06 Respiratory

SECTION 6

Pulmonology 43.

Chronic Cough - Diagnostic Dilema M Sabir, Sanjay Kochar, Sanjay Tundwal

197

44.

Non Resolving Pneumonia Devendra Prasad Singh

201

45.

Health Care Associated Pneumonias Atul Bhasin, RK Singal

205

46.

How to Manage Solitary Pulmonary Nodule (SPN) Keerat Kaur Sibia, Rajbir Singh, Akash Batta, Rishu Bhanot, RS Bhatia, SS Sibia

207

47.

Chronic Granulomatous Disorders: What we Know Dinesh Gupta, GursimranKaur

213

48.

Current Concepts and Controversies in the Treatment of Pulmonary Sarcoidosis Akashdeep Singh

216

49.

Approach to Difficult Asthma Amita Nene

219

50.

Newer Therapies in COPD Prem Parkash Gupta

222

51.

Interstitial Lung Diseases Ketaki Barve, Jyotsna M Joshi

228

52.

Fungal Infection in the Lung Udas Chandra Ghosh, Kaushik Hazra

232

53.

Tropical Pulmonary Eosinophilia Harpreet Singh

236

54.

Role of Bronchoscopy in Diffuse Parenchymal Lung Diseases Ajay Handa, Jyothi Ranganathan

238

55.

Role of Interventions in Pulmonology Agam Vora

244

56.

High Altitude and Respiratory System BNBM Prasad

256

57.

Acute Mountain Sickness Rajiv Raina, Sanjay K Mahajan

267

58.

Pulmonary Hypertension - Hope & Challenges Sudhir Varma, Samman Verma

273

Chronic Cough - Diagnostic Dilema

C H A P T E R

43

M Sabir, Sanjay Kochar, Sanjay Tundwal

Cough is an important natural defense mechanism of the respiratory tract, and it is one of the most common reasons for adults seeking medical treatment.

Under normal conditions, cough serves an important protective role in the airways and lungs as it helps in preserving the gas-exchanging functions of the lung by facilitating clearance of aspirate, inhaled particulate matter, accumulated secretions, and irritants that are either inhaled or formed at sites of mucosal inflammation.

Impaired cough reflex can have dire consequences.

On the contrary, cough is an important mechanism for the spread of life-threatening acute and chronic respiratory tract infections and it also adversely affect the quality of life in asthma, COPD, GERD, ILD, LRTIs including pulmonary tuberculosis and other lung diseases.

These contrasting functions and consequences of cough highlight the importance of early diagnosis and adoption of balanced therapeutic measures.

MECHANISM OF COUGH PRODUCTION

The cough reflex consists of three phases: an inhalation, a forced exhalation against a closed glottis, and a violent release of air from the lungs following opening of the glottis, usually accompanied by a distinctive sound.

Coughing may be voluntary or involuntary.

Cough receptors- Chemosensitive receptors and Mechanosensors receptors are located in the respiratory tract from the hypopharynx & larynx to the segmental bronchi:

Vagal sensory nerve plays major role in regulation of cough response, whereas bronchopulmonary sensory nerves innervating other viscera, as well as somatosensory nerves innervating chest wall, diaphragm and abdominal muscles also contribute in regulation of cough response.

Sensory afferent pathways finally terminate at the brainstem, at the nucleus of the solitary tract, and the spinal trigeminal tract.Voluntary control of cough is possible because of the influence of higher cortical centers on the cough centre. Efferent signals are then sent to the muscles that produce the forced expiratory effort.

CAUSES OF COUGH (TABLE 1)

Cough is a common symptom present more or less with all respiratory disorders. It is also present in cardiovascular, Gastro Intestinal diseases and some disorders related to chest wall. In India pulmonary tuberculosis should always be consider as an important cause of sub acute or chronic cough.

Depending upon the onset & duration arbitrary causes of cough can be divided •

Acute Cough - Acute or short-lived cough, which often occurs in association with upper respiratory tract infection, is usually self-limiting and usually resolves within three weeks.

•

Sub acute Cough - Cough lasting between 3 to 8 weeks’ period. Cough in tuberculosis, M. Pneumonae & B. Pertusis infections infection can be kept in this catagery.

•

Chronic Cough (CC)- Lasts more than 8 weeks duration. It is a common warning symptom of almost all chronic respiratory and some nonrespiratory illnesses with an estimated prevalence of 10 % to 20% of the population. Most patients with CC have dry cough or with minimum expectoration (LI 1-4). It poses a great diagnostic and management challenge, due to its variant etiologies.

Table 1: Common causes of cough Acute infections: Tracheobronchitis, Bronchopneumonia, Viral Pneumonia and Acute on Chronic Bronchitis

Tumours: Bronchogenic and alveolar cell carcinomas, and benign airway and mediastinal tumours

Chronic infections: Bronchiectasis, Tuberculosis & cystic fibrosis

Foreign body

Airway disease: Asthma, chronic bronchitis, COPD & chronic post-nasal drip Parenchymal disease: Interstitial fibrosis, emphysema

Cardiovascular: Left ventricular failure, pulmonary infarction and aortic aneurysm

Arbitrarily Chronic Cough can be further divided in: a.

Causes easy to recognize after clinical examination, chest radiography, and spirometry:

Other disease: Reflux oesophagitis, recurrent aspiration

•

Upper & lower respiratory tract infections (bacterial including tuberculosis)

•

Asthma (most cases)

Drugs: ACE inhibitors

• COPD

198

•

Pulmonary tuberculosis

PULMONOLOGY

• Sarcoidosis •

Interstitial lung disease

•

Lung cancer

•

Inhaled foreign body, and

•

Heart failure

b.

Causes difficult to recognize after clinical examination, chest radiography, and spirometry/ remained unrecognized:

•

Viral infections of the upper respiratory tract

•

Upper airway cough syndrome (UACS); postnasal drip syndrome)

•

Gastroesophageal reflux disease (GERD)

•

Cough-variant asthma,

•

Eosinophilic bronchitis

•

Mediastinal tumors

•

Pleural diseases

•

Early interstitial fibrosis

•

Use of an angiotensin converting enzyme-inhibitor (ACEI)

• Psychogenic •

Idiopathic (or unexplained) cough.

The latest American College of Chest Physicians (ACCP) Consensus Guidelines, which analyzed the data of 11 studies worldwide, reported that postnasal drip(or UACS), GERD, and cough-variant asthma were the most common causes of chronic cough in difficult to recognize causes of cough, comprising two-thirds of all diagnoses.

Upper airway cough syndrome (UACS)

The ACCP 2006 guidelines has suggested the term ‘UACS’ instead of the previously described ‘postnasal drip syndrome’, because it can also occur as a result of irritation or inflammation of the upper airway structures that directly stimulate the cough receptors independently or in addition to the postnasal drip. Rhinitis or rhinosinusitis commonly appears in the reported causes of cough in these patients. Common clinical signs and symptoms associated with UACS are: a feeling of drainage in the posterior pharynx, frequent throat clearing, nasal discharge, cobblestone appearance of the oropharyngeal mucosa, andmucopurulent secretions in the oropharynx.

In case patients do not respond to empirical treatment, sinus imaging, preferably with a CT scan, is indicated.

Asthma

Chronic dry cough, usually in the case of coughvariant asthma, often occurs at night, may present as a predominant symptom or even the only symptom in patients with asthma. In asthma dry cough can be explained by two mechanisms: sensitization of cough

receptors by increased levels of inflammatory mediators and stimulation of cough receptors through constriction of the bronchial smooth muscle.

Asthma as the cause of chronic dry cough has to be considered in patients who do not respond to empirical treatment for postnasal drip. Spirometry is the most reliable test for establishing the diagnosis of asthma.

Other tests e.g. Bronchoprovocation tests, sputum eosinophil count or increased exhaled nitric oxide (NO) concentration may also be required for making diagnosis.

Non-asthmatic Eosinophilic Bronchitis (NAEB)

NAEB also presents in a similar manner e.g. cough and sputum eosinophilia with or with ought dyspnea. Major characteristic distinguishing asthma from NAEB is the absence of variable airflow obstruction (spirometry) and bronchial hyper responsiveness. In the absence of objective tests, a trial of inhaled / oral corticosteroids should be considered in patients with unexplained chronic cough in order to rule out asthma and NAEB. Additional treatment options for patients with cough-variant asthma include long-acting bronchodilators, antileukotrienes, and/or low-dose theophylline. Patients with NAEB have a good response to corticosteroids, but not to bronchodilators.

Gastro-esophageal reflux disease (GERD)

Gastroesophageal reflux disease (GERD) is reported as a cause of chronic cough in as many as 40% of the patients.

These patients have cough alone or with gastrointestinal symptoms, such as, heartburn and regurgitation. GERD associated cough has been postulated to occur through three major mechanisms: oesophageal-tracheobronchial cough reflex, laryngo-pharyngeal reflux, and micro aspiration.

In up to 75% of the cases, patients with GERD-related cough may present with no gastrointestinal symptoms.

Some patients may need pH monitoring of reflux events and objective cough recording. Most of these patients respond to anti-reflux diet & lifestyle changes, a prokinetic agent (e.g. metoclopramide), with a proton pump inhibitor (PPI) It has been reported that 5 to 10 % of patients seeking medical advice and from 0% to 46% of patients referred to specialty cough clinics for CC, have persistent cough of unexplained origin .These patients have CC that persists often for many months or years, despite exhaustive investigations and treatment of known causes are often labeled as Unexplained Chronic Cough (UCC).

In recent past number of unconventional causes of unexplained chronic cough has been described.

Non-acid reflux and chronic cough

A subgroup of patients with CC suggestive of GERD, have failed to respond to intense acid suppression treatment and improved chronic cough after antireflux surgery, suggesting the involvement of a non-acidic gastric component.

CC due to non-acid reflux causes, a hypersensitive

199

Table 2: History Taking in Chronic Cough Symptoms

Variable

Related pathology/disease

Onset & Duration

Recent (Acute)

URTI, Viral resp. infections

Long standing (Chronic)

TB, Asthma, COPD, Bronchiectasis, ILD, Pertussis, Foreign body, Drugs

Brassy

Pressure on the trachea

Hollow/Bovine Barking

Laryngeal nerve palsy causing vocal cord dysfunction

Nocturnal

Early morning

Bronchial asthma

Precipitating factors

Triggers

Usually in asthma

Relieving factors

Precipitating factors

Usually in asthma

Sputum

Presence (Volume, Consistency, Pattern)

Infections including pulm. tub., COPD, CF, Bronchiectatsis, Asthma

Character

Acute Epiglottitis

GERD, Drugs (e.g. ACEI)

Haemoptysis

Colour, Volume,

Pulm. Tub., Heart Failure, RHD- MS, Lung Cancer, Suppurative lung diseases including Bronchiactasis, etc

Association

Breathlessness, Sputum, Chest pain, Wheeze, Hoarseness, Post nasal drip

Asthma, COPD, CV dis.

Infections including pulm. tub., COPD, CF, Bronchiectatsis, Lobar pneumonia, pulm. embolism, pleuritis Asthma Laryngeal diseases Allergic Rhynitis, Sinuisitis

cough reflex, possibly through the stimulation from the neurogenic airway inflammation and mast cell activation.

Impedance-pH monitoring is a powerful tool that helps in detecting acid and non-acid reflux events in patients on PPI therapy.

Sleep apnea and chronic cough

Several recent studies have suggested a possible association between chronic cough and obstructive apnea. It is proposed that increase in trans-diaphragmatic pressure during apnea episodes, which causes lower esophageal sphincter insufficiency may lead to GERD; also snoring and apnea may induce epithelial injury.

Vocal cord dysfunction and chronic cough

Patients with vocal cord dysfunction commonly experience stridor and dysphonia, owing to episodic, uncontrollable narrowing of the cords during inspiration may experience dyspnea and cough and are commonly misdiagnosed as asthma. The diagnosis of vocal cord dysfunction can be made with the use of direct laryngoscopy and flattening of the inspiratory flow-volume loop on spirometry.

Psychogenic or Habitual Cough

A habitual cough is a diagnosis of exclusion. Many patients with this condition do not cough during sleep and enjoyable distractions. It is suggested that some of these patients may have have more than one potential aggravating factor for production of cough.

Cough hypersensitivity syndrome: The new paradigm

In this view, CC is considered as a single syndrome with a common intrinsic mechanism of cough hypersensitivity.

It is suggested that there is increased expression of cough receptors in the airways of these patients with CC, and common diseases, such as rhinitis, eosinophilic bronchitis, asthma or gastroesophageal acidic refluxes are believed to be triggers rather than causes for production of cough.

CLINICAL EVALUATION

History

Relevant points in history taking in a patient of Chronic Cough are given in Table 2.

INVESTIGATIONS

•

ESR, TDLC, TEC

•

Sputum examination – AFB, malignant cell, eosinophils, fungus & culture sensitivity

•

X-ray chest, X-ray PNS

• Spirometry – Reversibility provocation tests,

test,

•

Exhaled nitric oxide (NO) concentration

•

Laryngoscopy & Bronchoscopy

•

Impedance-pH monitoring

•

HRCT/Contrast CT – chest, sinuses

Broncho-

CHAPTER 43

Dry

200

Chronic Cough

Investigate and Treat

PULMONOLOGY

Inadequate response to optimal Rx

A cause of cough is suggested

History, examination, chest x-ray

Smoking, ACE-I

Discontinue

Upper Airway Cough Syndrome (UACS) Empiric treatment Asthama Ideally evaluate (spirometry, bronchodilator reversibility, bronchial provocation challenge) or empiric treatment

No response

Non-asthmatic eosinophillic bronchitis (NAEB) Ideally evaluate for sputum eosinophillia or empiric treatment

Inadequate response to optimal Rx

Cough-specific Quality of Life Questionnaire (CQLQ),

-

Adverse Cough Outcome Survey (ACOS)

-

Chronic Cough Impact Questionnaire (CCIQ)

-

Cough and Sputum Assessment Questionnaire (CASA-Q).

-

Parent Cough-specific Quality-of-Life questionnaire (PC-QOL] for children.

-

Cough diary scores and Visual analog scales,

•

Objective ambulatory cough monitoring systems.

Several sound based monitering systems are in use for ambulatory patients e.g. Leicester, Vitalojak and Coughcount cough monitors.

Gastroesophageal reflux disease (GERD) Empiric treatment (for initial treatments see box below)

Further Investigations to Consider: - 24h esophageal pH monitoring - Endoscopic or videofluoroscopic swallow evaluation - Barium esophagram - Sinus Imaging - HRCT - Bronchoscopy - Echocardiogram - Environmental Assessment - Consider other rare causes (see section 26) Important General Considerations

Initial Treatments

Optimise therapy for each diagnosis

UACS - A/D

Check compliance

Asthma - ICS, BD, LTRA

Due to the possibility of multiple causes maintain all partially effective treatment

NAEB - ICCS GERD - PPI, diet/lifestyle For further detailed treatment see each section recommendations

Fig. 1: Algorithm for the management of Chronic Cough (Chronic Cough: in patients of ≥15 years of age cough lasting > 8 weeks); [ACE-I; ACE-inhibitor; BD = Bronchodilator; LTRA = Leukotrienes receptor antagonist; PPI = Proton Pump Inhibitor]; Cited from:De Blasio F, Virchow JC, et al. Cough management: a practical approach. Cough 2011; 7:7. © 2011 De Blasio et al; licensee BioMed Central Ltd. [This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/ licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.]

•

-

ECG, ECHO

QUANTITATIVE ASSESSMENT OF CHRONIC COUGH

•

Subjective quality of life questionnaires

-

Leicester Cough Questionnaire (LCQ),

The management of chronic cough is depicted in Figure 1.

REFERENCES

1.

Mahashur A. Chronic dry cough: Diagnostic and management approaches. Lung India 2015; 32:44-49.

2.

Gibson P, WANg G, McGarvey L, Vertigan AE, Altman KW, Birring SS. Treatment of unexplained chronic cough.

Chest guideline and expert panel report. Chest 2016; 149:2744.

3.

Canning BJ, Chang AB, Bolser DC, Smith JA, Mazzone SB, McGarvey L. Anatomy and neurophysiology of cough.

Chest Guideline and Expert Panel Report. Chest 2014; 146:1633-1648.

4. Morice AH, McGarvey L, Pavord I. Recommendation for the management of cough in adults. Thorax 2006; 61(SupplI):i1-i24.

5.

Irwin RS, Baumann MH, Bolser DC, Boulet LP, Braman SS et al. Diagnosis and management of cough executive summary. Chest 2006; 129(1 Suppl):1S-23S.

6.

Woodcock A, Young EC, Smith JA. New insights in cough.

Brit Med Bull 2010; 96:61-73.

7. Lai K. Chinese national guidelines on diagnosis and management of cough: consensus and controversy. J Thorac Dis 2014; 6(S7):S683-S688.

8. French CT, Diekemper RL, Irwin RS. Assessment of intervention fidelity and recommendations for researchers conducting studies on the diagnosis and treatment of chronic cough in the adult. Chest 2015; 148:32-54.

9.

Farugqi S, Song WJ. Chronic Cough: An Indian perspective.

Lung India 2015; 32:668-669.

10. De Blasio F, Virchow JC, Polverino M, Zanasi A, Behrakis PK et al. Cough management: a practical approach. Cough 2011; 7:7.

Non Resolving Pneumonia

C H A P T E R

44

Devendra Prasad Singh

INTRODUCTION

Non resolving pneumonia is a common problem faced by physicians. This is responsible for 15% of pulmonary consultations needing hospitalization and 8% of bronchoscopies. 10% of community acquired pneumonia (CAP) and 60% of hospital acquired pneumonia (HAP) show inadequate responses to empirical therapy initiated.

DEFINITION

The term NRP has been used to refer to “Persistence of radiological abnormalities beyond expected time of course”. The expected time course for resolution is controversial. In 1975 Hendin defined slow resolving pneumonia (SRP) as pulmonary consolidation persisting for more than 21 days. In 1991 Kirtland & winterbauer defined SRP in immune competent patients based upon radiological criteria ; Less than 50% clearings by 2 weeks or less than complete clearing 4 weeks.

Non resolving Pneumonia (NRP) is a clinical syndrome in which focal infiltrates begin with some clinical association of acute pulmonary infection and despite a minimum of 10 days of antibiotic therapy patients either don’t improve or worsen or radiographic opacities fail to resolve within 12 weeks.

NORMAL RESOLUTION OF PNEUMONIA

Normal resolution of pneumonia is not easy to define.

It depends upon the underline causes. Subjective improvement starts 3-5 days after initiated treatment.

Figure 1 showing rate of resolution of clinical, Laboratory and Radiological abnormalities.

Pneumonia resolution depends upon many key factors.

Rapid resolution of pneumonia occurs when Abnormalities

Duration

Fever

2 – 4 days

Cough

4 – 9 days

Tachycardia

2 days

Hypotension

2 days

Tachypnea

3 days

Crackles

3 – 6 days

Leukocytosis

3 – 4 days

C-reactive protein

1 – 3 days

Chest X-Ray (CXR) abnormality

4 – 12 weeks

Fig. 1: Resolution of Pneumonia

1.

Host is young, nonsmoker and non hospitalized.

2.

CAP is of mild severity.

3. Causative microorganisms are mycoplasma pneumoniae or Chlamydia pneumoniae.

CAUSES OF NON RESOLVING PNEUMONIA

There are numerous causes which can delay normal resolution of pneumonia. They can be broadly categorized into two groups.

Infectious Causes

40% of the causes are attributable to infections which may be primary, persistent or nosocomial infections.

Streptococcus pneumoniae, Legionella, Staphylococcus aureus and Pseudomonas aeruginosa are common organisms responsible for non resolution. Methicillinresistant S aureus (MRSA) [33%], enteric- Gram negative bacilli (24%) and P aeruginosa (14%) have been found in elderly patients with nosocomial infections.

S pneumonia resistance is less common if the treatment is appropriate and according to the guideline. The unusual microorganisms like tuberculosis and fungal infections are usually the cause of NRP.

Non Infectious Causes

In one study in an ICU Jacobs et al found 19% of noninfectious causes of NRP. They include drug induced pneumonitis, ARDS, PTE (Pulmonary thrombo-embolism, carcinomatous lymphangitis, and cardiogenic pulmonary edema.

This group of non infectious causes is also called pneumonia mimics. Pulmonary neoplasm is estimated to account for 1-8% in most series. Bronchoalveolar cell carcinoma, lymphoma bronchogenic carcinoma, carcinoid and pulmonary metastasis may present like pneumonia.

History

In order to resolve the mystery of non resolving pneumonia comprehensive history taking is very essential. Fever and productive cough indicates infectious cause but many patients may have no symptom, only radiological findings. A history of pulmonary infections which are notorious to cause delayed radiological resolution can be a harbinger of NRP. Past history of comorbid conditions like COPD, renal failure and alcoholism should also be sought as they delay radiological clearance. If we don’t find any clue of

202

Table 1: Showing Causes of non-resolving pneumonia (Infectious)

Table 2: Showing Causes of non-resolving pneumonia (Non Infectious)

Complications

Neoplasia

Bronchoalveolar cell carcinoma, Lymphoma, Lymphangitis carcinomatosis

Inflammatory disorders

Systemic Vasculitis, CTD (Connective Tissue Diseases), Diffuse alveolar hemorrhage, BOOP (Bronchiolitis Obliterance Organizing Pneumonia), Sarcoidosis

Drugs

Nitrofurantoin, Amiodarone, Methotrexate, Bleomcin

Cardiac causes

PTE, CHF

• Empyema, abscess • Metastatic infection (e.g. infective endocarditis)

Host factors

• Age > 60 years (radiographic clearance of pneumonic infiltrate on completion of antibiotic therapy decreases by 20% per decade after the age of 20 Years)

PULMONOLOGY

• C-morbid illnesses like COPD, congestive heart failure, diabetes mellitus, renal failure, alcoholism) • Smoking

Presence of resistant organisms

Pneumococcus

• Malnutrition.

Drug-resistant Streptococcus pneumonia suspected if :

Time to clearance

Residual radio graphical abnormalities

Bacteremic

3 to 5 months

25% to 35%

Non bacteremic

1 to 3 months

Rare

Haemophilus influenzae

1 to 5 months

Occasional

Legionella

2 to 6 months

10% to 25%

Mycoplasma

2 weeks to 2 months

Rare

• HAP in last 2 months

Chlamydia sp

1 to 3 months

10% to 20%

Methicillin- resistant Staphylococcus aureus MRSA) suspected if :

Gram negative

3 to 5 months

10% to 20%

Moraxella catarrhalis

1 to 3 months

Rare

• Treated with beta lactams within 6 months • Close exposure to young children • Pneumonia in last 1 year

• Advanced age • Prior antibiotic coverage, indwelling IV catheters, tertiary care centre, dialysis • Burns, surgical wounds CAP : especially S pneumonia, S aureus Nosocomial pneumonia : especially MRSA, pseudomonas aeruginosa, Acinetobacter Presence of unusual organisms

• Tuberculosis, atypical mycobacteria • Nocardis, Actinomyces • Pneumocystis jirovecci • Fungi ; Aspergillus, Cryptococcus, Histoplasma, coccidiodomycosis • Exposure to animals: Coxiella burnetii, Chlamydia, psitaci

Delayed radiological recovery

Table 3: Causative Agent and Clearance of Pneumonia

• Defects in defense (immunosuppressive/cytotoxic therapy, use of feeding tube, endotracheal tube, tracheostomy or sedating drugs)

• Extent of disease : multilobar or bilateral pneumonia, pleural effusion, bacteraemia • Casual micro-organism

Causative agent

Staphylococcus aureus 3 to 5 months

Common

infection a search for non infectious etiology should be thoroughly made.

