contain beryllium and have been recognized since ancient times. But beryllium as an element was first discovered in 1798 by the French chemist, Vauquelin, and reduced to its metallic form and named beryllium in 1828 by the German metallurgist, Wohler. Beryllium became a commercial product when it was used as an alloy first with aluminum and later with copper, nickel, and cobalt after World War I. The industry grew in the 1930s due to the increased use of beryllium-copper products during World War II and the use of beryllium oxide in the refractory and fluorescent lamp industries. During and after World War II, beryllium was used in the nuclear industry because of its ability to function as a neutron multiplier. Beryllium was used for both civilian nuclear reactors and for military weapons. With an increased industrial need for beryllium, acute chemical pneumonitis was first described by Weber and Engelhardt in Germany in 1933 and in the United States by van Ordstrand et al in 1943. This condition was usually limited

II. HARD-METAL LUNG DISEASE Introduction and Overview Clinical Manifestations in Hard-Metal−and Cobalt−Exposed Persons Interstitial Lung Disease Occupational Asthma Lung Cancer Mechanisms of Injury

to the upper respiratory tract, though it could extend to the bronchi, bronchioli, and alveoli if there was sufficient exposure. This condition peaked in the 1940s and with the implementation of industrial hygiene standards will now only be seen if there are plant explosions or other serious lapses in procedures. The last reported possible case in the United States occurred in the early 1980s. A second pulmonary complication of beryllium exposure was first described by Hardy and Tabershaw in 1946. This disease differed from the acute chemical pneumonitis because of the delayed onset, granulomatous response, and chronic course. Now known as chronic beryllium disease (CBD), this condition is a hypersensitivity reaction to beryllium and is the major hazard facing beryllium workers today.

Clinical Presentation CBD is primarily a pulmonary granulomatous disorder. Although involvement of other organ systems has been reported (e.g., lymph node, skin, and liver), the lungs are the principal organ affected and account for the morbidity and mortality of this disease. In the early stages, CBD may be asymptomatic. A positive blood proliferative response to beryllium (evidence for beryllium hypersensitivity) may be the earliest sign of

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CBD. Radiologic changes can also be detected on routine chest radiographs. Symptomatic disease usually begins with nonspecific respiratory complaints, such as exertional dyspnea and cough. Early in the disease process, routine chest radiography may not be helpful. Pulmonary function testing early in the disease may be normal or have an isolated abnormality of the diffusing capacity (DlCO ). As the disease progresses, symptoms become more characteristic for chronic interstitial lung disease with a nonproductive cough, substernal burning pain, and progressive exertional dyspnea. At this stage dry bibasilar crackles are observed on physical examination. A rare patient may have asthmatic-type complaints and physical findings. With advanced disease progressive weakness, easy fatigability, dyspnea at rest, anorexia, and weight loss may occur and acrocyanosis and clubbing may be observed. As cor pulmonale develops, peripheral edema, hepatomegaly, and distended neck veins are seen. Fever is unusual but can be seen. Hypercalcemia and nephrocalcinosis, hyperuricemia, joint pains, and severe cachexia have been described. Severe liver involvement has not been seen, but liver granulomas with mild elevation of the liver function tests occur. Skin involvement may occur in 10 to 30 percent of cases

and frequently involves small granulomatous nodules on the hands, arms, and chest.

Radiography Radiographic changes in CBD are nonspecific and cannot be differentiated from sarcoidosis (Fig. 56-1). The most common radiographic abnormalities are diffuse round and reticular abnormalities. While most patients have both round and reticular nodules, opacities may be only round or only reticular. These opacities are usually present diffusely throughout the lung but may be confined to the upper lobes. Hilar adenopathy similar to what is commonly observed in sarcoidosis may also be seen in up to 50 percent of cases. However, the large “potato type” node involvement is not seen. As the disease advances, radiologic evidence of scarring and retraction can be seen. The hila are retracted upward and conglomerate mass and emphysematous bullae may be present. Gross architectural distortion can occur from severe fibrosis. Pleural thickening can be seen in the presence of long-standing disease. In early disease complete resolution of radiographic abnormalities can occur secondary to corticosteroid therapy and may recur as the corticosteroids are

Figure 56-1 A 61-year-old male smoker who had worked at a beryllium processing facility for 20 years. He had a productive cough for 10 years but denied any shortness of breath. He had a positive response of both blood and bronchoalveolar lavage (BAL) cells to beryllium (SI for blood BeLPT = 13.8 [Nl < 3.0], SI for BAL BeLPT = 306 [Nl < 5.0]. His BAL also demonstrated a marked lymphocytosis (cell yield = 6 × 105 cells/ml [Nl < 3.0 × 105 cells/ml], lymphocytes = 55.2% [Nl < 20%]. A. Chest radiograph demonstrating nodular interstitial disease with adenopathy. B . Chest CT mediastinal window demonstrating calcified bilateral hilar and mediastinal lymph nodes. C . Chest CT lung window demonstrating a diffuse, fine-nodular pattern of interstitial lung disease that was most prominent in the mid and upper lung zones.

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tapered. Complete spontaneous disappearance of the radiographic lesions has not been observed. The computed tomographic appearance of CBD includes upper lobe or diffuse fibrosis, pulmonary nodularity, and hilar and mediastinal adenopathy. However, in biopsy-proven CBD the computed tomographic findings may be normal or demonstrate ground-glass changes.

Immunopathogenesis There are three important characteristics of CBD. First, this disease is usually associated with industrial exposure to beryllium. The only cases that have been described in nonindustrial workers have been in individuals who lived near beryllium plants and were either exposed to the airborne emissions from the plant or from family members who brought contaminated work clothes into the home. All other cases have been described in individuals who have been involved in the heating, grinding, abrading, or handling of beryllium metals, alloys, salts, or oxides. In addition, workers not directly handling beryllium may be exposed from processes occurring near them. Industrial hygienic practices today include efforts to remove potential airborne beryllium at the source to prevent beryllium from becoming airborne, limiting the number of workers with potential exposure to beryllium, limiting skin exposure, and trying to keep the airborne levels as low as possible. Recently the Department of Energy has used 0.2 µg/m3 as an action level because of the repeated reports of CBD with possible exposure below the Occupational Safety and Health Administration (OSHA) recommended threshold level of 2 µg/m3 /8 h shift. A second important characteristic of CBD is the long time interval or latency that occurs between initial exposure and the onset of disease. The average time to the onset of clinical symptoms is 10 years. This fact combined with the lack of a clear-cut dose-response relationship to CBD has hampered efforts to determine a safe level of beryllium. Thus, it is uncertain whether a peak exposure level or a total accumulated dose is more important for the development of CBD. Individuals have been described (i.e., secretaries with apparently little exposure) who have worked in industry for less than 1 year and yet still develop disease years to decades later. A third important characteristic of CBD is that not all exposed workers will develop the disease. Only 1 to 8 percent of exposed workers will ever develop the disease. This percentage appears to have remained the same despite dramatic efforts by industry to reduce the potential exposure in their workers. This last characteristic of CBD may be due to a genetic predisposition (see below). The suspicion that an immunologic reaction to beryllium caused CBD was based on the following observations. (1) Beryllium painted on the skin (patch testing) could elicit delayed-type hypersensitivity reactions in patients with CBD. However, because of the concern that patch testing could sensitize individuals to beryllium, skin testing has not been widely used. (2) CBD was associated with “immunologic granuloma.” (3) Finally, animal studies demonstrated that

Chronic Beryllium Disease and Hard-Metal Lung Diseases

a hypersensitivity could be demonstrated in animals and that this could be passed with cells. In vitro studies that simulated patch testing were developed in the 1970s and applied to patients with CBD. The blood cells from a large percent of patients with CBD had positive proliferative responses to beryllium. In addition, after stimulation with beryllium, blood cells from many patients with CBD could release the lymphokine, macrophage inhibition factor. However, all patients with CBD did not have positive responses with their blood cells. The confirmation that CBD was due to a cell-mediated response to beryllium came in the 1980s when cells harvested from the bronchoalveolar lavage fluid (BALF) from patients with CBD were examined. Not only was a marked increase in the number and percent of CD4+ T lymphocytes in the BALF noted, but also a positive proliferative response of bronchoalveolar lymphocytes to beryllium was observed. Positive proliferative responses to beryllium were observed in all cases of CBD and negative responses were noted in beryllium workers with biopsy-proven non-beryllium lung disease, patients with sarcoidosis and no history of beryllium exposure, and normal volunteers. Not only did all patients with CBD have a positive proliferative response of their bronchoalveolar cells to beryllium, but this response was more pronounced in their lung cells than their blood cells. Thus, there was the suggestion that there was an accumulation of beryllium-specific cells in the lungs of all patients with CBD. This has recently been confirmed using ELISPOT analysis. The CD4+ T-cell response to beryllium suggested that specific HLA class II molecules might be involved in CBD since HLA class II molecules present antigenic peptides to CD4+ T cells. A strong association of CBD with the marker HLA DPB1-glu 69 was first shown by Richeldi and subsequently confirmed in three other laboratories. However, rather then just a marker for CBD, this marker appears to be associated with the ability to develop an immune response to beryllium. However, individuals homozygous for this marker may be more likely to develop CBD rather than just have sensitization with no apparent disease. For the 10 to 20 percent of individuals with beryllium sensitization who are DPB1-glu69–negative, recent studies suggest that DR may be important in these individuals. Recent studies suggest that HLA DPB1-glu 69 is not just a marker for beryllium sensitization, but is strongly associated with the ability of beryllium to cause T-cell proliferation. The beryllium-induced T-cell response is blocked by anti-DP antibodies but not by anti-DR or anti-DQ antibodies. Only DPB1-glu 69 containing B-cell lines are able to stimulate sensitized T cells in the presence of beryllium. In addition, beryllium was shown to stimulate the release of the CLIP molecule only from glu-69–containing DP molecules. Finally, the DPB1 molecules containing glu-69 are necessary not only for the Tcell proliferative response but also for these cells to secrete interferon-γ (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), and numerous surface markers. The above studies suggest the following model for the pathogenesis of CBD. Beryllium is inhaled and deposited in

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Pulmonary Immunology Laboratories Hospital of the University of Pennsylvania Philadelphia, PA

tization will go on to develop CBD. In addition, the number of workers with beryllium sensitization that ultimately develop symptomatic CBD that requires treatment is unknown. In addition, the justification for a screening test requires that there must be some action that will alter the course of the disease. While it is generally believed that early treatment of CBD will alter the natural course of this condition this is not certain. In addition, removal from further exposure, a prudent but unproven practice, is possible for current workers but would not be applicable to former workers. Thus, the strongest recommendation for use of the beryllium lymphocyte proliferation test as a screening test can be made for current workers. Recommendations for screening former workers and residents of communities with past beryllium exposure from the ambient air are less certain. Nevertheless, because the risk of developing CBD is lifelong, the question of appropriate screening for exposed individuals remains.

Oak Ridge Institute for Science and Education Oak Ridge, TN

Differential Diagnosis

Table 56-1 Laboratories Performing Beryllium Proliferation Testing Immunopathology Laboratory Cleveland Clinic Foundation Cleveland, OH National Jewish Center for Immunology and Respiratory Medicine Denver, CO

Specialty Laboratories, Inc. Santa Monica, CAL

the periphery of the lung. Beryllium, either alone as a crystal or combined with a normal lung protein(s), is bound by glu69窶田ontaining DPB1 molecules and presented to berylliumspecific T cells. The beryllium protein or beryllium crystal is poorly digestible and cannot be removed by the immune response. Persistent inflammation leads to granuloma formation. The cells of the granuloma secrete enzymes that cause tissue destruction and fibrosis.

Diagnosis Because of the frequent need for corticosteroid treatment of patients with CBD, all patients should have tissue confirmation of their diagnosis. A confirmed diagnosis of CBD requires demonstration of a granulomatous reaction secondary to beryllium hypersensitivity. The former requires biopsy material. The latter can be most convincingly demonstrated by testing the proliferative response of bronchoalveolar cells to beryllium. If bronchoalveolar lavage cells cannot be easily or safely obtained, testing of blood proliferative responses to beryllium is a reasonable alternative. Laboratories performing these tests are listed in Table 56-1. In cases where biopsy demonstration of granulomatous inflammation is not possible, radiologic evidence of granulomatous inflammation may substitute. Because immunologic tests of beryllium hypersensitivity have been available only since the late 1980s, their use for screening worker populations is not clear. However, studies to date indicate that blood proliferative response to beryllium is the most sensitive screening test for CBD. The major difficulty with using the blood proliferative response to beryllium as a screening tool is that not all individuals with beryllium sensi-

The major challenge to making the diagnosis of CBD is to think of the possibility of beryllium exposure. Most cases of CBD that are misdiagnosed are diagnosed as sarcoidosis because either the exposure to beryllium was not known by the patient or the physician failed to elicit an occupational history. Because the radiographic and clinical presentation of CBD (Table 56-2) is similar to sarcoidosis, the differential diagnosis includes upper-lobe fibrotic processes (Table 56-3). In addition, as for sarcoidosis, other causes of granulomatous disease must be searched for and eliminated. The differential between sarcoidosis and CBD is the result of proliferation testing to beryllium. Patients with sarcoidosis do not respond to blood proliferation to beryllium, while CBD patients do. Cases of sarcoidosis among beryllium workers can be diagnosed in this manner. However, caution should always be used and repeatedly negative blood and lung tests should be determined before accepting a case of granulomatous lung disease in a beryllium worker as sarcoidosis.

Treatment No standard approach to the use of corticosteroids has been adopted in the treatment of CBD. Because of the side effects, corticosteroids should be reserved for patients with documented pulmonary impairment or those with progressive deterioration. Doses of corticosteroids should be tapered to the lowest dose that controls signs of active disease. Monitoring of patients with chest radiographs, pulmonary function tests, exercise tests, and serum angiotensinconverting enzyme may be useful. Most cases of CBD will be arrested with corticosteroid treatment. In cases of corticosteroid resistance or end-stage disease discovered at initial diagnosis, lung transplantation may be a reasonable approach. The long-term prognosis for CBD is uncertain. Followup of cases that were diagnosed in the 1940s and 1950s suggest that the mortality of the disease might be as high as 30 percent. Whether a similar mortality will be present in patients with

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Table 56-2 Comparision of Chronic Beryllium Disease and Sarcoidosis

Manifestations

Sarcoidosis

Chronic Beryllium Disease

Erythema nodosum

10–20%

Absent

Hilar adenopathy

50–75%

< 50%

Peripheral adenopathy

Occasional

Rare

Hypercalcemia

Occasional

Rare

Nephrocalcinosis

Rare

Bone changes

In chronic disease

Absent

Parotid involvement

Occasional

Absent

Posterior uveitis

Occasional

Absent

Liver involvement

Common

Frequent

Splenomegaly

Rare

Skin

Uncommon

Unusual

Central nervous system Occasional Response to steroids

Absent

Only active disease Only active disease

disease diagnosed in the 1980s or 1990s is not certain. Newer techniques to diagnose CBD (immunologic testing) enable the disease to be detected earlier. The natural history of this condition detected at the presymptomatic stage is unknown.

Table 56-3 Differential Diagnosis of Chronic Beryllium Disease Sarcoidosis Hypersensitivity pneumonitis Tuberculosis Histoplasmosis Silicosis Talc granulomatosis Eosinophilic granuloma Idiopathic pulmonary fibrosis

Chronic Beryllium Disease and Hard-Metal Lung Diseases

The two major questions are whether or not the disease detected early is inevitably progressive and whether the disease will be more responsive to corticosteroid therapy.

Beryllium and Lung Cancer Animal studies have clearly indicated that beryllium is carcinogenic. Whether beryllium is carcinogenic in humans is not clear. A National Institute for Occupational Safety and Health (NIOSH) study suggests that a small increase in lung cancer (SMR = 1.26) may occur in beryllium workers. However, this finding has been challenged because of the poor data with regard to cigarette smoking. This issue will remain controversial, as additional studies are not currently planned. Whatever the risk of cancer is in beryllium workers, the more significant medical concern is CBD.

HARD-METAL LUNG DISEASE Introduction and Overview Hard metal is an alloy of tungsten carbide in a matrix of cobalt into which smaller amounts of chromium, molybdenum, nickel, niobium, tantalum, titanium, and/or vanadium may be added. These components are milled to a fine powder, mixed together, pressed into the desired shape, and heated under pressure to between 800 and 1000◦ C, yielding a product with a chalklike consistency. The material may then undergo additional machining before being baked at 1500◦ C, which is above the melting point of cobalt and leads to the formation of an alloy that is 90 to 95 percent as hard as a diamond. Because of this property, hard metal is an important component in cutting tools, drill bits, armor plate, and jet engine parts. Hard metal was developed in the 1920s, and interstitial lung disease was first reported in hard-metal workers in 1940. Lung disease has been noted to occur in those working in both the initial production of hard metal and the machining and maintenance of hard-metal tool components. In addition, although hard metal is not used in the diamond-polishing industry, a similar spectrum of disease has been reported in diamond polishers using steel polishing disks whose cutting surfaces consist of microdiamonds cemented into a fine cobalt mesh. In contrast, workers in the cobalt-producing industry, who are more likely to be exposed to cobalt alone, may develop occupational asthma but appear to be much less likely to develop interstitial lung disease. The industrial processes associated with hard-metal lung disease produce respirable fine metallic dust particles. They also produce metallic ions that accumulate in the coolants used in the metalworking procedure and are absorbed through the skin or inhaled in vaporized coolant fluids. To counteract these exposures, the American Conference of Government Industrial Hygienists (ACGIH) have established current permissible exposure limits for cobalt metal, dust, and fumes at an 8-h threshold-weighted average (TWA) of 0.02 mg/m3 . NIOSH recommends an exposure limit of 0.05

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mg/m3 as a TWA for a 10-h workday and a 40-h workweek and OSHA requires an 8-h TWA of 0.1 mg/m3 .

Clinical Manifestations in Hard-Metalâ&#x2C6;&#x2019;and Cobaltâ&#x2C6;&#x2019;Exposed Persons A variety of respiratory syndromes have been associated with exposure to hard metal, most commonly: (1) asthmatic reactions; (2) a form of hypersensitivity lung disease; and (3) interstitial pulmonary fibrosis. The last two forms may be a continuum of the same process with subclinical or unrecognized hypersensitivity alveolitis proceeding to the development of fibrotic lung disease. Hard-metal disease has been used to describe all types of lung disease but is most often used to reference the parenchymal or interstitial lung disease rather than the airway-related manifestations of hard-metal inhalations.

Interstitial Lung Disease Interstitial lung disease has been seen in hard-metal workers and diamond polishers. Studies have attempted to determine the prevalence of interstitial lung disease (ILD) among hardmetal workers. The studies have been frequently limited by lack of appropriate control groups, loss of former workers who may have left the plant due to illness, inconsistent disease detection/definitions, and small numbers. However, despite these limitations it is clear that ILD develops in a small minority of exposed workers. Estimates range from 0.7 to 12.9 percent in cross-sectional studies. A more recent study found no ILD in its cohort but it was a small study with more recent exposure and may represent the effects of limiting exposure levels. Although ILD may occur after a short duration and low levels of exposure, longer duration or higher levels of exposure are associated with increased risk. Nonsmokers and former smokers also appear to be at higher risk. Interestingly, most studies suggest that workers exposed to cobalt alone without tungsten and other metals do not appear to develop ILD. A few cases of diamond polishers exposed to cobalt alone who have developed ILD have been reported, but this appears to be fairly rare. In some patients, hard-metal disease presents as a hypersensitivity pneumonitis, or allergic alveolitis. These patients manifest fever, anorexia, cough, dyspnea, inspiratory crackles, and fine reticulonodular infiltrates on chest radiograph. Pulmonary function testing typically shows a restrictive pattern, with a reduced DlCO . Symptoms may resolve when exposure is discontinued but may recur with re-exposure. Over time, progressive dyspnea, lung function impairment, and interstitial fibrosis may develop. Fibrosis may also occur in the absence of antecedent symptoms. Patients with advanced disease exhibit weight loss, hypoxemia, digital clubbing, pulmonary hypertension, and cor pulmonale. The histopathological manifestations of the interstitial disease in these patients can be varied, with findings consistent with bronchiolitis, desquamative interstitial pneumonitis,

usual interstitial fibrosis, and giant-cell interstitial pneumonitis (GIP). Granuloma formation does not occur. Lung biopsies may show heterogeneous patchy involvement, with foci of active alveolitis, fibrosis, and normal parenchyma. Bronchiolitis may be seen in areas with and without active alveolitis. GIP is characterized by lymphoplasmacytic infiltration, epithelial desquamation, and the presence of numerous multinucleated giant cells in the alveolar spaces. These giant cells are formed by both actively phagocytic alveolar macrophages and type II pneumocytes. Infiltration with eosinophils has also been described. Analysis of BALF may demonstrate hypercellularity, with increased numbers of macrophages and giant cells. A relative or absolute increase in the number of lymphocytes, with a reduced CD4/CD8 ratio as well as increased numbers of neutrophils, eosinophils, and mast cells, may also be seen. Additionally, the multinucleated giant cells can also be found in the BALF which can be diagnostic of hardmetal lung disease without requiring a surgical lung biopsy. Electron microscopy with energy dispersive x-ray analysis (EDAX) of the particulate material present in biopsy specimens may demonstrate the presence of the elements used to form hard metal. Because of its high solubility, significant amounts of cobalt may not always be present. Few studies have looked at the radiography of hardmetal disease. Many of the screening studies of cobalt workers rely on plain chest radiographs and use the profusion score of the International Labour Office (ILO). However, a consistent description of the typical findings has not been offered. More recently, with the advent of computed tomography (CT) scans a few case reports have described the CT findings of patients with hard-metal disease. Like the pathology, these findings show a wide variability and can include end-stage honeycombing with cystic changes and traction bronchiectasis, to less impressive reticulation and even areas of ground-glass opacities. No pathognomonic finding has been described. Treatment for this disease consists of discontinuation of exposure and administration of systemic corticosteroids. Although no clinical trials have been performed, dosage and duration of treatment similar to those used in other forms of active alveolitis or fibrosis should be considered. Patients with active alveolitis may show a dramatic response to steroids, whereas patients with more prominent fibrosis may show minimal response despite prolonged steroid treatment. Fibrosis can also progress despite cessation of exposure. GIP has been observed to recur after lung transplantation despite cessation of occupational exposure.

Occupational Asthma In contradistinction from ILD, asthma can occur in workers exposed to cobalt alone without tungsten. The reported prevalence of asthma or wheezing related to cobalt or hardmetal exposure is also low and ranges from 6.6 percent to 10.9 percent. This variation may be attributed to different levels of exposure and the criteria used by various authors to define occupational asthma. As with other forms of occupational asthma, patients may note cough, wheezing, dyspnea,

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chest tightness, conjunctivitis, and rhinitis. Throughout the workday, symptoms may increase in severity, and a progressive decline in peak flow may be demonstrated. Symptoms usually abate during weekends or vacations and often resolve when exposure is discontinued. Upper-airway symptoms may result from either direct airway irritation or atopic responses. In addition to demonstrating an association between workplace exposure and symptoms, the diagnosis may be confirmed by bronchoprovocation testing (BPT) with cobalt or cobalt salts. Testing with cobalt salts is preferable, as it is much easier to control dosage and delivery of soluble ion solutions than those of particulate substances. Immediate or delayed airway reactivity to cobalt chloride may be observed after BPT. Tungsten carbide has not been shown to produce bronchoconstriction. A positive radioimmunosorbent test (RAST) to cobalt-conjugated human serum albumin has also been reported in some patients, suggesting a type I allergic response. Skin patch testing with cobalt salts does not appear to be of use in diagnosing hard-metal asthma. Some studies have suggested a dose-response relationship between higher levels of cobalt exposures and lower forced expiratory volume in 1 second (FEV1 ) on spirometry and symptoms of asthma. A twofold increase in the relative odds ratio for work-related wheezing was noted when cobalt exposure exceeded 0.05 mg/m3 . However, asthma and reductions in FEV1 have been seen at levels below the allowable limit of 0.05 mg/m3 . This suggests that the current permissible exposure limit may not protect all workers against the development of cobalt-induced asthma. Because of findings of this sort, baseline evaluations and employee screenings should be performed in workers exposed to hard-metal dust. A reasonable strategy would include assessments for symptoms of rhinitis, conjunctivitis, wheezing, dyspnea, or chest tightness; the relationship of symptoms to work hours; smoking history; physical examination; pulmonary function testing; and chest radiography. In patients with symptoms or findings suggestive of occupational asthma, peak flow monitoring during working and nonworking hours should be performed and other causes of pulmonary function deterioration ruled out. Specific BPT and RAST results may provide additional positive criteria for diagnosis. Personal employee air sampling and measurement of urinary cobalt levels can provide information about ongoing exposure. The workplace should also be examined for levels of cobalt exposure and employee protective practices. Treatment for occupational asthma related to cobalt includes control of exposure as well as medical therapy with bronchodilators and inhaled corticosteroids. Systemic corticosteroid treatment is usually not required.

Lung Cancer Cobalt and cobalt-containing compounds have been shown to cause cancer in rats after local injection and intratracheal instillation. The International Agency for Research on Cancer reviewed the evidence for the carcinogenicity of cobalt in 1991

Chronic Beryllium Disease and Hard-Metal Lung Diseases

and concluded that although there was sufficient evidence for the carcinogenicity of cobalt metal powder and cobalt oxide in experimental animals, there was inadequate evidence for the carcinogenicity of cobalt and cobalt compounds in humans. Since that publication, however, there have been studies suggesting a relationship. One study of 709 French hard-metal workers found an excess of lung cancer mortality in their workers and the excess was greater in workers with the highest levels of exposures though no relationship with duration of exposure was found. However, this study was not powered to examine the effect of smoking as well so firm conclusions could not be drawn. A second study by the same group of researchers found a twofold higher risk of lung cancer among subjects exposed to both tungsten and cobalt and the odds ratio increased with cumulative exposure. This study was able to adjust for smoking and found the relationship between hard metal and lung cancer held.

Mechanisms of Injury The pathogenesis of the hard-metalâ&#x20AC;&#x201C;associated lung diseases is poorly understood. There are two predominant, competing hypotheses for the pathogenesis of hard-metal lung toxicity: (1) hypersensitivity with lymphocyte-driven toxicity; and (2) free-radical and cytokine-mediated injury. Several authors point out the similarities of hard-metal lung disease and hypersensitivity lung disease including the ability of cobalt to function as a hapten in complex with albumin and cause a contact dermatitis. Bronchoalveolar lavage (BAL) studies of both exposed workers and those with hardmetal disease have shown increased lymphocytes with reduction of the helper/suppressor T-cell ratios. Additionally, in at least one subject with hard-metal disease a lymphocyte transformation test was found to be positive in the presence of cobalt. Finally, a recent report suggests an association between a glutamic acid residue in position 69 of the HLA-DP beta chain and susceptibility to hard-metal disease. This is similar to CBD, a known hypersensitivity disorder. However, there are features of this disease that do not suggest a hypersensitivity reaction as the mechanism for the disease. Perhaps most obviously is the fact that granulomas, the hallmark of chronic hypersensitivity pneumonitis, are not typically found on biopsy. Additionally, the finding that both cobalt and tungsten are required for most (though not all) cases of hard-metal lung disease requires explanation. In vitro studies using peritoneal and alveolar macrophages from rats and mice have demonstrated that the combination of tungsten carbide and cobalt is highly cytotoxic, while cobalt and tungsten carbide alone produce minimal or no cytotoxicity. Additionally, the acute lung toxicity of tungsten carbide plus cobalt is much higher than that of each component after intratracheal instillation in rats. Lison has proposed a mechanism that might explain this interaction. He suggests that tungsten carbide can act as an electron carrier to transfer electrons from cobalt to oxygen. This then leads to the production of free radicals and reactive oxygen species which in turn causes pulmonary damage.

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Differences in susceptibility to disease would therefore be due to differences in subjects’ antioxidant defenses. Further research is required to elucidate the pathophysiology behind hard-metal lung disease.

SUGGESTED READING Amicosante M, et al: Beryllium binding to HLA-DP molecule carrying the marker of susceptibility to berylliosis glutamate beta 69. Hum Immunol 62:686–693, 2001. Amicosante M, et al: Identification of HLA-DRPhebeta47 as the susceptibility marker of hypersensitivity to beryllium in individuals lacking the berylliosis-associated supratypic marker HLA-DPGlubeta69. Respir Res 6:94, 2005. Bill JR, et al: Beryllium presentation to CD4+ T cells is dependent on a single amino acid residue of the MHC class II b-chain. J Immunol 175:7029–7037, 2005. Chou YK, et al: Activation pathways implicate anti-HLA-DP and anti-LFA-1 antibodies as lead candidates for intervention in chronic berylliosis. J Immunol 174:4316–4324, 2005. Department of Energy: Chronic beryllium disease prevention program; final rule. Fed Regist 64:68854–68914, 1999. Fontenot AP, et al: Beryllium presentation to CD4+ T cells underlies disease-susceptibility HLA-DP alleles in chronic beryllium disease. Proc Natl Acad Sci U S A 97:12717– 12722, 2000. Fontenot AP, et al: Frequency of beryllium-specific central memory CD4+ T cells in blood determines proliferative response. J Clin Invest 115:2886–2893, 2005. Gotway M, et al: Hard metal interstitial lung disease: Highresolution computed tomography appearance. J Thorac Imaging 17:314–318, 2002. Kelleher P, Pacheco K, Newman L: Inorganic dust pneumonias: The metal-related parenchymal disorders. Environ Health Perspect 108:685–696, 2000. Kennedy S, et al: Maintenance of stellite and tungsten carbide saw tips: Respiratory health and exposure-response evaluations. Occup Environ Med 52:185–191, 1995. Kinoshita M, et al: Giant cell interstitial pneumonia in two hard metal workers: The role of bronchoalveolar lavage in diagnosis. Respirology 4:263–266, 1999.

Kusaka Y, et al: Epidemiological study of hard metal asthma. Occup Environ Med 53:188–193, 1996. Kusaka Y, Kumagai S, Goto S: Decrease ventilatory function in hard metal workers. Occup Environ Med 53:194–199, 1996. Lasfargues G, et al: Lung cancer mortality in a French cohort of hard-metal workers. Am J Ind Med 26:585–595, 1994. Linna A, et al: Respiratory health of cobalt production workers. Am J Ind Med 44:124–132, 2003. Lison D: Human toxicity of cobalt-containing dust and experimental studies on the mechanism of interstitial lung disease (hard metal disease). Crit Rev Toxicol 26:585–616, 1996. Lombardi G, et al: HLA-DP allele-specific T cell responses to beryllium account for DP-associated susceptibility to chronic beryllium disease. J Immunol 166:3549–3555, 2001. Maier LA, et al: Influence of MHC class II in susceptibility to beryllium sensitization and chronic beryllium disease. J Immunol 171:6910–6918, 2003. Naccache JM, et al: Ground-glass computed tomography pattern in chronic beryllium disease: Pathologic substratum and evolution. J Comput Assist Tomogr 27:496–500, 2003. Newman LS, et al: Beryllium sensitization progresses to chronic beryllium disease: A longitudinal study of disease risk. Am J Respir Crit Care Med 171:54-60, 2004. Potolicchio I, et al: Susceptibility to hard metal lung disease is strongly associated with the presence of glutamate 69 in HLA-DPB. Eur J Immunol 27:2741–2743, 1997. Rossman MD: Chronic beryllium disease: A hypersensitivity disorder. Appl Occup Environ Hyg 16:615–618, 2001. Rossman MD, Kreider ME: Is chronic beryllium disease sarcoidosis of known etiology? Sarcoidosis Vasc Diffuse Lung Dis 20:104–109, 2003. Sawyer RT, et al: Beryllium-induced tumor necrosis factoralpha production by CD4+ T cells is mediated by HLA-DP. Am J Respir Crit Care Med 31:122–130, 2004. Tinkle SS, et al: Beryllium induces IL-2 and IFN-gamma in berylliosis. J Immunol 158:518–526, 1997. Wang Z, et al: Beryllium sensitivity is linked to HLA-DP genotype. Toxicology 165:27–38, 2001. Wang Z, et al: Differential susceptibilities to chronic beryllium disease contributed by different Glu69 HLA-DPB1 and -DPA1 alleles. J Immunol 163:1647–1653, 1999.

57 Coal Workers’ Lung Diseases and Silicosis Edward L. Petsonk

John E. Parker

I. COAL WORKERS’ LUNG DISEASES Introduction and History Coal and Coal Mining Epidemiology of Lung Disease in US Coal Miners Mortality Pathology of Coal Miners’ Lung Diseases Clinical Features of Coal Workers’ Lung Diseases Radiology of Coal Workers’ Pneumoconiosis Lung Function and Respiratory Impairment in Coal Miners Immunology of Coal Workers’ Pneumoconiosis Special Studies Management of Coal Workers’ Lung Diseases II. SILICOSIS Introduction Definition

COAL WORKERS’ LUNG DISEASES Introduction and History Coal miners are at risk for developing several distinct clinical illnesses in relation to their occupational exposures. Historically, some names applied to these conditions were miners’ asthma, phthisis, anthracosis, and in Scotland, miners’ black lung. It was recognized early that these afflictions were related to the occupation of mining; however, it wasn’t until the development of specialized techniques such as chest radiography, pulmonary function testing, the discovery of the tubercle bacillus, and sophisticated histological examination of tissue that respiratory diseases affecting miners could be separated and defined. Coal workers’ pneumoconiosis (CWP) is the parenchymal lung disease that results from the inhalation and deposition of coal mine dust, and the tissue’s reaction to its presence. This occupational lung disease was first described in the early

Workers in High-Risk Occupations and Industries Forms of Silicosis: Exposure History and Clinicopathological Descriptions Path ogenesis and the Association with Tuberculosis Clinical Picture of Silicosis Radiographic Patterns in Silicosis Lung Functional Abnormalities in Silicosis Complications and Special Diagnostic Issues in Silicosis Prevention of Silicosis Medical Screening and Surveillance in Silicosis Therapy, Management of Complications, and Control of Silicosis III. PREVENTION STRATEGIES FOR COAL WORKERS’ LUNG DISEASES AND SILICOSIS

1800s. In addition to CWP, coal mine dust exposures increase a miner’s risk of developing chronic bronchitis, chronic obstructive pulmonary disease, and pathological emphysema. Radon gas exposures in coal mines may exceed recommended levels and represent a risk for cancers of the lung and larynx. For a long time, the pneumoconiosis that affected coal miners was thought to be silicosis. In the 1930s, it was argued that silicosis, CWP, and bronchitis were distinct clinically and pathologically. Unfortunately, it was also suggested that coal dust was not harmful, in spite of reports of the adverse effects of coal dust among coal trimmers. It was not until washed coal, free of silica, was shown to produce a dust disease of the lungs in stevedores, who worked leveling coal in the holds of ships, that CWP was widely accepted as pathophysiologically distinct from silicosis. In the United States, little attention was given to coal miners’ respiratory diseases until the Public Health Service conducted a pilot prevalence study of CWP in the early 1960s. Since then, a large number of studies performed by

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Figure 57-1 Roof bolting in underground coal mine. A potentially high-risk operation for respiratory exposures to airborne silica. (Photo courtesy of U.S. Bureau of Mines.)

the National Institute for Occupational Safety and Health (NIOSH) have greatly increased the knowledge and understanding of the nature and extent of lung diseases from coal mining in the United States.

Coal and Coal Mining Coal is not a pure mineral. It is a spectrum of carbonaceous rocks derived from the accumulation of vegetation sedimented under swampy conditions and subjected to extreme pressure over long periods of time. Coals are characterized by rank, which relates to geologic age, hardness, carbon content, and the amount of heat released (BTUs) when they are burned. Thus, peat is the lowest rank (softest) coal, being geologically the newest, and anthracite is the highest rank (hardest) and oldest type of coal. Coal may be found in outcroppings and in seams that vary from a few feet to several thousand feet below the surface. Surface or strip mining, which currently accounts for the majority of US coal production, involves removal of the overburden and mining the coal seams with large earth-moving equipment. In some areas of the eastern United States, mountaintop removal mining has become the dominant form of mining. Mountaintop mining involves first removal of all vegetation and soil, and then drilling and blasting through hundreds of feet of strata to access the coal seam. The excess rock and soil is placed in the steep stream beds along the mountainsides, creating areas called valley fills. Occasionally, surface mining is also performed by boring into coal outcrops with an auger. Dust levels in the air at surface mines are generally less hazardous than in underground mines, with a few notable exceptions (discussed below).

Deep mines produce somewhat less than half of the coal mined in the United States. Coal outcrops of sufficient size can be mined deep into the hillsides. Deep seams are accessed through vertical shafts drilled from the surface to the coal seam where the mining process then follows the seam through a series of more or less horizontal tunnels. Not all coal mining jobs are equally exposed to respiratory hazards. In underground mines, airborne dust concentrations are highest at the coal-cutting face, where coal is removed from the intact seams. Face jobs include the loading of coal into transportation vehicles or train cars, and, depending on the techniques used in the mine, operation of continuous or long wall mining machines. Exposures to crystalline silica and thus risk of silicosis also occur in underground mines, particularly in miners involved in roof support, called roof bolting (Fig. 57-1), or drilling operations, and in motormen who operate underground coal trains and use sand for traction on the rails. Workers in some aboveground coal mining operations also may have important exposure to dusts. These include workers at tipples and preparation plants, where crushing, sizing, washing, and blending of coal is done, and coal is stored or loaded onto ships, railroad cars, or river barges. Workers at surface coal mines who work in or around the drilling rigs, to make holes in which explosives are placed, are exposed to silica and at risk for the development of silicosis rather than CWP.

Epidemiology of Lung Diseases in US Coal Miners The first major survey of the health of American coal workers was conducted by the US Public Health Service from 1969 to

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1971, evaluating symptoms, lung function, and chest radiographic findings. This study included over 9000 miners at 31 underground mines (2 were anthracite mines; 29 were bituminous mines). Participation in the survey was over 90 percent. The mines were chosen to represent different geographic areas, coal seams, and mining methods. After this initial study, subsequent surveys have been conducted to evaluate miners at these and other US mines. Radiographic Findings Radiographic data from the initial survey showed an overall prevalence of simple and complicated CWP of nearly 30 percent. There was variation by region of the country and the type (rank) of coal mined. Among eastern Pennsylvania anthracite (high rank) coal miners, 46 percent had simple and 14 percent had complicated CWP. In contrast, among the miners in the western plateau of Colorado and Utah mining a lower rank coal, only 5 percent had simple CWP, and none had the complicated form. Among underground miners, those working at the coal face and exposed to higher concentrations of coal mine dust, higher prevalences of CWP were found than among surface workers or those whose jobs caused them to enter the face area intermittently. Results from multiple studies have clearly demonstrated that the prevalence of radiographic changes of simple CWP is related to the duration and intensity of dust exposure, and CWP can develop even at current dust levels. British studies also clearly showed that the attack rate (incidence of new cases) and the probability of progressing to a higher category of simple CWP were related to the mass of respirable dust to which the miner was exposed during his or her lifetime. The same cannot be said for the complicated form of CWP, progressive massive fibrosis (PMF). Once an individual has inhaled sufficient coal mine dust into the lungs for the chest radiograph to be classified with at least International Labour Office (ILO) Category 2 pneumoconiosis (see below), the probability of progressing to the complicated form appears to be independent of any further dust exposure. The rate of progression to PMF appears to be influenced chiefly by the age at which the miner begins to show radiographic changes of CWP. Progression may also be influenced by the presence of a rheumatoid diathesis (see below for additional discussion of immunologic issues). Enforcement of dust control measures in the United States, fully enacted in 1973, resulted in a declining pneumoconiosis attack rate. Subsequently, many miners with CWP retired, and follow-up studies have demonstrated a marked decline in the prevalence of CWP in active US miners. This was confirmed through the federally mandated chest radiograph surveillance program for underground US miners. Between 1973 and 1978, CWP was found in over one-third of the miners who participated in the program and had worked 25 years or more underground. By 1996–2002, only 1 in 20 (5.4 percent) of these miners showed radiographic evidence of CWP (Fig. 57-2). Between 1999 and 2002, chest radiographic surveillance examinations were also offered to many

Figure 57-2 Trends in coal workers’ pneumoconiosis (CWP) prevalence by tenure among examinees employed at underground coal mines, US Coal Workers’ X-Ray Surveillance Program, 1987–2002.

surface coal miners, and 3.4 percent of miners with work tenure of 25 or more years demonstrated radiographic pneumoconiosis. In spite of the marked overall improvements in dust control in US underground coal mines, a recent evaluation of national surveillance data demonstrated onset of advanced CWP among miners who had worked their entire careers under the current dust enforcement regime. The authors of this report observed an increased risk of rapidly progressive pneumoconiosis among miners in smaller mines (less than 50 employees) and in certain geographic regions, and concluded that prevention measures in these settings were inadequate (Fig. 57-3). Ventilatory Lung Function Ventilatory function was also evaluated in the large studies of US miners mentioned above. Initial reports evaluated miners’ lung function in comparison to the radiographic findings of CWP. Miners with complicated CWP were found to consistently show an important deficit in lung function. In contrast to the ventilatory findings associated with PMF, obstructive abnormalities were noted in miners with simple pneumoconiosis; however, the findings were not consistent, and with increasing category of simple CWP, the average functional decrement was small and variable. Subsequently, studies in the United States and Great Britain evaluated lung function with respect to the miners’cumulative dust exposure, and have helped to clarify the adverse effect of dust on coal miners’ lung function. Miners show a progressively greater risk of lung function loss with increasing cumulative dust exposure, independent of the chest radiographic findings of CWP. The forced expiratory volume in 1 s (FEV1 ) loss is most severe in those who work for many years at the dustiest jobs. Among smoking miners, the effects of tobacco smoke appear to be additive to the dust effect but no disproportionate dust effect has been noted in relation to tobacco use. Also, there is evidence that miners experience a more rapid loss in spirometric function parameters over their first few years of mining, with slower dust-related declines after that time. In summary, the epidemiological evidence has shown that coal miners experience ventilatory lung function loss with increasing exposure to dust, either in the presence or

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Figure 57-3 Proportion of miners with rapidly progressive CWP by county (not shown are counties with fewer than five miners evaluated).

absence of CWP. Among smoking miners, the effects of tobacco and dust appear to be additive. Although, on average, functional losses associated with dust are small, it is estimated that 35 years of work at the current dust limit will cause a clinically important FEV1 loss in 8 out of 100 nonsmoking coal miners. When complicated CWP is present, an additional ventilatory deficit is likely.

Mortality Studies of mortality in coal miners have been reported from the United States and Britain. Findings from both countries have been generally consistent, and reveal that the miners experience increased mortality attributable to pneumoconiosis, emphysema, and chronic bronchitis. Radiographic findings of advanced CWP (PMF) consistently affect mortality, especially in categories B and C, whereas among miners with simple CWP, decreases in survival were smaller. Accelerated FEV1 decline is also associated with increased mortality from both cardiovascular and respiratory causes. Miners’ risks of dying from the obstructive airway diseases of emphysema and chronic bronchitis exhibit a different geographic pattern than the mortality from CWP, suggesting that these dust effects have different mechanisms.

Pathology of Coal Miners’ Lung Diseases The coal macule is the primary lesion of simple CWP (Fig. 57-4). This lesion is essential for the pathological diagnosis of CWP. The lesion consists of a focal collection of coal dust in pigment-laden macrophages around the respiratory bronchioles and tapering off toward the alveolar duct. A fine network of reticulin is present in the early stages and may include a small amount of collagen depending upon the char-

acter of the dust. Centriacinar emphysema, the dilation and injury of lung gas exchange units, is observed with increased prevalence in the lungs of coal miners. The severity is proportional to the miner’s cumulative dust exposure. Focal emphysema is the form of centriacinar emphysema that is seen as an integral part of the simple lesion of CWP. It is characterized by enlargement of the airspaces immediately adjacent to the dust macule. The pathological severity of the emphysema increases with increasing lung dust retention. Muscular thickening of pulmonary arteries, in conjunction with hypertrophy of the right ventricle, can be observed with both simple and complicated CWP, and is increasingly prominent when CWP is associated with other lung disorders. Pathological changes in the airways consistent with chronic bronchitis, including enlargement of mucous glands, have also been noted in miners’ lungs. With increasing dust exposure, due to the normal clearance mechanisms being overwhelmed, the lung lesions increase in size and number. These larger fibrotic lesions are called coal nodules and are palpable in lung specimens, whereas coal macules are not. Palpable coal nodules are classified as micronodular up to 7 mm in diameter and macronodular from 7 mm and larger. Classic silicotic nodules have been found in the lungs of 12 percent of coal miners at autopsy. Other patterns of interstitial disease (usual interstitial pneumonia, UIP) have also been reported among coal miners either alone or in combination with the typical pathology of the pneumoconioses. Complicated CWP or PMF is diagnosed when one or more nodules in a lung specimen are noted to attain a size of 2 cm or greater in diameter. The 2 cm is an arbitrary choice of a minimal diameter that permits better correlation with clinical and radiographic measurements. (In fact, when coal-induced radiographic shadows are >1 cm, PMF is said to be present.)

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Figure 57-4 A coal macule, microscopic section. (Courtesy of Dr. Val Vallyathan, National Institute for Occupational Safety and Health, Morgantown, WV.)

Lesions are solid, heavily pigmented, rubbery to hard, and occur most commonly in the apical posterior portions of the upper lobes or the superior segments of the lower lobes. They tend to occur symmetrically, but may be asymmetrical, and may cavitate. Airways and vessels adjacent to the lesions may be distorted, and within the lesions, they are destroyed. PMF generally occurs in association with background pathological changes of simple CWP.

Clinical Features of Coal Workers’ Lung Diseases Chronic cough and sputum production are more common with increasing dust-exposure, regardless of the presence or absence of simple pneumoconiosis. These symptoms are likely related to bronchitic changes in the large airways, including thickening of the airway wall with mucous gland enlargement and hypersecretion that result from continued inhalation of dust particles presenting a chronic burden to the mucociliary escalator. Some miners with simple pneumoconiosis may have no related symptoms or physical signs, but with severe airflow obstruction or advanced pneumoconiosis, dyspnea, cough, and sputum production are frequent. Edema of the lower extremities, and findings consistent with cor pulmonale, may occur. Melanoptysis (expectoration of black sputum) occasionally results from excavation of a PMF lesion. Clubbing and crackles are not generally considered features of coal miners’ lung diseases, and if noted, should prompt further studies. However, a series of 38 cases of a chronic interstitial pneumonia among coal miners has recently been reported. The clinical findings in these atypical cases included crackles, finger clubbing, restrictive impairment, diffusion block, and neutrophilic bronchoalveolar lavage (BAL). CWP has not been associated with increased risk for development of coexisting mycobacterial infection,

in contrast to silicosis. However, a minority of miners show classic silicotic nodules. Certainly, progressive infiltrates or cavitary lesions in PMF should prompt examination of the sputum for typical and atypical mycobacteria.

Radiology of Coal Workers’ Pneumoconiosis The diagnosis of CWP can be made with confidence, without histological confirmation, in the presence of an adequate history (at least 5 to 10 years) of coal mine dust exposure and a characteristic chest radiograph. The radiograph in simple pneumoconiosis shows small opacities, ranging in size from pinhead up to 1 cm in diameter. Rounded nodules predominate and tend to appear first in the upper zones and involve middle and lower zones as the number of opacities increase. PMF is characterized by one or more large opacities greater than 1 cm. Upper lobe predominance is also typical in complicated pneumoconiosis. High-resolution computed tomography (HRCT) scanning in coal miners may reveal parenchymal nodules and emphysema when standard radiographs are normal. In atypical cases, CT scans may show ground-glass opacities and honeycombing, at times without nodular findings typical of CWP. Radiographic evidence of bronchiectasis has also been reported in coal miners, particularly among those with CWP. Several schemes have been used for classifying the radiographic shadows of pneumoconiosis in epidemiological studies; currently the ILO 2000 classification is the most widely accepted. When using the ILO system, simple pneumoconiosis is divided into major categories 1, 2, and 3 according to the profusion of small opacities in the lung fields. Each major category, including 0, is subdivided into 3 subcategories, providing a full range of 12 categories of simple CWP. A reading of category 1/0 indicates the definite presence of opacities consistent with pneumoconiosis. Complicated pneumoconiosis (PMF) is divided into categories A, B, and C, based on

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the size of the large opacities. Findings of collapse, consolidation, and emphysema may be associated with the shadows of complicated pneumoconiosis. The clinician may be presented with the diagnostic dilemma of distinguishing primary or metastatic lung neoplasia from an unusual presentation of PMF or Caplan’s syndrome. When typical large opacities of PMF occur symmetrically and bilaterally on a background of simple CWP, one can be confident that the lesions are unlikely to represent neoplastic disease. Prior radiographs from medical screening programs are often obtainable, and can help confirm stability or progression over a long time interval. Positron emission tomography with fluorodeoxyglucose (FDG-PET) scanning may be useful in differentiating PMF lesions from malignancy when the mass lesion has a low level of glucose metabolism, although some massive pneumoconiotic lesions may demonstrate an uptake of fluorodeoxyglucose similar to neoplasms. On magnetic resonance imaging (MRI) with contrast enhancement, the pattern of change over time in signal intensity has been reported to be a differential criterion in this setting. When the imaging workup is equivocal, the differentiation of PMF from neoplasm may be impossible without a biopsy. Hemorrhagic complications may occur during biopsy of PMF lesions due to their vascular nature.

Lung Function and Respiratory Impairment in Coal Miners Coal mine exposures may result in several pathological processes (simple and complicated CWP, silicosis, chronic bronchitis, mineral-dust airway disease, emphysema, and dustrelated airflow limitation), each of which may contribute to adverse physiological consequences. In an individual miner, the pattern and severity of impairment found will be related to such recognized factors as the intensity and duration of respirable dust exposure, geologic factors (e.g., coal rank, silica content), residence time of dust in the lung, and exposure to other respiratory hazards (e.g., tobacco smoke). In miners with airway hyperresponsiveness, greater functional deficits and an increased risk of symptoms may be expected. Several other mining exposures may also contribute lung function loss in coal miners, including gases from underground explosive blasting and aerosols of potentially contaminated water used for dust control. Additional factors implicated in underground coal miners’ accelerated lung function declines include weight gain, childhood pneumonia, and childhood exposures to environmental tobacco smoke. Ventilatory Function Epidemiological studies, as discussed above, have extensively documented the occurrence of exposure-related deficits in FEV1 and forced vital capacity (FVC) in coal miners. The magnitude of the average dust effect has varied between studies. Over a working lifetime, average predicted losses in FEV1 under current US dust standards ranged from 124 ml to 610 ml. Subgroups of miners experience a more severe effect, and from 6 to 8 percent of miners may be expected to develop

clinically important airflow limitation. For example, a more severe effect of dust on loss of lung function was observed in a group 199 men who had chosen to leave coal mine work. These dust effects can be compared with those of another recognized respiratory hazard, cigarette smoking. For example, Attfield observed that when 1072 miners’ lung function was followed over an 11-year period, a year of work at coal face jobs resulted in lung function loss essentially similar to that due to smoking for 1 year. When tenure in less dusty work was included in the analysis, mine dust exposure resulted in average lung function losses about 38 percent of that attributable to smoking (average 13 cigarettes per day). Physiological findings consistent with small airways disease have been noted to develop in nonsmoking miners, consistent with the pathological findings with dust deposition. Gas Exchange Diffusing capacity has been studied in relation to radiographic changes of coal worker’s pneumoconiosis. The small rounded opacities seen in miners with simple CWP have not generally been associated with measurable reductions in DlCO . However, in subgroups of miners, abnormal diffusing impairment has been correlated with radiographic changes. Thus, gas transfer is often low when the large opacities of complicated CWP are present and may also be reduced in miners who show either predominantly pinpoint opacities (“p” type by the ILO classification) or small irregular opacities on their chest radiograph. Gas exchange on exercise has also been investigated in coal miners. Many of the reports have been based in patients referred for disability evaluations, and thus suffer from illdefined selection biases. Exposure-response relationships are also unclear with respect to findings in these series. Exertional hypoxia, pulmonary arterial hypertension, and excess ventilation have frequently been observed in miners, particularly those with complicated CWP or airflow obstruction. However, the proportion of miners who show exertional gas exchange abnormalities in the absence of either PMF or clinically important airflow obstruction is still a topic of investigation.

Immunology of Coal Workers’ Pneumoconiosis The potential role of immunologic factors in mineral dust pneumoconioses was noted by Caplan who observed the association between distinctive nodular radiographic opacities in the lungs of Welsh coal miners and rheumatoid arthritis. This observation was extended when similar radiographic appearances were described in miners without arthritis but with circulating rheumatoid factor (RF). Increased prevalence of circulating RF among miners with complicated pneumoconiosis (PMF) has also been reported. Soutar et al reported on a study of serum antinuclear antibodies (ANA) and RF among 109 miners with radiographic evidence of pneumoconiosis attending the London

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Pneumoconiosis Panel. They reported positive ANA in 17 percent and RF in 10 percent of the miners whereas about 2 to 3 percent positive ANA was expected in a healthy male population. The prevalence of ANA was 9 percent in simple CWP and 27 percent in those with category C (PMF). A similar trend was seen with RF, ranging from 6 percent in simple CWP to 18 percent in category C. Combining both ANA and RF resulted in prevalences of positive results in 13 percent of the miners with simple CWP and 45 percent of those with category C CWP. In 1973 Lippmann et al reported a prevalence study of circulating ANA and RF among coal miners in the United States. Sera from 207 coal miners were examined. Of the 196 miners with radiographic opacities of pneumoconiosis, 9 were positive for RF, while 34 percent had positive ANA. There were regional variations in ANA that seemed to parallel the prevalences of radiographic changes; namely, prevalence was higher in anthracite miners and lower in bituminous miners. Studies of serum immunoglobulins were conducted by Hahon et al among 155 US coal miners with chest radiographs demonstrating simple CWP, Caplan’s syndrome, or PMF. They found significantly higher serum concentrations of C3, α1 -antitrypsin, IgA and IgG in anthracite miners than in bituminous miners with PMF. Compared to normal controls, the miners’ C3, α1 -antitrypsin, and IgG and IgG values were elevated. There were few differences in these serum proteins among the miners with simple CWP. The authors did not find any association between the elevated immunoglobulins and FEV1 . There have been few studies of the peripheral lymphocytes in coal miners. Dauber et al examined the lymphocyte function of 15 miners with pneumoconiosis. They found decreased numbers of both T and B lymphocytes in the peripheral blood in the miners compared to controls. They also found that cell function, as determined by response to stimulation by concavalin A, was lower in the miners with complicated CWP than in either miners with simple CWP or controls. Autoantibodies directed at lung collagen and reticulin have been identified in the sera of coal miners. The lung autoantibodies tend to reside in the serum IgA. It is not clear whether these autoantibodies participate in the CWP reaction in the lungs or simply represent epiphenomena.

Special Studies Bronchoalveolar lavage (BAL) has been used in studying mechanisms in the pulmonary reactions in CWP. Rom et al studied 15 symptomatic, nonsmoking coal miners with simple CWP by BAL. They found no significant difference between miners with CWP and controls in the number of cells recovered, the percentage distribution, and in the release of superoxide anion or hydrogen peroxide. This contrasted with the findings in subjects with asbestosis and silicosis whose values for spontaneous release of oxidant superoxide and hydrogen peroxide were significantly higher than controls. With regard to fibronectin and alveolar macrophage–derived growth

Coal Workers’ Lung Diseases and Silicosis

factor, the miners with CWP had values that were elevated above controls and not different from the values obtained in subjects with asbestosis and silicosis. Wallaert demonstrated significantly increased total number of lung cells recovered from miners with simple and complicated CWP, as well as increased percentages of alveolar macrophages, lymphocytes, and neutrophils. Alveolar cells from miners with simple and complicated CWP spontaneously released significantly more superoxide demonstrated by chemiluminescence than controls.

Management of Coal Workers’ Lung Diseases There is no specific therapy for CWP. The primary prevention of lung disease in miners must include continuing efforts at reducing coal mine dust exposure. Medical management is best directed at prevention, early recognition, and treatment of complications. The major clinical challenges are the recognition and management of airflow obstruction, respiratory infection, hypoxemia, respiratory failure, cor pulmonale, arrhythmias, and pneumothorax. Improved mining methods and lower dust levels appear to be reducing exposures and new cases of both simple and complicated pneumoconiosis. Medical surveillance programs, using chest radiographs, allow early recognition of workers with simple pneumoconiosis. Workers with simple pneumoconiosis should be encouraged to exercise their rights to frequent dust measurements, and transfer to low dust jobs when necessary. Any worker with PMF should be carefully advised about the risks of further dust exposures. Workers presenting with respiratory symptoms should have careful evaluation. Initial history and examination should be supplemented by chest radiograph, spirometry with bronchodilators, diffusing capacity, electrocardiogram, and resting arterial blood gas measurement as indicated. A thorough initial database allows accurate assessment of the worker’s respiratory health and serves as a starting point for observing the response to therapy or progression of disease. For miners who smoke, cessation is important regardless of symptoms, radiographic abnormalities, or functional status. Physician encouragement to stop smoking should be supplemented by support from smoking cessation groups, use of nicotine replacement, pharmacologic aids, and behavior modification techniques. Symptomatic reversible airflow obstruction may benefit from treatment with inhaled and oral bronchodilators. Patients with severe obstruction and inadequate improvement from the usual measures should be considered for a monitored trial of corticosteroids. If improvement is objectively documented, continuation of inhaled and, rarely, oral steroids may be of benefit. Hypoxemia can be a serious complication in advanced pneumoconiosis. It may be present at rest, with exercise, or during sleep. Chronic hypoxemia can lead to additional complications including polycythemia, pulmonary hypertension, cor pulmonale, and cerebral dysfunction. Therapy with low flow oxygen is indicated when arterial oxygen tension is less

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than 55 torr. Oxygen therapy in this setting may improve exercise tolerance, reduce dyspnea, and prevent arrhythmias, polycythemia, and heart failure. Patients with significant airflow obstruction or PMF should receive appropriate immunization with influenza and pneumococcal vaccines. Bacterial and viral episodes of bronchitis or pneumonia should be promptly recognized and appropriately treated. Patients with complicated pneumoconiosis, especially those who have been exposed to silica as well as coal mine dust, deserve special attention with regard to mycobacterial infection. Patients with a history of weight loss, fever, sweats, or malaise should be promptly investigated with chest radiographs and sputum examination for acid-fast bacilli stains and cultures. Occasionally, the sputum may be negative and mycobacterial infection can only be documented by fiberoptic bronchoscopy with brushings and washings. Active tuberculosis in patients with CWP can, in general, be successfully treated with the usual drug regimens provided rifampin is one of the drugs used. However, some authorities would recommend that in coal miners with a significant history of concurrent silica exposure (such as motormen, roof bolters, drillers, and shaft development workers), the treatment for tuberculosis may need to be more aggressive, and long-term follow-up is indicated in view of several reports of recurrent pulmonary tuberculosis in patients with PMF after completion of apparently adequate therapy. Respiratory failure may complicate advanced disease in coal miners, as it does in other chronic obstructive respiratory diseases. Ventilatory support measures are indicated when the failure is precipitated by a treatable complication. The application of ventilatory support measures should be clarified in advanced directives before the need arises. Clinicians need to assess the contribution of occupational dust exposures to ventilatory impairments in their patients with a history of coal mine exposure. Factors which can assist in this include a careful work history with documentation of the mining region, duration and categories of coal mine employment, as well as the duration and intensity of any tobacco smoking. Factors associated with an increased risk of a clinically important dust effect are a history of prolonged exposures in dusty jobs, exposures to higher rank coals, a younger age at first employment, and the finding of radiographic changes of CWP. Physicians should assist their patients with job-related impairments in obtaining appropriate compensation through local and national programs.

SILICOSIS Introduction Silicosis is a fibrosing disease of the lungs caused by the inhalation, retention, and pulmonary reaction to crystalline silica. Despite knowledge of the cause of this disorder (inhalation of dust containing respirable crystalline silica), this se-

rious and potentially fatal occupational lung disease remains prevalent throughout the world. Silica, or silicon dioxide, is the predominant component of the Earth’s crust. Occupational exposure to silica particles of respirable size (aerodynamic diameter of 0.5 to 5 microns) is associated with mining, quarrying, drilling, tunneling, and abrasive blasting with quartz-containing materials (sandblasting). Silicosis risk is also recognized in masonry and refractory operations, cement and concrete production, and highway repair, and as well as during work in potteries, foundries, and dental laboratories. Among ornamental stone carvers in Brazil, the prevalence of disease remains over 50 percent. Because crystalline silica exposure is so widespread, and silica sand is an inexpensive and versatile component of many manufacturing processes, millions of workers throughout the world are at risk of disease. The disease is often unrecognized and underreported, and thus its true prevalence is substantially underestimated. In the United States, fatal cases of silicosis and multiple cases from the same worksite continue to be recognized.

Definition Silicosis is an occupational lung disease attributable to the inhalation of silicon dioxide, commonly known as silica, in crystalline forms, usually as quartz, but also as other important crystalline forms of silica (i.e., cristobalite and tridymite). These forms are also called “free silica” to distinguish them from the silicates. The silica content in different rock formations, such as sandstone, granite, and slate, varies from 20 percent to nearly 100 percent.

Workers in High-Risk Occupations and Industries Although silicosis is an ancient disease, new cases are still reported in both the developed and developing world. In the early part of the twentieth century, silicosis was a major cause of morbidity and mortality. Contemporary workers are still exposed to silica dust in a variety of occupations. When new technology lacks adequate dust controls, exposures may be more hazardous and dust levels higher than in nonmechanized work settings. Whenever the Earth’s crust is disturbed and silica containing rock or sand is used or processed, there are potential respiratory risks for workers. The development of silicosis is continuing to be reported among workers from industries and work settings not previously recognized to offer a risk of this disease, reflecting the nearly ubiquitous presence of silica. The type of silica exposure appears to affect the risk of disease—settings such as drilling or sandblasting in which silica is freshly fractured, represent an increased risk of silicosis. Even brief periods of exposure to high levels can result in a clear increased lifetime risk for disease. The development and progression of silicosis frequently occurs after exposures have ceased. In countries throughout the world, mining, quarrying, tunneling, abrasive blasting, construction, and foundry work continue to present major risks

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Coal Workersâ&#x20AC;&#x2122; Lung Diseases and Silicosis

Figure 57-5 Lung pathology showing classic silicotic nodule. (See text for description.) (Courtesy of Dr. Val Vallyathan, National Institute for Occupational Safety and Health, Morgantown, WV.)

for silicosis, and important exposures continue to occur, even in developed nations.

Forms of Silicosis: Exposure History and Clinicopathological Descriptions Chronic, accelerated, and acute forms of silicosis have been well characterized. These clinical and pathological expressions of the disease reflect differing exposure intensities, latency periods, and natural histories. The chronic or classic form usually follows one or more decades of exposure to respirable dust containing quartz. The accelerated form results from heavier exposures, often with a latency of 5 to 10 years. Accelerated silicosis develops more rapidly than the chronic form and generally progresses inexorably even after silica exposure is interrupted. The acute form of silicosis is a consequence of intense exposures to high levels of respirable dust which contain a significant proportion of silica. The reported exposure period is usually from several months up to about 5 years, and the clinical course is usually one of rapid progression. Chronic (or classic) silicosis may be asymptomatic or result in insidiously progressive exertional dyspnea or cough (often mistakenly attributed to the aging process). A latency of 15 years or more since onset of exposure is common. Radiographically, it presents with small (less than 10 mm) rounded opacities predominantly in the upper lung zones. The pathological hallmark in the lungs of patients with the chronic form is the silicotic nodule. The lesion is characterized by a cell-free central area of concentrically arranged, whorled

hyalinized collagen fibers, surrounded by cellular connective tissue with reticulin fibers (Fig. 57-5). When examined under polarized light, birefringent particles are typically seen most prominently in the periphery of the silicotic nodule. Electron microscopy using specialized techniques can identify the specific mineral content of the particles, but is rarely needed for routine diagnostic purposes. Silicotic nodules in the visceral pleura, regional lymph nodes, and occasionally in other organs, may also result from silica exposure. One or more groups of the small lung nodules of chronic silicosis may coalesce and result in larger shadows on the chest radiograph (greater than 10 mm), heralding the onset of complicated or conglomerate silicosis (often referred to as progressive massive fibrosis). This progressive illness may occur even after exposure to silica-containing dust has ceased. Progressive massive fibrosis (PMF ) is frequently associated with a clinically important compromise of lung structure and function, and as a consequence, symptoms of exertional dyspnea and reduced functional status. This form of silicosis is characterized by nodular opacities greater than 1 cm on the chest radiograph (Fig. 57-6). Common laboratory findings include a diminished carbon monoxide diffusing capacity, reduced arterial oxygen tension at rest or with exercise, and a demonstrable restrictive pattern on spirometry and lung volume measurement. Concomitant dust-induced bronchitis or distortion of the bronchial tree may also result in productive cough or airflow obstruction. Recurrent bacterial infection, not unlike that seen in bronchiectasis, may occur. Weight loss and cavitation of the large opacities should prompt concern for tuberculosis or other mycobacterial infection.

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with occupational dust exposure, such as chronic bronchitis and the associated emphysema. Progressive declines in lung function have been documented in workers from inhalation of silica and other occupational mineral dust exposures.

Pathogenesis and the Association with Tuberculosis

Figure 57-6 Complicated silicosis demonstrating progressive massive fibrosis.

Pneumothorax may be a life-threatening complication, since the fibrotic lung may be difficult to re-expand. Hypoxemic respiratory failure with cor pulmonale and congestive heart failure are common terminal findings. Accelerated silicosis results from exposures that are more intense and of shorter (5 to 10 years) duration than in the chronic form, while symptoms, radiographic findings, physiological measurements, and lung pathology are similar. Deterioration in lung function is more rapid, and many workers with accelerated disease develop superimposed mycobacterial infection. Findings consistent with autoimmune diseases, including scleroderma, rheumatoid arthritis, or systemic lupus, may be seen in association with silicosis, more often in the accelerated type. The progression of radiographic abnormalities and functional impairment can be very rapid when autoimmune disease occurs with silicosis. Acute silicosis may develop within a few months up to about 5 years after a massive inhalation of silica. Dramatic dyspnea, weakness, and weight loss are often presenting symptoms. The radiographic findings differ from those in the more chronic forms of silicosis, and are dominated by a diffuse alveolar filling pattern, with a lower lung zone predominance. Air bronchograms may be present. Histological findings similar to pulmonary alveolar proteinosis have been described, and extrapulmonary (renal and hepatic) abnormalities are occasionally reported. The usual clinical course is rapid progression to severe hypoxemic ventilatory failure and death. Tuberculosis may complicate all forms of silicosis, but people with acute and accelerated disease may be at higher risk. Silica exposure alone, even without silicosis may also predispose to this infection. Mycobacteria tuberculosis is the usual organism, but nontuberculous (atypical) mycobacteria are also seen. Even in the absence of radiographic silicosis, silicaexposed workers may also develop other diseases associated

The precise mechanism of silica toxicity is uncertain, but it is thought to be mediated by generation of reactive oxygen species, both by the surface of silica particles themselves and by activation of alveolar macrophages. The nature and the extent of the biologic response are in general related to the intensity of the exposure; however, there is growing evidence that freshly fractured silica may be more toxic than aged silica-containing dusts, perhaps related to reactive oxidant radical groups on the surface cleavage plane. An abundance of evidence implicates the interaction between the pulmonary alveolar macrophage and silica particles deposited in the lung. Release of chemotactic factors and inflammatory mediators result in recruitment of polymorphonuclear leukocytes, lymphocytes, and additional macrophages. Fibroblaststimulating factors are released that promote hyalinization and collagen deposition. The resulting pathological lesion is the silicotic nodule, containing a central acellular zone with silica particles surrounded by whorls of collagen and fibroblasts, and an active peripheral zone composed of macrophages, fibroblasts, plasma cells, and additional free silica (Fig. 57-5). The initiating toxic insult may occur with minimal immunologic reaction; however, a sustained immunologic response may be important in some of the chronic manifestations of silicosis. For example, ANA are noted in accelerated silicosis occurring with scleroderma, as well as in other collagen diseases among workers who have been exposed to silica. The susceptibility of silicotic workers to infections, such as tuberculosis and Nocardia asteroides, is likely related to the toxic effect of silica on pulmonary macrophages. The link between silicosis and tuberculosis has been recognized for nearly a century. Again, people with acute silicosis appear to be at considerably higher risk.

Clinical Picture of Silicosis When silicosis is symptomatic, the primary symptom is usually dyspnea, first noted with activity or exercise and later, as the functional reserve of the lung is lost, also reported at rest. However, in the absence of other respiratory disease, shortness of breath may be absent and the presentation may be an asymptomatic worker with an abnormal chest radiograph. The radiograph may at times show quite advanced disease with only minimal symptoms. The appearance or progression of dyspnea may herald the development of complications including tuberculosis, airways obstruction, PMF, or cor pulmonale. Productive cough is often present, secondary to chronic bronchitis from occupational dust exposure, tobacco use, or both. Cough may at times also be attributed to

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pressure from large masses of silicotic lymph nodes on the trachea or mainstem bronchi. Other chest symptoms are less common than dyspnea and cough. Hemoptysis is rare and should raise concern for complicating disorders, such as pulmonary neoplasms or mycobacterial infection. Wheeze and chest tightness may occur in the presence of silicosis, but usually as part of associated obstructive airways disease or bronchitis. Chest pain and finger clubbing are not features of silicosis. Systemic symptoms, such as fever and weight loss, suggest complicating infection or neoplastic disease. Advanced forms of silicosis are associated with progressive respiratory failure with or without cor pulmonale. Few physical signs may be noted unless complications are present.

Radiographic Patterns in Silicosis The earliest radiographic signs of uncomplicated silicosis are generally small, rounded opacities. These can be categorized using the ILO International Classification of Radiographs of Pneumoconioses by size, shape, and profusion category. In silicosis, rounded opacities of the “q” and “r” type dominate. Other patterns have also been described, including linear or irregular shadows. The opacities seen on the radiograph represent the summation of pathological silicotic nodules and associated changes. They are usually found to predominate initially in the upper lung zones and may progress to involve other zones. Hilar lymphadenopathy is also noted, sometimes in advance of nodular parenchymal shadows. Eggshell calcification of the lymph nodes is strongly suggestive of silicosis, although this feature is uncommon. PMF is characterized by the formation of large opacities. These are categorized by size using the ILO classification as categories A, B, or C. The large fibrotic lesions of PMF tend to contract to the upper lung zones, leaving areas of compensatory emphysema at their margins and in the lung bases. As a result of this process, small, rounded opacities that previously were evident on the radiograph may become less visible or at times disappear. Pleural abnormalities are not common on routine chest radiographs with silicosis, however, CT scanning often documents localized pleural thickening, particularly in association with conglomerate lesions. Pleural effusions are less frequently noted. Large opacities may pose a concern regarding neoplasm. The radiographic distinction between PMF lesions and lung malignancies may be difficult, particularly if previous radiographs are unavailable for comparison. As in complicated CWP, FDG-PET scanning may sometimes be helpful in this distinction. Although ischemic necrosis may occur in large silicotic lesions, the onset of cavitation or a rapid change in the radiographic appearance should prompt a search for active mycobacterial disease. Acute silicosis may present with a radiologic alveolar filling pattern with rapid development of PMF or complicated mass lesions.

Lung Functional Abnormalities in Silicosis Pulmonary function tests, such as spirometry and diffusing capacity, are helpful for the clinical evaluation of

Coal Workers’ Lung Diseases and Silicosis

people with suspected silicosis. Spirometry may also be of value in early recognition of the health effects from occupational dust exposures, as it can detect physiological abnormalities that may precede radiographic changes. No specific or characteristic pattern of ventilatory impairment is present in silicosis. Spirometry may be normal, or when abnormal, the tracings may show obstruction, restriction, or a mixed pattern. Obstruction may indeed be the more common finding. Silica and mixed dust exposures may lead to clinically important airflow limitation independent of radiographic abnormality. Functional changes tend to be more marked with advanced radiologic categories. However, no good correlation exists between radiographic abnormalities and ventilatory impairment, and workers experience lung function loss proportionate to the duration and intensity of silica dust exposure. Diffusing impairment may also occur in the absence of ventilatory impairment. In acute and accelerated silicosis, functional changes generally occur earlier, are more marked, and the progression is more rapid. In acute silicosis, radiographic progression is accompanied by increasing ventilatory impairment and gas exchange abnormalities, which leads to respiratory failure and eventually to death from intractable hypoxemia.

Complications and Special Diagnostic Issues in Silicosis With a history of sufficient exposure and a characteristic radiograph, the diagnosis of silicosis is generally not difficult to establish. Challenges arise only when the radiologic features are unusual or the history of exposure is not recognized. Lung biopsy is rarely required to establish the diagnosis. However, tissue samples are helpful in some clinical settings when complications are present or the differential diagnosis includes tuberculosis, neoplasm, or PMF. Biopsy material should be sent for culture, and in research settings, dust analysis may be a useful additional measure. When tissue is required, open or thoracoscopic lung biopsies are generally necessary for adequate material for examination, and to assure satisfactory hemostasis. Vigilance for infectious complications, especially tuberculosis and other mycobacteria, cannot be over-emphasized, and symptoms of change in cough or hemoptysis, and fever or weight loss should trigger a workup to exclude this treatable problem. Nocardia and fungal infections are also reported in association with acute silicosis. The International Agency for Research on Cancer has classified crystalline silica as a 2A carcinogen based on “sufficient” evidence of carcinogenicity in laboratory animals and “limited” evidence of carcinogenicity in humans. Uncertainty over the pathogenic mechanisms for the development of lung cancer in silica-exposed populations exists, and the possible relationship between silicosis (or lung fibrosis) and cancer in exposed workers continues to be studied. Regardless of the mechanism that may be responsible for neoplastic events, there is ample evidence of the link between occupational exposure to silica and lung cancer.

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Prevention of Silicosis Prevention remains the principal goal in dealing with this occupational lung disease. Effective exposure controls are available for most processes, and include process enclosure, wet abrasive techniques, and local exhaust ventilation, combined with a comprehensive approach to personal protection. Where possible, less hazardous industrial agents should be substituted for silica. The education of workers and employers regarding the hazards of silica dust exposure and measures to control exposure is also important. If silicosis is recognized in a worker, termination of any continuing exposures is advisable. Unfortunately, the disease often will progress even without further silica exposure. The finding of a case of silicosis is a “sentinel health event” and should prompt a thorough evaluation of workplace exposures and control measures by a competent authority, with the goal of recognizing the sources of the hazard and protecting other workers who may continue to be at risk.

Medical Screening and Surveillance in Silicosis Workers exposed to silica and other mineral dusts should be monitored on a regular basis for adverse health effects as a supplement to, but not a substitute for, exposure monitoring and control. Health screening commonly includes evaluation of respiratory symptoms, spirometric abnormalities, and radiographic changes. There is evidence that, if silicosis subsequently develops, workers who have participated in periodic health monitoring experience reduced severity of disease. Evaluation for tuberculosis infection with intradermal skin testing should also be performed. In addition to reporting of results to the individual workers, health data from all workers at a plant or operation should be periodically analyzed to assess the adequacy of prevention activities.

Therapy, Management of Complications, and Control of Silicosis When prevention has been unsuccessful and silicosis has developed, therapy is directed largely at complications of the disease. Therapeutic measures are similar to those commonly used in the management of airflow obstruction, infection, pneumothorax, hypoxemia, and respiratory failure complicating other pulmonary disease. Historically, the inhalation of aerosolized aluminum was attempted, unsuccessfully, as a specific therapy for silicosis. Polyvinyl pyridine-N-oxide, a polymer that has protected laboratory animals, is not available for use in humans. Laboratory work with tetrandrine has shown in vivo reduction in fibrosis and collagen synthesis in silica-exposed animals treated with this drug. However, evidence of human efficacy is currently lacking, and there are concerns about the potential toxicity, including mutagenicity, of this drug. Because of the high prevalence of disease in some countries, investigations of combinations of drugs and other interventions continue. Currently, no successful approach has

emerged, and the search for a specific therapy for silicosis has to date been unrewarding. For workers with a diagnosis of silicosis, further exposure to silica-containing dusts is undesirable. If the disease is advanced, or has occurred after a relatively short exposure (i.e., less than 15 years), then further dust exposure should be assiduously avoided. Advice on job reassignment should be considered in the context of the worker’s age, symptoms, functional status, and the current working conditions and measured silica exposures. Patients with silicosis may have few symptoms early in the disease; however, physicians should be aware that many states have a strict time limit dating from the physician’s diagnosis of silicosis regarding application for workers’ compensation and reimbursement of medical costs. In the medical management of silicosis, vigilance for complicating infection, especially tuberculosis, is critical. The use of bacillus Calmette-Gu´erin (BCG) vaccine in the tuberculin-negative silicotic patient is not recommended, but the use of preventive isoniazid (INH) therapy in the tuberculin-positive silicotic patient is advised. The diagnosis of active tuberculosis infection in patients with silicosis can be difficult. Clinical symptoms of weight loss, fever, sweats, and malaise should prompt radiographic evaluation and sputum acid-fast bacilli stains and cultures. Radiographic changes with infection may be subtle and atypical. Enlargement or cavitation in conglomerate lesions or nodular opacities is of particular concern. Bacteriologic studies on expectorated sputum may not always be reliable in silicotuberculosis. Fiberoptic bronchoscopy for additional specimens for culture and study may be helpful in establishing a diagnosis of active disease. The use of multidrug therapy for suspected active disease in silicotics is justified at a lower level of suspicion than in the nonsilicotic patient, due to the difficulty in firmly establishing evidence for active infection. To obtain satisfactory results in the presence of silicosis, antituberculous treatment must be more prolonged, with regimens lasting at least 8 months. A multiplicative increase in risk of mycobacterial infection is associated with the combination of silicosis and human immunodeficiency virus (HIV) infection, as has been encountered in South African gold miners. These infections represent major clinical and public health challenges. Prolonged treatment is essential, and there is potential for both adverse drug reactions and interactions between antiretroviral and antituberculous therapy. Recommended approaches continue to evolve, and clinicians should consult the latest authoritative recommendations. Ventilatory support for respiratory failure is indicated when precipitated by a treatable complication. Pneumothorax, spontaneous and ventilator-related, is usually treated by chest tube insertion. Bronchopleural fistula may develop, and surgical consultation and management should be considered. Acute silicosis may rapidly progress to respiratory failure. When this disease resembles pulmonary alveolar proteinosis and severe hypoxemia is present, aggressive therapy has included massive whole-lung lavage with the patient under general anesthesia in an attempt to improve gas exchange and remove alveolar debris. Although appealing in concept,

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the efficacy of whole lung lavage has not been established. Glucocorticoid therapy has also been used for acute silicosis; however, it is also of unproven benefit. Some young patients with end-stage silicosis may be considered candidates for lung or heart-lung transplantation by centers experienced with this expensive and high-risk procedure. Early referral and evaluation for this intervention may be offered to selected patients. The discussion of an aggressive and high-technology therapeutic intervention such as transplantation serves to dramatically underscore the serious and potentially fatal nature of silicosis, as well as emphasize the crucial role for primary prevention. The control of silicosis ultimately depends upon the control of workplace dust exposures. This is accomplished by rigorous and conscientious application of fundamental occupational hygiene and engineering principles, with a commitment to the preservation of worker health.

Coal Workers’ Lung Diseases and Silicosis

must be available to workers, employers, managers, and health care providers. Information on the cumulative burden of disease should be monitored over time for both silica and coal mine dust. Research into mining-related lung diseases should be encouraged, to improve recognition, monitoring, exposure reduction, and therapy, and to increase understanding of pathogenesis. Research efforts should supplement, not displace, attention to dust control. Clinicians who recognize coal-related diseases or silicosis in their patients should attempt to determine whether ongoing workplace exposures present a continuing risk to current workers, while maintaining the confidentiality of the patient-physician relationship. Assistance in this can often be obtained through local or state health departments, occupational medicine groups, and federal agencies. Reporting of occupational diseases is required in many states.

PREVENTION STRATEGIES FOR COAL WORKERS’ LUNG DISEASES AND SILICOSIS The control of coal workers’ lung diseases and silicosis in both the developed and developing world requires comprehensive prevention strategies, including exposure control, medical surveillance, research, and education. Example approaches include: Major efforts must be directed to installation of effective engineering controls and improvements in work practices to progressively reduce dust exposures to acceptable levels. These efforts are labeled primary prevention. Personal respiratory protection should also be used, particularly during short-term operations or unusual/emergency conditions, and while engineering controls are being modified or improved. The use of respirators will only be effective when part of a professionally managed comprehensive respiratory protection program, and should never be relied upon outside of such a program. Primary prevention should involve ongoing dust exposure monitoring, and include mechanisms for feedback to modify and improve working conditions if exposures are measured above mandated levels. Even exposure at currently permissible levels has been reported to represent a risk of disease. Secondary prevention through medical screening and surveillance should be designed to benefit the individual worker and other potentially exposed workers. Illness identified through medical screening represents a failure of primary prevention, and thus should trigger feedback to those involved in environmental monitoring and work practice evaluations. Education about the respiratory health hazards from uncontrolled exposures to silica and coal mine dust

SUGGESTED READING Alavi A, Gupta N, Alberini JL, et al: Positron emission tomography imaging in nonmalignant thoracic disorders. Semin Nucl Med 32:293–321, 2002. Altin R, Savranlar A, Kart L, et al: Presence and HRCT quantification of bronchiectasis in coal workers. Eur J Radiol 52:157–163, 2004. Antao VC, Petsonk EL, Sokolow LZ, et al: Rapidly progressive coal workers’ pneumoconiosis in the United States: Geographic clustering and other factors. Occup Environ Med 62:670–674, 2005. Attfield MD, Hodous TK: Does regression analysis of lung function data obtained from occupational epidemiologic studies lead to misleading inferences regarding the true effect of smoking? Am J Ind Med 27:281–291, 1995. Attfield MD, Hodous TK: Pulmonary function of U.S. coal miners related to dust exposure estimates. Am Rev Respir Dis 145:605–609, 1992. Attfield MD, Seixas NS: Prevalence of pneumoconiosis and its relationship to dust exposure in a cohort of U.S. bituminous coal miners and ex-miners. Am J Ind Med 27:137–151, 1995. Beeckman LA, Wang ML, Petsonk EL, et al: Rapid declines in FEV1 and subsequent respiratory symptoms, illnesses, and mortality in coal miners in the United States. Am J Resp Crit Care Med 163 (3 Pt 1):633–639, 2001. Brichet A, Tonnel AB, Brambilla E, et al and Groupe d’Etude: En Pathologie Interstitielle (GEPI) de la Societe de Pathologie Thoracique du Nord. Chronic interstitial pneumonia with honeycombing in coal workers. Sarcoidosis Vasc Diffuse Lung Dis 19:211–219, 2002. CDC: Silicosis: Cluster in sandblasters—Texas, and occupational surveillance for silicosis. MMWR 39:433–437, 1990.

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CDC/NIOSH: Criteria for a Recommended Standard, Occupational Exposure to Respirable Coal Mine Dust. DHHS (NIOSH) Publication No. 95-106, September 1995. Coggon D, Inskip H, Winter P, et al: Contrasting geographical distribution of mortality from pneumoconiosis and chronic bronchitis and emphysema in British coal miners. Occup Environ Med 52:554–555, 1995. Collins LC, Willing S, Bretz R, et al: High-resolution CT in simple coal workers’ pneumoconiosis. Lack of correlation with pulmonary function tests and arterial blood gas values. Chest 104:1156–1162, 1993. Corbett EL, Churchyard GJ, Clayton TC, et al: HIV infection and silicosis: the impact of two potent risk factors on the incidence of mycobacterial disease in South African miners. AIDS 14:2759–2768, 2000. Fields CL, Roy TM, Dow FT, et al: Impact of arterial blood gas analysis in disability evaluation of the bituminous coal miner with simple pneumoconiosis. J Occup Med 34:410– 413, 1992. Flanagan ME, Seixas NS, Becker P, et al: Silica exposure on construction sites: Results of an exposure monitoring data compilation project. J Occup Environ Hyg 3:144–152, 2006. Harrison J, Chen JQ, Miller W, et al: Risk of silicosis in cohorts of Chinese tin and tungsten miners and pottery workers (II): Workplace-specific silica particle surface composition. Am J Ind Med 48:10–15, 2005. Infante-Rivard C: Severity of silicosis at compensation between medically screened and unscreened workers. J Occup Environ Med 47:265–271, 2005. International Labour Office: Guidelines for the Use of the ILO International Classification of Radiographs of Pneumoconiosis, rev ed. 2000. Geneva, International Labour Organization, 2002. Jung JI, Park SH, Lee JM, et al: MR characteristics of progressive massive fibrosis. J Thoracic Imag 15:144–150, 2000. Kuempel ED, Stayner LT, Attfield MD, et al: Exposureresponse analysis of mortality among coal miners in the United States. Am J Ind Med 28:167–184, 1995.

Oxman AD, Muir DC, Shannon HS, et al: Occupational dust exposure and chronic obstructive pulmonary disease. A systematic overview of the evidence. Am Rev Respir Dis 148:38–48, 1993. Petsonk EL, Daniloff EM, Mannino DM, et al: Airway responsiveness and job selection: A study in coal miners and non-mining controls. Occup Environ Med 52:745–749, 1995. Pneumoconiosis prevalence among working coal miners examined in federal chest radiograph surveillance programs—United States, 1996–2002. MMWR 52:336– 340, 2003. Seixas NS, Robins TG, Attfield MD, et al: Exposure-response relationships for coal mine dust and obstructive lung disease following enactment of the Federal Coal Mine Health and Safety Act of 1969. Am J Ind Med 21:715–734, 1992. Steenland K, Goldsmith DF: Silica exposure and autoimmune diseases. Am J Ind Med 28:603–608, 1995. Wagner GR: The inexcusable persistence of silicosis [Editorial]. Am J Public Health 85:1346–1347, 1995. Wallaert B, Lassalle P, Fortin F, et al: Superoxide anion generation by alveolar inflammatory cells in simple pneumoconiosis and in progressive massive fibrosis of non-smoking coal workers. Am Rev Respir Dis 141:129–133, 1990. Wang ML, Petsonk EL, Beeckman LA, et al. Clinically important FEV1 declines among coal miners: An exploration of previously unrecognized determinants. Occup Environ Med 56:837–844, 1999. Wang ML, Wu ZE, Du QG, et al: A prospective cohort study among new Chinese coal miners: The early pattern of lung function change. Occup Environ Med 62:800–805, 2005. Wilt JL, Banks DE, Weissman DN, et al: Reduction of lung dust burden in pneumoconiosis by whole-lung lavage. J Occup Environ Med 38:619–624, 1996. Wright JL, Cagle P, Churg A, et al: State of the art: Diseases of the small airways. Am Rev Respir Dis 146:240–262, 1992.

58 Occupational Asthma, Byssinosis, and Industrial Bronchitis J. Allen D. Cooper, Jr.

I. INDUSTRIAL BRONCHITIS Byssinosis II. PULMONARY FUNCTION TEST ABNORMALITIES Grain Dustâ&#x2C6;&#x2019;Induced Industrial Bronchitis

Clinical Presentations Mechanisms and Pathology Diagnosis Management Specific Examples

III. OCCUPATIONAL ASTHMA Definition and List of Offending Agents Risk Factors

Inhalation of foreign material at the workplace can cause a number of pulmonary syndromes. Among the organs affected by occupational exposures, the lungs are secondary only to the skin with respect to organs commonly affected by occupational exposures. The lung parenchyma and airways, as well as the pleura, can be affected by inhalation of toxic material. This chapter discusses reactions of the airway to inhalation of toxic substances present in the workplace. Lung parenchymal and pleural reactions as well as obliterative bronchiolitis in response to inhaled materials are discussed elsewhere in this text. Occupational airway disease can manifest itself as chronic bronchitis, with variable airway hyperreactivity (industrial bronchitis or asthmalike syndrome), or with asthma accompanied by persistent hyperreactivity of the airways (occupational asthma). Four major differences exist between these syndromes: (1) Industrial bronchitis occurs most often without a latent period whereas occupational asthma commonly develops after a period of exposure. (2) Occupational asthma occurs after the airway has become sensitized to a substance, so that re-exposure to a very small amount of the substance will induce bronchospasm; in contrast, patients with industrial bronchitis may show attenuation of the response over time. (3) Compared to occupational asthma, industrial bronchitis is more often associated with systemic symptoms. (4) Industrial bronchitis is associated with a neu-

trophilic bronchitis whereas the bronchial inflammation that is associated with occupational asthma is made up predominantly of eosinophils, much like that seen in nonoccupational asthma. Some occupational exposures can cause both industrial bronchitis and asthma while others cause only one or the other. Cotton dust is the most common cause of industrial bronchitis without occupational asthma. Grain dust can cause both industrial bronchitis and asthma. In this chapter general and specific issues regarding industrial bronchitis and occupational asthma are discussed.

INDUSTRIAL BRONCHITIS Byssinosis History Adverse pulmonary reactions in cotton workers have been recognized for more than 100 years. In 1831, Kay described chest tightness and fever that commonly occurred on Monday after workers had been off work over the weekend. It was because of this observation that the term Monday morning fever was coined. The term byssinosis was proposed by the French physician Proust and is derived from the Greek word meaning linen or fine flax. Over the years, as cotton mills appeared in

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more and more countries, the association of chronic bronchitis with cotton dust exposure was confirmed. Epidemiology There is no doubt that recurrent exposure to cotton dust results in chronic bronchitis. In a prospective study, 16 percent of cotton mill workers in South Carolina developed symptoms of chronic bronchitis, as compared to only 1 percent of appropriate controls in the region. In another study, 4.5 percent of 2000 cotton workers screened by questionnaires and pulmonary function testing complained of Monday morning chest tightness and showed physiological impairment. The percentage of subjects with symptoms varied with the work area and was as high as 26 percent in certain areas. Another recent study of cotton textile workers in China found that the frequency of symptoms of byssinosis increased from 7.6 percent at baseline to 15.3 percent after 15 years of working in the textile mill. In this study, airway flow rates decreased significantly over time in textile workers when compared to silk workers. The appearance of symptoms during work or worsening of pulmonary function tests during the work shift predicted this accelerated loss of pulmonary function. There are over 800,000 textile workers in the United States. These individuals are predominantly at risk for developing symptoms due to inhalation of cotton dust. Flax and hemp workers are also at risk for developing the disease. Clinical studies suggest that approximately 65 percent of the general population will react significantly to de novo inhalation of components of cotton dust. Therefore, the majority of individuals who begin employment that entails the processing of cotton, flax, or hemp are at risk for developing respiratory symptoms. Why some individuals are more susceptible than others to the effects of cotton dust is unclear. Certain jobs in the textile mill are associated with a higher risk for development of bronchitis. Ginning, opening, or carding work carry a higher degree of risk. In addition, workers who clean out or maintain the various machines that divide up and clean the cotton are especially prone to develop symptoms. These are particularly high-risk jobs because of the high levels of cotton dust generated during the cleaning procedure. Strippers and grinders, who maintain the carding machinery that cleans and aligns the cotton, are particularly at risk for development of symptoms. Indeed, in the past, byssinosis was called “strippers’ asthma.” Clinical Presentation, Risk Factors, and Stages of Byssinosis Shortness of breath often occurs on the day back to work at the textile mill after several days off, as on a Monday after being off over the weekend. Over time, workers can develop more persistent symptoms. These have been graded by Schilling (Table 58-1) to allow comparison of symptomatology with physiological parameters. Using this grading system, it has been established that workers with a higher grade of symptoms tend to have a more rapid decline in pulmonary function. Risk factors for developing higher grades of byssi-

Table 58-1 Clinical Grading of Byssinosis as Proposed by Schilling Grade 0

No symptoms on first day of work

Grade 1/2 Occasional chest tightness or irritation of respiratory tract on the first workday of week Grade 1

Chest tightness on every first day of workweek

Grade 2

Chest tightness on first and other days of workweek

Grade 3

Chest tightness on first and other days of workweek and physiological evidence of permanent disability

nosis include (1) length of employment in a cotton mill and (2) level of dust exposure. Tobacco smoking has been shown to be synergistic with exposure to cotton dust in producing chronic bronchitis. Although it is controversial whether exposure to cotton dust without cigarette smoking causes chronic pulmonary disability unless associated with cigarette smoking, it appears that 7 percent of exposed individuals will develop irreversible airway obstruction that cannot be explained by smoking. Cross-shift pulmonary function tests that show a decrease in flow rates after work also predict chronic effects.

PULMONARY FUNCTION TEST ABNORMALITIES Characteristically, byssinosis is associated with a reduction in the forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1 ) on the day of return to work after an absence. The degree of reduction in these parameters increases over the workday. This change is generally more severe on the first day of work after an absence than on subsequent days. The mechanism by which this developed tolerance occurs is unknown. Whether subjects with byssinosis have airways that are hyperreactive to methacholine challenge is controversial. One study has shown a significant decrease in arterial oxygen tension after exposure to hemp dust. Pathology and Pathogenesis of Byssinosis The histopathology of byssinosis is similar to that of the bronchitis that is induced by tobacco smoke—with hyperplasia of mucous glands and infiltration of the bronchi with polymorphonuclear neutrophils. Several animal studies have demonstrated that different components of cotton dust can recruit

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Table 58-2 Evidence That Bacterial Endotoxin Is the Causative Agent in Byssinosis 1.

Measurable levels of endotoxin can be detected in cotton dust.

Inhaled endotoxin can include airway inflammation in animals and humans.

In a controlled setting, ambient levels of endotoxin correlate with degree of airflow reduction occurring in a simulated carding room.

Repeated inhalation of endotoxin results in an attenuation of the airway response similar to that noted in patients with byssinosis.

Measures that reduce levels of ambient endotoxin reduce the incidence of byssinosis.

neutrophils into bronchi. In addition, components of cotton dust can also stimulate resident pulmonary cells, such as mast cells and macrophages, to release molecules that attract neutrophils. There is now a large amount of information that points to a lipopolysaccharide (endotoxin) produced by bacterial contaminants of cotton as the causative agent of byssinosis. The evidence for this is listed in Table 58-2. The most compelling study that examines this issue was presented by Castellan and colleagues, who demonstrated that ambient concentrations of endotoxin in a simulated carding room correlated with reduction in airway flow rates in a time frame similar to that which occurs after exposure to cotton dust in the workplace. An interesting related finding is that byssinosis is less prevalent in Australia, probably because of the lower level of endotoxin on cotton grown in this drier climate. The acquired tolerance during the workweek displayed by patients with byssinosis can be simulated by administration of multiple aerosols of endotoxin in animals. Because airborne levels of endotoxin appear to be directly related to the pathogenesis of byssinosis, mechanisms to control the levels of endotoxin and other airborne components of cotton dust have been implemented in the textile industry. This intervention has met with success in controlling industrial bronchitis in this setting. There have also been reports implicating other components of cotton dust in the pathogenesis of byssinosis. An extract of cotton bract has been shown to induce bronchoconstriction in approximately 60 percent of normal volunteers. The level of this low-molecular-weight (MW) compound parallels the endotoxin level in certain cotton dust preparations, but it is not a component of endotoxin. Other reports have documented significant levels of histamine in cotton dust ex-

Occupational Asthma, Byssinosis, and Industrial Bronchitis

tracts. In addition, clinical studies have suggested that workers with byssinosis have elevated serum histamine levels. The role(s) that cotton bract or histamine play in the pathogenesis of byssinosis is not clear, since none have held up under scrutiny as a cause of this disorder as convincingly as has endotoxin. Treatment and Prevention The most important treatment for byssinosis is removal of the individual from the offending work environment. Screening pulmonary function testing at the workplace is important to identify susceptible individuals who exhibit airflow abnormalities. In addition, since the 1970s, measures have been taken in developed countries to control cotton dust levels in textile mills. One measure has been to steam-clean cotton while it is still in the bale. In 1970, Burlington Industries began a program for dust control and annual medical surveillance. With this program, the incidence of symptoms of byssinosis dropped from 4.5 percent in 1970 to 0.6 percent in 1979. In addition, the number of employees who had a significant decrease in FEV1 over the work shift decreased from 18 percent in 1971 to 3.5 percent in 1979. Similar measures have been taken in other textile plants, with good success in controlling byssinosis. Unfortunately these measures have not been implemented worldwide, and there remains a significant prevalence of byssinosis outside of the United States.

Grain Dustâ&#x2C6;&#x2019;Induced Industrial Bronchitis Exposure to grain dust can also result in the development of chronic bronchitis. Between 4 and 11 percent of grain workers show a reduction in FEV1 of 10 percent or greater over the work shift. This reduction in flow rates is directly related to the amount of dust in the air. Studies have suggested that the component of grain dust responsible for causing airway symptoms is endotoxin, the apparent active component of cotton dust (see above). Grain dust extract, possibly its endotoxin contaminant, can activate complement, and this may be a mechanism by which grain dust induces inflammation in bronchi. However, in contrast to cotton dust, grain dust can, in sensitive individuals, also precipitate an acute drop in airway flow rates rather than only the slow reduction in flow rates similar to that precipitated by cotton dust. This finding suggests that airway reactions to grain dust may be heterogeneous. Grain dust also tends to produce skin abnormalities in affected individuals, in contrast to cotton dust, which generally does not cause skin reactions.

OCCUPATIONAL ASTHMA Definition and List of Offending Agents Occupational asthma is characterized by variable airway obstruction resulting from exposure to ambient dusts, vapors, gases, or fumes incidentally present at a workplace. Bronchial

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Table 58-3 ACCP Case Definition of Occupational Asthma A. Physician diagnosis of asthma B. Onset of asthma after entering workplace C. Association between symptoms of asthma and work

reactions to specific airborne agents, possibly due to overall higher immunoglobulin E (IgE) levels in smokers as compared with nonsmokers. Recent studies have also suggested that there are genetic factors that predispose to occupational asthma. Major histocompatibility complex class II proteins are important for development of occupational asthma due to acid anhydrides, diisocyanates, western red cedar, platinum salts, latex, and animal proteins. Certain glutathione S-transferase and N-acetyltransferase genotypes also predict development of occupational asthma in certain settings.

D. One of the following: 1. Workplace exposure to agent known to cause occupational asthma 2. Work-related changes in FEV1 or PEF 3. Work-related changes in bronchial responsiveness 4. Positive response to specific inhalation challenge test 5. Onset of asthma with a clear association with a symptomatic exposure to an inhaled irritant agent in the workplace Definite occupational asthma requires A, B, C, and D(2) or D(3) or D(4) or D(5) Likely occupational asthma requires A, B, C, and D(1) Abbreviations: FEV1 = forced expiratory volume in 1 s; PEF = peak expiratory Flow.

hyperresponsiveness to nonspecific agents, such as methacholine or histamine, is usually present in these patients. In this setting, asthma may be caused de novo by the offending agent, as in the case of isocyanate-induced asthma, or underlying asthma may be exacerbated by the offending agent. The American College of Chest Physicians (ACCP) consensus statement for the diagnosis of occupational asthma includes several criteria that can be used for the definitive or probable diagnosis of the disease (Table 58-3). Agents that have been associated with induction of occupational asthma can be conveniently grouped into categories of high- and low-MW compounds (Table 58-4). All of these agents tend to sensitize the individual, so that low ambient concentrations of the substance can ultimately cause significant bronchoconstriction. In addition, certain agents can cause direct irritant-related bronchoconstriction and airway hyperreactivity.

Risk Factors Atopy appears to be the major risk factor for developing occupational asthma, particularly when the inciting agent is a high-MW compound. Family or personal history of atopy appears to put the subject at risk. Because low-MW agents can induce asthma through nonallergic as well as allergic mechanisms, atopy may not be as important. Smoking is also a risk factor for the development of occupational asthma, particularly in workers exposed to platinum salts and anhydride compounds. There have been several studies documenting that workers who smoke have a higher incidence of asthmatic

Clinical Presentations Occupational asthma presents in a similar manner as other forms of asthma. If the physician does not maintain a high index of suspicion, symptoms will be treated but the inciting agent will not be identified. Two general forms of occupational asthma have been identified. Most commonly patients develop symptoms after a period of exposure to the inciting agent (occupational asthma with latency) and less commonly they develop immediate symptoms with exposure to the agent (occupational asthma without latency or irritantinduced asthma). In general the former syndrome is associated with a true allergic reaction to the offending agent while the latter is generally mediated nonimmunologically. Occupational Asthma with Latency Most commonly patients who develop occupational asthma do so after a period of exposure to the inciting agent. Agents that induce this sort of pattern include high- and low-MW molecules. Individuals are usually exposed to the agent for weeks to months before developing symptoms. With the appearance of symptoms, nonspecific airway hyperreactivity, determined by methacholine or histamine challenge, is present. Also with appearance of symptoms, the individual develops hypersensitivity to low ambient concentrations of the offending agent. Therefore exposure to very low concentrations of the material in the workplace precipitates severe bronchoconstriction in these patients. Controlled exposure with the offending agent will elicit bronchoconstriction in patients with this syndrome, especially when asthma is due to a high-MW molecule. Occupational Asthma without Latency (Irritant-Induced Asthma) This syndrome is less common. Symptoms develop within hours of exposure. Pathological changes are generally similar to those occurring in the syndrome of occupational asthma with latency, although epithelial changes such as desquamation and subepithelial fibrosis may be more prominent. Agents that commonly cause this syndrome are irritant gases or fumes such as chlorine or ammonia. In addition, certain agents such as acid anhydrides and isocyanates can cause occupational asthma with and without latency. Cough and airway hyperreactivity occurring in emergency responders to the

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Table 58-4 Categories of Agents That Commonly Cause Occupational Asthma Categories

Occupations at Risk

Major Putative Component

High-molecular-weight compounds Animal products

Animal handlers Veterinarians

Pelt or urinary proteins

Seafoods

Crab or prawn processors Oyster farmers

Water-extractable proteins

Insects

Entomologists Grain workers Laboratory workers River workers Flight crews

Insect proteins

Plants

Grain handlers Bakers Tea workers Brewery chemists Tobacco manufacturers

Extractable plant proteins

Biologic enzymes

Detergent industry workers Pharmaceutical workers

Bacillus subtilis, trypsin, pancreatin, papain, pepsin Bakers

Latex

Health care workers Doll manufacturers Glove makers

Latex rubber extract

Gums

Printers Gum manufacturers

Gum acacia Gum tragacanth

Low-molecular-weight compounds Diisocyanates

Polyurethane workers Plastic workers Foundry workers Spray painters

Isocyanate-protein complex

Anhydrides

Epoxy resin workers Plastics workers

Phthalic anhydride-protein complexes

Wood dust

Carpenters Sawmill workers

Plicatic acid (western red cedar) Wood dust extracts

Fluxes

Aluminum solderers Electronics workers

Aminoethylethanol amine

Pharmaceuticals

Pharmaceutical manufacturers

Antibiotics, psyllium, piperazine

Fixatives

Hospital workers

Formaldehyde, glutaraldehyde

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World Trade Center collapse are probably due to this form of asthma.

Mechanisms and Pathology High-Molecular-Weight Compounds Most commonly, high-MW compounds, usually proteins produced at the workplace, induce asthma through IgEdependent classic immediate hypersensitivity reactions. Specific serum IgE antibodies to the protein can usually be demonstrated and skin tests using extracts of the substance show positive results. Atopic individuals are more at risk for developing the syndrome. Because specific IgE antibodies must be produced in this setting, the latent period for developing the reaction can be long, sometimes several months or years. Pathologically, asthma due to high-MW compounds is associated with bronchial infiltration of lymphocytes and eosinophils, indistinguishable from other forms of allergic asthma. Specific IgE antibodies to occupation-related allergens trigger mast cell degranulation in a similar manner as in the nonoccupational setting. In severe cases, bronchial epithelial desquamation and subepithelial fibrosis are exhibited pathologically. Low-Molecular-Weight Compound These agents also tend to cause IgE-dependent bronchoconstriction. However, in contrast to higher-MW agents, specific IgE or IgG antibodies produced in these individuals are directed at the low-MW compound coupled to a protein within the serum. There is also some evidence that low-MW compounds induce asthma through IgE-independent mechanisms, possibly by affecting T lymphocytes directly, as shown for cobalt and nickel salts as well as isocyanates. Interestingly, the bronchial pathology is similar whether or not the response is an IgE-dependent reaction. In addition, certain low-MW compounds can directly affect chemical pathways that are involved in airway tone. For example, organophosphates have been shown to induce bronchoconstriction through anticholinergic effects. Other agents may cause asthma simply through irritation of the airways.

Diagnosis History A high index of suspicion for occupational causes must always be present when patients with new-onset asthma are being evaluated. Because asthma can be induced by remote exposure to a substance, the current and previous occupational history is very important. Computerized lists of exposures that occur at various workplaces are available, and these facilitate this process. Included in the history should be documentation of specific jobs of the individual at the specific workplace as well as potential exposures during performance of those jobs. The history can be verified through the use of material safety data sheets (MSDS) as well as industrial hygiene data and employee health records from the workplace. Clinical history that suggests occupation-related asthma

includes symptoms that occur at work and improve when the patient is away from work for a period of time, as during vacations. The duration of symptoms prior to removal from the offending environment is important for predicting prognosis. Those individuals who have had symptoms for a longer period of time are more likely to develop chronic symptoms that do not remit after exposure has been discontinued. It should be noted that many compounds induce a late reaction, several hours after exposure. Therefore the relationship between the exposure and symptoms may not be entirely apparent to the patient. Questions should also be asked regarding other causes of obstructive pulmonary disease. Questions regarding a history of tobacco use are important. A past history or family history of asthma may suggest that the patientâ&#x20AC;&#x2122;s symptoms are not occupation-related. Therefore, questions to establish the degree of respiratory symptomatology prior to beginning a particular job are important. Questions aimed at assessing cardiac or upper-airway abnormalities are also very important. Physical Examination Signs of atopy should be assessed. As in cases of asthma due to other causes, the pulmonary examination may be entirely normal when the patient is seen outside of the workplace. However, wheezing, either during quiet respiration or on a forced maneuver, suggests airflow obstruction. Signs of dermatitis may support the diagnosis of work-related disease. Skin and Immunologic Tests General atopy is a risk factor for developing certain forms of occupational asthma when it is due to high-MW compounds. Therefore routine skin testing, using a panel of allergens, for wheal-and-flare reactions can be useful. In addition, extracts of a compound that is suspected to cause occupational asthma in a particular patient can be used for skin testing. Extracts from flour, animal by products, coffee, and other sources have been used for skin testing in various studies. Specific IgE antibodies to extracts that contain high-MW compounds or to low-MW compounds coupled to a serum protein, such as albumin, can also be detected by the radioallergosorbent test (RAST) or enzyme-linked immunoadsorbent assay (ELISA). In addition, specific IgE antibodies to low-MW compounds have been detected in patients with asthma due to these compounds. However, positive results in all of these tests do not necessarily indicate that disease is due to the specific agent; they simply suggest sensitization. All of these tests must be evaluated in the context of the individual patient. Pulmonary Function Tests Patients with workplace-induced asthma may present with normal pulmonary function tests when they are away from the inciting agent. For this reason pulmonary function tests should be assessed in the light of the time that has elapsed since the patient was exposed to a suspected agent. Pulmonary

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Figure 58-1 Examples of early, late, and combined reactions to inhalation of a specific agent (in this case, flour extract) implicated in causing occupational asthma. Flow rates are plotted vs. time after inhalational exposure.

function tests pre- and postwork can be very helpful in objectively evaluating respiratory function in relation to work. Peak-flow monitors are useful in the assessment of workplace-related symptoms because they can be used on the job. Initially, peak-flow measurements should be determined at least four times per day: on awakening, at the beginning and end of work, and before bed. Similarly timed measurements should also be performed on days that the subject is off work. Three measurements at each time period should be made and recorded; two of these should be within 20 L/min of each other to demonstrate reproducibility. Measurements should be performed each day over at least 4 weeks. In addition to this regimen, a more intense regimen of peak-flow measurements every 2 h has been proposed by Burge, but this schedule may be too cumbersome to be practical, and studies have suggested that a protocol using measurements performed four times a day is as predictive. Because peak-flow measurements are very effortdependent, they should be supplemented by other methods for assessing the degree of impairment. It is always important to document that patients who are being evaluated for occupational asthma are not malingering in order to obtain compensation. When pulmonary function is assessed in these patients, technicians should be alerted that a work-related disorder is suspected, so that they can evaluate the patientâ&#x20AC;&#x2122;s effort. In addition, reproducibility of the repeated maneuvers can be useful in determining degree of effort. If peakflow measurements suggest that there is an airway reaction to a substance at the workplace, a technician with a portable spirometer can be sent to the workplace to measure FVC and FEV1 at hourly intervals during work.

with either of these agents may be necessary for diagnosis. Such a challenge can also be used to choose the concentration(s) of specific allergen that should be employed in a specific bronchial provocation test, since studies have shown a good correlation between the degree of nonspecific bronchial reactivity and responses to specific allergens. Specific bronchoprovocation can be a valuable tool to determine whether a patientâ&#x20AC;&#x2122;s symptoms are due to a particular agent. This maneuver should be performed only by an experienced physician because it carries some risks. Bronchodilator and anti-inflammatory medication should be withheld prior to the exposure, which should be performed, if possible, in a whole-body chamber that allows more reproducibility of the work situation. Exposure levels should start low and gradually increase to levels that are consistent with ambient levels in the subjectâ&#x20AC;&#x2122;s workplace. Patterns of bronchoconstriction after exposure to specific agents can differ. The two most common patterns are an immediate reaction, occurring within a few minutes of challenge and peaking at 10 to 15 min after challenge, and a late reaction, occurring several hours after challenge and peaking at 5 to 8 h (Fig. 58-1). These responses can be seen individually or together in a given patient. Less frequent patterns have also been noted. One of these involves a reduction in flow rates 1 h after challenge, with resolution 3 to 4 h after exposure. In another, a reduction in flow rates occurs much later, the day after the exposure, and occasionally recurrent abnormalities can be manifest for several days. Recurrent symptoms of nocturnal asthma for several days have also been reported after exposure to a number of agents.

Management Bronchial Provocation Tests Patients who develop occupational asthma invariably develop bronchial hyperreactivity to nonspecific agents such as methacholine and histamine. An arbitrary cutoff of a provocative concentration producing a 20% decline in FEV1 (PC20 ) of 8 to 16 mg/ml has been chosen. In patients with normal spirograms at presentation, a bronchial challenge

Once it has been determined that an individual has developed asthma due to exposure in the workplace, he or she should be removed from the offending environment. In some instances reduction in exposure at the workplace can allow the worker to continue gainful employment without having progressive respiratory symptoms. Although some studies have suggested the use of certain therapeutic agents, such as inhaled

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cromolyn for bakers’ asthma, which can inhibit physiological changes triggered by the offending agent, protection is not complete. Because it is sometimes difficult to convince the patient to change jobs, an alternative to this is the use of a protective mask to prevent airway exposure to the offending agent. The inciting agent dictates the type of protective headgear employed. For example, subjects working with lowMW compounds require helmet respirators with an isolated air source to prevent exposure. If the subject continues to work in the implicated environment, pulmonary function tests should be done frequently to rule out progressive physiological impairment.

peared to be simply a marker of exposure, while IgE antibody was integrally associated with onset of asthma. Avoidance of exposure to laboratory animals is the best treatment for this condition. Although one study has documented that airway reactivity does not tend to worsen in these individuals even if they remain on the job, chronic exposure probably perpetuates airway inflammation. If the individual cannot avoid the exposure, use of a helmet respirator, enabling him or her to completely avoid inhalation of the protein allergen, can prevent symptoms. Worker education regarding avoidance of airborne allergens can also be useful in controlling symptoms.

Disability Determination Documentation of impairment associated with objective physiological changes that occur predominantly in the workplace suggests an occupation-related disorder. Patients with asthma due to an occupational exposure should be referred to the appropriate compensation or review board. The American Thoracic Society has developed guidelines for the evaluation of impairment and disability due to this disorder. Determination of initial impairment should be made after optimal treatment of the asthma has been delivered. Impairment should be assessed using lung function tests, or measurements of airway hyperresponsiveness using: (1) methacholine or histamine; (2) documentation of the type and amount of medication required to treat the patient; and (3) observation of the effect of the disease on the patient’s life-style.

Asthma in Crab Processors Approximately 16 percent of workers who process snow crab meat will develop asthma due to work exposure. The majority of individuals who develop this problem exhibit nonspecific airway hyperreactivity at the time of diagnosis. Studies have suggested that asthma in this setting is due to an immediate hypersensitivity reaction to a component of the crab. One study showed that immediate hypersensitivity skin reactivity, or the appearance of specific IgE antibody to crabmeat extracts or the cooking water used in crab processing, correlated with the development of asthma. Water extracts were more potent than the meat extract. Much as in other forms of occupational asthma, the syndrome in crabmeat processors can become chronic even after removal of the individual from the implicated work environment. In one study, 19 of 31 subjects with the syndrome continued to have symptoms of asthma after being removed from exposure for an average of 1 year. The propensity to develop chronic symptoms appeared to correlate with the duration of employment in the crab-processing plant. As with other causes of occupational asthma, it is important to identify susceptible individuals early, so that they can be removed from the offending environment.

Specific Examples Animal Handlers’ Asthma For several years it has been known that there is a high incidence of asthma and rhinitis among workers in animal care facilities. Development of symptoms tends to occur following months or years of exposure. Symptoms of asthma are often preceded by rhinitis, conjunctivitis, or urticaria that occur primarily at work. In one study, 56 percent of individuals who had been exposed to laboratory animals for 3 months or more complained of respiratory symptoms. Skin testing to animal-associated allergens may be helpful in determining individuals at risk for developing this syndrome. In addition, a prior history of atopy, elevated serum IgE levels, and positive skin tests against non-animal environmental allergens also predict the development of asthma in animal handlers. Approximately one-third of individuals with a history of atopy develop asthma when exposed to laboratory animals for more than 3 months. Although multiple allergens— including molecules found in the pelt, serum, and urine of the animal—may be involved, a major allergen is the rat urinary allergen. In one study, specific IgE antibody to this protein correlated very well with reported asthmatic symptoms in animal handlers. Serum IgG antibody to this protein was also present in animal handlers with symptoms, but it was additionally present in a significant number of asymptomatic subjects as well. Anti-rat urinary protein IgG antibody ap-

Bakers’ Asthma Cereal flours induce a specific IgE reaction in a high percentage of exposed subjects. Epidemiological studies of bakers’ asthma have been most complete in Germany, where it has been shown that IgE-mediated immediate skin test reactivity in bakers is directly related to their time in service. One study has shown that 20 percent of bakers’ apprentices develop positive skin tests after 5 years of service. However, exposed individuals can develop specific IgE antibodies and skin test reactivity to flour antigens without developing asthma, suggesting these tests are mainly a parameter of exposure. In one study, however, the percentage of bakers with documented occupation-related airway disease had a much higher concentration of IgE antibody than did unselected bakers who had been employed for a similar period of time. Overall, 7 to 20 percent of bakers develop allergic symptoms, including asthma, that occur predominantly in the workplace. Symptoms can be minimized by using properly occlusive masks, although most subjects find these devices difficult to wear

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during the entire work shift. Airway reactions to inhaled flour dust allergens can also be reduced by pretreatment with cromolyn sodium. However, no studies have documented that cromolyn can reduce symptoms at the workplace or prevent chronic respiratory abnormalities from developing. Biologic Enzyme−Induced Asthma Detergents containing proteolytic enzymes from bacteria were first noted to cause asthma in 1966. Enzymes associated with asthma include trypsin, pancreatin, papain, pepsin, flaviastase, and bromelain. These proteins induce an immediate hypersensitivity reaction; specific IgE antibodies have been demonstrated in some instances. Attempts to reduce this problem have included changes in detergent preparations so that the molecules will be less readily inhaled. Asthma Due to Latex Urticaria and asthma occur in a small number of individuals who are exposed to rubber latex by wearing gloves or working in doll factories. Risk factors for developing sensitization to latex are (1) frequent use of disposable gloves, (2) the presence of prior atopic disease, and (3) prior or current hand dermatitis. Approximately 80 percent of patients with asthma due to latex develop contact urticaria upon wearing gloves, a large percentage of patients also report rhinitis and conjunctivitis upon exposure to latex. Skin tests using extracts of latex are usually positive in affected individuals. Treatment is limited to avoidance of latex-based products. One study has shown that measures implemented to reduce exposure while working, such as use of powder-free gloves, can allow a sensitized individual to continue to remain on the job. Asthma Due to Acid Anhydrides These low-MW compounds are used in numerous industries, including the curing of epoxy and alkyl resins, production of plasticizers and adhesives, and the manufacture of drugs. Specific acid anhydride compounds used include trimellitic acid (TMA), phthalic acid (PA), tetrachlorophthalic acid (TCPA), and malic acid (MA). All of these compounds have been associated with induction of asthma. TMA exposure has been associated with several different syndromes: (1) an irritant syndrome, (2) early asthma and rhinitis, (3) late-onset dyspnea with systemic symptoms (“TMA flu”), and (4) pulmonary infiltrates with hemoptysis. The irritant syndrome does not require a latency period, while the other three syndromes require a period of exposure to the acid anhydride prior to development. Asthma caused by these compounds appears to be due to the development of specific antibodies to the acid anhydride coupled to a body protein. Specific IgE and IgG antibodies to TMA coupled to human serum albumin have been noted. In one study, total IgE levels were a good parameter of exposure, while specific IgE levels correlated with symptoms of asthma and skin test positivity. The absence of a specific IgE antibody to TMA strongly argues against TMA as the cause of asthma in a particular patient. Another study has shown that IgG in serum from sensitized patients can

Occupational Asthma, Byssinosis, and Industrial Bronchitis

trigger histamine release by basophils. In contrast to asthma caused by high-MW compounds, atopy does not appear to be a definite risk factor for development of asthma due to acid anhydrides. However, a history of smoking may be a risk for the development of asthma due to these agents. Removal of the employee from the environment is the best form of therapy for the disorder. Employee education regarding exposure can also be useful. Even with removal from the offending environment, affected subjects may continue to have symptoms for as many as 5 years after changing work. Specific IgE antibody may also be detected several years after discontinuation of exposure. Isocyanate-Induced Asthma Isocyanates are highly reactive chemicals used in a number of industries. Prominent in this regard is their use in the production of polyurethane, which is found in paints, varnishes, flexible foams, and adhesives. Major forms of isocyanates include toluene diisocyanate (TDI), diphenyl methane diisocyanate (MDI), and hexamethylene diisocyanate (HDI). Exposure to TDI has been most often associated with the development of asthma, and TDI is also the most chemically reactive isocyanate. Overall 5 to 30 percent of workers exposed to TDI develop airway symptoms. There is some evidence that HLA class II alleles are associated with increased risk for the development of isocyanate-induced asthma. In addition, asthma due to toluene diisocyanates is associated with the Ile105 /Ile105 phenotype of glutathione-S-transferase enzyme protein whereas the Val105 /Val105 protects against asthma in this setting. Also, slow acetylator genotypes of the Nacetyltransferase gene have an increased risk of diisocyanateinduced asthma. Isocyanates can cause an irritation syndrome similar to that due to acid anhydrides, occurring without significant time latency. In one reported case, a patient was exposed to large concentrations of TDI and developed airway symptoms within hours of the exposure. Twelve years after exposure, the patient continued to manifest hyperactivity to TDI as nonspecific airway hyperreactivity. More commonly, isocyanates induce an asthma syndrome that develops after exposure to the substance for weeks to years. When subjects develop asthma due to these agents, they also manifest bronchoconstriction after exposure to the substances in a controlled setting, such as an exposure chamber; usually these individuals will also manifest nonspecific airway reactivity to methacholine or histamine. Isocyanates may also induce chronic airway abnormalities in the absence of symptoms. One study, which examined the decremental fall in flow rates in workers exposed to TDI, predicted a 2-L greater loss in FEV1 over 40 years in these workers as compared with controls. Isocyanates cause asthma by inducing intense airway inflammation. Bronchoalveolar lavage studies have demonstrated increased numbers of neutrophils and eosinophils in the airways of subjects with asthma due to isocyanates, particularly those who manifest a late airway reaction upon controlled exposure. Bronchial biopsies of affected patients also

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show intense inflammation, much of which is lymphocytic. Why inflammation is induced by these agents is controversial. There are studies suggesting that isocyanates may interact directly with elements that modulate inflammation. Because these compounds are very reactive, they may affect membrane receptors or enzymes involved in inflammatory pathways. However, because of the latency period that is commonly required prior to the development of isocyanate-induced asthma, an immunologic mechanism is likely. Lymphocytemediated and humoral responses have been proposed. One study has demonstrated specific IgE and IgG antibodies to isocyanates coupled to human serum albumin in sera of individuals with symptoms and positive inhalation challenge tests with isocyanates. Although the levels of both of these subclasses of immunoglobulins tend to correlate with airway responsiveness to the isocyanate, the IgG level tends to be more predictive. As with other forms of occupational asthma, the most efficacious treatment for individuals affected with isocyanateinduced asthma is removal from the offending environment. Once the individual has become sensitized, very low concentrations of the particular agent can induce bronchospasm, so that transfer of the individual to an area that is in close proximity to an area of isocyanate use is not effective management. Bronchoconstriction following controlled isocyanate exposure can be attenuated by inhaled or oral corticosteroids. However, use of these agents should not replace removal of the patient from exposure at work. Use of respirators prophylactically in areas with high concentrations of isocyanates is important to prevent the development of asthma. There have been reports of persistent isocyanate-induced asthma even after removal of the subject from the offending environment. One study reported persistent respiratory symptoms in 83 percent of workers who had been away from isocyanate exposure for 4 years. Another study demonstrated that 7 of 12 subjects with TDI-induced asthma continued to have nonspecific airway hyperreactivity 2 years after removal from the work environment. Asthma in Emergency Responders at the World Trade Center Approximately 25 percent of firefighters who responded to the World Trade Center collapse developed airway hyperreactivity to methacholine from exposure to respirable particles, possibly because of high alkalinity of the dust. The predominant symptom associated with this exposure was cough. One study showed that airway hyperreactivity shortly after the disaster predicted airway hyperreactivity 6 months later. This syndrome is most consistent with occupational asthma without latency (irritant-induced asthma). Asthma Due to Western Red Cedar Wood Dust Workers are at risk for developing asthma due to wood dust exposure. Although a number of woods are associated with this problem, the syndrome due to western red cedar is best characterized and the causative agent within the dust has been

identified. Overall 5 percent of workers who are exposed to western red cedar dust develop symptoms of wheezing and cough after a latency period of months to years. The mean latency period prior to development of symptoms is 50 months. Workers who develop the syndrome usually have nonspecific airway hyperreactivity to methacholine or histamine. In addition, a specific airway reaction to plicatic acid, a component of the wood dust, is usually present and manifested by an early or late reduction in flow rates after exposure. Mechanisms of western red cedar–induced asthma are not totally defined. Plicatic acid, which makes up approximately 50 percent of the total extractable fraction of the wood dust, induces bronchoconstriction in affected subjects. Those subjects who manifest an early and late airway response to inhalation of plicatic acid generally have had a longer exposure to the western red cedar dust. Specific IgE antibodies to plicatic acid coupled with human serum albumin have also been detected in 28 to 40 percent of subjects with the syndrome. Like other forms of occupational asthma due to lowMW compounds, subjects with asthma due to western red cedar can continue to have symptoms even when they are removed from the offending environment. In one study, 60 percent of affected individuals continued to have symptoms after leaving the industry. For this reason, the identification of individuals and specific jobs that place individuals at risk is important. Use of protective devices may reduce exposure and subsequent development of asthma due to this dust, but this has not been systematically addressed. Asthma Due to Metal Salts Platinum used in electroplating, platinum refinery, and jewelry making has been noted to cause asthma. Smoking is a risk factor for development of asthma due to this metal. Airway responses to preparations of complex salts of platinum have been documented in affected workers. In addition, positive skin-prick tests and specific IgE antibodies to platinum conjugated to albumin have been found. There has been one report that hyposensitization is useful for prevention of symptoms, but this has not been verified. Exposure to nickel, chromium, cobalt, vanadium, and tungsten carbide has also been associated with development of asthma. Welders are commonly exposed to nickel fumes when welding stainless steel. Soldering Flux Asthma Various fluxes—including aluminum solder flux, which contains aminoethylethanolamine, and colophony—have been associated with, and thought to cause asthma. One study documented occupational asthma in 21 percent of workers in the plant of a manufacturer of consumer electronics. Colophony fumes can also induce bronchoconstriction in affected individuals when given as a controlled exposure. However, skin tests and RAST evaluations using extracts of colophony have failed to show positive results in affected workers. Thus, the mechanism(s) of these reactions is unknown. They may very well be secondary to the irritant properties of the fumes.

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SUGGESTED READING American Thoracic Society Ad Hoc Committee on Impairment/Disability Evaluation in Subjects with Asthma: Guidelines for the evaluation of impairment/disability in patients with asthma. Am Rev Respir Dis 147:1056–1061, 1993. Anto JM, Sunyer J, Rodriguez-Roisin R, et al: Community outbreaks of asthma associated with inhalation of soybean dust. N Engl J Med 320:1097–1102, 1989. Baldo BA, Krilis S, Wrigley CW: Hypersensitivity to inhaled flour allergens. Allergy 35:45–56, 1980. Banauch GI, Alleyne D, Sanchez R, et al: Persistent hyperreactivity and reactive airway dysfunction in firefighters at the World Trade Center. Am J Respir Crit Care Med 168:54–62, 2003. Bardana EJ Jr: Occupational asthma and related respiratory disorders. Dis Mon 41:143–199, 1995. Brooks SM: Bronchial asthma of occupational origin. Scand J Work Environ Health 3:53–72, 1977. Bryant DH, Boscato LM, Mboloi PN, et al: Allergy to laboratory animals among animal handlers. Med J Aust 163:415– 418, 1995. Chan-Yeung M, Malo J-L: Occupational asthma. N Engl J Med 333:107–112, 1995. Chan-Yeung M: Assessment of asthma in the workplace. ACCP consensus statement. American College of Chest Physicians. Chest 108:1084–1117, 1995. Chan-Yeung M, Brooks SM, Alberts WM, et al: Assessment of asthma in the workplace. Chest 108:1084–1117, 1995. Christiani DC, Wang X-R, Pan L-D, et al: Longitudinal changes in pulmonary function and respiratory symptoms in cotton textile workers: A 15-yr follow-up study. Am J Respir Crit Care Med 163:847–853, 2001.

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Hudson P, Cartier A, Pineau L, et al: Follow-up of occupational asthma caused by crab and various agents. J Allergy Clin Immunol 76:682–688, 1985. Hunt LW, Fransway AF, Reed CE, et al: An epidemic of occupational allergy to latex involving health care workers. J Occup Environ Med 37:1204–1209, 1995. Kay JP: Trades producing phthisis. 0 Med Surg 1:357, 1831. Proust A: Traite d’hygiene publique et privee. Paris, Masson, 1877, p 171. Mapp CE, Boschetto P, Maestrelli P, et al: Occupational asthma. Am Rev Respir Crit Care Med 172:280–305, 2005. Newill CA, Eggleston PA, Prenger VL, et al: Prospective study of occupational asthma to laboratory animal allergens: Stability of airway responsiveness to methacholine challenge for one year. J Allergy Clin Immunol 95:707–715, 1995. Orfan NA, Reed R, Dykewicz MS, et al: Occupational asthma in a latex doll manufacturing plant. J Allergy Clin Immunol 94:826–830, 1994. Rylander R: Diseases associated with exposure to plant dusts: Focus on cotton dust. Tubercle Lung Dis 73:21–26, 1992. Schachter EN: Occupational airway disease. Mt Sinai J Med 58:483–493, 1991. Subcommittee on “Occupational Allergy” of the European Academy of Allergology and Clinical Immunology: Guidelines for the diagnosis of occupational asthma. Clin Exp Allergy 22:103–108, 1992. Sunyer J, Anto JM, Rodrigo MJ, et al: Case-control study of serum immunoglobulin-E antibodies reactive with soybean in epidemic asthma. Lancet 1:179–182, 1989. Vandenplas O, Jamart J, Delwiche J-P, et al: Occupational asthma caused by natural rubber latex: Outcome according to cessation or reduction in exposure. J Allergy Clin Immunol 109:125–130, 2002.

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59 Acute and Chronic Responses to Toxic Inhalations Robert P. Dickson

David A. Schwartz

I. DETERMINANTS AND MECHANISMS OF IRRITANT-INDUCED PULMONARY INJURY II. PATHOGENESIS AND CLINICAL PRESENTATION OF TOXIC INHALATION INJURY Upper Airway Conducting Airways Lower Airways and Pulmonary Parenchyma III. EFFECTS OF SPECIFIC INHALED TOXINS ON THE RESPIRATORY SYSTEM Ammonia Chlorine, Chloramine, and Hydrochloric Acid Sulfur Dioxide

The lungs and airways are in constant contact with the outside world and thus are especially vulnerable to toxic substances present in the environment. Within seconds of exposure to an inhaled toxin, pathological events occur that may cause immediate distress, systemic illness lasting days, or even lead to the development of chronic lung disease. This chapter discusses the pathology and pathophysiology that can result from various inhaled toxins, and also highlights the role of several common and medically significant toxic inhalants that are known to cause acute and chronic pathophysiological responses in the lung. The chapter also discusses several systemic syndromes caused by acute toxic inhalations. The scope of this chapter does not include chronic exposure to low levels of toxins.

DETERMINANTS AND MECHANISMS OF IRRITANT-INDUCED PULMONARY INJURY Inhaled toxins exist in many forms and may be categorized by taking into account their physical properties. General

Nitrogen Oxides Phosgene Ozone Cadmium Mercury Zinc Chloride Mace and Tear Gas IV. SYSTEMIC ILLNESS FROM INHALED TOXINS Metal Fume Fever Polymer Fume Fever Organic Dust Toxic Syndrome V. SUMMARY

categories include gases, vapors, fumes, aerosols, and smoke. A variety of factors determine the pathological results of a toxic inhalation: the size of inhaled particles, solubility of the inhaled substance in water, concentration of the inhalant in ambient air, duration of exposure, presence or absence of ventilation, and a variety of host factors (age, smoking status, co-morbid diseases, use of respiratory protection, and perhaps even genetic susceptibility). While toxic inhalants provoke a broad range of chemical and biologic activities that contribute to pathogenesis, their physical properties, namely their particle size and water solubility, are of fundamental importance in determining the site and severity of pulmonary injury. Tables 59-1 to 59-3 summarize the physical properties of the discussed inhalants that substantially affect the resulting pathogenesis of these agents. The size of aerosolized particles is of critical importance in inhaled toxin pathogenesis. In general, larger aerosolized particles are more likely to deposit on the nasopharynx via impaction and not gain access to the lower airways, while smaller particles are able to penetrate smaller airways and effect toxicity at the level of the alveolus. Aerosolized

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Table 59-1 Definitions of Types of Inhaled Substances Gas: A formless state of matter in which molecules move freely about and completely occupy the space of enclosure. Aerosol: A relatively stable suspension of liquid droplets or solid particles in a gaseous medium. Coarse particles: Particles between 1 and 10 µm. Fine particles: Particles between 0.1 and 1 µm. Ultrafine particles: Particles smaller than 0.1 µm. Vapor: The gaseous form of a substance that normally exists as a liquid or solid and that generally can be changed back to a liquid or solid by either increasing ambient pressure or decreasing the temperature. Fume: An aerosol of solid particles, generally less than 0.1 µm in size, that arises from a chemical reaction or condensation of vapors, usually after volatilization from molten materials. Smoke: The volatilized gaseous and particulate products of combustion; the particles are generally less than 0.5 µm in size and do not settle readily. Source: Data from Kizer KW: Toxic inhalations. Emerg Med Clin North Am 2: 649–666, 1984.

particles larger than 30 to 80 µm are not inhalable through the nose, and particles larger than 5 µm typically do not reach the alveoli. Ultrafine particles (those smaller than 0.1 µm) have been specifically implicated in the toxicity due to the agents of polymer fume fever. Inhaled particles may have direct toxic effects themselves, or they may function as vehicles for adsorbed gaseous agents that are toxic to terminal bronchioles and alveolar cells. In addition to particle size, the relative solubility of an inhalant in water determines where along the respiratory tract toxicity will occur. Substances with high water solubility, such

as ammonia, sulfur dioxide, and hydrochloric acid provoke immediate and evident injury to the conjunctiva and mucosal surfaces of the upper airways; they are largely absorbed by the mucus lining the pharynx and larynx and often react there to form caustic acids and alkalis. The provoked symptoms quickly prompt exposed individuals to flee the area or contain the source of exposure, reducing the duration of exposure. These compounds also can activate irritant receptors in the upper airways, provoking a bronchoconstrictor reflex that may further limit access of the inhalant to lower airways. In contrast, compounds such as phosgene and ozone have low

Table 59-2 Water Solubility and Mechanisms of Lung Injury of Gaseous Respiratory Irritants Irritant Gas

Water Solubility

Mechanism of Injury

Ammonia

High

Alkali burns

Chlorine

Intermediate

Acid burns, reactive oxygen species, reactive nitrogen species

Hydrogen chloride

High

Acid burns

Oxides of nitrogen

Low

Acid burns, reactive oxygen species, reactive nitrogen species

Ozone

Low

Reactive oxygen species, reactive nitrogen species

Phosgene

Low

Acid burns, reactive oxygen species, protein acetylation

Sulfur dioxide

High

Acid burns, reactive oxygen species

Source: Data from Schwartz DA: Acute inhalational injury, in Rosenstock L (ed), Occupational Medicine: Occupational Pulmonory Disease. Philadelphia, Hanlay Belfus, 1987, pp 297–318.

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Table 59-3 Water Solubility and Site of Initial Impact of Toxic Irritants Initial Level of Impact

Inhalant

High

Nose Pharynx Larnyx

Ammonia Chlorine Sulfur dioxide

Medium

Trachea Bronchi

Ozone

Low

Bronchioles Alveoli

Nitrogen dioxide Phosgene

Water Solubility

Source: Data from Balkissoon R: Occupational upper airway disease. Clin Chest Med 23:717–725, 2002.

water solubility and thus fail to cause immediate irritation, promoting longer exposure to the inhalant and deeper penetration of the lower airways. Compounds of intermediate solubility (e.g., chlorine gas) typically have pathological effects throughout the respiratory tract. These differences in solubility can be overcome by differences in concentration and duration of inhalant exposure: Virtually any inhaled toxin (even the most soluble agents) can cause diffuse damage of the respiratory tract by overwhelming the absorptive capacity of the upper respiratory tract. Furthermore, adsorption of a toxic gas on particulate matter may permit a toxin access to otherwise unreachable airways. Host factors also play a significant role in predicting an individual’s response to a toxic inhalation. Underlying pulmonary or extrapulmonary disease may worsen a patient’s response to an exposure. Children deposit a smaller fraction of inhaled particles in their nasopharynx than adults and thus may be at elevated risk of lower airway exposure and pathology. Moreover, as some gases (e.g., chlorine, sulfur dioxide) are heavier than air, children may be subjected to a longer duration and higher concentration of gas than adults near the same site of toxin release. With particles greater than 0.5 µm, breathing through one’s nose increases upper airway particle deposition compared with mouth-breathing; this difference is absent with particles smaller than 0.5 µm. Tobacco smoking impairs ciliary clearance and cellular defense, limiting the exposed patient’s ability to clear inhaled particles and prolonging exposure. Patients with increased minute ventilation (e.g., those panicking at the scene of an irritant gas release) are at elevated risk of increased exposure and toxicity. An emerging literature in experiments with inbred strains of mice suggests that genetic variants may alter the risk of responding to various inhaled toxins. Injury from toxic inhalation may occur via a number of mechanisms. If the concentration of the inhalant is high

Acute and Chronic Responses to Toxic Inhalations

enough and if ventilation is inadequate, simple asphyxiation due to displacement of atmospheric oxygen may occur. The reflex bronchoconstriction triggered by upper-airway irritant receptor activation may itself cause inadequate oxygen inhalation. Cell injury from acute toxin exposure typically occurs via nonimmunologic mechanisms of injury and inflammation, generally via formation of an acid (chlorine, oxides of nitrogen, phosgene, sulfur dioxide), an alkali (ammonia), or reactive oxygen or nitrogen species (ozone, oxides of nitrogen, chlorine). Acid formation results in coagulation of underlying tissue, while alkali exposure causes a liquefaction of mucosa and characteristically deep lesions within the airways. Reactive oxygen and nitrogen species and their derivatives achieve local tissue damage via lipid peroxidation and protein oxidation, and may cause similar toxicity systemically. Free radicals may be direct derivatives of inhaled substances, or they may be released by alveolar macrophages that are activated by inhalant exposure. All three types of tissue damage generally lead to an increase in expression of proinflammatory cytokines that can perpetuate the acute injury and may be responsible for the development of later sequelae. Disruption and repair of injured airway epithelial tissue may compromise the host’s defenses against further infectious or irritant substances. A role played by the innate immune system in disease progression is evident in the case of endotoxin exposure in organic dust toxin syndrome (ODTS), and may be a host factor in the response to ozone and nitrogen dioxide.

PATHOGENESIS AND CLINICAL PRESENTATION OF TOXIC INHALATION INJURY Upper Airway Effects of toxins on the upper airways are typically sudden and short-lived compared with those more distal along the respiratory tract; thus, chronic pathology in this region is unusual. Compounds that provoke a response in the nose, pharynx, and larynx tend to be particulate with relatively large average particle size or gases with high water solubility. Acids, alkalis, and reactive oxygen and nitrogen species may all cause tissue injury in this region, depending on the inhaled compound and its reactions along airway epithelium. Characteristic tissue injury depends on dosage and ranges from slight edema of the nasopharynx and larynx to epithelial ulceration and frank hemorrhage. Once the airway epithelium is compromised, it fails to function as a protective barrier against the environment. Underlying inflammatory cells, nerves, muscles, and blood vessels become exposed, which may further the inflammatory response. An obstructive response to some irritants starts to occur at concentrations only barely perceivable as irritating. The typical presentation of patients with acute exposure of irritant substances to the upper airways includes burning sensations of the nasal passages and throat, copious sputum production, coughing, and sneezing. Extrapulmonary

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manifestations include burning of the eyes, profuse lacrimation, headache, and dizziness. The most serious risk in the exposed patient is airway obstruction due to reflex bronchoor laryngospasm, mucosal edema, increased secretions, and sloughed epithelial cells. Patients presenting with hoarseness or stridor should be carefully observed for further evidence of airway compromise. Although inhalational injury confined to the upper airways tends to be self-limited with no or few long-term sequelae, a chronic rhinitis following irritant exposure, reactive upper airway dysfunction syndrome (RUDS) has been described, and was observed among World Trade Center rescue workers following the attacks of September 11, 2001. Patients with acute toxic exposure to the upper airways should be immediately removed from the source, which may require removal of the patient’s clothes. The patient’s airway should be secured and monitored; racemic epinephrine may be used, but it should not delay endotracheal intubation if necessary. Frequent suction may be required. Profuse amounts of water should be irrigated over exposed surfaces. Supplemental oxygen should be provided if appropriate. Patients with extensive upper airway edema may benefit from corticosteroids,14 although this is unsupported by clinical trials. Ophthalmological consultation should be sought for management of eye exposure.

Conducting Airways Acute Injury As is the case with the upper airways, the conducting airways protect their submucosal structures with epithelia that may be compromised by acute inhalational injury. The resulting edema, inflammation, and bronchoconstriction may be life threatening if it results in an obstructed airway, and without its epithelial barrier the airway is vulnerable to infections and other environmental pathologies. This damage to the epithelium appears to occur at the tight junction interface between cells, resulting in increased epithelial permeability to other irritants, which gain direct access to effector cells within the subepithelial mucosa. Resulting bronchospasm may cause ventilation-perfusion mismatch. The smooth muscle of the airways can be hyperresponsive in the hours and days following irritant exposure, an effect probably mediated by the neutrophilic and eosinophilic inflammatory response inhalational injury provokes. Conducting airway injury may manifest as intrathoracic airflow obstruction hours after the initial insult. Patients with histories of exposure who present with any evidence of respiratory compromise should be hospitalized for observation, even if asymptomatic. Findings of concern include expiratory wheezing, decreased airflow on peak expiratory flow measurement or spirometry, and abnormalities of gas exchange or an abnormal chest x-ray. Likewise, patients with complaints of dyspnea or chest tightness should be observed carefully and treated symptomatically with inhaled steroids and bronchodilators, even in the absence of objective findings. When significant airflow obstruction is present, systemic steroids may be of some utility.

Chronic Injury Reactive Airways Dysfunction Syndrome

A persistent asthma-like disease following acute exposure to an irritant inhalant, known as reactive airway dysfunction syndrome (RADS, or “Brooks syndrome”)was named in 1985, but observed among World War I soldiers exposed to war gases. Investigation and diagnosis of the disease is generally limited by the absence of spirometry results in patients prior to exposure and the presence of confounding factors (e.g., cigarette smoking), but numerous reports exist of previously asymptomatic patients experiencing hyperreactive airway disease presenting soon after a single toxic exposure and persisting for months or years. RADS is distinguished from immunologic occupational asthma in that it follows a single exposure and does not follow a latency period of sensitization to the offending substance. The pathogenesis of RADS likely begins with the initial injury to and desquamation of the epithelium, which results in hemorrhage and edema followed by inflammatory changes, and finally long-term structural changes of the airways involving epithelial regeneration and fibrosis. Ensuing airway narrowing may be due to mucosal edema, inflammation, or structural changes to the architecture of the bronchial wall. RADS typically presents abruptly within 24 hours following exposure with the classic symptoms of obstructive airway disease: wheezing, chest tightness, dyspnea, and cough. The symptoms and obstructive findings on examination and spirometry are relieved by bronchodilators, although not as effectively as in other types of reactive airway disease (perhaps due to chronic fibrotic remodeling of the conducting airways). The disease can persist for months and may be permanent in some instances. Anecdotally, inhaled corticosteroids have shown benefit in relieving airflow obstruction. Systemic corticosteroids have been proven beneficial in an animal model of RADS. Vocal Cord Dysfunction

Vocal cord dysfunctionmay also follow a single acute irritant exposure and may be confused with RADS. The disorder may be caused by reflex response to nerve stimulation by irritants. Patients suspected of having RADS who do not respond appropriately to bronchodilators should be evaluated for vocal cord dysfunction; direct laryngoscopy is the gold standard of diagnosis.

Lower Airways and Pulmonary Parenchyma Acute Injury Although all toxic inhalants are capable of producing distal airway disease at extreme concentrations and durations, the gases most likely to do so are those with low water solubility such as phosgene and nitrogen dioxide, which bypass reflex bronchoconstriction and absorption by upper airway mucous (Fig. 59-1). The initial pathological events in distal

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Figure 59-1 Accidental exposure of 55-year-old mechanic to spill of liquid Cl2 , followed immediately by coughing and dyspnea. A. Day of exposure. Bilateral alveolar infiltrates, most marked on right. B . Two days later. Progression of alveolar infiltrates. C . Seven days later. Incomplete resolution of infiltrates associated with persistent shortness of breath.

airways are caused by the cellular toxicity of the inhaled agent and its derivatives, which compromise the impermeability of the alveolar-capillary interface. Some of this cytotoxicity may be derived indirectly from reactive oxygen species released from activated inflammatory cells. In the absence of an intact alveolar-capillary interface, profound pulmonary edema may develop that impairs gas exchange and can prove fatal. The severity of this pulmonary edema, which typically presents after a latent period of several hours following the initial insult, is likely dose related. This process may cause no more than slight dyspnea and cough with a mild alveolar infiltrate, or may progress via diffuse alveolar damage to adult respiratory distress syndrome (ARDS). For this reason, patients

with exposure to gases capable of causing distal airway disease should be hospitalized and monitored for symptoms of respiratory distress and with serial chest x-rays for at least 24 hours following exposure. Development of ARDS from toxin exposure likely shares a common pathway with other causes of acute lung injury, and management is similar: supportive care with mechanical ventilation, careful control of blood glucose, surveillance for infection, and deep venous thrombosis prophylaxis. Diuresis, IV corticosteroids, prone positioning, nitric oxide inhalation, and exogenous surfactant are all unsupported by clinical trials but are potentially of some benefit. Diffuse bronchiolitis also has been reported following acute exposure.

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Chronic Injury Bronchiolitis Obliterans

Bronchiolitis obliterans (BO) is a well-documented but infrequent long-term sequela of toxic gas exposure, especially of nitrogen dioxide, but also to ammonia, mercury, and sulfur dioxide. The disease typically presents 1 to 3 weeks following the initial lung injury and pulmonary edema (Fig. 59-2). The interim is often free of symptoms. When BO does develop, patients may present with dyspnea on exertion or obstructive findings on spirometry. Physical examination may be either unremarkable or remarkable only for early inspiratory crackles. Chest x-ray is either normal or demonstrates hyperinflation. Pulmonary function tests typically demonstrate airflow obstruction that may in some cases also be associated with restrictive defects. On biopsy, granulation tissue is seen in the lumen of small airways and bronchiole walls may be obliterated by fibrous scarring. Corticosteroids may be of benefit in preventing or alleviating BO if administered early in the course of the disease, although this is controversial. Bronchiolitis Obliterans Organizing Pneumonia

Bronchiolitis obliterans organizing pneumonia (BOOP) is another observed delayed sequela of toxic inhalation. Patients present in the weeks following exposure with fever, a persistent and nonproductive cough, sore throat, and malaise. Late inspiratory crackles may be observed. Chest x-ray may reveal bilateral patchy “ground glass” densities that start as focal lesions but may coalesce with time. Pulmonary function tests generally reveal a restrictive process with decreased diffusion capacity. Histologically, granulation tissue extends past the terminal bronchioles and into the alveolar spaces, sometimes with interstitial scarring. BOOP and BO are probably both chronic results of the initial inflammatory response to the toxic insult and the ensuing proliferative process. BOOP responds well to corticosteroids, although a small number of patients may develop progressive fibrosis. Duration of therapy should be guided by the patient’s clinical status.

EFFECTS OF SPECIFIC INHALED TOXINS ON THE RESPIRATORY SYSTEM (TABLE 59-4) Ammonia Ammonia (NH3 ) is a water-soluble nitrogen-containing compound that ranks among the most commonly spilled hazardous substances. Familiar to all as a household cleaner, it also has countless uses in industry: as a chemical coolant used for refrigeration, a fertilizer, a fixative in photocopiers, and in the manufacture of polymers and explosives. Small amounts are naturally present in the atmosphere as products of the putrefaction of vegetable and animal proteins. The smell of concentrated ammonia is immediately recognizable due to the prevalence of ammonia in household cleaners and its use

in smelling salts (which exploit the noxious effect of ammonia on nasal membranes to arouse consciousness). Ammonia is frequently dissolved into water for storage and transportation, and vaporizes readily on exposure to air. Most inhalation exposures are the result of accidental releases, including tank leaks and transportation mishaps, and most exposures occur in the industrial workplace. A recently reported source of exposure is via fumes produced in clandestine methamphetamine laboratories. Ammonia tends to affect the proximal airways, where it reacts rapidly with the water present on mucosal surfaces to form ammonium hydroxide, causing tissue liquefaction. This necrosis liberates formerly intracellular water, which serves as further reactant for ammonia, perpetuating the reaction. In addition to the alkali burns caused by the generated ammonium hydroxide, thermal burns can result from the heat generated by this exothermic reaction. The resulting injury, typical of alkali burns, penetrates deeply. The initial injury to the mucosa of the oropharynx can cause edema, hemorrhage, sloughing of tissue, and increased secretions that can bring about fatal upper airway obstruction. Ammonia is directly caustic to airways at concentrations of 1000 ppm and higher. Although concentrated at the proximal airways, the effects of ammonia have been observed at all levels of the respiratory tract. The penetration of the gas to the smaller airways and alveoli is a function of its concentration and the duration of exposure. Reported acute conditions associated with ammonia exposure include pulmonary edema, laryngitis/tracheobronchitis, bronchiolitis, and bronchopneumonia; reported chronic sequelae include bronchiectasis, bronchospasm/asthma (termed reactive airways dysfunction syndrome), and chronic obstructive pulmonary disease. There are several reports of interstitial lung disease following a single exposure to ammonia. A biphasic pattern of pulmonary response to ammonia inhalation has been reported, characterized by initial, acute pneumonitis that may clear over the next 2 to 3 days, followed in some individuals by the gradual development of airway obstruction and respiratory failure. There may be a correlation between the contraction of a bacterial superinfection after exposure with the ensuing development of bronchiectasis. In one review of published case reports, 21 percent of patients with acute ammonia inhalation died within 60 days of exposure. The most common causes of death were laryngeal edema and obstruction, noncardiogenic pulmonary edema, and extensive pneumonic complications. Management of a patient who has experienced ammonia inhalation requires removing him or her from the source of the irritant, securing the airway, and immediately irrigating all exposed surfaces (especially the eyes) with copious amounts of water. Airway management should be aggressive, given the frequency of laryngeal edema in exposed patients. Rales detected on physical exam are predictive of the subsequent hospital course, even in the absence of hypoxemia and chest x-ray abnormalities. Medical management is largely supportive. Corticosteroids and antibiotics are both frequently used, but both are unproved in human trials.

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Figure 59-2 Bronchiolitis obliterans in a 63-year-old man who had been exposed to a wide variety of unidentified fumes in his jobs, which included welding. A. Chest radiograph. Diffuse pulmonary fibrosis and honeycombing, most marked in the peripheral portions of the lungs. B . Sagittal section of lung from same patient showing markedly dilated airspaces. Microscopic sections revealed bronchiolitis obliterans and chronic interstitial pulmonary fibrosis. C . Normal lung from a 43-year-old man who died suddenly. The difference between B and C in the alveolar portions of the lungs is striking. (Courtesy of Dr. R. Ochs.)

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Table 59-4 Pulmonary Manifestations of Toxin Inhalation Acute Clinical Manifestations Substance

Onset

Upper Airway Irritation

Irritant gases Ammonia Chlorine Hydrogen chloride Oxides of nitrogen Ozone Phosgene Sulfur dioxide

Minutes Minutes to hours Minutes Hours Minutes to hours Hours Minutes

Metals Cadmium Mercury Zinc chloride Zinc oxide

Hours Hours Minutes Hours

Chronic Clinical Manifestations

Pneumonitis, ARDS

Bronchiolitis Obliterans, BOOP

Severe Moderate Severe Mild Mild Mild Severe

+ + + + + + +

+ − − + − +

+ + + + − + +

Mild Mild Mild Mild

+ + + +

− + − −

− − + −

RADS

Note: Abbreviations: + = exposure reported to be associated with clinical entity; − = exposure as yet not reported to be associated with clinical entity.

Chlorine, Chloramines, and Hydrochloric Acid Chlorine (Cl2 ) is a common gas of intermediate water solubility. The first reports of its toxicity followed its use as an agent of chemical warfare in World War I, and war gassings remain the largest historical source of chlorine gas exposure. Most exposures since then have occurred in the industrial setting, where chlorine is used in the manufacture of paper, cloth, antiseptics, and other products. More common in the household is the liberation of chloramines and other toxic chlorine derivatives from the reaction of chlorine-containing products (e.g., hypochlorite bleach) with ammonia or products containing hydrochloric or phosphoric acid. Numerous exposures to chlorine gas have occurred near swimming pools, where chlorine-releasing agents (e.g., calcium hypochlorite and chlorinated isocyanuritic acids) are used in water purification. Chlorine gas is greenish-yellow in color and is heavier than air. Although its odor is distinct, patient exposure to it may be prolonged compared with other toxic gasses due to its delayed irritation of mucosal surfaces and its high density, which keeps it low to the ground. The pathogenicity of chlorine gas derives directly from elemental chlorine’s effects on the respiratory tract and indirectly from its reaction with water to form hydrochloric acid (HCl) and hypochlorous acid (HOCl). The character and distribution of injury from chlorine exposure varies according to duration of exposure and the relative concentrations of elemental chlorine and its derivative compounds. HCl and HOCl possess considerable water solubility and are responsible for the tissue damage sustained by the upper airways and ocular conjunctivae. Irritation to trigeminal nerve end-

ings caused by these compounds can cause a reflex bronchoconstriction that may contribute to compromise airway diameter. In addition to causing the tissue coagulation typical of acid exposures (described above), these compounds ionize and enter cells, where they may form reactive oxygen species. HOCl has been shown to react with nitrite (NO− 2) to produce reactive nitrogen-containing compounds able to nitrate, chlorinate, and dimerize phenolic amino acids. As nitrite and nitric oxide (its parent compound) levels are elevated at sites of tissue inflammation, this potentially is another mechanism of injury. Although lower respiratory tract irritation has been reported following high-level exposures, less than 5 percent of inhaled chlorine gas penetrates beyond the upper airways. Fatal dosages from chlorine inhalation have ranged from 50 to 2000 ppm. The immediate clinical manifestations of acute chlorine exposure are typical of irritants of its solubility: rhinitis, cough, dyspnea, wheezing, and chest tightness, along with conjunctivitis and skin irritation. When chlorine gas exposure has resulted acutely in death, autopsies have revealed diffuse ulcerative tracheobronchitis, pulmonary edema, thrombi within pulmonary vessels, and denudation of respiratory tract epithelium. Acute respiratory symptoms are more prevalent and severe among patients who already have chronic respiratory disease. The lasting respiratory sequelae of chlorine gas exposure have been described since the years following use of the gas in World War I. Reported long-term pulmonary diseases following exposure have included both restrictive and obstructive processes, frequently resolving to normal function within a month and almost always before two years

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following exposure. Reactive airways dysfunction syndrome may be an infrequent sequela of high-level exposures to chlorine. Patients who have been exposed to chlorine gas should be managed according to the severity of their presenting symptoms similarly to other victims of irritant inhalation. Nebulized sodium bicarbonate has shown promise as a useful treatment, but lacks supporting clinical trials and showed no outcome benefit in a relatively large observational study of chloramine gas exposure. Beta agonist bronchodilators and humidified oxygen are frequently used and are probably of benefit. The reported benefit of corticosteroid administration is anecdotal and unconfirmed by clinical trial.

Sulfur Dioxide Sulfur dioxide is a heavy, colorless, and highly water-soluble gas that has the distinct, pungent odor of burnt matches. It is generated in the combustion of coal and petroleum and is often used as a preservative in alcoholic beverages and fruit. Industrial exposures have occurred around ore smelting, sugar refining, and the bleaching of wool and wood pulp. Sulfur dioxide is among the most harmful gases released to the atmosphere during volcanic eruptions. In 1986 the gases emitted from one eruption killed nearly 2000 people in Cameroon. Sulfur dioxide’s great density keeps it low to the ground and slow to dissipate from sites of release; thus, children may be at an increased risk of exposure. Sulfur dioxide reacts with water present on mucous membrane to form sulfuric acid, which causes tissue coagulation in underlying exposed surfaces. Sulfuric acid also further dissociates into hydrogen ions, sulfite, and bisulfite, which can then react with oxygen to produce reactive oxygen species; ensuing lipid peroxidation may be a contributing mechanism of injury to immediate tissues and elsewhere. Exposures of high enough intensity can irritate both upper and lower airways. Patients exposed typically present with dyspnea, burning of the nose and throat, rhinorrhea, cough, and airway obstruction. Proximal airway injury is characterized by acute denudation of the airway mucosa without inflammatory cell infiltrates. When lower airways are exposed, alveoli fill with fluid due to noncardiogenic pulmonary edema and the clinical picture is consistent with ARDS. Alveolar architecture is generally preserved. Extremely high-intensity acute exposures can lead within minutes to death from respiratory failure due to a combination of alveolar hemorrhage and edema, possible reflex vagal stimulation, and the asphyxiating effect of high concentrations of sulfur dioxide. Reactive airways dysfunction syndrome has been reported following single sulfur dioxide exposure. Bronchitis has also been observed. One pattern of postexposure progression reported is a rapid recovery followed several weeks later by the onset of irreversible airflow obstruction due to bronchiolitis obliterans. Sulfur dioxide is detectible to humans at 3 to 5 ppm and is lethal at levels exceeding 400 ppm for 1 minute. Care for patients who have been exposed to sulfur dioxide is supportive: humidified supplemental oxygen, bronchodilators, and intubation and ventilation if necessary. The

Acute and Chronic Responses to Toxic Inhalations

use of corticosteroids in the setting of ARDS following sulfur dioxide exposure has not been shown to be of benefit, but a trial is not unreasonable. Antibiotics may be reserved for use upon evidence of infectious complications.

Nitrogen Oxides Nitrogen oxides are ubiquitous air pollutants, released from automobile engines and the combustion of coal and petroleum and present in cigarette smoke. High-level acute exposure is most likely to occur in industrial settings, including mining, acetylene welding, and explosives manufacturing. A well-known form of exposure occurs in “Silo-filler’s disease,” in which farmers inhale concentrated nitrogen dioxide gas released within silos by decomposing nitrogenous biomaterial. Exposures to high levels of nitrogen dioxide have been attributed to blast furnaces, anesthetic gases, military incidents, and ice hockey arenas. Nitrogen dioxide is a liquid at room temperature and a reddish-brown gas above 70◦ F. Nitrogen dioxide is hydrolyzed by the water on mucosal surfaces to form nitric and nitrous acid, although much of its toxicity is explained via the free radical activity of nitrogen dioxide itself and the nitrites and nitrates that derive from it. Although the predominant site of toxicity from nitrogen dioxide exposure is the interface of the terminal bronchioles and alveolar membranes, the relative insolubility of nitrogen dioxide in water ensures that enough gas penetrates the upper airways such that injury can occur virtually anywhere along the respiratory tract. Nitrogen dioxide itself is a reactive nitrogen species that, along with other reactive derivatives, is capable of lipid peroxidation and protein oxidation, both of which may be significant contributors to the gas’s toxicity via disruption of the cell membrane. Mice with defective Toll-like receptor 4 expression exhibit a lessened response to nitrogen dioxide exposure compared with normal strains, suggesting that the patient’s innate immunity may play a role in disease development. There is also evidence that nitrogen dioxide exposure is mutagenic to lung cells. The initial effects of nitrogen dioxide exposure are relatively benign at all but very elevated concentrations: cough, fatigue, and occasionally nausea. With high-intensity exposure, patients also may experience headache and chest tightness, although even these symptoms tend to resolve promptly. Nitrogen dioxide is less irritating to mucosal surfaces than other toxic inhalants. Symptoms typically abate for a period of hours before an intense pulmonary edema consistent with ARDS occurs due to increased capillary permeability following extensive damage to vascular and airway epithelium. Patients who survive this are at risk for the development of bronchiolitis obliterans and bronchiolitis obliterans organizing pneumonia 1 to 4 weeks following exposure. This clinical course of nitrogen dioxide toxicity demands vigilant monitoring on the part of medical personnel. Patients who are relatively asymptomatic following exposure may rapidly progress to ARDS within hours or severely obstructive bronchiolitis obliterans within weeks. Treatment is largely supportive. In animal studies, antioxidant administration has proved protective against lung injury following

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nitrogen dioxide exposure, suggesting that aerosolized antioxidant medications are potentially of some utility in humans. Interestingly, nitric oxide (NO) has been used successfully as a pulmonary vasodilator in the treatment of ARDS following acute nitrogen dioxide toxicity. Individuals who survive the initial lung injury still require close following with serial assessment of pulmonary mechanics and gas exchange over the ensuing several weeks. Patients exhibiting evidence of progressive airflow obstruction may benefit from corticosteroids to prevent or decrease the severity of bronchiolitis obliterans.

Phosgene Phosgene (carbonyl chloride, COCl2 ), like nitrogen dioxide, has relatively low water solubility and penetrates deeply to the alveolar spaces. It is colorless, lacks a strong odor (in high concentrations it is reported to smell like moldy hay) and is not irritating to the nasal and oral mucosa. These traits were notoriously exploited in World War I, when phosgene was used by both sides of the conflict as a weapon, resulting in tens of thousands of fatalities. Modern uses include the production of pesticides, polyurethane resin, toluene diisocyanate, pharmaceutical products, and dyes. It also can be produced accidentally via the heat decomposition of various solvents, paint removers, dry cleaning fluids, and methylene chloride. Phosgene reacts with water to form hydrochloric acid and carbon dioxide, but its limited solubility results in little hydrolysis in the upper airways. In the relatively moist alveolar air spaces, however, the resulting acid is destructive of alveolar walls and small vessels, resulting in epithelial necrosis. Phosgeneâ&#x20AC;&#x2122;s lack of irritability in the upper airways precludes the reflex bronchoconstriction provoked by other toxic gases, ensuring open passage of the gas to the alveoli. Phosgene also causes tissue damage by rapidly acetylating the amino, hydroxyl, and sulfhydryl groups of proteins, resulting in protein denaturation and structural compromise of cell membranes, leading to a breakdown of the blood-air interface. Lipid peroxidation has also been shown to occur, and antioxidant therapy has been shown to attenuate phosgeneâ&#x20AC;&#x2122;s effects in animal models. On exposure to phosgene, patients may experience chest tightness, wheezing, or cough; some victims experience no immediate symptoms. Following exposure, the patient experiences a latent period of 30 minutes to 8 hours before the onset of symptoms. The duration of this latent period is thought to be inversely proportional to both the severity of exposure and the ensuing severity of disease. The latent period is typically followed by pulmonary edema: The patient experiences dyspnea, cough and respiratory distress, and rales and cyanosis are appreciable on physical examination. Although survival for patients with acute phosgene exposure is good, numerous long-term sequelae have been reported, including prolonged exertional dyspnea, chronic bronchitis, and emphysema.

