Hypersensitivity Pneumonitis Caused by Fungi Moise´s Selman1, Yves Lacasse2, Annie Pardo3, and Yvon Cormier2 1 Instituto Nacional de Enfermedades Respiratorias ‘‘Ismael Cosı´o Villegas’’, Tlalpan, Me´xico; 2Centre de pneumologie, Centre de recherche, Institut ˆ pital Laval) affilie´ a` l’Universite´ Laval, Quebec, Canada; and 3Facultad de Ciencias, Universitaire de Cardiologie et de Pneumologie de Que´bec (Ho Universidad Nacional Auto´noma de Me´xico, Mexico DF, Mexico
Hypersensitivity pneumonitis (HP) is a complex syndrome caused by an exaggerated immune response to the inhalation of a large variety of organic particles. The most frequent antigens that cause HP worldwide are bird proteins (pigeon breeders’ disease) and bacteria (Saccharopolyspora rectivirgula). However, fungi are also implicated in many cases, including occupational and nonoccupational outbreaks. The clinical course of the disease is highly variable and its diagnosis clinically challenging since no specific test or biomarker allows a consistent diagnosis. Therefore, a combination of symptoms, bronchoalveolar lavage findings, chest imaging, lab tests, and often biopsies are needed for an accurate diagnosis. Regardless of the cause or the responsible environment, the histopathology is similar and usually consists of a granulomatous interstitial bronchiolocentric pneumonitis characterized by the presence of poorly formed granulomas and a prominent interstitial infiltrate composed of lymphocytes, plasma cells, and macrophages. However, some patients may show a ‘‘nonspecific interstitial pneumonia’’ pattern, or even a usual interstitial pneumonia–like pattern. Importantly, patients with chronic HP may evolve to interstitial fibrosis or develop emphysematous changes, although the reason(s) for these different pathological responses are presently unclear. This review provides a general overview of HP, emphasizing its fungal etiologies, and also examines the currently used clinical criteria for diagnosis and proposes an alternative classification. Challenges for future research include identification of biomarkers that may predict outcome and progression (primarily of chronic HP), and the need for a better understanding of the underlying molecular and genetic mechanisms of the disease. Keywords: hypersensitivity pneumonitis; extrinsic allergic alveolitis; fungi; lung inflammation
DEFINITION Hypersensitivity pneumonitis (HP) is a complex syndrome caused by an exaggerated immune response to the inhalation of a large variety of organic particles (1, 2). The disease is characterized by interstitial mononuclear cell infiltration, nonnecrotizing poorly formed granulomas, cellular bronchiolitis, and fibrosis.
CAUSES OF HP The most frequent antigens that cause HP worldwide are bird proteins (bird fancier’s HP, pigeon breeders’ disease) and bacteria (Saccharopolyspora rectivirgula [SR], thermoactinomycetes). These bacteria are responsible for most cases of farmer’s lung. However, fungi are also implicated in a number of cases.
(Received in original form June 15, 2009; accepted in final form July 17, 2009) Correspondence and requests for reprints should be addressed to Moise´s Selman, M.D., Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, CP 14080, Me´xico DF, Me´xico. E-mail: mselmanl@yahoo.com.mx Proc Am Thorac Soc Vol 7. pp 229–236, 2010 DOI: 10.1513/pats.200906-041AL Internet address: www.atsjournals.org
In a prospective case-control study performed in France, Absidia corymbifera and to a lesser degree Eurotium amstelodami and Wallemia sebi were likely to be the main causes of farmer’s lung in that region (3). Modifications in agricultural practices over time could explain the emergence of new contributing antigens. Thus, a study in which microbiological analyses were performed on hay, silage, and flour samples from farms in Finland and France that use different methods of haymaking demonstrated significant differences between the contaminating fungi. As a result, high concentrations of A. corymbifera were found in approximately 35% of French hay samples and only 10% of Finnish hay samples, while high concentrations of W. sebi typified Finnish hay (38%) significantly more than French hay (8%) (4). Fungi have been implicated in HP from multiple sites. Aspergillus fumigatus can cause farmer’s lung, and Penicillium sp. are responsible for HP associated with peat moss exposure (5). Humidifier lung is caused by a variety of fungi (6). Pools of stagnant water in these systems often provide ideal environments for the growth of fungi, bacteria, and amoebae. The disease should not be confused with humidifier fever, which is due to water contamination with endotoxins (7). Trichosporon cutaneum is responsible for Japanese summer type HP (8). This fungus grows on moldy wood in Japanese houses and is responsible for the majority of HP cases in Japan. The causative antigens are present in a high-molecular-weight, polysacchariderich fraction of Trichosporon cutaneum (9). Also, it was demonstrated that Cryptococcus albidus may be an important etiologic agent of the disease (10). A more recent report suggests that Cladosporium sp. can also be a cause of HP in the homes (11). Fungi are also responsible for maple bark disease and possibly implicated in suberosis (cork molding) (12, 13). We have recently described cases of HP from exposure to wood processing plants contaminated with Paecilomyces (14). These thermophilic molds grow on wood planks during the drying process in heated kilns (14). Jacobs and coworkers reported cases of interstitial lung disease associated with the presence of fungi in the home or workplace (2). Although they suggested that the disease responsible for the interstitial involvement was HP, their patients did not meet the diagnostic criteria for HP (15). It is therefore likely that fungi or their toxins can cause interstitial lung disease by mechanism(s) other than the immune mechanisms that lead to HP. Fungi may also be implicated in nonoccupational HP outbreaks. Residents of a new building contaminated with extensive visible mold (especially Aspergillus versicolor) on interior surfaces developed several allergic respiratory diseases, including HP. After restoration of the building, the concentration of fungi was significantly reduced and no new or recrudescent cases were recorded after building re-entry (16). Regardless of the cause of HP or the responsible environment, it is likely that the pathophysiology is similar. The difference in outcomes in different forms probably reflects the type of exposure. For example, pigeon breeders who are chronically exposed to pigeon proteins usually develop a restrictive fibrotic lung damage (17), while farmers who are usually repeatedly
230
exposed to high concentrations of SR in winter and not exposed in summer tend to develop an emphysematous lung destruction (18). Although these patients were not tested for a1-antitrypsin deficiency, they had no history of familial emphysema, and the prevalence of emphysema among the patients with farmer’s lung was much higher than what could be expected from this rare hereditary disease.