Common chronic infections like mycobacterium tuberculosis, fungal and parasitic diseases should also be evaluated.

A history of angina and dyspnea may indicate cardiac cause of radiological opacity. A patient with history of heavy smoking, hemoptysis, cachexia or weight loss with non resolving opacities points to malignant etiology.

Hematuria may indicate DAH whereas joint pain or rashes indicate CTD. Asthma and persistent migratory opacities are suggestive of ABPA. Drugs history is important cause of pulmonary infiltrate. Similarly occupational history is also significant for NRP.

PHYSICAL EXAMINATION

Although the traditional finding of consolidation like dullness on percussion over the chest, tubular bronchial breathing may not be present in spite of persistent finding of radiological opacity, the examination of a patient with NRP should proceed in the comprehensive manner.

In HIV patients skin manifestation of a pulmonary

203

Persistant Pulmonary Opacity Clinical Evaluation, Assess co-morbidity, sputum for AFB/Culture, Gram staining/culture, PAP staining, Adequate antibiotic therapy Non Infectious Causes

Radiological Recovery

CHAPTER 44

No

Yes

Re evaluate host factors, review microbiological data, CT chest

Resolved

Diag not reached Bronchoscopy BAL, PBS, TBB, Sputum smear for AFB/Culture, Fungus, unusual pathogens, malignant cells

Diagnosis Reached

Diag reached

Diag not reached CT guided FNAC for peripheral lesions ECHO, Blood for c-ANCA, SACE

Final Diagnosis

Fig. 2: Flow Chart of NRP associated bacterial, fungal, viral or neoplastic disorder (Kaposi’s sarcoma). Pedal edema, raised JVP and basal crackles are signs of heart failure while clubbing of fingers and toes may indicate idiopathic pulmonary fibrosis, asbestosis and malignancy.

Involvement of eyes, joints, skin, kidneys, heart and salivary glands may suggest sarcoidosis.

LABORATORY EXAMINATION

In patients with non resolving pneumonia microbiological examinations are mandatory to confirm or deny the diagnosis of CAP because many microorganisms like Legionella are known for delayed resolution (Table 3). In a patient of pneumonia if reduction of leukocytosis and CRP strongly supports response to antibiotic therapy no further evaluation is necessary for NRP even if chest opacity is persistent.

Microbiological investigations are as follows:Sputum for gram staining, sputum for culture sensitivity Sputum for AFB, CBNAAT, LPA and Culture and Sensitivities if tuberculosis is suspected.

Staining for fungi in respiratory samples Blood Culture Direct immunofluorescence for legionella Urinary Legionella antigen and streptococcus pneumonia antigen assays Stains and culture for bacteria and anaerobes in plural fluid in case of pleural effusion.

D-dimer testing for PPE Rheumatoid factor, ANA & ANCA should also be ordered in CTD and vasculitis Serum angiotensin converting enzyme (SACE) in sarcoidosis.

IMAGING

Serial Chest X-Ray is an important investigation which confirms the persistence of radiological opacity. Chest CT is the most helpful in resolving NRP, which can detect plural diseases, empyema or abscess & mediastinal masses. CT is also very useful in non infectious causes of NRP. Active interstitial pneumonitis may be suggested by

204

ground glass opacity on HRCT. CT angiography is also indicated if PTE is suspected.

BRONCHOSCOPY

PULMONOLOGY

After laboratory and radiological evaluation if the diagnosis of NRP is not certain, fiber-optic bronchoscopy (FOB) is diagnostic in more than half of the cases of persistent pulmonary opacity.

Bronchoscopy allows direct visualization of affected area and the direct obtaining of samples. Protected brush specimen (PBS), broncho alveolar lavage (BAL) and trans bronchial biopsy (TBB) can be used to take the sample tissues. Microbiological studies of BAL and PBS may include staining in culture of usual bacteria, specific staining for AFB and culture, legionella, fungi, virus and direct immunofluorescence for legionella.

If FOB is not successful or doesn’t yield a definitive diagnosis transthoracic needle aspiration or open lung biopsy may be done.

TREATMENT

In the management of NRP choose appropriate antibiotics considering etiology, antibiotic resistance & compliance.

Treatment should include antipseudomonal B-lactams and IV fluoroquinolones. Complications and underline causes are treated. Treatment is changed if other diagnosis is confirmed. If NRP is not resolved respiratory experts should be consulted.

Figure 2 shows the Algorithm in approach to NRP.

REFERENCES

1. Rosario Menendez, Antoni Torres. Treatment failure in community-acquired pneumonia. Chest 2007; 132:13481355.

2.

Kirtland SH, Winterbauer RH. Slowly resolving, chronic, and recurrent pneumonia. Clin Chest Med 1991;12:303-18

C H A P T E R

45

Health Care Associated Pneumonias

INTRODUCTION

Health care–associated pneumonia (HCAP) is pneumonia acquired in health care environments outside of the traditional hospital setting. Increased numbers of patients are living outside hospital environment, in long-term– health care facilities (LTHC), rehabilitation facilities, and dialysis centers which brings them at risk of infections.

The patient population at risk is diverse and prone to Multidrug resistant Organisms. HCAP are category of pneumonias which are distinct from Hospital-acquired pneumonia (HAP), Ventilator-associated pneumonia (VAP) and Community acquired Pneumonia (CAP).1 Though both HCAP & CAP are acquired outside hospital surrounding, HCAP varies in pathogens involved, pathogenesis and prognosis. HCAP resembles HAP and VAP more closely as far as etiology, pathogenesis and treatment are concerned. These patients have major risk factors such malignancy, renal disease, COPD, immune suppression, dementia and impaired mobility.

DEFINITION

Patient, coming to an acute-care health facility from a non hospital environment, (Health care association but Non Hospital environment) consisting of already-ill population of nursing-home residents, patients in longterm care, patients undergoing same day procedures, patients receiving home- or hospital based intravenous therapy, and patients undergoing dialysis when develop pneumonia its called Health Care Associated Pneumonia.

EPIDEMOLOGY

Multidrug-resistant (MDR) bacteria are the commonest pathogens involved.2 This has clinical as well as microbiological similarity to HAP & VAP. HCAP has been associated with Methicillin-resistant S.aureus (MRSA), Pseudomonas aeruginosa, Streptococcus pneumonia, and Haemophilus species. Dialysis-associated pneumonia have higher incidence of above organisms along with Klebsiella. Higher colonization with MRSA was seen in dialysis, home infusion therapy, wound care and nursing care patients. Chemotherapy patients had higher incidence of Fungi and GNB especially MDR pathogens (Pseudomonas and Klebsiella). Frequent fungal pneumonias distinguish it from other HCAP’s.3 Colonization of rectum and nasal cavity is seen with other MDR organisms especially Providencia stuartii, Proteus mirabilis, Escherichia coli and Morganella morganii was high.4

Atul Bhasin, RK Singal

Risk factors for infection with multidrug-resistant (MDR) pathogens •

Residing in a extended health care facility

•

Home infusion therapy (including antibiotics)

• Dialysis •

Home wound care

•

Antimicrobial therapy within 90 days

•

Immunosuppressive disease and therapy

PATHOGENESIS

HCAP are more likely to occur once large number of microrganisms reach lower respiratory tract. This especially occurs when the host defenses are overwhelmed (aspiration or contaminated respiratory therapy equipments), defenses are impaired (immunodeficiency or steroids) or highly virulent organisms are present. Patients are repeatedly exposed to the microorganisms in health care facilities, especially Gram-negative bacteria (GNB).

Since patients under health care are repeatedly exposed to these organisms, they are more prone to infection with them. Vulnerability increases as other factors directly related to hospitalization increase exposure and patient resistance. Contaminated oropharyngeal secretions getting microaspirated is the most important factor. These organisms vary rarely cause CAP. Up to 70 % patients under sedation or with altered consciousness and 50 % of normal people micro aspirate during sleep. In presence of new pathogenic virulent organisms the previously benign microaspiration becomes a mechanism of pneumonia by virulent organisms.5

TREATMENT

The management of HCAP is complex where empirical therapy plays a major role, especially so when convincing data regarding same is not available. Clinical assessment plays an important role in therapy to avoid over treatment with an unnecessarily broad spectrum of antibiotics.

With major focus on MDR organisms many prefer to treat with empirical therapy of hybrid approach. Patients have multiple risk factors, the ones with at least 2 of the 3 risk factors i.e. severe illness, prior antibiotic therapy, and poor functional factors are more likely to be infected with MDR pathogens.6 While another set of patients with minimal risk factors may not require MDR empirical treatment. Thus broadly, antibiotic administration could be categorized into limited-spectrum therapy and broadspectrum therapy, where broad spectrum is reserved for

PULMONOLOGY

206

patients with 2 of the 3 identified risk factors for MDR pathogens.

Limited spectrum should include a respiratory Quinolone alone or, alternatively, combined with a selected Betalactam (activite against drug-resistant S. pneumonia), plus adding a Macrolide (especially if Legionella, Chlamydophila, or Mycoplasma) are suspected. Broadspectrum therapy is reserved for suspected MDR cases, especially if S. pneumoniae, P. aeruginosa, MRSA & Legionella. So combination of Beta-lactams / Carbapenem, with antipseudomonal Quinolone is initiated as empirical therapy, while Linezolid or Vancomycin should be added if MRSA is strongly suspected. All antibiotics need to be given parentrally in clinically severe cases after clinical assessment. Aminoglycosides should be used alternatively to Quinolones if there is history of allergy, intolerance or recent therapy with Quinolones in the past 3 months.

Though there are no randomized trials that provide evidence for dual therapy, but clinical data suggests that combination regimen therapy of an empirical antibiotic is more likely to succeed. Consideration of synergistic effects, development of resistance, and toxicity should be viewed with optimism.

MRSA infections, a common problem encountered by clinicians, results into significant morbidity and mortality.

There is increasing incidence of MRSA in hospitals and community but microbiological evidence of MRSA as a major pathogen in HCAP is less. Treatment of MRSA in HCAP is opinion based and should be treated with Vancomycin or Linezolid.7 To minimize exposure to broad-spectrum antibiotics the concept of “De-escalation” has been formulated.

It broadly engulfs the idea of discontinuation of some antibiotics, switching over from a broad to narrow spectrum antibiotic or discontinuation of antibiotics in absence of microbiological culture positive evidence.

Lower respiratory tract cultures are infrequently taken initially, while treatment is initiated on basis of most probable susceptible microbacteria. Thus De-escalation (modified or discontinued) is done three to seven days after initiation, on basis of clinical response to therapy i.e. usually when chest skiagram improves and respiratory rate returns to baseline.

With optimal selection of antibiotics, dose and duration of treatment an early response should be expected in three to seven days. Currently there is no data on duration of therapy in HCAP. The obvious benefits of a shorter therapy are lower cost, fewer adverse drug events and lesser chances of drug resistance.

SUMMARY

•

HCAP need therapy for multidrug resistant (MDR) pathogens.

• Appropriate Broad-spectrum antimicrobial therapy, in adequate doses should be given to high risk patients on basis of clinical criteria, pending microbiological culture reports.

•

Delay in obtaining lower respiratory tract culture should not delay initiation of empirical therapy.

•

Empirical therapy regimen should not include recently used antibiotic.

•

De-escalation of antibiotics should be considered early.

CONCLUSION

HCAP is a distinct pneumonia with an increased risk of MDR pathogens. Early identification of at risk patients, adequate and appropriate empirical therapy, reduces mortality and avoids overuse of antibiotics. Due to paucity of data much is still unknown about HCAP. Though severe CAP and HCAP are distinct entities in reference to MDR, but principles to treat are similar.

Empirical therapy, de-escalation of antibiotic therapy and duration of treatment may have distinct views, but in absence of data prognosis remains good in their discretionary use. Large-scale, multicenter, observational, cohort studies with rigorous microbiological data are needed to standardize the guidelines for HCAP.

REFERENCES

1. Friedman ND, Kaye KS, Stout JE, et al. Health care– associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann Intern Med 2002; 137:791–7.

2.

Kollef MH, Shorr A, Tabak YP, et al. Epidemiology and outcomes of health-care-associated pneumonia: results from a large US database of culture-positive pneumonia.

Chest 2005; 128:3854–62.

3.

El Solh AA, Pietrantoni C, Bhat A, Bhora M, Berbary E. Indicators of potentially drug- esistant bacteria in severe nursing home-acquired pneumonia. Clin Infect Dis 2004; 39:474–80.

4. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control 2004; 32:470–85.

5.

Marik PE, Kaplan D. Aspiration pneumonia and dysphagia in the elderly. Chest 2003; 124:328–36.

6.

Guidelines for the management of adults with hospitalacquired, ventilator- associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171:388–416.

7.

Jeffres MN, Isakow W, Doherty JA, et al. Predictors of mortality for methicillin-resistant Staphylococcus aureus health-care-associated pneumonia: specific evaluation of vancomycin pharmacokinetic indices. Chest 2006; 130:947– 55.

How to Manage Solitary Pulmonary Nodule (SPN)

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46

Keerat Kaur Sibia, Rajbir Singh, Akash Batta, Rishu Bhanot, RS Bhatia, SS Sibia

INTRODUCTION

Solitary pulmonary nodule on chest x-ray often poses a practical management problem, especially in view of possibility of malignancy. Early diagnosis is important particularly in case of patients with small asymptomatic lesions since chances of long-term survival in those with malignant disease are increased. The prevalence of solitary pulmonary nodule is around 1-2/1000 chest x-ray. A solitary pulmonary nodule is a shadow within the lung parenchyma with well circumscribed, or without smooth borders. It may affect the pleura, mediastinum, or diaphragm and may contain calcium or cavitations.

Multi-detector compound CT has increased the detection rate of SPN1 in recent times. Management of SPN by four management algorithms by 2015 BTS guidelines has made it surprisingly easy and cost effective2,3.

SPN

On a plain postero-anterior chest X-ray of an asymptomatic individual, a single, small, circular shadow may be noticed in the lung parenchyma. It is referred to as a Coin shadow or coin lesions. John Steel coined the term solitary pulmonary nodule (SPN), which has following features:

ETIOLOGY

The possible causes include; 1.

Bronchogenic carcinoma

2.

Granulomatous lesions such as tuberculosis, Histoplasmosis, Wegener’s granulomatosis

3.

Benign tumors adenoma, hamartoma

4.

Lung metastasis from a carcinoma in breast, thyroid, kidney, bone4

5.

Hydatid cyst or bronchogenic cyst

6.

Lung abscess

7.

Slowly resolving pneumonia lipoid pneumonia, Paraffinoma

8.

Pulmonary infract.

9.

A.V. fistula

10. Lymphoma 1 1.

Rheumatoid nodule, Amyloid nodule.

12.

Mucoid impaction

Solitary

13.

Haematoma post trauma.

Circumscribed margins

14.

Benign pleural effusion

Round, ovoid or lobulated

15.

Infected fluid filled bulla.

Completely surrounded by normal lung

16.

Chest wall tumors, skin tumor, the nipple

Smooth, speculated or notched border.

Primary bronchial carcinoma accounts for thirty three to fifty percent of solitary pulmonary nodules in patients over the age of 50 years, but the risk falls almost to zero in patients under the age of 40 years. A variety of benign tumors along with localized infection and granulomas form the majority of non-malignant causes of solitary pulmonary nodules. The prevalence of fungal infection in North America accounts for fifty percent of granulomatous lesions. Tables I & 2 outlines some common causes of solitary pulmonary nodules.

Minimal diameter i.e. double the cross-sectional diameter of blood vessel in its vicinity (1.5 cm). Homogeneous density without cavitation, or having a central calcified core.

Not associated with infiltration, volume loss, regional Iymphadenopathy or satellite lesions.

Chest CT is useful from diagnosing missed lung lesions while HRCT can differentiate alveolar lesions from ILDS.

Table 1: Common causes of solitary pulmonary nodule (SPN) Bronchial carcinoma Benign lung tumor, hamartoma being the commonest Infective granuloma, Tuberculoma, fungal granuloma.

Metastasis.

Lung abscess

MANAGEMENT

First step is to confirm that an opacity lies within the chest and that it is not caused by an overlying object such as nipple, hair plait, button, fibroma, lipoma or any soft tissue mass. Benign pleural thickening with unfolding of a lung segment may also mimic a tumor. A benign pleural plaque may be confused with a solitary pulmonary nodule but may be distinguished by tomography or fluoroscopy as

208

Table 2: Common causes of solitary pulmonary nodule (SPN) More Common

Primary bronchial carcinoma (PMEN)2 Pulmonary Metastasis from Breast Sarcoma Aminoma Hypernephroma Infection

Tuberculosis (Tuberculoma)

PULMONOLOGY

Localized Pneumonia Abscess Less common

Benign tumours

Hamartoma Bronchial Adenoma Chyloductoma Chondroma Fibroma Haemangioma Leiomyoma Myxoma Neurofibroma Papilloma Thymoma

Other malignant tumours

Alveolar Cell Carcinoma Lymphoma Mesothelioma

Chest wall lesions

Arteriovenolous malformation Lipoma Fibroma

Cysts

Bronchiectatic Bronchogenic Hydatid Endometriosis Foreign Body Infection

Mycosis and Parasitosis

Aspergillosis Coccidioidomycosis Histoplasmosis Nocardiosis Cryptoccosis

Miscellaneous

Intrapulmonary Lymph Node Pulmonary Infract Pulmonary Sequestration Post- Traumatic Hematoma Rheumatoid Nodule/ Systemic Lupus Erythematosus Wegener’s Granuloma

the pleural mass does not move relative to chest wall with respiration. General physical examination is important because the nodule may be a metastatic manifestation of the malignancy of breast, kidney, testes, or ovary.

Benign nodules are likely to be smaller than malignant lesions. An irregular lobulated or speculated contour is suggestive of malignancy, contrary to a smooth contour that suggests the nodule is benign, with exceptions.

The two most useful radiological features to exclude

malignancy are no growth over two years and the presence of calcium. No growth almost completely rules out malignancy on comparison with old chest x-ray. The diagnostic value of calcium depends on the radiological distribution pattern; a dense central nidus or a laminated or diffuse pattern are reliable signs of healed granulomas; nevertheless malignancy may still develop in relation to the granulomas. Pepper pot calcification is associated with hamartomas. Calcification may sometimes be seen within a malignant lesion and hence diagnosed as benign, simply because of presence of calcification may not be true.

In patients with cough or weight loss without fever diseases such as tuberculosis, histoplasmosis, blastomycosis, etc form the important differential diagnosis. Leukemic lung deposit can be excluded on clinical grounds or blood examination.

Two categories of further investigations are required to clinch in order to achieve specific diagnosis and also to assess the need for thoracotomy.

IMAGING MODALITIES

Plain Chest x-ray

Chest C-ray forms the cornerstone investigation5. The film in postero-anterior view is taken with the patient well positioned and in inspiration. Bronchial carcinomas may vary enormously in shape and radiographic density as well as in size and position. Notching in peripheral masses and speculation or corona maligna are said to be suggestive of malignancy. Nevertheless, such appearances are not pathoganomonic. Cavitation in a thick walled tumour and presence of atelectasis are features associated with a squamous cell carcinoma. The claim that a peripheral nodule is most likely to be due to an adenocarcinoma and that Iymphadenopathy is more often associated with small undifferentiated carcinoma, cannot he regarded as sufficiently specific to be conclusive.

Calcification within the solitary nodule is perhaps quite useful indicator of a benign lesion. Several different patterns of calcification are described, such as lamination, punctuate, central nidus, or popcorn; these may not always be discriminatory features. Calcification can also be seen in malignant tumours that engulf previously calcified lung tissue such as a Ghon’s focus, and some metastasis (for example from an osteosarcoma).

Penetrated Film

In addition penetrated chest X-Ray can be informative.

Other plain Film Views

Sometimes a useful information can be obtained from the posteroanterior view taken in expiration, which effectively alters the mediastinal shape, the filling or the pulmonary vasculature, and the relation of the lung parenchyma to the adjacent chest wall structure. (this effect can also be obtained with an anteroposterior view). Rarely an intrabronchial mass can lead to a ball valve effect with air trapping beyond an intermittent obstruction that occurs particularly in expiration. Decubitus films can be useful on confirming the presence of a liquid pleural reaction; so called horizontal beam film can be taken with the patient lung on the affected side, when free fluid drains from the top of the diaphragm along the chest wall; even small quantities may become obvious.

Fluoroscopy

It helps in locating abnormal shadows in the anteroposterior plane and also to detect the relationship of the suspected lesion to the thoracic cage and the intrathoracic mediastinal structure. For example, pulsation may occasionally be seen or alteration may be noted in the size or shape of the lesion with the changes in the respiratory phase, suggesting a vascular rather than a solid lesion.

Tomography6

Tomography apparently increases detail by its ability to blur out all planes except the plane of interest.

Therefore, the lesion at the apex of the lung are usually obscured by upper ribs on the standard chest film may be well seen by apical tomography and the anatomy of the carina and bronchi within the mediastinum may be better appreciated when the neighboring structures have blurred out of focus. Also flecks of calcium can be better revealed by tomography.

Tomography may also reveal a rather prominent but otherwise unremarkable pulmonary artery. Whole lung tomography may be used to exclude multiple lesions particularly while considering resection of an apparently solitary pulmonary nodule.

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CHAPTER 46

Computed tomography (CT) has been proposed as a reliable way of diagnosing benign disease. A history of previous malignancy should not prevent full investigations since resection of a solitary pulmonary metastasis may carry a good prognosis. Apart from routine haematology, specific precipitin (for example for aspergillus or histoplasmosis) or tuberculin testing may be indicated. If solitary pulmonary nodule is suspected to be extra thoracic metastasis; carcinoma of thyroid, breast, kidney or bone are common differential diagnosis.

This is a film taken after exposing at a much higher kilo-voltage (and also using an anti-scatter device). The radiograph produced is usually darker than the standard film as it utilizes the x-ray absorption at higher energies to pass through the denser structure of the chest, thus revealing the anatomy of the tracheobronchial tree within the mediastinum. Such a film may show widening of the carina, bronchial occlusions, or intrabronchial masses within the mediastinum. Abnormal shadows otherwise concealed behind the cardiac silhouette may also become obvious. The penetrated film may also reveal either central necrosis or calcification within a dense intrapulmonary nodule, and it can be particularly useful in demonstrating an air bronchogram, i.e. air contained within the bronchi in a segment of abnormal lung; the presence of which offers a conclusive evidence that the lesion is a form of consolidation and it definitely lies within the lung.

210

Table 3: Role of CT in solitary pulmonary nodule 1. To diagnose the nature of the nodule and to detect calcification in a nodule than conventional trims.

2. To demonstrate the spread of disease.

3. To localize accurately the nodule prior to bronchoscope or percutaneous needle biopsy.

PULMONOLOGY

CT

CT has clear advantages over standard radiographic technique. Third and fourth generation CT scanners allow increased spatial resolution (better with improved contrast resolving relative to conventional radiography) with which lesion of 3 mm or more can be demonstrated. It is claimed that measurement of the tissue attenuation can indicate the likelihood of malignancy. Metastasis is more commonly found in the lung periphery and, like small pleural effusion, small peripheral metastases are more radically seen by using CT. CT also usefully distinguishes vascular masses such as aneurysms from solid tumors. It differentiates pleural disease from intrapulmonary disease and effectively supports the need for diagnostic artificial pneumoperitonium or pneumothorax. CT can reveal a mass that is otherwise lost within distal consolidation in conventional radiography. For a bronchial neoplasm CT scanning alone cannot be used to assess operability; Nevertheless, CT examination of other parts of the body such as the liver may demonstrate metastasis. Utility of CT in SPN are listed in Table 3.