During the latent period following exposure, numerous therapeutic options exist that may prevent or lessen the severity of pulmonary edema. Corticosteroids are frequently used but of unproven benefit. Ibuprofen, N-acetylcysteine, aminophylline, and isoproterenol have all proven beneficial in animal models.

Ozone Ozone (O3 ) is a colorless, odorless gas of low water solubility. It is found throughout the atmosphere and occurs in greatest concentrations in the stratosphere, where it is protective against ultraviolet radiation. It is the main oxidant pollutant in smog and can reach hazardous levels at ground levels on days with elevated atmospheric temperature. Atmospheric levels are known to aggravate chronic lung diseases such as asthma99 and chronic obstructive pulmonary disease. Acute toxic exposures are associated with its uses in industry, including bleaching of fabrics, disinfecting water and surfaces, and the manufacture of plastics. Reports of acute ozone exposure have been reported in an airplane cabin on a high-altitude flight. Ozone is extremely reactive, and is almost entirely consumed before crossing a single bilayer membrane. It results in the formation of reactive nitrogen species and probably causes toxicity via the oxidation of membrane lipids. It induces epithelial necrosis and airway inflammation and in severe exposures can cause dyspnea, cyanosis, and pulmonary edema. A genetic component to the response to ozone has been reported. Treatment is supportive and no specific therapies have been shown to be beneficial.

Cadmium Cadmium is a highly corrosion-resistant metal with many industrial applications. Most cadmium is used in nickelcadmium batteries, although it is also found in alkaline accumulators, electroplating, bearings, solder, and as a barrier around nuclear fission generators. It is present in many metal ores, and cadmium-containing pigments are used in paints, artistsâ&#x20AC;&#x2122; colors, rubber, plastics, printing inks, wallpaper, leather, glass, and enamels. Most inhalations occur to workers who are involved with soldering, brazing, smelting, and refining. The heating of sheet metal electroplated in a cadmium cyanide bath has been reported to cause cadmium toxicity. The mechanisms involved with the acute lung injury due to cadmium inhalation are not well defined. Postmortem examinations of individuals who died after accidental acute inhalation exposure have revealed tracheobronchitis, consolidated lungs, denuded bronchial epithelium, intra-alveolar hemorrhage, and the presence of macrophages in the alveolar spaces. It is known that cadmium inhibits the synthesis of plasma alpha 1-antitrypsin, which may explain the correlation between cadmium exposure and the later development of emphysema. Rats exposed to cadmium fumes and cadmium chloride aerosols develop pulmonary edema and on necropsy show increased numbers of alveolar type II cells.

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When cadmium-containing materials are heated, cadmium vapors and cadmium oxide fumes are released. Patients who are exposed initially present similarly to those with metal fume fever (see below): They are asymptomatic for several hours before developing fever, malaise, and myalgias. These constitutional symptoms are often accompanied by or shortly followed by respiratory distress, including cough, chest tightness, and dyspnea. Cadmium may be detected in the urine if the identity of the toxin is uncertain. Fatal cases have been remarkable for initial pneumonitis that relentlessly progresses to ARDS and eventual death from respiratory failure. Management is supportive; there are no specific treatments for cadmium inhalation.

Mercury Although mercury has a low solubility in distilled water, its solubility increases in contact with plasma or whole blood, as at the blood-air interface. Sources of mercury gas exposure are primarily industrial and include ore smelting, cement production, fur and felt hat manufacture, fossil fuel combustion, and gold extraction. Mercury is found within the silver amalgam used by dentists, and a number of exposures, including several with fatal outcomes, have occurred in the home during amateur attempts to extract precious metals from amalgams that also contain mercury. Like phosgene and cadmium, mercury vapor has little or no immediate upper airway or mucosal surface irritant effects, and as a result exposed individuals may inadvertently remain in an area where the harmful vapors are present. Typical clinical presentations include symptoms of cough, dyspnea, and respiratory distress that develop 12 to 24 hours postexposure. Sometimes these initial symptoms are accompanied by fever, nausea, vomiting, diarrhea, and a metallic taste in the mouth, similar to what is often experienced by individuals with metal fume fever and associated transient pneumonitis. In fact, mercury vapor inhalation can be mistaken for metal fume fever or influenza. However, symptoms of mercury vapor inhalation do not spontaneously resolve as with metal fume fever. Instead, the pneumonitis may progress to ARDS; death has been preceded in several reports by tension pneumothorax. The toxicity of mercury vapors within the lung is thought to be due in part to the irritant effects of oxidized mercurous and mercuric ions and the disruption of enzyme systems containing sulfhydryl groups. Mercury coagulates protein, blocks cellular metabolism of carbohydrates at the pyruvic oxidase level, and as a result produces a metabolic acidosis. Lung pathology following acute exposure reveals pulmonary edema, capillary damage, and the desquamation and proliferation of airway epithelium followed by an obliteration of airspaces. Inhaled mercury vapor is absorbed rapidly into the blood, where it can achieve systemic toxicity; renal, hepatic, and nervous system pathology have been reported. Patients surviving the acute injury typically experience resolution of their symptoms within 1 week following onset, but have also progressed to develop interstitial fibrosis. Mortality due to exposure may be increased in children.

Acute and Chronic Responses to Toxic Inhalations

Blood levels of mercury may reflect acute uptake, and urine levels can monitor chronic stores. Treatment of mercury inhalation is supportive and addresses the acute lung injury. Mechanical ventilation, including positive pressure and high-frequency oscillating ventilation, may be beneficial in the treatment of mercury-induced ARDS. Corticosteroids have no proven benefit. Chelating agents, such as dimercaprol and d-penicillamine, are frequently used to increase the rate of mercury excretion after ingestion, but have not been shown to affect the outcome of the acute lung injury.

Zinc Chloride Zinc chloride (ZnCl2 , or hexite), a major ingredient of smoke bombs and smoke-generating devices, has been responsible for numerous toxic and fatal exposures. The compound forms when zinc oxide is ignited with hexachloroethane. Toxic inhalations have occurred in settings in which individuals have inhaled smoke in confined spaces, in most instances without functional protective breathing apparatus (Fig. 59-3). The smoke effect tends to contribute to the duration of exposure by obscuring vision, sometimes resulting in directional disorientation and the inability to quickly escape the area of exposure. When inhaled, zinc chloride is in particulate form with an average particle size of 0.1 µm, small enough to allow large amounts of it to penetrate through to the lower respiratory tract. After depositing on the airway and alveolar surfaces, zinc chloride reacts with water to form hydrochloric acid and zinc oxychloride. This directly causes irritation of exposed mucosal surfaces and is the probable mechanism behind the diffuse lung injury observed on exposure. Zinc chloride inhalation is commonly followed by tracheobronchitis and pneumonitis, reflecting the sites of particle deposition. Patients experience cough, dyspnea, and chest tightness followed by a period of relative stabilization before progressing to ARDS. Chest imaging may be normal initially but can reveal pleural effusions, pneumomediastinum, and bilateral infiltrates consistent with pneumonitis. There is evidence that prominence of ground glass opacities observed on high-resolution CT imaging is predictive of both severity of exposure and length of hospital stay. A urine zinc level may confirm the diagnosis of zinc inhalation toxicity. Patients should be monitored for progression to ARDS and treated with supplemental oxygen and mechanical ventilation if indicated. The administration of high doses of N-acetylcysteine may accelerate systemic zinc clearance, and thereby spare some oxidant-induced lung injury, although this is unsupported by clinical experience. Corticosteroid use is similarly controversial.

Mace and Tear Gas “Tear gas” is the name collectively given to chloroacetophenone (CN or “chemical mace”), ortho-chlorobenzylidene malonitrile (CS) and oleoresin capsicum (OC or “pepper spray”). All three agents are used by military and law

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Figure 59-3 Chest computed tomography (CT) scan and pulmonary function tests obtained on a person with inhalation injury after a smoke bomb was ignited in an underground cave. The CT scans were obtained 1 week and 12 weeks after the accident and demonstrated extensive interstitial lung disease, which resolved on radiographs. The pulmonary function tests obtained 1, 3, and 12 weeks after the exposure demonstrated marked restrictive lung function and abnormal gas exchange, which also resolved within 3 months of exposure.

enforcement agencies to control crowds and individuals, making use of their intense and immediate irritant effects on mucous membranes and lacrimal glands. Exposure to any of them results in immediate rhinorrhea, mucositis, chemical conjunctivitis, and profuse lacrimation. Immediate pulmonary effects include an intense burning sensation in the upper airways, reflex airway constriction, chest tightness, dyspnea, and cough. Exposure also may provoke nausea, headache, and photophobia. Severity of response depends on the concentration of the agent used, duration of exposure, and presence or absence of ventilation and protective breathing apparatus. The effects of tear gas are predominantly due to its upper airway irritant effects, and thus lower airway injury and parenchymal disease is rarely observed. Auscultation of the chest is typically clear, and the chest radiograph is usually without abnormality. Case reports of severe pulmonary disease exist, describing pneumonitis, pulmonary edema, reactive airways dysfunction syndrome, and acute bronchospasm in an asthmatic. These cases have in common prolonged peri-

ods of exposure with poor ventilation. A fatal hypersensitivity reaction to CS has been reported. The most immediate concern in the treatment of tear gas exposure is maintenance of a patent airway. Mucosal surfaces should be irrigated profusely, and suction may be useful in clearing the copious oral and nasal secretions that may compromise the airway. Humidified O2 should be administered and beta agonists should be used in the presence of bronchospasm. No benefit from corticosteroids has been observed. Patients with prolonged or intense exposure should be monitored carefully for evidence of progression to significant respiratory disease.

SYSTEMIC ILLNESS FROM INHALED TOXINS Systemic, flulike illness lasting under 2 days has been observed in patients exposed to organic dusts and fumes of heated

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metals and fluorocarbons. The disease course is self-limited and in all cases appears to be cytokine mediated.

Metal Fume Fever Since its first description by Potissier in 1822, metal fume fever has been known by a number of other names: brazier’s disease, smelter shakes, brass chills, zinc chills, welder’s ague, copper fever, foundry fever, and Monday morning fever. It is a self-limited syndrome characterized by the delayed onset of fever, chills, myalgias, and generalized malaise following exposure to fumes that contain metal oxides. Specific fumes that have been blamed include those of beryllium, cadmium, copper, magnesium, nickel, silver, and zinc. Welders are at the highest risk for metal fume fever contraction, although it has been reported in other metalworking occupations including soldering, brazing, cutting, metallizing, forging, melting, and casting. Episodes of varying severity of metal fume fever may be experienced by between 20 percent and 35 percent of all welders. Exposure is typically associated with confined spaces and poor ventilation. An estimated 2000 cases of metal fume fever are reported each year in the United States. The typical course of metal fume fever begins with sensations of dry throat and a sweet or metallic taste. Fever, chills, and myalgias develop 4 to 8 hours after exposure and spontaneously resolve within 48 hours. Respiratory-related symptoms of chest tightness, nonproductive cough, and dyspnea are sometimes observed. Laboratory findings are remarkable for transient leukocytosis. Chest x-ray is typically normal, although findings consistent with pneumonitis have been observed. Pulmonary function tests are usually normal, although obstructive and restrictive deficits, as well as abnormalities of diffusion, have been reported. Repeated exposure appears to lead to tachyphylaxis; the name “Monday morning fever” refers to the recurrence of acute disease on return to exposure following a short period of absence. The disease has been mistaken for influenza, atypical or community-acquired pneumonia, and a malaria-like illness because of overlapping presenting symptoms. Metal fume fever is generally thought to have no long-term sequelae. An association between it and the later development of occupational asthma has been observed, but a prospective study failed to show that a history of metal fume fever is predictive of later bronchial hyperresponsiveness. The pathogenesis of metal fume fever appears to involve an increase in proinflammatory cytokine activity in the lung; increased bronchoalveolar lavage fluid concentrations of tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-8 (IL-8) have been reported in subjects exposed to zinc oxide fumes, probably produced by pulmonary macrophages. Following exposure, bronchoalveolar lavage TNF-α levels peak earlier than other cytokines, suggesting that its role may be central to disease progression. Of the numerous components of metal fumes, it appears to be the soluble transition metal particles, which generate reactive oxygen species and deplete glutathione stores, that are responsible

Acute and Chronic Responses to Toxic Inhalations

for the fumes’ cytotoxicity. A proposed mechanism of the observed tolerance to metal fumes involves the increased synthesis of toxic metal-binding protein metallothionein in exposed patients. The treatment of metal fume fever is supportive, and includes antipyretics and analgesics. Metal fume fever must be distinguished from acute metal fume toxicity, as with cadmium or mercury, which can present similarly to metal fume fever but fails to resolve and instead progresses to respiratory distress. Prevention of metal fume fever involves provision of adequate ventilation, fume removal devices and respiratory protection for workers in environments in which metal oxide fumes are generated.

Polymer Fume Fever A syndrome similar to but less common than metal fume fever, polymer fume fever, was first reported in 1951. Fluorocarbon polymers are a class of compounds that are commonly used as nonstick coatings on cooking equipment (polytetrafluoroethylene [PTFE, or Teflon] is a famous example) but are also used as mold-release sprays, lubricants, and fabric or leather treatments. When fluorocarbon polymers are heated, fumes are produced that include carbonyl fluoride, perfluorinated alkanes, hydrofluoric acid, and carbon dioxide; extremely small particles capable of reaching alveolar sacs also may contribute to disease progression. Polymer fume fever presents similarly to metal fume fever: Initial symptoms include dry throat, rhinitis, chest tightness, and conjunctivitis. Constitutional symptoms (fever, chills, myalgias) typically follow exposure by about 4 to 8 hours and spontaneously resolve within 1 day. As with metal fume fever, a leukocytosis is observed concurrent with the patient’s constitutional symptoms. Individuals with preexisting obstructive lung disease may experience worsening obstruction after recurrent exposures to polymer fumes. Pneumonitis is more frequently observed than with metal fume fever, perhaps due to release of hydrofluoric acid. Tachyphylaxis, a hallmark observation of metal fume fever, is not observed in polymer fume fever, suggesting that different mechanisms are responsible for the two diseases. As with metal fume fever, the systemic response to particle inhalation appears to be cytokine mediated. Although exposure to pyrolized fluoropolymers occurs in industrial settings where it may be immediately suspected in the context of respiratory complaints, it also occurs in homes and via less obvious means of exposure. In one report, within an hour of an empty PTFE-coated pan being heated on a stove, five exposed pet birds died and their owner contracted polymer fume fever. Numerous reports have suggested that workers with skin exposed to fluoropolymers may have contracted polymer fume fever via smoking their selfcontaminated tobacco. Another may have contracted the disease via igniting his marijuana with cotton that had previously been impregnated with hairspray. Several recent episodes of polymer fume fever have occurred following exposure via the waterproofing spray used on horse rugs.

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Treatment of polymer fume fever is supportive. Workers exposed to fluoropolymers should both be provided adequate ventilation and also instructed of the risk of indirect exposure via skin contamination. Strict hand-washing should be required and tobacco smoking should be especially discouraged after exposure.

Organic Dust Toxic Syndrome Another systemic illness caused by inhalational exposure is organic dust toxic syndrome (ODTS), also known as silo unloader’s syndrome, atypical farmer’s lung, pulmonary mycotoxicosis, and toxic pneumonitis. As with metal fume fever and polymer fume fever, ODTS is a self-limited disease that presents with fever, chills, and myalgias several hours after exposure to the offending agent, in this case organic dusts. As with the other systemic diseases discussed, ODTS typically resolves spontaneously within 48 hours following exposure. Agricultural workers are at the highest risk for contracting ODTS, as it commonly follows exposure to hay or corn silage-containing silos, spoiled animal feed, and swine confinement facilities. Other settings of ODTS have included a college fraternity party in which hay was laid on the floor, a storehouse containing moldy oranges, a waste-sorting plant, a print-shop in which an air humidifier was colonized with gram-negative bacteria, fungi, and amoebae, and following exposure to wood chip mulch. Lifetime risk of contracting ODTS may be around 19 percent for farmers with exposure to organic dust. The specific agent or agents within organic dust responsible for ODTS have not been fully characterized, but bacterial cell wall components endotoxin and peptidoglycan are thought to play prominent roles. Fungal spores and actinomyces also are likely contributors to pathogenicity, and an ODTS-like response can be provoked with endotoxin-free grain extracts. The disease process is likely initiated or provoked by activation of the patient’s innate immune system by organic dust components, such as endotoxin’s activation of Toll-like receptor 4. Cytokine expression increases following organic dust exposure, especially of proinflammatory cytokines such as TNF-α and interleukin-6 (IL-6), suggesting a means by which local activation of innate immunity may provoke the observed systemic manifestations. Interleukin-1 (IL-1) is also thought to play a critical role in ODTS development. An intriguing correlation has been observed between patients with celiac disease and the development of ODTS, suggesting that some underlying disorder, perhaps a hyperactivity of innate immunity, may increase a patient’s susceptibility to both. Patients with ODTS frequently present with no findings on chest examination, although bibasilar crackles and scattered wheezes may be appreciated. A neutrophilpredominant leukocytosis is frequently found, and mild hypoxemia and bilateral infiltrates on chest x-ray have been reported. Although bronchoalveolar lavage may initially reveal a predominance of neutrophils, a lymphocytic response may come to dominate the BAL cellular population.

ODTS needs to be clinically distinguished from hypersensitivity pneumonitis (HP), which is also provoked by inhaled organic dust. HP typically follows low levels of exposure after a period of sensitization, while ODTS is an acute reaction to high levels of organic dust, potentially on first exposure. HP is a restrictive process detectable by pulmonary function testing, while ODTS sometimes presents with transient airflow obstruction and often with no appreciable functional abnormality. The early BAL findings in ODTS are overwhelmingly neutrophilic, unlike the lymphocytic findings in HP. Treatment of ODTS is symptomatic. Unlike with HP, corticosteroids appear to be of only marginal benefit in the treatment of ODTS.

SUMMARY Toxic inhalations may be due to numerous agents and produce a broad spectrum of pulmonary and systemic injuries. Treatment is largely supportive and should be guided by the patient’s clinical status. Specific attention should be paid to the patency of the airway following acute upper airway exposures, and providers should be aware of the risk of the development of severe pulmonary disease following an asymptomatic latent period. Given the unpredictable clinical course of these exposures, cautious monitoring of exposed patients is prudent. Materials safety data sheets and the National Library of Medicine’s TOXNET (http://toxnet.nlm.nih.gov/) are excellent information resources for specific toxins.

SUGGESTED READING Afane Ze E, et al: Respiratory symptoms and peak expiratory flow in survivors of the Nyos disaster. Chest 110:1278– 1281, 1996. Ando Y, et al: Elevated urinary cadmium concentrations in a patient with acute cadmium pneumonitis. Scand J Work Environ Health 22:150–153, 1996. Asano S, et al: Review article: acute inorganic mercury vapor inhalation poisoning. Pathol Int 50:169–174, 2000. Asgharian B, Menache MG, Miller FJ: Modeling age-related particle deposition in humans. J Aerosol Med 17:213–224, 2004. Backus-Hazzard GS, Howden R, Kleeberger SR: Genetic susceptibility to ozone-induced lung inflammation in animal models of asthma. Curr Opin Allergy Clin Immunol 4:349– 353, 2004. Baggs RB, Ferin J, Oberdorster G: Regression of pulmonary lesions produced by inhaled titanium dioxide in rats. Vet Pathol 34:592–597, 1997. Balkissoon R: Occupational upper airway disease. Clin Chest Med 23:717–725, 2002. Banauch GI, et al: Bronchial hyperreactivity and other inhalation lung injuries in rescue/recovery workers after the

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World Trade Center collapse. Crit Care Med 33:S102–106, 2005. Bhalla DK: Ozone-induced lung inflammation and mucosal barrier disruption: Toxicology, mechanisms, and implications. J Toxicol Environ Health B Crit Rev 2:31–86, 1999. Brautbar N, Wu MP, Richter ED: Chronic ammonia inhalation and interstitial pulmonary fibrosis: A case report and review of the literature. Arch Environ Health 58:592–596, 2003. Camus P, Nemery B: A novel cause for bronchiolitis obliterans organizing pneumonia: Exposure to paint aerosols in textile workshops. Eur Respir J 11:259–262, 1998. Chauhan AJ, et al: Exposure to nitrogen dioxide (NO2 ) and respiratory disease risk. Rev Environ Health 13:73–90, 1998. Cormier Y, et al: Reactive airways dysfunction syndrome (RADS) following exposure to toxic gases of a swine confinement building. Eur Respir J 9:1090–1091, 1996. D’Alessandro A, et al: Exaggerated responses to chlorine inhalation among persons with nonspecific airway hyperreactivity. Chest 109:331–337, 1996. de la Hoz RE, Schlueter DP, Rom WN: Chronic lung disease secondary to ammonia inhalation injury: A report on three cases. Am J Ind Med 29:209–214, 1996. Delgado JH, Waksman JC: Polymer fume fever-like syndrome due to hairspray inhalation. Vet Hum Toxicol 46:266–267, 2004. DeLorme MP, et al: Hyperresponsive airways correlate with lung tissue inflammatory cell changes in ozone-exposed rats. J Toxicol Environ Health A 65:1453–1470, 2002. Demeter SL, Cordasco EM, Guidotti TL: Permanent respiratory impairment and upper airway symptoms despite clinical improvement in patients with reactive airways dysfunction syndrome. Sci Total Environ 270:49–55, 2001. Demnati R, et al: Effects of dexamethasone on functional and pathological changes in rat bronchi caused by high acute exposure to chlorine. Toxicol Sci 45:242–246, 1998. Desqueyroux H, et al: Effects of air pollution on adults with chronic obstructive pulmonary disease. Arch Environ Health 57:554–560, 2002. Dhaliwal K, Sood A: Ammonia inhalational lung injury during illicit methamphetamine production. J Burns Surg Wound Care 2:15, 2003. Dube D, et al: Reactive airways dysfunction syndrome following metal fume fever. Tenn Med 95:236–238, 2002. Eiserich JP, et al: Formation of nitrating and chlorinating species by reaction of nitrite with hypochlorous acid. A novel mechanism for nitric oxide-mediated protein modification. J Biol Chem 271:199–208, 1996. El-Zein M, et al: Is metal fume fever a determinant of welding related respiratory symptoms and/or increased bronchial responsiveness? A longitudinal study. Occup Environ Med 62:688–694, 2005. El-Zein M, et al: Prevalence and association of welding related systemic and respiratory symptoms in welders. Occup Environ Med 60:655–661, 2003.

Acute and Chronic Responses to Toxic Inhalations

Epler GR: Bronchiolitis obliterans organizing pneumonia. Arch Intern Med 161:158–164, 2001. Evans RB: Chlorine: State of the art. Lung 183:151–167, 2005. Fakhrzadeh L, Laskin JD, Laskin DL: Deficiency in inducible nitric oxide synthase protects mice from ozone-induced lung inflammation and tissue injury. Am J Respir Cell Mol Biol 26:413–419, 2002. Fakhrzadeh L, et al: Superoxide dismutase-overexpressing mice are resistant to ozone-induced tissue injury and increases in nitric oxide and tumor necrosis factor-alpha. Am J Respir Cell Mol Biol 30:280–287, 2004. Galdi E, et al: Irritant vocal cord dysfunction at first misdiagnosed as reactive airway dysfunction syndrome. Scand J Work Environ Health 31:224–226, 2005. Gielen MH, et al: Acute effects of summer air pollution on respiratory health of asthmatic children. Am J Respir Crit Care Med 155:2105–2108, 1997. Gorguner M, et al: Reactive airways dysfunction syndrome in housewives due to a bleach-hydrochloric acid mixture. Inhal Toxicol 16:87–91, 2004. Harkonen H, et al: Long-term effects of exposure to sulfur dioxide. Lung function four years after a pyrite dust explosion. Am Rev Respir Dis 128:890–893, 1983. Hill AR, et al: Medical hazards of the tear gas CS. A case of persistent, multisystem, hypersensitivity reaction and review of the literature. Medicine (Baltimore) 79:234–240, 2000. Hsu HH, et al: Zinc chloride (smoke bomb) inhalation lung injury: Clinical presentations, high-resolution CT findings, and pulmonary function test results. Chest 127:2064– 2071, 2005. Johnston CJ, et al: Characterization of the early pulmonary inflammatory response associated with PTFE fume exposure. Toxicol Appl Pharmacol 140:154–163, 1996. Kakinoki Y, et al: Nitrogen dioxide compromises defence functions of the airway epithelium. Acta Otolaryngol 538:221–226, 1998. Karlson-Stiber C, et al: Nitrogen dioxide pneumonitis in ice hockey players. J Intern Med 239:451–456, 1996. Kaye P, Young H, O’Sullivan I: Metal fume fever: A case report and review of the literature. Emerg Med J 19:268–269, 2002. Kleeberger SR: Genetic aspects of pulmonary responses to inhaled pollutants. Exp Toxicol Pathol 57:147–153, 2005. Kleeberger SR, Zhang L-Y, Jakab GJ: Differential susceptibility to oxidant exposure in inbred strains of mice: Nitrogen dioxide versus ozone. Inhal Toxicol 9:601–621, 1997. Kuschner WG, et al: Tumor necrosis factor-alpha and interleukin-8 release from U937 human mononuclear cells exposed to zinc oxide in vitro. Mechanistic implications for metal fume fever. J Occup Environ Med 40:454–459, 1998. Leavey JF, et al: Silo-Filler’s disease, the acute respiratory distress syndrome, and oxides of nitrogen. Ann Intern Med 141:410–411, 2004. Lemiere C, Malo JL, Boutet M: Reactive airways dysfunction syndrome due to chlorine: Sequential bronchial biopsies

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and functional assessment. Eur Respir J 10:241–244, 1997. Martin CJ: Respiratory hazards of welding. Clin Pulm Med 4:194–204, 1997. McNeilly JD, et al: Soluble transition metals cause the proinflammatory effects of welding fumes in vitro. Toxicol Appl Pharmacol 196:95–107, 2004. Meng Z: Oxidative damage of sulfur dioxide on various organs of mice: Sulfur dioxide is a systemic oxidative damage agent. Inhal Toxicol 15:181–195, 2003. Ng’walali PM, et al: Fatalities by inhalation of volcanic gas at Mt. Aso crater in Kumamoto, Japan. Leg Med (Tokyo) 1:180–184, 1999. Nodelman V, Ultman JS: Longitudinal distribution of chlorine absorption in human airways: A comparison to ozone absorption. J Appl Physiol 87:2073–2080, 1999. Olajos EJ, Salem H. Riot control agents: Pharmacology, toxicology, biochemistry and chemistry. J Appl Toxicol 21:355– 391, 2001. Parimon T, Kanne JP, Pierson DJ: Acute inhalation injury with evidence of diffuse bronchiolitis following chlorine gas exposure at a swimming pool. Respir Care 49:291–294, 2004. Parrish JS, Bradshaw DA: Toxic inhalational injury: Gas, vapor and vesicant exposure. Respir Care Clin North Am 10:43–58, 2004. Pascuzzi TA, Storrow AB: Mass casualties from acute inhalation of chloramine gas. Mil Med 163:102–104, 1998. Perkner JJ, et al: Irritant-associated vocal cord dysfunction. J Occup Environ Med 40:136–143, 1998. Persinger RL, et al: Molecular mechanisms of nitrogen dioxide induced epithelial injury in the lung. Mol Cell Biochem 234–235:71–80, 2002. Pettila V, Takkunen O, Tukiainen P: Zinc chloride smoke inhalation: A rare cause of severe acute respiratory distress syndrome. Int Care Med 26:215–217, 2000. Promisloff RA, et al: Reactive airway dysfunction syndrome in three police officers following a roadside chemical spill. Chest 98:928–929, 1990. Pryor WA, Squadrito GL, Friedman M: The cascade mechanism to explain ozone toxicity: The role of lipid ozonation products. Free Radic Biol Med 19:935–941, 1995. Rivoire B, et al: Occupational acute lung injury due to Alternaria alternata: Early stage of organic dust toxic syndrome requires no corticosteroids. Int Care Med 27:1236– 1237, 2001. Rumack B: POISINDEX(R) Information System. Englewood, CA, Micromedex, 2005.

Sant’Ambrogio G, Widdicombe J: Reflexes from airway rapidly adapting receptors. Respir Physiol 125:33–45, 2001. Schlesinger RB: Disposition of inhaled particles and gases, in Pulmonary Immunotoxicology. Norwell Mass, Kluwer Academic Publishers, 2000, 85–105. Schwartz DA: Grain dust, endotoxin, and airflow obstruction. Chest 109:57S–63S, 1996. Sciuto AM, Hurt HH: Therapeutic treatments of phosgeneinduced lung injury. Inhal Toxicol 16:565–580, 2004. Sciuto AM, et al: Protective effects of N-acetylcysteine treatment after phosgene exposure in rabbits. Am J Respir Crit Care Med 151:768–772, 1995. Sexton JD, Pronchik DJ: Chlorine inhalation: The big picture. J Toxicol Clin Toxicol 36:87–93, 1998. Shusterman DJ, Murphy MA, Balmes JR. Subjects with seasonal allergic rhinitis and nonrhinitic subjects react differentially to nasal provocation with chlorine gas. J Allergy Clin Immunol 101:732–740, 1998. Steffee CH, et al: Oleoresin capsicum (pepper) spray and “incustody deaths”. Am J Forensic Med Pathol 16:185–192, 1995. Von Essen SG, et al: Grain dusts and grain plant components vary in their ability to recruit neutrophils. J Toxicol Environ Health 46:25–441, 1995. Wallace GM, Brown PH: Horse rug lung: Toxic pneumonitis due to fluorocarbon inhalation. Occup Environ Med 62:414–416, 2005. Wang Z, et al: Time course of interleukin-6 and tumor necrosis factor-alpha increase in serum following inhalation of swine dust. Am J Respir Crit Care Med 153:147–152, 1996. Williams PL, James RC, Roberts SM: Principles of Toxicology: Environmental and Industrial Applications. New York, Wiley, 2000, pp 183–184. Winder C: The toxicology of chlorine. Environ Res 85:105– 114, 2001. Wintermeyer SF, et al: Pulmonary responses after wood chip mulch exposure. J Occup Environ Med 39:308–314, 1997. Yost BL, et al: The changing role of eosinophils in long-term hyperreactivity following a single ozone exposure. Am J Physiol Lung Cell Mol Physiol 289:L627–635, 2005. Zhiping W, et al: Exposure to bacteria in swine-house dust and acute inflammatory reactions in humans. Am J Respir Crit Care Med 154:1261–1266, 1996. American Thoracic Society: Respiratory health hazards in agriculture. Am J Respir Crit Care Med 158:S1–S76, 1998.

SECTION TWELVE

Environmental Disorders

60 CHAPTER

Indoor and Outdoor Air Pollution Jonathan M. Samet

Mark J. Utell

I. OVERVIEW II. GENERAL PRINCIPLES AND CONCEPTS Principles of Inhalation Injury Adverse Health Effects of Air Pollution: Clinical and Public Health Concerns Concepts of Time-Activity and Total Personal Exposure Research Approaches to Air Pollution III. OUTDOOR AIR POLLUTION Overview: Sources and Classification of Outdoor Air Pollution Outdoor Air Pollutants: Exposures and Health Effects IV. INDOOR AIR POLLUTANTS AND HEALTH EFFECTS Overview: Sources and Classification of Indoor Air Pollution Carbon Monoxide

Both indoor and outdoor air pollution are of concern to pulmonary physicians. Exposures to indoor and outdoor air pollutants may both exacerbate and cause respiratory diseases and also increase the population’s risk for morbidity and mortality from malignant and nonmalignant diseases. This chapter provides a broad introduction to indoor and outdoor air pollution. It begins with a brief review of the emergence of indoor and outdoor air pollution as clinical and public health issues. The chapter then considers gen-

Nitrogen Dioxide Secondhand Smoke Wood Smoke Organic Compounds Radon Asbestos and Man-Made Fibers Biologic Agents V. CLINICAL SYNDROMES ASSOCIATED WITH INDOOR ENVIRONMENTS VI. SUSCEPTIBLE POPULATIONS Clinical Studies in Asthma and COPD Clinical Studies in Heart Disease VII. CONTROL STRATEGIES Patient-Oriented Strategies Community-Oriented Strategies

eral principles and concepts related to inhalation injury, exposure, and health outcomes. The health consequences of indoor and outdoor air pollution are covered separately, although this distinction is artificial, given the penetration of outdoor pollutants into indoor environments and the overlap between the pollutants found in indoor and outdoor locations. The chapter concludes by considering two issues of direct concern to clinicians: susceptible populations and control strategies.

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OVERVIEW Air pollution has probably had adverse effects on health throughout history. The use of fire for heating and cooking brought exposure to smoke, and the rise of cities concentrated the emissions of pollutants from dwellings and manufacturing facilities within restricted locales. Industrialization and electric power generation brought new point sources of pollution; that is, localized sources such as power plants, and sometimes immense emissions of combustion byproducts, particles, nitrogen oxides, and sulfur oxides into adjacent areas where people lived and worked. During the twentieth century, mobile sources, including cars, trucks, and other fossil fuel–powered vehicles, created a new type of pollution— photochemical pollution, or “smog”—first recognized in the Los Angeles air basin. The unprecedented growth of some urban areas to form “megacities,” such as Mexico City, S˜ao Paulo, and Shanghai, has led to unrelenting air pollution from massive vehicle fleets and snarled traffic and from polluting industries and power plants. During the twentieth century, there also has been increasing recognition that the problem of air pollution extends into indoor environments. In the less-developed countries, exposure to smoke from biomass fuel combustion is widespread, as it was in past centuries. In the more developed countries, indoor pollutants are generated by human activities and released from the materials used for construction and in furnishings, and often maintained at unhealthy concentrations by building designs that seal pollutants within. Health effects of air pollution have long been of concern. During the reign of Edward I (1272–1307), the pollution of London by coal smoke prompted a royal proclamation banning burning of “sea-coal” in open furnaces. In 1661, John Evelyn published Fumifugium or the Aer and Smoake of London Dissipated, describing an approach to the control of air pollution in London. However, air pollution was not regulated in England until approximately two centuries later with the passage of the Smoke Nuisance Abatement Act and the Alkali Act, directed at industrial pollution. In the United States, recognition of the public health dimensions of air pollution began in the middle of the twentieth century, driven by the rising problem of smog in southern California and the 1948 air pollution episode in Donora, Pennsylvania, which caused 20 excess deaths and thousands of illnesses. The first national legislation, the Air Pollution Control Act, was passed in the mid-1950s; the original Clean Air Act was passed in 1963 and most recently revised in 1990. The modern era of air pollution research and control dates to the episodes in Donora and other cities, during which extremely high levels of pollution caused clearly evident excess deaths. The most dramatic episode was the London Fog of 1952, which caused thousands of excess deaths. These episodes led to regulations for the control of outdoor air pollution and to the conduct of research designed to develop evidence on the health effects of outdoor air pollution as a foundation for control measures. The research included char-

acterization of the pollutants in outdoor air as to their sources, concentrations, and chemical and physical properties; toxicological investigation on the injury caused by air pollutants and the underlying mechanisms; and epidemiological studies of the health effects of air pollution in the community. These approaches remain fundamental to research on air pollution. We now have a large body of evidence on the health effects of air pollution gained over nearly 60 years of investigation and complex regulations that limit emissions and control concentrations of key pollutants in outdoor air. The health effects of indoor air pollution are a more recent concern. Only limited measurements were made of indoor air contaminant levels before the 1970s, and the findings of the first large-scale studies of the health effects of indoor air pollution were not reported until the late 1960s and early 1970s. Pollutants of initial interest included secondhand tobacco smoke (SHS) or environmental tobacco smoke (ETS), the mixture of side-stream smoke and exhaled mainstream smoke inhaled involuntarily by nonsmokers, and nitrogen dioxide (NO2 ) generated by gas cooking stoves and ranges and by space heaters. Research soon broadened to biologic agents, volatile organic compounds, and two respiratory carcinogens—radon and asbestos. Concern about the potential health effects of indoor air pollution was heightened by the design and construction of buildings with reduced exchange of indoor with outdoor air for the purpose of energy conservation; the reduction of air exchange was anticipated to diminish dilution and thereby increase indoor air pollutant concentrations. Beginning in the 1970s, outbreaks of nonspecific complaints started to occur among workers, who attributed their symptoms to the indoor environments in which they worked. Now referred to as sick-building syndrome, these outbreaks continue—but seemingly in smaller numbers than 10 years ago. Another recently described syndrome, multiple chemical sensitivity, has also been linked to indoor air pollution; persons with this syndrome, who may obtain consultation from pulmonary specialists, often report debilitating symptoms after exposure to indoor air contaminants, even at levels that may be considered generally safe. One new concern is disease resulting from potential exposure to mold in homes, particularly following water damage. The flooding of many homes in New Orleans and Houston by catastrophic hurricanes has served to reinforce the potential for chronic exposure to mold. Control of indoor air pollution has been enacted primarily through nonregulatory approaches, as the Environmental Protection Agency (EPA) does not directly regulate the levels of pollutants in indoor air. The cornerstone of the control of indoor air pollution has been education of the public, manufacturers, and employers on approaches for reducing exposures and for reducing emissions from indoor sources. The EPA has given a guideline value for an acceptable indoor radon concentration; it has also proposed that all homes be tested for radon and the homes modified if the concentration is above the guideline. The handling of asbestos in schools was regulated under the Asbestos Hazard Emergency Reduction

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Table 60-1 Criteria Pollutants, Sources, and National Ambient Air Quality Standards (NAAQS) Pollutant

Sources

Primary Standards

Averaging Time

Sulfur dioxide

Coal and petroleum combustion, smelting, and other manufacturing

0.14 ppm (365 µg/m3 ) 0.03 ppm (80 µg/m3 )

24 h Annual (arithmetic mean)

PM10

Coal and petroleum combustion, vehicles, industry, surface dust

150 µg/m3 50 µg/m3

24 h Annual (arithmetic mean)

PM2.5

Fuel combustion from automobiles, power plants, wood burning, industrial processes, and diesel powered vehicles

65 µg/m3 15.0 µg/m3

24 h Annual (arithmetic mean)

Nitrogen dioxide

Coal and petroleum combustion, vehicles, industry

0.053 ppm (100 µg/m3 )

Annual (arithmetic mean)

Carbon monoxide

Coal and petroleum combustion, vehicles

35 ppm (40 µg/m3 ) 9 ppm (10 µg/m3 )

1h 8h

Ozone

Secondary formation from NO2 and hydrocarbons

0.08 ppm

Maximum daily 1-h average

Lead

Gasoline, lead-containing dust

1.5 µg/m3

Maximum quarterly average

Act, and the agency has classified ETS as a class A carcinogen. In the United States and some other countries, a substantial proportion of households have banned smoking in the home in the absence of any regulatory policy. The Occupational Safety and Health Administration published Proposed New Rules on indoor air quality in 1994, but later withdrew the proposal. The literature on air pollution is now voluminous and has been published in a broad array of journals and technical reports. Of necessity, this chapter is selective in its review; emphasis has been placed on the most relevant findings for clinicians and on the newer literature. The documents prepared by the EPA on the six “criteria” pollutants (sulfur dioxide [SO2 ], particulate matter, NO2 , carbon monoxide [CO], ozone [O3 ], and lead) offer encyclopedic reviews that are updated periodically (Table 60-1). The American Thoracic Society (ATS) has occasionally published summary statements for health professionals on the health effects of outdoor air pollution, with several published in 1996. Several books address the topic of indoor air pollution generally or address specific aspects of indoor air pollution. The EPA has published an introductory primer on indoor air pollution. Key documents on specific pollutants are cited within the appropriate sections of this chapter.

GENERAL PRINCIPLES AND CONCEPTS Adverse responses to air pollutants reflect exposure and the delivery of the dose of the injurious agent to the target site within the respiratory tract. Air pollutants cause disease through various mechanisms. This section of the chapter covers principles of inhalation injury and the related spectrum of adverse health effects; it also covers principles of exposure assessment. The research methods used to characterize the effects of air pollutants are also detailed.

Principles of Inhalation Injury Atmospheric pollutants, whether indoors or outdoors, exist in both gaseous and particulate forms. In evaluating clinical consequences of specific exposures, the clinician should recognize that penetration into and retention within the respiratory tract of toxic gases can vary widely, depending on the physical properties of the gas (e.g., solubility), the concentration of the gas in the inspired air, the rate and depth of ventilation, and the extent to which the material is reactive. Gases that are highly water soluble, such as SO2 , are almost completely extracted by the upper airways of healthy

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subjects during brief exposures at rest. In contrast, removal of less water-soluble gases, such as NO2 or O3 , is much less complete, and these gases may penetrate to the airways and alveoli of the respiratory tract. CO is poorly soluble in water and is not removed in the upper airways. On reaching the lung, CO diffuses across the alveolar-capillary membrane and then binds avidly to hemoglobin. Exercise greatly augments penetration of gases into the deep lung and, thus, the total dose of pollutants delivered to targets in the airways. Exercise increases the dose directly by increasing minute ventilation; also, because many people switch from the nasal to the oral breathing route during moderate to heavy exercise, the more efficient pollutant removal in the nasal passages is replaced by the less efficient removal in the oral airway. Particulate pollutants usually occur in nature as aerosols. Small liquid droplets or solid particles are dispersed in the atmosphere with sufficient stability to remain in an aerosol suspension. Examples of common aerosols are sulfuric acid mists and sulfate and nitrate salts formed from SO2 and NO2 , respectively. Deposition of inhaled particles depends on many factors, including the aerodynamic properties of the particle (primarily size), airway anatomy, and breathing pattern. Particles larger than 10 µm are effectively filtered out in the nose and nasopharynx, where these relatively large particles are deposited efficiently because of impaction against surfaces and gravitational forces. Particles trapped in the nose and nasopharynx are cleared in secretions and coughed out or swallowed. Particles less than 10 µm in aerodynamic diameter (PM10 ) may be deposited in the tracheobronchial tree; deposition in the lung’s alveoli is maximal for particles less than 1 to 2 µm in diameter. Particles smaller than 0.5 µm move by diffusion to the alveolar level, where they collide with gas molecules by Brownian movement and are impacted on alveolar surfaces. Recent interest has focused on both environmental and man-made particles in the so-called “ultrafine” range, that is, particles less than 100 nanometers in size; despite their extremely small size, high deposition has been found in the respiratory tract and total deposition increases as the particles get smaller. Removal of particles from the larger airways by the mucociliary apparatus is efficient and occurs within hours of deposition; clearance from the deep lung by alveolar macrophages is much slower, requiring days to months. The mechanisms by which inhaled gases and particles injure the lung are diverse and not yet fully understood. Oxidant gases, O3 and NO2 , cause inflammation of the respiratory epithelium, presumably through the production of toxic oxidant species and release of potent mediators. SO2 is also an irritant gas. The response to particles likely depends on the chemical and physical nature of the particles. Oxidizing compounds on particles may dissolve into tissue fluids and induce an inflammatory response. Organic materials on particles may also produce inflammation or act as initiators or promoters of cancer. The respiratory track, of course, is exposed to multiple pollutants, and interactions among them may synergistically increase effects. Exposure to oxidant gases, for example, enhances responses to inhaled allergens.

Adverse Health Effects of Air Pollution: Clinical and Public Health Concerns The spectrum of adverse effects of air pollution is broad, ranging from the consequences of acute and dramatic exposures, which may cause death, to far more subtle and chronic effects on disease risk and well-being. This spectrum has been conceptualized as a pyramid with mortality at its tip and an increasingly common set of morbidities as the base. Perhaps the most common “adverse” effect is a loss of well-being from the diminished aesthetic value of a polluted environment. Clinicians are more likely to be concerned with the less common, more acute effects with clinical consequences—acute responses, often in asthmatics, for which a link to air pollution exposure may be made by history or challenge testing; the more subtle and long-term consequences are typically a focus for public health researchers and regulators. Nevertheless, clinicians may be asked to assess risks of long-term exposures or to estimate the contribution of exposures to disease causation in a particular patient. They may also be asked to guide their communities in evaluating air pollution as a local public health problem. To interpret the scientific evidence on the effects of air pollution, clinicians need a framework for determining whether an effect is “adverse.” Judgment on the adversity of responses is societal and reflective of prevalent valuations and perceptions of risk. The Clean Air Act uses the term “adverse” without definition. If a broad construct of health is used that includes a state of well-being as a component, adverse effects of air pollution include not only clinically evident disease but also more subtle symptom responses and physiological effects that may compromise well-being or increase the risk of disease. In a report issued in 2000, a committee of the ATS offered guidelines for defining adverse respiratory health effects in epidemiological studies of outdoor air pollution. The committee turned to a medical basis for this determination, defining adverse respiratory health effects as medically significant physiologic or pathologic changes. Indoor air pollution has a broad range of effects as well (Table 60-2). Cases of clinically evident disease caused by indoor air pollution occur, and an unquestionable causal link can often be established for specific persons from a careful history or appropriate diagnostic testing, as with hypersensitivity pneumonitis. Indoor air pollution can also exacerbate chronic respiratory diseases—e.g., house dust mite antigen and asthma in house-dust mite–allergic persons. More subtle effects have become of increasing concern as we have learned that indoor air pollution can adversely affect comfort and increase risk for future disease; consequently, even the perception of exposure to indoor pollutants may adversely affect well-being. Radon and asbestos, for example, are respiratory carcinogens, which are presumed to increase risk of lung cancer.

Concepts of Time-Activity and Total Personal Exposure Definitions of concentration, exposure, and dose are fundamental to considering the health effects of air pollution.

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Table 60-2 A Classification of the Adverse Effects of Indoor Air Pollution Clinically evident diseases: Diseases for which the usual methods of clinical evaluation can establish a causal link to an indoor air pollutant Exacerbation of disease: The clinical status of already established disease is exacerbated by indoor air pollution Increased risk for diseases: Diseases for which epidemiological or other evidence establishes increased risk in exposed persons; however, the usual clinical methods indicative of injury typically cannot establish the causal link in an individual patient Physiological impairment: Transient or persistent effects on a measure of physiological functioning that are of insufficient magnitude to cause clinical disease Symptom responses: Subjectively reported responses that can be linked to indoor pollutants or are attributed to indoor pollutants Perception of unacceptable indoor air quality: Sensing of indoor air quality as uncomfortable to an unacceptable degree Perception of exposure to indoor air pollutants: Awareness of exposure to one or more pollutants with an unacceptable level of concern about exposure source: Data from Samet JM: Indoor air pollution: A public health perspective. Indoor Air 3:219–226, 1993.

Concentration refers to the amount of material present in air. Exposure constitutes contact with a material at a portal of entry into the body—the respiratory tract, gastrointestinal tract, and skin. For the lung, exposure would constitute time spent in contaminated air. Exposure is the unit of concentration multiplied by time. Dose refers to the amount of material that enters the body; biologically effective dose is the amount of material reaching target sites for injury—e.g., the mass of respirable particles delivered to the small airways. For example, the concentration of particles less than 10 mm in aerodynamic diameter (PM10 ) might be 100 mg/m3 ; a person spending 10 h at this concentration would have an exposure of 10 h times 100 mg/m3 , or 1000 mg/m3 – h. Assuming lung deposition to be 50 percent of the total mass and a minute volume of 10 L/min, the dose of PM10 would be 600 mg. For most inhaled pollutants, dose will vary with activity level as ventilation rises and falls with the demands imposed by activities. With regard to impact on health, total personal exposure to a pollutant is the relevant index of exposure, not the exposures received separately within indoor and outdoor environments. The total personal exposure of a person to a pollutant can be conceptualized as the time-weighted average pollutant concentration in the “microenvironments” in which the person spends time (Fig. 60-1). The microenvironments are locations having relatively constant concentration of the pollutant during the time spent there. The principal microenvironments contributing to total personal exposure are those with relatively high concentrations or in which relatively large amounts of time are spent. For example, for exposure to particles, key microenvironments might include an office in which smoking is allowed and an urban environment in which a home is located and time is spent outdoors and indoors.

Studies of time-activity patterns indicate that residents of more developed countries spend most of their time indoors and, consequently, personal exposures to many pollutants take place largely in indoor microenvironments. However, pollutants generated by outdoor sources do penetrate indoors, so indoor microenvironments can contribute to exposures to pollutants typically considered outdoor pollutants, such as particles and CO. Data on time use in a number of countries showed that people spend an average of 65 to 75 percent of their time inside their residences and more than 90 percent of time indoors, counting time at home, work, and elsewhere. Data from a 1987 to 1988 survey of Californians show a similar pattern, with employed adults averaging 15 h per day indoors at home and 6 h per day in other indoor settings. In the California study, school-age children spent an average of 18 h indoors at home. While these data emphasize the predominance of indoor microenvironments in determining exposures to many pollutants, exposure outdoors may be the predominant determinant of dose for some pollutants. For example, the dose of O3 (which generally has low indoor levels) received by the lung’s airways may be dominated by exposure received outdoors, particularly for people exercising outdoors.

Research Approaches to Air Pollution Our understanding of the health effects of air pollution derives from a tripartite research approach: characterization of atmospheric pollutants and exposures, toxicological studies, and epidemiological studies. These approaches are complementary. There has long been research on the physical and chemical properties of air pollutants, and more recently, exposure assessment has emerged as a separate research discipline.

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Figure 60-1 Framework for conceptualizing exposure, dose, and health effects from outdoor and indoor air pollution. (Based on National Research Councfl data.)

The tools of the exposure assessor include questionnaires that capture activities and time use, personal and area monitors, statistical models for estimating exposures, and biomarkers of exposure and dose. Toxicological studies are often conducted to characterize the hazards of air pollutants; research may entail exposures of animals to one or more pollutants to assess patterns of injury and disease risk. Increasingly, toxicological approaches are used to characterize the relationship between exposure and dose and the mechanisms underlying injury. This mechanistic information addresses the appropriateness of extrapolating from animal studies to humans, particularly if parallel data from humans are available on dosimetry and mechanisms. Toxicological studies in which volunteers are exposed to pollutants, often referred to as clinical studies, have proved to be an informative approach for investigating

the acute consequences of pollution exposure. In addition to healthy volunteers, groups in the population considered susceptible to the effects of the pollutant(s) of concern may be selected for investigationâ&#x20AC;&#x201D;e.g., persons with asthma, chronic obstructive pulmonary disease (COPD), or coronary artery disease. Of necessity, exposures in clinical studies are of brief duration and ethically limited to levels that will have limited, transient effects. In addition to monitoring symptoms and physiological measures, clinical studies may be strengthened by more invasive collection of biologic specimens, using phlebotomy, nasal lavage, or fiberoptic bronchoscopy with biopsy of the mucosa or bronchoalveolar lavage, to elucidate mechanisms of injury. Molecular approaches using microarrays to analyze changes in gene expression are now being applied to cells (e.g., macrophages and blood monocytes) removed from humans following controlled exposure to pollutants.

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Table 60-3 Steps in Risk Assessment Hazard identification: The determination of whether an agent is causally linked to the health effect of concern Dose-response assessment: The determination of the relation between level of exposure and risk of the health effect Exposure assessment: Description of the extent of human exposure Risk characterization: Description of the human risk, including uncertainties source: Data from National Research Council (NRC), Committee on the Institutional Means for Assessment of Risks to Public Health. Risk Assessment in the Federal Government: Managing the Process. Washington, D.C., National Academy Press, 1983.

Clinical studies are also incorporating analyses to identify genetic polymorphisms that determine susceptibility to air pollutants. Epidemiological studies provide an assessment of the adverse effects of pollution exposures under the circumstances of “real world” exposure. The principle epidemiological study designs used for air pollution research include crosssectional studies or surveys, short-term cohort studies with intensive measurements of exposures and outcomes, “panel studies,” which are longer-term cohort studies directed at mortality and chronic disease risk, and time-series studies that assess short-term changes in outcomes, e.g., mortality counts, in relation to air pollution. The findings of epidemiological studies of air pollution have direct public health and regulatory relevance. The exposures are inherently representative of those received in the community, and the pollutants are inhaled in the form of the complex mixtures that actually exist in indoor and outdoor air. Additionally, the community members in a study can be selected from the full spectrum of potentially susceptible subjects. There are, however, weaknesses to the epidemiological approach. Exposures to pollutants may be difficult to measure accurately, particularly past exposures that may have determined current health; hence, exposure estimates in epidemiological studies are subject to substantial error. The effects of other exposures relevant to the health outcome of interest, termed confounding factors, may not be sufficiently controlled, and these extraneous exposures may artifactually increase or decrease the apparent effect of air pollution exposure. Epidemiological studies having inadequate sample size and, therefore, limited statistical power may supply imprecise and uninformative estimates of risk and not precisely answer public health questions. The technique of quantitative risk assessment has been increasingly applied to estimate the burden of disease associated with air pollution, particularly carcinogens. The 1990 Clean Air Act amendments include specific provisions on the use of risk assessment, particularly in regard to the hazardous air pollutants regulated under Section 112 of the Act. This process integrates the information on exposure and dose response to provide a characterization of the impact of an envi-

ronmental agent on the population’s health; as the evidence is systematically reviewed in the conduct of a risk assessment, gaps in the evidence and attendant uncertainties are identified, and assumptions are made to fill the gaps. The approach was also used by the World Health Organization in its Global Burden of Disease estimates, which covered indoor and outdoor air pollution. Risk assessment can be conceptualized as comprising the four steps outlined in the seminal 1983 report of the National Research Council (Table 60-3). A full risk assessment can be a large undertaking, requiring review of all relevant data and mathematical modeling to characterize the risk. In a risk assessment, gaps in the scientific evidence, which are sources of uncertainty, are catalogued and used to estimate the level of confidence attached to the risk characterization. The findings of risk assessment guide risk management, the process by which decisions are made about the need for risk reduction and the approaches to be implemented to reduce risks. Risk management means choosing among the options to control risk and balancing risk reduction, costs, and technological capability for reducing exposure. Uncertainties in the scientific information that have been catalogued in the risk assessment process may cloud risk management and introduce ambiguity regarding the optimum strategy. Nevertheless, risk managers need to make decisions in the face of uncertainty. Understanding the effects of complex mixtures of pollutants in indoor and outdoor air has proved particularly daunting for researchers. Exposures to pollutants rarely occur singly, without simultaneous exposures to other pollutants in the relevant microenvironments. Many outdoor sources inherently produce complex pollutant mixtures; for example, power plants release particles, nitrogen oxides, and sulfur oxides, and vehicle exhaust contains CO, nitrogen oxides, particles, and hydrocarbons. Indoor air is inevitably contaminated by complex mixtures, reflecting the multiplicity of sources in indoor environments. Synergistic or antagonistic interactions between components of complex pollutant mixtures can produce unanticipated effects, based on the toxicity of individual components. While this problem is well recognized, epidemiological and toxicological research approaches have provided

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little understanding of the interactions that may determine the toxicity of complex mixtures.

OUTDOOR AIR POLLUTION Outdoor air pollutants have diverse sources, both man-made and natural. This section begins with a review of the sources and then considers the effects of the principal man-made outdoor pollutants. The pollutants are grouped according to their designation by the EPA.

Overview: Sources and Classification of Outdoor Air Pollution Many pollutants, from both man-made and natural sources, can be found in outdoor air. Some naturally occurring pollutants in outdoor air are well documented as causing or exacerbating pulmonary diseases—e.g., pollens and fungi. This chapter does not address these biologic agents but considers the man-made pollutants. Researchers have focused more attention on the effects of man-made pollutants, which may reach potentially hazardous levels in urban areas or near point sources, such as power plants, smelters, or manufacturing facilities. In the United States, the principal outdoor pollutants are generally classified within the framework provided by the Clean Air Act, which identifies two sets of air pollutants, “criteria” pollutants (Table 60-1) and “toxic” air pollutants. The term criteria refers to the standard-setting process for these pollutants, which requires preparation of a criteria document reviewing all relevant evidence every 5 years. The criteria pollutants include primarily combustion-related pollutants (SO2 , NO2 , CO, and particles), the secondary pollutant O3 , and lead. The toxic pollutants are predominantly carcinogens; the sources are diverse but principally comprise industrial emissions and waste products. Examples of these pollutants are benzene, chlordane, ethylene oxide, hydrochloric acid, methane, parathion, propylene oxide, toluene, and vinyl chloride. These two groups of pollutants are regulated through different mechanisms. For the criteria pollutants, National Ambient Air Quality Standards (NAAQS) are set after extensive review of all relevant evidence; the standards must afford protection to the entire population, including those with heightened susceptibility, and offer an “adequate margin of safety.” The hazardous pollutants are predominantly carcinogens, such as asbestos and radionuclides, and standards for maximum concentrations are also intended to provide a margin of safety. The Clean Air Act includes mechanisms for achieving levels within the standards and enforcement. In spite of existing federal standards for ambient air quality, excesses are common in many areas of the country, particularly for O3 . Although the pollutants are considered in the following section on an individual basis, it should be re-emphasized that exposures of the population occur most often to mixtures, and synergism among individual pollutants may increase the effects of the mixture beyond the expected effect based on the components.

Outdoor Air Pollutants: Exposures and Health Effects The pollutants covered in this section are of public health significance throughout the world. Sulfur oxides, particles, nitrogen oxides, and CO are generated by combustion and are typically found together in the complex air pollutant mixtures in outdoor environments. O3 is a secondary pollutant. While the pollutants are considered individually, exposures to them typically occur in the form of inhaled mixtures. Sulfur Dioxide Sulfur oxides are produced by combustion of fuels containing sulfur, such as coal from the eastern United States and crude petroleum. Smelting of ores containing sulfur is also a prominent source in some regions, such as the southwestern United States. In the past, scientific research and regulatory concern in relation to the sulfur oxides were directed primarily at the health effects of SO2 , the criteria pollutant regulated by the EPA. SO2 is a water-soluble gas that is effectively scrubbed from inspired air by the upper airway; exercise, however, may increase the inhaled dose by its effect on minute ventilation and the switch to the oral breathing route. This pollutant has been shown to have adverse effects without concomitant exposures to other pollutants. In fact, exposures of volunteers to SO2 alone show that the gas may have adverse respiratory effects; asthmatics are particularly sensitive, with some showing particular sensitivity. Significant exposures to SO2 alone might result from plumes released by smelters processing sulfur-containing ores or from other industrial processes. Exposures to SO2 in outdoor air occur primarily with simultaneous exposures to other combustion-related pollutants, including nitrogen oxides and particles. Heavy industry and coal-burning power plants are predominant sources for this type of pollutant mixture. Tall smokestacks for power plants, used to control local pollutant concentrations, release sulfur oxides and nitrogen oxides high into the atmosphere, where residence time is prolonged. Through a series of chemical reactions, the sulfur oxides and nitrogen oxides form acidic sulfate and nitrate particles, which may undergo longrange transport. These acidic particles represent a regional air pollution problem—blanketing, for example, the central and northeastern United States and portions of Canada. Fortunately, concentrations of SO2 have fallen in the United States, in part due to controls implemented under the Environmental Protection Agency’s Acid Rain Program, and from changing patterns of fuel use and energy generation. From 1983 through 2002, the average annual concentration fell about 50 percent. The effects of particulate air pollution and acidic aerosols are considered separately below; this section considers the effects of gaseous SO2 . Asthmatics are particularly susceptible to SO2 , responding to exposure in chambers with increased airway resistance and reduced levels of lung function. With exercise and hyperventilation, which increase the dose delivered to the respiratory tract, some asthmatics are adversely affected at levels common in ambient air and well below those that might occur transiently with direct exposure to the plume from a

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power plant or factory. Inhalation of SO2 produces an immediate response and does not provoke delayed reactions or repetitive nocturnal attacks. The decrements in lung function on breathing of SO2 may be sufficient to produce symptoms of dyspnea, wheezing, and chest tightness. The bronchoconstriction resolves within an hour of exposure, and peak bronchoconstrictor responses may lessen on repeated challenge after a short recovery period. Responses to SO2 can be partly blocked by pretreatment with cromolyn sodium and anticholinergics and can be reversed by β-adrenergic agonists. Sequential exposures to SO2 and oxidant gases (O3 and NO2 ) have been performed in asthmatics; these clinical studies have provided little evidence of synergistic interactions in reducing airway function. Although some asthmatics have been shown to be affected by SO2 with exposure at low concentrations in the laboratory, complementary epidemiological data have not been reported that document parallel community morbidity. Recent epidemiological studies from Hong Kong have examined the consequences of a major reduction in sulfur content in fuels over a very short period of time. The investigators found an associated substantial reduction in health effects (childhood respiratory disease and all age mortality outcomes). Daily SO2 was significantly associated with daily mortality in 12 Canadian cities with an average concentration of only 5 µg/m3 . Nevertheless, there is still considerable uncertainty as to whether SO2 is the pollutant responsible for the observed adverse effects or, rather, a surrogate indicator for ultrafine particles (UFP) or some other correlated substance. For example, in Germany and the Netherlands a strong reduction of SO2 concentrations occurred over a decade. Although mortality decreased with time, the association of SO2 and mortality was judged as noncausal and attributed to a similar time trend of particulate matter. Nitrogen Dioxide Nitrogen oxides, like sulfur oxides, are produced by combustion processes and contribute to the formation of aerosols. Even though NO2 is regulated by the EPA as a criteria pollutant, substantial personal exposure in the United States occurs in indoor microenvironments contaminated by unvented gas stoves and space heaters. The principal source of NO2 in outdoor air is motor vehicle emissions, but power plants and industrial sources may also contribute. There have been few locations where point sources were strong enough to make NO2 alone a source of concern. The health effects of NO2 released into outdoor air probably arise principally from the formation of secondary pollutants. NO2 is an essential precursor of O3 , and one of the principal pathways by which NO2 in outdoor air adversely affects respiratory health may be through the formation of O3 . The nitrogen oxides also secondarily form acidic nitrate particles. NO2 is an oxidant gas of low solubility that penetrates to the small airways and alveoli of the lung. The toxicological evidence at exposures far greater than typically sustained in indoor and outdoor environments suggests that NO2 exposure can impair lung defenses against respiratory pathogens

Indoor and Outdoor Air Pollution

and cause airway inflammation, with associated effects on lung function and respiratory symptoms. In animal models, exposure to NO2 increases mortality after challenge with bacterial respiratory pathogens. Therefore, a wide range of health effects are of concern, including increased risk for respiratory infections, respiratory symptoms, reduced lung function, and exacerbation of chronic respiratory diseases. However, there have been only limited epidemiological data, largely derived from studies of children exposed to indoor sources of NO2 ; these studies and other evidence on indoor exposures are considered separately in the section on indoor air pollution. Several more recent studies link NO2 to indicators of morbidity, but the findings are inconsistent and are unlikely to reflect NO2 acting by itself. A number of clinical studies have been performed to investigate the acute effects of NO2 by itself on the status of persons with asthma. These studies were performed to assess the need for a short-term standard for outdoor NO2 concentration, as the present NAAQS provide only an annual standard for NO2 . NO2 could plausibly affect airway responsiveness by causing airway inflammation. The findings of the clinical studies have been inconsistent, and the discrepancies between the “positive” and “negative” studies have not been readily explained. One study showed consistent responses to NO2 of some asthmatics, suggesting that there might be a susceptible group among persons having asthma in general, but this susceptibility has not been found in other studies. The epidemiological evidence remains inconclusive, largely because of methodological problems arising in attempting to separate the effects of NO2 from those of other pollutants. Persons with COPD may represent a group with increased susceptibility to short-term exposure to NO2 outdoors. Particles Particles in outdoor air have numerous natural and manmade sources, including the same combustion processes that produce SO2 and NO2 . Particles are suspended in air by the action of wind on crustal material and road dust. The manmade sources are diverse and include power plants, industry, and motor vehicles, including diesel-powered vehicles that emit particles in the inhalable size range. Particles, of course, are present in indoor and outdoor air; consequently, personal exposures to particles reflect both indoor and outdoor microenvironments. Additionally, outdoor particles, particularly those of smaller size, penetrate indoors. The man-made particles are primary, i.e., emitted directly by combustion or other processes, or secondary, i.e., formed through chemical and physical transformation of gaseous pollutants, such as NO2 and SO2 . Because of the diversity of sources, particles comprise a rich mixture that may be quite variable, spatially and temporally. The toxicity of particles in a particular place thus reflects the source mix, which includes both local sources and those contributing to the regional background pollution. In the eastern United States, for example, much of the regional background of PM2.5 comes from transport of power plant emissions from the central portion of the country. Hypotheses proposed on determinants of

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particle toxicity have focused on issues related to particle acidity, particle content of transition metals, organic compounds on particles (e.g., diesel particles), bioaerosol, and UFP, i.e., particles smaller than 100 nm in aerodynamic diameter. Metals associated with particulate matter are capable of causing pulmonary inflammation and injury and the same chemical properties that allow metals to function as catalysts in reactions with molecular oxygen can generate oxygen-based free radicals and cause oxidative stress. UFP have a high specific surface area and carry an increased burden of reactive oxygen species and may be particularly important with regard to cardiovascular effects because of their potential for evading clearance mechanisms, and for entering the lung interstitium and vascular space. Historically, particle concentrations in outdoor air have been measured with several different techniques and over recent decades these technologies have been refined and directed at biologically relevant size fractions. Until 1987, the EPA specified the measurement of total suspended particulates (TSP), which included particles well above the inhalable size range. In 1987, the reference method for the NAAQS was changed to particulate matter less than 10 µm in aerodynamic diameter (PM10 ), and in 1997 24-hour and annual standards were added for PM2.5 . The PM10 standard, challenged in court, was set aside in a Supreme Court decision, and in 2005, the EPA proposed a standard for coarse mixes in urban areas, PM10–2.5 . This set of standards makes no provision with regard to the chemical composition of the particles. Equivalent mass concentrations of particles are hypothesized to have differing toxicity, depending on acidity, content of metals, or carcinogenic potency. The characteristics of particles that determine their toxicity is a focus of current research. The size distribution below the 10 and 2.5 µm cutoffs may also affect toxicity through its consequence for sites of deposition. In addition, the ultrafine component contributes little to the mass and the number count or surface area may turn out to be an important metric. Nationally PM10 concentrations have decreased 31 percent since 1988, mainly in regions of the country that had higher concentrations such as the Northwest (39 percent), the Southwest (33 percent), and southern California (35 percent). Since 1999, PM2.5 concentrations have decreased 10 percent nationally. PM2.5 has decreased the most in regions with the highest concentrations to start with, such as the Southeast (20 percent), southern California (16 percent), and the industrial Midwest (9 percent). Except for the Northeast, most regions of the country have had at least modest declines from 1999 to 2003. There has been extensive epidemiological and toxicological investigation of the effects of particles on health since the air pollution disasters at mid-century. The toxicological studies have used a range of approaches, from exposing volunteers to generated particles or concentrated air particles, to animal exposures, and to diverse in vitro assays. This extensive body of evidence shows that particles are injurious and indicates mechanisms by which particles could cause adverse effects on the respiratory and cardiovascular systems.

The epidemiological studies have addressed the relationship between exposures to particles and short- and longterm variations in mortality, both from all causes and from cardiovascular and respiratory causes. The studies have also addressed the relationship between exposures to particles and diverse indicators of respiratory morbidity, including the frequency of respiratory symptoms and illnesses, level of lung function and rates of lung function growth and decline, and outpatient visits and inpatient admissions. In the studies of particulate air pollution during the 1950s and 1960s, the measures of exposure were general; some studies included only surrogate measures of exposure, such as location of the place of residence. In spite of such crude exposure measures, these studies found adverse effects of exposure to particulate air pollution and became the basis for establishing air quality standards for particles. The standards were generally considered to be sufficiently protective of public health. Studies linked particulate air pollution to a number of adverse health effects. As levels of air pollution were reduced in the United States and other Western countries, excess mortality at times of higher concentrations was not readily evident and, since the 1970s, the focus of research and of public health concern has generally shifted to morbidity. However, studies of air pollution and daily variations in mortality, facilitated by new techniques for longitudinal data analysis, have shown statistically significant, positive associations between measures of particle concentration and daily mortality counts for cities in the United States and elsewhere. Several analyses have combined data for multiple cities in the United States and in Europe. These analyses pool the information from many locations to estimate precisely the effect of particulate matter and also to examine the variations in risk among the contributing locations. These analyses show a statistically significant effect of airborne particles on mortality, independent of the possible contributions of other pollutants or weather. In interpreting these findings, the extent to which life is lost from these shortterm effects is critical. Several prospective studies indicate that life-shortening from air pollution may be substantial. Many complementary studies of morbidity have also been reported. These studies have been directed at clinical indicators, such as hospitalization or the triggering of arrhythmias, myocardial infarction, or sudden death. They have also examined biomarkers and electrocadiographic parameters. A review in 2004 by the American Heart Association compiled a substantial body of evidence linking particulate air pollution to adverse cardiovascular effects. Additionally, in some studies, airborne particles have been shown to adversely affect persons with asthma and COPD. These findings suggest that the present NAAQS for particulate matter may not protect against adverse health effects with the “adequate margin of safety” mandated by the Clean Air Act. They also call into question other national and international standards and have led to tightening of the standards. It remains premature to offer specific clinical recommendations with regard to particulate air pollution until mechanisms of toxicity are better understood and the role of outdoor exposures

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in contributing to morbidity and mortality is further characterized.

and normal persons may have reduced oxygen uptake during exercise at low levels of CO exposure.

Carbon Monoxide Carbon monoxide (CO) is an invisible gas formed by incomplete combustion of fossil fuels and other organic materials. The most prominent outdoor source is vehicle exhaust; consequently, outdoor concentrations are highly variable in place and time, changing with vehicle density and traffic patterns. Urban locations with high traffic density tend to have the highest concentrations. CO also has indoor sources, such as cooking stoves and tobacco smoke. Exposures to CO can be conveniently assessed by using the level of carboxyhemoglobin as a biomarker of exposure or by measuring the concentration of CO in an end-tidal breath sample, following a breath hold. In regard to outdoor air, acute effects of CO on susceptible persons have been of particular concern, and the current U.S. standard is intended to protect susceptible persons with coronary artery disease. Inhaled CO binds to hemoglobin with high affinity (more than 200 times greater than for oxygen) to form carboxyhemoglobin (COHb) (see Chapter 12). The COHb complex is very stable; depending on ambient levels of CO, level of activity, and lung function, the half-life of CO in the body ranges from about 2.5 to 4 h. The rate of accumulation of ambient CO in the body above endogenous levels is affected by ambient CO concentrations, alveolar ventilation, lung diffusivity, total hemoglobin mass, and COHb level. People with impaired gas exchange (e.g., persons with COPD) have compromised ability to excrete CO. The binding of CO to hemoglobin reduces oxygen transport by red blood cells to tissues. The binding also displaces oxygen and causes an allosteric change in the hemoglobin molecule, which increases the affinity of heme groups for oxygen. Persons with cardiovascular disease are considered to be at greatest risk from CO exposure. Standard exercise tests on subjects with ischemic heart disease have demonstrated a decreased time interval to the onset of angina at COHb levels ranging from 2 to 6 percent. The 1-h 35-ppm and 8-h 9-ppm federal standards for outdoor air (Table 60-1) were selected to prevent COHb levels from rising above 1.5 percent, thereby protecting persons with ischemic heart disease from aggravation of myocardial ischemia with onset of angina and attendant loss of exercise capacity. Recent evidence indicates that controlled CO exposure during exercise of patients with stable coronary artery disease can induce subjective and objective evidence of myocardial ischemia earlier in the exposure than during exercise without CO. This effect can be induced at COHb levels as low as 2 to 4 percent. These studies are relevant to the urban environment, where people may be exposed to sufficient CO to reach blood COHb levels in this range. Furthermore, moderate exercise results in even greater CO uptake. In addition, at a COHb level of 6 percent, patients with coronary artery disease have an increased frequency of arrhythmias. Fetuses, as well as persons with COPD, may also be harmed by CO,

Ozone Photochemical pollution, or “smog,” is a complex oxidant mixture produced by the action of sunlight on hydrocarbons and nitrogen oxides in vehicle exhaust. Ozone (O3 ) is invariably present in photochemical pollution, and its concentration serves as an index of the level of this mixture. The problem of tropospheric O3 pollution, i.e., ground-level, is distinct from the problem of depletion of the stratospheric ozone layer. Photochemical pollution was first recognized over 50 years ago in southern California, where the combination of sunlight and heavy vehicle travel promotes its formation. O3 has now become a problem in many other locations, including Western cities with similar sprawling growth and heavy vehicle traffic and the Eastern United States during the summer. O3 is also produced naturally, but the exposure of concern for health almost exclusively reflects the O3 created by human activities. Since 1990, NOx emissions have decreased approximately 25 percent and VOC emissions have dropped by about 35 percent. National ozone levels in 2004 were 11 percent lower than in 1990 and 21 percent lower than in 1980 for the 8-hour standard (3-year average of the annual fourth highest daily maximum 8-hour average concentration is less than 0.08 ppm). Between 1990 and 2004 the most significant improvements in air quality were in the Northeast (17 percent decrease) and Southwest (16 percent decrease) regions of the country. The toxicology of O3 has been extensively investigated. Low-level exposures cause damage to the small airways of experimental animals; the demonstration of subtle fibrosis in one animal model has raised concern about permanent structural alteration in exposed populations. Volunteers exposed to O3 at concentrations in the range of the present standard—which are often present during pollution episodes—experience transient reductions in lung function; normal subjects have a range of responsiveness that is broad but repeatable for individuals. Evidence of an inflammatory response and biochemical changes in BAL fluid has been detected 18 h after an experimental exposure to O3 at levels that are commonly found. Taken together, the progressive decrements in pulmonary mechanics during exposure, coupled with the persistent biochemical changes many hours after cessation of exposure, indicate the potential for chronic effects from repeated inhalation. Surprisingly, in clinical studies, asthmatics have not been shown to have increased susceptibility to O3 compared with nonasthmatics. The evidence for short-term effects of O3 exposure on the lung function of normal volunteers has raised concern about possible long-term effects of living in southern California and other locations with sustained photochemical pollution. Relevant epidemiological data suggest that O3 may have chronic effects, but these data are not definitive, and a long-term study of southern California children found that ozone was not associated with

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reduced lung growth. The same study found evidence that ozone might contribute to the onset of asthma. Some timeseries studies have linked short-term exposure to ozone to increased risk of mortality. Lead Exposure to lead may occur through many environmental media, including ambient air. At present, ingestion is the principal pathway of concern in the United States. Fortunately, in the United States the importance of ambient air as a source of exposure of the population to lead has diminished with the removal of lead from gasoline. Children are particularly vulnerable to lead exposure. Even levels previously considered safe have been associated with adverse neurological effects, and there has been a progressive tightening of recommendations of blood lead levels by the Centers for Disease Control and Prevention. Toxic Air Pollutants The toxic air pollutants are predominantly carcinogens, but they demonstrate a variety of other toxicities. Approximately 200 â&#x20AC;&#x153;hazardous pollutantsâ&#x20AC;? are listed as air toxics in the 1990 Clean Air Act amendments. Examples of the hazardous pollutants are asbestos, benzene, cadmium compounds, chlorine, formaldehyde, and nickel. Although the sources are diverse, emission releases tend to be localized, often at industrial sites, or from municipal incinerators or waste sites. Only a small proportion of lung cancers can be attributed to air pollution, even though carcinogens are found widely in outdoor air. For example, polycyclic aromatic hydrocarbons (PAHs), in diesel exhaust, are widely dispersed and present in urban air throughout the world. The PAHs possess mutagenic and carcinogenic activity. But, to date, only limited epidemiological data on risks in humans are available. Analyses of occupational cohorts exposed to diesel exhaust for years are suggestive of a small excess risk of lung cancer. Given the difficulties of measuring exposure, confounding by cigarette smoke and by other occupations, and the small excess numbers of lung cancers, it is difficult to reach any definitive conclusion on the role of diesel exhaust in causing lung cancer in the general population. Nevertheless, as the percentage of light-duty vehicles powered by diesel fuel in the United States increases, there will be an increasing imperative to determine the carcinogenicity of the PAHs and diesel exhaust. There is also current concern that new types of fuels may introduce additional carcinogens into outdoor air. Some recent experimental and epidemiological evidence indicates that diesel particles may increase risk for allergic sensitization and asthma.

INDOOR AIR POLLUTANTS AND HEALTH EFFECTS Indoor environments are contaminated by numerous air pollutants, including outdoor air pollutants that have penetrated

indoors and indoor air pollutants generated by the numerous indoor sources. This section reviews exposures and health effects of the principal indoor pollutants. The organic compounds and biologic agents include myriad individual agents that may adversely affect health. As for outdoor air pollution, clinicians should consider that exposures to indoor air pollutants typically occur as exposures to mixtures, rather than as single agents.

Overview: Sources and Classification of Indoor Air Pollution Indoor air pollution has myriad sources, including the materials from which the space is constructed, its furnishings, processes operating within the environment, biologic agents, and even the occupants. Outdoor air pollutants can also penetrate indoors, as can soil gas. The broad source headings are combustion, evaporation, abrasion, biologic, and radon (Table 60-4). The principal combustion sources are gas cooking stoves, burning cigarettes, fireplaces and wood stoves, and unvented space heaters. Evaporation of volatile organic compounds from materials and products leads to ubiquitous contamination by these agents. Abrasion of friable asbestos is a principal source of this indoor contaminant. The biologic agents are heterogeneous, extending from infectious organisms to pets and the occupants themselves. Radon comes primarily from soil gas. The concentration of an indoor contaminant depends on the strength of its source, the rate of removal, the volume of the space, and the rate of exchange of air between the space and outdoors. This mass-balance formulation indicates that the concentration of a contaminant might be reduced by limiting source strength, increasing removal rate, or increasing exchange between indoor and outdoor air. In the typical modern building, the exchange of indoor with outdoor air is accomplished by a central heating, ventilating, and air-conditioning (HVAC) system. These systems are diverse, although all have the same purpose: the delivery of air of acceptable quality to building occupants. The volume of air to be delivered follows the recommendation of standards set by the American Society of Heating, Refrigerating, and Air-Conditioning Engineers. In most new buildings, occupants can no longer control the temperature of the work environment and cannot open windows to increase air exchange. Most residences, however, still rely on natural ventilation.

Carbon Monoxide Carbon monoxide, a byproduct of combustion of fuels, is released indoors by cooking and heating devices and also by smoking. Surveys conducted several decades ago of urban population exposures in Denver, Colorado, and Washington, D.C., indicate that residential concentrations of CO are typically low, ranging from 2 to 4 ppm during the winter, when windows of homes are generally closed and the homes heated. People living in homes with gas cooking ranges and those living with smokers have slightly higher levels of personal exposure. Measurements in the surveys of CO in

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Table 60-4 Sources of Common Air Contaminants Contaminant

Source

Asbestos Chrysotile

Some wall and ceiling insulation installed between 1930 and 1950

Crocidolite

Old insulation on heating pipes and equipment

Amosite

Old wood stove door gaskets

Tremolite

Some vinyl floor tiles Drywall joint-finishing material and textured paint purchased before 1977 Cement-asbestos millboard and exterior wall shingles Some sprayed and troweled ceiling finishing plaster installed between 1945 and 1973 Sprayed onto some structural steel beams as fire retardant

Combustion byproducts Carbon monoxide

Gas ranges

Nitrogen dioxide

Wood and coal stoves

Sulfur dioxide

Gas and propane engines

Particulate soot

Fireplaces

Nitrogenated compounds

Backdrafting of exhaust flues Candles and incense

Tobacco smoke Carbon monoxide

Cigarettes

Nitrogen dioxide

Pipes

Carbon dioxide

Cigars

Hydrogen cyanide Nitrosamines Aromatic hydrocarbons Benzo[a]pyrene Particles Benzene (Continued )

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Table 60-4 (Continued ) Contaminant

Source

Formaldehyde Nicotine Formaldehyde

Some particle board, plywood, pressed board, paneling Some carpeting and carpet backing Some furniture and dyed materials Urea-formaldehyde insulating foam Some household cleaners and deodorizers Combustion (gas, tobacco, wood) Some glues and resins Tobacco smoke Cosmetics Permanent-press textiles

Biologic organisms Fungal spores

Mold, mildew, and other fungi

Bacteria

Humidifiers with stagnant water

Virus

Water-damaged surfaces and materials

Pollens

Condensing coils and drip pans in HVAC systems

Arthropods

Drainage pans in refrigerators

Protozoa

Some thermophilics on dirty heating coils Animals Rodents Insects Humans

Radon Radon gas and radon progeny

Radon gas emanating from soil, rocks, and water that diffuses through cracks and holes in the foundation and floor Radon in well water

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Indoor and Outdoor Air Pollution

Table 60-4 (Continued ) Contaminant

Source Radon in natural gas used near the source wells Some building materials such as granite

Volatile organic compounds Alkanes

Solvents and cleaning compounds

Aromatic hydrocarbons

Paints

Esters

Glues and resins

Alcohols

Spray propellants

Aldehydes

Fabric softeners and deodorizers

Ketones

Combustion Dry-cleaning fluids Some fabrics and furnishings Stored gasoline Outgasing from water Some building materials Waxes and polishing compounds Pens and markers Binders and plasticizers

source: Data from Turner WA, Bearg DW, Brennan T: Ventilation, in: Seltzer JM (ed), Effects of the Indoor Environment on Health. Philadelphia, PA, Hanley & Belfus, 1995, pp 41â&#x20AC;&#x201C;58.

commercial and institutional buildings showed concentrations in the same range as in residences. The CO in residences and public buildings without combustion sources primarily reflects entry of motor vehicle exhaust from outdoor air into buildings through natural and mechanical ventilation. Intake vents at street level bring co-contaminated air into buildings. Elevated levels have been measured in commercial buildings with drive-in window operations (e.g., banks), buildings with underground parking garages, and enclosed ice rinks with ice-resurfacing machines without emission controls. Acute and chronic health effects may be caused by CO exposure. About 500 accidental deaths in the United States are attributed annually to asphyxiation by CO inhalation and approximately 15,000 people are treated each year in emergency departments for CO exposure. The majority of the

non-fatal cases occur in residences, with about 20 percent associated with faulty furnaces. A small proportion of cases occur in public buildings having faulty, unvented, or improperly ventilated combustion sources, such as charcoal stoves. The most common symptoms are nonspecific and include headache, nausea, and dizziness. The level of CO in the blood is a useful biomarker of dose, and the health effects of exposure to CO can be related to COHb levels. In nonsmokers who are not exposed to CO in the environment, COHb levels are approximately 0.5 percent. This endogenous COHb comes from catabolism of hemoglobin and heme-containing enzymes of the liver. In comparison, COHb levels of cigarette smokers average about 4 percent and may be much higher. Frank CO poisoning, as manifest in headache, loss of motor control, and

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coma, generally occurs with COHb levels above 20 percent. Clinicians have proposed the concept of â&#x20AC;&#x153;occultâ&#x20AC;? CO poisoning, arising from persistent exposure to low levels of CO in indoor environments. Headache and dizziness, early symptoms of CO poisoning, have been associated with COHb levels greater than 10 percent. Increased levels of COHb resulting from indoor exposures may, at times, extend to values at which clinical testing has demonstrated cardiovascular and neurobehavioral effects. The Centers for Disease Control and Prevention recommend use of battery-powered CO detectors in homes to avoid CO exposure.

Nitrogen Dioxide In the United States, with the exception of a few urban areas where outdoor NO2 levels are high, indoor environments are the predominant determinant of total individual exposure. Residential exposures from unvented gas cooking stoves and kerosene space heaters are the major sources contributing to total individual exposure. Although vented to the outside by building codes, gas furnaces and water heaters may pollute residences because of flue-gas spillage and backdrafting caused by improper installation, maintenance, and weather conditions. Levels in residences and the determinants of these levels have been characterized in many regions of the United States. Indoor NO2 levels are generally increased during the winter, when homes are closed; they may also be high in the summer, when homes are closed for air conditioning. During cooking, concentrations may reach 1000 ppb while the stove is in use, resulting in substantial, but brief, exposures for persons near the stove. High indoor NO2 concentrations have been documented in small inner-city apartments and when an oven is used for heating. Data on NO2 levels in commercial and institutional buildings are very limited, but they generally show low levels consistent with the lack of indoor sources. High concentrations of NO2 have been measured in ice-skating rinks, contaminated by emissions from resurfacing machines without emissions controls. Oxidant injury has been postulated to be the principal mechanism by which NO2 damages the lung. Inhaled NO2 is thought to combine with water in the lung to form nitric acid (HNO3 ) and nitrous acid (HNO2 ). At high concentrations, NO2 causes extensive lung injury in animals and humans. Fatal pulmonary edema and bronchopneumonia have been reported at extremely high concentrations; lower concentrations are associated with bronchitis, bronchiolitis, and pneumonia. Experimental evidence indicates that NO2 exposure adversely affects lung defense mechanisms. In experimental models, NO2 effects mucociliary clearance, the alveolar macrophage, and the immune system. In animal experiments employing challenge with respiratory pathogens, exposure to NO2 reduces clearance of infecting organisms and increases the mortality of the experimental animals. Adverse effects in these animal experiments have been demonstrated at concentrations that are an order of magnitude greater than those typically found in indoor environments.

The health effects of indoor NO2 have been investigated primarily in studies directed at the consequences of indoor exposures for children. The toxicology of NO2 implies that a wide variety of health effects are of potential concern, including reduced efficacy of host defenses against infectious organisms and the consequent increased risk of infection, exacerbation of asthma and chronic obstructive pulmonary disease, and respiratory tract inflammation with respiratory symptoms and a reduction in lung function. In spite of extensive investigation using laboratory and epidemiological approaches, the evidence still remains inconclusive with respect to each of these health outcomes. The hypothesis that NO2 increases the risk for respiratory infection has received the most intensive investigation. A number of epidemiological studies have compared the occurrence of respiratory infections in children in homes having gas stoves and higher concentrations of NO2 with the occurance in children in homes with electric stoves and lower concentrations of NO2 . In a cohort study of infants at risk for asthma, NO2 exposure during the first year of life was associated with respiratory symptoms including wheeze, cough, and shortness of breath. The findings of these studies have been inconsistent, largely because of the methodological complexities of investigating this association. Experimental exposures also have failed to provide consistent evidence that NO2 increases infectivity in humans. Inflammation of the airways by NO2 could plausibly be associated with increased respiratory symptoms and reduced lung function. These potential adverse effects of NO2 have been examined using data from epidemiological studies of children and adults. Many of these studies have included large numbers of participants studied cross-sectionally. The health outcome measures (e.g., reports of symptoms and levels of spirometric lung function) have been compared for participants living in homes with NO2 sources, such as gas stoves and space heaters, and participants living in homes without such sources. Despite the number of such studies, there is no clear pattern of results. A meta-analysis using data from 11 studies found that a long-term increase in NO2 exposure of approximately 15 ppb, consistent with the presence of a gas stove in the home, is associated with a 20 percent increase in the risk of respiratory illness in children. Inflammation of airways would be expected to worsen the health status of persons with asthma. Short-term effects of NO2 exposures on asthmatics have been studied by exposing volunteers and following the level of pulmonary function and nonspecific airway responsiveness. The evidence has been conflicting, and the findings are of limited generality because of the inclusion of relatively mild asthmatics in most studies. The NO2 exposures typically found in indoor and outdoor environments are not likely to cause clinically relevant effects for most persons with asthma. However, recent studies indicate that exposure to NO2 , in combination with allergens, may adversely affect persons with asthma. Studies have shown that exposure to NO2 increases the response to challenge with specific allergen at levels as low as 0.40 ppm. A study of asthmatic children in the United Kingdom showed that exposure

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to NO2 increased the severity of virus-caused exacerbations. An experimental study in Australia of reduction of NO2 exposures in schools showed that symptom rates in asthmatic children dropped following reduction of NO2 concentration in the classroom. Thus, for persons with asthma, indoor NO2 from unvented combustion sources could increase the adverse effects of exposure to common indoor allergens, such as those associated with house dust mites, cats, and cockroaches, and to viral pathogens. Little information is available on the effects of NO2 exposure on persons with COPD.

Indoor and Outdoor Air Pollution

Table 60-5 Established Health Effects of Involuntary Exposure to Tobacco Smoke Decrement in pulmonary function growth in childhood Increased frequency of acute lower respiratory illness in early childhood Increase in respiratory illness in children

Secondhand Smoke Although the prevalence of smoking in the United States has decreased among adults to 20.9 percent, smoking remains common in public places and homes. Secondhand smoke (SHS) is a term now widely used to refer to the combination of side-stream smoke that is released from the cigaretteâ&#x20AC;&#x2122;s burning end and the mainstream smoke exhaled by the smoker. Survey and biomarkers data on SHS exposure for nonsmokers and children have documented widespread exposures, but the most recent evidence shows substantial declines in exposure to secondhand smoke. Blood levels of cotinine, the nicotine biomarker, dropped sharply from 1988 to 1989 to 2000 among nonsmoking participants in the National Health and Nutrition Survey (NHANES). In the first survey, most participants had a detectable cotinine value, but a majority did not in the more recent report. If smokers are present, exposure received indoors at home may dominate total personal exposures of involuntary smokers for particles and some gaseous pollutants, such as benzene. Hundreds of chemical compounds have been identified in cigarette smoke; the indicators most often used to quantify its presence in the environment are respirable suspended particles (RSP), particles of mean aerodynamic diameter of less than 2.5 Âľm, CO, and nicotine, which is in the vapor phase of SHS. Nicotine is a highly specific marker for the presence of tobacco smoke; it can be monitored with both active and passive techniques. Largely because RSP can be readily monitored with area and personal sampling methods, levels of RSP have been widely used as a marker for SHS. The data show that smoking in the home approximately doubles the 24-h average indoor RSP concentration. Much higher shortterm exposures, not reflected in these longer-term integrated measurements, must occur in homes when smoking is actually taking place. Data on SHS levels in public buildings have shown high short-term measurements in bowling alleys, at cocktail parties, in bars, and in other locations with a high density of smokers. The adverse effects of environmental tobacco smoke (ETS) have been assessed in the context of the voluminous evidence on active smoking and health and of the detailed characterizations that have been made of the composition and toxicology of mainstream and sidestream cigarette smoke. Associations of SHS with disease and other adverse outcomes have been demonstrated (Table 60-5). The evidence has been reviewed by a number of expert panels, with the repeated

Increased frequency of middle ear disease Increased severity of asthma episodes and symptoms Onset of asthma Sudden infant death syndrome Lung cancer in nonsmokers Coronary heart disease Reduced birth weight conclusion that ETS causes both malignant and nonmalignant diseases in nonsmokers. Studies of children of smoking parents provided the first warning of the adverse effects of SHS on nonsmokers. Maternal smoking was found to increase risk of infants for lower respiratory tract illnesses, and smoking by household members, particularly the mother, was shown to increase the incidence of chronic respiratory symptoms and reduce the rate of lung growth in children. Children with asthma whose parents smoke have heightened airway responsiveness and increased morbidity, as documented by indexes of medical care utilization. Exposure to SHS is also a suspected cause of asthma, and infants of smoking parents have increased airway responsiveness shortly after birth. Epidemiological studies show that parental smoking is associated with persistent middle-ear effusions and other ear problems. Exposure to SHS was first linked to lung cancer in neversmokers in two reports published in 1981. Numerous epidemiological studies have addressed this association, and the weight of the evidence shows a consistent positive association between living with a smoker and the risk of lung cancer. By 1986, the evidence led to conclusions of the International Agency for Research on Cancer, the U.S. Surgeon General, and the U.S. National Research Council that SHS causes lung cancer in never smokers. The risk of lung cancer is increased by approximately 20 percent for never-smoking women married to smokers. Based on review of the epidemiological evidence, as well as the supporting toxicological data, the EPA classified SHS as a class A carcinogen, a designation applied to agents causally linked to cancer. Additional health effects of SHS have now been identified. A number of epidemiological studies have shown that marriage to a smoker increases risk for ischemic heart disease.

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Although the evidence is not as extensive as for the respiratory consequences of SHS exposure, the American Heart Association, the United Kingdom’s Scientific Committee on Tobacco, and the Environmental Protection Agency of the State of California have concluded that SHS exposure is a cause of cardiovascular disease and death. Estimates have been made that SHS causes between 22,669 to 69,553 cardiovascular disease–related deaths annually. Cited mechanisms include promotion of atherosclerosis, increased platelet aggregation, endothelial cell damage, and the consequences of CO exposure. SHS exposure at home and in the workplace has been linked to reduced lung function in some studies.

Wood Smoke The presence of wood smoke indoors can be assessed by measurements of particles, organic compounds, and CO. Available data for developed countries suggest that the routine operation of a properly installed and maintained wood stove does not greatly affect indoor air quality, and outdoor air contaminated with wood smoke of neighbors can enter and pollute the interior air of homes without wood stoves. By contrast, in developing countries, biomass fuel combustion for cooking and space heating leads to very high exposures for large numbers of households around the world and also contributes to outdoor air pollution. Wood smoke is a complex mixture, both in its physical and chemical characteristics and in its toxicological properties. The toxicology of some components of wood smoke, such as benzo[a]pyrene, other polycyclic organic compounds, and nitrogen oxides, has been extensively studied. Little research, however, has addressed the toxicology of wood smoke as a complex mixture. Most of the available epidemiological evidence on the health effects of wood smoke is derived from investigations in developing countries, where intense smoke exposure results from the use of cooking fires in poorly ventilated dwellings. Studies from less developed countries suggest that smoke exposure adversely affects children and adults, increasing the occurrence of acute respiratory illness in children and chronic respiratory morbidity in children and adults. The occurrence of COPD in never-smoking women exposed to wood smoke has been described as well. Data from more developed countries are sparse and do not clearly indicate adverse effects at the lower concentrations of wood smoke generally present. Several studies indicate an association with childhood asthma.

Organic Compounds Organic compounds are ubiquitous indoors, where they are released from furnishings and equipment, construction materials, and consumer and office products (Table 60-6). The organic compounds found in indoor air can be grouped by boiling point range as volatile (0 to 240◦ C), semivolatile (240◦ C to 380◦ C), and particulate (greater than 380◦ C). The volatile and semivolatile organic compounds are most relevant to human health. Volatile organic compounds exist as vapors over the normal range of air temperatures and pressures, whereas

semivolatile organic compounds are liquids or solids but also evaporate. Hundreds of organic compounds have been identified in indoor air. Although many of these agents are also released by outdoor sources such as chemical plants, indoor concentrations and sources have been shown to determine personal exposures to most of the organic compounds. The Total Exposure Assessment Methodology (TEAM) study conducted by the EPA showed the dominant contributions of indoor sources to personal exposures, even in locations with outdoor air polluted by industry. For example, benzene, a human carcinogen, may be emitted into outdoor air by industry and from gasoline. Among cigarette smokers in the TEAM study, however, the main source of personal exposure was benzene in mainstream cigarette smoke; passive smokers are also exposed to benzene. Formaldehyde, used in hundreds of products, is one of the most ubiquitous indoor organic compounds. The largest use of formaldehyde is in preparation of urea and phenol-formaldehyde resins, which are used to bond laminated wood products and to bind the wood chips in particle board. Formaldehyde-containing wood products are used as shelving, counters, bookcases, cabinets, floors, and wall coverings in homes, offices, and public buildings. Formaldehyde resins are also used to treat paper products and fabrics and are constituents of numerous other consumer products. In 2004, on the basis of sufficient evidence in humans and sufficient evidence in experimental animals, the International Agency for Research on Cancer (IARC) concluded that formaldehyde is carcinogenic to humans (Group 1), a higher classification than in previous IARC evaluations. The health risks of the organic compounds are diverse; the organics found in indoor air include several dozen carcinogens and mutagens (e.g., benzene), irritants (e.g., formaldehyde and terpenes), and neurotoxins (e.g., aromatic compounds). Despite the potential risks of the organic compounds in indoor air, few studies have shown specific exposure-disease associations, largely because of the difficulty of characterizing exposures and identifying effects of components of complex mixtures in indoor air. Indoor exposures to organics may contribute to the risks for several cancers, although few epidemiological studies have been directed specifically at assessing cancer risk in relation to indoor exposures to organics.

Radon Radon-222, a noble gas, is in the decay chain of naturally occurring uranium-238. It decays with a half-life of 3.8 days into a series of short-lived progeny: polonium-218, lead-214, bismuth-214, and polonium-214. Irradiation of respiratory epithelial cells by alpha particles released by polonium-218 and polonium-214 damages cellular DNA and causes lung cancer. The principal source of radon in buildings is naturally occurring gas in soil. The driving pressure for entry of soil gas into a building is the pressure gradient established by a structure across the soil. The soil gas enters through openings,

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Table 60-6 Common Organic Chemicals and Their Sources Measured Peak Nonoccupational Exposure (Âľg/m3 )

Major Sources of Exposure

Benzene

1000

Smoking, auto exhaust, passive smoking, driving, pumping gas

Tetrachloroethylene

1000

Wearing or storing dry-cleaned clothes, visiting dry cleaners

p-Dichlorobenzene

1000

Room deodorizers, moth cakes

Chloroform

250

Showering (10-min average)

Washing clothes, dishes

Methylene chloride

500,000

Paint stripping, solvent usage

1,1,1-Trichloroethane

1000

Wearing or storing dry-cleaned clothes, aerosol sprays, fabric protectors

Trichloroethylene

100

Unknown (cosmetics, electronic parts)

Carbon tetrachloride

100

Industrial strength cleansers

1000

Paints, adhesives, gasoline, combustion sources

1000

Paints, adhesives, gasoline, combustion sources

1000

Scented deodorizers, polishes, fabrics, fabric softeners, cigarettes, food, and beverages

10 100 100

Insecticide Termiticide Insecticide Transformers, fluorescent ballasts, ceiling tiles

Combustion products (smoking, wood burning, kerosene heaters)

Chemicals Volatile chemicals

Aromatic hydrocarbons Toluene, xylenes, ethylbenzene, trimethylbenzenes Alphatic hydrocarbons Octane, decane, undecane Terpenes Limonene, a-pinene Semivolatile chemicals Chlorpyrifos (Dursban) Chlordane, heptachlor Diazinon Polychlorinated biphenyls (PCBs) Polycyclic aromatic hydrocarbons (PAHs)

source: Data from Wallace LA: The Total Exposure Assessment Methodology (TEAM) Study: Summary and Analysis. Washington, D.C., U.S. Environmental Protection Agency, Office of Research and Development, 1987.

such as sump pump wells, drains, cracks, and utility access holes. In most locales, building materials and water used in the home do not contribute significantly to concentrations of radon indoors. Because radium, the parent radioisotope for radon, is ubiquitous, radon is present in outdoor air and in higher concentrations in indoor environments.

Extensive data on radon concentrations in homes in the United States show that the average value is about 1.5 picocuries per liter (pCi/L). Homes with high concentrations have been identified in all states, although the proportion exceeding the EPAâ&#x20AC;&#x2122;s action guideline of 4 pCi/L is variable among the states. In a national survey conducted from 1988 through

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1991, the EPA measured radon concentration in 6000 randomly selected homes in the United States. About 4 percent of homes were estimated to exceed the guideline of 4 pCi/L annual average. Exposure to radon progeny, the short-lived decay products of radon, has been causally linked to increased risk of lung cancer in uranium miners and other underground workers. Measurements made since the 1970s in the United States and elsewhere have shown that radon is present in most homes and can reach high concentrations—as high as those in underground mines—with a documented excess of lung cancer. Current risk models that assume that the risk follows a linear nonthreshold relationship imply that even values under current guidelines cause a significant number of lung cancer cases. Thus, any exposure is assumed to convey some risk, an assumption supported by experimental data. Additionally, epidemiological studies of indoor radon confirm that indoor radon concentration is positively associated with radon risk. The hazard posed by exposure to radon progeny in indoor air has been characterized primarily through risk estimation procedures. In the most widely applied risk assessment approach, the risks for the general population are projected by extrapolating risks observed in the studies of miners to the general population. The risk of radon indoors has also been directly estimated by carrying out case-control studies in the general populations. Estimates obtained by pooling the results of these studies are consistent with the extrapolated risks from studies in miners. Use of such models leads to the conclusion that radon contributes significantly to the incidence of lung cancer in the population. The burden of radon-related lung cancer in the general population reflects, in part, the synergism between radon and cigarette smoking assumed in the models. One risk model is based on a pooled analysis of data from 11 epidemiological studies of male miners, including 68,000 who accounted for more than 2700 cancer deaths. The analysis showed a positive linear relationship between the risk of lung cancer and occupational radon exposure, down to exposures only a fewfold greater than average lifetime exposure from indoor radon. Lung cancer risk was found to decline with increasing age and time since exposure; the risk was also found to increase as the rate of exposure decreased— the so-called inverse-dose rate effect. When the model was applied to the U.S. population, indoor exposure to radon at home was estimated to be responsible for about 12 percent of lung cancer deaths in the United States. Of the 15,000 to 22,000 lung cancer deaths attributed to radon in 1995, about 85 percent were assigned to smokers and 15 percent to never-smokers. The substantial lung cancer burden attributed to indoor radon has led to programs for reduction of exposure. The program in the United States, conducted by the EPA, calls for voluntary measurement of radon levels in single-family homes and modification if the annual concentration exceeds the agency’s guideline level of 4 pCi/L. Two types of passive measurement devices are available: short-term devices, which make measurements for a few days, and long-term devices,

which make measurements for periods of months up to a year. The short-term devices, primarily charcoal canisters, are often used when a measurement is quickly needed during a real estate transaction; the longer-term devices incorporate a piece of plastic that is etched by alpha particles released by progeny. Fortunately, increased radon concentrations can be lowered, often by such simple measures as sealing basement cracks and sump holes. Approaches also include ventilating the basement to the outside and, for homes built on concrete slabs, by providing a system to exhaust the soil gas from beneath the slab. In areas having a high potential for indoor radon problems, radon-resistant construction techniques can be applied in anticipation of high levels. The success of the EPA’s program for managing the indoor radon problem rests on voluntary action by the public. To engage the public, the Agency has developed a risk communication strategy that uses the media, voluntary health agencies (e.g., the American Lung Association), and healthcare providers. Its pamphlet, “A Citizen’s Guide to Radon,” informs readers about the risks and the recommended approaches for managing them.

Asbestos and Man-Made Fibers Asbestos, comprising several fibrous inorganic materials characterized by chemical formulation and crystalline structure, has been used extensively in building materials since the beginning of the century because of its high tensile strength and thermal properties. The broad categories of use are thermal and acoustic insulation, fire protection, and reinforcement of building products. In addition to its use in acoustic ceiling tiles and vinyl floor tiles, asbestos has been used in paints and wall and ceiling plaster; until banned in the late 1970s, asbestos materials were used to coat pipes, boilers, and steel structural beams. Asbestos-containing materials are present in homes, offices, and schools. The EPA has estimated that 20 percent of the nation’s buildings, or about 733,000 buildings (not including schools and residential dwellings with fewer than 10 units), contain some asbestos materials. Asbestos had been used widely in ceiling tiles, pipe wrap, plaster, floor tiles, shingles, and sprayed-on insulation, among other applications. Release of fibers from these materials may result from impact, abrasion, fallout, vibration, air erosion, and fire damage. Water damage and the normal aging of binders, leading to the friability of the material, increase the likelihood of release. Asbestos-contaminated surface dust may contribute to airborne concentrations in buildings. Man-made mineral fibers are now used increasingly as substitutes for asbestos in building materials. These are fibrous inorganic substances made primarily from rock, clay, slag, or glass; the principal types are glass fibers (comprising glass wool and glass filaments), rock wool, slag wool, and ceramic fibers. Fiberglass and glass wool refer to silica-based vitreous fibers manufactured by a number of different processes. The different types of fibers vary in their chemistry

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and dimensions, as well as in their durability in vivo. Because they are physically fibrous, there is concern about the same health effects as for asbestos. An enlarging database on airborne asbestos concentrations in buildings demonstrates extremely low average values under the conditions of normal building use. Occupant risk is determined by exposures to airborne fibers, rather than the presence of asbestos-containing materials in the building. Surveys of asbestos concentrations in commercial buildings demonstrate very low fiber concentrations under normal conditions. The Literature Review Panel Report published by the Health Effects Institute, Asbestos Research Committee, compiled all published data, as well as previously unpublished information, on buildings sampled for litigation and for other purposes. The total data set included 1,377 measurements made by transmission electron microscopy in 198 buildings. For fibers greater than 5 mm in length, which are considered most relevant to disease

Indoor and Outdoor Air Pollution

risk, the mean and median concentrations were low, at approximately 0.001 fiber per milliliter, or three or more orders of magnitude lower than concentrations in the occupational settings of the past. Individual buildings with levels much higher than the typical values in the data assembled by the Health Effects Institute, Asbestos Research Committee, have been reported. For office workers, visitors to buildings, and schoolchildren and teachers, mesothelioma and lung cancer are the principal health effects of concern; asbestosis would not be expected at usual exposures for these building occupants. The risks of indoor asbestos for the general population have been estimated by extrapolation of risks for occupationally exposed persons. Uncertainty is inherent in this approach, but the risks cannot be directly investigated by epidemiological methods. The Literature Review Panel Report of the Health Effects Institute, Asbestos Research Committee, has estimated risks for various scenarios of exposure (Table 60-7).

Table 60-7 Estimated Lifetime Cancer Risks for Different Scenarios of Exposure to Airborne Asbestos Fibers∗ Conditions

Premature Cancer Deaths (Lifetime Risks) per Million Exposed Persons

Lifetime, continuous outdoor exposure 0.00001 fiber/ml from birth (rural) 0.00001 fiber/ml (high urban)

4 40

Exposure in a school containing ACM, from age 5 to 18 years (180 days/year, 5 h/day) 0.0005 fiber/ml (average)† 0.005 fiber/ml (high)†

6 60

Exposure in a public building containing ACM, from age 25 to 45 years (240 days/year, 8 h/day) 0.0002 fiber/ml (average)† 0.002 fiber/ml (high)†

4 40

Occupational exposure from age 25 to 45 0.1 fiber/ml (current occupational levels)‡ 10 fiber/ml (historical industrial exposures)

2000 200,000

ACM = asbestos-containing material. Table represents the combined risk (average for males and females) estimated for lung cancer and mesothelioma for building occupants exposed to airborne asbestos fibers under the circumstances specified. These estimates should be interpreted with caution because of the reservations concerning the reliability of the estimates of average levels and of the risk assessment models. † The “average” levels for the sampled schools and buildings represent the means of building averages for the buildings reviewed herein. The “high” levels for schools and public buildings, shown as 10 times the average, are approximately equal to the average airborne levels of asbestos recorded in approximately 5 percent of schools and buildings with asbestos-containing materials. If the single highest sample value is excluded from calculation of the average indoor asbestos concentration in public and commercial buildings, the average value is reduced from 0.00021 to 0.00008 fiber/ml, and the lifetime risk is approximately halved. ‡ The concentration shown (0.1 fiber/ml) represents the permissible exposure limit proposed by the U.S. Occupational Safety and Health Administration. Actual worker exposure, expected to be lower, will depend on a variety of factors, including work practices and use and efficiency of respiratory protective equipment. source: Data from Health Effects Institute, Asbestos Research Committee, Literature Review Panel. Asbestos in Public and Commercial Buildings: A Literature Review and a Synthesis of Current Knowledge. Cambridge, MA, Health Effects Institute, 1991. ∗ This

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Custodial and maintenance workers in buildings with asbestos-containing materials may be exposed to higher levels of asbestos than other building occupants, since their activities disturb the materials and release fibers. These workers may be at particular risk if they are unaware that asbestos-containing materials are present or are untrained in dealing with these materials. Several studies have shown that custodial and maintenance workers may have pleural plaques and possibly asbestosis, causing concern that a “third wave” of asbestos-caused disease could occur in such workers. Because of the morphological and toxicological comparability of asbestos and man-made mineral fibers, there has been concern that exposure to man-made mineral fibers could produce the same diseases caused by asbestos. The relevant epidemiological data from exposed workers are less extensive than for asbestos. Animal studies have shown the fibers that are long and thin to be carcinogenic. Some have concluded from epidemiological evidence and toxicological properties of the materials that the health risk of man-made mineral fibers is likely to be negligible for exposures of building occupants. Recently, the IARC re-evaluated the carcinogenic risk of airborne man-made vitreous fibers. Epidemiological studies, published since a review in 1988, as well as research conducted on newer fibers, were evaluated. The IARC concluded that only the more biopersistent materials, such as refractory ceramic fiber (RCF), remain classified as possible human carcinogens. Continuous glass filaments and the more commonly used vitreous feber wools, such as insulation glass wool, rock wool, and slag wool, are now considered not classifiable as to their carcinogenicity to humans. Nevertheless, to date, no data are available linking RCF with tumors in humans.

Biologic Agents Indoor allergens and microbes—the principal biologic agents in indoor air relevant to human health—have diverse sources, both indoors and outdoors (Table 60-8). Indoor levels of allergens and microbes may be increased by accumulation of materials indoors, such as human and animal dander, and growth of fungi and bacteria on interior surfaces or in air conditioning systems. Indoor pollen is derived almost entirely from outdoor plants, and fungus spores from outdoors may also enter the indoor environment on air infiltration or inadvertently on people, animals, or objects. Some of the most severe and prevalent indoor biologic pollution problems result from the growth of microorganisms on interior surfaces that are wet and moist. Substrates which provide a source of both carbon and water can support the growth of microorganisms. High relative humidity, in excess of 70 percent, promotes condensation on interior surfaces (e.g., cool exterior walls or windowsills). Leaks from water pipes and roofs can also provide consistent sources of moisture. Other moisture sources are humidifiers, vaporizers,

Table 60-8 Sources of Biologic Air Pollutants Acarids Dust mites and spiders Insects Cockroaches, crickets, beetles, fleas, moths, flies, and midges Domestic animals Cats, dogs, other mammals, and birds Rodents Wild Mice and rats Pets Mice, gerbils, and guinea pigs Fungi Indoors (growing on interior surfaces or in air-conditioning systems) Penicillium, Aspergillus, Rhizopus, and Cladosporium Outdoors Numerous species entering with incoming air Pollens Derived from outdoor plants or plant materials brought inside Bacteria Legionella (introduced into ventilation systems by cooling towers and standing water reservoirs)

and air conditioners; once contaminated, these devices can distribute fungal fragments, spores, and dissolved allergens into room air. Mold has been a problem in homes flooded by storms. In recent years, the growth of molds in home, school, and office environments has been cited as the cause of a wide variety of human ailments and disabilities. So-called “toxic mold” has become a prominent topic in the lay press and is increasingly the basis for litigation when individuals, families, or building occupants believe they have been harmed by exposure to indoor molds. Molds and other fungi may adversely affect human health through allergy or infection. Some species of fungi, including some molds, are known to be capable of producing secondary metabolites, or mycotoxins and, possibly, of causing respiratory disease via a toxic syndrome. A controversial issue regarding mold in the home is that of “idiopathic pulmonary hemorrhage” associated with Stachybotrys chartarum. Following an initial report of 10 cases in Cleveland in 1994, additional case reports followed, linking mold exposure or mycotoxins with pulmonary hemorrhage in infants. Recent critical reviews of the literature have concluded that indoor

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airborne levels of microorganisms are only weakly correlated with human disease or building-related symptoms and that a causal relationship has not been established between these complaints and indoor exposures to S. chartarum. Limited information exists on levels of microbial particles in air. Indoor levels and, hence, personal exposure are highly variable and are probably affected by activities such as vacuuming, sweeping, dusting, making beds, scrubbing contaminated surfaces, and using electric fans. Further, airborne and dust concentrations of allergens probably have limited value for assessing the contribution of a particular allergen in causing disease. Factors such as aerodynamic behavior, respirability, solubility, and cross-reactivity with other allergens are also important in the process of immunological sensitization and the development of allergic disease. Dust mites (Dermatophagoides pteronyssinus, D. farinae, and Euroglyphus maynei) are commonly found in houses and are important sources of allergens, particularly for persons with asthma. These mites are approximately 0.3 mm in length and live in carpets, upholstered furniture, mattresses, and bedding, where they eat skin scales. Two major dust mite allergens have been identified, Der p I and Der p II. These proteins are derived from digestive enzymes in the gut of the mite and are found in high concentrations in the fecal pellets. Vacuum sampling and immunologic assays indicate that in the home, the highest levels of allergen occur in the bedroom in carpeting, mattresses, and bedding. Domestic cockroaches, including the German cockroach, Blattella germanica, are commonly found indoors and represent another source of allergen in residences, particularly in infested inner-city housing. Fecal material and saliva contain large amounts of the allergens Bla g I and Bla g II. In inner-city homes, mice infestations may contaminate residences with the mUS antigen. Cats and dogs are prevalent sources of allergen exposures. Fel d I is the most significant allergen associated with cats, and high levels of this protein are found in cat dander and fur and also in saliva and urine. The median level of Fel d I in samples of settled household dust in homes with a cat are reported to range from 2 to 130,000 ng/g of dust, with a median level of 90 ng of Fel d I/g of dust. In homes without a cat, much lower levels are observed, ranging from 2 to 7500 mg of Fel d I/g of dust; the antigen is persistent in indoor environments for long periods after a cat is no longer indoors. The presence of the allergen in the dust of homes and buildings in which cats are not kept suggests that the allergen can be transported on clothing. The major dog allergen, Can f I, is present in dog fur and saliva and is a relatively stable protein that may persist in dust for a long time. The content of Can f I in household dust from homes with a dog ranges from 10 to 10,000 mg/g of dust, compared with 0.3 to 23 ng/g of dust in homes without a dog. Mouse allergen, a cause of asthma in laboratory workers, is prevalent in homes. A national study of inner-city childhood asthma found widespread contamination with this allergen and frequent positivity to the allergen on skin testing.

Indoor and Outdoor Air Pollution

Fungi are present in the air of virtually all homes and public buildings. Commonly isolated genera include Cladosporium, Penicillium, Alternaria, Epicoccum, Aspergillus, and Drechslera. Biologic agents in indoor air may cause disease through various mechanisms, including direct toxicity, infections, and immune hyperresponsiveness. A complete review of these diverse effects is beyond the scope of this chapter. Selected examples of diseases caused by biologic agents are given; more extensive information is available in published reviews. The presence of dampness and mold, determined by questionnaire, has been associated with upper respiratory symptoms and eye irritation in large studies of children in the United States and elsewhere. These associations were adjusted for known determinants of respiratory symptoms, including maternal smoking, city, child’s age and sex, and parent education. There are also similar findings in adults. A recent systematic review concluded that dampness in buildings contributes to adverse health effects in persons with and without atopy, but a specific causal agent cannot be identified. The evidence on dampness was reviewed by an Institute of Medicine committee which did not find the evidence to be sufficient to conclude that dampness causes respiratory symptoms or asthma. Allergic rhinitis, or “hay fever,” is common, affecting approximately 20 percent or more adults in the United States. Identification of the specific indoor allergen associated with the symptoms may be accomplished by skin testing and in vitro measurement of antibody [radioallergosorbent test (RAST)]. Many persons with asthma are sensitive to specific antigens from pollens, animal fur, fungi spores, and house dust. The risk of acute or severe attacks of asthma is increased in residences with levels of Der p I in excess of 10 µg/g of house dust, and asthmatic patients have been reported to show a 25 percent prevalence of skin test positively to cat or dog allergen extracts. Building-related allergic respiratory disease and epidemic asthma have been reported in office buildings in association with air-handling systems and humidifiers contaminated with bacteria and fungi. Avian proteins are present in bird excreta (e.g., the droppings of pet birds such as parakeets), and fungal spores of thermophilic actinomycetes, Aspergillus species, Penicillium species, and Aureobasidium species may contaminate the indoor environment and cause hypersensitivity pneumonitis. A careful review of symptom pattern in relation to home and work environments and site evaluation may be needed to identify the source of exposure. The bacterium Legionella pneumophila, the agent of legionnaires’ disease, causes an often fatal pneumonia associated with exposure to the bacterium in aerosols of cooling towers and air-handling systems and in humidifiers and spas. It exemplifies a respiratory pathogen associated primarily with indoor environments, in both source and transmission. Of course, indoor environments are the locus of transmission of many infectious respiratory diseases, including influenza

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and tuberculosis. The risk of diseases depends on the strength of sources and the level of ventilation. A low air exchange rate increased the risk for pneumococcal infection among inmates in a large county jail.

CLINICAL SYNDROMES ASSOCIATED WITH INDOOR ENVIRONMENTS During the last 20 years, complaints attributable to indoor environments have generally been classified into one of two broad groups: specific building-related illnesses and sick building syndrome (SBS). Building-related illnesses have a number of etiologies, but the specific agent responsible for causing the disease is present in the indoor environment, e.g., hypersensitivity pneumonitis caused by fungi in the ventilation system or Legionnairesâ&#x20AC;&#x2122; disease resulting from transmission of the organism that grows in cooling-tower water. Sick building syndrome refers to nonspecific health problems related to indoor air quality in nonindustrial buildings. Irritation of mucosal surfaces and neurotoxic effects may contribute to the nonspecific symptom complex that often include headache, fatigue, and difficulty concentrating. Atopic individuals have been shown to have lower irritant thresholds than nonatopics. Multiple factors, including specific exposures, inadequate ventilation, and poor building maintenance have been linked to SBS. Panel studies in Denmark have found that complaints were most often attributed to the ventilation system, SHS, office machines, and other sources.

SUSCEPTIBLE POPULATIONS The legislative history of the Clean Air Act mandated that the primary NAAQS were to be set low enough to protect the health of all susceptible groups within the population except those requiring life-support systems. Only two diseases, asthma and emphysema, were specifically identified in the Clean Air Act as associated with increased susceptibility. Other groups in the population, accounting for large numbers of people, are also considered to be at increased risk from air pollutants: persons with coronary artery disease and, possibly, peripheral vascular disease; infants and the elderly in general; and children with chronic pulmonary ailments such as cystic fibrosis and bronchopulmonary dysplasia. In this section, we consider the evidence concerning these susceptible groups (Table 60-9). Pulmonologists are likely to be asked about the consequences of pollution exposures by persons with chronic lung diseases. Patients may report being adversely affected by exposures and may request guidance concerning control measuresâ&#x20AC;&#x201D;e.g., purchase of an air-cleaning device or additional medication use when exposed.

Clinical Studies in Asthma and COPD Clinical studies have provided much of the evidence on the effects of pollutants on persons with chronic respiratory diseases. Controlled laboratory studies of volunteers have attempted to identify specific effects of individual pollutants, as assessed primarily by pulmonary mechanics;

Table 60-9 Populations Considered Susceptible to Air Pollution Population

Potential Mechanism

Consequences

Asthmatics

Increased airway responsiveness

Increased risk for exacerbation and respiratory symptoms

Cigarette smokers

Impaired defense and clearance, lung injury

Increased damage through synergism

Elderly

Impaired respiratory defenses

Increased risk for respiratory infection

Reduced functional reserve

Increased risk for clinically significant effects on function

Infants

Immature defense mechanisms of the lung

Increased risk for respiratory infection

Persons with coronary heart disease

Impaired myocardial oxygenation

Increased risk for myocardial ischemia

Persons with chronic obstructive pulmonary disease

Reduced level of lung function

Increased risk for clinically significant effects on function

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however, other end points, including symptoms, have been assessed. The most striking effect of acute exposure to SO2 at concentrations under 1.0 ppm is the induction of bronchoconstriction in asthmatics after exposures lasting only 5 min. In contrast, inhalation of concentrations of SO2 in excess of 5 ppm causes only small decrements in airway function in normal subjects. Lung function responses to SO2 in asthmatics are greater when SO2 exposure is accompanied by increased ventilation, usually stimulated by exercise. SO2 induced bronchoconstriction can be exacerbated by breathing cold or dry air and oral (versus nasal) breathing. The SO2 bronchoconstrictor response can be reduced or inhibited in asthmatics by anticholinergic agents, mast cell stabilizers, or beta agonist bronchodilators. Inhalation of acidic aerosols generally produces little alteration in pulmonary function in normal subjects, even Permissible Exposure Limit of 1 mg/m3 in the workplace. As with SO2 , asthmatic subjects have been found to be susceptible to the effects of acidic aerosol exposure, although different laboratories have found differing concentrations for threshold exposure. Adult asthmatics exposed to aeorsols of 450 and 1000 Âľg/m3 of H2 SO4 demonstrate decrements in specific airway conductance. Adolescent asthmatics appear to be more sensitive to the effects of acidic aerosols than adult asthmatics. Functional decrements have been observed in adolescents at levels as low as 70 Âľg/m3 , concentrations occasionally noted in outdoor air and an order of magnitude lower than the level at which effects are observed in normal subjects. The apparent difference in sensitivity of adult and adolescent asthmatics may also be due to differences in the research protocols. In these studies, young asthmatics showed functional decrements at exposure levels that corresponded to near-peak outdoor levels in the northeastern United States. Field studies in summer camps of both normal and asthmatic children reported decrements in pulmonary function during pollution episodes that included exposure to increased levels of acidic aerosols, supporting the concern that children and adolescents may be particularly susceptible to effects of acidic atmospheres. Although several controlled human studies have found asthmatics to be responsive to low levels of NO2 , the findings have not been consistent. The conflicting results among these studies are probably related to the differences in subject selection and exposure protocols. Persons with COPD may represent a group with increased susceptibility to short-term exposure to NO2 . Further study of the issue is needed. Consonant with the provisions of the Clean Air Act and with its legislative history, a group that appears to be at potential risk from exposure to ozone consists of those characterized as having pre-existing respiratory disease. In the case of asthmatics, however, emerging data from controlled studies indicate no greater responsiveness to ozone in mild asthmatics than in normal, healthy populations. Pretreatment of healthy volunteers with Î˛-adrenergic agents before O3 exposure and exercise does not prevent bronchoconstriction, whereas pretreatment with atropine or indomethacin reduces the decre-

Indoor and Outdoor Air Pollution

ment in lung function. Since exercise greatly potentiates the response to ozone, the best strategy for clinical management includes avoiding outdoor exercise during periods of high O3 pollution.

Clinical Studies in Heart Disease Persons with coronary heart disease have also been identified as a group at risk from increased levels of air pollution. In the presence of coronary artery disease, there is limited ability to increase coronary blood flow in response to increased myocardial oxygen consumption during exercise. When myocardial blood flow is not sufficient to meet oxygen demand, the myocardium becomes ischemic, resulting in angina pectoris, ECG changes, or both. Several recent studies conducted at relatively low COHb levels have investigated the effects of CO exposure on exercise capacity and the occurrence of myocardial ischemia. These studies found a decrease in the time to the occurrence of myocardial ischemia in persons with coronary artery disease during exercise after CO exposure. The lowest CO dose to produce a decrease in time to the onset of angina was associated with a 2 percent COHb level. In this study, there was a mean decrease of 4.2 percent in the time to angina and a mean decrease of 5.1 percent in the time to ECG changes, indicative of myocardial ischemia at 2 percent COHb compared to control (air exposure) days; greater effects were noted at 3.9 percent COHb. Clinical studies have shown a significant dose-response relationship for the individual differences in time to the onset of ECG changes at increasing COHb levels. In addition, at a COHb level of 6 percent, patients with coronary artery disease experience an increase in the frequency of arrhythmias. Of note, at the same low levels of COHb, adverse effects have been observed in humans but not in animals.

CONTROL STRATEGIES Controlling the health effects of indoor and outdoor air pollution requires strategies oriented toward populations and toward individual patients. Clinicians can make practical recommendations to their patients in order to reduce risk for disease and for exacerbation of established disease. Clinicians may serve as consultants or as advocates in seeking to reduce the effects of indoor and outdoor air pollutants through population-oriented control approaches.

Patient-Oriented Strategies Approaches for limiting the health risks of breathing polluted ambient air have received little investigation. Present understanding of the determinants of exposure suggests that modifying time-activity patterns to limit time outside during episodes of pollution represents the most effective strategy. The levels of some reactive pollutants tend to be lower indoors than outdoors. O3 levels in buildings are lower than outdoor levels, but they can be driven upward by increasing the rate

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Table 60-10 Questions and Answers About Indoor Air Pollution Question

Answer

Do air cleaners work?

Air cleaners have not yet been shown to have direct health benefits.

Should the radon concentration in my home be measured?

Yes, radon can be readily measured at relatively low cost, and mitigation is feasible.

Should the air ducts in my home be cleaned?

There is no evidence on health benefits of cleaning air ducts.

Will controlling mites be beneficial?

Controlling mite levels is beneficial for persons with mite-sensitive asthma.

Should my home be humidified?

Humidification may increase allergen levels.

of exchange of indoor with outdoor air. Fine acid aerosols can penetrate indoors, but neutralization by ammonia produced by occupants, pets, and household products may reduce concentrations. Other types of particles in outdoor air may also enter indoor air. Nevertheless, health care providers can reasonably advise patients to stay indoors during pollution episodes. Vigorous exercise outdoors, which increases the dose of pollution delivered to the respiratory tract, should also be avoided at such times. Susceptible patients should be counseled concerning the nature and degree of their susceptibility. The use of medication should follow the usual clinical indications, and therapeutic regimens should not be adjusted because of the occurrence of a pollution episode without evidence of an adverse effect on symptoms or function. In the laboratory, inhalation of cromolyn sodium and bronchodilating agents blocks the response to some pollutants, but use of these drugs solely because of exposure to air pollution cannot be advised. Respiratory protective equipment has been developed for use in the workplace to minimize exposure to toxic gases and particles. Many of these devices, particularly those likely to be most effective, add to the work of breathing and cannot be tolerated by persons with respiratory disease. Under most circumstances, health care providers should not suggest respiratory protection as a method for reducing the risks of ambient air pollution. Similarly, air cleaners have not been shown to have health benefits, whether directed at indoor pollutants generated by indoor sources or at those brought in with outside air. Pulmonologists may be concerned with diverse issues related to the control of indoor air pollution, ranging from answering patients’ questions about pollutant health effects and control, to management of complex problems in large buildings. Some commonly asked questions and answers that reasonably reflect the state of the evidence are provided in Table 60-10. The clinically relevant microenvironments are

numerous, including the home, the workplace, public buildings, and places where leisure time is spent. Workplace problems, such as the “sick-building syndrome,” may be particularly challenging. The health care provider needs to establish the connection between the workplace and the occurrence of symptoms and then seek a solution that includes identifying and remediating the responsible factors in the workplace. The diagnostic task requires a sufficient awareness of the possible causal role of the indoor environment (Fig. 60-2). Resolution may require an evaluation and intervention by indoor air quality professionals. The physician may be unable to resolve the patient’s symptoms without motivating a building evaluation and resolution of underlying problems. Guidance for the clinician has been offered by the ATS.

Community-Oriented Strategies Frequently, communities become concerned about the effect of particular local sources—e.g., a power plant or manufacturing facility or vehicle depot. Exposures to air pollutants and other environmental contaminants may dispropotionately affect disadvantaged communities. The term “environmental justice” is used in addressing inequities between poorer and more well-to-do communities. Concern about the health risks may quickly lead to controversy and litigation. Thus, understanding the health risks posed by local sources may be difficult and may require skills in community health, as well as in epidemiology and toxicology. Local physicians may become active through concerns about the health of their patients or as advocates for the community’s environment or for the polluting facility. Most often the dimensions of such complex problems exceed the skills of local physicians. Involvement may be appropriate, but guidance should be obtained from appropriate public health and environmental agencies. In 1976, the EPA proposed cautionary statements for public reporting of outdoor air quality—the Pollutant

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Indoor and Outdoor Air Pollution

Figure 60-2 Medical approach to patient with complaints possibly related to indoor air pollution without an antecedent diagnosis. SBRI = Specific building-related illnesses; SBS = sick building syndrome. (Based on American Thooracic Society data.)

Standards Index—for criteria pollutants. In the 1999 revision, the name was changed to the Air Quality Index (AQI). The index provides AQI levels, descriptors of air quality, and guidelines for cautionary statements. The actions taken when “alert levels” are reached or expected to be reached include the issuance of health advisories (or cautionary statements) to the public. The EPA’s advice is intended to be applied by local air pollution agencies in preparing daily air quality summaries to be disseminated to the media. Although the cautionary statements require some revisions, especially as related to ozone exposures, useful guidelines are offered for the physician and public health officials.

SUGGESTED READING American Thoracic Society: What constitutes an adverse health effect of air pollution? Offical statement of the American Thoracic Society. Am J Resp Crit Care Med 161:665–673, 2000.

American Thoracic Society, Committee of the Environmental and Occupational Health Assembly: Health effects of outdoor air pollution. Part 1. Am J Resp Crit Care Med 153:3–50, 1996. American Thoracic Society, Committee of the Environmental and Occupational Health Assembly, Bascom R, Bromberg PA, Costa DA, et al: Health effects of outdoor air pollution. Part 2. Am J Resp Crit Care Med 153:477–498, 1996. Bell ML, Samet JM, Dominici F: Time-series studies of particulate matter. Annu Rev Public Health 25:247–280, 2004. Bornehag CG, Sundell J, Bonini S, et al: Dampness in buildings as a risk factor for health effects, EUROEXPO: A multidisciplinary review of the literature (1998–2000) on dampness and mite exposure in buildings and health effects. Indoor Air 14:243–257, 2004. Brook RD, Franklin B, Cascio W, et al: Air pollution and cardiovascular disease: a statement for healthcare professionals from the Expert Panel on Population and Prevention

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Science of the American Heart Association. Circulation 109:2655–2671, 2004. Burge HA: Bioaerosols. Boca Raton, FL, Lewis Publishers, 1995, pp 1–318. Darby S, Hill D, Auvinen A, et al: Radon in homes and risk of lung cancer: collaborative analysis of individual data from 13 European case-control studies. Br Med J 330:223, 2005. Health Effects Institute, Asbestos Research Committee, Literature Review Panel: Asbestos in Public and Commercial Buildings: A Literature Review and a Synthesis of Current Knowledge. Cambridge, MA, Health Effects Institute, 1991. Institute of Medicine: Damp Indoor Spaces and Health, Washington, D.C., National Academies Press, 2004. International Agency for Research on Cancer (IARC). Manmade Vitreous Fibers. IARC monograph 81. Lyon, France, International Agency for Research on Cancer, 2002. International Agency for Research on Cancer (IARC): Tobacco Smoke and Involuntary Smoking. IARC monograph 83. Lyon, France, International Agency for Research on Cancer, 2004. Jenkins RA, Guerin MR, Tomkins BA: The Chemistry of Environmental Tobacco Smoke Composition and Measurement, 2d ed. Boca Raton, FL, Lewis Publishers, 2000. National Research Council (NRC), Committee on Advances in Assessing Human Exposure to Airborne Pollutants: Human Exposure Assessment for Airborne Pollutants: Advances and Opportunities. Washington, D.C., National Academy Press, 1991. National Research Council (NRC), Committee on Air Quality in Passenger Cabins of Commercial Aircraft BoESaT: The Airliner Cabin Environment and the Health of Passengers and Crew. Washington, D.C.: National Academy Press, 2002.

National Research Council (NRC), Committee on Health Risks of Exposure to Radon, Board on Radiation Effects Research, Commission on Life Sciences: Health Effects of Exposure to Radon (BEIR VI). Washington, D.C., National Academy Press, 1999. National Research Council (NRC), Committee on Research Priorities for Airborne Particulate Matter: Research Priorities for Airborne Particulate Matter: IV. Continuing Research Progress. Washington, D.C., National Academies Press, 2004. National Research Council (NRC), Committee on the Institutional Means for Assessment of Risks to Public Health: Risk Assessment in the Federal Government: Managing the Process. Washington, D.C., National Academy Press, 1983. Nel AE, Diaz-Sanchez D, Li N: The role of particulate pollutants in pulmonary inflammation and asthma: Evidence for the involvement of organic chemicals and oxidative stress. Curr Opin Pulm Med 7:20–26, 2001. Samet JM: Epidemiology of Lung Cancer, New York, Marcel Dekker, 1994. Samet JM, Dominici F, Curriero FC, et al: Fine particulate air pollution and mortality in 20 U.S. cities, 1987–1994. N Engl J Med 343:1742–1749, 2000. Smith KR, Samet JM, Romieu I, et al: Indoor air pollution in developing countries and acute lower respiratory infections in children. Thorax 55:518–532, 2000. Spengler JD, Samet JM, McCarthy JF (eds): Indoor Air Quality Handbook, New York, McGraw-Hill, 2000. Utell MJ, Frampton MW: Acute health effects of ambient air pollution: The ultrafine particle hypothesis. J Aerosol Med 13:355–359, 2000. Wolkoff P: Volatile organic compounds: Sources, measurements, emissions, and the impact on indoor air quality. Indoor Air 3:9–73, 1995.

61 High-Altitude Physiology and Clinical Disorders Sukhamay Lahiri

Santhosh M. Baby

Camillo DiGiulio

I. ARTERIAL CHEMORECEPTORS AND CONTROL OF RESPIRATION Acute Responses to Hypoxia Chronic Responses to Hypoxia II. PHYSIOLOGICAL CHANGES AT HIGH ALTITUDE Pulmonary Circulation Sleep and Periodic Breathing

ARTERIAL CHEMORECEPTORS AND CONTROL OF RESPIRATION The responses of oxygen-sensing organs lie at the core of adaptations that take place with ascent to high altitude. This chapter focuses on these physiological adaptations and clinical disorders, including acute mountain sickness, high-altitude pulmonary edema, high-altitude cerebral edema, and chronic mountain sickness. Only since the late 1920s has it been recognized that the ventilatory response to hypoxia originates from peripheral chemoreceptors situated in the carotid and aortic bodies. Previously, the central chemoreceptors, as CO2 -sensing organs, were the focus of investigation of the respiratory control system. Even Haldane believed that hypoxia acted centrally by producing acid. Eventually, the basis of the hypoxic stimulus to breathing was discovered using simple cross-circulation experiments in dogs.

Acute Responses to Hypoxia The carotid body is composed of highly aerobic tissue that depends primarily on mitochondrial oxidative phosphorylation for adenosine triphosphate (ATP) production. Synthesis

Erythropoiesis Fluid Homeostasis and Renal Function III. COMMON CLINICAL DISORDERS OF HIGH ALTITUDE Acute Mountain Sickness High-Altitude Pulmonary Edema High-Altitude Cerebral Edema Chronic Mountain Sickness

of ATP by mitochondria is tightly coupled to oxygen consumption; that is, mitochondria respire only fast enough to replenish ATP as it is used. Decreased availability of oxygen first affects the ability of mitochondria to maintain the ratio [ATP]/[ADP][Pi], a measure of energy available when ATP is hydrolyzed to adenosine diphosphate (ADP) and inorganic phosphate (Pi). Respiration is stimulated by decreasing the ratio and, as a result, the rate of respiration does not decrease until oxygen deprivation is severe enough to exhaust the capacity of the control system. Inhibitors of mitochondrial function have been known for decades to transiently stimulate afferent activity of the carotid body, and many studies have used inhibitors of mitochondrial respiration and phosphorylation in both isolated carotid body preparations and glomus cells. Among the compounds causing a transient increase in afferent activity are reparatory chain inhibitors (e.g., cyanide); inhibitors of energy coupling (e.g., oligomycin); and uncouplers of oxidative phosphorylation (e.g., dinitrophenol [DNP]). Each can cause a transient increase in afferent activity in the carotid body and a significant increase in intracellular calcium concentration in glomus cells. In thin slices of the carotid body, catecholamine release increases with decreasing glucose concentration. Thus, a deficiency in the substrate for the citric acid cycle and oxidative

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phosphorylation mimics hypoxia. High levels of mitochondrial inhibitors abolish the oxygen chemosensory response in the carotid body, although carotid body afferent activity can still be stimulated, at least transiently, by changes in carbon dioxide or hydrogen ion concentrations. Collectively, inhibitor-uncoupler studies infer that oxygen sensing occurs through phosphorylation. Two main hypotheses regarding the oxygen sensor responsible for the rapid response to hypoxia have been advanced. One is that the oxygen sensor is mitochondrial cytochrome oxidase, which, through its effects on oxidative phosphorylation, transmits information to the rest of the cell. The other is that glomus cells have oxygensensitive potassium channels, the conductance of which are lowered with decreasing oxygen pressure. Although mitochondrial cytochrome oxidase is recognized as the primary oxygen sensor, it is possible that oxygen-dependent ion channels help to modulate sensitivity to changes in oxygen tension. In order for cytochrome oxidase to act as the oxygen sensor for rapid changes in oxygen pressure, mitochondrial oxidative phosphorylation must be sensitive to cellular oxygen tension in vivo. Blood flowing through the carotid body comes from the carotid artery, where the oxygen pressure is typically 80 to 100 mmHg. Carotid body afferent activity rises significantly when arterial oxygen pressure falls below 60 mmHg. However, oxygen pressure in the mitochondria is much lower, because as blood enters the carotid body, oxygen is extracted by cells. By the time an aliquot of arterial blood reaches the microvessels of the carotid body, its average oxygen pressure is about 50 mmHg; minimal values are likely near 20 mmHg. Although diffusion of oxygen from blood in the microvessels to the mitochondria is expected to further decrease the oxygen pressure, it is reasonable to expect an average mitochondrial oxygen pressure of about 40 mmHg and a minimum of about 15 mmHg. Thus, a significant portion of the mitochondria of glomus cells is exposed to an oxygen pressure of less than 20 mmHg when arterial oxygen pressure is 80 mmHg. Changes in ventilation due to changes in alveolar (PacO2 ) or alveolar PO2 (PaO2 ) are described in Figure 61-1. In the acute phase of hypoxia (e.g., the first 10 min), at a given rate of oxygen consumption, as PaO2 is decreased to below 60 mmHg, ventilation increases, resulting in a decrease in PaCO2 . In the chronic phase, ventilation is increased with reductions in PaO2 at all levels of PaO2 , and the curve is shifted downward, reflecting increased sensitivity of carotid chemoreception and restoration of pH after a period of hypocapnia-induced alkalemia. The diagram is particularly useful for describing the acclimatization process in response to altitude-associated chronic hypoxia. Hypoxemia is often accompanied by alterations in PaCO2 . In the carotid body, low PaO2 and high PaCO2 interact synergistically to stimulate glomus cells; i.e., the ventilatory effects of concurrent hypoxia and hypercapnia are greater than the sum of the two stimuli when they are ap-

Figure 61-1 Alveolar PO2 -PCO2 relationship in acute and acclimatized subjects. In acute hypoxia, a drop in alveolar PCO2 (due to hyperventilation) is observed when alveolar PO2 decreases below 60 mm Hg. However, with acclimatization, even at an alveolar PO2 above 60 mm Hg, arterial PCO2 decreases because of increased drive from the chemoreceptors. (From Rahn H, Otis AB: Man’s respiratory response during and after acclimatization to high altitude. Am J Physiol 157:445–462, 1949.)

plied separately. As the PaO2 level declines, the relationship between the sensory afferent nerve activity and PaCO2 becomes increasingly steeper (Fig. 61-2), leading to enhanced ventilatory drive.

Figure 61-2 Relationship between afferent chemosensory nerve discharge and PCO2 levels recorded from carotid body sinus nerve preparation in a cat. PCO2 levels were varied at different prevailing levels of PO2 . Note the increased slope of the relationship as O2 levels decline. (From Lahiri S, Delaney RG: Stimulus interaction in the responses of carotid body chemoreceptor single afferent fibers. Respir Physiol 24:249–266, 1975.)

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Figure 61-3 The HIF-1 hypoxia response pathway. With decreases in oxygen tension, the rate of proline hydroxylation decreases, leading to accumulation of HIF-1 . HIF-1 binds to HIF-1 to form a heterodimer that binds to, and activates expression of, various genes, including those encoding glycolytic enzymes (for anaerobic metabolism), VEGF (for angiogenesis), inducible nitric oxide synthase and heme-oxygenase-2 (for NO and CO production and vasodilatation), erythropoietin (for erythropoiesis), and possibly, tyrosine hydroxylase (for dopamine production and resultant effects on carotid body chemoreception). The gene products promote cell survival at low oxygen tension or act to restore normal oxygen levels. Some gene targets of HIF-1 are induced in most hypoxic cells, while others, like erythropoietin, are induced only in specific tissues, and, hence, require tissue-specific regulators. Mitochondrial inhibitors suppress HIF-1 , indicating that HIF-1 signaling is coupled to function of the mitochondrial respiratory chain. (Modified from Wilson DF, Roy A, Lahiri S: Immediate and long-term responses of the carotid body to high altitude. High Altitude Med Biol 6:97–111, 2005.)

Chronic Responses to Hypoxia The carotid body chemoreceptors are minimally sensitive to hypoxia at birth and become more sensitive over the first few days or weeks of life. The observation that chronic hypoxia increases hypoxia sensitivity applies to the carotid body of adult animals. In a state of chronic hypoxia (after 2 min of hypoxia), hypoxia-inducible factor (HIF-1α) becomes elevated (Fig. 61-3). Under normoxic conditions, HIF-1α is formed continuously and degraded in the cytoplasm. HIF-1α combines with a constitutively expressed component, HIF-1β to form HIF-1, which moves into the nucleus to produce gene transcription. HIF-1α is hydroxylated by the enzyme prolyl hydroxylases prior to its degradation. The prolyl hydroxylases have a relatively high Km for oxygen; hydroxylation leads to degradation under physiological conditions. Decreased oxygen pressure results in significant accumulation of HIF-1α in less than 2 min; HIF-1α is rapidly degraded upon reoxygenation. Recent studies reported that mice partially deficient in HIF-1α had a marked decrease in carotid body chemosensory response to acute hypoxia, but that the in vivo ventilatory response was not compromised. Furthermore, wild-type mice exposed to hypoxia for 3 days manifested an augmented ventilatory response to a subsequent acute hypoxic challenge. In contrast, chronic hypoxia resulted in a diminished ventilatory

response to acute hypoxia in the partially HIF-1α–deficient mice. Thus, partial HIF-1α deficiency has a significant effect on carotid body neural activity and ventilatory adaptation to chronic hypoxia. In the 1960s, Lahiri and Milledge working in the Himalayan high altitude, and Severinghaus et al. working in the South American altiplano found that adult natives showed a blunted ventilatory response to an acute reduction in inspired PO2 , both at rest and during exercise. The age at which this pulmonary adaptation occurred was not known; neither was it known whether it was acquired or genetic. The conclusion was that the responses to chronic hypoxia were determined by environmental rather than genetic factors. Recent investigations on the adaptive responses to hypoxia have demonstrated that increased expression of HIF-1α, VEGF, and iNOS normally present in young animals are less evident as animals age. Hence, oxygen-sensing mechanisms appear to decline with aging.

PHYSIOLOGICAL CHANGES AT HIGH ALTITUDE While a variety of physiological changes have been described during ascent to high altitude, several are particularly notable and are described briefly below.

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Pulmonary Circulation

Sleep and Periodic Breathing

In contrast to the systemic circulation, the pulmonary circulation is a high-flow, low-pressure system. Based upon a balance of hydrostatic and oncotic pressure gradients across pulmonary capillary microvessels, as represented in the Starling equation, the pulmonary interstitium and alveolar spaces are maintained “dry.” However, a disruption in hemodynamics, as may seen in hypoxic pulmonary vasoconstriction, may result in formation of excess lung water and overwhelming of the so-called “edema safety factors” (see Chapters 144 and 145). At high altitude, while respiratory mechanics do not change appreciably, changes in hemodynamics due to pulmonary hypertension may be dramatic. Pulmonary blood vessels are extensively supplied with sympathetic (vasoconstrictor) fibers and, to a smaller extent, parasympathetic (vasodilator) fibers. Despite this innervation, regulation of vasomotor tone is largely dictated by the local effects of PO2 and PCO2 . Alveolar hypoxia results in contraction of vascular smooth muscle, vessel narrowing, and shunting of pulmonary blood flow away from the hypoxic area. Furthermore, local CO2 accumulation leads to a decline in pH and resultant vasoconstriction (unlike the CO2 induced vasodilation seen in other tissues). The presence of pulmonary hypertension (both systolic and diastolic) at high altitude is well documented. It is more prominent in younger individuals than in older individuals and is related to the state of pulmonary vasoconstriction. Exercise accentuates pulmonary hypertension. Acute hypoxia causes a rise in pulmonary arterial pressure that falls when hypoxia is relieved if the hypoxia is present for only a few hours. Pulmonary artery pressure does not decline immediately if hypoxia is present for several days. After resolution of hypoxia, regression occurs in pulmonary hypertension and muscularization of the pulmonary arteries. The right ventricular hypertrophy associated with pulmonary hypertension also regresses upon return to sea level. The entire cardiac output passes through the lungs. At sea level, the low-pressure pulmonary circulation easily accommodates an exercise-related increase in blood flow, with little increase in pulmonary artery pressure and pulmonary vascular resistance. During acute hypoxemia, the relationship between pulmonary blood flow and pulmonary pressure is altered. During chronic hypoxia, structural remodeling of pulmonary arterioles results in increases in resting pulmonary arterial pressure and pulmonary vascular resistance. High-altitude residents show a widened pressure gradient from pulmonary artery to left atrium during exercise (as reflected in pulmonary artery occlusion or pulmonary capillary “wedge” pressure measured using a Swan-Ganz catheter). These findings suggest that at high altitude, vasomotor control of the pulmonary circulation resides in the lung arterioles, whereas at sea level it resides in the left heart. Altitude “resets” the regulatory mechanism, and exercise makes the difference obvious.

Sleep depresses ventilation, resulting in decreases in alveolar and arterial PO2 and increases in alveolar and arterial PCO2 . At altitude, these changes become critically important, stimulating breathing, increasing PO2 , and decreasing PCO2 which, in turn, decreases ventilation and initiates periodic breathing. At altitudes above 3000 m, subjects typically manifest periodic breathing, particularly during sleep. The quality of both REM and non-REM sleep becomes impaired. With acclimatization, the sleep pattern tends to become more normal. However, periodic breathing during non-REM sleep persists over time at higher altitudes.

Erythropoiesis Erythropoietin levels are increased at high altitude because of chronic hypoxia, resulting in increased numbers of erythrocytes. Hypoxia also increases ventilation, resulting in decreases in alveolar and arterial PCO2 and arterial [H+ ]; concomitantly, serum levels of 2,3-diphosphoglycerate (2,3DPG) are increased. While the reductions in PaCO2 and [H+ ] increase hemoglobin affinity for O2 , increases in 2,3-DPG diminish the affinity. Loading and unloading of O2 from hemoglobin depends upon the balance of these factors. As described previously, with chronic hypoxemia at high altitude, decreased hypoxic ventilatory drive is followed by decreases in arterial PO2 . Consequently, polycythemia and pulmonary hypertension arise, resulting in right ventricular hypertrophy, and eventually, in right heart failure and death. This syndrome of chronic mountain sickness (see below) is relieved only by descent to sea level.

Fluid Homeostasis and Renal Function In healthy individuals, ascent to high altitude normally results in a diuresis that persists during the stay. In addition, suppression occurs of voluntary sodium and water intake. Lung edema, cerebral edema, and peripheral edema may be seen (see below), with elevated levels of aldosterone and antidiuretic hormone.

COMMON CLINICAL DISORDERS OF HIGH ALTITUDE A variety of altitude-related clinical disorders are well recognized, including acute mountain sickness, high-altitude pulmonary edema, high-altitude cerebral edema, and chronic mountain sickness. While these entities may be observed at altitudes as low as 8000 feet (2500 m), their frequency increases with increasing altitude.

Acute Mountain Sickness Acute mountain sickness (AMS) affects previously healthy individuals who ascend rapidly to high altitude. After a delay of

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a few hours to 2 days, symptoms develop, including headache (usually frontal), nausea, vomiting, irritability, malaise, insomnia, and poor climbing performance. The simple or benign form of the condition is self-limiting, lasting 3 to 5 days. Typically, symptoms, once resolved, do not recur at a given altitude, although recurrence may be experienced if the subject ascends to higher altitude. In a small proportion of individuals, progression to the malignant forms of AMS—highaltitude pulmonary edema (HAPE), high-altitude cerebral edema (HACE), or a mixture of the two—may be seen (see below). If not treated, these conditions are frequently fatal in a matter of hours.

principal preventative pharmacologic measures; their benefits may be additive. Use of acetazolamide (250 mg at bedtime) for several days after arrival may improve sleep and ability to function during the day. Alternatively, the drug may be started 2 to 3 days before arrival at a dose of 250 to 500 mg twice daily. Prophylactic administration of acetazolamide is advisable for anyone with a prior history of AMS. Corticosteroids (e.g., dexamethasone at a dose of 4 mg every 6 hours) may be a suitable alternative for individuals unable to take acetazolamide (e.g., those with sulfa allergy). The drug is continued until acclimatization occurs after a few days.

Incidence The incidence of AMS depends upon the altitude attained and rate of ascent. With increased accessibility of high-altitude resorts and the feasibility of rapid ascent to high mountain locations in a very few days, the incidence of AMS has probably increased in recent years. A survey of alpine hut dwellers noted an incidence of 9 percent at 2850 m, 13 percent at 3050 m, 34 percent at 3650 m, and 53 percent at 4559 m. Among trekkers en route to an Everest base camp, the incidence was 43 percent at 4300 m; it was higher in those who had flown into an airstrip at 2800 m (49 percent) than those who had walked all the way (31 percent).

Treatment Simple or benign AMS is self-limiting and usually lasts about 3 days, so treatment is not essential; aspirin or paracetamol can be used to relieve headache, but they are not very effective. In a placebo-controlled trial, ibuprofen has been demonstrated to be useful. If the condition progresses to HAPE or HACE, urgent treatment is warranted, as described below. Acetazolamide and dexamethasone can alleviate symptoms of AMS. Acetazolamide is generally considered first-line treatment; dexamethasone can be used in sulfa-allergic individuals. A combination of the two agents can be used for rapidly evolving symptoms, particularly when descent may be delayed.

Mechanism Although hypoxia appears to be a trigger in the genesis of AMS, it is not the immediate cause, since symptoms are delayed by several hours after arrival at high altitude, despite the fact that hypoxia is most severe in the first few minutes. Symptoms are similar to those associated with increased intracranial pressure; in patients with high-altitude cerebral edema, evidence of increased intracranial pressure has been demonstrated. The most popular view is that even in simple AMS, a degree of cerebral edema (and, often subclinical pulmonary edema) causes the symptoms of AMS. In addition, a generalized disturbance of fluid balance or capillary permeability throughout the body is likely, accounting for other findings in AMS, including dependent or periorbital edema. Prevention A slow rate of ascent is the best way to prevent AMS. A suggested rule is that above 3000 m (10,000 ft), ascent should be at a rate less than 300 m (1000 ft) per day, with a “rest” day (i.e., no additional ascent) every 3 days. However, even this rate will be too fast for some and unnecessarily slow for others. An additional rule is, “If symptoms of AMS develop, go no higher. If they become severe, go down.” Individuals who ascend to high altitude should be advised to limit their activity for the first few days upon ascent. Adequate hydration should be encouraged. Although theophylline may be useful, and benzodiazepines have been investigated as prophylactic agents, acetazolamide, and dexamethasone constitute the

High-Altitude Pulmonary Edema In the great majority of cases, AMS is a minor affliction that resolves in a few days. However, in a small proportion of individuals ascending to high altitude, one or a combination of potentially lethal conditions may develop: acute pulmonary edema (HAPE) or cerebral edema (HACE). Their incidence depends on the rate of ascent and the population studied. Estimates are 0.5 to 2.0 percent. Individuals who have a previous history of HAPE are at greater risk of subsequent altituderelated disorders. Some demonstrate a “threshold” effect in which repeated ascents to a particular altitude are associated with development of HAPE at that altitude. In addition to lowlanders, individuals who normally reside at high altitude, but who descend and then return to high altitude are susceptible. Men and women of all ages may fall victim, although young males appear to be more at risk than others. Athletic fitness affords no protection. The typical patient is a previously fit young man who has climbed rapidly and is energetic on arrival. Moderate symptoms of AMS may be present initially as the individual becomes more breathless. A cough develops, which is initially dry, then productive of frothy white sputum, and later, bloodtinged. The climber may complain of chest discomfort. The pulse and respiratory rate are increased, and auscultation of the chest reveals crackles at the bases. An elevated jugular venous pressure and peripheral edema may be seen, and a right ventricular heave and accentuated pulmonary component of the second heart sound may be detected. Over a few hours, the

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patient’s condition may deteriorate further, with additional increases in pulse and respiratory rate. As breathing becomes “bubbly” due to pulmonary edema, cyanosis develops. In the absence of definitive treatment, coma and death ensue. Mechanism The mechanism underlying development of HAPE is unclear. Despite the clinical similarity to congestive heart failure, acute left ventricular failure does not appear to be the basis. Hemodynamic studies universally demonstrate a normal left atrial (pulmonary artery occlusion or “wedge”) pressure. The most popular hypothesis, originally proposed by Hultgren in the 1960s, is that susceptible subjects experience a brisk hypoxic pulmonary artery vasoconstrictor response that is uneven throughout the lung. In some areas, where there is a greater degree of vasoconstriction, blood flow is reduced and the areas are protected from development of pulmonary edema. In those areas in which vasoconstriction is less marked, increased blood flow is associated with edema formation, perhaps through flow-related capillary damage, or sheer stress on vessel walls, or increased intracapillary pressure. In addition, various kinins which have been identified in the edema fluid are likely to increase permeability further and to recruit additional leukocytes. Prevention Use of nifedipine prophylactically (slow-release formulation, 20 mg twice daily prior to ascent, then three times daily) appears to lower significantly the incidence of HAPE. Mean systolic pulmonary artery pressure is lowered with prophylaxis. The drug appears to be ineffective in preventing AMS. Prophylactic use of an inhaled beta agonist also reduces the risk of HAPE. Treatment Descent is critical for survival. Initial treatment while the subject awaits descent includes strict rest, supplemental oxygen, and, if available, use of a portable hyperbaric chamber. Although not yet studied in a well-controlled trial, nifedipine (10 mg sublingually) may be used. If clinically significant hypotension does not occur with the first dose of nifedipine, its administration can be repeated every 15 to 30 min. Future studies may establish a role for use of sildenafil and related compounds as prophylactic treatment in individuals at risk for HAPE.

High-Altitude Cerebral Edema The other malignant form of AMS is HACE. In its early stages, HACE is indistinguishable from simple AMS. Initially, headache, nausea, and vomiting are prominent symptoms. When ataxia develops, “benign” AMS has become “malignant.” Truncal ataxia (unsteadiness when sitting), hallucinations, clouding of consciousness, extensor plantar reflexes, and papilledema may follow. Concurrent signs of pulmonary

edema may also be noted. In the absence of treatment, coma arises. As for HAPE, descent is critical. While awaiting evacuation, supplemental oxygen should be given. Several hours in a portable hyperbaric chamber may be a useful and life-saving measure while descent is arranged; however, the beneficial effects of the portable chamber may develop more slowly in HACE than in HAPE, especially in severe cases. Administration of dexamethasone (4 to 8 mg), intramuscularly in severe cases, or orally in less severe cases, helps reduce cerebral edema and should be given while awaiting evacuation; doses can be repeated every 6 h.

Chronic Mountain Sickness In the 1920s, Carlos Monge reported cases of polycythemia in high-altitude residents of the Andes (Monge’s disease), and in 1942, Hurtado published detailed observations of eight cases, including symptomatology and hematological changes. The condition—chronic mountain sickness (CMS)—is quite different from AMS. CMS affects residents of high altitude, is more common in males, and develops in middle and later life. Its defining feature is extreme polycythemia, with hemoglobin concentrations as high as 23 gm/dL and hematocrits as high as 83 percent. Patients typically have rather vague neuropsychological complaints, including headache, dizziness, somnolence, fatigue, difficulty in concentration, and loss of mental acuity. Irritability, depression, and even hallucinations, may be observed. Dyspnea on exertion is not common, but poor exercise tolerance is; weight gain may also be seen. Characteristically, symptoms disappear on descent to sea level and reappear on return to high altitude. Although normal individuals are mildly cyanotic at an altitude of 4000 m, patients with CMS stand out with elevated hemoglobin concentrations, low oxygen saturations, and hence far higher concentrations of reduced hemoglobin. In Andean Indians, who have the highest prevalence of the disorder, signs may be florid, including black lips and winered mucosal surfaces. The conjunctivae are congested, and the fingers may be clubbed. In whites, the appearance is less striking, since it occurred at lower altitudes (e.g., in Leadville, CO, elevation 3100 m). Under these circumstances, affected individuals appear similar to patients with polycythemia secondary to hypoxic lung disease. Some patients show very few signs. As noted, symptoms and signs usually disappear upon descent to sea level, which is the definitive form of treatment. However, for many patients who wish to remain at altitude for family or economic reasons, phlebotomy and administration of supplemental oxygen are beneficial. Phlebotomy lowers the raised hematocrit and improves many of the neuropsychological symptoms. Pulmonary gas exchange and exercise performance are also improved in some subjects. An alternative to phlebotomy for residents at high altitude is the long-term use of respiratory stimulants. Medroxyprogesterone has been employed with some success; side

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effects, including loss of libido, limit its use. Although acetazolamide has been used in prevention of acute mountain sickness, trials addressing its use in CMS are lacking. However, the drug may be useful in improving oxygen saturation during sleep and in reducing the hematocrit. Further studies are necessary in establishing the role, if any, of sildenafil and related compounds in patients at risk for CMS.

ACKNOWLEDGMENT This work was supported in part by HL-43413 to SL from the U.S. National Institute of Health.

SUGGESTED READINGS Archer SL, Huang J, Henry T, et al: A redox-based O2 sensory in rat pulmonary vasculature. Circ Res 73:1100–1172, 1993. Bartsch P, Bailey DM, Berger MM, et al: Acute mountain sickness: Controversies and advances. High Alt Med Biol 5:110–124, 2004. Bartsch P, Maggiorini M, Ritter M, et al: Prevention of highaltitude pulmonary edema by nifedipine. N Engl J Med 1991;325:1284. Di Giulio C, Bianchi G, Cacchio M, et al: Oxygen and life span: Chronic hypoxia as a model for studying HIF-1α, VEGF and NOS during aging. Respir Physiol Neurobiol 147:31– 38, 2005. Di Giulio C, Cacchio M, Bianchi G, et al: Selected contribution: Carotid body as a model for aging studies: Is there a link between oxygen and aging? J Appl Physiol 95:1755– 1758, 2003. Dumont L, Mardirosoff C, Tramer MR: Efficacy and harm of pharmacological prevention of acute mountain sickness: Quantitative systematic review. Br Med J 321:267, 2000. Ghofrani HA, Reichenberger F, Kohstall MG, et al: Sildenafil increased exercise capacity during hypoxia at low altitudes and at mount Everest base camp: A randomized, doubleblind, placebo-controlled crossover trial. Ann Intern Med 141:169, 2004. Grissom CK, Roach RC, Sarnquist FH, et al: Acetazolamide in the treatment of acute mountain sickness: Clinical effi-

High-Altitude Physiology and Clinical Disorders

cacy and effect on gas exchange. Ann Intern Med 116:461, 1992. Heath D, Williams D: High Altitude Medicine and Pathology, 4th ed. Oxford, UK, Oxford Medical Publishers, 1995. Hoshi T, Lahiri S: Cell biology. Oxygen sensing: It’s a gas! Science 306:2050–2051, 2004. Katayama Y, Coburn RF, Fillers WS: Oxygen sensors in vascular smooth muscle. J Appl Physiol 77:2086–2092, 1994. Kline DD, Peng YJ, Manalo DJ: Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α. Proc Natl Acad Sci USA 99:821–826, 2002. Lahiri S, DiGiulio C, Roy A: Lessons from chronic and sustained hypoxia at high altitude. Respir Physiol Neurobiol 130:223–233, 2002. Lahiri S, Roy A, Baby SM, et al: Oxygen sensing in the body. Prog Biophys Mol Biol 91:249–286, 2006. Lahiri S, Roy A, Li J, et al: Role of Fe2+ in oxygen sensing in the carotid body. Adv Exp Med Biol 551:59–64, 2004. Maggiorini M, Buhler B, Walter M, et al: Prevalence of acute mountain sickness in the Swiss Alps. Br Med J 301:853– 855, 1990. Peers C: Interactions of chemostimuli at the single cell level: Studies in a model system. Exp Physiol 89:60–65, 2004. Rahn H, Otis AB: Man’s respiratory response during and after acclimatization to high altitude. Am J Physiol 157:445–462, 1949. Richalet JP, Gratadour P, Robach P, et al: Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. Am J Respir Crit Care Med 171:275, 2005. Roy A, Li J, Baby SM, et al: Effects of iron-chelators on ionchannels and HIF-1α in the carotid body. Respir Physiol Neurobiol 141:115–123, 2004. Semenza GL: Hydroxylation of HIF-1: Oxygen sensing at the molecular level. Physiology (Bethesda) 19:176–182, 2004. Tang XD, Xu R, Reynolds MF, et al: Haem can bind to and inhibit mammalian calcium-dependent Slo1 BK channels. Nature 425:531–535, 2003. Williams SE, Wootton P, Mason HS, et al: Hemoxygenase2 is an oxygen sensor for a calcium-sensitive potassium channel. Science 306:2093–2077, 2004. Wilson DF, Roy A, Lahiri S: Immediate and long-term responses of the carotid body to high altitude. High Alt Med Biol 6:97–111, 2005.