CLINICAL FEATURES The clinical manifestations of HP are heterogeneous. Suggestions have been made that they are determined by the intensity and frequency of exposure to etiologic antigens (19). Another hypothesis is that the immune response to antigens is different from one form to another (20, 21). We took advantage of the HP Study (15), a large prospective multicenter cohort study designed to develop clinical prediction rules for the diagnosis of hypersensitivity pneumonitis to compare the clinical presentation of the disease according to the offending antigens. In this secondary analysis, we hypothesized that the manifestations of HP are related to the offending antigen. Some of the results of this study have been previously reported in the form of an abstract (22). In the HP Study, consecutive patients aged 18 years or older presenting with a pulmonary syndrome for which active HP was considered in the differential diagnosis were enrolled. This cohort thus included patients with or without HP in unspecified proportions. Our secondary analysis involved only those whose final diagnosis was HP (n 5 199). Clinical data were systematically recorded in every patient before the final diagnosis was obtained. The final diagnosis of HP relied on high-resolution computed tomography (HRCT), bronchoalveolar lavage (BAL), and the opinion of experts. BAL lymphocytosis (> 30% for non- and ex-smokers, and > 20% for current smokers [23]) and HRCT findings compatible with HP were required for the diagnosis of HP to be accepted. When the association of both HRCT and BAL did not allow the investigators to confidently arrive at a final diagnosis, the decision regarding additional procedures (including surgical lung biopsy) was left to the investigators, according to their usual practice. An adjudication committee composed of four clinicians, one pathologist, and one radiologist was responsible for the final diagnosis. The distribution of diagnosis is presented in Table 1. Twenty-six patients (13%) had HP attributable to fungal exposure. During the initial evaluation (i.e., at first presentation), we found significant differences in a number of characteristics (Table 2) that did not correlate well with the usual classification of HP into ‘‘acute,’’ ‘‘subacute,’’ and ‘‘chronic.’’ Several differences became apparent when we compared the clinical presentation of HP according to the type of antigen. For example, patients with fungal-induced HP were predominantly males and showed a significantly higher frequency of acute symptoms, fever, and recurrent episodes in comparison with HP caused by avian antigens. Also, cyanosis and clubbing were virtually absent in patients with fungal-induced HP. An unexpected finding in our study was the high frequency of current or former smokers in patients with HP provoked by fungi (Table 2). It is widely accepted that development of HP is prevented in cigarette smokers who also show a lower incidence of precipitating antibodies (24, 25). Moreover, in a recent study of a large cohort of patients with farmer’s lung, 43% were reported to be cigarette smokers (26). Finally, in several small cohorts of patients with HP, high frequencies of smokers have been reported (27). The reasons for this discrepancy are presently unknown.
PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 7
2010
TABLE 1. DISTRIBUTION OF DIAGNOSES Number of patients Pigeon breeder’s/bird fancier’s disease Farmer’s lung Humidifier’s lung Suberosis Summer type hypersensitivity pneumonitis Various exposures to fungi Hypersensitivity pneumonitis of unknown origin Total
132 38 3 2 2 19 3 199
This stimulated our formal classification analysis that aims at determining whether the current classification of HP (i.e., ‘‘acute,’’ ‘‘subacute,’’ or ‘‘chronic’’) truly reflects categories of patients with distinct clinical features (28). In our study, we used cluster analysis to divide the study population into a limited number of categories (‘‘clusters’’) with maximally differing clinical patterns. This analysis consisted of merging the two closest individuals or clusters to form a new cluster that replaces them, and iterating the process with the new group until the regrouping was complete. A two-cluster solution best fitted the data. We found considerable disagreement between this new scheme of classification and Richerson’s classification (acute, subacute, and chronic HP). This disagreement comes in part from our finding that nodular opacities (which are often considered characteristic of subacute HP) were seen on HRCT as often in Cluster 1 as in Cluster 2. In the comparison of the clinical features of the patients in the two clusters, those in Cluster 1 had more recurrent systemic symptoms (chills, body aches) and normal chest X-rays than those in Cluster 2, who showed significantly more clubbing, hypoxemia, restrictive patterns on pulmonary function tests, and fibrosis on HRCT. Two thirds of our patients with HP from fungal origin were classified in Cluster 1. The most important contribution of this new scheme of classification would be in the investigation of patients presenting with respiratory disorders. HP (and specially HP from fungal origin) must be considered in the differential diagnosis of patients presenting with respiratory symptoms and manifestations of systemic inflammation. This classification, however, needs to be prospectively validated.