Ultrasound

Following radiologically demonstrated mass such as cyst, abscess or tumor which a bud the chest wall, ultrasound is used. Ideally this should be described under nonradiological investigation. Since only air tree structures can be visualized, ultrasound has a limited use in the assessment of chest pathology. It is better than chest radiography sand superior to physical examination and can obviate the need for CT thorax in certain situations.

Radial EBUS in SPN has been found quite useful. Lung ultrasound quickly rules out consolidation, atelectasis and pleural effusion, however it has limited role in obesity, chest wall oedema, chest wall dressing, subcutaneous air and heavy musculature7,8.

Radioisotope Studies

Radioisotopes allow the assessment of function rather than anatomy. As such, these techniques are useful in the search for bone, liver, and cerebral metastasis. Positron emission computer assisted tomography has increased the accuracy of evaluating utility in SPNF5. PET digital detector technology provides higher spatial resolution, thus improving image quality and making the evaluation of smaller nodules more reliable and with acceptable accuracy9.

Tumor - seeking agents such as gallium may sometimes be useful, particularly in the evaluation of lymphoma.

However, the technique is expensive and time consuming and lacks specificity as the isotope is also taken up in abscesses and pulmonary inflammation, especially

sarcoid10. Usually malignant thyroid tissue appears cold on scanning but this technique can be useful in demonstrating metastasis after the normal thyroid has been ablated. The uptake in metastases is relative to the differentiation of the thyroid tumor cells.

Lung perfusion scans are useful in diagnosing of pulmonary emboli when combined with ventilation studies. Nevertheless they may also be used in the preoperative assessment of patients with bronchial tumors; a lung cancer may markedly decrease pulmonary vascularity and this may be particularly so when the tumor abuts or lies at the hilum. Isotope angiography is less invasive than conventional arteriographic studies but may lack sufficient anatomical precision. However it helps to differentiate mediastinal structures from the aorta and major vessels; it allows confirmation of a suspected aortic aneurysm and readily demonstrate superior vena caval obstruction.

Nuclear Magnetic Resonance (NMR), like ultrasound, is non invasive and involves non ionizing radiation.

While its clinical application is still in its infancy, in NMR allows the production of two - dimensional crosssectional images derived from the suffering proton density of different tissue. As such, its theoretical value in the detection of cancer is obvious since changes occur early at the molecular level and become evident long before the neoplasm shows itself by virtue of the more gross anatomical distortion revealed by conventional radiography. However, the study of intrapulmonary masses surrounded by air filled long tissue is less encouraging.

Angiographic Techniques

CT has reduced the application of angiography.

Nevertheless, when there is an abnormal intrathoracic mass lesion either within or juxtaposed to the mediastinum, aortography is useful in excluding an aneurysm and thus may help in avoiding an unwise biopsy. Furthermore, when an intrapulmonary mass lesion is in fact due to a sequestrated lung segment (it is usually in the left base posteriorly) aortography can demonstrate the feeding arteries that arise from the descending thoracic aorta.

Pulmonary angiography is useful in diagnosing a pulmonary artery aneurysm. Various vascular techniques such as subclavian, thyroid, and internal mammary arteriography have been used on occasion to demonstrate masses of thymic, thyroid or parathyroid origin rarely, other techniques such as azygos and thymic venography may be of value in specific cases. Computerized digital vascular techniquehas a considerable potential for the use of digital image subtraction at different energies in chest radiography in particular, since the detection rate of low contrast intrapulmonary nodules is increased by the suppression of overlying rib detail.

NON RADIOLOGICAL DIAGNOSIS:

These investigations are very important in reaching the conclusive diagnosis11.

Sputum Examination

The presence of pus cells or bacteria may suggest that lesion is inflammatory. Malignant cells should always be sought in at least three early morning Sputum specimens.

Sputum induction can be utilized to improve the sample if sputum sample is not enough12.

Bronchoscopy13,14

Fibroptic transbronchial lung biopsy under local anesthesia has become increasingly useful16,17. The size of each biopsy is smaller but the range of vision, particularly of the upper lobes, is superior. With fluoroscopic guidance, the field is further improved18. The incidence of side effects is low. Pneumothorax occurs in 1-5 percent of cases. This rarely requires intercostals drainage.

Clinical, pathological and radiological responses are often blunted.

•

Serologic tests are useful only in pre-transplant setting.

•

Transplant patients are vulnerable to drug resistance.

•

Antimicrobials are often inadequately effective in the presence of undrained fluid collection.

•

Within 30 days of transplant, risk of microbial and drug resistance organism infection is higher.

•

In one to six months risk of developing opportunistic infections such as P. jirovevecci cryptocollosis, histoplasmosis, TB, cytomegalo, herpes, verisella zoster is ruled, Cryptosporidiosis, toxoplasmosis, strongiloidosis, listeriosis and nocardiosis is higher.

•

After six months (80%) community acquired viral pneumonia (influenza, para-influenza, respiratory syncytial virus and human metapneumo virus), bacterial infections (streptococcus pneumonia, haemophylus influenzae) and cryptococal infections are common. 15% chronic viral infections (adenovirus, polioma virus BK, hepatitis C and human papilloma virus) are common.

•

5% have cryptococcal neoformans cytomegalo virus, nocardia, Rhodococcus, and aspergilosis.

•

Smear of excised tissue may show the organism after diligent search or delayed / scanty growth may be obtained after prolonged incubation of culture.

Mediastinoscopy and Thoracoscopy

Medioastinoscopy through a small incision in the suprasternal notch is useful for the examination and biopsy of mediastinal glands. Mediastinal lymph nodes are involved in fifty percent of all patients with primary lung cancer19.

The presence of a pneumothorax allows the introduction of a thorascope into the pleural space, to investigate cases of pleural effusion and tumours.

Percutaneous needle biopsy20

This commonly used technique involves the insertion (under local anaesthesia) of a fine 23- gauge aspiration needle and alternatively of a small 20 guage screw-tipped needle and cannula. While the patient holds his breath, the needle is inserted through the chest wall, avoiding the intercostal bundle. Using fluoroscope guidance, the needle tip is positioned within the lesion and saline aspiration can be repeated several times. This method gives a better diagnostic yield than the transbronchial approach, with positive result in 80-90 percent of cases. However, the diagnostic accuracy of cell type may be less. The risk of both haemorrhage and pneumothorax is increased.

Spread of infection and seedlings of tumour cells along the needle track are insignificant risks. Both transbronchial and percutaneous lung biopsy are contraindicated in the presence of pneumothorax and bleeding diathesis.

Peripheral lesions over 2 cm in diameter are most suitable for this technique. The direct aspiration of intrathoracic lesions enables the diagnosis of primary carcinoma of the lung. Solitary pulmonary nodule in a renal transplant recipient may make difficulty in diagnosis because of immunosupression21.

•

Immuno-compromised hosts have interference with inflammatory responses.

COMMENTS

Applied strategies of management include careful observation, use of CT, FNAC, PET and bronchoscopy and surgery22 with accuracy and cost effectiveness23. A doctor has three possible options in managing a solitary pulmonary nodule: to do nothing, to undertake invasive investigations or to perform a thoracotomy. As an operation offers the only chance of curing local malignant disease, the initial approach is determined by the probability of malignancy and the possibility of surgery.

Primary bronchial malignancy is rare in non-smokers and patients under 35, but the possibility of a solitary secondary tumour from a breast or testicular primary tumour or a lymphoma must not be ignored. Geographical and ethnic factors may point towards granulomatous or hydatid disease. Endobronchial ultrasonography can be a useful tool to diagnose TB, sacoidosis and malignancy24,25 Controversy exists whether biopsy should be performed before a surgical operation. A negative result seldom excludes malignancy and a positive result in a fit patient leads to a thoracotomy. Therefore if a lesion seems to be operable and the patient could tolerate a thoracotomy, perform a compound tomography of the abdomen and thorax. If no mediastinal metastasis are found then thoracotomy is recommended for a cure or definitive diagnosis.

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CHAPTER 46

When the suspicion of malignancy remains high, Bronchoscopy is usually considered to be the next step.

Unless the lesion is clearly inoperable on clinical or radiographic grounds. Bronchoscopy is also indicated to asses’ operability even if sputum cytology reveals malignant cells. BAL analysis provides additional diagnostic information in concluding the aetiology of SPN15.

•

PULMONOLOGY

212

If surgery is contraindicated because of poor lung function, age, co-existent cardiovascular disease, or by the results of compound tomography, further management is influenced by symptoms and the probability of malignant disease. In an older patient with no symptoms, it is always better to watch and wait.

In younger patient or a patient with symptoms, further management will be influenced by whether malignancy is positively diagnosed. Bronchoscopy is well tolerated.

Biopsy or needle aspiration through the bronchoscope with fluoroscope improves the chance of a positive diagnosis. A diagnosis may be made by transbronchial lung biopsy in a quarter of cases in which the nodules are smaller than 2 cm and in about two third of cases in which these are larger. CT scan is informative and CT guided fine needle aspiration biopsy is diagnostic, particularly for malignant lesions. Percutaneous needle biopsy is simpler but is contraindicated in case the patient has a bleeding diathesis, severely compromised lung function, pulmonary hypertension, or suspicious of a hydatid cyst or arteriovenous malformation from sequestrated lung segment. In malignant lesions, the diagnostic yields from needle biopsy increases with increasing size, reaching 8090 percent for single sample from tumours larger than 3 cm and further potentiated to 95 per cent for two or three sample.

6. Naidich DP etal; Recommendations for management of subsolid pulmonary nodule detected at CT. Radiology 2013; 266:304-17.

An attempt has been made to evaluate the effect of these three management strategies (an operation, biopsy, or observation) on life expectancy by using decision analysis. The results vary with the management strategies.

However the difference between the strategies happens to be surprisingly small. Hence patient’s choice for opting a treatment modality should be given a preference. At the same time, excessive interventions in a high percentage of patients with SPN have lead to excessive radiation exposure and thus requires professional cautionary attention as well26.

18. White CS, etal; TBNA – guidance with CT fluoroscopy.

Chest 2000; 118:1630-38.

REFERENCES

23. Mosmann MP etal; SPN and F18DBG PET / CT in accuracy, cost effectiveness and current recommendations. Radiol Bras 2016; 49:104-111.

2.

24. Dhamija A; etal; Mediastinal adenopathy in India through EBUS. JAPI 2015; 63:15-18.

1. Kar M, Das Gupta A; an approach to SPN; Med update;2016;26:210-15.

Baldwin DR; management of pulmonary nodules according to 2015 BTS guidelines. Pol Arch Med Wew 2016; 126:262-74.

3. Callister MEJ etal; BTS guidelines for investigation and management of pulmonary nodules. Thorax 2015; 70:01-54.

4. Bhatia RS, Pulmonary manifestations of extra thoracic neoplasm; Med update API 1996; 16:229-33 5. Cruong MT et al. Update in the evaluation of SPN. Radiographic 2014; 34:1658-79.

7. Mishra R; Role of Ultrasound in a life threatening emergency; Med Update API 2014;24:580-87.

8.

Prasad BNBM et al. USG in chest diseases; Med update API; 2016;26;:1939-43.

9.

Solmka PJ et al; Recent advances and future progress in PET instrumentations. Semin Nucl Med 2016; 46:05-19.

10. Suryakant, RS Bhatia; Ed; Interstitial Lung Diseases;2015,JBS Foundation, Lucknow.

11. Jai Kishan, Bhullar NPS, Non radiological diagnosis of TB; IN: RS Bhatia, ED: Tuberculosis 2007; 10:57-61.

12. Bhatia RS, Singh R, Batta A; Utility of sputum induction in chest disorders; Med update API; 2016;26:448-50.

13. Bhatia RS, Sibia SS;Therapeutic use of FOB. Lung India 1994; 12:138-39.

14. RS Bhatia, GQ Khan, Ed Pulm Med; 2007;17:145-57 PP Publisher, New Delhi, 15. Bhatia RS; BAL indications – Present status. Lung India 1994; 12:27-29.

16. Hermens FH Wiedal; Diagnostic yield of TBNA in patients with mediastinal lymphnode enlargement. Respiration 2003; 70:631-35.

17. Chokhani R; TBNA in the diagnosis of respiratory disease.

Nepal Med Coll J 2014; 6:24-27.

19. RS Bhatia, GK Sidhu; Lung cancer elderly;2007;19:116-18 PP Publisher New Delhi.

in

the

20. Sharma SK; Pulmonary opportunistic infections in immunocompromised host; IN; SB Gupta; ED; PG Med; API; 2014; 28:525-43.

21. Soman R; Sunavala A; Kothari J; A puzzling pulmonary nodule in a renal transplant recipient. JAPI 2014; 62:38-42.

22. Tripathy S, Zen X; Differentiation of benign and malignant SPN. Advances in Lung Cancer 2015; 4:17-24.

25. Vora A; Endoscopic ultrasound – Indian prospective. JAPI 2015; 63:11-13.

26. Lumbreras B etal; The fate of patient with SPN - clinical management and radiation exposure associated; PLOS one/DOI:10:1371/journal.pone.0158458;July 8,2016.

Chronic Granulomatous Disorders: What we Know

C H A P T E R

47

Dinesh Gupta, GursimranKaur

Granulomatous disorders comprise a large family sharing the common histological denominator of granulomatous inflammation and granuloma formation. Granulomatous inflammation is best defined as a special variety of chronic inflammation in which cells of the mononuclear phagocyte system are predominant and take the form of macrophages, epithelioid cells and multinucleated giant cells.

In most instances these cells are aggregated into well demarcated focal lesions called granulomas. In this review, we have discussed etiopathogenesis and few commoNly encountered granulomatous diseases.

FUNCTION OF A GRANULOMA

The granuloma has a significant protective function.

The replicating or inanimate agents cause chronic tissue irritations and evoke a programmed tissue inflammatory response that isolates and walls off the offender. This is especially useful in the case of replicating intracellular invaders (Mycobacteria, Listeria) that can disseminate throughout the body. The macrophages that converge at the site of bacterial invasion ingest the bacteria and intracellularly kill them. These latent organisms may cause the flare-up of the disease decades later.

PATHOPHYSIOLOGY OF GRANULOMATOUS INFLAMMATION

The granuloma is the end result of a complex interplay between invading organism or antigen, chemical, drug or other irritant, prolonged antigenaemia, macrophage activity, a Th1 cell response, B cell overactivity, circulating immune complexes, and a vast array of biological mediators (Figure 1a).

Historically, the prototype of the lung granuloma is the tubercle induced in infected individuals by M. tuberculosis bacilli. Inhalation of the bacilli triggers the non-specific innate immune response expressed chiefly by ingestion (phagocytosis) of the bacilli by alveolar macrophages and dendritic cells.

Cytotoxic T cells can also be activated areas of inflammation or immunological reactivity attract monocyte macrophages which may fuse to form multinucleated giant cells, and a transformation of macrophages to epithelioid cells (Figure 1b).

The Granulomatous diseases exert effect in three ways: 1.

Pathogen/invader or foreign body- the intrinsic toxicity of the agents can damage the tissues

2.

The

vigorous

immune-inflammatory

T

cell-

mediated response and the activated monocyte macrophage system secrete tissue-damaging substances.

3.

Beside the local effect of the space occupying granulomatous lesion, some disorders like TB have caseation and there may occur the spread of necrosis to the surrounding tissues.

Infections are the commonest causes of disseminated granulomatous disease. Some experts regard an infection as the root cause of all such disorders, but that it still remains undetected in some (Table 1).

Mycobacterial infections

It is undoubtedly one of the most common cause of granulomatous inflammatory disease in India, and the most prevalent infection cause of the same.

Tuberculosis

It is estimated that one-third of the world’s population is infected with TB. This is a disease has pulmonary and extrapulmonary manifestations. Extrapulmonary tuberculosis develops when the bacterium overwhelms the immune system and disseminates by way of the lymphatics or bloodstream. PPD is used for TB screening. PPD test is usually positive in those infected with tuberculosis; however, this may be negative in immunocompromised patients. Sputum stains (ZiehlNeelsen) and cultures (L-J medium) should reveal acid fast bacilli (after 3-4 weeks). Extrapulmonary TB can be diagnosed by positive blood culture or biopsy. Biopsy will show necrotizing granulomas with acid fast bacilli.

First line drugs are ethambutol, isoniazid, rifampin, pyrazinamide and streptomycin. These are available under RNTCP- DOTS programme.

In Indian scenario, one is forced to think : Are all chronic granulomatous lesions tuberculosis?

The polymerase chain reaction (PCR) has uncovered mycobacterial DNA in sarcoid tissue and mycobacterial RNA has been extracted from sarcoid spleen by liquid phase DNA/RNA hybridisation giving rise to false speculations concerning the aetiology of sarcoidosis.

Leprosy

Mycobacterium Leprea is the organism that causes Leprosy (Hansen’s disease), a chronic granulomatous infection which involves superficial tissues such as the skin and peripheral nerves. The tuberculoid form is characterized by massive involvement of peripheral nerves resulting in severe pain and muscle atrophy. In lepromatous leprosy,

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Table 1: A Non-inclusive List of Granulomatous Diseases and their Causative Agents Inducers

Diseases

Inducers

Diseases

Bacteria

Tuberculosis

Inanimate agents

Silicosis

Fungi

Protozoa

Leprosy

Asbestosis

Brucellosis

Bagassosis

Syphillis Bartonellosis

Granulomatous inflammations to inanimate

Lymphogranulomavenereum

Surgical sutures Silicone

Histoplasmosis

Talc

Coccidioidomycosis

Tatoo pigment

Blastomycosis

Keratin

Leishmaniasis

Aspirated material

Toxoplasma Helminths

Malignancy

Filariasis

Hodgkin’s disease

Trichinosis

T cell lymphomas

Schistosomiasis Organic dust

Hypersensitivity pneumonitis

Metals

Berylliosis Zirconium granulomas

Dysgerminoma - Seminoma of the testis Large cell lung carcinoma Miscellaneous infections

Lymphogranuloma

Crohn’s disease

Buruli ulcer

Wegener’s granulomatosis Sarcoidosis Crohn’s disease Hepatic granulomatous disease Langerhan’s granulomatosis Hypogammaglobulinaemia Histiocytosis X Reticulosis Immune complex disease

cutaneous lesions are more common and peripheral nerve involvement is asymmetric.

Diagnosis is by nasal/skin scrapping, which on culture staining show the organism or can reveal granulomatous changes. Treatment for tuberculoid is usually dapsone and rifampin, for lepromatous it is usually dapsone, rifampin and clofazimine.

GRANULOMATOUS MYCOSES

Aspergillus

Kikuchi

Primary Biliary cirrhosis Granuloma annulare

Aspergillusfumigatus is ubiquitous in the environment.

Transmission is by inhalation of the spores. Those individuals with an underlying pulmonary disease such

Whipple’s disease Cat scratch

Sarcoidosis Immunological Aberrations

Malignant tumor-associated granulomas

as COPD, may harbor a chronic infection with long standing cough and often hemoptysis as a complaint.

Mucormycosis is more invasive and can cause vascular occlusion, thrombosis, and necrosis Diagnosis is by microscopic examination of the secretions, in addition to a culture. The hyphae may be differentiated from other fungi (especially mucormycosisgroup) by their morphology-septate, bifurcating hyphae. Computerized tomography will demonstrate sinus pathology. Treatment is surgical excision of the involved tissue, and if invasion is evident, treatment with Amphotericin B. Granulomatous fungal infections mimic Sarcoidosis worldwide. It is important to recognize or exclude fungi localised to one system or disseminated; in particular, granulomatous fungal meningitis needs to be distinguished from Sarcoidosis by all available techniques, like microscopy, culture, ELISA, RIA , etc.

IMUNOLOGICAL ABBERATIONS Sarcoidosis

Sarcoidosis is a multisystem disorder of unknown cause(s) most commonly affecting young adults, and frequently presenting with hilar lymphadenopathy, pulmonary infiltration, ocular and skin lesions. The diagnosis is establishedmost securely when well recognized clinicoradiographic findings are supported byhistological

215

Fig. 1a: The pathogenesis of granuloma formation. IFN-ã = interferon gamma; IL = interleukin; MHC =major histocompatibility complex; TNF = tumour necrosis factor). b :mature granuloma evidence of widespread epithelioidgranuomas in more than one system.

Diagnosis of sarcoidosis requires a combination of radiographic, clinical, and histologic positive findings (non-caseating granuloma). Angiotensin converting enzyme is also elevated in 80-90% of the patients and is helpful in diagnosis as well as monitoring disease status. Prednisone, or other immunosuppressive agents (Methotrexate) or antimalarial drugs (Hydroxychloroquine and chloroquine) are used for treatment.

Crohn’s disease

The commonest cause of granulomatous inflammation in the gastrointestinal tract is Crohn’s disease. This reaction seems to centre on the blood vessels of the intestinal wall causing multifocal gastrointestinal infarction. There may be associated lung changes, including pulmonary vasculitis, granulomatous interstitial lymphocytic infiltration, alveolitis, and interstitial fibrosis. Serum antibody increases include antireticulinantibody, antisaccharomycescerevisiae antibody (ASCA), and p-antineutrophil cytoplasmic antibody (ANCA).

Wegener’s Granulomatosis

Wegener’s Granulomatosis recently known as Granulomatosis with polyangiitis is a systemic disease, thought to be autoimmune, characterized by vasculitis and predominantly epithelioid necrotizing granulomas in the involved tissue. Typically, the patient has a triad of necrotizing granulomas of the upper airway and lungs (cavitating lesions), renal involvement (focal necrotizing glomerulonephritis) and disseminated vasculitis. Diagnosis is based on biopsy of the nasal mucosa. Laboratory evaluation should include a standard chemistry panel (BUN/Creatinine), sedimentation rate, rheumatoid factor, and anti-neutrophilcytoplasmic antibodies (specifically c-ANCA in >90%).

Langerhans Cell histiocytosis

Langerhans cell histiocytosis (LHC) is a granulomatous disease of unknown etiology and commonly affects children. Histology will show proliferation of Langerhans cells, eosinophils, macrophages and lymphocytes.

Electron microscopy shows Birbeck granules in cytoplasm of langerhan cells. Immunohistochemistry staining stains positive for S-100.

Neoplastic

There is often a granulomatous component in malignant.

There is diagnostic confusion between Sarcoidosis and Hodgkin’s disease, in which multisystem granulomas are also observed. Both disorders show depression of cell mediated immunity. In Hodgkin’s disease, the KveimSiltzbach test is negative and serum angiotensin converting enzyme levels are raised in only about 10% of patients, compared with 60% in Sarcoidosis. The evaluation, in most diseases, requires the tissue biopsy and microscopy , beside biochemical evaluation, to evaluate the cause of granulomatous disease.

REFERENCES

1. Bhatia A, Kumar Y and Kathpalia AS. Granulomatous inflammation in lymph nodes draining cancer: A coincidence or a significant association! International Journal of Medicine and Medical Sciences 2009; 1(2) pp. 013-016.

2.

James DG. A clinicopathological classification of granulomatous disorders. Postgrad Med J 2000; 76:457–465.

3.

Zumla A, James DG. Granulomatous infections: etiology and classification. Clin Infect Dis 1996; 23:146–58.

4.

Guler M, Abdullah S¸ OfluŎglu R, Erguden HC, Çapan N. Are all granulomatous lesions tuberculosis? Respiratory Medicine Case Reports 2012; 5:42-44.

5.