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62 Diving Injuries and Air Embolism James M. Clark

I. PULMONARY BAROTRAUMA Possible Sequelae of Alveolar Rupture during Decompression Arterial Gas Embolism Iatrogenic Arterial Gas Embolism II. DECOMPRESSION SICKNESS Clinical Manifestations of Decompression Sickness Pulmonary Decompression Sickness

Current estimates of active divers in the United States range from 1.6 to 2.9 million. The most accurate available statistics of diving related injuries are published online by the Divers Alert Network (DAN) in an Annual Review of Recreational Scuba Diving Injuries and Fatalities. Annual numbers of diving injuries treated at participating hyperbaric chamber facilities and reported to DAN America range from about 600 in 1987 to peaks of about 1160 in 1994 and 1999 to the most recent value of 1063 in 2002. During the period from 1970 to 2002, annual numbers of recreational diving fatalities in the United States and Canada range from a peak of 147 in 1976 to a low value of 66 in 1988 with an overall average of 99 per year. Of the 89 fatalities reported in 2002, 47 (53 percent) were attributed to drowning, 16 (18 percent) to air embolism, another 18 percent to cardiovascular problems, and only 1 (1 percent) to decompression sickness. It is likely that some of the drowning fatalities were precipitated by air embolism. Of all the possible causes of diving related injuries, this chapter will discuss only those caused by dissolved or embolic gas. The central role of gas in the pathogenesis of these injuries has been emphasized by referring to them collectively as gas lesion diseases. Although the incidence of arterial air embolism caused iatrogenically is not reported annually, it is likely that such statistics, if available, would add significantly to the morbidity and mortality of gas lesion diseases related to diving accidents. The adverse effects of diving-related gas lesions upon the lung and other vital organs originate from two major

III. CONTINUOUS PULMONARY EMBOLISM AS A MODEL OF PULMONARY DISEASE IV. HYPERBARIC OXYGEN THERAPY Hyperbaric Oxygen Therapy of Arterial Gas Embolism and Decompression Sickness V. LIMITATIONS IMPOSED BY OXYGEN TOXICITY

sources: (1) compression of gas within the lungs and other body spaces as ambient pressure is increased, with later expansion of that gas upon return to normal atmospheric pressure; and (2) solution of excess quantities of inert gas in blood and body tissues during exposure to increased ambient pressures, followed by evolution of venous and tissue bubbles when decompression occurs too rapidly. The former condition can cause pulmonary barotrauma, with arterial gas embolism as its most serious sequela, while the latter can result in decompression sickness with manifestations ranging from localized pain in a joint to massive neurological deficits from spinal cord infarction.

PULMONARY BAROTRAUMA If a diver were to descend while holding his or her breath, the gas within the lungs would be compressed progressively while maintaining a volume that is inversely proportional to the increasing pressure (Fig. 62-1). In order to prevent collapse of the lung to less than residual volume, with tearing of pulmonary parenchyma and blood vessels, the diver is obliged to breathe an oxygen-containing gas mixture at a pressure equal to that of the surrounding water. During return to normal atmospheric pressure, compressed gas within the lungs expands exponentially and must be exhaled if alveolar rupture is to be avoided.

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Figure 62-1 Relationship of relative gas volume to ambient pressure during compression from 1.0 to 6.0 atm (surface to 165 ft of sea water). Boyleâ&#x20AC;&#x2122;s law states that, at constant temperature, the volume of a gas is inversely proportional to its pressure. Bubbles on the left show the decrease in diameter that would occur during compression without access to a gas source at ambient pressure. Bubbles on the right show expansion that would occur during decompression after restoration of unit volume at a depth of 165 ft. Similar lung volume changes during diving are prevented by inhalation of compressed gas during descent and exhalation of expanding gas during ascent.

The greatest danger of alveolar bursting occurs within the last 33 ft of ascent to the surface, because the relative gas volume doubles during that transition (Fig. 62-1). Theoretically, a critical threshold for alveolar rupture could be reached by ascent from as shallow a depth as 4 ft (1.2 m) after full inspiration at that depth. Fatal arterial gas embolism has occurred following ascent from a depth of 7 ft (2 m).

Possible Sequelae of Alveolar Rupture during Decompression The sequelae of pulmonary overpressure accidents are determined by the nature and severity of associated tissue trauma as well as by the volume of expanding extra-alveolar gas. Following rupture of alveolar septa, expanding gas enters the interstitial spaces and dissects along perivascular sheaths to enter the mediastinum. Gas also may enter the pleural space to cause pneumothorax. Mediastinal gas may further dissect into the pericardial sac, the retroperitoneal space, or the subcutaneous tissues of the neck. Mediastinal emphysema is often associated with mild substernal discomfort that may be described as a dull ache

Figure 62-2 Supersaturation and bubble formation by countercurrent diffusion at the interface of a two-layer system. The two gas reservoirs are large, and their contents are well mixed. In this model, gas 1 (helium) diffuses more rapidly than gas 2 (nitrogen) through layer A (water), and the relative diffusivities of gases 1 and 2 are reversed in layer B (oil). Total gas pressure at any point in the system is the sum of partial pressures of both gases. Bubbles will form at the interface if suitable nuclei are present and if at least one of the two layers is a liquid. (From Graves DJ, Idicula J, Lambertsen CJ, Quinn JA: Bubble formation in physical and biological systems: A manifestation of counter-diffusion in composite media. Science 179:582â&#x20AC;&#x201C;584, 1973, with permission.)

or a feeling of tightness. Deep inspiration, coughing, or swallowing may exacerbate symptoms, and mild pain may radiate to the shoulders, neck, or back. Unless extensive, mediastinal emphysema is usually not associated with dyspnea, tachypnea, or other signs of respiratory distress. Clinically significant volumes of mediastinal gas have a distinctive appearance on the chest radiograph. Subcutaneous emphysema from pulmonary barotrauma causes swelling and crepitance in the neck and supraclavicular fossae. These signs may be associated with sore throat, dysphagia, or a change in voice tone. Subcutaneous gas can also be demonstrated radiographically. Recompression therapy is not needed for uncomplicated cases of mediastinal

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or subcutaneous emphysema. If symptoms are bothersome, resolution of gas can be hastened by breathing 100 percent oxygen at normal atmospheric pressure. Gas volumes within the pericardial sac or retroperitoneal space are seldom large enough to be clinically significant. Pneumothorax is not a frequent complication of pulmonary barotrauma. In one series of submarine escape ascents, pneumothorax occurred in 5 to 10 percent of the divers who had lung overinflation syndromes with arterial gas embolism. Recompression of an individual who is known to have a pneumothorax should be avoided if at all possible. Nevertheless, it must be carried out if neurological symptoms or any other manifestations of arterial gas embolism are present. Conversion from a simple to a tension pneumothorax will occur if a tear in the visceral pleura remains open during descent, thereby allowing compressed gas to enter the pleural space, and then becomes effectively sealed prior to ascent. Upon decompression, the gas in the pleural space will expand to compress the lung and interfere with venous return. Severe dyspnea, cyanosis, and hypotension may occur, especially if the inferior vena cava is kinked at the diaphragmatic hiatus. This is an emergency that will require immediate recompression to relieve symptoms and insertion of a chest tube before decompression is resumed. Smaller pneumothoraxes can be managed by inserting a large, 10- to 14-gauge catheter (Angiocath) through the appropriate intercostal space and attaching it to a flutter valve made from a Penrose drain or some other suitable material.

Arterial Gas Embolism When expanding extraalveolar gas is forced down a pressure gradient into torn septal vessels, it traverses the pulmonary veins to the left atrium and left ventricle, from which it is ejected into the systemic circulation as foamy particles or discrete bubbles. Distribution of the gas emboli is determined by their buoyancy relative to blood and orientation of the body with respect to gravity. It may also be influenced by local factors such as blood flow and vessel size. With the body in the head-up, erect position, most of the embolic air travels to the brain. Cerebral air embolism is a relatively frequent component of lung overinflation syndromes. In a series of 88 divers with pulmonary barotrauma, the incidence of neurological signs and symptoms was about 75 percent. Electroencephalographic evidence of abnormal neuronal activity after submarine escape training ascents in the absence of associated clinical manifestations indicates that the true incidence of cerebral gas embolism may be even higher than that established on the basis of positive historical and physical findings. Clinical manifestations of dysbaric arterial gas embolism have been grouped into two or three categories, based on the initial presentation and response to treatment. About 5 percent of the divers who experience arterial gas embolism are critically injured and often die even when recompression is initiated within minutes. These individuals develop apnea, unconsciousness, and cardiac arrest during ascent or

Diving Injuries and Air Embolism

immediately after surfacing from a dive. Possible causes of this frequently lethal condition include massive volumes of air in the central circulation, cerebral embolism, and/or direct embolization of the coronary arteries. The majority of patients with dysbaric arterial gas embolism present with neurological signs and symptoms, but spontaneous respiration and heart rate are maintained. Just as in the more seriously injured divers, onset of symptoms occurs during ascent or within minutes after surfacing. The clinical spectrum of neurological disturbances ranges from focal signs, such as monoparesis or discrete sensory deficits, to diffuse brain dysfunction, as manifest by confusion, stupor, or coma. In response to prompt recompression, most patients have complete resolution of all neurological deficits. For reasons that are not well understood, a subgroup of these patients fail to respond completely or experience initial improvement followed by recurrence of the presenting signs and symptoms. The probability of incomplete response or recurrence is increased as the time between onset of symptoms and initiation of definitive therapy is prolonged.

Iatrogenic Arterial Gas Embolism Accidental arterial gas embolism is a serious and sometimes lethal complication of many procedures that are widely used in modern medicine. It is often misdiagnosed or recognized only after a delay of several hours. Even when the diagnosis of arterial gas embolism is correctly made, many physicians who are not specifically trained in diving medicine are apparently unaware that hyperbaric oxygenation is the definitive and highly efficacious therapy for this condition. Arterial gas embolism has been reported in association with a variety of procedures including cardiac surgery; intravenous therapy, especially with the use of central venous catheters; neurosurgery; pulmonary diagnostic or surgical procedures; surgery of the aorta or cervical arteries; surgical procedures involving the head and neck; hemodialysis; arterial catheterization, especially for arteriography; mechanical ventilation; abdominal or retroperitoneal gas insufflation; liver transplantation; and uterine catheterization or insufflation, usually during criminal abortion (i.e., if performed under nonmedical, unsterile conditions). Most cases of accidental arterial gas embolism present with focal or diffuse manifestations of brain ischemia. Management is often made more difficult by the existence of concurrent medical or surgical complications. In many patients, hyperbaric oxygen therapy, if administered promptly, completely reverses all neurological deficits. It is generally remarkably efficacious even when initiated after a delay of several hours.

DECOMPRESSION SICKNESS Decompression sickness, which is characterized by a broad clinical spectrum with multiple manifestations, occurs when ambient pressure is reduced too rapidly to allow the inert gas dissolved in blood and body tissues to remain in

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physical solution. It usually occurs in the diver after inadequate decompression from prolonged exposure to increased ambient pressures, but it can also occur in the aviator or astronaut who is exposed to high altitude or space with blood and body tissues that are saturated with inert gas at normal atmospheric pressure. Although the precipitating cause of decompression sickness is the evolution of dissolved inert gas from body fluids, neither the physical mechanisms nor the locations of bubble formation are completely understood. Both intravascular and extravascular bubbles have been found in animals exposed to severe decompression stress. Intravascular bubbles are more likely formed in veins than in arteries, due to the greater hydrostatic pressure in the latter vessels. Primary effects caused by the physical presence of undissolved gas in vivo include the obstruction of blood vessels and the mechanical disruption of tissue. In addition, there are secondary effects, caused by tissue reactions to intravascular or extravascular bubbles, which include the concurrent activations of cellular components, such as leukocytes and platelets, and biochemical pathways, such as the complement, coagulation, and kinin systems. It is also possible during or after decompression from a dive to have circulating venous bubbles, as detected by Doppler ultrasonography, without precipitating the onset of decompression sickness.

Clinical Manifestations of Decompression Sickness Musculoskeletal pain in one or more extremities is the most common symptom of decompression sickness in military divers, commercial divers, and caisson workers. Sport divers, in contrast, more commonly present with neurological symptoms or signs. These apparent patterns may reflect both the reluctance of professional divers to report neurological symptoms due to the related occupational penalties and the tendency of many recreational divers to delay seeking medical assistance until neurological symptoms occur. However, neurological and pain-only manifestations of decompression sickness also appear to have different latencies. Among divers who present with neurological involvement, about 50 percent become symptomatic within 10 min of surfacing, and over 90 percent are symptomatic within 3 h. In about 90 percent of divers who present with musculoskeletal pain only, symptoms occur within 6 h after the dive. Onsets of decompression sickness 36 h or more after the dive have been reported, but delays exceeding 24 h are extremely rare. Relatively long delays prior to symptom onset sometimes occur during flights in commercial aircraft that are not pressurized to 1.0 atm and may have cabin altitudes as high as 8000 ft. It is generally recommended that flying should be delayed for at least 24 h after diving. Clinical manifestations of neurological decompression sickness usually reflect involvement of the spinal cord at the lower thoracic or upper lumbar levels. Paresthesias and sensory deficits may occur with or without associated weakness or paralysis. Transient or persistent abdominal pain may be

present. Bladder or bowel dysfunction may occur alone or with associated signs. A form of decompression sickness that is characterized by vestibular involvement may present with the sudden onset of vertigo and severe impairment of balance. Associated symptoms often include nausea, vomiting, nystagmus, tinnitus, and sometimes hearing loss. Vestibular decompression sickness can be unusually difficult to treat, as manifest by a slow or incomplete response to aggressive hyperbaric oxygen therapy.

Pulmonary Decompression Sickness This relatively rare form of decompression sickness occurs most frequently after short, deep dives or altitude decompressions. This condition, known to divers as the “chokes,” is manifest by substernal pain, cough, and dyspnea, often associated with extreme malaise. The onset of symptoms is often within minutes after decompression, but it may be delayed for several hours. In some instances, there is only a mild sensation of chest “tightness” that resolves spontaneously. Patients who are more severely affected characteristically manifest a progressive exacerbation of symptoms, entailing rapid, shallow breathing to avoid substernal pain and paroxysmal coughing whenever deep inspiration is attempted. If untreated by hyperbaric oxygenation, pulmonary decompression sickness can terminate in hypoxemia, pulmonary hypertension, shock, and death. The pathogenesis of pulmonary decompression sickness apparently involves accumulation in the lung of embolic bubbles along with entrapped aggregates of platelets, fibrin, leukocytes, and erythrocytes. These events may be accompanied by release of vasoactive substances, thromboxanes, and leukotrienes. Endothelial damage with increase in vascular permeability may also occur. Although these potential mechanisms were demonstrated in animal models that were subjected to extreme decompression stress or direct venous gas infusions, divers who remained asymptomatic after exposure to a single air decompression dive had significant reductions in arterial PO2 and pulmonary diffusing capacity for carbon monoxide concurrently with the detection of venous bubbles by precordial Doppler monitoring.

CONTINUOUS PULMONARY EMBOLISM AS A MODEL OF PULMONARY DISEASE Development of a unique experimental model of lung disease was stimulated by a series of unexpected observations during deep diving research in human subjects exposed in a hyperbaric chamber to ambient pressures equivalent to depths up to 1200 ft of seawater. When the respired inert gas was nitrogen or neon, with helium as the ambient inert gas at constant ambient pressure, the subjects experienced intense itching in association with maculopapular skin lesions and, on some occasions, developed severe vestibular derangements, with vertigo and nystagmus. The skin lesions were found to be caused by gas bubbles in the skin and subcutaneous tissues.

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The vestibular derangements were attributed to counterdiffusion of inert gases through the eardrum and middle ear to the inner ear. Subsequent experiments in pigs and in vitro systems revealed that the development of skin and subcutaneous tissue gas bubble lesions at constant pressure was caused by the more rapid inward diffusion of helium from the ambient atmosphere into skin capillaries than outward diffusion of nitrogen or neon from capillaries to atmosphere. The process has been designated “isobaric counterdiffusion gas lesion disease,” and Fig. 62-2 illustrates schematically its probable pathogenetic mechanism. In vivo systems are obviously much more complex than the simple two-layer system shown in Fig. 62-2. Continuous, steady-state venous gas embolism can be produced in an anesthetized pig by administration of a normoxic nitrous oxide–oxygen inspired gas mixture with all or part of the pig’s body enclosed in a helium-filled bag. This inert gas counterdiffusion model can be used to study adverse effects of gas embolization, interactions of bubble surfaces with blood and vascular constituents, and various methods of therapeutic intervention.

HYPERBARIC OXYGEN THERAPY The oxygen environment of any organ or tissue depends on several interacting factors that influence the balance between oxygen supply and its metabolic utilization. Arterial oxygen content is determined by oxygen partial pressure, hemoglobin

Diving Injuries and Air Embolism

concentration, and oxyhemoglobin percent saturation. Oxygen supply to any organ is also highly dependent on the blood flow. Diffusion distance between any individual cell and the nearest capillary is determined by the density of the capillary network. Finally, at the mitochondrial end of the oxygen pathway, tissue requirements for oxygen are determined by the level of metabolic activity. Many of the therapeutic benefits of hyperbaric oxygenation are associated with its capacity for increasing oxygen delivery to hypoxic tissues (Fig. 62-3). Although little additional oxygen can be combined with hemoglobin, which is 97 to 98 percent saturated at normal arterial PO2 , the quantity of physically dissolved oxygen increases linearly with arterial PO2 elevation (about 2.4 ml O2 per 100 ml blood per atmosphereinspired PO2 ). This important increment in arterial oxygen content is associated with a much larger elevation of the oxygen partial pressure gradient from capillary blood to metabolizing cell. The combined increments in oxygen content and diffusion gradient facilitate oxygen delivery to tissues that, due to ischemia or some other cause, remain hypoxic during air breathing. In many of these states, oxygen breathing at 1.0 atm would also be beneficial, but the associated increments in oxygen content and PO2 are often insufficient to ensure resumption of normal metabolic function in ischemic tissues. Medical uses of hyperbaric oxygen therapy now extend considerably beyond its initial applications in diving. Several conditions in which there is a physiological and/or experimental basis for its use and in which its clinical efficacy has been demonstrated are listed in Table 62-1. A comprehensive review of clinical experience with all of the medical

Figure 62-3 Hemoglobin-bound and physically dissolved oxygen in the arterial blood of normal men. Top: A typical range of arterial to mixed venous PO2 (A1 to V1 ) during air breathing and its relationship to oxyhemoglobin percent saturation. The points through which the curve is drawn represent measurements in arterial blood of normal men breathing air or low oxygen/gas mixtures. Hemoglobin is an important source of oxygen transport at this level of PO2 . Bottom: The increase in arterial PO2 and the additional oxygen uptake over that bound to hemoglobin when inspired PO2 is increased to 3.5 atm. The additional oxygen is transported as gas physically dissolved in blood water. Fall in PO2 from A2 to V2 indicates the decrement across brain capillaries predicted on the basis of same oxygen extraction that occurs during air breathing. Direct measurement shows that brain venous PO2 actually falls to V3 , because brain blood flow is reduced prominently during oxygen breathing at 3.5 atm. Lambertsen CJ: Effects of hyperoxia on organs and their tissues, in Robin ED (ed): Extrapulmonary Manifestations of Respiratory Disease. New York, Marcel Dekker, 1978, pp 239–303.

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Table 62-1 Current Indications for Hyperbaric Oxygen Therapy Approved by the Hyperbaric Oxygen Therapy Committee of the Undersea and Hyperbaric Medical Society Gas lesion diseases Decompression sickness Gas embolism Infections Clostridial myonecrosis Necrotizing soft tissue infections Chronic refractory osteomyelitis Vascular insufficiency states Radiation necrosis of bone or soft tissue Healing enhancement in problem wounds Compromised skin grafts or flaps Acute traumatic ischemias Thermal burns Postischemic reperfusion injury Carbon monoxide poisoning source: Modified after Clark JM. Hyperbaric oxygen therapy, in The Lung: Scientific Foundations, 2nd ed. Crystal RG, West JB, Weibel ER, et al (eds), Philadelphia, Lippincott-Raven, 1997. pp. 2667â&#x20AC;&#x201C;2676.

applications of hyperbaric oxygen therapy and what is currently known about mechanisms for the observed beneficial effects is beyond the scope of this chapter. Succinct summaries of therapeutic applications of hyperbaric oxygenation are updated and published every 3 or 4 years by the Hyperbaric Oxygen Therapy Committee of the Undersea and Hyperbaric Medical Society.

Hyperbaric Oxygen Therapy of Arterial Gas Embolism and Decompression Sickness Although arterial gas embolism and decompression sickness have different etiologies and clinical presentations, similar therapeutic principles are applied in both conditions. Primary aims of therapy in both cases are reduction in bubble size, acceleration of bubble resolution, and maintenance of tissue oxygenation. Resolution of bubbles in decompression sickness and air embolism is greatly hastened by breathing oxygen at increased pressure, because the associated elimination of nitrogen from all body tissues and concurrent bubble compression combine to maximize the outward diffusion gradient for bubble nitrogen. The pressure-oxygenation profile used to accomplish these aims in arterial gas embolism is shown in Fig 62-4. The rationale for initial compression to 165 ft is that reduction in bubble size to one-sixth of their original volume will allow at least some bubbles to traverse capillaries

Figure 62-4 Pressure-time profile for hyperbaric oxygen therapy of arterial gas embolism and severe decompression sickness. During the initial period of compression to a pressure equivalent to a depth of 165 fsw, 50 percent O2 in N2 is administered to the patient for up to 30 min. Upon decompression to 60 fsw over a 4-min interval, the patient breathes 100 percent O2 and chamber air intermittently for at least 75 min. After a 30-min period of decompression on oxygen to 30 fsw, the patient breathes oxygen and air intermittently for at least 150 min, followed by another 30-min decompression on oxygen to normal ambient pressure. (Modified from U.S. Navy Diving Manual, vol 5. Flagstaff, AZ, Best, 1999. with permission.)

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Figure 62-5 Manifestations of oxygen poisoning in specific organs and functions. (Modified from Clark JM, Thom SR: Oxygen under pressure, in Brubakk AO, Neuman TS (eds): Bennett and Elliott’s Physiology and Medicine of Diving, 5th ed. Philadelphia, Saunders, 2003, pp 358–418, with permission.)

and enter the venous circulation to be trapped in the lung. Although the patient cannot safely breathe 100 percent oxygen at 165 ft, administration of 50 percent oxygen throughout this phase will provide hyperoxygenation at a level slightly greater than that afforded by breathing 100 percent oxygen at 60 ft. Oxygen is administered intermittently throughout the remainder of the therapy to accelerate bubble resolution and maintain tissue oxygenation, while avoiding harmful effects of oxygen toxicity by allowing partial recovery during the air intervals. The profile in Fig. 62-4 may be extended in severe cases by adding oxygen intervals at 60 and 30 ft. Hyperbaric oxygen therapy of decompression sickness, which seldom involves cerebral gas embolism, is usually performed by compressing directly to 60 ft without prior pressurization to 165 ft. In both arterial gas embolism and decompression sickness, increased blood viscosity, hypovolemia, and other systemic effects of bubble interactions with blood components and vessels occur concurrently with the localized tissue ischemia caused by mechanical vascular obstruction. Isotonic fluids are administered intravenously to oppose at least some of these secondary effects. If the patient has other conditions that require medical or surgical intervention, such care is provided concurrently with the administration of hyperbaric oxygenation.

LIMITATIONS IMPOSED BY OXYGEN TOXICITY During oxygen breathing at increased ambient pressures, rate of intoxication increases progressively in proportion to inspired PO2 elevation. Duration of oxygen exposure at 1.0 to 2.0 atm is limited primarily by pulmonary effects of oxygen toxicity. At oxygen pressures of 3.0 atm or higher, visual impairment and convulsions usually occur before development of prominent pulmonary intoxication. Although the toxic effects of oxygen are numerous and varied (Fig. 62-5), they can be avoided by appropriate administration of hyperbaric oxygen therapy. Early stages of intoxication, even when associated with symptoms and detectable functional alterations, are fully reversible upon termination of exposure. The onset of toxic effects is delayed effectively by periodic interruption of oxygen exposure with scheduled “air breaks” (Fig. 62-4).

SUGGESTED READING Bove AA (ed): Bove and Davis’ Diving Medicine, 4th ed. Philadelphia, Saunders, 2004.

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Brubakk AO, Neuman TS (eds): Bennett and Elliott’s Physiology and Medicine of Diving, 5th ed. Philadelphia, Saunders, 2003. Clark JM, Lambertsen, CJ: Pulmonary oxygen toxicity: A review. Pharmacol Rev 23:37–133, 1971. Clark JM, Thom SR: Oxygen under pressure, in Brubakk AO, Neuman TS (eds): Bennett and Elliott’s Physiology and Medicine of Diving, 5th ed. Philadelphia, Saunders, 2003, pp 358–418. Divers Alert Network Report on Decompression Illness, Diving Fatalities and Project Dive Exploration. Durham, NC, Divers Alert Network, 2004. Dujic Z, Eterovic D, Denoble P, et al: Effect of a single air dive on pulmonary diffusing capacity in professional divers. J Appl Physiol 74:55–61, 1993. Elliott DH, Harrison JAB, Barnard EEP: Clinical and radiological features of 88 cases of decompression barotrauma, in Shilling CW, Beckett MW (eds): Underwater Physiology, vol 6. Bethesda, MD, FASEB, 1978, pp 527– 535. Evans DE, Kobrine AI, Weathersby PK, Bradley ME: Cardiovascular effects of cerebral air embolism. Stroke 12:338– 344, 1981. Francis TJR, Mitchell SJ: Manifestations of decompression disorders, in Brubakk AO, Neuman TS (eds): Bennett and Elliott’s Physiology and Medicine of Diving, 5th ed. Philadelphia, Saunders, 2003, pp 578–599. Francis TJR, Mitchell SJ: Pathophysiology of decompression sickness, in Brubakk AO, Neuman TS (eds): Bennett and Elliott’s Physiology and Medicine of Diving, 5th ed. Philadelphia, Saunders, 2003, pp 530–556.

Gesell LB (ed): Hyperbaric Oxygen 2007: Indications and Results. The Hyperbaric Oxygen Committee Report. Kensington, MD, Undersea and Hyperbaric Medical Society. In press. Graves DJ, Idicula J, Lambertsen CJ, Quinn JA: Bubble formation in physical and biological systems: A manifestation of counter-diffusion in composite media. Science 179:582– 584, 1973. Ingvar DH, Adolphson J, Lindemark C: Cerebral air embolism during training of submarine personnel in free escape. Aerospace Med 44:628–635, 1973. Lambertsen CJ: Effects of hyperoxia on organs and their tissues, in Robin ED (ed): Extrapulmonary Manifestations of Respiratory Disease. New York, Marcel Dekker, 1978, pp 239–303. Lambertsen CJ, Idicula J: A new gas lesion syndrome in man, induced by “isobaric gas counterdiffusion.” J Appl Physiol 39:434–443, 1975. Moon RE, Gorman DF: Treatment of the decompression disorders, in Brubakk AO, Neuman TS (eds): Bennett and Elliott’s Physiology and Medicine of Diving, 5th ed. Philadelphia, Saunders, 2003, pp 600–650. Neuman TS: Arterial gas embolism and pulmonary barotrauma, in Brubakk AO, Neuman TS (eds): Bennett and Elliott’s Physiology and Medicine of Diving, 5th ed. Philadelphia, Saunders, 2003, pp 557–577. Neuman TS, Thom SR (eds): Physiology and Medicine of Hyperbaric Oxygen Therapy. Philadelphia, Elsevier. In press. Pierce EC: Cerebral gas embolism (arterial) with special reference to iatrogenic accidents. HBO Rev 1:161–184, 1980. U.S. Navy Diving Manual, vol 5. Flagstaff, AZ, Best, 1999.

63 Thermal Lung Injury and Acute Smoke Inhalation Daniel L. Traber Perenlei Enkhbaatar

I. OVERVIEW AND EPIDEMIOLOGY II. THE FIRE ENVIRONMENT Toxic Smoke Compounds Carbon Monoxide Hydrogen Cyanide Other Toxic Chemicals

OVERVIEW AND EPIDEMIOLOGY Inhalation injury is a serious medical problem. In the case of smoke, more than 30 percent of thermally injured patients admitted to burn centers in the United States have a concomitant smoke inhalation injury. Similar percentages of fire victims who have sustained smoke inhalation appear in several other countries. Despite effective management of fluid resuscitation and early surgical excision of burned tissue, the mortality rate of patients who have combined burn and smoke inhalation injury is still high. In patients with combined injury, the lung is a critical organ and the progressive respiratory failure associated with pulmonary edema is a pivotal determinant of mortality. Although not as lethal, smoke inhalation alone is a serious problem. It is estimated by the World Health Organization that there are over 1 billion people who develop airway and pulmonary inflammation as a result of inhaling smoke from indoor cooking fires, forest fires, and burning of crops. The inhalation of smoke has been of interest for a number of years, especially as the result of the use of gas warfare. In the 1940s there were two very large fires that focused interest on the inhalation of smoke in fire victims. The first was a fire at a nightclub in Boston called the Cocoanut Grove, where a large number of people were trapped in a burning building and consequently sustained severe inhalation injury.

III. PATHOPHYSIOLOGY Tracheobronchial Area Lung Parenchyma Treatment

It is interesting that in recent times a similar fire occurred in a nightclub near Boston in Rhode Island. The second occurred in Texas City across the bay from Galveston, Texas. Here a ship exploded in a harbor and set off a chain of explosions and fires among some 50 refineries and chemical plants, resulting in over 2000 hospital admissions of patients with smoke inhalation alone, those with burn injuries, many of whom who had simultaneously inhaled smoke as well. In many ways the burn victims of the 9/11 disaster were similar to these individuals, since the burns and inhalation involved combustion of petroleum products. At any rate, these two disasters led to the establishment of centers for the care of burn victims and research into the pathophysiology of burn injury.

THE FIRE ENVIRONMENT Toxic Smoke Compounds Inhalation injury is caused by steam or toxic inhalants such as fumes, gases, and mists. Fumes consist of small particles dispersed in air with various irritants or cytotoxic chemicals adherent to the particles. Mists consist of aerosolized irritant or cytotoxic liquids. Smoke consists of a combination of fumes, gases, mists, and hot air. Heat, toxic gases, and low oxygen levels are the most common causes of death in fire

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Table 63-1 Origin of Selected Toxic Compounds Gases and Chemicals

Material

Source

Carbon monoxide

Polyvinyl chloride Cellulose

Upholstery, wire/pipe coating, wall, floor, furniture coverings Clothing, fabric Wood, paper, cotton

Cyanide

Wool, silk Polyurethane Polyacrylonitrile Polyamide Melamine resins

Clothing, fabric, blankets, furniture Insulation, upholstery material Appliances, engineering, plastics Carpeting, clothing Household and kitchen goods

Hydrogen chloride

Polyvinyl chloride Polyester

Upholstery, wire/pipe coating, wall, floor, furniture coverings Clothing, fabric

Phosgene

Polyvinyl chloride

Upholstery, wire/pipe coating, wall, floor, furniture coverings

Ammonia

Wool, silk Polyurethane Polyamide Melamine resins

Clothing, fabric, blankets, furniture Insulation, upholstery material Carpeting, clothing Household and kitchen goods

Sulfur dioxide

Rubber

Tires

Hydrogen sulfide

Wool, silk

Clothing, fabric, blankets, furniture

Acrolein

Cellulose Polypropylene Acrylics

Wood, paper, cotton jute Upholstery, carpeting Aircraft windows, textiles, wall coverings

Formaldehyde

Melamine resins

Household and kitchen goods

Isocyanates

Polyurethane

Insulation, upholstery material

Acrylonitriles

Polyurethane

Insulation, upholstery material

Source: Data from Prien T, Traber DL: Toxic smoke compounds and inhalation injury: A review. Burns 14:451â&#x20AC;&#x201C;460, 1988.

scenes. A large variety of toxic gases and chemicals can be generated depending on the fire environment (Table 63-1). Many of these compounds may act together to increase mortality, especially carbon monoxide and hydrogen cyanide, in which a synergism has been found to increase tissue hypoxia and acidosis and perhaps also decrease cerebral oxygen consumption and metabolism. Hydrogen sulfide would also be predicted to synergize with carbon monoxide since both cyanide and hydrogen sulfide are inhibitors of mitochondrial cytochrome oxidase. Victims may be incapacitated by the blinding and irritating effects of smoke, as well as the decreasing oxygen concentration that occurs with combustion and results in progressive hypoxia. Inhalation injury can be classified: (1) upper airway injury, (2) lower airways and pulmonary parenchyma injury,

and (3) systemic toxicity. The extent of inhalation damage depends on the fire environment: the ignition source, temperature, concentration, and solubility of the toxic gases generated. For instance, thermal and chemical compounds usually cause upper airway injury. The water-soluble materials such as acrolein and the other aldehydes damage the proximal airways and set off reactions that are inflammatory to the bronchi and parenchyma, whereas agents with lower water solubility, such as chlorine, phosgene, and nitrogen oxide, nitrogen dioxide, or N2 O3 or even N2 O4 are more likely to cause insidious injury. Toxic gases such as carbon monoxide and cyanide rarely damage the airway but affect gas exchange, producing more systemic effect. Thus, it is important to obtain information relative to the source of the fire and combustion products generated when treating a fire victim (Table 63-1). It is also

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important to know the duration of exposure and the extent to which the fire victim was in an enclosed area because this relates to the dose of toxic materials presented.

Carbon Monoxide

Thermal Lung Injury and Acute Smoke Inhalation

Table 63-2 Symptoms and Signs at Various Concentrations of Carboxyhemoglobin

Carbon monoxide (CO) is an odorless, colorless gas that is produced by incomplete combustion of many fuels, especially cellulolytic (cellulose products) such as wood, paper, and cotton. Carbon monoxide toxicity remains one of the most frequent immediate causes of death following smokeinduced inhalation injury. The predominant toxic effect of CO is its binding to hemoglobin to form carboxyhemoglobin (COHb). The affinity of CO for hemoglobin is approximately 200 to 250 times higher than that of oxygen. Inhalation of a 0.1 percent carbon monoxide mixture may result in generation of a carboxyhemoglobin level as high as 50 percent. The competitive binding of CO to hemoglobin reduces delivery of oxygen to tissues, leading to severe hypoxia, especially of the most vulnerable organs such as the brain and heart. The oxygenhemoglobin dissociation curve loses its sigmoid shape and is shifted to the left, thus further impairing tissue oxygen availability. In addition, the ability of CO to bind to intracellular cytochromes and other metalloproteins contributes to CO toxicity. This competitive inhibition with cytochrome oxidase enzyme systems (most notably cytochromes a and P450) results in an inability of cellular systems to use oxygen. Shimazu and colleagues have shown that extravascular binding of CO to cytochromes and other structures accounts for 10 to 15 percent of total body CO stores, which explains the two-compartment elimination of CO from the circulation. Miro and colleagues reported that CO inhibits cytochrome c oxidase activity in lymphocytes. The electron chain dysfunction by CO may cause electron leakage, leading to superoxide production and mitochondrial oxidative stress.

COHb%

Symptoms

0–10

None

10–20

Tightness over forehead, slight headache, dilation of cutaneous blood vessels

20–30

Headache and throbbing in the temples

30–40

Severe headache, weakness, dizziness, dimness of vision, nausea, vomiting, collapse

40–50

As above; greater possibility of collapse, syncope, increased pulse and respiratory rate

50–60

Syncope, increased pulse and respiratory rate, coma, intermittent convulsions, Cheyne Stokes respirations

60–70

Coma, intermittent convulsions, depressed cardiac and respiratory function, possible death

70–80

Weak pulse, slow respirations, death within hours

80–90

Death in less than 1 h

90–100

Death within minutes

Symptoms and Diagnosis The symptoms may predominantly manifest in organ and systems with high oxygen utilization. The severity of clinical manifestations is varied depending on the concentration of CO. For instance, central nervous system symptoms such as headache, confusion, and collapse may occur when the blood COHb level is 40 to 50 percent. Symptoms such as unconsciousness, intermittent convulsions, and respiratory failure may occur if the COHb level exceeds 60 percent, and eventually leading to death if exposure continues. The cardiovascular manifestations may result in tachycardia, increase in cardiac output, dysrhythmias, myocardial ischemia, and hypotension depending on severity of poisoning. The correlation of clinical manifestation and severity of CO poisoning is summarized in Table 63-2. The diagnosis should be based on direct measurement of COHb levels in arterial or venous blood by co-oximetry. Portable breath analyzers may be used at the scene. Inability to differentiate oxyhemoglobin from COHb limits the use of pulse oximeters. The use of blood gas analyzers that estimates SO2 based on measurement of dissolved PO2 should be avoided

Source: Data from Einhorn IN: Physiological and toxicological aspects of smoke produced during the combustion of polymeric materials. Environ Health Perspect 11:163–189, 1975; Schulte JH: Effects of mild carbon monoxide intoxication. Arch Environ Health 7:524–530, 1963.

also. The measurements of acid-base balance, plasma lactate levels, and bicarbonate are helpful in management of CO poisoning with accompanying lactic or metabolic acidosis. It is important to note that high oxygen concentrations are usually administered to the victim in transit to the hospital, and some delay from cessation of exposure to measurement of CO may limit evaluation of the true extent of exposure. A nomogram has been developed that can relate the carboxyhemoglobin levels of a patient to the values that may have been present at the time of smoke inhalation; this can be used to estimate the true degree of inhalation injury. Treatment The half-life of carboxyhemoglobin is 250 min (adult male) in room air and 40 to 60 min in a person breathing 100 percent oxygen at 1 atmosphere (atm). Those values are 30 percent

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shorter in females. Therefore, all fire victims should be isolated from fire site and given 100 percent oxygen en route to the hospital. This allows delivery of an inspired oxygen concentration of 50 to 60 percent, which is usually adequate. To adequately treat CO poisoning it is important also to establish COHb level as early as possible. In a patient with loss of consciousness, cyanosis, or an inability to maintain the airway, 100 percent oxygen should be delivered via mechanical ventilation through endotracheal tube until the COHb levels drop below 10 to 15 percent. The alternative method to rapidly decrease COHb is hyperbaric oxygen therapy. The hyperbaric oxygen therapy allows CO to dissociate from cytochrome a, a3 , and to increase PO2 despite impaired hemoglobin function. Chou and colleagues reported that children with CO poisoning alone who are treated with hyperbaric oxygen therapy (HBOT) are at low risk for dying regardless of initial COHb level. However, there is some debate on use of HBOT especially in patients with burn injury. Because of the difficulty of physiological monitoring and providing emergency procedures in small chambers, unstable hemodynamic conditions and other complications such as seizures or aspiration of severely burned patients limit the use of hyperbaric oxygen therapy.

Hydrogen Cyanide Hydrogen cyanide is a colorless gas with the odor of bitter almonds. However, it is difficult to detect it on the site of fire. Cyanide is a likely weapon for terrorists because of its notoriety, lethality, and availability. Hydrogen cyanide is produced in fires involving nitrogen-containing polymers (upholstery, furniture, nylon, wool, silk, and acrylics) and may produce rapid and lethal incapacitation of a victim at the fire source. Toxicity of cyanide is produced by inhibition of cellular oxygenation with resultant tissue anoxia, which is caused by reversible inhibition of cytochrome c oxidase. It is toxic to a number of enzyme systems. The mechanism includes combination with essential metal ions, formation of cyanohydrins with carbonyl compounds, and the sequestration of sulphur as thiocyanate. However, the main target enzyme is cytochrome c oxidase, the terminal oxidase of the respiratory chain, and involves interaction with the ferric ion of cytochrome a3 . Symptoms and Diagnosis Diagnosis at the fire scene may be difficult. Poisoning results in central nervous system, respiratory, and cardiovascular dysfunction, resulting from inhibition of oxidative phosphorylation. It may include dyspnea, tachypnea, vomiting, bradycardia, hypotension, coma, and seizures. Electrocardiographic S-T segment elevation, which mimics an acute myocardial infarction, may be suggestive. Laboratory findings of anion gap metabolic acidosis and lacticacidemia aid in confirming the diagnosis. The lactic acidosis that is not rapidly responsive to oxygen therapy may be good indicator for cyanide poisoning. Also, elevated mixed venous saturation is suggestive of cyanide toxicity. Cyanide increases ven-

Table 63-3 Hydrogen Cyanide Concentrations in Air and Associated Symptoms in Humans HCN Concentration ppm

Symptoms

0.2–5.0

Threshold of odor

(TLV-MAC)

18–36

Slight symptoms (headache) after several hours

45–54

Tolerated for 1/2–1 h without difficulty

100

Death in 1 h

110–135

Fatal in 1/2–1 h

181

Fatal in 10 min

280

Immediately fatal

Source: Data from Einhorn IN: Physiological and toxilogical aspects of smoke produced during the combustion of polymeric materials. Environ Health Perspect 11:163–189, 1975; Kimmerle G: Aspects and methodology for the evaluation of toxicological parameters during five exposure, in Polymer Conference Series: Flammability characteristics of materials. Salt Lake City, University of Utah, 1973.

tilation through carotid body and peripheral chemoreceptor stimulation. Increasing ventilation may augment toxicity in the early stages. Correlation of blood cyanide concentrations with clinical symptoms is summarized in Table 63-3. Hydrogen cyanide is found routinely in low levels in the blood of healthy individuals at levels of 0.02 µg/ml in nonsmokers and 0.04 µg/ml in smokers. Toxicity occurs at a level of 0.1 µg/ml, and death is likely at 1.0 µg/ml. Treatment Fire victims suspected to have cyanide poisoning should be removed from exposure and fully decontaminated. All victims should be given pure (100 percent) oxygen and resuscitated properly if cardiopulmonary failure is present. Oxygen therapy appears to have strong positive effect; however, hyperbaric oxygen therapy is not recommended for the reasons previously mentioned. Cyanide is metabolized by hepatic rhodanese, which catalyzes the donation of sulfur from the sulfone pool to cyanide to form nontoxic thiocyanate. The half-life time of cyanide is approximately 1 to 3 h in humans. Although there is still controversy surrounding the treatment of cyanide poisoning, a few antidotes are available that can be used by first responders. Kelocyanor (dicobalt edentate) may be useful, but it is dangerous, and requires experts to

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administer it. The following agents may be considered in an intensive care setting. Methemoglobin Generators

The therapeutic goal is to convert the ferrous ion of hemoglobin to ferric ion. The resultant methemoglobin chelates cyanide to form cyanmethemoglobin. The drugs of choice in this group are sodium nitrite (intravenously) and amyl nitrite (inhaled). These drugs reduce oxygen-carrying capacity; therefore, they should be used with caution, especially in patients with concomitant CO poisoning, which induces COHb that may further compromise oxygen transport. These drugs should be used with precaution in patients with burn shock, because they are also vasodilators and can cause hypotension. In addition, there is little evidence to suggest these measures are effective, and cardiac toxicity in people with heart disease may be problematic. Sulfur Donors

The therapeutic goal is to convert cyanide to thiocyanate. The drug of choice in this group is sodium thiosulfate (intravenously). Toxicity is minimal other than an osmotic diuretic action, which may be beneficial. However, the onset of action is quite slow. Direct Binding Agents

These are based on cobalt chemistry and chelate the cyanide ion directly. Hydroxocobalamin is the precursor of vitamin B12 and has very little toxicity. However, this drug is not available in the United States for treatment of cyanide poisoning.

Thermal Lung Injury and Acute Smoke Inhalation

resulting in cell damage and apoptosis. As mentioned, phosgene has delayed effects from 20 min up to 48 h, depending on the intensity of exposure. Phosgene inhalation produces severe pulmonary edema. Initially victims develop upper airway irritant symptoms (eye irritation, rhinorrhea, cough); then they develop lower respiratory symptoms such as shortness of breath, substernal burning, and chest tightness. The development of overt pulmonary edema within 4 h of exposure portends a poor prognosis. Chlorine is a greenish yellow gas, an oxidizing agent that is very reactive with water. It has a pungent odor. Upon contact with water, chlorine liberates hypochlorous acid, hydrochloric acid, and oxygen free radicals. It causes irritant effects throughout the respiratory tree but mostly nasal mucosa and upper airways. Cell damage is caused by its strong oxidizing capability. Phosgene and chlorine were used extensively during World War I. Ammonia is a colorless gas at room temperature with a very pungent odor. Ammonia readily dissolves in water to form ammonium hydroxide, a very caustic alkaline solution. It causes cutaneous, ocular, and pulmonary injuries. When inhaled, ammonia can rapidly produce laryngeal injury and obstruction. It also causes upper tracheobronchial mucosal necrosis with sloughing and severe pulmonary edema. There are no specific antidotes against irritant gases (phosgene, chlorine, and ammonia) toxicity. Depending on the severity of exposure, supportive therapy such as airway management and ventilation should be provided. Early intubation is required if any significant upper airway symptoms such as stridor are present.

Other Toxic Chemicals These may also contribute substantially to the morbidity and mortality in a burn victim. Hydrogen chloride is produced by polyvinyl chloride degradation and causes severe respiratory tract damage and pulmonary edema. Nitrogen oxides may also cause pulmonary edema and a chemical pneumonitis and may contribute to cardiovascular depression and acidosis. Aldehydes such as acrolein and acetaldehyde, which are found in wood and kerosene, may further contribute to pulmonary edema and respiratory irritability. Toxic industrial chemicals such as chlorine, phosgene, hydrogen sulfide, and ammonia are of central importance. Because of their wide spread availability and high toxicity, there is certain concern that these chemicals may be used as a weapon by terrorists. Phosgene is colorless, nonflammable, heavier-than-air gas at room temperature with an odor of newly mown hay. Under 8â&#x2014;Ś C phosgene is an odorless and fuming liquid. Phosgeneâ&#x20AC;&#x2122;s inadequate warning properties and delayed symptoms make it a potential terrorist weapon. Phosgene is only slightly soluble in water; hence, its deeper penetration in the pulmonary system. On contact with water it hydrolyzes into carbon dioxide and hydrochloric acid, resulting in direct caustic damage. It also undergoes acylation reactions with amino, hydroxyl, and sulfhydryl groups of cellular macromolecules,

PATHOPHYSIOLOGY Tracheobronchial Area With rare exceptions, such as the inhalation of steam, injury to the airway is usually from the chemicals in smoke. The heat capacity of air is low and the bronchial circulation is very efficient in warming or cooling the airway gases so that most are at body temperature as they pass the glottis. Flames must be in almost direct contact with the airway to induce thermal injury. The chemicals in smoke are dependent on the materials that are being burned; however, for the most part the host response is similar. In most instances biologic materials such as cotton fabric, wood, or grass, or the products of these such as cattle feces (commonly used as fuel in third world countries) are fuel for the fire. These contain caustic materials such as reactive oxygen (ROS) and nitrogen species (RNS) organic acids and aldehydes. These chemicals interact with the airway to induce an initial response to trigger an inflammatory response. Many of the studies concerning bronchial circulation following smoke inhalation injury have been performed in sheep, because these animals have a single bronchial artery and a single lymphatic draining the lung that allows the

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measure of pulmonary transvascular fluid flux. There was a tenfold increase in bronchial blood flow within 20 min of smoke inhalation. These same animals demonstrate a sixfold increase in pulmonary transvascular fluid flux and a fall in PaO2 /FiO2 ≤ 300, but these were delayed to 24 h. Similar findings have been reported in patients with smoke inhalation alone or the combination of a large cutaneous thermal injury and smoke inhalation. Hyperemia of the airway is such a consistent finding in smoke inhalation that it is used to diagnose the injury. Other variables used include injury in an enclosed space, singed nasal hair, and soot in sputum. However, these latter injuries may be present but the subject may still not develop the signs of low Pa and pulmonary edema characteristic of inhalation injury. Airway inflammation plays a major role in the overall response to inhalation injury. As noted, there is a large sustained increase in blood flow in the airway following smoke inhalation. These changes in blood flow are associated with increased bronchial microvascular permeability to protein and small particles and pressure. Simultaneous with the changes in the function of the bronchial microvascular, there is a loss or shedding of the bronchial columnar epithelium. These changes result in a perfuse transudate with a protein content similar to an ultrafiltrate of the plasma. There are also copious secretions from the goblet cells. Early in the response these secretions are fluid and form a foamy material in the airway that many mistake for severe pulmonary edema in human patients. After several hours this transudate/exudate solidifies or clots forming obstructive materials in the airways. The mechanism of airway obstructive cast formation is illustrated in Fig 63-1. These obstructive materials formed in the upper airway may appear in the lower airway and alveoli. The presence of fibrin

Figure 63-1 The pathophysiological processes involved in the formation of the airway obstructive material following injury. The bottom is a microscopic picture of a bronchiole almost completely blocked by airway obstructive material containing mostly mucus/fibrin and inflammatory cells. Sheep lung tissue was taken for histological analysis 48 h after combined burn and smoke inhalation injury.

Figure 63-2 Light micrograph showing the presence of fibrin (arrows) lining the lumen of a bronchus in sheep subjected to combined burn and smoke inhalation injury. Lung tissue for histological analysis (Formalin fixation, Zenker postfixation, modified Masson trichrome stain) was taken 48 h after the injury.

makes the removal of airway obstructive cast extremely difficult (Fig. 63-2). This obstructive material is problematic from several stand points. In some rare instances of severe airway injury these materials can induce total obstruction and cause a life-threatening problem (Fig. 63-3). Occlusion of some of the bronchi or bronchioles in high NO production can lead to a loss of hypoxic pulmonary vasoconstriction and thus increased shunt fraction. Loss of hypoxic pulmonary vasoconstriction with inhalation injury has been reported. Lastly, if single bronchi are occluded while the patient is on a volumelimited-ventilated ventilator, there could be over stretch and barotrauma to the alveoli of the nonoccluded portion of the lung. The airway is richly innervated with vasomotor and sensory nerve endings. It is also known that these fibers release neuropeptides in response to caustic materials. Neuropeptides release can cause activation of nitric oxide synthase, have chemokine activity, and change microvascular permeability. The resultant activities lead to the formation of reactive oxygen and nitrogen species. Some of the latter are very potent oxidants that can damage DNA. Damage to DNA causes the activation of a repair enzyme poly(ADPribose) polymerase (PARP). This enzyme depletes the cell of high-energy phosphates and causes the activation of nuclear factor κB (NF-κB). Activation of the nuclear factor causes the upregulation of iNOS and IL-8, thus creating accelerated production of reactive oxygen and nitrogen species (Fig. 63-4). NO and 3-nitrotyrosine, an index of ROS, iNOS mRNA, and protein have been reported to be in the airway after smoke inhalation. Poly(ADP-ribose) [PAR], the product of the constitutive enzyme PAR polymerase, was identified in the airway tissues following smoke inhalation. Inhibition of PARP prevented the formation of PAR, the up-regulation of NF-κB, and the formation of 3-nitrotyrosine. It is interesting to note that airway inflammation is not seen in a typical asthma model in

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Figure 63-4 The mechanism of lung parenchyma damage in smoke inhalation injury. NO, nitric oxide; iNOS, inducible nitric oxide synthase, PMNs, polymorphonuclear cells; PARP, poly(ADPribose) polymerase.

the presence of a PARP inhibitor or mice lacking the PARP gene.

Lung Parenchyma

Figure 63-3 A chest radiograph of patients suffering from smoke inhalation taken at the time of admission and after removal of solid airway obstructive cast. A. There was decreased transmission of the entire left pulmonary area, elimination of the heart shadow, and elevation of the left diaphragm before the removal of cast. B. Radiograph taken 30 min after removal shows improved transmission; also, the heart shadow became visible. C. The cast was removed with basket forceps from the main left bronchus to the bifurcation of the upper and lower lobe bronchi. (From Nakae H, Tanaka H, Inaba H: Failure to clear casts and secretions following inhalation injury can be dangerous: Report of a case. Burns 27:189â&#x20AC;&#x201C;191, 2001, with permission.)

As noted, the lung parenchyma changes, as reflected by reduced PaO2 /FiO2 , and reduced compliance and increased edema formation are delayed. The delay depends on the severity of airway injury. Lung injury is associated an increased pulmonary transvascular fluid flux. The degree of transvascular fluid is proportional to the duration of smoke exposure and is independent of the levels of CO in the inhalant gas. The factors responsible for fluid leak are codified in the Starling-Landis equation. The variables of this equation relate fluid movement to pressure and permeability variations. With inhalation of smoke there is a reduction in refection coefficient (permeability to protein), increase in filtration coefficient (permeability to small particles), and increase in pulmonary microvascular pressure. Figure 63-5 demonstrates that pulmonary transvascular fluid flux in sheep following smoke inhalation is due to changes in both microvascular permeability and pressure. It appears that microvascular changes may be responsible for early events. Animals that were exposed to smoke inhalation injury were also noted to have reduced PaO2 /FiO2 . The change in this variable showed a good relationship to the histology injury scores and the changes in transvascular fluid flux. In addition, there was a loss of hypoxic pulmonary vasoconstriction in the injured animals that helps to explain the loss of oxygenation.

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Figure 63-5 Diagram showing portion of edema resulting from either changes in pulmonary microvascular permeability or pressure at 24 and 48 h after inhalation injury. (From Isago T, Fujioka K, Traber LD, et al: Derived pulmonary capillary pressure changes after smoke inhalation in sheep. Crit Care Med 19:1407–1413, 1991, with permission.)

antibody. Treatment of the cells with an antibody to L-selectin prevents the changes in transvascular fluid flux and other aspects of parenchymal damage. The final proof of this hypothesis was to deplete the animals of their neutrophils and determine how this affected the response to inhalation injury. In these studies of sheep depleted of their leukocytes, a high percentage of the response to smoke inhalation was blocked. In addition to the depletion of antioxidants, it also has been reported that burned patients are depleted of arginine. When arginine levels are low the NOS produces superoxide rather than nitric oxide. Administration of arginine may assist in reducing the oxidation that occurs with inhalation injury. However, the necessity of administering the arginine as arginine hydrochloride (because of solubility) limits the amount that may be given intravenously without producing acidosis.

Treatment As in the airway, the injury is markedly reduced by the administration of iNOS or PARP inhibitors and is associated with the reduction of PAR and 3-nitrotyrosine. The venous outflow of the bronchial circulation drains into the pulmonary microcirculation at the precapillary level. The fact that initial damage to the airway appeared to drive the pathophysiology of the parenchyma led investigators to hypothesize that the bronchial blood might deliver cytotoxic materials or cells into the pulmonary microcirculation. To test this hypothesis, several investigators tied off the bronchial artery of sheep and then exposed the animals to smoke. The hypothesis was affirmed in these studies; lung parenchymal changes were reduced. What could be the linkage among the airway, bronchial venous drainage, and parenchymal injury to the lung? Neutrophils activated in the bronchial circulation flow out into the bronchial venous drainage. Activated polymorphonuclear cells (PMN), especially neutrophils, are stiff. The diameter of neutrophils that have been fixed is approximately 7 µm. Since these cells have been dehydrated in alcohol as part of the fixation process, unfixed cells are much larger, on the order of 12 µm. The pulmonary capillary is small, with an average diameter of 6 µm. Normally the large neutrophil can traverse the pulmonary capillary by changing shape. However, many neutrophils have been activated in the bronchial areas. Their F-actin is activated and the cells are stiff and cannot deform. These stiff cells are carried to the pulmonary microvasculature, where they are impaled by the narrow pulmonary capillaries. The activated neutrophils release ROS and proteases that damage the parenchyma. The following evidence supports this concept of neutrophil cytotoxicity. Oxidative processes are well known following inhalation injury. There is lipid peroxidation and release of proteolytic enzymes following injury. Administration of protease inhibitors or scavengers of ROS reduces the response to smoke inhalation when activated PMNs lose the L-selectin on their surface. This Lselectin shedding is prevented by treatment with an L-selectin

Some pretreatment for smoke inhalation can be accomplished. Some people are chronically exposed to smoke, such as farmers who burn crops, individuals with fires in their huts, and firefighters. There are reports that individuals who are chronically exposed to smoke are depleted of antioxidants. Consequently, antioxidant supplementation should be considered. The airway is a major concern in the post-inhalation period. This is very difficult to manage in patients with combined inhalation and burn injuries. Intubation is very difficult in patients with burns of the soft tissues of the face, oral pharynx, and neck. Burn injury to these soft tissues results in almost immediate and severe edema and swelling. Intubation in such an individual requires great skill. Securing the tube is difficult. Accidental removal of the endotracheal tube is easy and lethal. Often burns and/or the chemicals in smoke damage the larynx, and placement of the tube can cause damage and delay healing of such a wound. Tracheostomy is performed sometimes, but also can be difficult if it has to be placed through burned skin on the neck. For information on this, the reader is referred to the chapters of Fitzpatrick and Gioffi as well as Mlcak and Herndon, in Herndon’s Total Burn Care. To counter obstruction, vigorous toilet should be performed. The cast material contains fibrin. Experimentally, the use of heparin has been reported to be effective in reducing airway obstruction. However, heparin requires the presence of antithrombin to be effective, and this factor has been reported to be deficient following burn injury. Consequently, antithrombin has been reported to be effective in these situations in animal studies. Antithrombin and activated protein C also may act as anti-inflammatory agents. Once obstructive materials have formed in the airway, heparin and antithrombin are ineffective in removing them. Animal studies have demonstrated that tissue plasminogen activator might be effective in removing these materials. Aerosolized tissue plasminogen activator has been reported to be effective in

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removing bronchial obstructive material in patients who have had Fontan procedures. Many burn units nebulize heparin into the airway of their patients with inhalation injury. Many drugs have proved effective in reducing injury to the lung parenchyma of animal models of inhalation injury, including cyclooxygenase inhibitors, iNOS inhibitors, PARP inhibitors, and oxygen scavengers, as well as the anticoagulant factors mentioned in the preceding. However, only the latter are in clinical use and/or clinical trial. In many instances conventional methods of ventilation can no longer sustain the pulmonary function of burned patients. Extracorporeal membrane oxygenation has been used in these patients with some success. Techniques have now been developed in animal models of inhalation injury that involve a unique form of CO2 removal called arterial venous CO2 removal (AVCOR). Off the shelf CO2 removal devices, used in extracorporal bypass and cardiopulmonary bypass, have been modified to be driven by the subject’s own arterial pressure. These were tested in animal models and shown to be very successful in reducing pathophysiology, morbidity, mortality, and days of ventilatory support of inhalation injury models. AVCO2R is now in clinical trials for the treatment of severe ARDS associated with inhalation injury.

SUGGESTED READINGS American Burn Association: Inhalation injury: Diagnosis. J Am Coll Surg 196:307–312, 2003. Alpard SK, Zwischenberger JB, Tao W, et al: Reduced ventilator pressure and improved P/F ratio during percutaneous arteriovenous carbon dioxide removal for severe respiratory failure. Ann Surg 230:215–224, 1999. Hinton HL Jr: Combating Terrorism: Observations on the Threat of Chemical and Biological Terrorism. Washington, D.C., National Security and International Affairs Division, 1999. Beasley DM, Glass WI: Cyanide poisoning: Pathophysiology and treatment recommendations. Occup Med (Lond) 48:427–431, 1998. Borak J, Diller WF: Phosgene exposure: Mechanisms of injury and treatment strategies. J Occup Environ Med 43:110–119, 2001. Boulares AH, Zoltoski AJ, Sherif ZA, et al: Gene knockout or pharmacological inhibition of poly(ADP-ribose) polymerase-1 prevents lung inflammation in a murine model of asthma. Am J Respir Cell Mol Biol 28:322–329, 2003. Brown SD, Piantadosi CA: Reversal of carbon monoxidecytochrome c oxidase binding by hyperbaric oxygen in vivo. Adv Exp Med Biol 248:747–754, 1989. Bruno RS, Traber MG: Cigarette smoke alters human vitamin E requirements. J Nutr 135:671–674, 2005. Chou KJ, Fisher JL, Silver EJ: Characteristics and outcome of children with carbon monoxide poisoning with and

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without smoke exposure referred for hyperbaric oxygen therapy. Pediatr Emerg Care 16:151–155, 2000. Costello JM, Steinhorn D, McColley S, et al: Treatment of plastic bronchitis in a Fontan patient with tissue plasminogen activator: A case report and review of the literature. Pediatrics 109:e67, 2002. Cox RA, Burke AS, Soejima K, et al: Airway obstruction in sheep with burn and smoke inhalation injuries. Am J Respir Cell Mol Biol 29:295–302, 2003. Desai MH, Mlcak R, Richardson J, et al: Reduction in mortality in pediatric patients with inhalation injury with aerosolized heparin/N-acetylcysteine [correction of acetylcysteine] therapy. J Burn Care Rehabil 19:210–212, 1998. Efimova O, Volokhov AB, Iliaifar S, et al: Ligation of the bronchial artery in sheep attenuates early pulmonary changes following exposure to smoke. J Appl Physiol 88:888–893, 2001. Enkhbaatar P, Murakami K, Cox R, et al: Aerosolized tissue plasminogen inhibitor improves pulmonary function in sheep with burn and smoke inhalation. Shock 22:70–75, 2004. Enkhbaatar P, Murakami K, Shimoda K, et al: The inducible nitric oxide synthase inhibitor BBS-2 prevents acute lung injury in sheep after burn and smoke inhalation injury. Am J Respir Crit Care Med 167:1021–1026, 2003. Enkhbaatar P, Murakami K, Shimoda K, et al: Ketorolac attenuates cardiopulmonary derangements in sheep with combined burn and smoke inhalation injury. Clin Sci (Lond) 105:621–628, 2003. Enkhbaatar P, Murakami K, Traber LD, et al: The inhibition of inducible nitric oxide synthase in ovine sepsis model. Shock 25:522–527, 2006. Fitzpatrick DF, Gioffi WG: Diagnosis and treatment of inhalation injury, in Herndon D (ed): Total Burn Care, 2d ed. New York, W.B. Saunders, 2002, pp 232–242. Fontan JJ, Cortright DN, Krause JE, et al: Substance P and neurokinin-1 receptor expression by intrinsic airway neurons in the rat. Am J Physiol Lung Cell Mol Physiol 278:L344–355, 2000. Hinder F, Matsumoto N, Booke M, et al: Inhalation injury increases the anastomotic bronchial blood flow in the pouch model of the left ovine lung. Shock 8:131–135, 1997. Hughart JL: Industrial Chemicals and Terrorism: Human Health Threat Analysis, Mitigation Prevention. Washington, D.C., U.S. Public Health Service, n.d. Jordan MH, Hollowed KA, Turner DG, et al: The Pentagon attack of September 11, 2001: A burn center’s experience. J Burn Care Rehabil 26:109–116, 2005. Kobayashi K, Ikeda H, Higuchi R, et al: Epidemiological and outcome characteristics of major burns in Tokyo. Burns 31:S3–S11, 2005. Kowal-Vern A, Mcgill V, Walenga JM, et al: Antithrombin(H) concentrate infusions are safe and effective in patients with thermal injuries. J Burn Care Rehab 21:115–127, 2000.

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Kraneveld AD, Nijkamp FP: Tachykinins and neuro-immune interactions in asthma. Int Immunopharmacol 1:1629– 1650, 2001. Lund T: The 1999 Everett Idris Evans memorial lecture. Edema generation following thermal injury: An update. J Burn Care Rehabil 20:445–452, 1999. Mlcak R, Herndon D: Respiratory care, in Herndon D (ed): Total Burn Care, 2d ed. New York, W.B. Saunders, 2002, pp 242–267. Morocco AP: Cyanides. Crit Care Clin 21:691–705, 2005. Murakami K, Enkhbaatar P, Shimoda K, et al: Inhibition of poly (ADP-ribose) polymerase attenuates acute lung injury in an ovine model of sepsis. Shock 21:126–133, 2004. Murakami K, McGuire R, Cox RA, et al: Recombinant antithrombin attenuates pulmonary inflammation following smoke inhalation and pneumonia in sheep. Crit Care Med 31:577–583, 2003. Nguyen TT, Cox CS, Jr., Herndon DN, et al: Effects of manganese superoxide dismutase on lung fluid balance after smoke inhalation. J Appl Physiol 78:2161–2168, 1995. Pegg SP: Burn epidemiology in the Brisbane and Queensland area. Burns 31:S27–31, 2005. Perez Fontan JJ: On lung nerves and neurogenic injury. Ann Med 34:226–240, 2002. Pierre EJ, Zwischenberger JB, Angel C, et al: Extracorporeal membrane oxygenation in the treatment of respiratory failure in pediatric patients with burns. J Burn Care Rehabil 19:131–134, 1998. Pruitt BA Jr, Goodwin CW, Mason AD Jr: Epidemiological, demographic and outcome characteristics of burn injury, in Herndon DN (ed): Total burn care, 2d ed. London, W.B. Saunders, 2002, pp 16–32. Ramzy PI, Barret JP, Herndon DN: Thermal injury. Crit Care Clin 15:333–352, ix, 1999. Sakurai H, Schmalstieg FC, Traber LD, et al: Role of L-selectin in physiological manifestations after burn and smoke inhalation injury in sheep. J Appl Physiol 86:1151–1159, 1999. Schenarts PJ, Schmalstieg FC, Hawkins H, et al: Effects of an L-selectin antibody on the pulmonary and systemic manifestations of severe smoke inhalation injuries in sheep. J Burn Care Rehab 21:229–240, 2000. Schmalstieg FC, Chow J, Savage C, et al: Interleukin-8, aquaporin-1, and inducible nitric oxide synthase in smoke and burn injured sheep treated with percutaneous carbon dioxide removal. ASAIO J 47:365–371, 2001. Schwela D: Cooking smoke: A silent killer. People Planet 6:24– 25, 1997. Schwela DH, Goldammer JG, Morawska LH, et al: Health Guidelines for Vegetation Fire Events. Geneva, World Health Organization, 1999. Shimazu T, Ikeuchi H, Sugimoto H, et al: Half-life of blood carboxyhemoglobin after short-term and long-term exposure to carbon monoxide. J Trauma 49:126–131, 2000. Shimoda K, Murakami K, Enkhbaatar P, et al: Effect of poly(ADP ribose) synthetase inhibition on burn and

smoke inhalation injury in sheep. Am J Physiol Lung Cell Mol Physiol 285:L240–249, 2003. Soejima K, Schmalstieg FC, Sakurai H, et al: Pathophysiological analysis of combined burn and smoke inhalation injuries in sheep. Am J Physiol Lung Cell Mol Physiol 280:L1233–L1141, 2001. Soejima K, Traber LD, Schmalstieg FC, et al: Role of nitric oxide in vascular permeability after combined burns and smoke inhalation injury. Am J Respir Crit Care Med 163:745–752, 2001. Song C, Chua A: Epidemiology of burn injuries in Singapore from 1997 to 2003. Burns 31:S18–26, 2005. Starling EH: On the absorption of fluids from the connective tissue spaces. J Physiol 19:312–326, 1896. Staub NC, Bland RD, Brigham KL, et al: Preparation of chronic lung lymph fistulas in sheep. J Surg Res 19:315– 320, 1975. Stothert JC Jr, Ashley KD, Kramer GC, et al: Intrapulmonary distribution of bronchial blood flow after moderate smoke inhalation. J Appl Physiol 69:1734–1739, 1990. Sugi K, Theissen JL, Traber LD, et al: Impact of carbon monoxide on cardiopulmonary dysfunction after smoke inhalation injury. Circ Res 66:69–75, 1990. Terrill JB, Montgomery RR, Reinhardt CF: Toxic gases from fires. Science 200:1343–1347, 1978. Thom SR: Antagonism of carbon monoxide-mediated brain lipid peroxidation by hyperbaric oxygen. Toxicol Appl Pharmacol 105:340–344, 1990. Traber DL, Herndon DN, Stein MD, et al: The pulmonary lesion of smoke inhalation in an ovine model. Circ Shock 18:311–323, 1986. Traber DL, Schlag G, Redl H, et al: Pulmonary edema and compliance changes following smoke inhalation. J Burn Car Rehabil 6:490–494, 1985. Tung KY, Chen ML, Wang HJ, et al: A seven-year epidemiology study of 12,381 admitted burn patients in Taiwan—using the Internet registration system of the Childhood Burn Foundation. Burns 31:S12–17, 2005. Vincent JL: Infection/inflammation and hemostasis. Curr Hematol Rep 2:407–410, 2003. Virag L: Poly(ADP-ribosyl)ation in asthma and other lung diseases. Pharmacol Res 52:83–92, 2005. Wakeham MK, Van Bergen AH, Torero LE, et al: Long-term treatment of plastic bronchitis with aerosolized tissue plasminogen activator in a Fontan patient. Pediatr Crit Care Med 6:76–78, 2005. Westphal M, Cox RA, Traber LD, et al: Combined burn and smoke inhalation injury impairs ovine hypoxic pulmonary vasoconstriction. Crit Care Med 34:1428–1436, 2006. Xia Y, Roman LJ, Masters BS, et al: Inducible nitric-oxide synthase generates superoxide from the reductase domain. J Biol Chem 273:22635–22639, 1998. Yu YM, Ryan CM, Castillo L, et al: Arginine and ornithine kinetics in severely burned patients: increased rate of arginine disposal. Am J Physiol Endocrinol Metab 280:E509–E517, 2001.

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Yurt RW, Bessey PQ, Bauer GJ, et al: A regional burn center’s response to a disaster: September 11, 2001, and the days beyond. J Burn Care Rehabil 26:117–124, 2005. Zwischenberger JB, Savage C, Witt SA, et al: Arteriovenous CO2 removal (AVCO2R) perioperative management: Rapid recovery and enhanced survival. J Invest Surg 15:15–21, 2002. Zwischenberger JB, Wang D, Lick SD, et al: The paracorporeal artificial lung improves 5-day outcomes from lethal smoke/burn-induced acute respiratory distress syndrome

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in sheep. Ann Thorac Surg 74:1011–1016; discussion 1017– 1018, 2002. US Department of Health and Human Services: Medical management for phosgene, in Managing Hazardous Material Incidents. Atlanta, GA: US Department of Health and Human Services, 2001. US Army Medical Research Institute of Chemical Defense: Pulmonary agent, in US Army Medical Research Institute of Chemical Defense, Medical Management of Chemical Casualties Handbook. Aberdeen, MA, USAMRICD, 2000, pp 18–34.

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VI Drug-Induced Lung Diseases

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64 Pulmonary Toxicity Associated with Chemotherapeutic Agents Lynn T. Tanoue

John R. McArdle

I. APPROACH TO THE PATIENT WITH SUSPECTED CHEMOTHERAPY-INDUCED PULMONARY TOXICITY Pulmonary Physiological Testing Diagnostic Evaluation II. CYTOTOXIC ANTIBIOTICS Bleomycin Mitomycin C Actinomycin D III. ALKYLATING AGENTS Cyclophosphamide Busulfan Other Alkylating Agents IV. ANTIMETABOLITES Methotrexate

Toxicities related to medications comprise a major category of iatrogenic illness. Many chemotherapeutic agents are known to have potential for pulmonary toxicity. With an expanding understanding of biologic mechanisms fundamental to neoplasia, the horizons for treatment options broaden. As new therapeutic modalities become available, patients with cancer are living longer, and may in their long-term survivorship display delayed toxicities related to their treatment. For the pulmonologist, drug-induced lung disease is therefore necessarily an area of growing concern. Chemotherapeutic agents, therapeutic radiation, and biologic response modifiers are used in a wide range of regimens further complicated by the use of hematopoietic support and bone marrow or stem cell transplantation. Many can directly or indirectly be associated with pulmonary toxicity. An estimated 5 to 10 percent of patients undergoing chemotherapy will ultimately develop therapy-related pulmonary complications.

Cytosine Arabinoside Fludarabine Gemcitabine V. NITROSOUREAS Carmustine (BCNU) Other Nitrosoureas VI. BIOLOGIC RESPONSE MODIFIERS All-trans Retinoic Acid Interleukin-2 EGFR Inhibitors VII. MISCELLANEOUS AGENTS Procarbazine Taxines Vinca Alkaloids

APPROACH TO THE PATIENT WITH SUSPECTED CHEMOTHERAPY-INDUCED PULMONARY TOXICITY The diagnosis of drug-induced pulmonary toxicity is one of exclusion. Patients most often present with nonspecific constitutional or respiratory complaints. In many cases, symptoms and physical signs may be minimal or even absent. In these situations, the only evidence of an ongoing pulmonary process may be an abnormal chest radiograph (Table 64-1). The diagnosis of lung disease caused by chemotherapeutic agents poses a particular challenge to the clinician, as there are several complicating features inherent to the oncology patient population. First, treatment may be given in multidrug regimens or in combination with other modalities such as radiation therapy, bone marrow transplantation, or stem

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Table 64-1 Differential Diagnosis of Radiographic Abnormalities in Cancer Patients Infection Primary malignancy Lymphangitic tumor, metastatic disease, leukemic infiltration Drug toxicity Radiation injury

pulmonary reaction acutely following drug administration usually raises suspicion of drug toxicity, as patients survive for longer periods of time it is becoming increasingly clear that toxicity due to some chemotherapeutic agents may be delayed by months to even years after treatment. In such situations, clinical suspicion of drug toxicity may be low. Monitoring for potential pulmonary toxicity in the patient undergoing chemotherapy requires ongoing clinical vigilance. Symptoms such as cough, dyspnea, or chest discomfort may be mild or even absent. Radiographic findings may be equally subtle. Even if clinical symptoms and radiographic abnormalities are present and severe, they are usually nonspecific. The possibility of adverse drug effects must be considered within the complex medical context inherent to the patient with cancer undergoing physically challenging or immunosuppressive treatment.

Pulmonary edema ARDS Pulmonary hemorrhage Pulmonary emboli Leukoagglutinin reaction Pulmonary fibrosis

cell transplantation. Assigning pulmonary toxicity to a single drug or modality within such a regimen is often impossible. Moreover, the combined toxicity of two or more drugs or a single drug with radiation therapy may exceed the individual toxicities of those drugs. Second, patients undergoing chemotherapy are often immune suppressed, either from the malignancy itself or from myelosuppressive or immunosuppressive effects of their treatment. These patients are therefore susceptible to opportunistic infection, which may be indistinguishable radiographically from drug toxicity. It should be remembered that the lung is the most common site of serious infection in patients with cancer. It has been estimated that a relative minority (5 to 30 percent) of pulmonary complications in the immunocompromised host are actually due to drug toxicity. Since changing a treatment regimen may affect the chance for prolonging survival or cure, reasonable certainty of drug-related complications necessarily involves exclusion of infection as the cause of pulmonary disease. Third, cancers themselves may mimic lung disease. This is particularly true in cases of lymphangitic tumor spread or metastases to the lung parenchyma or pleura. Fourth, toxicity from some drugs appears to be related to cumulative dosage levels. However, adverse reactions may occur even with a low cumulative dose, when clinical suspicion for toxicity is low. Finally, pulmonary toxicity due to a single chemotherapeutic agent may present with several different syndromes that vary clinically, radiographically, and temporally. While a severe

PULMONARY PHYSIOLOGICAL TESTING Pulmonary physiological testing has received significant attention as a potential screening tool for drug-induced pulmonary disease. A multitude of investigations studying the utility of the pulmonary function test (PFT) in monitoring pulmonary effects related to administration of chemotherapy have been reported. Various physiological abnormalities have been described, the most common of which are decreases in lung volumes and diffusing capacity for carbon monoxide (DlCO ). The application of these findings to clinical management has been a subject of much debate. Monitoring patients receiving chemotherapy with pulmonary function testing frequently demonstrates physiological abnormalities in the absence of clinical signs of toxicity. Abnormalities in DlCO in particular have been felt in some studies to be indicative of early onset drug-related pulmonary injury. Most such studies have been performed in patients receiving bleomycin, busulfan, or carmustine. Discontinuation of drug with or without initiation of treatment including corticosteroids in such situations typically results in improvement. Whether such early intervention based on DlCO abnormalities in the absence of clinical symptoms does indeed diminish the likelihood of long-term pulmonary impairment related to toxicity is unclear. In such cases, consideration would have to be given to the knowledge that discontinuation of drug because of potentially unfounded concern for progressive pulmonary disease might lead to alteration of otherwise preferred therapy. In contrast, in situations of clinically evident drug toxicity accompanied by PFT abnormalities, clinical recovery may not necessarily be paralleled by improvement in physiological measurements. For example, in a study examining pulmonary function in 116 long-term (5 to 13 years after treatment) survivors of Hodgkinâ&#x20AC;&#x2122;s disease in Norway, nearly 30 percent of patients had exertional dyspnea with associated pulmonary function abnormalities. Multivariate analysis of these patients identified chemotherapy with a combination of bleomycin

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and anthracyclines as the sole significant predictor of lung function impairment. A number of factors further complicate the practice and interpretation of pulmonary function testing in the oncology population. Many physiological parameters are effort dependent. The ability of a patient to consistently perform test maneuvers may be affected by weakness, pain, or the use of analgesic or sedating medication. Reproducibility of results therefore is a significant issue in patients whose functional status and strength are potentially impaired by their malignancy or its treatment. Many patients will have anemia induced by malignancy, medication, or chronic illness. Since DlCO is affected by hemoglobin concentration, it is critical that appropriate corrections for anemia be made. Patients with cancers may also be subject to processes other than drug toxicity that will affect PFT results. Primary pulmonary malignancy, metastatic lung disease, infection, thoracic or abdominal surgical procedures, and a host of other clinical situations may all independently cause variation in physiological measurements. Therefore, identifying pulmonary physiological abnormalities specific to drug effect may be extremely difficult. Ultimately, despite the uncertainties in interpretation of physiological abnormalities, most clinicians will continue to rely on pulmonary function testing as a screening and monitoring tool in the hope of identifying toxicity early enough to prevent serious pulmonary disease. Unfortunately, the predictive value of baseline or serial pulmonary function testing remains unclear. Moreover, there are no definitive data that toxicity can be averted by serial monitoring. The presence of subclinical abnormalities does not imply that patients will develop irreversible lung disease, yet these abnormalities often dictate the withdrawal of drug. Conversely, normal physiology cannot predict abrupt toxicity that may produce profound pulmonary injury. As always, medical decisions based on pulmonary physiological findings must be made in the context of the patientâ&#x20AC;&#x2122;s clinical situation as a whole.

Diagnostic Evaluation Given the potential impact of pulmonary drug toxicity on a patientâ&#x20AC;&#x2122;s present and future treatment, it is important to establish this diagnosis as firmly as possible. The thoughtful and judicious use of invasive procedures plays an important role in that evaluation. The approach to the cancer patient in whom drug toxicity is suspected should parallel the approach to any immunocompromised patient with diffuse or localized lung disease. Because clinical features are usually not specific, sampling of respiratory tract secretions and/or lung tissue may be critical to this evaluation. Direct sputum examination or culture may suggest specific pathogens or may be diagnostic of infections such as invasive fungal disease, Pneumocystis jiroveci pneumonia, or tuberculosis. In the absence of diagnostic sputum findings, invasive procedures may be necessary. Fine-needle aspiration of the lung may be useful with focal lesions. However, the utility of this procedure in diffuse

Pulmonary Toxicity Associated with Chemotherapeutic Agents

lung disease is relatively low. This is particularly problematic for patients with drug-induced pulmonary toxicity, which typically presents with a diffuse interstitial pattern on chest radiograph. Fiberoptic bronchoscopy with bronchoalveolar lavage and transbronchial biopsy has become central to the evaluation of both diffuse and localized lung disease in the immunocompromised host. The procedure is associated with a low rate of major complications (less than 1 percent) and with a diagnostic yield ranging from as low as 37 percent to as high as 72 percent. This broad variation in yield is probably reflective of the wide range of disease processes that can involve the lung in the immunocompromised patient. Highest diagnostic yields are obtained in patients with infections; lower yields are seen in interstitial inflammatory processes, which may include toxicity from drugs. However, even in situations in which a specific etiology is not identified, exclusion of infection by bronchoscopy often provides clinically useful information. Open or thoracoscopic lung biopsy is associated with the highest diagnostic yield and can be performed with low complication rates even in critically ill patients. If drug-induced pulmonary injury is suspected, surgical biopsy may be necessary to definitively exclude other causes of lung disease. The evaluation of a patient in whom chemotherapyrelated pulmonary toxicity is a consideration clearly presents significant challenges. Clinicians must be vigilant in the evaluation and management of patients receiving chemotherapeutic regimens. An awareness of potential iatrogenic complications related to drug therapy is therefore essential. This chapter reviews the major pulmonary toxicities associated with various chemotherapeutic agents.

CYTOTOXIC ANTIBIOTICS (TABLE 64-2) Bleomycin Bleomycin is a cytotoxic antibiotic produced by Streptomyces vermiculus, and is used in the treatment of various malignancies, including lymphomas, germ cell tumors, and cancers of the head and neck. Bleomycin is concentrated in skin and lung, with its major toxicities manifested in these organs. Limitation of its use usually hinges on its known potential for pulmonary toxicity. The incidence of bleomycin-induced lung injury varies from 6 to 18 percent. Published data suggest that 1 to 2 percent of bleomycin-treated patients will succumb to pulmonary toxicity, although this rate may increase to as high as 10 percent in those receiving more than 550 units. The pulmonary toxicities of bleomycin have been studied extensively in animal models. Endothelial and epithelial injuries are noted in the most common form of bleomycininduced injury. Type I pneumocyte destruction is followed by type II pneumocyte hyperplasia and dysplasia leading to activation of fibroblasts, collagen deposition, and fibrosis (Fig. 64-1). A variety of mediators have been implicated in murine models of bleomycin-induced lung injury. In vitro

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Table 64-2 Cytotoxic Antibiotics Drug

Pulmonary Syndrome

Treatment

Comments

Bleomycin

Chronic pneumonitis/ pulmonary fibrosis

Corticosteroids Discontinue drug

Hypersensitivity-type lung disease Chest pain syndrome

Corticosteroids Discontinue drug Discontinue drug

Most common syndrome of bleomycin toxicity â&#x20AC;&#x153;Radiation recallâ&#x20AC;? effect Risk factors: Cumulative dose >400 u Oxygen therapy Therapeutic radiation Renal insufficiency Older age ? Concurrent use of other cytotoxic drugs Dyspnea, cough, skin rash, eosinophilia May not recur with rechallenge Associated with intravenous infusion of drug

Chronic pneumonitis/ pulmonary fibrosis

Corticosteroids Discontinue drug

Acute dyspnea/ bronchospasm Noncardiogenic pulmonary edema Hemolytic uremic syndrome

Supportive care Discontinue drug Corticosteroid

Mitomycin-C

Actinomycin-D

Exacerbation of radiation-induced injury

Most common syndrome of mitomycin-induced lung toxicity Risk factors: Oxygen therapy Therapeutic radiation Concurrent use of other cytotoxic drugs Occurs in patients also receiving vinca alkaloids Risk factor: Concurrent use of vinca alkaloids

Supportive care Discontinue drug

Microangiopathic hemolytic anemia thrombocytopenia, renal insufficiency, noncardiogenic pulmonary edema

Discontinue drug

Radiosensitizing effect may be long-standing Risk factor: Therapeutic radiation

Figure 64-1 Lung biopsy specimen from a patient with clinical and radiographic evidence of bleomycin-induced pulmonary toxicity shows drug effect with acute and chronic changes. The alveolus contains an exudate of fibrin, which is undergoing organization and is surrounded by alveolar macrophages. The large and atypical cells are markedly reactive alveolar type II pneumocytes. The alveolar wall itself is scarred with collagen deposition by the spindleshaped fibroblasts. (Courtesy of Dr. Darryl Carter, Professor of Pathology, Yale University School of Medicine.)

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data demonstrate that pulmonary microvascular endothelial cells exposed to bleomycin demonstrate a rapid up-regulation of interleukin-8 (IL-8) and intercellular adhesion molecule-1 (ICAM-1). This early response may lead to the development of an acute neutrophilic inflammatory response. Interleukin1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) are all present in increased quantities in bronchoalveolar lavage fluid (BALF) from mice treated with intratracheal bleomycin. TNF and IL-6 levels in BALF are elevated within 6 hours of instillation. These increases are followed by release of macrophage-inflammatory protein-1α (MIP-1α) from alveolar macrophages. MIP-1α is a member of the C-C chemokine family and mediates the recruitment of mononuclear phagocytes. Blockade of TNF and IL-6 are associated with a decrease in the early expression of MIP-1α, which has been implicated as an important mediator of fibrosis. One theory holds that TNF, IL-6, and IL-1 are released from alveolar epithelial cells and macrophages after exposure to bleomycin. A resultant increase in MIP-1α release from alveolar macrophages then leads to an expansion of the inflammatory response by recruiting mononuclear cells. The continued expression of TNF and IL-1 may ultimately predispose to the production of transforming growth factor-β (TGFβ), with the promotion of dysregulated collagen production and fibrosis. The importance of several of these mediators to the development of bleomycin pulmonary toxicity has been demonstrated by abrogation of the fibrotic response by neutralization of specific mediators. Antibodies against TGF-β, IL-1, and MIP-1α as well as neutralization of TNF via soluble receptors have all been demonstrated to reduce the development of fibrosis in rodent models. Several risk factors have been identified for the development of bleomycin-induced pulmonary toxicity. These include the following: (a) Toxicity appears to correlate with higher cumulative dosages. While injury has been observed after administration of as little as 20 units, there is a significant escalation in toxicity with total doses over 400 units. (b) Supplemental oxygen therapy is a synergistic toxin in patients previously treated with bleomycin. This is particularly problematic for those exposed to high oxygen concentrations in the setting of general anesthesia and in the postoperative period. The duration of this relationship is not well characterized, but exposures to bleomycin within the past 6 months are generally considered a significant risk in those treated with high inspired oxygen concentration. (c) Thoracic irradiation prior to, concomitant with, or subsequent to bleomycin administration has been associated with an increase in toxicity. This “radiation recall” may extend outside the original port of irradiation, and may last for years after bleomycin therapy. (d) Impaired renal function has been identified as a risk factor for the development of pulmonary toxicity. Bleomycin is excreted by the kidneys, and its half-life increases when creatinine clearance decreases below 35 mL per minute. (e) The risk for pulmonary toxicity rises in patients over 70 years of age. (f) Concurrent use of other cytotoxic agents may result in synergistic toxicity. Uncontrolled studies have suggested that toxicity is enhanced with coadministration of bleomycin and cy-

Pulmonary Toxicity Associated with Chemotherapeutic Agents

clophosphamide, doxorubicin, vincristine, or methotrexate. These synergistic effects have not been clearly reproducible, although convention has been to reduce bleomycin dosage in drug regimens in which this synergy is a concern. The clinical presentation of bleomycin toxicity is usually subacute and insidious, occurring within a few weeks to 6 months after treatment. A more fulminant presentation with acute respiratory failure has been reported but is less common. Patients generally present with dyspnea, nonproductive cough, and low-grade fever. Substernal or pleuritic chest pain occurs, but is infrequent. Up to 20 percent of patients may be asymptomatic. Chest radiograph usually shows bilateral reticular or fine nodular infiltrates with a basilar predominance, often beginning at the costophrenic angles (Fig. 64-2A,B). Loss of lung volume with diaphragmatic elevation is also commonly seen. However, various radiographic patterns including alveolar infiltrates, lobar consolidation, asymmetric lung involvement, and even lung nodules have been described. Computed tomographic (CT) scanning is more sensitive in the evaluation of radiographic abnormalities and may be useful in patients who have spirometric or clinical evidence of toxicity but negative chest x-rays (Fig. 64-3). Bleomycin also has been described to cause an acute syndrome of dyspnea, cough, and rash immediately following administration of drug. Lung biopsy in these cases shows eosinophilic infiltration, and changes consistent with hypersensitivity pneumonitis. Of interest, rechallenge with drug does not necessarily result in recurrence of the syndrome, suggesting that this is not a true hypersensitivity reaction. Bleomycin may also present with an acute chest pain syndrome. In one series of 286 patients, the incidence of severe chest pain was 2.8 percent. Chest pain in these patients was concurrent with bleomycin infusion and resolved after termination of drug. Clinical and radiographic evidence of pleuropericarditis are often observed. Overall mortality due to drug toxicity in patients receiving bleomycin is 1 to 2 percent. In patients who develop pulmonary toxicity, mortality rates are substantially increased. Discontinuation of drug alone in patients with mild toxicity may lead to reversal of abnormalities but treatment with corticosteroids is generally recommended for patients with clinically significant bleomycin-induced toxicity. Doses of corticosteroids are usually given in the range of 60 to 100 mg of prednisone per day, with tapering done slowly and according to the clinical stability of the patient. Improvement often occurs within weeks but complete resolution may take up to 2 years and patients may be left with residual radiographic and/or physiological abnormalities.

Mitomycin C Mitomycin-C is an alkylating cytotoxic antibiotic generally used in multidrug regimens for solid organ malignancies including breast, gastrointestinal, and gynecological cancers. The incidence of pulmonary toxicity due to mitomycin is variably reported between 3 and 39 percent. This variation may

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Figure 64-2 Posteroanterior chest radiographs of a 56-year-old woman with cervical carcinoma (A) before and (B ) after chemotherapy with a bleomycin-containing regimen. Note the decrease in lung volume and diffusely increased interstitial lung markings in the postchemotherapy radiograph.

Figure 64-3 Chest computed tomography (CT) scan of same patient as in Fig. 64-2, taken at the time of radiograph in Fig. 64-2. Note the patchy distribution of bilateral infiltrates, whose extent is clearly delineated by CT.

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be in part due to two factors. First, the drug is rarely given alone and toxicity seems dependent to some extent on concurrent administration of other agents or therapies. Though agreement about synergistic toxicity is not universal, pulmonary toxicity may be potentiated when mitomycin is used in conjunction with bleomycin, vinca alkaloids, cis-platinum, 5-fluorouracil, cyclophosphamide, and doxorubicin. Therapeutic thoracic irradiation and oxygen may also be co-toxins. Second, mitomycin-induced lung injury presents with at least three clinically distinct syndromes. The most common form of mitomycin-induced lung toxicity is a chronic pneumonitis with pulmonary fibrosis similar to that seen with bleomycin. The mechanism of injury is unknown though several have been proposed, including lipid peroxidant injury, hypersensitivity reactions, or immune complex mediated disease. Toxicity is felt to be potentiated by oxygen supplementation and therapeutic radiation. Toxicity does not appear to be dose related. Though it has been suggested that patients receiving doses greater than 30 mg/m2 are at increased risk of pulmonary injury, this dose dependency has not been substantiated. Pulmonary toxicity usually occurs after 2 to 12 months of therapy but may occur after a single dose. Clinically, patients present with a subacute syndrome of cough and progressive dyspnea, often with fatigue and sometimes with pleuritic chest pain. Fever is less common. Chest radiograph usually shows bilateral interstitial infiltrates, occasionally with alveolar or fine nodular patterns. Histologically, biopsy specimens show mononuclear cell infiltration, alveolar lining cell hypertrophy, collagen deposition, and alveolar septal thickening. Type II pneumocyte enlargement and lymphocytic or eosinophilic infiltration have also been described. Patients develop a clinical picture of interstitial pneumonitis and fibrosis. This syndrome may respond to discontinuation of drug and institution of corticosteroids. The second syndrome of mitomycin-induced pulmonary toxicity is seen in patients who have also received vinca alkaloids. While drugs of this latter category confer little in the way of risk of pulmonary toxicity when used as single agents, vinblastine, vinorelbine, and vindesine given concurrently or subsequent to administration of mitomycin have been described to precipitate a syndrome of acute pulmonary toxicity. Clinically, patients present with rapid onset of dyspnea or bronchospasm within hours after administration of vinca alkaloid. Pulmonary symptoms may be associated with hypoxia and bilateral interstitial infiltrates on chest radiograph. In a series of 126 patients, 6 percent developed this syndrome. A smaller number may go on to develop respiratory failure and noncardiogenic pulmonary edema. While the acute dyspnea syndrome usually subsides with supportive care, withdrawal of drug, and corticosteroids, long-term impairment of clinical and physiological parameters may persist. Re-challenge with vinca alkaloid will result in similar symptoms in most patients. The third syndrome of mitomycin toxicity is an association with the hemolytic uremic syndrome. A number of cases of microangiopathic hemolytic anemia, thrombocy-

Pulmonary Toxicity Associated with Chemotherapeutic Agents

topenia, and renal failure following mitomycin administration have been reported. Approximately one-half of these patients develop noncardiogenic pulmonary edema. Additionally, pulmonary alveolar hemorrhage in this setting has been described. The mechanism of toxicity appears related to endothelial injury in the pulmonary vasculature. Prognosis for patients with this syndrome is poor. In a series of 39 patients, overall mortality was 72 percent. In patients who also developed pulmonary edema, mortality increased to 95 percent. A variety of therapies have been tried in attempts to reverse the toxicity including administration of corticosteroids, plasmapheresis, heparin, and cytotoxic agents without clear benefit, although the removal of circulating immune complexes via immunoadsorption correlates with temporal improvement in renal function, and should be considered in patients with this disorder. Additionally, mitomycin has been implicated in two cases of fatal pulmonary venoocclusive disease in patients with lung cancer treated with mitomycin C prior to surgical resection.

Actinomycin D Actinomycin D is an antitumor antibiotic used in the treatment of sarcomas, Wilsonâ&#x20AC;&#x2122;s tumor, and gestational choriocarcinoma. While this drug is most often associated with primary lung toxicity, like bleomycin and mitomycin, it may exacerbate radiation-induced injury. Of note, this radiosensitizing effect may be long-standing.

ALKYLATING AGENTS (TABLE 64-3) The chemotherapeutic properties of the alkylating agents result from the formation of covalent linkages (alkylation) of DNA components. Nitrogen mustards are the prototypic alkylating agents and were the first drugs to be used as modern cancer chemotherapy, but many other drugs also exert antineoplastic effects by alkylation. Alkylating agents that have been associated with pulmonary toxicity include derivatives of nitrogen mustards (cyclophosphamide, melphalan, chlorambucil, ifosfamide), alkyl sulfonates (busulfan), and the nitrosoureas (carmustine/BCNU, lomustine/CCNU). The nitrosoureas are considered in a separate section below. As single drugs, the nitrogen mustard derivatives and busulfan are associated with less pulmonary toxicity than many other classes of chemotherapeutic agents. Increased pulmonary toxicity may occur in the setting of radiation therapy, oxygen supplementation, or combination treatment with other cytotoxic agents. Toxicities related to combination treatments are often difficult to specifically attribute to individual drugs or interactions between drugs. Further, the role of underlying pulmonary disease in predisposing to toxicities from drugs is difficult to discern in this patient population.

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Table 64-3 Alkylating Agents Drug

Pulmonary Syndrome

Treatment

Comments

Cyclophosphamide Chronic pneumonitis/ pulmonary fibrosis

Discontinue drug

Toxicity may occur several years after treatment Risk factors: Use of very high drug doses Concurrent use of other cytotoxic drugs Therapeutic radiation

Busulfan

Chronic pneumonitis/ pulmonary fibrosis

Discontinue drug

Toxicity may occur within weeks and as long as several years after treatment

Chlorambucil Melphalan Ifosfamide

Chronic pneumonitis/ pulmonary fibrosis

Discontinue drug Consider corticosteroids

Clinical pulmonary toxicity is rare

Cyclophosphamide Cyclophosphamide is widely used in the treatment of many malignancies, including lymphomas, breast and ovarian cancers, and a variety of other solid tumors. It is commonly used as part of myeloablative conditioning regimens prior to bone marrow or peripheral blood stem cell transplantation. Cyclophosphamide is also used in the treatment of nonneoplastic inflammatory disorders including autoimmune diseases and systemic vasculitides. While the incidence of pulmonary toxicity is reportedly less than 1 percent, these broad indications for its use make it likely that cyclophosphamideinduced lung injury will be encountered by the practicing pulmonologist. Cyclophosphamide appears to have an increased incidence of toxicity when used in multidrug regimens or when used in the setting of therapeutic thoracic irradiation. Cyclophosphamide is administered as an inactive prodrug that is metabolized by the liver to the active compound, phosphoramide mustard, and the bladder-toxic metabolite acrolein. The pharmacokinetics of both the inactive parent compound as well as its active alkylating derivative can be affected by variations in the cytochrome P450 superfamily of enzymes as well as by interactions with other drugs. Though the exact mechanism of cyclophosphamide-induced injury to the lung is unknown, cyclophosphamide has been shown in animal studies to deplete hepatic glutathione stores, which may render cells more susceptible to oxidant injury. Intratracheal or intraperitoneal administration of cyclophosphamide in animals causes lung injury manifested by type II cell abnormalities, inflammatory pneumonitis, and progressive interstitial fibrosis. While no definite dose-response relationship has been established for cyclophosphamide, higher exposure to active drug may occur in the setting of concurrent treatment with drugs that induce hepatic enzyme activity, such as

rifampin, phenytoin, and alcohol. Since the drug is excreted by the kidneys, renal dysfunction may result in increased exposure. As with a number of other chemotherapeutic agents, cyclophosphamide-induced pulmonary toxicity may present early on during the course of treatment, or in a delayed fashion even years after treatment is completed. Clinically, patients usually present insidiously with symptoms of cough and progressive dyspnea, often accompanied by fever. As noted, the timing of onset of pulmonary toxicity can be highly variable and may occur 2 weeks to as many as 13 years after initiation of treatment. When patients present in the acute treatment setting, an association with exposure to cyclophosphamide may be evident. However, in cases in which pulmonary symptoms occur long after exposure to the drug, such an association may be more difficult to identify. Chest radiograph usually shows evidence of bilateral interstitial lung disease, often accompanied by pleural thickening. This latter radiographic finding may be helpful in distinguishing cyclophosphamideassociated interstitial lung disease from the idiopathic interstitial pneumonias. Histologic findings in the lung, as with pulmonary toxicity from other cytotoxic drugs, are not specific. Lung biopsy in these patients is primarily useful for exclusion of other identifiable causes of interstitial lung disease in immunocompromised patients, including infection and malignancy. Cyclophosphamide-induced lung injury can cause significant morbidity. When used to treat nonneoplastic lung disease, concern is often raised that the underlying pulmonary disease may be exacerbated by superimposed drug toxicity. The distinction between the two processes is often very difficult to delineate. When used as a chemotherapeutic agent, identifying cyclophosphamide as the specific etiology of lung injury may be difficult as it is rarely used alone. As with all

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multi-drug or multi-modality regimens, pinpointing specific toxicity to a single agent may be impossible. Moreover, it appears that cyclophosphamide may have synergistic toxicity with therapeutic thoracic radiation as well as with other chemotherapeutic agents. For patients actively receiving cyclophosphamide, a high suspicion for pulmonary toxicity should result in discontinuation of the drug. Whether corticosteroids have a role in treating early toxicity is unclear. Prognosis in the setting of late-onset symptomatic pulmonary toxicity ascribed to cyclophosphamide is poor, as disease tends to progress to respiratory failure. Many authors recommend treatment with corticosteroids, though there is no definitive evidence of disease reversal with this intervention. As is often the case in such situations, randomized clinical trials addressing whether corticosteroids are effective would be difficult to conduct, and, thus, clinical experience typically guides the decisions about such interventions. While cyclophosphamide administered at conventional dosage confers relatively low risk for pulmonary injury, treatment with high doses may cause significant toxicity. In one study of patients with small cell lung cancer, treatment with radiation therapy and very high doses of cyclophosphamide was complicated by a 74 percent incidence of pulmonary fibrosis. By extrapolation, new dose-intensive regimens using drugs generally felt to be â&#x20AC;&#x153;safeâ&#x20AC;? from a pulmonary standpoint at conventional doses merit careful follow-up and prompt evaluation at any sign of pulmonary toxicity.

Busulfan Busulfan has historically been used in the treatment of chronic myeloproliferative disorders. Because of the nature of these hematopoietic malignancies, patients may require therapy for months to years. Busulfan in this situation is usually well tolerated, but cumulative dosage is of concern because of the duration of treatment. While a threshold dose for toxicity has not been determined, cumulative doses above 500 mg appear to be associated with increased risk of pulmonary toxicity. In older series, up to 46 percent of patients treated with busulfan had evidence of pulmonary fibrosis, but the majority had no clinically significant disease. Busulfan is also used in conditioning regimens prior to bone marrow and stem cell transplantation. Total body irradiation combined with cyclophosphamide has historically been the standard myeloablative therapy for patients undergoing bone marrow transplantation for hematopoietic malignancy, but an alternative regimen of busulfan with cyclophosphamide has also been widely used since the mid-1980s. Concern has been raised that busulfan-based conditioning regimens may be associated with late onset post-transplant pulmonary toxicity, including bronchiolitis obliterans (BO). In a report of over 6000 patients receiving allogeneic transplants for leukemia and followed by the International Bone Marrow Transplant Registry, multivariate analysis identified use of a busulfan-based conditioning regimen as a factor associated with an increased risk for BO. Of note, only 1.7 percent of all

Pulmonary Toxicity Associated with Chemotherapeutic Agents

patients in this report had BO at 2 years after transplantation, and other factors associated with increased risk for development of BO included the presence of graft-vs.-host disease (GVHD), peripheral blood stem cell transplant (as opposed to bone marrow transplant), female donor to male recipient, and a prior episode of interstitial pneumonitis. Symptoms of busulfan lung injury usually present insidiously, often within weeks, but sometimes years after initiation of therapy. Symptoms include cough, fever, fatigue, weight loss, and progressive dyspnea. Chest radiograph usually shows bilateral interstitial infiltrates with a basilar predominance. Pathological findings are consistent with other cytotoxic drugâ&#x20AC;&#x201C;induced pulmonary injury, with type II pneumocyte hyperplasia, dysplasia, and desquamation into alveolar spaces. Fibroblast proliferation, collagen deposition, and fibrosis are usually evident. Scattered cases of pulmonary ossification and pulmonary alveolar proteinosis have also been reported. There is no specific treatment for busulfan-induced pulmonary injury, except withdrawal of the drug. When clinically evident busulfan-induced pulmonary toxicity occurs, prognosis for recovery is poor. Corticosteroids have anecdotally been reported to be of benefit but as with most chemotherapeutic agents, no prospective studies are available. Given the possibility of late-onset pulmonary toxicity, it seems prudent that long-term follow-up of recipients of bone marrow or peripheral blood stem cell transplants with busulfan-based conditioning regimens should include pulmonary evaluation. However, guidelines for identification or treatment of pulmonary toxicity in this situation are lacking.

Other Alkylating Agents Chlorambucil and melphalan are slow acting nitrogen mustards. Chlorambucil has an important role in the treatment of lymphoreticular malignancies including chronic lymphocytic leukemia. Like cyclophosphamide, this drug has also been used in the treatment of nonneoplastic diseases, including sarcoidosis. Pulmonary toxicity is rare, occurring in less than 1 percent of patients. As with busulfan, chlorambucil as treatment for chronic hematologic disorders may be given over long spans of time. However, there does not appear to be an association of pulmonary toxicity with cumulative dosage. Since the number of cases of reported chlorambucil pulmonary toxicity are small, no distinct clinical patterns have emerged. In cases of interstitial pneumonitis thought related to chlorambucil, bronchoalveolar lavage has demonstrated a T-lymphocytic alveolitis with a CD8 predominance and the presence of eosinophils, suggesting the possibility of hypersensitivity. In cases in which interstitial pneumonitis is thought to be related to administration of chlorambucil, drugs should be discontinued. Given the possibility of drug hypersensitivity based on bronchoalveolar lavage findings, administration of corticosteroids should be considered in patients with progressive pulmonary disease.

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Drug-Induced Lung Diseases

Table 64-4 Antimetabolites Drug

Pulmonary Syndrome

Treatment

Comments

Methotrexate

Chronic pneumonitis/ pulmonary fibrosis Hypersensitivity-type lung disease Acute chest pain syndrome Noncardiogenic pulmonary edema

Corticosteroids Discontinue drug Corticosteroids Discontinue drug Discontinue drug

Most common syndrome of methotrexate-induced lung toxicity May resolve even if drug is continued, but can progress to fibrosis Often accompanied by pleural effusions

Supportive care Discontinue drug

Associated with intrathecal administration

Cytosine arabinoside

Noncardiogenic pulmonary edema

Supportive care Discontinue drug

Onset of symptoms usually occurs within days of initiation of treatment Risk factor: Cumulative dose

Fludarabine

Hypersensitivity reaction

Discontinue drug

Interstitial pneumonitis

Discontinue drug

Associated with increased incidence of opportunistic infections Toxicity is uncommon

Dyspnea

Usually self-limited, occurring within hours of dose Bronchodilators, corticosteroids Discontinue drug, corticosteroids

Gemcitabine

Bronchospasm Noncardiogenic pulmonary edema

Melphalan has been used in the treatment of multiple myeloma as well as solid tumors including ovarian cancer, rhabdomyosarcoma, and osteogenic sarcoma. Melphalaninduced pulmonary toxicity is rare; when it occurs it has typically manifested as interstitial lung disease. However, like other alkylating agents, melphalan is being used now in novel treatments for a variety of cancers. High-dose melphalan (greater than or equal to 200 mg/m2 ) used in conditioning regimens prior to stem cell transplantation has been reported to be associated with pulmonary toxicity. High-dose melphalan delivered by isolated lung perfusion is also being evaluated as a treatment for pulmonary metastatic disease. Since large series of such patients are not available, the incidence of pulmonary toxicity associated with high-dose melphalan given in these situations is not known. As these types of treatments become more widely available, new data should define whether pulmonary toxicity related to melphalan or other alkylating agents is indeed more prevalent than has been historically appreciated. Ifosfamide is an alkylating agent that is structurally related to cyclophosphamide. It is used in the treatment of lymphoma and acute and chronic leukemias, as well as in solid tumors including sarcomas, ovarian cancer, and breast cancer. Dose limitation is usually related to bladder toxicity.

Occurs in up to 8% of patients

Occurs in <1% of patients May resolve, but respiratory failure and death reported

Clinically evident ifosfamide-induced pulmonary toxicity appears to be rare, and typically presents as interstitial pneumonitis.

ANTIMETABOLITES (TABLE 64-4) Methotrexate Methotrexate is a folate antagonist used as a chemotherapeutic agent as well as in the treatment of nonneoplastic inflammatory diseases. When used in high doses for the treatment of cancers, the incidence of pulmonary toxicity is estimated at 7 percent. Toxicity does not appear to have dose dependency but may be related to frequency of administration. In one study, daily or weekly treatment carried more risk of pulmonary injury than treatment every 2 to 4 weeks. Synergistic toxicity has been reported with combination therapy using cyclophosphamide. Tapering of corticosteroid therapy or adrenalectomy may also increase the risk of methotrexateinduced toxicity. The mechanism of methotrexate-induced lung injury is unknown. Clinically, toxicity presents with several

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syndromes. The most common of these is the development of a symptom complex characterized by fever, dyspnea, cough, malaise, and myalgias, usually within weeks after initiation of therapy. Chest radiograph usually shows diffuse interstitial infiltrates. Occasionally, chest radiograph may show unilateral or bilateral effusions, a nodular appearance, or may even be normal. Additionally, hilar and mediastinal adenopathy have been observed. Skin rash is present in up to 17 percent of patients and peripheral blood eosinophilia in up to 40 percent of patients. Bronchoalveolar lavage in this setting may show a lymphocytic alveolitis, suggestive of a hypersensitivity reaction. However, illness may resolve even with continuation of the drug, and rechallenge does not necessarily result in relapse. These findings suggest that hypersensitivity may not be the true mechanism of injury. This presentation of methotrexate-induced pulmonary toxicity parallels the hypersensitivity-type syndrome that is sometimes observed with bleomycin. As some patients may go on to develop chronic pneumonitis and pulmonary fibrosis, the drug is generally withdrawn when toxicity occurs. Pulmonary toxicity from methotrexate may also present as a more insidious subacute syndrome of interstitial lung disease. Symptoms including cough, fever, dyspnea, headache, and malaise typically occur within 4 months after the initiation of treatment. Radiographically and clinically this syndrome more closely resembles the type of chronic pneumonitis seen with other cytotoxic drugs and has been described as complicating all routes of methotrexate administration (oral, intravenous, intrathecal). In contrast to many other chemotherapeutic agents, the pneumonitis caused by methotrexate appears in general to be responsive to corticosteroids. Pathological findings in the lung parallel those seen with lung injury due to other cytotoxic drugs, with interstitial and alveolar inflammation and fibrosis. Additionally, eosinophilic infiltration of the interstitium as well as granulomatous inflammation may be observed. These latter findings are again suggestive of a potential hypersensitivity-type mechanism of inflammation. Methotrexate-induced lung injury may also appear as an acute syndrome with pleuritis and pleural effusion. Respiratory distress progressing to noncardiogenic pulmonary edema has been described after intrathecal administration of the drug and may be neurogenic in origin. In patients with rheumatoid arthritis, polymyositis, and other collagen vascular diseases, the potential for a variety of pulmonary manifestations related to the underlying disease can make the diagnosis of methotrexate-induced pneumonitis challenging. The diagnostic criteria of Searles and McKendry (Table 64-5) are frequently employed in an effort to determine whether pulmonary involvement is related to methotrexate. Though they have not been validated in a prospective cohort, these criteria are commonly used to assist with this diagnosis. In a multicenter case-control study of methotrexate-induced lung toxicity in patients with rheumatoid arthritis, Alarcon and colleagues identified risk factors associated with the development of pneumonitis, including

Pulmonary Toxicity Associated with Chemotherapeutic Agents

Table 64-5 Diagnostic Criteria of Searles and McKendry for Methotrexate Pneumonitis Diagnostic criteria: Acute onset of shortness of breath Fever (>38.0◦ C) Tachypnea (≥28 breaths per minute) with nonproductive cough Radiographic evidence of interstitial or alveolar infiltrates WBC ≤15,000 Negative blood or sputum cultures for pathogenic organisms (required) Pulmonary function tests demonstrating restrictive disease with low diffusion capacity PaO2 < 55 mmHg on room air (at presentation) Biopsy histopathology consistent with bronchiolitis or interstitial pneumonitis with giant cells and without evidence of pathogenic microorganisms Presence of methotrexate pneumonitis: Definite: at least 6 of 9 criteria Probable: 5 of 9 criteria Possible: 4 of 9 criteria

age greater than 60 years (associated with a sixfold increase in risk of pneumonitis compared with those less than 50 years of age), prior history of rheumatoid pleuropulmonary disease, diabetes, previous use of disease-modifying antirheumatic drugs, and hypoalbuminemia. The prognosis with methotrexate-associated lung toxicity is generally felt to be favorable. As noted, symptoms and radiographic abnormalities may resolve even with continuation of treatment. The use of corticosteroids is generally recommended though prospective trials of this intervention are not available. The overall mortality rate with methotrexateinduced pneumonitis is approximately 10 percent.

Cytosine Arabinoside Cytosine arabinoside (Ara-C) is a pyrimidine nucleoside analog that rapidly inhibits DNA synthesis. It is important in the treatment of acute leukemias and nonHodgkin’s lymphoma. Pulmonary toxicity parallels intensity of treatment. High-dose regimens have been associated with a 5 to 44 percent incidence of acute or subacute respiratory insufficiency. Symptoms include fever, cough, dyspnea, and tachypnea and may coincide with chemotherapeutic treatment or may be delayed for up to several weeks after treatment is initiated. Hypoxemia may be present. Chest radiograph generally shows a diffuse interstitial or alveolar pattern. The pathogenesis of pulmonary toxicity due to Ara-C is unknown but appears to result in a syndrome of noncardiogenic pulmonary edema. In

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an autopsy series of 181 patients who died of acute leukemia, Haupt and colleagues described a group of 42 patients who had received Ara-C within 30 days of death and had moderate to severe pulmonary edema. Lung pathology showed highly proteinaceous infiltrates in both alveoli and interstitium. Twenty-eight of these 42 patients had no identifiable cause of their pulmonary edema. In these cases, Ara-C was felt to be the most likely precipitant. Cytosine arabinoside has also been associated with cryptogenic organizing pneumonia when administered with anthracyclines or interferon-α. The pulmonary manifestations typically occur within a few weeks to 2 months after drug exposure and are characterized by fever, shortness of breath, and radiographic infiltrates that may be either lobar or nodular. All patients reported to date have achieved resolution of their pulmonary disease, either spontaneously or with the use of corticosteroids Treatment for Ara-C lung toxicity is standard supportive care for noncardiogenic pulmonary edema. Administration of corticosteroids has been recommended by some authors but is of unclear benefit. Clinical and radiographic resolution may take 7 to 21 days. Overall mortality associated with Ara-C induced pulmonary toxicity ranges from 6 to 13 percent.

Fludarabine Fludarabine monophosphate is a purine nucleotide analog used in the treatment of chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin’s lymphoma, and a variety of other lymphoproliferative disorders. Pulmonary toxicity from fludarabine, including interstitial pneumonitis and acute eosinophilic pneumonitis, has been described. Helman and colleagues reported the largest series to date, which included nine patients with fludarabine-related pulmonary toxicity out of a total of 105 patients (8.6 percent) treated with fludarabine over an 11-year period at a single institution. Toxicity did not correlate with age, prior treatment regimens, or history of prior lung disease, but occurred more frequently in patients with CLL compared with patients being treated for other lymphoproliferative disorders. The onset of symptoms ranged from 3 to 6 days after therapy, with radiographs notable for new interstitial or mixed interstitial and alveolar infiltrates. BAL fluid revealed increased cellularity without a consistently predominant cell type. Multifocal nodular pulmonary infiltrates have also been described. Biopsy specimens most commonly reveal diffuse, chronic interstitial inflammation and fibrosis, although in some cases granulomas have been observed, suggesting the possibility of a hypersensitivity reaction. In the report by Helman and colleagues, patients with fludarabine-associated pulmonary toxicity generally demonstrated subjective and objective improvement with corticosteroid therapy. Most patients responded within days, although more delayed responses were possible. Therapy with fludarabine is associated with profound immunosuppression, which may persist for months after

treatment. The risk of opportunistic infections, including Pneumocystis jiroveci pneumonia is increased by the use of corticosteroids in this setting. Symptomatic pulmonary disease in patients treated with fludarabine within this time frame is most likely therefore to be related to infection. However, recrudescence of noninfectious pulmonary infiltrates has been described with fludarabine retreatment; thus fludarabine should be avoided in future regimens in patients who have developed drug-related pulmonary toxicity.

Gemcitabine Gemcitabine is a pyrimidine analog which is structurally similar to cytosine arabinoside and used in the treatment of cancers of the lung, pancreas, ovary, and uroepithelium. The drug is generally well tolerated, with myelosuppression as the major toxicity. Drug-related dyspnea has been reported to occur in 8 percent of treated patients. This dyspnea may occur within hours to days of treatment, and is generally self-limited. Bronchospasm has been rarely described. Severe pulmonary toxicity has been reported, with development of noncardiogenic pulmonary edema characterized radiographically by mixed interstitial and alveolar infiltrates. Though responses to corticosteroids have been noted, this syndrome can be fatal. Histologic evaluation most commonly reveals type II pneumocyte hyperplasia, interstitial inflammation, and hyaline membrane formation consistent with acute lung injury. Some patients with ultimately fatal outcome have demonstrated premonitory symptomatology including dyspnea, hypoxemia, and radiographic infiltrates to a milder degree with prior doses of gemcitabine. Such symptoms should raise consideration to discontinue gemcitabine.

NITROSOUREAS (TABLE 64-6) The nitrosourea group includes carmustine or BCNU (1,3bis-(2-chloroethyl)-1-nitrosourea), lomustine or CCNU (1(2-chloroethyl)-3-cyclohexyl-1-nitrosourea), semustine or methyl-CCNU, and chlorozotocin. These cytotoxic drugs are active against a variety of neoplasms. BCNU and CCNU are highly lipophilic and can cross the blood-brain barrier, which makes them particularly useful in the treatment of central nervous system malignancies. BCNU is also being increasingly used in high-dose conditioning regimens prior to bone marrow or stem cell transplantation for a variety of malignancies, including breast cancer, Hodgkin’s and non-Hodgkin’s lymphomas, multiple myeloma, and gliomas.

Carmustine (BCNU) Of the nitrosoureas, BCNU has been most extensively studied. Like bleomycin, this drug has been used in animal models of lung injury, but the mechanisms by which injury occurs are not well understood. Intraperitoneal injection of BCNU

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Table 64-6 Nitrosoureas Drug

Pulmonary Syndromes

Treatment

Comments

BCNU

Early onset pulmonary physiologic abnormalities and/or interstitial lung disease

Supportive care Discontinue drug ? Corticosteroids for early onset pulmonary physiological abnormalities

Toxicity may appear years after therapy Risk factor: Cumulative dose >1200 mg/m2

Supportive care Discontinue drug

By extrapolation, toxicities and risk factors probably parallel BCNU

Late-onset pulmonary fibrosis

CCNU Semustine Chlorozotocin

Chronic pneumonitis/ pulmonary fibrosis

in rats results in granulomatous inflammation and interstitial fibrosis, which progresses even after withdrawal of drug. Oxidant lung injury may play a role in the pathogenesis of toxicity as BCNU is known to inhibit glutathione reductase in pulmonary macrophages and reduces lung glutathione stores. Like bleomycin, the toxicity of BCNU appears to be dose related. In a study of 94 patients with Hodgkin’s disease who received chemotherapeutic regimens including BCNU, doses less than 475 mg/m2 were associated with a 15 percent incidence of pulmonary toxicity; doses ranging between 475 and 525 mg/m2 with a 32 percent incidence; and doses in excess of 525 mg/m2 with a 47 percent incidence of pulmonary toxicity. Treatment of intracranial gliomas can result in substantially higher cumulative BCNU doses. Very high doses (greater than 1200 to 1500 mg/m2 ) result in pulmonary toxicity in as many as 20 to 50 percent of patients. Risk factors contributing to the development of pulmonary toxicity with BCNU may include underlying lung disease, a history of smoking, previous or simultaneous treatment with other chemotherapy agents (including cyclophosphamide or bleomycin), chest radiotherapy, and female sex. Pulmonary toxicity related to BCNU may occur within days to weeks after treatment, but may also present years later. Early onset pulmonary injury appears to be an underappreciated event. In a study of 152 patients treated for breast cancer with a regimen of BCNU (600 mg/m2 ), cyclophosphamide, and cisplatin followed by stem cell transplantation, 59 percent developed a significant decrease in DlCO at a median time after treatment of 45 days. The vast majority of these patients had subclinical disease and appeared to have improvement in their pulmonary status with initiation of corticosteroid therapy. Early-onset toxicity can also present as fulminant lung injury with progression in some cases to fatal pulmonary fibrosis. Late-onset pulmonary toxicity, typ-

Possible risk factors: Female sex Concurrent use of other cytotoxic drugs Underlying pulmonary disease

ically presenting as pulmonary fibrosis, can occur years after BCNU treatment. O’Driscoll and colleagues in 1990 first reported their observations on this phenomenon in survivors of childhood brain tumors. Of 31 original patients, 14 died of their tumors. In their last report in 2004 of a 25-year follow-up of the 17 survivors, nine (53 percent) had died of complications related to pulmonary fibrosis. Two patients died within the first 3 years after chemotherapy, four died between 6 and 13 years after chemotherapy, and three died between 13 and 25 years after chemotherapy. Furthermore, of the remaining eight patients still surviving, seven had radiographic and physiological evidence of pulmonary fibrosis. Thus, in this population of children treated with high-dose BCNU, late toxicity in the lung was extremely common and of severe clinical consequence. The clinical presentation of BCNU-induced lung toxicity is variable. As noted, it may present fulminantly as acute respiratory failure but more commonly presents insidiously with asymptomatic physiological abnormalities or radiographic evidence of pulmonary fibrosis. Symptoms of this latter subacute course include cough, fatigue, and progressive dyspnea. Chest radiograph is rarely normal in symptomatic patients, usually showing bilateral interstitial infiltrates with a basilar predominance. However, in O’Driscoll’s series of patients with childhood brain tumors treated with high-dose BCNU and who developed late-onset pulmonary fibrosis, patients demonstrated an upper lobe predominance to the distribution of fibrotic changes. Patients with an acute presentation may present with confluent alveolar infiltrates. Pneumothorax has been described in a number of cases and may be bilateral (Fig. 64-4). Pulmonary physiology generally shows a restrictive ventilatory defect with diffusion abnormalities and eventually hypoxia. As with bleomycin, DlCO may decrease without radiographic or clinical evidence of

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Figure 64-4 Serial chest computed tomography scans of a 54-year-old man with a history of Hodgkinâ&#x20AC;&#x2122;s lymphoma, treated with a BCNU-containing regimen. The dates of the examinations span 6 months from ( A) to (D ). Note the progression of diffuse interstitial patchy infiltrates, starting with the baseline normal study in (A). Pneumomediastinum and left pneumothorax are seen in (C ) and (D ). Bronchoscopy was performed between examinations (B ) and (C ), and demonstrated no evidence of infection. The patient had progressive dyspnea and respiratory insufficiency and eventually died of respiratory failure.

disease. While it has been suggested that a decrease in DlCO may be the earliest sign of pulmonary toxicity, prospective evaluation of screening pulmonary function studies in the diagnosis of BCNU-induced lung toxicity has not been adequately studied. However, in light of the frequency and severity with which BCNU-associated pulmonary injury appears to occur, pulmonary function testing may be helpful in identifying patients at risk and in whom administration of corticosteroids might be considered. Pathological changes in the lung from BCNU parallel those seen with other cytotoxic agents. Type II pneumocyte hyperplasia and dysplasia, fibroblast proliferation, and deposition of proteinaceous material in alveoli have been described. However, inflammation tends not to be a prominent histological feature, and the cardinal feature of BCNUinduced lung toxicity appears to be interstitial fibrosis. In some cases, angiocentric necrotizing granulomatous inflammation or, more rarely, pulmonary veno-occlusive disease have been described.

The prognosis for patients with BCNU-induced lung injury is poor. For patients with early-onset lung toxicity, treatment with corticosteroids may be effective. One study of patients with breast cancer for whom BCNU was administered as part of treatment with high-dose chemotherapy followed by stem cell transplantation suggested that inhaled corticosteroid might be helpful in preventing pulmonary toxicity. Late-onset pulmonary fibrosis related to BCNU does not appear to respond to corticosteroid therapy. The primary approach to BCNU toxicity should be to administer the lowest possible effective dose and monitor closely for signs of toxicity. Long-term treatment remains supportive. With the known long potential delay in the onset of signs of toxicity, long-term follow-up is also warranted.

Other Nitrosoureas The other nitrosoureas used as chemotherapeutic agents, lomustine (CCNU), semustine (methyl CCNU), and

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chlorozotocin have also been described to cause pulmonary toxicity. In general, these drugs have been used less widely than BCNU and in smaller cumulative doses. Their described lower incidence of pulmonary toxicity is likely due to these factors. As with BCNU, toxicity tends to present insidiously with interstitial pneumonitis and pulmonary fibrosis. However, given their close chemical relation, the potential for severe lung toxicity as seen with BCNU must be taken into consideration when using other drugs of this class.

BIOLOGIC RESPONSE MODIFIERS (TABLE 64-7) All-trans Retinoic Acid All-trans retinoic acid (ATRA) is a vitamin A derivative that has proved beneficial in the treatment of acute promyelocytic leukemia. Activity of ATRA occurs through the induction of maturation of malignant cells into mature neutrophils. The “retinoic acid syndrome” was first described in 1991 in a series of 35 patients treated with ATRA, nine of whom developed the constellation of symptoms and signs defining the syndrome. Similar incidence (44 of 167 patients) was

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noted during Intergroup Study 0129. The retinoic acid syndrome usually occurs from 2 to 21 days after drug initiation and is characterized by fever, edema, weight gain, interstitial or alveolar infiltrates, pleural or pericardial effusions, diffuse alveolar hemorrhage, and renal insufficiency. The syndrome is frequently, although not universally, seen coincident with the development of a pronounced leukocytosis. Radiographic features of the syndrome include pleural effusions, cardiomegaly, increased pulmonary blood volume, and widened vascular pedicle. Less frequently seen are prominent septal lines, nodules, ground-glass opacities, or parenchymal consolidation with air bronchograms. In the setting of diffuse alveolar hemorrhage, high-resolution computed tomography (CT) reveals poorly defined centrilobular nodules and diffuse ground-glass opacification. Histological examination of lung tissue most commonly reveals infiltration of the lung parenchyma with maturing myeloid cells, with or without pulmonary hemorrhage. Fibrinoid necrosis and pulmonary capillaritis have also been described. The syndrome is thought to result from endothelial damage resulting in edema, hemorrhage, fibrinous exudates, and infiltration of neutrophils. The mechanism of ATRAmediated pulmonary toxicity is poorly understood, but increased expression of cell adhesion molecules on leukemic cells has been demonstrated after ATRA administration,

Table 64-7 Biologic Response Modifiers Drug

Pulmonary Syndrome

Treatment

Comments

All-trans retinoic acid

“Retinoic acid syndrome”

Corticosteroids Discontinue drug Supportive care

Treatment regimens using all-trans retinoic acid should include corticosteroids

Interleukin-2

Pleural effusions Focal or diffuse radiographic abnormalities

Supportive care Discontinue drug

Noncardiogenic pulmonary edema

Supportive care Discontinue drug

Radiographic abnormalities uncommon Usually reversible Risk factors: Increasing cumulative dose Administration of LAK cells IL-2-induced cardiac toxicity may contribute to pulmonary edema

Gefitinib

Diffuse alveolar damage

Supportive care Discontinue drug

Preexisting lung fibrosis a risk factor

Bevacizumab

Pulmonary hemorrhage

Supportive care Discontinue drug

More common with cavitary tumor, squamous cell histology, hemorrhage is usually from site of tumor

Rituximab

Interstitial pneumonitis/ cryptogenic organizing pneumonia

Corticosteroids Discontinue drug

Toxicity extremely rare

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as have increased endothelial expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). In addition, elevated levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor α (TNFα) have been observed, and may promote leukocyte activation, contributing to tissue injury. The incidence of the retinoic acid syndrome varies between 5 and 27 percent in the published literature. Several series suggest that coadministration of idarubicin may reduce the incidence, although this is not a universal finding. The mortality rates vary from 5 to 29 percent, with prompt initiation of corticosteroids seemingly associated with improved outcome. The continuation of ATRA does not appear to be absolutely contraindicated as long as corticosteroids are administered in a timely fashion. In cases with severe manifestations, discontinuation of ATRA seems reasonable, although reintroduction of drug on resolution of the syndrome is only infrequently met with recurrence.

Interleukin-2 Interleukin-2 (IL-2) is a glycoprotein secreted by activated lymphocytes. IL-2 therapy alone or in conjunction with lymphokine activated killer (LAK) cells has proved beneficial in patients with metastatic renal cell carcinoma or melanoma. However, significant treatment-related pulmonary toxicities have been observed. In a series of 54 patients who received high dose IL-2 and LAK therapy, 80 percent of patients were noted to have focal or diffuse parenchymal lung opacities. Pleural effusions were also a common finding. The spectrum of pulmonary toxicities range from subclinical restrictive and obstructive physiological abnormalities often associated with a decline in the DlCO , to more severe clinically evident cases of respiratory insufficiency. The latter generally presents as a syndrome of noncardiogenic pulmonary edema and may be associated with hypotension and renal insufficiency. Several mechanisms have been identified that may explain the increase in capillary permeability. IL-2 activated lymphocytes produce a variety of cytokines, including tumor necrosis factor and IL-1. These may alter endothelial permeability and are thought, for example, to contribute to the septic shock syndrome. IL-2 also may promote the adhesion of natural killer cells to the capillary endothelium, thus altering vascular integrity. Furthermore, IL-2 is also associated with toxicity in multiple other organs, including the heart. Therefore, IL-2–induced cardiac dysfunction may contribute to the development of pulmonary interstitial edema. IL-2 appears to have a cumulative dose-dependent lung toxicity that seems to be compounded by LAK cell administration. Lung toxicity does appear to be reversible. In most cases, clinical and radiographic abnormalities resolve within several days after cessation of therapy. IL-2 has also been administered via inhalation to treat pulmonary metastases in patients with renal cell carcinoma and melanoma. The inhalational route of IL-2 appears to abrogate the risk of pulmonary toxicity, while demonstrating efficacy against intrapulmonary metastatic disease.

EGFR Inhibitors Gefitinib Gefitinib is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, and has been used in the treatment of non–small-cell lung cancer (NSCLC). Toxicities most commonly associated with gefitinib administration include skin rash and diarrhea. Postmarketing experience with this agent was notable for reports of acute pneumonitis in patients exposed to this agent. The incidence of this side effect has been reported to be 1 percent in 50,500 patients treated worldwide, although reported incidence in single institution series is as high as 10.9 percent. In patients with preexisting pulmonary fibrosis, this complication has been noted in 33 to 56 percent of patients. Gefitinib-induced pulmonary toxicity may occur within days of initiation of therapy, though median exposure times vary from 24 to 42 days prior to the development of toxicity. The clinical syndrome is marked by the development of rapidly progressive dyspnea and hypoxemia with diffuse ground-glass opacities noted on chest CT scan. Progression to respiratory failure and death has been noted in one-third of patients. It is unclear whether corticosteroids modulate this disease process. Histologic evaluation in patients who have succumbed to this illness has revealed diffuse alveolar damage. The mechanism of gefitinib-induced lung injury remains a subject of investigation. EGFR is known to be upregulated in response to lung injury, and may be important in promoting type II pneumocyte hyperplasia in response to injury. In murine models, gefitinib has been demonstrated to result in more severe lung fibrosis in animals exposed to bleomycin. The increased frequency of this toxicity in patients with preexisting pulmonary fibrosis lends credence to the hypothesis that gefitinib impairs the regeneration of alveolar epithelial cells in response to injury. Erlotinib Interstitial lung disease has also been described with erlotinib, another agent with activity against the EGFR tyrosine kinase. However, the incidence is similar to that seen in placebo-treated patients, and thus a specific risk of interstitial pulmonary diseases associated with erlotinib has not been defined. Bevacizumab Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF) that has demonstrated activity against breast, colon, renal, and NSCLCs. Increased response rates for locally advanced and metastatic NSCLC are observed when bevacizumab is added to traditional chemotherapy. In a series including 99 patients with newly diagnosed stage IIIB or IV or recurrent NSCLC, six patients developed serious bleeding complications including hemoptysis or hematemesis. Four of the six patients died as a result of the hemorrhage. All six cases of hemorrhage appeared to be tumor related, with four of the six patients having

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Table 64-8 Miscellaneous Agents Drug

Pulmonary Syndrome

Treatment

Comments

Doxorubicin

Noncardiogenic pulmonary edema

Supportive care Discontinue drug

Increases risk of radiation pneumonitis Risk factor: Therapeutic radiation

Procarbazine

Hypersensitivity-type pneumonitis Chronic pneumonitis/ pulmonary fibrosis

Discontinue drug

Pulmonary toxicity uncommon

Discontinue drug

Vinca Alkaloids Vindesine Vinblastine Vinorelbine

Noncardiogenic pulmonary edema, interstitial pneumonitis, bronchospasm

Supportive care Discontinue drug Corticosteroids

Risk factor: Concurrent treatment with mitomycin-C

Taxines Paclitaxel

Dyspnea, bronchospasm

Discontinue drug Supportive care

Noncardiogenic pulmonary edema

Discontinue drug Supportive care

Pretreatment with histamine antagonists and corticosteroids reduces incidence of toxicity Toxicity is related to cumulative dose

Docetaxel

squamous cell histology. Radiographically visible cavitation or necrosis was seen in five of the six cases of hemorrhage. Current clinical investigations of regimens including bevacizumab generally exclude patients with cavitary pulmonary disease or squamous cell histology.

Rituximab Rituximab is a monoclonal antibody directed against the CD-20 antigen on B lymphocytes, and has demonstrated activity against B-cell nonHodgkinâ&#x20AC;&#x2122;s lymphoma as well as refractory immune thrombocytopenic purpura. Cases of acute interstitial pneumonitis have been reported with rituximab use alone or in combination with cytotoxic chemotherapy. The incidence of rituximab-induced interstitial lung disease is estimated to be extremely low, on the order of 0.03 percent. The clinical syndrome typically begins insidiously with cough and dyspnea, which may progress with subsequent exposure to rituximab. The development of hypoxemia in association with parenchymal ground-glass opacification on CT scan has been noted. Histological examinations have revealed reactions typical of cryptogenic organizing pneumonia/bronchiolitis obliterans-organizing pneumonia as well as interstitial inflammation with T lymphocytes and extensive arterial thrombosis. While fatal outcome has been reported, generally this entity has responded well to withdrawal of rituximab and administration of corticosteroids.

MISCELLANEOUS AGENTS (TABLE 64-8) Procarbazine Procarbazine is a cytotoxic drug used primarily in the treatment of lymphoma. Though uncommon, procarbazine has been associated with hypersensitivity pneumonitis. This syndrome typically is seen after the second or third cycle of chemotherapy, although toxicity can occur after the first cycle or after later cycles. Cough, dyspnea, and fever are the most common symptoms with the development of interstitial and/or alveolar infiltrates. Patients have a variable response to corticosteroids in published cases, and rechallenge with procarbazine is associated with recurrence of the syndrome in the majority of patients.

Taxines Paclitaxel is a member of the taxane family, which functions through inhibition of microtubule disassembly and disruption of the G2 and M phases of the cell cycle. Paclitaxel has activity against a variety of carcinomas, including breast, ovarian, and NSCLC. There is a high incidence (up to 30 percent) of acute hypersensitivity reactions associated with paclitaxel administration, with symptoms including dyspnea, bronchospasm, urticaria, and hypotension. The administration of corticosteroids and histamine antagonists with paclitaxel greatly reduces the frequency of this reaction to 1 to

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2 percent. Paclitaxel has also been associated with the development of corticosteroid responsive hypersensitivity pneumonitis occurring several days to weeks after paclitaxel administration, and should be suspected in those who develop interstitial infiltrates following paclitaxel therapy. Docetaxel has a much lower incidence of acute hypersensitivity reactions when compared to paclitaxel. Docetaxel is associated with a syndrome of fluid retention related to capillary leak. This syndrome is associated with the development of peripheral edema, pleural effusions, or ascites, and is lessened in frequency by pretreatment with corticosteroids. Interstitial pneumonitis has been associated with docetaxel administration, and may progress to respiratory failure and death. This syndrome occurs 1 to 2 weeks after administration of the drug. Biopsies have been reported to reveal histologic changes consistent with drug-induced hypersensitivity pneumonitis or diffuse alveolar damage. As opposed to many cases of drug-induced hypersensitivity, this reaction may have a protracted course prior to recovery.

Vinca Alkaloids The vinca alkaloids given as sole agents are rarely associated with pulmonary toxicity. However, the combination of vinblastine, vindesine, or vinorelbine with mitomycin C has been reported to be associated with noncardiogenic pulmonary edema, interstitial pneumonitis, and bronchospasm, often in conjunction with more diffuse endothelial dysfunction. This synergistic toxicity is discussed in more detail in the preceding section on cytotoxic antibiotics. Vinorelbine as a sole agent has been associated with dyspnea in less than 5 percent of cases, which is usually acute in origin, occurs within hours of dosing, and generally responds to bronchodilators and corticosteroids. Respiratory distress with pulmonary edema and interstitial pneumonitis has also been described.

SUGGESTED READING Akasheh MS, Freytes CO, Vesole DH: Melphalan-associated pulmonary toxicity following high-dose therapy with autologous hematopoietic stem cell transplantation. Bone Marrow Transplant 26:1107–1109, 2000. Alarcon GS, Kremer JM, Macaluso M, et al: Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis. A multicenter, case-control study. Methotrexate-Lung Study Group. Ann Intern Med 127:356–364, 1997. Andersson BS, Cogan BM, Keating MJ, et al: Subacute pulmonary failure complicating therapy with high-dose AraC in acute leukemia. Cancer 56:2181–2184, 1985. Beinert T, Dull T, Wolf K, et al: Late pulmonary impairment following allogeneic bone marrow transplantation. Eur J Med Res 1:343–348, 1996. Cao TM, Negrin RS, Stockerl-Goldstein KE, et al: Pulmonary toxicity syndrome in breast cancer patients undergoing

BCNU-containing high-dose chemotherapy and autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant 6:387–394, 2000. Cooper JA Jr, White DA, Matthay RA: Drug-induced pulmonary disease. Part 1: Cytotoxic drugs. Am Rev Respir Dis 133:321–340, 1986. Helman DL Jr, Byrd JC, Ales NC, et al: Fludarabine-related pulmonary toxicity: A distinct clinical entity in chronic lymphoproliferative syndromes. Chest 122:785–790, 2002. Johnson DH, Fehrenbacher L, Novotny WF, et al: Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non–small-cell lung cancer. J Clin Oncol 22:2184–2191, 2004. Jules-Elysee K, White DA: Bleomycin-induced pulmonary toxicity. Clin Chest Med 11:1–20, 1990. Kreisman H, Wolkove N: Pulmonary toxicity of antineoplastic therapy. Semin Oncol 19:508–520, 1992. Limper AH: Chemotherapy-induced lung disease. Clin Chest Med 25:53–64, 2004. Lohani S, O’Driscoll BR, Woodcock AA: 25-Year study of lung fibrosis following carmustine therapy for brain tumor in childhood. Chest 126:1007, 2004. Lund MB, Kongerud J, Nome O, et al: Lung function impairment in long-term survivors of Hodgkin’s disease. Ann Oncol 6:495–501, 1995. Malik SW, Myers JL, DeRemee RA, et al: Lung toxicity associated with cyclophosphamide use. Two distinct patterns. Am J Respir Crit Care Med 154:1851–1856, 1996. O’Sullivan JM, Huddart RA, Norman AR, et al: Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours. Ann Oncol 14:91–96, 2003. Rivera MP, Kris MG, Gralla RJ, et al: Syndrome of acute dyspnea related to combined mitomycin plus vinca alkaloid chemotherapy. Am J Clin Oncol 18:245–250, 1995. Rubio C, Hill ME, Milan S, et al: Idiopathic pneumonia syndrome after high-dose chemotherapy for relapsed Hodgkin’s disease. Br J Cancer 75:1044–1048, 1997. Sandler A, Gray R, Perry M, et al: Paclitaxel-carboplatin alone or with bevacizumab for non–small-cell lung cancer N Engl J Med 355:2542–2550, 2006. Santo Tomas LH, Loberiza FR Jr, Klein JP, et al: Risk factors for bronchiolitis obliterans in allogeneic hematopoietic stem-cell transplantation for leukemia. Chest 128:153– 161, 2005. Searles G, McKendry RJ: Methotrexate pneumonitis in rheumatoid arthritis: Potential risk factors. Four case reports and a review of the literature. J Rheumatol 14:1164– 1171, 1987. Sostman HD, Matthay RA, Putman CE, et al: Methotrexateinduced pneumonitis. Medicine (Baltimore) 55:371–388, 1976.

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Takano T, Ohe Y, Kusumoto M, et al: Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non–small-cell lung cancer treated with gefitinib. Lung Cancer 45:93–104, 2004. Tallman MS, Andersen JW, Schiffer CA, et al: Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome. Blood 95:90– 95, 2000.

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Todd NW, Peters WP, Ost AH, et al: Pulmonary drug toxicity in patients with primary breast cancer treated with highdose combination chemotherapy and autologous bone marrow transplantation. Am Rev Respir Dis 147:1264– 1270, 1993. Wong P, Leung AN, Berry GJ, et al: Paclitaxel-induced hypersensitivity pneumonitis: Radiographic and CT findings. AJR Am J Roentgenol 176:718–720, 2001.

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65 Drug-Induced Lung Disease Due to Nonchemotherapeutic Agents Hilary C. Cain

I. APPROACH TO THE PATIENT WITH SUSPECTED DRUG-INDUCED LUNG DISEASE II. RISK FACTORS FOR DISEASE III. MECHANISMS OF PULMONARY INJURY IV. HISTOPATHOLOGICAL PATTERNS OF INJURY AND CLINICAL SYNDROMES Interstitial Lung Disease Organizing Pneumonia and Bronchiolitis Obliterans Eosinophilic Lung Disease Hypersensitivity Syndromes Diffuse Alveolar Hemorrhage, Vasculitis, and Pulmonary-Renal Syndromes Noncardiogenic Pulmonary Edema and ARDS Airways Disease Pulmonary Hypertension V. DRUGS USED TO TREAT CARDIOVASCULAR DISORDERS Amiodarone Procainamide

Drugs have been recognized as having the potential to cause pulmonary disease at least since the report of opiate-related pulmonary edema published by Osler in 1890. In recent decades, numerous authoritative reviews have addressed this topic. As the number of therapeutic drugs continues to increase, so do case reports of well-established and suspected drug reactions. Web-based databases are devoted to the topic and can serve as useful tools for the clinician (www.pneumotox.com).

Angiotensin Converting Enzyme (ACE) Inhibitors β-Adrenergic Receptor Blockers Hydralazine Hydrochlorothiazide VI. ANTICONVULSANTS Diphenylhydantoin/Phenytoin and Carbamazepine VII. ANTI-INFLAMMATORY AND IMMUNOSUPPRESSIVE AGENTS Aspirin Methotrexate D-Penicillamine Gold Salts Sirolimus VIII. ANTIMICROBIAL DRUGS Nitrofurantoin Interferon-alpha and Pegylated Interferon-α2 b IX. OPIATES AND ILLICIT DRUGS Heroin Cocaine X. TREATMENT AND DISEASE RESOLUTION

APPROACH TO THE PATIENT WITH SUSPECTED DRUG-INDUCED LUNG DISEASE The diagnosis of drug-induced pulmonary toxicity may be challenging to confirm. For most drugs, there are no definitive diagnostic criteria by which to establish the diagnosis. Recognition of the patient’s risk of disease is the first step in diagnosis

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because the clinical presentation of drug-induced lung injury may be similar to that of other disorders, including infection, hypersensitivity pneumonitis due to environmental antigens, eosinophilic lung disease, collagen vascular disease, and idiopathic interstitial pneumonitis. Drug-induced lung disease occurs not only with prescribed drugs, but also with over-thecounter preparations, herbal or alternative medicine preparations (many of which can contain a variety of substances that could be implicated as the culprit agents), and illicit drugs. Patients may be reluctant to offer accurate information about their use of these agents, and thus the history must be skillfully elicited by the clinician. A diagnosis of drug-induced lung toxicity is also difficult to establish, because patients with this condition typically come to medical attention with nonspecific symptoms, radiological findings, and laboratory data. Even among those who have lung tissue obtained by biopsy, histopathological patterns similar to those of other disorders may be seen. The challenge of diagnosis is further compounded by the fact that the latency from the onset of drug use to development of a toxic reaction can be highly variable, such that the temporal relationship between the pulmonary findings and the culprit drug is not readily apparent. Furthermore, many drugs (e.g., amiodarone and nitrofurantoin) can cause acute, subacute, or chronic pulmonary toxicity. In many cases, drug reactions are idiopathic, rather than dosedependent reactions, and risk factors that predispose individuals to the development of pulmonary toxicity are not well characterized. A common challenge in the diagnostic work-up is that the underlying disease can produce pulmonary findings similar to drug-induced lung disease. For example, rheumatoid arthritis can cause pulmonary infiltrates with similar radiographic appearance and histology to toxic reactions induced by methotrexate, gold, and penicillamine used to treat the rheumatoid arthritis itself. Finally, new drugs will continue to come on the market, some of which will inevitably cause lung disorders. Often the potential for drugs to cause toxic reactions will only be recognized once the drug has been in use for a sufficient length time to allow a low frequency event, such as drug-induced toxicity, to be recognized. As a result of these various factors, the diagnosis of drug-induced lung disease may only be established once other etiologies of disease are excluded.

RISK FACTORS FOR DISEASE Several observations can be made that are relevant to understanding drug-induced pulmonary toxicity. One is that the lung has an enormous surface area on which blood-borne substances (e.g., therapeutic medications, nutritional supplements, illicit drugs, or toxins), may exert their effects. Despite this, pulmonary toxicity is a rare event, which occurs in the smallest minority of individuals exposed to a given

agent. In addition, while certain histological patterns of lung injury may occur more frequently than others, there is no single clinical presentation, nor pathognomonic histological pattern of injury induced by a given drug. Furthermore, for most drugs the histological pattern of injury is unrelated to the pharmacologic properties of the drug. Most nonchemotherapeutic drugs cause pulmonary toxicity idiosyncratically, rather than in a dose-dependent reaction. Exceptions include: (1) amiodarone, for which there is increased risk of toxicity with higher daily maintenance dosages and for which the associated histopathology is related to amiodaroneâ&#x20AC;&#x2122;s pharmacologic properties; and (2) heroin, methadone, aspirin propoxyphene, ethylchorvynol, and colchicines that cause pulmonary toxicity only in the setting of overdose. Thus, for most drugs neither dose, duration of exposure, the patientâ&#x20AC;&#x2122;s clinical demographics, nor the pharmacologic nature of the drug determines toxicity. Based on these observations, it may be inferred that there are likely host-specific risk factors that influence the development of pulmonary toxicity. The factors influencing individual susceptibility may be: (1) genetically determined; (2) due to concurrent exposures to medications or environmental factors; (3) related to the individualâ&#x20AC;&#x2122;s co-morbid disease; or (4) a function of some or all of these. The specifics of the host-drug interaction are not fully characterized, but may include host-specific enzyme polymorphisms affecting drug metabolism. Drug biotransformation occurs predominantly in the liver, largely through the cytochrome P450 family of enzymes, but the lung is a site of active drug metabolism as well. The lung has cytochrome P450 enzymes levels estimated at 10 to 15 percent of that of the liver. In addition, there are lung specific cytochrome P450 isoenzymes, which imply lung-specific metabolism of drugs. Exogenous inhalational exposures may exert a harmful effect through a variety of mechanisms. The harmful effect of concurrent oxygen administration in association with the chemotherapeutic agent, bleomycin, has been well established. It has been suggested that the apparent increased risk of amiodarone toxicity in patients who have had thoracic surgery (see below) may be a result of the impact of intraoperative high oxygen tensions. However, high oxygen tension does not substantially increase the risk of toxicity for most nonchemotherapeutic agents. It is plausible that the additive effect of oxidant injury may be more relevant for some individuals than others. There are evolving data that other exogenous factors, such as cigarette smoke, may influence lung injury through induction of cytochrome P450 enzymes. It also has been hypothesized that leukocyte transfusions increased the risk of toxic injury to the lung in the setting of amphotericin use. Acute onset of respiratory symptoms accompanied by interstitial infiltrates has been reported in a series of 14 of 22 patients (64 percent) receiving amphotericin B (non-liposomal) concurrently with daily leukocyte transfusions in the setting of profound neutropenia. In half of the cases, respiratory failure began acutely after amphotericin infusion and it contributed to the death of five affected

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patients. The deleterious effect of leukocyte transfusions has not been observed for other drugs.

Drug-Induced Lung Disease Due to Nonchemotherapeutic Agents

ity syndromes are commonly induced by drugs, particularly the aromatic anticonvulsants. In addition, drugs (e.g., phenytoin) can cause the clinical picture of a pulmonary-renal syndrome, with evidence for pulmonary and renal vasculitis and renal failure.

MECHANISMS OF PULMONARY INJURY In general, specific mechanisms of lung injury due to nonchemotherapeutic drugs are less well defined that those associated with chemotherapeutic agents. This topic has been recently reviewed by Delaunois and earlier by Cooper and colleagues. It appears evident that drugs affect lung homeostasis, but the effect may vary from individual to individual. Proposed mechanisms of lung injury include oxidant injury, immunological and inflammatory cell-mediated injury (including immune complexâ&#x20AC;&#x201C;mediated injury), and interference with cellular repair processes and matrix formation. The role of drug-induced oxidant injury is best established for nitrofurantoin, paraquat (a herbicide used as a defoliant), and bleomycin, but may have relevance for other drugs as well. Biotransformation of these drugs results in generation of reactive oxygen species, including hydrogen peroxide, the hydroxyl radical, and superoxide anion, all of which promote lipid peroxidation and consequently cellular dysfunction. Immunologically mediated injury is undoubtedly important as well. Lymphocytic or neutrophilic alveolitis and inflammatory cell interstitial infiltrates are present in many cases of drug-induced lung injury and the elaboration of chemokines and proteases by these cells may lead to cellular injury. Complement mediated injury has bee implicated for drugs causing noncardiogenic pulmonary edema or ARDS, particularly opiates and beta agonists. Amphiphilic compounds, such as amiodarone, quinidine and some beta blockers are passively sequestered in the lung within macrophages and type II alveolar cells. The role of disruption of phospholipid metabolism as a consequence of this sequestration has been well established for amiodaronemediated lung injury as is discussed below.

HISTOPATHOLOGICAL PATTERNS OF INJURY AND CLINICAL SYNDROMES The entire respiratory system, including the muscles of respiration, is susceptible to the adverse effects of drugs. Drugs may induce disease in the lung parenchyma, airways, pleura, pulmonary vasculature, and lymph nodes. Of these areas, the parenchyma is most commonly affected, and the tissue injury may manifest itself as interstitial disease, alveolar disease, and/or vasculitis. Pulmonary disease may occur as the sole effect of drug toxicity or it may be one manifestation of a systemic syndrome. For example, systemic lupus erythematosus (SLE) may occur, with or without pulmonary involvement, from exposure to beta blockers, amiodarone, ACE inhibitors, hydralazine, procainamide, isoniazid, methyldopa, minocycline, and tetracycline, among others. Systemic hypersensitiv-

Interstitial Lung Disease Of the processes affecting the lung parenchyma, interstitial involvement is among the most common. All the major histopathological forms of interstitial disease have been reported to occur as a result of drugs. It should be recognized that among the many case reports citing the presence of interstitial lung disease (ILD), many have no tissue confirmation of the precise histological pattern of ILD, and older case reports were published before the current guidelines for classification of ILDs were published. However, it seems likely that much of the previously reported drug-induced ILD would now be classified as either cellular or fibrotic NSIP. Virtually all histopathological types of ILD have been reported to occur in association with drugs, including organizing pneumonia (with and without obliterative bronchiolitis), usual interstitial pneumonitis, eosinophilic pneumonia, desquamative interstitial pneumonitis, and hypersensitivity pneumonitis. Alveolar disease occurs in the form of pulmonary edema, diffuse alveolar damage/ARDS, and diffuse alveolar hemorrhage (both bland and vasculitic). It is important to recognize that few drugs have been reported to cause a single histopathologic pattern of parenchymal injury and in the cases of many drugs, several patterns of injury can occur (Table 65-1).

Organizing Pneumonia and Bronchiolitis Obliterans Organizing pneumonia (OP) with or without histopathological evidence of obliterative bronchiolitis is a frequently reported pulmonary reaction to medications. Many of the drugs that have been reported to cause bronchiolitis obliterans organizing pneumonia (BOOP) are commonly used medications, and therefore knowledge of their potential toxicity is advisable. Among the antimicrobials implicated are cephalosporins, minocycline, nitrofurantoin, amphotericin B, and interferons. One of the most utilized antiarrhythmic agents, amiodarone, is know to cause BOOP; as are the anticonvulsants carbamazepine and phenytoin; and the antiinflammatory agents gold, penicillamine, and sulfasalazine. In patients treated for rheumatoid arthritis (RA) with gold or penicillamine, it is important to distinguish between druginduced OP and infiltrates reflecting a pulmonary manifestation of the underlying RA itself. A variety of other agents reported to cause obliterative bronchiolitis are listed in Table 65-1. The clinical presentation of drug-associated OP or BOOP is similar to that of the idiopathic disease, which is now referred to as cryptogenic organizing pneumonia (COP). Symptoms include shortness of breath, nonproductive cough, and in some cases low-grade fever and/or pleuritic chest pain.

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Table 65-1 Major Histopathological Diagnoses and Syndomes Associated with Drug Toxicity Histopathological Diagnosis

Drug

Strength of Association

Interstitial Infiltrates/Fibrosis (acute, subacute, or chronic)

Amiodarone β-adrenergic blockers Carbamazepine Gold salts Hydralazine Interferon-α Methotrexate Nitrofurantoin Penicillins Phenytoin

+++ + + ++ + ++ (Sarcoidosis) +++ +++ ++ ++

OP/BOOP

Amiodarone Amphotericin B β-Adrenergic blockers Carbamazepine Cephalosporins Cocaine Interferon-α Minocycline Nitrofurantoin Phenytoin

++ + + ++ + ++ ++ ++ + +

Eosinophilic lung disease

ACE inhibitor Anti-TB Carbamazepine Cephalosporins Erythromycin Gold salt Minocycline NSAIDS Penicillins Sulfonamides Tetracycline L-tryptophan (OTC preparation)∗

+ + +

Pulmonary or systemic hypersensitivity

Aspirin Carbamazepine Minocycline NSAIDs Phenytoin Sulfonamides

+ +++ ++ ++ +++ ++

Systemic lupus erythemtosus

ACE inhibitor Amiodarone β-Adrenergic blockers Isoniazid Methyldopa Minocycline Procainamide Tetracycline

+ + ++ +++ ++ ++ +++ ++

++ + +++ ++ ++ ++ ++ +++

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Table 65-1 (Continued ) Histopathological Diagnosis

Drug

Strength of Association

Airways disease

Aspirin ACE inhibitor Adenosine β-Adrenergic blockers NSAIDs

++ +++ ++ +++ ++

Noncardiogenic pulmonary edema/ARDS

Amiodarone Amphotericin Aspirin/NSAID overdose HCTZ Heparins Methotrexate Prostacyclines Opiate overdose Radiographic contrast Tocolytic agents (e.g., terbutaline, ritodrine) Tricyclic antidepressants

++ (ARDS) ++ ++ +++ + + ++ +++ ++ +++ +

DAH/vasculitis

Amiodarone Cocaine LTRAs Methotrexate Minocycline Nitrofurantoin Penicillamine Propylthiouracil Sulfonamides Anorexigens L-tryptophan (OTC preparation)∗

+ (bland) ++ (bland) ++ (vasculitis) + (bland) + (vasculitis) ++ (vasculitis) ++ (bland) + + + (vasculitis) ++ (vasculitis) +++ +++

Aminoglycosides Corticosteroids Opiates Sedative/hypnotics

+ ++ +++ +++

Pulmonary hypertension

Alveolar hypoventilation

∗,

withdrawn from the market ACE, angiotensin converting enzyme; ARDS, acute respiratory distress syndrome; BOOP, bronchiolitis obliterans organizing pneumonia; INH, isoniazid; LTRA, leukotriene receptor antagonist; OTC, over the counter; NSAID, nonsteroidal anti-inflammatory drug; PAS, para-aminosalicylic acid; TB tuberculosis.

The chest radiograph typically shows bilateral patchy infiltrates that may be migratory over serial radiographs, with interval normal chest radiographs despite continuous drug exposure. As with other interstitial lung disease, the utility of bronchoalveolar lavage (BAL) is primarily to exclude an infectious etiology of the infiltrates; there is no specific BAL cellular profile characteristic of OP or BOOP. Lung biopsy reveals characteristic histopathology, identical to that of COP. Patients with drug-induced OP or BOOP may have spontaneous resolution of disease when the offending drug is discontinued, but oral corticosteroids may be used to accelerate

disease resolution if the patient is more profoundly symptomatic.

Eosinophilic Lung Disease Drug-induced eosinophilic lung disease can mimic other eosinophilic pulmonary syndromes including: simple eosinophilic pneumonitis (Loeffler’s syndrome), chronic eosinophilic pneumonia, acute eosinophilic pneumonia, pulmonary infiltrates, peripheral eosinophilia (PIE), and ChurgStrauss syndrome. Suspicion of a drug-induced condition is

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warranted in all cases of eosinophilic lung disease and a search for a culprit drug is an integral part of the evaluation. While the presentation of drug-induced eosinophilic pneumonia may be identical to idiopathic conditions, several distinctions can be made between idiopathic eosinophilic processes and drug-induced conditions. In idiopathic eosinophilic pneumonia, symptoms affect the lung exclusively, while in druginduced eosinophilic pneumonia, respiratory symptoms may be accompanied by systemic symptoms such as rash and fever. Marked peripheral blood eosinophilia (>1000 cells/ml) suggest drug-induced pneumonitis rather than acute idiopathic eosinophilic pneumonia in which the eosinophilia is more modestly elevated or normal. Laboratory tests may support the diagnosis of druginduced eosinophilic pneumonia. Specific testing for drug allergies, such as the lymphocyte transformation test, have been used to implicate a culprit drug; however, the clinical utility of such tests is uncertain, as negative test results may be obtained even when there is high suspicion of a drug reaction. The diagnosis of drug-induced eosinophilic pneumonia is supported by peripheral blood and/or pulmonary eosinophilia in a setting of exposure to a suspect drug and may be established when other eosinophilic lung diseases are excluded. Pulmonary eosinophilia is a common finding among patients with drug-induced lung disease. Drugs are a significant cause of BAL eosinophilia; 12 percent of patients with eosinophilia of >5 percent on BAL had drug-induced lung disease. Of 19 patients undergoing BAL for suspected druginduced lung disease, 42 percent had elevated BAL eosinophil counts and 95 percent had elevated lymphocytes on lavage, so the presence of eosinophilia does not imply a drug-induced process. When evaluating a patient with pulmonary eosinophilia, it is particularly important to exclude infectious causes of eosinophilia so as to avoid promoting progressive infection and/or death by use of corticosteroid treatment for presumptive drug-induced eosinophilic pneumonia. Tropical pulmonary eosinophilia caused by filarial infection should be suspected if the patient has a consistent travel history; Schistosoma and Paragonimus westermani are other potential pathogens to be excluded. Strongyloides, Ascaris, and Toxocara are indigenous to the United States and are known to cause pulmonary infiltrates and peripheral blood eosinophilia. Missing the diagnosis of a fungal infection can be particularly catastrophic. Aspergillus is a ubiquitous fungus that can be difficult to diagnose as a pulmonary pathogen. BAL eosinophilia may be present without definitive evidence of invasive fungal infection, which may require a tissue biopsy for diagnosis. Coccidioides immitis is endemic in the southwestern United States and infection can result in peripheral blood eosinophilia and pulmonary infiltrates. Serological testing for antibodies to Coccidioides and sputum or BAL cultures are useful studies to exclude coccidioidomycosis. Successful management of drug-induced eosinophilic lung disease is achieved by identification and discontinuation of the inciting drug. Typically, resolution of symptoms

in drug-induced eosinophilic lung disease occurs with discontinuation of the culprit drug, and frequently without the need for treatment with corticosteroids. In contrast, idiopathic chronic eosinophilic pneumonia can require months of treatment with corticosteroids and relapse may occur as steroids are tapered. Relapse of the disease as the steroids are tapered is rare in drug-induced eosinophilic lung disease and recrudescence of the infiltrates should suggest an alternate diagnosis.

Hypersensitivity Syndromes Systemic hypersensitivity syndromes may be caused by a number of drugs, most commonly the aromatic anticonvulsants, phenytoin and carbamazepine, as well as nonsteroidal anti-inflammatory drugs (NSAIDs), minocycline, and sulfonamides, among others. Drug rash with eosinophilia and systemic symptoms (DRESS) has been reported primarily with the anticonvulsants, and is in some cases accompanied by pulmonary disorders such as BOOP, ILD, or granulomatous inflammation. Not all cases of pulmonary hypersensitivity are accompanied by rash or other systemic symptoms. The clinical presentation of drug-related pulmonary hypersensitivity is typically acute onset of dyspnea, cough, and fever. The radiographic pattern is one of diffuse reticular or peripheral alveolar infiltrates, sometimes accompanied by pleural effusion. In most cases, drug withdrawal with or without oral corticosteroids, results in disease resolution. A minority of individuals (10 percent) show persistent radiographic abnormalities after several months, and rarely, progressive disease may occur despite drug withdrawal.

Diffuse Alveolar Hemorrhage, Vasculitis, and Pulmonary-Renal Syndromes Drug-induced diffuse alveolar hemorrhage (DAH) is infrequently reported in the literature on drug-induced pulmonary disease. Mechanistic classification of DAH is based on histopathological findings, and includes: (1) capillaritis; (2) bland hemorrhage; and (3) bleeding due to druginduced coagulopathies caused by anticoagulants, thrombolytic agents, and drug-induced thrombocytopenia. Pulmonary capillaritis is induced by relatively few drugs. In the case of propylthiouracil, the DAH can be a manifestation of a systemic vasculitic syndrome characterized by leukocytoclastic vasculitis, glomerulonephritis, and pulmonary capillaritis, with antibodies to neutrophil cytoplasmic myeloperoxidase (p-ANCA). The presence of leukocytoclastic vasculitis appears to be more common in cases of drug-induced vasculitis (63 percent of 14 cases), than it is in idiopathic vasculitis (25 percent of 57 cases). Numerous cases of pulmonary or systemic vasculitis also have been reported for sulfonamides, nitrofurantoin, and leukotriene receptor antagonists. In the latter case, there has been considerable discussion as to whether the vasculitis was a toxic effect of the leukotriene antagonists or

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whether withdrawal of oral steroids leads to identification of pre-existing Churg-Strauss granulomatous vasculitis. At least some reported cases of Churg-Strauss syndrome are unrelated to steroid withdrawal and appear to represent a rare complication of leukotriene antagonists. Bland hemorrhage, without capillaritis, can occur in the setting of drug-induced diffuse alveolar damage (DAD). DAH accompanying DAD has been reported for amiodarone, nitrofurantoin, minocycline, methotrexate, gold, cocaine, and chemotherapeutic agents, but may occur with other drugs that cause DAD as well.