PATHOLOGY The most frequent histopathology observed in HP consists of a granulomatous interstitial bronchiolocentric pneumonitis characterized by a prominent interstitial infiltrate composed predominantly of lymphocytes, plasma cells, monocytes, and macrophages that usually begins near the terminal bronchioles but may extend widely into the parenchyma (29) (Figure 1A). The granulomas are usually small, poorly formed, loosely arranged, and contain high amounts of lymphocytes. This constellation of changes can be found in both the subacute and chronic forms of the disease (30), and it is similar in all types of HP, independent of the etiologic agent, that is, bird antigens or fungi (31, 32). Around 20% of patients with HP show a histopathologic pattern similar to nonspecific interstitial pneumonia (NSIP) (33, 34). Some bronchiolocentric lesions and the presence of giant multinucleated cells may support the diagnosis of HP. Small airways are usually involved in HP. In the case of fungi or thermophilic bacteria bronchiolar abnormalities are characterized by proliferative bronchiolitis obliterans, consisting of intraluminal organizing exudate composed of fibroblasts, a mu-
Selman, Lacasse, Pardo, et al.: HP Caused by Fungi
231
TABLE 2. CLINICAL HISTORY/SYMPTOMS AND PHYSICAL SIGNS IN HYPERSENSITIVITY PNEUMONITIS AT INITIAL EVALUATION ACCORDING TO THE OFFENDING ANTIGEN
Demographics Sex, male, % Age, yr, mean (SD) Clinical history/symptoms Exposure to antigens Dyspnea Cough Chills Tightness of chest Weight loss Body aches Wheezing Chest (pleuretic) pain Symptoms 4–8 h after exposure Recurrent episodes of symptoms Smoking status: Current smoker Ex-smoker Never smoked Physical signs Fever Inspiratory crackles Wheezing Cyanosis Clubbing Supraclavicular or cervical adenopathies
Total Cohort
Pigeon Breeder’s/Bird Fancier’s Disease
Farmer’s Lung
Exposure to Various Fungi
P Value
27% 49 (12)
11% 49 (13)
55% 49 (12)
65% 49 (12)
, 0.0001 0.99
97% 98% 93% 26% 28% 38% 19% 32% 6% 21% 36%
98% 99% 95% 13% 15% 39% 14% 33% 4% 8% 20%
100% 97% 95% 53% 68% 42% 32% 34% 8% 45% 71%
100% 100% 85% 58% 38% 31% 27% 15% 15% 58% 69%
5% 17% 78%
1% 16% 83%
8% 8% 84%
19% 38% 42%
, 0.0001
15% 87% 15% 42% 28% 2%
8% 93% 17% 58% 39% 2%
18% 84% 5% 11% 8% 0%
42% 58% 15% 4% 0% 4%
, 0.0001 , 0.0001 0.16 , 0.0001 , 0.0001 0.43
copolysaccharide matrix, and mixed chronic inflammatory cells (35). By contrast, HP provoked by avian antigens is associated primarily with peribronchiolar inflammation and fibrosis (constrictive bronchiolitis) (36). Small amounts of organizing pneumonia, typically involving the respiratory bronchioles, are common, and occasionally organizing pneumonia is the predominant pattern. Variable degrees of fibrosis are usually noticed in chronic HP, and can be severe in advanced cases (Figure 1B). Importantly, chronic HP may closely mimic usual interstitial pneumonia (UIP) or fibrotic NSIP (33, 37, 38). In these cases, the presence of mild or moderate lymphocytic infiltration, or some multinucleated giant cells, or poorly formed granuloma, suggests the diagnosis of HP. An important problem is that patients with irrefutable idiopathic pulmonary fibrosis (IPF)/UIP may have had antigen exposures as well as specific serum antibodies, and there may be no consistent morphologic changes that allow a confident diagnosis (30). Making the diagnosis of fibrotic HP with a UIP-like pattern instead IPF/UIP is relevant for therapeutic decisions and outcome. Antigen avoidance and cortico-
, ,
, ,
1.00 0.54 0.18 0.0001 0.0001 0.65 0.03 0.18 0.05 0.0001 0.0001
steroid therapy may (occasionally) reverse the process or at least delay or prevent progression in fibrotic HP, but these therapies have virtually no effect on IPF. However, prominent fibrosis significantly worsens the prognosis (17, 38–40). Although severe fibrotic HP has been associated mainly with exposure to birds, fungal exposure may cause the same response (39, 41).
PATHOGENESIS Hypersensitivity pneumonitis occurs only in few exposed individuals, strongly suggesting that genetic susceptibility and other factor(s) may contribute to the development of the disease. Genetic predisposition linked to class II alleles of the major histocompatibility complex (MHC) confers higher risk of developing the disease in different ethnic populations (42–46). More recently, it was found that transporters associated with antigen processing (TAP) genes, which play an important role transporting peptides across the endoplasmic reticulum membrane for MHC class I molecules assembly, may also be Figure 1. Morphological changes in hypersensitivity pneumonitis (HP). (A) Bronchiolocentric granuloma and cellular interstitial infiltrate in a patient with subacute HP (hematoxylin and eosin, 310). (B) Chronic interstitial pneumonia with fibrosis and architectural distortion in a patient with chronic HP. Focally, areas of poorly formed granulomas (red arrow) are still present (Masson trichrome, 310). Panel A reprinted by permission from Reference 84.
232
involved in the HP genetic susceptibility (47). In this case, HP appears to be associated with the allele Gly-637 and the genotypes Asp-637/Gly-637 and Pro-661/Pro-661. TNF bioactivity and increased frequency of the TNFA2 allele, a genotype associated with increased TNF-a expression, have been found to be higher in patients with farmer’s lung than in control subjects or in patients with pigeon breeders disease (PBD) (48). In contrast, promoter polymorphisms in tissue inhibitor of metalloproteinase-3 (TIMP-3) seem to protect for the development of the disease in two different ethnic populations (49, 50). Some environmental factors may contribute to the risk of developing the disease. For example, high pesticide exposure events and the use of organochlorine and carbamate pesticides have been associated with farmer’s lung in mutually adjusted models (26). Primarily, the insecticides dichlorodiphenyltrichloroethane (DDT), lindane, and aldicarb were positively associated with the disease. Superimposed viral infection may also play a role. Cormier and colleagues have demonstrated that mice exposed to S. rectivirgula and parainfluenza 1 Sendai virus show long-term enhancement of the lung inflammatory response as evidenced by histopathologic changes, the cell subpopulations present in BAL fluid and enhanced cytokine production when compared with animals exposed to the offending antigen alone (51, 52). In humans with acute HP, an increase of influenza A virus has been found in BAL macrophages (53). Mechanisms of Damage
The acute form of the disease seems to be mediated by immune complexes. Evidence supporting this notion includes the presence of specific antibodies and immune complexes in both bronchoalveolar lavage and peripheral blood. Also, BAL from patients with the acute form of the disease or after antigen inhalation challenge contains activated complement components and increased numbers of neutrophils (54, 55). Neutrophils from patients with farmer’s lung are primed for an enhanced respiratory burst (56). These molecules may provoke serious lung damage by overwhelming the antiproteinase and antioxidant defense mechanisms. The increase of neutrophils seems to be mediated by CXCL8 (interleukin-8), produced at least in part by alveolar macrophages (57). The subacute/chronic forms (cluster 2) of the disease are T cell–mediated (58, 59). Patients with these clinical forms, irrespective of the antigen, show consistent histopathologic features, a significant increase of T cells in BAL fluid, and cytokine production by antigen-stimulated lung T cells. In mice, HP can be transferred by CD41 T cells, whereas B cells and antibodies failed to transfer the disease in response to the sensitizing antigen (60, 61). Increased migration, local proliferation, and decreased programmed cell death participate in the expansion of T cells in the affected lungs (59, 62). Interestingly, T cell clones developed from cells isolated from lungs or peripheral blood express similar, sometimes identical, junctional regions, indicating that the same T cell clones are present in both tissues (63). Some studies have determined that HP results from a Th1type immune response. BAL and peripheral blood T cells obtained from individuals with HP display abundant interferon (IFN)-g–producing T cells, perhaps resulting from a reduction in IL-10 production (64). Supporting a pivotal role in the Th1 response in HP development, it was recently demonstrated that overexpression of GATA-3, a key regulator of Th2 differentiation, attenuates the development of HP by blocking Th1polarization (65). In a recent study, however, it was reported that patients with chronic fibrotic HP have different phenotypic and functional BAL T cell subsets compared with patients with subacute
PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 7
2010
disease (66). These differences include a skewing toward Th2 as opposed to the Th1 response that is observed in subacute patients. In addition, chronic patients exhibit an increase in CD41/CD81 ratio, a decrease of gdT cells, and exhaustion of effector CD81 T cells. Also, patients with chronic HP evolving to fibrosis display an increased number of neutrophils in the lung tissue, many of them loaded with matrix metalloproteinases (MMP-9 and MMP-8 [collagenase-2]) (67). This finding suggests that an exaggerated traffic of neutrophils with the secretion of some matrix metalloproteinases may participate in abnormal lung remodeling.