Inoue Y, Suga M. Kekkaku. Granulomatous diseases and pathogenic microorganism. 2008; 83:115-30.

6. Mukhopadhyay S and Gal AA (2010) Granulomatous Lung Disease: An Approach to the Differential Diagnosis.

Archives of Pathology & Laboratory Medicine: 2010; 134:667-690.

CHAPTER 47

b.

C H A P T E R

48

Current Concepts and Controversies in the Treatment of Pulmonary Sarcoidosis

Sarcoidosis is a multisystem inflammatory disease of unknown etiology characterized histopathologically by noncaseating granulomas. Sarcoidosis may involve any organ, but the most frequently affected sites are the lungs, lymph nodes, skin, eyes, and liver. Usually at presentation most of the patients with pulmonary sarcoidosis are asymptomatic. When symptomatic, dyspnea, cough, or nonspecific chest discomfort are the common presentations. Spontaneous resolution of the disease is common, but progressive lung disease occurs in approximately 25 percent and disabling organ failure in up to 10 percent.

ORAL GLUCOCORTICOID THERAPY

Corticosteroids have long been the most commonly used agents for the treatment of pulmonary sarcoidosis.

Most patients with pulmonary sarcoidosis do not require treatment, as a large chunk of patients have an asymptomatic, nonprogressive disease or experience spontaneous remission. For those with more severe pulmonary involvement, therapy is aimed at reducing the burden of inflammation and preventing the development of irreversible end-organ damage while avoiding excess toxicity from medications.

Prior to initiating corticosteroid therapy, patients should be assessed for comorbid diseases like infection, heart failure, thromboembolic disease, pulmonary hypertension.

MECHANISM OF ACTION OF GLUCOCORTICOIDS

Glucocorticoids appear to exert their effects on sarcoid granulomas through transcriptional regulation of glucocorticoid-receptor target genes and also nongenomic signal transduction pathways in lymphocytes and alveolar macrophages.

The usual indication for therapy of pulmonary sarcoidosis include •

Troublesome respiratory symptoms

•

Worsening lung function, as assessed by successive pulmonary function testing at three to six month intervals, that demonstrates one or more of the following: a fall in total lung capacity (TLC) ≥ 10%; a fall in forced vital capacity (FVC) of ≥ 15%; a decrease in diffusing capacity (DLCO) of ≥ 20%; or worsened gas exchange at rest

•

Progression radiographic changes including: worsening of opacities, development of cavities,

Akashdeep Singh

progression of fibrosis or development of signs of pulmonary hypertension.

Therapy is not indicated in •

Asymptomatic patients with Stage I radiographic changes as approximately 60 to 80% of patients will have a spontaneous remission.

•

Asymptomatic patients with Stage II radiographic changes and normal or mildly abnormal lung function as approximately 50 % of untreated patients will have radiographic resolution by 36 months.

DOSAGE AND ADMINISTRATION

Initial therapy

The optimal dose of glucocorticoids in sarcoidosis is not known, choosing a dose requires balancing the likelihood of response against the risk of adverse effects. Therapy is usually initiated with oral prednisone at a daily dose of 0.3 to 0.6 mg/kg ideal body weight (usually 20 to 40 mg/ day), depending on the severity of disease activity. The initial dose is usually continued for four to six weeks and the patients are re-assessed, clinically; radio graphically and with pulmonary function tests for stability or improvement. If the patient is stable or has improved the dose of steroids is tapered (by 5 to 10 mg decrements every four to eight weeks) down to 0.2 to 0.4 mg/kg (usually 10 to 20 mg/day). If these parameters are unimproved, continue the initial dose for another four to six weeks.

High-dose oral glucocorticoid therapy (80 to 100 mg/ day) may be warranted rarely in patients with acute respiratory failure or concomitant cardiac, neurologic, ocular, or upper airway disease.

Maintenance therapy

Recurrence of symptoms is common (occurring in about 60 percent of patients), so a continuation of the maintenance dose for at least six to eight months prevents it. A maintenance dose of prednisone in the range of 0.25 to 0.5 mg/kg (usually 10 to 20 mg) per day will prevent worsening of disease. During the maintenance phase, the patient is reassessed at four to twelve week intervals for evidence of symptomatic worsening or development of glucocorticoid-related adverse effects.

Assessing the response

A favorable response to glucocorticoid therapy is defined by: •

Improvement in symptoms

•

A decrease in or clearance of radiographic abnormalities.

for MTX therapy. MTX is contraindicated in pregnancy and those with creatinine clearance < 30 mL/min.

•

Physiologic improvement, including a ≥ 10 to 15% improvement in FVC or TLC, a ≥ 20% improvement in DLCO, or an increase in gas exchange.

Dosage and administration

A failure to respond to therapy (or a relapse) is often defined as: A drop of 10 percent or more in FVC or TLC

•

Worsening of radiographic opacities, especially with development of cavities, honeycombing, or signs of pulmonary hypertension

•

Reduction in gas exchange at rest or with exercise

Duration of therapy

The appropriate duration of therapy in patients who respond to therapy is not known.

Treatment must be given for at least three to six months to be effective and to prevent relapse. Relapses are common following reduction or withdrawal of therapy. Lifelong low dose therapy (≤0.25 mg/kg per day) may be required in minority of the patients who suffer frequent relapses.

Treatment of Relapses

If there is relapse of the disease after tapering of the prednisone, the dose is increased to the last effective dose and continued for a subsequent three to six months. If there is no improvement after three months, prednisone is increased back to the initial effective dose (20 to 40 mg daily) until there is improvement (usually three to six months).

Failure of therapy

The patients who are unable to tolerate the adverse effects of glucocorticoids or whose disease cannot be controlled on the equivalent of prednisone 10 to 15 mg or less, or who have evidence of disease progression despite a moderate dose of prednisone, an alternative immunosuppressive agent may be of benefit. A variety of immunosuppressive agents have been used to treat refractory pulmonary sarcoidosis. The evidence in support of individual second-line agents is largely observational. The agents that appear to have the greatest likelihood of benefit with an acceptable side effect profile are methotrexate, azathioprine, and antimalarial agents. All of the alternative agents for patients with refractory pulmonary sarcoidosis carry substantial risk for toxicity, particularly myelosuppression, hepatotoxicity, and opportunistic infection. A trial of at least six months should last to allow adequate assessment of effectiveness.

METHOTREXATE

Methotrexate (MTX) is the most commonly used nonglucocorticoid immunosuppressive agent for sarcoidosis affecting the lungs, skin, eyes, and central nervous system.

Patients with evidence of underlying liver disease or chronic infection with hepatitis B or C are not candidates

The usual initiating dose is with oral therapy at a dose of 7.5 mg weekly. The dose is gradually increased (eg, by increments of 2.5 mg every two weeks) until a dose of 10 to 15 mg per week is achieved. Switch to intramuscular MTX if the patients have refractory nausea or have not achieved a beneficial effect after three to six months of oral therapy at 15 mg per week.

Adverse effects

The most serious side effects of immunosuppressive MTX therapy are hepatic fibrosis (in up to 10 percent of cases when the dose exceeds 5 g), leukopenia, and interstitial pneumonitis, resulting in pulmonary fibrosis. Other toxicities include nausea, alopecia, and skin rash.

AZATHIOPRINE

Azathioprine affects synthesis of RNA and DNA, thus inhibiting lymphocyte proliferation. Azathioprine is used as second line therapy for pulmonary sarcoidosis, generally as a supplement to glucocorticoids.

Dosage and administration

The usual starting dose of azathioprine is 50 mg per day, given as a single daily oral dose.

The dose is slowly increased by 25 mg every two to three weeks to reduce the likelihood of gastrointestinal side effects. The typical maintenance dose is 2 mg/kg (up to a maximum of 200 mg/day). Monitor the white blood cell count and reduce the azathioprine dose if the count falls to 4000/mm.

Adverse effects

Gastrointestinal complaints (eg, nausea, vomiting, and diarrhea), mild transaminitis, rash, fever, and malaise are the most common side effects. Hematologic side effects include depression of all cell lines. Azathioprine is a teratogenic.

Antimalarial agents

Chloroquine and hydroxychloroquine have immunomodulating properties. Clinical experience with chloroquine for pulmonary sarcoidosis is limited, and its relative efficacy versus other therapies has not been assessed. Due to the limited benefit and substantial toxicity, these drugs are avoided except in circumstances where other options have failed or are contraindicated.

Dosage and administration

For patients with a normal G6PD level, the dose of chloroquine is approximately 250 mg/day (maximum daily dose ≤2.3 mg/kg real body weight).

Adverse effects

The major adverse effect of chloroquine is irreversible retinopathy and blindness.

Tumor necrosis factor antagonists

Tumor necrosis factor alpha (TNFa) is thought to

CHAPTER 48

•

217

PULMONOLOGY

218

accelerate the inflammatory process in sarcoidosis via its role in maintenance of granuloma formation. Due to the potential toxicity of these agents, they are reserved for patients who have persistent disease despite treatment with glucocorticoids (eg, prednisone â&#x2030;Ľ15 mg/day) and at least one second-line immunosuppressive agent (eg, methotrexate, azathioprine, leflunomide) . Various tumor necrosis factor antagonists studies in sarcoidosis include Infliximab, Adalimumab and Etanercept. Studies of the efficacy of TNFa antagonist agents in the treatment of sarcoidosis have yielded mixed results. Therapy with TNFa antagonists has been associated with reactivation of a variety of latent infections including tuberculosis and hepatitis B.

Experimental Drugs

Several medications proposed for pulmonary sarcoidosis are still considered experimental (eg, endothelin receptor antagonists, and pentoxifylline) or are used infrequently due to their side effect profile (eg, cyclophosphamide).

The role of mycophenolate in the treatment of pulmonary sarcoidosis requires further study.

Drugs to be avoided

Several medications proposed for use in pulmonary sarcoidosis are now avoided due to the lack of adequate supportive data or an adverse effect profile; these agents include colchicine, chlorambucil, cyclosporine, nonsteroidal anti-inflammatory agents, tetracyclines, and thalidomide.

REFERENCES

1. Baughman RP. Pulmonary sarcoidosis. Clin Chest Med 2004; 25:521.

2.

Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007; 357:2153.

3.

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 1999; 160:736.

4.

Bradley B, Branley HM, Egan JJ, et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax 2008; 63 Suppl 5:v1.

5.

Schutt AC, Bullington WM, Judson MA. Pharmacotherapy for pulmonary sarcoidosis: a Delphi consensus study.

Respir Med 2010; 104:717.

6.

Sabbagh F, Gibbs C, Efferen LS. Pulmonary sarcoidosis and the acute respiratory distress syndrome (ARDS). Thorax 2002; 57:655.

7.

Fazzi P. Pharmacotherapeutic management of pulmonary sarcoidosis. Am J Respir Med 2003; 2:311.

8. Baughman RP, Costabel U, du Bois RM. Treatment of sarcoidosis. Clin Chest Med 2008; 29:533.

9.

Bradley B, Branley HM, Egan JJ, et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax 2008; 63 Suppl 5:v1.

10. Bakker JA, Drent M, Bierau J. Relevance of pharmacogenetic aspects of mercaptopurine metabolism in the treatment of interstitial lung disease. Curr Opin Pulm Med 2007; 13:458.

Approach to Difficult Asthma

C H A P T E R

49

Amita Nene

INTRODUCTION

There are 300 million asthmatics worldwide. The correct diagnosis of asthma is usually easily made and most patients with asthma respond to therapy. Approximately 5% of patients with asthma, however, have disease that is difficult to control despite taking maximal doses of inhaled medications.

DEFINITION

Previously, difficult asthma has been defined as a disease that causes severe, life-threatening attacks or frequent hospitalization. More recently, the definition of difficult asthma has been expanded to include patients with asthma who require very high doses of inhaled corticosteroids (ICS) along with other controller agents (Table 1), or require near continuous oral steroid treatment to maintain asthma control Other Names for difficult asthma •

Severe asthma

•

Refractory asthma

•

Difficult to control asthma

•

Therapy-resistant asthma

•

Steroid-dependent asthma

difficult-to-control asthma is critically important because it identifies the patients who may benefit from novel and, sometimes, expensive treatments.

A systematic evaluation of patients with difficult asthma should include: 1.

Confirming that patient with ‘‘difficult asthma’’ actually has asthma

2.

Evaluation of risk factors and triggers

3.

Management of Comorbid conditions

4.

The initial determination of phenotypes which may be useful in optimising therapy

5.

Ensuring compliance to treatment

6. Controlling other factors that prohibit asthma control

Reassessing the Diagnosis of Asthma

When there is a lack of response to standard therapy, the diagnosis of asthma should be questioned and revisited.

Obtaining pulmonary function testing with flow/volume curves and documenting reversible airway obstruction become essential. A flattened inspiratory curve, for example, is indicative of upper airway obstruction which can mimic asthma.

APPROACH TO A PATIENT WITH DIFFICULT ASTHMA

Table 1: High Daily Dose ICS – Definition

In patients with a history of asthma but normal lung function, methacholine challenge testing can help confirm airway hyper-responsiveness and thus confirm or rule out the diagnosis of asthma. Normal test results will point away from asthma and lead to a search for other causes of respiratory difficulty

Inhaled corticosteroid

Threshold daily dose in mg considered as high

Alternate Diagnoses to Consider in patients with Difficult Asthma • Hyperventilation

A high percentage of patients who are labelled with severe or difficult asthma actually do not have severe refractory asthma. Distinguishing severe refractory asthma from

Age 6–12 years

Age >12 years

Beclomethasone dipropionate

≥800 (DPI or CFC MDI) ≥320 (HFA MDI)

≥2000 (DPI or CFC MDI) ≥1000 (HFA MDI)

Budesonide

≥800 (MDI or DPI)

≥1600 (MDI or DPI)

Ciclesonide

≥160 (HFA MDI)

≥320 (HFA MDI)

Fluticasone propionate

≥500 (HFA MDI or DPI)

Mometasone furoate Triamcinolone acetonide

•

Vocal cord dysfunction

•

Congestive heart failure

•

Chronic obstructive pulmonary disease

•

Gastro-esophageal reflux disease

≥1000 (HFA MDI or DPI)

•

Restrictive lung disease

≥500 (DPI)

≥800 (DPI)

•

Obstructive Sleep apnea

•

Central airway obstruction / Endobronchial lesions

≥1200

≥2000

•

Recurrent aspiration

220

•

Drug side effects (e.g. ACE inhibitor-induced cough)

•

Pulmonary embolism

Concomitant Disorders that worsen Asthma

Sometimes patients have asthma that is difficult to control because it is associated with another undiagnosed or untreated illness that worsens asthma, such as • Gastroesophageal reflux disease

PULMONOLOGY

• Allergic rhinitis • Chronic rhinosinusitis • Endocrinopathies (eg, hyperthyroidism, carcinoid syndrome) • Allergic bronchopulmonary aspergillosis • Aspirin-exacerbated respiratory disease • Churg-Strauss syndrome/other vasculitides The minimum evaluation of the patient with difficult asthma includes the following: Complete blood count with eosinophil count, serum total IgE level, chest radiograph, pulmonary function tests with both careful inspection of the inspiratory and expiratory flow–volume loop and reversibility testing, and home PEF monitoring.

If clinically indicated, a methacholine challenge test, chest CT scan, fiberoptic bronchoscopy, echocardiogram, sleep study, plasma brain natriuretic peptide, sputum for eosinophil count and culture, serum IgE for aspergillus, antineutrophil cytoplasmic antibodies and thyroid function tests should be performed.

have been identified. These phenotypes are characterised by different clinical and physiological features, probably reflecting separate immuno-pathologies. Thus, characterisation of sub-phenotypes of severe asthma may be very helpful in understanding the underlying pathophysiology and may be used to target treatment.

Identified phenotypes of severe refractory asthma •

Early onset severe allergic asthma

•

Late onset non-atopic, inflammation predominant asthma with fixed airflow limitation

•

Late onset obese female preponderant asthma

Socioeconomic Factors and Psychological Factors

When there is no obvious medical reason for difficult asthma, socioeconomic factors must be taken into account.

These include issues like poverty, access to medical care and environmental risk factors.

Negative emotions can influence the symptoms and management of asthma and should be addressed.

Asthmatics with comorbid depression are especially difficult to treat and depression should be treated at the earliest.

When patients present with atypical symptoms or do not respond properly to medications, functional symptoms should be suspected.

TREATMENT OF DIFFICULT ASTHMA

Corticosteroids

Corticosteroids have numerous beneficial effects in asthma on both inflammatory and structural cells.

•

Identifying and eliminating triggers will help with asthma management. These include

They address most of the causes of airflow obstruction in asthma, including :

-

Airway smooth muscle contraction

•

Cigarette smoking

-

Mucosal edema

•

Allergens such as dust mites or cockroaches,

-

Airway inflammation

•

Pets like cats and dogs

-

Increased mucus secretion, and

•

Medications such as aspirin, NSAIDs and betablockers

-

Perhaps airway remodeling.

•

Monosodium gluatamate (Ajinomoto)

•

Corticosteroids decrease the number of eosinophils, mast cells, and dendritic cells in the airway.

•

They decrease cytokine production from T lymphocytes and macrophages

Aggravating Factors and Triggers

• Wine •

Occupational Allergens

Compliance and Correct Inhaler Technique

Resistant Inflammation In Difficult Asthma

Even when patients are compliant, use of improper inhaler techniques may prevent appropriate delivery of the drug. Therefore, a patient demonstration of proper techniques should be part of every physician visit.

There is considerable evidence to suggest that many patients with difficult asthma have “resistant” inflammation with a persistent inflammatory state in the airway. Patients with difficult asthma should receive maximal doses of inhaled corticosteroids. There is evidence that regular use of inhaled corticosteroids in general is associated with decreased risk of death from asthma

Sub-phenotypes of severe refractory asthma

Long acting β2 Agonists (LABA)

It is important to ensure adherence to the medication regimen. Poor adherence is common and even more so with inhalers compared with oral medications

Severe refractory asthma is a heterogeneous condition, and over the past few years several clinical phenotypes

Regular long-acting and as-needed short-acting β2-

agonist use is recommended for patients with difficult asthma. β2-Agonists act mainly to cause bronchodilation but may also decrease : •

Mast cell mediator release

•

Plasma exudation

•

Cholinergic transmission and

•

Improve mucociliary clearance.

Leukotriene modifiers

The leukotriene modifier montelukast decreases airway eosinophilic inflammation and improves asthma control in adult patients with persistent asthma.

Leukotriene modifiers may be particularly beneficial in patients with aspirin sensitivity where leukotriene production is typically increased.

Anti-cholinergic agents

Anti-cholinergic agents can be used in addition to β2agonists in the treatment of patients with difficult asthma.

The long-acting anticholinergic agent, tiotropium bromide improved lung function and symptoms in moderate to severe asthma patients not controlled on moderate to high dose ICS with or without LABAs. In patients taking high doses of ICSs and LABAs, the addition of tiotropium bromide provided improvements in FEV1, reduced as needed use of short acting β2-agonists and modestly reduced the risk of a severe exacerbation

Slow release Theophylline

Novel targeted therapies that may be of benefit for patients with severe asthma include antiTh2 targets such as antiIL5 antibody, mepolizumab; antiIL5Rα antibody, benrazilumab; antiIL13 antibody, lebrikuzimab and antiIL4Rα antibody, dupilumab. These treatments will likely be targeted towards patients with an eosinophilia, and in some cases towards patients who express high levels of Th2 biomarkers, such as serum periostin.

Bronchial thermoplasty

Preliminary investigations with radiofrequency ablation of airway smooth muscle have offered a novel promising treatment option in severe refractory asthma. Several studies showed improved pulmonary function testing, airway hyper-responsiveness, asthma-related quality of life and symptom scores. No clinical complications were observed in the long run, and pulmonary function remained stable over a period of 5 years. Therefore, this approach might be a reasonable option for patients with difficult asthma not responding to current treatment.

REFERENCES

1.

Chung KF, Wenzel SE, Brozek Jl et al. International ERS/ ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014; 43:343-73.

2. Wener RR, Bel EH. Severe refractory asthma: an update.

Eur Respir Rev 2013; 22:227-35.

3. Kerstjens HA, Disse B, Schro der-Babo W, et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J Allergy Clin Immunol 2011; 128:308–314.

4.

Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med 2012; 367:1198–1207.

These are poor bronchodilators as compared to β2agonists and therefore the latter are preferred. However when patient has severe asthma, these are also used.

5. Flood-Page P, Swenson C, Faiferman I, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med 2007; 176:1062–1071.

Anti IgE Therapy

6. Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011; 365:1088–1098.

In patients with allergic asthma and an elevated IgE level, administration of the monoclonal antibody against IgE, omalizumab, can result in •

Decreased airway inflammation

•

Improved asthma control and

•

May allow tapering of corticosteroid medications.

The dose and frequency of injections are determined by serum IgE level and weight. This medication is given subcutaneously every 2 or 4 weeks. Treatment for a minimum of 12 week is recommended before assessing the response.

Macrolides

The role of microorganisms such as Chlamydia and Mycoplasma remains a subject of debate, both in exacerbations and in the chronicity of bronchial asthma.

Clarithromycin seems to play a beneficial role as an antiinflammatory agent in infectious and predominantly neutrophilic asthma.

221

7. Castro M, Mathur S, Hargreave F, et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med 2011; 184:1125–1132.

8. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, shamcontrolled clinical trial. Am J Respir Crit Care Med 2010; 181:116–124.

9. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med 2011; 11:8.

10. Le AV, Simon RA. The Difficult-to-Control Asthmatic: A Systematic Approach. Allergy Asthma Clin Immunol 2006; 2:109-16.

CHAPTER 49

Numerous studies have documented that the addition of salmeterol or formoterol to inhaled corticosteroid therapy improves asthma control more than increasing or doubling the dose of corticosteroids.

Novel Therapies

Newer Therapies in COPD

C H A P T E R

50

Prem Parkash Gupta

INTRODUCTION

Chronic Obstructive Pulmonary Disease (COPD), a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute significantly to the overall severity in individual patients.

COPD affects nearly 8% of the worldâ&#x20AC;&#x2122;s population concerning 160 million people. COPD is a leading cause of morbidity and mortality worldwide and results in an economic and social burden that is both substantial and increasing. The prevalence of COPD is directly related to the prevalence of tobacco smoking (being the strongest risk factor ever known), although, outdoor, occupational and indoor air pollution are also major COPD risk factors.

The burden of COPD is likely to increase in the coming decades due to continued exposure to COPD risk factors and due to increased life expectancy. A varying degree of inhalational injury & genetic susceptibility lead to phenotypic heterogeneity - a hallmark of COPD.

THERAPEUTICS IN COPD

The management of COPD encompasses preventative measures, pharmacological treatment, nonpharmacological management, and surgical options in appropriate patients (Table 1). Smoking cessation is the only intervention established to influence the natural history of COPD. Various forms of nicotine replacement

Table 1: Management of COPD Management subtype

Modality

Preventative

Smoking cessation Avoidance of toxic exposures Improvement in airways pollution

Pharmacological

Established drugs recommended by guidelines Newer drugs

Nonpharmacological

Supplemental oxygen Pulmonary rehabilitation

Surgical

Lung volume reduction surgery, Endoscopic lung volume reduction Lung transplantation.

therapies are available for the patients with difficulties in smoking cessation like withdrawal symptoms. In some countries, influenza and pneumococcal vaccinations are also recommended as a preventive therapy as a part of National Guidelines.