Noncardiogenic Pulmonary Edema and ARDS Noncardiogenic pulmonary edema can be precipitated by numerous drugs, including aspirin, opiates, calcium channel blockers, some diuretics (e.g., hydrochlorothiazide and acetazolamide), intravenous and inhaled pulmonary vasodilators (e.g., epoprostenol and nitric oxide), methotrexate, TNFα, radiographic contrast media, tocolytics, and oxytocin. Although the mechanisms of pulmonary edema may vary for these drugs, frequently the resolution of symptoms is prompt within days of drug discontinuation. ARDS is an infrequent pulmonary reaction to drugs, but has been reported as an uncommon toxic reaction to amiodarone and nitrofurantoin.

Airways Disease Cough and bronchospasm may be induced by the ingestion of a number of therapeutic drugs. Bronchospasm can be triggered by use of β-adrenergic blockers, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs). The effects of these agents can range from mild chest tightness and dyspnea on exertion to respiratory failure in susceptible individuals. Aspirin and NSAIDs induce bronchoconstriction by diverting arachidonic acid metabolites toward the lipoxygenase metabolic pathway, thereby leading to enhanced leukotrienemediated airway inflammation and bronchoconstriction. Airway irritation manifested as nonproductive cough is an adverse effect of angiotensin converting enzyme inhibitors as a class, and can limit use of the these agents in affected individuals. Inhalation of illicit drugs, especially “crack” cocaine, can precipitate bronchoconstriction and thermal injury of the upper and lower airways.

Pulmonary Hypertension Pulmonary hypertension is a relatively infrequent complication of drug therapy, but because of the subtlety of the onset of disease, paucity of symptoms until significant vascular compromise has occurred, and potential for vascular collapse and death, it is critical to recognize drug-induced pulmonary hypertension. Among the drugs known to cause pulmonary hypertension are cocaine, other illicit stimulants, anorexigens, and toxic contaminants of food and additives to nutritional supplements (e.g., tryptophan).

Drug-Induced Lung Disease Due to Nonchemotherapeutic Agents

The history of the association of appetite suppressants and pulmonary hypertension dates to the late 1970s when reports of unexplained “primary” pulmonary hypertension were first published. The “epidemic” of pulmonary hypertension was linked the use of aminorex fumarate, an amphetamine-derived appetite suppressant that came into use because its potential for addiction and abuse was lower than that of amphetamine. The mechanism of action on the pulmonary vasculature is through the release of catecholamines, including dopamine. The use of aminorex was associated with a significant rise in the incidence of pulmonary hypertension, primarily among women in Germany, Austria, and Switzerland. The development of disease occurred as early as weeks to months from the onset of use of the drug, with a dose-dependent risk as high as 2 in 100. The epidemic subsided as the drug’s use declined. This was followed by the introduction of fenfluramine, which, like amphetamine and aminorex, is a phenylethylamine. It had been shown to be equally effective for weight reduction as an amphetamine, without the potential for abuse. Satiety is normally accompanied by the release of serotonin, which acts on central serotonin 2C receptors. Fenfluramine and the racemic dexfenfluramine effectively mimic normal satiety through competitive inhibition of the serotonin transporter, leading to release of serotonin from intracellular stores. These agents were used primarily in Europe throughout the 1980s. Case reports of users with pulmonary hypertension were published in Britain as early as 1981, but use of these agents persisted through the decade of the 1980s. Two landmark reports supported a causal relationship between the use of fenfluramine and dexfenfluramine and pulmonary hypertension. The first of these was published in 1993, describing a cohort of young to middle-aged users of the anorexigens who developed pulmonary hypertension indistinguishable from idiopathic primary arterial pulmonary hypertension. This was followed in 1996 by the findings of the International Primary Pulmonary Hypertension Study Group, which published a case-control series of 192 patients with pulmonary arterial hypertension. An eightfold increased risk of development of the disease was found among those who had used and anorexigen for >3 months, with an estimated incidence of one to two cases per million users per year. Further support for a causal link is contained in the surveillance study of pulmonary hypertension among anorexigen users in the United States. Fenfluramine was withdrawn from the market in 1995 due to its association with increased risk of pulmonary hypertension, as well as its role in the development of valvular heart disease in users of the fenfluramine-phentermine combination anorexigen, known as fen-phen. Epidemics of pulmonary hypertension also have been reported due to contaminants in a specific manufacturer’s rapeseed oil in Spain, and from use of an overthe-counter L-tryptophan preparation that resulted in the eosinophilic myalgia syndrome, characterized by a systemic syndrome, which included acute lung injury and pulmonary hypertension.

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The reason(s) that some individuals develop drugrelated pulmonary hypertension while others do not has not been clearly defined. One putative risk may be polymorphisms of a cytochrome P450 enzyme, CYP 2D6, which is the primary enzyme to metabolize fenfluramine. Reports have suggested that as many as 21 percent of subjects who develop anorexigen-related pulmonary hypertension may be abnormal metabolizers. Other risk factors are yet to be characterized.

Amiodarone

were published in 1980 and were followed subsequently by larger series of patients as amiodarone was tested in the United States in early to middle 1980s. Based on two trials published in 1987, the clinical picture of amiodarone pulmonary toxicity emerged as a syndrome of respiratory symptoms, most often cough and dyspnea of subacute or chronic onset, accompanied by pulmonary infiltrates. In one series, 11 of 171 patients (6.4 percent) treated with 400 to 1200 mg of amiodarone developed pulmonary disease and in the second series, 15 of 154 subjects (9.7 percent) developed disease. The duration of therapy before onset of symptoms was reported as 61 to 465 days in one series and 30 to 720 days in the other. Approximately one-half of the patients in each series had fever and malaise, and one-third had chest pain. Many subjects had underlying lung disease. Subsequent reports have further refined these initial observations, as discussed in the following.

Amiodarone is an iodinated, benzofuran-derivative antiarrhythmic used for management of life-threatening supraventricular and ventricular arrhythmias. Both amiodarone and its major metabolite, desethyl-amiodarone are cationic, amphiphilic compounds with high lipid solubility causing the drug to accumulate in, and clear slowly from, a variety of tissues. The elimination half-life of amiodarone is between 30 to 60 days. The concentration of amiodarone in lung tissue can be 100- to 500-fold higher than serum levels, and the drug has been found in lung tissue as long as 1 year after discontinuation of therapy. These pharmacokinetic characteristics of amiodarone contribute to its potential to cause toxicity and have an impact on treatment strategies for amiodarone pulmonary toxicity, as discussed in the following. As with many other medications, the radiographic and histological findings associated with amiodarone pulmonary toxicity are not stereotypic. While the most common histological pattern observed over the decades has been that of a subacute ILD, there are also many reports of organizing pneumonia, pulmonary fibrosis, fewer reports of nodules (which can be fluorodeoxyglucose [FDG]-avid on PET imaging), ARDS, and systemic lupus erythematosus (SLE), and rare reports of PIE and diffuse alveolar hemorrhage. Amiodarone toxicity may involve a number of etiological mechanisms. One of amiodaroneâ&#x20AC;&#x2122;s biochemical effects is to impair normal phospholipid catabolism by phospholipases. The accumulation of phospholipids in the cell may cause direct cellular injury and tissue inflammation, and some evidence supports tissue injury as a result of immunological mechanisms. The impairment of phospholipid metabolism results in the histopathological findings of lamellar inclusions and lipid-laden foamy macrophages that characterize the amiodarone effects seen on lung biopsy and bronchoalveolar lavage (BAL). Adverse reactions to amiodarone have been reported in a variety of tissues, including the lung, liver (liver function abnormalities and increased tissue attenuation on radiographic imaging), thyroid (thyrotoxicosis), skin (discoloration), and cornea. The first reports of amiodarone pulmonary toxicity

Risk Factors for Toxicity Predisposing risk factors for the identification of amiodarone pulmonary toxicity include the daily dose and pre-existing lung disease. A less firmly established risk factor may be high concentrations of inhaled oxygen. Duration of therapy or cumulative dose does not appear to confer increased risk. The risk of pulmonary toxicity is daily dose dependent; 0.1 to 0.5 percent of patients on 200 mg per day typically develop amiodarone pulmonary toxicity, and as many as 50 percent of those using the highest dosages (e.g., 1200 mg/day) become affected. Most reports of amiodarone toxicity have been in subjects receiving >400 mg day. Although lower doses of amiodarone are considered to be safer than higher doses, toxicity has been reported at doses as low as 200 mg/day, with symptom onset ranging from 3 months to 5 years into therapy. While the tendency to use lower doses of amiodarone has resulted in a lower incidence of disease, it is felt that the severity of disease, when it occurs, has been unchanged by this dosing strategy. Several authors have suggested that the onset of amiodarone pulmonary toxicity may be triggered by high concentrations of oxygen or that oxygen may act in synergy with amiodarone to enhance cellular injury. A high index of suspicion for amiodarone toxicity, therefore, should be maintained in the postoperative setting, especially if high concentrations of oxygen were used intraoperatively or high loading doses of amiodarone were used in the management of perioperative cardiac arrhythmias. A less substantiated risk factor may be use of intravenous iodinated contrast media; two cases of rapidly progressive fatal ARDS attributed to amiodarone toxicity have been reported following pulmonary angiograms. Pre-existing lung disease was identified as a risk factor for pulmonary toxicity in the earlier publications, but not all subsequent studies have identified it as a risk. It is not clear that the incidence of toxicity is actually higher or if preexisting lung disease results in earlier perception of symptoms and a focused attention to pulmonary rather than cardiac causes of dyspnea. The recent AFFIRM (Atrial Fibrillation

DRUGS USED TO TREAT CARDIOVASCULAR DISORDERS

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Follow-up of Rhythm Management) trial reported that there was a higher risk of diagnosis of amiodarone lung toxicity if the patient had pre-existing pulmonary disease; however, there was no higher risk of either pulmonary death or allcause mortality. Based on the literature to date, it is acceptable to use amiodarone in the setting of pre-existing lung disease if vigilance is maintained for the development of symptoms suggesting amiodarone toxicity. Prospective studies have suggested that a decrement in diffusing capacity from baseline is a poor predictor of amiodarone toxicity. Therefore, there are no formal recommendations for screening pulmonary function tests, but a reasonable approach would be performance of a baseline pulmonary function test, including diffusing capacity and symptom-driven testing thereafter. Clinical Presentation The clinical presentation of amiodarone pulmonary toxicity is typically nonproductive cough and dyspnea, sometimes accompanied by pleuritic chest pain, fever, malaise, and/or weight loss. The onset of symptoms is unpredictable, but most cases occur within the first 1 or 2 years of therapy. Most subjects have an insidious onset of symptoms over several months, but fatal amiodarone-induced pulmonary toxicity occurring 2 weeks into therapy has been reported. The earliest abnormality identifiable on pulmonary function testing of affected individuals is impairment in diffusing capacity for carbon monoxide (DlCO ). There may be an accelerated decline in the DlCO as the disease progresses, accompanied by mild restrictive physiology. Since a low DlCO is not specific for amiodarone toxicity, a decline should not necessarily prompt discontinuation of the drug, but should trigger evaluation for possible cause(s) of the impairment. Radiographic Findings Typical radiographic findings in patients with subacute or chronic onset of disease are diffuse or patchy, interstitial, or mixed alveolar-interstitial infiltrates, which are either bilateral or unilateral. Chest x-ray may underestimate the extent of disease apparent on high resolution CT (HRCT) imaging. Mild cases of toxicity may be characterized by a diffuse ground-glass pattern on HRCT, often in a peripheral, subpleural distribution. Focal and patchy areas of higher attenuation may be superimposed on the ground-glass opacification. Alveolar opacities may correspond to areas of organizing pneumonia that are indistinguishable from idiopathic BOOP. Amiodarone toxicity should be considered in cases of migratory infiltrates consistent with BOOP that are unresponsive to steroids. The infiltrates of BOOP resolve after discontinuation of amiodarone. Amiodarone-induced fibrosis occurs in 5 to 7 percent of patients diagnosed with amiodarone pneumonitis and may be present at disease presentation. A coarse interstitial pattern in the periphery of the lung, accompanied by traction bronchiectasis, is characteristic, but honeycombing is rare.

Drug-Induced Lung Disease Due to Nonchemotherapeutic Agents

Laboratory Data The earlier trials of amiodarone identified elevated sedimentation rates (ESR) (i.e., range of 39 to 150 mm/hour) in 9 of 11 patients with pulmonary toxicity, but nonspecificity of the ESR makes this test only marginally useful in the clinical setting. Identification of a brain naturetic peptide (BNP) value that is normal, or at a patientâ&#x20AC;&#x2122;s baseline, may be useful in distinguishing pulmonary causes of dyspnea from congestive heart failure, but is nonspecific for amiodarone toxicity. Other common laboratory abnormalities include mild leukocytosis and serum LDH elevation. Laboratory findings that are investigational and do not yet have a place in routine clinical evaluation are elevated serum levels of KL-6, a mucinlike glycoprotein secreted by proliferating type II pneumocytes, and surfactant protein SP-D. Elevations of the latter may be an early marker of amiodarone pulmonary toxicity, but the sensitivity and specificity of these tests is uncertain. Diagnostic Evaluation and Therapeutic Management The challenge to the practitioner considering the diagnosis of amiodarone pulmonary toxicity is that the differential diagnosis of acute and subacute dyspnea with pulmonary infiltrates in the patient with known cardiac disease is extensive. Cardiogenic and noncardiogenic etiologies must be excluded. Consideration must be given to cardiac conditions, including ischemic and nonischemic cardiomyopathies, diastolic dysfunction, mitral valve disease, aortic stenosis, and atrial fibrillation. Noncardiogenic causes may include infections; the broad range of idiopathic interstitial pneumonitides; malignant causes of infiltrates (e.g., lymphangitic spread of tumor or lymphoma); systemic diseases such as sarcoidosis, amyloidosis, or autoimmune disease; and exposures to inhaled agents (e.g., occupational inorganic dust exposures, or organic inhalations with subsequent development of hypersensitivity pneumonitis), in addition to exposures to drugs other than amiodarone. The risk of invasive work-up must be weighed against the risks of empiric therapy, which may include oral corticosteroids. Bronchoalveolar lavage may reveal a lymphocytosis, often with a predominance of CD8+ lymphocytes, reflective of a lymphocytic alveolitis. This finding is not consistently reported, and some affected individuals may have elevated BAL neutrophils as well. Significant BAL eosinophilia is rare. Abundant alveolar macrophages with a â&#x20AC;&#x153;foamyâ&#x20AC;? cytoplasm, indicative of undigested phospholipids, is found is all subjects chronically exposed to amiodarone and is not indicative of pulmonary toxicity per se. Hemosiderin laden macrophages are infrequently found, since alveolar hemorrhage is rare. As the BAL findings are neither sensitive nor specific for pulmonary toxicity, the role of BAL in the diagnosis in controversial. Lung biopsy findings, however, may be diagnostic of amiodarone toxicity. The earlier reports of amiodarone pulmonary toxicity describe diffuse alveolar damage (DAD) of variable severity in all affected subjects. The more severely

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affected had evidence of acute DAD, with abundant hyaline membranes and reactive type II pneumonocytes lining the alveoli, while others showed organizing DAD with interstitial and intraalveolar proliferation of fibroblasts and prominent type II pneumocytes. All cases had abundant “foamy” macrophages, both singly and in clusters in the alveolar spaces. The foamy appearance of the cytoplasm is due to the presence lamellar bodies (∼1 µm in diameter) containing lipid particles, reflecting the disrupted lipid metabolism caused by amiodarone. The foamy macrophages or histiocytes are not indicative of toxicity, in fact similar vacuolated histiocytes and parenchymal cells may be found in thyroid, liver, and skin of treated individuals without clinical evidence of cellular dysfunction. The diagnosis of amiodarone pulmonary toxicity is supported by the presence of lamellar bodies in macrophages, pneumocytes, bronchiolar epithelium, and/or endothelial cells, but the diagnosis cannot be made unless there is also evidence of interstitial lymphocytic infiltrates or fibrosis and alveolar distortion. Histological findings may also fit the description of fibrotic NSIP or bronchiolitis with organizing pneumonia, and combinations of the above histological findings may occur. Despite the early reports, few patients have DAD pathologically unless they fit the clinical picture of ARDS. Alveolar hemorrhage may be present but is not a common feature of amiodarone toxicity. In contrast to the treatment of many other types of drug-induced pulmonary toxicity, the treatment of amiodarone-induced toxicity may require more than discontinuation of the drug alone. Depending on the severity of respiratory symptoms, practitioners may often need to treat affected patients with oral corticosteroids. Specific dosages of prednisone have not been studied for efficacy, but 0.5 to 1 mg/kg is a reasonable starting point in most cases requiring steroids. Amiodarone becomes sequestered in tissues and the clearance of drug is typically prolonged. Due to these pharmacokinetic characteristics, the required duration of therapy is often as long as several months and recrudescent disease is common.

respiratory muscle function and result in ventilatory insufficiency, perhaps contributed to by competitive blockade of the acetylcholine receptor by procainamide. The pleuritis of DI-SLE may produce pleural fluid with characteristics indistinguishable from those of spontaneous SLE: high pleural fluid ANA (≥1:160), high pleura to serum ratio of ANA (≥1), and LE cells. The absence of renal or central nervous system involvement may suggest DI-SLE, but it is otherwise difficult to differentiate drug-induced disease from other SLE on clinical grounds. Serological markers may be useful, however. The absence of anti–double-stranded DNA and normal complement levels and identification of antibodies to histone complex H2A-H2B support the diagnosis of DI-SLE. Unlike idiopathic SLE, DI-SLE may resolve over several weeks simply with discontinuation of the drug, without use of corticosteroids or immunosuppressants. More severely affected patients may benefit from oral corticosteroids, which appear to accelerate the speed of symptom resolution. A positive ANA without signs or symptoms of local or systemic disease need not warrant discontinuation of procainamide. Relapse after symptom resolution does not occur unless the drug is reintroduced.

Angiotensin Converting Enzyme (ACE) Inhibitors Airway irritation presenting as dry cough occurs to varying degrees in 5 to 25 percent of individuals using ACE inhibitors and is not accompanied by pulmonary parenchymal disease. Bronchial irritation is likely due to a direct effect of the drug, inducing kinin and substance P accumulation in the airway. Therefore, cough is a class effect of ACE inhibitors and typically recurs if one type is substituted for another. The cough can be severe enough to warrant discontinuation of the medication. Discontinuation of the offending drug typically results in symptom resolution in 10 days. Angiotensin II receptor antagonists may be substituted for ACE inhibitors without recurrence of symptoms. Much less common pulmonary side effects of ACE inhibitors include PIE, SLE, and subacute ILD.

Procainamide

β-Adrenergic Receptor Blockers

Procainamide, used in the treatment of supraventricular and ventricular arrhythmias, is frequently cited as a cause of druginduced systemic lupus erythematosus (DI-SLE). Of patients using procainamide for over 2 months, as many as 50 to 90 percent will develop serum antinuclear antibodies (ANA), and of these, 10 to 20 percent may develop symptomatic DISLE. Symptoms associated with drug-induced disease are indistinguishable from those of idiopathic SLE, and may include fever, rash, arthralgias, Raynaud’s disease, myositis, vasculitis, and serositis. Among these subjects, 40 to 80 percent will exhibit pulmonary manifestations of SLE, such as pleuritis with pleural effusion and/or diffuse parenchymal infiltrates. Of these two findings, pleural disease is more common, while parenchymal infiltrates are present in less than half of affected individuals. The more severe myositis also may affect

The most common adverse effect of β-adrenergic blockers on the respiratory system is precipitation of bronchospasm in asthmatics and patients with COPD and reactive airways. The high frequency of clinically significant bronchospasm in hypertensive asthmatics treated with nonselective β-adrenergic blockers, such as propranolol, requires that these agents generally be avoided in asthmatics. β1 Receptor–selective agents and the mixed α and β receptor blocker labetalol are better tolerated, but should be used with considerable caution in these subjects. The use of β-adrenergic blockers for patients with COPD is not contraindicated; many of these individuals tolerate initiation of β-adrenergic blockers without significant decrement in their lung function. Patients with COPD who have clinical or spirometric evidence of variable airflow obstruction responsive to bronchodilators should be

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observed carefully for bronchospasm upon initiation of these agents, but the cardiac benefit of β blockade may be substantial in these subjects, who have a high likelihood of having concomitant coronary artery disease as a result of smoking. Pulmonary parenchymal injury associated with the use of β-adrenergic blockers is not common, but it warrants mention because of the ubiquitous use of these agents. Subacute interstitial infiltrates, PIE, and pulmonary edema have been reported in conjunction with the use of acebutolol, propranolol, labetalol, nadolol, and/or pindolol; thus, the clinician should be vigilant for these reactions from β-adrenergic blockers as a class. Systemic lupus erythematosus (SLE) has reported with the use of acebutolol, propranolol, labetalol, and pindolol.

most often been consistent with NSIP, but lymphocytic interstitial pneumonitis and BOOP are described as well. In some cases, the parenchymal findings are accompanied by peripheral blood eosinophilia, suggesting PIE syndrome, and the presence of cold hemagglutinins has been reported. Carbamazepine, similarly to phenytoin, has been reported to cause systemic and pulmonary hypersensitivity syndromes.

Hydralazine

The most common pulmonary reaction associated with aspirin use is bronchospasm, which may occur in aspirinsensitive individuals at therapeutic dosing. Less common reported pulmonary complications include PIE syndrome, diffuse alveolar hemorrhage, pulmonary hypersensitivity, vasculitis, and ARDS. Acute salicylate poisoning produces symptoms of central nervous system toxicity ranging from tinnitus, vertigo, nausea, vomiting, and hyperventilation in mild to moderate overdose, to coma, severe metabolic acidosis, and noncardiogenic pulmonary edema in more critical overdose. Risk factors for salicylate toxicity are age and chronic aspirin ingestion. Pulmonary edema occurs in as many as 30 percent of patients with severe salicylate poisoning, and may result in respiratory failure, often exacerbated by severe metabolic acidosis. Management of severe toxicity includes supportive intensive care and sodium bicarbonate infusion to promote drug excretion.

Hydralazine-induced pulmonary disease is not common, but can be associated with systemic toxicity. The most commonly reported complication of the use of hydralazine is systemic lupus erythematosus (SLE), but subacute ILD/NSIP, organizing pneumonia, and diffuse alveolar hemorrhage also have been documented infrequently in the literature.

Hydrochlorothiazide The most commonly reported pulmonary side effect of the diuretic hydrochlorothiazide (HCTZ) is noncardiogenic pulmonary edema or ARDS. Pulmonary edema was first reported in 1968 as a potentially life-threatening complication of HCTZ use. The onset of symptoms be acute or may occur later in the course of use. Typical symptoms are acute dyspnea and hypoxemia, but fever, tachycardia, hypotension, and shock may accompany the dyspnea. Immunologically mediated capillary leak has been suggested as a possible mechanism of action by several authors. IgG deposition in the alveolar membrane and elevated serum IgM have been reported. Management is supportive care and symptom resolution typically occurs in a few days. Rechallenge with HCTZ can cause recrudescent pulmonary edema and is not recommended. Since HCTZ is a widely used diuretic, frequently used in patients with cardiovascular disease and prone to pulmonary edema, the true incidence of noncardiogenic pulmonary edema may be underreported.

ANTICONVULSANTS Diphenylhydantoin/Phenytoin and Carbamazepine Numerous types of pulmonary injury can result from exposure to phenytoin. Among the reported patterns of injury are pulmonary hypersensitivity reactions, which may be a component of systemic hypersensitivity (see the discussion of DRESS), and two fatal cases of apparent polyarteritis nodosum and necrotizing vasculitis have been reported. The histological findings in subacute phenytoin lung toxicity have

ANTI-INFLAMMATORY AND IMMUNOSUPPRESSIVE AGENTS Aspirin

Methotrexate Methotrexate is a dihydrofolate reductase inhibitor used as an anti-inflammatory and immunosuppressant as well as a chemotherapeutic agent. Despite the availability of newer antirheumatic drugs, methotrexate has retained its position as a first-line disease-modifying agent for the management of rheumatoid arthritis (RA). Methotrexate affects cell replication through inhibition of dihydrofolate reductase, which serves to reduce tetrahydrofolates, allowing them to serve as one-carbon carriers in the synthesis and repair of DNA. The major nonpulmonary side effects of methotrexate correlate with the degree of folate deficiency. In contrast, pulmonary toxicity does not correlate with folate deficiency and may be seen at doses as low as 7.5 mg/week, a conventional starting dose for treatment of RA. Methotrexate-induced pulmonary toxicity typically occurs within the first 2 years of treatment and can occur as early as 1 month into therapy. Conditions that have been identified as risk factors for toxicity include diabetes (odds ratio [OR] 35.6), hypoalbuminemia (OR 19.5), rheumatoid pleuropulmonary disease (OR 7.1), previous use of other disease-modifying agents (e.g., gold, sulfasalazine, or penicillamine), and older age (OR 5.1).

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Methotrexate-induced reactions may be acute in onset, presenting clinically as an acute hypersensitivity pneumonitis with dyspnea, cough, and fever, or as a subacute hypersensitivity with development of symptoms over several weeks. Radiographic changes are interstitial and bilateral in 50 percent of cases, but may also include a mixed alveolarinterstitial pattern that may appear as ground-glass opacities on high-resolution CT imaging. Fibrotic changes are less common. Diagnosis is challenging in cases of suspected methotrexate-induced pulmonary toxicity and RA, because similar clinical presentations may occur as a manifestation of RA itself. A diagnosis of methotrexate-induced lung disease is suggested by lymphocytosis on bronchoalveolar lavage (BAL) in contrast to the neutrophilic lavage, which characterizes pulmonary infiltrative disease associated with RA. The lymphocytic lavage of methotrexate-induced pneumonitis typically has CD8 predominance (low CD4:CD8 ratio). Histopathology is varied and may demonstrate illformed granulomas suggestive of hypersensitivity pneumonitis, changes of chronic interstitial pneumonitis, BOOP, and/or DAD. PIE syndrome has also been reported due to methotrexate. As with other pulmonary toxicities, prompt drug withdrawal is critical and resolution follows in the majority of patients. Corticosteroids may accelerate recovery in those with severe disease and/or symptoms refractory to drug withdrawal alone. Fatalities have been reported in subjects rechallenged with methotrexate, but rechallenge has been tolerated in others, arguing against hypersensitivity as the mechanism of injury in some subjects.

D-Penicillamine D-Penicillamine is used as an anti-inflammatory agent in the management of rheumatoid arthritis. Although it is now used less frequently than methotrexate, its pulmonary manifestations are important to recognize, as mortality is as high as 50 percent. It is one of relatively few drugs that causes a pulmonary-renal syndrome. Penicillamine is a heavy metal chelating agent that has inhibitory effects on T-lymphocytes, impairs fibroblast proliferation, and decreases rheumatoid factor and immune complex levels. DAH and subacute interstitial infiltrates are the two most frequently reported histological patterns of penicillamine-induced lung toxicity. Other patterns of pulmonary injury associated with use of penicillamine are chronic alveolitis, PIE, and hypersensitivity pneumonitis. A pulmonary-renal syndrome similar in clinical presentation to Goodpastureâ&#x20AC;&#x2122;s syndrome is associated with penicillamine use. It occurs infrequently among patients with RA on penicillamine therapy and also has been reported in patients prescribed penicillamine as a chelating agent in Wilsonâ&#x20AC;&#x2122;s disease, supporting the hypothesis that the pulmonary findings are not simply a manifestation of the underlying collagen vascular disease. Symptoms at disease presentation

include cough, dyspnea, hemoptysis, and hematuria. The syndrome may progress to include respiratory and/or renal failure. Symptom onset has been reported after a wide range of duration of exposure from 10 months to 20 years. No definitive dose-response relationship has been defined; there are reports of toxicity at doses as low as 300 mg/day and as high as 3.5 g/day. No specific risk factors have been identified for penicillamine-induced pulmonary-renal syndrome. Coalescing, bilateral alveolar infiltrates characterize the radiographic findings, resulting in severe hypoxia. Diagnosis is supported by high serum titers of antinuclear antibodies (ANA), but anti-glomerular basement membrane (anti-GBM) antibodies are typically absent from the serum, although rare reports of positive anti-GBM antibodies exist. Bronchoalveolar lavage reveals an increase in red blood cell count on serial lavage and the presence of hemosiderin-laden macrophages, both of which characterize DAH. Pulmonary vasculitis, however, is absent. Renal histopathology is that of crescentic glomerulonephritis similar to that of Goodpastureâ&#x20AC;&#x2122;s syndrome, but linear anti-GBM immunofluorescence is rare. Mortality from penicillamine-induced pulmonaryrenal disease has been reported to be as high as 50 percent. Survivors in one series were all left with residual radiographic abnormalities and many patients are hemodialysis dependent despite treatment. Therefore, prompt identification and treatment are warranted. Drug withdrawal accompanied by high-dose corticosteroids is the cornerstone of therapy, and adjunctive treatment with cyclophosphamide or azathioprine is often offered, although studies definitively supporting their use do not exist. In the absence of anti-GBM antibodies, plasmapheresis is probably not warranted. Penicillamine can also induce interstitial lung disease characterized by and hypersensitivity and/or bronchiolitis obliterans, in some cases accompanied by alveolitis. A sister drug, bucillamine, has also been reported to cause centrilobular, ground-glass opacities and thickening of interlobular septae.

Gold Salts The immunomodulatory properties of gold have been recognized since the 1920s when the first cases of rheumatoid arthritis treated with chrysotherapy were first reported. The first reports of gold-induced pulmonary toxicity followed in 1948. Gold remains a therapeutic option for the treatment of rheumatoid arthritis that is refractory to other agents, and it also has a role in the management of juvenile RA, ankylosing spondylitis, and pemphigus. As with methotrexate and penicillamine, the toxic reaction must be distinguished from pulmonary disease related directly to the underlying rheumatoid arthritis. One of the largest reviews of 140 patients treated with gold therapy who developed pulmonary toxicity, identifies distinguishing features of this gold toxicity. The pattern that emerges from this review is that cough and dyspnea are

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the most common presenting symptoms, with half of the patients exhibiting fever. More than one-third of patients had an erythematous skin rash, and peripheral blood eosinophilia is a common finding. The onset of symptoms is typically early in the course of treatment, usually within the first 4 months of therapy. Gold-induced pulmonary toxicity affects women more than men, at a ratio of 4:1, and the mean age of onset of disease is in the sixth decade of life. A restrictive ventilatory defect characterizes the disease and the diffusing capacity is reduced in over 90 percent of affected individuals. Diagnostic evaluation may include BAL, which typically shows a lymphocytic predominant fluid with a CD8+ lymphocyte predominance. This finding, in conjunction with a positive in vitro gold lymphocyte proliferation assay, strongly supports the diagnosis of gold-induced pulmonary toxicity. These diagnostic features provide evidence that the gold-induced toxicity is a hypersensitivity reaction. Treatment necessitates discontinuation of the drug. Longitudinal data reveal that gold-induced impairments in diffusing capacity may take months to resolve. Rarely, disease progression may occur after discontinuation of the gold. Refractory or progressive symptoms may be treated with prednisone at 30 to 60 mg/day.

Sirolimus Sirolimus is a potent immunosuppressive agent used in the management of patients with solid organ transplant. It serves to suppress organ rejection through its inhibition of growth factorâ&#x20AC;&#x201C;induced smooth muscle cell proliferation and migration, and inhibits T- and B-cell activation as well. Sirolimus was introduced into clinical use in the late 1990s. Case reports of sirolimus-induced pulmonary toxicity began to appear in the literature in 2000, when it was implicated as the cause of biopsy-proven BOOP in a renal transplant recipient. A recent case series of 24 patients further characterizes the drug reaction. In that series, most patients exhibited a radiographic pattern of patchy peripheral consolidations consistent with BOOP, while four patients had reticular and ground-glass opacities. The BAL was lymphocytic in 19 subjects with â&#x2030;Ľ5 percent eosinophilia in four. Neither lymphocyte subsets nor biopsies were reported in this series, but other authors have reported CD4+ predominance in one case. Several authors have described both BOOP and granulomatous interstitial pneumonitis, characterized by noncaseating granulomas in the bronchial wall with surrounding granulomatous inflammation. Discontinuation of sirolimus is necessary for syndrome resolution, and complete recovery is typically achieved in all patients by 6 months. A dose-response relationship is suggested by this series, in which dose reduction appeared to ameliorate the pneumonitis. However, toxicity can occur despite therapeutic serum sirolimus levels and can occur as early as 2 weeks into therapy, although it more often oc-

Drug-Induced Lung Disease Due to Nonchemotherapeutic Agents

curs after at least 6 weeks. Sirolimus-induced pneumonitis in solid organ transplant recipients is an important consideration in the differential diagnosis of dyspnea with interstitial infiltrates.

ANTIMICROBIAL DRUGS The most commonly reported clinical syndrome reported for all classes of antimicrobials is pulmonary infiltrates with peripheral eosinophilia (PIE). Among the reports of antibioticassociated PIE syndrome are many cases of minocycline- and erythromycin-induced PIE, and fewer cases associated with penicillins, tetracycline, sulfonamides, and cephalosporins. Cases of PIE have also been reported with the use of antituberculous drugs, including isoniazid, rifampin, and ethambutol.

Nitrofurantoin Nitrofurantoin is one of the most commonly implicated antimicrobial agents that cause pulmonary toxicity. Although its peak usage worldwide was probably in the 1980s, it remains a widely used antibiotic for the management of chronic urinary tract infections. Pulmonary toxicity may have significant clinical impact if the affected patient has underlying cardiopulmonary disease. Since the drug is used primary in the elderly population, in whom cardiopulmonary disease is common, recognition of its potential contribution to a patientâ&#x20AC;&#x2122;s respiratory decline is important. In addition, the clinical spectrum of respiratory disease caused by nitrofurantoin is wide: The onset of symptoms is highly unpredictable, the severity of disease is variable, and the histopathology is diverse. Ninety percent of cases in the earliest reports of nitrofurantoin pulmonary toxicity have been reported to be acute in onset, within days to weeks of treatment initiation. These patients presented with fever (80 percent), cough, dyspnea, rash (20 percent), arthralgias, and peripheral eosinophilia. As reports of toxicity have continued to fill the literature, it has become clear that subacute and chronic presentations are common as well. It is inevitable that many cases may be missed due to the long latency between the first dose of drug and the onset of clinical onset of symptoms. The median time to diagnosis in one series was 4 months and as long as 5 years. Among those with chronic symptoms, the most common histopathological pattern is that of chronic interstitial pneumonitis, with fewer reported cases of BOOP. In one recent publication, high-resolution CT findings in 18 patients with chronic nitrofurantoin lung injury showed bilateral groundglass opacities seen in all subjects (diffuse in 30 percent and exhibiting a middle to upper lung zone predominance in 40 percent), irregular linear opacities in 30 percent, consolidation in 30 percent, and traction bronchiectasis in 10 percent (one subject).

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Many other histopathological patterns and clinical syndromes have been reported, including pulmonary edema, ARDS, vasculitis, DAH, SLE, PIE, and nodules.

Interferon-alpha and Pegylated Interferon-α2 b The rising prevalence of chronic hepatitis C worldwide and its treatment with interferon-alpha, and more recently with the longer-acting pegylated interferon-α2 b, has brought with it reports of pulmonary toxicity, most commonly interstitial infiltrates and BOOP. Systemic side effects are common among patients using interferon, and typically include flulike symptoms, with fatigue, headache, anorexia, and myalgias, whereas pulmonary symptoms occur infrequently. Ribavirin, a synthetic nucleoside analog is often used in conjunction with either interferon-alpha or pegylated interferon-α2 b, to enhance the antiviral activity of the interferons. Ribavirin is associated with dyspnea and cough, but has not been reported to cause pulmonary toxicity when used alone. The reported rate of significant pulmonary interstitial disease and/or BOOP is as high as 6 percent among patients receiving high-dose daily interferon for hepatitis C, and <1 percent among patients on conventional three-times-weekly dosing schedules of interferon-alpha and ribavirin. The occurrence of interstitial disease among users of interferonalpha is not exclusive to those with hepatitis, and has been reported in patients on interferon therapy for chronic myelogenous leukemia and myelofibrosis as well. Most cases of pulmonary toxicity occur within several weeks of initiation of therapy and resolve with discontinuation of the medications. Several case reports or small series of cases characterize the association of de novo sarcoidosis and recrudescent sarcoidosis with interferon-α and interferon-α2 a use for chronic hepatitis C. The incidence of sarcoidosis among patients receiving interferon is not well established, but has been reported to be as high as 5 percent (three cases) in a reported series of 60 patients receiving treatment with interferon-α2 a for hepatitis C. Although most of the reports of sarcoidosis have been of patients undergoing treatment for hepatitis C, it also can occur in the setting of treatment of hematological malignancy. Pulmonary manifestations of sarcoidosis occur along with other sites of disease involvement, including cutaneous, parotid, liver, ocular, and cardiac disease. The spectrum of sarcoidosis in the setting of interferon has been reviewed recently (Celik et al.). Vigilance for pulmonary symptoms among patients treated with interferon is warranted, and prompt withdrawal of the drug in cases of documented toxicity is indicated.

OPIATES AND ILLICIT DRUGS Complications of illicit drug use are numerous and encompass toxic injury to the lung related to use of the drug it-

self, and conditions associated with infectious sequelae of venous cannulation, such as endocarditis, septic embolization, and HIV-associated opportunistic infection. The prevalence of tuberculosis among drug users puts these individuals at high risk of active tuberculosis as well. Opiates or other sedatives may cause altered mental status and impairment of the gag reflex, substantially increasing the risk of aspiration pneumonia. Pulmonary parenchymal disease may also be caused by talc or other inert substances used to “cut” the drugs. Recognition of these conditions unrelated to direct toxicity of the drug will broaden the differential diagnosis of pulmonary symptoms in users of illicit drugs.

Heroin Overdoses of heroin and other narcotics have long been known to cause pulmonary edema. One of the earliest reports of drug-induced lung disease was by Osler in 1880, in which he described pulmonary edema in an opiate addict, and ascribed the edema to the opiate use. The frequency with which heroin-induced pulmonary edema (HIPE) occurs appears to have decreased in recent decades for unknown reasons. In one series of patients compiled between 1968 and 1970, 48 percent of 149 patients with heroin overdose had pulmonary edema on presentation. The presence of pulmonary edema was associated with increased mortality (18.3 percent vs. 8.7 percent if pulmonary edema was absent). A more recent case series describes a much lower incidence of pulmonary edema: 2.1 percent of cases of heroin overdose. It is unclear whether the change in the epidemiology of HIPE relates to a change in the additives to illicit heroin or other factors. In the latter series, one-third of the patients required intubation and mechanical ventilation, but the hypoxia of HIPE resolved within 48 hours of presentation. The literature does not conclusively indicate the mechanism of HIPE. Some studies have reported higher protein levels in pulmonary edema fluid of HIPE than in cardiogenic pulmonary edema, supporting increased capillary permeability as the mechanism, while other investigators have suggested that HIPE is the result of an anaphylactoid reaction based on high serum levels of tryptase and eosinophilic cationic protein in subjects who died of heroin overdose. Other reactions associated with heroin use include acute bronchospasm. Pulmonary disease associated with illicit injection drug use can be unrelated to the drug itself. Talc used to cut heroin or inert substances used in pills that are crushed and injected produce foreign-body granulomatous reactions in the pulmonary vasculature and interstitium. A longitudinal study of six patients with pulmonary talcosis describes characteristic radiographic findings, consisting initially of a diffuse, micronodular pulmonary infiltrate that evolves into coalescent conglomerates, often in the upper lobes, similar in appearance to those of progressive massive fibrosis. These changes may be accompanied by emphysematous changes in the lower lobes, which may result in pneumothoraces. Other pulmonary

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complications of injection drug use include septic emboli, abscess formation, bronchiectasis, and bullae independent of apical fibrotic reactions.

Cocaine Cocaine may be injected intravenously, inhaled nasally, or smoked. It is the latter route of ingestion that is most frequently associated with respiratory symptoms and pulmonary injury. Cocaine is typically smoked as â&#x20AC;&#x153;crackâ&#x20AC;? cocaine, an alkaloid derivative of cocaine hydrochloride that is mixed with ether or alcohol. Respiratory symptoms typically develop acutely within hours of use, and include cough, hemoptysis, chest pain, and shortness of breath. Bronchospasm, which may be severe enough to precipitate respiratory failure, has been reported with and without a prior history of asthma.

TREATMENT AND DISEASE RESOLUTION Prompt recognition of drug-induced lung disease before irreversible lung injury occurs, affords patients the greatest chance of clinical and radiographic recovery. In most cases of drug-induced pulmonary injury, discontinuation of the culprit drug is sufficient for regression of clinical symptoms along with most or all of the radiographic findings. The decision to accompany this strategy with corticosteroid treatment must be individualized based on the severity of the clinical picture, and the expected rapidity of symptom resolution. For example, amiodarone pulmonary toxicity frequently requires oral corticosteroid administration, unless the symptoms are very mild, because of the long serum half-life of the drug. Moreover, recrudescent disease has been reported during steroid tapers in the case of amiodarone toxicity, presumably due to the tissue sequestration of this drug. Recrudescence is rare among other implicated drugs. Overall, corticosteroids are used with apparent success, but controlled studies to determine therapeutic efficacy are lacking, and the infrequent occurrence of most drug toxicities will never allow this treatment to be convincingly studied in clinical trials.

SUGGESTED READING Akira M, Ishikawa H, Yamamoto S: Drug-induced pneumonitis: Thin-section CT findings in 60 patients. Radiology 224:852, 2002. Avitzur Y, Jimenez-Rivera C, Fecteau A, et al.: Interstitial granulomatous pneumonitis associated with sirolimus in a child after liver transplantation. J Pediatr Gastroenterol Nutr 37:91, 2003. Azzam I, Tov N, Elias N, et al.: Amiodarone toxicity presenting as pulmonary mass and peripheral neuropathy:

Drug-Induced Lung Disease Due to Nonchemotherapeutic Agents

The continuing diagnostic challenge. Postgrad Med J 82:73, 2006. Babu KS, Marshall BG: Drug-induced airway diseases. Clin Chest Med 25:113, 2004. Bonaci-Nikolic B, Nikolic MM, Andrejevic S, et al.: Antineutrophil cytoplasmic antibody (ANCA)-associated autoimmune diseases induced by antithyroid drugs: Comparison with idiopathic ANCA vasculitides. Arthritis Res Ther 7:R1072, 2005. Camus P, Bonniaud P, Fanton A, et al.: Drug-induced and iatrogenic infiltrative lung disease. Clin Chest Med 25:479, 2004. Camus P, Martin WJ 2nd, Rosenow EC 3rd: Amiodarone pulmonary toxicity. Clin Chest Med 25:65, 2004. Celik G, Sen E, Ulger AF, et al.: Sarcoidosis caused by interferon therapy. Respirology 10:535, 2005. Champion L, Stern M, Israel-Biet D, et al.: Brief communication: sirolimus-associated pneumonitis: 24 cases in renal transplant recipients. Ann Intern Med 144:505, 2006. Cooper JA Jr, White DA, Matthay RA: Drug-induced pulmonary disease. Part 2: Noncytotoxic drugs. Am Rev Respir Dis 133:488, 1986. Cooper JA Jr, Zitnik RJ, Matthay RA: Mechanisms of drug-induced pulmonary disease. Annu Rev Med 39:395, 1988. Delaunois LM: Mechanisms in pulmonary toxicology. Clin Chest Med 25:1, 2004. Dupont P, Warrens AN: The evolving role of sirolimus in renal transplantation. QJM 96:401, 2003. Epler GR: Drug-induced bronchiolitis obliterans organizing pneumonia. Clin Chest Med 25:89, 2004. Handschin AE, Lardinois D, Schneiter D, et al.: Acute amiodarone-induced pulmonary toxicity following lung resection. Respiration 70:310, 2003. Higenbottam T, Laude L, Emery C, et al.: Pulmonary hypertension as a result of drug therapy. Clin Chest Med 25:123, 2004. Howard L, Gopalan D, Griffiths M, et al.: Sirolimus-induced pulmonary hypersensitivity associated with a CD4 T-cell infiltrate. Chest 129:1718, 2006. Kharabsheh S, Abendroth CS, Kozak M: Fatal pulmonary toxicity occurring within two weeks of initiation of amiodarone. Am J Cardiol 89:896, 2002. Kumar KS, Russo MW, Borczuk AC, et al.: Significant pulmonary toxicity associated with interferon and ribavirin therapy for hepatitis C. Am J Gastroenterol 97: 2432, 2002. Lardinois D, Handschin A, Weder W: Acute amiodaroneinduced pulmonary toxicity after lung operation. Ann Thorac Surg 73:2033, 2002. Lee-Chiong T Jr, Matthay RA: Drug-induced pulmonary edema and acute respiratory distress syndrome. Clin Chest Med 25:95, 2004. Lock BJ, Eggert M, Cooper JA Jr: Infiltrative lung disease due to noncytotoxic agents. Clin Chest Med 25:47, 2004.

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Drug-Induced Lung Diseases

Malhotra A, Muse VV, Mark EJ: Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 12-2003. An 82-year-old man with dyspnea and pulmonary abnormalities. N Engl J Med 348:1574, 2003. Mendez JL, Nadrous HF, Hartman TE, et al.: Chronic nitrofurantoin-induced lung disease. Mayo Clin Proc 80:1298, 2005. Olshansky B, Sami M, Rubin A, et al.: Use of amiodarone for atrial fibrillation in patients with preexisting pulmonary disease in the AFFIRM study. Am J Cardiol 95:404, 2005.

Ott MC, Khoor A, Leventhal JP, et al.: Pulmonary toxicity in patients receiving low-dose amiodarone. Chest 123:646, 2003. Schwarz MI, Fontenot AP: Drug-induced diffuse alveolar hemorrhage syndromes and vasculitis. Clin Chest Med 25:133, 2004. Umetani K, Abe M, Kawabata K, et al.: SP-D as a marker of amiodarone-induced pulmonary toxicity. Intern Med 41:709, 2002. Wolff AJ, Oâ&#x20AC;&#x2122;Donnell AE: Pulmonary effects of illicit drug use. Clin Chest Med 25:203, 2004.

PART

VII Interstitial and Inflammatory Lung Diseases

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SECTION THIRTEEN

Immunologic and Interstitial Diseases

66 CHAPTER

Interstitial Lung Disease: A Clinical Overview and General Approach Michael A. Nead David G. Morris

I. EPIDEMIOLOGY II. CLINICAL APPROACH TO PATIENTS WITH INTERSTITIAL LUNG DISEASE Clinical History Physical Examination Laboratory Evaluation Chest Radiographic Patterns: Computed Tomography and High-Resolution CT Images

The interstitial lung diseases are a clinically challenging and diverse group of over 150 disorders characterized by varying degrees of fibrosis and inflammation of the lung parenchyma or interstitium. The interstitium of the lung spans the region between alveolar epithelium and pulmonary vascular endothelium. This region includes a variety of cell types (fibroblasts, myofibroblasts, and macrophages) and matrix components (collagens, elastin, and proteoglycans). The interstitium extends from the alveolar space proximal to the terminal and respiratory bronchioles. However, for clinical purposes, some disorders that primarily affect the alveolar space (e.g., pulmonary alveolar proteinosis or cryptogenic organizing pneumonia) also typically fall under the heading of interstitial lung diseases. The classification, prognosis, and treatment of interstitial lung diseases continue to evolve as

Pulmonary Physiology Testing Bronchoalveolar Lavage Bronchoscopy with Transbronchial Biopsy Surgical Lung Biopsy: Thoracoscopy-Guided and Open Lung Biopsy Clinicopathological Correlation in the Diagnosis of Interstitial Lung Diseases III. TREATMENT

our understanding of them improves. With this improved understanding has come an increased complexity of the field with new and altered terminology now used to characterize each disease (Table 66-1). This chapter provides a framework by which to evaluate patients with suspected interstitial lung disease.

EPIDEMIOLOGY The actual incidence of interstitial lung diseases remains unknown. Current estimates of the incidence and prevalence of interstitial lung disease are higher than historical estimates. The higher numbers stem from increased

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Table 66-1 Current and Historical Terminology of Select Interstitial Lung Diseases Current Clinical Terminology

Current Histopathologic Terminology

Historical Terminology

Idiopathic pulmonary fibrosis (IPF) Cryptogenic fibrosing alveolitis (CFA)

Usual interstitial pneumonia (UIP)

Hamman-Rich syndrome Chronic interstitial pulmonary fibrosis Cryptogenic fibrosing alveolitis (CFA) Lone cryptogenic fibrosing alveolitis (lone-CFA)

Acute interstitial pneumonia (AIP)

Diffuse alveolar damage (DAD)

Likely the original Hamman-Rich cases

Nonspecific interstitial pneumonia (NSIP)

NSIP pattern

Desquamative interstitial pneumonia (DIP)

DIP pattern

Lymphoid interstitial pneumonia (LIP)

LIP pattern

Respiratory bronchiolitis interstitial lung disease (RB-ILD)

Respiratory bronchiolitis

Cryptogenic organizing pneumonia (COP)

Organizing pneumonia

Bronchiolitis obliterans organizing pneumonia (BOOP) Bronchiolitis obliterans with usual interstitial pneumonia (BIP)

Langerhansâ&#x20AC;&#x2122; cell granulomatosis aka Pulmonary histiocytosis X aka Eosinophilic granuloma Obliterative bronchiolitis aka Constrictive bronchiolitis Hypersensitivity pneumonitis aka Extrinsic allergic alveolitis Hard metal pneumoconiosis

awareness, improved imaging modalities, changing disease definitions, and prior incomplete data collection. Estimates of the prevalence of one subset of interstitial lung disease, idiopathic interstitial pneumonia, from one county in New Mexico, are 81 per 100,000 for males and 67 per 100,000 for females. The prevalence of all interstitial lung disease is estimated at 1 in 3000 to 4000 in the United Kingdom. Different interstitial lung diseases show specific age predilections. Unique forms of interstitial lung disease oc-

Giant-cell interstitial pneumonia

cur in infancy and childhood. These include follicular bronchitis, cellular interstitial pneumonia, and acute idiopathic pulmonary hemorrhage of infancy. After adolescence and before age 40, familial idiopathic pulmonary fibrosis (IPF), metabolic storage disorders, Hermansky-Pudlak syndrome, and other inherited interstitial lung diseases need to be considered. Collagen vascular disease-associated interstitial lung disease is more likely to occur in this age group, as are lymphangioleiomyomatosis and pulmonary Langerhansâ&#x20AC;&#x2122; cell granulomatosis. Sarcoidosis can present at any age, but tends

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Interstitial Lung Disease

and adjustment as the results of diagnostic studies become available for each patient. However, the cornerstone upon which the initial differential rests is a comprehensive history. Diseases outside of the classic realm of interstitial lung disease should not be overlooked, although they do not receive extensive discussion in this overview. Infectious causes, such as community acquired and atypical pneumonias, can be confused with acute interstitial lung diseases. Chronic or remote mycobacterial infections, which are both associated with a significant postinflammatory fibrotic response, can be confused with idiopathic interstitial lung disease. Immunodeficiency necessarily broadens consideration of other infectious etiologies that can mimic the radiographic appearance of interstitial lung diseases, such as Pneumocystis jiroveci (carinii) pneumonia, and other noninfectious possibilities, such as lymphoproliferative disorders. Cardiac pathology, acute respiratory distress syndrome from a variety of causes, and neoplastic disorders are also possibilities. A systematic approach is important to avoid missing a progressive but eminently treatable disease that, left untreated or incompletely treated, could result in significant morbidity or even death (e.g., polymyositis, acute interstitial pneumonia, etc.). The following paragraphs include a discussion of the most common interstitial lung disease considerations for each sign and symptom. Several excellent resources are available that provide a more encyclopedic discussion.

to be a disease of young to middle-aged people. IPF is more common after age 50, and is present in nearly 1 in 500 people over the age of 75. Gender also impacts disease prevalence for some interstitial lung diseases. Traditional occupational roles have placed men at greater risk of pneumoconiosis, which are scarring lung diseases that develop after particular environmental exposures. Women are more likely to have collagen vascular diseaseâ&#x20AC;&#x201C;associated interstitial lung disease, due to increased risk of autoimmune disease. Women are also almost exclusively affected by lymphangioleiomyomatosis and tuberous sclerosisâ&#x20AC;&#x201C;associated interstitial lung diseases. Particular ancestry also increases the likelihood of some interstitial lung diseases. For example, sarcoidosis occurs 10- to 12-fold more often in blacks than their white counterparts in the United States, United Kingdom, and South Africa. Hermansky-Pudlak syndrome occurs in 1 in 1800 people of Puerto Rican descent.

CLINICAL APPROACH TO PATIENTS WITH INTERSTITIAL LUNG DISEASE Combining clinical, radiologic, and pathological information is pivotal to accurate diagnosis in interstitial lung diseases (Fig. 66-1). A working differential diagnosis requires review

Thorough clinical history, physical exam, chest radiograph, high resolution CT scan, pulmonary function tests

Clear etiology or exposure? Yes

Remove offending agent or begin appropriate therapy

Generate differential diagnosis. Order discriminating laboratory tests/serologies No

Objective improvement? Consider bronchoscopy if infection or disease from Table 66-7 on differential

Yes Follow up as necessary

Definitive diagnosis? No Obtain surgical lung biopsy, and/or review prior pathology

Yes Initiate appropriate therapy or clinical trial No Objective improvement? Yes

Clinicopathologic correlation

Follow up as necessary

Figure 66-1 Diagnostic evaluation of a patient with interstitial lung disease.

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Table 66-2 Interstitial Lung Diseases by Duration of Symptoms Acute onset: days to weeks Acute interstitial pneumonia Acute pneumonitis from collagen vascular disease (especially SLE) Cryptogenic organizing pneumonia Drugs Diffuse alveolar hemorrhage Eosinophilic lung disease Hypersensitivity pneumonitis Subacute: weeks to months Collagen vascular disease–associated ILD Cryptogenic organizing pneumonia Drugs Subacute hypersensitivity pneumonitis Chronic: months to years Chronic hypersensitivity pneumonitis Collagen vascular disease–associated ILD Idiopathic pulmonary fibrosis Nonspecific interstitial pneumonia Occupation-related lung disease (e.g., silicosis, asbestosis) Note: Abbreviations: ILD = interstitial lung disease; SLE = systemic lupus erythematosus.

Clinical History Dyspnea The majority of patients with interstitial lung diseases complain of difficulty in breathing. A detailed history of the onset and duration of symptoms may help frame the differential diagnosis. Depending on the nature of the underlying disease, the difficulty in breathing may be acute (hours to days), subacute (2 weeks to months), or chronic (Table 66-2). Travel to an unaccustomed altitude or an increase in activity level may unmask a chronic disease previously insidious in onset. Cough A substantial percentage of patients with interstitial lung diseases complain of cough, making it a very nonspecific initial finding. Unfortunately, cough in these patients can be disabling, particularly in idiopathic pulmonary fibrosis and diseases that primarily affect airways, such as bronchiolitis, cryptogenic organizing pneumonia, and sarcoidosis. Lymphangitic carcinomatosis can also cause an irritating cough that stems from submucosal lymphatic involvement. Gastroesophageal reflux is one of the most common causes of chronic cough, and gastric aspiration should be considered in a patient with cough and interstitial lung disease. Hemoptysis occurs in one-third of patients with diffuse alveolar hemor-

rhage, and should raise the possibility of pulmonary capillaritis due to pulmonary vasculitis or interstitial lung disease associated with collagen vascular disease. Hemoptysis is the presenting complaint in about 20 percent of patients with lymphangioleiomyomatosis. Fever With most interstitial lung diseases, constitutional complaints such as fevers, chills, and weight loss are absent. The presence of complaints often suggests either an underlying collagen vascular disease or a more acute disease, such as cryptogenic organizing pneumonia or acute interstitial pneumonia. Up to one-third of patients with sarcoidosis present with fever and systemic symptoms. Some types of hypersensitivity pneumonitis, such as farmer’s lung, may present with fevers, chills, and shortness of breath. Patients with tropical pulmonary eosinophilia often experience fever and a nocturnal hacking cough, and patients with chronic eosinophilic pneumonia may have fevers and night sweats. Chest Pain/Pleurisy Some forms of pulmonary vasculitis and collagen vascular diseases affect the pleural surface and give rise to pain. Chest pain is most common in systemic lupus erythematosus, but occurs sometimes in such diseases as mixed connective tissue disease, Wegener’s granulomatosis, and rheumatoid arthritis. Sarcoidosis may present with symptoms ranging from vague chest discomfort to outright pleurisy. Pneumothorax is also a possibility in a patient with suspected interstitial lung disease and chest pain. Smoking History Two-thirds of patients with idiopathic pulmonary fibrosis are current or former tobacco smokers at the time of diagnosis. Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), desquamating interstitial pneumonitis (DIP), and eosinophilic granuloma (EG, or Langerhans’ cell granulomatosis) all occur nearly exclusively in smokers. Goodpasture’s syndrome occurs most frequently in patients with a smoking history. Sarcoidosis and hypersensitivity pneumonitis occur less often in smokers. An interstitial lung disease may also aggravate the health effects beyond those that accompany tobacco use. Examples include worsened lung function in smokers with coal workers’ pneumoconiosis, and the increased risk of bronchogenic carcinoma in patients with silicosis. Exposure and Occupational History A detailed history of past and present employment may reveal a specific etiology for a patient’s interstitial lung disease. Identifying the offending agent is imperative in order to limit contact by both the patient and others who may be at risk. For most agents, the minimal exposure needed to produce interstitial lung disease remains unknown. Accordingly, an astute clinician is needed to seek out information in individuals who are only temporarily employed. Respirable materials capable of inducing interstitial lung

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Table 66-3 Selected Occupational and Recreational Exposures Associated with Interstitial Lung Disease Exposure

Associated Lung Disease

Bird breeders and fanciers

Hypersensitivity pneumonitis

Automotive mechanics Electricians Pipefitters Shipyard workers

Asbestosis

Electronic and computer industry workers

Berylliosis

Farmers

Farmer’s lung (hypersensitivity pneumonitis)

Hot tub, sauna, humidifiers

Hypersensitivity pneumonitis

Metal workers (tool and die)

Metal-induced pneumoconioses

Miners Sandblasters Ceramic workers

Silicosis

Miners (specifically coal)

Coal workers’ pneumoconiosis

Bark strippers Woodworkers

Hypersensitivity pneumonitis

disease are common. Selected exposures along with their associated diseases are listed in Table 66-3. Recreational activities may also cause interstitial lung disease and are included in Table 66-3. Part V provides a more thorough discussion of occupational and environmental causes of interstitial lung disease. Medication and Drug Use History As with occupational exposures, the list of medications associated with pulmonary reactions continues to expand. A complete history of prescription and nonprescription medications, including both current and prior medications, is part of the routine clinical assessment of these patients. Some of the more common offenders are listed in Table 66-4. Recreational drugs and contaminants (i.e., talc) should also be considered. Continuously updated, comprehensive resources that catalogue drug-induced pulmonary side effects are available.

Interstitial Lung Disease

Family History A family history of lung disease or connective tissue diseases is important to consider during the evaluation of a patient with interstitial lung disease. Familial pulmonary fibrosis is associated with an autosomal dominant pattern of inheritance, and studies from the United Kingdom and Finland suggest that the familial form accounts for 0.5 to 3.7 percent patients with pulmonary fibrosis. Sarcoidosis also has a significant genetic association. Similarly, a family history suggestive of tuberous sclerosis (hamartomas, epilepsy, or mental retardation) may suggest lymphangioleiomyomatosis or multifocal micronodular pneumocyte hyperplasia. Miscellaneous Symptoms of chronic sinusitis occur in diffuse panbronchiolitis and Wegener’s granulomatosis. Esophageal reflux occurs more frequently in patients with idiopathic pulmonary fibrosis, but may also be a sign of otherwise occult systemic sclerosis. Some specific clinical syndromes are virtually pathognomonic of particular diseases. One example is the syndrome of uveitis, parotiditis, and erythema nodosum that may occur as an initial presentation of typically self-limited sarcoidosis. Such syndromes, while diagnostically helpful, are relatively rare. A careful travel history may suggest a parasitic infection as the cause of an eosinophilic pneumonia. Close questioning may also uncover symptoms suggestive of a possible collagen vascular disease. Among such manifestations are Raynaud’s phenomenon, proximal muscle weakness, and joint swelling/pain.

Physical Examination Many of the interstitial lung diseases may show dermatologic or systemic signs detectable by the astute clinician. Some of these are mentioned in the following paragraphs. Any unexplained abnormalities discovered during a comprehensive review of systems and physical examination should be pursued as potential clues to the cause of the patient’s interstitial lung disease. These clues are often extrapulmonary. In contrast, the lung examination, per se, is quite nonspecific in patients with interstitial lung disease. The classical “Velcro rales,” or inspiratory crackles, occur not only in most patients with idiopathic pulmonary fibrosis, but also in many other interstitial lung diseases. The crackles last throughout inspiration and usually predominate at the lung bases initially. As the disease progresses, the crackles eventually may extend to the apices. In only a minority of patients with sarcoidosis or other granulomatous interstitial lung disease are rales chronically audible (5 to 20 percent). Mid inspiratory squeaks suggest airway-centered diseases, including cryptogenic organizing pneumonia, constrictive bronchiolitis, or hypersensitivity pneumonitis. Squeaks may occur with nonspecific interstitial pneumonia. Patients with constrictive bronchiolitis may have an expiratory wheeze that is refractory to inhaled bronchodilators. Eighty percent of patients with clubbing have a respiratory disorder. Among patients with interstitial lung disease,

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Table 66-4

Acetylsalicylic acid Amiodarone

X X

ACE inhibitors

X X

Anticoagulants

Beta blockers

Bleomycin

Bromocriptine

Busulfan

Carbamazepine

X X

Cyclophosphamide

Ergots

Fenfluramine/dexfenfluramine

Iodine (contrast material)

L-tryptophan

Minocycline Mitomycin C

X X

Nilutamide Nitrofurantoin

Hydrochlorothiazide

Carmustine (BCNU)

Methotrexate

Alveolar Hemorrhage

Mineral Oil Pneumonia

Diffuse Alveolar Damage

Lung Nodules

Lymphocytic Interstitial Pneumonia

Desquamative Interstitial Pneumonia

Organizing Pneumonia

Infiltrate + Eosinophilia

Acute Hypersensitivity Pneumonitis

Medication

Pulmonary Fibrosis

Selected Medications Associated with Interstitial Lung Disease

X X

X (continued )

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Interstitial Lung Disease

Table 66-4

NSAIDs

Alveolar Hemorrhage X

Propylthiouracil

Sulfamides-sulfonamides

Sulfasalazine

Mineral Oil Pneumonia X

Phenytoin Practolol

Diffuse Alveolar Damage

Paraffin (mineral oil) Penicillamine

Lung Nodules

Lymphocytic Interstitial Pneumonia

Desquamative Interstitial Pneumonia

Organizing Pneumonia

Infiltrate + Eosinophilia

Nitrosoureas

Acute Hypersensitivity Pneumonitis

Medication

Pulmonary Fibrosis

(Continued) Selected Medications Associated with Interstitial Lung Disease

Vinblastine

Source: Adapted from: Foucher P, Camus P, Geppi T. www.pneumotox.com; Abbreviations: ACE = angiotensin converting enzyme; NSAIDs = nonsteroidal anti-inflammatory drugs.

clubbing is found in 25 to 50 percent of patients with idiopathic pulmonary fibrosis, and 50 percent of patients with desquamative interstitial pneumonia. Patients with sarcoidosis, cryptogenic organizing pneumonia, and collagen vascular disease–associated interstitial lung disease rarely have clubbing. However, clubbing occurs in up to 75 percent of patients with interstitial lung disease from rheumatoid arthritis. An insidious onset of proximal muscle weakness before the onset of interstitial lung disease, with or without muscle tenderness, should raise the concern of polymyositis/ dermatomyositis. Myositis may also occur with sarcoidosis, Sj¨ogren’s syndrome, scleroderma, and mixed connective tissue disease.

Laboratory Evaluation Laboratory tests are insufficiently specific and sensitive to be diagnostic in the patient with interstitial lung disease.

In individual patients, even serologic markers, which are helpful when markedly abnormal, require substantial clinical correlation before a final diagnosis can be rendered. However, laboratory tests can provide important supporting evidence for a suspected clinical diagnosis. The routine tests that should be ordered in all patients in whom interstitial lung disease is suspected include a complete and differential blood count, a blood chemistry panel including calcium, liver function tests, and a urinalysis. The clinical picture should dictate additional laboratory testing, such as a hypersensitivity panel, or complement levels in suspected cases of systemic lupus erythematosus, rheumatoid arthritis, hypersensitivity, or vasculitis. Table 66-5 provides data concerning the sensitivity of immunologic tests with respect to the diagnosis of rheumatic diseases. However, sensitivity may vary when patients with interstitial lung disease, per se, are considered. For example, anti-Jo1 antibodies, directed against histidyl-tRNA synthetase, are present in only 13 percent of patients with systemic polymyositis-dermatomyositis without

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Table 66-5 Sensitivity of Some Immunologic Tests Associated with Rheumatic Disorders That May Cause Interstitial Lung Disease Disease

dsDNA ssDNA

1–5

SLE

60–70

Drug LE

Rare

Sj¨ogren’s syndrome

Mod

Diffuse scleroderma

Mod 72–85

anti-RNP anti-Sm anti-Scl-70 anti-Jo-1 anti-Ro anti-La cANCA pANCA 10

30–50

25–30

25–35

0–1

5–20

1–5

8–70

14–60

25–33

15–50

PM/DM granulomatosis

Low

20–50

Low

Wegener’s

75–95

Goodpasture’s syndrome

Rare

10–38

MPA

10–50

Churg-Strauss syndrome

Source: Adapted from: Laboratory Assessment. Primer on the Rheumatic Diseases, 11th ed. Atlanta, Arthritis Foundation, 1997; Hellmann D: Arthritis and musculoskeletal disorders, in Tierney LM, Papadakis MA (eds), Current Medical Diagnosis and Treatment. East Norwalk, CT, Appleton & Lange, 1997, pp. 750–799; Reichlin M. Measurement and clinical significance of antinuclear antibodies. UpToDate, 2005; Schwarz MI, King TE (eds): Interstitial Lung Disease, 4th ed., Hamilton, Ontario, BC Decker, 2003. Note: Abbreviation: Mod = moderate.

interstitial lung disease, but 50 percent of those with pulmonary manifestations. Both the erythrocyte sedimentation rate (ESR) and angiotensin converting enzyme (ACE) level are too nonspecific to warrant inclusion in a standard diagnostic panel.

Chest Radiographic Patterns: Computed Tomography and High-Resolution CT Images With rare exception, patients with clinically significant interstitial lung disease have abnormalities detectable by radiologic imaging of the chest. Unfortunately, plain chest radiographs can be misleadingly negative in up to 10 percent of all patients with clinically significant interstitial lung disease and up to 90 percent of patients with hypersensitivity pneumonitis. Conventional computed tomography (CT) of the chest is a better but still relatively insensitive supplement. Consequently, high-resolution computed tomographic (HRCT) imaging of the chest is the current gold standard for imag-

ing patients with interstitial lung disease. Diagnostic certainty is associated with particular patterns of abnormality on HRCT scans of the chest and can obviate the need for lung biopsy in selected diseases. Among these diseases are idiopathic pulmonary fibrosis, sarcoidosis (Fig. 66-2), and some forms of hypersensitivity pneumonitis (Fig. 66-3). Several diseases manifest classic findings that are highly suggestive of a diagnosis, including pulmonary alveolar proteinosis (Fig. 664), lymphangioleiomyomatosis (Fig. 66-5), and eosinophilic granuloma (pulmonary Langerhans’ cell histiocytosis) (Fig. 66-6). The features of an HRCT for the radiographic diagnosis of definite usual interstitial pneumonia include a reticular pattern with associated honeycombing and/or traction bronchiectasis in a basal, predominantly subpleural distribution (Figs. 66-7 and 66-8). Nodules and consolidation should be absent. The diagnostic utility of HRCT is often substantially augmented by combining both inspiratory and expiratory imaging to increase the detection of coexisting airways disease as manifested by regional air-trapping

1113 Chapter 66

Figure 66-2 Sarcoidosis. High-resolution computed tomography of the chest of a patient with sarcoidosis, demonstrating septal beading (arrows) and nodules abutting bronchovascular bundles.

during exhalation. Nevertheless, the value of careful review of all prior chest radiographs in patients with interstitial lung disease cannot be overstated. Information from these studies offers invaluable insight into the time of onset, clinical course, and current trajectory of a given patientâ&#x20AC;&#x2122;s pulmonary disease. Tables 66-6 and 66-7 summarize helpful radiographic patterns that may guide formulation of the differential diagnosis and ensuing work-up. The value of a skilled thoracic radiologist on the interstitial lung disease team has been demonstrated repeatedly in the literature (see Clinicopathological Correlation in the Diagnosis of Interstitial Lung Diseases).

Figure 66-3 Hypersensitivity pneumonitis. High-resolution computed tomography of the chest of an individual with hypersensitivity pneumonitis from the pigeons he raised. Subacute hypersensitivity classically has ground-glass opacities, lymphadenopathy, and centrilobular nodules, which are identified by the sparing of pleural surfaces. Ground-glass and nodules (arrows indicate representative nodules) are visible in this frame. (Image courtesy of Dr. Erica Herzog.)

Interstitial Lung Disease

Figure 66-4 Pulmonary alveolar proteinosis. Standard resolution (5 mm) computed tomography of a 53-year-old patient with pulmonary alveolar proteinosis demonstrates ground-glass opacities demarcated by thickened interlobular septae. The findings are bilateral and symmetric in this patient, but may occur unilaterally or asymmetrically. (Image courtesy of Dr. John McArdle.)

Pulmonary Physiology Testing Interstitial diseases alter mechanical and gas exchange properties of the lungs. In general, the hallmarks of interstitial lung diseases are restrictive changes in pulmonary physiology (i.e., reduced total lung capacity, reduced residual volume, decreased static compliance, and a reduced VC, often with an increased FEV1 /FVC ratio), and a reduced diffusing capacity for carbon monoxide (DlCO ). A few diseases also manifest substantial components of airflow obstruction. Among these diseases are sarcoidosis, lymphangioleiomyomatosis, Langerhansâ&#x20AC;&#x2122; cell histiocytosis (eosinophilic granuloma), constrictive

Figure 66-5 Lymphangioleiomyomatosis. Standard resolution (5 mm) computed tomography of the chest demonstrates the diffusely distributed, bilateral, thin-walled cysts that are typical of lymphangioleiomyomatosis. (Image courtesy of Dr. Richard Matthay.)

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Figure 66-6 Eosinophilic granuloma (pulmonary Langerhansâ&#x20AC;&#x2122; cell histiocytosis). The high-resolution computed tomogram demonstrates the irregular cysts and centrilobular nodules (arrows) typical of eosinophilic granuloma. Changes occur predominantly in the upper and mid lung zones, and pneumothoraces may be seen. (Image courtesy of Dr. Michael Gotway.)

bronchiolitis, respiratory bronchiolitisâ&#x20AC;&#x201C;interstitial lung disease, and hypersensitivity pneumonia. In some patients, the coincidence of both restrictive and obstructive components, as occurs in interstitial lung disease associated with asthma or chronic obstructive pulmonary disease, can lead to normalization of lung volumes. As such, a careful examination of the flow-volume loop should be made for each patient, and chest imaging studies should be checked for correlation with pulmonary function tests. Respiratory muscle weakness may cause low maximal voluntary ventilation and decreased maximal inspiratory pressure, suggesting possible systemic lupus erythematosus, polymyositis, or scleroderma. Formal measures of lung compliance may be necessary to differentiate respiratory muscle weakness from the physiological effects of interstitial fibrosis.

Figure 66-8 Idiopathic pulmonary fibrosis. Traction bronchiectasis (dark arrows) and bilateral, basal honeycombing (white arrows) are demonstrated on this high-resolution computed tomogram of the chest. In addition, a confident radiographic diagnosis of usual interstitial pneumonia requires the absence of nodules and consolidation.

The diffusing capacity for carbon monoxide (DlCO ) may be the first and only abnormality found in the early stages of interstitial lung disease. In diseases such as idiopathic pulmonary fibrosis, the diffusing capacity for carbon monoxide is often decreased out of proportion to the restrictive defect. A DlCO less than 35 to 40 percent predicted for idiopathic pulmonary fibrosis and less than 40 percent for systemic sclerosis has been shown to predict worse outcomes. Quantitative studies suggest that virtually all of the hypoxemia at rest in patients with interstitial lung disease is due to ventilation-perfusion inequality. In patients in whom gas exchange is apparently normal at rest, exercise testing may be helpful in unmasking these defects and therefore useful in understanding patientsâ&#x20AC;&#x2122; dyspnea on exertion. In sarcoidosis, a 6-minute bicycle test detected pulmonary dysfunction sooner than did standard investigative methods. The 6-minute walk test (6MWT) has been used extensively in obstructive lung diseases, and is gaining favor in assessing interstitial lung diseases and the outcomes of therapeutic interventions. Performance in the 6MWT has been shown to correlate with disease severity and prognosis in patients with idiopathic interstitial pneumonias, and it appears to provide information beyond pulmonary function studies in predicting injury due to radiation.

Bronchoalveolar Lavage

Figure 66-7 Idiopathic pulmonary fibrosis. This high resolution computed tomogram of the chest demonstrates classic bilateral honeycombing.

Beyond radiologic imaging and physiological testing, most patients with suspected interstitial lung disease require invasive studies to establish a final diagnosis. These studies range from bronchoscopy with bronchoalveolar lavage (BAL) to surgical lung biopsy. Whether a patient should undergo bronchoscopy prior to a surgical lung biopsy hinges on the assembled clinical and radiographic information. A poor candidate for the operative risks of a surgical biopsy might undergo

Table 66-6 Common Computed Tomography Findings of Interstitial Lung Diseases Peripheral disease

Asbestosis Collagen vascular disease–associated Interstitial Lung Diseases Eosinophilic pneumonia Organizing pneumonia Usual interstitial pneumonia

Upper lobe predominance

Berylliosis Coal workers’ pneumoconiosis Cystic fibrosis Eosinophilic pneumonia Hypersensitivity pneumonitis Langerhan’s cell histiocytosis Sarcoidosis Silicosis

Lower lobe predominance

Asbestosis Collagen vascular disease associated ILD Nonspecific interstitial pneumonia Organizing pneumonia Usual interstitial pneumonia

Peribronchovascular disease

Lymphangitis carcinomatosis Lymphoproliferative disorders Nonspecific interstitial pneumonia Organizing pneumonia Sarcoidosis Usual interstitial pneumonia

Small nodules

Bronchiolitis obliterans Cryptogenic organizing pneumonia Hypersensitivity pneumonitis Panbronchiolitis Pneumoconiosis Respiratory bronchiolitis Silicosis Vasculitis (Infection: fungal, tuberculosis; malignancy)

Large nodules/ masses

Pleural nodules

Amyloidosis Churg-Strauss syndrome Langerhans cell histiocytosis Rounded atelectasis, asbestos Sarcoidosis Silicosis Wegener’s granulomatosis (Lymphoma metastatic cancer, infection: fungal) Lymphangitic carcinoma Pneumoconiosis (coal workers’ silicosis) Sarcoidosis (Infection: fungal, tuberculosis; hematogenous metastatic disease)

Cystic disease

Desquamative intersititial pneumonia Langerhan’s cell histiocytosis Lymphangiomyomatosis Lymphoid interstitial pneumonitis (rule out emphysema)

Honeycombing

Asbestosis Collagen vascular disease–associated ILD End-stage ARDS Hypersensitivity pneumonitis (chronic) Sarcoidosis Usual interstitial pneumonia

Consolidation

Acute interstitial pneumonia ARDS Cryptogenic organizing pneumonia Eosinophilic pneumonia Lipoid pneumonia Pulmonary alveolar proteinosis (Bronchoalveolar cell carcinoma)

Ground-glass opacities

Acute interstitial pneumonia ARDS Bronchioloalveolar carcinoma Churg-Strauss syndrome Cryptogenic organizing pneumonia Desquamative interstitial pneumonia Diffuse alveolar hemorrhage Eosinophilic pneumonia (acute, chronic) Nonspecific interstitial pneumonia Pulmonary alveolar proteinosis Radiation pneumonitis Respiratory bronchiolitis interstitial lung disease Sarcoidosis (Infection, pulmonary edema)

Lymphadenopathy (hilar or mediastinal)

Amyloidosis Asbestosis Berylliosis Collagen vascular disease–associated ILD Hypersensitivity pneumonitis Sarcoidosis Silicosis Systemic sclerosis with ILD Usual interstial pneumonia (Infection lymphoma)

Pneumothorax

Ankylosing spondylitis Langerhans’ cell granulomatosis Lymphangioleiomyomatosis Neurofibromatosis Tuberous sclerosis (Cystic fibrosis)

Note: Abbreviations: ARDS = Adult respiratory distress syndrome; ILD = interstitial lung disease. Diseases in parenthesis are not classically cateroized as interstitial lung diseases but should be considered. Sources: Adapted from Lynch DA, Travis WD, Muller NL, et al: Idiopathic interstitial pneumonias: CT features. Radiology 236:10–21, 2005; Lynch DA: Imaging of diffuse parenchymal lung diseases, in Schwarz MI, King TE Jr (eds.), Interstitial Lung Disease, 4th ed. Hamilton, Ontario, BC Decker, 2003, pp 75–113; Webb RW, Muller NL, Naidich DP: High-resolution CT of the Lung, 3rd ed. Philadelphia, Lippincott Williams & Wilkins, 2001.

UIP pattern

Poor response to corticosteroids or cytotoxic agents.

Histology

Treatment

Organizing pneumonia, Masson bodies

Cellular: Corticosteroid Corticosteroid responsive. May responsive. May require additional require additional immunosuppresimmunosuppressants. sants, particularly Fibrotic: Similar to with underlying IPF. collagen-vascular disease.

NSIP (cellular, fibrotic, mixed)

Corticosteroid responsiveness unknown, but high-dose “pulse” therapy often used.

Diffuse alveolar damage

Acute. Most >40 y. Fever, cough, SOB, rales. May have family history or prior episode.

Peripheral, subpleural, Peripheral, subpleural, Subpleural or Diffuse, bilateral. basal. Reticular basal, symmetric. peribronchial. Patchy Ground-glass opacities. Ground-glass consolidation. opacities, often with Honeycombing. opacities. Rare Nodules. lobular sparing. Traction consolidation. Lower lobe volume loss. bronchiectasis. Architectural Subpleural sparing distortion. Rare focal may occur. ground glass.

Subacute. Age 50–60s. NS to smokers 2:1. Many assoicated conditions. Restriction on PFTs.

HRCT: Range of findings

Subacute to chronic. Age 30–70. CVD associated in some cases.

AIP

Chronic. Age >50 y. Velcro rales, clubbing.

COP

Clinical pearls

NSIP

IPF

Feature

Clinical, Radiographic, and Treatment of the Idiopathic Interstitial Pneumonias Chronic. Any age, most >30 y, female. Autoimmune or systemic disorder– associated.

LIP

Corticosteroid responsive. Smoking cessation is primary therapy.

Corticosteroid responsive. HAART if HIV positive.

DIP pattern respiratory LIP pattern bronchiolitis

Diffuse. Centrilobular DIP: Diffuse ground-glass opacity nodules. in middle and lower Ground-glass lung zone. opacity. Septal and RB-ILD: Bronchial wall bronchovascular thickening, thickening. Thin-walled cysts. centrilobular nodules, patchy ground glass opacity.

Subacute. Most 30–40s. Smokers >90%. Dyspnea and cough.

DIP, RB-ILD

Part VII

Table 66-7

1116 Interstitial and Inflammatory Lung Diseases

SLE

60% with pleuropulmonary disease Pleurisy +/− effusion, acute pneumonitis, DAH, interstitial disease, thromboembolism, pulmonary HTN.

Interlobular septal thickening, honeycombing. Ground glass opacities. Bronchiectasis. Pleural thickening.

NSIP pattern, interstitial fibrosis, foci of organizing pneumonia, inflammation of arterioles.

Corticosteroids. Azathioprine, cyclophosphamide, methotrexate, pheresis have been used.

Feature

Clinical pearls

HRCT: Range of findings

Histology

Treatment

Proximal muscle weakness/pain. Heliotrope rash, Gottren papules, finger ulcerations, dyspnea, cough. First, 50s–60s.

PolymyositisDermatomyositis

Not corticosteroid responsive. Cyclophosphamide with significant disease.

NSIP pattern, often fibrotic. Intimal thickening.

Organizing pneumonia, LIP or UIP pattern, bronchiolitis obliterans. Focal clumps of mononuclear cells (“pseudolymphoma”)

Bronchial wall thickening. Ground-glass opacities. Small nodules.

Xerostomia and keratoconjunctivitis, with cough and dyspnea. Primary: Postmenopausal women. Secondary: In-presence of connective tissue disease.

Sj¨ogren’s Syndrome

Corticosteroids Corticosteroids or generally insufficient immunosuppressive alone with ILD. therapy.

Lymphocytic infiltrate with lymphoid aggregates. Diffuse alveolar damage possible.

Honeycombing initially Patchy consolidation. basilar. Basal and Reticular changes. paravertebral cysts. Scattered Pleural thickening. ground-glass Pneumothorax. opacities. Bronchiectasis. Pleural effusion.

Dyspnea and cough. Pulmonary fibrosis, vascular disease, and pleural disease. Pulmonary HTN. Esophageal disease.

Scleroderma

(continued)

Fibrosis of pleura and parenchyma. Bronchiectasis. Pneumothorax.

Apical fibrobullous disease, with thickening of pleura, linear septa, interlobular septa.

Whites: 30s–40s. Males 50× more likely to have ILD. PFTs: decreased TLC and VC, increased FRC and RV.

Ankylosing Spondylitis

Chapter 66

Corticosteroid and immunosuppressant responsive.

Diffuse fibrosis with lymphocytic infiltration. Follicular bronchiolitis.

Nodules Bronchiectasis. Pleural thickening. Ground-glass opacities. Honeycombing.

Cough, dyspnea, clubbing. Pleural involvement most common. Interstitial disease, nodules, bronchiolitis obliterans, pulmonary HTN. Restriction with low diffusing capacity.

Rheumatoid Arthritis

(Continued ) Clinical, Radiographic, and Treatment of Collagen Vascular–Associated Interstitial Lung Diseases

Table 66-7

1117

Interstitial Lung Disease

Sarcoidosis

Rare crackles. Smoking protective. May have fever, constitutional symptoms. Any organ, including uveitis, cardiac, neurologic.

Upper and mid lung. Nodular opacities along septae, peribronchovascular bundles, pleura. Ground-glass opacities. Honeycombing possible. Hilar and/or mediastinal adenopathy.

Tightly formed, noncaseating granulomas.

Corticosteroid responsive, but indications for use are controversial.

Clinical pearls

HRCT: Range of findings

Histology

Treatment

Wegener’s Granulomatosis Churg-Strauss

Eliminate exposure. Corticosteroids if chronic.

Poorly formed granulomas, some giant cells. Lymphocytic infiltrate.

May be normal. Acute: noncardiac pulmonary edema, adenopathy. Upper and mid lung. Subacute: Poorly defined, centrilobular, micronodules. Ground-glass opacities, with air trapping. Chronic: mid/upper lobe, UIP pattern.

Corticosteroids and cyclophosphamide.

Corticosteroids insufficient. Consider cyclophophamide, corticosteroids, and plasma exchange.

Granulation tissue Granulomatous lesions surrounding necrotic with eosinophils, area. giant cells, and necrosis involving arteries and capillaries.

Rounded nodules up to Parenchymal several centimeters, consolidation. 50% cavitary. Varying Solitary or bilateral. ground-glass May have diffuse opacities. alveolar infiltrate.

Smoking protective. Upper and lower Allergic background or Acute: Dyspnea, cough, respiratory tracts, asthma. Peripheral fever. glomerulonephritis, eosinophilia. Chronic: Fatigue, and small-vessel weight loss, dyspnea, vasculitis. cough. >90% white. Mean age 45. Initially fevers, arthralgias, myalgias, malaise, weight loss.

Hypersensitivity Pneumonitis

Corticosteroids and cyclophosphamide.

Hemosiderin-laden macrophages. Evidence of vasculitis.

Alveolar filling. Interstitial thickening with repeat hemorrhage. Often perihilar.

Pulmonary hemorrhage and focal segmental glomerulonephritis.

Microscopic Polyangiitis

Corticosteroids, cyclophosphamide/ azathioprine, and plasmapheresis.

Hemosiderin-laden macrophages. Alveolar capillaritis. Linear deposits of immunoglobulin alveolar basement membranes.

Alveolar filling. Interstitial thickening with repeat hemorrhage. Often perihilar.

Anti-glomerulobasement membrane antibodies. Pulmonary hemorrhage and renal disease. Onset usually 17–27 years old.

Goodpasture’s Syndrome

Part VII

Feature

(Continued ) Clinical, Radiographic, and Treatment of Miscellaneous Interstitial Lung Diseases

Table 66-7 1118 Interstitial and Inflammatory Lung Diseases

Granulomatous inflammation. S100 and CD1a positive cells.

Smoking cessation. Consider Avoid pregnancy. Consider steroid trial. oophrectomy, progesterone, antiestrogens, clinical trials.

Histology

Treatment

Acute Eosinophilic Pneumonia

Often central and symmetric. Intra- and interlobular septal thickening. Ground-glass opacities. “Crazy paving.”

90+% nonsmokers. 2:1 female:male. Peak age 30–45. Peripheral eosinophilia common.

Chronic Eosinophilic Pneumonia

Dramatically corticosteroid responsive.

Infiltration by eosinophils, lymphocytes, and macrophages. May have giant cells. Intraluminal fibrosis. Granulomas may be seen. Chapter 66

Note: Abbreviations: AIP = acute interstitial pneumonia; COP = cryptogenic organizing pneumonia; CVD = collagen vascular disease; DIP = desquamative interstitial pneumonia; HIV = human immunodeficiency virus; HAART = highly active antiretroviral therapy; HTN = hypertension; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; NS = nonsmokers; NSIP = nonspecific interstitial pneumonia; PFTs = pulmonary function tests; RB-ILD = respiratory bronchiolitis–interstitial lung disease.

Corticosteroid unresponsive. Dramatically corticosteroid Lavage, GM-CSF therapy. responsive.

Diffuse alveolar damage with interstitial edema. Eosinophilic infiltration of alveoli, bronchioles, and bronchial walls.

Intralobular septal Upper zones and thickening. Poorly defined peripheral. Irregular nodules. Ground-glass airspace consolidation. opacities. Majority with Ground-glass opacities. pleural effusions. Mediastinal nodes in up to 50%. Rare effusions, usually small.

Progressive dyspnea, cough. Dyspnea, fever, myalgias, May have thick sputum. rapidly progressive Elevated shunt fraction respiratory failure. and LDH. Associated with Eosinophils in BAL but GM–CSF deficiency. not serum.

PAP

Smooth muscle nodules in PAS-positive material filling walls of cysts, vessels, alveoli, distal airways. airways. HMB45 staining.

Upper and mid lung. Diffuse, but apical sparing. Nodules, usually <5 mm. Regular shaped, May cavitate. Cysts, thin thin-walled cysts. or thick-walled, esp. Pneumothorax. Pleural upper zones, may be effusion. Renal angiomyolipomas. irregular. Some ground glass in up to 20%. Mediastinal or pretracheal adneopathy in one-third.

HRCT: Range of findings

LAM

Smokers. Women. Age 20–50. Mainly whites. Mean age 30–36 years old. Recurrent pneumothorax. Progressive obstruction. Constitutional symptoms Present with in 15%–30%. pneumothorax, hemoptysis, or chylothorax.

Langerhan’s Cell Granulomatosis

Clinical pearls

Feature

1119

Interstitial Lung Disease

1120 Part VII

Interstitial and Inflammatory Lung Diseases

Table 66-8 Diffuse Parenchymal Diseases Diagnosable by Bronchoscopy with Lavage and/or Biopsy Disease

Diagnostic Bronchoscopic Findings

Berylliosis

Granulomatous or mononuclear cell interstitial inflammation AND positive beryllium lymphocyte proliferation test (BAL for blood)

Chronic eosinophilic pneumonia

Eosinophils >50% on BAL with typical clinical history and radiographs

Diffuse alveolar hemorrhage

Increasing red cell count on sequential BALs, >20% hemosiderin-laden macrophages

Infections

Postive stains/cultures

Langerhans’ cell granulomatosis

Langerhans’ cells >3% total BAL cell count (CD1a and S100 positive)

Lymphangitic carcinomatosis

Malignant cells.

Pulmonary alveolar proteinosis

Milky BAL fluid with debris and foamy macrophages

Sarcoidosis

Noncaseating granulomas

obvious airway abnormalities (e.g., sarcoidosis, lung cancer with lymphangitic spread, Kaposi’s sarcoma in HIV infected patients), most are not. The absence of finding on BAL may also be helpful. A normal differential on a technically sound BAL largely excludes eosinophilic pneumonia and ChurgStrauss syndrome. In general, bronchoalveolar fluid analysis in patients with interstitial lung disease should include total and differential cell counts (with particular attention to eosinophilia); cytologic examination both for neoplasia and microorganisms such as Pneumocystis jiroveci (carinii); culture and stains for bacterial, fungal, and mycobacterial pathogens; and assays for viral and other “atypical” pathogens such as Mycoplasma pneumoniae. Specific clinical concerns warrant more specialized testing, such as cytologic analysis for hemosiderincontaining alveolar macrophages in cases of suspected acute or chronic alveolar hemorrhage; PAS staining of the proteinaceous debris and vacuolated alveolar macrophages from the opalescent, milky lavage fluid of pulmonary alveolar proteinosis (Fig. 66-9); cultures for unusual viral pathogens; flow-cytometric analysis of lymphocyte subsets in cases of suspected hypersensitivity pneumonitis, sarcoidosis, or lymphoid malignancy; staining for anti-CD1a for Langerhans’ cell histiocytosis; or fat staining (oil red O or Sudan III) of the lipid-laden macrophages in aspiration. In general, in cases of interstitial lung diseases, BAL is substantially more useful in ruling out particular conditions such as infection, than in determining a specific noninfectious cause. Bronchoalveolar lavage has a limited utility in assessing the prognosis of interstitial lung disease and response to treatment. One exception is that an increased percentage of BAL neutrophils appear to portend a worse prognosis in sarcoidosis, idiopathic pulmonary fibrosis, and hypersensitivity pneumonitis.

Bronchoscopy with Transbronchial Biopsy bronchoscopy with BAL in search of specific diagnostic features or a typical BAL cell pattern to strengthen the clinicalradiographic diagnosis. Any significant concern for infection necessitates a bronchoscopy, with specific consideration given to mycobacterial and fungal diseases, as well as Pneumocystis jiroveci (carinii) pneumonia. A bronchoscopy may also be pursued if the differential diagnosis includes diseases with pathognomonic findings likely to be discovered by bronchoscopy (Table 66-8). Included on this list are the infections mentioned in the preceding, alveolar hemorrhage, and pulmonary alveolar proteinosis. An eosinophil count higher than 25 percent suggests Churg-Strauss or eosinophilic pneumonia, even though diseases from idiopathic pulmonary fibrosis to asthma to allergic bronchopulmonary aspergillosis may, on rare occasion, present with such an elevated eosinophil count. Although the lack of specificity limits the diagnostic utility for diseases other than those listed in Table 66-8, cellular profiles that may be found with other interstitial lung diseases are depicted in Table 66-9. Although some interstitial lung diseases occasionally are associated with bronchoscopically

Endobronchial and transbronchial biopsies (TBB) may augment the visual inspection and BAL of bronchoscopy. In general, bronchoscopic biopsies are of limited utility in the evaluation of interstitial lung diseases. The notable exception to this generalization is sarcoidosis. In sarcoidosis, endobronchial biopsy has a sensitivity of up to 90 percent in patients in whom bronchial abnormalities are seen, and “blind” TBBs have a sensitivity of 80 percent or greater in patients in whom no bronchial abnormalities are seen. Depending on the stage, 6 to 10 TBBs are required to achieve this sensitivity. Instead, surgical biopsies are preferable in most cases of interstitial lung disease because the amount of tissue obtained is substantially larger, allowing a vastly improved visualization of the pattern and nature of the pathological abnormalities.

Surgical Lung Biopsy: Thoracoscopy-Guided and Open Lung Biopsy Combining clinical information with an HRCT that depicts ‘definite usual interstitial pneumonia’ can provide a diagnosis of idiopathic pulmonary fibrosis that is sufficiently certain

1121 Chapter 66

Interstitial Lung Disease

Table 66-9 Bronchoalveolar Lavage Cellular Profile Normal Adults (nonsmokers) Total Cell Count (106 )∗ Cell Types

Never Smokers 18 (Mean Percent)

Current Smokers 60 (Mean Percent)

Alveolar macrophages

85%

93%

Lymphocytes

12%(T4:T8 ratio 0.9–2.5)∗

Neutrophils

≤1%

Eosinophils

≤1%

Elevated T Lymphocytes

Elevated Eosinophils

Elevated Neutrophils

Sarcoidosis†

Sarcoidosis (±)

Berylliosis Hypersensitivity pneumonitis

Hypersensitivity pneumonitis (±)

Collagen vascular diseases

Systemic lupus erythematosus

Collagen vascular diseases

Idiopathic pulmonary fibrosis†

Idiopathic pulmonary fibrosis§

Idiopathic pulmonary fibrosis

Drug induced

Radiation pneumonitis

Eosinophilic pneumonias

Lymphoma/pseudolymphoma

Hodgkin’s disease

Aspiration pneumonia

Silicosis Lung rejection

Bone marrow transplant

AIDS

Infection: tuberculosis, viral

Infection: bacterial, fungal helminthic, pneumocystis

Infection: bacterial, fungal

Bronchitis

Asthma Churg-Strauss syndrome Allergic bronchopulmonary aspergillosis ∗ Individual

Asbestosis Adult respiratory distress syndrome

laboratories should have their own reference values. increased and decreased CD4:CD8 T-cell ratios have been described. The increased ratio is most common in sarcoidosis. ‡ Associated with favorable prognosis. § Associated with poor prognosis. BAL values for smokers and never smokers derived from Anonymous: Bronchoalveolar lavage constitutents in healthy individuals, idiopathic pulmonary fibrosis, and selected comparison groups. The BAL Cooperative Group Steering Committee. Am Rev Respir Dis 141:S169–202, 1990. † Both

1122 Part VII

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Table 66-10 ATS/ERS Criteria for Diagnosis of IPF in Absence of Surgical Lung Biopsy

Figure 66-9 Bronchoalveolar lavage (BAL) fluid from a patient with pulmonary alveolar proteinosis. The patient underwent 25 L of sequential lavage with concomitant chest physiotherapy. The first three and last three liters of BAL fluid are demonstrated from left to right. Note the decreasing amount of precipitant, which represents protein- and lipid-rich material, including large amounts of surfactant proteins, and some foamy macrophages.

that a tissue diagnosis is not required (Table 66-10). For most other situations, a surgical biopsy is required. Multiple well-designed studies have shown conclusively that videoassisted thoracoscopic (VATS) biopsies are equivalent in diagnostic yield to open lung biopsies, resulting in improved morbidity and mortality rates. As a result of these improvements, lung biopsies have become outpatient surgical procedures in some centers. Sampling multiple lobes increases both the diagnostic yield and the prognostic utility of surgical lung biopsies. The thoracic surgeon should avoid merely sampling regions of severe honeycombing, but instead, obtain tissue from the spectrum of disease based on gross appearance and CT findings. Concerns about the diagnostic utility of biopsies from the lingula and right middle lobe, where nonspecific fibrotic and vascular changes are often found, led initially to avoidance of biopsying these lobes. More recent data from both immunocompromised and immunocompetent patients suggests that this is no longer a concern.

Clinicopathological Correlation in the Diagnosis of Interstitial Lung Diseases A multidisciplinary collaboration is strongly encouraged prior to beginning therapy on any patient with interstitial lung disease because of the complexity and inter-relatedness of the clinical, radiographic, and pathological manifestations of illness and the lack of a truly diagnostic “gold standard.” This approach has been incorporated into the recommendations of the American Thoracic Society/European Respiratory Society in their consensus statement on idiopathic interstitial pneumonias. Such collaboration typically necessitates person-toperson, real-time interaction between a radiologist who has an interest in diseases of the chest, a consulting pulmonologist, and a pathologist who is expert in the interpretation of non-neoplastic lung pathology. Considerable motivation

Major criteria∗ Exclusion of other known causes of ILD such as certain drug toxicities, environmental exposures, and connective tissue diseases Abnormal pulmonary function studies that include evidence of restriction (reduced VC, often with an increased FEV1/FVC ratio) and impaired gas exchange [increased P(A-a)O2 , decreased PaO2 , with rest or exercise or decreased DlCO ] Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT scans Transbronchial lung biopsy or BAL showing no features to support an alternative diagnosis Minor criteria Age >50 y Insidious onset of otherwise unexplained dyspnea on exertion Duration of illness >3 mo Basilar, inspiratory crackles (dry or “Velcro”-type in quality) In the immunocompetent adult, the presence of all of the major diagnositic criteria as well as at least three of the four minor criteria increases the likelihood of a correct clinical diagnosis of IPF. ∗ Reprinted with permission from: American Thoracic Society and European Respiratory Society: American Thoracic Society/European Respiratory Society. International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. [Erratum appears in Am J Respir Crit Care Med 166:426, 2002]. Am J Respir Crit Care Med 165:277–304, 2002.

is required to develop, coordinate, and nurture such highintensity multispecialty collaboration. Nevertheless, collaborative efforts of radiologists and pathologists interacting with clinicians increase the accuracy of the diagnosis as well as patient survival. As noted in the ATS/ERS consensus statement, further revision and refinement of the “final” clinical diagnosis is to be expected as additional history or laboratory studies are obtained. Although the pathological or radiologic diagnosis may be tempting, it is the responsibility of the clinician to determine the final diagnosis and management. The clinician must be familiar with the myriad of radiographic and histopathological patterns associated with each of these diseases.

TREATMENT The optimal therapy for interstitial lung diseases is an area of intense investigation. Supportive care, providing oxygen

1123 Chapter 66

to hypoxemic patients, and pulmonary rehabilitation should be considered in all patients. Pulmonary rehabilitation is underutilized in patients with interstitial lung disease and should be considered earlier and more frequently than is done at present. Pneumococcal and influenza vaccination should not be overlooked. National and local organizations exist for many diseases that provide support and information for patients and their families. Patients require counseling concerning the removal of offending environmental agents, such as tobacco smoke in desquamative interstitial pneumonia and respiratory bronchiolitis–interstitial lung disease, specific antigens in hypersensitivity pneumonitis, and medications in drug-induced pulmonary reactions. If possible, disease modifying therapies should be withheld until diagnostic lung tissue has been obtained. Table 66-7 includes information on the steroid-responsive nature of some of the interstitial lung diseases. Since the field continues to evolve, readers are directed to other chapters in this text as well as current literature for specific treatment guidelines once a diagnosis has been made. Even the optimal dose and duration of prednisone for steroid-responsive diseases is often based on case series and clinical experience rather than controlled trials. Clinicians also should consider enrolling patients in relevant clinical trials. Care should be taken to minimize the iatrogenic effects of medical therapy. Patients should be carefully monitored for symptoms or serologic evidence of adverse drug reactions. Prophylactic measures should be taken, such as giving calcium, vitamin D, and bisphosphonate therapy to appropriate patients on prednisone, and folic acid to appropriate patients on methotrexate. Opportunistic infections such as Pneumocystis jiroveci (carinii) appear to occur less often with iatrogenic immunosuppression in patients with interstitial lung disease than in patients with hematologic or central nervous system malignancies. Nevertheless, opportunistic infections have been reported, particularly in patients with Wegener’s granulomatosis, but also in patients with a range of interstitial lung diseases. Consideration should be given to prophylaxis in patients receiving immunosuppression. The clinician should consider lung transplantation as an option once the diagnosis of an interstitial lung disease with an unfavorable prognosis has been rendered. The time required for a transplant center to evaluate a candidate combined with a shortage of available lungs and age limitations makes early consideration mandatory.

SUGGESTED READING American Thoracic Society and the European Respiratory Society: American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and

Interstitial Lung Disease

by the ERS Executive Committee, June 2001.[Erratum appears in Am J Respir Crit Care Med 166:426, 2002.] Am J Respir Crit Care Med 165:277–304, 2002. Anonymous: Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med 160:736–755, 1999. Arakawa H, Webb WR: Expiratory high-resolution CT scan. Radiol Clin North Am 36:189–209, 1998. Ayed AK, Raghunathan R: Thoracoscopy versus open lung biopsy in the diagnosis of interstitial lung disease: A randomised controlled trial. J Roy Coll Surg Edinburgh 45:159– 163, 2000. Benatar SR: Sarcoidosis in South Africa. A comparative study in Whites, Blacks and Coloureds. South Afric Med J 52: 602–606, 1977. Costabel U, Guzman J: Bronchoalveolar lavage, in Interstitial Lung Disease. Schwarz MI, King T Jr (eds), Hamilton, Ontario, BC Decker, 2003, p 114. Crouch R, MacIntyre NR: Pulmonary rehabilitation of the patient with nonobstructive lung disease. Respir Care Clin North Am 4:59–70, 1998. Drent M, Jacobs JA, de Vries J, et al: Does the cellular bronchoalveolar lavage fluid profile reflect the severity of sarcoidosis? Eur Respir J 13:1338–1344, 1999. Flaherty KR, King TE Jr, Raghu G, et al: Idiopathic interstitial pneumonia: What is the effect of a multidisciplinary approach to diagnosis? Am J Respir Crit Care Med 170:904– 910, 2004. Flaherty KR, Travis WD, Colby TV, et al: Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med 164:1722–1727, 2001. Foucher P, Camus P, Geppi T: www.pneumotox.com Hallstrand TS, Boitano LJ, Johnson WC, et al: The timed walk test as a measure of severity and survival in idiopathic pulmonary fibrosis. Eur Respir J 25:96–103, 2005. Hodgson U, Laitinen T, Tukiainen P: Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: Evidence of founder effect among multiplex families in Finland. Thorax 57:338–342, 2002. Hunninghake GW, Zimmerman MB, Schwartz DA, et al: Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 164:193– 196, 2001. Johnson S: Rare diseases. 1. Lymphangioleiomyomatosis: clinical features, management and basic mechanisms. Thorax 54:254–264, 1999. Lacasse Y, Selman M, Costabel U, et al: Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care Med 168:952–958, 2003. Latsi PI, du Bois RM, Nicholson AG, et al: Fibrotic idiopathic interstitial pneumonia: The prognostic value of longitudinal functional trends. Am J Respir Crit Care Med 168:531– 537, 2003.

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Latsi PI, Wells AU: Evaluation and management of alveolitis and interstitial lung disease in scleroderma. Curr Opin Rheumatol 15:748–755, 2003. Lok SS: Interstitial lung disease clinics for the management of idiopathic pulmonary fibrosis: A potential advantage to patients. Greater Manchester Lung Fibrosis Consortium. J Heart Lung Transplant 18:884–890, 1999. Marie I, Hachulla E, Cherin P, et al: Opportunistic infections in polymyositis and dermatomyositis. Arthritis Rheum 53:155–165, 2005. Markovitz GH, Cooper CB: Exercise and interstitial lung disease. Curr Opin Pulmon Med 4:272–280, 1998. Marshall RP, Puddicombe A, Cookson WO, et al: Adult familial cryptogenic fibrosing alveolitis in the United Kingdom. Thorax 55:143–146, 2000. Mauer JR: Non-neoplastic advanced lung disease, in Lung Biology in Health and Disease, vol 176. New York, Marcel Dekker, 2003. Medinger AE, Khouri S, Rohatgi PK: Sarcoidosis: The value of exercise testing. Chest 120:93–101, 2001. Miller KL, Kocak Z, Kahn D, et al: Preliminary report of the 6-minute walk test as a predictor of radiation-induced pulmonary toxicity. Int J Radiat Oncol Biol Phys 62:1009– 1013, 2005. Miller JD, Urschel JD, Cox G, et al: A randomized, controlled trial comparing thoracoscopy and limited thoracotomy for lung biopsy in interstitial lung disease. Ann Thorac Surg 70:1647–1650, 2000. Mogulkoc N, Brutsche MH, Bishop PW, et al: Pulmonary function in idiopathic pulmonary fibrosis and referral for lung transplantation. Am J Respir Crit Care Med 164:103– 108, 2001. Morris DG: Gold, silver, and bronze: metals, medals, and standards in hypersensitivity pneumonitis. Am J Respir Crit Care Med 168:909–910, 2003. Nasser-Sharif FJ, Balter MS: Hypersensitivity pneumonitis with normal high resolution computed tomography scans. Can Respir J 8:98–101, 2001.

Nicholson AG: Classification of idiopathic interstitial pneumonias: Making sense of the alphabet soup. Histopathology 41:381–391, 2002. O’Donnell D, Fitzpatrick M: Physiology of interstitial lung disease, in Mi S, King TE (eds), Interstitial Lung Disease. Hamilton, Ontario, BC Decker, 2003, p 54. Pagano L, Fianchi L, Mele L, et al: Pneumocystis carinii pneumonia in patients with malignant haematological diseases: 10 years’ experience of infection in GIMEMA centres. Br J Haematol 117:379–386, 2002. Patel RA, Sellami D, Gotway MB, et al: Hypersensitivity pneumonitis: Patterns on high-resolution CT. JCAT 24:965– 970, 2000. Raghu G, Johnson WC, Lockhart D, et al: Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: Results of a prospective, open-label Phase II study. Am J Respir Crit Care Med 159:1061–1069, 1999. Rena O, Casadio C, Leo F, et al: Videothoracoscopic lung biopsy in the diagnosis of interstitial lung disease. Eur J Cardiovasc Surg 16:624–627, 1999. Scholand MB: Clinical approach to interstitial lung disease. Semin Ultrasound CT MR 23:269–274, 2002. Schwarz MI, King TE: Interstitial Lung Disease. Hamilton, Ontario, BC Decker, 2003. Tobin RW, Pope CE 2nd, Pellegrini CA, et al: Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 158:1804– 1808, 1998. Ullmer E, Mayr M, Binet I, et al: Granulomatous Pneumocystis carinii pneumonia in Wegener’s granulomatosis. Eur Respir J 15(1):213–216, 2000. Ward MM, Donald F: Pneumocystis carinii pneumonia in patients with connective tissue diseases: the role of hospital experience in diagnosis and mortality. Arthritis Rheum 42:780–789, 1999. Wells A: High resolution computed tomography in sarcoidosis: A clinical perspective. Sarcoidosis Vasculitis Diffuse Lung Dis 15:140–146, 1998.

67 Systemic Sarcoidosis David R. Moller

I. HISTORICAL PERSPECTIVE

VIII. DIAGNOSTIC APPROACH

II. EPIDEMIOLOGY

IX. CLINICAL ASSESSMENT

III. ETIOLOGY

X. CLINICAL COURSE AND PROGNOSIS

IV. GENETICS

XI. TREATMENT Indications Systemic Treatment

V. PATHOLOGY VI. PATHOPHYSIOLOGY Immunopathology Th1 Immunity VII. CLINICAL FEATURES Classification Associated Conditions

Sarcoidosis is a multisystem disorder of unknown origin characterized by noncaseating granulomatous inflammation at sites of disease. Although any organ can be involved, the disease most commonly affects the lungs and intrathoracic lymph nodes. Since the cause of sarcoidosis is uncertain, a diagnosis is most securely established from compatible clinicoradiologic findings, together with histologic evidence of noncaseating epithelioid granulomas in more than one organ and the exclusion of granulomatous disorders of known cause. Clinical, epidemiologic, and family studies support the hypothesis that sarcoidosis is triggered by exposure to microbial agents in individuals with a genetic susceptibility to the disease. The clinical course is highly variable, with a mortality rate of 1 to 5 percent. Corticosteroids remain the mainstay of treatment for patients with threatened organ failure or progressive disease.

HISTORICAL PERSPECTIVE Jonathan Hutchinson was the first to describe a case of sarcoidosis in 1887; he called it Mortimer’s malady, after one

of his patients who presented with face and limb skin lesions. In 1889, Besnier of Paris described a 34-year-old man with violaceous skin lesions of the nose, ear lobules, and central face; he proposed that the lesions were a variant of lupus erythematosus leading to its designation as “lupus pernio.” In 1899, Caesar Boeck first described the characteristic noncaseating granulomas in a patient with peripheral lymphadenopathy and skin nodules. He proposed the term multiple benign sarcoids of the skin because he thought the granulomatous changes resembled sarcomatous tissue. Subsequently, descriptions of sarcoid-type lesions in the eyes, bones, lungs, and salivary glands were made, but the systemic and unifying nature of sarcoidosis was not recognized for almost 20 years. The view that sarcoidosis is a systemic disorder is largely based on the work of Jorgen Schaumann, a Swedish dermatologist, who in 1914 presented the view that Besnier’s lupus pernio and Boeck’s multiple sarcoids were manifestations of the same disease termed “lymphogranulomatose benigne,” thought to represent a variant of tuberculosis. In 1935, Williams and Nickerson reported that intradermal inoculation of a suspension of sarcoidosis tissue resulted in firm papules in patients with suspected sarcoidosis. Ansgar

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Kveim, a dermatologist in Oslo, demonstrated in 1941 that these papules contained sarcoidlike granulomas on biopsy. Louis Siltzbach and others would demonstrate in worldwide studies that this “Kveim” reaction was positive (showed granulomas) in up to 80 percent of sarcoidosis and was highly specific for the disease. The next major breakthrough in understanding sarcoidosis was based on the pioneering observations of Sven L¨ofgren of Sweden in the 1940s and 1950s, who noted that sarcoidosis frequently begins with asymptomatic bilateral hilar adenopathy or with acute erythema nodosum. In the 1950s, corticosteroids were reported to be successful in treating sarcoidosis. The development of bronchoalveolar lavage (BAL) as a research tool in the 1970s allowed the study of local cellular mechanisms in pulmonary sarcoidosis and led to the paradigm shift that sarcoidosis is associated with compartmentalized, enhanced T-cell immunity at sites of inflammation. More recently, the tools of cell and molecular biology have advanced our understanding of the immunologic, genetic, and etiologic basis of sarcoidosis, but have not yet led to breakthroughs in the development of safe, effective therapies.

EPIDEMIOLOGY Sarcoidosis is found worldwide, although the frequency of the disease varies among different geographic regions. Estimates of disease prevalence are not known with certainty because many people with sarcoidosis are asymptomatic, and there is no sensitive nor specific diagnostic test. Prevalence rates of between 10 and 40 cases per 100,000 population are reported in North America, southern Europe, and Japan. Higher prevalence rates are noted in Sweden, Denmark, and US blacks. The lifetime risk for developing sarcoidosis has been estimated as 1.4 and 1.0 percent in women and men of Scandinavian countries, respectively, whereas one US study calculated a lifetime risk of 2.4 percent for blacks and 0.85 percent for whites living in a midwestern city. Worldwide, the disease is reported to be slightly more frequent in women. More than 80 percent of cases occur in persons between 20 and 40 years of age, with a second peak in women more than 50 years of age. Sarcoidosis is rare in the preadolescent period. The frequency of different clinical manifestations of sarcoidosis also varies among geographic regions and ethnic groups. Erythema nodosum is common in Scandinavian countries and Ireland, but found in less than 5 percent of black or Japanese patients. In contrast, lupus pernio appears more frequently among black populations. In Japan, over 50 percent of patients may have cardiac sarcoidosis. Several studies suggest that race is an important determinant of disease severity with black populations more likely to have persistent disease and greater mortality than white populations. In the United States, 40 to 80 percent of mortality from sarcoidosis is from advanced pulmonary disease. In Sweden and Japan, cardiac involvement is the leading cause of death from sarcoidosis. Overall, mortality rates directly related to

sarcoidosis approximate 1 to 5 percent according to hospital statistics.

ETIOLOGY The cause of sarcoidosis remains uncertain. Since sarcoidosis was first described, investigators as early as Boeck in 1905 have postulated an infectious cause of the disease based on the clinical similarities to tuberculosis. Environmental exposures are linked to sarcoidosis due to seasonal clustering of the disease with a predilection for winter and early spring months in both northern and southern hemispheres. Geographic variation and time–space clustering also support a role for environmental triggers in sarcoidosis. Occupational associations have been described for health care professionals, firefighters, military personnel, and workers involved in the lumber industry. Chronic beryllium disease causes a granulomatous pneumonitis histologically identical to pulmonary sarcoidosis in less than 5 percent of exposed workers following immunologic sensitization to beryllium. However, there is no evidence that beryllium is a cause of systemic sarcoidosis. A recent US-based multicenter study of sarcoidosis etiology called ACCESS (A Case Control Etiologic Study of Sarcoidosis) compared 706 newly diagnosed, biopsy-proven sarcoidosis cases to age-, sex-, and race-matched controls. Results from the study showed an absence of environmental or occupational associations positively linked to sarcoidosis risk that carried an odds ratio (OR) greater than 2.0 and an exposure prevalence of greater than 5 percent (prestudy goal). Weak positive associations (OR approximately 1.5) were found for insecticide use at work, mold/mildew exposures at work, and musty odors, suggesting possible links to microbial-rich environments. Sarcoidosis was not associated with exposure to heavy metals including beryllium, wood dusts, or rural residence as previously hypothesized. The ACCESS study found a robust negative association of smoking and sarcoidosis risk, confirming earlier studies. The lack of a single, dominant exposure associated with sarcoidosis risk is consistent with the concept that gene-environmental interactions are important in causing disease. Many studies over decades have directly examined a role for infectious agents in sarcoidosis. Investigators in the 1960s reported the presence of a transmissible agent in sarcoidosis tissue, but these studies could not be reproduced, and despite many attempts, no mycobacterial or other infectious organisms have been reproducibly cultured from sarcoidosis tissue. More recently, US, European, and Japanese investigators report the presence of mycobacterial DNA in 0 to 80 percent of biopsy specimens, but also in 0 to 30 percent of control tissues using highly sensitive polymerase chain reaction techniques. Japanese investigators find Propionibacterium acnes DNA in 80 to 98 percent of sarcoidosis tissues from Japan and Europe but also in 0 to 60 percent of control tissues. Other microbial agents, such as Borrelia burgdorferi, Chlamydia pneumonia, or Rickettsia helvetica have been implicated in sarcoidosis from

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tissue or serologic studies, but these latter studies all lack wider confirmation. High titers of antibodies against lymphotropic DNA viruses (Epstein-Barr virus, cytomegalovirus, and human herpesvirus type 6) and HTLV1 have been described in patients with sarcoidosis but may reflect generalized B-cell activation in sarcoidosis, since a viral origin has not been substantiated by viral cultures or tissue analysis. Despite a lack of consistent results, reports of systemic sarcoidosis developing in na¨ıve transplant recipients receiving organs from known or suspected sarcoidosis patients support a transmissible agent as a cause of sarcoidosis. Some investigators hypothesize an etiologic association with autoimmunity, perhaps triggered by an infectious agent through molecular mimicry. In support of this concept, sarcoidosis is associated with features of autoimmunity, such as antinuclear antibodies, rheumatoid factor, hypergammaglobulinemia, and immune complexes. Recently the author and his colleagues used a limited proteomic approach to identify potential pathogenic antigens in sarcoidosis tissues based solely on the biochemical properties of the Kveim reagent and not on a priori hypotheses regarding specific infectious or autoimmune causes. This approach detected the mycobacterial catalase-peroxidase protein (mKatG) in over 50 percent of sarcoidosis tissues. IgG responses to mKatG were detected in approximately 50 percent of sarcoidosis patients, supporting the premise that mKatG is a pathogenic antigen and that mycobacterial organisms trigger a subset of sarcoidosis. Although direct demonstration of an infectious etiology remains unproven, many investigators favor the hypothesis that certain classes of microbial organisms trigger sarcoidosis in those with genetic susceptibility.

GENETICS Family and case control association studies provide strong evidence for a genetic influence on the risk of developing sarcoidosis and in determining clinical expression of the disease. Familial clustering of sarcoidosis occurs in 3 to 14 percent of patients, with a greater frequency among black compared with white populations. The US ACCESS study found siblings of sarcoidosis cases have a higher relative risk (OR approximately 5.8) than parents (OR approximately 3.8). The significantly higher adjusted familial relative risk (RR) estimates reported for whites in both the US ACCESS study (RR approximately 18) and in a UK study with mostly whites (RR approximately 36 to 73) and blacks (RR approximately 2.8), suggest that genetic factors have a greater influence in susceptibility to sarcoidosis in whites than blacks. Early studies examined the role of HLA class I alleles using serologic techniques. The HLA-B8 allele has most consistently been associated with disease susceptibility, increasing sarcoidosis risk in whites from the United States and Europe but not in blacks or Japanese. A recent Scandinavian study found HLA-B∗ 07 and B∗ 08 increased risk of sarcoidosis independent of class II alleles.

Systemic Sarcoidosis

The role of HLA class II alleles has been intensively studied in sarcoidosis. HLA-DR3 has been associated with sarcoidosis susceptibility, while HLA-DR1 and -DR4 alleles have been associated with disease protection in Scandinavian and European populations. Using molecular genotyping, the ACCESS study found a significant association between HLA-DRB1∗ 1101 in both blacks and whites, while HLA-DRB1∗ 1501 was associated with sarcoidosis risk only in whites. Other studies find the class II HLA-DR17 (DR3) haplotype and specifically HLA DRB1∗ 0301 or the closely linked DQB1∗ 0201 alleles to be associated with favorable outcomes (L¨ofgren syndrome, acute arthritis, stage I chest radiograph, or remission within 2 years) in European and Japanese populations. The DRB1∗ 1501 or the closely linked DQB1∗ 0602 alleles were associated with more severe or chronic disease in a Danish cohort. HLA-DPB1 and DQB1 alleles have been associated with disease susceptibility in some studies, although linkage disequilibrium makes it difficult to separate from effects of HLA-DR alleles. These data support a consensus view that MHC class II alleles are the major contributor to disease susceptibility across different ethnic populations in sarcoidosis. Non-HLA genes have also been the subject of multiple case control studies (Table 67-1). The tumor necrosis factor (TNF) gene located inside the MHC locus is associated with sarcoidosis outcome in some studies. Two studies report associations with sarcoidosis and the CC chemokine receptors (CR), CCR2 and CCR5. Only one of several studies report the angiotensin converting enzyme, complement receptor 1 or macrophage inhibitory factor to be associated with sarcoidosis risk. Family linkage studies employing genomewide microsatellite analysis confirm the importance of genes from the MHC locus in determining susceptibility to sarcoidosis. A German study found strongest linkage to the MHC class II locus on chromosome 6p with minor linkage peaks on chromosomes 1, 3, 9, and X. A US-based study of blacks called SAGA (Sarcoidosis Genetic Analysis Consortium) found the highest linkage peak on chromosome 5q and minor peaks on chromosome 1, 2, 9, 11, and 20. No significant linkage to the MHC region on chromosome 6 was found, possibly due in part to the influence of white gene admixture among blacks in the United States. More recently, using fine mapping of the MHC locus in both families and case control samples, German and US investigators report that the butyrophilin-like 2 (BTNL2) gene is associated with sarcoidosis risk in white and to a lesser extent, black populations. Since BTNL2 is a member of the B7 receptor family that functions in T-cell costimulation, a plausible hypothesis links the BTNL2 gene with T-cell immunity and sarcoidosis susceptibility.

PATHOLOGY The pathological hallmark of sarcoidosis is the presence of discrete, noncaseating, epithelioid cell granulomas (Fig. 67-1).

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Table 67-1 Major Clinical Manifestations of Sarcoidosis Organ System (Percent Clinical Disease)

Major Clinical Features

Pulmonary (>90%)

Restrictive and/or obstructive disease, fibrocystic disease, bronchiectasis

Upper respiratory tract and oral cavity (5–10%)

Hoarseness, laryngeal or tracheal obstruction, nasal congestion, sinusitis

Ocular (20–30%)

Anterior and posterior uveitis, chorioretinitis, conjunctivitis, optic neuritis

Skin (20–30%)

Erythema nodosum, chronic nodules and plaques, lupus pernio, alopecia

Hepatic/Abdominal (10–20%)

Hepatosplenomegaly, jaundice, cirrhosis, abdominal/retroperitoneal lymphadenopathy

Cardiac (5–10%)

Arrhythmias, heart block, cardiomyopathy, sudden death

Neurologic (5–10%)

Facial and other cranial neuropathies (e.g., Bell’s palsy) aseptic meningitis brain mass, seizures, obstructing hydrocephalus, hypothalamic hypopituitarism, myelopathy, polyneuropathy

Exocrine gland (10–20%)

Salivary, lacrimal, and parotid gland enlargement, sicca syndrome

Hematologic (20–30%)

Peripheral or retroperitoneal lymphadenopathy, splenomegaly, hypersplenism, anemia, lymphopenia

Joints and musculoskeletal (10–20%) Endocrine (10–30%)

Polyarthritis, Achilles tendinitis, heel pain, polydactylitis, bone cysts, myopathy Hypercalciuria, hypercalcemia, hypopituitarism, diabetes insipidus

Renal (<5%)

Renal calculi, nephrocalcinosis, renal failure

Genitourinary (<5%)

Ovarian or uterine mass, dysmenorrhea, testicular mass, epididymitis

Psychosocial manifestations (30–60%)

Depression

The dominant cell in the central core is the epithelioid cell, thought to be a differentiated form of a mononuclear phagocyte. CD4 lymphocytes and mature macrophages are typically interspersed throughout the epithelioid core, whereas both CD4+ and CD8+ lymphocytes may be seen in the periphery of the granuloma. Occasionally, focal fibrinoid but not caseating necrosis may be seen. Giant cells, often containing cytoplasmic inclusions such as calcium and iron-laden Schaumann bodies, are scattered throughout the inflammatory locus. These features are not specific for sarcoidosis, as similar histopathologic findings can be seen in infections, berylliosis, Crohn’s disease, and local “sarcoid reactions” that occur near neoplastic, foreign body, or chronic inflammatory areas. In the lung, granulomas tend to form along perivascular, peribronchial, and septal regions, areas rich in lymphatic

vessels. In the lung, a mononuclear cell infiltration composed predominantly of lymphocytes is often present in the adjacent interstitium. Granulomas in sarcoidosis may resolve or undergo fibrosis, leaving a stellate scar or hyalinized ghost of a former granuloma.

PATHOPHYSIOLOGY Immunopathology Experimental models indicate that the first step in granuloma formation involves the tissue deposition of poorly soluble antigenic material. This material is phagocytosed by antigen presenting cells such as macrophages or dendritic

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Systemic Sarcoidosis

Figure 67-1 Photomicrographs of noncaseating granulomatous inflammation in sarcoidosis. A. Thoracoscopic lung biopsy showing extensive parenchymal involvement with granulomas, multinucleated giant cells, and mononuclear cell inflammation (×80). B . Extensive granulomatous inflammation of the myocardium in a fatal case of cardiac sarcoidosis (×100).

cells that degrade proteins and display peptide:class II MHC complexes on the cell surface for analysis by CD4+ T cells. Immune-mediated granulomatous inflammation can be driven by either Th1 cytokines (IFNγ) or Th2 cytokines (IL4, IL5, IL13) depending on the nature of the inciting agent in association with the release of critical cytokines such as TNF and chemokines. Granulomatous inflammation is down-regulated with clearance of antigen; persistent stimulation from a lack of clearance of antigens is associated with chronic inflammation and fibrosis. The immunopathology of sarcoidosis can be modeled in this experimental context (Fig. 67-2). Sites of granulomatous inflammation such as the lung contain activated T cells and mononuclear phagocytes that express the same proinflammatory cytokines and chemokines that have been shown experimentally to be critical in granuloma formation. Lung T cells are predominantly of the CD4 T helper, CD45R0 “memory” phenotype, express the activation markers, VLA-1 (very late activation antigen-1, CD49a) and HLA-DR molecules. Sarcoidosis alveolar macrophages (AMs) spontaneously pro-

duce TNF, interleukin-6 (IL-6), IL1α, IL15, osteopontin and the Th1 regulatory cytokines, IL-12 and IL18 as well as increased amounts of lysozyme, angiotensin-converting enzyme (ACE), and reactive oxygen species. Sarcoidosis AMs express increased density of the costimulatory molecules, CD80, CD86, and CD40, consistent with their enhanced antigen presenting capability. Sarcoidosis AMs also release increased amounts of transforming growth factor-β (TGF-β), fibronectin, insulinlike growth factor-1 (IGF-1), and laminin that are important in fibroblast recruitment and replication. TNF is considered to be a major effector cytokine of granuloma formation in sarcoidosis (and therapeutic target) as enhanced release of TNF by BAL cells, is associated with persistent disease. Studies of T-cell receptor (TCR) gene expression provide direct evidence that sarcoidosis is an antigen-driven disorder. Oligoclonal expansions of T cells expressing specific Vβ- or Vα-specific TCR gene segments have been found in the lung (BAL T cells), skin (Kveim biopsy sites), and blood. The best studied example involves the remarkable expansion

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Figure 67-2 Hypothetical model of the pathogenesis of sarcoidosis. Mycobacterial proteins such as mKatG from an occult mycobacterial infection induce antigen-driven granulomatous inflammation orchestrated by Th1 cytokines, IFN , and IL-2. Macrophages and dendritic cells (antigen presenting cells, APC), activated directly by the microbial derived components, produce the Th1-promoting cytokines IL12 and IL18. Both APCs and T cells produce enhanced amounts of TNF and other cytokines and chemokines that orchestrate the complex process of granuloma formation surrounding poorly soluble aggregates of microbial and host proteins. Removal of the inciting antigens in association with the immunosuppressive effects of TGF! results in granuloma regression and disease remission. Failure to remove the microbial antigens or possibly the induction of autoimmunity, results in persistent inflammation, tissue injury, and resultant fibrosis mediated in part by the profibrotic effects of TGF!.

of VÎą2.3 (AV2S3)+ BAL T cells from HLA-DR17(3) Scandinavian patients with sarcoidosis. Together, these studies provide evidence that oligoclonal T-cell expansions in sarcoidosis are driven by conventional antigens. The specific antigens driving these clonally expanded T cell populations remain unknown.

sis is uncertain. Older studies indicate that acute sarcoidosis is associated with circulating immune complexes in almost 100 percent of patients. Whether immune complexes and humoral immunity play a role in disease remission remains speculative.

Th1 Immunity There are compelling data that sarcoidosis is characterized by dominant Th1 cytokine production at sites of inflammation. Multiple studies confirm that pulmonary sarcoidosis is associated with enhanced expression of Th1 associated IFNÎł, IL12, and IL18 in the lung but low or undetectable levels of IL4 or IL5. Characteristic of a Th1 response, most sarcoidosis BAL T cells express a functional, high affinity IL12 receptor and the chemokine receptors CXCR3 and CCR5. This dominant Th1 polarization is characteristic of sarcoidosis at time of diagnosis and in some patients after years of known disease. There are no data on cytokine profiles in fibrotic sarcoidosis to know whether this Th1 polarization persists or whether there is a later evolution to a more profibrotic Th2 profile in chronic, fibrotic disease, a possibility supported by findings of increased IL13 expression in some patients with sarcoidosis. The role of humoral immunity in sarcoidosis pathogene-

CLINICAL FEATURES Classification The clinical manifestations and course of sarcoidosis vary greatly (see Table 67-1). Although any organ of the body can be affected, the lungs or intrathoracic lymph nodes are involved in more than 90 percent of patients with sarcoidosis. Patients may manifest with no symptoms or develop acute, subacute, or indolent manifestations. Systemic constitutional symptoms such as fever, fatigue, malaise, and weight loss are seen in over 20 percent of patients and may be disabling. One classification scheme with prognostic information categorizes patients based on their initial manifestations as follows: asymptomatic, acute sarcoidosis with or without erythema nodosum, intermediate sarcoidosis with symptoms or signs of pulmonary disease for less than

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Systemic Sarcoidosis

Table 67-2 Rare Manifestations of Sarcoidosis Based on Organ Systems Organ System

Rare Clinical Features

Pulmonary

Pulmonary vasculitis Mycetomas Cavitating nodules Lobar atelectasis Tracheal, bronchial stenosis Superior vena cavae syndrome Pleural disease Pneumothorax Saddle nose deformity Respiratory failure from upper airway obstruction Sleep apnea Tonsillar sarcoidosis Pharyngeal sarcoidosis Periodontal disease Tongue mass Subcutaneous sarcoidosis Ichthyosis Alopecia Scar granulomas Optic neuritis Retinal vasculitis Granulomatous orbital inflammation Massive hepatomegaly Jaundice with pruritus Cirrhosis with portal hypertension Massive splenomegaly Pancreatic mass Gastric involvement Small or large intestine involvement Appendicitis Optic chiasmal involvement Aseptic meningitis Cerebritis (white matter involvement) Cerebral vascular occlusion Encephalitis Hypothalamic/pituitary involvement

Upper airway

Oropharynx

Skin

Ocular

Hepatic

Gastrointestinal

Nervous system

Corpus callosum involvement Hydrocephalus Horner’s syndrome, Argyll Robertson or Adie’s pupil Cerebellar involvement Pseudotumor cerebrei Brain stem involvement Transverse myelitis, intraspinal mass Cauda equina or spinal root involvement Mononeuritis multiplex Peripheral neuropathies Small fiber neuropathy (common?) Cardiac/vascular Valvular disease Pericardial disease Ventricular or atrial mass Sudden death (not rare?) Joints/ Polymyositis musculoskeletal Bone cysts—Long bones, skull, vertebrae Hematologic Hypogammaglobulinemia Lymphedema Idiopathic thrombocytopenic purpura (ITP) Endocrine/ Heerfordt’s syndrome exocrine gland Hypopituitarism, diabetes insipidus Thyroid mass, thyroiditis Parotid mass Lacrimal gland, dacryoadenitis Sicca syndrome Renal/ Renal failure genitourinary Uterine mass Ovarian involvement Menometrorrhagia Testicular mass Epididymitis Intermittent azoospermia

Source: Adapted with permission from Moller DR: Rare manifestations of sarcoidosis, in Drent M, Costabel U (eds), Sarcoidosis. Eur Respir Monog 32: 233–250, 2005.

2 years, chronic pulmonary sarcoidosis of more than 2 years, and dominant extrapulmonary sarcoidosis. Two years represent an arbitrary but useful reference point for distinguishing patients who usually, but not always, have long-term disease. Rare manifestations of sarcoidosis include unusual patterns of organ involvement, the result of granulomatous inflammation developing in unusual locations for sarcoidosis, or when sarcoidosis is associated with a second disorder

(Table 67-2). In general, rarer manifestations reflect the known pathophysiology and clinical behavior of more common organ involvement.

Asymptomatic Sarcoidosis Up to two-thirds of patients are asymptomatic but have sarcoidosis diagnosed after an incidental radiographic finding of bilateral hilar adenopathy. Occasionally, interstitial

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infiltrates are seen in association with intrathoracic adenopathy in asymptomatic patients, most commonly in whites. Acute Sarcoidosis with or without Erythema Nodosum Sarcoidosis may manifest with the acute onset of erythema nodosum associated with bilateral hilar adenopathy, fevers, polyarthritis, and often uveitis, known as L¨ofgren syndrome. Erythema nodosum is characterized by tender reddish nodules several centimeters in diameter, usually located on the lower extremities; histologic examination shows panniculitis, not granulomas. The polyarthritis is often severe and incapacitating, typically involving the ankles, feet, knees, and occasionally, wrists, and elbows. Approximately 10 percent of patients with this syndrome have a normal chest radiograph. L¨ofgren syndrome is more common in European and white populations, but found in less than 5 percent of blacks with sarcoidosis. Some patients manifest acute arthritis, bilateral hilar lymphadenopathy, and constitutional symptoms without erythema nodosum. In either case, the prognosis is excellent for remission in 70 to 80 percent of patients. Resolution of symptoms usually occurs within weeks to several months.

Pulmonary Sarcoidosis Respiratory symptoms occur in 40 to 60 percent of patients. The most common symptoms are cough and shortness of breath, usually of a progressive, insidious nature. The cough is usually nonproductive and may be severe. Dyspnea is typically worse with exertion. Sputum production and hemoptysis are frequent in patients with fibrocystic sarcoidosis that is often associated with bronchiectasis. Ill-defined chest pain is a frequent complaint, possibly caused by nerve irritation from inflammation, scarring, or lymph node enlargement in the chest. Chest tightness and wheezing are common with endobronchial disease or fibrocystic changes. These symptoms are usually poorly responsive to bronchodilators, except in those with reversible airway hyperreactivity. Segmental atelectasis and bronchial or tracheal stenosis are rare. Physical findings are infrequent, with lung crackles heard in less than 20 percent of patients; clubbing is rare. Chest Imaging

The chest radiograph is abnormal in more than 90 percent of known cases and carries prognostic information. By international convention, the chest radiograph is divided into stages or types. A normal chest radiograph, or stage 0, is found in 5 to 10 percent of patients with sarcoidosis, often those with extrapulmonary manifestations. A stage I chest radiograph is characterized by hilar adenopathy without evidence of interstitial infiltrates and is found in approximately 40 percent of patients. Often, hilar adenopathy has a discrete, symmetric “potato node” appearance, and is accompanied by right paratracheal adenopathy. A stage II chest radiograph is characterized by bilateral hilar adenopathy and pulmonary infiltrates and is seen initially in 30 to 50 percent of patients (Fig. 67-3 A). Commonly, the infiltrates demonstrate fine linear markings

Figure 67-3 Chest radiographs of pulmonary sarcoidosis. A. Stage II sarcoidosis pattern with prominent, discrete ‘‘standaway” hilar nodes, right paratracheal adenopathy, and fine reticulonodular infiltrates. B . Fibrocystic sarcoidosis with extensive scarring, bullous and cystic changes, hilar retraction, and parenchymal infiltrates.

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and small reticulonodules, particularly in mid- and upper lung zones. Occasionally, the infiltrates consist of discrete nodules or areas of fluffy “alveolar” consolidation that can mimic eosinophilic pneumonia, tumor, Wegener’s granulomatosis, or infection. A miliary pattern can also be seen in sarcoidosis that resembles miliary tuberculosis, hypersensitivity pneumonitis, chronic beryllium disease, or lymphangitic carcinomatosis. Calcification of hilar lymph nodes is uncommon, but can occur with long-standing disease. When interstitial infiltrates are seen without evidence of hilar adenopathy, the chest radiograph is designated as stage III and is seen in approximately 15 percent of patients. Patients with extensive fibrocystic changes and scarring on chest radiograph are often grouped separately (stage IV) because of their poor prognosis. Characteristic features include cephalad hilar retraction, volume loss, coarse fibrous strands, small and large bullae, cystic changes, and honeycombing (Fig. 67-3B). Unusual radiographic signs of sarcoidosis include pneumothorax, mycetoma, isolated nodule or mass, lobar atelectasis, or pleural effusions. Chest computed tomography (CT) demonstrates that infiltrates tend to be central, following bronchovascular structures, but may also reveal ground-glass infiltrates or honeycombing. CT of the chest is often useful in the evaluation of patients with suspected sarcoidosis and to help plan bronchoscopic biopsy of enlarged lymph nodes, define unusual radiographic features, fibrocystic disease or bronchiectasis. Pulmonary Function Tests

Pulmonary function may be normal even when the chest radiograph demonstrates pulmonary infiltrates. However, restrictive impairment with reduction in lung volumes, forced vital capacity (FVC) and forced expiratory volume in 1 sec (FEV1 ), is common, particularly when pulmonary infiltrates are present on chest radiograph. Reduction in diffusing capacity can be seen in association with restrictive impairment or as an isolated deficit. Obstructive impairment is as common as restrictive impairment, particularly in advanced fibrocystic disease or endobronchial disease. A subgroup of patients have bronchial hyperresponsiveness and airway obstruction that may respond to bronchodilators. Resting hypoxemia and exercise O2 desaturation are typical when there is severe obstructive or restrictive impairment. CO2 retention is unusual except in advanced pulmonary disease. Pulmonary Hypertension

Findings of pulmonary hypertension or cor pulmonale are seen in 1 to 4 percent of patients, usually from advanced fibrotic lung disease. Rarely, a granulomatous pulmonary vasculitis is seen that is not explained by the degree of interstitial lung disease.

Systemic Sarcoidosis

variant of pulmonary sarcoidosis. Patients may be asymptomatic or have cough, dyspnea, fever, chest pain, or constitutional symptoms. Chest radiographs typically demonstrate multiple, usually noncavitating, nodules. Pleural disease with pleurisy or pleural effusions occurs in the majority of patients and may be a clue to the diagnosis. Most patients have spontaneous improvement or a rapid response to corticosteroid therapy. Extrapulmonary Sarcoidosis Many patients have manifestations of granulomatous inflammation in one or more organ systems either in addition to pulmonary involvement or without evidence of pulmonary disease (see Table 67-1). More common manifestations are discussed below. Sarcoidosis of the Upper Respiratory Tract and Oral Cavity

Sarcoidosis of the upper respiratory tract (SURT) occurs in 5 to 10 percent of patients, usually involving the nasal sinuses or laryngeal structures. Symptoms of nasal congestion, sinusitis, and intermittent epistaxis are often chronic, unresponsive to decongestants or inhaled steroids. Chronic disease or surgical intervention may result in destruction of the nasal septum and a “saddle nose” deformity. Laryngeal sarcoidosis may manifest with severe hoarseness, stridor, or acute respiratory failure secondary to upper airway obstruction. Frequently, laryngeal sarcoidosis is associated with chronic skin lesions, lupus pernio, or sinus disease. Oral and pharyngeal sarcoidosis is rare, but may manifest with macroglossia, tongue mass, or palatal mass with cartilaginous or bone destruction. Ocular Sarcoidosis

Ocular involvement is detected in approximately 20 to 30 percent of patients, more frequently in black populations. Uveitis is the most common manifestation and is often associated with bilateral hilar adenopathy. The uveitis is more commonly anterior, and may be unilateral or bilateral, with either granulomatous or nongranulomatous features. Granulomatous conjunctivitis is less common. Optic neuritis, or severe chorioretinitis, may present dramatically with blindness. Cutaneous Sarcoidosis

Chronic skin sarcoidosis is seen in approximately 25 percent of patients, usually manifesting as plaques or subcutaneous nodules and is more common and severe in blacks. Typically, the plaques are located around the hairline, eyelids, ears, nose, and extensor surfaces of the arms and legs. Lupus pernio is a disfiguring form of cutaneous sarcoidosis of the face, with violaceous plaques and nodules covering the nose, nasal alae, malar areas, and areas around the eyes. Hepatic Sarcoidosis

Necrotizing Sarcoid Granulomatosis

This disorder is characterized by large, confluent, noncaseating granulomas involving both pulmonary arteries and veins but without systemic vasculitis, and is often considered a

Liver biopsies show granulomatous inflammation in over 50 percent of patients, but clinical manifestations are much less frequent. Active hepatic inflammation may be associated with fever, tender hepatomegaly, or pruritus that may mimic

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primary biliary cirrhosis except that antimitochondrial antibodies are absent. Characteristically, the serum alkaline phosphatase and γ-glutamyltransferase are elevated proportionately higher than the transaminases or bilirubin, although all patterns can be seen. Elevated serum liver function frequently reverts to normal spontaneously or after treatment with corticosteroids. Progressive cirrhosis occurs in a subset of patients if not treated. Gastrointestinal Sarcoidosis

Sarcoidosis involvement of the gastrointestinal tract is rare. Occasionally, direct esophageal involvement may cause dysphagia, but more commonly this symptom may be caused by extensive mediastinal lymphadenopathy that impinges esophageal motility. Gastric sarcoidosis may manifest as dyspepsia, abdominal pain, or gastric nodule. Although autopsy studies show scattered granulomas in the gut, clinically symptomatic intestinal sarcoidosis is rare. Abdominal Sarcoidosis

A variant of sarcoidosis, often called abdominal sarcoidosis, manifests with liver, spleen, and often bone marrow involvement with hypercalcemia or abdominal lymphadenopathy. Constitutional symptoms are frequent with fevers and fatigue. This “triad” pattern may be seen with or without pulmonary involvement; in the latter instance, intra-abdominal malignancy must be excluded. Cardiac Sarcoidosis

Although myocardial sarcoidosis is clinically apparent in less than 5 to 10 percent of cases in the United States, autopsy studies suggest the prevalence may be greater than 20 percent in the United States and greater than 50 percent in Japan. Arrhythmias, heart block, or sudden death may be the initial manifestation due to involvement of the conduction system. Myocardial inflammation can lead to dilated cardiomyopathy and congestive heart failure, local akinesia, or aneurysms. Myocardial mass, valvular dysfunction from papillary muscle dysfunction, pericarditis, and myocardial ischemia are rarer manifestations. Neurosarcoidosis

Neurologic manifestations occur in approximately 5 to 10 percent of patients with sarcoidosis. The most common manifestation are cranial neuropathies with bilateral or unilateral seventh nerve (Bell’s) palsy most common. Often the palsies resolve spontaneously or with corticosteroids, but may recur years later. Optic neuritis may result in sudden blindness. Spinal cord involvement is rare but can cause paraparesis, hemiparesis, back and leg pains either from a transverse myelitis, or tumorlike granulomatous involvement. Peripheral neuropathies account for about 15 percent of cases of neurosarcoidosis, typically presenting as mononeuritis multiplex or a predominant sensory deficit. Small fiber neuropathy is found in many patients with diffuse musculoskeletal pain and fatigue.

Hematologic Sarcoidosis

Persistent, bulky, painful, or disfiguring adenopathy is seen in less than 5 percent of patients, most commonly involving the cervical, supraclavicular, axillary, or epitrochlear lymph nodes. Splenomegaly occurs in less than 10 percent of patients, and may be massive and associated with hypersplenism. Peripheral blood lymphopenia is common in sarcoidosis; probably more often as a result of altered trafficking of lymphocytes than splenic trapping. Granulomas in the bone marrow are found in about 20 percent of patients who come to autopsy but usually do not cause symptoms. A known feature of sarcoidosis is the impaired cutaneous response to common antigens that elicit delayed-type hypersensitivity reactions, seen in 30 to 70 percent of patients. The mechanism is unknown. Joint and Musculoskeletal Sarcoidosis

Arthralgias are a frequent complaint in sarcoidosis. A shortlived polyarthritis is typical of acute sarcoidosis, usually associated with erythema nodosum. Chronic joint disease is found in less than 5 percent of patients. Joint cartilaginous erosion is rare, but “punched out” bony lesions with cystic changes and loss of bony trabeculae may be seen in subchondral locations. Cystic lesions of the long bones, pelvis, sternum, skull, and vertebrae are uncommon. Symptomatic myopathy with weakness and tenderness is uncommon. Rarely, a polymyositis with profound weakness associated with marked elevation of serum creatine phosphokinase and aldolase occurs in sarcoidosis. Exocrine Gland Sarcoidosis

Granulomatous inflammation of salivary, parotid, and lacrimal glands results in enlarged, tender glands, and/or sicca syndrome with dry mouth and dry eyes in less than 5 percent of patients with sarcoidosis. The association of fever, parotid enlargement, facial palsy, and uveitis is known as uveoparotid fever, or Heerfordt syndrome, and is usually accompanied by bilateral hilar adenopathy. Endocrine Sarcoidosis

Abnormal calcium metabolism is found in sarcoidosis; hypercalciuria is more frequent than hypercalcemia. Evidence supports the concept that these abnormalities are due primarily to increased conversion of vitamin D metabolites to active 1,25(OH)2 vitamin D by tissue macrophages and epithelioid cells at sites of granulomatous inflammation. Hypothalamic/pituitary insufficiency may be a manifestation of neurosarcoidosis. Renal Sarcoidosis

Kidney stones are the most frequent manifestation of renal sarcoidosis, usually related to abnormal calcium metabolism. Renal failure due to nephrocalcinosis may result from chronic, often asymptomatic hypercalcemia or hypercalciuria. Granulomatous involvement of the kidneys occurs but is rarely the cause of significant renal dysfunction.

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Systemic Sarcoidosis

Genitourinary Sarcoidosis

Autoimmune Disorders

Sarcoidosis of the reproductive system has been estimated to occur in less than 1 percent of clinically diagnosed cases and in 5 percent of autopsy cases. Genitourinary manifestations of sarcoidosis in men include testicular masses and acute epididymis-orchiditis. In women, sarcoidosis may manifest with uterine or ovarian involvement that may cause dysmenorrhea or mimic malignancy or fibroids.

Sarcoidosis is associated with a variety of disorders of the immune system, such as Crohn’s disease, ulcerative colitis, primary biliary cirrhosis, scleroderma, Sj¨ogren’s syndrome, autoimmune hemolytic anemia, and autoimmune endocrinopathies (Table 67-3). Given the rarity of some of these disorders, it is reasonable to postulate that these associations are the result of a common immune disturbance, with altered Th1 immunity that may predispose to both disorders.

Psychosocial Manifestations

A Dutch study found the prevalence of depression was 4 percent in asymptomatic patients and 30 percent in symptomatic patients with sarcoidosis. The prevalence of depression was found to be 60 percent in a US study of both white and black patients with sarcoidosis. In this latter study, depression was associated with the female sex, lower socioeconomic status, poor access to care, and increased disease severity, but not race. The prevalence of pain in sarcoidosis is unclear, but clinical experience suggests it is common and multifactorial with frequent reports of arthralgias, myalgias, headache, chest pain, and fatigue. A subset of patients meets diagnostic criteria for fibromyalgia.

Associated Conditions Sarcoidosis and Pregnancy There is usually little long-term effect on the course of sarcoidosis from pregnancy. Spontaneous improvement in chronic sarcoidosis is seen in some patients during pregnancy, although exacerbations often follow several months after delivery. The reasons for the temporary clinical improvement are not known but might be related to suppressed Th1 immunity during pregnancy. Altered Th1 Immunity Sarcoidosis is associated with several clinically disparate situations associated with altered, enhanced Th1 immunity. The clearest example involves the administration of Th1promoting therapeutics such as IFNα, IFNγ, IL2, and IFNβ that may be associated with initiation or recrudescence of sarcoidosis. Common Variable Immunodeficiency

There is a well-established association of sarcoidosis with common variable immunodeficiency (CVID). Since CVID occurs at any age, a high index of suspicion must be maintained, particularly in sarcoidosis patients who have recurrent infections or in any child with sarcoidosis given the low frequency of sarcoidosis in this age group. Human Immunodeficiency Virus

Sarcoidosis may develop in HIV-infected patients with immune reconstitution following initiation of highly active antiretroviral therapy, perhaps from reconstituted Th1 immunity. Granulomatous inflammation of the lungs or skin is most often reported.

Cancer

Noncaseating granulomas may be seen in or nearby 3 to 10 percent of tumors and in approximately 4 percent of regional draining lymph nodes. Much less commonly, multisystem granulomas consistent with systemic sarcoidosis develop in patients with a recent or past diagnosis of cancer or following chemotherapy treatment. Often the diagnosis is established by biopsy of enlarged lymph nodes or lung where the presurgical diagnosis is recurrent malignancy. There is usually little functional lung impairment from pulmonary sarcoidosis in these instances, and treatment is often unnecessary with eventual remission. A possible link involves dysregulated Th1/Th2 immunity, a premise supported by several cases of sarcoidosis developing in patients with 5q-myelodysplasia that results in deletion of several Th2 genes (IL4, IL13, CSF2).

DIAGNOSTIC APPROACH A diagnosis of sarcoidosis is established on the basis of a compatible clinical picture, evidence of noncaseating granulomas on biopsy, and exclusion of other granulomatous disorders of known cause. Although histologic evidence is needed from only a single site, clinical involvement of more than one system helps exclude local granulomatous reactions to foreign bodies, infections, or tumor. In general, the easiest accessible biopsy site is used to confirm a diagnosis of sarcoidosis. Biopsy of a skin or conjunctival nodule, enlarged superficial lymph node, or lacrimal gland may help to establish a diagnosis. Noncaseating granulomas on a liver or bone marrow biopsy are nonspecific and support a diagnosis only when competing diagnoses such as infection, drug reaction, or malignancy are excluded. In the absence of clinical involvement of an easily accessible site, biopsy by fiberoptic bronchoscopy is usually performed because of its high yield and relative safety. The diagnostic yield from transbronchial biopsy (TBB) ranges from 40 to 90 percent if at least four biopsies are taken, and is higher when there are pulmonary infiltrates on the chest radiograph or chest CT scan. Sampling intrathoracic lymph nodes by transbronchoscopic needle aspiration biopsy can increase the diagnostic yield when technically feasible, with greater than 90 percent sensitivity in combination with TBB for stage I or II disease. Several studies find that bronchial mucosal biopsies show noncaseating granulomas in 40 to 60 percent of patients even in the absence of endobronchial nodules or

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Table 67-3 Rare Associations of Sarcoidosis with Other Systemic and Organ-Specific Diseases Organ System

Clinical Disorder

Pulmonary

Scleroderma

Oropharyngeal

Melkersson-Rosenthal syndrome

Skin

Pyoderma gangrenosum Scleroderma Porphyria cutanea tarda Vitiligo

Ocular

Idiopathic granulomatous orbital inflammation?

Abdominal

Primary sclerosing cholangitis Primary biliary cirrhosis Celiac disease Crohn’s disease Ulcerative colitis

Neurologic

Progressive multifocal leukoencephalopathy

Joint/ Rheumatoid arthritis musculoskeletal Lupus erythematosis Scleroderma Mixed connective tissue disease and overlap syndromes Marfan syndrome Hematologic

Common variable immunodeficiency HIV with immune reconstitution Autoimmune hemolytic anemia Thrombocytopenia

Exocrine gland

Sj¨ogren’s syndrome Hashimoto thyroiditis

Renal

Membranoproliferative glomerulitis Amyloidosis

Systemic diseases

Autoimmune diseases Vasculitis Granulomatous vasculitis overlap with sarcoidosis

Malignancy

Lymphoma GU cancers—renal, testicular, bladder, ovarian, prostate Myeloproliferative disorders Thyroid cancer

Source: Adapted with permission from Moller DR: Rare manifestations of sarcoidosis, in Drent M, Costabel U (eds), Sarcoidosis. Eur Respir Monogr. 32:233–250, 2005.

cobblestoning. Transbronchial lung biopsy in advanced fibrocystic sarcoidosis has a low yield, owing to extensive fibrotic changes. Some studies suggest an elevated BAL T cell CD4:CD8 ratio greater than 3.5 to 4.0 supports a diagnosis of sarcoidosis with a test specificity of approximately 95 percent and sensitivity of greater than 50 percent. Other studies find wide variability in this parameter with overlap of infectious, inflammatory, and malignant diseases. When bronchoscopy is nondiagnostic, mediastinoscopy is generally recommended for patients with mediastinal lymphadenopathy, particularly in cases in which lymphoma, metastatic disease, or infection must be excluded. In patients with pulmonary infiltrates, a video-assisted thoracoscopic surgical lung biopsy or open lung biopsy establishes a diagnosis of pulmonary sarcoidosis with greater than 90 percent diagnostic yield. Most experts agree that a confirmatory biopsy in L¨ofgren syndrome is usually not needed. Bronchoscopy is recommended prior to initiation of corticosteroid therapy in patients with L¨ofgren syndrome in areas where histoplasmosis is endemic or when mycobacterial or fungal infection cannot be reasonably excluded. There is controversy over the need for tissue confirmation in persons manifesting with isolated asymptomatic bilateral hilar adenopathy. Some authorities recommend biopsy for all cases of bilateral hilar adenopathy to exclude malignancy, while others cite evidence from studies that suggest these manifestations almost always are due to sarcoidosis if not accompanied by symptoms or abnormal physical findings. A diagnosis of neurosarcoidosis is usually confirmed by biopsy of a non-CNS site. Rarely, brain biopsy is needed to exclude infectious or malignant disease. Similarly, a diagnosis of cardiac sarcoidosis is usually established by a noncardiac biopsy confirming systemic sarcoidosis along with consistent myocardial imaging studies or rhythm disturbances (Figs. 674 and 67-5). Endomyocardial biopsy is positive in less than 10 to 25 percent of cardiac sarcoidosis owing to sampling inefficiencies and the infrequency of right ventricular involvement. For organs that are rarely involved in sarcoidosis or rare manifestations in commonly affected organs, directed biopsy of the involved tissue is often recommended to exclude alternative causes, even when there is documentation of a prior biopsy that confirmed an original diagnosis of sarcoidosis. For organs that are difficult to biopsy, imaging techniques such as gallium 67 scans or more recently, 18 F-fluorodeoxyglucosepositron emission tomography (FDG-PET) scanning may help to define sites of clinically occult inflammation that could provide an alternative biopsy approach. One case series suggests that a gallium 67 scan demonstrating the combination of uptake in the bilateral hilar and right paratracheal node region (lambda sign) as well as the parotid, salivary, and lacrimal gland region (panda sign) is pathognomic for sarcoidosis. Other patterns are not specific for sarcoidosis. PET scanning is replacing gallium scanning as the preferred method to detect active inflammatory sites as the test has much less radiation exposure and greater resolution, although has a similar lack of specificity.

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Figure 67-4 Images of cardiac sarcoidosis. Single-photon emission computed tomography (SPECT) image of a technetium 99m Tc sestamibi myocardial scan in a patient with corticosteroid responsive cardiomyopathy secondary to systemic sarcoidosis. A fixed defect in myocardial uptake of technetium 99m Tc sestamibi is seen in the myocardial septum (arrow).

Laboratory tests are generally not helpful in confirming a diagnosis of sarcoidosis but may assist in establishing an alternative diagnosis. Serum angiotensin-converting enzyme (SACE) levels are elevated in 30 to 80 percent of patients with clinically active disease, probably originating from activated epithelioid cells and macrophages at sites of inflammation. Although SACE was originally proffered as a diagnostic marker, elevated levels are seen in infectious granulomatous diseases, lymphoma, hepatitis, diabetes, and thyroid disease among others; thus, SACE is not recommended as a diagnostic tool.

CLINICAL ASSESSMENT Once a diagnosis is established or suspected, an initial evaluation should consist of tests to evaluate the presence and extent of pulmonary involvement and screen for extrathoracic disease (Table 67-4). Specialized testing is indicated when symptoms or signs suggest extrapulmonary involvement. Guidelines for when and how to screen for potential cardiac involvement remain uncertain. Given the risk for sudden death and the potential for underdiagnosis, screening for cardiac sarcoidosis is recommended whenever symptoms such palpitations, unexplained chest pain, or dyspnea are reported. Most authorities screen with echocardiography to assess cardiac function and Holter monitoring to exclude serious arrhythmias. Thallium or sestamibi myocardial scanning is more sensitive

Systemic Sarcoidosis

than echocardiography for detecting patchy defects consistent with myocardial inflammation or fibrosis. Cardiac MR with gadolinium enhancement or cardiac PET scanning offers greater resolution if uncertainty persists, although experience remains limited with the latter technique. Electrophysiological testing may be indicated to exclude arrhythmias undetected by routine studies and assess indications for prophylactic cardiac pacemaker or implantable defibrillator to reduce the risk of sudden death. Evaluation for possible CNS and spinal sarcoidosis should include MRI with gadolinium enhancement, now considered the optimal test to detect characteristic inflammatory lesions. The distribution of inflammatory loci has a propensity for periventricular and leptomeningeal areas, although the images are nonspecific, and can be produced by infectious, malignant, or occasionally demyelinating disease. A normal scan does not exclude neurosarcoidosis, particularly for cranial neuropathies or in the presence of corticosteroid therapy. Examination of the cerebrospinal fluid is less often performed today, but may be useful by demonstrating characteristic lymphocytic pleocytosis and/or elevated protein levels. In suspected cases of peripheral neuropathy or myopathy, EMG or nerve conduction studies or rarely, tissue biopsy, may help to establish a link to sarcoidosis.

CLINICAL COURSE AND PROGNOSIS A clinical framework can be constructed to assist in decisions regarding monitoring and planning treatment strategies. First, organ involvement usually defines itself early in the disease. For example, only 23 percent of patients in the ACCESS study were found to have one or more new organ systems involved with sarcoidosis during a 2-year follow-up evaluation; the presence of extrapulmonary involvement at presentation was a risk factor for new organ development. Second, patients who undergo remission usually do so within the first 2 to 3 years. Clinical experience suggests sarcoidosis rarely recurs after a prolonged period of remission, with exceptions most often involving neurological or ocular manifestations. Third, patients with chronic sarcoidosis comprise 30 to 50 percent of all known sarcoidosis cases, and generally have progressive, unremitting organ impairment. In these patients, the rate of progression varies from individual to individual, as does their response to treatment. A waxing-waning clinical course is uncommon except for a subset of patients with neurological or ocular manifestations or occasionally recurrent erythema nodosum. Fourth, prognosis in sarcoidosis is strongly influenced by the initial manifestations of disease. Patients with LÂ¨ofgren syndrome have remission rates of 70 to 80 percent. An initial stage I chest radiograph is associated with a 60 to 90 percent remission rate. Patients manifesting with type II chest radiographs have a poorer outcome, with spontaneous remission occurring 40 to 70 percent of the time. A stage III chest radiograph is associated with remission in

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Figure 67-5 A,B. 18 F-Fluorodeoxyglucose (FDG)-PET scanning shows 18 F-FDG uptake in the inferior myocardium (red arrow). C . 18 F-FDG uptake level is reduced by more than 50 percent after 1 month of corticosteroid therapy. (Images courtesy of Jens Sorensen, MD of Uppsala University, Sweden.)

only 10 to 20 percent of patients. Patients with extensive pulmonary fibrosis (stage IV) rarely undergo remission. Currently, a consensus recommendation is that treatment decisions are best based on repeated clinical examinations and direct measurement of organ function and not

on laboratory markers of disease â&#x20AC;&#x153;activity.â&#x20AC;? SACE levels tend to correlate with the extent of granulomatous inflammation throughout the body and usually decrease in response to corticosteroids or with disease remission, but the test is highly variable and has no prognostic value. Similarly, BAL

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Systemic Sarcoidosis

Table 67-4

Table 67-5

Recommended Tests for Clinical Evaluation of Systemic Sarcoidosis

Indications for Treatment of Sarcoidosis

All Patients

Organ-Specific Testing for Suspected Organ Involvement

Threatened organ failure—severe ocular, cardiac, or neurological disease Progressive or persistent pulmonary disease Uveitis unresponsive to topical corticosteroids

Chest radiograph

Pulmonary function tests: Spirometry, diffusion capacity, lung volumes

Cardiac: Echocardiogram, Holter monitoring, thallium or sestamibi myocardial scan, cardiac MR, cardiac PET Neurological: Brain or spine MRI with gadolinium enhancement, cerebrospinal fluid examination, nerve conduction studies

Ophthalmologic examination

Upper respiratory tract: Flow-volume loop, ENT evaluation

Complete metabolic panel

Endocrine: Pituitary function tests; thyroid function tests

Complete blood count with differential count Electrocardiogram Purified protein derivative (PPD) skin test

parameters such the proportion of CD4 lymphocytosis or the CD4:CD8 ratio of BAL T cells have been inconsistent in predicting outcomes. Monitoring for at least 3 years following presumed “disease remission” is recommended; longer periods of observation are indicated for patients with serious pulmonary or extrapulmonary manifestations.

TREATMENT Indications Indications for treatment must take into account the overall excellent prognosis for most patients with sarcoidosis, particularly for patients with stage I disease, for whom systemic therapy is usually not required. Symptomatic or local therapy is recommended whenever possible. L¨ofgren syndrome is usually managed with bed rest and nonsteroidal antiinflammatory drugs; corticosteroids are recommended when

Persistent hypercalcemia, renal or hepatic dysfunction Palpable splenomegaly or hypersplenism Severe myopathy Disfiguring skin disease Painful lymphadenopathy Severe fatigue and weight loss

symptoms, particularly arthritis, are disabling and persistent. Most physicians agree that corticosteroid or other systemic therapy is indicated for the manifestations listed in Table 675. Typical dosing regimens and side effects for the drugs listed below are provided in Table 67-6.