DIAGNOSTIC APPROACH Unfortunately, there are currently no specific tests or biomarkers that allow a consistent diagnosis of HP. Therefore, a constellation of symptoms, BAL findings, chest imaging, lab tests, and often the biopsy are required.
IMAGING Chest Radiography
Chest radiography is often the initial step in the investigation of a patient presenting with a pulmonary syndrome suggestive of HP. The first objective of chest X-rays is not to rule in HP but rather to rule out other diseases for the patient’s illness. A variety of distributions of markings have been described. No pattern is HP specific, however. In the HP Study, 30% of those with HP from fungal origin had a normal chest radiograph, 30% had diffuse markings, and 40% had bibasal markings (22). HRCT
In the appropriate clinical setting and irrespective of the antigen, HRCT may show changes that are consistent with the diagnosis of hypersensitivity pneumonitis. Patchy or diffuse bilateral ground-glass opacities, poorly defined centrilobular micronodules, and mosaic pattern (areas of decreased attenuation and air trapping) are commonly seen in patients with subacute HP (or Cluster 1) (Figure 2). CT features in chronic HP include irregular reticular pattern with traction bronchiectasis and bronchiolectasis, lobar volume loss, and honeycombing (Figure 3). In some patients, the CT findings may mimic those of usual interstitial pneumonia. However, the presence of areas of ground-glass attenuation, and/or centrilobular micronodules and/or mosaic pattern, supports the diagnosis of HP (27, 34). Patients with chronic farmer’s lung may show predominantly emphysematous changes that can be detected by conventional chest X-ray or HRCT (Figure 4). In one study, radiologic evidence of emphysema was observed in one-third of the scans evaluated; of these, 13 patients were former smokers, 1 was a current smoker, and 17 had never smoked (68). In another study, emphysematous changes were found in 23% of the patients with farmer’s lung, and it was noticed that recurrences of acute attacks increased the risk of emphysema (69). Centrilobular and bullous emphysema predominated at the base of the lung, whereas paraseptal emphysema was evenly distributed. These results support the notion that emphysema is a prevalent long-term outcome of farmer’s lung, and that may be even higher than interstitial lung fibrosis. Pulmonary Function Tests
The utility of pulmonary function tests is primarily to describe the physiologic abnormalities and the associated impairment.
Selman, Lacasse, Pardo, et al.: HP Caused by Fungi
233
Figure 2. High-resolution computed tomography image on (A) inspiration and (B) expiration in a patient with subacute HP. There are ill-defined centrilobular nodules, ground glass opacities, and mosaic pattern (A) that increase during expiration (B).
The results of pulmonary function tests may also guide therapy by helping the clinician select those patients for whom a treatment with corticosteroids may be justified. Pulmonary function tests have no discriminative properties in differentiating HP from other interstitial lung diseases (15). In the HP Study, 42% of those with HP from fungal origin had a normal physiologic profile (i.e., FEV1, FEV1/FVC, and total lung capacity all in the normal range). Also, a currently held belief is that a decreased lung diffusion capacity (DLCO) is always present in HP. Nevertheless, in the HP Study, 22% in whom DLCO could be measured had normal results (defined as a DLCO > 80% predicted) at the time of diagnosis (22). Bronchoalveolar Lavage
Bronchoalveolar lavage provides a relatively safe and welltolerated procedure to recover alveolar epithelium fluids and has proved to be useful in the evaluation of patients with interstitial lung diseases. The BAL cell profile in HP is characterized by a remarkable increase in the percentage of lymphocytes, which often exceeds 50% (66). In general, BAL lymphocyte percentage of less than 30% makes the diagnosis of HP uncertain, although current smokers may present lower percentages (15). CD41/CD81 ratio in HP is variable and is probably affected by the clinical form (acute versus chronic), exposure to tobacco smoke, the type and dose of inhaled antigen, and, possibly, the time elapsed since antigen exposure. A predominant increase in CD81 T cells is observed in nonsmokers with acute HP, while a prevalence of CD41 T cells is often found in smokers or those with chronic/fibrotic forms of the disease. Other changes in HP that may help to diagnosis is the increment of plasma cells, which are higher at 2 to 7 days after the last antigen exposure and then progressively decrease over time (70, 71).
Specific Serum Antibodies
The finding of circulating antibodies against the putative offending antigen(s) is useful for diagnosis. However, it is important to emphasize that exposed individuals may have antibodies without disease, and some patients may give (false) negative results. In addition, diagnostic panels are usually incomplete, and lab techniques may be insensitive to detect low levels of antibodies. Recently, Fenoglio and colleagues (72) examined the diagnostic value of a panel of specific antigens tested by two techniques (electrosyneresis and double diffusion) to discriminate active HP (31 patients) from other interstitial lung diseases (91 patients). Five antigens from the panel were selected for the serologic scores (A. corymbifera, E. amstelodami, W. sebi, S. rectivirgula, and mesophilic Streptomyces sp). Electrosyneresis was more discriminative than the doublediffusion technique. A similar study was performed in a region in the east of France with high prevalence of farmer’s lung. The consistency of four serologic techniques (electrosyneresis, Ouchterlony double diffusion, ELISA, and Western blot) was evaluated. Electrosyneresis on cellulose acetate with A. corymbifera antigen was the most relevant diagnostic tool for discriminating patients from healthy exposed farmers (73). Inhalation Challenge
When the diagnosis is uncertain, a provocation test may be performed using aerosolized materials of the suspected causative agent (74). This test can be achieved by either re-exposing the patient to the suspected agent in the suspected causative natural environment, or it can be conducted in the hospital using controlled antigen inhalation. However, inhalation challenge is not commonly performed because of the lack of standardized antigens, and limited access to a specialized center to conduct the study. Also, aerosols prepared in the laboratory
Figure 3. High-resolution computed tomography images of a patient with chronic HP. Left, upper lobe; right, lower lobe. There are patchy irregular reticular opacities, distortion of the lung architecture and peribronchial fibrosis, and ground glass attenuation.