PHARMACOTHERAPIES ESTABLISHED IN VARIOUS GUIDELINES

Primary intention of any pharmacological therapy in COPD is to reduce symptoms, decrease the frequency and severity of exacerbations, and improve health related quality of life status and exercise tolerance. COPD medicines available presently have not been conclusively shown to modify the long-term decline in lung function that is the hallmark of this disease. The recommended medications as per Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines (2016) are mentioned in tabular form in Table 2.

Inhaled bronchodilator therapy is uniformly accepted across numerous Guidelines as a first-line therapy for symptomatic COPD, in contrast to asthma where the anti-inflammatory properties of inhaled corticosteroids warrant them as the first-line therapy. Inhaled bronchodilators in COPD have been shown to improve dyspnea, exercise performance, and overall health status.

They are also found to be useful in reducing acute COPD exacerbations. The improvement in exercise performance carries potential benefit of an active life often debilitated in severe COPD patients. Exacerbations are uncomfortable and distressing to people with COPD, and often reduce health related quality of life. A reduction of exacerbations is also having significant impact on health status, health care expenditure, exercise performance, and survival.

The accumulated data across various studies suggests the beneficial effect of bronchodilator therapy in term of disease progression in COPD possibly due to a significant reduction in exacerbations thereby portending a mortality benefit. Inhaled corticosteroids are recommended in severe persistent COPD (forced expiratory volume in 1 second [FEV1] < 50% of predicted). They are usually combined with a LABA as additional benefits include an improvement in pulmonary function and reduction in frequency of exacerbation; it is hypothesized that a reduction in airway inflammation and bronchial wall edema account for pulmonary function improvement.

Group wise treatment in COPD as recommended by GOLD Guidelines is shown in Table 3. The selection of a particular drug amongst its class is largely guided by

Table 2: GOLD recommended COPD Medications Beta2-agonists Short-acting beta2-agonists Fenoterol Levalbuterol Salbutamol (albuterol)

of this disease and for prevention of its progression have been identified. Many of new molecules are under different trial phases and yet to achieve desired acceptance and recommendations. Table-4 enlists some of these promising molecules.

New Long-Acting Long-Acting Muscarinic Antagonists (LAMA) Aclidinium

Tulobuterol

Glycopyrronium

Long-acting beta2-agonists Formoterol Arformoterol Indacaterol Olodaterol

Tiotropium

Glycopyrronium bromide has a relative kinetic selectivity for the M3 versus M2 receptors that facilitates airway smooth muscle relaxation. It has proven bronchodilator effects, and, in comparison with tiotropium, has shown a faster onset of action and achieves a significantly higher FEV1. Glycopyrronium significantly reduces the risk of COPD exacerbations and also improves exercise endurance time. Glycopyrronium was approved in the EU in 2012 and is delivered via a dry-powder inhaler.

Umeclidinium

Umeclidinium

Anticholinergics Short-acting anticholinergics Ipratropium bromide Long-acting anticholinergics Aclidinium bromide Glycopyrronium bromide

Combination short-acting beta2-agonists & Anticholinergic in one inhaler Combination long-acting beta2-agonist & anticholinergic in one inhaler Methylxanthines Aminophylline Theophylline (SR) Inhaled corticosteroids Beclomethasone Budesonide

Umeclidinium bromide has been found to be suitable both as monotherapy and in combination for maintenance use in COPD. Sustained bronchodilatation over a period of 24hour permits once a day therapy. It improves pulmonary function (weighted mean FEV1), breathlessness, and health status. Umeclidinium has been approved by the US FDA since April 2014 as a monotherapy with a dose of 62.5 Îźg once daily. It is formulated as a dry powder to be delivered via an inhaler.

New Long-Acting Beta2-Agonist Monotherapy Indacaterol

the cost, availability in the local market and acceptance by the patient in term of adverse drug reactions/ drug interactions.

Indacaterol has a stronger affinity for β-2 adrenergic receptors and its proven advantages include longer duration of bronchodilatation and faster onset of action with improved cardiovascular safety profile when compared to salmeterol. Indacaterol has been shown to improve health status and exercise enduration time and to reduce COPD exacerbations. The addition of indacaterol to tiotropium synergistically potentiates bronchodilator effect of later. It appears to have low arrhythmogenic potential. Presently, indacaterol has been approved in more than 50 countries for the maintenance treatment of COPD. It was approved in the EU in 2009 and in US in 2011.

The drug is currently available in India as monotherapy as well as a combination with Glycopyrronium.

NEWER THERAPIES FOR COPD

Vilanterol

Fluticasone Combination long-acting beta2-agonists & corticosteroids in one inhaler Systemic corticosteroids Prednisolone Methyl Prednisolone Phosphodiesterase-4 inhibitors Roflumilast

Our understanding of pathophysiology of COPD has reached to new heights during last couple of decades, and as a result new potential targets for the management

Vilanterol trifenatate has a preferential affinity to β-2 adrenoreceptors similar to salmeterol, but with a significantly faster onset of action and a dose-dependent

CHAPTER 50

Salmeterol

Aclidinium bromide has been approved in United States and Europe since 2012 for maintenance therapy of COPD. The clinical trials have observed aclidinium to significantly improve pulmonary function (FEV1), dyspnea, and health status. It is formulated as dry powder and delivered via a multidose inhaler. The drug was well tolerated in patients with COPD due to rapid plasma hydrolysis, which might account for reduced systemic exposure and a lower reported incidence of anticholinergic adverse effects.

Terbutaline

223

224

Table 3: Group wise treatment in COPD as recommended by GOLD Guidelines COPD Patient Groups â&#x2020;&#x2019;

Group A

Group B

Group C

Group D

Recommended first choice of treatment

Short-acting anticholinergic as needed

Long-acting anticholinergic

Inhaled corticosteroid + longacting beta2-agonist

or

Long-acting beta2agonist

Inhaled corticosteroid + long-acting beta2agonist or

Long-acting anticholinergic

PULMONOLOGY

Short-acting beta2agonist as needed Alternative treatment Long-acting anticholinergic or Long-acting beta2agonist

or

Long-acting anticholinergic and long-acting beta2agonist

Long-acting anticholinergic Long-acting anticholinergic and long-acting beta2agonist or Long-acting anticholinergic

or

and/or

Inhaled corticosteroid + longacting beta2-agonist and long-acting anticholinergic or

Inhaled corticosteroid and phosphodiesterase-4 + long-acting beta2-agonist and inhibitor phosphodiesterase-4 or inhibitor Long-acting beta2or agonist Long-acting and anticholinergic and phosphodiesterase-4 long-acting beta2inhibitor agonist

Short-acting beta2agonist and shortacting anticholinergic

or Long-acting anticholinergic and phosphodiesterase-4 inhibitor Other options

Theophylline

Short-acting beta2agonist

Short-acting beta2agonist

Carbocysteine

and/or

and/or

Short-acting anticholinergic

Short-acting anticholinergic

Short-acting beta2agonist

Theophylline

Theophylline

and 24-hour lasting bronchodilatation in patients with COPD. Combination therapy with both fluticasone and umeclidinium has been shown to improve lung function and reduce exacerbations when compared to monotherapy. In US, vilanterol is approved only as a fixed-combination therapy for the maintenance treatment of COPD.

Olodaterol

Olodaterol is reported to have a dose-dependent bronchodilator action lasting up to 24 hours. Olodaterol and formoterol improved FEV1 when compared to placebo; additionally, olodaterol also improved COPD reported symptoms. Studies indicate olodaterol to have a potential role to counter the detrimental effect

N-acetylcysteine

and/or Short-acting anticholinergic, Theophylline

of the Th-17 immune response in the development of COPD. Olodaterol is a relatively safe drug, approved as maintenance treatment in COPD and currently permitted as a monotherapy in over 30 countries.

Abediterol

Early clinical trials indicate that abediterol to be a potent bronchodilator with rapid onset and long lasting action. A higher selectivity to β-2 adrenoreceptors subtype permits better cardiovascular safety and tolerability profile.

NEW COMBINATION THERAPY

New LAMA + LABA Combination Therapy

During the last decade, various combinations of new LAMA and new LABA have been studied; many of them

225

Table 4: New COPD Therapies Group

Drugs

Group

Drugs

New LAMA monotherapy

Aclidinium

New LABA+ICS Combination

Vilanterol & Fluticasone

Glycopyrronium Umeclidinium

Indacterol & Mometasone Formetrol & Ciclesonide Formetrol & Fluticasone

New LABA monotherapy

Indacterol Vilanterol

Triple drug LABA+LAMA+ Tiotropium + Salmetrol + ICS Combination fluticasone

Abediterol New LAMA+ LABA Combination

Umeclidinium & Vilanterol Oral Medications

Roflumilast

Glycopyrronium & Indacterol

Simvastatin N-acetylcysteine

Tiotropium & Olodetrol Aclidinium & Formoterol Glycopyrrolate & Formoterol

terms of both efficacy and tolerability. Formoterol and fluticasone has been approved in Japan and European Union for GOLD groups C and D.

Triple LABA-LAMA-ICS therapy

Fig. 1: Role of phosphodiesterase (PDE) inhibitors in COPD were found to be promising and approved in various countries. Umeclidinium and vilanterol combination has been approved in US and European Union for GOLD groups C and D. The combinations of glycopyrronium and indacaterol as well as that of aclidinium and formoterol have been permitted in European Union for GOLD groups C and D.

New LAMA + ICS Combination Therapy

The combinations of LABA and ICS have been reported to have synergistic effects. ICS potentiates LABA effects by preventing the reduction of cell surface expressed β-receptors - a hallmark of airway inflammation. On the other hand, LABA has steroid-sparing, anti-inflammatory and antiproliferative properties. The Cochrane metaanalysis suggests ICS/LABA combination to have significant improvement in both the SGRQ and FEV1 compared to LAMA, LABA, and ICS therapy alone.

The combination of vilanterol and fluticasone has been permitted in US and European Union for GOLD groups C and D. Formoterol and ciclesonide combination was found to be noninferior to fluticasone & salmeterol in

Triple therapy has been observed to be associated with a 40% reduction in mortality compared with ICS/ LABA combination and improve lung function and health related quality of life compared to tiotropium monotherapy. GOLD 2013 update recommends the use of triple therapy in patients with COPD group D. Currently, there are several inhaled therapy containing LAMA + LABA + ICS combinations undergoing clinical trials, including glycopyrronium + formoterol + budesonide, umeclidinium + vilanterol + fluticasone, and tiotropium + formoterol + ciclesonide.

Phosphodiesterase Inhibitors Roflumilast- Oral Phosphodiesterase Inhibitors

Oral phosphodiesterase (PDE) inhibitors have been shown to suppress the activation of inflammatory cells, modulate the activity of pulmonary nerves, and relax smooth muscle (Figure-1). Roflumilast has been observed to improve FEV1 comparable to ICSs in clinical trials, but not found to be consistently efficacious in term of reduction in frequency of exacerbation and quality of life.

Roflumilast as a selective PDE4 inhibitor is recommended in US and European Union for treatment in severe COPD associated with frequent exacerbations. The safety profile of roflumilast still limits its use only in advanced COPD as an add-on therapy.

Inhaled Phosphodiesterase Inhibitors

Dual PDE3 and PDE4 inhibitors, such as RPL554 and the PDE4 inhibitor CHF6001, are under trial phase in asthma and COPD. CHF6001 was shown to be more potent than roflumilast. In four exploratory studies, inhaled RPL554 was found to be an effective and well-tolerated bronchodilator as well as anti-inflammatory drug.

CHAPTER 50

Glycopyrronoum + Formoterol + Budesonide

Olodaterol

226

TARGETED DRUG THERAPY IN COPD

CXCR2 Antagonists

Antagonists of the human CXCR2 receptors target neutrophil trafficking in COPD inflammatory pathway.

MK-7123, a CXCR2 antagonist, is being investigated in Phase II clinical trials and has shown significant improvement in FEV1 compared to placebo in patients with COPD.

PULMONOLOGY

P38 Mitogen-Activated Protein Kinase (P38 MAPK) Inhibitors

P38 mitogen-activated protein kinase pathway involves a signaling cascade controlling cellular responses to cytokines and stress. Table-5 represents the various molecules under study. The molecule PH-797804 studied had shown improvements in dyspnea symptom index and FEV1. Losmapimod (GW856553X) the other potent oral p38α/β MAPK inhibitor, is in a phase II clinical trial for the treatment of COPD. The efficacy and safety of two inhaled p38 MAPK inhibitors, RV-568 and PF-03715455 are under various phases of clinical trials. Inhaled delivery of p38 MAPK inhibitors may enhance p38 inhibition in the lung while reducing unwanted systemic effects.

Selective Matrix Metalloproteinases (MMP) Inhibitors

As we know COPD is an inflammatory disorder in which protease and antiprotease imbalance plays an important role, antagonizing matrix metalloproteinases (MMP) with selective MMP inhibitors provided an option to revert back to this fine balance. The search for ideal drug in this group goes on; some of the studied molecules are listed in Table-6.

Table 5: P38 Mitogen-Activated Protein Kinase (P38 MAPK) Inhibitors Drug

Group

Present status

PH-797804

Oral p38 MAPK inhibitor

Phase II trials of this agent have recently been discontinued.

Oral p38α/β MAPK inhibitor

Phase II human clinical trial

Acumapimod

Orally p38 MAPK inhibitor

Active development

RV-568

Inhaled p38 Evaluated in MAPK inhibitors clinical trials

PF-03715455

Inhaled p38 Evaluated in MAPK inhibitors clinical trials

GW856553X/ Osmapimod

Humanized monoclonal antibodies targeted to alpha subunit of the interleukin (IL)-5 receptor (IL-5Rα)

The interlukin (IL) -5 receptor is composed of an α and a βc chain, α subunit has affinity for IL-5 only whereas βc subunit has affinity for IL-5, IL-3 and Granulocytemacrophage Colony-stimulating Factor (GM-CSF).

Humanized monoclonal antibodies targeted to alpha subunit of the interleukin (IL)-5 receptor (IL-5Rα) selectively blocks IL-5 (Table 7). This action is particularly beneficial in management of asthmatic inflammation as well as COPD exacerbations. Soluble IL-5Rα is also found to be increased during virus-induced COPD exacerbations.

Antihuman IL-17R Antibodies

Interlukin (IL) -17A has been found to induce neutrophilic inflammation by releasing CXCL1, CXCL8 and GM-CSF from airway epithelial cells and smooth-muscle cells. IL17A can induce IL-6 expression in bronchial epithelial cells and fibroblasts. IL-17A is involved in human airway smooth-muscle contraction. Th17 cells also mediate glucocorticoid-resistant airway inflammation and airway hyperresponsiveness. Antihuman IL-17R antibodies including Ixekizumab, Brodalumab and Ustekinumab are under trial for possible clinical efficacy in asthma and COPD.

Phosphoinositide 3-kinases (PI3K) Inhibitors

The phosphoinositide 3-kinases (PI3K) are a family of proteins that are involved in the control of intracellular signaling pathways.

Phosphoinositide 3-kinases inhibitors prevent recruitment of inflammatory cells including t-lymphocytes and neutrophils, prevent release of proinflammatory mediators, and also may restore steroid effectiveness. One molecule with promising phosphoinositide 3-kinases inhibitor property is GSK2269557, which is being further evaluated.

CONCLUSIONS

During last decade, a large number of molecules have been investigated for possible potential to be used in treatment of COPD; increasing numbers of therapeutic agents may appear confusing but brings new optimism for COPD management. With current knowledge, it is perhaps advisable to recommend: 1. SABA & SAMA will continue to be necessary for the relief of intermittent symptoms and for use as rescue medication.

2. LABA and LAMA are suitable as maintenance (daily) treatment in patients with persistent symptoms.

Table 6: Selective Matrix Metalloproteinases (MMP) Inhibitors under study Drug/ Molecule

Group

Action

Status

AZ11557272

Dual MMP9–MMP12 inhibitor

Prevent emphysema, small airway fibrosis, and inflammation in guinea pigs

Clinical development has recently been stopped

AZD1236

Orally Dual MMP9–MMP12 inhibitor

Failed biomarker endpoints, initial promising results

Further development aborted

Table 7: Humanized monoclonal antibodies targeted to alpha subunit of the interleukin (IL)-5 receptor (IL-5Rα) Status

Action

Benralizumab

Phase III development

Reduce COPD exacerbations and improve symptoms in patient with higher blood eosinophils Improvement in lung functions, and diseasespecific health status

Mepolizumab

Phase III development

Approved by the U.S. FDA in severe asthma EU in December 2015

3. After cost of therapy reduces to sensible level, UltraLAMA and Ultra-LABA appear tempting due to once daily convenience and lesser adverse reactions as claimed by their developers.

4. Patients with COPD Group D or with Asthma-COPD Overlap Syndrome may be ideal for triple-inhaler therapy (LABA+LAMA+ICS).

5. Frequent exacerbators COPD patients, those with lower respiratory tract bacterial colonization, or those with coexistent bronchiectasis may achieve beneficial efficacy with selective PDE4 inhibitor and/or longterm antibiotic prophylaxis.

FUTURE ANTICIPATIONS

Patients with uncontrolled disease despite taking both LAMA and LABA would likely be referred for specialist evaluation at a dedicated COPD centre in hopes to identify a specific COPD phenotype that might be suitable for specific and tailored targeted therapeutic pharmacotherapy. Of course, the objectives shall remain to reduce symptoms, to prevent and reduce the number

227

REFERENCES

1. Vestbo J, Hurd SS, Agustí AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.

Am J Respir Crit Care Med 2013; 187:347-65.

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Eisner MD, Anthonisen N, Coultas D, et al. An official American Thoracic Society public policy statement: Novel risk factors and the global burden of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010; 182:693718.

3. Tashkin DP, Fabbri LM. Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents. Respir Res 2010; 11:149.

4. Kornmann O, Dahl R, Centanni S, et al. Once-daily indacaterol versus twice-daily salmeterol for COPD: a placebo-controlled comparison. Eur Respir J 2011; 37:273-9.

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Nannini LJ, Cates CJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease.

Cochrane Database of Systematic Reviews 2007; 4: Art. No.: CD003794.

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Joos GF. Potential for long-acting muscarinic antagonists in chronic obstructive pulmonary disease. Expert Opin Investig Drugs 2010; 19:257-64.

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Cazzola M, Page CP, Rogliani P, Matera MG. β2-agonist therapy in lung disease. Am J Respir Crit Care Med 2013; 187:690-96.

8. Tashkin DP, Ferguson GT. Combination bronchodilator therapy in the management of chronic obstructive pulmonary disease. Respir Res 2013; 14:49.

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Matera MG, Page C, Cazzola M. PDE inhibitors currently in early clinical trials for the treatment of asthma. Expert Opin Investig Drugs 2014; 23:1267-75.

10. Caramori G, Adcock IM, Di Stefano A, Chung KF. Cytokine inhibition in the treatment of COPD. Int J Chron Obstruct Pulmon Dis 2014; 9:397-412.

11. Khorasani N, Baker J, Johnson M, Chung KF, Bhavsar PK. Reversal of corticosteroid insensitivity by p38 MAPK inhibition in peripheral blood mononuclear cells from COPD. Int J Chron Obstruct Pulmon Dis 2015; 10:283-91.

CHAPTER 50

Drug

of exacerbations, to prevent the rapid decline in lung function, to achieve reversal of corticosteroid insensitivity and to control the fibrotic progression while reducing the emphysematous process.

C H A P T E R

51

DEFINITION

The interstitial lung diseases (ILD) are a group of disorders that predominantly, but not exclusively involve the lung interstitium. The term ILD is imprecise clinical term for a diverse range of diseases that involve inflammation and fibrosis of the alveoli, distal airways, and septal interstitium of the lungs. The lungs are affected in three ways. The lung tissue is damaged in some known or unknown way, followed by inflammation of the alveolar wall, and finally there is fibrosis in the interstitium that results in end stage lung. The stiff lungs cause a restrictive type of functional abnormality and affect gas exchange.

The prevalence of ILD in several countries has increased over time. The causes of ILD are many. Despite significant improvement in our knowledge of pathogenesis of ILD, the etiology of a large number of cases remains unknown and these are called the idiopathic interstitial pneumonias (IIPs). Idiopathic pulmonary fibrosis (IPF) is the commonest example of this group.

DIAGNOSIS OF ILD (BOX 1)

Clinical Features

Dry cough and dyspnoea are the main symptom of ILD. Symptoms of the associated disorders like RA, scleroderma, sarcoidosis may be present. When the disease is severe and prolonged, symptoms of right heart failure may occur. Clubbing is a feature of IIPs. Pallor due to anemia of chronic inflammation may also be present in most cases. Raynaud’s phenomenon, sclerodactyly, and telangectasia are seen with the CTD. Skin, eye, bone and joint involvement and hepato-splenomegaly are features of sarcoidosis. The findings of respiratory system examination are fine, bibasilar, and end inspiratory crackles also called “velcro rales”.

Interstitial Lung Diseases Ketaki Barve, Jyotsna M Joshi

Investigations

Chest X-ray, pulmonary function tests, and blood tests are important baseline tests. High-resolution computerized tomography (HRCT) is an important new diagnostic tool in the evaluation of ILD. Lung biopsy, trans-bronchial (TBLB) or open (OLB) may be required for diagnosis and to predict response to therapy in some cases. To monitor disease progression and response to therapy symptoms, PFT and 6 MWT are used.

Laboratory Tests

The routine laboratory tests are not very useful for diagnosis of ILD except in few cases. Total and differential white cell count (WBC) to diagnose eoninophilia, along with liver and renal function tests should be performed in all cases of ILD. Rheumatoid arthritis (RA) factor, lupus erythematosus (LE) cells, antinuclear antibody (ANA) anti double stranded DNA (dsDNA) are positive in collagen vascular disorders and also in cases of IPF. Positive cytoplasmic anti neutrophilic cytoplasmic antibody (C-ANCA) is diagnostic for WG. Serum angiotensin converting enzyme (SACE) is positive in 75% of cases of sarcoidosis but is neither specific nor useful for monitoring response to therapy.

Chest Radiograph

The chest radiograph helps to confirm the clinical diagnosis and in some cases certain radiographic patterns (Box 2) are helpful in establishing a specific diagnosis.

The chest radiographs in cases of ILD typically show an “interstitial” pattern (Figure 1) .

Box 1: Diagnosis of ILD • • • • • • •

Dry cough Progressive dyspnoea Exercise desaturation Clubbing Fine, bibasilar, end inspiratory (“Velcro”) crackles CXR showing reticular/ nodular opacities Spirometry showing restrictive abnormality, reduced DLCO • Features of associated disorders like RA, SLE, SS, sarcoidosis • Later stages features of right heart failure

Fig. 1: X-ray chest showing interstitial lung disease

Box 2: Helpful Chest Radiograph Patterns • Upper zone predominance: hypersensitivity pneumonitis, sarcoidosis, silicosis, coal workers pneumoconiosis, berylliosis, ankylosing spondylitis, rheumatoid arthritis, radiation fibrosis and drug induced (gold, amiodarone) • Lower zone predominance: asbestosis, scleroderma, IPF • Miliary pattern: miliary TB, metastasis from adenocarcinoma, malignant melanoma, hypernephroma

• Pleural involvement: RA, SLE, scleroderma and mixed connective tissue disorders, asbestosis, lymphangitis carcinomatosis, drug induced ILD (nitrofurantoin), sarcoidosis (rare), and radiation pneumonitis ( due to lymphatic blockage)

High Resolution Computed Tomography (HRCT)

The HRCT is a most useful diagnostic test available for evaluation of ILD. The findings are sufficiently specific in some cases to be diagnostic. It is also useful to assess the extent of pulmonary, pleural and mediastinal involvement and to guide lung biopsy.