Systemic Treatment Corticosteroid Therapy Corticosteroids remain the cornerstone of therapy for sarcoidosis. Although controversy exists regarding the overall effectiveness of corticosteroids in altering the long-term course of the disease, there is no disagreement that corticosteroids provide prompt symptomatic relief and reverse organ dysfunction in most patients with the degree of reversibility dependent on the extent of preexisting fibrosis. Case series and several but not all clinical trials support the view that corticosteroids favorably affect disease outcome in chronic pulmonary sarcoidosis. One large study by the British Thoracic Society found long-term improved lung function in patients with stage I or II pulmonary disease treated with daily corticosteroid therapy compared with a group treated intermittently with corticosteroids based on symptoms. Optimal dosing of corticosteroid therapy has not been established by clinical trials. Most authorities suggest that initial treatment of pulmonary sarcoidosis usually does not require more than 20 to 40 mg per day of prednisone followed by a slow taper to a maintenance dose of 5 to 15 mg per day of prednisone. A qod regimen of prednisone in patients may be effective in some but not all patients. Treatment is usually continued for a minimum of 8 to 12 months, since premature attempts to taper off steroids are likely to result in relapse of disease. Inhaled steroids appear to have limited effectiveness in chronic pulmonary sarcoidosis and are not

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Table 67-6 Therapies for Systemic Sarcoidosis Drug

Typical Dose/Regimen

Major Adverse Effects

Corticosteroids

Prednisone 20–40 mg/d for 2 wk; decrease by 5 mg every 2 wk until 10–15 mg/d; maintain for 8–12 mo, then taper 2.5 mg/d every 2–4 wk; reinstitute for relapse

Weight gain, hypertension, hyperglycemia, osteoporosis, cataracts, psychosis

200 mg once or twice daily

Ocular toxicity (rare), gastrointestinal upset, rashes Ocular toxicity, gastrointestinal upset

Antimalarial drugs Hydroxychloroquine Chloroquine Anti-inflammatory drugs Minocycline, doxycycline

Pentoxifylline Thalidomide Immunosuppressive therapies Methotrexate Mycophenolate mofetil

500 mg every other day for 6 mo followed by 6 mo drug holiday 100 mg twice daily

Gastrointestinal upset, skin hyperpigmentation, headaches, dizziness, pseudotumor cerebri Gastrointestinal upset, headaches Teratogenicity, peripheral neuropathy, sedation

400 mg 3 or 4 times a day 100–200 mg once at bedtime

10–20 mg per week + folate 1 mg daily 1000–2000 mg per day

Azathioprine

100–200 mg per day

Antitumor necrosis factor agents

Infliximab, adalimumab; dosing varies

recommended as sole therapy. Overall, recurrent progressive pulmonary disease occurs in 16 to 74 percent of patients as oral corticosteroids are tapered or discontinued.

Alternative Agents Several classes of drugs have been reported to be beneficial in subgroups of patients with sarcoidosis (Table 67-6). None of these drugs has been proved effective by rigorous clinical trials. Nonimmunosuppressive Drugs

Case series suggest hydroxychloroquine is effective in many patients with mucocutaneous sarcoidosis, hypercalcemia and occasionally, as a steroid-sparing agent in systemic sarcoidosis. Ocular toxicity is rare, and its overall safety profile provides a rationale for an early trial of this drug. Chloroquine

Hepatic, pulmonary, bone marrow toxicity Bone marrow and hepatic toxicity, gastrointestinal upset, ?oncogenic potential Bone marrow and hepatic toxicity, gastrointestinal upset, ?oncogenic potential Hypersensitivity reaction, severe infection, reactivation TB, autoimmune phenomena, malignancy (rare)

may be efficacious in treating lupus pernio, SURT, or sinus disease, which is often recalcitrant to other therapies, although ocular toxicity has limited its use. The tetracyclines, minocycline, and doxycycline, may be effective in a subgroup of patients with cutaneous sarcoidosis and occasionally as a steroid sparing drug in systemic disease. These antibiotics have mild anti-inflammatory effects, which probably account for their mechanism of action given that other antibiotics with similar antimicrobial activity have not been found effective in sarcoidosis. Pentoxifylline is a phosphodiesterase inhibitor with anti-inflammatory effects that was found to be effective in early pulmonary sarcoidosis in one study. Other experiences have not been as favorable with responses in less than 10 percent of patients, generally those with mild pulmonary or systemic sarcoidosis. Melatonin was found to be beneficial in a small case series of patients with generally mild disease.

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Thalidomide was found in one study to be beneficial in over 80 percent of patients with severe skin sarcoidosis (lupus pernio unresponsive to other therapies), but was not effective in pulmonary sarcoidosis. Given the drugâ&#x20AC;&#x2122;s well-known teratogenicity and potential to cause peripheral neuropathy and sedation, the drug is recommended only in patients refractory to other treatments. Immunosuppressive Drugs

Methotrexate is often the first immunosuppressive therapy used as an alternative therapy for refractory pulmonary or systemic sarcoidosis when corticosteroid and antimalarial therapies are ineffective or poorly tolerated. Studies suggest methotrexate is effective in 50 to 70 percent of patients, although responses may take longer than 6 months and lowdose corticosteroids may be needed. Hepatic, pulmonary, and renal toxicities limit the use of the drug. Clear advantages of methotrexate over low-dose corticosteroids in the routine management of sarcoidosis have not been established. Other immunosuppressive agents, such as azathioprine or cyclophosphamide, have been found beneficial in a small series of patients with severe manifestations of sarcoidosis refractory to corticosteroids. More recently, mycophenolate mofetil has been used with anecdotal effectiveness for serious neurologic, ocular, pulmonary, and hepatic sarcoidosis. Several studies have shown that cyclosporine, a drug known to inhibit T-cell activation, is not effective in sarcoidosis, with the possible exception of a few patients with treatment resistant, severe neurosarcoidosis.

Systemic Sarcoidosis

is usually not feasible because of the severe restrictive lung disease. Pulmonary Hypertension

Moderate or severe pulmonary hypertension is an independent predictor of reduced survival in patients with advanced lung disease awaiting lung transplantation. A role for drugs used to treat primary pulmonary hypertension is under investigation. Cardiac Sarcoidosis

Several large case series find prognosis in cardiac sarcoidosis, and response to treatment is related to the degree of cardiac dysfunction. Treatment of cardiac sarcoidosis consists of antiarrhythmic therapy, diuretics, and afterload-reducing agents for specific cardiac abnormalities. Although randomized trials are lacking, studies from Japan, Europe, and the United States consistently report that corticosteroids in moderate doses are associated with improved cardiac function and outcomes. Maintenance doses often range between prednisone 10 to 25 mg a day, although higher doses may be needed for intractable arrhythmias. Immunosuppressive drugs are frequently used as steroid-sparing agents since treatment often must be maintained for years. Automatic implantable cardioverter-defibrillators (ICDs) may prevent sudden death in patients with serious arrhythmias; guidelines for prophylactic placement of ICDs or pacemakers have not yet been established. Neurosarcoidosis and Ocular Sarcoidosis

Anti-TNF Therapies

The scientific basis for the use of TNF inhibitors in sarcoidosis is firmly established based on the role of TNF in experimental models of granuloma formation. Preliminary reports from a recent multicenter study found infliximab to be effective in one of several primary end points (improved FVC after 24 weeks of therapy), although the effect was modest. Etanercept was not shown to be effective in a smaller clinical trial of pulmonary sarcoidosis. Anecdotal cases suggest adalimumab may be effective in some patients with sarcoidosis, although larger studies are lacking. Given the risk profiles of current immunosuppressive drugs, additional clinical trials of these agents are anticipated. Special Circumstances Fibrocystic Sarcoidosis

Advanced pulmonary sarcoidosis may be complicated by mycetomas, usually from Aspergillus fumigatus that colonize preexisting cystic spaces. The fungi rarely cause invasive disease, spontaneous resolution may be seen and the benefit of antifungal agents has not been established. Massive hemoptysis associated with mycetomas or bronchiectasis may be lifethreatening, requiring therapeutic embolization of the appropriate bronchial or collateral artery for control. Surgery

High doses of oral corticosteroids or high-dose pulse intravenous therapy are often indicated for serious ocular or CNS disease, such as optic neuritis or encephalitis followed by maintenance corticosteroid or immunosuppressive therapy. Anterior uveitis can usually be treated with topical ophthalmologic steroid drops. Pregnancy

Corticosteroids are the only drugs recommended for use during pregnancy because of the potential of other steroidsparing drugs to cause fetal toxicity or teratogenicity. In general, pregnancy has little effect on the long-term course of sarcoidosis. Sometimes, spontaneous abatement of chronic sarcoidosis occurs in pregnant patients, allowing a temporary reduction in steroid dosage. After pregnancy, however, an exacerbation often occurs, requiring a return to the original maintenance dose. Quality of Life

There is increasing recognition of the need to treat depression and pain to improve quality of life in patients with these manifestations. The utility of nonpharmacologic treatments, such as exercise training or rehabilitation, merit investigation because of the impact of these problems in sarcoidosis patients.

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Lung and Heart Transplantation

Successful lung, heart-lung, and heart transplantations have been performed in patients with advanced pulmonary sarcoidosis or cardiomyopathy. Although noncaseating granulomas have been found in some transplanted lungs or hearts, these findings do not appear to significantly affect outcome, although experience remains limited.

SUGGESTED READING Arcasoy SM, Christie JD, Pochettino A, et al: Characteristics and outcomes of patients with sarcoidosis listed for lung transplantation. Chest 120:873, 2001. Baughman R (ed): Sarcoidosis. New York, Marcel Dekker, in press. Baughman RP, Lynch JP: Difficult treatment issues in sarcoidosis. J Intern Med 253:41, 2003. Baughman RP, Tierstein AS, Judson MA, et al: Clinical characteristics of patients in a case control study of sarcoidosis. Am J Resp Crit Care Med 164:1885–1889, 2001. Chapelon-Abric C, de Zuttere D, Duhaut P, et al: Cardiac sarcoidosis: A retrospective study of 41 cases. Medicine (Baltimore) 83:315, 2004. Drent M, Costabel U (eds): Sarcoidosis, vol. 10. Wakefield, UK, The Charlesworth Group, 2005. Gibson GJ, Prescott RJ, Muers MF, et al: British Thoracic Society Sarcoidosis Study: Effects of long term corticosteroid treatment. Thorax 51:238, 1996. Hance AJ: The role of mycobacteria in the pathogenesis of sarcoidosis. Semin Respir Infect 13:197, 1998. Iannuzzi MC, Iyengar SK, Gray-McGuire C, et al: Genome wide search for sarcoidosis susceptibility genes in African Americans. Genes Immunol 6:509, 2005. Johns CJ, Michele TM: The clinical management of sarcoidosis. A 50-year experience at the Johns Hopkins Hospital. Medicine (Baltimore) 78:65, 1999. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG): Adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Statement on sarcoidosis. Am J Respir Crit Care Med 160:736, 1999.

Katchar K, Wahlstrom J, Eklund A, et al: Highly activated Tcell receptor AV2S3(+) CD4(+) lung T-cell expansions in pulmonary sarcoidosis. Am J Respir Crit Care Med 163:1540, 2001. Mana J, Gomez-Vaquero C, Montero A, et al: L¨ofgren syndrome revisited: A study of 186 patients. Am J Med 107:240, 1999. Mitchell DN, Scadding JG: Sarcoidosis. Am Rev Respir Dis 110:774, 1974. Moller DR: Treatment of sarcoidosis: From a basic science point of view. J Intern Med 253:31, 2003. Moller DR: Rare manifestations of sarcoidosis, in Drent M, Costabel U (eds): Sarcoidosis, vol. 10. Wakefield, UK: The Charlesworth Group, 32:233–250, 2005. Muller-Quernheim J: Sarcoidosis: Immunopathogenetic concepts and their clinical application. Eur Respir J 12:716, 1998. National Heart, Lung, and Blood Institute (NHLBI): Sarcoidosis. Available at: http://www.nhlbi.nih.gov/health/ dci/Diseases/sarc/sar whatis.html Newman LS, Rose CS, Bresnitz EA, et al: A case control etiologic study of sarcoidosis: Environmental and occupational risk factors. Am J Respir Crit Care Med 170:1324, 2004. Rybicki BA, Iannuzzi MC, Frederick MM, et al: Familial aggregation of sarcoidosis: A case control etiologic study of sarcoidosis (ACCESS). Am J Resp Crit Care Med 164:2085, 2001. Schurmann M, Lympany PA, Reichel P, et al: Familial sarcoidosis is linked to the major histocompatibility complex region. Am J Respir Crit Care Med 162:861, 2000. Song Z, Marzilli L, Greenlee BM, et al: Mycobacterial catalaseperoxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis. J Exp Med 201:755, 2005. Stern BJ: Neurological complications of sarcoidosis. Curr Opin Neurol 17:311, 2004. Valentonyte R, Hampe J, Huse K, et al: Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat Genet 37:357, 2005. Yazaki Y, Isobe M, Hiroe M, et al: Prognostic determinants of long-term survival in Japanese patients with cardiac sarcoidosis treated with prednisone. Am J Cardiol 88:1006, 2001.

68 Idiopathic Pulmonary Fibrosis Eric B. Meltzer

Paul W. Noble

I. HISTORICAL PERSPECTIVE II. DEFINITIONS III. EPIDEMIOLOGY Incidence, Prevalence, and Vital Statistics Risk Factors Familial and Genetic Factors IV. CLINICAL PRESENTATION Diagnosis Natural History and Prognosis V. PATHOGENESIS Inflammation Epithelial Cell Apoptosis

Idiopathic pulmonary fibrosis (IPF) is a distinctive type of interstitial lung disease (ILD) of unknown cause that has come to be recognized by a unique compilation of clinical, radiographic and pathological abnormalities leading to progressive breathlessness and death in most instances. While there are many causes of ILD, IPF is one of the more common forms and certainly the most serious. IPF is characterized by an inexorable progression of interstitial fibrosis resulting in restrictive lung disease and worsening gas exchange leading to death from respiratory failure within 5 years of diagnosis in the majority of patients. IPF typically comes to medical attention later in life, beginning in the sixth decade. IPF is rarely the cause of ILD in patients under the age of 40. The predominant presenting symptoms of IPF are exertional breathlessness and a dry, harassing cough. These are nonspecific complaints shared by a variety of pulmonary and cardiac diseases. In particular, exertional breathlessness is often attributed to advancing age by patients in their sixties and seventies, leading to delays in seeking medical evaluation. In addition, many patients are poorly conditioned and overweight and attribute their

Basement Membrane Injury Growth Factors Th1 and Th2 Cytokines Angiogenesis and Angiostasis Matrix Turnover The Fibroblast Progression through Various Path ological Patterns (NSIP to UIP) Multiple Hits and Host Defense Gastroesophageal Reflux Disease VI. TREATMENT Pharmacotherapy Nonpharmacological Therapy

symptoms of breathlessness to these circumstances. In addition to the nonspecific clinical symptoms the nonspecific plain chest radiographic findings in IPF do not often trigger prompt medical evaluation. Fine peripheral linear opacities predominantly in the lower lung zones may be interpreted as chronic and nonspecific pulmonary fibrosis, which often does not elicit an alarming concern in primary care physicians reading a radiology report. Coupled with subtle clinical symptoms, the result is often a failure to refer for a pulmonary evaluation. The unknown etiology of IPF and the lack of a therapy of proven efficacy have generated a culture of nihilism that further promulgates a delay in diagnosis. However, in recent years there have been important advances in the understanding of the pathogenesis of IPF and new therapeutic trials are being performed that have increased the enthusiasm for early diagnosis of IPF. This chapter describes the recent advances in improving the accuracy of the diagnosis of IPF and describes new insights into pathogenesis that are prompting a multitude of attempts to find new treatments for patients who suffer from this devastating disease.

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HISTORICAL PERSPECTIVE A brief review of the evolution in our understanding of IPF will illustrate the contributions made by earlier investigators and account for much of the confusion that many clinicians have regarding IPF. One of the challenges in defining IPF has been the variety of antiquated terms formerly used to describe pulmonary fibrosis. While there are many causes of ILD in general, and pulmonary fibrosis in particular, it is important to note that IPF is a unique disease, although it had not been formally codified until recently when a group of expert pulmonologists, radiologists, and pathologists collaborated on a classification of ILD. Reviewing the history of IPF will both clarify the present terminology and distinguish contemporary nomenclature from the outmoded terms encountered in earlier literature. Fibrosis of the lung was long recognized in association with infection or dust inhalation. In the nineteenth century, pulmonary fibrosis was known as “cirrhosis” of the lung. Yet little attention was paid to this form of respiratory illness. Interest in pulmonary fibrosis was ignited in 1944 when Louis Hamman and Arnold Rich published a seminal paper describing “acute diffuse interstitial fibrosis of the lungs.” Hamman and Rich reported a series of unusual cases that shared a unique clinical presentation featuring idiopathic subacute respiratory failure followed by death. Their report was complete with pathological findings from autopsy. They described thickening of the alveolar interstitium and areas of dense fibrotic scar tissue within the lung. This was the first pathological depiction of pulmonary fibrosis and, to this day, is considered an accurate portrayal. In retrospect, the cases of Hamman and Rich best fit a diagnosis of the fibrosing interstitial pneumonia known as acute interstitial pneumonitis (AIP). Yet in the 1940s, the “Hamman-Rich syndrome” became synonymous with IPF. So it remained for the next three decades. Over the years, clinical reports of pulmonary fibrosis suggested a number of alternate presentations that were referred to as “variants” of the Hamman-Rich syndrome. This included cases that exhibited a rather protracted duration of illness compared to the “classic” Hamman and Rich cases. It was also noted that pulmonary fibrosis occurred in patients who suffered from the “rheumatoid group of collagen diseases.” An assortment of abnormal patterns was noted under the microscope. Eventually, the breadth of the Hamman-Rich syndrome encompassed a heterogeneous mixture of clinical manifestations and a variety of histological forms of pulmonary fibrosis with no distinction made between systemic and limited illness, nor any concession to the prognostic implications of an acute versus chronic presentation. In the 1960s authors began to regularly substitute the term idiopathic pulmonary fibrosis for acute diffuse interstitial fibrosis. A debate began concerning the chronicity of this disease, with some authors suggesting a slow course punctuated by “terminal complications,” while others reported an average illness of no more than 2 years.

The term fibrosing alveolitis was introduced in England in 1964. Cryptogenic fibrosing alveolitis (CFA) became the preferred term for pulmonary fibrosis in the European literature and it is essentially synonymous with IPF. This term was originally meant to improve upon its predecessor by capturing pathological features in a manner that was more precise and descriptive. CFA refers to the inter-alveolar location of the inflammation in pulmonary fibrosing as compared with the intra-alveolar inflammation of infectious pneumonia. This inter-alveolar septal inflammation was dubbed alveolitis. It was maintained that alveolitis was responsible for the subsequent development of fibrosis and it was first suggested that corticosteroids be used to treat alveolitis and therefore pulmonary fibrosis. The most important advance came in 1964 with the publication of an improved and safe technique for performing open lung biopsy. With this procedure, it became possible to carry out a widespread analysis of lung tissue from patients with suspected pulmonary fibrosis. Before long there were new insights into the pathology associated with fibrotic lung disease. In 1969 Liebow and Carrington heralded the modern era of interstitial lung disease histopathology with the notion that idiopathic interstitial pneumonia (IIP) could be split into separate pathological subtypes. They described distinct patterns of IIP, which were identified by examination of lung biopsy specimens with light microscopy. Moreover, these subtypes were found to predict prognosis and response to treatment. Based on their research findings, Liebow and Carrington produced the first detailed histopathological classification of IIP. They created five categories termed usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), bronchiolitis obliterans interstitial pneumonia (BIP), lymphoid interstitial pneumonia (LIP), and giant-cell interstitial pneumonia (GIP). More recent observations have led to a modification of this classification of IIP subtypes. New categories have been added such as respiratory bronchiolitisassociated interstitial lung disease (RB-ILD) and nonspecific interstitial pneumonia (NSIP). Simultaneously, a revolution in thinking about the pathogenesis of IPF affected the way in which experts talked about the disease. Researchers at the National Heart, Lung and Blood Institute (NHLBI) were major proponents of an “inflammatory theory” of pathogenesis as originally proposed by European investigators. This theory was based on studies at the NHLBI throughout the 1970s during which excessive amounts of inflammatory cells were identified in bronchoalveolar lavage fluid obtained from IPF patients. The NHLBI agreed with European researchers who had coined the term “alveolitis” and the NHLBI also endorsed corticosteroid treatments. The inflammatory theory has since fallen from favor, mostly as a consequence of corticosteroid inefficacy, and the term alveolitis has also fallen out of vogue. A new hypothesis has replaced the inflammatory theory of IPF. This new concept proposes that IPF is the result of alveolar epithelial injury which is then followed by

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aberrant repair mechanisms. This theory emerged from landmark ultrastructural studies performed in the mid-1980s. Using electron microscopy, it was discovered that the alveolar epithelial cells were injured in IPF. In addition, foci of subepithelial fibrosis were first described. This concept of injury and repair was modified and expand on by subsequent investigators. In 1997 a modified version of Liebow’s pathological classifications were proposed. The new classification scheme reinforced acceptance of certain categories within the context of an updated understanding of interstitial lung disease pathogenesis. For instance, DIP and UIP categories were retained in the new classification scheme. Some original categories were discarded and two modern categories were added. RB-ILD was recognized in the spectrum of smoking-related lung diseases and a provisional category, NSIP, was also added. This modern pathological classification became the basis for a consensus statement that finally standardized the nomenclature of ILD and IPF for the very first time. In 2002 a panel of experts convened sponsored jointly by the American Thoracic Society and the European Respiratory Society. This panel released an official statement for the purpose of providing a new and comprehensive classification of IIP that considered all clinical, radiographic, and pathological features. This statement offers strict definitions for each subtype of IIP with practical guidelines for diagnostic purposes. The benefit of utilizing precise definitions is a uniformity of diagnostic decisions in both clinical practice and future research. The current classification system relies upon an assumption that each specific IIP is a discrete clinical entity, to an extent sufficient for its designation as a separate disease. The diseases recognized by the 2002 ATS/ERS classification of IIP are idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), acute interstitial pneumonia (AIP), respiratory bronchiolitis–associated interstitial lung disease (RB-ILD), desquamative interstitial pneumonia (DIP), and lymphocytic interstitial pneumonia (LIP). These diseases are each associated with a distinct pathological pattern upon surgical lung biopsy. IPF is associated with the UIP pattern.

DEFINITIONS PF is defined as a specific form of chronic fibrosing interstitial pneumonia that is limited to the lung and associated with the histological appearance of UIP on a surgical lung biopsy. The diagnosis of IPF can only be made after the exclusion of other known causes of interstitial lung disease such as drug toxicities, environmental exposures, and collagen vascular diseases. Within the hierarchical structure of the interstitial lung diseases (ILD), IPF belongs to the subset of diseases known as the idiopathic interstitial pneumonias (IIP). ILD is a collection of non-neoplastic lung disorders, both acute and chronic,

Idiopathic Pulmonary Fibrosis

that present with variable degrees of inflammation and fibrosis. ILD is also termed diffuse parenchymal lung diseases (DPLD), which highlights the focus on the interstitium but does not exclude some involvement of airway abnormalities. DPLD can be subdivided into four groups. IIP includes the subset of DPLD that are of unknown etiology. DPLD can also be associated with identifiable causes of lung disease, such as environmental exposures or systemic illnesses such as the collagen vascular diseases. Granulomatous diseases, such as sarcoidosis and hypersensitivity pneumonitis, comprise another group of DPLD. Finally, a few rare forms of DPLD are recognized by their distinctive pathology. These include pulmonary Langerhans’ cell histiocytosis (PLCH) and lymphangioleiomyomatosis (LAM). The IIPs are defined by the ATS/ERS consensus classification as seven distinct disease entities. IPF is the most common IIP and its diagnosis is reserved for patients whose biopsy reveals the UIP pathology or in whom the clinical presentation and high-resolution computed tomography (HRCT) reveal a characteristic pattern. It is important to maintain this strict definition of IPF. Historically, several forms of IIP were grouped under the heading of IPF. This has made it difficult to assess the scientific literature. Misclassification has also contributed to confusion concerning the responsiveness of IPF to corticosteroids since some IIP such as COP and NSIP are more responsive than IPF. The latest investigations of IPF, using the strict definition of IPF, have reported a natural history and response to treatment that differs from those reported in older studies. This is likely explained by the change in definitions.

EPIDEMIOLOGY Incidence, Prevalence, and Vital Statistics The epidemiology of IPF is difficult to determine and the available data are of limited value. The epidemiology has been principally assessed by large population studies. The main criticism of these studies is that surgical lung biopsy was rarely performed, although biopsy remains the gold standard of diagnosis. Studies from the United Kingdom and the United States suggest that IPF is widely underreported. Studies that have examined the accuracy of diagnostic coding on death certificates have identified discrepancies among patients who otherwise carried a diagnosis of pulmonary fibrosis. Most experts agree that the currently reported epidemiologic figures underestimate the magnitude of the problem of idiopathic pulmonary fibrosis. The precise incidence and prevalence of IPF cannot be known but the best estimates are based upon a few studies performed in the United States and have been supported by case series from around the world. The yearly incidence of IPF is estimated at 10.7 cases per 100,000 persons for males, and 7.4 cases per 100,000 persons for females. The prevalence of IPF is slightly higher at 20.2 cases per 100,000 men and 13.2 cases per 100,000 women. Mortality data are scant and

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vary by country as well as race. This likely reflects differences in reporting practices rather than an actual disease pattern.

Risk Factors Idiopathic pulmonary fibrosis has been reported worldwide. There are no apparent preferences for urban or rural settings. Neither is there a predilection toward any particular race or ethnicity. Age-adjusted rates of mortality appear to differ among blacks and whites in the United States, but these differences are likely related to inadequate reporting. The incidence of IPF undoubtedly increases with age. Patients with IPF are usually between 40 and 70 years old. Two-thirds of IPF cases present in patients over the age of 60 years, with a mean age of 66 years at the time of diagnosis. IPF occurs infrequently among those younger than 40 years and rarely affects children, if at all. In one U.S. populationâ&#x20AC;&#x201C; based study the prevalence was stratified by age. Among adults aged 35 to 44 years the prevalence was 2.7 cases per 100,000 persons. In contrast, the prevalence for individuals older than 75 years was greater than 175 cases per 100,000. Besides age, several other risk factors have been identified by case-control studies. A strong association has been demonstrated between cigarette smoking and pulmonary fibrosis. An odds ratio of 2.3 (95 percent confidence interval, 1.3 to 3.8) was reported for those with a history of smoking between 21 to 40 pack-years. Another study associated antidepressants with an increased risk of developing IPF. A number of papers have implicated environmental exposures to such particulate materials as metal and wood dusts. In a related finding, an increased incidence of IPF was noted in industrial centers of the southeastern United States and central regions of the United Kingdom. Several articles have implicated a variety of viruses, such as the Epstein-Barr virus, influenza virus, cytomegalovirus, and hepatitis C. All are found with higher incidence among patients with IPF. The significance of these findings is unclear. No evidence exists for a pathogenic mechanism involving viruses or involving any of the other aforementioned risk factors. However, a recent report made the intriguing observation of a marked high prevalence of HSV in biopsies from IPF patients.

Familial and Genetic Factors Familial cases of IPF have been described in dozens of reports. The clinical features of familial IPF are indistinguishable from those of the non-familial form, except that the familial form may have an earlier age of onset. Familial IPF or familial interstitial pneumonia (FIP) is defined by at least two members of a primary biologic family (parent, child, siblings) presenting with a characteristic appearance of IPF that is confirmed by biopsy. Evidence of lung inflammation has also been reported in unaffected family members of those with FIP. Familial IPF seems to account for 0.5 to 2 percent of all cases of IPF. In 2000, a report was published describing 25 families and comprising 67 cases of familial IPF. In this report

the mean age at time of diagnosis was 56 years. Only half of the patients were smokers. The male-to-female ratio was 2:1 in contrast to earlier reviews of FIP, which suggested an inverted male-to-female ratio. One shortcoming of this particular study was the lack of biopsy confirmation for 68 percent of the cases. A more recent study of FIP was published in 2005. This impressive report described a much larger cohort of 111 families with 309 affected family members. Most of these subjects were identified as having probable or definite IPF by the American Thoracic Society/European Respiratory Society diagnostic criteria. This study revealed a mean age at diagnosis of 68.3 years, with a slight male predominance (55 percent) and an increased association with cigarette smoking (even after controlling for age and gender differences). Analysis of pedigrees confirmed vertical transmission and provided strong evidence for an autosomal-dominant inheritance pattern of this disease. These accounts of FIP provide compelling evidence for the existence of genetic factors that predispose to the development of IPF. However, specific hereditary markers for IPF have yet to be identified. The difficulty in identifying such genes is due to several factors, including the rarity of FIP in the general population. Several candidate genes have been selected, because of their bearing on proposed mechanisms of the disease, and these genes are currently under investigation. Genes that code for a variety of inflammatory cytokines have been examined for genetic polymorphisms. These studies have been uninformative mainly because of small sample sizes. Limited data have suggested a role for the HLA loci, as well as genes encoding surfactant proteins.

Clinical Presentation Diagnosis Differential In the setting of exertional breathlessness, the hallmark of IPF is a predominance of radiographically visualized lower lung zone reticular opacities that spread out over time to involve an ever-enlarging area of lung parenchyma (Fig. 68-1). The differential diagnosis of IPF frequently includes the other IIP, connective tissue diseases (principally scleroderma and rheumatoid arthritis), environmental exposures, chronic aspiration, and chronic hypersensitivity pneumonitis. The aforementioned disorders have in common symptoms of dyspnea on exertion coupled with radiographic abnormalities indicative of an interstitial pulmonary disorder. High-resolution computed tomography (HRCT) has emerged as the single most important diagnostic modality in ILD. A number of diseases share a radiographic pattern that is similar to IPF, in other words, reticular abnormalities are demonstrated by HRCT with a tendency to involve the lower lobes. Examples include asbestosis, chronic aspiration, radiation pneumonitis, chronic hypersensitivity pneumonitis, end-stage sarcoidosis, and congenital disorders such as Gaucherâ&#x20AC;&#x2122;s disease, Niemann-Pick disease, and tuberous

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It is critical to obtain a detailed occupational history with particular attention paid to the identification of exposures to asbestos, silica, or any other respiratory toxins. This history is necessary to exclude the presence of pneumoconiosis. It is equally important to inquire about exposure to molds and/or pets in the home environment as this information may provide evidence suggesting a diagnosis of hypersensitivity pneumonitis. A general health history, including an accounting of all medications, can be revealing. A review of systems may uncover photosensitivity, Raynaud’s phenomenon, dry eyes or dry mouth that implies a connective tissue disorder. Certain drugs have been associated with pulmonary fibrosis, most notably nitrofurantoin, bleomycin, and amiodarone.

Figure 68-1 Posteroanterior chest radiograph of a 67-year-old man with progressive dyspnea revealing bilateral reticular infiltrates with lower lobe predominance.

sclerosis–lymphangioleiomyomatosis. The presence of extensive ground-glass opacities on HRCT should prompt the consideration of an alternative diagnosis, such as desquamative interstitial pneumonia, cellular nonspecific interstitial pneumonia, or acute hypersensitivity pneumonitis. Other IIP that are included in the differential diagnosis of IPF are fibrotic NSIP and COP. History Patients with IPF typically present with exertional dyspnea and a nonproductive cough. The dyspnea begins insidiously and is usually progressive. Dyspnea is the most prominent symptom in IPF. Associated systemic symptoms can occur but are not common. Systemic symptoms may include weight loss, low-grade fevers, fatigue, arthralgias, or myalgias. Patients often have symptoms longer than 6 months before seeking a medical evaluation. It is not unusual for symptoms to be present for up to 2 years before an initial consultation is arranged with a pulmonary specialist. Patients are frequently evaluated and treated for other ailments, such as asthma or heart failure before IPF is identified as the diagnosis. Because most patients present over the age of 60, in which coronary artery disease is highly prevalent, most primary care physicians refer patients for a cardiology evaluation before a pulmonary evaluation for the exertional breathlessness. The patient’s age is an essential clue to the recognition of IPF. While IPF mostly occurs in patients beyond 50 years of age, several other interstitial lung diseases commonly present in the young or middle-aged (e.g., sarcoidosis, lymphangioleiomyomatosis, and pulmonary Langerhans’ cell histiocytosis). A history of cigarette smoking is a vital piece of information. While IPF, DIP, and PLCH are diseases found in former and current smokers, other diseases such as hypersensitivity pneumonitis are rare among a smoking population.

Physical Examination In most patients the physical examination reveals fine, bibasilar inspiratory crackles, known as “Velcro rales.” As the disease progresses, rales can extend toward the upper lung zones. Clubbing is found in up to 50 percent of patients with IPF. Resting arterial oxygen saturation may be normal but frequently falls with exercise. Extrapulmonary involvement does not occur in IPF. Thus, the physical examination is otherwise unremarkable in the early stages of the disease. Later in the course of disease weight loss, cyanosis, and signs of pulmonary hypertension with cor pulmonale may become apparent. Findings at this stage include an accentuated pulmonic second heart sound, presence of a third heart sound, a right ventricular heave, and edema of the lower extremities. Routine Laboratory Evaluation A routine laboratory evaluation is not helpful except for its role in ruling out other causes of diffuse parenchymal lung disease. Polycythemia is a rare finding despite the frequency of chronic hypoxemia. Elevation of systemic inflammatory markers (i.e., erythrocyte sedimentation rate or C-reactive protein level) or the presence of hypergammaglobulinemia is found in IPF, yet such findings are nondiagnostic. The lactate dehydrogenase activity is often elevated but is also nonspecific. Up to 30 percent of patients with IPF may have positive tests for antinuclear antibodies or rheumatoid factor. These titers generally are not high. The presence of a high titer of autoantibodies suggests connective tissue disease, while an elevated angiotensin-converting enzyme level or antineutrophil cytoplasmic antibodies indicate alternative diagnoses. Pulmonary Function and Physiology Pulmonary function tests in IPF normally identify a restrictive ventilatory defect with reductions of total lung capacity (TLC), functional residual capacity (FRC), and residual volume (RV). These changes are the result of diminished lung compliance. Pressure-volume studies will yield a curve that is shifted downward and to the right, indicative of lost lung compliance. As the disease progresses, compliance decreases

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further. Forced expiratory volume in one second (FEV1 ) and forced vital capacity (FVC) also are decreased. Unless a complicating airways disease is present (e.g., chronic obstructive pulmonary disease), isovolume flow rates are preserved. While functional alterations associated with small airways disease have been reported in IPF, this description is exclusive to smokers and likely represents a concurrent smoking-related airways disorder. Impaired gas exchange is demonstrated by the measurement of a lowered diffusing capacity. The decline of diffusion capacity may even precede the development of abnormal lung volumes. Resting arterial blood gases are usually normal in IPF or else they will reveal mild hypoxemia with a respiratory alkalosis. Patients with IPF have tachypnea and often develop a pattern of rapid shallow breathing. The work of breathing is increased in IPF. While no chemical changes can explain the observed hyperventilation, it is felt that rapid respiratory rates are secondary to altered mechanical reflexes resulting from an increase in elastic recoil and elastic load. The major cause of hypoxemia is ventilation and perfusion (V/Q) mismatching, not anatomic shunting or reduced oxygen diffusion, as was previously suspected. Patients with IPF have been shown to develop sleep disturbances, highlighted by fragmented sleep phases and REMrelated cyclical hypoxemia. These disturbances are present even in the absence of sleep apnea. As a result, the Joint Statement of the ATS/ERS on the diagnosis and treatment of IPF recommends the use of supplemental oxygen for all patients with IPF who demonstrate nocturnal hypoxemia. During exercise, patients with IPF and may exhibit evidence of pulmonary hypertension, even in early cases that have preserved lung function at rest. Pulmonary hypertension can also be present at rest, and is an expected finding, once the vital capacity drops below 50 percent of predicted or the diffusing capacity falls below 45 percent of predicted. The presence of pulmonary hypertension may be a predictor of poor outcome yet may not correlate with lung function. Exercise Testing The alveolar-to-arterial oxygen gradient (A-a gradient) is wide in patients with IPF reflecting V/Q mismatching. With exercise the A-a gradient widens further. Diffusion impairment also becomes a relevant factor during exercise. As a result, arterial oxygen pressure (Pao2 ) and arterial oxygen saturation (Sao2 ) fall during exercise. It is important to note that measures of blood oxygen tension at rest do not accurately predict the magnitude of abnormality seen during exercise. The most sensitive method for monitoring gas exchange abnormalities in IPF is formal cardiopulmonary exercise testing. Normal persons will increase their minute ventilation during exercise by means of increased tidal volume (VT ). Persons with IPF can only increase their minute ventilation during exercise through an increase in respiratory rate. In IPF, the fraction of dead space-to-tidal volume (VD /VT , dead space fraction) is elevated at baseline yet remains stable during exercise due to subsequent increases in perfusion. An increase of

the dead space fraction during exercise should raise concern for concurrent pulmonary vascular disease. Radiology Conventional Chest Radiograph

The chest radiograph is abnormal in nearly all patients with IPF (Fig. 68-1). Yet, in up to 10 percent of patients with histologically proven IPF, the chest film might be normal. In most of these cases, the use of HRCT uncovers evidence of the disease. The most common abnormalities seen on a conventional chest film are reticular opacities. In other words, there is an appearance of net-like linear and curvilinear densities. These markings are found bilaterally, asymmetrically at times, and have a predilection for the lower lobes. A course reticular pattern, which takes the form of translucent “honeycombing,” will emerge late in the course of disease and portends a poor prognosis. The chest radiograph lacks specificity for the diagnosis of IPF. The correct diagnosis is made on the conventional radiograph in fewer than 50 percent of cases. In addition, the interpretation of conventional radiographs with an interstitial pattern shows poor interobserver agreement. Studies have examined this particular characteristic and report that concordance between radiologists is only 70 percent. High-Resolution Computed Tomography

The development of the high-resolution CT scanner has revolutionized the diagnostic evaluation of the interstitial lung diseases. HRCT allows a detailed examination of the lung parenchyma by creating 1- to 2-mm-thin slices of the chest. HRCT uses a computerized reconstruction algorithm that maximizes spatial resolution. This generates much improved image clarity such that the specificity of interpretations is increased, interobserver variability is reduced, and the overall accuracy of diagnosis is enhanced. HRCT scanning allows for the earlier diagnosis of IPF and permits the identification of alternate patterns of disease. The primary role of HRCT in the diagnostic evaluation of ILD is the discrimination of typical IPF from the other interstitial lung diseases. The appearance of IPF on HRCT is characterized by patchy, predominantly peripheral, predominantly subpleural, and bibasilar reticular opacities (Fig. 68-2). Groundglass opacities can be found, but should occupy no more than a limited amount of territory. Areas that are severely involved with reticular markings may also demonstrate traction bronchiectasis. The presence of subpleural honeycombing (small, round translucencies with a density equal to that of air), traction bronchiectasis and thickened interlobular septae will increase the specificity of the CT scan for diagnosing IPF. These findings constitute the HRCT pattern that defines a “confident” or “certain” radiographic diagnosis of IPF. Several studies have examined the diagnostic accuracy of HRCT scans in IPF. Studies were conducted in which observers were asked to determine a radiographic diagnosis that was then compared with the histopathology of UIP as

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Figure 68-2 Computed tomography scan illustrates the ‘‘classic” features of idiopathic pulmonary fibrosis (IPF). Bilateral, peripheral, and subpleural reticular infiltrates are evident. The presence of advanced fibrosis is indicated by honeycomb changes (arrowhead) and traction bronchiectasis (arrow). These features permit experienced clinicians to make a confident radiographic diagnosis of IPF.

the “gold standard.” In the hands of experienced observers, the “confident” radiographic diagnosis of IPF has a reported specificity for IPF histology, which exceeds 90 percent. Therefore it has become apparent that, in the right clinical setting, an experienced radiologist can diagnose IPF by the HRCT with considerable accuracy, obviating the need for biopsy. However, the “confident” HRCT is not a sensitive tool for the diagnosis of IPF. The full spectrum of a “confident” radiographic pattern will only be seen in two-thirds of biopsy proven IPF. One-third of IPF cases will not show a “confident” CT pattern and would be missed if the HRCT was relied upon exclusively (Fig. 68-3). HRCT patterns other than the “confident” pattern should proceed to surgical lung biopsy for further evaluation. Some of these biopsies will identify an alternative disease. Some features of the HRCT have been identified that suggest a diagnosis other than IPF. These features include ground-glass opacities, multiple nodules, the presence of significant lymphadenopathy, or a predominance of lesions in the upper lobes. The appearance of ground glass on a HRCT invokes a differential diagnosis that includes heart failure, NSIP, COP, DIP, RB-ILD, and hypersensitivity pneumonitis. Fine nodules are suggestive of hypersensitivity pneumonitis, granulomatous infection, or metastatic malignancy. Upper lobe disease is the predominant pattern in PLCH, hypersensitivity pneumonitis, a variety of pneumoconioses, sarcoidosis, and eosinophilic pneumonia. Lymphadenopathy is associated with sarcoidosis and other granulomatous diseases. These atypical features may yet represent IPF when seen in conjunction with reticular opacities. The specificity as regards

Idiopathic Pulmonary Fibrosis

Figure 68-3 Computed tomography scan of an 81-year-old man with biopsy-proven idiopathic pulmonary fibrosis. A peripheral distribution of reticular opacities is demonstrated. Honeycombing and traction bronchiectasis are notably absent. In the absence of specific findings, a surgical lung biopsy was needed to make a diagnosis.

the diagnosis of IPF is markedly reduced when an atypical pattern is found on HRCT. Expert observers have described such equivocal CT scans using terms such as “probable IPF,” “possible IPF,” and “likely IPF.” The specificity of “likely IPF” is estimated to be around 75 percent. Patients with a “likely” CT scan should be referred for biopsy. Bronchoalveolar Lavage An enormous amount of scientific information has been obtained by analyzing the content of bronchoalveolar lavage (BAL) fluid from patients with IPF. Notable increases of immune cells (neutrophils, eosinophils, and activated alveolar macrophages) are present in BAL fluid from IPF. In addition, BAL has aided in the identification of cytokines, growth factors, and other cellular products that are now implicated in the pathogenesis of IPF. As a research tool, BAL has been immensely valuable. The role of BAL in the clinical diagnosis of IPF remains limited. Though much effort has been invested in evaluating the clinical utility of this modality, study results have been contradictory and generally disappointing. Increased numbers of neutrophils are found in the BAL in 70 to 90 percent of all patients with IPF. Increased numbers of BAL eosinophils are found in 40 to 60 percent of IPF patients. A lymphocytosis of the BAL fluid is noted in 10 to 20 percent of IPF. Most samples of BAL from IPF demonstrate simultaneous increases of several effector cell types. Other fibrosing lung diseases exhibit similar increases of inflammatory cells. Unfortunately, studies have failed to demonstrate a clear distinction among pulmonary diseases based upon the predominant type of cell in the BAL fluid. The diagnosis of IPF calls for the exclusion of alternative diagnoses and, in this regard, BAL fluid analysis can

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be helpful. Appropriate laboratory studies of the BAL fluid may demonstrate the presence of tumor, infection, Langerhans’ cells, or occupational dusts. Any of these findings may substantiate a diagnosis other than IPF. The presence of a lone increase in BAL lymphocytes is unusual for IPF as this occurs in less than 10 percent of IPF patients. Lone BAL lymphocytosis should suggest a differential diagnostic list that includes mycobacterial infection, sarcoidosis, hypersensitivity pneumonitis, NSIP, COP, LIP, and drug-induced alveolitis. Pathology A surgical lung biopsy is recommended to confirm all cases of suspected IPF. A biopsy may not be necessary in cases with a “confident IPF” HRCT pattern in which the diagnosis is already clear. Biopsy may be achieved by either open thoracotomy or by video-assisted thoracoscopy (VATS). VATS is preferred as it has been associated with less morbidity and shorter hospital stays compared with open biopsy. A surgical lung biopsy provides the best sample from which to distinguish UIP form other forms of IIP. Transbronchial biopsies are not helpful in identifying IPF lesions because of the small size of the sample. The decision to perform a surgical lung biopsy can be difficult. Relative and absolute contraindications to surgery must be considered before electing to perform a surgical lung biopsy. The decision to obtain a surgical biopsy requires a balance of the cost and complications of surgery against the benefit of an accurate diagnosis. While a biopsy provides vital information in all cases of ILD, the biopsy is particularly useful in the setting in which clinical or radiographic features are not typical for IPF. In this situation, it is possible to uncover a different diagnosis with resultant change in the prognosis and approach to therapy.

The gross appearance of an IPF sample may be normal but often has a distinctive nodular pleural surface that has been likened to cirrhosis. The histopathological lesion associated with IPF is usual interstitial pneumonia (UIP). This lesion is defined by a variegated structure. Normal lung alternates with patchy collagen fibrosis (Figs. 68-4 and 68-5). The fibrosis takes the form of alveolar septal thickening with a predominantly subpleural distribution. Whirls of fibroblasts embedded in a loose extracellular matrix embody the fibroblastic foci that are found in numerous quantities at the leading edge of dense scar (Figs. 68-4 and 68-5). Interstitial inflammation is present but remains scant and confined to areas of fibrosis. This limited inflammation consists of lymphocytes and plasma cells. Associated hyperplasia of the type 2 pneumocytes is found within areas of active inflammation. Areas that contain dense collagen may develop cystic structures that may be filled with mucin or lined by bronchiolar epithelium. These cysts are referred to as microscopic honeycomb change. Hyaline membranes and organized alveolar exudates are absent. Occasionally alveolar macrophages are present. The UIP pathological pattern exhibits a wide range of severity with regard to the extent of honeycomb change and the extent of involved lung. A history of smoking may alter the histopathological appearance of UIP. Emphysematous change can be superimposed upon UIP. Pigmented alveolar macrophages, the hallmark feature of RB-ILD and DIP pathological patterns, may be present in small number in UIP lesions from former or current smokers. The UIP pattern can be found in other diseases besides IPF. The presence of granulomas in a UIP lesion favors a diagnosis of fibronodular sarcoidosis or chronic hypersensitivity pneumonitis. Asbestos bodies found within a UIP pattern suggest the diagnosis of asbestosis. The histopathological

Figure 68-4 A. Low-magnification photomicrograph of usual interstitial pneumonia (UIP) showing the characteristic heterogeneous involvement of the parenchyma. Zones of interstitial fibrosis are seen alternating with areas of normal lung. B . Higher magnification demonstrates enlarged cystic airspaces lined with hyperplastic alveolar epithelium (arrowheads). Beneath the mucosal layer is an advancing region of young fibrosis containing loose extracellular matrix (pale pink staining) and fibroblasts (arrows).

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mended by the consensus opinion of a panel of experts who are endorsed by the American Thoracic Society and the European Respiratory Society. These guidelines were published in the year 2000. According to these guidelines the diagnosis of IPF is considered “likely” if the patient is an immunocompetent adult and all four major criteria are satisfied in addition to three out of the four minor criteria. Although these criteria have not been prospectively analyzed, they are useful in situations where a surgical lung biopsy is not possible. The criteria are as follows: Major criteria ◦ Exclusion of other known causes of ILD, such as certain drug toxicities, environmental exposures, and connective tissue diseases ◦ Abnormal pulmonary function studies that include evidence of restriction (reduced VC often with an increased FEV1 /FVC ratio) and impaired gas exchange [increased AaPO2 with rest or exercise or decreased DlCO ] ◦ Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT scans ◦ Transbronchial lung biopsy or bronchoalveolar lavage (BAL) showing no features to support an alternative diagnosis Minor criteria ◦ Age greater than 50 years ◦ Insidious onset of otherwise unexplained dyspnea on exertion ◦ Duration of illness greater than or equal to 3 months ◦ Bibasilar, inspiratory crackles (dry or “Velcro” type in quality)

Figure 68-5 Scanning view of usual interstitial pneumonia (UIP) demonstrates the characteristic variegated appearance of UIP. Note the honeycomb change (arrowheads) present in the region of dense fibrosis adjacent to the pleural surface. A fibroblast focus (arrow) is seen at the leading edge of advancing fibrosis.

pattern of UIP can also be found in several conditions other than IPF. UIP can be found in association with connective tissue diseases, asbestosis, chronic hypersensitivity pneumonitis, the Hermansky-Pudlak syndrome, neurofibromatosis or in the setting of a toxic drug reaction (typically after administration of either bleomycin, methotrexate, nitrofurantoin or amiodarone [this is a partial list]). The identification of these conditions is largely a matter of correlation with the clinical history. It is important to note that the presence of honeycombing on biopsy is a nonspecific finding with a broad differential. Honeycombing is a common end point for a myriad of pathological processes. Although honeycombing carries the connotation of end-stage fibrosis it can also occur in a focal distribution after any lung injury. Seen alone, honeycombing is not indicative of idiopathic pulmonary fibrosis. Diagnostic Criteria and Algorithm Definite Diagnosis

The definite diagnosis of IPF can only be made in the presence of a surgical (thoracoscopic or open) lung biopsy. Criteria for the definite diagnosis of IPF include: (a) a biopsy with the histologic appearance of UIP; (b) exclusion of other known causes of interstitial lung disease such as connective tissue disease, radiation, drug, or environmental exposures; (c) abnormal pulmonary physiology with evidence of restriction and/or impaired gas exchange (at rest or with exercise); (d) bibasilar reticular abnormalities with minimal appearance of ground-glass opacities seen by either conventional chest radiography or HRCT. In the very early stages of disease the pulmonary function tests or imaging studies may be nearly normal. The ‘‘Probable” or ‘‘Likely” Diagnosis

In the absence of a surgical biopsy, the diagnosis of IPF remains uncertain. However, a set of clinical criteria are recom-

Since the publication of these criteria, several studies have demonstrated the poor predictive value of BAL fluid concerning the diagnosis of ILD. Without a history to suggest a diagnosis other than IPF, the yield of a BAL examination or a transbronchial biopsy specimen is inherently low. Meanwhile, additional data have accumulated to highlight the accuracy of HRCT. It seems that bronchoscopy may no longer be warranted as a routine part of the evaluation for IPF. Until more research is done, this remains a matter of opinion.

Natural History and Prognosis The natural history of IPF has never been fully defined. It is has been demonstrated that physiological function declines over time. Studies utilizing the modern definition of IPF have reported median survival between 2 to 5 years from the time of diagnosis. There are few, if any, reports of long-term survival with biopsy proven IPF/UIP. Early studies identified older age, male sex, significant dyspnea, severe physiological abnormalities, advanced fibrosis and a poor response to therapy as factors predictive of shortened survival. One limitation of these earliest studies was their retrospective design. In addition, the first studies of IPF prognosis did not adhere to the modern, pathologically based definition of IPF.

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Additional factors have combined to create barriers preventing the further, more rigorous description of the natural history of IPF. First, the diagnosis of IPF can be challenging and, not infrequently, the presence of “early” disease gets overlooked. Patients develop IPF in the later decades of life and often attribute their symptoms to old age. When their disease eventually comes to medical attention, there may be further delay in diagnosis because the symptoms are nonspecific. Most patients with IPF are evaluated for other diseases before a diagnosis of pulmonary fibrosis is considered. Moreover, the interstitial markings found on a chest radiograph are subtle and tend to go unnoticed or else simply get disregarded as clinically unimportant. Experts in IPF agree that patients usually have symptoms for 2 or more years prior to receiving a definitive diagnosis. Therefore it is apparent as to why most cases of known IPF present with an advanced disease state. The epidemiologic and prognostic data that describe IPF have been derived from such cohorts of “late” disease. “Early” disease is infrequently encountered and information describing the course of “early” disease has come from retrospective analyses of cohorts with “late” disease. A cohort of patients with “early IPF” has never been followed prospectively. However, the advent of CT scanning to search for cancer has had the secondary benefit of identifying patients with IPF in the “preclinical” stage of the disease, during which the symptom of breathlessness has yet to surface. In addition, clinical trials are now enrolling patients with preserved lung function in prospective studies that will provide valuable new insights into the natural history of IPF. Pathological Predictors One of the most important features of the spectrum of illness encompassed by IIP is the fact that pathological patterns predict survival. In the late 1990s it was recognized that the UIP pathological pattern had a precise correlation with clinical parameters and with outcome. Survival is significantly worse among patients whose biopsy contains a UIP pattern as compared to either NSIP or other patterns of fibrosis. Within biopsy specimens, specific traits have also been correlated with survival. The degree of cellularity does not seem to affect survival nor does the degree of fibrosis. However, the presence of “young” connective tissue, characterized by multiple fibroblastic foci, is predictive of shorter survival. Fibroblastic foci have been linked to high mortality and large declines in physiological measures such as the forced vital capacity and diffusion capacity. Physiological Predictors Recently, three groups of researchers working independently made similar observations concerning the relationship between physiological changes and survival in IPF. Interestingly, it was observed that physiology might be a stronger predictor of outcome than histopathological pattern. One study examined a cohort of patients with fibrotic lung disease who underwent surgical biopsy. Half of these patients had a UIP pattern, while the other half had fibrotic

NSIP. The goal was to determine the prognostic significance of pathological patterns compared with the predictive value of baseline pulmonary function or 1-year trends in pulmonary function. It was found that trends in pulmonary function were the only significant prognostic determinant. Neither pathology nor baseline pulmonary function was predictive of outcome. Another study exclusively examined patients with biopsy-proven IPF. It was discovered that a change in physiological parameters predicts survival. Specifically, at 6 and 12 months, a 10 percent decline in forced vital capacity or a 5 mmHg increase in AaPO2 were associated with a poor prognosis. This observation was unrelated to baseline pulmonary function that exhibited no predictive value of its own. Yet another group looked at patients with UIP and NSIP pathologies. In a multivariate regression analysis examining the prognostic contribution of several factors, a 6-month decrease in forced vital capacity was found to be an independent risk for mortality. The regression model controlled for pathological diagnosis, gender, smoking history, and the baseline vital capacity. None of these other factors yielded significant prognostic information. An issue that affects the predictive value of physiological variables in IPF is the confounding influence of coexistent emphysema. This problem is addressed by the composite physiological index (CPI), which corrects for emphysema by combining several physiological measures into a single weighted score. The formula for the CPI includes diffusion capacity, FVC and FEV1 in its calculations. The CPI was validated by comparison to HRCT. In addition, it was shown that the CPI is a more accurate prognostic determinant than any individual test of pulmonary function. Radiographic Predictors The utility of HRCT in predicting the outcome of IPF has been demonstrated. When biopsy-proven IPF patients were followed for 3 years it was found that HRCT honeycombing predicts the worst survival. Fibrosis measured by HRCT and fibrosis seen on histology were equivalent with respect to ensuing death or disease progression. This finding is supported by another study comparing HRCT patterns to biopsy patterns and outcomes. Patients who had both a HRCT and a biopsy were analyzed and it was found that a HRCT pattern consistent with UIP correlated pathologically with the UIP pattern. However, an indeterminate HRCT pattern could be a manifestation of either UIP or NSIP. Patients with combined pathological UIP and radiographic “confident UIP” had a worse outcome compared to patients with pathological UIP and an indeterminate HRCT. Composite Scores Some authors have proposed that a composite scoring system for IPF would have better predictive value than measuring individual disease-related factors. The first clinical, radiological and physiological (CRP) scoring system was developed in 1986 and employed seven variables that accounted

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for parameters such as dyspnea, specific radiographic findings, and physiological function. This CRP score was validated through comparison to histopathology in a group of 26 patients. No single component of the CRP score had a better correlation than the composite score. In 2001, a new CRP score was derived to predict death rather than just histopathology. A large cohort of patients was followed prospectively to devise the new CRP score, utilizing multivariate statistical models to identify significant diseaserelated parameters. The new CRP score accounts for age, smoking status, the presence of clubbing, total lung capacity, arterial oxygen during maximal exercise, radiographic infiltrates, and radiographic findings consistent with pulmonary hypertension. The total score is calculated on a scale from 0 to 100, with higher scores indicating more severe disease. Fiveyear survival can be predicted in individual patients by calculating a CRP score employing the published formulas and then referencing published survival curves. An abbreviated version of the CRP score was simultaneously derived using a similar statistical model. Yet the abbreviated CRP score offers simplicity by omitting the exercise test, which may be impractical for patients with advanced disease. The abbreviated CRP score provides prognostic information comparable to the complete score and has a practical advantage. An abbreviated CRP score can be calculated for any patient following a single office visit. Acute Exacerbation of IPF Japanese investigators made the initial observation that patients with IPF can experience episodes of sudden decline, which they characterized as acute exacerbations. Recent observations from the placebo arm of two randomized clinical trials have suggested that acute exacerbations may be more common that previously appreciated. The acute exacerbation of IPF (AE-IPF) is characterized by a sudden worsening of symptoms and has been associated with hypoxemia and new radiographic infiltrates. It is important in making the diagnosis of AE-IPF to rule out infection, congestive heart failure, and pulmonary embolism. AE-IPF typically occurs in patients with established IPF; however, it has been recognized that AE-IPF can form the initial presentation of IPF as well, mimicking AIP. Patients with established IPF satisfy the criteria for an acute exacerbation if they have: (a) acute worsening of dyspnea within the last month; (b) deterioration from baseline in measures of pulmonary function or gas exchange; (c) new infiltrates on plain chest film or CT; and (d) the absence of other identifiable causes for decline. The initial presentation of IPF as AE-IPF is recognized when a patient with acute respiratory failure meets the ATS/ERS diagnostic criteria for definite IPF (biopsy reveals UIP) or presumptive IPF (satisfies major and minor diagnostic criteria, including a confident HRCT). The radiograph in AE-IPF demonstrates ground-glass opacification superimposed on the usual subpleural linear opacities. Histopathological examination of AE-IPF commonly reveals a UIP pattern with superimposed diffuse alveolar damage (DAD) characterized

Idiopathic Pulmonary Fibrosis

by diffuse alveolar septal thickening within a pale matrix that includes hyaline membranes and fibrin. UIP with superimposed organizing pneumonia has also been reported in AE-IPF. The prognosis of AE-IPF is poor. Series of patients with AE-IPF reported in-hospital mortality rates between 78 and 96 percent. Mortality is strongly associated with the need for mechanical ventilation.

PATHOGENESIS IPF is a complex disorder and many pathogenic events have been observed. No unifying hypothesis explaining all of the abnormalities has yet emerged. The inciting event for lung injury is still unknown. In fact, it is not certain that the inciting event is exogenous or endogenous. Although more questions than answers currently exist, great strides are being made in elucidating new mechanisms in pathogenesis. We seem to be entering a new era in the understanding of the biology of IPF.

Inflammation The concept that dominated the field in the 1970s and 1980s has been described as the â&#x20AC;&#x153;inflammatory theoryâ&#x20AC;? of pulmonary fibrosis. This paradigm was based largely on the observation that bronchoalveolar lavage fluid from patients with IPF had increased numbers of inflammatory cells (mostly neutrophils and eosinophils) relative to normal individuals. The concept that permeated the literature in that era was that IPF resulted from an unremitting inflammatory response to an exogenous insult, culminating in progressive fibrosis. By targeting the inflammatory response, the belief was that fibrosis could be limited or prevented. Unfortunately, it now appears that the data are more likely explained by structural abnormalities in lung architecture (traction bronchiectasis) such that inflammatory cell trafficking is altered. That is to say, the airway inflammation is likely a result, rather than a cause, of the fibrosis. Although the importance of chronic inflammation in the pathogenesis of IPF remains controversial, one should be cautious in omitting its contribution to disease progression.

Epithelial Cell Apoptosis An emerging body of literature suggests that alveolar epithelial cell injury and apoptosis are important features of pulmonary fibrosis. Studies of human IPF tissue using electron microscopy have demonstrated injury and apoptosis of alveolar epithelial cells. Bronchoalveolar lavage from patients with IPF has established the presence of pro-apoptotic proteins. In the bleomycin model of lung injury and fibrosis in animals, fibrosis can be abrogated by various approaches to inhibit epithelial cell apoptosis. Studies have observed a decrease in experimental fibrosis by inhibiting the Fas-Fas ligand pathway. Inhibitions of angiotensin production and caspase activation have also been shown to reduce experimental fibrosis.

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Evidence suggests that fibroblasts produce angiotensin peptides that lead to epithelial apoptosis. Other researchers have demonstrated that transforming growth factor-β (TGF-β) is involved with promoting epithelial cell apoptosis. Oxidant injury may also promote epithelial cell death and several studies of IPF patients have confirmed excessive oxidant production as well as glutathione deficiency. Tumor necrosis factor-β (TNF-β) has been shown to promote alveolar epithelial cell apoptosis in vitro. In a mouse model, knockout of the TNF-β receptor confers resistance to bleomycin-induced lung fibrosis; while overexpression of TNF-β in the mouse has been associated with an increase in experimental fibrosis. Patients with IPF are known to exhibit an exaggerated expression of TNF-β which may contribute to epithelial injury.

Basement Membrane Injury A unique feature of the UIP pathological pattern is a loss of integrity of the subepithelial basement membrane. This has been definitively demonstrated through the use of electron microscopy. Basement membranes in IPF are denuded of the usual type I pneumocytes. It is theorized that loss of this protective epithelial barrier results in further oxidative injury that degrades basement membranes. At the same time it appears that hyperplastic type II pneumocytes are abundantly present. This likely represents an attempt at epithelial cell regeneration. While the exposed basement membrane may provide the signal for epithelial growth, new epithelial cells cannot attach to a damaged membrane. The result is a “frustrated” epithelial cell response with failure to signal a termination of epithelial cell proliferation. Further examination of tissue from patients with IPF has confirmed an irregular pattern of alveolar epithelial cell proliferation, concurrent with dysregulation of the proteins that control the cell cycle. An accumulation of growth factors in IPF may originate from the persistent proliferative response of epithelial cells. A downstream consequence of “frustrated” epithelial cell regeneration would be recruitment of fibroblasts and myofibroblasts, through the release of such growth factors. In essence, the signal to recruit and maintain a pool of mesenchymal cells (fibroblasts) might originate from an inability to successfully re-epithelialize the alveolar lining surface.

Growth Factors Various growth factors that influence fibroblast function have been shown to be produced in the lung tissue of patients with IPF and also shown to mediate the pathogenesis of experimental fibrosis. Examples include keratinocyte growth factor, TGF-α, TGF-β, insulin-like growth factor-1 (IGF-1), platelet-derived growth factors (PDGF-A and PDGF-B), fibroblast growth factor-2, and hepatocyte growth factor. Many of these growth factors activate tyrosine kinase signaling pathways that promote fibroblast proliferation and matrix production. Growth factors such as IGF-1 may also promote fibroblast survival. IGF-1 has been shown to inhibit

apoptosis by activating the Akt survival pathway, which may have important consequences for maintenance of a profibrotic environment. TGF-β is a critical mediator of lung fibrosis in animal models and has attracted the attention of researchers attempting to control fibrogenesis. Several studies have shown that antagonizing TGF-β prevents the development of lung fibrosis. Targeted overexpression of TGF-β been shown to produce progressive pulmonary fibrosis. Recent evidence suggests that TGF-β has the capacity to promote epithelial cell transformation into a mesenchymal phenotype.

Th1 and Th2 Cytokines Data suggest that a cytokine imbalance may exist in IPF. The link between Th2 cytokines and tissue fibrosis has been established in animal models. Overexpression of interleukin-13 (IL-13) in the lung using transgenic mice has been shown to result in accumulation of active TGF-β and increased tissue fibrosis. Human data demonstrating a cause and effect relationship for Th2 cytokines are lacking. However, studies have shown that there is increased expression of mRNA for Th2 cytokines (IL-4, IL-5, and IL-13) in lung tissue of patients with IPF. In addition, data have been reported suggesting that IPF may represent a relative Th1 deficiency (e.g., IFNγ). In a small study, patients with IPF who received IFN-γ for 12 months were found to have an improvement in lung function. However, a phase 3 randomized, double-blinded, placebo-controlled trial evaluating the efficacy of IFN-γ1b found no effect on either the forced vital capacity or the resting alveolar–arterial oxygen gradient after 48 weeks. This same phase 3 trial observed an unanticipated trend toward a survival benefit from IFN-γ1b. A survival benefit must still be confirmed through prospective study before any conclusions can be made regarding the efficacy of IFN-γ in the treatment of IPF.

Angiogenesis and Angiostasis Parallels have been drawn between the biology of IPF and the biology of cancer. The unremitting recruitment and maintenance of an altered fibroblast phenotype with generation of myofibroblasts that fail to die is reminiscent of the transformation of cancer cells. A hallmark of tumorigenesis is the production of new blood vessels that facilitate tumor growth. An important aspect of progressive fibrosis is increased angiogenic activity, which has been established in studies done on animals and humans. An imbalance between angiogenic chemokines (e.g., IL-8 and ENA-78) and angiostaxic chemokines (e.g., IP-10) has been suggested as a possible mechanism promoting angiogenic activity in IPF. IP-10 is induced by IFN-γ and this may partially explain the beneficial effects of IFN-γ described above. In addition to reports of increased angiogenesis in IPF, there are conflicting reports suggesting that angiogenesis is hampered in IPF by decreased expression of VEGF and a reduction of endothelial cell proliferation. The fibroblast foci

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are particularly lacking in the expression of angiogenic proteins. This is most evident when a direct comparison is made to protein expression within the granulation tissue of organizing pneumonia. It is possible that enhanced angiogenesis may occur during some stage of the development of UIP, whereas angiostaxis is dominant during other stages.

Matrix Turnover The hallmark of IPF is an exorbitant production of extracellular matrix molecules, including collagen, hyaluronan, and a variety of proteoglycans. There is clearly an imbalance between the production of extracellular matrix and its subsequent degradation. Fibroblasts isolated from IPF tissue demonstrate an increased production of TIMPs (tissue inhibitor of metalloproteinases). TIMPs are inhibitors of matrix degradation. One property of TGF-β is to promote the production of TIMPs. It is unclear what role matrix degradation plays in the pathogenesis of progressive fibrosis. On the one hand, matrix degradation is essential for removal of scar tissue. Meanwhile, a recent study suggests that matrix degradation products are the stimulus for inflammation that promotes progressive fibrosis. One possibility is that matrix degrading enzymes are involved in the destruction of basement membranes, triggering a cascade of events beginning with “frustrated” epithelial cells and resulting in a fibroproliferative response. Gene expression profiles, measured by microarray analysis, provide further evidence for the involvement of matrix degrading enzymes in IPF. One microarray study implicated matrilysin, a novel matrix degrading enzyme, in the pathogenesis of IPF.

The Fibroblast The concept that fibroblasts from patients with IPF have a unique phenotype is generally accepted, although the specifics of this phenotype differ from one study to the next. Two groups have observed that a large number of fibroblast foci within lung biopsy correlates with a poor prognosis, highlighting the importance of fibroblasts in IPF. Phenotypes First, it was observed that fibroblasts from different regions of the lung had dissimilar growth rates. Subsequently other properties of IPF fibroblasts have been found which differentiate them from normal lung fibroblasts. These properties include altered rates of proliferation and apoptosis, different expression of TNF-α receptors, and differing rates of production of TIMPs, prostaglandins, hyaluronan, and other mediators. Some discrepancy exists as to whether IPF fibroblasts proliferate more or less rapidly in comparison to normal lung fibroblasts. Studies have also suggested increased apoptosis consistent with rapid turnover of fibroblast populations. Much attention has been focused recently on the role of the myofibroblast in the pathogenesis of IPF. Myofibroblasts have been described in a contractile phase in fibroblastic foci from IPF lung biopsies. The defining characteristic of

Idiopathic Pulmonary Fibrosis

the myofibroblast is the production of new collagen while simultaneously staining positive for α-smooth muscle actin. Myofibroblasts have contractile properties and, in normal wound healing, myofibroblasts appear transiently. Mechanisms that regulate the phenotype and maintenance of myofibroblasts in IPF are largely unknown. Myofibroblasts have been shown to accumulate in bleomycin-induced lung fibrosis. Immunohistochemical studies have suggested that they are important in the production of newly synthesized collagen. In the bleomycin model, however, myofibroblasts are present transiently and largely vanish from the lung within 21 days. Telomerase-expressing fibroblasts have been described in an animal model of pulmonary fibrosis. It has been demonstrated that this fibroblast phenotype differentiates in vitro under the influence of basic fibroblast growth factor. Telomerase catalyzes the addition of telomeric DNA, which has been associated with increased cellular life span and cellular immortality. Some evidence suggests that telomeraseexpressing fibroblasts may represent an intermediate cell that can further differentiate to the myofibroblast. The role of telomerase-expressing fibroblasts in human disease is unclear. Fibroblast Recruitment and Maintenance Differentiation from Normal Fibroblasts

TGF-β has been shown, in vitro, to induce the expression of α-smooth muscle actin in normal lung fibroblasts and promote contractile activity. TGF-β has also been shown to inhibit apoptosis of myofibroblasts that are challenged with IL-1. It is not known whether normal fibroblasts can differentiate into myofibroblasts in vivo. PDGF-A has been shown to be required for lung alveolar myofibroblast development during mouse embryogenesis. PDGF-A is important for fibroblast migration in vitro. The role of PDGF-A, in vivo, is less well characterized. In addition to growth factors, thrombin has been shown to differentiate normal lung fibroblasts to a myofibroblast phenotype in vitro. Bone Marrow–Derived Precursors

Evidence is accumulating that suggests that bone marrow– derived cells may contribute to the pool of lung fibroblasts in IPF. In an animal model it has been shown that bone marrow–derived cells migrate to the lung and assume a fibroblast phenotype after injury. These bone marrow–derived cells do not express α-smooth muscle actin, nor do they express α-smooth muscle actin when stimulated in vitro with TGF-β. These fibroblasts do not seem capable of acquiring the myofibroblast phenotype. Another group of researchers observed that fibrocytes migrate into the lungs of animals following bleomycin injury. The fibrocyte is a recently recognized cell type of hematopoietic origin which circulates in the peripheral blood and has been shown to play a role in wound repair. Fibrocytes have been implicated in the pathogenesis of hypertrophic scars, scleroderma, and airway fibrosis in asthma. Recent evidence suggests that fibrocytes may play a similar role to the fibroblast in IPF.

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Epithelial-Mesenchymal Transformation

Another possibility is that the fibroblasts in IPF are derived from the alveolar epithelium. A transformation of cell type from epithelium to mesenchyme is a well-documented phenomenon that takes place during embryogenesis. Epithelialmesenchymal transition (EMT) has been demonstrated in tissue culture in response to stimuli with various growth factors. Recently, researchers have observed EMT occurring in adult cells in fibrotic kidney tissue. A new study has described lung tissue from patients with IPF that expressed both epithelial and fibroblast markers, suggesting that EMT plays a role in IPF. A unifying theory might suppose that “frustrated” epithelial regeneration could lead to activation of aberrant signaling pathways, i.e. growth factors, which triggers mesenchymal transformation. Evidence to support this phenomenon has been provided by the finding of Wnt/β-catenin signaling in IPF epithelium. The Wnt/β-catenin pathway is present in early lung development and its presence in adult disease suggests recapitulation of morphogenesis.

Progression through Various Pathological Patterns (NSIP to UIP) The natural history of IPF is not well understood. In the absence of longitudinal studies of biopsy specimens from IPF patients, controversy exists concerning the difference between “early” and “late” disease. Leading pathologists have promoted the concept that “early” and “late” IPF manifest the same UIP pathological pattern, only “late” disease has more of it. Several observations suggest that the UIP pattern cannot represent an “early” stage of disease but rather corresponds to the intermediate or possibly end-stage of illness. For example, a UIP specimen contains heterogeneous areas of lung. Normal lung is juxtaposed with areas of active fibrosis while other regions comprise end-stage honeycomb fibrosis. This has often been described as “temporal” heterogeneity with the connotation that the variegated pathological patterns are of different ages. Therefore UIP is an advanced lesion with evidence in the histopathology that a disease process has been underway for some considerable amount of time. This “temporal” heterogeneity has never been proved, since a biopsy specimen can only represent a single point in time. The time course of the UIP lesion has never been described, largely because serial lung biopsies are never obtained. However, a hint of this time course was suggested by analyzing the pathological patterns of multiple biopsy specimens obtained at a single time from patients with fibrotic lung disease. One such study examined biopsies from 109 patients and found that 26 percent had a UIP pattern in one lobe coexistent with an NSIP pattern in another lobe. Eight out of 11 patients who had two biopsies from a single lobe had coexistent UIP and NSIP in that lobe. This illustrates that IPF, even when defined by ATS/ERS diagnostic criteria, can frequently contain more than one histologic pattern. This has prompted some authors to suggest that NSIP could represent an “early” IPF lesion, which progresses over time to an “intermediate” stage comprising coexistent UIP and NSIP patterns, as areas of NSIP transform to UIP. This is an important concept because, if

true, it would suggest that early intervention with immunosuppressive therapy to treat NSIP may be beneficial after all for IPF, albeit with a short window of opportunity.

Multiple Hits and Host Defense A report suggests that herpesvirus DNA is consistently detected in lungs of patients with IPF. Viral DNA is detected in airway epithelial cells. This observation raises the possibility that epithelial injury occurs in response to viral infections, and repeated episodes of infection could be a source of recurrent injury or “multiple hits.” Another observation emerges from analysis of the placebo arm of a large prospective treatment trial involving IPF patients. It was noted that while physiological variables remained stable during the course of the study, a significant number of patients suffered a sudden and fatal deterioration. This suggests that such sudden exacerbations must represent renewed injury or another “hit.” Abnormalities in host defense could predispose to “multiple hits” and may be an underappreciated aspect of pathogenesis in IPF. One endogenous mediator of host defense is prostaglandin E2 (PGE2), which has also been shown to have antifibrotic properties. Evidence points to a reduction of PGE2 in IPF. Fibroblasts from patients with IPF have been shown to have diminished capacity to produce PGE2. IFN-γ is a pleiotropic cytokine that plays an important role in host defense against infection. The intriguing observation that there may be a survival advantage conferred by IFN-γ, if confirmed, suggests that augmenting host defense mechanisms may be a novel approach to therapy for IPF. The concept of targeting the next “hit” is an important notion in devising future treatments for IPF.

Gastroesophageal Reflux Disease It has been observed that IPF patients have a high prevalence of gastroesophageal reflux disease (GERD). The contribution of this observation to the pathogenesis of the disease is unknown as no rigorous prospective studies have been performed. Nevertheless, pursuing the diagnosis of GERD in patients with IPF appears warranted and, when identified, treatment according to established practice guidelines is appropriate.

TREATMENT Pharmacotherapy The management of IPF presents several challenges, namely, (a) whom to treat; (b) when to treat; and (c) how to select treatment. The third issue remains the most contentious since there is no evidence to date conclusively demonstrating that any drug or drugs unequivocally confers either survival benefit, physiological improvement, or quality of life benefit. However, a number of promising treatments are in various stages of investigation.

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Historically, treatment strategies have been directed at suppressing the inflammatory processes of IPF. This strategy was employed despite histologic evidence demonstrating that inflammation is but a meager component of this disease. Alternative therapeutic agents were then developed to inhibit cytokines, proteases, oxidants, and mesenchymal growth factors. The new target for treatment has become the fibrotic processes, including the effector cell of these processes, the fibroblast. Then again, there remains little evidence to support the notion that mature fibrosis can ever be reversed. In selecting patients for treatment, the ATS/ERS consensus statement on IPF suggests that careful consideration be paid to the risk-to-benefit ratio. The ATS/ERS statement asserts that therapy is not indicated for all patients. Patients should understand the substantial risk of side effects from treatment alongside any potential merits of therapy before deciding upon a course of action. Furthermore, treatment should be reserved for patients who possess clinical features suggesting a more favorable outcome. Meanwhile, treatment should be withheld from patients with unfavorable prognostic indices and a negative net benefit. Patients of older age with worse dyspnea, impaired physiology and advanced fibrosis on HRCT are the least likely to receive benefit. Patients with concomitant chronic diseases (e.g., heart failure, diabetes, or osteoporosis) are most likely to suffer the complications of treatment. For the patient with favorable prognostic features and for whom therapy may be indicated, the exact time to initiate therapy is unknown. Theoretically, it would be ideal to start treatment during an early phase of disease before pathological changes become irreversible. Still, it is difficult to justify the risks of treatment in physiologically stable patients, asymptomatic or well-compensated patients who have little to gain in terms of a treatment benefit. Such patients require frequent monitoring to identify the onset of impairment or physiological decline. At the first sign of decline, therapy is warranted and should then be considered. The advent of placebo-controlled clinical trials in IPF represents an extraordinary advance in the approach to managing patients with IPF. Since there is no drug of proven benefit, the placebo arm is of critical importance. However, not all patients will have access to clinical trials or desire to participate. A recent study employed a panel of experts to rate the evidence of treatment options in IPF. This study concluded that it was most appropriate to either enroll eligible patients in clinical trials or refer them for a lung transplant evaluation. For patients without access to clinical trials, a corticosteroid as the sole agent was considered inappropriate. Corticosteroids used in conjunction with azathioprine were considered acceptable. With progressive disease interferon Îł-1b was recommended. These recommendations based on expert opinion provide guidance for discussion with patients. Conventional Therapy, Corticosteroids, and Immunosuppressants In 2000, the ATS/ERS consensus statement on IPF produced treatment guidelines despite several reservations and

Idiopathic Pulmonary Fibrosis

misgivings. This statement acknowledges the lack of evidence to support any treatment benefit. Unfortunately, corticosteroids have never been studied in a head-to-head trial against placebo to determine their benefit in treating IPF. Nonetheless, first-line recommendations by the ATS/ERS are to use a combination of corticosteroids (prednisone or equivalent) and an immunosuppressant agent (azathioprine or cyclophosphamide). This recommendation is qualified by a statement suggesting that therapy be reserved â&#x20AC;&#x153;for those patients who have been given adequate information regarding the merits and pitfalls of treatment and who possess features consistent with a more likely favorable outcome.â&#x20AC;? The following regimen is advised: (a) prednisone at a dose of 0.5 mg/kg lean body weight (LBW) per day orally for 4 weeks, 0.25 mg/kg LBW per day for 8 weeks, then tapered to 0.125 mg/kg LBW daily (or 0.25 mg/kg LBW every other day); and (b) azathioprine or cyclophosphamide starting at a dose of 25 to 50 mg per day orally, increasing by 25-mg increments every 7 to 14 days until a maximum dose of 150 mg daily is achieved. Although corticosteroids are usually tolerable, adverse effects are common and can be serious. Approaches to reduce the risk of steroid-induced osteoporosis are recommended, even during short-term therapy, and should constitute calcium supplementation plus a bisphosphonate drug as necessary. Corticosteroid therapy may suppress the immune response; therefore, tuberculin skin testing is advised before the initiation of therapy. Routine use of trimethoprim/sulfamethoxazole as prophylaxis against Pneumocystis carinii may be considered. Cytotoxic therapy is also associated with numerous adverse effects. Cyclophosphamide and azathioprine use can lead to leukopenia and thrombocytopenia. If the white blood cell count decreases to less than or equal to 4000/mm3 and the platelet counts fall below 100,000/mm3 , then the dose of azathioprine or cyclophosphamide should be stopped or lowered immediately by 50 percent of the current dose until these hematologic abnormalities recover. Both drugs have oncogenic potential and are also associated with gastrointestinal irritation and alopecia. Cyclophosphamide can lead to hemorrhagic cystitis. Forced diuresis is recommended with this prescription. Cyclophosphamide use poses a risk of cardiotoxicity with higher doses. Azathioprine is considered less toxic than cyclophosphamide as it does not induce bladder injury and has less oncogenic potential. It can, however, induce hepatocellular injury and rash. Azathioprine should be stopped if hepatic enzymes climb to three times the normal level. Monthly blood tests (complete blood count and hepatic function) and urinalysis are required during treatment with cytotoxic agents. N-Acetylcysteine Previous studies have demonstrated both an increased oxidant burden in the epithelial lining fluid from patients with IPF as well as diminished antioxidant capacity. These studies formed the basis for a controlled study comparing prednisone and azathioprine with prednisone, azathioprine, and

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N-acetylcysteine (NAC). The results of this study showed that NAC slowed the deterioration of forced vital capacity and diffusion capacity after 1 year to a statistically significant extent. There was a high dropout rate in both arms and there was no difference in mortality. Interestingly, there was a significant reduction in bone marrow toxicity in the NAC group. This suggests that NAC may confer protection from the toxic side effects of azathioprine. Interferon- 1b IFN-γ1b is the agent that has drawn the most interest over the last 5 years as a potential therapy for IPF due to the results of several promising clinical trials. The first trial was a small randomized pilot study involving 18 patients with progressive IPF who had already failed treatment with corticosteroids. Patients in this study received either IFN-γ1b and low-dose prednisolone or low-dose prednisolone alone. They were followed prospectively for 1 year. It was found that patients in the interferon group had significant improvement in physiological parameters such as total lung capacity, oxygenation, exercise desaturation, and dyspnea. This pilot study motivated a large multicenter randomized controlled trial to further evaluate IFN-γ1b in IPF. The results of the large study failed to confirm findings from the pilot study; there was no apparent physiological benefit in patients receiving IFN-γ1b. In the multicenter study, 330 patients with steroidunresponsive IPF were randomized to receive either IFN-γ1b or placebo. Patients were treated for 48 weeks and some received concurrent therapy with up to 15 mg of prednisone daily. The primary endpoint of progression-free survival (a composite end point including death and physiological decline) showed no significant difference. Yet, an unanticipated benefit of IFN-γ1b was suggested by analysis of secondary end points. The study revealed a trend toward improved survival in the interferon group with an absolute reduction in risk of death equaling 7 percent, approaching statistical significance ( p = 0.08). Furthermore, post hoc analysis indicated that the survival effect may be even more pronounced in the subgroups of treatment-adherent patients and patients with less severe baseline pulmonary function. A second interferon trial, enrolling 800 patients to be followed over 2 years, will examine the primary endpoint of mortality. This trial is currently ongoing and will determine if interferon-γ1b is efficacious in the treatment of IPF. Pirfenidone Pirfenidone is an oral antifibrotic compound that has been evaluated in phase I and II trials in IPF. A study from Japan examined the role of pirfenidone in 105 patients with IPF using a 2:1 randomization and a physiological end point incorporating gas exchange with exertion. The study was discontinued prematurely due to concern over excess morbidity in the placebo group and failed to demonstrate efficacy as measured by the primary end point. However, there were differences in forced vital capacity at the end of the study that have stimulated interest in additional clinical trials.

Etanercept A phase II placebo-controlled trial was performed with the anti-TNF compound etanercept that has shown efficacy in the treatment of rheumatoid fibrosis. The results of this study were presented at the American College of Chest Physicians meeting in Montreal in November 2005. The primary end points of the study involving physiological parameters were not met. However, there may have been some subsets of patients showing benefit that could warrant further study. Imatinib Mesylate Imatinib mesylate is a tyrosine kinase inhibitor that has provided a major advance in the treatment of chronic myelogenous leukemia. This wide-ranging inhibitor has activity against the PDGF receptor pathway. Data from animal models suggest that blockade of this pathway could be a promising approach to limit the formation of fibrosis. A randomized and placebo-controlled phase II trial is underway. Bosentan Bosentan is an endothelin receptor antagonist that has been an important advance in the treatment of pulmonary arterial hypertension. There is evidence that endothelin expression is increased in lung tissue from IPF patients and experimental evidence that endothelin may be a profibrotic molecule. A randomized and placebo-controlled phase II trial was completed in patients with IPF that has not yet been published in the peer-reviewed literature. Preliminary disclosure of the results revealed that the primary end point of an improvement in 6-minute walk distance was negative. However, subset analysis suggested that there may be a benefit in physiological parameters in some patients and the results were encouraging enough to propose a larger study. Anticoagulation Previous studies demonstrated that augmenting the fibrinolytic cascade may inhibit the development of fibrosis. A Japanese trial randomized IPF patients in hospital to receive either prednisolone or prednisolone plus warfarin. Warfarin therapy was managed according to established clinical practice guidelines. Patients were followed for approximately 3 years and a survival advantage was found in favor of warfarin treatment. These results warrant further investigation.

Nonpharmacological Therapy Lung Transplantation Lung transplant remains the only therapeutic intervention of proven benefit in IPF. Transplant has been reserved for patients at the advanced stages of IPF and the 5-year survival data approach 50 percent. However, complications of lung transplant remain common and severe. Among the most important complications and the major cause of long-term mortality following lung transplant is bronchiolitis obliterans syndrome (BOS). BOS is an enigmatic process characterized by progressive fibrosis of terminal and respiratory bronchioles

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leading to an inexorable decline in transplant function. New therapeutic approaches are sought to control BOS. Therapy for BOS is limited at this time. Supplemental Oxygen Patients with hypoxemia (PaO2 less than 55 mmHg or SpO2 less than 88 percent) at rest or during exercise can be managed with supplemental oxygen. There is evidence in patients with chronic obstructive pulmonary disease, which suggests that supplemental oxygen relieves exercise-induced hypoxemia and improves exercise performance. Studies examining quality of life (QOL) in patients with IPF emphasize the importance of maintaining a patient’s independence and participation in physical activities. In one study that examined QOL in IPF patients, no difference was found between patients receiving supplemental oxygen compared to those who were not receiving oxygen. Thus, any concern can be put to rest that supplemental oxygen would have a deleterious effect on QOL domains such as self-esteem, dependence on therapy, and body image. Pulmonary Rehabilitation Patients with IPF should be encouraged to enroll in pulmonary rehabilitation programs. Although pulmonary rehabilitation has not yet been shown to be effective in the IPF population, recent evidence suggests the possibility of benefit from a tailored exercise program. Exercise capacity in the IPF population has been correlated with quadriceps strength, which implies that training of the lower extremities would increase exercise capacity in IPF much the same as it does in COPD. Furthermore, it has been shown that overall quality of life is impaired in IPF, with specific defects in areas of physical health and perceived social independence. Therefore, it has been suggested that pulmonary rehabilitation programs for IPF be designed to include education and psychosocial support elements with the goal of improving coping skills affecting a better quality of life.

ACKNOWLEDGEMENT We would like to thank Robert J. Homer for providing photomicrographs of lung pathology.

SUGGESTED READING American Thoracic Society: Idiopathic pulmonary fibrosis: Diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 161:646–664, 2000. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of

Idiopathic Pulmonary Fibrosis

the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 165:277–304, 2002. Azuma A, Nukiwa T, Tsuboi E, et al: Double-blind, placebocontrolled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 171:1040– 1047, 2005. Bjoraker JA, Ryu JH, Edwin MK, et al: Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 157:199–203, 1998. Collard HR, King TE Jr, Bartelson BB, et al: Changes in clinical and physiological variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 168:538– 542, 2003. Demedts M, Behr J, Buhl R, et al: High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 353:2229– 2242, 2005. Douglas WW, Ryu JH, Schroeder DR: Idiopathic pulmonary fibrosis: Impact of oxygen and colchicine, prednisone, or no therapy on survival. Am J Respir Crit Care Med 161:1172–1178, 2000. Flaherty KR, Travis WD, Colby TV, et al: Histopathological variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med 164(9):1722–1727, 2001. Flaherty KR, Mumford JA, Murray S, et al: Prognostic implications of physiological and radiographic changes in idiopathic interstitial pneumonia. Am J Respir Crit Care Med 168:543–548, 2003. Gay SE, Kazerooni EA, Toews GB, et al: Idiopathic pulmonary fibrosis: Predicting response to therapy and survival. Am J Respir Crit Care Med 157:1063–1072, 1998. Hunninghake GW, Lynch DA, Galvin JR, et al: Radiologic findings are strongly associated with a pathological diagnosis of usual interstitial pneumonia. Chest 124:1215– 1223, 2003. Katzenstein AL, Myers JL: Idiopathic pulmonary fibrosis: Clinical relevance of pathological classification. Am J Respir Crit Care Med 157:1301–1315, 1998. Kondoh Y, Taniguchi H, Kawabata Y, et al: Acute exacerbation in idiopathic pulmonary fibrosis. Analysis of clinical and pathological findings in three cases. Chest 103:1808–1812, 1993. Latsi PI, du Bois RM, Nicholson AG, et al: Fibrotic idiopathic interstitial pneumonia: The prognostic value of longitudinal functional trends. Am J Respir Crit Care Med 168:531– 537, 2003. Lettieri CJ, Nathan SD, Barnett SD, et al: Prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis. Chest 129:746–752, 2006. Martinez FJ, Safrin S, Weycker D, et al: The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med 142:963–967, 2005. Nicholson AG, Fulford LG, Colby TV, et al: The relationship between individual histologic features and disease

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progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 166:173–177, 2002. Noble PW, Homer RJ: Idiopathic pulmonary fibrosis: New insights into pathogenesis. Clin Chest Med 25:749–758, vii, 2004. Noble PW, Homer RJ: Back to the future: Historical perspective on the pathogenesis of idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 33:113–120, 2005. Phan SH: Fibroblast phenotypes in pulmonary fibrosis. Am J Respir Cell Mol Biol 29:S87–92, 2003. Raghu G, Brown KK, Bradford WZ, et al: A placebocontrolled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 350:125–133, 2004.

Shah NR, Noble P, Jackson RM, et al: A critical assessment of treatment options for idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis 22:167–174, 2005. Steele MP, Speer MC, Loyd JE, et al: Clinical and pathological features of familial interstitial pneumonia. Am J Respir Crit Care Med 172:1146–1152, 2005. Strieter RM: Pathogenesis and natural history of usual interstitial pneumonia: The whole story or the last chapter of a long novel. Chest 128:526S–32S, 2005. Wells AU, Desai SR, Rubens MB, et al: Idiopathic pulmonary fibrosis: A composite physiological index derived from disease extent observed by computed tomography. Am J Respir Crit Care Med 167:962–969, 2003.

69 Hypersensitivity Pneumonitis Richard I. Enelow

I. EPIDEMIOLOGY AND ETIOLOGIES

V. DIAGNOSIS

II. CLINICAL FEATURES

VI. HISTOPATHOLOGY

III. RADIOGRAPHIC FEATURES

VII. IMMUNOPATHOGENESIS

IV. LABORATORY FINDINGS

VIII. PROGNOSIS AND TREATMENT

EPIDEMIOLOGY AND ETIOLOGIES Hypersensitivity pneumonitis (HP), or extrinsic allergic alveolitis, is a spectrum of interstitial, alveolar, and bronchiolar lung diseases resulting from immunologically induced inflammation in response to inhalation of a wide variety of different materials that are usually organic or low-molecularweight chemical antigens (or haptens) that may lead to irreversible lung damage. Despite the terms hypersensitivity and allergic, HP is not an atopic disease and is not associated with increased IgE or eosinophils. The prevalence of HP is quite variable in different populations, presumably because of differing intensity, frequency, and duration of inhalation exposure, and also probably because of host factors that have yet to be identified. Once thought to be a relatively rare disease, it is becoming more frequently recognized as awareness of the limitations of classical diagnostic criteria has increased. Among pigeon breeders, 8 to 30 percent of pigeon-breeding clubs members who participated in surveys exhibited evidence of HP, so-called pigeon breeder’s disease. Among farmers, 0.5 to 5 percent have symptoms compatible with HP, so-called farmer’s lung disease. The prevalence of symptoms is lower in farms that use hay-drying methods that decrease exposure to the responsible antigens and increased after a wet summer season. The population at risk and the season of exposure vary with the type of HP. For example, most cases of farmer’s lung disease occur in cold, damp climates in late winter and early spring, when farmers (usually male) use stored hay to feed

their livestock. Pigeon breeder’s disease occurs chiefly in men in Europe and the United States but predominantly in women in Mexico, owing to differing patterns of exposure, but without a seasonal preference in either population. Bird fancier’s disease in Europe and the United States occurs in subjects who keep domestic birds and does not exhibit a predilection to either sex. Japanese summer-type HP occurs mostly in women without an occupation outside the home in June to September in warm, moist parts of the country. The disease has been reported in children as well, although rarely. In contrast to other pulmonary diseases, there is a curious predominance (80 to 95 percent) of nonsmokers in all examples of HP, which is substantially higher than the proportion of nonsmokers in similarly exposed individuals without HP. The mechanisms of this phenomenon are unknown, but could include anti-inflammatory effects of nicotine. This clinical finding suggests that the presence of active smoking may be evidence against the diagnosis of HP, although this has not been consistently observed. An important feature of HP is the great variability of susceptibility among exposed populations and the apparent resistance to illness of most exposed persons. Possible reasons include differences in exposure, or differences in the host response to exposure, which may be inborn and/or acquired. There are no differences in the prevalence of atopy or HLAA, B, or C haplotypes in exposed subjects with and without HP, although there may be an alteration in the prevalence of several HLA-DR and -DQ alleles. An increased prevalence of a particular polymorphism in the TNF-α (tumor necrosis factor-α) promoter has also been reported in patients with

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pigeon breeder’s disease compared with exposed subjects without pigeon breeder’s disease, as well as protective variants in the TIMP3 (tissue inhibitor of metalloproteinase-3) promoter in exposed subjects without pigeon breeder’s disease, the possible significance of which is discussed below (see Immunopathogenesis). A large number of agents are associated with HP, as shown in Table 69-1. Some types of HP have apparently disappeared from their originally described clinical settings (e.g., bagassosis in Louisiana), but presumably exist in areas with similar agricultural or industrial settings. In addition, other forms of HP are being newly recognized (e.g., potato riddler’s lung and machine operator’s lung). Both the disappearance of previously described examples of HP and the appearance of new examples are due to changing agricultural or industrial practices that result in changes of exposure of subjects to antigenic material that can cause HP. At the present time farmer’s lung disease, bird fancier’s disease, ventilator lung, and Japanese summer-type HP are the most commonly recognized forms of HP. Recognition of new examples of HP usually requires a cluster of new cases with a unifying exposure history. Since complete occupational and avocational histories are at times not obtained from patients presenting with “pneumonia,” it is likely that there are substantially more examples of HP that have not yet been recognized and described. For example, introduction of a new metalworking fluid led to recognition of machine operator’s lung in an auto parts–manufacturing facility due to clustering of cases and a common unusual exposure (Pseudomonas in cooling fluid).

CLINICAL FEATURES The manifestations of the disease may be acute, subacute, or chronic. The stereotypical acute clinical presentation includes transient fever, hypoxemia, myalgias, arthralgias, dyspnea, and cough that occur 2 to 9 h after exposure and resolve in 12 to 72 h without specific treatment (sometimes longer after a particularly intense exposure). Patients exhibit tachypnea, bibasilar rales, and occasionally cyanosis. There is usually peripheral blood leukocytosis with neutrophilia and lymphopenia (without eosinophilia), and bronchoalveolar lavage (BAL) neutrophilia. Subacute or intermittent disease may result from repeated exposures, and manifest as productive cough, dyspnea, fatigue, and weight loss. There may be BAL lymphocytosis, frequently (although not always) with a predominance of CD8+ T lymphocytes. The chronic form is clinically more insidious, and patients may lack a history of acute episodes, but present with a gradual onset of cough, dyspnea, fatigue, and weight loss. Symptoms are usually present for months to years. There is typically no fever, but tachypnea and bibasilar dry rales are usually present. This form of the disease may be difficult to distinguish from idiopathic pulmonary fibrosis. Symptoms

and signs of cor pulmonale are not uncommon at presentation. The reasons for the different clinical presentations (i.e., acute, subacute, and chronic) of HP are not clear, but could include differences of intensity and duration of exposure (lowintensity long-duration exposure tending to cause chronic HP; high-intensity short-duration exposure tending to cause acute HP). This is most clearly demonstrated in HP due to bird exposure. Long-term exposure to low amounts of bird antigens is associated with chronic HP. Pigeon breeder’s disease has different presentations in different geographic areas, manifesting as an acute HP in some and chronic HP in others. Intermittent exposure of pigeon breeders to large amounts of pigeon antigens in the United States and Europe is associated with acute disease and a good prognosis, whereas chronic exposure to a few household pigeons in Mexico is associated with chronic disease and a much poorer prognosis. In the United States and Europe, pigeon breeders keep their animals in an enclosure separate from their living areas, which they visit periodically so that exposure is intermittent. In Mexico, birds are often kept in living quarters so that exposure is constant. It is of interest that bird antigens can persist in a room for substantial lengths of time (more than 18 months) after removal of the birds, so Mexicans with pigeon breeder’s disease might be exposed to pigeon antigens for prolonged periods even after removal of the pigeons. Therefore, pigeon breeder’s disease in Mexico resembles bird fancier’s disease in the United States and Europe in type of exposure, clinical presentation, and prognosis. It differs greatly from the acute HP that characterizes the pigeon breeder’s disease in the United States and Europe. Since the relevant antigens are similar in these two examples of bird-associated HP, it is likely that the type of exposure, and not the antigen characteristics, determines clinical presentation and prognosis. The recognition of a new example of HP is usually associated with the acute form, which is likely related to the relative ease in making the association of acute disease and an acute exposure. The preceding discussion indicates that HP, and particularly chronic HP, may be more prevalent than is readily apparent and may often be confused with other diseases, such as chronic bronchitis or idiopathic pulmonary fibrosis (IPF). The latter may be particularly important because detailed histories are not always obtained from patients with IPF, the serum antibody levels to the agents responsible for HP tend to wane after cessation of exposure, and chest high-resolution computed tomography (CT) scans of chronic HP can resemble those of IPF.

RADIOGRAPHIC FEATURES The chest radiographs of patients with acute and chronic HP differ significantly. In acute HP, chest radiographs demonstrate diffuse poorly defined nodular radiodensities, often with areas of ground-glass radiodensities or occasionally even consolidation. These radiodensities tend to occur in the lower

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Table 69-1 Etiologies of Hypersensitivity Pneumonitis Disease

Antigen Source

Probable Antigen

Farmer’s lung disease

Moldy hay

Thermophilic actinomycetes M. faeni (S. rectivirgula) T. vulgaris Aspergillus spp.

Bagassosis

Moldy pressed sugarcane (bagasse)

Thermophilic actinomycetes T. sacchari T. vulgaris

Mushroom worker’s disease

Moldy compost and mushrooms

Thermophilic actinomycetes M. faeni T. vulgaris Aspergillus spp. Mushroom spores

Suberosis

Moldy cork

Penicillium spp.

Malt worker’s lung

Contaminated barley

Aspergillus clavatus

Maple bark disease

Contaminated maple logs

Cryptostroma corticale

Sequoisis

Contaminated wood

Graphium spp., redwood dust, Pullularia spp.

Soybean lung

Soybeans in animal feed

Soybean hull antigens

Wood pulp worker’s disease

Contaminated wood pulp

Alternaria spp.

Wood dust HP

Contaminated wood dust

Bacillus subtilis Alternaria

Compost lung

Compost

Aspergillus spp. T. vulgaris

Cheese worker’s disease

Cheese or cheese casings

Penicillium spp.

Wood trimmer’s disease

Contaminated wood trimmings, at times in sawmills

Rhizopus spp. Mucor spp.

Thatched roof disease

Dried grasses and leaves

Saccharomonospora viridis

Greenhouse lung

Greenhouse soil

Aspergillus spp., Penicillium spp., Cryptostroma corticale

Coffee worker’s lung

Green coffee dust

Unknown

Potato riddler’s lung

Moldy hay around potatoes

Thermophilic actinomycetes, M faeni, T. vulgaris, Aspergillus spp.

Tobacco worker’s disease

Mold on tobacco

Aspergillus spp.

Wine grower’s lung

Mold on grapes

Botrytis cinerea (Continued )

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Table 69-1 (Continued) Disease Antigen

Source

Probable Antigen

Woodman’s disease

Mold on bark and fuel chips

Penicillium spp.

Soy sauce brewer’s lung

Fermentation starter for soy sauce

Aspergillus oryzae

Domestic allergic alveolitis

Decayed wood

Fungi Serpula lacrymans, Leucogyrophana pinastr, Paecilomyces variottiii, Aspergillus fumigatus

Riding school lung

Hay in horse stall

Thermophilic actinomycetes, M. faeni (S. rectivirgula), T. vulgaris

Stipatosis

Esparto grass (Stipa tenacissima), used to make plaster

Esparto grass antigens

Pigeon breeder’s disease

Avian droppings, feathers, serum

Altered serum/feather proteins

Turkey handler’s disease

Turkey products

Turkey proteins

Chicken breeder’s lung

Chicken feathers

Chicken feather proteins

Bird fancier’s lung

Domestic and wild bird products

Bird proteins

Duvet lung

Duvet and pillow

Goose proteins

Laboratory worker’s HP

Rat fur

Rat urine protein

Pituitary snuff taker’s disease

Pituitary powder

Vasopressin

Shell lung

Oyster or mollusk shell

Shell proteins

Miller’s lung

Grain weevils in wheat flour

Sitophilus granarius proteins

Sericulturist’s lung

Silkworm larvae

Silkworm larvae proteins

TDI HP

Toluene di-isocyanate

Altered proteins (albumin + others)

MDI HP

Diphenylmethane di-isocyanate

HDI HP

Hexamethylene di-isocyanate

TMA HP

Trimetallic anhydride

Altered proteins

Ventilator lung

Contaminated humidifiers, dehumidifiers, air conditioners, heating systems

Thermophilic actinomycetes, T. candidus, T. vulgaris, Penicillium spp., Cephalosporium spp. Amoebae Klebsiella spp. Candida spp.

Basement lung

Contaminated basement (sewage or mold)

Cephalosporium spp. Penicillium spp.

Sauna taker’s disease

Sauna water

Aureobasidium spp.

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Table 69-1 (Continued) Disease Antigen

Source

Probable Antigen

Detergent worker’s disease

Detergent enzymes

Bacillus subtilis

Japanese summer house HP

House dust, bird droppings(?)

Trichosporon cutaneum

Hot-tub lung

Mold on ceiling

Cladosporium spp.

Tractor lung

Contaminated tractor, cab air conditioner

Rhizopus spp.

Machine operator’s lung

Contaminated metal working fluid

Pseudomonas spp.

Fertilizer lung

Contaminated fertilizer

Streptomyces albus

Sax lung

Saxophone mouthpiece

Candida albicans

lobes and spare the apices. Linear radiodensities (presumably representing areas of fibrosis from previous episodes of acute HP) may also be present. The nodular and ground-glass densities tend to disappear after cessation of exposure, so the chest radiograph may be normal after resolution of an acute episode of HP (Fig. 69-1). High-resolution CT scans often demonstrate ground-glass densities better than chest radiographs and at times reveal diffusely increased pulmonary radiodensities. They may also become normal after resolution of an acute episode. Pleural effusions or thickening, calcification, cavitation, atelectasis, localized radiodensities (coin lesions or masses), and intrathoracic lymphadenopathy are rare. In chronic HP, chest radiographs are notable for diffuse linear and nodular radiodensities, with sparing of the bases and upper-lobe predominance, and volume loss (Fig. 69-2). Pleural effusions and thickening are very unusual, although subcutaneous emphysema (presumably as a consequence of pleural rupture due to bronchiolitis and lobular overinflation) has been reported. High-resolution CT scans of patients with chronic HP demonstrate several patterns. Most commonly there are multiple centrilobular nodules 2 to 4 mm in diameter throughout the lung fields, with some areas of ground-glass radiodensities, especially in the lower lobes (Fig. 69-3). Unlike sarcoidosis, the nodules are seldom attached to the pleura or bronchovascular bundles, and the border between the nodules and the surrounding lung is well demarcated. There are also well-delineated areas of increased radiolucency, which are presumably overinflated pulmonary lobules subserved by partly occluded bronchioles. The ground-glass densities and micronodules tend to resolve after cessation of exposure. Although these findings are suggestive of HP, they are found in only a subset (50 to 75 percent) of patients with HP, and

high-resolution CT scans of the lungs of patients with HP can resemble those of patients with IPF. Emphysematous abnormalities are also commonly detected by high-resolution CT scans in nonsmoking patients with farmer’s lung disease.

LABORATORY FINDINGS Patients with acute HP often have a peripheral blood leukocytosis with neutrophilia and without eosinophilia. Prominent cellular abnormalities may also seen in their BAL fluid, which may be useful in supporting the diagnosis of HP. At time points greater than 5 days after the last exposure, a twoto fourfold increase in BAL fluid leukocytes and lymphocytosis (typically 30 to 70 percent of total cells) are frequently noted. In most instances of HP, the BAL fluid lymphocytes are virtually all CD3+ (T lymphocytes), with a relative increase of CD8+ cells, so that the CD4:CD8 ratio is usually less than 1 (normally 2 to 2.5, as in peripheral blood). This profile varies significantly with the stage of disease. Furthermore, BAL lymphocytosis may persist for years following clinical improvement and apparent removal from antigen exposure. Conversely, exposed asymptomatic individuals may exhibit BAL lymphocytosis, further limiting its utility in diagnostic evaluation. After recent (less than 48 h) exposure, as well as in advanced disease, the lavage is frequently characterized by BAL fluid neutrophilia. The concentrations of IgG, IgM, IgG, and albumin are increased in BAL fluid, presumably a nonspecific manifestation of pulmonary inflammation. Many patients with HP have easily demonstrable antibodies (typically IgG, IgM, and IgA) to the offending material

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Figure 69-1 A. Chest radiograph of a patient with pigeon breeder’s disease with fever, dyspnea, and bibasilar rales. The patient had kept pigeons for 5 years and presented with fever, dyspnea, and myalgias approximately 8 h after cleaning the pigeon coop. He had serum antibody to pigeon dropping extract. Note bilateral lower lobe 2- to 3-mm nodules. B . Chest radiograph of the same patient 2 weeks later without specific treatment. Note clearing of the lowerlobe nodules and the staples in the left chest from the open lung biopsy.

in the serum, detectable by a variety of methods. Since antigen preparations are not standardized, it is difficult to be confident of the meaning of a negative result; therefore, negative “hypersensitivity pneumonitis panel” does not exclude the diagnosis of HP. Furthermore, since serum antibody is also present in many exposed, but not ill, subjects in virtually the same amounts as in patients with HP, the presence of antibody should be considered supporting data in the proper clinical context. In asymptomatic pigeon breeders, the prevalence of antibody to pigeon antigens is 30 to 60 percent. In farmers, the prevalence of anti–Micropolyspora faeni serum antibody is 2 to 27 percent. The occurrence of serum antibody is not consistently related to apparent exposure (i.e., hours of exposure or intensity of exposure) in most instances of HP. This may be related to a threshold effect, so that most exposures are above the minimum required to induce antibody and increases above that threshold are not associated with increases of the prevalence of antibody. In addition, serum antibody tends to wane after cessation of exposure, so patients with chronic HP who have not been exposed for some time may not have demon-

strable antibody. In farmer’s lung disease, approximately 50 percent of patients with initially positive serum antibody to M. faeni (Saccharopolyspora rectivirgula) lose demonstrable antibody 6 years after cessation of exposure. Farmers who continue to farm also lose detectable antibody (35 to 50 percent in 5 years), and some asymptomatic farmers who were initially negative later develop antibody without farmer’s lung disease. In pigeon breeder’s disease and bird fancier’s disease, approximately 50 percent of patients with initially positive serum antibody to avian antigens lose demonstrable antibody 2 to 3 years after cessation of exposure. Therefore, it is possible that patients with HP will have no detectable serum antibody owing to either use of an inappropriate antigen in the assay or the waning of antibody in time since the last exposure. Serum markers of systemic inflammation, such as increased sedimentation rate and C-reactive protein, are often elevated during an acute episode of HP, although they are quite nonspecific. There is increased uptake of gallium-67 in the lungs of patients with active HP, which declines with resolution of the disease, although this is also nonspecific.

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Pulmonary function tests may be restrictive, obstructive, or mixed. There is an increased lung elastic recoil, and usually decreased diffusing capacity. Arterial hypoxemia with hypocapnia reflecting an increased A-a oxygen gradient either at rest or after exercise is common. Many patients with HP (20 to 40 percent) exhibit increased nonspecific airway reactivity, and 5 to 10 percent also develop clinical asthma. The increased airway reactivity and asthma tend to diminish after cessation of exposure.

DIAGNOSIS

Figure 69-2 Chest radiograph of a patient with bird fancierâ&#x20AC;&#x2122;s disease who presented with progressive dyspnea and weight loss. She had kept two to three parakeets in her home for 15 years and did not notice episodic fever or acute dyspnea. She had positive serum precipitins to parakeet serum, severe restrictive disease, and resting hypoxemia. Note the diffuse radiodensities, loss of volume of the upper lobes, and pulmonary hypertension.

In contrast to sarcoidosis, the serum angiotensin-converting enzyme levels are usually not elevated. Skin tests (either immediate or delayed type) to detect sensitization to the suspected antigens are not useful, since extracts of agents that cause HP produce nonspecific reactions that do not indicate sensitization and do not discriminate between sensitized and nonsensitized subjects.

Figure 69-3 High-resolution computed tomography scan of a nonsmoking patient with exposure to both birds and shells who presented with progressive dyspnea and weight loss and had hypoxemia and a restrictive ventilatory defect. Note the diffuse nodular radiodensities in the lower lobes, with areas of groundglass densities posteriorly.

The symptoms, signs, and laboratory findings of acute HP can resemble those of many other lung diseases, including pulmonary edema, organic dust toxic syndrome, inhalation fever, chronic bronchitis, and some pneumoconioses. Acute HP is also often confused with infectious pneumonia (viral, mycoplasma, or chlamydia in subjects exposed to birds). Subacute HP is characterized by a more gradual onset of cough, fatigue, dyspnea, and weight loss, and such symptoms may also develop with intermittent acute attacks. There is considerable overlap in the presentations of acute and subacute HP, in contrast to chronic progressive HP (discussed in the following). Chronic bronchitis in nonsmoking farmers and bird breeders is more common than HP, and may share overlapping immunopathogenic mechanisms with HP. The finding of serum precipitins is more frequent in farm workers with chronic bronchitis than those who are asymptomatic. Organic dust toxic syndrome (ODTS) has been seen in some of the same populations exposed to materials that cause HP, although its cause is likely mycotoxins from bioaerosols contaminated with toxin-producing fungi. ODTS can occur in a larger proportion of the exposed population than HP and is characterized by transient fever, dyspnea, nonproductive cough, peripheral blood leukocytosis, and BAL fluid neutrophilia. The manifestations commonly include diffuse opacities on chest radiograph, restrictive ventilatory defects, reduced DlCO , and bronchiolitis obliterans without granulomas on lung biopsy. Diffuse alveolar damage may occur in severe cases. In contrast to HP, prior sensitization is not required (as indicated by the absence of serum antibodies). Patients presenting with ODTS tend to have more intense exposure of shorter duration than those who present with farmerâ&#x20AC;&#x2122;s lung disease. Another disease caused by exposure to the some of the same agents associated with HP is inhalation fever. This is manifest as fevers, chills, malaise, headaches, and myalgias without prominent pulmonary findings, although mild dyspnea and cough may occur. The onset usually occurs 4 to 12 hours after exposure. Usually there are normal lung volumes and diffusing capacity. The clinical syndrome remits after 12 to 24 h without specific therapy. Symptoms and signs are exaggerated following an exposure that occurs after a period of nonexposure (such as

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vacations or weekends), but then become blunted despite continued exposure (“Monday illness”). All signs and symptoms of inhalation fever remit after cessation of exposure, and there are no permanent physiological or radiographic changes. In contrast to acute and subacute HP, the classic or typical clinical findings are usually not present in chronic HP. The chronic form of HP often resembles IPF, and these entities may be extremely difficult to distinguish. The differential diagnoses also includes other causes of pulmonary fibrosis (e.g., drug reactions, rheumatologic disease, asbestosis, radiation). Further complicating matters is the frequent lack of clear history of acute episodes. In addition, removal from the presumptive offending agent may result in little or no clinical improvement at this stage. A thorough and complete occupational and avocational history is essential to the diagnosis of all forms of HP. The history should seek to establish a link between a particular exposure (at work, at home, or elsewhere) and previous episodes of “pneumonia.” Knowledge of other exposed persons with similar symptoms should be sought. Evidence of repetitive appropriate symptoms and laboratory and radiologic abnormalities associated with exposure to a particular environment is also highly suggestive of HP. In questionable instances, a “natural exposure” (i.e., documentation of appropriate symptoms and laboratory abnormalities after exposure to a suspect environment) can be used to diagnose HP. A “natural exposure” challenge should not be considered positive unless there is objective evidence of a change in temperature, total peripheral white blood cell count, chest radiograph (or highresolution CT scan), or a decrease in diffusing capacity (or arterial Po2 ). If the history suggests a relationship between exposure and pulmonary symptoms, evidence of sensitization and the nature of the pulmonary inflammatory response should be determined. Sensitization is indicated by the presence of serum antibody to an agent known to cause HP. A large proportion of lymphocytes in BAL fluid (usually over 40 percent) is highly suggestive of, although not specific for, HP. A variety of tools exist that have utility in the diagnosis of HP, all having certain advantages and disadvantages (summarized in Table 69-2). One of the difficulties in assessing the value of diagnostic methods in HP is the vagueness of the “gold standard.” Although most would agree that the presence of poorly formed, airway-centered non-necrotizing granuloma on lung biopsy in a patient with exposure to a known offending agent is supportive enough to be “diagnostic,” these features are commonly absent, and a number of histologic variants have been described. Since the utility of lung biopsy, absent classic features, is largely supportive, several prediction rules have been devised to determine the probablility of a diagnosis of HP based upon clinical features. One such model, developed by the Hypersentitivity Pneumonitis Study Group, examined a cohort of 400 patients with suspected HP and found six significant predictors retrospectively (116 were ultimately diagnosed with HP). These were then validated prospectively in 261 patients (83 of whom were

eventually given the diagnosis). It should be noted that the ultimate determination, or gold standard, was the consensus of experts, in many cases without tissue. Although not ideal, at the current level of understanding of the nature of HP, this may be the best method available. The criteria used in this study were: (a) exposure to a known offending antigen; (b) positive precipitating antibodies to the offending agent; (c) recurrent episodes of symptoms; (d) inspiratory crackles on physical examination; (e) symptoms occurring 4 to 8 hours after exposure; and (f) weight loss. The probability of having HP was determined based upon the presence or absence of these predictors (Table 69-3). The probability of HP ranged from 0 percent in those patients with none of the predictors to 98 percent in patients with all six of these features. Exposure to a known offending antigen was the strongest clinical predictor with an odds ratio of 38.8; absent this critical feature the diagnosis was made only after further investigation and supportive findings on lung biopsy (discussed in the following). It should be emphasized that these clinical prediction rules are of little value in chronic HP, which is usually a more difficult diagnostic problem (often even when histopathology is available). Of course, in the evaluation of individual patients, the threshold for further investigation clearly depends upon the clinical setting and the consequences of the diagnosis.

HISTOPATHOLOGY A lung biopsy specimen is generally required when there is significant doubt about the diagnosis. Transbronchial lung biopsies often do not provide sufficient material to fully establish the presence and interrelationships of granulomas, bronchiolitis, and interstitial inflammation, so either open or thoroscopically obtained lung biopsies may be necessary. These often reveal chronic interstitial and alveolar inflammation with infiltration of plasma cells, mast cells, macrophages, and lymphocytes, usually with poorly formed nonnecrotizing granulomas (Figs. 69-4 and 69-5). The inflammation usually extends from the terminal bronchioles into the parenchyma. Foamy macrophages are usually evident in the alveoli. There is often bronchiolitis as well as bronchiolitis obliterans. Organizing pneumonia is also present in up to 50 percent of patients with HP (Fig. 69-6). Conversely, patients with recognized bronchiolitis obliterans with organizing pneumonia (BOOP) may have underlying HP, whether or not other histologic manifestations are evident. Varying degrees of interstitial fibrosis are also often present. The granulomatous interstitial inflammatory responses of HP and sarcoidosis can be difficult to differentiate, although in HP they are usually smaller, poorly differentiated, loosely arranged, and contain more lymphocytes and fewer multinucleated giant cells. In contrast to sarcoidosis, the interstitial inflammatory cell infiltrate in HP occurs distal as well as proximal to the granulomas. The granulomas of HP also tend not to occur in groups and tend not to occur near bronchi or in subpleural locations.

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Table 69-2 Advantages and Disadvantages of Methods Used in the Diagnosis of Hypersensitivity Pneumonitis Method

Advantages

Disadvantages

Clinical history

Simple, sensitive

Low specificity

Precipitins

Relatively sensitive

False negatives (lack of standardized extracts)

IgG ELISA

More sensitive

Identifies IgG production not disease

Radiologic evaluation Chest x-ray CT scan

Simple affordable More sensitive

Can be normal, nonspecific

Pulmonary spirometry

Relatively simple, affordable

Not specific for HP; HP not ruled out by a normal test

Gas exchange (DlCO )

Simple sensitive

Not specific for HP; HP not ruled out by a normal test

Lymphocyte proliferation test with specific antigens

More reliable in distinguishing disease from mere exposure

Few specialized centers, lack of adequate reagents (antigens), not validated yet

Bronchoalveolar lavage

Assess inflammation, normal lymphocyte count rules out active HP

Different stages of inflammation; affected by time lapse since last antigen exposure; typical but not specific

Lung biopsy

Histopathology highly suggestive

Different stages of disease; not pathognomonic

Specific inhalation challenge in the laboratory

If positive, confirmatory

If negative diagnosis not ruled out; few specialized centers; not standardized

“Natural challenge” with clinical and functional monitoring

If negative under usual exposure conditions rules out diagnosis; but if positive, is confirmatory

Difficult to differentiate from ODTS; requires collaboration (patient and staff)

Note: Abbreviations: HP = hypersensitivity pneumonitis; ODTS = organic dust syndrome. Source: From: Fink Y, Ortega H, Reynolds H, et al: Needs and opportunities for research in hypersensitivity pneumonitis. Am J Respir Crit Care Med 171:792, 2005; Copyright © 2005 American Thoracic Society, with permission.

Instead, they are usually adjacent to bronchioles and are often single. In the absence of granulomas, the pattern may remble that of nonspecific interstitial pneumonitis, although the bronchiolocentric nature of the lesions and the presence of giant cells or organizing pneumonia may be clues suggesting underlying HP. The specific histologic changes of HP, when present, are quite helpful in making the diagnosis. However, the granulomas and respiratory bronchiolitis may not be present years after cessation of exposure, so only interstitial inflammation and fibrosis remain in many subacute and most chronic cases.

Although these findings might be useful in supporting the clinical diagnosis of HP, they would be insufficient to confirm it.

IMMUNOPATHOGENESIS Although poorly understood, the bulk of the evidence obtained in the past 25 years suggests a primary role for T-cell–mediated events in the pathogenesis of HP; however,

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Table 69-3 Clinical Probability of Having Hypersensitivity Pneumonitis Crackles, % +

−

Serum Precipitins

Exposure to a Known Offending Antigen

Recurrent Episodes of Symptoms

Symptoms 4–8 h After Exposure

Weight Loss

−

+ + + + + + + + − − − − − − − −

+ + + + − − − − + + + + − − − −

+ + − − + + − − + + − − + + − −

+ − + − + − + − + − + − + − + −

98 97 90 81 95 90 73 57 62 45 18 10 33 20 6 3

92 85 62 45 78 64 33 20 23 13 4 2 8 4 1 1

93 87 66 49 81 68 37 22 26 15 5 2 10 5 1 1

72 56 27 15 44 28 10 5 6 3 1 0 2 1 0 0

All the predictors are dichotomous variables: − = absent; + = present. Source: From: Lacasse Y, Selman M, Costabel U, et al. Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care Med 168:952, 2003; Copyright © 2003 American Thoracic Society, with permission.

a contribution of humoral immunity, especially in acute HP, has not been excluded. The presence of serum antibody in patients with HP and the timing of symptoms after exposure (2 to 9 h) led to the hypothesis that HP represents an exam-

ple of immune complex–mediated lung disease. Therefore, it is possible that immune complexes initiate the injury upon antigen exposure, which is then perpetuated and amplified by T-cell activities. By the time the disease is clinically evident,

Figure 69-4 Low power view (20×) of H&E-stained section of surgical lung biopsy from a patient with bird fancier’s disease. There is nonspecific interstitial mononuclear inflammation and loosely formed granulomatous lesions.

Figure 69-5 Higher-power view (40×) of the section shown in Fig. 69-4.

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Figure 69-6 Organizing pneumonitis in a patient in a patient with bird fancier’s disease.

lung tissue gene expression profiles indicate T-cell–driven inflammation (in contrast to the profiles of IPF and NSIP). The T cell responses evident in HP are notable for the predominance of CD8+ cells and the expression of interferon-γ , the prototypic cytokine of type 1 inflammatory processes. Expression of interferon-γ –dependent chemokines, such as CXCL9 and CXCL10, is also observed in HP lungs, which undoubtedly serves to amplify the type 1 inflammation. Not unexpectedly, CD8+ T cells in BAL of HP patients strongly express CXCR3, the receptor for both of these chemokine. In animal models of HP, macrophage-derived cytokines such as IL-1, IL-6, IL-12, and TNFα (as well as a variety of chemokines) play a central role in models that entail intrapulmonary administration of various antigenic substances. TNF-α, produced by activated macrophages as well as CD8+ T cells, likely participates both in the amplification of the inflammation and the activation/degranulation of neutrophils recruited to the alveolar space. Interestingly, polymorphisms in the TNF-α promoter have been reported in a group of patients with farmer’s lung disease, which correlated with higher serum levels of TNF-α after challenge with hay dust, compared with a group of sensitized asymptomatic controls. Two small genetic susceptibility studies in Mexican and Dutch patients with bird fancier’s disease found protective polymorphisms in the tissue inhibitor of metalloproteinase-3 (TIMP3) gene, which is involved in the inhibition of metalloproteinases associated with extracellular matrix turnover. TIMP3 has also been identified recently as the primary inhibitor of TNF-α–converting enzyme (TACE/ADAM-17), and this enzyme is responsible for processing TNF-α to its soluble form, which is intensely proinflammatory. The TIMP-3 polymorphism was not found in patients with IPF or NSIP. Therefore, it is reasonable to speculate that the expression and/or proteolytic processing of TNF-α is important in the pathogenesis of HP, although clearly this leaves much to be explained concerning the varying clinical pictures of the disease.

Prognosis varies considerably with the type of HP and even the geographic location. For example, farmer’s lung disease has a good prognosis in Quebec, even in farmers who continue to farm. However, farmer’s lung disease in Finland often results in significant physiological impairment and even death. Pigeon breeder’s disease has a good prognosis in the United States and Europe, whereas the same disease in Mexico has a 30 percent 5-year mortality. The reasons for these differences are not clear but may include differences in the nature of the antigen and the exposure. Identification of the offending antigen is critical to effective avoidance, which is the primary intervention in all forms of HP. This is not always practical when the exposure is occupational, such as in farmer’s lung disease. In addition most farmers who continue to be exposed may fare no worse than those who leave their farms. Nevertheless, removal from exposure to the offending antigen(s) is usually sufficient to resolve symptoms and physiological abnormalities. Measures to reduce antigenic burden may include protective equipment and reducing microbial contamination of the home or work environment. Elimination of excess moisture, reduction in humidity, repair of water damaged materials, regular cleaning of humidifiers, ventilation, and air conditioning equipment all contribute to reduction in mold and other microbial colonization that may predispose to sensitization. Removal of birds from the home of patients with bird fancier’s disease is a critical aspect of treatment, but antigens may persist for extended periods despite thorough cleaning of the home environment. Systemic glucocorticosteroids are usually required to treat severely symptomatic patients, although there is no formal evidence that such treatment is associated with longterm abatement of symptoms or radiologic or pulmonary function test abnormalities. The usual treatment is prednisone or prednisolone, 40 to 60 mg a day for 2 weeks, followed by a gradual decrease over 2 to 4 weeks. Patients with farmer’s lung disease treated with prednisolone, compared to those not treated with prednisone, demonstrated slightly more rapid resolution of some radiologic (ground-glass opacities) and some physiological abnormalities than untreated patients (slight improvement of diffusing capacity, no difference in lung volumes or arterial PO2 ). However, there were no differences between the groups 6 months after the diagnosis of HP. The above evidence suggests that systemic steroids may slightly increase the rate of resolution of acute pulmonary inflammation but have little or no effect on chronic residue of HP. If patients are removed from exposure before there are permanent radiologic or physiological abnormalities, the prognosis is excellent, with little evidence of long-term ill effects. If removal from exposure is impossible, the use of efficient masks during exposure can result in prevention of acute HP and an excellent prognosis. The prognosis varies considerably with different types of HP. In general, bird fancier’s disease carries a worse prognosis than other forms of HP,

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although even this varies considerably depending on the specific nature of the exposure. It appears that long-term lowlevel exposure is associated with a poorer prognosis, whereas short-term intermittent exposure is associated with a more favorable one. Unfortunately, many patients with chronic HP present with pulmonary fibrosis and physiological abnormalities that are only partly reversible after cessation of exposure. The specific nature of histopathologic findings on biopsy in these patients at the time of diagnosis may help predict subsequent clinical course of the disease. Not surprisingly, patients with organizing pneumonia/BOOP or cellular NSIP have a better prognosis than those with fibrotic NSIP or other patterns of fibrosing pneumonitis. In conclusion, HP is an immunologically mediated lung disease likely mediated primarily by T-cell responses to inhaled antigens. The diagnosis requires careful history, appropriate laboratory tests, and lung biopsy in selected cases. Avoidance of exposure is usually associated with a good prognosis, and corticosteroids are indicated in severely symptomatic patients. Because of constantly changing environmental exposures, new examples of HP are continually being described, and represent an ongoing challenge in patients presenting with undefined interstitial lung disease.

SUGGESTED READING Agostini C, Calabrese F, Poletti V, et al: CXCR3/CXCL10 interactions in the development of hypersensitivity pneumonitis. Respir Res 6:20, 2005. Camarena A, Juarez A, Mejia M, et al: Major histocompatibility complex and tumor necrosis factor-alpha polymorphisms in pigeon breeder’s disease. Am J Respir Crit Care Med 163:1528–1533, 2001. Chen B, Tong Z, Nakamura S, et al: Production of IL-12, IL-18 and TNF-alpha by alveolar macrophages in hypersensitivity pneumonitis. Sarcoidosis Vasc Diffuse Lung Dis 21:199–203, 2004. Churg A, Muller NL, Flint J, et al: Chronic hypersensitivity pneumonitis. Am J Surg Pathol 30:201–208, 2006. Coleman A, Colby TV: Histologic diagnosis of extrinsic allergic alveolitis. Am J Surg Pathol 12:514–518, 1988. Cormier Y, Belanger J: Long-term physiologic outcome after acute farmer’s lung. Chest 87:796–800, 1985. Costabel U, Guzman J: Bronchoalveolar lavage in interstitial lung disease. Curr Opin Pulm Med 7:255–261, 2001. Craig TJ, Hershey J, Engler RJ, et al: Bird antigen persistence in the home environment after removal of the bird. Ann Allergy 69:510–512, 1992. Denis M, Bedard M, Laviolette M, et al: A study of monokine release and natural killer activity in the bronchoalveolar lavage of subjects with farmer’s lung. Am Rev Respir Dis 147:934–939, 1993.

Drent M, van Velzen-Blad H, Diamant M, et al: Bronchoalveolar lavage in extrinsic allergic alveolitis: Effect of time elapsed since antigen exposure. Eur Respir J 6:1276–1281, 1993. Hill MR, Briggs L, Montano MM, et al: Promoter variants in tissue inhibitor of metalloproteinase-3 (TIMP-3) protect against susceptibility in pigeon breeders’ disease. Thorax 59:586–590, 2004. Janssen R, Kruit A, Grutters JC, et al: TIMP-3 promoter gene polymorphisms in BFL. Thorax 60:974, 2005. Kokkarinen JI, Tukiainen HO, Terho EO: Effect of corticosteroid treatment on the recovery of pulmonary function in farmer’s lung. Am Rev Respir Dis 145:3–5, 1992. Kokkarinen JI, Tukiainen HO, Terho EO: Recovery of pulmonary function in farmer’s lung. A five-year follow-up study. Am Rev Respir Dis 147:793–796, 1993. Lacasse Y, Selman M, Costabel U, et al: Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care Med 168:952–958, 2003. Monkare S, Haahtela T: Farmer’s lung—a 5-year follow-up of eighty-six patients. Clin Allergy 17:143–151, 1987. Morris DG: Gold, silver, and bronze: Metals, medals, and standards in hypersensitivity pneumonitis. Am J Respir Crit Care Med 168:909–910, 2003. Ohtani Y, Saiki S, Kitaichi M, et al: Chronic bird fancier’s lung: histopathological and clinical correlation. An application of the 2002 ATS/ERS consensus classification of the idiopathic interstitial pneumonias. Thorax 60:665–671, 2005. Perez-Padilla R, Salas R, Chapela M, et al: Mortality in Mexican patients with chronic pigeon breeder’s lung compared with those with usual interstitial pneumonia. Am Rev Respir Dis 148:49–53, 1993. Schaaf BM, Seitzer U, Pravica V, et al: Tumor necrosis factoralpha-308 promoter gene polymorphism and increased tumor necrosis factor serum bioactivity in farmer’s lung patients. Am J Respir Crit Care Med 163:379–382, 2001. Schuyler M, Gott K, Cherne A: Mediators of hypersensitivity pneumonitis. J Lab Clin Med 136:29–38, 2000. Selman M, Pardo A, Barrera L, et al: Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis. Am J Respir Crit Care Med 173:188– 198, 2006. Smookler DS, Mohammed FF, Kassiri Z, et al: Tissue inhibitor of metalloproteinase 3 regulates TNF-dependent systemic inflammation. J Immunol 176:721–725, 2006. Terho EO, Husman K, Vohlonen I: Prevalence and incidence of chronic bronchitis and farmer’s lung with respect to age, sex, atopy, and smoking. Eur J Respir Dis Suppl 152:19–28, 1987. Vourlekis JS, Schwarz MI, Cool CD, et al: Nonspecific interstitial pneumonitis as the sole histologic expression of hypersensitivity pneumonitis. Am J Med 112:490–493, 2002.

70 Radiation Pneumonitis Kenneth B. Roberts Sara Rockwell

I. BRIEF OVERVIEW OF RADIOLOGIC PHYSICS II. RADIOBIOLOGY OF RADIOTHERAPY III. PATHOPHYSIOLOGY OF RADIATION PNEUMONITIS IV. CONFOUNDING EFFECTS OF CHEMOTHERAPY V. CLINICAL SYNDROMES Acute Manifestations Late Manifestations

VI. DEFINING THE RADIATION TOLERANCE OF THE LUNGS VII. WHOLE-LUNG IRRADIATION VIII. PARTIAL-LUNG IRRADIATION Assessment of Risk Lung Cancer: Local Tumor Boosting Breast Cancer Early-Stage Hodgkin’s Disease IX. PROGNOSTIC ASSAYS AND FUTURE TRENDS

The discovery of x-rays by Roentgen in 1895 and the discovery of radium by the Curies in 1898 revolutionized medicine at the turn of the twentieth century. Roentgen’s first paper on x-rays illustrated the power of diagnostic imaging with a radiographic image of Frau Roentgen’s hand. As researchers around the world built vacuum tubes and acquired radioactive sources for their studies, it rapidly became apparent that these invisible radiations could produce dangerous and even lethal injuries. Erythema, chronic dermatitis, ulceration, loss of hair, and eye injuries were soon reported in patients who received large doses of radiation during prolonged fluoroscopy procedures. Even greater injuries were reported among the physicians, technicians, and scientists who performed diagnostic procedures or laboratory studies using unshielded x-ray generating equipment and highly radioactive sources. The development of these radiation injuries suggested that radiation might be useful in the treatment of cancer, and cancer patients were treated with radiation therapy as early as 1896. Radiation was found to inhibit the growth of tumors, but this benefit came with the cost of injury to the normal tissues within the irradiated area. Because of the very low energy of the early x-ray and gamma-ray sources, radiotherapy in its early days was limited to using poorly penetrating radiations, which delivered much higher doses of radiation to skin than to even very superficial tumors. As a result, severe early radi-

ation reactions in the skin limited the doses of radiation that could be delivered to tumors. Studies of these skin reactions led to the development of the concept of normal tissue tolerance and an appreciation of the benefits of “fractionated” radiotherapy, using multiple treatments with small doses of radiation. The relative sensitivity of the lung to injury from radiation became apparent early in the development of radiation oncology. The clinical syndromes of dyspnea, cough, fever, and radiographic infiltrates occurring weeks to months after irradiation of the thorax were dramatic enough to be described as early as 1922. The field of radiation oncology has matured immeasurably over the last century and has incorporated significant advances from fields as diverse as theoretical and applied physics, radiation biology, pathology, cell biology, and immunology. The importance of advances in physics and engineering to the maturation of radiation oncology is especially notable. These advances have led to the development of modern linear accelerators capable of delivering very high-energy, deeply penetrating radiations, which can be used to deliver high radiation doses with great precision to tumors deep within the body. Precise systems for radiation dose measurement, or dosimetry, rapid computers and precise algorithms for the rapid computerized three-dimensional planning of individualized radiotherapy treatments based on computed

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tomography (CT) scans and magnetic resonance imaging (MRI) studies have been developed. These advances have changed the dose-limiting toxicities of radiation therapy from painful early reactions in the skin to life-threatening late reactions in the normal tissues invaded by and surrounding the tumors, including the lung. To the readers of this book, understanding radiation pneumonitis is important for two reasons. First, an understanding of radiation injury to the lung can be useful in understanding other lung diseases. Because the chemical mediators of radiation effects, both beneficial and harmful, are free radicals, the pathway leading to radiation injury overlaps with those leading to many other lung injuries. Second, understanding radiation pneumonitis has practical value to physicians in many areas of medicine. Approximately one in three people in the United States will be diagnosed with cancer at some point in their lifetimes. Over half of these patients will be permanently cured of their malignancies. Approximately 65 percent of all cancer patients now receive radiotherapy at some point in the treatment of their malignancies, and radiotherapy seems destined to remain an important component of cancer treatment for the foreseeable future. Because of this, every physician can expect to care for many patients who are receiving radiotherapy or have received radiotherapy at some point in the past. In addition, recent studies of plutonium workers have shown an excess incidence of pulmonary fibrosis. These findings, which are supported by data from a large number of studies in experimental animals, show that lung injury can be produced by inhalation of insoluble particulate radionuclides that are deposited in lung tissue and produce long-term irradiation of the tissue. Therefore, radiation injury to lung is possible in cases in which people are exposed to high levels of inhaled radionuclides through their occupations, accidents, or acts of war or terrorism. A working knowledge of the basics of radiobiology and radiation oncology is important to every physician and health care provider. An understanding of the potential toxicities of radiotherapy, including radiation pneumonitis, can be critical to patient care. Many neoplasms involving the thorax are treated with regimens that include the use of radiotherapy to produce either cure or palliation. Radiotherapy is principally a localized, anatomically based modality. The success of radiotherapy hinges on delivering radiation selectively to the sites of malignant disease, while sparing to the maximal extent possible the uninvolved normal tissues. To plan radiotherapy treatments effectively, the radiation oncologist must have a sophisticated appreciation of the malignancy being treated and must understand its biologic behavior, its patterns of local and metastatic spread, its radiosensitivity, and the factors that influence the responses of individual patients to therapy. The radiation oncologist must also consider the effects of radiation on the normal tissues within the treatment volumes. Many factors, including the radiation dose, the fractionation pattern of the radiotherapy, the volume of the tumor and involved margins, the prior or planned use of other therapies such as surgery or systemic chemotherapy, and the presence of other diseases, influence both the probability of controlling the neoplasm and the probability of producing toxic reactions. For cancers

of the lung, esophagus, pleura, breast, and chest wall, as well as for lymphomas involving the thorax, optimal treatment frequently involves the use of multiple overlapping x-ray beams and possibly electron beams, planned to encompass all of the cancer-containing tissues. Although treatments are carefully planned to include the smallest possible amount of healthy normal tissue, some normal tissue will necessarily be included in the radiation fields. The radiation sensitivity of the specific tissues in the irradiated fields and the acceptable level of risk for complications combine to limit the dose of radiation that can be administered. The planning of radiotherapy always involves a balance of benefit and risk, because the probabilities of controlling the malignancy increase with increasing radiation dose, but the probabilities and severities of the potential complications increase with dose as well. To illustrate the mechanisms involved in planning radiotherapy treatments, a relatively straightforward treatment plan is depicted in Fig. 70-1A, which shows the isodose distribution for treatment of a stage IIIB nonâ&#x20AC;&#x201C;small-cell lung cancer. Such intrathoracic tumors are often treated initially using daily irradiations through both anterior and posterior portals. The volume of normal tissue, in particular the lung, within the region receiving a full dose of radiation can be readily appreciated. After reaching the maximum dose that could be delivered safely to the spinal cord, boost fields using obliqued x-rays beams were then delivered, as shown in Fig. 70-1B. The radiation dose delivered both to the tumor and to the lungs is summarized by a â&#x20AC;&#x153;dose-volume histogram,â&#x20AC;? shown in Fig. 70-1C , which integrates the proportion of the targeted organ or tumor receiving a certain cumulative radiation dose. While this dose-volume relationship loses important spatial and functional information, this formalism has become important in analyzing radiation dose delivery to correlate dosimetry with treatment outcome. In this illustration, the volume of lung receiving greater than 20 Gy is referred to as the V20 . In this case it is greater than 30 percent, which roughly predicts for an increased risk of pneumonitis. In fact, a follow-up chest radiograph (Fig. 70-2A) and CT scan (Fig. 70-2B) reveal a pattern of radiation-induced inflammatory changes corresponding to the high-dose region of the radiotherapy. In a case such as this, if the malignancy is cured or the patient experiences the desired improvement in the symptoms from the malignant disease with minimal or manageable toxicity from the radiotherapy, then the treatment has produced a desirable result even if it produces radiographic changes or measurable clinical damage to the lung or other organs. Overt pulmonary toxicity is, however, a potential consequence of thoracic radiotherapy, which sometimes overshadows the benefits of treatment.

BRIEF OVERVIEW OF RADIOLOGIC PHYSICS External-beam radiotherapy is generally delivered using x-rays or gamma rays. Both of these radiations are highenergy electromagnetic waves or photons that are able to

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Figure 70-1 A 73-year-old man with stage IIIB nonâ&#x20AC;&#x201C;small-cell lung cancer was treated with radical radiotherapy and concurrent cis-platinum chemotherapy. The plans for his radiation treatments are summarized. A. Initial anterior and posterior x-rays beams with simulation film on left and isodose distribution overlaid on computed tomography scan on right. B . Anterior port (i.e., treatment) film. C . Oblique boost fields with simulation film on left and axial view of radiation dose distribution off the spinal cord on right. D . Dose-volume histogram of the entire treatment course, for tumor (solid line) and lung (dashed line). The V20 (39.45) is derived from the lung histogram.

cause ionizations when interacting with matter. The only difference between them lies in the manner in which they are produced: Gamma-ray photons are emitted from atomic nuclei during the decay of radioactive atoms and x-rays are produced when high-energy electrons strike a target material and interact with the electron shells of atoms in that target, causing them to emit x-ray photons (i.e., the Bremsstrahlung effect). After its emission, an individual x-ray photon is indistinguishable from a gamma-ray photon. Thus, although our discussion uses x-rays for its examples, the discussions would be equally applicable to radiotherapy given using high-energy gamma rays, for example, from cobalt-60 teletherapy units. The x-rays used for diagnostic imaging are in a relatively low energy range in which the dominant interaction of the photons with matter is through the photoelectric effect. In this process, absorption of an x-ray photon causes an electron to be ejected from the inner shell of an atom. The probability of photoelectric interactions increases as a function of the cube of the atomic number, that is as Z3 . Because of this, large, heavy atoms absorb low-energy diagnostic x-rays much more efficiently than smaller, lighter atoms. Diagnostic

radiology capitalizes on the large differences between the absorption of these low-energy x-rays in materials with different compositions, e.g., air, soft tissue (which is 70 percent water and therefore comprised primarily of the small atoms hydrogen and oxygen), bone (with its high calcium content), and administered contrast agents containing barium, iodine, or other heavy atoms. The difference in absorption is used to image anatomical structures. In contrast, the high-energy x-rays used in radiotherapy interact with matter primarily by a phenomenon called the â&#x20AC;&#x153;Compton effectâ&#x20AC;? in which x-rays cause ionization of atoms via interactions with their outer electron shells. The Compton effect is not dependent on the atomic number but is instead a function of the electron density. Because the electron densities of most biologic tissues are relatively uniform, it is a reasonable approximation for the purposes of most radiotherapy dosimetry to assume that a patient has a uniform density, equivalent to water. An important caveat to radiation dosimetry relevant to this chapter involves the standard specification of doses in tissues that include a large proportion of air, such as the lung. As a single x-ray beam penetrates through water or tissue, the

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Figure 70-2 Same patient as in Fig. 70-1, developed radiation pneumonits at 6 months following completion of radiotherapy. Baseline posterior chest x-ray ( A) and computed tomography (CT) scan (B ) are compared to follow-up chest x-ray (C ) and CT scan (D ) showing characteristic interstitial infiltrates corresponding to the radiation treatment portals.

dose received by the tissue falls progressively, generally as an exponential function of the depth. Because of its markedly lower density, air will absorb less radiation, and therefore attenuate the x-rays less than would tissue or water. With the quantitative knowledge of lung density that can now be derived from CT scanning, algorithms have been devised to estimate the inhomogeneity in the absorbed dose resulting

from the differences in the density of lung and soft tissue. These heterogeneity corrections show that routine dosimetric calculations, which assume uniform density, underestimate the radiation doses to lung and tissues beyond the lung by factors that range from 5 to 25 percent. Although this is a very important consideration when quantifying the radiation dose delivered to the lungs, one must remember that

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doses delivered to the thorax and the lungs historically have been reported in the medical literature without heterogeneity corrections. Moreover, because the preponderance of clinical data concerning lung tolerance have been determined and reported using older algorithms, which assume for dosimetric purposes that the lung has water-equivalent density, the impetus to change dose reporting is limited by a desire to avoid confusion between the new and older literature. Therefore, the reader should assume, unless explicitly stated otherwise, that the radiation doses given in this chapter, or for that matter any publication, are not corrected for lung density. Radiation dose is currently reported using the unit of the System International (SI), the gray (Gy). The Gy is a measure of the energy absorbed by 1 kg of tissue; 1 Gy = 1 J/kg. The former unit of absorbed dose, called the “rad” (an acronym for “radiation absorbed dose”) was measured with the cgs system; by definition, 1 rad = 100 ergs per gram. To compare old and recent literature, one must therefore recall that 1 Gy = 100 rad. Despite the fact that it is not an approved SI unit, some radiotherapy literature avoids this conversion by giving the dose in centigray (cGy), where 1 cGy = 0.01 Gy = 1 rad. Other measures of radiation dose seen in the literature include the roentgen, the Sievert, and the rem. The roentgen measures radiation exposure, rather than energy absorption, and refers specifically to the amount of ionization produced in air under standard conditions (1 R = 1 electrostatic unit/cc = 2.58 × 10–4 coulombs/kg of standard air given that air has a density of 1.29 × 10–4 g/cm3 at 0◦ C and 760 torr). This unit is frequently encountered in the radiation dosimetry literature, not only because it was historically a measure of dose, but also because many widely used radiation monitors (e.g., ionization chambers) directly measure radiation exposure at the surface of the body. The dose absorbed by tissue is then calculated from this exposure. The radiation protection literature uses the unit of “equivalent dose,” the Sievert (Sv), which is calculated as the absorbed dose (in Gy) multiplied by a “weighting factor” that considers the differing biologic effects of different radiations. Although the weighting factors for some radiations, such as neutrons and alpha particles, can be as high as 20, the weighting factors for x-rays, gamma rays, and electrons are defined as 1. For most purposes in diagnostic and therapeutic radiology, therefore, 1 Sv = 1 Gy. The Sv replaces the older unit of equivalent dose, the rem (1 Sv = 100 rem). Unfortunately, the literature on radiation-induced lung injury includes papers using all of these different units, creating great confusion for the casual reader. For simplicity, all doses given in this chapter have been converted to Gy.

RADIOBIOLOGY OF RADIOTHERAPY When x-rays pass through tissue, a complex series of physical and chemical reactions occurs. As the x-rays interact with atoms along their path, as described, energy is absorbed, and energetic fast electrons are ejected. These fast electrons travel through tissue, producing secondary ionizations, which lead

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within milliseconds to the generation of a variety of highly reactive free-radical species. Because biologic materials are about 70 percent water, ions and free radicals derived from water (e.g., H·, OH·, H2 O+ , H3 O+ ) are the main reactive species produced. These ions and radicals react with each other and other nearby molecules, creating a wide variety of chemically reactive species and producing many kinds of damage in biologic macromolecules. Because the DNA contains information that is critical to the cell while most other molecules can be replaced readily, damage to DNA is the most important biologic effect of irradiation. Radiation produces a wide variety of lesions in DNA, including single- and double-strand breaks, damaged bases and loss of bases, as well as chromosomal breaks and rearrangements. If these lesions are not repaired, the result can be permanent mutations or changes in chromosomal structure that lead to the death of the cell or changes in its behavior. The cytotoxic effects of radiation are the basis for both the antineoplastic effects and the toxicities of radiotherapy. A theoretical concern is that radiotherapy may produce a mutation in a previously normal cell that leads to the development of a new malignancy. Although radiation-induced malignancies do occur, malignant transformation is, fortunately, a rare enough event at the doses used in radiotherapy that the risk of inducing a second cancer is acceptably small relative to the great benefit of curing the existing malignancy. The greater risk to the patient lies in the fact that radiation is not selectively toxic to the tumor cells but instead kills both normal and malignant cells within the treatment field. Although the radiochemical reactions that lead to cytotoxic damage are complete within milliseconds after the end of irradiation, cells dying from radiation injury do not die immediately. In fact, soon after irradiation, radiationsterilized cells are indistinguishable from cells that will ultimately survive irradiation in their appearance, metabolic activities, and even rates and patterns of proliferation. Most radiation-sterilized cells ultimately die during a mitosis but may first undergo one or even several divisions, producing an abortive clone of sterile cells, all of which ultimately die and disintegrate through apoptosis, necrosis, mitotic catastrophe, senescence, or other pathways of cell death. This delayed cytotoxicity underlies many of the effects seen in radiotherapy. Rapidly growing tumors, for example, generally begin shrinking sooner than slowly growing tumors, and many tumors continue to shrink progressively for months after radiotherapy. Analogously, radiation reactions in normal tissues reflect the normal patterns of cell turnover in the tissue. After irradiation, nonproliferating, terminally differentiated cells will continue to perform their differentiated functions throughout their normal life spans. Other cells that are not proliferating at the time of irradiation will likewise continue to function normally until they are recruited into proliferation, perhaps months or even years later; when they begin to proliferate their progeny will die. Rapidly proliferating cells such as epithelium or nucleated blood/marrow cells die within a few days of irradiation, leading to the familiar early radiation reactions of epilation, desquamation, mucositis, and hematologic

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Figure 70-4 Survival of lung cells treated with different doses of radiation. Cells were explanted from mouse lungs, irradiated in vitro, and assayed for viability using a colony formation assay. (Redrawn from Guichard M, Deschavanne PJ, Malaise EP: Radiosensitivity of mouse lung cells measured using an in vitro colony method. Int J Radiat Oncol Biol Phys 6:441â&#x20AC;&#x201C;447, 1980 with permission.)

depression. There is increasing evidence that some cell types, especially hematopoietic cells, can be induced by radiationinduced damage to enter a pathway of programmed cell death that leads to apoptosis; the role of early and delayed apoptosis in determining the response of tumors and normal tissues to radiotherapy is the subject of intensive investigation. A typical survival curve for mammalian cells, obtained using mouse lung cells, is shown in Fig. 70-3. To a first approximation, cell survival falls exponentially as the radiation dose increases. Statistically, this implies that each incremental dose of radiation has the same cytotoxic effect; that is, each incremental dose kills the same proportion of the viable cells present in the population at the beginning of that irradiation. Very low doses of radiation have somewhat lesser effects; this shoulder on the cell survival curve reflects the ability of the cells to accumulate and tolerate or repair some of the damage produced by radiation. The effect of the repair of radiation damage can be seen when the radiation dose is divided into two or more treatments separated by hours or days, rather than being delivered in a large single dose. Dividing, or â&#x20AC;&#x153;fractionating,â&#x20AC;? the radiation dose allows cells to repair damage to their DNA between treatments. As a result, there is less cytotoxicity from a fractionated treatment regimen than from the same total radiation dose delivered as a large single fraction (Fig. 70-4). Smaller fractions produce less cytotoxicity than larger fractions. Similarly, the cytotoxic effects of radiation are diminished when the radiation is delivered continuously at a low dose rate, over hours or days, to allow repair and proliferation to occur during irradiation (Fig. 70-4). Fractionating therapeutic irradiations or delivering the radiation at low dose

Figure 70-3 Effect of fractionated irradiation and low-dose rate irradiation on cell survival. The survival curve for lung cells treated with a single dose of radiation is redrawn from Fig. 70-3. The calculated effect of dividing the radiation dose into several daily treatments with 5 Gy/fraction or 2.5 Gy/fraction is illustrated. The dashed line illustrates the survival curve that would be expected for irradiation delivered continuously at a low dose rate over several hours, allowing repair and proliferation to occur during treatment. Changes in the cytotoxicity of radiation with fractionation and at low dose rates lead to decreased injury in lungs irradiated with analogous regimens.

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Figure 70-5 The therapeutic ratio is the critical factor determining the success of cancer therapy.

rates generally appears to increase the therapeutic ratio, by protecting normal tissues against radiation injury but producing a smaller increase in the relative radioresistance of the tumor, thereby improving the outcome of treatment. This increase in the therapeutic ratio is thought to reflect qualitative and quantitative differences between the normal and malignant cell populations, including differences in the intrinsic radiosensitivity of the critical cells and differences in the patterns of cell proliferation and cell loss, as well as differences in the ability of the normal and malignant cells to repair radiation damage. Empiric observations of patients treated with radiotherapy, laboratory experiments with tumors and normal tissues in rodents, and studies with cells in culture have all been used to guide the development of the clinical fractionation schedules now in use. This optimization process is ongoing and will undoubtedly continue, incorporating new information about the repair of radiation damage in normal and malignant cells and about the physiological factors that modulate the development of late radiation injuries in specific normal tissues. In this process, as in any change in cancer therapy, the parameter of critical importance is always the therapeutic ratio (Fig. 70-5). A new treatment regimen is superior only if it produces an increased effect on the tumor, without producing an equivalent increase in toxicities to critical normal tissues, thereby increasing the therapeutic ratio and producing therapeutic gain. The art of radiotherapy lies in the design of treatment fields that minimize radiation doses to normal tissues and in the development of treatment regimens that use all available information on the biology of the tumor and of the critical normal tissues to design treatment protocols that maximize the therapeutic ratio.

PATHOPHYSIOLOGY OF RADIATION PNEUMONITIS Much of our current understanding of the pathophysiology of radiation injury to the lungs is derived from animal experimentation. Translation of animal data to human conditions

is always problematic, because differences in the biology and physiology of different species may preclude direct and definitive extrapolation from animals to humans. Instead, studies with experimental animals must be designed to identify physiological factors and biologic mechanisms that can be used to interpret clinical data and suggest avenues for clinical investigations. Data on radiation pneumopathy in humans is fragmentary and complicated by the variability in the patients treated with thoracic irradiation. Most studies of radiation pneumonitis include patients with a variety of malignancies, treated with different irradiation regimens, often in combination with chemotherapy and surgery. Moreover, the patients vary widely in age and the presence of other diseases and risk factors. Therefore, our current understanding of radiation injury to the lung remains incomplete. What is known suggests a complex, multifactorial mechanism of injury and disease progression that reflects cytotoxic effects on both epithelial and endothelial tissues, inflammatory responses that include disordered cytokine and cellular signaling, and the induction of interstitial fibrosis. Similarities to lung injuries resulting from cancer chemotherapy, other drugs, inhaled chemicals, oxygen toxicity, and idiopathic pulmonary fibrosis are intriguing, especially when one considers that many of these diseases include pathological responses to free-radical chemical species and are likely to reflect similar underlying initial lesions. Partial lung resection and localized irradiation have certain similarities, because their effects are largely localized to the treated areas and consequently depend on the number of pulmonary lobules or alveolar窶田apillary units functionally destroyed. Thus the volume of lung irradiated is an important determinant of toxicity. Consequently, the radiation oncologist plans the treatment to minimize the volume of lung receiving high radiation doses, just as the thoracic surgeon plans a lobectomy or pneumonectomy to consider the residual capacity of the lungs. Of course this simple analogy has its limitations. For example, inactivation of enough lobules by radiation increases the ventilatory dead space and could lead to shunting and ventilation-perfusion mismatching. However, in clinical practice, extensive

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shunting generally is not observed. In fact, postradiation radionuclide ventilation-perfusion scans tend to show underperfusion rather than underventilation in the irradiated areas of partially irradiated lungs. In most cases, radiation injury in lung conforms to the radiation treatment fields, but in some instances effects outside the treated areas are observed, with localized radiation inducing a more generalized or diffuse hypersensitivity pneumonitis. The effects of radiotherapy on the lung reflect the proliferation patterns of the different cellular components of the terminal capillary-alveolar units. Type I pneumocytes are the dominant epithelial cells of the lung, covering about 83 percent of the alveolar surface. Type I pneumocytes are normally nonproliferating and do not proliferate in response to injury. Because of this, they are thought to be relatively resistant to the cytotoxic effects of radiation. Type II pneumocytes, which comprise about 16 percent of the cells in the human lung, are the principal source for the surfactant that modifies alveolar surface tension to prevent atelectasis. Type II pneumocytes have turnover times of about 1 month. In response to certain injuries, these granular pneumocytes can be induced both to undergo rapid mitosis and to differentiate into type I pneumocytes. Endothelial cells comprise about 30 percent of the cells in human lungs and form a continuous layer between the blood and lung tissue. Although endothelial cells are classified in most tissues as stromal cells, endothelial cells in lung are actually parenchyma, because they are critical to the function of this organ. Capillary endothelial cells are a constantly renewing population. The turnover time of these cells has been estimated to be on the order of 2 months. Endothelial cells can be induced into rapid compensatory proliferation after injury; therefore, radiation can result in the depletion of both type II pneumocytes and endothelial cells. Several lines of evidence suggest that radiation injury is related primarily to cytotoxic damage, especially to the surfactant-producing type II pneumocytes and vascular endothelial cells. Although clinical signs of pneumonitis require weeks to develop, laboratory studies reveal evidence of lung injury within hours after large single doses of radiation. Shortly after irradiation, electron microscopy can detect abnormalities in surfactant-containing lamellar bodies. There is an increase in surfactant in bronchoalveolar lavage specimens within hours of irradiation that persists for several weeks. Ultrastructural evidence of endothelial cell damage is also seen soon after lung irradiation, and a rapid increase in capillary permeability occurs, reflecting loss of integrity of cell junctions, intracellular vacuolization, cellular pleiomorphism, and sloughing of the basement membrane. Capillary occlusion by cellular debris and microthrombi may occur at high doses. The clinical course of lung injury occurs later and includes a pneumonitic phase, developing weeks to months after radiation, followed by a fibrotic phase, developing months to years later. To explain the two clinical phases, Rubin and Casarett’s original model of radiation lung toxicity suggested that the pneumocytes and endothelium represented two separate and distinct cellular targets and that damage to pneu-

mocytes led to pneumonitis, while vascular damage led to fibrosis. This older model is now thought to be incorrect. The current weight of evidence from Rubin and others suggests that the pneumonitic and fibrotic processes both are manifestations of a common pathway of injury and response. Histologically, one can recognize a typical sequence of events developing in the lung after large doses of radiation. Within days to weeks, vascular congestion and intra-alveolar edema and exudation occur, followed by infiltration of inflammatory cells and epithelial desquamation. Weeks later, collagen fibrils are deposited within areas of injury and interstitial edema, leading to a thickening of alveolar septa similar to that in hyaline membrane disease. The probability and severity of these changes are quite variable and depend on such factors as the radiation dose and treatment volume. The severity of the damage and volume of tissue affected determine whether a pneumonitic picture will become clinically evident. Resolution of inflammatory infiltrates and alveolar exudates, which can be improved by anti-inflammatory agents such as glucocorticoids, correlates with symptomatic improvement and resolution of radiographic opacities in the affected lung. Inflammatory cells, particularly alveolar macrophages, migrate into areas of radiation injury. This induces an ensuing cytokine cascade and mediates the host response, similar to that which occurs in other inflammatory conditions, which can lead to pulmonary fibrosis. Rubin and his collaborators have detected a biphasic increase in mRNA expression for the proinflammatory cytokines IL-1α, IL-1β, and TNF-α at 2 and 8 weeks after radiation. Preliminary clinical trials also suggest that elevated serum levels of IL-6 before and during radiotherapy predict for an elevated risk of radiation pneumonitis. Beginning at 2 weeks, TGF-β, a cytokine that mediates fibrotic responses, increases. Clinical data implicating TGF-β as a predictive marker for pneumonitis, however, have been mixed. Collagen gene expression is also appreciably increased, corresponding to the fibrotic changes seen histologically. These studies suggest that early and persistent elevations of cytokine production and alterations of intercellular signaling are critical to the development of radiation reactions in the lung. There is increasing evidence from studies with inbred mice that genetic differences modulate the development and severity of fibrosis and hyaline membrane formation and thus determine the nature of the late toxic lesion and the time of development of radiation pneumotoxicity. The processes described in the preceding lead to pathological changes that conform spatially to the areas in which localized radiation was administered. Interestingly, it has been discovered that radiation can also induce an allergic alveolitis. This is observed infrequently as a diffuse pneumonitis or even more rarely as patchy, transient pneumonitis occurring outside the treated fields. In its most severe form, this leads to adult respiratory distress syndrome. Morgan and Breit have suggested that this form of radiation pneumonitis be termed “sporadic”; however, the subclinical occurrence of this syndrome actually may be fairly common. Bronchoalveolar lavage in humans and in experimental animals frequently

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shows a significant increase in activated T-helper (CD4+) lymphocytes, temporally related to irradiation and occurring equally in the irradiated lung and the contralateral, unirradiated lung. Gallium scanning in these subjects may also show bilateral uptake, not corresponding to the treated regions. Frequent reports of autoantibodies, including antibodies to collagen, in the sera of human cancer patients even before treatment suggest the possibility that malignancy-associated autoimmune reactions may be involved in this syndrome.

CONFOUNDING EFFECTS OF CHEMOTHERAPY Many cytotoxic drugs employed as antineoplastic agents can produce pulmonary toxicity. Bleomycin, which kills cells by generating reactive free-radical species, can give rise to both pneumonitis and fibrosis. Mitomycin C and doxorubicin have both been associated with lung toxicity. As high-dose alkylating agent chemotherapy is used more frequently in the setting of bone marrow or peripheral stem cell transplantation, agents such as cyclophosphamide, BCNU, and busulfan have been associated increasingly with clinically significant pneumonitis. The direct toxicity of anticancer drugs to the lungs sounds a note of caution for those considering the development of treatment protocols combining systemic chemotherapy with lung irradiation. Animal studies looking at changes in respiratory rates and/or death resulting from lung injury show that the severity of the lung injury can be increased when doxorubicin, bleomycin, cyclophosphamide, mitomycin C, dactinomycin, and vincristine are administered along with radiation. No enhancement has been documented in studies with 5-fluorouracil, cis-platinum, carboplatinum, hydroxyurea, vinblastine, or methotrexate, despite reports of lung toxicity from methotrexate alone. As a wide variety of cytokines are now available for pharmacologic administration, modulation of radiation injury by these biologic agents has received increasing study. Interferons have been shown both to increase and decrease radiation lung toxicity, whereas interleukins 1 and 2 may have protective effects. Some radiationdrug interactions in the lung have been shown to be schedule dependent, with the effect of the combination varying with the sequence and the time between treatments with the two agents. Additive, subadditive, and even supra-additive toxicities may be observed in rodents when single treatments with the same dose of radiation and drug are given over a 24-h period, but in different sequences and different times between treatments. Such findings highlight the complexities of combined modality therapy and the difficulty of using animal data to plan clinical treatment regimens. Data from several specific clinical situations show that regimens combining radiation with particular chemotherapy agents can produce significant risks of pneumonitis. As summarized in a recent review of radiation pneumonitis in patients treated for lung cancer, cis-platinum, taxanes, mit-

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omycin C, gemcitabine, and irinotecan concurrent with radiotherapy using a variety of fractionation regimens seem to elevate the risk of pneumonitis or lung toxicity. Older clinical data from pediatric trials strongly suggest that administration of concurrent doxorubicin or actinomycin D with thoracic radiotherapy generally should be avoided or, alternatively, that the radiation doses should be reduced significantly where these drugs are used. Sequential treatment with these drugs and radiation is less likely to produce lung injury. However, a phenomenon termed â&#x20AC;&#x153;radiation recallâ&#x20AC;? has been well described, in which either of these two drugs given even several months after radiotherapy will produce an inflammatory reaction in the region corresponding to the radiation treatment fields. Although this reaction is best known in skin, it also has been well documented in the lungs in several case reports and has been produced in experimental animals. Radiation recall probably reflects the fact that the irradiated areas of the lung still retain residual, subclinical injury, which is exacerbated into clinical pneumonitis as a result of the additional injury from the drug. Therefore, the biologic basis of the recall phenomenon is analogous to that of the residual radiation injury, which decreases the ability of heavily irradiated lung tissue to tolerate a second course of radiotherapy delivered months or years later.

CLINICAL SYNDROMES Radiation oncologists conventionally divide clinical toxicities into acute and late effects, with both radiation pneumonitis and fibrosis considered late toxicities. Several grading systems for pneumonitis have been developed for scoring lung injury during clinical trials (Table 70-1).

Acute Manifestations It is relatively uncommon to observe acute pulmonary toxicity during the administration of fractionated radiotherapy. At relatively high therapeutic doses (50 to 60 Gy), however, acute radiation injuries to the tracheobronchial tree can be expected. Bronchoscopic examination of these patients is likely to reveal erythematous mucosa, with thickened secretions that can accumulate in and obstruct the airways. Although a majority of patients remain asymptomatic, occasional patients experience an irritative, dry cough. Antitussive agents such as codeine, adequate hydration, and reassurance are usually all that are required to manage this problem. Once the radiotherapy has been completed, the bronchial epithelium regenerates and heals over several weeks with a corresponding resolution of any symptoms.

Late Manifestations The clinical course of late radiation injury to the lungs is biphasic with both inflammatory and fibrotic components.