234
PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 7
2010
Figure 4. Posterior-anterior and lateral chest radiograph in a patient with farmer’s lung that developed emphysema. Rarefaction of the lung structure and pulmonary vessels (frontal view), flattened diaphragms, and increased retrosternal airspace (lateral view) can be observed, indicating the presence of hyperinflation.
may contain an imprecise mixture of the antigen or may be contaminated with nonspecific irritants. In this context, safety precautions are an essential issue with this procedure. Standardized exposure tests with moldy hay have been performed in patients with farmer’s lung and with avian antigens in patients with pigeon breeder’s disease (56, 74, 75). After 6 to 8 hours, challenged patients with HP usually present an increase of body temperature, peripheral leukocytosis, a decrease in forced vital capacity and oxygen saturation, and the development of respiratory symptoms, including cough and dyspnea.
TREATMENT The obvious best treatment for HP is removal of the offending antigen. This, however, can be difficult when the antigen is in the home or workplace (e.g., farmers). It is common belief that once the antigen is removed, the disease progression will stop. This, however, can be questioned. For example, in animal models of smoke-induced emphysema, the destructive CD8 T cell–mediated immune response persists after smoking cessation (76). Also, in patients with COPD, the lung inflammation persists long after cigarette smoking cessation (77). Whether this also occurs in HP is currently unknown, but it is reasonable to assume that such mechanisms can also exist in HP, especially in chronic forms which develop emphysema or progressive fibrosis (78). In our experience, we have seen HP cases that clearly progressed after contact avoidance was implemented to the best of our ability to ascertain zero exposure. Acute episodes usually recover fully and the disease probably does not progress if contact is stopped, but this may not be true in cases in which permanent damage has occurred. When complete avoidance is impossible, respiratory protection can be used effectively if appropriate filters are properly used (78–80). Technologies are also available to reduce the amount of antigens in the environment. A good example of this is dairy farmers. The use of proper equipment in hay making and storage makes it possible to decrease molding and thus the levels of airborne antigens. The only known medical treatment of HP is with oral corticosteroids. Although steroids will improve initial recovery, there is little support for their use except in severe acute attacks since they do not seem to improve long-term outcome (81). Recommended doses of corticosteroids go from 20 mg prednisone for prolonged use to 50 mg daily in severe acute cases (82).
Prednisone is also used in chronic HP, although its long-term effect has not been clearly established. In these cases, the most widely used scheme consists of 0.5 mg per kg per day of prednisone for a month, followed by a gradual reduction until a maintenance dose of 10 to 15 mg per day is reached. Prednisone is discontinued when the patient is considered to be healed or when there is no clinical and/or functional response. If pulmonary abnormalities recur or deteriorate during the prednisone taper, the maintenance regimen should be prolonged indefinitely. There are no clinical trials involving other immunosuppressive drugs (i.e., azathioprine). It has been shown that thalidomide induces in alveolar macrophages from patients with HP a dose-dependent inhibition in the expression of TNF-a, IL-12p40, and IL-18 (83). However, its putative effects in patients with HP are unknown. Conflict of Interest Statement: M.S. served as a consultant for Boehringer Ingelheim ($5,001–$10,000). Y.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Y.C. received grant support from Asmacure ($100,001 or more) and owns patents on Nicotinic receptor agonists for the treatment of inflammatory diseases (patents 10/46999 and 11/632.051). He receives royalties from Asmacure ($10,001–$50,000) and owns stocks or options of Asmacure ($100,001 or more).
References 1. Fink JN, Ortega HG, Reynolds HY, Cormier YF, Fan LL, Franks TJ, Kreiss K, Kunkel S, Lynch D, Quirce S, et al. Needs and opportunities for research in hypersensitivity pneumonitis. Am J Respir Crit Care Med 2005;171:792–798. 2. Jacobs RL, Andrews CP, Coalson J. Organic antigen-induced interstitial lung disease: diagnosis and management. Ann Allergy Asthma Immunol 2002;88:30–41. 3. Reboux G, Piarroux R, Mauny F, Madroszyk A, Millon L, Bardonnet K, Dalphin JC. Role of molds in farmer’s lung disease in Eastern France. Am J Respir Crit Care Med 2001;163:1534–1539. 4. Reboux G, Reiman M, Roussel S, Taattola K, Millon L, Dalphin JC, Piarroux R. Impact of agricultural practices on microbiology of hay, silage and flour on Finnish and French farms. Ann Agric Environ Med 2006;13:267–273. 5. Cormier Y, Israel-Assayag E, Be´dard G, Duchaine C. Hypersensitivity pneumonitis (HP) in peat moss processing plant workers. Am J Respir Crit Care Med 1998;158:412–417. 6. Yamamoto Y, Osanai S, Fujiuchi S, Yamazaki K, Nakano H, Ohsaki Y, Kikuchi K. Extrinsic allergic alveolitis induced by the yeast Debaryomyces hansenii. Eur Respir J 2002;20:1351–1353. 7. Ohnishi H, Yokoyama A, Hamada H, Manabe S, Ito R, Watanabe A, Katayama H, Yasuhara Y, Ikezoe J, Higaki J. Humidifier lung:
Selman, Lacasse, Pardo, et al.: HP Caused by Fungi
8.
9.
10.
11.
12.
13. 14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25. 26.
27.