Pulmonary Function Tests and Arterial Blood Gas (ABG) Analysis

Simple spirometry is adequate for initial evaluation and subsequent follow up. Reduced forced vital capacity (FVC) with a normal ratio of forced expiratory volume in 1 second (FEV1) to FVC (FEV1 /FVC) suggests a restrictive abnormality. Diffusion capacity of lung for carbon monooxide (DLCO) is reduced.

Electrocardiography (ECG) and Echocardiography (ECHO)

The findings of p pulmonale, right axis deviation, R /S ratio >1 in V1, ST depression and T wave inversion in V1-V4, and incomplete or complete right bundle branch block on electrocardiography (ECG) identify presence of pulmonary hypertension and cor pulmonale. 2-D ECHO should be performed to confirm pulmonary hypertension and cor pulmonale.

Tuberculin Skin Test (TST)

Tuberculin Skin Testing or Mantoux (MT) testing is important for several reasons in cases of ILD. It may serve as an aid to diagnosis of miliary TB, although in these cases it is often negative due to anergy. Negative MT test supports the diagnosis of sarcoidosis although reports from India suggest that positive test is not incompatible with the diagnosis of sarcoidosis. Positive test is important to initiate isoniazid (INH) prophylaxis along with corticosteroid therapy in cases of ILD. In cases of sarcoidosis a nodule may develop at the site of MT test at 6 to 8 weeks, which can be used for histological confirmation.

TREATMENT OF INTERSTITIAL LUNG DISEASES

The most important aspect of treatment of the ILD is

229

Idiopathic Interstitial Pneumonias (IIPs)

When all known causes of interstitial lung disease have been ruled out, the condition is called idiopathic interstitial pneumonias (IIP). Idiopathic Pulmonary Fibrosis (IPF) is the most common variety of the IIPs. It is classified as UIP (usual interstitial pneumonitis), DIP (desquamative interstitial pneumonitis) and NSIP (nonspecific interstitial pneumonitis). AIP (acute interstitial pneumonia) is a rapid fulminant form of IIP with poor response to therapy and about 90 % mortality.

A correct histological classification is of utmost importance based on the fact that prognosis and survival vary largely depending on the subset of IIP. Pathologybased diagnoses are, however, only available in a minority of patients with IIP, since the majority do not undergo surgical lung biopsy. Conversely, it has been shown that high-resolution computed tomography (HRCT) scanning, in particular, but also other clinical features, may be of discriminative diagnostic value. Therefore, integrated clinical, radiological and histological classifications and definitions are mandatory. In response to this, the American Thoracic Society (ATS) and the European Respiratory Society (ERS) recently (2013) published an international consensus statement on IIP (Box 3). The characteristic histopathological features of UIP are a heterogeneous appearance with alternating areas of normal lung, interstitial inflammation, fibrosis, and honeycombing. The changes are most severe subpleurally and there is temporal heterogeneity such that the pathological processes are at different stages of development. The term IPF is now restricted to the specific condition characterised by the histopathological pattern of UIP. The different types of IIP need to be recognized because of important implications of treatment and prognosis.

DuBois has raised the issue of “discordant” pathology.

This concept pertains to 2 different pathologies, usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonitis (NSIP), being found in the same patient who has been biopsied (appropriately) at multiple sites.

In such situations, patients behave as if they have the worst of the 2 diagnoses, and UIP becomes the default diagnosis. The characteristic features of IPF are dry cough and progressive dyspnoea usually of some year’s duration, clubbing and bibasilar crackles. The chest radiograph shows a reticulonodular pattern predominant at lung bases. This may be associated with reduction of lung volumes and later typical “honey comb” lung.

CHAPTER 51

• Hilar/ mediastinal lymphadenopathy: sarcoidosis, miliary TB, lymphoma, lymphangitis carcinomatosis, berylliosis

early diagnosis and removal of the offending / inciting agent, if identifiable. Specific treatment can be offered in cases of infective etiology e.g. TB. Early treatment with corticosteroids to reverse the inflammation is vital. In advanced cases symptomatic treatment to provide relief, preventive vaccines to reduce pulmonary infections, oxygen therapy and physical and occupational rehabilitation can be offered to the patients. Lung transplantation (single or double) can be performed in end stage lung, if facilities for the same are available.

230

Box 3: Revised Classification of IIP (ATS/ERS13)

Box 4: Indications for Lung Biopsy in Interstitial Lung Disease

Major Idiopathic Interstitial Pneumonia

• Age <65 years

Chronic Fibrosing IP: IPF and Fibrotic NSIP

• Presence of systemic symptoms like fever and weight loss

Smoking –related IP: RBILD and DIP Acue/Subacute IP: COP and AIP Rare Idiopathic Interstitial Pneumonia Idiopathic lymphoid interstitial pneumonia

PULMONOLOGY

Idiopathic pleuroparenchymal fibroelastosis Rare histological variants Acute fibrosing organising pneumonia(AFOP) Airway centered interstitial fibrosis (ACIPF) Unclassifiable Idiopathic Interstitial Pneumonias Evidence of pulmonary hypertension and cor pulmonale may be present in the form of enlargement of the right descending pulmonary artery and the cardiac size.

High resolution computed tomography (HRCT) findings are characteristic. These are presence of ground glass opacification suggestive of alveolitis along with simultaneous presence of fibrosis and honey combing.

This feature where different stages of disease active and inactive are present simultaneously is called as loss of temporal relationship and is typical of UIP/IPF. The distribution of lesions is typically subpleural and in the lower lobes (Figure 2). In advanced disease “honey comb” cysts are seen throughout the lungs (Figure 3a and 3b).

These features are also seen in AIPF and asbestosis, which can be excluded by history and clinical examination.

Pulmonary function test (PFT) must include spirometry and shows a restrictive abnormality indicated by reduced FVC with a normal FEV1 /FVC. DLCO is reduced though this is not diagnostic. Reduction in arterial oxygen PaO2 as also increase in alveolar arterial gradient (PAO2PaO2) particularly after exercise is commonly seen. Post exercise oxygen desaturation has been demonstrated to predict survival.14 2-D ECHO with colour Doppler should be performed to assess pulmonary hypertension and cor pulmonale, if possible. Lung biopsy, transbronchial (TBLB) or open (OLB) may be required under certain circumstances (Box 4).

Treatment of UIP/IPF the most common variety of IIP (ATS/ERS/JRS/ALAT Statement 2011) incorporates the antifibrotic molecules Pirfenidone and Nintedanib.

These have largely replaced the previous therapy involving steroids and immunosupressants. This radical change is based on the recent insights pertaining to that pathophysiology of the condition which emphasizes underling oxidative stress and pulmonary fibrosis as the culprits rather than inflammation as previously believed. Treatment of pulmonary hypertension in IPF is controversial because of scarce evidence available regarding its efficacy. Pulmonary rehabilitation, oxygen therapy and lung transplantation have a documented beneficial role in terms of improvement in the quality of life. No therapy has shown to have proven favourable

• Extrapulmonary manifestations like hemoptysis, peripheral vasculitis and unexplained pulmonary hypertension • Absence of family history • Atypical radiographic features like nodular or patchy opacities superimposed on interstitial pattern, hilar or mediastinal lymphadenopathy, pleural effusion or rapid progression of lesions • Rapid deterioration of pulmonary functions. effects as far as survival is concerned. However, some IIPs such as NSIP and DIP may respond well to therapy with oral corticosteroids e.g. prednisolone given in the dose of 1 mg/kg/day.

Follow up of cases is best done clinically and by spirometry. Response to treatment is defined in terms of change in PFT as follows i) Improved if increase of >10% in FVC or TLCO without decrease of >10% in either ii) Unchanged if increase or decrease by, 10% in FVC and DLCO; or increase of >10% in FVC or DLCO with decrease of >10% in the other and iii) Worse if decrease of >10% in FVC or DLCO without increase of >10% in either.

Oxygen therapy should be prescribed for some patients with IPF, particularly those cases with hypoxaemia at rest, presence of pulmonary hypertension and cor pulmonale and exercise induced or nocturnal desaturation.

Pneumococcal vaccine and yearly influenza vaccine may help prevent infections. Pulmonary rehabilitation and education programs help to improve the quality of life. Although, currently not available in India, lung transplantation offers hope for selected people with severe IPF and other advanced ILDs. The Gender Age Physiology (GAP) risk assessment system is a clinical prediction tool that estimates prognosis in patients with IPF (GAP-IPF) and ILDs (ILD-GAP).

ACUTE EXACERBATION OF IPF

Some patients of IPF suffer from acute deteriorations of unknown etiology with periods of relative stability.

These have been termed acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. Clinical features consist of cough, fever, and flulike symptoms severe hypoxemia, and respiratory failure that may require mechanical ventilation. Treatment of acute exacerbation of IPF has generally consisted of high-dose corticosteroids, but there are no data from controlled trials to prove their efficacy. Mortality rates range from 20 to 86%.

REFERENCES

1.

Hutchinson J, Fogarty A, Hubbard R, McKeever T. Global incidence and mortality of idiopathic pulmonary fibrosis: A systematic review. Eur Respir J 2015; 46:12.

2.

Vij R, Strek ME. Diagnosis and Treatment of Connective Tissue Disease-Associated Interstitial Lung Disease. Chest 2013; 143:814-824.

3.

Travis WD, Costabel U, Hansell DM. An official american thoracic society/european respiratory society statement: Update of the international multidisciplinary classification or the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013; 188:733–748.

5.

Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK et al. An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management. Am J Respir Crit Care Med 2011; 183:788–824.

231

7. Bradley B, Branley HM, Egan JJ, Greaves MS, Hansell DM, Harrison NK, et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax 2008; 63 Suppl 5:v1-58.

8.

Ley B, Ryerson CJ, Vittinghoff E, Ryu JH, Tomassetti S, Lee JS et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med 2012;156:684-691. Wells A U, Kokosi M, Karagiannis K. Treatment strategies for idiopathic interstitial pneumonias.

Curr Opin Pulm Med 2014; 20:442–448

9.

Ley B, Ryerson CJ, Vittinghoff E, Ryu JH, Tomassetti S, Lee JS, et al. A Multidimensional Index and Staging System for Idiopathic Pulmonary Fibrosis. Annals of Internal Medicine Ann Intern Med. 2012; 156:684-91.

10. Ryerson C, Vittinghoff E, Ley B, Lee J, Mooney J, Jones K et al. Predicting Survival Across Chronic Interstitial Lung Disease. Chest 2014; 145:723-728.

CHAPTER 51

4. Mueller-Mang C, Grosse C, Schmid K, Stiebellehner L, Bankier AA. What every radiologist should know about idiopathic interstitial pneumonias. Radiographics 2007; 27:595-615.

6. Maheshwari U, Gupta D, Aggarwal AN, Jindal SK. Spectrum and diagnosis of idiopathic pulmonary fibrosis.

Indian J Chest Dis Allied Sci 2004; 46:23-6.

C H A P T E R

52

Fungal Infection in the Lung

INTRODUCTION

Pneumonia is the leading infectious cause of death in developed countries1, 2. Though the fungal cause of pneumonia occupies a minor portion in the immunecompetent patients, but it causes a major role in immunedeficient populations.

Fungi may colonize body sites without producing disease or they may be a true pathogen, generating a broad variety of clinical syndromes.

Fungal infections of the lung are less common than bacterial and viral infections and very difficult for diagnosis and treatment purposes. Their virulence varies from causing no symptoms to death. Out of more than 1 lakh species only few fungi cause human infection and the most vulnerable organs are skin and lungs3, 4.

RISK FACTORS

Workers or farmers with heavy exposure to bird, bat, or rodent droppings or other animal excreta in endemic areas are predisposed to any of the endemic fungal pneumonias, such as histoplasmosis, in which the environmental exposure to avian or bat feces encourages the growth of the organism. In addition, farmers and gardeners are at higher risk of acquiring sporotrichosis because of their chance of cuts or puncture wounds while working with soil.

With advances in critical care medicine and introduction of broad-spectrum antibiotics, the incidence of invasive fungal infections in intensive care is on the rise, especially in patients with immunosuppression 5.

Table 1: Fungi causing Pneumonia Endemic fungal pneumonia pathogen Histoplasma capsulatum causing histoplamosis.

Coccidioides immitis causing coccidioidomycosis.

Blastomyces dermatitidis causing blastomycosis.

Paracoccidioides brasiliensis causing paracoccidioidomycosis Opportunistic fungal pneumonia pathogen Candida spp. causing candidiasis Aspergillus spp. causing aspergillosis Mucor spp. causing mucormycosis Cryptococcus neoformans causing cryptococcosis Zygomycetes

Udas Chandra Ghosh, Kaushik Hazra

The following risk factors may predispose to develop fungal infections in the lungs 6 1.

Acute leukemia or lymphoma during myeloablative chemotherapy

2.

Bone marrow or peripheral blood stem cell transplantation

3.

Solid organ transplantation on immunosuppressive treatment

4.

Prolonged corticosteroid therapy

5.

Acquired immunodeficiency syndrome

6.

Prolonged neutropenia from various causes

7.

Congenital immune deficiency syndromes

8.

Postsplenectomy state

9.

Genetic predisposition

EPIDEMIOLOGY OF FUNGAL PNEUMONIA

The incidences of invasive fungal infections have increased during recent decades, largely because of the increasing size of the population at risk. This population includes the patients of cancers of immune cells of the blood, bone marrow, and lymph nodes, and those with human immunodeficiency virus (HIV) infection, as they are immunosupressed.

The basic pulmonary pathologic process again can be broadly classified as (a) allergic manifestation or (b) actual infection 5, 7 TLR1 (Toll like receptors) and TLR6 polymorphisms in the recipient have been associated with susceptibility to invasive aspergillosis after allogeneic stem cell transplantation.5 The invasive fungal infections (termed mycoses) can be divided into two broad categories: endemic mycoses and opportunistic mycoses (Table 1).

True pathogenic or endemic fungi

The endemic pathogens that most frequently infect healthy individuals. True pathogenic fungi produce a different form in tissue or at 37°C in contrast to mycelial form in culture at 25-30°C. These fungi are referred to as dimorphic fungi and include Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, Paracoccidioides brasiliensis, Penicillium marneffei and Sporothrix schenckii. Fortunately, they are not commonly found in the Indian subcontinent and are natural inhabitants

Table 2: ISHAM Diagnostic Criteria for ABPA Predisposing conditions (one must be present): Asthma Cystic fibrosis (CF) Obligatory criteria (both must be present):

These are the most common fungal infections in lung in our country-

PULMONARY ASPERGILLOSIS

According to the lung invasion or allergic response of lung to aspergillus species, the pathogenic reactions in human beings can be varied like 4 1.

Elevated total serum IgE concentration (typically >1000 IU/mL, but if the patient meets all other criteria, an IgE value <1000 IU/mL may be acceptable)

Allergic alveolitis - by inhalation of high density of spores

2.

Allergic broncho pulmonary aspergillosis (ABPA).

3.

Aspergilloma - Colonisation in damaged lung parenchyma.

Precipitating serum antibodies to A. fumigatus

4.

Radiographic pulmonary opacities consistent with ABPA

Invasive Aspergillosis - in immunodeficient individuals.

5.

Mixed syndromes

Other criteria (at least two must be present):

of North and South America. H. capsulatum and B. dermatitidis have a worldwide distribution.

In India, histoplasmosis and blastomycosis are reported from different states, but Penicilliosis marneffei is restricted to Manipur state. There is only one report of systemic sporotrichosis due to S. schenckii var. luriei and represents the only report from an Asian country7,8.

P. marneffei is restricted to south-east Asia possibly remaining with its habitat bamboo rats9,10. Along with emergence of AIDS in India, histoplasmosis is increasingly reported.

Opportunistic fungal infections involve ubiquitous fungi and occur predominantly in individuals whose immune systems are compromised. These include species like Aspergillus, Candida, Cryptococcus and Zygomycetes (big four).6,11 Invasive pulmonary aspergillosis and systemic candidiasis are the most prevalent opportunistic fungal infections. These infections do not follow any particular geographic distribution and are seen with increasing frequency worldwide.

However, recently changes have occurred, and newer pathogens are being recognized especially with the emergence of AIDS. Sometimes, it is not just a single fungus, but rather a combination of fungi i.e. species under Candida, Cryptococcus, Pneumocystis, Histoplasma, Coccidioides, Aspergillus and zygomycetes, which may produce concomitant and/or successive opportunistic systemic fungal infections.

Diagnosis of fungal infections

The diagnosis of this disease entity is based on indirect evidences like

ABPA

This is an immune mediated bronchial pathology, manifested in susceptible individual.

Manifestations are haemoptysis and episodic wheezing, mimicking acute asthmatic episode.

Diagnostic criteria of ABPA11

Although not prospectively validated, we favor the following diagnostic criteria proposed by the International Society for Human and Animal Mycology (ISHAM) working group for ABPA that simplify prior diagnostic schema (Table 2):

Stages of ABPA4,13-15 1.

acute stage

2.

stage of remission

3.

stage of exacerbation

4.

stage of steroid dependent asthma

5.

stage of fibrosis

RADIOLOGICAL PICTURE4,16-18

Chest Xray

Massive areas of consolidation Inflamed vascular and bronchial walls (Tram line shadows) Blocked bronchi with fungal debris (Tooth paste shadows) & gloved finger appearance) Ring shadows (Bronchiectasis) Parenchymal appearance (Nodular shadows) Local areas of atelectesis & emphysema

CT scan bronchogram:

a.

Skin hypersensitivity test

Hallmark is proximal bronchiectasis with distal sparing.

b.

Serological evidence of raised antibody titre

Management of ABPA16,19,20

c.

Convincing demonstration of fungi from body fluids or tissue specimens.

Steroid and Antifungal (Itraconazole or Amphotericin B).

Steroid is used in acute phase with tapering dose till the resolution.

CHAPTER 52

Aspergillus skin test positivity or detectable IgE levels against Aspergillus fumigatus

Total eosinophil count >500 cells/microL in glucocorticoid-naïve patients (may be historical)

233

234

Resolution

Pneumocystis jiroveci Pneumonia23,24

1.

Control of asthmatic attacks

2.

Reduction of IGE level more than 35% with reduction of peripheral eosinophilia

3.

Disappearance of pulmonary opacities

Pneumocystis jiroveci pneumonia (PJP), previously known as Pneumocystis carinii pneumonia (PCP), is still the most common opportunistic infection in HIV positive patients, though the incidence is decreasing.

Typically resolution has been defined as-

PULMONOLOGY

Aspergilloma4

Growth of aspergillus fungal ball inside pre existing pulmonary cavities (e.g. TB, sarcoid, cavities in RA).

Clinical features are characterised byRecurrent Hemoptysis with recurrent respiratory tract infection.

Diagnosis: confirmed by

Chest X ray-mass within cavity with air cresent level on the top, especially in upper lobe (Monods sign) Positive precipitin test to Aspergillus antigen Demonstration of fungal hyphae in respiratory secretions or from tissue specimen.

Raised IgE levels.

Treatment

Only observations for asymptomatic individuals and interventions like bronchial artery embolisation & surgical resection, radiotherapy, systemic antifungal for rest of the patients.

Invasive Aspergillosis

4, 16, 21

It is the dissemination of the fungus aspergillus especially in immune-compromised host by invasion into viable tissue or blood vessels. Clinically characterized by tracheitis, bronchitis and pneumonia.

Pneumocystis is a unicellular fungus.

Before the widespread use of prophylaxis for P jiroveci pneumonia (PJP), the frequency of Pneumocystis infection in lung transplant patients and HIV patients before starting HAART was very high.

The taxonomic classification of the Pneumocystis genus was debated and previously thought to be a protozoan but biochemical analysis of the nucleic acid composition of Pneumocystis rRNA and mitochondrial DNA identified it as a unicellular fungus rather than a protozoan.

Symptoms of PJP includes progressive exertional dyspnea, fever, nonproductive cough, chest discomfort The physical examination findings of PJP are nonspecific and includes tachypnea, tachycardia, and pulmonary symptoms are few mild crackles and rhonchi but otherwise normal findings Diagnosis is done from chest x-ray CT scan thorax, induced sputum by hypertonic saline, broncho alveolar lavage or from tissue specimen. Sputum induction is the quickest and least-invasive method Though it is fungal pneumonia, P jiroveci pneumonia (PJP) does not respond to antifungal treatment. The treatment of choice is TMP-SMX, with second-line agents including pentamidine, dapsone, pyrimethamine, or atovaquone.

Pulmonary mucormycosis4

Diagnosis is confirmed by Chest X-ray (round pneumonia, cavitations) & by broncho alveolar lavage.

Occurs specially in immunocompromised and diabetic patients by granulomatous invasion into upper airways and sinuses with high mortality rate.

Treatment is systemic antifungal drugs (Amphotericin B).

Pulmonary Cryptococcosis4

Chronic necrotising Aspergillosis

It is intermediate form of aspergillloma in immunecompetent patients.

Pulmonary Candidiasis16,22

Opportunistic fungal infections especially in immunecompromised patients, like old mal nourished diabetic patients or in patients with prolonged steroid therapy.

For last 2 decades, there is a change in the distribution of Candida spp. causing nosocomial infections frequently a life threatening complication in patients admitted in ICUs and emerging species are C. tropicalis, C. glabrata, C. parapsilosis, C.krusei, and C. lusitaniae.

Diagnosis is by demonstration of fungus by fibre optic bronchoscopy.

Treatment is by systemic antifungals like ketoconazole, fluconazole and amphotericin B.

Invasive fungal pneumonia of immunocompromised patients from avian excreta through aerosols.

Other invasive pulmonary mycoses which are not very common in our country are histoplasmosis, coccidioidomycosis and para coccidioidosis occurs mainly in laboratory workers, diagnosed by atypical pneumonia with demonstration fungi from broncho alveolar lavage or precipitin tests. Treatment is systemic antifungals.

CONCLUSION

Incidence of fungal pneumonia is increasing in not only immune-deficient but also in immune- competent patients.

Though it is very difficult to diagnose fungal pneumonia by routine investigations, but it should be kept in mind that the known risk factors, history & clinical profile and early treatment may help to prevent significant morbidity and mortality also.

REFERENCES

1.

Kisch B. Forgotten leaders in modern medicine: Valentin,

Gruby, Remark, Auerback. Trans Am Philos Soc 1954; 44:139-317.

2. Ajello L. Systemic mycoses in modern medicine. Contr Microbiol Immunol 1977; 3:2-6.

3.

Singh T, Kashyap AK, Ahluwalia G, Chinna D, Sidhu SS. Epidemiology of fungal infections in critical care setting of a tertiary care teaching hospital in North India: a prospective surveillance study. J Clin Sci Res 2014; 3:14-25 B.N. Panda, Fungal infections of lungs : the emerging scenario. Indian J Tuberc 2004; 51:63-69.

5.

Kobayashi CC, de Fernandes OF, Mirande KC, de Sousa ED, Silva Mdo R. Candiduria in hospital patients: a prospective study. Mycopathologia 2004; 158:49-52.

6.

Chakrabarti A,microbiology of systemic fungal infections.

J Postgrad Med 2005; 51 Suppl 1, page 1

7.

Ranjana KH, Priyokumar K, Singh TJ, et al. Disseminated Penicillium marneffei infection among HIV-infected patients in Manipur state, India. J Infect 2002; 45:268-71.

8.

Padhye AA, Kaufman L, Durry E, et al. Fatal pulmonary sporotrichosis caused by Sporothrix schenckii var. luriei in India. J Clin Microbiol 1992; 30:2492-4.

9.

Denning DW. Invasive aspergillosis. Clin Infect Dis 1998; 26:781-805.