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Table 70-1 Toxicity Criteria for Pneumonitis Grade Scoring System

CTCAE

Asymptomatic; radiographic findings only

Symptomatic; not interfering with ADL

Symptomatic; interfering with ADL; O2 indicated

Life-threatening ventilatory support indicated

Death

RTOG/EORTIC (LENT-SOMA)

Asymptomatic or mild symptoms (dry cough), with radiographic findings

Moderately symptomatic (severe cough fever)

Severely symptomatic

Severe respiratory insufficiency; continuous oxygen/assisted ventilation

Death

SWOG (33)

Asymptomatic or symptoms not requiring steroids with radiographic findings

Initiation of or increase in steroids required

O2 required

Assisted ventilation necessary

Death

Notes: Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; ADL = activities of daily living; RTOG = Radiation Therapy Oncology Group; EORTC = European Organization for the Research and Treatment of Cancer; LENT-SOMA = Late Effects on Normal Tissue-Subjective, Objective, Management and Analytic Scales; SWOG = Southwest Oncology Group. source: Modified from Mehta V.: Int J Radiat Oncol Biol. Phys 63:5–24, 2005, with permission.

Radiation Pneumonitis A pneumonitic process frequently becomes evident 6 weeks to 6 months following radiotherapy. At this time radiographs show alveolar opacities that generally conform to the treatment portals. The severity of radiation pneumonitis varies dramatically from patient to patient, even in those receiving identical therapeutic regimens. In most cases, the pneumonitis is asymptomatic, even though radiologic abnormalities are quite common, having been found in some prospective studies in as many as 50 percent of patients who have completed a course of thoracic radiotherapy. When symptomatic, this syndrome is often characterized by the abrupt onset of fever, cough, and dyspnea. The severity of symptoms depends on the extent of radiotherapy, increasing with the treated volume and the radiation dose. Symptoms in patients irradiated to limited lung volumes or to relatively low doses may consist of low-grade fever, cough, congestion, and chest fullness or discomfort. Any hemoptysis tends to be minimal. In more severe situations, dyspnea, high fever, and cough occur. When more than three-fourths of the total lung volume is irradiated to doses of 45 Gy—a situation to be avoided— acute radiation pneumonitis is highly likely and can be extremely severe, producing respiratory distress. The radiation oncologist is probably most likely to see clinically significant radiation pneumonitis that can be life-threatening when it

occurs as a rare and unanticipated consequence of standard treatment, despite appropriate treatment planning designed to minimize the volume of lung treated with high doses of radiation. Fortunately, with well planned radiotherapy severe radiation pneumonits is a rare event, while milder forms are not uncommon and are manageable. It is important to distinguish radiation pneumonitis from infection, recurrent tumor (particularly with lymphangitic spread), drug reactions, congestive heart failure, and other respiratory ailments. These distinctions may not be easy; one series from Duke suggested that up to 28 percent of patients with radiation associated lung toxicity have complex co-morbidities that make it difficult to assign a definitive diagnosis. Bacterial, fungal, viral, and pneumocystis pneumonias can be quite difficult to differentiate from pneumopathy induced by chemotherapy or radiation. Aids in the differential diagnosis include the clinical course and the temporal relationship between the irradiation and respiratory illness. Definition of the radiographic pattern of the infiltrate is also very useful, because radiation pneumonitis often conforms to the outline of the sharply demarcated radiation portal (Figs. 70-2 and 70-6). Bronchoscopy and lung biopsy can also be important diagnostic tools to direct therapeutic decisions. Ruling out infection is particularly important, because treatment of symptomatic radiation pneumonitis relies on supportive care

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Figure 70-6 A 52-year-old woman found a nontender lump in her right breast and subsequently underwent a lumpectomy for a localized 1.4-cm diameter infiltrating ductal carcinoma. The axillary lymph nodes were negative. The patient was placed on Tamoxifen and underwent radiotherapy to the right breast, using tangential fields, to 50 Gy in 25 fractions over 36 days. A. A radiation dose distribution of the such photon fields overlying the right breast and chest wall.This was followed by boost radiation treatments to the surgical bed for an additional 14 Gy in 7 fractions. B ,C . The simulation and port films, respectively, of the whole-breast treatments, again highlighting the different interactions of low-energy and high-energy x-rays with tissues. Four months after radiotherapy, the patient developed radiation pneumonitis characterized by fever, cough, and dyspnea requiring hospitalization. D . A right-lung opacity that does not correspond to normal anatomic structures but does correspond to her treatment fields. E . The patient responded dramatically to steroids, with resolution of radiographic findings on follow-up chest radiographs.

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severe fibrosis with respiratory compromise, chronic cor pulmonale, cyanosis, and finger clubbing. At the severe end of the spectrum, the syndrome can be life-threatening. In general, in the absence of other underlying lung disease, symptoms are mild when less than 25 to 30 percent of total lung parenchyma is involved. Radiation-induced Pleural Reactions Pleuritis can also be seen 2 to 6 months following radiation. It can be associated with plueritic chest pain, a pleural friction rub, and an exudative pleural effusion. Large effusions are, however, distinctly unusual in the absence of other pathology. Like radiation pneumonitis, radiation-induced pleuritis can heal without significant residuae or can proceed through a fibrotic phase that generates pleural thickening.

Figure 70-6 (Continued )

in conjunction with steroids, which is contraindicated with an active infection. Doses of glucocorticoids generally can be tailored to the severity of the symptoms. Asymptomatic pneumonitis can be managed with close observation. Severe cases generally warrant treatment with 0.5 to 1 mg/kg per day of prednisone (or its equivalent) in divided doses. Response rates to steroid therapy between 20 and 100 percent have been reported, and dramatic clinical and radiographic responses are not infrequently seen. Steroids should be tapered slowly after the patient is stabilized, because it is common to see a recrudescence of symptomatology when steroids are discontinued too rapidly. Failure to respond to steroid therapy is an adverse prognostic factor that suggests the prospect of rapid disease progression. Radiation Fibrosis A more indolent fibrotic process can follow either subclinical or symptomatic radiation pneumonitis. This begins several months after radiotherapy and peaks in radiographic severity several years later. Fibrosis tends to occur in or adjacent to areas of prior pneumonitis, but it can also occur in the absence of clinically overt radiation pneumonitis. Fibrotic changes and the retraction of the lung parenchyma from scarring occur in the irradiated regions (Fig 70-2). When the volume of lung irradiated is relatively small and the remaining lung parenchyma contains sufficient respiratory surface area, these changes tend to be asymptomatic. With increasing relative volumes of pulmonary fibrosis, a spectrum of symptomatology is possible, ranging from mild dyspnea on exertion to

Radiation-induced Bronchial Stenosis With improvements in the technical delivery of radiotherapy, recent clinical trials for lung cancer have emphasized escalation of the administered radiation dose. As a result there is an increasing appreciation that radiation-induced fibrosis can result in bronchial stenosis, which can itself cause postobstructive atelectasis, volume loss, and functional impairments with respiration. Clinically, such fibrosis needs to be differentiated from recurrent tumor; bronchoscopy or positron emission tomography (PET) imaging may be of help in this process. One retrospective series in which radiation doses ranged from 60 Gy to as high as 86 Gy demonstrated that radiation-induced bronchial stenosis may occur in up to 25 percent of patients, with incidence directly correlating with radiation dose.

DEFINING THE RADIATION TOLERANCE OF THE LUNGS Whereas we customarily speak of radiation doses that can be delivered safely either to the whole body or a particular organ, radiation tolerance is usually defined as the dose that will yield a 5 percent risk of late radiation injury. When discussing the tolerance of the lungs, one must consider several different therapeutic situations. The tolerance of the lung varies with the volume of lung tissue irradiated. In addition, singledose irradiations, fractionated irradiations, and irradiations given at low dose rates pose different risks of injury and must be considered separately. Additional injury from surgery or chemotherapy or from a prior course of radiotherapy also must be considered, as must the confounding effects of injury to lung tissue from coexisting cardiopulmonary disease and the underlying malignancy. Infections and immunologic reactions are also important. The clinical endpoints used to define a case of radiation pneumonitis vary as well, because the severity of the lung injury spans a wide spectrum of diagnostic signs and clinical symptoms. Given the heterogeneity of clinical circumstances and biologic data in general, it is not

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surprising that the medical literature that defines the risks for radiation pneumonitis and fibrosis is extremely complex and often difficult to interpret.

WHOLE-LUNG IRRADIATION A good starting point when discussing lung tolerance is to consider the effects of irradiating the entire lung. This has direct clinical relevance because there are several circumstances in which the entire lung is irradiated. These include total body irradiation for bone marrow or hematologic stem cell transplantation, hemibody irradiation for palliation of widespread metastatic disease, and whole-lung irradiation electively or therapeutically for relatively radiosensitive tumors such as Wilms’ tumor, Ewing’s sarcoma, or Hodgkin’s lymphoma. These are often circumstances in which chemotherapy is being administered as well. Published experience from the Princess Margaret Hospital in Toronto provides some of the best data regarding whole lung tolerance. Investigators from that institution have an extensive experience with delivering upper hemibody irradiation to different doses and varying fractionation patterns. They reported in 1978 on a cohort of 245 patients, most with metastatic solid tumors, who received single-fraction upper hemibody irradiation at dose rates of 0.3 to 0.8 Gy/min to doses of up to 10 Gy. The actuarial incidence of acute radiation pneumonitis, defined as the sudden onset roughly 16 weeks after irradiation of cough, dyspnea, and opacities visible on chest radiographs, was strikingly dose dependent (Table 70-2). The doses shown in Table 70-2 were not corrected for heterogeneity in density. When doses were corrected for heterogeneity, producing an upward estimation of the doses actually received by the lungs, analysis yielded the sigmoid-shaped curve shown in Fig. 70-7.

Table 70-2 Actuarial Incidence of Radiation Pneumonitis after Single Fraction Whole-lung Irradiation Uncorrected Dose

Patients

Pneumonitis

<6 Gy

2.7%

6 Gy

17.5%

8 Gy

149

35.6%

10 Gy

83.9%

Source: Data from Fryer Fitzpatrick PJ, Rider WD; CJH, et al: Int J Radiat Oncol Biol Phys 4:931–936, 1978. Doses are not corrected for heterogeneity in tissue density.

Figure 70-7 Incidence of radiation pneumonitis in patients receiving single-dose, whole-lung irradiation at dose rates of 0.3 to 0.8 Gy/min. Unlike most doses given in the text, doses on this figure are corrected for heterogeneity. The effect of this correction can be seen by comparing these data with those in Table 70-1, which were derived from an earlier analysis by the same group and are presented using uncorrected doses. (Data are redrawn from Van Dyk, J, Keane TJ, Kan S, et al, Int J Radiat Oncol Biol Phys 7:461-467, 1981.)

Using heterogeneity-corrected data, the incidence of pneumonitis is estimated to be negligible for single doses less than about 7.5 Gy. Other published data regarding upper hemibody single-fraction irradiation are in general agreement with these findings. The careful reader would be struck by the fact that the single-fraction data might predict an unacceptable risk for pneumonitis when single-fraction, total-body irradiation (TBI) is utilized in the setting of bone marrow transplantation. The most important treatment factor making singlefraction TBI in the range of 8 to 10 Gy (uncorrected for heterogeneity) tolerable is that these treatments generally are given at a low dose rate (less than or equal to 0.1 Gy/min), so that the treatment is delivered over times of 1 to 2 h. In Seattle, where hundreds of patients with leukemia have undergone bone marrow transplantation (BMT) with total-body irradiation, using single fractions of 10 Gy (uncorrected) delivered at dose rates on the order of 0.08 Gy/min, the incidence of pneumonitis is roughly 25 percent. Review of transplant-related single-fraction TBI with variable dose rates shows incidences of clinical lung injury varying from 25 to 70 percent. Studies in mice show that the toxicities of TBI can be improved further by fractionating the irradiation as well as by delivering radiation at a low dose rate. This concept is supported by a randomized clinical trial comparing low-dose rate single-fraction TBI (10 Gy) with low-dose rate fractionated TBI (12 Gy in 6 fractions over 3 days) for patients with acute myelogenous leukemia in first remission, which showed a significant improvement in event-free survival with fractionation, mainly because of an improvement in early mortality. Interstitial pneumonitis in these patients was decreased from 26 to 15 percent with fractionation. Ongoing trials are seeking to optimize irradiation regimens for TBI. Many fractionation patterns have been and are being tested, including daily fractions and 2 or 3 daily fractions with doses of 1.5 to 2.25 Gy per fraction. Other trials are testing different dose rates. At

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many transplant centers it has become common practice to utilize lung transmission blocks to attenuate the lung dose and thereby reduce the risk of pneumonitis, in effect by compensating for the heterogeneity in tissue density due to the air within the lungs. Pneumonitis in the BMT setting has a multifactorial etiology, reflecting not only the effects of radiation but also the effects of chemotherapy, graft-vs.-host disease (GVH), lung injury from tumor, opportunistic infections, and other risk factors. Cyclophosphamide is almost universally given with TBI. The addition of other drugs is based on institutional treatment policies. As described, many anticancer drugs are known to injure the lung. BMT conditioning regimens that do not use TBI (which tend to use high-dose busulfan in place of radiation) in fact have rates of interstitial pneumonitis comparable to regimens including TBI. The presence of GVH is also important, not only because GVH causes lung injury directly but also because the drugs used to control GVH injure the lung. Whole-lung irradiation has been used in the treatment of widespread lung metastases. In two published series a combined total of 70 patients with osteosarcoma who received elective whole-lung irradiation to prevent pulmonary metastases (which is not currently a standard practice pattern) received 15 to 17.5 Gy in 10 fractions. None of these patients developed pneumonitis. Similarly, in a series of 40 patients who received 20 to 25 Gy of thoracic irradiation in 1.5-Gy fractions to treat pulmonary metastasis, no cases of pneumonitis were reported. This and other clinical experience with fractionated whole-lung irradiation in the nontransplant setting and in the absence of chemotherapy indicate that the following dose schemes should have a relatively low risk (less than 5 percent) for radiation pneumonitis: 25 Gy given in 20 fractions over 4 weeks or 20 Gy given in 10 fractions over 2 weeks. (As a reminder, all doses are given without heterogeneity corrections.) Historically, radiotherapy for Hodgkinâ&#x20AC;&#x2122;s disease has used whole-lung treatment in situations in which there is massive mediastinal adenopathy, hilar adenopathy, or overt pulmonary disease treated with chemotherapy. Risks of symptomatic pneumonitis ranging from 7 to 35 percent have been reported, with the risk highly dependent on the total radiation dose and the fractionation pattern. When the whole lung is to be irradiated, the available data suggest that the lungs should be treated through transmission blocks rather than using open fields. This reduces the total dose and the dose per fraction to the lungs, thereby reducing the risk of symptomatic pneumonitis to 4 to 7 percent, over a broad range of total lung doses of 10 to 20 Gy. There is a suggestion that the addition of mediastinal irradiation to fractionated whole-lung radiotherapy increases the risk of pneumonitis. To many oncologists, the risk of radiation pneumonitis from such treatment seems too great. As a result such patients are often treated primarily with chemotherapy (often with adjuvant low-dose radiotherapy), even though these regimens also produce significant risks for lung toxicity. In the setting of pulmonary metastases, the addition of low-dose radiotherapy

to the whole lung after chemotherapy is controversial. There are few clinical data to quantify risks and benefits, but doses of 10 to 16 Gy, given in 0.7- to 1.5-Gy fractions, are associated with only modest risk. Lung radiotherapy using 12 to 14 Gy for pulmonary metastases in pediatric patients with Wilmsâ&#x20AC;&#x2122; tumor (who also receive sequential doxorubicin and actinomycin D) is associated with a 10 percent incidence of pneumonitis. Long-term follow-up in such children also shows restrictive lung disease, with total lung and vital capacities approximately 70 percent of the predicted values. In children receiving thoracic irradiation, inhibition of the normal growth and development of the lung parenchyma and bones as a result of radiotherapy also produces significant morbidity. The effects of radiation on growth and development and the radiosensitivity of growing tissues raise special concerns in the treatment of pediatric patients.

PARTIAL-LUNG IRRADIATION Assessment of Risk Estimating the risks of radiation pneumopathy for individual patients receiving fractionated external-beam radiotherapy is a daunting task, because so many confounding factors must be considered. With lung cancer, the tumor size and location influence the volume of adjacent normal lung that must be irradiated. The volume irradiated should determine the number of capillary-alveolar units destroyed and therefore influence the risk of symptomatic radiation pneumonitis and fibrosis. This qualitative prediction is borne out by clinical experience, but quantifying the risks is not straightforward. The location irradiated is also important because the upper lobe is less well perfused and therefore less important to gas exchange. Irradiation of this region produces less change in lung function than irradiation of areas lower in the lung. Treatment-related factors such as total dose, dose per fraction, and overall treatment time are also important, as are the other confounding factors described in the preceding sections. Patients begin radiotherapy with a wide range of pulmonary functions, reflecting their age, smoking history, and the presence or absence of underlying cardiopulmonary disease. Because regional pulmonary fibrosis can be partially compensated by functional lung parenchyma, pretreatment lung status influences the severity of the symptoms. The clinical endpoints used to measure lung injury are quite varied and include symptom and quality-of-life scores, radiographic changes such as changes in CT-assessed lung density, pneumonitis, fibrosis, and other objective measures. Pulmonary function tests are global organ measures that correlate quite crudely with symptomatology after partial-lung irradiation. A large tumor mass can cause localized obstructive or restrictive changes in lung function or phrenic nerve dysfunction, any of which may either improve or worsen as the tumor shrinks with treatment. These factors add to the variability produced by patient-to-patient

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differences in the treatment volume, dose, fractionation, and so on. Thus the changes from radiotherapy in global lung function with regard to gas exchange, physiological dead space, shunting, V/Q mismatch, and respiratory surface area as measured by arterial blood gases, spirometry, and CO diffusing capacity (DlCO ) are complex and highly individualized. Several clinical studies have attempted to correlate predicted changes in FEV1 from radiotherapy by superimposing radiation treatment portals on quantitative ventilation and perfusion scans. The simple notion that the proportion of lung irradiated should match the drop in FEV1 , akin to the highly useful preoperative assessment of predicted postresection lung function, unfortunately has not been verified. In fact, a report from the Massachusetts General Hospital examining global and regional pulmonary function in patients with lung cancer showed improvement in pulmonary function in 52 percent of patients, a mild decline in 37 percent, and the decline predicted from changes in radionuclide scans in only 11 percent. Similar observations have been made in nonoperative lung cancer patients. Whereas the mean pretreatment FEV1 of 1.71 ± 0.67 L declined in these patients to an average of 1.15 ± 0.43 L after treatment, the posttreatment FEV1 was improved in 19 percent of the patients, unchanged in 53 percent, mildly decreased in 22 percent, and decreased below predicted levels in 5 percent. Thus, the technique of superimposing radiation treatment portals over quantitative lung perfusion scans is of limited utility in predicting pneumonitis in individual patients. In fact it has been suggested that the diffusing capacity is a more sensitive indicator of tolerance to radiotherapy. Unfortunately, there are no firm tests or data to guide the development of tolerable regimens of radiotherapy for patients with borderline lung function, except we know that treatment volumes should be minimized. If the initial FEV1 is below 1.0 L or DlCO is less than 50 percent of normal, large-volume radiotherapy (e.g., elective nodal irradiation for lung cancer) may well be excessively hazardous. Despite the limitations described, quantitative perfusion scanning in selected patients may give a worst-case scenario to help the radiation oncologist decide on dose and volume of treatment. The quantitative importance of the volume of lung irradiated to the toxicity has only recently been studied in any systematic fashion. An interesting set of mouse data published by investigators at MD Anderson showed a clear shift in dose-response curves for changes in respiratory rate and pulmonary death as a function of the volume of lung irradiated. As expected, the site irradiated was also important: Effects were more pronounced when the well-perfused base of the lung was irradiated, rather than the less well perfused apex. The response to lung irradiation was quite heterogeneous, even within mice of the same age and sex, from a single highly inbred mouse strain maintained in microbiological isolation under rigorously controlled environmental conditions. Histologic damage did not always predict morbidity in individual mice. In patients, preliminary dose-volume histogram analyses derived from detailed three-dimensional treatment evaluations and applied to an empirical normal-tissue com-

Radiation Pneumonitis

Figure 70-8 Regional changes in ventilation, perfusion, and computed tomography (CT) density from partial lung radiotherapy as a function of regional radiation dose: data from Duke University (Duke) and Netherlands Cancer Institute (NKI). Symbols in graph represent: (•) reduction in perfusion-Duke; (◦) increase in CT density-Duke; ( ) change in air-filled fraction-NK; ( ) reduction in perfusion-NKI; and (%) reduction in ventilation-NKI. (Redrawn from Marks LB, Yu X, Vujaskovic Z, et al: Semin Radiat Oncol 13:333345, 2003)

plication model show only a fair correlation between volume and complication risk. Nevertheless, it is common practice to evaluate dosimetric parameters such as Vdose or mean lung dose. The Vdose (i.e., V20Gy or V30Gy ) parameter is defined as the percent of total volume receiving equal to or greater than the threshold dose (i.e., 20 Gy or 30 Gy, respectively). The mean lung dose is defined as the average dose delivered to the whole lungs. Investigators at Duke and the Netherlands Cancer Institute have attempted to refine the correlation of dose-volume histograms with toxicity by factoring out nonfunctioning lung using lung perfusion scans. In lung cancer patients, particularly with chronic obstructive pulmonary disease (COPD), areas of hypoperfusion separate from tumor are seen frequently; irradiation of such irreversibly hypo perfused lung may not contribute additional toxicity. Such a “functional” dose-volume histogram analysis has not yet been shown to be of clinical value but it does provide an interesting and promising analytical framework. Nevertheless, there is a direct correlation between the change in ventilation, perfusion, or CT density regionally with increasing radiation dose (Fig. 70-8). Perhaps the most accurate and clinically relevant means to estimate risks for radiation pneumopathy is to study a large group of patients who receive a relatively standard dose and fractionation scheme for a given disease. As described, the variability of the treatment volume for diseases such as lung cancer, as well as the frequent coexistence of other lung disease, especially COPD from tobacco use, makes this a difficult task. Increasing emphasis in prospectively evaluating the risk for pneumonitis involves the analysis of dosimetric parameters, especially V20 or V30 , i.e., the volume of lung receiving a threshold radiation dose of 20 or 30 Gy usually expressed as a percent of the total lung volume. A large series from Australia, for instance, found that V30 was a reasonable predictor of radiation pneumonits. The actuarial risk of pneumonits

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was 16 percent at 6 months and 24 percent at 1 year followup in a series of 156 patients with non–small-cell lung cancer treated with primary radiotherapy with curative intent. Of several dosimetric parameters, V30 was the best predictor of pneumonits on both univariate and multivariate analysis. For instance a V30 greater than 22 percent was associated with a 30 percent risk of pneumonits at 1 year follow-up. Other data reviewed by Rodriguez et al. suggest trends of increasing risk of pneumonitis for V20 over 30 percent or mean lung dose over 20 Gy. More complex prediction models that factor in baseline DlCO , serum cytokine levels, or tumor locations in upper versus low lobes have yielded variable improvements in prognostication. Similar data regarding the incidence of radiation fibrosis are quite difficult to obtain, largely because of the wide spectrum of severity in symptomatology. Clinical experience suggests that radiographic fibrosis is rare below 20 Gy and common above 40 to 50 Gy, with symptoms of respiratory insufficiency dependent on the volume of injured lung and the presence of coexisting lung disease.

Lung Cancer: Local Tumor Boosting In the treatment of lung (and perhaps esophageal) cancer, it is quite standard to boost the primary tumor and a small volume of the lung to total cumulative doses beyond 50 Gy, commonly to 60 to 70 Gy. Clinical data, notably the doseescalation lung cancer trials of the Radiation Therapy Oncology Group, suggest that increasing doses to small volumes from approximately 50 to approximately 65 Gy is not associated with a significant increase in lung toxicity, probably because the number of nonfunctional alveoli is not increased by this increase in dose. In most series of patients receiving radical thoracic radiotherapy, the risk of symptomatic radiation pneumonitis is usually around 10 to 20 percent, and some degree of radiographic fibrosis is almost universal.

Breast Cancer Breast cancer radiotherapy, whether after lumpectomy or mastectomy, typically uses opposed tangential beams, as depicted in Fig. 70-6, which irradiate a volume of lung anterolateral to a plane demarcating the mid chest to the lateral axillary line to doses of 45 to 50 Gy in 23 to 25 fractions. The volume of the ipsilateral lung irradiated can be estimated for individual patients from the simulator films and is typically about 20 percent of the lung volume. If supraclavicular and axillary nodes are irradiated as well, anterior treatment portals are matched to the tangential chest wall fields. As a result the apex of the lung (roughly another 10 to 15 percent of ipsilateral lung volume) is also irradiated. The incidence of symptomatic pneumonitis from tangential fields alone is roughly 0.5 percent, with some series documenting an increased risk with increasing lung volume. It is desirable to keep the irradiated volume below approximately 25 percent, if possible. Nodal irradiation increases the risk for pneumonitis to 0.5 to 1.5 percent. Risk further increases to as high as 9

percent when chemotherapy is given concurrently. The risk of pneumonitis is much lower when chemotherapy and radiation are given sequentially.

Early-Stage Hodgkin’s Disease Radiotherapy for early-stage Hodgkin’s lymphoma, using moderate doses (40 to 45 Gy in 1.5 to 2 Gy fractions) and large volumes to treat lymph node–bearing regions, has represented a remarkable success story in oncology. Because it now has produced very high cure rates in a young patient population, allowing for extended follow-up over several decades, this experience also has produced considerable data regarding late radiation toxicities. In these protocols, the chest is irradiated with treatment portals, generically called “mantle fields,” as depicted in Fig. 70-9. With modern radiation techniques that use sequential shrinking fields, the incidence of symptomatic radiation pneumonitis is 3 to 4 percent. The risk of pneumonitis increases to roughly 10 percent when full doses of both chemotherapy (MOPP or ABVD-type combinations) and radiation to a mantle field are given sequentially. Studies on pulmonary function in Hodgkin’s disease patients suggest that a transient reduction in FEV1 and vital capacity, on the order of 5 to 20 percent, occurs 3 to 9 months after radiotherapy, corresponding to the period of pneumonitis. There tends to be some recovery by roughly 1 year. Late follow-up of pulmonary function in Hodgkin’s disease patients at Stanford further suggests that mantle field radiotherapy is associated with small, and for the most part clinically insignificant, reductions in vital capacity and DlCO . These decreases in pulmonary function tests were associated with minor, if any, symptomatology, even for treatment regimens that included sequential chemotherapy with doxorubicin or bleomycin. Primary radiotherapy for Hodgkin’s disease is now rarely practiced. Decades of follow-up in patients cured of their lymphomas show a steady increase in secondary cancers as well as cardiac complications. As a consequence, clinical trials have shown improved disease-free survival over 5 to 10 years with primary chemotherapy. In this setting in which lower-dose (20 to 30 Gy) involved-field radiotherapy is often delivered after chemotherapy, the incidence of clinical pneumonitis is quite low, although small changes in spirometric and diffusion capacity parameters can still be detected in up to 50 percent of the patients. Longer-term follow-up of toxicities from combined modality therapy in Hodgkin’s disease is in progress.

PROGNOSTIC ASSAYS AND FUTURE TRENDS Our understandings of the molecular and cellular mechanisms of radiation injury in general and radiation pneumonitis in particular are still evolving and improving. We hope increased understanding of these processes will lead to

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approaches for avoiding radiation injury to the lung, for modulating the development of injury or ameliorating its symptomatology, and for identifying patients at unusually high risk of injury. Several different lines of investigation leading to these ends are being pursued. Innovations in radiation therapy techniques are under active investigation. These include modifications in the dose rates, fractionation patterns, and radiation dose distributions used in radiation therapy regimens for specific diseases. Improvements in diagnostic imaging that allow better identification of tumor-involved regions, computerized treatment planning and dosimetry systems, improved patient immobilization systems, the use of multiple “noncoplanar, noncoaxial” radiation portals (three-dimensional conformal radiotherapy), and the use of multiple radiation fields that have variable rather than uniform spatial intensities (intensity modulated radiotherapy) all are being explored in the hope that they will enable the radiotherapist to increase the dose to the tumor while decreasing the volume of surrounding normal tissue irradiated to high doses. Conformal radiotherapy will be more complex, and more costly, than current radiotherapy approaches. It may also be difficult to prove whether this technology results in improved clinical outcomes. Refinements in combined-modality therapy may lead to the development of regimens that decrease pulmonary toxicity and therefore increase the therapeutic ratio for the treatment of thoracic tumors. Consequently, improvements in the delivery of antineoplastic therapy may decrease the risk and severity of radiation pneumonitis. The risk of developing radiation pneumonitis varies dramatically in different patients. To a certain extent, increased risk can be predicted from identifiable risk factors, such as prior treatment with thoracic radiotherapy, treatment with pneumotoxic drugs, or the existence of lung disease from other causes. However, even when the known risk factors are considered, the risk of symptomatic injury after radiotherapy varies dramatically from patient to patient. Studies with mice indicate that genetic factors contribute to individual variability in the development of late radiation injury in the lung. This raises the possibility that pretreatment measurements of enzyme or cytokine levels in the lung, analyses ←

Figure 70-9 (A) shows the port film for a typical mantle used for treatment of a patient with Hodgkin’s lymphoma. Note the effect of the lung blocks in reducing the dose to large volumes of the lung. (In this example, the whole heart/pericardium is not being treated.) A 30-year-old female underwent mantle field and subdiaphragmatic radiotherapy (not shown) for early-stage Hodgkin’s lymphoma. Ten years later, a recurrence in the right lower lobe and mediastinum was treated with MOPP-type chemotherapy and low-dose involved-field radiotherapy. The treatment field to the right lung, shown in (B ), was irradiated to 15 Gy in 10 fractions, in addition to the 40 Gy given to the mantle field ten years previous. Radiation pneumonitis occurred 6 months later, as seen in (C ). This responded to prednisone. Sixteen years later, the patient remains well and free of recurrence.

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during treatment of changes in cytokine levels or of tissue response to cytokines, or some other relevant measure may be useful in predicting patients at high risk for the development for pneumotoxicity. Assays of surfactant levels shortly after irradiation predict radiation pneumonitis in some rodent studies but have not predicted radiation pneumonitis in individual patients in the clinical trials performed to date. TGF-β, a cytokine that mediates fibrosis, is currently the subject of intense investigation. Serum levels of TGF-β have been reported to predict pulmonary toxicity after highdose chemotherapy for breast cancer, but its application to radiotherapy for lung cancer has been tenuous and controversial. Assays of other cytokines such as IL-6 are being explored clinically. Similarly, analyses of the intrinsic radiosensitivity in vitro of fibroblasts from patient biopsies have been suggested as a possible approach to measuring the general risks of individual patients for radiation injury. Such assays have proved useful in planning treatments for patients with the genetic disease ataxia telangectasia, which leads to unusual radiosensitivity. Prognostic assays predicting high or low risk for radiation pneumopathy could be used to guide clinical decision making and plan therapy to minimize risks for individual patients. Insights into the physiology underlying the development of radiation pneumopathy may also lead to the development of regimens that prevent the development of disease or ameliorate its symptomology. The use of “radioprotectors” such as amifostine (Ethyol, WR2721) has been of variable benefit in reducing mucositis or xerostomia in head and neck cancer patients undergoing radiotherapy (without apparent effect on tumor control). This has led to analogous clinical investigations of amifostine to prevent pneumonitis, given its widespread distribution into most normal tissues and its activity as a free radical scavenger. Several small phase III trials in lung cancer suggested a benefit to amifostine during thoracic radiotherapy, in regard to the prevention of not only pneumonits, but also radiation esophagitis as well. A large multi-institutional trial sponsored by the Radiation Therapy Oncology Group involving 242 patients, however, failed to document a difference in pneumonits rates with amifostine. The trial has been criticized for its twice a day fractionation scheme in which amifostine was administered with only one fraction each day, an unusually high patient drop out rate of 19 percent due to toxicity, and the fact that 52 percent of patients did not receive their intended dose of amifostine. The development of radiation pneumopathy has not been appreciably altered by the use of prophylactic steroids, antibiotics, or anticoagulants. The use of gamma interferon in conjunction with radiation actually worsened pneumonitis in recent clinical trials. Beta interferon has been under clinical investigation. Nutritional factors merit further consideration, as subclinical vitamin A deficiency has been shown to increase radiation injury in the rat lung. Numerous other approaches are being investigated in laboratory studies, including the use of captopril, lovastatin, pentoxifylline, interleukin-11, and the modulation of TGF-β production. Captopril, which is an angiotensin-converting enzyme (ACE) inhibitor clinically

used for the treatment of hypertension and heart failure, is of particular interest as it has several different potential mechanisms of action. As a thiol compound, it may act as a free radical scavenger. It can also forms copper complexes which has superoxide dismutase–like activity. Moreover, in animal studies captopril has vascular effects and can inhibit platelet aggregation perhaps mediated by IL-2 release that ameliorates radiation injury of pulmonary endothelium along with a decrease in pulmonary fibrosis. One retrospective review failed to demonstrate a benefit for ACE inhibitors but did not specifically evaluate captopril only. Lovastatin, a cholesterollowering drug that inhibits 3HMG coenzyme A reductase, also has potent anti-inflammatory effects. A murine model of whole-lung irradiation showed improved survival and reduced pulmonary infiltration of macrophages and lymphocytes by treatment with statins. This approach has not yet been investigated in the clinic. All attempts to modulate the development of radiation pneumonitis must be pursued cautiously, however, because these therapeutic strategies are based on biologic epiphenomena and an incomplete understanding of the mechanisms by which radiation pneumopathies are produced. In testing such interventions, as with any alteration of cancer therapy, it will be critical to consider the effects of the intervention on the response of the malignancy, as well as its effects on normal tissue injury, because the intervention will be of value only if it increases the therapeutic ratio.

SUGGESTED READING Deeg HJ, Sullivan KM, Buckner CD, et al: Marrow transplantation for acute nonlymphoblastic leukemia in first remission: Toxicity and long-term follow-up of patients conditioned with single dose or fractionated total body irradiation. Bone Marrow Transplant 1:151–157, 1986. Fay M, Tan A, Fisher R, et al: Dose-volume histogram analysis as predictor of radiation pneumonitis in primary lung cancer patients treated with radiotherapy. Int J Radiat Oncol Biol Phys 61:1355–1363, 2005. Fryer CJH, Fitzpatrick PJ, Rider WD, et al: Radiation pneumonitis: Experience following a large single dose of radiation. Radiat Oncol Biol Phys 4:931–936, 1978. Hall EJ, Giaccia AJ (eds): Radiobiology for the Radiologist, 6th ed. Philadelphia, Lippincott Williams & Wilkins, 2005. Haston CK, Zhou X, Gumbiner-Russo L, et al: Universal and radiation-specific loci influence murine susceptibility to radiation-induced pulmonary fibrosis. Cancer Res 62:3782–3788, 2001. Horning SJ, Adhikari A, Rizk N, et al: Effect of treatment for Hodgkin’s disease on pulmonary function: Results of a prospective study. J Clin Oncol 12:297–305, 1994. Johnston CJ, Williams JP, Okunieff P, et al: Radiationinduced pulmonary fibrosis: Examination of chemokine and chemokine receptor families. Radiat Res 157:256–265, 2002.

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Kahn FM (ed): The Physics of Radiation Therapy, 3rd ed. Philadelphia, Lippincott Williams & Wilkins, 2003. Kocak Z, Evans ES, Zhou SM, et al: Challenges in defining radiation pneumonitis in patients with lung cancer. Int J Radiat Oncol Biol Phys 62:635–638, 2005. Lingos TI, Recht A, Vicini F, et al: Radiation pneumonitis in breast cancer patients treated with conservative surgery and radiation therapy. Int J Radiat Oncol Biol Phys 21:355– 360, 1991. Mah K, Van Dyk J, Keane T, et al: Acute radiation-induced pulmonary damage: A clinical study on the response to fractionated radiation therapy. Int J Radiat Oncol Biol Phys 13:179–188, 1987. Marks LB, Yu X, Vujaskovic Z, et al: Radiation-induced lung injury. Semin Radiat Oncol 13:333–345, 2003. Mehta V: Radiation pneumonitis and pulmonary fibrosis in non-small-cell lung cancer: Pulmonary function, prediction, and prevention. Int J Radiat Oncol Biol Physics 63:5– 24, 2005. Miller KL, Shafman TD, Anscher MS, et al: Bronchial stenosis: an underreported complication of high-dose external beam radiotherapy for lung cancer? Int J Radiat Oncol Biol Phys 61:64–69, 2005. Morgan GW, Breit SN: Radiation and the lung: A reevaluation of the mechanisms mediating pulmonary injury. Int J Radiat Oncol Biol Phys 31:361–369, 1995.

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Newman LS, Mroz MM, Ruttenber AJ: Lung fibrosis in plutonium workers. Radiat Res 164:123–131, 2005. Perez CA, Brady LW, Halperin EC, et al (eds): Principles and Practice of Radiation Oncology, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2005. Phillips TL: 50 years of radiation research: Medicine. Radiat Res 158:389–417, 2002. Rockwell S: Radiobiology. Encycl Human Biol 6:441–453, 1991. Rockwell S: Experimental radiotherapy: A brief history. Radiat Res 150:S157–169, 1998. Rodrigues G, Lock M, D’Souza D, et al: Prediction of radiation pneumonitis by dose-volume histogram parameters in lung cancer: A systematic review. Radiother Oncol 71:127–138, 2004. Rubin P, Johnston CJ, Williams JP, et al: A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys 33:99–109, 1995. Travis EL: Organizational response of normal tissue to irradiation. Semin Radiat Oncol 11:184–196, 2001. Van Dyk J, Keane TJ, Kan S, et al: Radiation pneumonitis following large single dose irradiation: A re-evaluation based on absolute dose to lung. Int J Radiat Oncol Biol Phys 7:461– 467, 1981. Von der Maase H, Overgaard J, Vaeth M: Effect of cancer chemotherapeutic drugs on radiation-induced lung damage in mice. Radiother Oncol 5:245–257, 1986.

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71 Pulmonary Manifestations of the Collagen Vascular Diseases Gregory P. Cosgrove Marvin I. Schwarz

I. HISTOLOGICAL SPECTRUM OF PARENCHYMAL REACTIONS IN COLLAGEN VASCULAR DISEASE Interstitial Lung Disease Pulmonary Vascular Disease Diffuse Alveolar Hemorrhage Bronchiolitis Parenchymal Nodules

Scleroderma Polymyositis-Dermatomyositis Mixed Connective-Tissue Disease Sj¨ogren’s Syndrome Ankylosing Spondylitis

II. CLINICAL FEATURES OF THE COLLAGEN VASCULAR DISEASES Systemic Lupus Erythematosus Rheumatoid Arthritis

The pleuropulmonary complications associated with the collagen vascular diseases are frequent occurrences, and it would be the exception rather than the rule for an individual to avoid one of these during the course of such an illness. All the elements of the respiratory system may be affected, either separately or in combination. This includes the respiratory muscles, the pleura, the conducting airways, and the lung parenchyma—the small airways, the interstitium, or the pulmonary vessels. Moreover, these patients experience an increased incidence of community-acquired pneumonia as well as pneumonia associated with the immunosuppressive drugs employed for treatment. Anti-tumor necrosis factor-α (TNF-α) agents increase the risk for infections, particularly mycobacterial pathogens, both tuberculous and nontuberculous. Cytotoxic drugs, particularly methotrexate and gold, can also induce various noninfectious interstitial reactions, which are often difficult to distinguish from a primary interstitial complication of a collagen vascular disease. Although most pulmonary complications appear in an established case of a collagen vascular disease, lung dis-

ease may precede the more typical systemic manifestations. For example, in both rheumatoid arthritis and polymyositisdermatomyositis, the interstitial lung disease may precede the joint and muscle disease for several months to several years. This is also the case, but to a lesser extent, for scleroderma. In one study, 19 percent of patients initially diagnosed with idiopathic pulmonary fibrosis developed a collagen vascular disease over a period of 1 to 11 years, primarily rheumatoid arthritis or polymyositis-dermatomyositis. These individuals were younger and more likely to be women. Pleuritis with or without effusion sometimes heralds the onset of rheumatoid arthritis or systemic lupus erythematosus. An acute immunologic pneumonitis or diffuse alveolar hemorrhage has been reported to be the signal event in systemic lupus erythematosus, polymyositis-dermatomyositis, and mixed connective-tissue disease. The actual incidence of the pleuropulmonary complications (Table 71-1) is variable. Interstitial lung disease is reported to be as high as 60 percent in premortem and 100 percent in postmortem studies in scleroderma. In contrast,

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Table 71-1 Pulmonary Complications of the Collagen Vascular Diseases Relative Frequency (0–4) Manifestation

SLE

PM-DM

MCTD

Sj¨ogren’s

Respiratory muscle dysfunction

Aspiration pneumonia

Primary pulmonary hypertension

Vasculitis

Interstitial lung disease

Capillaritis + DAH

Bland DAH

Diffuse alveolar damage

Nonspecific interstitial pneumonitis

Lymphocytic interstitial pneumonitis

Usual interstitial pneumonitis

Honeycomb lung

Bronchiolitis obliterans organizing pneumonia

Bronchiolitis

Obliterative bronchiolitis

Pleural effusion

Parenchymal nodules

Abbreviations: SLE = systemic lupus erythematosus; RA = rheumatoid arthritis; SS = systemic sclerosis (scleroderma); PM-DM = polymyositis-dermatomyositis; MCTD = mixed connective-tissue disease; AS = ankylosing spondylitis; Sj¨ogren’s = Sj¨ogren’s syndrome; DAH = diffuse alveolar hemorrhage.

interstitial lung disease in ankylosing spondylitis is an uncommon event. In general, the incidence of interstitial lung disease is increasing for most of the collagen vascular diseases, primarily due to increased recognition and more sensitive screening techniques such as high-resolution computed

tomography and bronchoalveolar lavage, which will detect abnormalities in both asymptomatic as well as symptomatic patients with normal chest radiographs. Moreover, many of the earlier incidence studies relied on physiological testing, which included spirometry, lung volumes, and diffusing

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capacity but did not measure rest and exercise gas exchange, which is the most sensitive physiological marker of interstitial lung disease as well as pulmonary vascular disease.

HISTOLOGICAL SPECTRUM OF PARENCHYMAL REACTIONS IN COLLAGEN VASCULAR DISEASE Interstitial Lung Disease Interstitial involvement is a common respiratory manifestation of the collagen vascular disorders, presenting with a number of different inflammatory responses within the lung. Each response may represent a different form of lung injury or response to injury. Defining which response is underlying a patient’s interstitial lung disease has important prognostic and therapeutic significance. Diffuse alveolar damage (DAD) is the underlying histological lesion that is also seen in the acute respiratory distress syndrome, idiopathic acute interstitial pneumonitis (Hamman-Rich syndrome), severe viral pneumonias, and cytotoxicity from some drugs. This damage consists of a mixed interstitial inflammatory infiltrate, interstitial edema and fibrin deposition, and the characteristic intra-alveolar hyaline membrane formation. Intra-alveolar red blood cells (diffuse alveolar hemorrhage) may be present in severe cases. With progression, there is intra-alveolar organization, intraalveolar and interstitial fibrosis, alveolar collapse, and the development of an end-stage fibrotic or “honeycomb” lung. An acute immunologic pneumonia, seen in systemic lupus erythematosus (acute lupus pneumonitis) and in polymyositisdermatomyositis, may demonstrate this underlying histological appearance. Nonspecific interstitial pneumonitis (NSIP) refers to a spectrum of histological features with varying degrees of lymphoplasmacytic infiltration of the interstitium and collagen deposition (Fig. 71-1). In the cellular form, lymphoplasmacytic interstitial inflammation exists with associated type II alveolar epithelial cell hyperplasia. In the fibrosing form, the inflammation is accompanied by a temporally and spatially homogeneous deposition of collagen (fibrosis). Architectural distortion or honeycombing may occur in advanced cases and the presence of fibrosis dramatically changes the clinical course and prognosis to one resembling that seen in usual interstitial pneumonitis (see below). NSIP is most frequently seen in patients with rheumatoid arthritis, polymyositisdermatomyositis, mixed connective-tissue disease, and scleroderma. Lymphocytic interstitial pneumonitis refers to a monotonous infiltration of the interstitium by mature lymphocytes (Fig. 71-2). These lymphocytes tend to form germinal centers within the interstitium as well as displaying an angiocentric distribution. Other features of lymphocytic interstitial pneumonia include macrophagic giant cells, gran-

Figure 71-1 Nonspecific interstitial pneumonitis (NSIP) in rheumatoid arthritis. There is a lymphoplasmacytic infiltration of the interstitial compartment with minimal collagen deposition.

uloma formation, and amyloid deposition. Lymphocytic interstitial pneumonitis can progress to usual interstitial pneumonitis and end-stage honeycomb lung. Among the collagen vascular diseases, this pneumonitis most commonly accompanies the primary form of Sj¨ogren’s syndrome and, to a lesser extent, the secondary form of Sj¨ogren’s syndrome appearing with other collagen vascular diseases, particularly rheumatoid arthritis. Usual interstitial pneumonitis (UIP) is the underlying lesion of idiopathic pulmonary fibrosis and can also appear in all the collagen vascular diseases. It consists of varying degrees of mononuclear cell infiltration and fibroblastic proliferation leading to collagen deposition within the alveolar interstitium (Fig. 71-3). With progression, this fibrotic reaction results in marked distortion of the lung architecture and what remains are 2- to 3-mm cystic spaces lined by metaplastic epithelium, the so-called honeycomb lung (Fig. 71-4). Other features of UIP include type II epithelial cell hyperplasia producing a “hob-nailed” appearance on the alveolar surface, collections

Figure 71-2 Lymphocytic interstitial pneumonitis in a pa¨ tient with primary Sjogren’s syndrome. There is a dense lymphocytic infiltrate, broadening the interstitium and lymphoid follicles.

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Figure 71-3 Usual interstitial pneumonia (UIP) in a patient with rheumatoid arthritis. There is broadening of the interstitium by varying degrees of mononuclear cell infiltration and collagen deposition.

of intra-alveolar macrophages, and smooth-muscle proliferation within the interstitium. Additional abnormalities seen in collagen vascular disease-associated UIP but not in patients with idiopathic pulmonary fibrosis may include: focal chronic pleuritis, lymphoid follicles with germinal center formation, perivascular collagen deposition, and an increase in CD4+ T lymphocytes, especially in rheumatoid arthritis. Bronchiolitis obliterans organizing pneumonia is a distinctive histological lesion that follows a variety of insults to the alveolar structures including drugs, infection, radiation, and an idiopathic variety. Bronchiolitis obliterans organizing pneumonia can also complicate the collagen vascular diseases, particularly rheumatoid arthritis and polymyositisdermatomyositis. Three features comprise the histological picture: (1) intra-alveolar space and intra-alveolar ductal fibroblastic proliferation with early collagen deposition (Masson bodies), (2) inflammatory polyps consisting of fibroblasts and mononuclear cells protruding into the lumens of respiratory and terminal bronchioles, and (3) alveolar septal lym-

Figure 71-4 Advanced UIP in a patient with scleroderma (honeycomb lung). Normal alveolar tissue is replaced with broad bands of fibrous tissue lined by metaplastic epithelium and filled with inspissated mucus producing a cystlike network.

Figure 71-5 Bronchiolitis obliterans organizing pneumonia in a patient with rheumatoid arthritis. There is a mononuclear cellular infiltration of the interstitium without collagen deposition as well as alveolar duct and intra-alveolar fibroblastic proliferation and early collagen production.

phoplasmacytic infiltrate with type II pneumocyte hyperplasia within affected areas (Fig. 71-5). Bronchiolitis obliterans organizing pneumonia has the potential for being a completely reversible lesion; however, with continuing injury it may progress to end-stage fibrosis and honeycomb lung.

Pulmonary Vascular Disease A form of pulmonary artery hypertension, which most commonly appears in patients with scleroderma and is now being increasingly recognized in systemic lupus erythematosus, rheumatoid arthritis, and mixed connective-tissue disease, is histologically identical to the syndrome of idiopathic pulmonary artery hypertension (IPAH) seen in young women without collagen vascular disease, formerly known as primary pulmonary hypertension. This is a proliferative disorder (plexogenic arteriopathy) affecting the arterioles and small muscular pulmonary arteries. This form of pulmonary hypertension must be differentiated from secondary forms as a result of hypoxic vasoconstriction induced by interstitial lung disease or severe emphysema. In the plexogenic variety, there is endothelial cell intimal proliferation and smoothmuscle cell proliferation causing medial thickening with a resultant â&#x20AC;&#x153;onion ringâ&#x20AC;? configuration and luminal obliteration. In the secondary forms of pulmonary hypertension due to hypoxia, medial hypertrophy is the primary finding. In patients with systemic lupus erythematosus and the antiphospholipid syndrome, pulmonary artery hypertension may develop as a result of recurrent pulmonary emboli and mimic the clinical picture of IPAH. Vasculitis refers to an acute inflammatory angiodestructive process resulting in fibrinoid necrosis of the vascular wall. In the collagen vascular diseases, this is most often a small-vessel vasculitis involving arterioles and small muscular pulmonary arteries. Although uncommon, this is seen with greatest regularity in systemic lupus erythematosus and less frequently in rheumatoid arthritis,

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Figure 71-6 Bland diffuse alveolar hemorrhage in SLE. There is little if any interstitial reaction except for type II pneumocyte epithelial cell hyperplasia. The alveolar spaces are filled with red blood cells.

Figure 71-7 Low-power view of pulmonary capillaritis in a patient with SLE. There is marked thickening of the interstitial compartment and infiltration by acute and chronic inflammatory cells. The alveolar spaces are filled with red blood cells and neutrophils.

polymyositis-dermatomyositis, and mixed connective-tissue disease. Often accompanying the arteriolitis is the lesion of pulmonary capillaritis (see below).

Bronchiolitis

Diffuse Alveolar Hemorrhage Diffuse alveolar hemorrhage is recognized by the accumulation of red blood cells within the alveolar spaces, and with recurrent episodes, intra-alveolar and interstitial hemosiderin is deposited and fibrosis may result. There are two different histological subtypes seen in diffuse alveolar hemorrhage. One is devoid of inflammation and is referred to as bland hemorrhage (Fig. 71-6). It is therefore similar in histological appearance to idiopathic pulmonary hemosiderosis. The other, pulmonary capillaritis, is a unique neutrophilic infiltration of the alveolar interstitium, which results in necrosis and loss of integrity of the alveolar-capillary basement membrane, capillary destruction and thrombosis, and a leakage of red blood cells into the alveolar space (Fig. 71-7). A unique feature in pulmonary capillaritis is that many of the infiltrating neutrophils are undergoing fragmentation (leukocytoclasis), and others appear as densely staining apoptotic cells. Nuclear debris (“dust”) subsequently accumulates within the necrotic, edematous interstitium and intra-alveolar compartments while red blood cells freely leak into the interstitial matrix due to capillary destruction. Capillary and arteriolar thrombosis, organizing pneumonia, and type II epithelial cell hyperplasia may also be seen. Capillaritis is most commonly seen in the systemic vasculitides, particularly Wegener’s granulomatosis and microscopic polyangiitis, the small-vessel variant of polyarteritis nodosa. Of the collagen vascular diseases, both bland pulmonary hemorrhage and diffuse alveolar hemorrhage secondary to pulmonary capillaritis appear most commonly in systemic lupus erythematosus. Cases of pulmonary capillaritis have also been reported to occur in rheumatoid arthritis, Sj¨ogren’s syndrome, polymyositis-dermatomyositis, and mixed connective-tissue disease.

Bronchiolitis refers to an inflammatory-fibrotic process involving the terminal and respiratory bronchioles and possibly the surrounding alveolar structures. Respiratory bronchiolitis is primarily seen in smokers with or without an associated collagen vascular disease. There is also a primary form of cellular bronchiolitis that complicates the collagen vascular diseases, most often appearing in rheumatoid arthritis and Sj¨ogren’s syndrome. Histologically, there is a mononuclear cell infiltration of the wall of the bronchiole without impingement of the bronchiolar lumen. In contrast, in bronchiolitis obliterans, or obliterative bronchiolitis, there is a concentric fibrous obliteration of the bronchiolar lumen leading to a severe obstructive lung disease (Fig. 71-8). Bronchiolitis obliterans is most often reported as a complication of rheumatoid arthritis.

Figure 71-8 Obliterative bronchiolitis in rheumatoid arthritis. There is a marked reduction of the luminal diameter due to concentric fibrous obliteration and dense chronic inflammation. (From Schwarz MI, Lynch DA, Tuder R: Bronchiolitis obliterans: The lone manifestation of rheumatoid arthritis. Eur Respir J 7:817–820, 1994, with permission.)

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Table 71-2 Acute Lung Syndromes in Systemic Lupus Erythematosus Community-acquired or immunocompromised pneumonias Pleurisy Pulmonary embolization Uremic pneumonitis Figure 71-9 Typical subpleural location of a necrobiotic rheumatoid nodule. There is a central area of fibrinoid debris surrounded by palisading histiocytes.

Cardiogenic pulmonary edema

Parenchymal Nodules

Acute lupus pneumonitis

Noninfectious inflammatory parenchymal nodules occur in both rheumatoid arthritis and Sj¨ogren’s syndrome. In rheumatoid arthritis the nodules are referred to as the necrobiotic or rheumatoid nodules. These lesions are found both in the pleura and lung parenchyma and are identical in appearance to a subcutaneous rheumatoid nodule. In the lung parenchyma, these nodules are located in the interlobular septa and in the subpleural parenchyma. The necrobiotic nodule is comprised of palisading histocytes, giant cells, and other mononuclear cells surrounding an area of fibrinoid debris (Fig. 71-9). In Sj¨ogren’s syndrome, a rounded lesion known as pseudolymphoma can occasionally be detected on the chest radiograph. Pseudolymphoma is considered to be a localized form of lymphocytic interstitial pneumonia and is made up of a dense infiltrate of lymphocytes and histiocytes with occasional granuloma formation. There is a potential risk for malignant transformation in pseudolymphoma as well as in the other forms of lymphocytic interstitial pneumonia.

CLINICAL FEATURES OF THE COLLAGEN VASCULAR DISEASES Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is characterized by the production of antibodies against various cellular antigens derived from the nucleus, cytoplasm, or cell membrane. Tissue injury appears to be associated with the development of immune complexes, the presence of low serum complement levels, and the production of antibodies to native DNA. The pulmonary complications are thought to be the result of an immune complex-mediated injury. A number of syndromes (Table 71-2) are associated with acute respiratorytype illness in SLE. A patient with SLE who presents with a febrile illness, cough with or without productive sputum,

Acute reversible hypoxemia syndrome

Diffuse alveolar hemorrhage

and new pulmonary infiltrates must be considered to have an infectious pneumonia, although acute lupus pneumonitis and diffuse alveolar hemorrhage may have a similar presentation. Infection can be community-acquired or result from immunosuppressive treatment. Infectious pneumonia represents the most common cause of pulmonary disease in SLE, and infections in general represent the most common reason for death (33 to 77 percent) in these patients. Bronchoalveolar lavage is often helpful in excluding an infectious pneumonia in the immunocompromised SLE patient. Another important consideration in an acutely dyspneic SLE patient is pulmonary embolization, a complication reportedly occurring in up to 25 percent of patients and a significant cause of mortality. The occurrence of thromboembolic disease correlates with the presence in the serum of acquired antiphospholipid antibodies (lupus anticoagulant or anticardiolipin). The most common epitope(s) to which antibodies exist in these patients is β2 - glycoprotein I. A more appropriate term may therefore be anti-β2 –glycoprotein syndrome. Up to a third of patients with SLE have the antiphospholipid syndrome. Thrombocytopenia, recurrent venous or arterial thrombosis, hemolytic anemia, leg ulcers, and recurrent fetal loss are also manifestations of antiphospholipid syndrome. Other causes for acute respiratory failure in patients with SLE include a volume overload state, due either to renal failure or to congestive heart failure secondary to myocarditis. Uremic pneumonitis with underlying DAD is also a possible cause of an acutely dyspneic SLE patient with renal failure. A syndrome, acute reversible hypoxemia, occurring in acutely ill SLE patients who are experiencing systemic exacerbations has been described. These patients have hypoxemia and a

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widened alveolar-arterial oxygen gradient, but both the chest radiograph and ventilation-perfusion lung scans are normal. It is postulated that there is complement-activated neutrophil aggregation in the pulmonary vasculature. The hypoxemia improves with immunosuppressive therapy. Given the high incidence of antiphospholipid syndrome in SLE, acute reversible hypoxemia should be considered only after excluding thromboembolic disease. Acute Lupus Pneumonitis Acute lupus pneumonitis is a clinical syndrome with an underlying histology of DAD, bronchiolitis obliterans organizing pneumonia, NSIP, or a combination of these. Acute lupus pneumonitis mimics an acute infectious pneumonia and may be the presenting manifestation of SLE in up to 50 percent of patients. In those with an established diagnosis, it also appears during a flare-up of the other systemic manifestations of SLE, particularly pleuritis, pericarditis, arthritis, and nephritis. Acute lupus pneumonitis is reportedly more common in the postpartum period. It frequently recurs and cases have been documented that have progressed to a more chronic interstitial lung disease (UIP). Fortunately, acute lupus pneumonitis is a relatively uncommon complication, occurring in less than 5 percent of patients. Bilateral alveolar infiltrates, which can be patchy or densely consolidated and often accompanied by pleural effusions and cardiomegaly due to underlying pericardial effusion or myocarditis (Fig. 71-10 A), are present on chest radiographs at presentation. White blood cell counts and sedimentation rates are elevated and serum complement is often low. Immunopathologic studies reveal the presence of complement as well as antibodies to IgG and DNA in some patients, supporting the concept of an immune complex pathogenesis (Fig. 71-10B). Because of the difficulty in distinguishing acute lupus pneumonitis from an infectious pneumonia, a bronchoalveolar lavage and sometimes an open (thorascopic) lung biopsy are indicated prior to instituting anti-inflammatory and immunosuppressive therapy. Acute respiratory failure in acute lupus pneumonitis often requires assisted mechanical ventilation. The mortality rate has been reported to be as high as 50 percent, with the causes of death in patients with acute lupus pneumonitis being either respiratory failure, another complication of SLE (nephritis, cerebritis), or a superimposed infection. Diffuse Alveolar Hemorrhage Diffuse alveolar hemorrhage, although rare, may be a presenting manifestation of SLE. In several cases, recurrent diffuse alveolar hemorrhage was present for years prior to the diagnosis of SLE. The majority of cases, in contrast to acute lupus pneumonitis, first appear in a well-documented case of SLE. Diffuse alveolar hemorrhage accounts for 1 to 4 percent of SLE-related hospitalizations. Diffuse alveolar hemorrhage can also present with symptoms reminiscent of an infectious pneumonia or acute lupus pneumonitis, and the additional symptom of hemop-

Figure 71-10 Acute lupus pneumonitis. The chest radiograph demonstrates diffuse alveolar filling with cardiomegaly (pericardial effusion vs. myocarditis). A. There is also a left pleural effusion. B . The immunofluorescent study demonstrates granular immune complex deposition in the alveolar interstitium.

tysis raises the possibility of this diagnosis. Hemoptysis is present in 30 to 50 percent of patients during their initial presentation, but up to 90 percent will have hemoptysis during their subsequent course. Routine laboratory work demonstrates a falling hematocrit, and in 60 to 90 percent of patients an active glomerulonephritis is invariably present. A progressively serosanguineous bronchoalveolar lavage may be the first clue to this diagnosis. Diffuse alveolar infiltrates are present on chest radiography (Fig. 71-11), but in contrast

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Figure 71-11 Diffuse alveolar hemorrhage in SLE. There are diffuse alveolar infiltrates without cardiomegaly or pleural effusions.

to acute lupus pneumonitis, pleuritis and pericarditis are not prominent features. Pathological changes that are reminiscent of both acute lupus pneumonitis (DAD and NSIP) and diffuse alveolar hemorrhage with or without pulmonary capillaritis are not unusual in a single biopsy specimen. The mortality rate is approximately 50 percent and is independent of the underlying histopathology (bland hemorrhage vs. pulmonary capillaritis). Recurrence is the rule rather than the exception. There are no controlled clinical trials for the treatment of either acute lupus pneumonitis or diffuse alveolar hemorrhage. Once infection has been excluded, corticosteroids are the mainstay of therapy. Intravenous methylprednisolone, 1 to 2 grams daily in divided doses for 3 to 4 days prior to tapering, should be considered. Concomitant oral or parenteral cyclophosphamide or azathioprine is commonly administered, given the associated incidence of lupus nephritis. Plasmapheresis and immunoglobulin therapy, although logical in lieu of the proposed immune complex pathogenesis, have no proven efficacy to date. Lupus Pleuritis Pleurisy and pleural effusion are the most common primary pulmonary complications of SLE, occurring in 50 to 80 percent of patients. Pleurisy and/or a pleural effusion may also be the presenting and sole manifestation of the disease. They are usually recurrent and may accompany more severe complications such as acute lupus pneumonitis or nephritis. Patients complain of pleuritic pain, fever, and dyspnea. The chest radiograph may be normal (dry pleurisy) or demonstrate small to moderate pleural effusions (massive effusions are rare), which are bilateral in 50 percent of patients. When unilateral, there is no predilection for either side. Effusions are serous or serosanguineous and exudative in nature. The white cell counts range from 5 to 10,000 cells/mm3 . Early on, neutrophils predominate, but with time

mononuclear cells appear. These characteristics are nonspecific and are often seen with infectious parapneumonic effusions. In contrast to rheumatoid arthritis, the pleural fluid glucose concentration is not reduced. As in rheumatoid pleural effusions, the rheumatoid factor may be positive, and the pleural fluid complement, both the total levels and the individual components, is reduced. A positive double-stranded pleural fluid DNA titer is nonspecific as opposed to the serum test, since it has been found in pleural effusions due to malignancy and tuberculosis. The most helpful measurement is the pleural fluid antinuclear antibody titer. Levels greater than 1:160 are very suggestive of lupus pleuritis. Examination of the pleural tissue reveals infiltration with plasma cells and lymphocytes, and, with repeated episodes, pleural fibrosis supervenes. Occasionally, a vasculitis of the pleural vessels is detected, and immune complex deposition has been reported. Corticosteroid treatment is effective for relief of pleural pain, but time to resolution of the pleural effusion is quite variable and probably unaffected by this treatment. In the unusual case, recurrent lupus pleuritis may result in massive pleural fibrosis and lung entrapment, necessitating a pleural stripping procedure. While pleural effusions and pleurisy are common in patients with SLE, a broad differential diagnosis should be considered. The increased incidence of infectious complications, thromboembolic disease, and pulmonary hypertension in SLE predisposes patients to parapneumonic effusions and empyema, congestive heart failure, and effusions secondary to thromboembolic disease. Interstitial Lung Disease Clinically significant interstitial lung disease is an uncommon pulmonary manifestation in SLE but UIP, lymphocytic interstitial pneumonitis, NSIP, and bronchiolitis obliterans organizing pneumonia have all been reported. UIP is known to appear following acute lupus pneumonitis and in some cases has been documented to appear as an independent insidious disease. In more recent studies using highresolution computed tomography, 38 percent of patients with SLE patients with normal chest radiographs demonstrated pulmonary abnormalities consistent with some form of interstitial lung disease. In those who develop interstitial lung disease, a prior episode of acute lupus pneumonitis and an insidious onset of dyspnea are often noted. The prevalence of interstitial lung disease is increased in the subset of SLE patients with features suggestive of an mixed connective-tissue disease. In patients who develop the insidious form of interstitial lung disease, the diagnosis of SLE is present for several years, and no other pattern of organ involvement predicts its appearance. These patients have progressive dyspnea and cough with interstitial infiltration on the chest radiograph. High-resolution computed tomography indicates combinations of ground-glass attenuation, inter- and intralobular septal thickening, and honeycomb change. Pulmonary function tests reveal a restrictive pattern with reduction in the diffusing

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capacity and hypoxemia accentuated by exercise. Response to therapy, either corticosteroids alone or in combination with cyclophosphamide or azathioprine, depends upon the underlying histology. Those cases with underlying NSIP or organizing pneumonia are more likely to respond to treatment than those who demonstrate excess collagen deposition and cystic honeycomb formation. Pulmonary Vascular Disease Idiopathic pulmonary hypertension due to plexogenic arteriopathy was previously thought to be an uncommon complication of SLE. It is now estimated to occur in 1 to 9 percent of patients. This form of pulmonary hypertension is associated with Raynaudâ&#x20AC;&#x2122;s phenomenon, digital vasculitis, serositis, antibodies to ribonucleoprotein, rheumatoid factor, antiphospholipid antibodies, and most recently anti-endothelial cell antibodies. Patients complain of dyspnea and fatigue but have normal chest radiographs. In advanced cases, pulmonary arterial enlargement appears. Spirometry and lung volumes are normal, but there is often an isolated reduction of the diffusing capacity for carbon monoxide as well as gas exchange abnormalities. Ventilation-perfusion lung scanning and, occasionally, pulmonary arteriography are indicated, particularly in those patients with the antiphospholipid syndrome who have a potential for recurrent small pulmonary emboli. Therapeutic options include vasodilator therapy, anticoagulation, immunosuppression with cyclophosphamide, and transplantation. Vasculitis in SLE is more likely to be discovered in lung biopsy specimens, that demonstrate either diffuse alveolar hemorrhage or acute lupus pneumonitis as opposed to being an isolated finding. Autopsy series indicate small-vessel vasculitis in 20 percent of cases. Bronchiolitis Five percent of SLE patients are reported also to have obstructive physiology. Obliterative bronchiolitis has been documented in SLE, but is rare in contrast to rheumatoid arthritis. Bronchiolitis obliterans organizing pneumonia, with inflammatory polyps protruding into bronchiolar lumens, is one of the interstitial patterns that occurs in acute lupus pneumonitis and in chronic interstitial lung disease in SLE, but this entity causes restriction rather than obstructive lung disease. Bronchiectasis may occur in up 20 percent of patients but is often asymptomatic. Large airway involvement including tracheal and subglottic stenosis, vocal fold paralysis, epiglottitis, and necrotizing tracheitis have all been reported but are rare. Respiratory Muscle Dysfunction It is estimated that weakness of the diaphragm and other respiratory muscles is found in 25 percent of patients with SLE. This accounts for the previously unexplained findings of dyspnea without evidence of interstitial or pulmonary vascular disease. These patients have subsegmental atelectasis, an elevated diaphragm on chest radiograph (Fig. 71-12), and restrictive physiology. This has been referred to as unexplained

Figure 71-12 Diaphragmatic dysfunction in SLE. There is diaphragmatic elevation resulting in platelike atelectasis.

dyspnea and shrinking lungs syndrome. Although there is a reduction in static lung volumes, the diffusing capacity, when corrected for alveolar volume, remains normal, thereby distinguishing respiratory muscle dysfunction from interstitial lung disease. The likely explanation for this is a reduction in the transdiaphragmatic pressure generated during maximal inspiration, which in turn reduces static lung compliance, producing the linear atelectasis seen on the chest radiograph. Moreover, in the patients with respiratory muscle weakness, no evidence for a generalized neuromuscular disease can be found. The pathogenesis of respiratory muscle dysfunction remains unexplained, although phrenic nerve conduction abnormalities have been excluded. Abnormal diaphragmatic activation, due in part to voluntary inhibition due to pleuritic pain, may contribute to diaphragmatic dysfunction in this disorder. Corticosteroids are not a frequently effective treatment modality. Progression is uncommon and most patients stabilize. Positive pressure ventilation (CPAP or BiPAP), particularly at night, may improve these patientsâ&#x20AC;&#x2122; daytime symptoms, although there is limited evidence available to support noninvasive nocturnal ventilation.

Rheumatoid Arthritis Rheumatoid arthritis primarily affects the articular surfaces, but pleuropulmonary complications are responsible for an increased morbidity and mortality. Most often cited is a 50 percent incidence for these complications, but it is likely that this underestimates their frequency. Pleuropulmonary complications are more apt to occur in patients with more severe chronic articular disease, with high titers of rheumatoid factor, and in patients who have subcutaneous nodules, as well as other systemic complications such as cutaneous vasculitis, myocarditis, pericarditis, ocular inflammation, and Feltyâ&#x20AC;&#x2122;s syndrome. An association between smoking and an increased

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risk for the development of pleuropulmonary disease, radiographic progression, and nodule formation in rheumatoid factor–seropositive patients has been reported. Pleuropulmonary disease may occur in seronegative patients and both methotrexate and gold compounds, commonly employed for treatment, can induce an interstitial lung disease, which is often difficult to distinguish from the primary forms complicating rheumatoid arthritis. Moreover, interstitial lung disease, pleuritis, and occasionally obliterative bronchiolitis may be the first and only manifestation of the rheumatoid state in up to 20 percent of patients, preceding the articular manifestations by months to years. Pleurisy and Pleural Effusion Pleural disease in a postmortem series was found in 40 percent of patients with rheumatoid arthritis. The incidence of clinically apparent pleural disease is closer to 5 percent, and the majority of patients experience mild symptoms. In approximately 20 percent of the patients who develop pleural complications, they do so prior to the onset of articular disease. In patients with rheumatoid arthritis, pleural complications are more common in men and occur most frequently during episodes of active articular disease and in patients with subcutaneous rheumatoid nodules. Pleural disease is often first discovered on routine chest radiograph, and both pleural fibrosis and effusions have been reported to occur in asymptomatic patients. The pleural effusion can be unilateral or bilateral and coexist with interstitial lung disease or necrobiotic nodules. Symptomatic patients present with pleuritic pain, dyspnea, and occasionally fever. The effusion is an exudate by protein and lactic dehydrogenase criteria, and, if chronic, cholesterol concentrations are increased. Other characteristics include a low pleural fluid pH (less than 7.2), thought to be due to impaired carbon dioxide exit from the pleural space. The leukocyte counts can be as high as 15,000 cells per cubic millimeter and consist of a mixture of neutrophils and mononuclear leukocytes. As in SLE, the total and individual complement components are low, and the rheumatoid factor level is increased. The presence of rheumatoid factor in pleural fluid has also been reported with tuberculosis, malignancy, and other infectious diseases. A low pleural fluid glucose concentration, thought to be due to a defect in glucose transport, is characteristic of rheumatoid effusions. Up to 40 percent of patients have pleural fluid glucose levels less than 10 mg/dl, and 75 percent have levels under 50 mg/dl. It has been stated that cytologic examination of the pleural fluid, which demonstrates a background of necrotic debris, spindle-shaped macrophages, and multinucleated histiocytes, is characteristic of a rheumatoid effusion. Necrobiotic nodules are thought to be involved in the pathogenesis of the pleural effusions, but transthoracic pleural biopsy only occasionally will demonstrate this finding. Treatment is not indicated for asymptomatic cases; however corticosteroids, when used for active articular disease, are also effective in hastening the resolution of the pleural

effusion. Rarely, is any other form of intervention such as intrapleural corticosteroids necessary for these patients. In the unusual case, pleural fibrosis with resultant lung entrapment occurs, requiring surgical intervention. Spontaneous pneumothorax due to rupture of a necrobiotic nodule, another uncommon complication, necessitates tube thoracostomy, and with persistence of the bronchopleural fistula, surgical intervention is indicated. Pulmonary Vascular Disease In general, pulmonary vascular disease is the least common pleuropulmonary complication in rheumatoid arthritis. The fibroproliferative plexogenic arteriopathy typical of scleroderma and SLE is an infrequent complication. When it does occur, Raynaud’s phenomenon is commonly present. The chest radiograph reveals normal lung fields and enlarged pulmonary arteries, and there is an isolated reduction of the diffusing capacity for carbon monoxide as well as hypoxemia. Small-vessel vasculitis in rheumatoid arthritis occurs in the setting of diffuse alveolar hemorrhage due to pulmonary capillaritis and is a very rare event in rheumatoid arthritis. Several cases have been well documented and, in one, antineutrophilic cytoplasmic antibody to myeloperoxidase (p-ANCA) was present in the serum. Treatment with intravenous methylprednisolone, followed by oral corticosteroid preparations in addition to cyclophosphamide, is indicated for this complication. Necrobiotic (Rheumatoid) Nodule Radiographically visible lung parenchymal rheumatoid nodules are infrequently seen in a rheumatoid population (less than 1 percent). When they do occur, they are more common in men, particularly those who smoke, with active articular disease and high rheumatoid factors, and in those who have subcutaneous nodules. The nodules are primarily a chest radiograph finding, since most are asymptomatic. The major problem is differentiating the necrobiotic nodule from either malignant or infectious granulomatous diseases. Occasionally, cough and hemoptysis are the presenting symptoms. Radiographically, the nodules can be single or multiple with upper and midzone predilection, and approximately 50 percent will undergo cavitation due to the large amounts of proteolytic enzymes in these lesions. The size is variable, and nodules up to 7 cm have been reported. Spontaneous resolution and recurrence are to be expected. Continuous growth, although possible, should prompt a more aggressive diagnostic approach. In most cases, no treatment is required. Caplan’s syndrome refers to a radiographic picture that developed in Welsh coal miners with rheumatoid arthritis. It consists of the sudden appearance of discrete nodules primarily in the upper lobes that are histologically identical to the necrobiotic nodule (Fig. 71-13). The incidence of necrobiotic nodules is higher in rheumatoid patients with underlying pneumoconiosis, including coal workers’ pneumoconiosis, silicosis, and asbestosis, than it is in a general rheumatoid population.

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Figure 71-13 Caplanâ&#x20AC;&#x2122;s syndrome in a patient with rheumatoid arthritis and silicosis (hard-rock miner). There are multiple small nodules in the middle and upper lung representing the silicosis. In addition, multiple upper-zone rheumatoid nodules are present.

Airway Disease Upper-airway involvement by the rheumatoid process is most likely to involve the cricoarytenoid joint, causing difficulty with inspiration and occasionally resulting in stridor. A sore throat, hoarseness, and globus sensation are other common complaints. The prevalence of this complication, although asymptomatic in the majority of cases, approaches 50 percent when computed tomography screening is employed. Clinically significant disease can be detected by performing flow-volume loops, which indicate a variable extrathoracic obstruction of the inspiratory loop. Cricoarytenoid arthritis may further complicate endotracheal intubation and should be considered in all patients with rheumatoid arthritis requiring general anesthesia. Bronchiolitis obliterans or obliterative bronchiolitis is a well-recognized cause of progressive and often severe obstructive lung disease in patients with rheumatoid arthritis. This complication was first thought to be a consequence of either penicillamine or gold therapy, but many cases have appeared in the absence of either treatment. The onset of obliterative bronchiolitis is insidious, with patients complaining of progressive dyspnea and cough while having a normal or hyperinflated chest radiograph (Fig. 71-14A). Initially, it was thought that this complication was limited to women, but this is not the case. Physical examination reveals a generalized reduction of breath sounds and occasionally an inspiratory squeak. Physiological testing reveals varying degrees of airflow limitation and hyperinflation, and the diffusing capacity may be normal or reduced. High-resolution computed tomography demonstrates adjacent areas of decreased and increased attenuation (geographic pattern), suggesting air trapping, which

Pulmonary Manifestations of the Collagen Vascular Diseases

Figure 71-14 Obliterative bronchiolitis in a patient with rheumatoid arthritis. A. The chest radiograph is normal except for hyperinflation. B . A high-resolution computed tomography demonstrating areas of increased and decreased attenuation (arrows).

may be further identified by expiratory imaging (Fig. 7114B). Some patients have responded to treatment with a combination of corticosteroids and cyclophosphamide, but the majority of cases progress to hypercapnic respiratory failure. Another form of bronchiolitis seen in rheumatoid arthritis is a respiratory or follicular bronchiolitis, consisting

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Figure 71-15 Follicular bronchiolitis in rheumatoid arthritis. High-resolution computed tomography demonstrating multiple centrilobular nodules.

of a dense infiltration of lymphocytes and plasma cells surrounding the terminal and respiratory bronchioles. Cough and dyspnea are common symptoms. Chest radiographs may be normal or demonstrate a fine nodular pattern more predominant in the middle and lower lung zones. Highresolution computed tomography demonstrates centrilobular nodules and bronchiectasis (Fig. 71-15). There is usually no physiological evidence for airflow limitation or reduced lung volumes, but rather gas exchange abnormalities dominate the physiological picture. Treatment with corticosteroids yields variable results. Diffuse panbronchiolitis has been reported in Japanese patients with rheumatoid arthritis. In both diffuse panbronchiolitis and rheumatoid arthritis, an association with HLADR4 and B54 haplotypes has been reported, suggesting a common genetic predisposition. Interstitial Lung Disease Interstitial lung disease is a relatively common complication in patients with rheumatoid arthritis. In contrast to most connective-tissue diseases, interstitial lung disease is more common in males than females (3:1), individuals who have late-onset disease, high-titer rheumatoid factors, and in those who smoke. It is not unusual for interstitial lung disease to precede the articular manifestations for a period of months to years. The incidence of this complication in a rheumatoid population is difficult to determine, being reported in 5 to 40 percent of patients depending upon the methods of detection. The use of bronchoalveolar lavage indicating alveolar inflammation and high-resolution computed tomographic scans indicating various interstitial changes, often in the face of a negative chest radiograph, are difficult to interpret. This is because follow-up studies determining whether these patients

developed clinically apparent interstitial lung disease are lacking. Furthermore, some parenchymal changes described on computed tomography such as bronchiectasis have very little, if any, clinical significance. It is likely that clinically important interstitial lung disease occurs in 5 to 10 percent of patients with rheumatoid arthritis, the most common forms being UIP and degrees of NSIP. These patients are dyspneic and complain of cough. Physical examination reveals bibasilar crackles, clubbing of the digits in up to 75 percent, and evidence of cor pulmonale when pulmonary hypertension appears secondary to hypoxic vasoconstriction. The chest radiograph and computed tomographic scan demonstrate varying degrees of interstitial infiltrates with predilection for the lung bases and lung periphery (Fig. 71-16A). Other features include ground-glass attenuation on computed tomography with mixed alveolar-interstitial infiltrates on chest radiograph indicating a component of NSIP. Both imaging studies in advanced disease reveal the presence of honeycomb lung (Fig. 71-16B). Several other interstitial reactions which produce subacute or chronic symptoms complicate rheumatoid arthritis. The first is bronchiolitis obliterans organizing pneumonia, which can present with identical symptoms to UIP and preempt the onset of the articular disease as well. The chest radiograph (Fig. 71-17) and computed tomography scan differ from that seen in UIP because the infiltrates are primarily alveolar and localized, patchy, or diffuse. The second interstitial reaction is lymphocytic interstitial pneumonia, which occurs when rheumatoid arthritis is complicated by SjÂ¨ogrenâ&#x20AC;&#x2122;s syndrome. In addition to dyspnea and cough, these patients complain of dry mouth and eyes (xerophthalmia and xerostomia). The chest radiograph indicates patchy alveolar infiltrates primarily seen at the lung bases. Eosinophilic pneumonia has recently been reported as a pleuroparenchymal complication of rheumatoid arthritis and may be the primary presentation of the disease. Acute interstitial pneumonitis is a rare, acute form of interstitial lung disease in rheumatoid arthritis. While it may occur as a result of an immunologic injury to the lung, medication-related pulmonary toxicity and opportunistic infections should be considered. Lastly, fibrobullous disease, similar to that seen in ankylosing spondylitis, has been reported in rheumatoid arthritis and may precede the articular manifestations of the disease. It is important to establish the underlying histology, since response to therapy and prognosis differs. Unless the imaging studies indicate end-stage honeycomb lung, which can also result from unresponsive or recurrent bronchiolitis obliterans organizing pneumonia, lymphocytic interstitial pneumonia, or UIP, further evaluation is indicated. Bronchoalveolar lavage will not necessarily help differentiate between these three histological pictures, but the finding of increased lymphocytic percentages as opposed to neutrophils and eosinophils indicates the potential for therapeutic responsiveness. Alveolar infiltrates and increased lymphocyte percentages are seen in lymphocytic interstitial pneumonitis. Bronchiolitis obliterans organizing pneumonia is associated with increases in neutrophil, eosinophil, and lymphocyte

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Figure 71-16 UIP in rheumatoid arthritis. A. Chest radiograph demonstrating lower zone and peripheral reticulonodular infiltrates. B . High-resolution computed tomography demonstrating a cystic network (honeycomb lung) at the lung base in a patient with advanced disease.

percentages as well as radiographic alveolar infiltrates. The finding of increased neutrophil and eosinophil percentages in suspected underlying UIP is an indicator of poor prognosis. Therefore, patients with lymphocytic interstitial pneumonitis and bronchiolitis obliterans organizing pneumonia are more treatment-responsive when compared to those with UIP. If imaging studies and bronchoalveolar lavage cellular analysis are not definitive, thorascopic open lung biopsy should be considered. Treatment consists of a corticosteroid preparation and often the addition of cytotoxic drugs in the nonresponsive cases. As opposed to the idiopathic variety of bronchiolitis obliterans organizing pneumonia, in which 66 percent of cases have favorable responses to corticosteroid medications, those associated with collagen vascular diseases are less responsive to treatment, often recur with tapering of the treatment regimen, and can progress to honeycomb lung. While the histopathology may be similar between rheumatoid arthritis and idiopathic pulmonary fibrosis, improved survival exists for those with rheumatoid arthritisâ&#x20AC;&#x201C;associated UIP but the long-term prognosis remains poor. Gold-induced pneumonitis must be differentiated from the primary forms of interstitial lung disease in patients with rheumatoid arthritis, particularly since the underlying histology can be similar, indicating varying degrees of NSIP and bronchiolitis obliterans organizing pneumonia. Dyspnea and cough usually begin 4 to 6 weeks following initiation of therapy, and peripheral eosinophilia occurs in a minority of cases. Occasionally, the chest radiograph will demonstrate upper- as opposed to lower-zone mixed alveolar interstitial

infiltration. Bronchoalveolar lavage indicates a predominance of lymphocytes, and differentiation from rheumatoid interstitial lung disease can only be made after withdrawal of the drug results in remission. In severe cases with marked gas

Figure 71-17 Bronchiolitis obliterans organizing pneumonia in rheumatoid arthritis. Chest radiograph demonstrating lowerzone mixed alveolar-interstitial infiltrates.

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exchange abnormalities, corticosteroid therapy will occasion prompt reversal. Methotrexate given in relatively low weekly doses (10 to 20 mg) is associated with the development of an interstitial disease in rheumatoid patients. No correlation with age, sex, duration of disease, or weekly or cumulative dose could be found. Conflicting data suggest that rheumatoid patients with underlying primary rheumatoid lung disease are predisposed to develop methotrexate pneumonitis. In rheumatoid patients treated with methotrexate, the incidence of methotrexate pneumonitis is 1 to 11 percent. The clinical onset is relatively acute with cough, fever, dyspnea, and new mixed alveolar and interstitial pulmonary infiltrates on chest radiograph. Increased white blood cell counts with mild eosinophilia, elevated sedimentation rates, and increased serum lactic dehydrogenase are nonspecific findings. Bronchoalveolar lavage indicates lymphocytosis and should be performed to rule out an infectious etiology. Lung tissue reveals an NSIP, organizing pneumonia, and granuloma formation reminiscent of a hypersensitivity pneumonitis. In patients who develop this clinical syndrome while on methotrexate, the drug should be discontinued since progression to end-stage fibrosis may occur. With life-threatening respiratory failure, corticosteroids given intravenously is an effective therapy. The advent of TNF-Îą antagonists have revolutionized therapy for patients with rheumatoid arthritis. Their efficacy in the treatment of pleuroparenchymal complications remains unknown, with conflicting data having been reported. Of concern in those patients being treated with these agents should be the increased risk of infections, particularly both typical and atypical mycobacteria and fungi, as well as common bacterial pathogens.

Scleroderma Scleroderma or systemic sclerosis is an inflammatory-fibrotic disease that results in deposition of excessive extracellular matrix in the skin and several visceral organs including the lungs, heart, kidneys, and gastrointestinal tract. Two subtypes of systemic sclerosis exist: diffuse and limited. In diffuse systemic sclerosis, extensive skin involvement of the extremities, face, and torso exists with accompanying marked visceral involvement that is progressive in nature. The limited form, or CREST variant (c alcinosis, Raynaudâ&#x20AC;&#x2122;s phenomenon, esophageal dysmotility, s clerodactyly, and telangiectasias), has a more protracted course in most patients and usually affects an older subset of patients. Pulmonary disease contributes significantly to both the morbidity and mortality of patients. The pathogenesis, although not well understood, involves a complex interaction among immune cells, endothelial cells, and fibroblasts. In addition to the excessive extracellular matrix, which in the lung results in interstitial fibrosis, endothelial cell damage with intimal thickening of pulmonary and systemic arteries occurs, leading to luminal obliteration. This results in a form of idiopathic pulmonary hypertension. The lung is involved in the great majority of cases, and postmortem series indicate a 70 to 100 percent incidence.

Most patients with scleroderma develop dyspnea during the course of their illness due either to interstitial lung disease or pulmonary hypertension. Both bronchoalveolar lavage and high-resolution computed tomographic scans, in the face of normal chest radiographs, have indicated interstitial lung disease in both symptomatic and asymptomatic patients (Fig. 71-18). Although unusual, interstitial lung disease and pulmonary hypertension have preceded the dermatologic manifestations, defined as systemic sclerosis sine scleroderma. Despite the lack of skin involvement, the course in systemic sclerosis sine scleroderma does not significantly differ from the more common forms, with exception of a greater tendency toward the development of pulmonary hypertension. Pleural Disease Although pleural fibrosis and adhesions are reported to be present in 40 percent of patients with scleroderma in postmortem studies, clinically apparent pleural thickening or pleural effusions on chest radiographs are considerably less frequent. The exception to this is pleural effusions secondary to congestive heart failure due to a scleroderma-associated cardiomyopathy. Interstitial Lung Diseases Interstitial lung disease, progressing to honeycomb lung, is the most common pulmonary complication of scleroderma, occurring in 30 to 100 percent of cases. A high-resolution computed tomographic study indicated a greater than 90 percent incidence of this abnormality with up to two-thirds of patients having normal chest radiographs. As many as 60 percent of patients who undergo bronchoalveolar lavage will demonstrate an abnormal inflammatory cell distribution. Chest radiographic and physiological screening indicate somewhat lower prevalence. The significance of the bronchoalveolar lavage and computed tomographic findings remain unclear, since no longitudinal follow-up is available. Following the histological reclassification of idiopathic interstitial pneumonias, the most common underlying histology in systemic sclerosis is NSIP with honeycomb lung. UIP, unclassifiable fibrosing interstitial lung disease, and rarely, organizing pneumonia and granulomatous lung disease resembling sarcoidosis have also been reported. It was previously thought that interstitial lung disease in scleroderma was primarily a fibrotic disorder. However, recent information derived from high-resolution computed tomography demonstrating ground-glass attenuation which indicates more cellular disease, bronchoalveolar lavage revealing increased inflammatory cell populations, and biopsy material demonstrating cellular infiltration of the interstitium indicates the presence of a cellular inflammatory response. This predates the development of fibrosis, consistent with the cellular subtype of NSIP. It is likely that the inflammatory phase in most cases is clinically silent. Interstitial lung disease is more likely to occur in diffuse systemic sclerosis, although it may also complicate limited systemic sclerosis, formerly referred to as the CREST syndrome. Dyspnea on exertion progressing to dyspnea at rest

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Figure 71-18 A. Normal chest radiograph in a dyspneic patient with scleroderma. B . High-resolution computed tomography of the same patient demonstrating reticular interstitial infiltrates.

and cough are the predominant symptoms. Bibasilar crackles are heard, but clubbing is unusual due to the capillary destruction in the nail beds. Physical findings of cor pulmonale eventually appear. Bibasilar interstitial infiltrates followed by more diffuse changes, loss of lung volume, honeycomb cysts, and pulmonary hypertension are the typical radiographic features. Scleroderma was the first interstitial lung disease in which scar carcinoma (adenocarcinoma or alveolar cell carcinoma) was reported. Physiological testing eventually reveals restrictive lung disease, preserved flow rates, and a reduced diffusing capacity. Early on, the aforementioned measurements may be normal, and hypoxemia and a widened alveolar-arterial oxygen gradient at rest and heightened by exercise may be the only physiological abnormalities. A disproportionally greater reduction of the diffusing capacity, when compared to lung volumes, most likely indicates the presence of idiopathic pulmonary hypertension due to plexogenic arteriopathy, particularly in the limited form of systemic sclerosis. Other forms of interstitial lung disease seen in scleroderma include lymphocytic interstitial pneumonitis in those cases associated with SjÂ¨ogrenâ&#x20AC;&#x2122;s syndrome; rare cases of diffuse alveolar hemorrhage have been reported. Immunosuppression is the mainstay of treatment, with corticosteroids and cyclophosphamide being the agents of choice. The recent NHLBI-sponsored Scleroderma Lung

Health Study confirmed prior retrospective studies suggesting improved lung function in those patients treated with cyclophosphamide. Although the improvement in lung function is of questionable clinical significance, a therapeutic effect is expected in those with ground-glass attenuation on HRCT imaging, a lymphocytic or eosinophilic predominant bronchoalveolar lavage, and a cellular interstitial pneumonia on lung biopsy. Pulmonary Vascular Disease Pulmonary hypertension, due to a plexogenic arteriopathy involving the pulmonary arteries, occurs in approximately 10 percent of cases of scleroderma and is primarily seen in the limited form (CREST syndrome). In this form of scleroderma, pulmonary hypertension may coexist with interstitial lung disease. Patients present with a gradual onset of dyspnea and increasing fatigue. Physical examination and chest radiograph may initially be normal, and, with disease progression, physical and radiographic signs of pulmonary hypertension appear. Lung volumes and airflow parameters are maintained, unless there is concomitant interstitial lung disease. Typically there is an isolated reduction in the diffusing capacity as well as progressive hypoxemia. Prior to the use of vasodilator therapy, the mean survival following a diagnosis of pulmonary hypertension was approximately 2 years. Treatment with continuous intravenous prostacyclin, phosphodiesterase

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involvement of the airways and pleura do not occur. Pulmonary hypertension secondary to plexogenic arteriopathy has been reported on several occasions, most often in cases in which a crossover with scleroderma was suspected. Aspiration Pneumonia Aspiration pneumonia is a common pulmonary complication, occurring in 10 to 20 percent of patients with polymyositis-dermatomyositis; almost half of the patients complain of dysphagia as well. This complication results from an inflammatory myositis affecting the striated muscle of the hypopharynx and upper esophagus. As a result, there is loss of normal swallowing function and failure to protect the airway. Aspiration is more likely in those patients with extensive skin or muscle involvement.

Figure 71-19 Mild peripheral, linear, ground-glass opacities in both lungs with marked thickening of the esophageal wall and severe dilatation of esophageal lumen with extensive debris filling the lumen in a patient with limited systemic sclerosis.

type 5 inhibitors, and endothelin antagonists have improved the quality of life and exercise performance. Improved survival has been suggested with the use of these agents but has not been adequately studied. Aspiration Pneumonia There is a high incidence of esophageal dilatation and decreased peristalsis (dysmotility) in patients with scleroderma, particularly in the limited variety (Fig. 71-19). This leads to dysphagia, heartburn, gastroesophageal reflux, and recurrent aspiration pneumonia. It has long been held that aspiration contributes to the development of interstitial lung disease. A definitive study has indicated that direct measurements of gastroesophageal reflux did not correlate with physiological impairment (low lung volumes and diffusing capacity) in these patients. Aggressive treatment to reduce the risk of aspiration is recommended despite conclusive evidence to suggest an association.

Polymyositis-Dermatomyositis Polymyositis is a systemic autoimmune disorder characterized by an inflammatory myopathy. Dermatomyositis differs from polymyositis in that prominent skin involvement, characterized by a heliotropic rash and/or erythematosus scaling over the proximal interphalangeal joints, termed Gottronâ&#x20AC;&#x2122;s papules or rash, occurs with less severe myositis. In polymyositis-dermatomyositis, pulmonary complications are common and important causes of morbidity and mortality and often predate or overshadow the muscle or skin manifestations. Pulmonary involvement has been reported in up to 40 percent of cases. In contrast to the other collagen vascular diseases, in polymyositis-dermatomyositis primary

Respiratory Muscle Dysfunction Hypercapnic respiratory failure requiring assisted ventilation, due to extensive myositis involving the respiratory muscles and diaphragm, is an uncommon event (less than 5 percent prevalence). In those patients presenting with unexplained hypercapnic respiratory failure, polymyositisdermatomyositis as well as demyelinating neuromuscular disorders should be considered. With less extensive involvement of these muscles, however, there is a reduction in cough generation and the potential for the development of hypostatic pneumonia and atelectasis due to mucous plugging. Weakness can also cause a restricted physiological defect with resulting tachypnea and dyspnea in the face of a normal diffusing capacity, normoxemia, and hyperventilation. Respiratory muscle dysfunction as the cause of restrictive lung disease can best be demonstrated by measurement of the maximal pressure generated during both phases of the respiratory cycle. Sequential measurements are useful for monitoring the disease course and response to treatment. Interstitial Lung Disease The prevalence of interstitial lung disease in polymyositisdermatomyositis ranges from 5 to 30 percent. The incidence is significantly higher in certain populations. In Japan, it approached 40 to 80 percent in one series. As in the other collagen vascular diseases, the use of bronchoalveolar lavage and high-resolution computed tomography for screening increases the documented incidence. Although UIP was previously reported to be the predominant histological type of interstitial lung disease seen in polymyositis-dermatomyositis, NSIP now appears to be most common, based on the revised classification system for idiopathic interstitial pneumonias. Diffuse alveolar damage (DAD), bronchiolitis obliterans organizing pneumonia, and diffuse alveolar hemorrhage secondary to pulmonary capillaritis may also occur. All forms of interstitial lung disease may precede, appear simultaneously with, or follow the muscle or skin manifestations. There is no relationship between interstitial lung disease and the extent of muscle or skin disease, the level of creatine phosphokinase elevation, or the presence of

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serum rheumatoid factor or antinuclear antibodies. There is, however, a relationship between interstitial lung disease and a serum antibody directed against the cellular enzyme histidyltRNA-synthetase, known as anti-Jo-1. This antibody appears in 25 percent of patients with polymyositis-dermatomyositis in total, but in 50 percent of patients with interstitial lung disease and in 13 percent of patients without lung disease. All forms of interstitial lung disease in polymyositisâ&#x20AC;&#x201C; dermatomyositis are more common in women. Several clinical syndromes occur and are associated with the underlying interstitial lung disease. The most common presentation is chronic cough and progressive dyspnea due to NSIP with varying degrees of fibrosis. Digital clubbing is rarely, if ever, seen. Chest radiographs demonstrate reticulonodular infiltrates, and with disease progression there is a reduction of the lung volume and the development of radiographic honeycomb lung and pulmonary hypertension. Physiological testing indicates a restrictive pattern with a low diffusing capacity. Response to treatment depends upon the underlying histology, the more cellular disease being more responsive. In corticosteroid-resistant patients, cyclophosphamide, cyclosporine, and tacrolimus have been used with efficacy. In polymyositis-dermatomyositis, an acute pulmonary presentation with a clinical and radiographic picture reminiscent of a diffuse infectious pneumonia occurs. The underlying lesion is DAD. Severe respiratory failure occurs, and recovery is unusual in spite of aggressive anti-inflammatory and immunosuppressive therapy. Bronchiolitis obliterans organizing pneumonia may have either an acute or subacute presentation (Fig. 71-20). The differentiation from DAD becomes important because of the marked disparity in treat-

Figure 71-20 Bronchiolitis obliterans organizing pneumonia in a patient with polymyositis-dermatomyositis and acute symptoms. Chest radiograph demonstrating diffuse patchy alveolar infiltrates.

Pulmonary Manifestations of the Collagen Vascular Diseases

ment outcome and survival. In bronchiolitis obliterans organizing pneumonia, corticosteroid responsiveness with or without an additional agent is the rule rather than the exception. Diffuse alveolar hemorrhage due to pulmonary capillaritis may also occur. This complication appears simultaneously with the onset of the muscle disease. Hemoptysis may or may not be present. As with other forms of pulmonary capillaritis, immunosuppression with corticosteroids and cyclophosphamide is efficacious.

Mixed Connective-Tissue Disease Patients with mixed connective-tissue disease have features of SLE, polymyositis-dermatomyositis, and scleroderma. Mixed connective-tissue disease is characterized by elevated titers of a specific antinuclear antibody directed against nuclear ribonucleoprotein (anti-RNP). Because of the similarity of mixed connective-tissue disease to the aforementioned collagen vascular diseases, pleuropulmonary complications are frequent, occurring in 20 to 80 percent of cases. Pleural Disease Although pleurisy has been reported to occur in 40 percent of cases, pleural effusions are uncommon, appearing in approximately 5 percent of cases. It is an exudative effusion, but very little information concerning its characteristics is available in the literature. Pulmonary Vascular Disease Pulmonary hypertension may be caused by recurrent pulmonary emboli, hypoxic vasoconstriction secondary to interstitial lung disease, or plexogenic arteriopathy, as occurs in SLE and scleroderma. This is a significant problem for these patients; however, the incidence is unknown. These patients, primarily women, present with dyspnea and fatigue. They have normal chest radiographs except for pulmonary arterial enlargement and an isolated reduction in the diffusing capacity for carbon monoxide. The prognosis in pulmonary hypertension secondary to mixed connective-tissue disease is similar to that noted in pulmonary hypertension seen in scleroderma and SLE. Medium-size pulmonary artery vasculitis has been reported in mixed connective-tissue disease, with evidence suggesting immunologic-mediated injury with deposition (IgG, C3 ) in the vascular walls. Circulating lupus anticoagulant (antiphospholipid syndrome) may also complicate the course of patients with mixed connective-tissue disease, predisposing them to thromboembolic disease. It is in these patients that recurrent small pulmonary emboli may mimic the clinical picture of idiopathic pulmonary hypertension. Aspiration Pneumonia Patients with mixed connective-tissue disease, presenting with predominant features of scleroderma or polymyositisdermatomyositis, are predisposed to esophageal dysmotility and dilatation, which can be a significant problem leading to

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reflux esophagitis and recurrent aspiration pneumonia. The incidence of abnormal esophageal manometry in one series was greater than 50 percent. Respiratory Muscle Dysfunction In those patients with features of polymyositisdermatomyositis, an inflammatory myositis with respiratory muscle involvement may lead to hypercapnic respiratory failure or a restrictive lung disease with the development of hypostatic pneumonia. Interstitial Lung Disease The incidence of interstitial lung disease in mixed connectivetissue disease is increased in comparison to other collagen vascular diseases. If one applies physiological as opposed to radiographic criteria, the incidence approaches 80 percent. The histological pattern is NSIP and/or UIP, both of which may progress to honeycomb lung, particularly in those patients with the features of scleroderma. As with the other connective-tissue diseases, this interstitial lung disease manifests as progressive dyspnea, bibasilar reticulonodular infiltrates on chest radiograph, and physiological parameters, which indicate low lung volumes and a reduction in the diffusing capacity for carbon monoxide. Diffuse alveolar hemorrhage has been reported in a few cases of mixed connective-tissue disease and is similar in presentation to that in SLE. It is assumed that the histology is one of either bland pulmonary hemorrhage or pulmonary capillaritis but remains unknown.

¨ Sjogren’s Syndrome Sjögren’s syndrome refers to a triad of xerophthalmia, xerostomia, and polyarthritis. This autoimmune exocrinopathy is characterized by lymphocytic infiltration of the lacrimal and salivary glands. A primary form, occurring in the absence of another collagen vascular disease, and a secondary form, associated with one of the other collagen vascular diseases, most frequently rheumatoid arthritis, exist. A strong female predominance exists in Sjögren’s syndrome (greater than 90 percent). A positive rheumatoid factor (95 percent) and antinuclear antibodies in a speckled pattern (80 percent) are to be expected, as well as positive tests for antibodies to extractable nuclear antigens (anti-SSA, anti-SSB), which are specific for the primary form of the syndrome. Airway Disease Lymphocytic infiltration and destruction of airway mucous glands results in dessication of the tracheobronchial tree in Sjögren’s syndrome. Patients may develop hoarseness, cough, inspissation of secretions resulting in atelectasis, recurrent pneumonias, and bronchiectasis. There is a high incidence of obstructive ventilatory dysfunction in these patients, secondary to follicular bronchiolitis. Obliterative bronchiolitis, constrictive bronchiolitis, and bronchiolectasis have also been reported.

Figure 71-21 Multiple cysts of varying sizes scattered through¨ out both lungs in a patient with Sjogren’s syndrome and lymphocytic interstitial pneumonia.

Interstitial Lung Disease In primary Sj¨ogren’s syndrome, patients present with a nonproductive cough, dyspnea on exertion, or asymptomatic radiographic abnormalities. As occurs in the lacrimal and salivary glands, interstitial lung disease in these patients is the result of lymphocytic infiltration of the lung parenchyma. This occurs in two forms, lymphocytic interstitial pneumonitis and, less commonly, pseudolymphoma. Both of these lesions have the potential for lymphomatous conversion. Lymphocytic interstitial pneumonitis is an interstitial lung disease, and therefore cough, dyspnea, and a restrictive lung disease are to be expected. Because lymphocytes also infiltrate the alveolar spaces as well as the interstitium, the radiologic studies indicate mixed alveolar and interstitial infiltrates. In a subset of patients, variably sized cystic lesions with associated ground glass may be the only radiographic abnormality (Fig. 71-21). The development of pleural effusion or the appearance of hilar or mediastinal adenopathy often, but not always, indicates a malignant transformation to a lymphoma. Lymphocytic interstitial pneumonia is responsive to anti-inflammatory agents such as corticosteroids. Occasionally, cytolytic therapy, such as azathioprine or cyclophosphamide, is required but remains of unproven benefit. Cyclosporine has also been recommended as an additional agent in corticosteroid-resistant cases. While the majority of patients will respond to immunosuppressive therapy, a subset of patients progress to fibrotic lung disease with honeycomb change. Pseudolymphoma is a tumorlike proliferation appearing as single or multiple masses on the chest radiograph. It is often difficult to distinguish from a malignant lymphoma and it has been suggested that pseudolymphoma, which is considered to be a localized form of lymphocytic interstitial pneumonitis, is a premalignant lesion. When associated with a monoclonal gammopathy, malignant transformation to lymphoma is likely.

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Interstitial lung disease occurs more commonly in the secondary forms of Sjögren’s syndrome and most likely represents a complication of the associated collagen vascular disease. The histological pattern in secondary Sjögren’s syndrome mimics that seen in rheumatoid arthritis, with NSIP, UIP, and bronchiolitis obliterans organizing pneumonia reported. UIP, however, is uncommon in the primary form of Sjögren’s syndrome.

Ankylosing Spondylitis Ankylosing spondylitis is one of the seronegative spondyloarthropathies that may eventually result in fixation of the chest wall and a mild to moderate restrictive lung disease. Muscular involvement, in contrast to polymyositisdermatomyositis, does not occur and diaphragmatic function is preserved. Ventilatory failure due to chest wall fixation does not occur given preserved respiratory muscle function. The incidence of interstitial lung disease complication is reportedly less than 2 percent. In contrast to the other collagen vascular diseases that primarily affect the basilar portion of the lung, ankylosing spondylitis has a predilection for the upper lung zones, only appears late in the course of the chronic spondylitis, and never precedes it. Interstitial lung disease often appears as fibrocystic disease on the chest radiograph (Fig. 71-22) and is difficult to distinguish from tuberculosis. Histologically, it is a fibrosing process with cystic formation. Progressive dyspnea and cough are the predominant symptoms, and treatment with corticosteroids is ineffective and therefore not indicated. The most serious complication of this apical fibrocystic disease is infection with invasive aspergilla species as well as atypical mycobacteria. Further, saprophytic

Figure 71-22 Ankylosing spondylitis. Chest radiograph demonstrating bilateral upper-zone fibronodular infiltrates.

Pulmonary Manifestations of the Collagen Vascular Diseases

colonization of the cysts by aspergilla species (aspergilloma) may induce life-threatening hemoptysis.

SUGGESTED READING Abramson SB, Dobro J, Eberle MA, et al: Acute reversible hypoxemia in systemic lupus erythematosus. Ann Intern Med 114:941–947, 1991. Alarcon-Segovia D, Deleze M, Oria CV, et al: Antiphospholipid antibodies and the antiphospholipid syndrome in systemic lupus erythematosus: A prospective analysis of 500 consecutive patients. Medicine 89:353–365, 1989. Alspaugh MA, Tan EM: Antibodies to cellular antigen in Sjögren’s syndrome. J Clin Invest 55:1067–1073, 1973. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. [This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001.] Am J Respir Crit Care Med 165(2):277–304, 2002. Badesch DB, Tapson VF, McGoon MD,et al: Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med 132(6):425–434, 2000. Bankier AA, Kiener HP, Wiesmayr MN, et al: Discrete lung involvement in systemic lupus erythematosus: CT assessment. Radiology 196:835–840, 1995. Barrear P, Laan R, vanRiel P, et al: Methotrexate related pulmonary complications in rheumatoid arthritis. Ann Rheum Dis 53:434–439, 1994. Bernstein RM, Morgan SH, Chapman J, et al: Anti-Jo-1 antibody: A marker for myositis with interstitial lung disease. Br Med J 289:151–152, 1984. Block KG, Buchanan WW, Wohl MJ, et al: Sjögren’s syndrome. Medicine 44:187–231, 1965. Bouros D, Wells AU, Nicholson AG, et al: Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med 165:1581–1586, 2002. Caplan A: Certain unusual radiographic appearances in the chest of coal miners suffering from rheumatoid arthritis. Thorax 8:19–37, 1953. Clawson K, Oddis CV: Adult respiratory distress syndrome in polymyositis patients with the anti-Jo-1 antibody. Arthritis Rheum 35:1519–1523, 1995. Kadota J, Kusano S, Kawakami K, et al: Usual interstitial pneumonia associated with primary Sjögren’s syndrome. Chest 108:1756–1758, 1995. Keane J, Gershon S, Wise RP, et al: Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 345:1098–1104, 2001.

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Khanna D, Clements PJ, Furst DE,et al: Correlation of the degree of dyspnea with health-related quality of life, functional abilities, and diffusing capacity for carbon monoxide in patients with systemic sclerosis and active alveolitis: Results from the Scleroderma Lung Study. Arthritis Rheum 52:592–600, 2005. Lee HK, Kim DS, Yoo B,et al: Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease. Chest 127:2019–2027, 2005. Love PE, Santoro SA: Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant systemic lupus erythematosus (SLE) and in non-SLE disorders. Ann Intern Med 112:682–698, 1990. Matthay RA, Schwarz MI, Petty TL, et al: Pulmonary manifestations of systemic lupus erythematosis: Review of 12 cases of acute lupus pneumonitis. Medicine 54:397–409, 1975. Rosenow EC, Sirimlan CV, Muhm JR, et al: Pleuropulmonary manifestations of ankylosing spondylitis. Mayo Clin Proc 52:641–649, 1977.

Schurawitzki H, Stiglbauer R, Graninger W, et al: Interstitial lung disease in progressive systemic sclerosis: High resolution CT versus radiography. Radiology 176:755–759, 1990. Schwarz MI: Pulmonary and cardiac manifestations of polymyositis-dermatomyositis. J Thorac Imaging 7:46–54, 1992. Schwarz MI, Matthay RA, Sahn SA, et al: Interstitial lung disease in polymyositis-dermatomyositis: Analysis of 6 cases and review of the literature. Medicine 55:89–104, 1976. Schwarz MI, Sutarik JM, Nick J, et al: Pulmonary capillaritis and diffuse alveolar hemorrhage: A primary manifestation of polymyositis. Am J Respir Crit Care Med 151:2037–2040, 1995. Shannon TM, Gale ME: Non-cardiac manifestations of rheumatoid arthritis in the thorax. J Thorac Imaging 7:19– 29, 1992. Tazelaar HD, Viggiano RW, Pickersgill J, et al: Interstitial lung disease in polymyositis and dermatomyositis: Clinical features, and prognosis is correlated with histological findings. Am Rev Respir Dis 141:727–733, 1990.

72 The Eosinophilic Pneumonias Kristina Crothers

Carolyn L. Rochester

I. EOSINOPHILIC PNEUMONIAS WITH ACUTE PRESENTATIONS Loeffler’s Syndrome (Simple Pulmonary Eosinophilia) Parasitic Infections Drug and Toxin-Induced Pulmonary Eosinophilic Syndromes Idiopathic Acute Eosinophilic Pneumonia II. TROPICAL PULMONARY EOSINOPHILIA

IV. ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (MYCOSIS) V. CHURG-STRAUSS SYNDROME (ALLERGIC GRANULOMATOSIS AND ANGIITIS) VI. IDIOPATHIC HYPEREOSINOPHILIC SYNDROME VII. APPROACH TO THE EVALUATION OF EOSINOPHILIC PNEUMONIAS

III. CHRONIC EOSINOPHILIC PNEUMONIA

In 1932, Loeffler first identified the association between pulmonary infiltrates and eosinophilia. Subsequently, Crofton separated the eosinophilic pneumonias into five groups on the basis of clinical criteria: Loeffler’s syndrome, prolonged pulmonary eosinophilia, pulmonary eosinophilia associated with asthma, tropical eosinophilia, and periarteritis nodosa. In 1952, Reeder and Goodrich coined the term pulmonary infiltrates with eosinophilia (PIE syndrome) to refer to these disorders. However, it was subsequently appreciated that pulmonary infiltration with eosinophils can occur in the absence of peripheral blood eosinophilia. As a result, in 1969, Liebow and Carrington broadened the description of the term eosinophilic pneumonia to include all disorders characterized by infiltration of the lungs with eosinophils, with or without an excess of eosinophils in the peripheral blood. Subsequent studies also demonstrated that in numerous disorders, peripheral blood eosinophilia can occur without tissue eosinophilic infiltration. As a result, the eosinophilic pneumonias are now recognized as a heterogeneous group of disorders characterized by varying degrees of pulmonary parenchymal or blood eosinophilia. The precise role that eosinophils play in the pathogenesis of the different eosinophilic pneumonias is not clear. Our knowledge of the biology of eosinophils (see Chapter 21) does, however, suggest that they play a variety of roles, including

initiation, perpetuation, and amplification of tissue inflammation and injury. These effector functions are no doubt the result of the ability of the eosinophils to release numerous soluble mediators, including granule-derived proteins, arachidonic acid metabolites, cytokines, superoxide anions, and hydroxyl radicals. The different roles of eosinophils in these disorders can be appreciated when comparisons are made of parasitic infections and disorders such as asthma or allergic bronchopulmonary aspergillosis. In the former, eosinophils play a crucial role in eradicating the infectious pathogen; in the latter, the eosinophils accumulate in the lung as a result of immune hypersensitivity and are prominent mediators of tissue injury. The spectrum of diseases that can be primarily or secondarily associated with blood or pulmonary eosinophilia is shown in Table 72-1. It is beyond the scope of this chapter to discuss each of these disease entities in detail. Instead, discussion will focus on diseases of known or unknown causes in which eosinophilic infiltration of lung tissue is a characteristic feature, including acute eosinophilic pneumonias, tropical pulmonary eosinophilia, chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, Churg-Strauss syndrome, and idiopathic hypereosinophilic syndrome. Since eosinophilic granuloma of the lung is frequently seen in the absence of blood or tissue eosinophilia, it is considered separately in Chapter 74.

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Table 72-1

Table 72-2

Diseases Associated with Pulmonary Infiltrates and Eosinophilia

Parasitic Infections Associated with Eosinophilic Pneumonia

Pulmonary Eosinophilic Syndromes of Known Cause Parasitic-induced eosinophilic pneumonias (including Loeffler’s syndrome) Drug-or toxin-induced eosinophilic pneumonias Tropical pulmonary eosinophilia Allergic bronchopulmonary mycosis

Ancylostoma spp.

Opisthorchis spp.

Ascaris spp.

Paragonimus westermani

Brugia malayi

Schistosoma spp.

Clonorchis sinensis

Strongyloides stercoralis

Dirofilaria immitis

Toxocara gondii

Echinococcus spp.

Trichinella spiralis

Entamoeba histolytica

Trichosporon terrestre

Necator americanus

Wuchereria bancrofti

Pulmonary Eosinophilic Syndromes of Unknown Cause Idiopathic acute eosinophilic pneumonia Chronic eosinophilic pneumonia Churg-Strauss syndrome (allergic granulomatosis and angiitis) Idiopathic hypereosinophilic syndrome Other Lung Diseases Variably Associated with Eosinophilia Asthma/allergy Bronchocentric granulomatosis Bronchiolitis obliterans-organizing pneumonia Infections Fungal (esp. coccidioidomycosis, Aspergillus, Pneumocystis jirovecii) Tuberculosis Interstitial lung disease Idiopathic pulmonary fibrosis Collagen-vascular disease associated Sarcoidosis Eosinophilic granuloma (pulmonary histiocytosis X) Malignancy Non–small-cell cancer of lung Non-Hodgkin’s lymphoma Myeloblastic leukemia Miscellaneous (e.g., lung transplantation, ulcerative colitis)

EOSINOPHILIC PNEUMONIAS WITH ACUTE PRESENTATIONS Loeffler’s Syndrome (Simple Pulmonary Eosinophilia) In 1932, Loeffler first described a clinical syndrome characterized by mild respiratory symptoms, peripheral blood eosinophilia, and transient, migratory pulmonary infiltrates. The term Loeffler’s syndrome, or simple pulmonary eosinophilia, has been used to define the numerous similar cases reported subsequently. Immune hypersensitivity to Ascaris lumbricoides has been recognized as the likely cause of most of the earliest reported cases, although several other par-

asitic infections and exposures to numerous drugs and other agents have also been recognized to induce a Loeffler’s-like syndrome (see below and Tables 72-2 and 72-3). An identifiable etiologic agent may be lacking in up to one-third of patients. Loeffler’s syndrome affects people of all ages. It is characterized clinically by the presence of low-grade fever, nonproductive cough, dyspnea (mild to severe), and occasionally hemoptysis. The respiratory manifestations of Loeffler’s syndrome are usually self-limited, typically resolving in 1 to 2 weeks. Laboratory examination of peripheral blood from patients reveals moderate to extreme eosinophilia, which may be at peak levels as respiratory symptoms resolve. Expectorated sputum, if present, frequently contains eosinophils. Transient, migratory, nonsegmental interstitial and alveolar infiltrates (often peripheral or pleural based) are evident on the chest radiograph. Pulmonary function evaluation typically reveals a mild to moderate restrictive ventilatory defect with a reduced diffusing capacity for carbon monoxide (DlCO ). When Loeffler’s syndrome is due to A. lumbricoides, the pulmonary manifestations are believed to result from a hypersensitivity reaction to the Ascaris larvae. Following ingestion of ova, larvae hatch within the small intestine, then cross the intestinal wall to enter the splanchnic and ultimately the pulmonary circulation. Subsequently, the larvae migrate across pulmonary capillaries into alveoli, mature into adult worms, ascend the large airways, and are swallowed into the gastrointestinal (GI) tract, where they complete their life cycle. The pulmonary manifestations of Loeffler’s syndrome begin approximately 9 to 12 days following ingestion, and occur during the migration of larvae through the lung. Ascaris suum, a large roundworm endemic to pigs, can cause a nearly identical syndrome.

1215 Chapter 72

Table 72-3 Drugs and Other Exposures Causing Eosinophilic Pneumonia Acetaminophen Acetylsalicylic acid∗ Aluminum Amiodarone∗ Ampicillin Azathioprine Beclomethasone dipropionate Beryllium Bleomycin∗ Captopril∗ Carbamazepine∗ Chlorpromazine Chlorpropamide Clarithromycin Clofibrate Cocaine (inhalation) Cromolyn (inhalation) Dantrolene Dapsone Desipramine Diclofenac Ethambutol Fenbarbamate Fenbufen Glafenine Gold salts∗ Granulocyte-macrophage colony-stimulating factor Heroin (inhalation) Ibuprofen Imipramine Indomethacin Interleukins Iodinated contrast agents∗ Isoniazid

l-Tryptophan∗ Maloprim Mecamylamine Mephenesin carbamate Methotrexate∗ Methylphenidate Minocycline∗ Naproxen Nickel Nilutamide∗ Nitrofurantoin∗ Nomifensine Para-aminosalicylic acid Penicillamine∗ Penicillin Pentamidine (inhaled) Phenytoin∗ Piroxicam Procarbazine Prontosil Propylthiouracil∗ Pyramethamine Rapeseed oil Red spider antigens Salicylazosulfapyridine Streptomycin Sulfa-containing antibiotics∗ Sulfasalazine∗ Sulindac Tamoxifen Tetracycline Thiazides Tolazamide Tolfenamic acid Trazodone Trichloroethane Venlafaxine

Note: Drugs commonly or occasionally reported to cause pulmonary eosinophilia are marked with an asterix ( ∗)

The Eosinophilic Pneumonias

During the pneumonic stage of the illness, Ascaris larvae may be identified in sputum or gastric aspirates. In keeping with the life cycle of Ascaris, stool examination for ova and parasites is typically negative until 8 weeks after the onset of the respiratory syndrome. Histological evaluation of lung tissue is not required for confirmation of the diagnosis. When tissue has been obtained, a characteristic and striking eosinophilic infiltration of interstitium and alveolar-capillary units has been noted. Increased numbers of macrophages have also been appreciated. Tissue necrosis and vasculitis are not features of the disorder. Since Loeffler’s syndrome may be induced by a variety of exposures, a search for an etiologic agent (e.g., parasitic infection or drug reaction) should be undertaken. Bronchodilators and rarely corticosteroids may be used for alleviation of pulmonary symptoms, although these are usually self-limited. In cases due to Ascaris, treatment with oral mebendazole (100 mg twice a day for 3 days) should be given to prevent late GI manifestations of Ascaris infestation, which may include malnutrition, diarrhea, abdominal pain, and/or intestinal obstruction typically 8 weeks or more after onset of respiratory symptoms. Since stool specimens are negative for ova and parasites early in the illness, clinical follow-up over a 2- to 3-month period is indicated.

Parasitic Infections Infections with parasites other than Ascaris species are also commonly associated with pulmonary infiltrates and blood or pulmonary eosinophilia. The parasites associated with the development of pulmonary eosinophilic syndromes are listed in Table 72-2. The prevalence of infection with each of these organisms varies with geographical location, socioeconomic status, and host immunity. In addition to Ascaris species, Strongyloides stercoralis (an intestinal nematode), Ancylostoma brasiliensis (cutaneous helminthiasis, “creeping eruption”), and Toxocara canis (dog roundworm, “visceral larva migrans”) are the parasitic agents most commonly associated with pulmonary eosinophilia in the United States. Strongyloides is widely distributed in the tropical and subtropical regions. Following initial transcutaneous infection, a Loeffler’s-like syndrome may occur as larvae migrate through the lungs. Chronic strongyloidiasis occurs as a result of autoinfection, whereby the noninfectious rhabditiform larvae transform within the GI tract into infectious filariform larvae, penetrate the colonic wall or perianal skin, and reinfect the host. Chronic strongyloidiasis can be associated with recurrent asthma-like symptoms that may worsen with the administration of corticosteroids. The hyperinfection syndrome results from accelerated autoinfection, and usually occurs in persons with defects in cell-mediated immunity (such as lymphoma, human immunodeficiency virus [HIV] infection, and with chronic corticosteroid use) as well as in persons with underlying GI disease, but it may also occur in healthy persons. Respiratory manifestations include cough, dyspnea, chronic bronchitis, wheezing, hemoptysis, and pulmonary

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Interstitial and Inflammatory Lung Diseases

infiltrates, in association with blood eosinophilia. Rarely, acute respiratory distress syndrome (ARDS) has been reported in patients with hyperinfection. GI manifestations are also common, including abdominal pain, paralytic ileus, nausea and vomiting, bowel perforation, and secondary sepsis from gram-negative bacteria. Central nervous system (CNS) manifestations such as meningitis have also been noted. The diagnosis of Strongyloides infection may be established by identification of larvae in sputum, bronchoalveolar lavage (BAL) fluid, bronchial brushings, or transbronchial biopsy specimens. Serologic testing, while sensitive but less specific, can also be used to establish a diagnosis. Thiabendazole or ivermectin may be used for the treatment of uncomplicated or disseminated strongyloidiasis; ivermectin is generally better tolerated in terms of side effects. Albendazole is an alternative agent. The hyperinfection syndrome associated with Strongyloides can be difficult to cure. Therapy should be continued until the clinical syndrome resolves and larvae are no longer detectable in the GI tract. Ancylostomiasis is a nematodal infection endemic to the southeastern coastal regions of the United States, Mexico, and Central and South America. The organism is present in soil contaminated by stool from infected domestic animals. It penetrates human skin most commonly through the feet. This results in the development of the “creeping eruption” lesion—a raised, erythematous, serpiginous, tunnel-like, and often itchy lesion on areas of exposed skin. A Loeffler’s-like syndrome occurs in up to 50 percent of cases of “creeping eruption.” Specific treatment for pulmonary involvement is typically not required as illness is usually self-limited. Infection with T. canis may occur throughout the world and leads to the clinical syndrome of “visceral larva migrans.” This syndrome is characterized by hepatomegaly, leukocytosis, fever, hypergammaglobulinemia, and persistent blood eosinophilia. Because the disease most commonly affects young children, a high degree of clinical suspicion is necessary to establish the diagnosis in adults. Respiratory symptoms, including cough and wheezing, may occur after ingestion of substantial numbers of larvae. Laboratory evaluation reveals peripheral blood and BAL eosinophilia, elevated serum levels of immunoglobulin E (IgE), and poorly defined, diffuse nodular alveolar infiltrates on chest radiograph. Although the disease may be self-limited, treatment with albendazole, mebendazole, or corticosteroids may hasten recovery in patients who are severely ill.

lective serotonin-reuptake inhibitors. In addition to medications, a number of toxic exposures may also be associated with eosinophilic pneumonia. For example, eosinophilic pneumonia has been described following radiation therapy for breast cancer, exposure to iodinated contrast agents, and after inhalation of cocaine or heroin. The precise incidence of drugor toxin-induced pulmonary eosinophilia is difficult to assess, considering that most of the literature pertaining to these syndromes is published in the form of case reports, rather than large series or controlled trials. For the same reason, the precise pathogenesis and the definition of the clinical syndromes associated with individual exposures are difficult to characterize. In general, drug-induced pulmonary eosinophilic syndromes have an acute or subacute onset and are not always related to either the cumulative dose of drug used or the duration of treatment. Respiratory symptoms vary widely in severity, from a mild Loeffler’s-like illness with dyspnea, cough, and fever to severe fulminant respiratory failure. Wheezing may be present, but obstructive physiology is not common on pulmonary function testing. Although radiographic findings are not specific, interstitial or alveolar infiltrates are typically evident on chest radiograph (Fig. 72-1), and common high-resolution chest computed tomographic (CT) findings include bilateral consolidation and ground-glass opacities, both of which are frequently peripherally located. A diagnosis of drug- or toxin-induced eosinophilic pneumonia is based upon a careful review of drug and other exposures (including nonprescription drugs, herbal

Drug and Toxin-Induced Pulmonary Eosinophilic Syndromes A vast number of drugs and toxic exposures have been associated with the development of pulmonary infiltrates and blood or pulmonary eosinophilia. A partial list of these medications and exposures is given in Table 72-3, and information regarding pulmonary drug toxicities may also be found on the Internet on the regularly updated web site www.pneumotox.com. Of the medications implicated, many are commonly used antibiotics, nonsteroidal anti-inflammatory agents, and se-

Figure 72-1 Chest radiograph of a 23-year-old woman with acute sulfasalazine-induced eosinophilic pneumonia. Bilateral interstitial and alveolar infiltrates are present.

1217 Chapter 72

The Eosinophilic Pneumonias

preparations, street drugs, and environmental exposures). Other causes of eosinophilic lung disease should be excluded. A concomitant skin rash and pleural effusion can support the diagnosis of drug-induced eosinophilic pneumonia. In some cases, testing with lymphocyte proliferation assays may reveal T-cell sensitization to specific drugs. However, the utility of such assays is limited as negative tests do not rule out a drug-induced disorder, and these assays are not widely available for routine clinical use. The prognosis is favorable in most cases. Elimination of exposure to the drug or other toxin usually leads to resolution of symptoms, eosinophilia, pulmonary infiltrates, and normalization of lung function within a month. Supplemental therapy with corticosteroids is not universally required, but it may hasten recovery in patients who are severely ill.

Idiopathic Acute Eosinophilic Pneumonia In contrast to the typically benign Loefflerâ&#x20AC;&#x2122;s syndrome, a more severe idiopathic form of eosinophilic pneumonia termed acute eosinophilic pneumonia (AEP) has been recognized as a distinct clinical entity. Although seen in patients of both genders and any age group, AEP tends to be slightly more common in younger men, with a mean age of approximately 30 years reported in two of the largest studies to date. AEP occurs commonly in previously healthy persons. Similar cases have been reported in persons with a history of chronic myelogenous leukemia or HIV infection. Although none of the patients in the original reported series had atopy or asthma, cases have since been described in persons with a history of atopy. In addition, cases have been reported in patients who have recently commenced smoking and who have been involved in activities with unusual exposures (such as cave exploration, plant repotting, woodpile moving, and indoor renovations). While no definite seasonal variation has been identified, a preponderance of cases have occurred during the summer. Idiopathic AEP presents as an acute illness with fever, myalgias, cough, dyspnea, pleuritic chest pain, and hypoxemia (arterial PO2 under 60 mmHg). Symptom duration is on average 3 days, although longer courses of up to 30 days have been described. Patients often have diffuse crackles on chest auscultation and develop overt respiratory failure requiring mechanical ventilation. A moderate leukocytosis is typical, but in contrast to other forms of AEP, blood eosinophilia is usually absent. Serum IgE levels may be moderately elevated. Striking eosinophilia (25 to 50 percent) is present in BAL fluid. Pulmonary function tests reveal a restrictive ventilatory defect with a reduced DlCO . Early in the course of illness, the chest radiograph reveals subtle, patchy infiltrates with Kerley B lines. Diffuse, symmetric alveolar and interstitial infiltrates resembling ARDS with a ground-glass or micronodular appearance (Fig. 72-2) develop within 48 hours. Historically, the presence of bilateral infiltrates is a defining feature of the disease, although a more recent study also described AEP with unilateral infiltrates. Small to moderate bilateral pleural effusions

Figure 72-2 Radiographic appearance of idiopathic acute eosinophilic pneumonia (AEP). A. Diffuse bilateral alveolar and interstitial infiltrates apparent on chest radiograph. B . Diffuse parenchymal ground-glass opacity and consolidation evident on computed tomography scan.

are common. Fluid analysis typically reveals a high pH and marked eosinophilia. CT scanning confirms the presence of diffuse parenchymal ground-glass attenuation and consolidation (Fig. 72-2), with prominence along bronchovascular bundles and septae, as well as pleural effusion. Light microscopic examination of lung tissue reveals prominent eosinophil infiltration in alveolar spaces, bronchial walls, and, to a lesser degree, the interstitium. The pathological pattern of diffuse alveolar damage with eosinophilic infiltrates should suggest the possibility of AEP. There is no evidence of vasculitis or extrapulmonary involvement. The pathogenesis of idiopathic AEP is poorly understood. The occurrence of cases following unusual environmental exposures (such as plant repotting, cave exploration,

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Interstitial and Inflammatory Lung Diseases

wood pile moving, smokehouse cleaning, gas tank cleaning, and indoor renovation work) and recent commencement of cigarette smoking as noted above suggests these exposures as possible disease-inciting events, perhaps as triggers for a hypersensitivity reaction to an unidentified antigen. Of note, elevated levels of the fungal cell wall component Î˛-d-glucan have been described in the BAL fluid of patients with AEP, suggesting a possible association between exposure to fungus and development of disease. However, the role of the eosinophil in this disorder has not been fully elucidated. Elevated levels of interleukin (IL)-5, a cytokine involved in activation and recruitment of eosinophils, have been described in the BAL of patients with AEP. Levels of vascular endothelial growth factor (VEGF), a cytokine induced by IL-5, have also been shown to be elevated and to correlate with number of eosinophils and levels of IL-5. Elevated BAL levels of IL-18, a cytokine capable of inducing several cytokines known to induce or enhance eosinophilia, have also been identified among patients with acute (and other) forms of eosinophilic pneumonia. It remains unknown, however, whether the eosinophils initiate the disease process or are a secondary manifestation of the disorder. Idiopathic AEP is a diagnosis of exclusion and should be considered in a patient who presents with apparent acute lung injury (ALI) or ARDS without a typical antecedent illness. A careful search must be undertaken for other causes of pulmonary infiltrates. Specimens of blood, sputum, stool, BAL, and often transbronchial biopsy specimens should be obtained for stain and culture as well as serologic testing to rule out bacterial, mycobacterial, fungal, and parasitic infection. Idiopathic AEP carries an excellent prognosis. Although fatalities have been reported, most patients demonstrate rapid dramatic responses to corticosteroid therapy, with abatement of fever and respiratory symptoms within hours and complete resolution of infiltrates usually within 1 month. The optimal steroid regimen for the treatment of AEP has not been determined. However, initial doses of methylprednisolone typically used range from 60 to 125 mg administered every 6 hours. After resolution of respiratory failure, oral prednisone (in doses of 40 to 60 mg per day) may be continued for 2 to 4 weeks with a subsequent slow taper over the next several weeks. Despite the apparent clinical success of steroid treatment, there is no definitive proof that steroids alter the natural history of the disease. Spontaneous disease regression has been reported, and absence of clinical relapse is characteristic. Follow-up pulmonary function testing is generally normal, although a small number of patients may demonstrate mild reductions in DlCO or lung volumes.

TROPICAL PULMONARY EOSINOPHILIA Tropical pulmonary eosinophilia (TPE) was first described in the early 1940s as a syndrome characterized by fevers,

malaise, anorexia, weight loss, paroxysmal dry cough with dyspnea or wheezing, marked peripheral blood eosinophilia, and spontaneous resolution over several weeksâ&#x20AC;&#x2122; time. In the 1950s and 1960s, filarial infections were recognized as the cause of this disorder. TPE is most prominent in India, Africa, and Southeast Asia, but it may be seen worldwide in filarialendemic regions. Disease may also present in nonendemic regions among immigrants or travelers. A rare manifestation of parasitic infection, TPE occurs in less than 1 percent of patients infected with lymphatic filariae and results from a hypersensitivity reaction to microfilariae from Wuchereria bancrofti and Brugia malayi. Illnesses resembling TPE have also been reported following infection with other parasites. Approximately 4 times more common in men, most patients with TPE manifest the disease between the age of 25 and 40 years, although children and older adults may also be affected. There is no known seasonal or genetic propensity to this disease, and it remains unclear why only such a small percentage of patients with filarial infection develop TPE. The most common symptom of TPE is cough that usually occurs at night. Other typical symptoms include lowgrade fevers, weight loss, fatigue, and malaise. Dyspnea and wheezing, which can be severe, are common, and the clinical presentation may resemble status asthmaticus. Chest pain, muscle tenderness, and cardiac, pericardial, and CNS involvement have also been reported. Rarely, patients remain asymptomatic. Physical examination of patients with TPE is notable for coarse rales or rhonchi and wheezing, although no abnormalities are found in approximately 20 percent of patients. Generalized lymphadenopathy and hepatosplenomegaly may be present, but they are far less common in adults than in children. Laboratory findings in TPE include extreme peripheral blood eosinophilia (usually more than 3000 eosinophils per cubic millimeter and up to 90 percent of the leukocyte differential) that persists for several weeks, although the degree of eosinophilia generally does not correlate well with clinical disease severity or radiographic findings. Total serum IgE is usually elevated (more than 1000 U/ml), and high titers of filarial-specific IgE and IgG, measured by complement fixation or hemagglutination techniques, are crucial diagnostic findings. The erythrocyte sedimentation rate (ESR) may be moderately elevated, and patients may also have an abnormal electrocardiogram (ECG). Eosinophils may be identified in the sputum, and, in those with active disease, BAL may reveal intense eosinophilic alveolitis. Microfilariae are not found in blood or sputum, and examination of stool or urine for ova and parasites is negative (although patients from endemic countries may be simultaneously infected with other parasites). In contrast, microfilariae have been identified in lung and lymph node tissue, especially when lymphadenopathy is present. Pulmonary function tests reveal an obstructive ventilatory defect in up to 30 percent of patients, particularly when symptoms have been present less than 1 month. A restrictive ventilatory defect and reduced DlCO , with or without a concomitant obstructive defect, are typical of long-standing

1219 Chapter 72

disease. Ill-defined, diffuse reticulonodular infiltrates with a mottled appearance are characteristic radiographic findings in TPE. The mid- to lower lung fields are most commonly affected, but disease may appear anywhere in the lung. Bronchovascular markings may be prominent and hilar adenopathy and pleural effusions have occasionally been reported. The chest radiograph may be normal at the time of presentation in as many as 20 percent of patients. In rare cases where Dirofilaria is the causative agent, the chest radiograph may reveal solitary or multiple nodules thought to represent infarcts caused by parasitic emboli. The histopathological findings in TPE depend on the tissue examined, as well as the stage and duration of the disease. Studies of lung pathology have shown that the early stage of the disease (within the first 2 weeks) is characterized by histiocytic inflammation in the alveolar, interstitial, peribronchial and perivascular spaces, with preservation of lung architecture. Tiny nodules may be palpable within the lung tissue. One to three months after symptom onset, eosinophilic infiltration with eosinophilic bronchopneumonia and microabscesses is present in lungs of untreated patients. Degenerating microfilariae may be present within the center of the microabscesses, and some destruction of alveolar walls may be evident. Local bronchial walls are also edematous and inflamed, with evidence of epithelial disruption. Longstanding untreated disease is associated with the presence of chronic mixed-cell inflammation in a nodular pattern and the development of pulmonary fibrosis. Foreign bodyâ&#x20AC;&#x201C;type granulomatous lesions are often present. Lymph node biopsies may reveal degenerating microfilariae or adult worms, surrounded by aggregates of eosinophils, their granule products, and giant cells. The clinical features of TPE are believed to result from an intense hypersensitivity reaction to microfilarial antigens of Wuchereria bancrofti and Brugia malayi. Although a broad spectrum of clinical disease may be caused by filaria, patients with TPE rarely have other systemic features of filariasis. Canine filarial forms (e.g., Dirofilaria immitis) are rarely transmitted to humans but also may be recovered from lung and lymph node specimens. Disease occurs when larvae introduced into the body via insect bites develop into mature filariae. The adult worms, dwelling within the lymphatics, produce microfilariae, which are then trapped in the pulmonary vasculature. The release of antigens from degenerating microfilariae leads to an intense local and systemic inflammatory response. A striking antibody and eosinophilic response, similar to that seen in peripheral blood, is present within the lung. Increased numbers of total cells and eosinophils (up to 50 percent of differential), elevated levels of total IgE, and filarial-specific IgG, IgM, and IgE are present in fluid obtained by BAL. Although little is known about the precise mechanisms by which filariae are cleared in patients with TPE, both antibody-dependent mechanisms and eosinophils probably play a role. In vitro, both granulocytes and macrophages can bind microfilariae in the presence of IgG, IgE, or complement, leading to the death of the organism. The finding of an

The Eosinophilic Pneumonias

intense lymphocytic- and plasma-cell infiltrate around microfilariae in tissues suggests that lymphocytes may be important for clearance of the organism. In vitro lymphocyte transformation in response to stimulation with microfilarial antigens can be demonstrated in some cases. The precise mechanisms by which eosinophils accumulate in the lung and contribute to tissue inflammation in patients with TPE are incompletely understood. Elevated levels of eosinophilderived neurotoxin, an RNase capable of damaging the lung epithelium, have been observed in the BAL fluid of patients with TPE. IgE and eosinophil-, mast cell-, or basophil-derived products may contribute to the wheezing and airway hyperresponsiveness that can occur in this disorder. The diagnosis of TPE is usually established on the basis of the clinical and laboratory findings described above. Lung or other tissue biopsies are not typically required. Biopsy of enlarged lymph nodes (e.g., scalene) may assist in establishing the diagnosis in some cases. A rapid treatment response may provide confirmatory evidence that the correct diagnosis has been made. The differential diagnosis includes Loefflerâ&#x20AC;&#x2122;s syndrome, chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis, drug reactions, other parasitic infections, hypereosinophilic syndrome, and lymphangitic spread of carcinoma. In nonendemic areas, the disease may also masquerade as asthma, atypical pneumonia, sarcoidosis, Churg-Strauss syndrome, Wegenerâ&#x20AC;&#x2122;s granulomatosis (WG), or tuberculosis (TB). Diagnosis in nonendemic regions is often delayed, and a careful review of travel history and a high index of suspicion are necessary to prompt the diagnosis. Diethylcarbamazine, a piperazine derivative used widely in the treatment of filarial infections, is the therapy of choice for TPE, typically at a dose of 2 mg/kg three times daily for 14 to 21 days. Diethylcarbamazine acts by both direct and indirect mechanisms. It is directly filaricidal to both adult worms and microfilariae. It can also enhance the binding of granulocytes, macrophages, antibodies, and complement to the surface of microfilariae. A marked clinical improvement and decrease in eosinophil count usually occurs in the first 7 to 10 days of therapy. Clinical improvement following diethylcarbamazine treatment has been correlated temporally with the resolution of eosinophilic alveolitis. In addition, improvement in pulmonary function, reduction in BAL eosinophilia, a decrease in total and filarial-specific IgE and IgG, and radiographic clearing generally occur within 1 to 3 weeks of treatment. The course and prognosis of the acute disease in patients treated with diethylcarbamazine are generally benign, and 3 weeks of diethylcarbamazine therapy is curative in most patients. However, acute relapses do occur in up to 20 percent of patients. Patients who experience acute relapses often respond to additional treatment with diethylcarbamazine at higher doses of 2 to 4 mg/kg three times a day for 21 to 30 days. Alternatively, mild, chronic inflammation may persist, causing chronic interstitial lung disease, with persistent respiratory symptoms, radiographic findings, and hematological and serologic abnormalities. Persistent clinical symptoms have been reported over 2- to 5-year follow-up periods in

1220 Part VII

Interstitial and Inflammatory Lung Diseases

up to 13 percent of patients with TPE treated with a standard course of therapy. BAL in these patients reveals a mild, persistent eosinophilia. Persons with symptoms of longer duration are less likely to have a favorable treatment response. Alternative antifilarial drugs (e.g., ivermectin) or a trial of corticosteroids may be useful therapies for the chronic variant of the disease, although controlled studies of these agents are lacking. A subset of patients with apparent TPE may fail to respond to diethylcarbamazine; whether these patients have diethylcarbamazine-resistant TPE or disease due to other parasites is unclear, as current serologic testing does not distinguish between human lymphatic filarial antigens and antigens on certain other parasites. Untreated disease usually persists for weeks to months. Untreated TPE may remit spontaneously, but it commonly recurs within months to years. Although seldom fatal, untreated TPE often leads to the development of chronic interstitial lung disease.

CHRONIC EOSINOPHILIC PNEUMONIA Chronic eosinophilic pneumonia (CEP) was first described as a clinical entity by Carrington and coworkers in 1969. Although CEP may develop in people of any age, the peak incidence occurs in persons 30 to 40 years of age. Women are affected approximately twice as often as men, and CEP has been reported during pregnancy. The female predominance is less obvious among patients whose disease begins after the age of 60. Most cases occur in Caucasians. Approximately one-third to one-half of patients have antecedent atopy, allergic rhinitis, or nasal polyps. In addition, up to two-thirds have adult-onset asthma preceding (by several months to years) or arising concurrently with the occurrence of CEP. Although prior data questioned an association with cigarette smoking, more recent analysis suggests that CEP is not associated with smoking; in fact, the prevalence of smoking among patients with CEP is generally quite low. In contrast to idiopathic AEP, CEP typically has a subacute presentation, with symptoms present for several months before diagnosis. Common presenting complaints include low-grade fevers, drenching night sweats, and moderate (10to 50-pound) weight loss. Cough, often dry initially and later productive of small amounts of mucoid sputum, is a virtually universal finding. Two of the nine patients described in Carrington’s original series had minor hemoptysis. Patients ultimately develop progressive dyspnea, which may be associated with wheezing in those with adult-onset asthma. Infrequently, some patients with CEP may also have severe acute respiratory failure or ARDS, with severe hypoxemia requiring mechanical ventilation. There are no major extrapulmonary manifestations of CEP. Rarely, arthralgias, skin rash, pericarditis or unexplained heart failure have been described, raising questions as to whether there is a continuum between CEP and Churg-Strauss syndrome.

Patients with CEP frequently manifest a moderate leukocytosis. The majority (66 to 95 percent) have peripheral blood eosinophilia, with eosinophils constituting more than 6 percent of their leukocyte differential. Leukocyte differentials with up to 90 percent eosinophils have been noted in this disorder. However, a lack of peripheral blood eosinophilia does not rule out the diagnosis, since eosinophilia was absent in one-third of the cases originally described. A moderate normochromic, normocytic anemia and thrombocytosis may be present. The ESR is typically elevated (greater than 20 mm per hour), and IgE levels are elevated in up to one-half of cases. Analysis of BAL fluid reveals increased eosinophils, typically accounting for 40 percent or more of the white blood cell (WBC) differential, with a range from 12 to 95 percent reported. Blood and sputum cultures routinely fail to identify an infectious etiology in these patients. The severity of pulmonary function abnormalities depends on the stage and severity of the disease. In the initial stage prior to treatment with corticosteroids, testing may reveal restrictive, obstructive, or normal physiology. Obstructive ventilatory defects, while more common in patients with a history of asthma, are also encountered in patients without preexisting asthma. Restrictive physiology may result from changes in lung compliance due to acute eosinophilic infiltration of lung parenchyma. Diffusing capacity may be reduced and the alveolar-arterial oxygen gradient may be mildly elevated. In the original series, Carrington and colleagues described three radiographic features that are characteristic for CEP: (1) peripherally based, progressive dense infiltrates; (2) rapid resolution of infiltrates following corticosteroid treatment, with recurrences in identical locations; and (3) the appearance of infiltrates as the “photographic negative of pulmonary edema.” In contrast to Loeffler’s syndrome, the pulmonary infiltrates associated with CEP are typically nonmigratory and affect the outer two-thirds of the lung fields (Fig. 72-3). Infiltrates are most commonly bilateral, are located in the mid- to upper lung zones, and may mimic loculated pleural fluid. The areas of consolidation are patchy and dense and can have ill-defined margins. They are frequently nonsegmental, subsegmental, or lobar in distribution and apposed to the pleura. The characteristic “photographic negative of pulmonary edema” appearance (which occurs in less than 50 percent of cases) results if extensive infiltrates surround major portions of or the entire lung. Pleural effusions are not usually seen. Occasionally, the chest radiograph can be normal. Common CT scan findings include ground-glass opacities without clear consolidation, as described in approximately half the cases of CEP in one series. In addition, apparent unilateral or isolated lower lung zone involvement noted on chest radiography may prove to be bilateral and diffuse on CT scanning. Mediastinal adenopathy, which may be evident on conventional chest radiograph, may also be identified on CT scan. Less typical radiographic findings include nodular infiltrates, linear oblique or vertical densities, and areas of fibrosis unassociated with anatomic divisions. Findings on CT

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Figure 72-3 Radiographic appearance of chronic eosinophilic pneumonia (CEP). Variable computed tomography appearance of infiltrates in two patients with chronic eosinophilic pneumonia. Peripheral upper-lobe predominant infiltrates may have a ground-glass appearance (A) or may appear as regions of dense consolidation or nodular opacity (B).

scan may vary depending on the timing of the CT relative to the onset of symptoms. Typical areas of dense, peripherally located airspace consolidation are found in most cases within the first several weeks of disease onset. Streaky bandlike opacities may appear when symptoms have been present for more than 2 months. The pulmonary lesions of CEP are characterized histopathologically by varying degrees of leukocytic infiltration of the alveolar airspaces and interstitium. These infiltrates are predominantly eosinophilic, with some associated macrophages, a small to moderate number of lymphocytes, and occasional plasma cells. They disrupt alveolar wall architecture, usually without causing wall necrosis. Focal edema of the capillary endothelium, focal type II epithelial cell hyperplasia, proteinaceous alveolar exudates, and multinucleated histiocytes within alveolar spaces can also be appreciated. Histological evidence of proliferative bronchiolitis obliterans may occur in up to one-third of cases, and a mild, nonnecrotizing microangiitis affecting predominantly

The Eosinophilic Pneumonias

the small venules may be seen. A small percentage of lesions (less than 20 percent) may have frank intra-alveolar necrosis, eosinophilic microabscesses, or noncaseating granulomas. Biopsy specimens of lymph nodes from patients with intrathoracic lymphadenopathy reveal lymphoid hyperplasia and eosinophil infiltration. The cause of CEP is unknown. No specific genetic predisposition for the disease has been identified, although CEP has been reported in identical twins, raising the question of a familial tendency toward the disease. Although the precise immunopathogenesis of CEP is unknown, a variety of lines of evidence suggest that eosinophils play a primary pathogenetic role in the pulmonary tissue damage seen in this disorder. Increased numbers of eosinophils appear in the peripheral blood and bone marrow before the onset of clinical disease, and an eosinophilia is the predominant abnormality in BAL fluid. These eosinophils appear to be activated, since eosinophil-derived granule proteins (EDGP) have been identified microscopically within the pulmonary parenchyma and microvasculature, increased concentrations of EDGP are identified in BAL fluid from patients with CEP compared to controls, and BAL-derived eosinophils express activation markers including class II major histocompatibility (MHC) antigens. The processes that regulate eosinophil activation and degranulation in CEP are not clear. Evidence showing that class II MHC and other activation markers are expressed by BAL- but not blood-derived eosinophils suggests the presence of an immune inflammatory response compartmentalized within the lung. Data also suggest that eosinophils from the BAL fluid are more resistant to apoptosis than peripheral blood eosinophils in subjects with CEP. Of interest are the findings that immunoglobulins can augment eosinophil chemotaxis and degranulation in vitro, and that circulating immune complexes and elevated titers of IgE are noted in the context of clinical flares of the disease. To date, however, no clear causal relationship has been established between immunoglobulins and eosinophil activation in CEP. The diagnosis of CEP is based on clinical, radiographic, and BAL findings, and on the inability to document pulmonary or systemic infection. The clinical signs and symptoms of CEP are nonspecific, however, and blood eosinophilia and typical radiographic features may be absent in some cases. In most reported series, open lung biopsy has been required only rarely to establish the diagnosis. Transbronchial biopsy, usually performed to rule out other diagnostic entities, may reveal eosinophil and mononuclear cell infiltrates. Because of the rapid and dramatic responsiveness of CEP to steroid treatment, a therapeutic trial of steroids is often useful in establishing the diagnosis. Failure to document rapid clinical improvement should alert the clinician to consider other diagnoses. The differential diagnosis of CEP includes infection (especially TB and fungal diseases like cryptococcosis), sarcoidosis, Loefflerâ&#x20AC;&#x2122;s syndrome, desquamative interstitial pneumonitis, bronchiolitis obliterans-organizing pneumonia, chronic hypersensitivity pneumonitis, and eosinophilic granuloma.

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Interstitial and Inflammatory Lung Diseases

Corticosteroids are the mainstay of therapy for CEP. Dramatic clinical, radiographic, and physiological improvements have been documented following steroid treatment in all series reported. Even patients presenting with severe respiratory failure may respond well to steroid treatment. In most cases, treatment with steroids leads to defervescence within 6 hours, reduced dyspnea, cough, and blood eosinophilia within 24 to 48 hours, resolution of hypoxia in 2 to 3 days, radiographic improvement within 1 to 2 weeks, complete resolution of symptoms within 2 to 3 weeks, and normalization of the chest radiograph within 2 months. No comparative studies exist to determine optimum treatment doses or duration of steroids, but one recommended regimen is prednisone (40 to 60 mg a day) continued until 2 weeks after resolution of symptoms and radiographic abnormalities. The dose of prednisone can then be tapered slowly. Treatment is usually maintained for at least 3 months and optimally for 6 to 9 months. The prognosis of CEP is generally favorable. Spontaneous remissions seldom occur in untreated patients. In steroid-treated patients, morbidity and mortality directly related to CEP are low. Patients may require 1 to 3 years of initial steroid treatment to control the disease, and up to 25 percent may require long-term maintenance treatment (2.5 to 10 mg prednisone a day) to remain disease-free. The lowest possible dose of steroid that suppresses disease activity should be used. Some patients may respond to inhaled corticosteroids, allowing discontinuation of oral steroids, although inhaled steroids alone as initial therapy are inadequate. Clinical, hematological, or radiographic evidence of relapse occurs in approximately one-third to one-half of patients when steroids are tapered or discontinued. Relapses may involve radiographic infiltrates in the same or different anatomic distribution compared to the original disease. Relapsing CEP must be distinguished from the development of new or worsening asthma. No obvious factors exist to identify persons who are likely to relapse or require long-term steroids, although relapses are more common in persons treated initially with a short course (less than 6 months) of steroids. Relapses may be less common in patients with asthma at the time of CEP, likely related to increased long-term inhaled steroid use in this population. Multiple recurrences may occur in anyone. The reinstitution of steroids generally leads to improvement, and relapses do not appear to indicate a worse prognosis, increased likelihood of treatment failure, or increased morbidity.

ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (MYCOSIS) Allergic bronchopulmonary aspergillosis is a disorder caused by a complex hypersensitivity response to inhaled fungal antigens. Since the disease is most commonly induced by Aspergillus species, it is usually known as allergic bron-

Table 72-4 Diagnostic Criteria for Allergic Bronchopulmonary Aspergillosis Major Asthma Positive immediate hypersensitivity skin-prick test to Aspergillus Precipitating antibodies against Aspergillus Elevated total IgE Elevated serum Aspergillus–specific IgE, IgG History of pulmonary infiltrates Peripheral blood eosinophilia +/− Proximal bronchiectasis Minor Mucous plugs containing Aspergillus Dual cutaneous reaction to Aspergillus

chopulmonary aspergillosis (ABPA). When induced by nonAspergillus species, the syndrome is called allergic bronchopulmonary mycosis. A comprehensive discussion of ABPA is provided in Chapter 49. ABPA complicates approximately 7 to 14 percent of cases of chronic steroid-dependent asthma and occurs in up to 15 percent of patients with cystic fibrosis. Rare cases lacking a history of asthma but meeting the other major diagnostic criteria (summarized in Table 72-4) have been reported. The diagnosis of ABPA is based on appropriate clinical features in combination with supporting serologic and radiologic findings. Greenberger and Patterson have proposed five minimal essential criteria needed to establish the diagnosis, including: (1) asthma, (2) positive immediate hypersensitivity skin test to Aspergillus, (3) serum precipitins to Aspergillus fumigatus (AF) or other relevant fungus, (4) total IgE greater than 1000 ng/ml, and (5) elevated serum antiAF IgE and IgG. A history of current or previous pulmonary infiltrates and peripheral blood eosinophils (approximately 10,000 cells/ml), expectoration of brown mucous plugs, identification of Aspergillus (or other relevant fungus) in the sputum, and dual (immediate and delayed) cutaneous reactions to challenge with Aspergillus are also common clinical features of ABPA. Five clinical stages of ABPA have been recognized: acute illness (stage 1); remission (stage II); exacerbation (stage III); steroid-dependent asthma (stage IV); and fibrotic lung disease (stage V). The clinical features of these stages are shown in Table 72-5. Typical radiographic manifestations of ABPA include transient, irregular pulmonary infiltrates with a predilection for the upper lobes (Fig. 72-4). Other common radiographic features include “finger-in-glove opacities,” “tramline shadows,” “toothpaste shadows,” “ring shadows,” and lobar consolidation (Fig. 72-4). These findings result from bronchial and bronchiolar wall inflammation, edema, and

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Table 72-5 Clinical Stages of Allergic Bronchopulmonary Aspergillosis Stage I: Acute Acute asthma symptoms Elevated serum IgE (typically > 1000 ng/ml) Infiltrate on chest radiograph Peripheral blood eosinophilia Positive precipitating antibodies to Aspergillus fumigatus Stage II: Remission Resolution of symptoms Radiographic clearing Reduction or stabilization of IgE levels Stage III: Exacerbation Recurrence of elevated IgE levels Development of a new pulmonary infiltrate on chest radiograph +/â&#x2C6;&#x2019; Escalation of asthma symptoms Stage IV: Steroid-dependent Asthma Difficult to control, steroid-dependent asthma Persistently elevated total IgE, Aspergillus precipitins and Aspergillus-specific IgE and IgG despite corticosteroid therapy Stage V: Fibrotic lung disease Persistent steroid-dependent asthma Fibrotic lung disease with gas exchange disturbances Chronic sputum production and frequent infections common

remodeling, and from mucoid impaction of the bronchi with or without parenchymal involvement. Central (proximal) bronchiectasis, another characteristic radiographic manifestation of ABPA, occurs in many, although not all, patients, particularly when the disease has been present over an extended period of time. Although lung biopsy is usually not required to establish the diagnosis, histopathological findings of ABPA include intense bronchocentric inflammation with eosinophils, lymphocytes, plasma cells, and monocytes, as well as mucoid impaction of bronchi. The features of ABPA are believed to result from a complex immunologic reaction to chronic airway colonization by Aspergillus (or other relevant fungal species) that includes features of type I, type III, and type IV immune responses. T-helper lymphocytes, neutrophils, eosinophils, and the fungus itself all also likely contribute to the pathogenesis of the disease. The diagnosis of ABPA should be entertained in any patient with difficult to control asthma and/or the combination of asthma and eosinophilia, as well as patients with

The Eosinophilic Pneumonias

cystic fibrosis with progressive worsening of symptoms. However, ABPA may go unrecognized, due to overlap of clinical features with allergic, mold-sensitive asthma as well as other pulmonary eosinophilic disorders such as Churg-Strauss syndrome. ABPA may also be challenging to recognize due to the varying clinical presentations at different stages of disease. Goals of treatment are to control symptoms, prevent exacerbations and preserve normal lung function. Systemic corticosteroids, with careful patient monitoring of clinical symptoms, IgE levels, and chest radiograph, are the mainstay of therapy. Corticosteroid doses that reduce IgE levels by at least half of acute stage levels and induce clearing of radiographic infiltrates must be used to control the disease; such doses are typically higher than those needed to control symptoms alone. Treatment with the antifungal agent itraconazole can also help control the symptoms and immunologic features of the disease. Bronchodilators and antibiotics help control bronchospasm and secondary respiratory infections.