28.
possible contribution of endotoxin-induced lung injury. Intern Med 2002;41:1179–1182. Yoshida K, Suga M, Nishiura Y, Arima K, Yoneda R, Tamura M, Ando M. Occupational hypersensitivity pneumonitis in Japan: data on a nationwide epidemiological study. Occup Environ Med 1995;52:570–574. Mizobe T, Yamasaki H, Doi K, Ando M, Onoue K. Analysis of serotype-specific antibodies to Trichosporon cutaneum types I and II in patients with summer-type hypersensitivity pneumonitis with monoclonal antibodies to serotype-related polysaccharide antigens. J Clin Microbiol 1993;31:1949–1951. Miyagawa T, Hamagami S, Tanigawa N. Cryptococcus albidus-induced summer-type hypersensitivity pneumonitis. Am J Respir Crit Care Med 2000;161:961–966. Chiba S, Okada S, Suzuki Y, Watanuki Z, Mitsuishi Y, Igusa R, Sekii T, Uchiyama B. Cladosporium species-related hypersensitivity pneumonitis in household environments. Intern Med 2009;48:363–367. Winck JC, Delgado L, Murta R, Lopez M, Marques JA. Antigen characterization of major cork moulds in Suberosis (cork worker’s pneumonitis) by immunoblotting. Allergy 2004;59:739–745. Emanuel DA, Lawton BR, Wenzel FJ. Maple-bark disease. Pneumonitis due to Coniosporium corticale. N Engl J Med 1962;26:333–337. Veillette M, Cormier Y, Israel-Assayaq E, Meriaux A, Duchaine C. Hypersensitivity pneumonitis in a hardwood processing plant related to heavy mold exposure. J Occup Environ Hyg 2006;3:301–307. Lacasse Y, Selman M, Costabel U, Dalphin JC, Ando M, Morell F, Erkinjuntti-Pekkanen R, Muller N, Colby TV, Schuyler M, et al. Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care Med 2003;168:952–958. Jarvis JQ, Morey PR. Allergic respiratory disease and fungal remediation in a building in a subtropical climate. Appl Occup Environ Hyg 2001;16:380–388. Perez-Padilla R, Salas J, Chapela R, Sanchez M, Carrillo G, Perez R, Sansores R, Gaxiola M, Selman M. Mortality in Mexican patients with chronic pigeon breeder’s lung compared with those with usual interstitial pneumonia. Am Rev Respir Dis 1993;148:49–53. Lalancette M, Carrier G, Laviolette M, Ferland S, Rodrique J, Begin R, Cantin A, Cormier Y. Farmer’s lung: long-term outcome and lack of predictive value of bronchoalveolar lavage fibrosing factors. Am Rev Respir Dis 1993;148:216–221. Rose CS. Hypersensitivity pneumonitis. In: Mason RJ, Broaddus VC, Murray JF, Nadel JA, editors. Textbook of respiratory medicine. Amsterdam: Elsevier Saunders; 2005. pp. 1783–1799. Ando M, Konishi K, Yoneda R, Tamura M. Difference in the phenotypes of bronchoalveolar lavage lymphocytes in patients with summer-type hypersensitivity pneumonitis, farmer’s lung, ventilation pneumonitis, and bird fancier’s lung: report of a nationwide epidemiologic study in Japan. J Allergy Clin Immunol 1991;87:1002–1009. Morais A, Winck JC, Delgado L, Palmares MC, Fonseca J, Moura e Sa J, Marques JA. Suberosis and bird fancier’s disease: a comparative study of radiological, functional and bronchoalveolar lavage profiles. J Investig Allergol Clin Immunol 2004;14:26–33. Lacasse Y, Selman M, Costabel U, Dalphin JC, Morell F, Ando M, Erkinjuntti-Pekkanen R, Muller N, Colby TV, Schuyler M, et al.; HP Study Group. Clinical manifestations of hypersensitivity pneumonitis from various origins [abstract]. Am J Respir Crit Care Med 2003;167: A359. The BAL Cooperative Group Steering Committee. Bronchoalveolar lavage constituents in healthy individuals, idiopathic pulmonary fibrosis, and selected comparison groups. Am Rev Respir Dis 1990; 141:S169–S202. Baldwin CI, Todd A, Bourke S, Allen A, Calvert JE. Pigeon fanciers’ lung: effects of smoking on serum and salivary antibody responses to pigeon antigens. Clin Exp Immunol 1998;113:166–172. Warren CP. Extrinsic allergic alveolitis: a disease commoner in nonsmokers. Thorax 1977;32:567–569. Hoppin JA, Umbach DM, Kullman GJ, Henneberger PK, London SJ, Alavanja MC, Sandler DP. Pesticides and other agricultural factors associated with self-reported farmer’s lung among farm residents in the Agricultural Health Study. Occup Environ Med 2007;64:334– 341. Sahin H, Brown KK, Curran-Everett D, Hale V, Cool CD, Vourlekis JS, Lynch DA. Chronic hypersensitivity pneumonitis: CT features comparison with pathologic evidence of fibrosis and survival. Radiology 2007;244:591–598. Lacasse Y, Selman M, Costabel U, Dalphin JC, Morell F, ErkinjunttiPekkanen R, Mueller NL, Colby TV, Schuyler M, Jomphe V, et al.
235
29. 30.
31. 32.
33.
34.
35. 36.