10. Moore RD, Chaisson RE. Natural history of opportunistic disease in an HIV infected urban clinical cohort. Ann Intern Med 1996; 124:633-42.

11. Agarwal R, Chakrabarti A, Shah A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clin Exp Allergy 2013; 43:850.

12. Patterson R, Greenberger PA, Holwig M, Liotta JC,Roberts M. Allergic Broncho Pulmonary Aspergillosis:Natural History and Classification of Early disease by Serological and Roentgenographic studies. Arch Int Med 1986; 916-918.

13. Seaton A, Seaton 0, Leitch AG. Fungal and Actinomycotic Diseases. In: Crofton and Douglas’s Respiratory Diseases 4th Ed. Oxford University Press Delhi 1989; 448-475.

235

15. Davies SF, Saros GA. In: Fungal Infection in Murray JG,Nadel JA, edit Text Book of Respiratory Medicine. WB Saunders Co. Philadelphia: 1994; 1161-1170.

16. Patterson R, Greenberger P, Radin RC, Robert M. Allergic Broncho Pulmonary Aspergillosis - Staging as an aid to Management. Am J Med 1982; 96:286-91.

17. Fraser RS, Pare JAP, Eraser RG, Pare PD. In: Infectious Diseases of Lungs in Synopsis of Diseases of Chest 2nd Ed. WB Saunders & Co; Philadelphia: 1994; 332-54.

18. Cushion MT, Stringer JR. Has the name really been changed? It has for most researchers. Clin Infect Dis 2005; 41:1756-8.

19. Fujii T, Nakamura T, Iwamoto A. Pneumocystis pneumonia in patients with HIV infection: clinical manifestations, laboratory findings, and radiological features. J Infect Chemother 2007; 13:1-7.

20. Denning DW. Invasive aspergillosis. Clin Infect Dis 1998; 26:781-805.

21. Fraser RS, Pare JAP, Eraser RG, Pare PD. In: Infectious Diseases of Lungs in Synopsis of Diseases of Chest 2nd Ed. WB Saunders & Co; Philadelphia: 1994; 332-54.

22. Mohapatra LN, Pande JN. Pulmonary Mycotic Infections.

In: Ahuja MMS, Ed. Progress in Clinical Medicine in India, Heinemann A. New Delhi 1978; 235-39.

23. Cushion MT, Stringer JR. Has the name really been changed? It has for most researchers. Clin Infect Dis 2005; 41:1756-8 24. Fujii T, Nakamura T, Iwamoto A. Pneumocystis pneumonia in patients with HIV infection: clinical manifestations, laboratory findings, and radiological features. J Infect Chemother 2007; 13:1-7.

CHAPTER 52

4.

14. Mc Carthy DS, Simon G, Hargreave E. Radiological Appearance in Allergic Broncho Pulmonary Aspergillosis.

Clinical Radiology 1970; 21:366-375.

C H A P T E R

53

Tropical Pulmonary Eosinophilia

INTRODUCTION

Tropical pulmonary eosinophilia is a distinct syndrome of wheezing, fever, nocturnal cough, and eosinophilia seen predominantly in the Indian subcontinent and other tropical areas like Brazil, Guyana. It results from an immunological hyper responsiveness to filarial parasites in some infected individuals. Its etiological link with Wuchereria bancrofti and Brugia malayi has been well established. It affects males and females in a ratio of 4:1 and often during the third decade of life.

EPIDEMIOLOGY

TPE is endemic in the tropical and subtropical regions of the Indian subcontinent, South East Asia, South America, South Pacific islands and Africa. In India, it is mostly found around the coastal regions from Maharashtra to Kerala and West Bengal to Tamil Nadu. The prevalence of TPE in various settings in India has varied from 0.5 per cent among children in Tamil Nadu to 9.9 per cent among jail inmates in Patna. TPE is seen in only less than 1% of 120 million persons infected with filarial infections worldwide. Due to a tremendous increase in the number of individuals travelling from filarial endemic areas to other parts of the world, TPE has been increasingly reported from countries that are not endemic to filarial infection.

PATHOLOGY

Open lung biopsy studies have demonstrated that three types of histopathological reactions can be seen in TPE: i.

interstitial, peribronchial and perivascular exudates consisting of histiocytes,

ii.

acute eosinophilic infiltrations of interstitial, peribronchial and perivascular tissues and

iii.

a mixed cell type of infiltration consisting of histiocytes, eosinophils and lymphocytes with well-marked interstitial fibrosis. A predominant histiocytic response develops 2 years after the onset of the disease, and ultimately progresses to fibrosis with marked scarring. In some cases, if untreated, a picture resembling fibrosing alveolitis with honeycombing develops in the end stage.

Lung biopsies after 1 month of treatment with DEC demonstrate incomplete histological regression, although symptoms subside within 7 days of therapy, and peripheral eosinophilia returns to normal.

Harpreet Singh

PATHOGENESIS

Adult filarial worms, living in the lymphatics, release the microfilariae which are trapped in the pulmonary circulation; the degenerating microfilariae in the pulmonary circulation then release their antigenic constituents, triggering a local inflammatory process.

Though the lung bears the major brunt of the disease as a result of the trapped microfilariae in the pulmonary circulation, the antigenic material released from the microfilariae can reach the systemic circulation and cause extra pulmonary manifestations. BAL studies have demonstrated an intense eosinophilic inflammatory process in the lower respiratory tract. Eosinophil degranulation products, eosinophil derived neurotoxin (EDN), eosinophilic cationic protein (ECP) and major basic proteins (MBP) have been found to be critical to some of the pathology seen in TPE. The Bm23-25, an IgE inducing antigen of the infective L3 stage larvae of B. malayi has been detected in patients with TPE. There is molecular mimicry between this antigen and the human gamma-glutaryl transpeptidase present on the surface of the pulmonary epithelium. In BAL studies IgE against Bm23-25 has been detected. This may hence play an important role in the pathogenesis of TPE.

CLINICAL FEATURES

The disease occurs predominantly in males, with a male to- female ratio of 4: 1, and is mainly seen in older children and young adults from 15â&#x20AC;&#x201C;40 years of age.

The systemic symptoms include fever, weight loss and fatigue. Respiratory symptoms are paroxysmal cough, breathlessness, wheezing and chest pain. Symptoms occur predominantly at night probably related to the nocturnal periodicity of microfilariae. Sputum is usually scanty, viscous and mucoid, often shows clumps of eosinophils, and Charcot-Leyden crystals are rarely observed. Severe cough can lead to fracture of the ribs.

Bilateral scattered rhonchi and rales may be heard on auscultation. The hallmark of TPE is leucocytosis with an absolute increase in eosinophils (> 3000 eosinophils/ÂľL) in the peripheral blood. Extra pulmonary manifestations include lymphadenopathy, hepatosplenomegaly, pericarditis, pericardial effusion and cor-pulmonale.

Gastrointestinal, musculoskeletal and central nervous system manifestations are also reported in TPE.

CHEST IMAGING CHANGES

The

chest

radiological

features

of

TPE

include

reticulonodular shadows, predominantly seen in mid and lower zones, and miliary mottling of 1–3mm diameter – often indistinguishable from miliary tuberculosis. Normal chest radiographs are observed in 20% of patients. In patients with a long-standing history, a few have honeycomb lungs. Computerized tomography (CT) scan often reveals bronchiectasis, air trapping, lymphadenopathy, cavitation, consolidation or pleural effusions in addition to the miliary mottling and interstitial shadows. Radiologic findings very often regress on treatment with DEC but many patients may show residual changes.

DIFFERENTIAL DIAGNOSIS

Infestations with helminths are the commonest causes of pulmonary eosinophilia in tropical countries. Noninfectious causes of pulmonary eosinophilia include bronchial asthma, acute eosinophilic pneumonia, chronic eosinophilic pneumonia, idiopathic hyper eosinophilic syndrome, cryptogenic pulmonary fibrosis, Wegener’s granulomatosis, lymphomatoid granulomatosis and eosinophilic granuloma of the lung, Churg-Strauss syndrome, and drug hypersensitivity reactions.

Differentiating TPE from eosinophilic pneumonia due to Strongyloides stercoralis is especially important, as corticosteroids which are useful in the treatment of TPE can cause life threatening disseminated strongyloidiasis, particularly in immunocompromised individuals.

Until a diagnostic test is available to differentiate filarial TPE from other TPE-like syndromes, the following diagnostic criteria can be used for the diagnosis of TPE: 1.

Appropriate exposure history (e.g. mosquito bite) in an endemic area of filariasis.

2.

History of paroxysmal nocturnal cough and breathlessness.

3. Chest radiographic infiltrations.

evidence

of

2.

Jai B.Mullerpattan, Zarir F. Udwadia & Farokh E. Udwadia.

Indian J Med 2013;138:295-302.

3.

Manabe, K., Nishioka, Y., Kishi, J., Inayama, M., Aono, Y., Nakamura, and Y.et all Elevation of macrophage derived chemokine in eosinophilic pneumonia: a role of alveolar macrophages. J Med Invest 2005; 52:85–92.

4.

Mylonas, K. J., Nair, M. G., Prieto-Lafuente, L., Paape, D., Allen, J. E. Alternatively activated macrophages elicited by helminth infection can be reprogrammed to enable microbial killing. J Immunol 2009; 182:3084-3094.

5.

Voehringer, D., van Rooijen, N., Locksley, R. M. Eosinophils develop in distinct stages and are recruited to peripheral sites by alternatively activated macrophages. J Leukoc Biol 2007; 81:1434–1444.

6.

Magnaval JF, Berry A. Tropical pulmonary eosinophilia.

Clin Infect Dis 2005; 40:635–636.

7.

Bouree P. Parasite-induced hypereosinophilia [in French].

Presse Med 2006; 35:153–166.

8.

Marti H, Hatz CF. Diagnosis of parasite infections: significance of serological examinations [in German].

Internist (Berl) 2006; 47:788–790.

9.

Gyapong JO, Twum-Danso NA. Editorial: Global elimination of lymphatic filariasis: facts or fantasy? Trop Med Int Health 2006; 11:125–128.

pulmonary

4.

Leucocytosis in blood.

5.

Peripheral blood eosinophils more than 3000 cells/ mm3.

6.

Elevated serum IgE levels.

7.

Elevated serum antifilarial antibodies (IgG and/or IgE).

8.

Clinical response to DEC.

MANAGEMENT

REFERENCES

1. Vijayan VK. Immunopathogenesis and treatment of eosinophilic lung diseases in the tropics. In: Sharma OP, editor. Lung biology in health and disease: tropical lung disease, 2nd ed. New York: Taylor & Francis; 2006. pp. 195– 239.

The standard treatment recommended by the WHO for treatment of TPE is oral Diethylcarbamazine (6 mg/

10. Ottesen EA. Lymphatic filariasis: treatment, control and elimination. Adv Parasitol 2006; 61:395–441.

237

CHAPTER 53

PULMONARY FUNCTION CHANGES

Lung function tests primarily reveal a restrictive ventilation defect with superimposed airways obstruction. The main pulmonary function abnormality in untreated TPE is a reduction in single breath transfer factor for carbon monoxide (TLCO), which has been found to be reduced in 88% of untreated patients.

kg per day) in three divided doses for 3 weeks. Most patients show marked symptomatic and radiographic improvement one month after the start of treatment, and significant improvement in almost all aspects of lung function. A mild alveolitis persists despite treatment.

Treatment with prednisolone significantly reduces lower respiratory tract inflammation and release of oxidants.

Relapses occur in 20% of patients followed-up for 5 years. The persistent mild interstitial lung disease and the high relapse rates in TPE have suggested that repeated monthly courses of DEC at 2–3 monthly intervals for a period of 1–2 years may be useful. TPE can be controlled if the mosquito-borne lymphatic filariasis is eliminated.

The World Health Assembly has resolved to eliminate lymphatic filariasis as a public health problem by the year 2020. The strategy proposed by the WHO to eliminate filariasis is to prevent transmission of parasites through mosquitoes from the blood of infected individuals. The aim is to treat the entire population at risk for lymphatic filariasis through yearly, single-dose treatment with a combination of two drugs (DEC and albendazole) and to continue to cover the reproductive lifespan of adultstage parasites for 4–6 years. The combination regimen can be given in a dosage of 6 mg/kg DEC and 400mg albendazole. A community-based study from Egypt has reported success in such a programme.

C H A P T E R

54

Role of Bronchoscopy in Diffuse Parenchymal Lung Diseases

ABSTRACT

Diffuse parenchymal lung diseases (DPLD) constitute a group of over 200 diverse etiologic entities which present with respiratory symptoms and diffuse lung infiltrates. Flexible bronchoscopy is a useful tool for the early diagnosis of DPLD so that definitive treatment can be instituted and long term outcomes are improved. In immune compromised patients presenting with DPLD, Bronchoalveolar lavage analysis is helpful in establishing diagnosis of infections. Bronchoscopic lung biopsy has a high yield in certain DPLD such as Sarcoidosis, Hypersensitivity pneumonitis, Organizing pneumonias, Eosinophilic pneumonias and Pulmonary alveolar proteinosis.Bronchoscopic biopsy can help in making clinical decisions in majority of DPLD by excluding differential diagnosis such as infections and malignancy.

INTRODUCTION

Diffuse parenchymal lung diseases (DPLD) constitute a group of over 200 diverse etiologic entities (listed in table 1) which present with respiratory symptoms and diffuse lung infiltrates and account for 15% of patients seenby a pulmonaryphysician.1 Bronchoscopy is an important tool in the practice of Pulmonary Medicine in the era of Evidence based medicine. Flexible bronchoscopy gives easy access to respiratory samples for cytological studies and lung tissue for histopathology in DPLD. Lung biopsy studies have unravelled the complex cellular and molecular events in pathogenesis of various types of interstitial lung diseases and have led to development of novel therapeutic agents for idiopathic pulmonary fibrosis.2 Over the last five decades, greater awareness and easy availability of CT thorax and fibreoptic bronchoscopy has led to diagnosis ofdiseases such as sarcoidosis, which were earlier considered to be rare in our country.3 While dealing with DPLD, the aim is to make early diagnosis for institution of definitive treatment and improvement in long term outcomes. The focus of this chapter would be on immense impact that flexible bronchoscopy has made on the diagnosis of DPLD.

BRONCHOSCOPY IN DPLD

Till the development of fibreoptic bronchoscope by Prof Shigeto Ikeda in 1966 treatment of diffuse lung diseases was largely empirical and rigid bronchoscopy was done only in selected cases. First trans-bronchial lung biopsy was obtained through rigid bronchoscopy under general anaesthesia in 1965 and being cumbersome it was infrequently done. Flexible bronchoscopy has

Ajay Handa, Jyothi Ranganathan

revolutionized the practice of pulmonary medicine over the last five decades by providing access to lower respiratory tract in a minimally invasive manner. With better equipment and training in bronchoscopy, expertise of pulmonologists in doing bronchoscopic lung biopsy has increased and complications are very few. As a result, TBLB is the most common lung biopsy submitted for evaluation of DPLD.2,4 Using flexible bronchoscope under local anaesthesia with or without sedation,various lower respiratory cytology and tissue samples can be obtained for diagnosis of DPLD. These include Bronchoalveolar lavage fluid (BAL), bronchial brushings, endo-bronchial biopsy (EBB), bronchoscopic lung biopsy (BLB) andtransbronchial needle aspiration (TBNA) of mediastinal lymph nodes, TBNA with endobronchial ultrasound bronchoscope (EBUS-TBNA). Often in patients with DPLD such as Sarcoidosis and Tuberculosis most or all of the above samples areobtained in the same sitting to increase the diagnostic yield by adding microbiological and molecular tests and saving precious time for diagnosis.

BRONCHOALVEOLAR LAVAGE (BAL)

BAL sample is obtained by wedging the bronchoscope in the segment of maximum radiological abnormality and instilling aliquots of sterile saline (total 100-150 ml) followed by aspiration into a sterile chamber. BAL fluid appearance is helpful for the diagnosis of certain DPLD. Appearance of uniformly hemorrhagic BAL fluid (Figure 1) suggests diffuse alveolar hemorrhage in appropriate settings. Milky BAL (Figure 2) is characteristic of pulmonary alveolar proteinosis. Floating oily layer on top of BAL fluid is suggestive of lipoid pneumonia.

BAL cytology and cellular subtype analysis is helpful in various pulmonary diseases (listed in Table 2). BAL flow cytometry for CD1a positive cells >5% confirms the diagnosis of Pulmonary Langerhansâ&#x20AC;&#x2122; cell histiocytosis.5 BAL fluid sample can be subjected to many microbiological tests including special stains (eg Grams,ZN, PAS, Grocott stains), appropriate cultures (bacterial, fungal, mycobacterial) and molecular testing (eg PCR for mycobacterium tuberculosis, fungal, Pneumocystis jerovecii, CMV etc). The yield of BAL is high (70-80%) in patients with infectious causes of DPLD especially in Immuno-compromised hosts such as post chemotherapy neutropenia, post bone marrow transplantation, solid organ transplant recipients and HIV infection.6

239

Table 1: Classification of DPLD 1.

Idiopathic Interstitial Pneumonias (IIP) :

e.

Sjogren’s syndrome

a.

Usual Interstitial Pneumonia (UIP) -Idiopathic pulmonary fibrosis (IPF)

f.

Mixed connective tissue disease

b.

Non UIP IIP:

g.

Overlap syndrome

i. Non-specific Interstitial Pneumonia (NSIP)

7.

Drug induced DPLD:

ii.

Desquamative Interstitial Pneumonia (DIP)

iii.

Cryptogenic organizing pneumonia (COP)

iv.

Lymphocytic Interstitial Pneumonia (LIP)

v.

Acute Interstitial Pneumonia (AIP)

vi.

a. Amiodarone b. Methotrexate c. Nitrofurantoin Chemotherapeutic drugs (Bleomycin,Busulfan, Paclitaxel, Gemcitabine)

Respiratory bronchiolitis- interstitial lung disease (RB-ILD)

8.

Diffuse alveolar hemorrhage with or without vasculitis :

2.

Granulomatous DPLD:

a.

Pulmonary Sarcoidosis

a. Granulomatosis granulomatosis

b.

Hypersensitivity pneumonitis ( Farmer’s lung, Bird fancier’s lung etc)

b.

Microscopic polyangitis

c.

3.

Occupational DPLD:

Allergic angitis& granulomatosis ( Churg Strauss syndrome)

d.

Systemic lupus erythematosus (SLE)

e.

Good Pasture’s syndrome (Anti Glomerular basement membrane disease)

f.

IgA mediated lung disease

g.

Idiopathic pulmonary hemosiderosis (IPH)

9.

Rare DPLD:

a.

Lymphangioleiomyomatosis (LAM),

b.

Pulmonary Langerhans cell histiocytosis (PLCH),

a. Silicosis b.

Coal workers pneumoconiosis

c. Asbestosis 4.

Infectious DPLD:

a.

Miliary Tuberculosis

b.

Fungal : Candidiasis

c.

Viral pneumonias: CMV, Influenza

d.

Pneumocystis jerovecii pneumonia

5.

Eosinophilic DPLD :

a.

Tropical pulmonary eosinophilia (TPE)

b.

Acute eosinophilic pneumonia

c.

Chronic eosinophilic pneumonia

d.

Allergic bronchopulmonary aspergillosis (ABPA)

6.

Connective tissue diseases with DPLD:

a.

Systemic Lupus Erythematosus

b.

Progressive systemic sclerosis

c.

Polymyositis – dermatomyositis

d.

Rheumatoid arthritis

Histoplasmosis,

BRONCHOSCOPIC LUNG BIOPSY (BLB)

Aspergillosis,

The distribution of lesionsin lung parenchyma has an impact on the yield of lung biopsy in DPLD. The yield of BLB is high in diseases where the lesions are peri-bronchial in distribution such as in Sarcoidosis, hypersensitivity pneumonitis and organizing pneumonias. The yield of BLB is also high in diseases which haveeasily identifiable pattern such as eosinophilic pneumonias pulmonary

polyangitis

c. Inherited ILD ( Neurofibromatosis)

or

Tuberous

Wegener’s

Sclerosis,

10.

Neoplastic DPLD:

a.

Lymphangitis carcinomatosis

b.

Miliary metastasis

c.

Radiation pneumonitis

11.

Miscellaneous DPLD:

a.

Pulmonary alveolar proteinosis

b.

Alveolar microlithiasis

c.

Mitral stenosis with pulmonary hemosiderosis

d.

Pulmonary veno-occlusive disease (PVOD)

e.

Pulmonary capillary hemangiomatosis (PCH)

alveolar proteinosis and diffuse alveolar hemorrhage.

Ensminger et al found the information from bronchoscopic lung biopsy to be immensely usefulin clinical decision making in almost 75% of their cases by excluding other differential diagnosis as infections and malignancy.7 BLB is a safe procedure for making the diagnosis in miliary tuberculosis, with 67% cases showing granulomatous lung lesions.8

CHAPTER 54

d.

240

Table 2: Analysis of BAL cytology in DPLD Predominant BAL Cells

Lymphocyte > 25%

Neutrophils > 50%

Eosinophils > 25%

Diseases

Tuberculosis

IPF

TPE

Sarcoidosis

Pneumonia

Drugs induced

Hypersensitivity pneumonitis

ARDS

Eosinophilic Pneumonias

CTD related ILD

AIP

Churg Strauss syndrome

PULMONOLOGY

Organizing pneumonia

Hypereosinophilic syndrome

Table 3: Contraindications for BLB 1.

2.

3.

4.

5.

6.

7.

Advancedinterstitiallung disease withrespiratory failure and /or pulmonary hypertension Cardiovascular diseases: Unstable angina, acute myocardial infarction (< 6 weeks),heart failure Recent or ongoingexacerbation of DPLD or recent pneumonia (<6 weeks ) Severe hypoxemia : PaO2< 75 mmHg on oxygen (Venturi mask FiO2=0.5) Coagulopathy ( INR 1.5, PTTK> 1.5 times control) Thrombocytopenia (platelet count< 1lakh/uL) Renal failure (Serumcreatinine >3.5 mg/dl)

On the flip side, BLB has a very poor yield in idiopathic interstitial lung diseases especially in Idiopathic Pulmonary Fibrosis (IPF) and fibrotic Nonspecific Interstitial Pneumonia (NSIP) and Desquamative interstitial pneumonias (DIP). Due to small size of BLB tissue, classical findings of UIP such as spatial and temporal heterogeneity of inflammation, fibroblastic foci and honeycombing cannot be recognized and there are large inter-observer variations in interpretation among pathologists. Current guidelines recommend surgical lung biopsy (SLB) for accurate diagnosis in these diseases.9

Fig. 1: Hemorrhagic BAL in alveolar hemorrhage

Bronchoscopic cryo-biopsy is an exciting addition to the armamentarium of the pulmonologist in the last few years. The use of cryobiopsy resulted in larger lung biopsy (mean size 1-2 cm), had greater diagnostic yield 70-80% and reduced the need for SLB in idiopathic ILD to 1.2%.10 In view of larger biopsy there is increased risk of bleeding and pneumothorax following cryobiopsy in 2-4%cases and patients need to be observed. The initial encouraging results of cryobiopsy need to be compared with SLB in idiopathic ILD in larger randomized trials.

ENDO-BRONCHIAL BIOPSY (EBB)

In cases of pulmonary sarcoidosis, bronchial mucosal infiltration, nodularity and erythema may be present and bronchial biopsies are positive in 35-50 %. Even when bronchial mucosa is normal in appearance, bronchial biopsy may show classical non caseating granulomas and must be done in all cases.