CHURG-STRAUSS SYNDROME (ALLERGIC GRANULOMATOSIS AND ANGIITIS) In 1939, Rackemann and Greene reported a subgroup of patients with polyarteritis nodosa and concomitant allergic disease. Similar findings were reported in the early 1940s by Harkavy. The histopathology and clinical features associated with this disease entity were first described in 1951 by Churg and Strauss, who reported a form of necrotizing vasculitis in several organs, associated with eosinophilic tissue inflammation and extravascular granulomas, occurring in asthmatics, with associated fever and peripheral hypereosinophilia. This disease entity, now recognized as Churg-Strauss syndrome (CSS), is an uncommon systemic disease. A case frequency of 2.4 to 6.8 cases per million persons per year is estimated among the general population, and 64 cases per million persons per year is estimated among patients with a history of asthma. The mean annual incidence has been estimated at 1 to 2.4 per million population across various countries. Approximately 10 percent of all patients with vasculitis prove ultimately to have CSS. Nevertheless, the precise incidence of CSS is unknown due to uncertainties regarding diagnosis and variable clinical presentation. The true incidence of CSS may be higher than is generally recognized, since the syndrome has many clinical, radiographic, and histological features in common with other vasculitic, eosinophilic, and granulomatous disease states. The diagnosis of CSS may be missed if not carefully entertained. CSS may occur in patients of any age, but it develops most commonly in patients between the ages of 38 to 50. There is no clear gender predominance. Among women, disease onset has been reported during pregnancy. CSS tends to follow a subacute course, with symptoms ranging over months to years. Three distinct clinical phases

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Interstitial and Inflammatory Lung Diseases

Figure 72-4 Radiographic appearance of allergic bronchopulmonary aspergillosis (ABPA). Extensive infiltrates with tubular configuration and ‘‘gloved finger” appearance are present, in this case predominantly in the lower lobes (A). The bronchogram (B) and computed tomography (CT) of the chest (C) reveal extensive proximal bronchiectasis. Extensive mucoid impaction of the bronchi is evident on CT scan (C). Central bronchiectasis and tram-track shadows in a patient with ABPA may also be present without mucoid impaction (D).

of the disease have been recognized: the prodromal phase, the eosinophilic phase, and the vasculitic phase. The prodromal phase is characterized by “late-onset” (in the second or third decade) allergic rhinitis and atopy in persons often lacking a family history of atopy. Severe allergic rhinitis, sinusitis, drug sensitivity, and asthma are usually present for 8 to 10 years, and up to 30 years before CSS disease recognition. The eosinophilic phase is typified by the development of marked peripheral blood eosinophilia and eosinophilic tissue infiltration, most commonly of the lung, GI tract, and skin. The vasculitic phase is characterized by vasculitis of the small and medium vessels with vascular and extravascular granulomas. The onset of the vasculitic phase is often heralded by development of constitutional symptoms, including fever, malaise, weight loss, and increased allergic or asthmatic symptoms. Although the vasculitis tends to occur several years after the onset of allergic manifestations of the disease, in some cases it develops within months of, or concomitant with, the onset of asthma. A short duration between the onset of asthma

and vasculitis is associated with increased severity of vasculitis. During the vasculitic stage, the asthma symptoms may persist and worsen, or they may diminish. When asthma dissipates, it often flares later in the course of illness and may require prolonged steroid treatment. Although CSS typically affects multiple-organ systems, limited forms of disease have also been described. Manifestations in the lungs, heart, skin, and nervous system are most common. Most of the respiratory manifestations of CSS occur in the prodromal and eosinophilic phases of the disease. Nearly all patients have asthma at some point in the illness. Upperairway allergic disease, including sinusitis, rhinitis, and polyposis, is seen in 75 to 85 percent of patients and may be the presenting symptom. Unlike WG, necrotizing granulomas involving the upper airway are unusual in CSS. The asthma and upper-airway disease usually are long-standing and often require steroid therapy (systemic or inhaled) to maintain control of symptoms. Spirometry may reveal an obstructive ventilatory defect. In rare instances, recurrent respiratory

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infection leads to bronchiectasis. A Loefflerâ&#x20AC;&#x2122;s-like syndrome with eosinophilic infiltration of the lung parenchyma is seen in 38 to 40 percent of patients. These patients may develop dyspnea, cough, and wheezing. Their chest radiographs have transient, migratory nonlobar, nonsegmental, often peripheral pulmonary infiltrates, with no regional predilection. Nodular lesions, interstitial lung disease, and hilar adenopathy are less common findings. In contrast to WG the CSS nodules rarely cavitate. Up to 30 percent of patients develop unilateral or bilateral pleural effusions, which may be associated with pleuritic chest pain. The chest radiograph may occasionally be normal. High-resolution CT scanning has demonstrated patchy peribronchial thickening, pulmonary artery enlargement (in comparison to the corresponding bronchi), irregular stellate configuration of some vessels, areas of septal thickening, and scattered patchy parenchymal opacities with ground-glass or consolidated appearance. These findings have been reported to correlate with pathological findings evident on open lung biopsy such as eosinophilic pneumonia, alveolar hemorrhage, eosinophilic infiltration of the bronchial wall, and septum. Further studies are necessary to determine whether high-resolution CT is useful to stage the disease or establish the diagnosis without tissue biopsy. Cardiac manifestations generally are not present on initial presentation of CSS. However, they typically occur during the vasculitic phase of the disease and are a major source of morbidity and the principal cause of death (in up to 50 percent of cases) from the disorder. Progressive congestive heart failure (CHF) occurs in 47 percent of cases because of myocardial infiltration by eosinophils or ischemic cardiomyopathy resulting from necrotizing vasculitis of the coronary arteries. This coronary vasculitis is fatal up to 60 percent of the time. Acute pericarditis is present in approximately one-third of cases, and cardiac tamponade has been reported. Constrictive pericarditis may develop over time. A wide array of neurological manifestations may develop in CSS. Mono- or polyneuropathy (most notably mononeuritis multiplex) is present in 69 to 75 percent of cases. CNS manifestations occur in approximately two-thirds of patients and include cranial nerve impairment (especially optic neuritis), seizure, subarachnoid hemorrhage, and cerebral infarction. Cerebral hemorrhage and infarction are common causes of patient death. Skin, GI, renal, and other systemic alterations have been well described in CSS. Skin findings are present in approximately two-thirds of cases and may develop in localized crops. They can manifest as nonthrombocytopenic purpura, tender cutaneous or subcutaneous nodules (which may ulcerate), urticaria, a maculopapular rash, petechiae, ecchymoses, or livedo reticularis. GI manifestations of CSS are present in up to 60 percent of cases. They can include eosinophilic gastroenteritis or vasculitis that can lead to diarrhea, abdominal pain, intestinal obstruction, cholecystitis, pancreatitis, bleeding, liver function test abnormalities, and bowel perforation. GI disease is the fourth leading cause of death in patients with CSS (after cardiac, CNS, and renal impairment). Re-

The Eosinophilic Pneumonias

nal insufficiency occurs in up to 50 percent of patients with CSS. Interstitial nephritis, focal segmental glomerulonephritis (often with necrotizing features), hematuria, and albuminuria are common. Severe, difficult-to-control hypertension is also a major sequela of CSS (in 25 to 75 percent of cases) and may be due to recurrent renal infarction. In contrast to WG, overt renal failure is not commonly seen in CSS. Mild lymphadenopathy (in 30 to 40 percent), rheumatological manifestations (migratory polyarthralgias, myalgias, temporal arteritis), urological disease (ureteral, urethral, prostatic), and ocular manifestations have also been described. Although there are no laboratory tests specific for a diagnosis of CSS, a majority of patients with CSS have a striking but fluctuating degree of peripheral blood eosinophilia (20 to 90 percent of the WBC differential), generally greater than that seen with asthma alone. The degree of eosinophilia may be suppressed by corticosteroid treatment of asthma. Serum total IgE levels are typically elevated (range, 500 to 1000 U/ml) and may parallel disease activity. Most patients have a normochromic, normocytic anemia and moderate elevation of their ESR. Some 70 to 75 percent of patients have positive antinuclear cytoplasmic antibody with a perinuclear staining pattern (pANCA). The majority of these are directed against myeloperoxidase (MPO-ANCA) and a minority against proteinase 3 (PR3-ANCA). As many as 50 percent of patients have low titers of rheumatoid factor; hypergammaglobulinemia and circulating immune complexes may also be seen. Laboratory examination of pleural fluid, if present, reveals an acidotic eosinophilic exudate with low glucose levels. Pleural biopsy shows chronic pleuritis with eosinophilic infiltration. BAL reveals an increased percentage of eosinophils, the magnitude of which is generally less than that seen with CEP or idiopathic hypereosinophilic syndrome. However, patients have been described whose BAL fluid leukocyte differential contained 81 percent eosinophils. 18 FDG/13 N ammonia positron emission tomography (PET) imaging may be useful to identify cardiac involvement in CSS. The histopathological hallmarks of CSS vary depending on the stage of illness but include tissue (interstitial, blood vessel, and alveolar) infiltration by eosinophils; necrotizing vasculitis of small arteries, arterioles, and, to a lesser extent, small veins, venules, and capillaries and extravascular and interstitial eosinophilic granulomas (typically microscopic). Both pulmonary and systemic vessels may be affected. The precise histopathology of vascular impairment depends on the stage of the lesion. Early lesions demonstrate eosinophilic infiltration of the vessels and perivascular region (Fig. 72-5). Later lesions are characterized by necrotizing arteritis or vessel obliteration and scarring. The extent of vascular impairment varies from mild, eosinophilic perivascular cuffing to severe transmural inflammation with necrotization. Lesions may be sparse or widespread. Eosinophilic lymphadenopathy may also be present. The pathogenesis of CSS remains poorly understood. The strong association with allergy, atopy, and elevated levels of IgE (especially during the vasculitic phase of the disease) has raised the question of immune hypersensitivity. As

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Interstitial and Inflammatory Lung Diseases

Figure 72-5 Pathological appearance of small arteriole in Churg-Strauss vasculitis. Intense perivascular inflammation with eosinophilia is present.

a result, it has been proposed that repeated antigenic stimulation in patients with a heightened T-cell and eosinophil response may be important in the development of the disorder. Heightened humoral immunity with immune complex disease may also play a role. The pathogenic role of antineutrophil cytoplasmic antibody (ANCA) remains uncertain. ANCA may contribute to tissue inflammation and injury by activation of inflammatory cells and generation of oxidative stress. Eosinophils likely also contribute significantly to the tissue injury. No genetic predisposition or HLA association with the disease has been identified. The relationship between the pathophysiology of asthma in CSS to that of asthma without CSS also remains uncertain. A strong association has been noted between the use of leukotriene receptor antagonists (LTRA) and 5-lipoxygenase inhibitors and the development of CSS. The appearance of CSS following reduction in systemic corticosteroid dosing in many of these reports raises the possibility that preexisting, underlying CSS that was being treated with corticosteroids is unmasked by the administration of these agents and the reduction in corticosteroid dose. However, it remains uncertain whether these agents may be causally related to the onset of CSS. Patients with steroid-dependent asthma, in whom the diagnosis of CSS has not been demonstrated or entertained, should be monitored closely for evidence of CSS when steroid doses are tapered. In 1990, the American College of Rheumatology published diagnostic criteria for CSS, based on assessments of the sensitivity and specificity of the diagnostic criteria used previously. The presence of at least four out of six of the following criteria yielded 85 percent sensitivity and 99.7 percent specificity in establishing the diagnosis: (1) asthma, (2) peripheral eosinophilia greater than 10 percent, (3) mono- or polyarthropathy, (4) migratory or transient pulmonary infiltrates, (5) paranasal sinus abnormality, and (6) extravascular eosinophils in a blood vessel on a biopsy specimen. The presence of asthma or allergy as well as more than 10 percent eosinophilia was 95 percent sensitive and 99 percent

specific in distinguishing CSS among a subgroup of patients with well-documented systemic vasculitis. Subsequently, the Chapel Hill Consensus Conference recommended that diagnostic criteria for CSS include (1) appropriate clinical setting and histopathology and (2) eosinophil-rich and granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small and medium vessels with associated asthma and eosinophilia. However, these criteria require tissue biopsy and are less sensitive for CSS than others that have been proposed, hence they may be less useful to assist diagnosis in the routine clinical setting. Open lung biopsy is the gold-standard site for tissue biopsy. Transbronchial biopsy may reveal the diagnosis if there is alveolar involvement, but is often nondiagnostic. Biopsy of other sites (e.g., skin, pericardium, muscle, nerve, gut), with or without immunostaining, may assist in establishing the diagnosis in selected cases, although demonstration of characteristic histopathological changes are not essential for establishing the diagnosis. The differential diagnosis of CSS includes polyarteritis nodosa, microscopic angiitis, WG, CEP, ABPA, idiopathic hypereosinophilic syndrome, Loeffler’s syndrome, asthma, fungal or parasitic infection, drug-induced vasculitis, sarcoidosis, and Hodgkin’s lymphoma. CSS can be distinguished from WG since compared with WG, patients with CSS have nasal polyps and allergic rhinitis but lack significant necrotizing upper-airway lesions and cavitation of lung nodules, and are more likely to have pANCA (in contrast to the c-ANCA seen in WG). Also, patients with CSS are less likely to develop renal failure, and vasculitic neuropathy and asthma/eosinophilia are not typical features of WG. CSS can be distinguished from MPO-ANCA–positive microscopic angiitis since patients with the latter syndrome have leukocytoclastic vasculitis without granulomas and do not have upper-airway involvement, asthma, and eosinophilia. Further, unlike CSS, cardiac involvement is rare in MPO-ANCA–positive vasculitis. Patients in whom CSS goes untreated have a poor prognosis; up to 50 percent die within 3 months after the onset of vasculitis. As such, efforts at early recognition and treatment are important. No large randomized, controlled trials exist comparing various treatment methods, largely because of the rarity of the disorder. Thus, it is difficult to define the optimal treatment for the disease. Nevertheless, it is clear that corticosteroid treatment generally leads to dramatic clinical improvement, with disease stabilization or cure. Prednisone, 0.5 to 1.5 mg/kg/day (or 60 mg/day in adults) is given for 6 to 12 weeks, aiming to eliminate constitutional symptoms and cardiac, renal, neurological, or other vasculitic manifestations. Higher doses are occasionally required. Severe hypertension and mononeuritis multiplex often require prolonged steroid treatment, and may be difficult to eliminate. Once the vasculitic phase is controlled, steroids may be tapered, with doses titrated to maintain disease control. Low-dose prednisone is often given every day or every other day for up to 1 year. Although relapses are uncommon, patients should be followed closely for evidence of clinical deterioration, and should have periodic screening of total WBC and differential,

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ESR, and IgE levels. Most reports suggest the pANCA is not useful to monitor disease activity or direct therapeutic intervention. Treatment with cytotoxic immunosuppressive agents such as azathioprine, cyclophosphamide, high-dose methylprednisolone, or chlorambucil may prove effective and should be considered in patients whose condition fails to improve with steroid treatment or who have severe systemic involvement or poor prognostic features, including cardiac or GI involvement, renal insufficiency or proteinuria greater than 1 g/day. Cyclophosphamide (2 mg/kg/day orally or 0.6 g/m2 intravenously per month) may be given concurrently with corticosteroids. Patients treated with cyclophosphamide should be monitored closely for hemorrhagic cystitis, renal insufficiency, bone marrow suppression, bladder fibrosis, and urological malignancies. Intravenous immunoglobulin may be beneficial for reducing symptoms and organ involvement and improving long-term disease control among persons with severe organ involvement. The immunoregulatory cytokine interferon-α (IFN-α) has led to improved pulmonary function tests, reduction in corticosteroid dose, and decreased WBC count and may be considered as another alternative treatment in persons with refractory disease. Plasma exchange may also be a successful adjunct treatment in some patients. Beta blockers should be avoided in the management of CSSrelated hypertension, owing to the risk of bronchospasm and congestive heart failure (CHF). Long-term overall remission can be achieved in approximately 81 to 92 percent of patients; relapses, if they occur, are most common within 1 year. In a series of 30 patients collected over the period 1950 to 1974, a median survival of more than 9 years was reported in patients treated with steroids; 1-year survival was 90 percent, 3-year survival was 76 percent, and 62 percent survival was noted at 5 years. A more recent study suggested 72 percent survival at 5 years. Patients with severe disease treated with corticosteroids and cyclophosphamide have better survival than those treated with corticosteroids alone.

IDIOPATHIC HYPEREOSINOPHILIC SYNDROME Idiopathic hypereosinophilic syndrome (IHS) is a rare disorder first described in 1968 by Hardy and Anderson. Over the ensuing years, many case reports of severe peripheral eosinophilia and diffuse organ infiltration with eosinophils were described. Several names—including eosinophilic leukemia, Loeffler’s fibroplastic endocarditis, and disseminated eosinophilic cardiovascular disease—were used to describe this disease entity. In 1975, Chusid and colleagues revised the definition of IHS to include only cases in which no other underlying cause of hypereosinophilia could be found. IHS is now recognized as a clinically heterogeneous syndrome with a wide range of disease severity. Whereas some patients experience a mild, limited form of the disease with minimal involvement

The Eosinophilic Pneumonias

of noncritical organs (e.g., skin), others have life-threatening multi-organ dysfunction. Emerging evidence suggests that IHS may indeed represent several diseases of distinct etiology that share several features in common. IHS predominantly affects males, although the gender association is less prominent in older patients. Although persons of any age may be affected, disease onset is most common between 20 and 50 years of age. There is no known racial or ethnic predisposition. Symptoms vary according to the organ system(s) affected. Presenting complaints are often nonspecific and include weakness, fatigue, low-grade fevers, myalgias, cough, angioedema, rash, retinal lesions, and dyspnea. Involvement of virtually every organ system has been described. The three principal clinical features defining IHS are: (1) persistent blood eosinophilia greater than 1500/µl for more than 6 months; (2) symptoms and signs of end-organ dysfunction; and (3) no other identifiable underlying cause of eosinophilia. The respiratory system is affected in an estimated 40 percent of patients with IHS. A majority of patients develop a predominantly nocturnal cough, which is either nonproductive or productive of small quantities of nonpurulent sputum. Wheezing and dyspnea are also common, without evidence of airflow obstruction on spirometric examination. Pulmonary hypertension, ARDS, and pleural effusions (which may be due to CHF) have been reported. In patients with pulmonary manifestations, the chest radiograph may reveal transient focal or diffuse pulmonary infiltrates (with no predilection for any particular distribution) and/or pleural effusion(s). Histopathological examination of affected lung specimens most commonly reveals intense interstitial infiltration with eosinophils. Less commonly, necrotic areas of parenchyma are found. These are believed to be due to pulmonary microemboli. In contrast to CSS, significant vasculitis is not present. Cardiac disease, which occurs in most patients with IHS, is the major cause of morbidity and mortality. The most common cardiac manifestations are relentlessly progressive CHF due to eosinophilic myocarditis and endocarditis, intracardiac thrombi, and endocardial fibrosis. Cardiac involvement in IHS, which may be clinically silent, is believed to progress from an initial acute necrosis stage, followed by endocardial thrombus formation and eventually development of fibrosis which may lead to restrictive cardiomyopathy or valvular dysfunction such as mitral regurgitation. Bacterial endocarditis has also been noted. The cardiac damage is believed to be mediated at least in part by eosinophil-derived granule proteins. Disturbingly, cardiac involvement correlates poorly with the peripheral blood eosinophilia, hence echocardiographic follow-up at 6-month intervals is recommended. Involvement of the central or peripheral nervous system, which occurs in up to 60 percent of patients, is also a major cause of morbidity. Neurological manifestations of IHS include encephalopathy with neuropsychiatric dysfunction, memory loss, gait disturbances with or without signs of upper motor neuron injury, visual changes, and sequelae

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of thromboembolic events, including hemiparesis. Peripheral neuropathy with sensory and/or motor axonal loss (no vasculitic or eosinophilic infiltration) is extremely common in IHS. The bone marrow is universally affected with a striking eosinophilia (up to 25 to 75 percent of the differential). Other hematological manifestations are venous and arterial thromboembolism, anemia, thrombocytopenia, elevated vitamin B12 levels, hepatosplenomegaly, and lymphadenopathy (in 12 to 20 percent). GI (20 to 30 percent of patients), cutaneous (25 to 56 percent), renal (10 to 20 percent), musculoskeletal, ocular, and endocrine manifestations are all also well described. Laboratory findings associated with IHS include an elevated total serum IgE (25 to 38 percent), hypergammaglobulinemia, circulating immune complexes (32 to 50 percent), and an ESR above 15 mm/h (68 percent). Elevated serum B12 and leukocyte alkaline phosphatase levels are also noted. Fungal and parasitic serologies, as well as aspirates of body fluids for ova and parasites, are negative. Of interest is that whereas blood and BAL eosinophilia are both prominent in persons with pulmonary involvement, blood eosinophilia is present and BAL eosinophilia is absent in persons lacking pulmonary manifestations of the disease. This finding has raised the question whether BAL eosinophilia may serve as a marker for the development of pulmonary disease associated with IHS. The organ damage in IHS is believed to be due both to eosinophilic infiltration of tissues and to tissue injury caused by thromboembolic events. Eosinophils probably contribute to tissue damage via antibody-mediated cytotoxicity and the release of toxic granule products such as major basic protein and eosinophil cationic protein. Elevated serum levels of eosinophil cationic protein and major basic protein have been reported, but they do not correlate universally with clinical disease severity. The precise events inciting the extreme eosinophilia in IHS are unknown, but several mechanisms have been proposed, including overproduction or abnormal activity of cytokines leading to eosinophilia, and defects in cytokine signaling or signal transduction. A variety of chromosomal abnormalities (including the Philadelphia chromosome) and immunologic abnormalities have been described in patients with IHS. Three major pathogenetic and clinical variants of IHS have been reported: (1) patients with clonal abnormalities in eosinophils; (2) patients with features of myeloproliferative disorder and chromosomal aberrations leading to abnormal constitutive production of tyrosine kinases; and (3) patients with dysregulation of T lymphocytes with overproduction of IL-5, a cytokine important for eosinophil growth, differentiation, and chemotaxis. The clinical presentation of IHS may vary, depending on the pathogenetic variant. Recognition of these variants also has potential implication for choice of therapy (noted below). The diagnosis of IHS is established by demonstrating multi-organ dysfunction, severe peripheral blood eosinophilia (greater than 1500/ﾂｵL) for at least 6 months (or with death before then), and an absence of any other known causes of peripheral blood eosinophilia. Occasionally, the disease presents with the incidental finding of blood eosinophilia before development of other complications. The total pe-

ripheral leukocyte count is typically elevated to above 10,000 (typical range, 10,000 to 30,000), with a preponderance of eosinophils (up to 70 percent). The leukocytosis may be progressive. Eosinophilic blast transformation was reported to occur at some time during the course of the disease in 28 percent of 51 patients in one series. The differential diagnosis of IHS includes parasitic infection, acute eosinophilic leukemia, CSS, episodic angioedema with eosinophilia, tuberculous or fungal infection, allergic or autoimmune disease, other acute or CEPs, TPE, and other lymphoproliferative disorders. Patients with eosinophilic leukemia have immature eosinophils or blasts in the bone marrow and/or blood, whereas patients with IHS typically do not. Patients with IHS do not have asthma or vasculitis characteristically associated with CSS, and patients with episodic angioedema typically lack the multi-organ involvement associated with IHS. Before the discovery of an effective therapy, the prognosis of IHS was poor. In one early series, 81 percent of 48 patients died within 1 year of diagnosis. Overall, without therapy, average survival was 9 months, and 3- to 4year survival was estimated at 10 to 12 percent. The greatest mortality occurs within the first year after diagnosis. Death may occur from refractory CHF, azotemia, hepatic failure, venous thromboembolism, a perforated abdominal viscus, or infection. The advent of effective therapy for IHS has led to a marked improvement in median survival to more than 10 years. Patients with the incidental finding of peripheral eosinophilia but without evidence of end-organ dysfunction can be followed closely at 3- to 6-month intervals without specific treatment, as they tend to follow a benign course. The mainstay of therapy for IHS with organ involvement includes corticosteroids such as prednisone at 1 mg/kg/day for several weeks, with taper of dose attempted to an every-other-day regimen once eosinophil levels are reduced. The mechanisms by which steroids are effective in this disorder are not fully clear. If the disease stabilizes or resolves, alternate-day corticosteroids should be continued for approximately 1 year at the minimal dose that effectively controls disease activity. Hydroxyurea (0.5 to 1.5 g per day) may be added to the regimen if there is evidence of further disease progression, with the aim of reducing the peripheral leukocyte count to the range of 5000 to 10,000. Vincristine may be used as a chemotherapeutic inducing agent in patients with extremely high peripheral WBC counts. Etoposide and chlorambucil are effective alternative agents for cases that prove refractory to standard treatment with corticosteroids. Cyclosporine may also be of benefit in controlling the disease, especially when used in combination with corticosteroids. IFN-ﾎｱ, a mediator that suppresses eosinophil function in vitro, has been beneficial in management of IHS, perhaps by inhibiting eosinophil proliferation and differentiation. IFN-ﾎｱ should be tried as a second-line agent among patients with IHS who fail to respond to corticosteroid treatment. Existing data suggest that another anti-eosinophil strategy, the anti窶的L-5 antibody, may reduce symptoms and eosinophilic organ involvement associated with IHS, and may be particularly helpful in patients with

1229 Chapter 72

The Eosinophilic Pneumonias

high IL-5 levels (e.g., persons with dysregulated T lymphocytes). Moreover, tyrosine kinase inhibitors such as imatinib mesylate (Gleevec) may also be beneficial for treatment of the myeloproliferative variant of IHS. Allogeneic bone marrow transplantation has also been reported anecdotally to be successful in selected severe cases of IHS in which endorgan damage is potentially reversible. Leukapheresis affords no clear benefit unless there is elevated blood viscosity with associated coagulation. Antiparasitic agents and radiation therapy are ineffective. Favorable prognostic features include a rapid clinical response to treatment with reduction in blood eosinophilia and the presence of angioedema, an elevated IgE, and absence of findings associated with myeloproliferative disorder. Factors associated with a poor prognosis include presence of total blood WBC greater than 100,000/mm3 , myeloblasts in the peripheral blood, refractory CHF, basophilia above 3 percent, identifiable chromosomal abnormalities in bone marrow cells, and elevated serum B12 levels. The mechanisms by which these features are associated with a given prognosis are largely unknown.

APPROACH TO THE EVALUATION OF EOSINOPHILIC PNEUMONIAS In approaching the patient with pulmonary infiltrates and eosinophilia, one must first establish whether the patient has one of the eosinophilic disorders described in this chapter or a disease process that is secondarily associated with eosinophilia (Table 72-1). A useful algorithmic approach to the evaluation of patients with pulmonary infiltrates and eosinophilia (blood or lung) is shown in Fig. 72-6. A careful search for the cause of the disease should be undertaken. A comprehensive medical history should be elicited, with particular attention paid to any antecedent illness (e.g., atopy, rhinitis, asthma, steroid use, immunosuppression), disease exposures, travel, and the duration and nature of the patientâ&#x20AC;&#x2122;s symptoms. One should take special notice of the sequence and timing of events during the course of the illness. In addition to a careful chest examination, a search should be undertaken for physical findings suggestive of extrapulmonary disease (e.g., skin lesions, CHF, hypertension, neurological abnormalities, musculoskeletal disorders, or GI illness). The nature, distribution, and duration of infiltrates on chest radiograph should be noted. CT scanning of the chest can also provide additional information that may not be apparent on the chest radiograph. The workup should include the following additional laboratory data: complete blood count (CBC) with differential, ESR, IgE level, ECG, blood urea nitrogen (BUN), creatinine, liver function tests, urinalysis, sputum cultures, and, when appropriate, sputum cytology. Serologies (e.g., Aspergillus precipitins, ANCA, antiparasitic antibodies) are indicated in selected cases. Bronchoscopy with BAL or transbronchial biopsy is important in the evaluation of pulmonary

Figure 72-6 Algorithmic approach to evaluation of patients with pulmonary infiltrate and eosinophilia. (Based on data from Allen JN, Davis WB: Eosinophilic lung diseases. Am J Respir Crit Care Med 150:1423â&#x20AC;&#x201C;1438, 1994.)

eosinophilic syndromes. The advent of BAL has allowed diagnosis of most cases of eosinophilic pneumonia without open lung biopsy. Normally, BAL fluid contains less than 2 percent eosinophils. In contrast to diseases associated secondarily with eosinophilia, all the primary pulmonary eosinophilic syndromes are characterized by striking BAL eosinophilia (more than 20 percent of the BAL leukocyte differential). The finding of more than 20 percent BAL eosinophils, viewed in combination with appropriate clinical and radiographic features, is strongly suggestive of the diagnosis of one of these syndromes. BAL and transbronchial biopsy are also useful in ruling out infections (bacterial, fungal, tuberculous, and parasitic), malignancies, and other causes of eosinophilassociated disease. It must be kept in mind that in the context of the overall list of pulmonary diseases associated with more than 5 percent BAL eosinophilia, the true pulmonary eosinophilic syndromes are rare. The pulmonary eosinophilic syndromes are at times difficult to distinguish from one another, owing to the substantial amount of overlap among their clinical, radiographic, and histological features, as well as variable features at different stages of disease. The comparative features of the eosinophilic pneumonias described in this chapter, with regard to several key features, are shown in Table 72-6. The clinical presentation may be acute, subacute, or chronic. Disease may range from mild and self-limited to severe and

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Table 72-6 Comparative Features of the Pulmonary Eosinophil Syndromes Loeffler’s

AEP

TPE

Clinical course

Acute

Acute, subacute, chronic

H/o allergic disease/asthma

—

+/−

—

Blood eosinophilia

Extreme, transient

Absent

Extreme

Sputum/BAL eosinophilia

Prominent

Striking

Prominent

Elevated serum IgE

+/−

Moderate elev. in some

Highly elev.

Etiologic agent

Ascaris spp. or other parasites, drugs

Unknown

Filarial infection

Radiographic findings (CXR, CT)

Patchy, often peripheral unilateral or bilateral consolidation and GGO; usually transient, migratory

Diffuse, alveolar and interstitial GGO and airspace opacities, interlobular septal thickening, pleural effusion

Diffuse, reticulonodular

PFTs

RVD

OVD early, RVD late, or mixed pattern

Characteristic diagnostic findings

Ascaris larvae in sputum, gastric aspirate

None

Filaria-specific IgE, IgG, microfilaria in LN/lung

Vasculitis

None

Extrapulmonary manifestations

GI late, if untreated

None

Cardiac, CNS rare

Therapy

Mebendazole, if parasitic; removal of drug or toxin exposure +/− steroids

Corticosteroids

Diethylcarbamazine

Chronic/recurrent disease

None

Infrequent

Note: + = yes or present; − = no or not present; elev. = elevated; GGO = ground-glass opacity; h/o = history of; LN = lymph node; mod. = moderately; OVD = CXR = chest x-ray (radiograph); GI = gastrointestinal

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Table 72-6 (Contintued ) CEP

ABPA

CSS

IHS

Subacute

Acute, subacute, chronic

Subacute, chronic

+ (30–60%)

Nearly 100%

100%

—

Mild–mod. in most

Typical

Extreme, fluctuating

Extreme, persistent

Striking

In some

Prominent

Striking

Mod.–elev. in 30%

Marked elev., fluctuates w/disease

Mod.–elev.

Mod.–elev. in some

Unknown

Aspergillus (or other fungus)

Unknown

Predominately, peripheral consolidation and GGO; “photographic negative of pulmonary edema”

Upper lobe predominant proximal bronchiectasis

Transient, migratory peripheral, rarely diffuse; patchy peribronchial and septal thickening, patchy parenchymal GGO or consolidation

Transient, focal or diffuse

Normal, OVD, or RVD

OVD +/− RVD

Mild RVD in some

None

See Table 72-4

Histopathology plus appropriate clinical setting

Extreme persistent eosinophilia and multi-organ dysfunction (no other evident cause)

Occasionally mild, non-necrotic

None

Characteristic (see text)

None

Very rare reported

None

Typical of vasculitic phase

Cardiac, neurological, GI, hematological, other

Corticosteroids

Corticosteroids, bronchodilators, antibiotics, antifungals

Corticosteroids, other immunosuppressives (see text)

Common

Typical

Infrequent after Rx

Chronicity typical

obstructive ventilatory defect; PFTs = pulmonary function tests; RVD = restrictive ventilatory defect; BAL = bronchoalveolar lavage; CT = computed tomograph;

1232 Part VII

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life-threatening illness. To varying degrees in all the pulmonary eosinophilic syndromes, dyspnea, malaise, low-grade fever, cough, and wheezing are common presenting complaints. Of the diseases considered in detail in this chapter, only CSS and IHS are consistently associated with significant extrapulmonary manifestations. Radiographic infiltrates may be transient in Loeffler’s syndrome, TPE, CSS, ABPA, and IHS. Blood eosinophilia is present in all the diseases discussed except idiopathic AEP and in a minority of cases of CEP. Variable degrees of elevation of serum IgE are also present. Pulmonary function abnormalities are not specific for these disorders. Except for the diseases caused by parasites, corticosteroids are the mainstay of therapy. Although the eosinophilic pneumonias can, at times, pose diagnostic difficulties, it is crucial to establish an accurate diagnosis whenever possible. An accurate diagnosis is important because the dose and duration of steroid treatment, prognosis, and follow-up measures for each of these diseases vary widely, and initiation of other specific therapeutic interventions improves outcomes in selected situations. Furthermore, chronic fibrotic lung disease may result from failure to accurately diagnose and treat some of these disorders in a timely fashion, and misdiagnosis with resultant inappropriate therapy (e.g., high-dose steroid treatment of invasive fungal infection masquerading as CEP) may be catastrophic.

SUGGESTED READING Allen JN, Davis WB: Eosinophilic lung diseases. Am J Respir Crit Care Med 150:1423–1438, 1994. Allen JN: Drug-induced eosinophilic lung disease. Clin Chest Med 25:77–88, 2004. Butterfield JH, Gleich GJ: Interferon-alpha treatment of six patients with the idiopathic hypereosinophilic syndrome. Ann Intern Med 121:648–653, 1994. Carrington CB, Addington WW, Goff AM, et al: Chronic eosinophilic pneumonia. N Engl J Med 280:787–798, 1969. Chang HW, Leong KH, Koh DR, et al: Clonality of isolated eosinophils in the hypereosinophilic syndrome. Blood 93:1651–1657, 1999. Chusid MJ, Dale DC, West BC, et al: The hypereosinophilic syndrome: Analysis of fourteen cases with review of the literature. Medicine (Baltimore) 54:1–27, 1975. Cottin V, Cordier JF: Eosinophilic pneumonias. Allergy 60:841–857, 2005. Danieli MG, Cappelli M, Malcangi G, et al: Long term effectiveness of intravenous immunoglobulin in Churg-Strauss syndrome. Ann Rheum Dis 63:1649–1654, 2004. Durieu J, Wallaert B, Tonnel AB: Long-term follow-up of pulmonary function in chronic eosinophilic pneumonia. Groupe d’Etude en Pathologie Interstitielle de la Societe de Pathologie Thoracique du Nord. Eur Respir J 10:286–291, 1997. Garrett JK, Jameson SC, Thomson B, et al: Anti-interleukin5 (mepolizumab) therapy for hypereosinophilic

syndromes. J Allergy Clin Immunol 113:115–119, 2004. Gleich GJ, Leiferman KM, Pardanani A, et al: Treatment of hypereosinophilic syndrome with imatinib mesilate. Lancet 359:1577–1578, 2002. Greenberger PA, Patterson R: Allergic bronchopulmonary aspergillosis. Model of bronchopulmonary disease with defined serologic, radiologic, pathologic and clinical findings from asthma to fatal destructive lung disease. Chest 91:165S–171S, 1987. Greenberger PA: Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 110:685–692, 2002. Hardy RW, Anderson RE: The hypereosinophilic syndromes. Ann Intern Med 68: 1220–1229, 1968. Hellmich B, Ehlers S, Csernok E, et al: Update on the pathogenesis of Churg-Strauss syndrome. Clin Exp Rheumatol 21:S69–S77, 2003. Johkoh T, Muller NL, Akira M, et al: Eosinophilic lung diseases: Diagnostic accuracy of thin-section CT in 111 patients. Radiology 216:773–780, 2000. Marchand E, Reynaud-Gaubert M, Lauque D, et al: Idiopathic chronic eosinophilic pneumonia. A clinical and follow-up study of 62 cases. The Groupe d’Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM“O”P). Medicine (Baltimore) 77:299–312, 1998. Moss RB: Pathophysiology and immunology of allergic bronchopulmonary aspergillosis. Med Mycol 43(Suppl 1):S203–S206, 2005. Noth I, Strek ME, Leff AR: Churg-Strauss syndrome. Lancet 361:587–594, 2003. Ong RK, Doyle RL: Tropical pulmonary eosinophilia. Chest 113:1673–1679, 1998. Philit F, Etienne-Mastroianni B, Parrot A, et al: Idiopathic acute eosinophilic pneumonia: A study of 22 patients. Am J Respir Crit Care Med 166:1235–1239, 2002. Ramakrishna G, Midthun DE: Churg-Strauss syndrome. Ann Allergy Asthma Immunol 86:603–613; quiz 13, 2001. Roufosse F, Cogan E, Goldman M: The hypereosinophilic syndrome revisited. Annu Rev Med 54:169–184, 2003. Savani DM, Sharma OP: Eosinophilic lung disease in the tropics. Clin Chest Med 23:377–396, ix, 2002. Seo P, Stone JH: The antineutrophil cytoplasmic antibodyassociated vasculitides. Am J Med 117:39–50, 2004. Stevens DA, Moss RB, Kurup VP, et al: Allergic bronchopulmonary aspergillosis in cystic fibrosis—state of the art: Cystic Fibrosis Foundation Consensus Conference. Clin Infect Dis 37(Suppl 3):S225–S264, 2003. Stevens DA, Schwartz HJ, Lee JY, et al: A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med 342:756–762, 2000. Vlahakis NE, Aksamit TR: Diagnosis and treatment of allergic bronchopulmonary aspergillosis. Mayo Clin Proc 76:930– 938, 2001. Weller PF, Plaut M, Taggart V, et al: The relationship of asthma therapy and Churg-Strauss syndrome: NIH workshop summary report. J Allergy Clin Immunol 108:175– 183, 2001.

SECTION FOURTEEN

Depositional and Infiltrative Disorders

73 CHAPTER

Depositional Diseases of the Lungs Robert J. Homer

I. AMYLOIDOSIS Nature of Amyloid Pulmonary Involvement in Amyloidosis Diagnosis of Amyloidosis II. DIFFUSE PULMONARY CALCIFICATION III. ALVEOLAR MICROLITHIASIS

Antiphospholipid Antibody-Associated Alveolar Hemorrhage Collagen Vascular Disease and Immune Complex−Associated Pulmonary Hemorrhage Drug-Induced Pulmonary Hemorrhage Nonimmunologic Causes of Diffuse Alveolar Hemorrhage

IV. ALVEOLAR HEMORRHAGE SYNDROMES Goodpasture’s Syndrome ANCA-Associated Pulmonary Vasculitis

Deposits of endogenous body constituents or exogenous materials in amounts sufficient to deform structure and impair function can occur virtually anywhere in the body. Deposits of endogenous materials in the lungs or airways cause a variety of diseases (Table 73-1). These may have different clinical manifestations, depending on localization (i.e., pulmonary parenchyma or conducting airways). This chapter deals with a few of these manifestations: amyloidosis; diffuse pulmonary calcification; alveolar microlithiasis; diffuse alveolar hemorrhage syndromes; and idiopathic pulmonary hemosiderosis. Others are discussed elsewhere in this text.

AMYLOIDOSIS Nature of Amyloid Amyloidosis refers to the extracellular deposition of amyloid, a fibrillar proteinaceous insoluble material that has charac-

teristic light, ultrastructural, and histochemical features (Fig. 73-1). Electron microscopic examination of amyloid reveals a dominant (95 percent) fibrillar component with distinctive periodicity, associated with a lesser (5 percent) pentagonal doughnut-shaped glycoprotein component, physically and chemically identical in all forms of amyloid, which is derived from a soluble plasma protein, soluble amyloid P protein (SAP). Amyloid also includes various glycosaminoglycans and certain apolipoproteins (E and J). Radiographic diffraction studies of amyloid show the fibrils to be arrayed in a β-pleated sheet configuration. This accounts for the ordered binding of the histochemical stain Congo red such that Congo red–stained amyloid appears apple-green under polarized light. The main fibrillar component of amyloid can be derived from any one of 23 precursor proteins. In systemic disease, the most important sources of amyloid are immunoglobulin light-chain, serum amyloid-associated (SAA) protein and

1234 Part VII

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Table 73-1 Depositional Diseases of the Lungs Biological Material

Disease

Interstitium Amyloid Water Calcium

Amyloidosis Interstitial edema Metastatic calcification

Alveoli Surfactant Water Calcium Blood and hemosiderin

Alveolar proteinosis Alveolar edema Alveolar microlithiasis Alveolar hemorrhage syndromes

transthyretin. Less common sources of amyloid include β2 microglobulin in patients with chronic renal failure on dialysis and various mutant amyloid precursor proteins. Finally, there are a number of organ-specific amyloid syndromes, the most important of which is Alzheimer’s disease. A related entity to amyloidosis is light-chain deposition disease (LDCC) in which tissue deposits are also derived from immunoglobulin light chains and are similar to amyloid by light microscopy, but show granular deposition by electron microscopy and do not stain with Congo red. It seems likely that the biochemical properties of the light chain determine the nature of the deposit produced. When amyloid is deposited in tissues it may produce atrophy of parenchymal cells (e.g., glomeruli), interference with mechanical function (e.g., heart and lungs), or impaired vasoconstriction of blood vessels, leading to hemorrhage (e.g., lungs and gastrointestinal tract). Amyloidosis may be a systemic disease with deposition of amyloid in multiple sites. In such cases, the amyloid is derived from a soluble-circulating plasma precursor. Localized amyloid deposition, involving a single body site, is thought to be derived from protein produced at the site of deposition. Systemic amyloid light chain (AL) usually occurs in association with a clonal proliferation of B cells or plasma cells which produce a monoclonal immunoglobulin or immunoglobulin fragment (monoclonal gammopathy). The neoplastic clone may clinically manifest as multiple myeloma or lymphoma (generally lymphoplasmacytic lymphoma) or may be subclinical (formerly known as primary amyloidosis), causing bone marrow plasmacytosis. Most often the source protein is a λ-light chain, either intact or the amino terminal fragment. AA amyloidosis is a far less common cause of symptomatic amyloidosis of the respiratory tract. The AA protein is derived from an acute-phase reactant found in normal plasma known as serum amyloid associated (SAA) protein

and produced by the liver. Chronic increase in serum acutephase reactants is an important precondition for the deposition of AA amyloid. AA amyloidosis (previously referred to as secondary amyloidosis) was formerly more common in patients with chronic infections (e.g., tuberculosis, leprosy, and chronic osteomyelitis) but is now seen more commonly with noninfectious chronic inflammatory diseases (e.g., rheumatoid arthritis, familial Mediterranean fever, Crohn’s disease, and heroin abuse with “skin popping”). Amyloid derived from plasma transthyretin (senile amyloidosis) is not uncommon but only infrequently produces clinical disease. This most often takes the form of restrictive cardiomyopathy due to cardiac deposition, and dyspnea due to diffuse interstitial pulmonary deposition is quite rare.

Pulmonary Involvement in Amyloidosis Amyloidosis may involve any portion of the respiratory tract. For example, deposits in the tongue may be extensive enough to cause obstructive sleep apnea. Deposits in the tracheobronchial tree may cause signs of bronchial obstruction or hemorrhage. Persistent pleural effusions may be due to both pleural and cardiac disease. Diffuse interstitial pulmonary amyloidosis may lead to dyspnea or pulmonary hemorrhage. Diaphragmatic deposition may lead to respiratory failure. Pulmonary hypertension is a rare complication. Tracheobronchial amyloid deposition and nodular parenchymal amyloid deposition (amyloidoma) (Fig. 73-1A) most often occur as isolated phenomena, whereas diffuse interstitial deposition is more often seen in systemic amyloidosis. The vast majority of cases of pulmonary amyloidosis can be categorized as tracheobronchial amyloidosis, nodular parenchymal amyloidosis, and diffuse septal amyloidosis. Nodular Parenchymal Amyloidosis As a rule, solitary amyloid nodules (amyloidomas) are incidental radiographic findings in asymptomatic individuals (Fig. 73-1). When multiple, such nodules may be associated with cough, dyspnea, or hemoptysis. These nodules have no distinctive features, although occasionally, they may show radiographic evidence of calcification or cavitation. Usually the diagnosis of an amyloid nodule is made after surgical resection. Occasionally, the diagnosis has been made by transbronchial biopsy or percutaneous fine-needle aspiration. However, surgical excision of one or more nodules seems prudent, since, on rare occasion, amyloid deposition occurs within a pulmonary neoplasm (e.g., a primary neoplasm such as atypical carcinoid or a metastatic neoplasm such as medullary carcinoma from the thyroid). Nodular parenchymal amyloidosis most often represents a localized abnormal immune response of bronchialassociated lymphoid tissue. Histologically, the amyloid deposit is often associated with an intense inflammatory reaction consisting of plasma cells, macrophages, and multinucleated giant cells. Only occasional chemical analyses are

1235 Chapter 73

Depositional Diseases of the Lungs

Figure 73-1 Amyloid deposition. A. Amyloidoma. Cut surface of lung with white arrows indicating a dense, waxlike lesion that is characteristic of nodular amyloid. Incidental finding at autopsy. (Courtesy of Leslie A. Litzky, M.D., Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia.) B. The typical amorphous appearance of amyloid is seen deposited within the wall of a pulmonary venule. Green birefringence on polarized light examination after staining with Congo red will confirm the amyloid nature of the deposit (H&E Ă&#x2014;700). C . Amorphous amyloid in the alveolar interstitial space. Arrow indicates a thickened alveolar septum (H&E Ă&#x2014;420).

available, and these have revealed that most nodular deposits are of light-chain derivation, although rare cases of amyloidassociated (AA) amyloid have been reported. Interestingly, when the accompanying plasma cells have been analyzed for clonality, they are more often polyclonal than monoclonal. In such cases, the inflammatory cells may therefore be a local

reaction to the presence of amyloid, rather than the source of the amyloid precursor light chains. In a few instances, nodular amyloidosis has been associated with a low-grade pulmonary lymphoma. Clinical followup of nodular parenchymal amyloidosis unassociated with systemic or neoplastic disease is generally benign.

1236 Part VII

Interstitial and Inflammatory Lung Diseases

Tracheobronchial Amyloidosis Amyloid deposition in the tracheobronchial tree can produce either plaques or tumoral masses. The more common presentation as plaques is diffuse, multifocal, and represents submucosal deposition of amyloid. Less commonly, deposition of amyloid in the tracheobronchial tree produces a solitary mass which mimics an endobronchial neoplasm. Tracheobronchial amyloid deposition is most often of light-chain derivation and a localized phenomenon, suggesting that this also represents a localized abnormal immune response of bronchial-associated lymphoid tissue rather than a systemic immune response. Like nodular amyloidosis, this form is virtually never associated with systemic disease. Diffuse involvement of the airways is apt to be symptomatic, producing cough, stridor, or hemoptysis. In contrast, localized mass lesions are more likely to produce evidence of localized bronchial obstruction (i.e., atelectasis or air trapping), with or without hemoptysis. Both types of lesions can be readily identified by bronchoscopic examination. However, as is the case with amyloid deposition at all sites, with biopsy there is a risk of hemorrhage. Although localized tumoral masses may be treated by excision or observation, more diffuse involvement may be treated by laser ablation. Diffuse Interstitial Amyloidosis Widespread, diffuse interstitial amyloidosis of the pulmonary parenchyma may produce either a reticulonodular or miliary pattern on the chest radiograph. Such pulmonary involvement occurs most often in patients with systemic amyloidosis, derived from either immunoglobulin light-chain or amyloidassociated protein. Pulmonary interstitial amyloid deposition is rarely sufficiently severe to produce clinical manifestations but, uncommonly, it may produce progressive dyspnea, hemoptysis, or restrictive pulmonary function tests. The deposition of amyloid in the lungs is microscopic and may involve the alveolar septal interstitium, the walls of small blood vessels, or both (Fig. 73-1B and C ). Transbronchial biopsy with Congo red staining is diagnostic, again bearing in mind the potential risk of biopsy-induced hemorrhage. It may be difficult in such cases to determine the relative contribution of pulmonary vs. concurrent cardiac amyloid deposition to the patientâ&#x20AC;&#x2122;s symptoms.

ysis has not been done with patients with isolated pulmonary disease.

DIFFUSE PULMONARY CALCIFICATION Calcification of the pulmonary parenchyma can occur by a variety of mechanisms. Dystrophic calcification refers to the deposition of calcium salts, most often crystalline hydroxyapatite, in dead tissue such as within the healing granulomas of tuberculosis. This type of calcification is usually localized; its distinctive radiographic features are sometimes diagnostically helpful. Metastatic calcification refers to the deposition of calcium salts, usually amorphous, in normal tissues (Fig. 73-2). This latter type of calcification occurs in association with some derangement of calcium metabolism, such as primary hyperparathyroidism, secondary hyperparathyroidism of chronic renal failure, hypervitaminosis D, the milk alkali syndrome, sarcoidosis, or increased bone turnover due to multiple myeloma or metastatic carcinoma. Although metastatic calcification can occur in almost any tissue of the body, it occurs most often in the lungs, kidneys, and the stomach (tissues with more alkaline pH), and the walls of blood vessels. Metastatic calcification in the lungs usually affects the interstitium of the alveolar septa and the walls of bronchioles and pulmonary vessels, sometimes localizing on elastic fibers. Clinical manifestations of diffuse pulmonary calcification are unusual, occurring most often in patients who are in chronic renal failure, particularly in those on chronic hemodialysis. Radiographically, metastatic calcification usually takes the form of a diffuse interstitial infiltrate, sometimes with fine nodularity. Less often, confluent patchy consolidation mimicking pneumonia may be seen. Although the calcific nature of the infiltrate is often apparent on routine chest radiograph, computed tomography (CT) scan is more sensitive both in detecting the interstitial deposits and in revealing their calcific

Diagnosis of Amyloidosis Diagnosis of amyloidosis requires tissue examination and Congo red staining and/or electron microscopy. Immunohistochemistry for amyloid precursor proteins including immunoglobulin light chains, amyloid-associated protein, and transthyretin among others can be used to classify patients, although AL disease may be technically difficult to document in this way. It has been shown that a significant number of patients with systemic amyloidosis and small light-chain clones do not necessarily have AL disease but rather have a hereditary form of amyloidosis. It has been suggested therefore that a genetic analysis be performed in any patient in whom a definitive diagnosis of AL cannot be reached. A similar anal-

Figure 73-2 Metastatic calcification of alveolar septa in a renal dialysis patient. Photomicrograph shows calcium forming a dark red precipitate within the alveolar septa (Alizarin red Ă&#x2014;280).

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nature. Moreover, CT scan may also demonstrate calcification of chest wall blood vessels, circumstantially implicating calcification as the cause of pulmonary parenchymal abnormalities. Recognition of the calcific nature of the infiltrate is furthered by scanning with 99m technetium. Only rarely do the patients manifest dyspnea or arterial hypoxemia, and pulmonary function tests tend to not show signs of restrictive pulmonary disease. Unexplained dyspnea in a patient with chronic renal failure or hypercalcemia in the presence of a normal chest radiograph should lead to consideration of high-resolution computed tomography (HRCT) or technetium scanning. The mechanism responsible for diffuse pulmonary calcification is unknown. Although high levels of parathyroid hormone or a marked increase in the calcium-phosphate solubility product occur in some patients, diffuse calcification can occur in the absence of either. Ultrastructural observations of minimal, presumably early, lesions show selective deposition of calcium on elastic fibers, suggesting that they may serve as the initial nidus. In contrast to their apparent role in alveolar microlithiasis, extracellular matrix vesicles do not appear to be involved.

ALVEOLAR MICROLITHIASIS This rare disorder usually presents as an abnormal chest radiograph from an asymptomatic patient (Fig. 73-3). The chest radiograph is diagnostic, showing a sandlike micronodulation throughout the lung fields. This is caused by the presence of innumerable minute calcified spherules filling the alveolar spaces. The calcification is usually sufficiently dense as to constitute the signature of the disease on the routine radiograph. In some patients, concentration of the spherules in subpleural, paraseptal, and peribronchiolar alveoli can produce linear strands of calcification parallel to or perpendicular to the pleural surface, readily apparent on HRCT. The spherules also bind 99m Tc, which can be a diagnostic adjunct. Although not usually required, bronchoalveolar lavage or biopsy can confirm the diagnosis. Biopsy shows calcified spherules filling alveolar spaces (Fig. 73-3). The spherules have a concentric lamellated appearance, suggesting that they grow by the addition of successive layers; the spherules contain both calcium and phosphorus. Although the microliths are intra-alveolar, one ultrastructural study has suggested that their formation is initiated in the pulmonary interstitium by the deposition in a collagenous matrix of hydroxyapatite crystals produced by extracellular matrix vesicles. These membrane-bound vesicles are derived from mesenchymal cells and can concentrate calcium ions and liberate phosphate from membrane phospholipids. Although usually asymptomatic at the time of presentation, alveolar microlithiasis, on rare occasion, can produce functional abnormalities. When it does, the findings are those of restrictive pulmonary disease or exercise-induced pulmonary hypertension. In general, no therapy, including bronchoalveolar lavage, has proved effective, although one

Depositional Diseases of the Lungs

case report indicates improved oxygenation using nasal continuous positive airway pressure ventilation. Lung transplantation has also been performed in a few patients. The etiology of alveolar microlithiasis is unknown, but some cases appear to be familial.

ALVEOLAR HEMORRHAGE SYNDROMES Pulmonary hemorrhage most commonly arises from endobronchial diseases (tumors, bronchiectasis, bronchitis). However, there is a subset of patients in whom bleeding originates at the level of the alveoli and who are referred to as having diffuse alveolar hemorrhage (DAH). Symptoms range from cough, fever, and dyspnea alone to respiratory failure. While hemoptysis is common, it is not universal, even when DAH is severe. In these cases, the diagnosis can be suspected due to a falling hemoglobin level. Evaluation of serial bronchoalveolar lavage aliquots in such patients may show a progressive increase in bloody return, as opposed to endobronchial disease, in which bleeding tends to clear. Bronchoalveolar lavage is also useful to exclude infection in patients with DAH. The damage to alveolar septa may either be due to immunologic mechanisms (immune complex, antineutrophil cytoplasmic antibody [ANCA], antiglomerular basement membrane, antiphospholipid antibodies) or to nonimmunologic causes. This distinction is largely, although not perfectly, captured in the presence or absence of the pathological finding of capillaritis (Fig. 73-4 and Table 73-2). Capillaritis is characterized by infiltration of alveolar walls by inflammatory cells, usually neutrophils, but sometimes eosinophils or monocytes, with fibrinoid necrosis of the alveolar and vessel wall. However, due to the absence of supporting structures, alveolar necrosis leads to wall breakdown so rapidly that this latter feature may be hard to appreciate. In order to distinguish this process from simple margination of neutrophils, there should be evidence for neutrophils undergoing apoptosis (pyknosis and nuclear fragments). Distinction from infection requires determination that there is minimal accumulation of inflammatory cells within alveoli. The pathological diagnosis of pulmonary hemorrhage itself requires that there is either hemosiderin-laden macrophages or evidence of hemophagocytosis, since the blood that is commonly seen in lung biopsies may be due to surgery alone. If this evidence is absent, clinical criteria for DAH should be used. Nonimmunologic mechanisms are quite diverse and include diffuse alveolar damage, inhalation of toxins, coagulopathy, and mitral valve disease, among others listed (Table 73-2). While the presence or absence of capillaritis is a useful way to think about these diseases, the decision about whether to actually perform a biopsy in these cases is challenging as interpretation of these biopsies is difficult, there is potential sampling error, and there is a significant risk of surgery to these patients. These problems limit this procedureâ&#x20AC;&#x2122;s utility while alternative diagnostic schemes usually allow diagnosis in absence of biopsy.

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Interstitial and Inflammatory Lung Diseases

Figure 73-3 Alveolar microlithiasis in a 46-year-old man admitted for nonpulmonary problems. History included slight dyspnea on exertion and previous episodes of ‘‘pneumonia” during 1947, 1950, and 1952. Clinical examination revealed severe restrictive lung disease, pulmonary hypertension, and cor pulmonale. Diagnosis confirmed by lung biopsy. A and B . Posterior-anterior and lateral chest radiographs demonstrate innumerable, tiny calcified nodules throughout both lung fields. Thin, lucent lines on each side represent normal pleura visualized between the calcified pulmonary parenchyma and the chest wall. Emphysematous blebs in the apices displace the calcifications. C . Cut surface of explanted lung from a patient undergoing lung transplantation for primary alveolar microlithiasis. Note the fine nodularity which correlated with the chest radiographs. (Courtesy of Leslie A. Litzky, M.D., Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia.) D . Photomicrograph demonstrating a typical calcospherite in an alveolar space (H&E ×1120).

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Depositional Diseases of the Lungs

Table 73-2 Causes of Diffuse Alveolar Hemorrhage

Figure 73-4 Capillaritis as a cause of pulmonary hemorrhage. Note the neutrophils in the alveolar septum (in center of image) and the blood and fibrin in the alveolar spaces (H&E ×100).

Goodpasture’s Syndrome This entity was originally described as an association of alveolar hemorrhage with glomerulonephritis. It was later determined that pulmonary and renal damage in many such patients was mediated by antibodies that are specifically directed against a component of glomerular and other capillary basement membranes, most often the α3 -chain of type IV (basement membrane) collagen. The anti-basement membrane antibodies cause pulmonary hemorrhage only in genetically predisposed individuals, after some injury such as cigarette smoke, viral respiratory infection, or hydrocarbon vapor inhalation exposes alveolar capillary basement membranes to the immune system. Although there are other causes of concomitant alveolar hemorrhage and glomerulonephritis, Goodpasture’s syndrome is generally reserved for disease mediated by antiglomerular basement membrane antibodies (anti-GBM antibodies). Goodpasture’s syndrome can present with a broad spectrum of clinical findings. The “classic” patient presents with massive hemoptysis, dyspnea, diffuse alveolar infiltrates on chest radiograph (Fig. 73-5), and overt glomerulonephritis, often with acute renal failure. However, some patients present with only hemoptysis and subsequently develop overt renal disease months or even years later. On occasion, patients present with acute glomerulonephritis due to anti-GBM antibodies and either develop pulmonary hemorrhage subsequently or never develop pulmonary hemorrhage. Without pulmonary hemorrhage, the entity should not be called “Goodpasture’s syndrome.” The histological findings on lung biopsy in Goodpasture’s syndrome are not diagnostic. Routine light-microscopy reveals intra-alveolar hemorrhage, usually associated with intra-alveolar hemosiderin-laden macrophages (Fig. 73-5). There may be no evidence of vasculitis, capillaritis, interstitial or intra-alveolar inflammation, or necrosis. In some cases,

Diffuse Alveolar Hemorrhage without Pulmonary Capillaritis Inhalational toxins (trimetallic anhydride, crack cocaine) Mitral stenosis Severe coagulopathy (iatrogenic, renal failure, thrombocytopenia) Nonspecific inflammation (diffuse alveolar damage, pulmonary gangrene, endocarditis) Neoplasm/hamartomatous (angiosarcoma, lymphangioleiomyomatosis, tuberous sclerosis) Pulmonary vascular disease (pulmonary venoocclusive disease, capillary hemangiomatosis) Idiopathic pulmonary hemosiderosis Diffuse Alveolar Hemorrhage with Pulmonary Capillaritis ANCA-associated vasculitis (Wegener’s granulomatosis, microscopic polyangititis, Churg-Strauss syndrome) Immune complex–associated and collagen vascular disease (Behc¸et’s disease, Henoch-Sch¨onlein purpura, systemic lupus erythematosus, rheumatoid arthritis, mixed connective-tissue disease, polymyositis) Isolated pauci-immune pulmonary capillaritis Diffuse Alveolar Hemorrhage with or without Capillaritis Goodpasture’s syndrome Systemic lupus erythematosus Primary or secondary antiphospholipid syndrome Drug-induced pulmonary hemorrhage

subtle capillaritis may be present. In either case, nonspecific reparative proliferation of the alveolar-lining cells may be present. While the diagnosis of Goodpasture’s syndrome can be made by detecting anti-GBM antibody in the patient’s serum, the sensitivity and specificity of various methods to detect these antibodies varies considerably. The gold standard remains the detection of the linear pattern of immunofluorescence on a lung or kidney biopsy. However, only occasionally will immunofluorescence microscopy show diagnostic linear deposits of immunoglobulin and/or complement along alveolar capillary walls (Fig. 73-5D). In contrast, kidney biopsy in Goodpasture’s syndrome is usually diagnostic. Conventional light microscopy shows nonspecific focal or diffuse glomerulonephritis which may be crescentic and necrotizing. When pulmonary hemorrhage due to Goodpasture’s syndrome is life-threatening, plasmapheresis for rapid lowering of circulating levels of anti-GBM antibody and administration of intravenous corticosteroids and cyclophosphamide to suppress antibody synthesis can be life-saving. If the patient is not in advanced renal failure at the time of

Figure 73-5 Goodpasture’s syndrome. A. Chest radiograph showing bilateral alveolar infiltrates, predominantly in the middle and lower lung fields. B . Autopsy specimen showing cut surface of lung with massive alveolar hemorrhage. (Courtesy of Dr. Richard Garnett, Reid Memorial Hospital, Richmond, IN.) C . Photomicrograph of intact alveoli, containing both red blood cells and hemosiderin-laden macrophages (H&E ×45). D. Immunofluorescent demonstration of immunoglobulin lining alveolar surfaces in a uniform distribution (fluoresceinated anti-IgG ×113). E . Smear of bronchoalveolar lavage demonstrating hemosiderin-laden macrophages (Prussian blue stain; original magnification ×132). (Courtesy of Dr. David Lyon, Iankenau Hospital, Wynnewood, PA.)

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diagnosis, chronic immunosuppression with a combination of corticosteroids and cyclophosphamide can prevent progressive renal damage. If irreversible renal failure has already occurred, the patient can eventually be successfully transplanted once anti-GMB antibodies have disappeared from the serum. Elimination of the antibodies usually can be achieved by immunosuppression alone; in some instances, pre-transplant nephrectomy may be required.

ANCA-Associated Pulmonary Vasculitis The ANCA-associated vasculitides, Wegenerâ&#x20AC;&#x2122;s granulomatosis (WG) and microscopic polyangiitis (MPA), represent the most common cause of immunologically mediated DAH. These have been associated with the development of autoantibodies directed against cytoplasmic components of neutrophils (and monocytes), the antineutrophil cytoplasmic antibodies (ANCAs). Detection of ANCAs entails the use of indirect immunofluorescence and heterologous antibodies against human immunoglobulin to detect autoantibodies bound to neutrophils of affected patients. Ethanol fixation of the neutrophils prior to antibody staining produces one of two patterns when autoantibodies are present: (1) a finely granular centrally accentuated cytoplasmic localization (c-ANCA) or (2) a perinuclear localization (p-ANCA). The usual targets of these antibodies have been identified as proteinase 3 for cANCA and myeloperoxidase for p-ANCA. Both antigens are found in the primary azurophilic granules of neutrophils. When ethanol is used as the fixative, the cellular granules are disrupted; the positively charged myeloperoxidase molecules then migrate toward the negatively charged nucleus to produce the perinuclear pattern, and the neutral proteinase 3 molecules remain dispersed in the cytoplasm to produce the cytoplasmic pattern. To maximize diagnostic accuracy, dual testing by fluorescence and an antigen-specific solid phase assay is required. Otherwise, a high degree of clinicopathological correlation is required for correct interpretation of these tests. Some patients with ANCA-associated alveolar hemorrhage also have anti-basement-membrane antibodies in the serum. These antibodies are directed against basement antigens other than those seen in Goodpastureâ&#x20AC;&#x2122;s syndrome and are thought to be a secondary phenomenon, rather than of pathogenic significance. Overt DAH occurs in approximately 15 percent of patients with WG or MPA. Depending on the specific syndrome present, alveolar hemorrhage may be isolated, associated with glomerulonephritis, or associated with widespread systemic vasculitis. In patients with ANCA-associated vasculitis, the occurrence of DAH is a poor prognostic indicator, although among survivors, complete recovery of lung function is common. Therapy does not depend on diagnosis of MPA vs. WG, and is based on immunosuppression with steroids and cyclophosphamide possibly augmented with plasmapheresis. Nevertheless, patients with WG/c-ANCA/proteinase 3 have worse outcomes with higher mortality and recurrence rate. While Churg-Strauss syndrome (CSS) is classified among the ANCA-associated vasculitides, DAH due to CSS is extraordinarily rare.

Depositional Diseases of the Lungs

Rarely, patients have presented with isolated pulmonary capillaritis with no serologic or clinical evidence for a systemic disorder. These patients responded to immunosuppression but relapses did occur.

Antiphospholipid Antibody-Associated Alveolar Hemorrhage Patients with serum antibodies directed against membrane phospholipid (antiphospholipid syndrome or APS) display hypercoagulability. Clinically, this manifests as peripheral arterial and venous thrombosis, fetal wastage in pregnant women, and thrombocytopenia. Pulmonary involvement can include pulmonary thromboembolism, pulmonary hypertension, diffuse alveolar damage, or rarely DAH. The latter produces fever, dyspnea, and diffuse pulmonary infiltrates on chest radiograph. Alveolar hemorrhage in APS has been associated with alveolar capillaritis with or without immune complex deposition and with microvascular thrombosis in the lungs. The combination of both thrombosis and hemorrhage greatly complicates therapy. Antiphospholipid antibodies were first detected in patients with systemic lupus erythematosus (SLE) and were formerly known as the lupus anticoagulant because they prolong some laboratory test of clotting. APS can occur in the absence of SLE. How often these antibodies play a role in pulmonary hemorrhage due to SLE is unknown, as there are other possible mechanisms in that syndrome (see below). In patients with isolated APS and alveolar hemorrhage, corticosteroid treatment, sometimes supplemented by cyclophosphamide, can result in a favorable outcome.

Collagen Vascular Disease and Immune Complexâ&#x2C6;&#x2019;Associated Pulmonary Hemorrhage DAH also occurs as a rare complication of certain connectivetissue disease syndromes, most often SLE but also rheumatoid arthritis, progressive systemic sclerosis, and mixed connective-tissue disease. Particularly in SLE, other causes of alveolar hemorrhage must be considered, including infection, uremia, and coagulopathy. When such causes have been eliminated, alveolar hemorrhage is sometimes found to be associated with capillaritis, with interstitial pneumonitis, or with immunofluorescent or ultrastructural evidence of immune complex deposition in alveolar septa. However, none of these disorders is consistently associated with pulmonary hemorrhage in SLE. Early diagnosis and treatment with corticosteroids and cytotoxic drugs is associated with favorable outcome, although relapse is not uncommon.

Drug-Induced Pulmonary Hemorrhage There is a long list of drugs, both therapeutic and drugs of abuse, associated with vasculitis. The clinical spectrum ranges from isolated mild skin disease to severe multi-organ systemic disease, usually due to a small vessel vasculitis. Some of these drugs can induce an ANCA-associated vasculitis. DAH

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Interstitial and Inflammatory Lung Diseases

due to ANCA-associated pulmonary capillaritis is well documented for propylthiouracil, D-penicillamine, allopurinol, diphenylhydantoin, and minocycline. Drug-induced ANCAassociated vasculitis should be treated with cessation of all potential causative agents as well as immunosuppression. Once the offending drug has been eliminated, the possibility of relapse seems low.

Nonimmunologic Causes of Diffuse Alveolar Hemorrhage There is a wide range of conditions that is associated with DAH with no capillaritis seen on biopsy and which are due to a wide variety of specific conditions, including toxins, neoplasms, nonspecific inflammation, infection, toxins, coagulopathy, and pulmonary vascular disease. When all the above diseases and syndromes have been excluded as likely possibilities, there still remains a small group of patients who develop recurrent DAH in the absence of extrapulmonary disease and with no evidence of an immune etiology. These patients are considered to have idiopathic pulmonary hemosiderosis, a diagnosis of exclusion (Fig. 73-6). Clinically, the patients form a heterogeneous group with respect to the onset and course of disease, which range from fulminant and fatal, to chronic relapse with eventual chronic pulmonary insufficiency due to interstitial fibrosis, to spontaneous remission with little or no residual deficit. The disease usually affects children and young adults. Pathological examination reveals nonspecific alveolar hemorrhage without evidence of inflammation, vasculitis, or immune complex deposition. Only a few observations on ultrastructure are available. These include focal disruption, smudging, or lamination of alveolar capillary basement membranes. The pathogenesis of this condition remains unknown, and there are no associated antibodies or other serum markers in the idiopathic cases. However, the clinical and morphologic similarities to some cases of alveolar hemorrhage of known immune pathogenesis, the occasional responsiveness to immunosuppressive therapy, the occasional association with celiac sprue—a presumably immunologic disease of the small intestine—and frequent association with a nonspecific elevation of serum IgA all point to an as yet unelucidated immune pathogenesis. Rarely, children with hypersensitivity to cow’s milk (Heiner’s syndrome) can present with DAH. If the diagnosis proves to be idiopathic pulmonary hemosiderosis, high-dose corticosteroid therapy with or without cyclophosphamide and plasmapheresis is useful in controlling acute bleeding, but the long-term effectiveness of these measures in preventing recurrence or progression of this disease is unknown.

SUGGESTED READING Beer TW, Edwards CW: Pulmonary nodules due to reactive systemic amyloidosis (AA) in Crohn’s disease. Thorax 48:1287, 1993.

Figure 73-6 Idiopathic pulmonary hemosiderosis in a 21month-old child with anemia soon after birth. Iron stain of the sputum showed hemosiderin-laden macrophages. A. Chest radiograph showing extensive, bilateral, almost punctate densities throughout both lung fields, most prominent in the perihilar regions where an alveolar filling pattern appears. B. Photomicrograph of lung at autopsy, showing intact alveoli containing degenerating red blood cells and hemosiderin-laden macrophages. Immunofluorescence studies for immunoglobulin and complement deposition were negative (H&E ×131). (Courtesy of Department of Pathology, St. Christopher’s Hospital for Children, Philadelphia.)

Berk JL, O’Regan A, Skinner M: Pulmonary and tracheobronchial amyloidosis. Semin Respir Crit Care Med 23:155, 2002. Chan ED, Morales DV, Welsh CH, et al: Calcium deposition with or without bone formation in the lung. Am J Respir Crit Care Med 165:1654, 2002. Colby TV, Fukuoka J, Ewaskow SP, et al: Pathologic approach to pulmonary hemorrhage. Ann Diagn Pathol 5:309, 2001. Dacic S, Colby TV, Yousem SA: Nodular amyloidoma and primary pulmonary lymphoma with amyloid production: A differential diagnostic problem. Mod Pathol 13:934, 2000. Dingli D, Utz JP, Gertz MA: Pulmonary hypertension in patients with amyloidosis. Chest 120:1735, 2001.

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Espinosa G, Cervera R, Font J, et al: The lung in the antiphospholipid syndrome. Ann Rheum Dis 61:195, 2002. Gertz MA, Comenzo R, Falk RH, et al: Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): A consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18–22 April 2004. Am J Hematol 79:319, 2005. Hogan SL, Nachman PH, Wilkman AS, et al: Prognostic markers in patients with antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J Am Soc Nephrol 7:23, 1996. Ioachimescu OC, Sieber S, Kotch A: Idiopathic pulmonary haemosiderosis revisited. Eur Respir J 24:162, 2004. Jennings CA, King TE Jr, Tuder R, et al: Diffuse alveolar hemorrhage with underlying isolated, pauciimmune pulmonary capillaritis. Am J Respir Crit Care Med 155:1101, 1997. Kelly PT, Haponik EF: Goodpasture syndrome: molecular and clinical advances. Medicine (Baltimore) 73:171, 1994. Khoor A, Myers JL, Tazelaar HD, et al: Amyloid-like pulmonary nodules, including localized light-chain deposition: Clinicopathologic analysis of three cases. Am J Clin Pathol 121:200, 2004. Klemmer PJ, Chalermskulrat W, Reif MS, et al: Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small-vessel vasculitis. Am J Kidney Dis 42:1149, 2003. Lachmann HJ, Booth DR, Booth SE, et al: Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med 346:1786, 2002. Lauque D, Cadranel J, Lazor R, et al: Microscopic polyangiitis with alveolar hemorrhage. A study of 29 cases and review of the literature. Groupe d’Etudes et de

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Recherche sur les Maladies “Orphelines” Pulmonaires (GERM“O”P). Medicine (Baltimore) 79:222, 2000. Lee AS, Specks U: Pulmonary capillaritis. Semin Respir Crit Care Med 25:547, 2004. Niles JL, Bottinger EP, Saurina GR, et al: The syndrome of lung hemorrhage and nephritis is usually an ANCA-associated condition. Arch Intern Med 156:440, 1996. O’Regan A, Fenlon HM, Beamis JF, Jr., et al: Tracheobronchial amyloidosis. The Boston University experience from 1984 to 1999. Medicine (Baltimore) 79:69, 2000. Russell KA, Wiegert E, Schroeder DR, et al: Detection of antineutrophil cytoplasmic antibodies under actual clinical testing conditions. Clin Immunol 103:196, 2002. Salama AD, Dougan T, Levy JB, et al: Goodpasture’s disease in the absence of circulating anti-glomerular basement membrane antibodies as detected by standard techniques. Am J Kidney Dis 39:1162, 2002. Salama AD, Pusey CD: Immunology of anti-glomerular basement membrane disease. Curr Opin Nephrol Hypertens 11:279, 2002. Savige J, Gillis D, Benson E, et al: International Consensus Statement on Testing and Reporting of Antineutrophil Cytoplasmic Antibodies (ANCA). Am J Clin Pathol 111:507, 1999. Utz JP, Swensen SJ, Gertz MA: Pulmonary amyloidosis. The Mayo Clinic experience from 1980 to 1993. Ann Intern Med 124:407, 1996. Westermark P, Benson MD, Buxbaum JN, et al: Amyloid: Toward terminology clarification. Report from the Nomenclature Committee of the International Society of Amyloidosis. Amyloid 12:1, 2005. Zamora MR, Warner ML, Tuder R, et al: Diffuse alveolar hemorrhage and systemic lupus erythematosus. Clinical presentation, histology, survival, and outcome. Medicine (Baltimore) 76:192, 1997.

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74 Pulmonary Langerhans’-Cell Histiocytosis Talmadge E. King, Jr.

I. EPIDEMIOLOGY

V. HISTOPATHOLOGY

II. NATURAL HISTORY AND CLINICAL PRESENTATION

VI. PATHOGENESIS

III. RADIOLOGY Chest Radiograph Computed Tomography Magnetic Resonance Imaging

VII. DIAGNOSTIC EVALUATION VIII. TREATMENT AND PROGNOSIS

IV. PHYSIOLOGICAL TESTING Pulmonary Function Exercise Physiology

Pulmonary Langerhans’-cell histiocytosis is also called pulmonary Langerhans’-cell histiocytosis, eosinophilic granuloma of the lung, and pulmonary Langerhans’-cell granulomatosis. Like Letterer-Siwe disease and Hand-Sch¨ullerChristian disease, it is characterized by abnormal organ infiltration by Langerhans’ cells. Langerhans’ cells are highly differentiated cells in the monocyte-macrophage line that are also found in the dermis of the skin, the reticuloendothelial system, the pleura, and the lung. These related disorders have been grouped under the classification of histiocytosis X. However, the three disorders are clinically distinct. Letterer-Siwe disease is an acute, often fulminant disease of children less than 2 years of age that is characterized by widespread infiltration of the reticuloendothelial system, bones, and lungs. Hand-Sch¨uller-Christian disease is a more indolent disorder of children and young adults that also typically affects the bones and the lungs. Diabetes insipidus, exophthalmos, and osteolytic skull lesions form the classic clinical triad associated with this disorder. There is some overlap in the clinical manifestations of these diseases; some children present with isolated pulmonary manifestations, and some adults demonstrate more malignant-appearing, disseminated disease. Pulmonary Langerhans’-cell histiocytosis is an uncommon, smoking-related, interstitial lung disease that primarily affects young adults. Less frequently, solitary osteolytic bone

lesions are also seen. Rarely, multifocal or widely disseminated disease more closely approximating the pediatric histiocytoses is described. Advanced disease may mimic idiopathic pulmonary fibrosis but generally follows a more benign and protracted course. Although there is some similarity to other diffuse interstitial lung diseases, pulmonary Langerhans’-cell histiocytosis, as a specific disease entity, is distinct in its clinical, radiologic, and pathological manifestations.

EPIDEMIOLOGY The true incidence and prevalence of pulmonary Langerhans’-cell histiocytosis are unknown. Pulmonary Langerhans’-cell histiocytosis is clearly an uncommon, if not rare, disease. No occupational or geographical predisposition has been reported. Among 28 patients seen by our group, we found higher than expected connections to farming (21 percent), woodworking (25 percent), and domestic exposure to animals (77 percent). Of note, nearly all affected persons report a prior smoking history. Thus, tobacco smoke is thought to be an etiologic factor. Other diffuse parenchymal lung diseases associated with cigarette smoking are respiratory bronchiolitis-associated interstitial lung disease and desquamative interstitial pneumonitis.

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Most patients present to medical attention in young adulthood (20 to 40 years of age). Pulmonary Langerhans’cell histiocytosis can, however, present in any age group. The older literature suggested a male preponderance; however, the recent literature suggests an equal sex distribution, with increasing presentations in middle age. In general, women tend to present at an older age than do men. If the demographics of pulmonary Langerhans’-cell histiocytosis have truly changed, as the literature would suggest, this may reflect the changing smoking habits of women in our society. Racial factors may also be important in the pathogenesis of the disease. Whites are affected much more commonly than are blacks or Asians, in whom this disease is very rare. Pulmonary Langerhans’-cell histiocytosis has reportedly been associated with a number of malignancies and may be a premalignant condition. Lymphoma, both Hodgkin’s and non-Hodgkin’s, has been reported in association with pulmonary Langerhans’-cell histiocytosis. However, the evidence regarding this association is inconclusive. The carcinogenic effects of cigarette smoke are probably etiologic for some of these tumors; thus, the relative effects of tobacco in pulmonary Langerhans’-cell histiocytosis are difficult to discern.

NATURAL HISTORY AND CLINICAL PRESENTATION Patients with pulmonary Langerhans’-cell histiocytosis come to medical attention in a variety of ways: as an incidental diagnosis that is suggested by a screening chest radiograph, after pneumothorax, or with respiratory or constitutional symptoms. Symptomatic patients most often have a nonproductive cough (56 to 70 percent) and, in decreasing order of frequency, dyspnea (40 percent; 87 percent of our patients had breathlessness with exertion on close questioning), chest pain (10 to 21 percent), fatigue (∼30 percent), weight loss (20 to 30 percent), and fever (15 percent). In our clinic, a history of rhinitis has been elicited in 50 percent of the patients with pulmonary Langerhans’-cell histiocytosis. Pleuritic pain and acute dyspnea with a spontaneous pneumothorax can be a recurrent problem in as many as 25 percent of patients. Pleural thickening or effusion is rarely seen in the absence of a history of pneumothorax. Hemoptysis (13 percent) is occasionally reported, and it should prompt consideration of superimposed infection (e.g., Aspergillus) or tumor. Cystic bone lesions are present in 4 to 20 percent of patients with pulmonary Langerhans’-cell histiocytosis and may produce localized pain or a pathological bone fracture. The precise number of patients with bone lesions is not known because complete bone surveys are not routinely performed. Skeletal involvement may be either the sole symptomatic manifestation of pulmonary Langerhans’-cell histiocytosis or may precede the more typical pulmonary manifestations. The radiographic pattern is not diagnostic. In most instances, the lesions are solitary and affect the flat bones.

Central nervous system involvement with diabetes insipidus (approximately 15 percent of patients) is also seen with pulmonary Langerhans’-cell histiocytosis and is believed to portend a poor prognosis. The physical examination is usually unremarkable. On chest examination, crackles are uncommon. Digital clubbing is also uncommon. Secondary pulmonary hypertension can occur and is probably under recognized. Manifestations of cor pulmonale are seen in advanced stages. Routine laboratory studies are usually unrevealing; the peripheral eosinophil count is normal.

RADIOLOGY Chest Radiograph The radiographic appearance of pulmonary Langerhans’-cell histiocytosis can be very characteristic if not diagnostic. The combination of ill-defined or stellate nodules (2 to 10 mm in size), reticular opacities, upper-zone cysts or honeycombing, preservation of lung volume, and costophrenic angle sparing are believed to be highly specific for this disorder. Typically, in keeping with the pathology, the reticular or nodular opacities are seen in the middle to upper zone (Fig. 74-1). The total lung volume is most often normal, although both hyperinflation and reduced volume have been described. In addition to pulmonary Langerhans’-cell histiocytosis, other interstitial diseases that may present with an increased lung volume are

Figure 74-1 Pulmonary Langerhans’-cell histiocytosis in a 22year-old woman. Chest radiograph demonstrates the classic features of profuse ill-defined nodules, reticulonodular opacities, cysts, costophrenic angle sparing, and preservation of lung volumes.

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lymphangioleiomyomatosis, tuberous sclerosis, chronic hypersensitivity pneumonitis, stage III sarcoidosis, constrictive bronchiolitis, and any interstitial lung disease in an individual with emphysema. Small cysts and nodules are the radiographic hallmark of pulmonary Langerhans’-cell histiocytosis (Fig. 74-2); occasionally miliary disease is seen. Hilar or mediastinal adenopathy in pulmonary Langerhans’-cell histiocytosis is rare and should prompt consideration of malignancy as a secondary diagnosis. Pleural thickening is most often due to treated pneumothorax, since pleural involvement by the primary disease process is uncommon. Bone lesions can occur in any bone, including the ribs. On rare occasions, patients come to medical attention with a solitary pulmonary nodule that, on biopsy, proves to be pulmonary Langerhans’-cell histiocytosis.

Computed Tomography The combination of multiple cysts and nodules with a middleto upper-zone predominance with interstitial thickening in a young smoker is so characteristic as to be diagnostic of pulmonary Langerhans’-cell histiocytosis (Fig. 74-2B). The nodules can be well or poorly defined. Occasionally they can be large and bizarrely shaped (Fig. 74-2C ). Honeycombing can be seen in advanced disease. Serial chest computed tomography (CT) scanning often suggests a sequence of progression from nodular to cavitating to cystic lesions over time. The degree of cyst formation is often underappreciated with routine chest radiography. Thus, this progression may explain a number of “spontaneous remissions” in the literature reported before the routine use of thin-section CT scanning.

Magnetic Resonance Imaging The role of magnetic resonance imaging in pulmonary Langerhans’-cell histiocytosis is limited to the evaluation of bony and central nervous system lesions. B

PHYSIOLOGICAL TESTING Pulmonary Function Pulmonary function testing of subjects with pulmonary Langerhans’-cell histiocytosis can potentially demonstrate all → Figure 74-2 Pulmonary Langerhans’-cell histiocytosis in a 33year-old man. A. Chest radiograph reveals reticulonodular opacities in midlung zones, cysts, costophrenic angle sparing, and preservation of lung volumes. B . Conventional CT scan helps confirm the presence of bilateral reticulonodular opacities and cysts. C . High-resolution CT with thin section shows more clearly that the reticulonodular or emphysematous changes on chest radiography are actually cysts. In this instance, few nodules are present. The cysts vary markedly in size and may be larger than 10 mm. The cysts are bizarre in shape, and many are closely related to pulmonary arteries, often mimicking bronchiectasis. C

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possible patterns of function abnormality—normal, obstructive, restrictive, or mixed. In general, total lung capacity is well preserved, with nearly normal airflow. Most often, the diffusing capacity is disproportionately reduced. This pattern of pulmonary function abnormality suggests pulmonary vascular involvement by the disease process. Airflow limitation occurs in a minority of patients and is sometimes associated with reactive airways; significant improvement occurs after administration of a bronchodilator. When present, reactive airways disease may reflect coexisting chronic obstructive pulmonary disease (COPD). Classical manifestations of asthma are unusual in pulmonary Langerhans’-cell histiocytosis. We recently reviewed our experience at the San Francisco General Hospital in 23 patients with pulmonary Langerhans’-cell histiocytosis we found two major subgroups. The first demonstrated a normal total lung capacity, with normal or near-normal airflow. In this group, testing of pulmonary mechanics revealed normal elastic recoil. The second group demonstrated predominantly restrictive disease, with reduced total lung volume and increased elastic recoil. In both groups, the diffusing capacity was markedly reduced. The patients in the restrictive group tended to have longer-standing disease. Only one subject demonstrated predominantly obstructive pulmonary dysfunction even though obstructive pathophysiology, with airflow limitation and hyperinflation, is well described in the literature. The mean alveolar-arterial difference in PO2 (AaPO2 ) was normal at rest in both subgroups but a subset of five subjects with more severe disease did have a markedly elevated AaPO2 difference and required supplemental oxygen. The resting pH and PaCO2 were most often normal. Thus, the resting arterial blood gas was a very insensitive indicator of disease.

Exercise Physiology Clinically, we have observed that patients with established pulmonary Langerhans’-cell histiocytosis generally demonstrate limitation in physical activity and intolerance for exercise that is out of proportion to their pulmonary function abnormalities. In our cross-sectional study of 23 subjects with pulmonary Langerhans’-cell histiocytosis, we found a marked decrease in exercise capacity as measured by either work achieved (54 ± 4 mean ± SEM percent of predicted) or oxygen utilization (VO2 , 44 percent ± 3) at maximal exercise. The oxygen pulse at maximal exercise was reduced to 56 ± 3 percent. The anaerobic threshold was decreased to 33 percent ± percent of expected VO2max ; specifically, it was less than or equal to 40 percent in all subjects in whom it was measured. The maximal ventilatory response (VEmax , 83 ± 5 percent) was excessive for the maximal level of work. The maximal ventilatory response was not limiting, and the Ve was well below predicted ventilatory ceilings. Gas exchange abnormalities were reflected in increasing AaPo2 differences as the level of exercise increased. Alveolar dead space to tidal volume ratio (VD /VT ), a parameter believed to reflect pulmonary vascular function, was either abnormally elevated or failed to decrease in most

Figure 74-3 Dead space to tidal volume ratio (VD /VT %) at rest and maximal exercise (max ex) in patients with pulmonary Langerhans’-cell histiocytosis (n = 23). Seventeen patients demonstrated either an abnormal VD /VT at rest or response to exercise (left panel). Six patients had a normal VD /VT at rest and normal response to exercise (right panel). (Based on data from Crausman RS, Jennings CA, Tuder R, et al: Pulmonary histiocytosis X: Pulmonary function and exercise pathophysiology. Am J Respir Crit Care Med 153:426–435, 1996, with permission.)

patients (Fig. 74-3). This abnormality suggested either pathological or functional involvement of the pulmonary vasculature by the disease process. Two linear regression models derived from pulmonary function indices predicted 73 percent (r2 = 0.73) and 75 percent (r2 = 0.75) of the variability in the maximal achieved workload and predicted oxygen consumption at maximal exercise (% cmax ex ), respectively. The following equation was derived for the maximal achieved workload: maximal achieved workload = 0.884 − (0.0088 ∗ VD /VT baseline) − (0.002 ∗ RV) + (0.0044 ∗ DlCO ). Here the partial r2 was VD /VT baseline (r2 = 0.40, p = 0.0007), RV (0.19, 0.001), and DlCO (0.15, 0.004). Figure 74-4 shows the regression model for the predicted oxygen consumption at maximal exercise. Our analysis of the composite results concluded that exercise intolerance in subjects with pulmonary Langerhans’cell histiocytosis was due to a combination of mechanical factors and pulmonary vascular involvement by pulmonary Langerhans’-cell histiocytosis.

HISTOPATHOLOGY The pathological cell type of pulmonary Langerhans’-cell histiocytosis is the Langerhans’ cell, a differentiated cell of the monocyte-macrophage line (Fig. 74-5). Langerhans’ cells are normally found in the dermis, the reticuloendothelial system, the lung, and the pleura. They are distinguished by a pale-staining cytoplasm and large nucleus and nucleoli. Electron microscopy can demonstrate the classic pentilaminar cytoplasmic inclusion or Birbeck granule (X-body) (Fig. 74-6). Although this cell can be found in association with

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Figure 74-4 Correlation between predicted oxygen consumption at maximal exercise (VO 2max ) and predicted VO 2max from the linear regression model: VO 2max = 0.062 − (0.0074 ∗ baseline VD /VT ) − (0.0014 ∗ RV) + (0.0017 ∗ baseline P(Aa)o2 ) + (0.0011 ∗ DLCO ); r2 0.75 (Based on data from Crausman RS, Jennings CA, Tuder R, et al: Pulmonary histiocytosis X: Pulmonary function and exercise pathophysiology. Am J Respir Crit Care Med 153:426–435, 1996, with permission.)

Figure 74-5 Lung tissue in pulmonary Langerhans’-cell histiocytosis . The histiocytosis X cells (Langerhans’ cells) are typical. A characteristic longitudinal groove is seen along the center of some cells (×96.)

Figure 74-6 Electron micrograph of Langerhans’ cell (Lg) of the lung. Typical X bodies (Birbeck granules) are seen in the two inserts.

Pulmonary Langerhans’-Cell Histiocytosis

cigarette smoking in otherwise healthy persons and with other pulmonary pathologies (e.g., idiopathic pulmonary fibrosis) or in normal lung, its presence is characteristic of pulmonary Langerhans’-cell histiocytosis. In pulmonary Langerhans’cell histiocytosis, the Langerhans’ cells are characteristically found in clusters and significantly outnumber those seen in other lung diseases. Absolute quantitative guidelines for diagnosis of pulmonary Langerhans’-cell histiocytosis have not been established. Early inflammatory lesions center around the smaller bronchioles and usually contain a mixture of eosinophils, lymphocytes, and neutrophils. Pulmonary Langerhans’-cell histiocytosis is not a granulomatous disorder. Moreover, the lesions are often devoid of eosinophils. Thus, the older term, eosinophilic granuloma, is a misnomer. The lesions often affect pulmonary arterioles and venules so that the disorder can be described as having a bronchovascular distribution. Pseudo-desquamative interstitial pneumonia (characterized by the accumulation of alveolar macrophages in the alveolar parenchyma between pulmonary Langerhans’-cell lesions) and respiratory (smoker’s) bronchiolitis (with pigmented macrophages filling the lumen of bronchioles and the surrounding alveolar spaces) have also often been found on lung biopsy. In addition, intraluminal fibrosis was often present (86 percent of specimens), the fibrosis was characterized by mural incorporation, alveolar obliteration, and intraluminal buds. It was mild in extent in 59 percent of specimens, moderate in 20 percent, and marked in 9 percent. These findings support the hypothesis that intraluminal fibrosis serves as a mechanism for alveolar collapse, with progression to interstitial fibrosis and lung remodeling. Interstitial fibrosis and small cyst formation with a middle- to upper-zone predominance occur in advancing disease. This middle- to upper-zone predominance differs from that of idiopathic pulmonary fibrosis, which generally has a lower zone predominance. More advanced lesions extend widely into the parenchyma of the lung that surrounds the bronchovascular structures and produce the so-called stellate lesions that are characteristic of this disorder. Kambouchner and colleagues used three-dimensional reconstructions of serial histological sections to demonstrate that pulmonary Langerhans’-cell histiocytosis lesions are elongated, sheathlike structures of variable diameter that extend proximally and distally along bronchioles and do not necessarily have a spherical morphology (Fig. 74-7). Older lesions are relatively acellular and produce a diffuse interstitial pathology that can be difficult to distinguish from other forms of end-stage pulmonary fibrosis, with extensive areas of fibrosis and honeycombing accompanying the cystic lesions. The mechanism for cyst formation is unknown. It may be a consequence of central necrosis of older stellate lesions. Alternatively, the cysts may occur as a result of secondary inflammatory foci in relatively avascular areas distal to more advanced bronchovascular lesions. Finally, these cysts may form, in part, because of obstruction of the more proximal airway by the stellate lesions.

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Figure 74-7 Three-dimensional appearance of a pulmonary Langerhans’-cell histiocytosis (PLCH) lesion. Artist’s rendering, based on the reconstructions by Kambouchner et al, illustrates the elongated morphology and variable cellular and fibrotic composition of PLCH with correlative histological sections. As a PLCH lesion evolves, the nodule of densely packed cells (bottom, a) is centripetally replaced by fibrous tissue and ultimately becomes a stellate scar (top, c). This continuum of change may be evident within a single lesion. PLCH lesions are bronchiolocentric and propagate both proximally and distally along the small airways. The involved bronchiolar lumen may become either dilated or obliterated. The histological sections correspond to the early, middle, and late phases of PLCH. In the early phase (a), there is a densely cellular nodule with delicate stellate extensions along the adjacent alveolar walls (original magnification, ×12; H&E stain). As the disease progresses (b), cellularity diminishes as fibroblasts replace the lesion (original magnification, ×19.2; H&E stain). Note that the stellate extensions have become more prominent, the central bronchiole (∗) is dilated, and adjacent alveolar spaces have coalesced because of focal destruction of alveolar walls (paracicatricial airspace enlargement). In the final phase (c), the characteristic Langerhans’-cell histiocytosis is absent and only a fibrous, stellate scar remains (original magnification, ×24; H&E stain). This phase is often accompanied by paracicatricial airspace enlargement (∗∗). (From Abbott GF, Rosado-de-Christenson ML, Franks TJ, et al: From the Archives of the AFIP: Pulmonary Langerhans cell histiocytosis. RadioGraphics 24:821–841, 2004, with permission.)

tactic for monocytes, are mitogenic for epithelial cells and fibroblasts, and stimulate cytokine secretion. Thus, several attractive features support the hypothesis that these peptides contribute to the inflammation and fibrosis observed in pulmonary Langerhans’-cell histiocytosis. Tobacco glycoprotein and other regulatory glycopeptides (e.g., granulocytemacrophage colony-stimulating factor) have been touted as being potentially important in the pathogenesis of this disease. Attention has been focused on the processes that may regulate white blood cell traffic in this disorder. These studies suggest that the pathogenesis of pulmonary Langerhans’-cell histiocytosis entails alterations of the expression of the adhesion molecules that regulate interactions between white blood cells and endothelial cells. One important adhesion molecule for neutrophils that is expressed by endothelial cells is intercellular adhesion molecule-1 (ICAM-1). ICAM-1 expression by Langerhans’ cells has been demonstrated in biopsy specimens of subjects with Langerhans’-cell histiocytosis. Expression of other leukocyte adhesion molecules, such as the ß1 and ß2 integrins, has also been noted. The significance of these findings and their relevance to pulmonary Langerhans’-cell histiocytosis remain to be elucidated. Alternatively, a viral infection has been suggested as the underlying cause of generalized Langerhans’-cell histiocytosis. However, there are no convincing data to suggest a role for viral infection as a cause of pulmonary Langerhans’-cell histiocytosis. Abnormalities in immune function, with a nonspecific increase in immunoglobulin G (IgG) in bronchoalveolar fluid, circulating and tissue-bound immune complexes, and abnormalities in T-cell function, have been observed in association with pulmonary Langerhans’-cell histiocytosis and may be important in the pathophysiology of this disorder. It is also possible, however, that these findings represent nonspecific consequences of a generalized activation of immune effector cells. Although it is not a monoclonal disorder, the clinical similarities between pulmonary Langerhans’-cell histiocytosis and Langerhans’-cell histiocytosis and the frequent association with lymphoma do suggest a relationship with malignancy. At present, it is reasonable to think that pulmonary Langerhans’-cell histiocytosis may be a premalignant condition.

PATHOGENESIS DIAGNOSTIC EVALUATION The pathogenesis of pulmonary Langerhans’-cell histiocytosis is unknown. However, the nearly universal association with cigarette smoking strongly implies causation. One hypothesis of disease pathogenesis, the bombesin hypothesis, contends that increased bombesinlike peptide production plays a central role (Fig. 74-8). Bombesin is a neuropeptide produced by neuroendocrine cells, which are increased in the lungs of smokers. Bombesinlike peptides are chemo-

The history and physical examination are the first steps in the diagnostic evaluation of a patient suspected of having pulmonary Langerhans’-cell histiocytosis. Unfortunately, the signs and symptoms of pulmonary Langerhans’-cell histiocytosis are generally nonspecific and often point to other, more common pulmonary diagnoses. For example, wheezing, cough, and dyspnea in a 50-year-old patient

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Pulmonary Langerhans’-Cell Histiocytosis

Figure 74-8 The primary event in the pathogenesis of pulmonary Langerhans’-cell histiocytosis probably involves cigarette-smoke–induced recruitment and activation of Langerhans’ cells to the lung, a process that may result from a variety of potential mechanisms. Cigarette smoke may activate alveolar macrophages through bombesin-like peptides (BLP) released from airway neuroendocrine cells. Other antigens in cigarette smoke, including tobacco glycoprotein (TGP), may stimulate alveolar macrophages to produce cytokines (such as tumor necrosis factor [TNF-α] or granulocyte-macrophage colony-stimulating factor [GM-CSF]) or other factors that enhance recruitment and activation of Langerhans’ cells. Cigarette smoke may also directly activate Langerhans’ cells to secrete cytokines (such as TNF or GM-CSF) that mediate local accumulation of inflammatory cells, with resultant formation of nodules. Uptake of cigarette-smoke antigens by alveolar macrophages or Langerhans’ cells may also promote local expansion of T lymphocytes and further inflammation. Through the action of tobacco glycoprotein, reduced interleukin-2 secretion by lymphocytes may occur, thereby enhancing local survival and proliferation of Langerhans’ cells. T lymphocytes may further stimulate B-lymphocyte activation, promoting secretion of antibodies and immune-complex formation. Fibroblast activation and fibrosis may result from the local synthesis of tumor growth factor-ß (TGF-ß) and TNF by alveolar macrophages. (From Vassallo R, Ryu JH, Colby TV, et al: Pulmonary Langerhans’-cell histiocytosis. N Engl J Med 342:1969–1978, 2000, with permission.)

with a prominent smoking history are much more commonly due to COPD than to pulmonary Langerhans’-cell histiocytosis. However, when present, the history of recurrent pneumothorax, diabetes insipidus, or bone pain can be helpful. A smoking history is a consistent but not essential historical feature, since pulmonary Langerhans’-cell histiocytosis can occur without an antecedent history of smoking. Most evaluations for pulmonary Langerhans’-cell histiocytosis are prompted by an abnormal chest radiograph. As previously noted, the chest CT, if classic, can be diagnostic, and should therefore be obtained in all who are suspected of having this disease. We recommend high-resolution chest CT as a prebiopsy step in the evaluation of any patient with diffuse interstitial lung disease suspected of having pulmonary Langerhans’-cell histiocytosis. A sufficiently characteristic chest CT in association with the appropriate history is believed by many to obviate the need for tissue confirmation. It should be noted that most often chest CT scans in pulmonary Langerhans’-cell histiocytosis are not diagnostic and can be confused with the chest CT scans of pulmonary lym-

phangioleiomyomatosis, tuberous sclerosis, hypersensitivity pneumonitis, sarcoidosis, or idiopathic pulmonary fibrosis. In these instances, further diagnostic evaluation is warranted. Bronchoalveolar lavage (BAL) can be of diagnostic value in cases of suspected histiocytosis X. The total number of cells recovered is usually increased (as expected in smokers), and a modest increase in the concentration of neutrophils and eosinophils is common. In active disease, the total number of lymphocytes recovered may also be increased, and the CD4:CD8 ratio may be decreased. Langerhans’ cells in BAL can be recognized by their characteristic staining for S-100 protein or peanut agglutination antigen. These cells are also OKT-6 (CD-1) positive, are identified by a specific monoclonal antibody (MT-1), and contain characteristic Birbeck or pentilaminar bodies on electron microscopic evaluation (Fig. 74-6). Quantitative criteria for the definitive diagnosis of histiocytosis X based on BAL Langerhans’-cell numbers have not been conclusively established. A BAL cell differential with more than 5 percent Langerhans’ cells strongly suggests the diagnosis. Lesser proportions of Langerhans’ cells can be seen in current smokers and in patients with other interstitial lung

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disorders or bronchoalveolar carcinoma and even in normal subjects. Thus, the mere presence of Langerhans’ cells is of little diagnostic value. When tissue confirmation is sought, transbronchial biopsy can be sufficient to make the diagnosis. Sampling error and insufficient tissue may account for the substantial number of false-negative or nondiagnostic biopsies. Open, video-guided thoracoscopic lung biopsy, is generally definitive and can be done with a minimum of operative risk. Tissue immunostaining with the monoclonal antibody CD-1 (OKT-6) distinguishes Langerhans’ cells from other histiocytes and can be a useful diagnostic adjunct. It can be performed on routinely fixed tissue and is less expensive than electron microscopy. In patients with progressive disease and extensive fibrosis, the number of Langerhans’ cells in either tissue specimens or BAL fluid decreases dramatically. Diagnosis at this stage can be difficult regardless of the laboratory methods used. In most cases, the combination of transbronchial lung biopsy and BAL, supplemented with the identification of CD-1–positive cells in tissue and BAL fluid, is highly likely to result in the correct diagnosis.

TREATMENT AND PROGNOSIS The natural history of pulmonary Langerhans’-cell histiocytosis is extraordinarily variable, with some patients experiencing spontaneous remission of symptoms and others progressing to end-stage fibrotic lung disease (Table 74-1). Poor outcome in pulmonary Langerhans’-cell histiocytosis has been associated with an older age at the time of diagnosis, severe airway obstruction, reduced carbon monoxide diffusing capacity, and the need for corticosteroid therapy during follow-up.

Figure 74-9 Follow-up chest radiograph in a 22-year-old woman taken 4 months after the initial film shown in Fig. 74-1. After an open lung biopsy performed on the left hemithorax, she was told to stop smoking and treated with prednisone. The chest radiograph shows marked clearing of the ill-defined nodules and preservation of lung volumes.

Most subjects who continue to smoke demonstrate gradual progression and regression of disease following smoking cessation. Therefore, it is important to stress smoking cessation (Fig. 74-9). The condition of patients with radiographic sparing of the costophrenic angle is more likely to remain stable or

Table 74-1 Clinical Course of Pulmonary Langerhans’-cell Histiocytosis Reference

Years of Follow-Up

% Improved

% Stable

% Deteriorated

% Deaths

Basset, et al (1978)

1–3

Friedman, et al (1981)

Not stated

55∗

Colby and Lombard (1983)

Not stated

74†

Lacronique et al (1982)

1–12‡

∗ Forty

patients had essentially no symptoms of residual disease at least 6 months after diagnosis; 13 of these had persistent radiographic abnormalities. or with partial or complete resolution. ‡ Twenty-six of 37 were followed for >3 years; mean = 5.4 years. Source: Data from Marcy TW, Reynolds HY. Pulmonary histiocytosis X. Lung 163:129–150, 1985. † Stable

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to improve than the condition of patients with involvement of the costophrenic angle. Corticosteroids have not been shown to be of any value in the treatment of histiocytosis X. Nor has cytotoxic therapy, which may be of value in the treatment of disseminated disease. Reports of improved outcome with interleukin-2 and anti–tumor necrosis factor-α therapy in pediatric patients with disseminated histiocytoses may lead to similar trials in pulmonary Langerhans’-cell histiocytosis. Radiotherapy for symptomatic bone lesions can be palliative. Radiation is not useful in the treatment of the pulmonary manifestations. Lung transplantation has been successfully accomplished in a number of centers. It is a viable option for selected patients with end-stage disease. Recurrence of pulmonary Langerhans’-cell histiocytosis after lung transplantation has been reported, especially in patients who resumed smoking after lung transplantation. Potential therapies that are apt to be of value in the future include gene therapy, monoclonal antibody therapy, and cytokine-based therapies. Given the vascular impairment seen with this disease and the occasional reports of pulmonary hypertension, it is also tempting to think about vasodilator therapy for symptomatic patients. However, these approaches remain speculative. There is a high rate of recurrence of pneumothoraces in the absence of interventions to prevent additional episodes. Pleurodesis may be needed in patients with recurrent pneumothoraces. See Fig. 74-10 for an analysis of expected and observed survival among adults with pulmonary Langerhans’-cell histiocytosis.

Figure 74-10 Kaplan-Meier analysis of expected and observed survival among 102 adults (40 men and 62 women) with pulmonary Langerhans’-cell histiocytosis. The expected survival was defined as that for age- and sex-matched members of the general US population. The median follow-up period after the diagnosis of pulmonary Langerhans’-cell histiocytosis was 4 years (range, 0 to 23). There were 33 deaths, 15 of which were attributable to respiratory failure. Survival was significantly shorter than that expected for healthy persons of the same sex and calendar year of birth ( p < 0.001). (From Vassallo R, Ryu JH, Schroeder DR, et al: Clinical outcomes of pulmonary Langerhans’-cell histiocytosis in adults. N Engl J Med 346:484–490, 2002, with permission.)

Pulmonary Langerhans’-Cell Histiocytosis

SUGGESTED READING Abbott GF, Rosado-de-Christenson ML, Franks TJ, et al: From the Archives of the AFIP: Pulmonary Langerhans cell histiocytosis. RadioGraphics 24:821–841, 2004. Colby TV, Lombard C: Histiocytosis X in the lung. Hum Pathol 14:847–856, 1983. Collins J, Hartman MJ, Warner TF, et al: Frequency and CT Findings of Recurrent Disease after Lung Transplantation. Radiology 219:503–509, 2001. Crausman RS, Jennings CA, Tuder R, et al: Pulmonary histiocytosis X: Pulmonary function and exercise pathophysiology. Am J Respir Crit Care Med 153:426–435, 1996. Danel C, Israel-Biet D, Costabel U, et al: The clinical role of BAL in rare pulmonary diseases. Eur Respir Rev 2:83–88, 1991. de Graaf JH, Tamminga RY, Kamps WA, et al: Langerhans’ cell histiocytosis: Expression of leukocyte cellular adhesion molecules suggests abnormal homing and differentiation. Am J Pathol 144:466–472, 1994. Housini I, Tomashefski JF Jr, Cohen A, et al: Transbronchial biopsy in patients with pulmonary eosinophilic granuloma. Comparison with findings on open lung biopsy. Arch Pathol Lab Med 118:523–530, 1994. Kambouchner M, Basset F, Marchal J, et al: Threedimensional characterization of pathologic lesions in pulmonary Langerhans cell histiocytosis. Am J Respir Crit Care Med 166:1483–1490, 2002. Kulwiec EL, Lynch DA, Aguayo S, et al: Imaging of pulmonary histiocytosis X. RadioGraphic 12:515–526, 1992. Ladisch S, Gadner H: Treatment of Langerhans cell histiocytosis—evolution and current approaches. Br J Cancer (Suppl) 23:S41–S46, 1994. Marcy TW, Reynolds HY: Pulmonary histiocytosis X. Lung 163:129–150, 1985. McClain K, Weiss RA: Viruses and Langerhans cell histiocytosis: Is there a link? Br J Cancer (Suppl) 23:S34–S36, 1994. Mendez JL, Nadrous HF, Vassallo R, et al: Pneumothorax in pulmonary Langerhans cell histiocytosis. Chest 125:1028– 1032, 2004. Mierau GW, Wills EJ, Steele PO: Ultrastructural studies in Langerhans cell histiocytosis: A search for evidence of viral etiology. Pediatr Pathol 14:895–904, 1994. Ruco LP, Stoppacciaro A, Vitolo D, et al: Expression of adhesion molecules in Langerhans’ cell histiocytosis. Histopathology 23:29–37, 1993. Sch¨onfeld N, Frank W, Wenig S, et al: Clinical and radiologic features, lung function and therapeutic results in pulmonary histiocytosis X. Respiration 60:38–44, 1993. Sundar KM, Gosselin MV, Chung HL, et al: Pulmonary Langerhans cell histiocytosis: Emerging concepts in pathobiology, radiology, and clinical evolution of Disease. Chest 123:1673–1683, 2003.

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ten Velde GP, Thunnissen FB, van Engelshoven JM, et al: A solitary pulmonary nodule due to eosinophilic granuloma. Eur Respir J 7:1539–1540, 1994. Travis WD, Borok Z, Roum JH, et al: Pulmonary Langerhans cell granulomatosis (histiocytosis X). A clinicopathologic study of 48 cases. Am J Surg Pathol 17:971–986, 1993. Tsele E, Thomas DM, Chu AC: Treatment of adult Langerhans cell histiocytosis with etoposide. J Am Acad Dermatol 27:61–64, 1992. Vassallo R, Ryu JH, Colby TV, et al: Pulmonary Langerhans’cell histiocytosis. N Engl J Med 342:1969–1978, 2000.

Vassallo R, Ryu JH, Schroeder DR, et al: Clinical outcomes of pulmonary Langerhans’-cell histiocytosis in adults. N Engl J Med 346:484–490, 2002. Von Essen S, West W, Sitorius M, et al: Complete resolution of roentgenographic changes in a patient with pulmonary histiocytosis X. Chest 98:765–767, 1990. Youkeles LH, Grizzanti JN, Liao Z, et al: Decreased tobaccoglycoprotein-induced lymphocyte proliferation in vitro in pulmonary eosinophilic granuloma. Am J Respir Crit Care Med 151:145–150, 1995.

75 Pulmonary Lymphangioleiomyomatosis Talmadge E. King, Jr.

I. LYMPHANGIOLEIOMYOMATOSIS Epidemiology Clinical Presentation Pathology Pathogenesis Pulmonary Physiology

LYMPHANGIOLEIOMYOMATOSIS Pulmonary lymphangioleiomyomatosis is a rare, idiopathic, diffuse, progressive interstitial lung disease that afflicts young women of childbearing age. It occurs as a sporadic disease or with tuberous sclerosis complex, which can be inherited as an autosomal-dominant disorder involving multi-organ hamartomas. In the tuberous sclerosis complex, patients frequently develop lung and kidney lesions which are pathologically and genetically similar to those seen in lymphangioleiomyomatosis. Pathologically, the tuberous sclerosis complex is characterized by interstitial proliferation of smooth muscle and cyst formation that mimics pulmonary emphysema. It has been variously called myomatosis, angiomyomatosis hyperplasia, lymphangiomatous malformation, diffuse pulmonary leiomyomatosis, and muscular hyperplasia of the lung. Although pulmonary lymphangioleiomyomatosis is commonly included among the diffuse interstitial lung diseases, lymphangioleiomyomatosis has more in common clinically, radiographically, and physiologically with pulmonary emphysema than with either idiopathic pulmonary fibrosis (IPF) or sarcoidosis. Like emphysema, lymphangioleiomyomatosis generally manifests with clinically significant airflow limitation and is often misdiagnosed as asthma or chronic obstructive pulmonary disease (COPD). Many subjects are evaluated for Îą1 -antitrypsin deficiency. However, lymphangioleiomyomatosis is an interstitial lung disease and should rightly be included with pulmonary histiocytosis X and (stage IV) cystic sarcoidosis as part of a subgroup of cystic interstitial

Radiology Diagnosis Prognosis Treatment II. TUBEROUS SCLEROSIS

lung diseases. Tuberous sclerosis can be associated with pulmonary disease that is indistinguishable pathologically from lymphangioleiomyomatosis.

Epidemiology The incidence and prevalence of pulmonary lymphangioleiomyomatosis is unknown. It is a rare disease that presents almost exclusively in premenopausal women. Most patients (70 percent) are 20 to 40 years of age at the time of onset of symptoms or diagnosis. Until now, only 5 percent of patients have been more than 50 years of age at the time of presentation. However, currently more older women (usually without a history of pneumothorax) are being diagnosed with lymphangioleiomyomatosis. The few instances of the disease that have been reported in postmenopausal women have been associated most often with estrogen replacement therapy. Caucasians are afflicted much more commonly than are other racial groups. No features in the family history, perinatal events, or early life events have been associated with the occurrence of lymphangioleiomyomatosis.

Clinical Presentation Women with lymphangioleiomyomatosis come to medical attention in various ways. Most often, the subjective complaint of dyspnea or fatigue prompts medical evaluation. Early in the course of the disease, patients are often misdiagnosed as having asthma. However, as the disease progresses inexorably, the

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Insterstitial and Inflammatory Lung Diseases

Table 75-1 Age and Clinical Manifestations of Patients with Pulmonary Lymphangioleiomyomatosis at Presentation or During Follow-up∗

Reference

Mean Age at Onset (Range)

Chest Cough Dyspnea Pain (%) (%) (%) 91†

18†

Taylor (1990)

32 33 (range 41 not reported)

Kitaichi (1995)

46 32 (20–63)

Crausman (1996)

16 32 (26–39)

100

—

196 41.4 (18–76) 32

not 32 reported

—

Silverstein (1974)

32 39 (18–69)

Corrin (1975)

28 33 (17–47)

Ryu (2006)

†n

9†

Chylous Hemoptysis Pneumothorax Chylothorax Ascites (%) (%) (%) (%)

= 22

∗ Wheezing

was noted in only 92 of 309 subjects. Chyluria was noted in only 3 of 154. Chylopysis was noted in 16 of 350 subjects. Fatigue was reported in 72% of subjects in a recent survey (Cohen, 2005).

disease is either correctly diagnosed or reclassified as having pulmonary emphysema. At the time of diagnosis, virtually all patients complain of dyspnea (Table 75-1). Spontaneous pneumothorax is common and occurs in almost two-third of cases. A history of pneumothorax is more common in younger patients (77 percent of women are under 40 years old at diagnosis) compared to only 50 percent of those who are more than 60 years of age. The disease is often recurrent, can be bilateral, and may necessitate pleurodesis. Barotrauma and cyst rupture can still occur after pleurodesis. Cyst rupture may be manifested as pneumomediastinum, pneumoretroperitoneum, pneumoretropharynx, and subcutaneous emphysema. Management of these complications after pleurodesis usually requires only observation since the complications are rarely associated with significant morbidity. In contrast, tension pneumomediastinum or pneumopericardium calls for decompression. Although chylothorax, due to obstruction of the thoracic duct or rupture of the lymphatics in the pleura or mediastinum by proliferating smooth-muscle cells, is a characteristic feature of this disease, it is present in only a minority of patients at the time of diagnosis. Chyle can be recognized by its milky white appearance, high triglyceride level—usually greater than 110 mg/dl—and the presence of chylomicrons. Chylothorax, which is typically associated with nutritional wasting and some degree of immunocompromise, can be difficult to manage. Chyloperitoneum (chylous ascites) occurs in approximately 10 percent of patients. More rarely, chyluria

(due to abnormal connections between dilated retroperitoneal lymphatics and the renal collecting system) and chylopericardium may also occur. Renal angioleiomyomata, a characteristic pathological finding in tuberous sclerosis, are also common in lymphangioleiomyomatosis (in as many as 50 percent of subjects). These lesions may grow to enormous size prior to clinical detection but uncommonly affect renal function. Hemoptysis of mild to moderate severity, a welldescribed clinical manifestation, may be life-threatening. The physical examination can be unrevealing or may disclose end-expiratory rales (22 percent), hyperinflation, decreased or absent breath sounds, ascites, and intra-abdominal or adnexal masses. Clubbing is uncommon (less than or equal to 5 percent).

Pathology In lymphangioleiomyomatosis, the predominant pathology, proliferation of atypical smooth muscle, occurs around the bronchovascular structures. However, this abnormal proliferation is not limited to the bronchovascular sheath but also progresses through the pulmonary interstitium. In addition, another unique pathological feature of lymphangioleiomyomatosis is the occurrence of diffuse cystic dilatation of the terminal airspaces (Fig. 75-1). Some degree of hemosiderosis is common and is thought to be a consequence of small amounts of hemorrhage that stem from the rupture of dilated and tortuous venules.

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Pulmonary Lymphangioleiomyomatosis

Figure 75-1 Histopathology of lymphangioleiomyomatosis. A. Smooth muscle is irregularly distributed throughout the pulmonary parenchyma. The muscle bundles are often found near blood vessels but extend into the alveolar walls. Intra-alveolar collections of macrophages and lymphocytes are also present (right side of figure). B . Higher-power view reveals the abnormal smooth-muscle proliferation. The cells appear shorter and more immature than normal smooth muscle. Mitotic figures are rarely encountered.

The atypical proliferating cells resemble vascular smooth-muscle cells but are often somewhat shortened and pleomorphic (Fig. 75-1B). The origin of the atypical cell is assumed to be a myocyte, but this is controversial. The cells are polyclonal in nature. Grossly and microscopically, the normal architecture is distorted by multiple small cysts which range from 0.1 cm to several cm in diameter (Fig. 75-2). The interstitium is thickened by smooth-muscle-like proliferation around and within the pulmonary lymphatics, venules, and airways. The lymphatic and venous vessels can also be quite tortuous and dilated. Hilar, mediastinal, and retroperitoneal lymph nodes are often involved and enlarged. The thoracic duct is frequently thickened and dilated. Extrapulmonary involvement with renal, retroperitoneal, intra-abdominal, and pelvic angioleiomyomata is common.

Figure 75-2 Pulmonary lymphangioleiomyomatosis causes thin-walled emphysematous spaces leading to the distinctive type of honeycombing. (From Cornog JL Jr, Enterline HT: Lymphangiomyoma, a benign lesion of chyliferous lymphatics synonymous with lymphangiopericytoma. Cancer 19:1909â&#x20AC;&#x201C;1930, 1966, with permission.)

Pathogenesis Lymphangioleiomyomatosis is primarily a disease of smoothmuscle-like cell proliferation throughout the interstitium of the lungs and within and around the lymphatics of the body. It is unknown whether the proliferation results from abnormality in the proliferating cells or if the abnormally proliferating cells are simply responding to abnormal stimulation from circulating mediators. The abnormal smooth-musclelike cells have lost heterozygosity and inactivating mutations in one of the two tuberous sclerosis complex genes. Most mutations have been described in tuberous sclerosis complex-2 (16p13); mutations in the tuberous sclerosis complex-1 gene (9q34) have been less common. In the pulmonary lesions of lymphangioleiomyomatosis, loss of heterozygosity or other somatic mutations in either tuberous sclerosis complex gene have been reported. Renal angiomyolipomas contain abnormal blood vessels and adipose cells in addition to the smoothmuscle-like lymphangioleiomyomatosis cells. Based on loss of heterozygosity as the second genetic hit, all three types of renal angiomyolipoma cells appear to be neoplastic.

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It is very likely that estrogen plays a central role in progression of the disease. The disease does not become manifest prior to menarche and only rarely after menopause. The few occurrences that have been reported in postmenopausal women have most often been in association with hormonal supplementation. The disease is known to accelerate during pregnancy and to abate after oophorectomy. In those patients in whom pulmonary disease is part of tuberous sclerosis, female preponderance is marked. Moreover, estrogen and progesterone receptors have been demonstrated in tissue biopsies. A recent study showed that estradiol and tamoxifen stimulated the growth of lymphangioleiomyomatosisassociated angiomyolipoma cells and activated both genomic and nongenomic signaling pathways. The mechanism by which interstitial smooth-muscle proliferation causes cyst formation and emphysema-like disease is unknown. Although it has been proposed that the cysts and emphysema-like disease are due to compression of the conducting airways by the proliferating smooth muscle in the interstitium, this hypothesis is controversial. An alternate hypothesis is that smooth-muscle proliferation within the airways creates a “ball-valve” obstruction which leads to distention of the terminal airspaces. Finally, it has also been suggested that degradation of elastic fiber related to an imbalance in the elastase/α1 -antitrypsin system is a major mechanism leading to the emphysema-like changes. Some combination of these mechanisms probably affords the best explanation for the pathogenesis.

Pulmonary Physiology Pulmonary function testing may be very helpful in providing a clue to the diagnosis of lymphangioleiomyomatosis. Lymphangioleiomyomatosis is one of the few interstitial lung diseases that presents with reticulonodular opacities on the chest radiograph, increased lung volumes, and an “obstructive” or “mixed” pattern on pulmonary function testing. Lymphangioleiomyomatosis patients are often hyperinflated with an increased total lung capacity (TLC) and increased thoracic gas volume (Vtg). Increased gas trapping is commonly manifested by an increase in the residual volume (RV) and in the RV/TLC ratio, even when TLC and Vtg are relatively normal. Often evidence of airflow limitation is manifested by a decrease in forced expiratory volume in 1 s (FEV1 ) and vital capacity (FVC). Studies of pulmonary mechanics show that mean elastic recoil is decreased and that upstream resistance (Rus) is increased. A decrease in elastic recoil and an increase in pulmonary resistance contribute to the observed airflow limitation. Gas exchange is often abnormal. A markedly reduced diffusing capacity (DlCO ) is a characteristic feature. The alveolar-arterial oxygen difference is also increased. In most patients exercise performance is decreased, with a reduced oxygen consumption and a low anaerobic threshold. Exercise causes an abnormal and excessive ventilatory response with high respiratory rate, excessive minute ventilation, and reduced breathing reserve. The baseline or exercise dead space to tidal volume ratio (VD /VT ) is frequently abnormal

Figure 75-3 Pulmonary lymphangioleiomyomatosis. Dead space to tidal volume ratio- (VDS /VT ) percent at rest and maximal exercise in patients with lymphangioleiomyomatosis (n = 15). Left panel. Twelve patients demonstrated an abnormal VDS /VT either at rest or in response to exercise. Right panel. The three subjects with a normal VDS /VT at rest and normal response to exercise are shown. (Adapted from Crausman RS, Jennings CA, Mortenson RL, et al: Lymphangioleiomyomatosis: The pathophysiology of diminished exercise capacity. Am J Respir Crit Care Med 153:1368–1376, 1996, with permission.)

(Fig. 75-3). Thus, the primary determinants of the exercise limitation are related to airflow limitation and mechanical factors (i.e., decreased breathing reserve, work of breathing) (Fig. 75-4). However, pulmonary vascular involvement also exerts a significant physiological effect upon the exercise performance, probably because the accompanying increase in physiological dead space can produce excessive ventilatory requirements. The interdependence between airflow limitation (which produces a decrease in the ventilatory ceiling) and pulmonary vascular dysfunction/destruction leads to severe impairment in exercise performance in many patients with pulmonary lymphangioleiomyomatosis.

Radiology Chest Radiograph The findings on the chest radiograph in lymphangioleiomyomatosis are variable, ranging from normal early in the course of the disease to severe emphysematous-like changes in advanced disease. Pneumothorax can be an early feature, and chylous pleural effusion can develop at any time during the course (Fig. 75-5). Initial reports of lymphangioleiomyomatosis described a pseudoreticular or nodular pattern of irregular opacities. These opacities result from the compression of smooth-muscle–rich interstitial tissue by more dilated cystic airspaces. Lymphatic obstruction, with the development of Kerley B septal lines, also contribute to the pattern. Cross-sectional studies show that the lungs of 33 to 62 percent of the patients are hyperinflated with cystic dilatation of the airspaces, resulting in relatively radiolucent lung fields. Chest Computed Tomography Chest computed tomography (CT) is very useful for demonstrating the cystic nature of this disease. High-resolution, thin-section CT scanning is much more sensitive than routine

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Figure 75-4 Linear stepwise regression model derived to determine the variability in exercise capacity. Correlation between percent predicted oxygen consumption achieved by the patients at maximal exercise (VO 2max ) and VO 2max predicted from the linear regression equation VO 2max = 0.40 − (0.0081∗ baseline VDS /VT ) (0.0070∗ sGaw), r2 = 0.91. Both resting VDS /VT and sGaw are independent variables in this regression model. For this model, sGaw alone was able to predict 76 percent of the variability, and the addition of baseline VDS /VT predicted an additional 15 percent of the variability. None of the other airflow or gas exchange variables added significantly to this model’s ability to predict maximal achieved oxygen consumption. The stepwise regression procedure determined that the best model for maximal achieved workload should include sGaw and baseline VDS /VT : maximal achieved workload = 0.37 − (0.0081∗baseline VDS /VT ) (0.0096∗sGaw). This model was able to predict 76 percent of the variability in maximal achieved workload. (From Crausman RS, Jennings CA, Mortenson RL, et al: Lymphangioleiomyomatosis: The pathophysiology of diminished exercise capacity. Am J Respir Crit Care Med 153:1368–1376, 1996, with permission.)

chest radiography. Moreover, the findings of diffuse, homogenous, small (less than 1 cm diameter) thin-walled cysts can be pathognomonic in the appropriate clinical context (Fig. 75-6). Bilateral lung cysts (100 percent) and ground-glass opacities (59 percent) were the most frequent CT findings in 38 women in the Kyoto study. Nodular opacities (5 percent) were uncommon and linear densities were not seen. The correlation is close between the extent of the cystic parenchymal replacement in patients with lymphangioleiomyomatosis (as measured by quantitative highresolution chest CT) and the severity of the disease (as determined by spirometry, diffusing capacity, lung volume, or exercise performance). Thus, chest CT may be of both diagnostic and prognostic importance. Abdominal CT and ultrasonographic findings are common in patients with thoracic lymphangioleiomyomatosis. The most common abdominal findings include renal angiomyolipoma (54 percent), enlarged abdominal lymph nodes (39 percent), lymphangiomyoma (16 percent), ascites (10 percent), dilatation of the thoracic duct (9 percent), and

Pulmonary Lymphangioleiomyomatosis

Figure 75-5 Posteroanterior radiograph of the chest showing minimal increase in markings in the lower lung zones. A chylothorax is present on the left.

hepatic angiomyolipomatosis (4 percent). Diurnal variation in size of lymphangioleiomyomas may explain worsening of symptoms during the day.

Diagnosis Lymphangioleiomyomatosis can be readily diagnosed by its characteristic histological features on open lung or thoracoscopic biopsy. Often, transbronchial lung biopsy can yield an adequate sample for pathological evaluation especially when immunohistochemical stains specific for smoothmuscle components; actin or desmin and, more recently, HMB-45 have been employed to improve diagnostic sensitivity and specificity. In general, the diagnosis should be strongly suspected in any young woman who presents with emphysema, recurrent pneumothorax, or a chylous pleural effusion. Highresolution chest CT can often confirm the diagnosis and tissue confirmation may not be necessary, although tissue confirmation is usually recommended because of the devastating nature of this disorder. The differential diagnosis includes: emphysema, α1 -antitrypsin deficiency, asthma, chronic extrinsic allergic alveolitis, pulmonary histiocytosis X, cystic sarcoidosis, and panacinar emphysema due to intravenous drug use.

Prognosis The most common reasons for hospitalization are for the management of spontaneous pneumothorax, chylothorax, or renal angiomyolipomas that are acutely bleeding, or at risk for spontaneous hemorrhage. The natural history of this disorder is thought to be progressive with a median survival of 8 to 10 years after diagnosis. The prognosis for women with

1260 Part VII

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Figure 75-6 Same patient as in Fig. 75-5, 32 months later. A.The current posteroanterior radiograph of the chest shows increased lung volume and difficult-to-see cystic changes in the all lung zones. The pleural changes on the left are secondary to the prior effusion and to an open lung biopsy. B . The high-resolution CT scan demonstrates multiple thin-walled cystic airspaces.

lymphangioleiomyomatosis is variable but generally poor, with about 22 to 62 percent succumbing to progressive respiratory failure after 8.5 years after diagnosis (Fig. 75-7). Although uncommon, long-term survival 20 years after diagnosis has been reported. In the most recent large case series, there

Figure 75-7 Kaplan-Meier plots of actuarial survival of patients with pulmonary lymphangioleiomyomatosis from the onset of symptoms. Five separate reports were analyzed: Silverstein and coworkers in 1974 described the outcome in 31 patients (solid line); Corrin and coworkers in 1975 described survival in 23 patients (dotted line); Kitaichi and colleagues in 1995 described the survival of 46 Asian women reported at the 1993 Kyoto Pulmonary Lymphangioleiomyomatosis Congress (dashed line). Urban and coworkers showed the survival probability of being alive was 91 percent after 5 years, 79 percent after 10 years, and 71 percent after 15 years of disease duration. Matsui and colleagues showed survival probabilities of 85 percent after 5 years and 71 percent after 10 years.

was an apparent improvement in survival. The reasons for this improved survival are unknown, but include the possibility of bias inherent in the methods, hormonal interventions, better supportive treatments, or a change in the natural history of the disease. These data also suggest that the rate of progression is quite variable and can occur many years after diagnosis and after menopause. Sudden onset of rapid deterioration is rare later in the course of the disease. Pregnancy and the use of supplemental estrogen are known to accelerate the disease process. Interestingly, twothirds of subjects enrolled in the Lymphangioleiomyomatosis (LAM) Registry had been pregnant. Of 353 pregnancies, 66.9 percent had resulted in live birth, 16.7 percent spontaneous abortion, 15.0 percent therapeutic abortion, and 1.4 percent in stillbirth. However, only 25 patients (21.7 percent of those who had been pregnant and able to recall symptoms) had experienced worsening of respiratory symptoms during pregnancy. Pulmonary function and histological pattern of disease have been shown to be predictive of poor survival. An elevated total lung capacity (percent predicted TLC) and reduced FEV1 /FVC ratio were associated with poor survival 2 to 5 years after initial examination. Further, a predominantly cystic pattern of histopathology predicted a worse prognosis than a predominantly muscular pattern. It is unknown whether these patterns represent two distinct histopathologies or different stages in the evolution of the disease.

Treatment Thus far, treatment regimens have been unsatisfactory. There is no role for either corticosteroids or cytotoxic agents and

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there have been few advances since the early recognition that female hormones likely play an etiologic role in the pathogenesis. Oophorectomy, progesterone (10 mg/day), and more recently tamoxifen (20 mg/day) and luteinizing hormonereleasing hormone (LHRH) analogs have been employed with some anecdotal support. Alpha-interferon has also been tried, but in our experience has not been of any benefit, primarily because side effects limit its use. Only oophorectomy and treatment with progestational agents appear to provide reliable benefit. A recent meta-analysis summarized the results of 30 treated cases. Of patients treated early in the course of disease prior to widespread tissue destruction, five of seven stabilized or improved after oophorectomy; two patients who underwent both oophorectomy and treatment with progesterone stabilized or improved by objective criteria; only four of eight treated with progesterone alone stabilized or improved. Thus, combination therapy with oophorectomy and either progesterone and/or tamoxifen should be considered. Chemical oophorectomy with LHRH analogs may replace surgical oophorectomy as the primary treatment of this disorder; however, data are currently lacking. To date, only lung transplantation offers any hope for cure and should be considered as definitive therapy for any failing patient. Compared with all lung transplant recipients, patients who have undergone lung transplantation for lymphangioleiomyomatosis experience increased morbidity and mortality due to complications related to their underlying disease (native lung pneumothorax, chylous pleural

Pulmonary Lymphangioleiomyomatosis

effusions and ascites, hemorrhagic renal angiomyolipomas, and recurrence of disease). Furthermore, reports of recurrent disease in transplanted lungs raise concern regarding this therapy. Recurrent lymphangioleiomyomatosis cells within donor lungs after transplantation were of recipient origin, suggesting metastatic spread.

TUBEROUS SCLEROSIS Tuberous sclerosis (Bourneville’s disease) is a rare (varies from 1 per 27,000 to 1 per 100,000 population) autosomaldominant disorder, but up to 68 percent of cases may be new mutations. It affects men or women equally. Mental retardation, seizures, and facial angiofibroma (adenoma sebaceum) form the classic clinical triad. However, the features are variable and in some affected individuals intelligence is normal. Skin lesions are a prominent feature of tuberous sclerosis and are usually present in childhood. These lesions are characterized by hypopigmented spots on the trunk followed by adenoma sebaceum (wartlike lesions distributed in a butterfly pattern over the face and cheeks). In less than 1 percent of cases, tuberous sclerosis can be associated with pulmonary manifestations that are indistinguishable from those of lymphangioleiomyomatosis (Table 75-2). The onset is generally in the fourth decade of life, rarely

Table 75-2 Features of Tuberous Sclerosis with and without Involvement of the Lungs Without Pulmonary Involvement

With Pulmonary Involvement

Age at onset, years

< 20

30–35

Sex incidence (male:female)

1:1

1:5

Family heredity

Yes

Presenting symptom

Central nervous system disorder

Dyspnea or spontaneous pneumothorax

Mental retardation

Frequent (∼60 percent)

Uncommon (∼40 percent)

Seizures

Frequent (70–90 percent)

Uncommon (∼20 percent)

Facial angiofibroma

Frequent

Pneumothorax

Not known (rare)

Frequent

Chylothorax

Not known (rare)

Rare

Angiomyolipoma

Frequent

Source: Hauck RW, Konig G, Permanetter W, et al: Tuberous sclerosis with pulmonary involvement. Respiration 57:289–292, 1990, with permission.

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before age 20 years. Some have referred to lymphangioleiomyomatosis as a forme fruste of tuberous sclerosis. The complete triad of tuberous sclerosis is not commonly present in those who develop pulmonary involvement. In patients with pulmonary involvement female predominance is marked. Dwyer and colleagues reported that in 29 of 34 cases in their series the patients were female. Pulmonary lymphangioleiomyomatosis has been described in a phenotypically normal man with tuberous sclerosis complex and confirmed XY genotype. Most patients with tuberous sclerosis present with dyspnea. In some, the onset is heralded by a spontaneous pneumothorax. Pneumothorax occurs in approximately one-third of patients. Hemoptysis and chest pain are other important features. The radiographic appearance is similar to that of pulmonary lymphangioleiomyomatosis described above. Chylothorax is a rare complication. The primary histological lesion is a hamartoma. Similar lesions occur in the brain and may calcify. A micronodular hyperplasia of type II pneumocytes has been described. The frequency of renal lesions, angioleiomyomata, is also high. Other associations include cardiac rhabdomyoma, sclerotic bone, and periungual fibromas. Survival of patients with tuberous sclerosis is less than in the general population. Renal disease and brain tumors are the most common cause of death. Pulmonary involvement in tuberous sclerosis is associated with a poor prognosis. Progressive disease is common, and death usually occurs, secondary to respiratory insufficiency, within 5 years of the onset of symptoms. Long-term survivors have been described and may occur more often today because of improved management of the potential complications, especially cor pulmonale and pneumothorax. No effective treatment for tuberous sclerosis has been found. However, because of similarities to lymphangioleiomyomatosis, treatment with progesterone and/or oophorectomy in women is recommended.

SUGGESTED READING Aubry M-C, Myers JL, Ryu JH, et al: Pulmonary lymphangioleiomyomatosis in a man. Am J Respir Crit Care Med 162:749–752, 2000. Avila NA, Bechtle J, Dwyer AJ, et al: Lymphangioleiomyomatosis: CT of diurnal variation of lymphangioleiomyomas. Radiology 221:415–421, 2001. Avila NA, Kelly JA, Chu SC, et al: Lymphangioleiomyomatosis: Abdominopelvic CT and US findings. Radiology 216:147–153, 2000. Bernstein SM, Newell JD, Adamczyk D, et al: How common are renal angiomyolipomas in patients with pulmonary lymphangioleiomyomatosis? Am J Respir Crit Care Med 152:2138–2143, 1995.

Cohen MM, Pollock-BarZiv S, Johnson SR: Emerging clinical picture of lymphangioleiomyomatosis. Thorax 60:875– 879, 2005. Collins J, Hartman MJ, Warner TF, et al: Frequency and CT findings of recurrent disease after lung transplantation. Radiology 219:503–509, 2001. Crausman RS, Jennings CA, Mortenson RL, et al: Lymphangioleiomyomatosis: The pathophysiology of diminished exercise capacity. Am J Respir Crit Care Med 153:1368–1376, 1996. Crausman RS, Lynch DA, Mortenson RL, et al: Quantitative computed tomography (QCT) predicts the severity of physiological dysfunction in patients with lymphangioleiomyomatosis (LAM). Chest 109:131–137, 1996. Crooks DM, Pacheco-Rodriguez G, DeCastro RM, et al: Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis. Proc Natl Acad Sci USA 101:17462–17467, 2004. Hauck RW, Konig G, Permanetter W, et al: Tuberous sclerosis with pulmonary involvement. Respiration 57:289–292, 1990. Johnson SR, Tattersfield AE: Clinical experience of lymphangioleiomyomatosis in the UK. Thorax 55:1052–1057, 2000. Karbowniczek M, Astrinidis A, Balsara BR, et al: Recurrent lymphangiomyomatosis after transplantation: Genetic analyses reveal a metastatic mechanism. Am J Respir Crit Care Med 167:976–982, 2003. Kitaichi M, Nishimura K, Itoh H, et al: Pulmonary lymphangioleiomyomatosis: A report of 46 patients including a clinicopathologic study of prognostic factors. Am J Respir Crit Care Med 151:527–533, 1995. Matsui K, Beasley MB, Nelson WK, et al: Prognostic significance of pulmonary lymphangioleiomyomatosis histologic score. Am J Surg Pathol 25:479–484, 2001. Ryu JH, Doerr CH, Fisher SD, et al: Chylothorax in lymphangioleiomyomatosis. Chest 123:623–627, 2003. Ryu JH, Moss J, Beck GJ, et al: The NHLBI Lymphangioleiomyomatosis Registry: Characteristics of 230 Patients at Enrollment. Am J Respir Crit Care Med 173:105–111, 2006. Shepherd CW, Gomez MR, Lie JT, et al: Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 66:792– 796, 1991. Stefansson K: Tuberous sclerosis. Mayo Clin Proc 66:868–872, 1991. Taylor JR, Ryu J, Colby TV,et al: Lymphangioleiomyomatosis. Clinical course in 32 patients. N Engl J Med 323:1254–1260, 1990. Urban T, Lazor R, Lacronique J, et al: Pulmonary lymphangioleiomyomatosis. A study of 69 patients. Groupe d’Etudes et de Recherche sur les Maladies “Orphelines”

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Pulmonaires (GERM”O”P). Medicine 78:321–337, 1999. Whale CI, Johnson SR, Phillips KG, et al: Lymphangioleiomyomatosis: A case-control study of perinatal and early life events. Thorax 58:979–982, 2003. Yu J, Astrinidis A, Henske EP: Chromosome 16 loss of heterozygosity in tuberous sclerosis and sporadic lymphan-

Pulmonary Lymphangioleiomyomatosis

giomyomatosis. Am J Respir Crit Care Med 164:1537–1540, 2001. Yu J, Astrinidis A, Howard S, et al: Estradiol and tamoxifen stimulate LAM-associated angiomyolipoma cell growth and activate both genomic and nongenomic signaling pathways. Am J Physiol Lung Cell Mol Physiol 286:L694– 700, 2004.

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76 The Lungs in Patients with Inborn Errors of Metabolism Masazuni Adachi Francis A. Caccavo

I. NIEMANN-PICK DISEASE Clinical Features Genetics Pathological Features Histology Ultrastructure Biochemical Features Diagnosis II. GAUCHER’S DISEASE Clinical Features Genetics Pathological Features Ultrastructure Biochemical Features Therapy Diagnosis III. GM1 GANGLIOSIDOSIS (β-GALACTOSIDOSIS) Genetics Pathological and Ultrastructural Features Biochemical Features Diagnosis IV. SULFATIDE LIPIDOSIS (METACHROMATIC LEUKODYSTROPHY) Genetics Pathological and Biochemical Features Diagnosis

Pathological and Biochemical Features Diagnosis VI. FABRY’S DISEASE (α-GALACTOSIDASE A DEFICIENCY) Clinical Features Genetics Pathological Features Biochemical Features and Diagnosis VII. MUCOPOLYSACCHARIDOSIS Genetics Pathological Features Biochemical Features Diagnosis VIII. GLYCOGEN STORAGE DISEASE Genetics Pathological and Biochemical Features Diagnosis IX. DISORDERS OF AMINO ACID METABOLISM Genetics and Biochemical Features Diagnosis X. CYSTINE STORAGE DISEASE (LIGNAC-FANCONI DISEASE) XI. CONCLUSIONS

V. GALACTOSYLCERAMIDE LIPIDOSIS: GLOBOID-CELL LEUKODYSTROPHY (KRABBE’S DISEASE) Clinical Features Genetics

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A variety of diseases can be referred to collectively as being inborn errors of metabolism. As a result of increasingly sophisticated and complex biochemical and genetic approaches, our knowledge of these disorders has recently expanded greatly. Although many viscera and the central nervous system have been extensively studied in these disorders, comparatively little attention has been paid to the lungs. Most characterizations note that the â&#x20AC;&#x153;storedâ&#x20AC;? material is sometimes deposited in the interalveolar septa or alveoli, that these pathological changes occasionally lead to pulmonary hypertension and severe pulmonary arteriosclerosis, and that, in some instances, characteristic alterations in the lungs can be demonstrated on radiographic examination. The manifestations of these diseases are diverse.

NIEMANN-PICK DISEASE Niemann-Pick disease (NPD) is characterized by the excessive accumulation of sphingomyelin (types A, B and F) and cholesterol (types C, D, and E) in the cells of reticuloendothelial and parenchymal tissues of the viscera and/or the brain. The classification of NPD is based on the nature of the primary molecular defect. Types A, B, C, D, E, and F have distinct abnormalities. All types are autosomal-recessive disorders. Reticular or reticulonodular abnormalities are visible in chest radiographs of most patients with this disease.

Clinical Features Type A NPD is an acute disorder that affects infants and involves viscera and the nervous system. Almost one-half of affected infants are of Jewish extraction. The onset is insidious, and the children manifest difficulties in feeding and fail to thrive during the early months. The infants experience progressive psychomotor deterioration and hepatosplenomegaly. The chest radiograph (Fig. 76-1) shows diffuse reticular infiltration. The infants generally die during the second year of life. Type B is a chronic infantile form without neurological involvement. It is less common than types A and C. These infants often undergo hepatosplenomegaly and lymphadenopathy, which may develop as early as in infants with type A. However, most patients are in good health until late infancy. The children manifest increased susceptibility to pneumonia due to diffuse reticular infiltration by the lipids. They die during the juvenile stage. In type C NPD the clinical manifestations are heterogeneous. Type C NPD involves viscera and the central nervous system. The initial symptoms usually occur after the first or second year and occasionally after the sixth year of life. Psychomotor deterioration is progressive. Hepatosplenomegaly is less striking than in types A and B. These patients occasionally survive to adolescence: most often they die between the fifth and fifteenth years of life. In types C, D and E, NPD neurological symptoms progress slowly in late childhood (types C and D) and adulthood (type E).

Figure 76-1 Chest radiograph of a patient with Niemann-Pick disease (type A) showing bilateral diffuse reticular infiltration.

Type F NPD patients have a heat-labile form of acid sphingomyelinase.

Genetics The locus of the genes for types A and B NPD has been identified to be in chromosome 11p15.1 to p15.4. The molecular genetics have been derived from three cDNA (designated types 1, 2, and 3), and a total of 12 mutations have been identified as causing the type A and type B disorders. Nine were found to be single-base substitutions, and three were small deletions. Type 1 cDNA expressed catalytically active enzyme, and types 2 and 3 cDNA did not express catalytically active enzymes. In type C, the lesion has been mapped to chromosome 18p at genomic marker D18S40 (Fig. 76-1).

Pathological Features Particularly in type A NPD, the lungs are frequently increased in weight, and their cut surfaces show yellow mottling. The liver is markedly enlarged and reaches two to three times its normal weight. Cut surfaces are diffusely yellow but the original architecture is usually preserved. The weight of the spleen is often 5 to 6 times normal, and sections show a yellow color with peculiar salmon-pink spots that represent malpighian bodies. The lymph nodes are also enlarged. The brains of the patients with types A and C NPD are uniformly reduced in size; on section, the cortex and the white and deep gray matters are atrophic.

Histology Although some patients have no respiratory disturbances, foamy cells are usually contained in the pulmonary septa

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Figure 76-2 Sections from lung of a patient with Niemann-Pick disease (type A) exhibiting foamy cells in the alveoli (H&E, × 200).

and alveoli of most affected individuals (Fig. 76-2). These cells measure 15 to 90 µm in diameter and contain a single nucleus and cytoplasm with numerous fine vacuoles (Fig. 76-3). Similar foamy cells have been observed in other visceral organs and the nervous system. Although the foamy

cells are characteristic of this disease, they are not diagnostic without histochemical proof of sphingomyelin (types A and B) or cholesterol (type C). Because the cytoplasmic vacuoles seen in routine sections represent a partly soluble material that is dissolved during histological preparation,

Figure 76-3 Under higher magnification, the foamy cells from a patient with Niemann-Pick disease (type A) contain one or two nuclei and numerous fine vacuoles (H&E, × 640).

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Figure 76-4 Electron micrograph of a portion of a foamy cell from a patient with Niemann-Pick disease containing cytoplasmic inclusion bodies which are membrane-bound and contain loosely arranged membranous structures (× 7200).

frozen sections are often required for this biochemical analysis (Fig. 76-2).

Ultrastructure The foamy cells seen in the tissues of patients with NPD are filled with round to oval cytoplasmic bodies that range from 0.5 to 5 µm in diameter. These bodies are membrane-bound and contain loosely arranged membranous structures in types A and B NPD (Fig. 76-4). Electron-lucent vacuoles that are frequently accompanied by electron-dense membranes are seen in type C NPD. Histochemical preparations for lysosomal enzymes reveal reaction granules in the cytoplasmic inclusion bodies that are residua of a cellular effort to eliminate the accumulated lipid material.

Diagnosis Once suspicion of the disease is aroused types A and B NPD can be diagnosed by biochemical assays of sphingomyelinase in fresh blood samples and frozen tissue. The diagnosis of type C NPD requires analysis of cellular cholesterol esterification and the demonstration of filipin-cholesterol staining in cultured fibroblasts during low-density lipoprotein uptake. Enzyme analysis is not reliable for heterozygote studies, and molecular genetic identification is required. The peripheral smear, bone marrow, and/or lymph nodes or liver should be examined for foamy cells by special histochemical preparations. Types D and E also demonstrate abnormal cholesterol metabolism. Type F has heat-labile acid sphingomyelinase.

GAUCHER’S DISEASE Biochemical Features An increase of 2 to 30 times normal in the sphingomyelin content of the viscera and/or brain is the basis for the diagnosis of types A and B NPD. The esterified cholesterol content of the viscera is increased in type C. A deficiency of sphingomyelinase is the primary defect in types A and B, whereas impaired cholesterol metabolism occurs in types C, D, and E. Type F shows heat-labile acid sphingomyelinase.

Gaucher’s disease is a hereditary disorder which is transmitted as an autosomal-recessive trait. It is characterized by the accumulation of glucosyl ceramide in various organs in association with a deficiency of β-glucosidase.

Clinical Features Three types of Gaucher’s disease are usually recognized. Type 1, the “adult form,” is the most common and usually

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occurs in Ashkenazi Jews. It is a chronic disorder that may start soon after birth and usually lasts into childhood. It differs from the other types in its lack of neurological manifestations. Type 2 is the acute form. It occurs in infants and is characterized by progressive neurological deterioration. The incidence in Jewish families is less than in type 1. Type 3 is the subacute variety. It occurs in juveniles and undergoes a more protracted course of neurological deterioration than the type 2 disorder. Some type 1 patients with the adult form of Gaucher’s disease die early in life due to thrombocytopenia, severe anemia, and pulmonary infections. Hepatosplenomegaly and Gaucher’s cells in the bone marrow are regular features. The concentration of acid phosphatase in serum is also markedly increased. Pulmonary hypertension and severe pulmonary arteriosclerosis occur in some patients. The reticular pattern of pulmonary infiltration that is characteristic of NPD is rare. Repeated episodes of bone pain are common, and fractures after minor trauma sometimes lead to permanent deformity. On radiologic examination, osteolytic changes are frequently seen. In type 2 patients, the children develop normally until the age of 3 to 6 months. Thereafter, hepatosplenomegaly and lymphadenopathy become prominent, and Gaucher’s cells are found in the bone marrow. High levels of serum acid phosphatase are sometimes found as early as at 3 months of age. Progressive psychomotor deterioration then sets in, and the patients die within 2 years. In patients with the type 3 disorder, the course of neurological changes is more protracted. These patients also show splenomegaly and slowly progressive hepatomegaly. On radiologic examination, the children often display pulmonary infiltration. However, the typical reticular pattern is rare. Osteolytic lesions are frequent. About one-half of the patients with this variant have been reported from four interrelated families in the province of Norrbotten in northern Sweden. The mode of inheritance is also consistent with an autosomal-recessive trait. E-rosette–forming peripheral lymphocytes are defective in Gaucher’s disease. This abnormality is caused by serum factors, one of which involves increased levels of ferritin, which have been found in these patients. The ferritin dysregulation may play a role in the high incidence of cancer in patients with Gaucher’s disease.

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Pathological Features The spleen, liver, and lymph nodes of patients with this disease are markedly enlarged. Gaucher’s cells are the histological hallmark of the disease (Fig. 76-5). They are round or polygonal in shape, measure 20 to 80 µm in diameter, and fibrils of varying sizes in their cytoplasm give the appearance of striation. Histochemically, Gaucher’s cells show a characteristic reaction; they stain pink to red by the modified periodic acid– Schiff stain for cerebroside. These cells are primarily derived from the reticuloendothelial system. An unusual patient with Gaucher’s disease has been reported: the patient is a 25-yearold black woman who had Gaucher’s disease since 1 year of age with cardiac and renal involvement with pulmonary hypertension. Although pulmonary infiltrates are typical on the chest radiograph, the infiltrates have not been extensively described in the literature. Severe involvement of the lungs in the adult disorder has been described in three patients with symptoms since infancy followed by the juvenile onset of dyspnea (Fig. 76-5). The lungs of these patients were heavy, and the cut surfaces revealed diffuse interstitial infiltrates. Gaucher’s cells were found in the alveolar septa. The Gaucher’s cells were located perivascularly and blocked gas exchange since they filled the alveoli. Also reported have been glomoid lesions in pulmonary arterioles with dilatation of postglomoid vessels which form angiomatoids typical of grade A3 hypertensive pulmonary vascular disease (Fig. 76-6), and

Genetics The gene coding acid β-glucosidase is located on chromosome 1 at q21. The gene for the enzyme is approximately 7 kb in length and contains 11 exons. A variety of mutations of this gene have been found to cause Gaucher’s disease including missense mutations, frameshift mutations, a splicing mutation, deletions, gene fusions with a pseudogene, and gene conversions. The most common mutation in the Ashkenazi Jewish population is at nucleotide 1226, where an alteration in A-to-G causes an amino acid substitution in acid β-glucosidase.

Figure 76-5 Gaucher’s cells from an infant with Gaucher’s disease. They contain numerous fibrils and appear striated (H&E, × 1090).

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Figure 76-6 A & B. Low- and high-powered photomicrographs of pulmonary parenchymal infiltration by Gaucher’s cells. The vascular bed appears to be absent in much of the tissue and what remains shows distension of capillaries with blood. C . Atherosclerotic lesion from the main pulmonary artery. D . Glomoid lesion in a pulmonary arteriole with dilatation of postglomoid vessels forming an angiomatoid, typical of grade A3 hypertensive pulmonary vascular disease. (Courtesy of Dr. G.M. Hutchins, Am J Med 65:356, 1978.)

numerous marrow emboli of various ages containing Gaucher’s cells. In one series, malignant tumors associated with Gaucher’s disease have been reported in 35 of 275 patients.

The associated malignancies were myeloma, Hodgkin’s disease, acute myelogenous leukemia, lymphatic leukemia, carcinoma of the lung, breast, kidney, liver, colon, pancreas, skin, mouth, larynx, prostate, and brain.

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Figure 76-7 Electron micrograph of a portion of a Gaucher’s cell showing pleomorphic Gaucher’s bodies (GB) which contain tubular structures (× 43,000).

Ultrastructure

Therapy

The Gaucher’s cells contain pleomorphic cytoplasmic inclusion bodies enveloped in a single limiting membrane. These inclusions, called “Gaucher’s bodies,” contain tubular structures measuring 120 to 250 ˚A in diameter (Fig. 76-7), each of which consists of 10 to 12 fibrils in a characteristic arrangement. The inclusion bodies are derived from the cisternae of the endoplasmic reticulum. Acid phosphatase preparations disclose reaction granules within the Gaucher’s bodies which indicate the lysosomal character of the inclusion material (Figs. 76-6 and 76-7).

Bone marrow transplantation has been employed in severe Gaucher’s disease. It was successful in restoring β-glucosidase in mononuclear white blood cells and plasma with complete engraftment of the enzymatically normal donor cells. However, Gaucher’s cells persisted in the bone marrow. The 8-year-old patient with type 3 Gaucher’s disease died of sepsis 13 months after bone marrow transplantation.

Biochemical Features The organs of patients with the three types of Gaucher’s disease almost always have a marked increase in the concentration of glucose-1-ceramide, occasionally exceeding 100 times normal. The enzyme defect in Gaucher’s disease is a deficiency of β-glucosidase which catalyzes the cleavage of glucose from glycosyl ceramide.

Diagnosis All suspected cases of Gaucher’s disease should undergo a careful radiologic survey of the lungs and bones, identification of Gaucher’s cells in smears from the bone marrow, and assays of β-glucosidase in leukocytes, or cultured fibroblasts. Should liver biopsy or splenectomy be undertaken, enough fresh frozen tissue (1.0 g) should be preserved for determination of the levels of glycosyl ceramide and β-glucosidase activity. Portions of these tissues should be studied histologically and

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electron microscopically. For heterozygote studies, molecular genetic identification is required.

GM1 GANGLIOSIDOSIS (β-GALACTOSIDOSIS) Three types of GM1 gangliosidosis have been recognized. The type 1 disorder is an infantile form with generalized gangliosidosis, accompanied by bone involvement and psychomotor retardation. Early in the disease, the lungs are unremarkable. Later, bronchopneumonia is common, and the patients usually die of bronchopneumonia before the age of 2 years. Radiologically, abnormalities similar to Hurler’s disease are observed after 6 months. Foamy cells are demonstrable in smears of bone marrow. The type 2 disorder is a late infantile, juvenile form with milder bone abnormalities and progressive motor and mental deterioration. The average life span of children with this variant varies from 3 to 10 years. Visceral histiocytosis is less common, but neuronal lipidosis occurs more often than in type 1. The type 3 disorder is an adult, chronic form with juvenile onset of progressive cerebellar dysarthria and slow but progressive motor and intellectual impairment. Long-term survival is characteristic of this variant.

Genetics The β-galactosidase gene has been mapped to chromosome 3p21-3q21. The cDNA coding for this enzyme has been cloned, and the genomic organization of the gene has been determined. Molecular genetic analysis has demonstrated heterogeneous genetic mutations in infantile GM1 gangliosidosis.

Pathological and Ultrastructural Features Grossly, the liver, spleen, and kidneys of patients with this disease are usually increased in size and weight, but their lungs generally appear normal. The most striking histological finding is the presence of foamy histiocytes in many visceral organs. In the lungs, these cells are observed in the alveoli and septa. The material in their cytoplasmic vacuoles consists of complex proteolipid compounds. These cells also contain membrane-bound inclusions which consist of moderately electron-dense material mixed with fine granules (Fig. 76-8).

Biochemical Features A deficiency of β-galactosidase is the underlying basis of this disorder. The deficiency causes ganglioside G M1 to accumulate in the different organs. The deficiency of β-galactosidase apparently also interferes with the degradation of mucopolysaccharides (Fig. 76-8).

Diagnosis The diagnosis of β-galactosidosis can be confirmed by analysis of β-galactosidase activity in leukocytes, urine, and skin.

Ultrastructural studies of biopsies of rectal mucosa can also be useful. Since enzyme studies are unreliable for heterozygotes, gene analysis is required for detection of carriers.

SULFATIDE LIPIDOSIS (METACHROMATIC LEUKODYSTROPHY) Five categories of sulfatide lipidosis have been identified based on the age of onset of clinical manifestations: congenital, late infantile, early juvenile, late juvenile, and adult. In addition, two other types have been identified: multiple sulfate deficiency (MSD) and cerebroside 4-6 sulfatase activator deficiency. The clinical manifestations of these disorders predominantly reflect the striking changes in the white matter of the brain that occur during the course of the disease. MSD, however, begins with respiratory difficulty in early infancy followed by progressive psychomotor deterioration.

Genetics The arylsulfatase A gene is located on chromosome 22 at q13. The mutations underlying the disorder have been identified in 60 to 70 percent of the arylsulfatase A gene. Therefore, carrier studies using genetic analysis are not feasible. The cerebroside sulfatase activator gene is located on chromosome 10 at q21-q22. Its mutations in patients with this disorder are incompletely understood.

Pathological and Biochemical Features Grossly, the visceral organs from patients with sulfatide lipidosis are unremarkable. In contrast, microscopic changes are widespread and characterized by metachromatic cytoplasmic inclusion bodies, commonly affecting the lungs. These metachromatic granules are within histiocytes in the interalveolar septa but not in the alveolar spaces or in the vascular walls of the septa. Ultrastructural examination indicates that the cytoplasmic inclusion bodies are composed primarily of lamellar structures and irregular whorls. Patients afflicted with this disease show a marked increase in the concentration of cerebroside sulfatides in their brain and viscera. This abnormality is secondary to the reduced activity of arylsulfatase A and to a lesser degree arylsulfatase B. Arylsulfatase C is affected only in MSD.

Diagnosis The most important diagnostic procedure for βgalactosidosis is the quantification of arylsulfatase A activity levels in the leukocytes or cultured skin fibroblasts from patients who are suspected of having the disorder. Analysis for sulfatase A in the urine is rapid and simpler but less reliable. Heterozygotes can be identified by leukocyte

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Figure 76-8 Electron micrograph of a portion of a foamy cell from a patient with GM1 gangliosidosis showing cytoplasmic membrane-bound inclusion bodies (B) which contain electron-lucent material mixed with fine granules (Ă&#x2014; 15,000).

and fibroblast assays for arylsulfatase A and cerebroside sulfatase.

GALACTOSYLCERAMIDE LIPIDOSIS: GLOBOID-CELL LEUKODYSTROPHY (KRABBEâ&#x20AC;&#x2122;S DISEASE) Clinical Features Three clinical forms of galactosylceramide lipidosis (GL) have been described based on the age of the patient at the onset

of the disease. In most patients the disease occurs in early infancy, exhibiting its first clinical symptoms at 3 to 6 months of age. The disease is characterized by progressive psychomotor deterioration that generally culminates in death within 2 years. The late infancy form is rare and manifests as mental deterioration, pyramidal signs, and visual impairment in children 2 to 6 years old. The duration of this variant is approximately 1 to 5 years. In the adult form, the main clinical manifestation is visual impairment that starts between the ages of 10 and 35 years. Patients with this disease variant also exhibit slowly progressive motor deterioration and usually survive 2 to 10 years after presentation.

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Genetics

Diagnosis

GL is transmitted as an autosomal-recessive trait. The galactosylceramidase gene has been mapped to chromosome 14. The cDNA or the gene coding for the enzyme has not been cloned and the mutations underlying the disorder have not been characterized.

In infants suspected of having GL serum, leukocytes or cultured fibroblasts should be studied to quantitate the activity of galactocerebroside β-galactosidase.

Pathological and Biochemical Features In β-galactosidosis the gross pathological changes are generally confined to the brain. The white matter of all lobes of the brain is extensively affected whereas the cortices and deep gray matter are relatively preserved. Although the visceral organs appear normal, giant cells, similar to the globoid cells in the nervous system, also occur in the lungs, lymph nodes, spleen, and bone marrow. The globoid cells, which are derived from histiocytes, are characterized by large round cell bodies, several peripherally placed nuclei which are 20 to 50 µm in diameter, and fine cytoplasmic granules (Fig. 76-9). Similar lesions have been found in a variety of animal models of this disease in sheep, dogs, and the twitcher mouse (Fig. 76-9). The primary defect in this disorder involves the enzyme galactocerebroside β-galactosidase. This leads to a marked increase in the galactosylceramide concentrations in the white matter of the brain and subsequent cerebral dysfunction.

FABRY’S DISEASE (α-GALACTOSIDASE A DEFICIENCY) Fabry’s disease (FD) is the only sphingolipidosis that is transmitted by the gene on the X chromosome that controls the hydrolytic enzyme α-galactosidase A. The clinical picture results from the progressive accumulation of globotriaosyl (ceramide) in most visceral organs as well as the brain.

Clinical Features The clinical manifestations of this disease most often occur in men but occasionally occur in heterozygote women. FD presents in childhood or adolescence with two types of symptoms: severe pain and telangiectasis. The pain is often in the form of a lightning or burning sensation in the fingers or toes that extends to the palms and soles, respectively. Attacks of abdominal or flank pain simulate those of appendicitis or renal colic. The telangiectases are symmetrical, involve the superficial layers of the skin, do not blanch on pressure, and are progressive. The oral mucosa, conjunctivae, hips, back, thighs, buttocks, penis, and scrotum are most commonly involved. The area between the umbilicus and the knees is involved less often but can be severely affected. Some patients with this disease develop abnormalities in the lungs. These abnormalities range from obstructive disease of the airways to diffuse interstitial abnormalities. Pulmonary function tests in older patients may reveal significant airflow obstruction, a reduced diffusing capacity, and a reduction in the Vmax25 values. Pulmonary complications are a frequent cause of death.

Genetics The gene that is responsible for this disease has been localized to chromosome Xq22. The α-galactosidase A cDNA and genomic sequences have been isolated, characterized, and used to analyze the mutations that cause the disease. Partial gene rearrangements, splice-junction defects, and point mutations have been identified.

Pathological Features

Figure 76-9 The globoid cell from a child with Krabbe’s disease is characterized by large, round cell bodies containing several peripherally placed nuclei and many cytoplasmic fine granules (H&E, × 1100).

Compared to appropriate controls, the lungs from patients with FD are increased in weight and have cut surfaces that are often congested and edematous. Multiple vacuoles also occur in the alveolar epithelium, airway, and vascular smoothmuscle cells and capillary endothelial cells. Ultrastructural examination shows that both the capillary endothelium and the alveolar type II cells contain laminated inclusions with a periodicity of 50 to 60 A. This pattern contrasts with the variable periodicity of the lamellar bodies contained within the type

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II cells in the normal lung. The cytoplasmic inclusion bodies in the ciliated epithelial cells and goblet cells stain darkly with toluidine blue. Ultrastructurally, these inclusion bodies are limited by a single membrane and contain electron-dense lamellae arranged in either a parallel or concentric fashion. Alveolar macrophages are devoid of these inclusions.

Biochemical Features and Diagnosis The primary enzyme defect in this disorder is the absence of α-galactosidase A activity. Affected males can be identified by demonstrating an increase in globotriaosylceramide and by assaying hydrolase activity in serum, leukocytes, tears, and cultured skin fibroblasts.

MUCOPOLYSACCHARIDOSIS The term mucopolysaccharidosis (MPS) refers to a group of genetic diseases manifested by abnormal tissue deposition of acid mucopolysaccharide (glycosaminoglycans). Seven major forms of the disease have been recognized: Hurler’s syndrome (MPS I), Scheie’s syndrome (MPS IS, formerly V), Hunter’s syndrome (MPS II), Sanfilippo’s syndrome (MPS III), Morquio’s syndrome (MPS IV), Maroteaux-Lamy syndrome (MPS VI), and Sly’s syndrome (MPS VII). The most severely affected patients (except for those with type IS) commonly have respiratory involvement, particularly obstructive disease of the airways.

Genetics The MPS diseases are transmitted in an autosomal-recessive pattern, except for MPS II, which is X-linked. The MPS I gene has been assigned to chromosome 22 at 4p16.3, the MPS II locus to Xq27-28, the gene of the very rare MPS III D (Sanfilippo D) to 12q14, the MPS IV A (Morquio A) gene to 16q24, the MPS VI gene to 5q13-q14, and the MPS VII gene to 7q21-q22.

Pathological Features The visceral organs from patients with MPS can be grossly abnormal. However, the exact pattern of involvement varies with the type of disease that is manifested. Interestingly, in these patients, the lungs are rarely visibly abnormal. In type I, MPS histological alterations are seen in almost all organs, including the lungs. The characteristic feature is the presence of an abnormal deposited material in cells that are variously called clear cells, gargoyle cells, Hurler’s cells, or balloon cells. The cells are large, oval or polygonal, measure 20 µm in diameter, and contain pale central nuclei. Frozen sections exhibit metachromatic material that stains with toluidine blue and gives a positive reaction in Alcian blue preparations. Characteristically the cells also contain round or oval inclusion bodies that are membrane-bound and display an electron-lucent or low electron-dense material, occasionally mixed with fine

The Lungs in Patients with Inborn Errors of Metabolism

granules or lamellae. The histological changes in types II and III MPS are similar to those of type I. The histological findings in the other types are less well documented.

Biochemical Features Patients with types I and IS MPS have a deficiency of αl-iduronidase and increased urinary excretion of dermatan sulfate and heparin sulfate. The deficiency in type II MPS involves iduronate sulfatase. Dermatan sulfate and heparin sulfate are also excreted in abnormally large quantities in the urine of patients with this disorder. Although about 80 percent of the extracted mucopolysaccharide is dermatan sulfate in type I, in type II that portion is about 55 percent. In type III MPS, lesions have been found in the four enzymatic steps involved in the excretion and accumulation of heparin sulfate. The abnormalities are in heparin N-sulfatase in type III A; N-acetyl-α-d-glucosaminidase in type III B; acetyl CoA: α-glucosaminide-N-acetyltransferase in type III C; and N-acetyl-α-d-glucosaminide-6-sulfatase in type III D. The enzymatic defects in type IV MPS involve galactosamine6-sulfate sulfatase in type IV A and β-galactosidase in type IV B. As a result these patients have increased levels of urinary keratan sulfate. Type VI MPS is due to a deficiency of arylsulfatase B activity, which results in increased urinary excretion of dermatan sulfate; type VII MPS is the result of the defective degradation of dermatan sulfate and heparin sulfate due to a deficiency of β-glucuronidase.

Diagnosis The excretion of urinary mucopolysaccharides is markedly increased in many of these disorders. Although metachromatic material can be demonstrated in polymorphonuclear leukocytes and lymphocytes, the diagnosis can only be established by measuring urine mucopolysaccharides with precise identification of the substance excreted. The characteristic enzyme defect of each disorder should also be studied in leukocytes, serum, or fibroblasts from the patient.

GLYCOGEN STORAGE DISEASE Among the major groups of glycogen storage disorders (GSD), Pompe’s disease (GSD, type II) frequently shows cardiorespiratory disturbances. Hypotonia, which often develops by 2 months of age, is the cardinal feature of this disorder. The heart is markedly enlarged, and heart failure is common. Most patients die within the first year of life. However, a few survive up to 15 years.

Genetics The disease is transmitted as an autosomal-recessive trait. It is believed to result from the dysfunction of the structural gene for acid α-glucosidase, which is located at chromosome 17 q23.

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fections within the first year. However, with the help of a synthetic diet, some patients have survived for as long as 13 years. Despite severe clinical symptoms in early life, at autopsy only the brain shows specific changes. Grossly, it exhibits microcephaly and microgyria. Histologically it shows a deficiency in myelin sheaths, presumably a result of reduced synthesis of proteolipids.

Genetics and Biochemical Features

Figure 76-10 Intra-alveolar and interstitial macrophage laden with glycogen granules (black granules). (Best’s glycogen stain.) (From Spencer H: Pathology of the Lung. Oxford, Pergamon Press, 1985, pp 753–754, with permission.)

MSUD is an autosomal-recessive disorder that is thought to result from abnormalities in the genes of the branched chain α-ketoacid dehydrogenase complex (E1-E3). These genes are on different chromosomes: E1α to chromosome 19q13.1q13.2, E1β to 6p21-p22, E2 to 1p31, and E3 to 7q31-q32. The mutations in these enzymes cause a deficiency of branchedchain α-ketoacid dehydrogenase resulting in increased levels of urinary amino acids (leucine, isoleucine, and valine) and plasma branched-chain ketoacids.