37. 38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
Classification of hypersensitivity pneumonitis: a hypothesis. Int Arch Allergy Immunol 2009;149:161–166. Coleman A, Colby TV. Histologic diagnosis of extrinsic allergic alveolitis. Am J Surg Pathol 1988;12:514–518. Katzenstein AL, Mukhopadhyay S, Myers JL. Diagnosis of usual interstitial pneumonia and distinction from other fibrosing interstitial lung diseases. Hum Pathol 2008;39:1275–1294. Selman M. Hypersensitivity pneumonitis: a multifaceted deceiving disorder. Clin Chest Med 2004;25:531–547. Tsushima K, Fujimoto K, Yamazaki Y, Takamizawa A, Amari T, Koizumi T, Kubo K. Hypersensitivity pneumonitis induced by spores of Lyophyllum aggregatum. Chest 2001;120:1085–1093. Vourlekis JS, Schwarz MI, Cool CD, Tuder RM, King TE, Brown KK. Nonspecific interstitial pneumonitis as the sole histologic expression of hypersensitivity pneumonitis. Am J Med 2002;112:490–493. Silva CI, Churg A, Muller NL. Hypersensitivity pneumonitis: spectrum of high-resolution CT and pathologic findings. AJR Am J Roentgenol 2007;188:334–344. Reyes CN, Wenzel FJ, Lawton BR, Emanuel DA. The pulmonary pathology of farmer’s lung disease. Chest 1982;81:142–146. Perez-Padilla R, Gaxiola M, Salas J, Mejia M, Ramos C, Selman M. Bronchiolitis in chronic pigeon breeder’s disease: morphologic evidence of a spectrum of small airway lesions in hypersensitivity pneumonitis induced by avian antigens. Chest 1996;110:371–377. Churg A, Muller NL, Flint J, Wright JL. Chronic hypersensitivity pneumonitis. Am J Surg Pathol 2006;30:201–208. Ohtani Y, Saiki S, Kitaichi M, Usui Y, Inase N, Costabel U, Yoshizawa Y. Chronic bird fancier’s lung: histopathological and clinical correlation. An application of the 2002 ATS/ERS consensus classification of the idiopathic interstitial pneumonias. Thorax 2005;60:665–671. Ohtani Y, Ochi J, Mitaka K, Takemura T, Jinta T, Kuramochi J, Miyazaki Y, Inase N, Yoshizawa Y. Chronic summer-type hypersensitivity pneumonitis initially misdiagnosed as idiopathic interstitial pneumonia. Intern Med 2008;47:857–862. Vourlekis JS, Schwarz MI, Cherniack RM, Curran-Everett D, Cool CD, Tuder RM, King TE Jr, Brown KK. The effect of pulmonary fibrosis on survival in patients with hypersensitivity pneumonitis. Am J Med 2004;116:662–668. Dawkins P, Robertson A, Robertson W, Moore V, Reynolds J, Langman G, Robinson E, Harris-Roberts J, Crook B, Burge S. An outbreak of extrinsic alveolitis at a car engine plant. Occup Med (Lond) 2006;56: 559–565. Flaherty DK, Braun SR, Marx JJ, Blank JL, Emanuel DA, Rankin J. Serologically detectable HLA-A, B, and C loci antigens in farmer’s lung disease. Am Rev Respir Dis 1980;122:437–443. Rittner C, Sennekamp J, Mollenhauer E, Rosinger N, Niese D, Luttkenhorst M, Baur MP, Stroehmann I. Pigeon breeder’s lung: association with HLA-DR 3. Tissue Antigens 1983;21:374–379. Selman M, Teran L, Mendoza A, Camarena A, Martinez-Cordero E, Lezama M, Rubio HM. Increase of HLA-DR7 in pigeon breeder’s lung in a Mexican population. Clin Immunol Immunopathol 1987;44: 63–70. Ando M, Hirayama K, Soda K, Okubo R, Araki S, Sasazuki T. HLADQw3 in Japanese summer-type hypersensitivity pneumonitis induced by Trichosporon cutaneum. Am Rev Respir Dis 1989;140:948–950. Camarena A, Juarez A, Mejia M, Estrada A, Carrillo G, Falfan R, Zuniga J, Navarro C, Granados J, Selman M. Major histocompatibility complex and tumor necrosis factor-alpha polymorphisms in pigeon breeder’s disease. Am J Respir Crit Care Med 2001;163:1528– 1533. Aquino-Galvez A, Camarena A, Montano M, Juarez A, Zamora AC, Gonzalez-Avila G, Checa M, Sandoval-Lopez G, Vargas-Alarcon G, Granados J, et al. Transporter associated with antigen processing (TAP) 1 gene polymorphisms in patients with hypersensitivity pneumonitis. Exp Mol Pathol 2008;84:173–177. Schaaf BM, Seitzer U, Pravica V, Aries SP, Zabel P. Tumor necrosis factor-alpha -308 promoter gene polymorphism and increased tumor necrosis factor serum bioactivity in farmer’s lung patients. Am J Respir Crit Care Med 2001;163:379–382. Hill MR, Briggs L, Montano MM, Estrada A, Laurent GJ, Selman M, Pardo A. Promoter variants in tissue inhibitor of metalloproteinase-3 (TIMP-3) protect against susceptibility in pigeon breeders’ disease. Thorax 2004;59:586–590. Janssen R, Kruit A, Grutters JC, Ruven HJ, van Moorsel CM, van den Bosch JM. TIMP-3 promoter gene polymorphisms in BFL. Thorax 2005;60:974.
236 51. Cormier Y, Israel-Assayag E, Fournier M, Tremblay GM. Modulation of experimental hypersensitivity pneumonitis by Sendai virus. J Lab Clin Med 1993;121:683–688. 52. Cormier Y, Tremblay G, Fournier M, Assayag E. Longterm viral enhancement of lung response to Saccharopolyspora rectivirgula. Am J Respir Crit Care Med 1994;149:490–494. 53. Dakhama A, Hegele RG, Laflamme G, Israel-Assayag E, Cormier Y. Common respiratory viruses in lower airways of patients with acute hypersensitivity pneumonitis. Am J Respir Crit Care Med 1999;159: 1316–1322. 54. Fournier E, Tonnel AB, Gosset P, Wallaert B, Ameisen JC, Voisin C. Early neutrophil alveolitis after antigen inhalation in hypersensitivity pneumonitis. Chest 1985;88:563–566. 55. Yoshizawa Y, Nomura A, Ohdama S, Tanaka M, Morinari H, Hasegawa S. The significance of complement activation in the pathogenesis of hypersensitivity pneumonitis: sequential changes of complement components and chemotactic activities in bronchoalveolar lavage fluids. Int Arch Allergy Appl Immunol 1988;87:417–423. 56. Vogelmeier C, Krombach F, Munzing S, Konig G, Mazur G, Beinert T, Fruhmann G. Activation of blood neutrophils in acute episodes of farmer’s lung. Am Rev Respir Dis 1993;148:396–400. 