Pathological and Biochemical Features The lungs and brains of patients with GSD are grossly normal. In contrast, the heart is usually markedly enlarged and increased in weight (Fig. 76-10). About one-fifth of the patients show thickening of the endocardium similar to that seen in endocardial fibroelastosis. Hepatomegaly is also frequent. Histologically, GSD is characterized by the massive accumulation of glycogen granules in the cytoplasm of the parenchymal cells of most organs including the lungs. Foamy alveolar macrophages filled with glycogen-like material also occur (Fig. 76-10). Glycogen is present in smaller amounts in cartilage cells and mucosal and bronchial epithelial cells. Ultrastructurally, the cytoplasmic inclusion bodies are membrane-bound and contain electrondense glycogen granules. The massive accumulation in this disorder of tissue glycogen is due to a deficiency in acid maltase (acid α-glucosidase) activity.

Diagnosis The diagnosis of GSD can be established by demonstrating increased concentrations in tissues of glycogen and a deficiency of α-glucosidase activity. Studies of urine, muscle tissue, and cultured fibroblasts are helpful in this regard.

DISORDERS OF AMINO ACID METABOLISM Among the various types of amino acid metabolic disorders, only maple syrup urine disease (MSUD) (leucinosis, branched-chain ketonuria) is occasionally associated with bouts of respiratory difficulty for which there is no infectious explanation. In affected infants, respiratory distress develops within the first week of life. The infants often become apneic and require respiratory assistance. Severe psychomotor deterioration and episodes of seizures occur during the course of the disease, and the children usually die from intercurrent in-

Diagnosis Patients with this disease classically have a maple-syrup-like odor of their urine which can be detected within the first weeks of life. Although the odor is clinically the most distinctive sign of this disease, the diagnosis should be verified by studies of the amino acids and ketoacids in blood and urine. The diagnosis is confirmed by enzymatic studies of leukocytes or cultured skin fibroblasts and lymphoblasts.

CYSTINE STORAGE DISEASE (LIGNAC-FANCONI DISEASE) This disorder causes widespread pathological changes in many organs. It is inherited as a simple Mendelian recessive and manifests in children as severe rickets or dwarfism with marked photophobia, amino aciduria, and death from infection or renal dysfunction. The disease affects the lungs, bones, kidneys, lymph nodes, spleen, and liver. The deposits provoke no cellular reaction and do not alter pulmonary function. The deposits may be mistaken for calcium with von Kossa’s stain if they contain traces of cystine. The cystine is water-soluble, and thus sections are best fixed in absolute alcohol. In tissue sections, the crystals are birefringent and form clumps of radiating needlelike crystals when treated with concentrated sulfuric acid and phosphotungstic acid. The crystals in the lungs are mainly distributed within the peribronchial and periarterial reticuloendothelial cells in the alveolar septa.

CONCLUSIONS Enzyme replacement therapy for these storage diseases is not totally successful at present. However, the birth of children

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afflicted with inborn errors of metabolism can be prevented by prenatal diagnosis through amniocenteses and analysis of enzyme activity of cultured amniotic cells. Therefore, advice for genetic counseling seems to be one of the important functions of the physician if the parents are homozygotes or carriers and may produce a child afflicted with one of these disorders.

SUGGESTED READING Beutler E, Grabowski GA: Gaucher disease, in Scriver CR, Beam AL, Sly WS, et al (eds), The Metabolic and Molecular Bases of Inherited Diseases, 7th ed, Vol 2. New York, McGraw-Hill, 1995, pp 2641–2670. Carstea ED, Polymeropoulos MR, Parker CC, et al: Linkage of Niemann-Pick disease type C to human chromosome 18. Proc Natl Acad Sci USA 90:2002–2004, 1993. Chaung DT, Shih VE: Disorders of branched chain amino acid and keto acid metabolism, in Scriver CR, Beaudet AL, Sly WS, et al (eds), The Metabolic and Molecular Bases of Inherited Disease, 7th ed, Vol 1. New York, McGraw-Hill, 1995, pp 1239–1277. Desnick RJ, Ioannou YA, Eng CM: α-galactosidase A deficiency Fabry disease, in Scriver CR, Beaudet CR, Sly WS, et al (eds), The Metabolic a nd Molecular Bases of Inherited Diseases, 7th ed (Vol 2). New York, McGraw-Hill, 1995, pp 2741–2784. Hirschhom R: Glycogen storage type II: Acid cr-glucosidase (acid maltase) deficiency, in Scriver CR, Beaudet AL, Sly WS, et al (eds), The Metabolic and Molecular Bases of Inherited Diseases, 7th ed, Vol 2. New York, McGraw-Hill, 1995, pp 2443–2464. Holtshmidt H, Sandhoff K, Furst W, et al: The organization of the gene for the human cerebroside sulfate activator protein. FEBS Lett 280:267, 1991. Kolodny EH, Fluharty AL: Metachromatic leukodystrophy and multiple sulfatase deficiency: Sulfatide lipidosis, in Scriver CR, Beaudet AL, Sly WS, et al (eds), The Metabolic and Molecular Bases of Inherited Diseases, 7th ed, Vol 2. New York, McGraw-Hill, 1995, pp 2693–2739. Neufeld EF, Muenzer J: The mucopolysaccharidoses, in Scriber CR, Beaudet AL, Sly WS, et al (eds), The Metabolic and Molecular Bases of Inherited Diseases, 7th ed, Vol 2. New York, McGraw Hill, 1995, pp 2465–2494.

The Lungs in Patients with Inborn Errors of Metabolism

O’Brien JS: Sanfilippo syndrome: profound deficiency of aacetyl-glucosaminidase activity in organs and skin fibroblasts from type B patients. Proc Natl Acad Sci USA 69:1720– 1723, 1970. Okada S, O’Brien JS: Generalized gangliosidosis: Betagalactosidase deficiency. Science 160:1002–1004, 1968. Patrick AD: A deficiency of glucocerebrosidase in Gaucher’s disease. Biochem J 97:17c, 1965. Pentchev PG, Comly ME, Kruth HS, et al: The cholesterol storage disorder of the mutant BALB/c mouse. A primary genetic lesion closely linked to defective esterification of exogenously derived cholesterol and its relationship to human type C Niemann-Pick disease. J Biol Chem 261:2772– 2777, 1986. Pereira L, Desnick RJ, Adier D, et al: Regional assignment of the human acid sphingomyelinase gene (SMPDI) by PC analysis of somatic cell hybrids and in situ hybridization to 11p15.1-pl5.4. Genomics 9:229–234, 1991. Quintem L, Schuchman EH, Levran O, et al: Isolation of cDNA clones encoding human acid sphingomyelinase. Occurrence of alternatively spliced transcripts. EMBO J 8:2469–2473, 1989. Scuchman EH, Desnick RJ: Niemann-Pick disease types A and B: Acid sphingomyelinase deficiencies, in Scriver CR, Beaudet AL, Sly WS, et al (eds), The Metabolic and Molecular Bases of Inherited Diseases, 7th ed, Vol 2. New York, McGraw-Hill, 1995, pp 2601–2624. Schuchman EH, Suchi M, Takahashi T, et al: Human acid sphingomyelinase. Isolation, nucleotide sequence and expression of the full-length and alternatively spliced RNAs. J Biol Chem 266:8531–8539, 1991. Suzuki K, Suzuki Y, Suzuki K: Galactosylceramide lipidosis: Globoid-cell leukodystrophy (Krabbe disease), in Scriver CR, Beaudet AL, Sly WS, et al (eds), The Metabolic and Molecular Bases of Inherited Diseases, 7th ed, Vol 2. New York, McGraw-Hill, 1995, pp 2671–2692. Suzuki Y, Sakuraba H, Oshima A: β-galactosidase deficiency (β-galactosidosis): GM1 gangliosidosis and Morquio B disease, in Scriber CR, Beaudet AL, Sly WS, et al (eds), The Metabolic and Molecular Bases of Inherited Diseases, 7th ed, Vol 2. New York, McGraw-Hill, 1995, pp 2785–2823. Yamano T, Shimada M, Okada S, et al: Ultrastructural study of biopsy Ziotogora J, Charkraborty S, Knowleton RG, et al: Krabbe disease locus mapped to chromosome 14 by genetic linkage. Am J Hum Genet 47:37–44, 1990.

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VIII Alveolar Diseases

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77 Alveolar Hemorrhage Syndromes Joseph P. Lynch, III

James W. Leatherman

I. AUTOIMMUNE CAUSES OF ALVEOLAR HEMORRHAGE: DIFFERENTIAL DIAGNOSIS II. CLINICAL FEATURES OF AUTOIMMUNE ALVEOLAR HEMORRHAGE III. DIAGNOSIS The Role of Lung Biopsy The Role of Percutaneous Kidney Biopsy IV. THERAPY OF IMMUNE-MEDIATED ALVEOLAR HEMORRHAGE

Diffuse alveolar hemorrhage (DAH) is a potentially catastrophic complication of myriad immune and nonimmune disorders. Clinical features are broad, but hemoptysis, infiltrates on chest radiographs, hypoxemia, and progressive respiratory insufficiency are common to diverse etiologies. Nonimmune causes of alveolar hemorrhage include endobronchial tumors, arteriovenous malformations or aneurysms, ulcerative tracheobronchitis, hemorrhagic pneumonia, bronchiectasis, congestive heart failure, uremia, thrombocytopenia or coagulopathy, pulmonary venoocclusive disease, and massive pulmonary embolism. These nonimmune causes need to be excluded in patients with severe alveolar hemorrhage. Depending upon the clinical scenario, coagulation profiles and ancillary tests (e.g., echocardiogram, chest computed tomographic [CT] pulmonary angiography, fiberoptic bronchoscopy) may be required to establish a specific diagnosis. In addition, other causes of diffuse parenchymal infiltrates (but without severe alveolar hemorrhage) share features in common with DAH syndromes (e.g., cryptogenic organizing pneumonia, hypersensitivity pneumonitis, pulmonary alveolar proteinosis, and diverse interstitial or alveolar lung disorders). A discussion of these disorders is beyond the scope of this chapter, which focuses primarily on immune-mediated causes of DAH.

V. SPECIFIC SYNDROMES Goodpasture’s Syndrome Systemic Vasculitis Alveolar Hemorrhage in Immunocompromised Hosts Alveolar Hemorrhage Complicating Bone Marrow Transplantation Alveolar Hemorrhage Complicating HIV Infection Alveolar Hemorrhage Due to Exogenous Agents Alveolar Hemorrhage Due to Exogenous Environmental Molds

AUTOIMMUNE CAUSES OF ALVEOLAR HEMORRHAGE: DIFFERENTIAL DIAGNOSIS Autoimmune DAH results from diffuse injury to the pulmonary microvasculature (termed capillaritis or endotheliitis) (Table 77-1). Systemic necrotizing vasculitides (principally microscopic polyangiitis [MPA] and Wegener’s granulomatosis [WG]) account for the majority of cases of autoimmune DAH. Other causes of autoimmune DAH include antiglomerular basement membrane antibody (anti-GBM) disease, collagen vascular disorders (principally systemic lupus erythematosus [SLE]), exogenous agents (e.g., trimellitic anhydride, isocyanates), or drugs (e.g., d-penicillamine, propylthiouracil, etc.). In many of these disorders, rapidly progressive glomerulonephritis (RPGN) is present concomitantly. In most patients with autoimmune DAH and glomerulonephritis (GN), anti-GBM antibody and immune complexes are lacking. The term pauci-immune glomerulonephritis has been used to refer to this group of patients, who encompass a heterogenous group of disorders (discussed in detail below). Idiopathic pulmonary hemosiderosis, a rare cause of recurrent DAH with no renal or extrapulmonary component, occurs primarily in children and remains a diagnosis of exclusion.

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Table 77-1 Etiology of Autoimmune Diffuse Alveolar Hemorrhage Antiglomerular basement membrane antibody disease (Goodpastureâ&#x20AC;&#x2122;s syndrome) Antineutrophil cytoplasmic antibody (ANCA) mediated vasculitis (e.g., Wegenerâ&#x20AC;&#x2122;s granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, pauci-immune glomerulonephritis) Idiopathic rapidly progressive glomerulonephritis

graphs typically reveal bilateral alveolar infiltrates, often with a bat-wing appearance. However, focal, and even unilateral, patterns indistinguishable from pneumonia may occur. Following cessation of bleeding, infiltrates markedly improve or normalize within 24 to 72 h (Fig. 77-1). A presumptive diagnosis of DAH can often be made by a combination of clinical and serological findings and bronchoalveolar lavage (BAL) fluid. Grossly bloody BAL fluid (with progressively more blood with serial aliquots), large numbers of hemosiderinladen macrophages, and the absence of purulent secretions or ancillary evidence for infection strongly support DAH as a cause of pulmonary infiltrates. Ancillary studies including serologies, renal function tests, and urinalysis may support the diagnosis.

Collagen vascular disease (e.g., systemic lupus erythematosus) Immunocompromised status (e.g., bone marrow transplant, AIDS) Exogenous agents or drugs (e.g., trimellitic anhydride, isocyanates, d-penicillamine, cocaine) Idiopathic pulmonary hemosiderosis (pathogenesis unknown)

Differentiation of these diverse syndromes can usually be accomplished by serological studies and by kidney biopsy. In such cases, lung biopsy is not required. GN can be demonstrated in the great majority of patients with DAH complicating WG or MPA. By contrast, the kidneys may be spared in DAH associated with collagen vascular disease, bone marrow transplant recipients, or immunocompromised patients. Urinalysis (to look for microscopic hematuria, red cell casts, and proteinuria) and measurement of renal function should always be done in the diagnostic evaluation of DAH. Findings consistent with GN warrant a prompt and aggressive evaluation that should include percutaneous needle biopsy of the kidney.

CLINICAL FEATURES OF AUTOIMMUNE ALVEOLAR HEMORRHAGE Irrespective of etiology, the clinical, radiographic, and histopathological features of DAH may be similar. Classical findings are hemoptysis, diffuse alveolar infiltrates, hypoxemia, renal failure, and iron-deficiency anemia. However, the clinical spectrum is wide, and many of these features may be subtle or absent. In this context, the diagnosis of DAH may be difficult, as signs and symptoms overlap with diverse etiologies of diffuse alveolar infiltrates. Prompt diagnosis and institution of therapy is vital to avert early mortality from DAH and late sequelae from end-stage renal failure. Chest radio-

DIAGNOSIS The Role of Lung Biopsy The role of lung biopsy in the diagnosis of DAH and the determination of its etiology is controversial. We believe the risks of open or thoracoscopic lung biopsy are excessive in patients with severe DAH and respiratory failure. Postoperative complications such as infection and air leaks may be exacerbated by the corticosteroid or immunosuppressive agents used to treat many of these immune-mediated DAH syndromes. Furthermore, histological features are usually nonspecific. Predominant findings are extensive intra-alveolar hemorrhage and necrotizing pulmonary capillaritis (endotheliitis) (Fig. 77-2). Capillaritis is characterized by neutrophilic infiltration of capillaries, fragmented neutrophils (leukocytoclasis), and necrosis of the capillary walls (Fig. 77-3). Loss of the integrity of the alveolar-capillary basement membrane results in leakage of red blood cells and neutrophils into the alveolar space. Hemosiderin-laden macrophages (siderophages) accumulate within the alveolar spaces and interstitium; their presence is a clue to prior episodes of alveolar hemorrhage (Fig. 77-4). Capillaritis was initially described as a marker of systemic vasculitis, but may also be observed in myriad disorders associated with DAH (e.g., SLE, collagen vascular disorders, anti-GBM disease, bone marrow transplant recipients, and drug-induced DAH). An associated venulitis and arteriolitis may sometimes be present, but larger vessels are spared. Capillaritis is subtle and often overshadowed by DAH filling the alveolar spaces. Pulmonary capillaritis can be diagnosed by transbronchial biopsy, but this diagnosis is made with greater confidence when a larger biopsy specimen is obtained by video-assisted thoracoscopy or limited thoracotomy. Additional pathological features may be seen in patients with underlying granulomatous vasculitis (e.g., granulomas, necrosis, or eosinophils). Nongranulomatous inflammation in airways and lung interstitium, interstitial fibrosis, diffuse alveolar damage (DAD), fibrinous pleuritis, and cryptogenic

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Figure 77-1 A. Idiopathic rapidly progressive glomerulonephritis. Posterior-anterior (PA) chest radiograph from a 52-year-old man with rapidly progressive glomerulonephritis, hemoptysis, and bilateral alveolar infiltrates, consistent with alveolar hemorrhage. Bronchoalveolar lavage demonstrated blood-tinged fluid and numerous hemosiderin-laden macrophages. B . Idiopathic rapidly progressive glomerulonephritis. PA chest radiograph from the same patient 18 months later with diffuse bilateral alveolar infiltrates representing recurrent massive alveolar hemorrhage. He was treated with pulse methylprednisolone (1 g daily for 3 days), followed by a gradual corticosteroid taper. C . PA chest radiograph from the same patient 3 weeks later demonstrating complete resolution of the alveolar infiltrates. C

organizing pneumonia have also been described in DAH associated with antineutrophil cytoplasmic antibody (ANCA) vasculitic syndromes. Histological findings of alveolar hemorrhage and capillaritis, although distinctive, are nonspecific. Immunofluorescent stains (of lung or kidney) or serological markers (e.g., anti-GBM antibody or ANCA) are required to differentiate the various causes of autoimmune DAH (Table 77-2). Linear deposits of immunoglobulin G (IgG) along alveolar septa is pathognomonic for anti-GBM disease. A granular, or “lumpy-bumpy” pattern of immune complex deposits may be seen in SLE, systemic necrotizing vasculitis, or immune complex-mediated idiopathic RPGN. In patients with ANCA-associated capillaritis, immune complexes are usually lacking (hence the term pauci-immune). When immune DAH is suspected, a portion of the lung biopsy can be frozen for immunofluorescent (IF) stains, but IF stains of lung tissue are logistically difficult, and nonspecific background staining may lead to misinterpretation. When GN is present concomitantly, kidney IF stains are more sensitive and reliable.

Figure 77-2 Postmortem lung biopsy demonstrates large numbers of red blood cells within alveolar spaces in a patient with alveolar hemorrhage due to Wegener’s granulomatosis. There is no gross evidence for necrosis or granulomas. The alveolar architecture and septae are well preserved. These histopathological features are nonspecific (H&E). (From Gravelyn TR, Lynch III JP: Alveolar hemorrhage syndromes, IM–-Internal Medicine for the Specialist 8(1):63–83, 1987, copyright Medical Economics Company.)

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Figure 77-3 Pulmonary capillaritis. Intense inflammatory infiltrate involving pulmonary capillaries with intra-alveolar hemorrhage (H&E). (Courtesy of Thomas Colby, M.D. From Leatherman J: Autoimmune diffuse alveolar hemorrhage. Clin Pulm Med 1:356â&#x20AC;&#x201C;364, 1994, with permission.)

Despite the greater accuracy of surgical lung biopsy in evaluating DAH, we believe fiberoptic bronchoscopy with BAL is usually adequate to exclude infectious etiologies and support the diagnosis of DAH. Bloody or serosanguineous BAL fluid (consistent with active or recent bleeding) or hemosiderin-laden macrophages (a clue to prior episodes of alveolar hemorrhage) may be sufficient to justify initiation of therapy provided clinical and serological features are consistent. Thoracoscopic lung biopsy may be useful in noncritically ill patients with suspected DAH when ancillary studies, kidney biopsy, and BAL are nondiagnostic.

The Role of Percutaneous Kidney Biopsy Necrotizing GN is a cardinal (albeit nonspecific) feature of most immune-mediated DAH syndromes. The histological

spectrum is varied, ranging from mild mesangial thickening to severe crescentic GN. Vasculitis of renal arterioles is rarely found, even in granulomatous vasculitides. Because of the strong association of autoimmune DAH and GN, percutaneous kidney biopsy should be performed in any patient with suspected DAH who has abnormalities on urinalysis or renal function tests. Conventional hematoxylin and eosin (H&E) stains are nonspecific, but the demonstration of glomerular inflammation with necrosis and crescents supports the diagnosis of an immune-mediated etiology (Fig. 77-5). IF stains may clarify the nature of the underlying disorder. Bright linear IF staining along glomerular basement membranes is pathognomonic for anti-GBM disease (Fig. 77-6). A lumpy-bumpy IF pattern, consistent with deposits of immune complexes, is found in collagen vascular disorders and in idiopathic immune complex-mediated GN. Negative

Figure 77-4 Hemosiderin-laden macrophages (siderophages) are prominent in the alveolar interstitium in a patient with recurrent alveolar hemorrhage (H&E). (Courtesy of Joseph Fantone, M.D.)

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Table 77-2 Autoimmune Diffuse Alveolar Hemorrhage: Pathology and Serology Lung Pathology

Renal Pathology

Histopathology

Immunofluorescence Histopathology

Immunofluorescence Serology

ABMA disease (Goodpasture’s syndrome)

±Capillaritis

Linear

Wegener’s granulomatosis

Capillaritis Negative (±granulomatous)

Segmental necrosis, Paucicrescents immune

ANCA (c-ANCA>>> p-ANCA)

Microscopic polyangiitis

Capillaritis

Negative

Segmental necrosis, Paucicrescents immune

ANCA (p-ANCA or c-ANCA)

Systemic lupus erythematosus

Capillaritis

Granular

Variable

Granular

ANA

Negative

Normal

—

Negative

Idiopathic pulmonary ±Capillaritis hemosiderosis

Variable

ABMA (±p-ANCA)

ABMA = anti-basement membrane antibody; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody: p-ANCA = perinuclear antineutrophilcytoplasmic antibody; c-ANCA = cytoplasmic antineutrophil cytoplasmic antibody.

IF stains are characteristic of the pauci-immune GN of necrotizing vasculitis. Serologies are critically important in defining the underlying disorder responsible for DAH (particularly ANCA, anti-GBM antibody, and antinuclear antibodies). Recognizing the different pathogenetic mechanisms of these DAH syndromes is important, as the prognosis and treatment strategies differ.

THERAPY OF IMMUNE-MEDIATED ALVEOLAR HEMORRHAGE Because of the rarity of the immune-mediated pulmonaryrenal syndromes, controlled, randomized trials evaluating therapy are lacking. Corticosteroids are considered part of

Figure 77-5 Segmental necrotizing and crescentic glomerulonephritis due to vasculitis (H&E). (Courtesy of John Crosson, M.D. From Leatherman J: Autoimmune diffuse alveolar hemorrhage. Clin Pulm Med 1:356–364, 1994, with permission.)

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Figure 77-6 Linear immunofluorescent staining along glomeruli due to deposition of anti-basement membrane (anti-GBM) antibody. (Courtesy of John Crosson, M.D. From Leatherman J: Autoimmune diffuse alveolar hemorrhage. Clin Pulm Med 1:356–364, 1994, with permission.)

standard therapy for all the immune-mediated DAH syndromes (to be discussed in detail later in this chapter). For systemic necrotizing vasculitis, cyclophosphamide (or occasionally other immunosuppressive agents) are combined with corticosteroids. The role of cytotoxic agents in other immunemediated DAH syndromes needs to be individualized. For severe, fulminant autoimmune DAH, high-dose intravenous (IV) (“pulse”) methylprednisolone (1 g daily for 3 days) is advised (irrespective of underlying etiology), even while pursuing a diagnostic workup. Delaying pulse therapy in a critically ill patient for even a few hours may be catastrophic. Rapid resolution of bleeding can occur, often within 24 to 72 h of initiation of therapy (Fig. 77-7). Following the 3-day pulse, corticosteroids (dose of methylprednisolone 60 to 120 mg per day or equivalent) should be continued for a few days, until control of the bleeding and extrapulmonary manifestations has been achieved. The subsequent dose and rate of corticosteroid taper need to be individualized, based upon clinical, radiographic, and serological response. Cyclophosphamide or other immunosuppressive agents should be withheld until a specific diagnosis mandating treatment with these agents has been substantiated. The specific therapeutic regimen is dictated by the underlying disorder (discussed in detail below). Plasmapheresis is a central component of therapy for anti-GBM disease but has no routine role for other disorders. However, plasmapheresis may have an adjunctive role in patients with DAH and severe renal insufficiency (i.e., serum creatinine greater than 4 mg%) and in patients with severe or progressive DAH refractory to corticosteroids or immunosuppressive agents. Measures to ensure adequate oxygenation are also essential. Mechanical ventilatory support, often

Figure 77-7 A. Alveolar hemorrhage due to microscopic polyarteritis (MPA). Posterior-anterior (PA) chest radiograph demonstrating massive alveolar infiltrates involving all lobes. Because of the severity of respiratory failure (requiring 16 cm H2 O of positive end-expiratory pressure to achieve acceptable oxygenation), no lung biopsy was performed. Urinalysis demonstrated numerous red cells and occasional red cell casts. Serum creatinine was 1.4 mg%. Pulse methylprednisolone (1 g daily × 3 days) was initiated, and renal biopsy was scheduled for the following morning. B . Alveolar hemorrhage due to MPA. PA chest radiograph from the same patient 12 h following initiation of pulse methylprednisolone. Marked improvement in alveolar infiltrates is evident. Renal biopsy demonstrated glomerulonephritis and a necrotizing vasculitis involving renal arterioles; no granulomas were present. Cyclophosphamide (2 mg/kg per day) was instituted, and corticosteroids were continued. Within 5 days, the infiltrates had cleared completely and serum creatinine was 0.6 mg%.

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with positive end-expiratory pressure, may be necessary in fulminant cases of DAH, to prevent death due to refractory hypoxemia. Transfusion of red blood cells may be required to maintain an acceptable hematocrit (more than 25 percent) and adequate blood pressure. In the sections that follow, we will discuss each of the autoimmune DAH syndromes individually.

SPECIFIC SYNDROMES Goodpasture’s Syndrome Clinical Features Antiglomerular basement membrane (anti-GBM) disease (Goodpasture’s syndrome), the prototype of pulmonaryrenal syndromes, accounts for 18 to 32 percent of immunemediated DAH. Classically, anti-GBM disease manifests as DAH and RPGN. Anti-GBM disease typically affects individuals between 20 and 45 years of age with a distinct male predominance. The incidence has been estimated as 0.3 cases per 100,000 population per year. The etiology is not known, but exposure to inhaled hydrocarbons and antecedent viral illnesses, particularly influenza, have been cited as risk factors. The demonstration of anti-GBM antibodies in tissue (typically kidney) or in serum is the cornerstone of the diagnosis. The clinical expression of anti-GBM disease is highly variable. Most patients present with progressive dyspnea, widespread alveolar infiltrates, and hypoxemia; hemoptysis occurs in 80 to 94 percent. A cardinal feature of Goodpasture’s syndrome is the presence of GN. Microscopic hematuria, red cell casts, or proteinuria are almost always present. Gross hematuria occurs in up to 41 percent of patients. Azotemia is noted in 55 to 71 percent of patients at presentation. Fatigue and weakness are common. In the absence of therapy, progressive renal insufficiency ensues, often resulting in endstage renal failure within days to weeks of the onset of symptoms. Oliguria, severe renal failure, or greater than 50 percent crescents on renal biopsy are associated with a poor prognosis and low rate of recovery of renal function. The course may be fulminant, with severe renal failure and explosive, life-threatening DAH. In up to one-third of patients with anti-GBM disease, GN occurs without DAH; DAH alone is exceptionally rare. Chest radiographs typically reveal dense bilateral alveolar infiltrates, often with air-bronchograms. With cessation of bleeding, infiltrates may resolve within 24 to 36 h. Pleural effusions are rare and suggest an alternative diagnosis. Pulmonary function tests are rarely helpful in the acute setting of DAH. Increases in the diffusing capacity for carbon monoxide (DlCO ) occur, due to uptake of carbon monoxide by extravasated alveolar blood. Bloody or serosanguineous BAL fluid (that worsens with serial aliquots) suggests DAH but is nonspecific. Anemia is present in more than 90 percent of cases and may be profound. Serum iron and ferritin levels are usually decreased, reflecting diminished iron stores. Factors associated with a higher incidence of DAH include

Alveolar Hemorrhage Syndromes

cigarette smoking, exposure to high concentrations of oxygen, upper respiratory tract infections, and increased hydrostatic (pulmonary capillary) pressures. Serological assays for anti-GBM antibody are invaluable in confirming the diagnosis and monitoring the adequacy of therapy. Radioimmunoassays or enzyme-linked immunosorbent assays (ELISA) for anti-GBM antibody are highly sensitive (greater than 95 percent) and specific (greater than 97 percent) but are performed in only a few laboratories. Results are usually not available for several days. Since delay in institution of therapy may preclude a favorable outcome, percutaneous renal biopsy is usually performed while awaiting the results of serum assays. Although the height of serum antiGBM antibody titer does not correlate with severity of disease, changes in titer over time may be a guide to efficacy of therapy. Rises in titer presage relapse; titers fall as the disease remits. Treatment can be tapered and discontinued after the antibody has disappeared from the circulation. Patients with circulating anti-GBM antibodies and ANCA have been described. Other serological studies are negative or nondiagnostic. Histopathology Percutaneous kidney biopsy is the preferred invasive procedure to substantiate the diagnosis of anti-GBM disease. Light microscopy demonstrates nonspecific features of a proliferative or necrotizing GN, often with cellular crescents. Over time, the crescents may fibrose, and frank glomerulosclerosis, interstitial fibrosis, and tubular atrophy may be observed. Although these microscopic features are nonspecific, IF stains are the cornerstone of the diagnosis. Bright linear deposits of immunoglobulin G (IgG) and complement (C3) along glomerular basement membranes are pathognomonic of anti-GBM disease (Fig. 77-6). All four subclasses of IgG are represented, but IgG1 predominates. Rare cases of linear deposits of IgM or IgA have been described. Lung biopsies are rarely necessary, as the histological features on renal biopsy are usually adequate to establish the diagnosis. When lung biopsy has been done, extensive hemorrhage predominates, with accumulation of hemosiderin-laden macrophages within the alveolar spaces. Foci of neutrophilic “capillaritis,” hyaline membranes, and DAD may also be found. Interstitial or intra-alveolar inflammation is minimal or absent. Extensive necrosis or large-vessel vasculitis is not found. Similar histopathological features may be seen with a wide gamut of immune-mediated DAH syndromes. IF stains of lung tissue may be diagnostic, provided a clear linear pattern of immunofluorescence is present. However, IF stains are technically difficult in lung tissue, and autofluorescence may obscure the linear IgG deposits. Pathogenesis Antibodies are directed against the α3 chain of type IV collagen, an antigen highly expressed in both alveolar and glomerular basement membranes. The pathogenesis of antiGBM disease remains speculative, but both genetic and environmental factors may play a role. Patients with anti-GBM

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disease preferentially express certain immunoglobulin Gm allotypes and links between anti-GBM disease and the HLA DR2 histocompatibility antigen have been noted. Anecdotal cases of anti-GBM disease have been described in siblings, first cousins, and identical twins, suggesting that a genetic susceptibility may exist. Exposure to cigarette smoke, hydrocarbon-containing solvents, hard-metal dust, influenza A2 virus, chlorine gas, and d-penicillamine have been associated with anti-GBM disease. These exogenous factors may injure the basement membrane, resulting in increased capillary permeability, exposing the Goodpasture antigen (α3 chain) which is then recognized as foreign, eliciting a T-helper cell response. Immunoglobulin synthesis and deposits of IgG along the alveolar and glomerular capillary basement membranes then ensue. Anti-idiotypic (blocking) antibodies and activated T-suppressor (CD8+) cells may modulate the process, but this remains speculative. Treatment Before the availability of the current therapy and renal dialysis, mortality exceeded 90 percent, with a mean survival of less than 4 months. Currently, with the combination of plasmapheresis, corticosteroids, and cyclophosphamide, mortality has been reduced to less than 20 percent. Since its introduction as a therapeutic option for anti-GBM disease in the mid-1970s, plasmapheresis was quickly adopted worldwide and has been incorporated in all clinical trials. Because of the rarity of anti-GBM syndrome, only one randomized trial compared immunosuppressive therapy with the combination of immunosuppressive therapy plus plasma exchange. In that study, plasmapheresis together with immunosuppressive therapy was associated with more rapid disappearance of anti-GBM antibody and improved renal function than treatment with immunosuppressive agents alone. The optimal extent and duration of plasma exchanges have not been defined. Most investigators advocate plasma exchange daily or every other day for 2 to 3 weeks, until the clinical course has improved and serum anti-GBM antibodies are nondetectable. However, less frequent exchanges (i.e., every 3 days) for 30 days may be adequate. Immunosuppressive therapy is required to inhibit antibody production and rebound hypersynthesis which may occur following discontinuation of plasma exchange. Either cyclophosphamide (2 mg/kg per day) or azathioprine (2 mg/kg per day), combined with prednisone (1 mg/kg per day) have been used. Most investigators favor oral cyclophosphamide over azathioprine, but studies comparing these agents have not been performed. Treatment of acute, life-threatening DAH in Goodpasture’s syndrome is similar to other autoimmune disorders. Pulse methylprednisolone (1 g daily for 3 days) is given, followed by a gradual corticosteroid taper. Cyclophosphamide can be initiated once the diagnosis of anti-GBM disease is substantiated by serologies or a pattern of linear immunofluorescence in tissue. This dose of cyclophosphamide is maintained for the duration of therapy, unless complications such as leukopenia necessitate dose reduction. The corticosteroid dose is gradually tapered

over the next several weeks. Immunosuppressive or cytotoxic therapy may be discontinued within 3 to 6 months provided a sustained remission has been achieved and anti-GBM antibodies have disappeared. With few exceptions, circulating anti-GBM antibodies clear within 8 weeks, irrespective of the initial titer. Early relapse (within the first 2 months) may occur when circulating antibodies are still present. This typically manifests as DAH. Risk factors for relapse include infection, volume overload, and cigarette smoking. Late recurrence, associated with renewed antibody synthesis following a remission, has only rarely been documented. In summary, aggressive therapy with plasmapheresis, corticosteroids, and immunosuppressive agents has dramatically improved prognosis. With this approach, 5-year survival exceeds 80 percent, and fewer than 30 percent of patients require chronic dialysis. Early recognition and treatment of this syndrome are critical, as the prognosis for recovery of renal function depends upon the initial extent of injury. Recovery of renal function can be expected in patients with minor functional impairment. By contrast, patients manifesting initial serum creatinine greater than 4 mg/dl, oliguria, or greater than 50 percent crescents on renal biopsy rarely recover and usually progress to end-stage renal failure requiring chronic dialysis. Renal transplantation has been successful in patients with irreversible renal failure, provided serum anti-GBM antibodies are undetectable.

Systemic Vasculitis DAH is a well-recognized complication of microscopic polyangiitis (MPA) and Wegener’s granulomatosis (WG) but rarely complicates Churg-Strauss syndrome (CSS), Behc¸et’s disease, mixed cryoglobulinemia, and other systemic necrotizing vasculitides. Classic polyarteritis nodosa (PAN) rarely involves the lung. Necrotizing small-vessel vasculitis accounts for the majority of autoimmune DAH syndromes. RPGN is usually present in each of these DAH syndromes, but the disease is sometimes limited to the kidneys or lungs. Circulating antibodies directed against cytoplasmic components of neutrophils and monocytes (ANCA) have been detected in most patients with these “pulmonary renal syndromes,” suggesting a common pathogenesis and mechanism of lung injury in these diverse vasculitic disorders. ANCA-Associated Vasculitides Goodpasture’s syndrome (anti-GBM disease) was the first of the pulmonary renal syndromes to be immunologically characterized. Subsequent studies documented immune complexes in serum or renal tissue in subsets of patients with pulmonary renal syndromes, particularly SLE, WG, and immune complex-mediated GN. However, more than two-thirds of patients with pulmonary renal syndromes are not mediated by either anti-GBM antibody or immune complexes. The term pauci-immune glomerulonephritis has been applied to this group of patients. Some patients with pauci-immune GN and DAH have clinicopathological features of WG. Others exhibit a multisystemic small-vessel vasculitis but lack

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granulomatous inflammation of the respiratory tract. Historically, these patients were considered to have microscopic PAN. Currently, the term microscopic polyangiitis (MPA) is preferred. Some patients have acute DAH and pauci-immune RPGN but lack evidence for vasculitis elsewhere. The term idiopathic RPGN has been used to refer to these patients. The availability of serum assays for ANCAs has profoundly influenced the classification of immune DAH and GN. Most patients with pauci-immune DAH and GN have circulating ANCA. ANCA-positive patients formerly given a diagnosis of idiopathic RPGN and DAH are now considered to have MPA. The spectrum of ANCA-associated diseases is not limited to patients with pulmonary renal syndromes but includes individuals with MPA limited to the lung (i.e., manifesting as DAH) or kidney (i.e., necrotizing GN). To avoid further confusion, brief definitions of the major ANCA-associated vasculitides are outlined below. Wegenerâ&#x20AC;&#x2122;s Granulomatosis

Wegenerâ&#x20AC;&#x2122;s granulomatosis (WG), the most common of the pulmonary vasculitides, typically involves the upper respiratory tract (e.g., sinuses, ears, nasopharynx, oropharynx, trachea), lower respiratory tract (bronchi and lung), and kidney, with varying degrees of disseminated vasculitis (see Chapter 83). Alveolar hemorrhage is a rare complication of WG, reflecting diffuse injury to the lung microvasculature (i.e., capillaritis) (Fig. 77-8). In this context, RPGN is present in more than 90 percent of patients. The salient histopathological features of WG include small-vessel vasculitis (involving capillaries, arterioles, venules), geographic necrosis, hemor-

Alveolar Hemorrhage Syndromes

rhagic infarcts, a mixed inflammatory cellular infiltrate, and a granulomatous component. Circulating antibodies directed against cytoplasmic components of neutrophils (c-ANCA) have been detected in more than 90 percent of patients with active generalized WG and in 40 to 70 percent with active regional WG. Oral cyclophosphamide (2 mg/kg per day) and prednisone is the initial treatment of choice for WG. With this regimen, remissions are achieved in 70 to 93 percent of patients, with early mortality rates of less than 15 percent. By 3 to 6 months, assuming complete remissions are achieved, azathioprine or methotrexate can be substituted for cyclophosphamide. Treatment should be continued for a minimum of 12 to 18 months (total duration). Relapses can be treated with cyclophosphamide and prednisone. Methotrexate may be used in patients with limited disease or those experiencing significant toxicity from cyclophosphamide. Trimethoprim/sulfamethoxazole may have an adjunctive role (together with cyclophosphamide and prednisone) to reduce relapse rates, but should not be considered as primary therapy. Churg-Strauss Syndrome (Allergic Angiitis and Granulomatosis)

Churg-Strauss syndrome (CSS), also termed allergic angiitis and granulomatosis, is a rare, small-vessel vasculitis associated with a prominent allergic component, asthma, and eosinophils in blood or involved tissues (see Chapter 83). The annual incidence has been estimated at two to three cases per million. Pulmonary involvement, primarily asthma, is present in virtually all cases. Focal infiltrates are present on chest radiographs in 30 to 70 percent of cases. DAH is a rare complication. Circulating ANCAs (either p-ANCA

Figure 77-8 Wegenerâ&#x20AC;&#x2122;s granulomatosis (WG). Posterior-anterior (PA) chest radiograph demonstrated bilateral alveolar infiltrates in a 13-year-old girl with hemoptysis and respiratory failure. A right chest tube is in place from an open lung biopsy performed 2 days earlier. Open lung biopsy demonstrated capillaritis and massive alveolar hemorrhage. Pulse methylprednisolone, followed by oral cyclophosphamide and prednisone, was associated with a complete remission.

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or c-ANCA) have been detected in 30 to 70 percent of patients with CSS. As with other ANCA-associated vasculitides, small vessels (capillaries, venules, and arterioles) are involved. Granulomas, eosinophils, and palisading histiocytes in extravascular tissues are hallmarks of the disorder. Pronounced granulomatous and eosinophilic components distinguish CSS from other vasculitides. In the classic form of CSS, vasculitis develops after a several-year history of atopy or asthma. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and blood eosinophil count are elevated in more than 80 percent of patients during the acute phase of vasculitis or exacerbations. The diagnosis of CSS can be made, even when histological features are less than definitive, provided the clinical and laboratory features are characteristic. Because of the rarity of CSS, data on therapy are limited. A variety of treatment regimens employing corticosteroids, immunosuppressive or cytotoxic agents, and plasmapheresis (alone or in combination) have been tried and generally were equally efficacious. Corticosteroids achieve remissions in more than 80 percent of patients with CSS and are first-line therapy for mild to moderate cases of CSS. Oral or pulse cyclophosphamide (or other immunosuppressive agents such as azathioprine or mycophenolate mofetil) should be added for severe or multisystemic disease or corticosteroid-recalcitrant cases or when unfavorable prognostic factors are present (such as central nervous system or gastrointestinal involvement, cardiomyopathy, severe renal insufficiency, or proteinuria greater than 1 g per day). Plasmapheresis should be considered only as adjunctive therapy in patients who are failing or those experiencing adverse effects from combined therapy.

Microscopic Polyangiitis

Microscopic polyangiitis (MPA, formerly termed microscopic polyarteritis or polyangiitis overlap syndrome) typically presents with GN and pulmonary capillaritis manifesting as DAH. Clinical and serological features of MPA overlap with WG and CSS. MPA is rare, with an estimated prevalence of two to five cases per million. As its name implies, MPA involves small vessels (arterioles, venules, or capillaries); extension to larger vessels occurs in a minority of cases. Small vessels are always spared in classic PAN. In contrast to WG or CSS, neither granulomas nor eosinophils are prominent in MPA. Circulating ANCA are present in 50 to 90 percent of patients with MPA, suggesting a relationship with other ANCA-associated vasculitides. By contrast, circulating ANCA are present in fewer than 20 percent of patients with classic (macroscopic) PAN. A necrotizing, crescentic pauci-immune GN is nearly invariably present in MPA but is rare in classic PAN. Alveolar hemorrhage, which is rarely observed in classic PAN, occurs in 30 to 50 percent of patients with MPA and is often the dominant and most life-threatening manifestation. Prednisone, cyclophosphamide, and plasmapheresis, alone or in combination, have been used to treat MPA. Response rates and long-term survival have generally been similar with the various regimens. Most investigators use oral cyclophosphamide (2 mg/kg per day) plus prednisone (1 mg/kg

per day, with gradual taper), similar to the regimen used for WG. With this approach, favorable responses are achieved in more than 80 percent of patients; 10-year survival exceeds 70 percent. By 3 to 6 months, once complete remissions have been achieved, azathioprine, methotrexate, or mycophenolate mofetil may be substituted for the cyclophosphamide. ANCA-Associated Pulmonary Renal Syndromes: Clinical Features The clinical and radiologic manifestations of ANCAassociated DAH are similar to other immune causes. Acute necrotizing GN is nearly always present, but the renal lesion is nonspecific. Distinguishing the specific underlying disorder may be difficult. The pathological lesions in ANCA-associated diseases share characteristic features, regardless of the organ affected. The three key histopathological findings are a segmental (focal) distribution of vascular injury, infiltration with neutrophils, and fibrinoid necrosis. The latter results from lysis of the vascular wall, allowing plasma coagulation factors to enter the interstitium and come into contact with thrombogenic substances, generating fibrin. Neutrophils that infiltrate vessel walls undergo disruption and karyorrhexis, leading to the typical leukocytoclastic pattern of injury in capillaries and venules. ANCA-associated vascular injury is accompanied by few, if any, immune deposits (pauci-immune). The salient lesion of renal vasculitis is a segmental necrotizing GN, usually accompanied by extracapillary proliferation of Bowmanâ&#x20AC;&#x2122;s capsule (crescents) (Fig. 77-5). Depending on the duration and extent of renal injury, varying degrees of glomerular fibrosis and sclerosis may be seen. Vasculitis affecting the kidney often involves only the glomerular capillaries; macroscopic arteritis is seldom apparent. When the lung is involved, the histopathology is nonspecific, demonstrating only capillaritis and intra-alveolar hemorrhage. Immune deposits are absent. Clinical features of ANCA-associated DAH syndromes overlap. Striking elevations in the ESR and CRP may be observed in all the syndromes, particularly when disseminated vasculitis is present. Anemia and leukocytosis are common. Marked eosinophilia is characteristic of CSS but is not a feature of MPA or WG. Extrapulmonary and extrarenal manifestations suggesting small-vessel vasculitis (e.g., palpable purpura, leukocytoclastic vasculitis, mononeuritis multiplex, arthralgias or arthritis, ocular disease, sinusitis) may direct biopsies at these sites. Histological features of granulomatous vasculitis are consistent with WG or CSS whereas granulomas are lacking in MPA. Radiographic features may discriminate granulomatous vasculitides from MPA. In WG (and less commonly in CSS), focal nodular or cavitary mass lesions may be seen. These are not found in MPA. The diagnosis of CSS can usually be readily established by a pronounced eosinophilic component in the blood or in extravascular sites. However, discriminating WG from MPA may be difficult or impossible as small-vessel vasculitis is common to both disorders. By definition, WG is associated with concomitant granulomatous inflammation, typically, but not invariably involving

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Figure 77-9 Indirect immunofluorescent stains demonstrating two distinct types of antineutrophil antibodies. On the left panel, note the perinuclear pattern of immunofluorescence characteristic of pANCA (myeloperoxidase epitope). On the right panel, a coarse granular pattern of immunofluorescence within the cytoplasm is evident, characteristic of c-ANCA (proteinase-3 epitope).

the upper and lower respiratory tracts. The latter may lead to the highly distinctive features attributed to WG including sinusitis, otitis media, nasal or laryngotracheal ulcerations, subglottic stenosis, and cavitary pulmonary nodules. Characteristics of ANCA The identification of circulating antibodies directed against cytoplasmic components of neutrophils and monocytes (i.e., ANCA) represented a major advance in the classification and understanding of vasculitis. Using ethanol-fixed granulocytes incubated with patient serum, two distinct patterns of ANCA are identified by IF techniques: cytoplasmic (c-ANCA) and perinuclear (p-ANCA) (Fig. 77-9). The p-ANCA pattern is an artifact of fixation causing movement of the target antigens to a perinuclear location. These differing IF patterns reflect distinct antigenic specificities. In both radioimmunoassays and ELISA, the antibody responsible for c-ANCA is directed against proteinase 3 (PR3). The p-ANCA pattern is usually due to an antibody to myeloperoxidase (MPO). MPO-ANCA is usually associated with small-vessel vasculitis, but multiple p-ANCA antibodies directed against a variety of antigens (e.g., cathepsin G, lactoferrin, and elastin) may be seen in nonvasculitic inflammatory disorders including collagen vascular diseases and inflammatory bowel or liver disease. Therefore, while c-ANCA is more than 90 percent specific for small-vessel vasculitis, pANCA is nonspecific. In untreated WG, circulating c-ANCA (PR3-ANCA) is detected in more than 70 percent of patients; the incidence is lower (40 to 65 percent) in patients with limited disease (e.g., involvement confined to the upper respiratory tract). By contrast, p-ANCA (MPO-ANCA) is rarely found in WG. Circulating ANCAs are present in more than 70 percent of patients with MPA and 30 to 70 percent of patients with CSS. In MPA either c-ANCA or MPO-ANCA may be present, but MPO is slightly more common. Serum ANCA, typically p-ANCA, has been detected in more than

50 percent of patients with pauci-immune GN. Circulating ANCAs have been found in fewer than 20 percent of patients with classic PAN. When present, antibodies have shown MPO antigenic specificity. Individual patients almost never have both c-ANCA and p-ANCA. Most ANCAs are of the IgG class. However, IgM ANCAs associated with severe DAH have been described, either concomitant with IgG-ANCA or in the absence of IgG-ANCA. It is unknown how often patients with ANCA-negative vasculitis would be ANCA-positive if reagents that detected IgM antibodies were used. The antigenic specificities of ANCA (i.e., PR3 or MPO) may provide clues to the nature of the underlying disorder and may assist in categorizing the type of disease, but overlap exists. Biopsies are important to differentiate the nature of the underlying vasculitic disorder. For example, patients with cANCA and small-vessel vasculitis may be misclassified as MPA if clinically inapparent areas of granulomatous inflammation are overlooked. For clinical purposes, distinguishing WG from MPA is not critical, because therapy and management are similar. Circulating p-ANCA (MPO) or c-ANCA (PR3) are present in more than 70 percent of patients with pauciimmune necrotizing GN (renal vasculitis). ANCA-negative patients usually have disease limited to the kidney. Nearly all patients with concomitant DAH have circulating ANCA. Indeed, a negative ANCA provides very strong evidence against vasculitis as the cause of DAH and GN. When applied to patients with RPGN, a positive ANCA almost invariably predicts pauci-immune necrotizing GN. In the setting of clinical, laboratory and radiologic features that are highly suggestive of DAH and RPGN, a positive c-ANCA or MPO-ANCA, together with a negative anti-GBM and ANA assay, is virtually diagnostic of systemic vasculitis (e.g., WG or MPA). Similarly, a positive ANCA (usually MPO-ANCA) is sufficient to diagnose lung-limited MPA, provided the clinical presentation is typical of DAH and nonimmune causes of DAH have been excluded. Most patients previously diagnosed as having

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idiopathic pulmonary hemosiderosis likely had lung-limited MPA or ANCA-associated pulmonary capillaritis. Problems with using serum ANCA to diagnose vasculitis arise when the clinical presentation is ambiguous. The low incidence of vasculitis in the general population dictates that the positive predictive value of ANCA will be low when applied indiscriminately. Routine assay of serum ANCA in patients with nonspecific respiratory complaints yields a high rate of false-positive results. Given the risks of immunosuppressive therapy, misinterpretation of ANCA may lead to devastating consequences. Accordingly, results of serum ANCA assays must be interpreted in light of the entire clinical picture. Anti-GBM disease and vasculitis have traditionally been viewed as distinct clinicopathological entities. However, recent studies have found that up to 30 percent of patients with anti-GBM disease (as evidenced by anti-GBM antibody in serum and linear deposits of IgG in kidney biopsy) also have serum MPO-ANCA. The coexistence of ANCA and antiGBM antibodies is almost certainly not a chance occurrence, given the rarity of both antibodies in the general population. It is possible that ANCA initiates vascular injury, and antiGBM antibody then forms in response to the damaged basement membrane. The prognosis for recovery of renal function is better among patients with both anti-GBM antibody and ANCA compared to patients with anti-GBM alone. The role of ANCA in the pathogenesis of vasculitis is uncertain, but these antibodies probably mediate vascular damage. Sera from patients with either c-ANCA or MPO-ANCA induce neutrophils to undergo a respiratory burst with release of reactive oxygen species and proteolytic enzymes. Cytokineprimed neutrophils are stimulated by ANCA to damage human endothelial cells in vitro. These observations, together with correlations of ANCA titer with clinical disease in humans (although imperfect), suggest that ANCAs are not innocent markers of vasculitis but play a crucial role in mediating vessel injury.

munosuppression alone (prednisolone, cyclophosphamide, or azathioprine) or immunosuppression plus plasma exchange. Patients were stratified according to severity of renal function at the time of entry into the study. Patients not already on dialysis responded equally well to both regimens (more than 90 percent improvement). However, among patients with severe renal failure requiring dialysis at the time of entry into the study, plasmapheresis conferred significant benefit. Short-term improvement in renal function was noted in 10 of 11 patients in the plasmapheresis group, compared to only 3 of 8 responses in the control group (immunosuppressive therapy only). This study and subsequent studies suggest that combining plasmapheresis and immunosuppression may have a role in patients with acute DAH and severe GN requiring dialysis. When plasma exchange is used to treat ANCAassociated DAH, it may be preferable to use an apparatus that efficiently removes both IgM and IgG, because of the reported association of IgM-ANCA and DAH. Protein A immunoadsorption has also been used to treat patients with DAH and GN, in the hope of removing pathogenic antibodies without producing the side effects of plasma exchange. Additional strategies for patients resistant to conventional therapies include high-dose, intermittent intravenous immunoglobulin G (IVIG). The mechanism of action is uncertain but may involve binding of ANCA idiotype by anti-idiotype antibodies in the intravenous IgG preparation. The role of serial ANCA determinations in following patients with vasculitis is controversial. We do not base therapeutic decisions on the ANCA titer alone. However, a rising titer should alert the clinician to the possibility of disease exacerbation and clinical follow-up should be intensified. Serial ANCA titers may help differentiate disease relapse from nonimmune causes of pulmonary infiltrates. However, ANCA titers do not obviate the need to aggressively evaluate patients with vasculitis presenting with a new pulmonary process while receiving immunosuppressive therapy.

Therapy Therapy of DAH due to ANCA-associated syndromes depends on the underlying disorder and the extent and severity of symptoms. However, irrespective of etiology, the most immediate concern in patients with severe immune DAH is to control intrapulmonary bleeding, which may be fatal. Besides general supportive measures, high-dose â&#x20AC;&#x153;pulseâ&#x20AC;? methylprednisolone (followed by a tapering regimen of corticosteroids) should be given. The presence of renal involvement or progression of DAH on corticosteroids is an indication for adding cyclophosphamide (with or without empiric plasma exchange). Plasma exchange has been used, with anecdotal successes, as therapy for ANCA-associated systemic vasculitis. Because ANCA may play a pivotal role in mediating tissue injury, plasmapheresis may be beneficial in selected patients (particularly those with severe renal failure, i.e., serum creatinine greater than 4 mg%). One controlled trial randomized 52 patients with focal necrotizing GN (without anti-GBM antibodies) to either im-

Systemic Lupus Erythematosus Alveolar hemorrhage is a potentially catastrophic complication of systemic lupus erythematosus (SLE), with mortality rates as high as 50 percent. Approximately 10 percent of cases of immune-mediated DAH have been attributed to SLE. Alveolar hemorrhage complicating SLE is usually accompanied by other manifestations of active SLE. Circulating antinuclear antibody (ANA) is present in more than 99 percent of patients. Alveolar hemorrhage is rarely the sole or presenting feature of SLE. Clinical and radiographic features of DAH complicating SLE are similar to other DAH syndromes. However, in SLE-associated DAH, GN is usually lacking. Diffuse, bilateral alveolar infiltrates, dyspnea, hypoxemia, and hemoptysis are characteristic (Fig. 77-10). With minor episodes, hemoptysis or hypoxemia may be lacking, obscuring the diagnosis. The diffuse pulmonary infiltrates must be differentiated from other pulmonary complications of SLE including lupus pneumonitis, opportunistic infections, congestive heart failure, uremia, or pulmonary embolism.

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nisolone or equivalent by the fourth day, with a gradual taper thereafter. For mild cases, high-dose prednisone (1 mg/kg per day) may be adequate as initial therapy. Symptoms, serial chest radiographs, complete blood counts, and anti-DNA titers reflect efficacy of therapy and guide the rate of taper of corticosteroid. Immunosuppressive or cytotoxic agents may be considered for DAH refractory to corticosteroids, but data are limited. Plasmapheresis (usually combined with corticosteroids or immunosuppressive agents) has been associated with anecdotal successes for acute flares of SLE or DAH. However, randomized, controlled trials found that plasmapheresis plus prednisone and cyclophosphamide was no more effective than prednisone and cyclophosphamide alone for severe lupus nephritis. Plasmapheresis is expensive, logistically cumbersome, and should be reserved for patients with severe DAH refractory to corticosteroids and/or cytotoxic agents.

Figure 77-10 Systemic lupus erythematosus (SLE). Posterioranterior (PA) chest radiograph reveals extensive bilateral alveolar infiltrates in a 22-year-old woman with SLE, hemoptysis, and anemia.

Lung biopsy may be needed to exclude alternative diagnoses and corroborate the diagnosis of DAH. However, the risk of lung biopsy may be substantial in critically ill patients with fulminant DAH and respiratory failure. In addition, as with other immune DAH syndromes, histopathological features of DAH complicating SLE are nonspecific. The dominant feature is intra-alveolar hemorrhage and capillaritis, without macroscopic necrosis. The small-vessel necrotizing vasculitis rarely extends to arterioles and small muscular arteries in addition to capillaries. Granular deposits of IgG or C3 (consistent with immune complexes) have been found in up to 50 percent of cases of DAH complicating SLE. As noted earlier, because of its potential morbidity, we rarely advise open or thoracoscopic lung biopsy to diagnose DAH. Provided clinical features are consistent, the diagnosis of DAH can often be established by fiberoptic bronchoscopy with BAL and transbronchial lung biopsies. Transbronchial biopsies may demonstrate foci of capillaritis with intra-alveolar hemorrhage, but due to sampling error, these features may be missed. However, the presence of gross blood in the airways or serosanguineous BAL fluid, large numbers of hemosiderinladen macrophages, absence of purulent sputum, and lack of infectious organisms by appropriate stains strongly supports the diagnosis of autoimmune DAH and justifies institution of therapy. Transbronchial lung biopsies may be deferred in acutely ill patients with severe DAH and respiratory failure. In this context, BAL alone is adequate, primarily to exclude local or infectious causes of bleeding. Due to the rarity of this syndrome, prospective, controlled trials evaluating therapy have not been performed. As with other causes of immune DAH, we recommend high-dose IV pulse methylprednisolone (1 g daily for 3 days) for severe DAH. The dose may be tapered to 60 to 120 mg of methylpred-

Other Collagen Vascular Disorders Anecdotal reports of DAH, with or without capillaritis, have been described in association with rheumatoid arthritis, scleroderma, mixed-connective tissue disease, polymyositis, antiphospholipid antibody syndrome, Henoch-Sch¨onlein syndrome, and Behc¸et’s disease. The clinical spectrum ranges from minimal hemoptysis to life-threatening respiratory failure. In addition to capillaritis and DAH, additional histopathological features on lung biopsies include vasculitis of small and medium muscular pulmonary arteries, diffuse alveolar damage (DAD), and cryptogenic organizing pneumonia. In view of the rarity of DAH complicating these diverse collagen vascular disorders, data regarding therapy are limited. High-dose (pulse) intravenous methylprednisolone is advised as initial treatment. In patients with fulminant or corticosteroid-recalcitrant disease, cyclophosphamide, alone or combined with plasmapheresis, should be added.

Alveolar Hemorrhage in Immunocompromised Hosts Alveolar hemorrhage may occur in immunocompromised patients. Alveolar hemorrhage may reflect injury to pulmonary endothelial or epithelial cells (secondary to chemotherapy or radiation toxicity), thrombocytopenia (secondary to bone marrow toxicity), pulmonary edema, pulmonary malignancies, and diverse infectious and nonspecific interstitial pneumonias. The incidence of DAH in severely immunocompromised hosts with hematologic malignancies or bone marrow transplants has varied from 11 to 64 percent. The variable frequency in large part is due to differing diagnostic criteria for the diagnosis of DAH. Subclinical alveolar hemorrhage (as evidenced by increased numbers of hemosiderin-laden macrophages in BAL) occurs in up to one-third of immunocompromised hosts with pulmonary infiltrates and may reflect pulmonary endothelial or epithelial injury from diverse causes. Nonimmune causes of DAH in this patient population include coagulopathy, thrombocytopenia or platelet dysfunction, renal failure, congestive heart failure, bronchopulmonary Kaposi’s sarcoma, and diverse

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infections (e.g., invasive fungi—particularly Aspergillus spp, viruses, Mycobacteria, Legionellae, and bacteria).

Alveolar Hemorrhage Complicating Bone Marrow Transplantation DAH occurs in approximately 15 percent (range 2 to 31 percent) of hematopoietic stem cell transplantation (HSCT) or bone marrow transplant (BMT) recipients receiving preBMT conditioning with high-dose chemotherapy or radiation therapy. Opportunistic infections or thrombocytopenia account for some cases of DAH, but a distinct syndrome of DAH in this population unrelated to infection is well accepted. The incidence of DAH is similar among autologous and allogeneic HSCT recipients. Risk factors for DAH which have been cited include age over 40 years, underlying solid tumors, severe oral mucositis, renal failure, airway injury prior to institution of chemotherapy, increased proportions of airway (bronchial) neutrophils and eosinophils, and leukocyte recovery. DAH usually develops within 10 to 40 days after BMT, but case reports of DAH developing immediately following autologous bone marrow transfusion suggest that components within the transfusion (e.g., dimethylsulfoxide [DMSO] for cryopreservation of blood stem cells) may mediate acute lung injury in some cases. Progressive dyspnea, hypoxemia, and respiratory failure is typical. Despite extensive DAH, hemoptysis is uncommon. Chest radiographs initially demonstrate predominantly interstitial opacities, which evolve to diffuse alveolar opacities, with a confluent alveolar pattern involving all lobes. Serosanguineous or frankly bloody BAL fluid, with negative stains for infectious organisms, support the diagnosis of DAH. However, BAL fluid may be normal even in the face of severe DAH. Lung biopsies or necropsies typically reveal histological features of both DAD and DAH. The clinical course is variable, but acute, fatal respiratory failure may develop. Mortality rates in patients requiring mechanical ventilatory support typically exceed 50 percent. Secondary infections are serious and potentially lethal. Coexisting pulmonary processes, most commonly DAD or infections, were noted in 10 of 11 BMT recipients with DAH in one necropsy series. Multiple mechanisms may mediate alveolar hemorrhage in this patient population. Diffuse injury to the pulmonary microvasculature, secondary to chemotherapy or radiation therapy, coupled with a heightened inflammatory response in the airways, appear to be operative. Bleeding may be amplified by a precipitating factor such as coagulopathy, pulmonary edema, graft-vs-host disease (GVHD), or infections. DAD, a pathological hallmark seen in toxic lung injury from chemotherapy, radiation therapy, or viral infections, is frequently observed in lung biopsies or necropsies in bone marrow recipients with DAH. An association between microangiopathy and DAH in patients receiving BMT for hematologic malignancies has also been cited. Neutrophils and other inflammatory cells likely play important roles in the pathogenesis of DAH. The onset of DAH frequently coincides with marrow recovery and reappearance of neutrophils

within the circulation or BAL fluid. Influx of neutrophils may promote the lung injury by release of oxygen radicals, proteases, and other phlogistic mediators. Hematopoietic growth factors (e.g., granulocyte colony-stimulating factor) may exacerbate alveolar damage and capillary leakage by increasing neutrophil influx into the lungs. Although randomized controlled studies have not been done, high-dose corticosteroids (generally 125 to 250 mg of methylprednisolone every 6 h for 3 to 5 days, followed by oral corticosteroids) are considered standard of care. Unfortunately, DAH or bloody BAL fluid may be seen in infectious causes of pneumonia (particularly due to cytomegalovirus or Aspergillus spp), and high-dose corticosteroids could be disastrous under these circumstances. Infectious etiologies must be rigorously excluded. Among patients who respond favorably to corticosteroids, the dose can be gradually tapered over 2 to 6 weeks. A more prolonged course is appropriate for patients with GVHD or other complications requiring long-term corticosteroid therapy.

Alveolar Hemorrhage Complicating HIV Infection DAH can complicate human immunodeficiency virus (HIV) infection. The incidence and clinical significance of DAH is not clear, as additional pulmonary processes (e.g., opportunistic infections, Kaposi’s sarcoma) are usually present. Subclinical episodes of alveolar hemorrhage are common, as studies in HIV-infected patients with pulmonary infiltrates detected more than 20 percent hemosiderin-laden macrophages in BAL fluid in 15 to 44 percent of patients. Pulmonary capillaritis has been cited in occasional patients, most of whom had concomitant opportunistic infections. Cytomegalovirus (CMV) pneumonitis has been implicated as a cause of DAH in HIV-infected patients. CMV exhibits tropism for endothelial cells, and CMV may induce vascular injury or thrombotic microangiopathy. Antiviral therapy (e.g., ganciclovir) may be curative for CMVassociated DAH. Undoubtedly, opportunistic pathogens or endobronchial Kaposi’s sarcoma account for the majority of cases of DAH in HIV-infected individuals. The incidence and appropriate therapy of DAH of unknown etiology in the setting of acquired immunodeficiency syndrome (AIDS) needs to be defined in prospective studies.

Alveolar Hemorrhage Due to Exogenous Agents Certain exogenous agents or drugs (e.g., trimellitic anhydride, isocyanates, d-penicillamine, cocaine, diphenylhydantoin, propylthiouracil, all-trans-retinoic acid) are rare causes of DAH. Pulmonary capillaritis is the most frequent underlying histology. GN has occurred in DAH associated with d-penicillamine, hydralazine, and carbimazole but not with the other agents. Few lung biopsies have been performed in these cases of DAH. When biopsies were done, histological findings were nonspecific. Alveolar hemorrhage dominates without immune deposits.

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All-trans-retinoic acid (ATRA), a therapeutic agent for acute promyelocytic leukemia, may be associated with “retinoic acid syndrome,” which is characterized by fever, thrombosis, pulmonary infiltrates, and DAH. The onset is 2 to 21 days after initiation of treatment. In this circumstance, ATRA is continued but high-dose IV corticosteroids should be administered. Propylthiouracil can cause a systemic small vessel vasculitis with necrotizing GN, leukocytoclastic vasculitis, and DAH secondary to pulmonary capillaritis. Withdrawal of the drug may be associated with resolution of the disease, but corticosteroids or immunosuppressive agents are indicated in patients with severe DAH or renal failure. A variety of chemotherapeutic agents (e.g., bischloroethyl nitrosourea [BCNU], carmustine, cyclophosphamide, methotrexate, bleomycin, or busulfan) may cause lung injury and fibrosis. In some cases, DAH may result from epithelial injury and injury to the alveolar capillary basement membranes. In this context, fatality rates are high (more than 50 percent). High-dose corticosteroids are recommended, but efficacy is uncertain. Trimellitic anhydride (TMA), a chemical used in manufacturing plastics and epoxy resins, may elicit pulmonary hemorrhage and anemia. Most patients with DAH secondary to TMA exposure recover within a few days following removal from the offending environment. An immune mechanism is likely, as circulating IgG antibodies against trimellitic protein were found in some patients with DAH, suggesting TMA acts as a hapten. TMA may cause asthma, rhinitis, and hemolytic anemia mediated by IgE antibodies directed against trimellitic protein. Animal models of TMA-induced lung disease have also been developed. Induction of serum antibodies against epitopes of TMA produced acute lung injury in guinea pigs, mediated by at least two types of humoral antibodies. It is also possible that TMA may exert a direct toxic effect on alveolar endothelium. This syndrome is exceptionally rare, since only sporadic cases have been described. Exposure to isocyanates in spray paint has been linked to severe DAH in a few cases. The mechanism is likely mediated by high levels of IgE and IgG antibodies against diisocyanates. Thus, exposure to TMA or isocyanates, and possibly other chemicals, can elicit hemorrhagic pneumonitis, likely mediated by circulating antibodies (IgG or IgE) and immune complexes. Mild alveolar hemorrhage occurs in approximately 1 in 3000 patients receiving lymphangiogram dye. The mechanism is not clear. A latency period of 2 to 10 days precedes the onset of dyspnea, pulmonary infiltrates, or hemoptysis. This syndrome is usually mild and self-limited, but at least one fatality has been cited. Extrapulmonary involvement does not occur. Smoking, snorting, or intravenous “crack” cocaine has been associated with hemoptysis and varying degrees of DAH, including rare fatalities. Histopathological features of cocaine-induced DAH are nonspecific, but include DAD, acute or chronic DAH, interstitial pneumonitis/fibrosis, and intra-alveolar edema. The mechanism of DAH is not clear but may relate to direct toxic injury from cocaine or its

Alveolar Hemorrhage Syndromes

contaminants, vasospasm, or a combination of both mechanisms. This syndrome typically reverses with cessation of exposure. The frequency of clinically significant DAH associated with inhaled or intravenous use of cocaine has not been established. When drug or hapten-induced DAH is suspected, immediate avoidance of the implicated agent or drug is essential. For acute or severe cases, a brief course of high-dose corticosteroids is warranted. Plasmapheresis or cytotoxic agents may be considered for fulminant cases refractory to corticosteroids, but data supporting their use are lacking. Finally, coagulopathies, severe thrombocytopenia, or the use of anticoagulants, thrombolytic agents, or platelet inhibitors may rarely cause DAH. In this context, the histology is “bland” without evidence for capillaritis or acute inflammation.

Alveolar Hemorrhage Due to Exogenous Environmental Molds Acute, life-threatening DAH in infants identified fungal contamination as the etiology. Exposure to Stachybotrys chartarum and other toxigenic fungi elicits the syndrome. Stachybotrys chartarum produces several classes of toxins including hemolysins, proteinases, macrocyclic trichothecenes, phenylspirodrimanes, and others. Acute respiratory distress, progressing to respiratory failure requiring mechanical ventilatory support, may occur. High-dose IV corticosteroids are warranted for acute DAH. Long-term management mandates removal of infants from the residential environment to avoid relapse. This syndrome has rarely been reported in adults, but must be considered in water-damaged homes or environs where mold/fungal contamination exists. Idiopathic Pulmonary Hemosiderosis Idiopathic pulmonary hemosiderosis (IPH) is an exceptionally rare cause of DAH that occurs primarily in infants and children. The estimated incidence is 0.2 to 1.2 cases per million. Many children with IPH have a history of milk or gluten sensitivity. A subset of adults with celiac sprue manifest IPH, which may respond to elimination of gluten from the diet. Clinical features of IPH are similar to immune causes of DAH, but extrapulmonary or renal involvement is lacking. Serum or tissue antibodies (including ANCA, immune complexes, anti-GBM antibody) are also absent. A diagnosis of IPH can be made only when other specific causes of DAH have been reliably excluded. The largest series of IPH, published in 1962, included 112 patients but antedated the availability of anti-GBM antibody or ANCA. Antibodies to lung or kidney were assayed in only six patients. In recent years, with the advent of immunological and serological assays, the diagnosis of IPH has rarely been substantiated. It now seems likely that most cases formerly diagnosed as IPH in adults had ANCA-associated vasculitis, MPA, or underlying collagen vascular disorders. The clinical course of IPH is variable, but recurrent episodes of DAH over several years are characteristic.

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Figure 77-11 Idiopathic pulmonary hemosiderosis (IPH). Posterior-anterior (PA) chest radiograph demonstrates bilateral reticulonodular infiltrates in a 28-year-old woman with IPH confirmed 10 years earlier by open lung biopsy. (Note the surgical staples in the left lower lobe from a prior open lung biopsy.)

Spontaneous remissions without long-term sequelae have been cited in up to 25 percent of cases.One-third to one-half of patients die within 3 years of onset, usually from severe DAH. Sequelae of recurrent episodes of DAH include pulmonary fibrosis, progressive respiratory failure, and cor pulmonale. During acute episodes, chest radiographs demonstrate bilateral alveolar infiltrates. Following cessation of bleeding, chest radiographs may normalize within 1 to 2 weeks. Reticulonodular infiltrates may be observed as the process is resolving or with recurrent episodes (Fig. 77-11). CT reveals areas of ground-glass opacification, representing foci of alveolar hemorrhage. Thickening of interlobular septae and honeycombing may be observed in a subset of patients who progress to pulmonary fibrosis. Hemoptysis may be absent, particularly

in young children who may be unable to expectorate blood. Iron-deficiency anemia is characteristic and can be profound. Iron deficiency may persist despite normal total body iron stores, because hemosiderin within alveolar macrophages is not available to developing erythrocytes. Siderophages may be found in sputum, BAL fluid, or tracheal or gastric aspirates in patients with recent episodes of DAH. Lung biopsies may reveal fresh areas of alveolar hemorrhage or patchy interstitial fibrosis and aggregates of hemosiderin-laden macrophages from prior episodes of alveolar hemorrhage (Fig. 77-12). Capillaritis has been described in some cases, but macroscopic vasculitis is not found. The pathogenesis of IPH is not known. In children, associations between IPH and cowâ&#x20AC;&#x2122;s milk hypersensitivity, celiac disease, IgA monoclonal gammopathy, autoimmune hemolytic anemia, and autoimmune thyrotoxicosis have been suggested, but a pathogenetic link has not been substantiated. Resolution of pulmonary symptoms following elimination of mild products or gluten from diet supports a role for exogenous factors in the pathogenesis in at least some cases. No genetic basis has been found, but clusters within families have been described. In view of the rarity of IPH, optimal therapy is not clear. Controlled studies evaluating therapeutic regimens have not been done. Corticosteroids are considered the mainstay of therapy, but an epidemiological survey of 30 children with IPH concluded that corticosteroids did not alter the longterm course or prognosis. Because IPH is life-threatening, most physicians treat acute episodes with daily corticosteroids and taper to the lowest dose which appears to control the disease. Long-term (and possibly indefinite) therapy may be required to prevent recurrences. To minimize side effects, alternate dose corticosteroids should be considered after the acute hemorrhage has resolved. Favorable responses have been cited with azathioprine, cyclophosphamide, and plasmapheresis in patients failing corticosteroids. Chronic immunosuppressive agents may improve prognosis for patients with

Figure 77-12 Idiopathic pulmonary hemosiderosis (IPH). Photomicrograph demonstrating extensive deposits of hemosiderin within alveolar interstitium (Prussian blue stain).

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corticosteroid-recalcitrant disease or patients experiencing repetitive relapses of DAH. In this context, we prefer azathioprine over cyclophosphamide given the heightened risk of neoplasia and gonadal toxicities associated with the longterm use of cyclophosphamide.

SUGGESTED READING Afessa B, Tefferi A, Litzow, et al: Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 166:641–645, 2002. Afessa B, Tefferi A, Litzow, et al: Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 166:1364–1368, 2002. Ben-Abraham R, Paret G, Cohen R, et al: Diffuse alveolar hemorrhage following allogeneic bone marrow transplantation in children. Chest 124:660–664, 2003. Bligny D, Mahr A, Le Toumelin P, et al: Predicting mortality in systemic Wegener’s granulomatosis: A survival analysis based on 93 patients. Arthritis Rheum 51:83–91, 2004. Booth A, Harper L, Hammad T, et al: Prospective study of TNFα blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol 15:717–721, 2004. Bourgarit A, Le Toumelin P, Pagnoux C, et al: Deaths occurring during the first year after treatment onset for polyarteritis nodosa, microscopic polyangiits, and ChurgStrauss syndrome. A retrospective analysis of causes and factors predictive of mortality based on 595 patients. Medicine (Baltimore) 84:323–330, 2005. Collard HR, Schwarz MI: Diffuse alveolar hemorrhage. Clin Chest Med 25:583–592, 2004. Conron M, Beynon HL: Churg-Strauss syndrome. Thorax 55:870–877, 2000. Dearborn DG, Smith PG, Dahms BB, et al: Clinical profile of 30 infants with acute pulmonary hemorrhage in Cleveland. Pediatrics 110:627–637, 2002. Fullmer JJ, Langston C, Dishop MK, et al: Pulmonary capillaritis in children: A review of eight cases with comparison to other alveolar hemorrhage syndromes. J Pediatr 146:376–381, 2005. Frasca GM, Soverini ML, Falaschini A, et al: Plasma exchange treatment improves prognosis of antineutrophil cytoplasmic antibody-associated crescentic glomerulonephritis: A case-control study in 26 patients from a single center. Therapeutic Apheresis Dialysis 7:540–546, 2003. Guillevin L, Pagnoux C: Indications of plasma exchanges for systemic vasculitides. Therapeutic Apheresis Dialysis 7:155–160, 2003. Guillevin L, Pagnoux C, Mouthon L: Churg-Strauss syndrome. Semin Respir Crit Care Med 25:535–546, 2004.

Alveolar Hemorrhage Syndromes

Hicks K, Peng D, Gajewski JL: Treatment of diffuse alveolar hemorrhage after allogeneic bone marrow transplant with recombinant factor VIIa. Bone Marrow Transpl 30:975– 978, 2002. Ioachimescu OC, Sieber S, Kotch A: Idiopathic pulmonary hemosiderosis revisited. Eur Respir J 24:162, 2004. Klemmer PJ, Chalermskulrat W, Reif MS, et al: Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small-vessel vasculitis. Am J Kidney Dis 42: 1149–1153, 2003. Kokolina E, Alexopoulos E, Dimitriadis C, et al: Immunosuppressive therapy and clinical evolution in forty-nine patients with antineutrophil cytoplasmic antibody-associated glomerulonephritis. Ann NY Acad Sci 1051:597–605, 2005. Laque D, Cadranel J, Lazor R, et al: Microscopic polyangiitis with alveolar hemorrhage. A study of 29 cases and review of the literature. Groupe d’Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM”O”P). Medicine (Baltimore) 79:222–233, 2000. Le Clainche L, Le Bourgeois M, Fauroux B, et al: Long-term outcome of idiopathic pulmonary hemosiderosis in children. Medicine (Baltimore) 79:318–326, 2000. Lee AS, Specks U: Pulmonary capillaritis. Semin Respir Crit Care Med 25:547–556, 2004. Levy JB, Turner AN, Rees J, et al: Long-term outcome of antiglomerular basement membrane antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med 134:1033–1042, 2001. Lynch JP III, White E, Tazelaar H, et al: Wegener’s granulomatosis: Evolving concepts in treatment. Semin Respir Crit Care Med 25:491–522, 2004. Mahr A, Guillevin L, Poissonnet M, et al: Prevalences of polyarteritis nodosa, microscopic polyangiitis, Wegener’s granulomatosis, and Churg-Strauss syndrome in a French urban multiethnic population in 2000: A capturerecapture estimate. Arthritis Rheum 51:92–99, 2004. Schwarz MI, Brown KK: Small vessel vasculitis of the lung. Thorax 55:502–510, 2000. Schwarz MI, Fontenot AP: Drug-induced diffuse alveolar hemorrhage syndromes and vasculitis. Clin Chest Med 25:133–140, 2004. Sinico RA, Di Toma L, Maggiore U, et al: Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome. Arthritis Rheum 52:2926– 2935, 2005. Smythe L, Gaskin G, Pusey CD: Microscopic polyangiitis. Semin Respir Crit Care Med 25:523–534, 2004. Travis WD: Pathology of pulmonary vasculitis. Semin Respir Crit Care Med 25;483–490, 2004. Weidner S, Geuss S, Hafezi-Rachti S, et al: ANCA-associated vasculitis with renal involvement: An outcome analysis. Nephrol Dial Transplant 19:1403–1411, 2004.

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78 Mechanisms of Aspiration Disorders Richard D. Zorowitz

I. NORMAL ANATOMY AND PHYSIOLOGY OF THE AERODIGESTIVE PASSAGE II. NEUROMUSCULAR MECHANISMS Dysphagia Gastroesophageal Reflux Disease (GERD)

IV. IATROGENIC MECHANISMS Nonoral Enteral Feeding Tracheal Intubation and Tracheostomy General Anaesthesia Head and Neck Cancer Treatments

III. MECHANICAL MECHANISMS

Aspiration involves a spectrum of clinical situations, from laryngeal penetration to frank pulmonary aspiration. Aspiration presumes that the airways and lungs become soiled with nongaseous materials including consistencies that are solid or liquid, caustic or bland, infected or sterile. Pulmonary aspiration can involve segmental or lobar areas of the lung, can be associated with either focal or diffuse inflammatory reactions, and can evolve to include systemic effects such as bacteremia, sepsis, end-organ consequences of hypoxia, and death. Aspiration pneumonitis implies the presence of an inflammatory response to aspirated material not associated with infection, whereas aspiration pneumonia implies the presence of infection with pneumonitis. Aspiration may be categorized by several different schemas. For instance, aspiration may be described in terms of the degree of the event. Microaspiration reflects the entry of subclinical amounts of bacterial and nonbacterial matter into the tracheobronchial tree but may predispose a patient to a more serious event. Macroaspiration involving the entry of nonendogenous materials into the lung from oropharyngeal or gastrointestinal sources represents the more serious clinical situation. Aspiration also may be described as a function of oropharyngeal, esophageal, and gastrointestinal disorders with neuromuscular or mechanical (obstructive) etiologies. Further, medical or surgical interventions meant to treat conditions related or unrelated to swallowing or ventilation unintentionally may cause aspiration and should be considered separately from organic conditions. With an understanding

of the normal anatomy and physiology of the larynx, pharynx, esophagus, stomach, and intestine, the clinician may better identify the mechanisms of aspiration and the preventable strategies which minimize aspiration and its complications.

NORMAL ANATOMY AND PHYSIOLOGY OF THE AERODIGESTIVE PASSAGE Aspiration occurs when the integrity of the neuromuscular system used for swallowing becomes altered or impaired anatomically or physiologically (Figs. 78-1 and 78-2). Deglutition is a neurogenically controlled phenomenon requiring intricate cognitive and motor control, integration of sensory information, and multiple levels of central and peripheral reflex control. Normal deglutition consists of four phases: (1) oral preparatory; (2) oral; (3) pharyngeal; and (4) esophageal. A list of the muscles, their innervations and functions, and the phases in which they are associated is found in Table 78-1. During the oral preparatory phase (Fig. 78-3A), food is manipulated in the mouth and masticated if necessary. Mastication involves a repeated cyclical pattern of rotary lateral movement of the labial and mandibular musculature. Some food normally falls into the pharynx during this phase but does not enter the respiratory tree. Once broken down into particles, food is collected into a bolus and held anterolaterally by the tongue against the palate. Liquids usually do not

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Figure 78-1 Lateral view of pharynx. A. Schematic view. B . Radiographic view. This view focuses on structures below the level of the mandible (m). The epiglottis (black arrows) tilts downward during a normal swallow but is not necessary for protection of the airway. It separates the valleculae (v) from the laryngeal vestibule (white arrows) and is tilted upward during the resting state. The valleculae and piriform sinuses (p) are sites for residue which may be aspirated when pharyngeal weakness is present. The upper esophageal sphincter (u) is actively contracted, and the hyoid bone (h) is in its resting position.

Figure 78-2 Anteroposterior view of pharynx. A. Schematic view. B . Radiographic view. The tonsillar pillars (t) are visualized in this view. The median glossoepiglottic fold (small arrow) delineates the two cupâ&#x20AC;&#x201C;shaped valleculae (v). The epiglottis (large arrows) appears as an inverted U. The piriform sinuses (p) lay along the anterior wall of the midhypopharynx.

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Table 78-1 Muscles Involved in Swallowing Muscle

Nerve

Stage

Action

Temporalis

Elevates, retracts mandible

Masseter

Elevates mandible

Pterygoideus medialis

Elevates, protracts mandible

Pterygoideus lateralis

Depresses, protracts mandible; moves mandible laterally

Obicularis oris

VII

OP,O

Opens, closes, protracts lips

Zygomaticus major

VII

OP,O

Elevates mouth angle upward, backward

Levator labii superioris

VII

OP,O

Elevates upper lip, mouth angle

Depressor labii inferioris

VII

OP,O

Depresses lower lip

Levator anguli oris

VII

OP,O

Elevates mouth angle

Depressor anguli oris

VII

OP,O

Depresses mouth angle

Mentalis

VII

OP,O

Elevates, protracts lower lip

Risorius

VII

OP,O

Retracts mouth angle

Buccinator

VII

OP,O

Flattens, retracts cheek, mouth angle

Hyoglossus

XII

OP,P

Depresses tongue

Genioglossus

XII

OP,P

Depresses, protrudes tongue

Musculus uvulae

IX,X,XI

Elevates uvula

Palatoglossus

IX,X,XI

Elevates posterior tongue; narrows fauces

Levator veli palatini

IX,X,XI

Elevates soft palate

Tensor veli palatini

Stretches soft palate

Mylohyoideus

Elevates tongue base, mouth floor, hyoid bone; depresses mandible

Digastricus

Elevates hyoid bone, tongue base

Geniohyoideus

XII,C1

Elevates hyoid bone, tongue

Stylohyoideus

VII

Elevates hyoid, tongue base

Thyrohyoideus

XII,C1

Depresses larynx, hyoid bone; elevates thyroid cartilage

Styloglossus

XII

Elevates, retracts tongue

Palatopharyngeus

IX,X,XI

Narrows oropharynx; elevates pharynx

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Table 78-1 Muscles Involved in Swallowing (Continued ) Muscle

Nerve

Stage

Action

Stylopharyngeus

Elevates, dilates pharynx

Salpingopharyngeus

IX,X,XI

Elevates nasopharynx

Aryepiglotticus

IX,X

Tilts epiglottis downward

Cricoarytenoideus lateralis

IX,X

Closes glottis, approximates vocal folds

Thyreoarytenoideus

IX,X

Closes glottis, shortens vocal folds

Constrictor pharyngeus superioris

IX,X,XI

Compresses pharynx

Constrictor pharyngeus intermedius

IX,X,XI

Compresses pharynx

Constrictor pharyngeus inferioris

X,XI

Compresses pharynx

Cricopharyngeus

Closes upper esophageal sphincter

OP = oral preparatory stage; O = oral stage; P = pharyngeal stage.

require mastication and may be transported into the oropharynx in one smooth, continuous motion. During the oral phase (Fig. 78-3B), the tongue pushes upward and forward, contacting the hard palate anteriorly. As the tongue surface moves upward, the area of contact between the tongue and palate expands from the front of the palate posteriorly, resulting in propulsion of the bolus through the faucial arches into the oropharynx. The bolus may remain in the oropharynx for many additional chewing cycles, and the oral phase may repeat several times before the pharyngeal phase is initiated. A labial seal is maintained to prevent food or liquid from leaking from the mouth. Tension of the buccal musculature prevents food from falling into the lateral sulci between the mandible and the cheek. The oral phase is mediated through cranial nerves VII and XII. During the pharyngeal phase (Fig. 78-3C ), ventilation ceases temporarily. The nasopharynx closes when the soft palate makes contact with the lateral and posterior pharyngeal walls. The true vocal folds close tightly to prevent aspiration. The larynx pulls forward under the base of the tongue. The bolus deflects away from the laryngeal opening when the epiglottis tilts back. The tongue pushes the bolus posteriorly and inferiorly into the hypopharynx. The upper esophageal sphincter (UES), which usually is held closed between swallows by tonic contraction of the cricopharyngeus muscle, relaxes and opens. The hyoid bone and larynx are pulled forward and upward by contraction of the suprahyoid and thyrohyoid muscles. This pulls the cricoid cartilage and the attached anterior pharyngeal wall away from the posterior pharyngeal wall and underlying vertebral column, opening the pharyn-

goesophageal sphincter. The pressure of the descending bolus also contributes to the opening of the UES. The pharyngeal constrictor muscles clear the residual bolus from the pharynx by contracting sequentially from top to bottom. After the bolus enters the esophagus, ventilation resumes, and the pharyngeal and laryngeal structures return to their original anatomic position. Sensory receptors of the faucial arches, tonsils, soft palate, tongue base, and posterior pharyngeal wall transmits messages centrally through cranial nerve VII and through the superior laryngeal nerve via the tractus solitarius. Motor impulses are mediated through cranial nerves IX and X. The tracheobronchial tree normally provides protection against foreign matter by a medullary reflex arc, mediated through the vagus nerve, which produces a cough. The larynx and carina are especially sensitive to irritation, and the terminal bronchioles and alveoli are very sensitive to corrosive chemical stimuli, such as chlorine. Activation of the reflex results in a deep breath; closure of the epiglottis and vocal folds; forceful contraction of the abdominal and internal intercostal muscles; opening of the epiglottis and vocal folds; and a strong compression of the lungs resulting in air velocities as high as 75 to 100 miles per hour. The generated cough usually extracts any foreign matter present in the respiratory tree. During the esophageal phase, the bolus moves from the pharynx to the stomach. When the bolus reaches the gastroesophageal junction, the lower esophageal sphincter (LES) relaxes, allowing the bolus to enter the stomach. The esophagus consists of striated muscle in the upper third and smooth muscle in the lower two-thirds. The esophagus is

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Figure 78-3 Phases of deglutition. A. Oral preparatory phase. The barium bolus (solid arrow) is masticated using a repeated cyclical pattern of rotary lateral movement of the labial and mandibular musculature. The soft palate (s) is not elevated to allow breathing. The hyoid bone (h) is positioned well below the mandible, and the epiglottis (e) is tilted upward. B . Oral phase. The bolus (arrows) has been pushed into the pharynx by elevation and posterior propulsion of the tongue. The soft palate contacts with the posterior pharyngeal wall to obliterate the velopharyngeal port and prevent nasal regurgitation. The hyoid bone (h) is still in its resting position, and the laryngeal vestibule (lv) and hypopharynx (p) are still visible. C . Pharyngeal phase. The pharyngeal constrictor muscles shorten and elevate the pharynx while the base of the tongue pushes the bolus toward the esophagus. The nasal passages are still sealed. The hyoid bone (h) is in its most superior and anterior position, correlating with closure of the larynx and the true vocal, false vocal, and aryepiglottic folds. The laryngeal vestibule is closed and cannot be visualized. The upper esophageal sphincter has relaxed, thus allowing the bolus (arrows) to pass into the esophagus.

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innervated throughout its length by two nerve networks: myenteric (Auerbach’s) and submucosal (Meissner’s). The myenteric plexus serves as a relay between smooth muscle and the vagus nerve, but its function with respect to striated muscle is unclear. The submucosal plexus primarily controls gastrointestinal secretion and local blood flow. Active movement within the esophagus occurs by peristalsis. For peristalsis to be effective, contractions must be orderly and sequential from the superior end of the esophagus caudally to the gastroesophageal sphincter. Adequate saliva must be present to propel the bolus toward the stomach. Different types of contractions assist with bolus propulsion. Primary peristalsis, which is initiated by a pharyngeal swallow, is the chief mechanism to carry a bolus through the esophagus. Primary peristalsis also produces a stripping wave to empty refluxed gastric contents back into the stomach. If the subject swallows again during esophageal peristalsis, primary peristalsis is interrupted and starts again at the top of the esophagus. If the bolus does not empty into the stomach by primary peristalsis, esophageal distention activates secondary peristalsis, which is mediated intrinsically by the myenteric plexus and does not require vagal input. Secondary peristalsis also assists in transport of bicarbonate-containing saliva produced in the mouth to the distal esophagus, where it neutralizes any remaining gastric acid refluxed into the esophagus. In pathological conditions, nonperistaltic contractions known as tertiary contractions may occur and are nonfunctional in the transport process. High-amplitude tertiary contractions causing esophageal spasm usually are perceived as one form of noncardiac chest pain. The esophagus contains a number of protective mechanisms against reflux and aspiration. First, the tonic contractions of the UES and LES act as physical barriers against gastric contents during the resting state. Pressures in the UES range up to 250 to 350 mmHg in the anteroposterior direction and 80 to 120 mmHg in the lateral direction. In the LES, pressures up to 10 to 30 mmHg relative to intragastric pressure have been recorded and prevent movement between the positive pressure of the abdomen and the negative pressure of the chest. Second, a small portion of the distal esophagus adjacent to the LES is located in the abdomen. Positive intra-abdominal pressure tends to keep the stomach and lower esophagus collapsed thereby preventing the transit of boluses into the intrathoracic esophagus. Third, the esophagus enters into the stomach at an acute angle (angle of His), which acts as a oneway valve. The angle decreases when deep inspiration causes descent of the diaphragm and gastric fundus. Even so, the right crus of the diaphragm usually contracts at the same time, preventing reflux by occluding the esophageal lumen. In addition to afferent and efferent paths, the neural organization of swallowing consists of two centers. One is thought to be located in two regions of the pontine reticular formation—i.e., (1) dorsal, including the nucleus of the solitary tract and adjacent reticular formation, and (2) ventral, corresponding to the lateral reticular formation above the nucleus ambiguus. The dorsal portion appears to initi-

ate and organize the swallowing motor sequence. The ventral portion distributes the motor impulses to the various motor neurons involved with swallowing. In animals, stimulation of the solitary tract or its nucleus in the cat, rat, or sheep can elicit a swallow. A second swallowing center has been described just anterior to the orbital gyrus in the occipital lobe. In animals, single-pulse stimulation of this cortical center causes rhythmic activation of the ipsilateral nucleus of the solitary tract, resulting in a rapid decrease of the frequency of deglutition. Each cortical center is thought to receive information from its contralateral cortical center and oropharyngeal and laryngeal receptors. The center’s purpose is not well understood but may be important for repeated swallowing or initiation of the motor sequence of deglutition. Studies with transcranial magnetic stimulation demonstrate that swallowing musculature is discretely, somatotopically, and asymmetrically represented on the motor and premotor cortex of both hemispheres independent of handedness. Following stroke, dysphagia appears to be associated with smaller pharyngeal representation on the intact hemisphere, which increases in size with recovery of swallowing. Swallowing is integrated with ventilation so that a bolus inadvertently does not enter the lower respiratory tract. Swallowing usually interrupts the expiratory phase of ventilation, and the completion of expiration occurs at the conclusion of the swallow. If a swallow is initiated during the inspiratory phase of ventilation, inspiration is interrupted, and a short expiration usually follows the completion of the swallow. Tidal volume may increase in the breaths following the swallow. Apnea occurs earlier in older adults and with larger boluses, but later with increased bolus viscosity. Vomiting, which is diametrically opposed to swallowing, normally should not result in aspiration because of protective mechanisms observed during this reflex. Vomiting can be stimulated from several sources (Table 78-2). Stimuli reach

Table 78-2 Afferent Input Involved in Vomiting Symptom

Source

Gastrointestinal tract irritation and overdistention

Vagal, sympathetic afferents

Drugs (e.g., narcotics, digoxin)

Chemoreceptor trigger zone

Vestibular stimuli

Labyrinth, vestibular nuclei, cerebellum, chemoreceptor trigger zone

Psychic stimuli (visual, auditory)

Cerebral, unknown origin

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the vomiting center, located bilaterally in the medulla near the tractus solitarius at the level of the dorsal motor nucleus of the vagus nerve. Activation of the vomiting reflex results in a deep breath; elevation of the hyoid bone and larynx with UES opening; glottic and velopharyngeal port closure; simultaneous contraction of the diaphragm and abdominal wall musculature to increase intragastric pressure; and LES relaxation resulting in expulsion of gastric contents through the esophagus.

NEUROMUSCULAR MECHANISMS Dysfunction of the central nervous system, lower sensorimotor neurons, neuromuscular junction, or muscle cells may result in aspiration. Neuromuscular disorders may cause sensory impairment or motor weakness or incoordination which hinders or circumvents the normal protective mechanisms of the gastroesophageal and tracheobronchial systems. Conditions affecting cognitive function may significantly impair intellectual controls which allow swallowing mechanisms to guide boluses safely toward the stomach. Etiologies of aspiration by neuromuscular mechanisms may be divided into two types: (1) dysphagia and (2) gastroesophageal reflux.

Dysphagia Dysphagia, or swallowing difficulty, refers to symptoms manifested by a disease state but is not itself a disease. However, dysphagia is a convenient way to categorize certain neuromuscular disorders causing aspiration, since aspiration is a serious and prominent manifestation of swallowing problems. Swallowing difficulties resulting in aspiration occur in a variety of neuromuscular disorders (Table 78-3). Many of these conditions result in abnormalities affecting more than one phase of swallowing. One framework for understanding swallowing and dysphagia involves adaptation, compensation, and decompensation of deglutition. Normal swallowing involves continuous adaptation of motor function in response to the ongoing conditions during each swallow, such as bolus size and consistency, head and neck position, and changes in pharyngeal diameter at different phases of respiration and phonation. When swallowing is impaired, compensation can be observed as a supranormal protective or reserve ability to prevent aspiration. Compensation involves a variety of voluntary strategies such as chewing food more thoroughly or limiting bolus size, as well as involuntary processes such as contraction of the superior constrictor muscles to close the velopharyngeal opening in the setting of palatal deficiency or kinking of the soft palate in apposition to weak or atrophied tongue to prevent premature leakage and laryngeal penetration. When compensatory strategies fail, decompensation or failure of the swallowing apparatus results. Decompensation occurs both from singular or multiple compromises in adaptational and compensatory mechanisms, including global suppression of

Mechanisms of Aspiration Disorders

Table 78-3 Examples of Neuromuscular Conditions Causing Aspiration Upper motor neuron Stroke Traumatic brain injury Parkinsonism Multiple sclerosis Huntington’s disease Alzheimer’s disease Neurosyphilis Encephalitis Meningitis Spinocerebellar degeneration Olivopontocerebellar atrophy Progressive supranuclear palsy Lower motor neuron Poliomyelitis Amyotrophic lateral sclerosis (ALS) Guillian-Barr´e syndrome Polyneuritis Neuromuscular junction Myaesthenia gravis Botulism Eaton-Lambert syndrome Muscle Polymyositis Dermatomyositis Muscular dystrophies—Duchenne (DMD), limb-girdle (LGMD), myotonic (MD), facioscapulohumeral (FSHMD) Spinal muscular atrophy (SMA) Scleroderma and collagen vascular diseases Achalasia Metabolic myopathy

the swallowing mechanism by fatigue or impairment of consciousness. Symptoms consistent with dysphagia and possible clinical indicators of aspiration are summarized in Table 78-4. Mechanisms of aspiration due to dysphagia usually are classified temporally with respect to the onset of the pharyngeal swallow. Aspiration before the swallow is related to abnormalities in the oral or pharyngeal phases (Fig 78-4). Weak or abnormal tongue movements may cause premature spillage of the bolus into the pharynx. A lesion of the nucleus ambiguus or the brain stem or cortical swallowing centers may result in delay or absence of the onset of the pharyngeal swallow. In either case, the pharynx is unprepared to transport the bolus safely into the esophagus. The bolus may enter

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Table 78-4 Symptoms of Dysphagia Dry mouth Drooling Nasal regurgitation Vomiting Difficulty clearing phlegm Postnasal drip Globus (obstruction) Odynophagia (pain in throat, chest, or stomach) Exhaustion after eating or drinking Dysphonia with or without “wet” voice Dyspnea Coughing or choking while eating or drinking Mouth odor Heartburn Chest pain Weight loss

the unprotected trachea, progressing into the bronchial tree if no protective cough is elicited. Aspiration during the swallow usually reflects dysfunction of the laryngeal and pharyngeal musculature (Fig 78-5). Reduced elevation of the larynx and pharynx results from impaired hyoid bone elevation or thyrohyoid or palatopharyngeal dysfunction and may cause defective closure of the laryngeal vestibule. Vocal cord paresis or paralysis may produce an incompetent laryngotracheal port through which food or liquid boluses may pass. Aspiration after the swallow can represent problems in the pharyngeal and esophageal phases of deglutition (Fig. 78-6). Weakness of the pharyngeal constrictor muscles may produce residue of the bolus in the valleculae or piriform sinuses, which subsequently spills into the laryngeal vestibule and trachea. The UES may fail to open due to impaired relaxation or distensibility, hypertrophy or hyperplasia, or fibrosis (Fig. 78-7). The obstruction may cause filling of the hypopharynx and overflow into the airway. Similarly, the LES may remain contracted due to defective innervation of the smooth muscle of the esophagus and LES resulting in achalasia (Fig. 78-8). The primary etiology of achalasia usually is idiopathic, but secondary causes may include gastric carcinoma extending to the esophagus, lymphoma, Chagas’ disease, irradiation, and certain medications and toxins. Patients with achalasia may experience dysphagia, chest pain, and regurgitation, but pulmonary aspiration may occur due to overflow of saliva and ingested food lodged in the esophagus. Cerebral lesions can interrupt voluntary control of the preparatory and oral phases. Cortical lesions involving the precentral gyrus may produce contralateral impairment

Figure 78-4 Aspiration before the swallow. Because of poor lingual control, a liquid bolus has spilled into the vallecula (small arrow), through the laryngeal vestibule (lv), and into the trachea (large arrow). The hyoid bone (h) and epiglottis (e) remain in their resting positions, and the laryngeal vestibule (lv) remains open. The hypopharynx (p) ends at the contracted upper esophageal sphincter.

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Figure 78-5 Aspiration during the swallow. Because of pharyngeal weakness represented in part by partial deflection of the epiglottis (long arrow), a portion of a liquid bolus enters the laryngeal vestibule and passes through the true vocal folds (short arrow) into the trachea (t), while the remainder successfully passes into the esophagus (e). Note that the hyoid bone (h) is in its most elevated position.

in facial, lip, and tongue motor control and contralateral compromise in pharyngeal peristalsis. A patient with impairments in cognitive function such as concentration or selective attention may not fully masticate food boluses. Oral apraxia seen in stroke or Alzheimer’s dementia may result in nonpurposeful sequencing of food by the tongue, lips, and teeth. The bradyphrenia and bradykinesis of Parkinson’s disease may challenge attentional vigilance during eating and slow pharyngeal transit. In all these cases, boluses may spill prematurely into an open airway due to abnormal or absent lingual control.

Figure 78-6 Aspiration after the swallow. A portion of a liquid bolus pools in the piriform sinuses (p) as a result of pharyngeal weakness. Eventually it spills over the aryepiglottic fold into the trachea (arrow). Note that the hyoid bone (h) is in its resting position.

Brain-stem lesions may result in compromised sensation of the mouth, tongue, and cheek, delay or absence of the pharyngeal reflex, reduced laryngeal elevation and vocal cord adduction with incomplete glottic closure, and poor cricopharyngeal relaxation. In stroke, for example, a delay or absence of the pharyngeal swallow may cause a bolus to enter

Figure 78-7 Cricopharyngeal dysfunction. The upper esophageal sphincter does not completely relax resulting in a ‘‘bar” (arrow) that may divert much of this liquid bolus from the esophagus into the airway.

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Figure 78-8 Achalasia. The esophagus has a characteristic ‘‘bird beak” appearance (arrows) where the gastroesophageal junction does not relax and allow passage of boluses. Residue may fill the esophagus and overflow into the airway (e = esophagus; s = stomach).

an unprotected airway even when the oral stage is normal. Pharyngeal weakness allows accumulation of residue in the valleculae and piriform sinuses which may spill into the larynx after the swallow. In Parkinson’s disease, failure of contraction of the pharyngeal constrictor muscles against an unrelaxed cricopharyngeus results in trapping a food bolus in a highpressure segment of the lower pharynx, ultimately hurling the bolus back toward the pharyngeal and nasopharyngeal opening. During vomiting, weakness or incoordination of the pharyngeal musculature may decrease protection of the larynx allowing vomitus to enter the tracheobronchial tree. Much investigation of the predictors of aspiration has been directed toward cerebrovascular diseases or stroke. Dysphagia is reported to occur in at least 50 percent of stroke survivors. Of those, aspiration is reported to occur in up to 75 percent. “Silent” aspiration, or aspiration without reflexive cough, is demonstrable in about one-third to one-half of patients. Lesion site or bilaterality is not predictive of dysphagia, aspiration, or their related symptoms. The absence of the gag reflex is neither predictive nor protective of dysphagia and aspiration. The presence of “wet,” dysphonic vocalizations may indicate aspiration risk, but its absence does not rule out this possibility. Thinner liquids, such as water, have a

higher risk of being aspirated because they are more difficult to manipulate during the oral phase and present less afferent sensory stimulation to trigger the pharyngeal and esophageal reflexes. The single best predictor of aspiration is the presence of an involuntary cough during or for 1 minute after being challenged to drink and swallow 3 ounces of water without interruption. A voluntary cough, however, does not necessarily indicate an effectively protective cough reflex. The absence of voluntary cough, however, should preclude further oral intake until further investigation. Bedside examination by clinicians may miss up to 40 percent of aspirations seen radiographically. During videofluorographic examination of dysphagic stroke survivors, slow or delayed initiation of the pharyngeal swallow and pharyngeal constrictor weakness were the best predictors of aspiration. Penetration of more than 10 percent of a bolus beyond the true vocal folds during videofluorographic evaluation is associated with increased risk of aspiration pneumonia, but findings of residue in the valleculae and piriform sinuses are not associated with aspiration pneumonia. Stroke survivors with bilateral cranial nerve dysfunction are at the greatest risk of aspiration. Of the 40 percent of dysphagic stroke survivors who aspirate silently, these patients may express fewer subjective complaints and have a weaker cough. Dysphonia is the most common symptom associated with aspiration. The relative risk of pneumonia in stroke survivors who aspirate radiographically is almost seven times greater than stroke survivors who do not aspirate. The risk of aspiration pneumonia is about five-and-one-half times greater in patients with silent aspiration when compared to nonaspirating stroke survivors. Aspiration pneumonia in stroke survivors occurs about three-and-one-half times more commonly from aspirating liquids than from aspirating solids. Data have been collected on the incidence of aspiration in other diagnoses. In nonambulatory patients with Parkinsonism, aspiration occurs in up to 46 percent and is seen more commonly with liquid swallows than with solids or semisolids. Over 30 percent of persons with multiple sclerosis experience dysphagia, including 15 percent of those with mild disability. After resection of basal skull tumors, 75 percent of patients aspirated during videofluorographic swallowing studies.

Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) typically presents with symptoms of heartburn and regurgitation and less typically with anginalike chest pain. Tracheopulmonary manifestations of reflux include chronic hoarseness (reflux laryngitis) associated with inflammation of the posterior larynx and vocal cords, nocturnal episodes of nonallergic asthma, chronic cough, or sustained hiccups. For GERD to cause aspiration, gastric secretions and/or bacteria must traverse the LES, esophagus, and UES (Fig. 789). Gastric secretions normally have a pH of approximately

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Figure 78-9 Gastroesophageal reflux. Incompetence in the LES (small arrows) permits liquid barium to reflux from the stomach (s) to the esophagus (e). A hiatal hernia (hh) may commonly be associated with gastroesophageal reflux.

0.8 when produced by parietal cells of the stomach. Chemical burns of the airways and lung parenchyma may result when gastric juices have a pH of less than 3.0. Mild desquamation of the parenchyma with delayed regeneration may occur when food particles have a pH greater than 3.0. Conditions such as Zollinger-Ellison syndrome worsen the risk of GERD due to the propensity for hyperacidity. Increases in gastric pH create an environment more conducive to supporting bacterial colonization in the stomach. With administration of histamine-2 (H2 ) antagonists, antacids, or continuous enteral feedings, bacteria typically found in the duodenum (e.g., Escherichia coli, Streptococcus faecalis, Proteus mirabilis, Pseudomonas maltophilia) may reflux into and colonize within the stomach independent of oropharyngeal flora. Tracheobronchial contamination then may ensue when GERD occurs. Also, duodenal contents combined with reduced or absent acid secretion may reflux after gastrectomy or in the presence of pyloric dysfunction, resulting in alkaline reflux esophagitis and chronic aspiration. LES incompetence is most commonly due to transient or chronic reductions in LES tone. The intra-abdominal length of the esophagus correlates negatively with the degree

Mechanisms of Aspiration Disorders

of gastroesophageal reflux. Conditions and agents that decrease LES pressure are found in Table 78-5. The association between hiatal hernia and GERD remains controversial. Hiatal hernias may be found in a large percentage of people, many of whom may be asymptomatic. However, current information suggests that gastric acid may become trapped in the hernial sac, making it more available to reflux into the esophagus when the LES relaxes. A recent study demonstrates that patients with large hiatal hernias tend to have lower LES pressures susceptible to reflux by abrupt increases in intra-abdominal pressure. Esophageal motility must be dysfunctional for gastric secretions to ascend to the UES. However, the primary mechanism that links primary peristaltic dysfunction with reflux is unknown. In patients who aspirate due to GERD, peristalsis usually is not organized but is characterized by tertiary contractions. The amplitude of peristalsis is significantly decreased throughout the esophagus in GERD, while the amplitude of peristalsis is reduced only in the lower esophagus in patients with esophagitis. Absent or incomplete peristaltic contractions result in little or no volume clearance from the involved segments. The degree of peristaltic dysfunction is correlated with the amount of reflux. The UES represents the final obstacle to aspiration of gastric contents. In patients with aspiration associated with GERD, the resting pressure of the UES is lower than that of normal patients or those with gastroesophageal reflux alone. The primary mechanism for the onset of UES hypotonia is unknown. In addition, UES tone is virtually absent during sleep, during which time reflux does not cause any reflex increase in UES pressure. Without preventive measures such as raising the head of the bed to increase the influence of gravitational forces, gastric secretions have easy access into the respiratory tree.

MECHANICAL MECHANISMS There are numerous mechanical etiologies of dysphagia, including inflammatory (e.g., Ludwig’s angina, retropharyngeal infections), anatomic (e.g., Zenker’s diverticulum), traumatic, and cancer-related, but few actually lead to aspiration. Mechanical problems may divert the path of a bolus from the esophagus into the trachea; they may compress nerves resulting in abnormal sensory input or motor function which can cause aspiration. Treatment of these conditions may alleviate or exacerbate symptoms of aspiration. Ludwig’s angina is a submandibular space infection caused by abscesses, caries, or postextraction dental infection. The floor of the mouth becomes erythematous, edematous, and indurated, and the tongue is displaced. The suprahyoid region of the neck becomes swollen and stiff. Asphyxia, aspiration pneumonia, and lung abscess may be potential complications and require intravenous antibiotics. The submandibular abscess may require surgical incision and drainage.

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Table 78-5 Examples of Agents and Conditions Causing Decreased LES Pressure Medications

Hormones and Peptides

Foods

Medical Conditions

Surgical Conditions

Anticholinergics

Calcitonin gene-related peptide

Carminatives (spearmint, peppermint)

Amyloidosis

Lower esophageal sphincter myotomy (Heller)

Barbiturates

Cholecystokinin

Chocolate

Diabetes mellitus

Lower esophageal sphincter resection

Calcium channel blockers

Estrogen

Ethanol

Hypothyroid

Caffeine

Glucagon

Fat

Pregnancy

Diazepam

Neuropeptide Y

Scleroderma

Dopamine

Progesterone

Transient lower esophageal sphincter relaxation

Meperidine

Somatostatin

Prostaglandins E1 and E2

Secretin

Theophylline

Vasoactive intestinal polypeptide

Retropharyngeal infections occur in the space between the posterior pharyngeal wall and the spine. They may be caused acutely by abscesses from the lateral pharyngeal wall or complications from neck trauma, or chronically by complications of osteomyelitis of the cervical spine. Epiglottitis, mediastinitis, meningitis, spontaneous rupture of the larynx with aspiration and asphyxiation, bronchial erosion, pyopneumothorax, and purulent pericarditis may complicate the course of the infection. Antibiotic therapy and surgical drainage may be required to alleviate the condition. Zenkerâ&#x20AC;&#x2122;s diverticulum is an abnormal muscular outpouching that occurs in the cervical esophagus (Fig. 78-10). This outpouching may be located in the midline or laterally and inferior to the cricopharyngeus muscle insertion on the cricoid cartilage (Killian-Jamieson type). The etiology of Zenkerâ&#x20AC;&#x2122;s diverticulum is unknown but may be associated with esophageal diseases such as varices, carcinoma, hiatal hernia, and achalasia. These diseases occur more commonly in men in their sixth or seventh decade. Symptoms include coughing, choking, or wheezing. Aspiration occurs most often at night, but aspiration pneumonitis occurs in fewer than 10 percent of patients.

Traumatic alteration of the pharyngeal mucosa may lead to aspiration. Blunt trauma due to motor vehicle accidents, gunshot or knife wounds, or falls from significant heights can transform oropharyngeal anatomy or cause nerve damage which results in aspiration. Fistulae allow food to travel directly between the esophagus and the trachea. Finally, primary tumors and their sequelae may cause aspiration. Tumors of the tongue or floor of the mouth may limit movements of the mandible and tongue resulting in premature spillage of a bolus into an open airway. Pharyngeal or esophageal tumors may obstruct the alimentary canal, cause backflow into the hypopharynx, and result in spillage of a bolus into the airway (Fig. 78-11).

IATROGENIC MECHANISMS Nonoral Enteral Feeding Aspiration not only is an indication for but also is a complication of enteral nutritional support. Nasoenteric, gastrostomy,

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Mechanisms of Aspiration Disorders

Figure 78-10 Zenkerâ&#x20AC;&#x2122;s diverticulum. This abnormality is located in the midline just inferior to the upper esophageal sphincter in the cervical esophagus (arrows). Residue may reflux into the pharynx and may be aspirated. A. Lateral view. B . Anteroposterior view (v = vallecula; e = epiglottis; p = piriform sinus).

and jejunostomy tubes all have been implicated as a cause of aspiration. The mechanical interruption of the pharynx, gastroesophageal junction, and pylorus of the stomach is presumed to augment any underlying predisposing factors. Patients with neurogenic dysphagia receiving enteral nutrition by nonoral feeding methods have a higher incidence of aspiration pneumonia than those with dysphagia of mechanical origin. Further, the use of the nasoenteric route for enteral feeding is associated with higher rates of aspiration pneumonia and higher mortality from aspiration pneumonia than gastrostomy or jejunostomy. However, tube size, distal tube location, and feeding schedules (continuous or intermittent) have not been shown to influence the recurrence of aspiration. The use of gastrostomy versus jejunostomy with respect to aspiration risk remains controversial. One review of complications associated with gastrostomy and jejunostomy feedings in patients with neurogenic dysphagia reported no significant difference in aspiration risk. However, another study suggested that patients with clinical or videofluorographic evidence of gastroesophageal reflux, aspiration, gastric atony, and/or gastric outlet obstruction may have a reduced risk of aspiration when jejunostomy tube feedings are used. When these contraindications for the use of a gastrostomy tube are present, the feeding tube should be placed distal to the gastroesophageal and pyloric sphincters, increasing protection against aspiration. Nosocomial pneumonia may be related to enteral nutrition. Gastrostomy feedings may alkalinize the gastric environment, facilitating bacterial overgrowth (see â&#x20AC;&#x153;Gastroesophageal Reflux Diseaseâ&#x20AC;? above). The use of jejunostomy

feedings may result in less alkalinization of the gastric environment but may still result in lowering bacterial colony counts even when reflux and aspiration are present. Models simulating the effects of environmental influences on the upper gastrointestinal flora of patients receiving enteral feedings suggest that a gastric pH of less than 4 is not sufficient to prevent microbial overgrowth. Monitoring of tracheal secretions in critically ill hospitalized patients requiring tube feeding, especially when mechanically ventilated, using techniques such as methylene blue dye detection and glucose monitoring (glucose-positive indicating reflux and aspiration), may be useful. However, commonsense interventions, such as keeping these patients in at least a 30-degree semirecumbent position during and up to 1 to 2 hours after enteral feeding, may be more important in preventing aspiration.

Tracheal Intubation and Tracheostomy Mechanical interruption of the larynx with a tracheostomy or endotracheal tube is associated with increased risk of aspiration in patients receiving both oral and enteral feedings. For example, in one study, 71.4 percent of the aspirations observed in patients receiving enteral feedings occurred in patients who had artificial airways. A tracheostomy or endotracheal tube will interfere with both laryngeal elevation and laryngeal closure during the pharyngeal phase of swallowing. Further, the cough reflex may be compromised such that there is insufficient subglottic pressure generated by a reflexive cough when laryngeal penetration occurs. Inflation of the tracheostomy cuff is thought to limit, however incompletely, laryngeal and upper-airway entry of nongaseous materials.

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Head and Neck Cancer Treatments Treatments for head and neck cancer may exacerbate swallowing problems which increase the incidence of aspiration. Resections of the retromolar trigone, base of the tongue, and floor of the mouth cause aspiration due to loss of bolus control and premature spillage of the bolus into the pharynx. Resections of the tonsils and superior or lateral pharynx may interfere with bolus transport because of altered sensation or decreased propulsion usually supplied by the pharyngeal constrictor muscles. Resection of the submental muscles impairs the laryngeal elevation and forward movement required to protect the larynx from foreign bodies. Hemilaryngectomy decreases the contact between the base of the tongue and the excised larynx, thus raising the risk of aspiration. Supraglottic laryngectomy, which includes resection of the aryepiglottic folds and one or both of the superior laryngeal nerves, can cause persistent aspiration when the arytenoid cartilage, piriform sinuses, and tongue base are removed. Tracheoesophageal puncture for placement of a prosthetic valve to facilitate voice after laryngectomy can be a site for liquid or secretions to leak into the trachea through the fistula and through the prosthesis. Even irradiation of resected tissues may result in tissue necrosis and fibrosis which can limit a significant amount of protective laryngeal movement.

SUGGESTED READING Figure 78-11 Esophageal carcinoma. This adenocarcinoma of the esophagus has a characteristic ‘‘ apple core” appearance. Boluses may lodge in the esophagus or reflux into the pharynx with subsequent aspiration.

General Anesthesia The use of general anesthesia for surgical procedures globally depresses consciousness as well as adaptational and compensatory mechanisms that are thought to protect from aspiration. The risk of aspiration is even higher when emergent surgical intervention allows inadequate time for gastric emptying of recently ingested food. Further, when the surgical procedure involves manipulation of the stomach or bowels, the possibility of regurgitation of gastric contents is high. Some investigators have explored the use of artificial airways that aim to prevent the aspiration of regurgitated gastric materials during surgical procedures. These artificial airways provide an esophageal seal that prevents passage of more solid gastric materials yet allows drainage of distal esophageal fluid. The efficacy of these types of airways is not yet established.

Barakate MS, Jensen MJ, Hemli JM, et al: Ludwig’s angina: Report of a case and review of management issues. Ann Otol Rhinol Laryngol 110(5 Pt 1):453–456, 2001. Hamdy S, Aziz Q, Rothwell JC, et al: The cortical topography of human swallowing musculature in health and disease. Nat Med 2:1217–1224, 1996. Hiss SG, Strauss M, Treole K, et al: Effects of age, gender, bolus volume, bolus viscosity, and gustation on swallowing apnea onset relative to lingual bolus propulsion onset in normal adults. J Speech Lang Hear Res 47:572–583, 2004. Monte FS, da Silva-Junior FP, Braga-Neto P, et al: Swallowing abnormalities and dyskinesia in Parkinson’s disease. Mov Disord 20:457–462, 2005. O’May GA, Reynolds N, Macfarlane GT: Effect of pH on an in vitro model of gastric microbiota in enteral nutrition patients. Appl Environ Micro 71:4777–4783, 2005. Peterson KL, Fenn J: Treatment of dysphagia and dysphonia following skull base surgery. Otolaryngol Clin North Am 38:809–817, 2005. Prosiegel M, Schelling A, Wagner-Sonntag E: Dysphagia and multiple sclerosis. Int MS J 11:22–31, 2004.

79 Pulmonary Alveolar Proteinosis Bruce C. Trapnell

Jonathan Puchalski

I. PATHOGENESIS Surfactant Homeostasis Animal Models of PAP GM-CSF and Innate Immunity Antibodies against GM-CSF in Primary PAP Secondary PAP Congenital PAP II. EPIDEMIOLOGY III. CLINICAL FEATURES Presentation Radiographic Appearance

Pulmonary alveolar proteinosis (PAP) is a syndrome characterized by progressive accumulation of surfactant phospholipids and proteins within alveoli and terminal airways. Our understanding of this rare and fascinating syndrome has improved greatly over the past decade due to important contributions from clinical, basic, and translational research. While improving our understanding of disease pathogenesis, these studies have also identified a critical role for granulocytemacrophage colony-stimulating factor (GM-CSF) in surfactant homeostasis and host defense. Based on clinical, histopathological, and pathogenic differences, PAP is now recognized to occur as one of three distinct forms: primary, secondary, and congenital. Primary PAP (also referred to as acquired or idiopathic PAP) is a disorder of unknown etiology believed to result from decreased surfactant clearance by alveolar macrophages. Primary PAP is also complicated by secondary infections that contribute to increased mortality and suggest the presence of a defect in systemic immunity. Secondary PAP is a clinically heterogeneous syndrome occurring as a consequence of a co-morbid condition that impairs surfactant clearance. Congenital PAP is a pathogenically het-

Laboratory Findings Lung Function Bronchoscopic Findings Lung Pathology Secondary Infections IV. DIAGNOSIS V. NATURAL HISTORY VI. THERAPY Whole Lung Lavage Experimental Approaches

erogeneous group of genetic disorders resulting in production of abnormal surfactant.

PATHOGENESIS In their initial description of PAP in 1958, Rosen et al established that the alveolar material in PAP was composed of lipids, proteins, and a small amount of carbohydrate. Although the etiology of primary PAP remains unknown, strong evidence now supports a mechanism in which interruption of GM-CSF signaling impairs the terminal differentiation of alveolar macrophages and their ability to catabolize surfactant lipids and proteins. GM-CSF is a 23-kDa glycoprotein cytokine produced by various cell types including the respiratory epithelium. It was initially identified by its ability to stimulate the formation of macrophage and granulocyte colonies from hematologic progenitors and subsequently shown to stimulate functions in mature myeloid and other cells. The gene encoding GM-CSF is expressed similarly in humans and mice, and its biologic effects are mediated by binding

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Alveolar Diseases

to heterodimeric cell surface receptors composed of a GMCSF-binding α-chain (CD116) and an affinity-enhancing β-chain.

tabolize both surfactant lipids and surfactant proteins, a process believed to be regulated by GM-CSF.

Animal Models of PAP Surfactant Homeostasis Surfactant is vital to the mechanical function of the lungs where it acts to reduce the surface tension at the air-liquidtissue interface, thus preventing alveolar wall collapse. Surfactant is composed of approximately 90 percent lipids (largely phospholipids), 10 percent proteins (surfactant protein [SP] -A, -B, -C and -D]), and less than 1 percent carbohydrate. SPB and SP-C are hydrophobic phosphoproteins and contribute significantly to the surface active properties of surfactant. SP-A and SP-D are hydrophilic protein members of the collectin family of proteins that contribute to lung host defense. Surfactant lipids and proteins are synthesized, stored, and secreted into the alveoli by type II alveolar epithelial cells. In the extracellular space, large aggregates of surfactant develop and contribute to the formation of a film that stabilizes the alveolus by lowering surface-tension. Surfactant is expelled from the film as small aggregates that are taken up by both type II cells and alveolar macrophages (Fig. 79-1). While type II cells are capable of recycling surfactant, alveolar macrophages ca-

An important clue to the pathogenesis of PAP was provided by the serendipitous discovery that GM-CSF knockout mice develop a pulmonary phenotype biochemically, histologically and ultrastructurally indistinguishable from that of primary PAP (Fig. 79-2). Detailed studies of these mice revealed that production of surfactant lipids and proteins by type II cells is not increased and that surfactant uptake by alveolar macrophages is not decreased. In contrast, catabolism of both surfactant lipids and proteins by alveolar macrophages is markedly impaired. PAP could be corrected in GM-CSF knockout mice by replacement of GM-CSF in the lungs, adenoviral transfer of the GM-CSF gene into the pulmonary epithelium, or genetic reconstitution of GM-CSF expression specifically in the lungs. Ablation of the GM-CSF receptor β gene also caused PAP, confirming that GM-CSF signaling is critical for surfactant homeostasis in mice. PAP in this latter model was corrected by bone marrow transplantation, confirming that the defect was in macrophages, not lung epithelial cells. Surfactant catabolism in alveolar macrophages

Figure 79-1 Schematic illustration depicting mechanisms of surfactant production, recycling and catabolism. Surfactant phospholipids and proteins are synthesized in type II alveolar epithelial cells that line pulmonary alveoli. Surfactant B and C precursor proteins are processed, transported to lamellar bodies, and then secreted into the alveolar space where they interact with surfactant protein A to form tubular myelin. Surfactant monolayers and multilayers are formed from tubular myelin and function to reduce surface-tension at the air-liquid-tissue interface, thus stabilizing the alveoli. Surfactant remnants are taken up and either catabolized or re-utilized by type II alveolar epithelial cells. Alveolar macrophages play a critical role in surfactant homeostasis by taking up and catabolizing surfactant remnants. GM-CSF is required to maintain surfactant homeostasis and acts by stimulating catabolism of surfactant lipids and proteins in alveolar macrophages. (From Whitsett JA, Wert SE, Trapnell BC: Genetic disorders influencing lung formation and function at birth. Hum Mol Genet 13[Spec No 2]:R207–R215, Fig. 2, 2004, with permission.)

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Other animal models of PAP exist. For example, over-expression of either interleukin (IL)-4 or IL-13 in the lungs of transgenic mice is associated with increased production of surfactant proteins and lipids and development of PAP. Genetically modified mice deficient in SPB, SP-C, or ABCA3 have been created as animal models of congenital PAP. Naturally occurring mice with severe combined immunodeficiency (SCID) also develop PAP, presumably as a secondary consequence of the effects on alveolar macrophages.

GM-CSF and Innate Immunity GM-CSF knockout mice have increased susceptibility to bacterial, fungal, parasitic, and mycobacterial infection and increased mortality from spontaneous infections. Alveolar macrophages from these mice have impaired cellular adhesion, cell-surface pathogen recognition receptors, phagocytosis, lipopolysaccharide-stimulated proinflammatory cytokine secretion, and antimicrobial killing activity. Importantly, as for the defect in surfactant catabolism, retroviral expression of PU.1 in alveolar macrophages corrects all of these macrophage immune defects (Fig. 79-3). The diversity and number of functions regulated by PU.1 in alveolar macrophages strongly suggest that GM-CSF, via PU.1, regulates alveolar macrophage terminal differentiation in mice. Translational studies show that GM-CSF also regulates expression of PU.1 and a number of PU.1-dependent genes in human alveolar macrophages, suggesting that it may also regulate terminal differentiation of human alveolar macrophages. While these observations suggest that defects in alveolar macrophagemediated immunity likely contribute to impaired host defense in GM-CSF knockout mice, GM-CSF deficiency may also be important to the functions of other components of immunity.

Antibodies against GM-CSF in Primary PAP

Figure 79-2 Ultrastructural appearance of the sediment from the lungs of a human patient with primary PAP (A) and a GMCSF–deficient mouse (B ). Note the presence of lamellated, fused membrane structures and amorphous debris (uranyl acetate, ×30,000).

from GM-CSF knockout mice can be rescued by retroviral expression of PU.1, a transcription factor normally expressed in murine alveolar macrophages in vivo under tight regulatory control of pulmonary GM-CSF. Together, these studies established that GM-CSF has a critical role in surfactant homeostasis in mice and acts by stimulating surfactant catabolism in alveolar macrophages via PU.1 (Fig. 79-3).

A second clue regarding pathogenesis was the observation that high levels of anti–GM-CSF autoantibodies were present in blood and lungs of individuals with primary PAP, but not in those with secondary or congenital PAP or other lung diseases or in normal individuals (Fig. 79-4). Anti–GM-CSF antibodies in primary PAP are polyclonal, comprise all four immunoglobulin G (IgG) subclasses, have a very high affinity for GM-CSF, and are capable of neutralizing up to 50,000-fold more GM-CSF than is normally present, thus eliminating GM-CSF bioactivity in vivo. Primary PAP appears to comprise a human functional deficiency of GM-CSF. Notwithstanding their high specificity for primary PAP, levels of serum anti–GM-CSF antibodies do not correlate well with disease severity. This is not unexpected in the context of a mechanism in which anti–GM-CSF antibodies are not directly toxic but contribute to molecular and cellular pathology by neutralizing GM-CSF bioactivity and thereby impairing GM-CSF– dependent macrophage functions.

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Alveolar Diseases

Figure 79-3 Role of GM-CSF in modulating the function of alveolar macrophages in mice. Pulmonary GM-CSF stimulates increased levels of the transcription factor PU.1 in alveolar macrophages in the lungs in vivo. Alveolar macrophages from mice deficient in GM-CSF have a number of functional defects including defects in cellular adhesion, catabolism of surfactant proteins and surfactant lipids, expression of pathogen-associated molecular pattern receptors (e.g., toll-like receptors and the mannose receptor), toll-like-receptor signaling, phagocytosis of pathogens, intracellular killing of bacteria (independent of uptake), pathogen-stimulated secretion of cytokines (tumor necrosis factor-α, interleukin [IL]-12, and IL-18), and Fc- receptor–mediated phagocytosis. Cytoskeletal organization is abnormal and may in part account for defects in phagocytosis. The ability of alveolar macrophages to release IL-12 and IL-18 severely impairs the interferon-γ response to pulmonary infection, thus impairing an important molecular connection between innate and adaptive immunity in the lung. Retroviral-mediated expression of PU.1 in alveolar macrophages from GM-CSF knockout mice corrects all these defects, suggesting that GM-CSF stimulates terminal differentiation of the macrophages primarily through the master transcription factor PU.1. The blue arrows represent the functions regulated by PU.1 that are affected by the absence of GM-CSF. (From Trapnell BC, Whitsett JA, Nakata K: Pulmonary alveolar proteinosis. N Engl J Med 349:2527–2539, Fig. 4, 2003, with permission.)

Secondary PAP PAP can occur after exposure to an etiologic agent or clinical condition that results in either a functional impairment or reduced numbers of alveolar macrophages. Conditions associated with development of secondary PAP include heavy inhalation exposure to inorganic dusts (e.g., silica, titanium, aluminum) or fibrous insulation and various hematologic or oncologic disorders (e.g., chronic myeloid leukemia, myelomonocytic leukemia, acute myeloid leukemia, acute lymphoid leukemia, hairy cell leukemia, lymphoma, myelofibrosis, aplastic anemia, myelodysplasia, thrombocythemia, polycythemia vera, idiopathic thrombocytopenic

purpura, myeloma, macroglobulinemia, Fanconi’s anemia, and glioblastoma). Secondary PAP can also occur as a consequence of systemic infections, for example, during human immunodeficiency virus (HIV) infection. Pneumocystis carinii produces PAP-like lung histology, which can be identified by specific histological staining. Secondary PAP can be distinguished from primary PAP on the basis of the clinical context and histological or immunohistochemical evaluation of lung biopsy specimens. Although not well-studied, secondary PAP presumably occurs when the capacity for surfactant catabolism in the lungs is markedly impaired by a reduction in either the numbers or function of alveolar macrophages.

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CLINICAL FEATURES Presentation Primary PAP typically presents in previously healthy adults as progressive exertional dyspnea of insidious onset. Most individuals present between the ages of 20 and 50 years, although primary PAP has been diagnosed in children as young as 8 years old. About one-third of individuals complain of cough and less commonly, fever, chest pain, or hemoptysis, especially if secondary infection is present. Occasionally, the diagnosis is made in an asymptomatic individual when radiographic imaging is obtained for other reasons. A history of pneumonia poorly responsive or unresponsive to antibiotic therapy is sometimes present and should raise the suspicion of PAP. The physical examination is often normal, although there are crackles in up to 50 percent of patients, cyanosis in 25 percent, and digital clubbing in a small percentage. Figure 79-4 High levels of antibodies against GM-CSF in the serum of patients with primary PAP but not in congenital or secondary PAP, other lung diseases, or in normal individuals. (From Trapnell BC, Whitsett JA, Nakata K: Pulmonary alveolar proteinosis. N Engl J Med 349:2527–2539, Fig. 5, 2003, with permission.)

Congenital PAP PAP rarely occurs in neonates, infants, and children due to a specific homozygous defect in the genes encoding SP-B, SP-C, or ABCA3—a lipid transporter expressed in type II alveolar epithelial cells. In contrast to primary and secondary PAP, which occur due to defective surfactant clearance, these disorders result from abnormal surfactant production. Although convincing evidence of genetic mutations in the genes encoding GM-CSF or its receptor has not been found in human PAP, deficiency of the GM-CSF receptor itself has been reported.

Radiographic Appearance The plain chest radiograph in uncomplicated primary PAP usually reveals bilateral symmetrical alveolar opacities located centrally in mid- and lower-lung zones, often with a perihilar predominance resembling the “bat wing” appearance of pulmonary edema but without other signs of left-sided heart failure (Fig. 79–5A). The peripheral lung is commonly spared, resulting in lucency along the diaphragmatic and mediastinal borders. High-resolution computed tomography scanning reveals a characteristic, geographical pattern of ground-glass opacifications with superimposed interlobular septal and intralobular thickening, commonly referred to as “crazy paving” (Fig. 79–5B). While characteristic of PAP, this pattern is not diagnostic and is observed in patients with various other pulmonary disorders. The extent of radiographic abnormalities is often disproportionately increased relative to the severity of the symptoms and physical findings but correlates with the degree of impairment in pulmonary function as measured by arterial blood gas analysis.

EPIDEMIOLOGY The annual incidence and prevalence of PAP have been estimated to be 0.36 and 3.7 cases per million individuals, respectively. A recent meta-analysis of published reports of PAP by Seymour in 2002 identified 410 separate cases, representing most, if not all, of the cases reported at that time. More than 90 percent of cases were idiopathic and no familial predispositions or genetic mutations were identified. The average age at onset was 39 years; 72 percent of individuals had a history of smoking; and the male to female ratio was 2.65 to 1.0. The gender difference is not present in nonsmokers. Primary PAP occurs in various ethnic backgrounds including Hispanic, Asian, black, and white. Secondary PAP occurs in about 5.3 percent of hematologic malignancies overall, and is slightly higher (8.8 percent) in neutropenic patients and in individuals with acute myeloid leukemia (10 percent). The incidence of congenital PAP is not well established.

Laboratory Findings Routine blood counts and chemistries are usually normal in primary PAP except for a mild elevation of the serum lactate dehydrogenase (LDH) in the range of about one to two times the upper limit of normal. The specific association of anti– GM-CSF autoantibodies with primary PAP has prompted the widespread use of antibody testing for identification of this disease. Results from ongoing clinical research studies indicate that the sensitivity and specificity of anti–GM-CSF autoantibody testing for primary PAP approaches 100 percent. Serum LDH correlates well with the degree of functional impairment as determined by physiological testing and arterial blood gas analysis and is useful in following the disease course. Serum levels of SP-A, SP-D, mucin KL-6, cytokeratin 19, and carcinoembryonic antigen are elevated in primary PAP; their potential use as biomarkers of disease is currently under study.

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Alveolar Diseases

Figure 79-6 Lavage fluid obtained during the whole lung lavage procedure has a characteristic turbid appearance and a sediment that forms upon standing. The marked opacity and sediment of the fluid observed at the beginning (left bottle) shows progressive clearing by the end of the procedure (right bottle).

Bronchoscopic Findings

Figure 79-5 Radiographic appearance of primary PAP. A. Posteroanterior chest radiograph of a 25-year-old woman showing the typical features of PAP including bilateral, diffuse airspace disease. This individual had a disease severity of class 2 at the time of these studies (see Table 79-1). B . Corresponding high-resolution computed tomographic scan of the chest showing patchy areas of ground-glass opacification in a geographical distribution with superimposed interlobular thickening.

Lung Function The results of lung function tests can be normal but most commonly show a restrictive pattern with modest impairment of the vital capacity and total lung capacity (TLC) and a disproportionate reduction of the carbon monoxide diffusing capacity (DlCO ). Arterial blood gas analysis in symptomatic patients reveals hypoxia caused by ventilation-perfusion inequality and intrapulmonary shunting, resulting in a widened alveolar-arterial diffusion gradient (A-aDO2 ).

The bronchoscopic appearance of the airways in uncomplicated PAP is normal but white, frothy proteinosis material is occasionally seen. The bronchoalveolar lavage (BAL) fluid is opaque and has a milky or waxy appearance and develops a thick layer of sediment upon standing overnight (Fig. 79-6). The sediment consists of large, acellular, eosinophilic bodies in a diffuse background of granular material that stains with periodic acidâ&#x20AC;&#x201C;Schiff (Fig. 79-7A). It also contains large, foamy macrophages (Fig. 79-7B) or monocyte-like macrophages and lymphocytes with relatively few neutrophils. Surfactant protein levels are markedly elevated and electron microscopy reveals the presence of lamellar bodies and tubular myelin that are characteristic of surfactant. GM-CSF, monocyte chemotactic protein-1 (MCP-1), and IL-8 levels are elevated in the lungs of individuals with primary PAP (and GM-CSF knockout mice) and may be of prognostic value as a biomarker of disease severity.

Lung Pathology Macroscopically, the cut surface of the lung in primary PAP reveals a patchwork of 2 to 3 cm, grayish-yellow regions of firm consolidation that exudes fatty material. Microscopically, alveoli and terminal airspaces are filled with a fine eosinophilic material (Fig. 79-7C) that stains strongly for surfactant proteins (Fig. 79-7D). The alveolar wall and interstitial architecture are relatively well preserved but lymphocyte accumulation and, occasionally, fibrosis can be seen. The vasculature appears normal. Electron microscopy, which is seldom necessary, reveals characteristic, concentrically laminated surfactant structures within the granular material and in alveolar macrophages.

1319 Chapter 79

Pulmonary Alveolar Proteinosis

bronchial biopsy can usually establish the diagnosis. However, open lung biopsy remains the gold standard. The highly sensitive and specific anti–GM-CSF autoantibody assay provides a simple blood-based assay for diagnosis of primary PAP, and its potential predictive value and diagnostic accuracy is currently under evaluation. It is likely that a combination of routine clinical and radiographic information together with antibody testing may simplify the diagnosis of primary PAP in the near future.

NATURAL HISTORY

Figure 79-7 Cytological, pathological, and immunohistochemical appearance of the lipoproteinaceous material from patients with primary alveolar proteinosis. A. Positive periodic acid– Schiff staining of the sediment from bronchoalveolar lavage (×100). B . Cytological appearance of a typical ‘‘foamy” alveolar macrophage. C . Histopathological appearance of the lungbiopsy specimen from a 10-year-old child with primary PAP. Note the homogenous staining pattern, normal alveolar wall architecture, and the absence of inflammatory cells (H&E, ×200). D . Immunohistochemical staining reveals the presence of abundant accumulation of surfactant protein A in a lung biopsy specimen (human anti-surfactant protein A immunostain, ×200).

Secondary Infections Individuals with primary PAP have an increased risk of infections, which contribute significantly to increased morbidity and mortality. Although pathogens commonly seen in community- and hospital-acquired lung infections are sometimes identified, more commonly, Nocardia, Mycobacterium, Aspergillus, Cryptococcus, and other opportunistic organisms are found. Infections occur at both pulmonary and extrapulmonary sites and suggest the possibility of a systemic hostdefense defect, which may be explained by defects in the antimicrobial functions of macrophages and neutrophils.

DIAGNOSIS A diagnosis of primary PAP is suspected on the basis of history, physical examination, radiographic studies, and pulmonary function testing but requires further investigation to exclude other conditions in the differential diagnosis such as cardiogenic pulmonary edema, atypical pneumonia, interstitial lung diseases, and lysinuric protein intolerance. In clinically suspected cases, bronchoscopic findings including trans-

Individual cases of primary PAP fall into one of three categories: spontaneous improvement, stable but with persistent symptoms, or progressive deterioration. A retrospective analysis of cases for which sufficient information was available found spontaneous improvement in 8 percent of 303 cases and an overall 5-year survival rate of 85 percent in 343 cases. Of the deaths attributable to PAP, 47 were due to respiratory failure from alveolar proteinosis, 12 were due to uncontrolled infections, and one was due to cardiac arrest during lavage. A classification scheme for the disease severity in PAP (Table 79-1) has recently been proposed (Y. Inoue, personal communication) and its potential clinical use is currently under evaluation in several longitudinal studies of PAP.

THERAPY The treatment of PAP depends on the underlying cause. Therapy for congenital PAP is supportive, although SP-B deficiency has been treated successfully by lung transplantation. Treatment for secondary PAP is aimed at the underlying clinical condition, the successful treatment of which generally corrects the associated PAP. In primary PAP, some patients

Table 79-1 Classification of Disease Severity in PAP Class

Descriptor

Symptoms∗

PaO2 (mmHg)

Mild

≥70

Yes

≥70

Yes

≥60 and ≤70

Yes

≥50 and ≤60

Yes

≤50

2 3

Moderate

4 5

Severe

∗ Symptoms

can include dyspnea, cough, and, less frequently, fever.

1320 Part VIII

Alveolar Diseases

are asymptomatic despite significant radiographic abnormalities; others undergo spontaneous remission and do not require treatment. Consequently, treatment should be initiated when symptoms become limiting. Although a number of treatment approaches have been used in isolated cases, whole lung lavage emerged early as a successful approach for primary PAP and has remained the most widely accepted and effective form of treatment for more than four decades. While specific indications for whole lung lavage have not been clearly established, recommendations have included a definitive histological diagnosis and (1) PaO2 less than 60 to 65 mm Hg; (2) A-aDO2 gradient greater than 40 mmHg; (3) shunt fraction greater than 10 to 12 percent; or (4) severe dyspnea at rest or with exercise.

11 of 20 individuals in these studies showed symptomatic, physiological, or radiographic improvement. In another report that described administration of GM-CSF directly to the lungs via aerosol in three individuals, clinical improvement was observed in all three in parallel with a reduction in the GM-CSF–neutralizing capacity in lung lavage fluid, improved alveolar macrophage function, and improved respiratory function. Other strategies targeting the anti–GM-CSF autoantibody include plasmapheresis and anti–B-lymphocyte immunotherapy. Limited data are available regarding the potential use of these approaches, and further studies are warranted.

SUGGESTED READING Whole Lung Lavage First described by Ramirez-Rivera in the 1960s, the technique of whole lung lavage has evolved considerably since its inception. The procedure is performed under general anesthesia using a double-lumen endotracheal tube so that one lung can be ventilated while the other is lavaged with warmed saline. The volume of saline infused as well as the method of instillation and drainage varies among centers performing the procedure. Additionally, some lavateurs use either manual or mechanical chest percussion in an attempt to improve surfactant clearance. Other variations have included extracorporeal oxygenation and hyperbaric oxygen. While a careful methodologic inventory has not been undertaken, in most centers, each lung is lavaged with 15 to 40 L of saline during separate procedures separated by one to two days. Although no established response criteria exist for therapeutic whole lung lavage, most patients experience clinical, physiological, and radiographic improvement following whole lung lavage. Physiological parameters demonstrated to improve with lavage include increases in forced vital capacity (FVC), TLC, DlCO , PO2 at rest and with exercise, and a decrease in A-aDO2 and shunt fraction. In one study, whole lung lavage increased the 5-year survival rate (94 ± 2 percent with lavage as compared to 85 ± 5 percent without). While some individuals resolve without treatment and some require only one or several treatments, more than half of individuals require repeated therapeutic lavage. The median duration of response to therapeutic lavage has been reported to be 15 months. Successful treatment of PAP by repeated, sequential lobar lavage is used in some centers, although the practical clinical use of this approach is unclear.

Experimental Approaches Specific knowledge of disease pathogenesis has prompted development of alternative treatment approaches for primary PAP. One strategy targeting the GM-CSF signaling deficiency involves administration of exogenous GM-CSF. The therapeutic potential of GM-CSF administered subcutaneously in daily doses ranging from 5 to 20 µg/kg has been evaluated in several small, limited-dose escalation studies. Altogether,

Ben-Dov I, Kishinevski Y, Roznman J, et al: Pulmonary alveolar proteinosis in Israel: Ethnic clustering. Isr Med Assoc J 1:75–78, 1999. Bewig B, Wang XD, Kirsten D, et al: GM-CSF and GM-CSF beta c receptor in adult patients with pulmonary alveolar proteinosis. Eur Respir J 15:350–357, 2000. Cordonnier C, Fleury-Feith J, Escudier E, et al: Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients. Am J Respir Crit Care Med 149:788–794, 1994. DeMello DE, Lin Z: Pulmonary alveolar proteinosis: A review. Pediatr Pathol Mol Med 20:413–432, 2001. Dranoff G, Crawford AD, Sadelain M, et al: Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. Science 264:713–716, 1994. Goldstein LS, Kavuru MS, Curtis-McCarthy P, et al: Pulmonary alveolar proteinosis: Clinical features and outcomes. Chest 114:1357–1362, 1998. Hoffman RM, Rogers RM: Serum and lavage lactate dehydrogenase isoenzymes in pulmonary alveolar proteinosis. Am Rev Respir Dis 143:42–46, 1991. Ikegami M, Ueda T, Hull W, et al: Surfactant metabolism in transgenic mice after granulocyte macrophage-colony stimulating factor ablation. Am J Physiol 270:L650–658, 1996. Kitamura T, Tanaka N, Watanabe J, et al: Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor. J Exp Med 190:875–880, 1999. Kitamura T, Uchida K, Tanaka N, et al: Serological diagnosis of idiopathic pulmonary alveolar proteinosis . Am J Respir Crit Care Med 162:658–662, 2000. Lee KN, Levin DL, Webb WR, et al: Pulmonary alveolar proteinosis: High-resolution CT, chest radiographic, and functional correlations. Chest 111:989–995, 1997. Prakash UB, Barham SS, Carpenter HA, et al: Pulmonary alveolar phospholipoproteinosis: Experience with 34 cases and a review. Mayo Clin Proc 62:499–518, 1987. Presneill JJ, Nakata K, Inoue Y, et al: Pulmonary alveolar proteinosis. Clin Chest Med 25:593–613, viii, 2004.

1321 Chapter 79

Rosen SG, Castleman B, Liebow AA: Pulmonary alveolar proteinosis. N Engl J Med 258:1123–1142, 1958. Rubinstein I, Mullen JB, Hoffstein V: Morphologic diagnosis of idiopathic pulmonary alveolar lipoproteinosis revisited. Arch Intern Med 148:813–816, 1988. Ramirez-Rivera J, Schultz RB, Dutton RE: Pulmonary alveolar proteinosis: A new technique and rational for treatment. Arch Intern Med 112:173–185, 1963. Seymour JF, Doyle IR, Nakata K, et al: Relationship of antiGM-CSF antibody concentration, surfactant protein A and B levels, and serum LDH to pulmonary parameters and response to GM-CSF therapy in patients with idiopathic alveolar proteinosis. Thorax 58:252–257, 2003. Seymour JF, Presneill JJ: Pulmonary alveolar proteinosis: Progress in the first 44 years. Am J Respir Crit Care Med 166:215–235, 2002. Shibata Y, Berclaz PY, Chroneos ZC, et al: GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1. Immunity 15:557–567, 2001. Shulenin S, Nogee LM, Annilo T, et al: ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med 350:1296–1303, 2004.

Pulmonary Alveolar Proteinosis

Stanley E, Lieschke GJ, Grail D, et al: Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci USA 91:5592–5596, 1994. Tazawa R, Hamano E, Arai T, et al: Granulocyte-macrophage colony-stimulating factor and lung immunity in pulmonary alveolar proteinosis. Am J Respir Crit Care Med 171:1142–1149, 2005. Trapnell BC, Whitsett JA: GM-CSF regulates pulmonary surfactant homeostasis and alveolar macrophage-mediated innate host defense. Annu Rev Physiol 64:775–802, 2002. Trapnell BC, Whitsett JA, Nakata K: Pulmonary alveolar proteinosis. N Engl J Med 349:2527–2539, 2003. Uchida K, Beck DC, Yamamoto T, et al: N Engl J Med 356:567– 579, 2007. Whitsett JA, Weaver TE: Hydrophobic surfactant proteins in lung function and disease. N Engl J Med 347:2141–2148, 2002. Whitsett JA, Wert SE, Trapnell BC: Genetic disorders influencing lung formation and function at birth. Hum Mol Genet 13(Spec No 2):R207–215, 2004.

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Appendixes

A Normal Values: Typical Values for a 20-Year-Old Seated Man Ventilation (BTPS) Tidal volume (VT ), L Frequency (f), breaths/min Minute volume (VE ), L/min Respiratory dead space (VD ), ml Alveolar ventilation, VA , L/min Lung Volumes and Capacities (BTPS) Inspiratory capacity (IC), L Expiratory reserve volume (ERV), L Vital capacity (VC), L Residual volume (RV), L Functional residual capacity (FRC), L Total lung capacity (TLC), L Residual volume/total lung capacity × 100 (RV/TLC), % Mechanics of Breathing Forced vital capacity (FVC), L Forced expiratory volume, first second (FEV1 ), L Maximum voluntary ventilation (MVV), L/min Forced expiratory volume in 1 s/forced vital capacity × 100 (FEV1 /FVC), % Forced expiratory volume in 3 s/forced vital capacity × 100 (FEV3 /FVC), % Forced expiratory flow during middle half of FVC (FEF25−75 ), L/s Forced inspiratory flow at the middle of FIVC (FIF50 ), L/s

0.6 12 7.2 150 5.4 3.0 1.9 4.9 1.4 3.2 6.3 22

4.9 4.0 170 83 97 4.7 5.0

Static compliance of the lungs (Cst, l), L/cm H2 O Compliance of lungs and thoracic cage (CRS, respiratory system compliance) L/cm H2 O Airway resistance at FRC (Raw), cm H2 O/L/s Pulmonary resistance at FRC, cm H2 O/L/s Airway conductance at FRC (Gaw ), L/s/cm H2 O Specific conductance (Gaw /V1 ) Maximum inspiratory pressure, mmHg Maximum expiratory pressure, mmHg Distribution of Inspired Gas Single-breath N2 test ("N2 from 750 to 1250 ml in expired gas), % N2 Alveolar N2 after 7 min of breathing O2 , % N2 Closing volume (CV), ml CV/VC × 100, % Closing capacity (CC), ml CC/TLC × 100, % Slope of phase III in single-breath N2 test, % N2 /L Gas Exchange O2 consumption at rest (STPD), ml/min CO2 output at rest (STPD), ml/min Respiratory exchange ratio (R), CO2 output/O2 uptake

0.2

0.1 1.5 2.0 0.66 0.22 −75 120 <1.5 <2.5 400 8 1900 30 <2

240 192 0.8

1324 Appendix A

alveolar gas PAO2 , mmHg PACO2 , mmHg arterial blood PaO2 , mmHg SaO2 , % pH PaCO2 , mmHg PaO2 , while breathing 100% O2 , mmHg Alveolar Ventilation Alveolar ventilation, L/min Physiological dead space/tidal volume × 100 (VD /VT ), % Alveolar-arterial oxygen-gradient, (A-a) PO2 , mmHg Diffusing Capacity Diffusing capacity at rest for CO, single-breath (DlCOsb ), ml CO/min/mmHg

105 40 95 98 7.41 40 640

Diffusing capacity per unit alveolar volume (Dl/Va) Control of Ventilation Ventilatory response to hypercapnia, L/min/per " PaCO2 mmHg Ventilatory response to hypoxia, L/min per "SO2 (%) Arterial blood PO2 during moderate exercise, mmHg

Pulmonary Hemodynamics 4.2 Pulmonary blood flow (cardiac output), <30 L/min Pulmonary artery systolic/diastolic pressure, 10 mmHg Pulmonary capillary blood volume, ml 29 Pulmonary “capillary” (wedge) blood pressure, mmHg

4.8

>0.5 >0.2 95

5.4 25/8 100 <10

B Terms and Symbols in Respiratory Physiology GENERAL SYMBOLS

QUALIFYING SYMBOLS

Partial pressure in blood or gas. PO2 = partial pressure of O2

¯ X

A bar over the symbol indicates a mean value. P¯ = mean pressure, as distinct from instantaneous pressure

X˙

A time derivative (rate) is indicated by a dot above the symbol V˙ O2 = oxygen consumption per minute, ml

V˙ CO2 = CO2 production per minute, ml

an p f max

Inspired Vi = inspired volume Expired Ve = expired volume ˙ = expired volume per minute Ve Alveolar Va = alveolar volume V˙ = alveolar ventilation per minute Tidal Vt = tidal volume Dead space Vd = volume of dead space ˙ = dead-space ventilation per minute Vd Barometric Pb = barometric pressure Standard conditions: temperature 0◦ C, pressure 760 mmHg, and dry (0 mmHg water vapor) Body conditions: body temperature and ambient pressure, saturated with water vapor at these conditions Ambient temperature and pressure, dry Ambient temperature and pressure, saturated with water vapor at these conditions Anatomic Physiological Respiratory frequency, per minute Maximum

Time

Percent sign preceding a symbol indicates percentage of the predicted normal value

X/Y%

Percent sign following a symbol indicates a ratio function with the ratio expressed as a percentage. Both components of the ratio must be designated.

FEV1 /FVC, % = 100 × FEV1 /FVC Xa, Xa

A small capital letter or a lower-case letter on the same line following a primary symbol is a qualifier to further define the primary symbol. Alternatively, subscript letters may be used. Xa = XA , Xa = Xa Additional qualifiers of the primary symbol may be identified as shown. PeCO2 = Pressure of CO2 in the expired air, mmHg

GAS PHASE SYMBOLS Primary Symbols V V˙

Volume of gas Flow of gas

Fractional concentration of a gas

STPD

BTPS

ATPD ATPS

BLOOD PHASE SYMBOLS Primary Symbols Q Volume of blood Q˙ Blood flow Q˙ = cardiac output, L/min

1326 Appendix B

Concentration in the blood phase CO2 = concentration of oxygen in blood, ml of O2 per 100 ml of blood

Lung Capacities∗ IC Inspiratory capacity. The sum of IRV and TV.

Saturation in the blood phase SO2 = Saturation of hemoglobin with O2 , percent

IVC

Inspiratory vital capacity. Maximum volume of air inspired from the point of maximum expiration, i.e., from RV

Vital capacity. Maximum volume of air expired from the point of maximum inspiration, i.e., from TLC

FRC

Functional residual capacity. Sum of RV and ERV. FRC is the volume of air remaining in the lungs at the resting end-expiratory position.

TLC

Total lung capacity. Volume of air in the lungs after maximum inspiration. Also, the sum of all volume compartments of the lungs.

RV/TLC,%

Residual volume to total lung capacity ratio, expressed as a percentage.

Closing capacity. Closing volume plus residual volume, may be expressed as a percentage of TLC: CC/TLC, %.

Qualifying Symbols a

Arterial CaO2 = concentration of O2 in arterial blood, ml of O2 per 100 ml of blood

Capillary CcO2 = concentration of O2 in capillary blood, ml of O2 per 100 ml of blood

c′

Pulmonary end-capillary Pc′O2 = partial pressure of O2 in end-capillary blood, mmHg

Venous CvO2 = concentration of O2 in venous blood, ml of O2 per 100 ml of blood

v¯

Mixed venous C¯vO2 = concentration of O2 in mixed venous blood, ml of O2 per 100 ml of blood

VENTILATION AND LUNG MECHANICS TESTS AND SYMBOLS

Forced Respiratory Maneuvers During Spirometry† FVC Forced vital capacity. The maximum volume of air forcibly expired from total lung capacity. FIVC

Forced inspiratory vital capacity. Maximum volume of air forcibly inspired starting from residual volume.

FEVt

Timed forced expiratory volume. Volume of air expired in a specified time in the course of the forced vital capacity maneuver. FEV1 = volume of air expired during the first second of the FVC.

FEVt/FVC, %

Expiratory reserve volume. Maximum volume of air expired from the resting end-expiratory level.

Ratio of time forced expiratory volume to forced vital capacity, expressed as a percentage.

FEFx

Tidal volume. Volume of air inspired or expired with each breath during quiet breathing. When tidal volume is used in gas-exchange formulations, this symbol is used.

Forced expiratory flow, related to some portion of the FVC curve. Modifiers refer to the amount of the FVC that has been expired at the time of measurement.

FEF200−1200

Forced expiratory flow between 200 and 1200 ml of the FVC (formerly called the maximum expiratory flow rate).

FEF25−75

Forced expiratory flow during middle half of the FVC (formerly called the maximum midexpiratory flow rate or MMEF).

Static Lung Volumes∗ Primary Compartments RV

Residual volume. Volume of air remaining in the lungs after maximum expiration.

Closing volume. Volume of air expired from the onset of airways closure to residual volume. May be expressed as a fraction of VC: CV/VC, %.

ERV

IRV

Inspiratory reserve volume. Maximum volume of air inspired from the end-tidal inspiratory level.

∗ ∗

Expressed as BTPS.

†

Combinations of volumes for practical purposes. All values at BTPS.

1327 Appendix B

PEF V˙ maxx

FIFx

MVV

PImax

PEmax

Peak expiratory flow. Highest value for expiratory flow. Maximum flow when x percent of the FVC has been expired. V˙ max75 = flow (instantaneous) when 75 percent of the FVC has been expired.

Pressure Terms Paw Pressure at any point along the airways Pao

Pressure at the airway opening

Ppl

Pleural pressure

Alveolar pressure

Forced inspiratory flow. As in the case of the FEF, appropriate modifiers designate the volume at which flow is being measured. Unless otherwise specified, the volume qualifiers indicate the volume inspired from RV at the point of measurement. FIF25−75 = forced inspiratory flow during the middle half of the FIVC.

Pbs

Pressure at the body surface

Pes

Esophageal pressure: used to estimate Ppl

Pa–Pbs

Transthoracic pressure

Pa–Ppl

Transpulmonary pressure

Ppl–Pbs

Pressure difference across the chest wall

Maximum voluntary ventilation. Volume of air exhaled during maximum breathing efforts within a specified time period. If breathing frequency is set by the examiner, it is indicated by the qualifier. MVV60 = MVV at a breathing frequency of 60 per minute.

Paw–Ppl

Transbronchial pressure, estimated as difference between airway and pleural pressures.

Maximum inspiratory pressure. The maximum pressure generated during an inspiratory effort. Maximum expiratory pressure. The maximum pressure generated during an expiratory effort.

Measurements Related to Ventilation V˙ E Expired volume per minute (BTPS) V˙ I

Inspired volume per minute (BTPS)

V˙ CO2

Carbon dioxide production per minute (STPD)

V˙ O2

Oxygen consumption per minute (STPD)

Respiratory exchange ratio, the ratio of CO2 output to O2 intake in the lungs

V˙ A V˙ D

Mechanics of Breathing∗

Flow-Pressure Relationships† R

General symbol for frictional resistance, defined as the ratio of pressure difference to flow.

Raw

Airway resistance, calculated from pressure difference between airway opening (Pao ) and alveoli (Pa) divided by the airflow, cmH2 O/L/s.

Total pulmonary resistance, measured by relating flow-dependent transpulmonary pressure to airflow at the mouth.

Rti

Tissue resistance (viscous resistance of lung tissue), calculated as difference between Rl and Raw.

Rus

Resistance of the airways on the upstream (alveolar) side of the point in the airways where intraluminal pressure equals Ppl, i.e., equal pressure point. Measured during a forced expiration.

Rds

Resistance of the airways on the downstream (mouth) side of the point in the airways where intraluminal pressure equals Ppl, i.e., equal pressure point. Measured during a forced expiration.

Gaw

Airway conductance, reciprocal of Raw.

Gaw/Vl

Specific conductance, airway conductance, expressed per liter of lung volume at which Gaw is measured.

Alveolar ventilation per minute (BTPS) Ventilation per minute of the physiological dead space (BTPS) defined by the equation PaCO2 − PeCO2 V˙ D = V˙ E PaCO2 − PiCO2

Volume of the physiological dead space, calculated as V˙ D /f.

Vd/Vt

Ratio of dead space to tidal volume. The fraction, usually expressed as a percentage, of each breath that does not contribute to CO2 elimination.

∗ All

pressures expressed relative to ambient pressure unless otherwise specified. † Unless otherwise specified, resistance measurements are assumed to be made at FRC.

1328 Appendix B

Volume-Pressure Relationships C

General symbol for compliance of the lungs, chest wall, or total respiratory system. Volume change per unit change in applied pressure. For the lungs, the applied pressure is the pressure difference across the lungs, or transpulmonary pressure, Pao–Ppl; for the chest wall, the applied pressure is the transthoracic pressure, Ppl–Pbs; for the entire respiratory system, the applied pressure is Pao–Pbs.

Capillary blood volume. This should be Qc for consistency with other symbols, but Vc is entrenched in the literature. In the equation that follows for 1/Dl, Vc represents the effective pulmonary capillary blood volume, i.e., capillary blood volume in intimate association with alveolar gas.

1/Dl

Total resistance to diffusion, including resistance to diffusion of test gas across the alveolar-capillary membrane, through plasma in the capillary, and across the red blood cell membrane (1/Dm), the resistance to diffusion with the red cell arising from the chemical reaction of the test gas and hemoglobin (1/θ Vc), according to the formulation

Lung compliance. Value for the volume change divided by the transpulmonary pressure.

Chest wall compliance. Value for the volume change divided by the transthoracic pressure.

Cdyn

Dynamic compliance. Value for compliance determined at time of zero gas flow at the mouth during uninterrupted breathing. The respiratory frequency appears as a qualifier. Cdyn40 = dynamic compliance at a respiratory frequency of 40 per minute.

Dl/Va

Static compliance, value for compliance determined on the basis of measurements made during a period of zero airflow.

BLOOD GAS SYMBOLS

Specific compliance. Compliance divided by the lung volume at which it is determined, usually FRC.

PaCO2

Arterial CO2 tension, mmHg

SaO2

Arterial O2 saturation, percent

CcO2

Oxygen content of pulmonary end-capillary blood, ml of O2 per 100 ml of blood

(A-a)Po2

Alveolar-arterial difference in the partial pressure of O2 , mm Hg

CaO2 –C¯vO2

O2 content difference between arterial and mixed venous blood (arteriovenous O2 difference), ml of O2 per 100 ml of blood

Cst

C/Vl

Pst

Static pulmonary pressure at a specified lung volume. PstTLC = static recoil pressure of the lung measured at TLC (maximum recoil pressure)

DIFFUSING CAPACITY TESTS AND SYMBOLS Dlx Diffusing capacity of the lung expressed as volume (STPD) of gas (x) uptake per minute per unit alveolar-capillary pressure difference for the gas used. A modifier can be used to designate the technique: DlCO /sb = Single-breath CO diffusing capacity

Dm θ

DlCO /ss = Steady-state CO diffusing capacity Diffusing capacity of the alveolar-capillary membrane (STPD). Reaction rate coefficient for red blood cells. Determined as the volume of gas (stpd) that will combine per minute with 1 unit volume of blood per unit of gas tension. If the specific gas is not stated, θ is assumed to refer to CO and is a function of existing O2 tension.

1 1 1 = + DL DM θVc Diffusing capacity per unit of alveolar volume. Dl is expressed STPD, and Va is expressed in liters, BTPS.

Symbols for these values are readily composed by combining general symbols. Some examples include the following:

PULMONARY SHUNT SYMBOLS Q˙ s Flow of blood via shunts. This is usually ˙ determined as percent of cardiac output (Q) while breathing 100% O2 , according to the equation CcO2 − CaO2 Q˙ s = × 100 CcO2 − C¯vO2 Q˙ where CcO2 = O2 content of end-capillary blood CaO2 = O2 content of arterial blood C¯vo 2 = O2 content of mixed venous blood