57. Fujishima S, Nakamura M, Nakamura H, Inoue T, Yogo Y, Okubo Y, Aikawa N, Kanazawa M, Yamaguchi K. Flow cytometric detection of cell-associated interleukin-8 in alveolar macrophages in vivo from patients with hypersensitivity pneumonitis and sarcoidosis. Scand J Clin Lab Invest 2004;64:237–243. 58. Salvaggio JE, Millhollon BW. Allergic alveolitis: new insights into old mysteries. Respir Med 1993;87:495–501. 59. Selman M, Pardo A, Barrera L, Estrada A, Watson SR, Wilson K, Aziz N, Kaminski N, Zlotnik A. Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis. Am J Respir Crit Care Med 2006;173:188–198. 60. Schuyler M, Gott K, Shopp G, Crooks L. CD31 and CD41 cells adoptively transfer experimental hypersensitivity pneumonitis. Am Rev Respir Dis 1992;146:1582–1588. 61. Schuyler M, Gott K, Mapel V, Cherne A, Nikula KJ. Experimental hypersensitivity pneumonitis: influence of Th2 bias. Int J Exp Pathol 1999;80:335–348. 62. Laflamme C, Israel-Assayag E, Cormier Y. Apoptosis of BAL lymphocytes in hypersensitivity pneumonitis. Eur Respir J 2003;21:225–231. 63. Facco M, Trentin L, Nicolardi L, Miorin M, Scquizzato E, Carollo D, Baesso I, Bortoli M, Zambello R, Marcer G, et al. T cells in the lung of patients with hypersensitivity pneumonitis accumulate in a clonal manner. J Leukoc Biol 2004;75:798–804. 64. Yamasaki H, Ando M, Brazer W, Center DM, Cruikshank WW. Polarized type 1 cytokine profile in bronchoalveolar lavage T cells of patients with hypersensitivity pneumonitis. J Immunol 1999;163: 3516–3523. 65. Matsuno Y, Ishii Y, Yoh K, Morishima Y, Haraguchi N, Kikuchi N, Iizuka T, Kiwamoto T, Homma S, Nomura A, et al. Overexpression of GATA-3 protects against the development of hypersensitivity pneumonitis. Am J Respir Crit Care Med 2007;176:1015–1025. 66. Barrera L, Mendoza F, Zuniga J, Estrada A, Zamora AC, Melendro EI, Ramirez R, Pardo A, Selman M. Functional diversity of T-cell subpopulations in subacute and chronic hypersensitivity pneumonitis. Am J Respir Crit Care Med 2008;177:44–55. 67. Pardo A, Barrios R, Gaxiola M, Segura-Valdez L, Carrillo G, Estrada A, Mejia M, Selman M. Increase of lung neutrophils in hypersensitivity pneumonitis is associated with lung fibrosis. Am J Respir Crit Care Med 2000;161:1698–1704.
PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 7
2010
68. Cormier Y, Brown M, Worthy S, Racine G, Muller NL. High-resolution computed tomographic characteristics in acute farmer’s lung and in its follow-up. Eur Respir J 2000;16:56–60. 69. Malinen AP, Erkinjuntti-Pekkanen RA, Partanen PL, Rytkonen HT, Vanninen RL. Long-term sequelae of Farmer’s lung disease in HRCT: a 14-year follow-up study of 88 patients and 83 matched control farmers. Eur Radiol 2003;13:2212–2221. 70. Drent M, Velzen-Blad H, Diamant M, Wagenaar SS, DonckerwolckBogaert M, van den Bosch JM. Differential diagnostic value of plasma cells in bronchoalveolar lavage fluid. Chest 1993;103:1720– 1724. 71. Drent M, Wagenaar S, Velzen-Blad H, Mulder PG, Hoogsteden HC, van den Bosch JM. Relationship between plasma cell levels and profile of bronchoalveolar lavage fluid in patients with subacute extrinsic allergic alveolitis. Thorax 1993;48:835–839. 72. Fenoglio CM, Reboux G, Sudre B, Mercier M, Roussel S, Cordier JF, Piarroux R, Dalphin JC. Diagnostic value of serum precipitins to mould antigens in active hypersensitivity pneumonitis. Eur Respir J 2007;29:706–712. 73. Reboux G, Piarroux R, Roussel S, Millon L, Bardonnet K, Dalphin JC. Assessment of four serological techniques in the immunological diagnosis of farmers’ lung disease. J Med Microbiol 2007;56:1317– 1321. 74. Ramirez-Venegas A, Sansores RH, Perez-Padilla R, Carrillo G, Selman M. Utility of a provocation test for diagnosis of chronic pigeon breeder’s disease. Am J Respir Crit Care Med 1998;158:862–869. 75. Ohtani Y, Kojima K, Sumi Y, Sawada M, Inase N, Miyake S, Yoshizawa Y. Inhalation provocation tests in chronic bird fancier’s lung. Chest 2000;118:1382–1389. 76. Motz GT, Eppert BL, Sun G, Wesselkamper SC, Linke MJ, Deka R, Borchers MT. Persistence of lung CD8 T cell oligoclonal expansions upon smoking cessation in a mouse model of cigarette smoke-induced emphysema. J Immunol 2008;181:8036–8043. 77. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, Coxson HO, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645–2653. 78. Hendrick DJ, Marshall R, Faux JA, Krall JM. Protective value of dust respirators in extrinsic allergic alveolitis: clinical assessment using inhalation provocation tests. Thorax 1981;36:917–921. 79. Kusaka H, Ogasawara H, Munakata M, Tanimura K, Ukita H, Denzumi N, Homma Y, Kawakami Y. Two-year follow up on the protective value of dust masks against farmer’s lung disease. Intern Med 1993;32: 106–111. 80. Dalphin JC, Pernet D, Roux C. Investigation of the protective value of breathing masks on thermophilic actinomycetes. Am Rev Respir Dis 1993;147:A903. 81. Kokkarinen JI, Tukiainen HO, Terho EO. Effect of corticosteroid treatment on the recovery of pulmonary function in farmer’s lung. Am Rev Respir Dis 1992;145:3–5. 82. Cormier Y, Israel-Assayag E, Desmeules M, Lesur O. Effect of contact avoidance or treatment with oral prednisolone on bronchoalveolar lavage surfactant protein A levels in subjects with farmer’s lung. Thorax 1996;51:1210–1215. 83. Ye Q, Chen B, Tong Z, Nakamura S, Sarria R, Costabel U, Guzman J. Thalidomide reduces IL-18, IL-8 and TNF-alpha release from alveolar macrophages in interstitial lung disease. Eur Respir J 2006;28: 824–831. 84. Selman M, et al. Hypersensitivity pneumonitis. In: Pulmonary arterial hypertension and interstitial lung diseases. Baughman RP, Carbone RG, Bottino G, editors. New York: Humana Press; 2009. pp. 139–157.