MULTIPRONGEDAPPROACH IN DPLD

A recent meta-analysis shows the yield of sarcoidosis in BLB is 68% and EBB is 49% when used singly but

Fig. 2: Milky BAL in Pulmonary alveolar proteinosis goes up to 81.4% when both are combined together.

The yield increases to 86.9% when BLB and EBB are combined with transbronchial needle aspiration (TBNA) of hilar and mediastinal lymph nodes. Endobronchial ultrasound guidance bronchoscopy (EBUS-TBNA) improves sensitivity over conventional TBNA from 22% to 57%. When conventional TBNA is combined withBLB + EBB the diagnostic yield is equivalent to EBUS TBNA

to arrive at the diagnosis. The chest radiographs may be normal in 10% of DPLD especially in early phase of illness. High resolution CT chest is imaging of choice in DPLD and shows extent and patterns of involvement to narrow down the differential diagnosis and site of lung biopsy.12 Biopsy samples must be taken from sites of maximum ground glass opacity, nodularity or interstitial fibrosis. Also biopsy must be taken from relatively normal looking adjacent lungs.

combined with BLB +EBB, 86.9 vs 86.4%. Therefore,using the multipronged approach doing TBNA, EBB and BLB using conventional bronchoscopy in same sitting,majority of sarcoidosis can be diagnosed.11

SURGICAL LUNG BIOPSY IN DPLD

Many pathologists consider bronchoscopic lung biopsy to be unsuitable in idiopathic pulmonary fibrosis and Non- specific interstitial pneumonia. Problems with BLB are that samples may not be from representative area of disease and small tissue size. As a result, pathologists are not able to pick up the classical findings to make confident diagnosis. Surgical lung biopsy (SLB) is the gold standard till date for diagnosis of IPF and NSIP.9 Adequate lung tissue samples from multiple lobes can be obtained by mini thoracotomy or video-assisted thoracoscopic lung surgery (VATS) under general anesthesia. The invasive nature and morbidity of open lung biopsy causes hesitation among patients and are reasons for SLB being done rarely in DPLD. But SLB has definite role in DPLD especially if BLB iscontraindicated or is unsuccessful in arriving at the diagnosis. In patients with contraindications for bronchoscopy (Table 3) option of SLB should be discussed. For example Miliary sarcoidosis with severe hypoxemia on mechanical ventilation,should be taken up for surgical lung biopsy as the risks of BLB are higher and with specific diagnosis appropriate treatment can be instituted which may be life-saving.

Overall SLB has high yield over 95 % but carries average mortality of 1-3%, median mortality 4-6%at 30 days which may be as high as 28% in acute exacerbation of IPF and morbidityof 5â&#x20AC;&#x201C;20% in various series.12 At present,with greater emphasis on cosmesis and minimalaccess surgery, VATS lung biopsy is the preferred method wherever available.VATS lung biopsy has less morbidity, shorter hospital stay and lesser costs.

CLINICIAN-RADIOLOGIST-PATHOLOGISTINTERACTION

In every case of DPLD, the clinician must take into account various factors as presentation of illness (acute, subacute or chronic), radiological pattern and clinical background

Bronchoscopic lung biopsies clinch the diagnosis in a few DPLD as in Sarcoidosis, Organizing pneumonia, pulmonary alveolar proteinosis, Eosinophilic pneumonias and hypersensitivity pneumonitis. More often BLB shows abnormal patterns which may be seen in several diseases which cause diffuse involvement of the lungs.14 This pattern based diagnostic approach needs close coordination between the clinician, pathologist and radiologist for arriving at the correct diagnosis.

Histopathological patterns on BLB can be broadly of following types14 1.

Cellular Interstitial pneumonias (acute)

2.

Fibrotic interstitial pneumonia (chronic)

3.

Granulomatous lesions: Sarcoidosis, Tuberculosis

4.

Eosinophilic pneumonias

5.

Organizing pneumonia

6.

Specific diagnosis:malignancy/alveolar proteinosis/ alveolar hemorrhage

7.

Normal lung tissue

8.

Inadequate lung biopsy ( less than 20 alveoli in the lung biopsy)

In the succeeding paragraphs a few cases of DPLD seen at our centre are discussed with histopathological photomicrographs to make the reader aware of the dilemma faced by the pulmonary physician and pathologists.

Usual Interstitial Pneumonia (UIP)

Histopathological pattern seen in idiopathic pulmonary fibrosis (IPF). There is sub-pleural interstitial fibrosis with loss of lung architecture with or without honey combing.

Key pathologic features of UIP are spatial and temporal heterogeneity of the lesions and presence of fibroblastic foci (FF) of varying ages interspersed with normal areas (Figure 3). UIP pattern may be seen in other diseases as Chronic hypersensitivity pneumonitis, Pneumoconiosis, Rheumatoid arthritis ILD and Amiodarone induced lung

CHAPTER 54

Fig. 3: Usual Interstitial pneumonia

Relevant clinical and epidemiological data must be provided to the pathologistat the time of lung biopsy to help them in analysis. These should include age, gender, duration of illness, occupational exposure (silicosis, asbestosis), recreational exposure (eg bird keepers), immune status of the patient, prior drug use (amiodarone, chemotherapy), radiological picture and clinical diagnosis suspected (eg Connective tissue disease ILD etc).

241

PULMONOLOGY

242

Fig. 4: Nonspecific Interstitial pneumonia

Fig. 6: Pulmonary sarcoidosis

Fig. 5: Organizing pneumonia pattern in case of drug induced ILD fibrosis. These alternative causes of UIP must be excluded by in depth history and relevant investigations as they have much better prognosis than IPF.

Nonspecific Interstitial Pneumonia (NSIP)

Idiopathic NSIP now a distinct entity, hasdiffuse and temporally homogenous interstitial inflammation with or without fibrosis (Figure 4). Two patterns of NSIP are seen. Cellular NSIP, when chronic inflammatory cells predominate in the alveoli and interstitium. Fibrotic NSIP when fibrosis involves the lung diffusely. Unlike UIP,fibroblastic foci and honeycombing are rare findings and disease is homogeneous in lungs. NSIP may be caused by connective tissue diseases or drugs and relevant investigations are required to be done. Most patients with idiopathic NSIP have a good response to treatment with glucocorticoids. The 5 year mortality rate is estimated to be 10 to 15 percent as compared to IPF which has mortality of 75-80% at 5 years.

Organizing Pneumonias (OP)

Earlier called as bronchiolitis obliterans organizing pneumonia (BOOP). If no secondary cause is found, cryptogenic organizing pneumoniais diagnosed.

Secondary causes of OP include viral infections, mycoplasma pneumonia, drug reaction (Figure 5), connective tissue disease and post bone marrow transplantation. Numerous buds of granulation tissue are

Fig. 7: Tubercular Granuloma seen within alveoli which may extend to alveolar ducts and small airways. Later on these can be replaced by fibrotic changes. The cases with OP show good steroid response if initiated early in the illness.

Granulomatous Lesions

Tuberculosis and Sarcoidosis are the common DPLD with this pattern. The lesions in Sarcoidosis are peribronchovascular and peri-lymphaticin distribution hence yield of BLB is good.There are non-caseating compact granulomas with or without fibrosis. Sarcoid granulomas (Figure 6) are generally non-necrotic and are naked without inflammatory cellular ring around the lesions.

Tubercular lesions favour the upper lobes in lungs and may show cavity or miliary pattern. TB granulomas have caseation necrosis and may show acid fast bacilli on ZN stain (Figure 7). Other Granulomatous lesions in lungs include fungal infections, Hypersensitivity pneumonitis, Granulomatosis with polyangitis (Wegenerâ&#x20AC;&#x2122;s) ChurgStrauss syndrome and Hodgkinâ&#x20AC;&#x2122;s lymphomas.

Eosinophilic Pneumonias

Variety of diseases can cause EP. Tropical pulmonary eosinophilia is a common DPLD associated with filarial

243

CHAPTER 54

Fig. 8: Tropical pulmonary eosinophilia infection and is characterized by peripheral blood eosinophiliaand BAL eosinophilia > 25 %. It is seen in residents of coastal India and Eastern states of India.

BLB (Figure 8) shows intense eosinophilic infiltration of interstitium with other chronic inflammatory cells. They recover with treatment with Diethylcarbamazine over 4-6weeks. If left untreated it results in significant residual fibrosis and loss of lung functions.

Pulmonary Alveolar Proteinosis

Rare DPLD which results from defective surfactant metabolism in alveoli due to anti GMCSF antibodies.

HRCT chest shows crazy pavement pattern which is a combination of diffuse ground glass opacity superimposed on smooth interlobular septal thickening. BAL shows amorphous pink appearance with PAS positive material.

The BLB is usually diagnostic, showing alveoli filled with acellular pink surfactant material which is PAS positive.

There is complete absence of alveolar inflammation in PAP (Figure 9).

CONCLUSIONS

Flexible bronchoscopyis an important toolfor making early diagnosis of DPLD. Bronchoalveolar fluid analysis is useful in establishing diagnosis of infections in immune compromised hosts with DPLD. Bronchoscopic lung biopsy has a high yield in DPLD such as Sarcoidosis, hypersensitivity pneumonitis, organizing pneumonias, eosinophilic pneumonias and pulmonary alveolar proteinosis. Small samples of BLB make it unpopular with pathologist in diseases like Idiopathic pulmonary fibrosis and Nonspecific interstitial pneumonia and surgical lung biopsy is considered gold standard at present. Bronchoscopic cryobiopsy may overcome these limitations and needs to be compared with SLB in randomized trials.

REFERENCES

1.

BTS Guidelines on diagnosis and assessment of diffuse parenchymal lung diseases. Thorax 1999; 54:S1-S30

2. Wollin L, Wex E, Pautsch A, et al. Mode of action of Nintedanib in the treatment of idiopathic pulmonary fibrosis. EurRespir J 2015; 45:1434–1445.

Fig. 9: Pulmonary alveolar proteinosis 3. Jindal SK, Gupta D and Aggarwal AN. Sarcoidosis in developing countries. Current Opinion in Pulmonary Medicine 2000; 6:448–454.

4. Leslie KO, Gruden JF, Parish JM, Scholand MB. Transbronchial biopsy interpretation in the patient with diffuse parenchymal lung disease. Arch Pathol Lab Med 2007; 131:407-23.

5.

Meyer KC. Role of Bronchoalveolar lavage in Interstitial lung diseases. Clinics in Chest Medicine 2004; 25:637-649

6.

Joos L, Chajjed PN, Wallner J et al. Pulmonary infections diagnosed by BAL: A 12 year experience in 1066 immunocompromised patients. Respiratory Medicine 2007; 101:93-97

7.

Ensminger SA, Prakash UBS. Is bronchoscopic lung biopsy helpful in management of diffuse lung disease? Eurresp J 2006; 28:1081-4

8.

Aggarwal AN, Gupta D, Joshi K, Jindal SK. Bronchoscopic lung biopsy for diagnosis of miliary tuberculosis. Lung India 2005; 22:116-118

9.

Raghu G, Collard HR, Egan JJ et al. ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/ JRS/ALAT statement: Idiopathic Pulmonary Fibrosis: evidence-based guidelines for diagnosis and management. Am J RespirCrit Care Med 2011; 183:788–824.

10. Fruchter O, Fridel L, Raouf BAet al.Histological diagnosis of interstitial lung diseases by cryo-transbronchial biopsy.

Respirology 2014; 19:683–688 11. Agarwal R,Aggarwal AN, Gupta D.Efficacy and Safety of Conventional Transbronchial Needle Aspiration in Sarcoidosis: A Systematic Review and Meta-analysis.

Respir Care 2013;58:683–693.

12. Ryu JH, OlsonEJ, Midthun DE et al.Diagnostic Approach to the Patient With Diffuse Lung Disease. Mayo Clin Proc 2002; 77:1221-1227 13. Luo Q, HanQ, Chen X et al. The diagnosis efficacy and safety of video-assisted thoracoscopy surgery (VATS) in undefined interstitial lung diseases: a retrospective study. J Thorac Dis 2013; 5:283-288.

14. Kulshrestha R, Menon BK, Rajkumar et al. Role of a Patternbased Approach in Interpretation of Transbronchoscopic Lung Biopsy and Its Clinical Implications. Indian J Chest Dis Allied Sci 2012;54:9-17

C H A P T E R

55

Role of Interventions in Pulmonology

Interventions are increasingly becoming an indispensable tools in the practice of pulmonology. They are useful as diagnostic as well as therapeutic tools. In this chapter, an attempt is made to provide an overview of some of the most common interventions in pulmonology.

THORACENTESIS (PLEURAL TAP)

Thoracentesis is one of the most common medical procedures performed today1. It is a percutaneous procedure during which a needle is inserted into the pleural space and pleural fluid is removed either through the needle or a small bore catheter. Before the procedure, bedside ultrasonography can be used to determine the presence and size of pleural effusions and to look for loculations.2 During the procedure, it can be used in real time to facilitate anesthesia and then guide needle placement.

Diagnostic thoracentesis is performed to obtain a small volume of fluid (50–100 mL) for the purpose of analysis, which is accomplished with a single percutaneous needle aspiration. A therapeutic thoracentesis is performed to relieve symptoms, such as dyspnea, to relieve hemodynamic compromise or to evacuate the pleural space of infection. The therapeutic thoracentesis is normally accomplished using a temporary catheter that is removed at the end of volume removal.1Each technique requires familiarity with the principles of pulmonary and pleural anatomy and physiology.

Indications

Thoracentesis is indicated for the symptomatic treatment of large pleural effusions or for treatment of empyemas.

It is also indicated for pleural effusions of any size that require diagnostic analysis.3

Contraindications

There are no absolute contraindications for thoracentesis.

Relative contraindications include the following: •

Uncorrected bleeding diathesis

•

Chest wall cellulitis at the site of puncture

Procedure

Consent should be obtained from the patient or a family member. Once the procedure has been explained to the patient and informed consent obtained, the patient is positioned for the procedure. Thoracentesis is usually performed with the patient in a sitting position, sitting upright with his or her arms resting on a surface, such

Agam Vora

as a bedside table. The lateral recumbent position can be used if the patient is unable to sit upright.

Bedside ultrasonography is a useful guide for thoracentesis. It can determine the optimal puncture site, improve the administration of local anesthetics, and minimize the complications of the procedure.

In circumstances when ultrasound is not available, patients with a nonloculated, free-flowing effusion, may undergo thoracentesis guided by the physical examination to select the puncture site, using the following landmarks: •

One to two interspaces below the level at which breath sounds decrease or disappear on auscultation, percussion becomes dull, and fremitus disappears

•

Above the ninth rib, to avoid subdiaphragmatic puncture

•

Midway between the spine and the posterior axillary line, because the ribs are easily palpated in this location.

Preparation of puncture site

Thoracentesis is a sterile procedure. A wide area surrounding the puncture site should be sterilized with 0.05 percent chlorhexidine or 10 percent povidone-iodine solution, prior to placement of sterile drapes around the puncture site.

A sterile drape is placed over the puncture site, and sterile towels are used to establish a large sterile field within which to work. Once the puncture site and surrounding skin is sterilized, local anesthetic should be administered.

The epidermis is initially infiltrated with anesthetic using a syringe and 25-gauge needle. Next, a syringe with 1 or 2 percent lidocaine with a 22-gauge needle is inserted, advanced toward the rib, and then “walked” over the superior edge of the rib. Passing the needle over the superior aspect of the rib decreases the risk of injury to the neurovascular bundle, which traverses the inferior rib margin.

As the needle is advanced, aspiration should be attempted every several millimeters by intermittently pulling back on the plunger of the syringe. Anesthetic is injected if there is no return of blood or pleural fluid into the syringe.

Once pleural fluid is aspirated, stop advancing the needle and inject additional lignocaine to anaesthetise the highly sensitive parietal pleura. Note the depth of penetration before withdrawing the needle. Attach an 18G cannula to

a syringe and advance the needle along in the same plane as the local anaesthetic was injected, ensuring that you continuously pull back on the plunger.

Once pleural fluid is obtained, remove the needle leaving the cannula in place. Cover the open hub of the catheter with a finger to prevent the entry of air into the pleural cavity.

A “dry” thoracentesis occurs in 7.4 percent of procedures and may result from absence of pleural fluid, incorrect needle placement, thick pleural fluid, or use of an inappropriately short needle. The needle can be withdrawn and reinserted in a slightly different angle if the patient tolerated the initial dry tap.

Indications •

Unresolved primary pneumothorax greater than 2 cm after 2 attempts at aspiration

•

Secondary pneumothorax greater than 2 cm

•

Unilateral pleural effusion causing breathlessnesss – insert drain to relieve symptoms and aid diagnosis

• Empyema •

Bilateral pleural effusions if decompensated despite optimal medical management

•

Tension pneumothorax after needle decompression

•

Palliation of breathlessness in malignant pleural effusions

•

To facilitate pleurodesis

Procedure7

Complications4: Potential complications of thoracentesis include pain at the puncture site, bleeding (eg, hematoma, hemothorax, or hemoperitoneum), pneumothorax, empyema, soft tissue infection, spleen or liver puncture, vasovagal events, seeding the needle tract with tumor, and adverse reactions to the anesthetic or topical antiseptic solutions.

The most appropriate site for chest tube placement is the 4thor 5th intercostal space in the mid- or anterior- axillary line. Attention to technique in placing the chest tube is vital to avoid complications from the procedure.

•

Ultrasound and operator (for effusions)

Risk factors for complications associated with thoracentesis

-

Sterile ultrasound sheath

•

Sterile field

-

Sterile dressing pack and gloves

-

2% Chlorhexadine swabs

5

•

Patient-related factors

-

Small effusion (< 250 mL)

-

Multiloculated effusion

- Obesity -

Patient position (supine position)

-

Mechanical ventilation

•

Procedure-related factors

-

Inexperienced or poorly trained operator

-

Lack of ultrasound guidance

-

Drainage of large volumes (> 1,500 mL) of fluid

Post-procedure care •

Perform a post aspiration chest X-Ray

•

Provide appropriate analgesia

•

Monitor for evidence of any complications: pneumothorax, post expansion pulmonary oedema, bleeding, intra-abdominal organ injury (rare), infection (delayed and rare)

INTERCOSTAL DRAIN

An adequate chest drainage system aims to drain fluid and air and restore the negative pleural pressure facilitating lung expansion.6An intercostal drain is a flexible plastic tube that is inserted through the chest wall

245

Equipment required for an intercostal drain (chest drain/ pleural drain)

• Analgesia -

4mls of 1% or 2% Lidocaine

-

Orange (25G) needle (x1)

-

Green (19G) needle (x1)

-

5ml Syringe (x1)

•

Seldinger chest drain kit

•

Chest drain tubing and bottle

•

Sterile water/saline

•

Suture kit

-

Straight needle is ideal

•

Sterile dressing

Pre-procedure

Written consent should be gained for: Pain, failure of procedure, bleeding, infection, damage to surrounding structures and pneumothorax if the procedure is for an effusion.

CHAPTER 55

Attach a 50ml syringe with a 3 way tap to the catheter hub and open the tap to the patient and syringe to aspirate 50ml of pleural fluid for diagnostic analysis. Close the 3 way tap to the patient as you distribute the fluid into relevant specimen containers. If performing therapeutic thoracentesis, then attach the extension set to the third port with the free end in a container to collect the pleural fluid.

into the pleural space. It is used to drain pneumothoraces or effusions from the intrathoracic space. All intercostal drains inserted for pleural effusions should be real time ultrasound guided.

PULMONOLOGY

246

gently but firmly insert the dilator over the wire through the skin and intercostal muscles

Pre-procedure set-up •

Set up sterile trolley

•

Prepare drain

-

Warn the patient they will feel some pushing

•

Pour sterile water/saline into chest drain bottle up to the prime line

-

Do not be too forceful as you will kink the wire

•

Attach chest drain tubing ensuring the end stays within the package and sterile

-

If the dilator is not advancing it may indicate you are pushing in the wrong plane or against bone

•

Review imaging and examine patient to confirm side of insertion

•

Once dilated remove the dilator and pass the chest drain over the wire

•

It is advised to have a nurse and a helper to assist during the procedure

-

Ensure that you have a hold of the wire out the end of the drain before advancing

•

Position the patient with leaning forward with arms out stretched or sat at 90 degrees with arm lifted and hand resting behind their head. In elderly or frail patients the nurse may be required to help support this position.

•

Insert the drain over the wire and remove the wire

•

Attach three way tap to the drain and ensure it is closed

•

Then confirm air or fluid aspiration with a syringe via the 3-way tap

•

Close 3-way tap once position confirmed and suture drain in place

Procedure for intercostal drain insertion (chest drain/pleural drain)

-

This needs to be firm but not pinch the skin or occlude the drain

•

Wash hands and don sterile gown and gloves

•

Dress the drain so the insertion sight is visible

•

Clean insertion site: either the site identified by ultrasound or – for pneumothorax – insert drain in the “safe triangle”

•

Attach drain to chest drain tubing

•

If drain is for a pleural effusion then ultrasound area to identify insertion site

-

Lower border of axilla to the 5th intercostal space; the lateral edge of pectorails major and the lateral edge of latissimus dorsi

•

Apply sterile field

•

Insert lignocaine cutaneously, subcutaneously and then into the pleural space.

-

Fluid or air should be able to be aspirated with the green needle

•

Take the Seldinger needle and attach this to the 10ml syringe provided

•

Insert needle in the same plane as the lignocaine, aspirating as you advance. Insert needle to the same distance as air was aspirated with the green needle. Once air is aspirated inset 0.5cm further and confirm ongoing air aspiration

•

Remove the 10ml syringe ensuing you place your thumb over the open needle

•

Take the Seldinger wire and insert through the needle. Ensure you hold the wire and needle at all times

•

Remove Seldinger needle over the wire

•

Take scalpel and make a 0.5cm incision in the skin

-

Scalpel sharp edge should always be facing away from the wire

•

Take the Seldinger dilator and pass it over the wire,

Post-procedure o

Place drain on free drainage but monitor closely

-

If the patient has a chronically collapsed lung and you drain more than 1-1.5l in the first 24 hours there is risk of re-expansion pulmonary oedema

• Analgesia •

Post procedure CXR

•

Document procedure clearly and document length of drain inserted

•

Advise patient to always hold drain bottle below level of insertion

•

Respiratory review management

and

advise

on

onward

Contraindications

Anticoagulation, coagulopathy, or a bleeding diathesis are relative contraindications in a patient undergoing elective chest tube placement.

Complications - frequently occurring when the tube is inserted with a steel trocar - include hemothorax, dislocation, lung lacerations, and injury to organs in the thoracic or abdominal cavity.7

NEWER DRAINAGE DEVICES

A chest tube is a flexible plastic tube that is inserted through the chest wall and into the pleural space or mediastinum.

It is used to remove air in the case of pneumothorax or fluid such as in the case of pleural effusion, blood, chyle, or pus when empyema occurs from the intrathoracic space.

247

Anatomical resection* Apply DDS at-20 cmH2O Immediate post-extubation CXR YES

Continue at -20 cmH2O

NO

Lung expanded

Good lung quality NO Change to -8 cmH2O

ICD to stay for day 2

ICD to stay with daily assessment Persistent air leak at 5th day in the absence of other physical abnormalities YES Hemlisch valve/protex bag

NO

NO

Air leak < 40 mL/min and drainage < 400 mLs/24 hrs

ICD to stay with daily assessment and managed as per suction protocol

Remove ICD

CXR if patient unwell**

Lung collapse

NO

Discharge and review in nurse led clinic

YES or surgical emphysema or patient is felling unwell Reconnect to DDS***

Fig. 1: Flow chart with recommendations of chest tube management following lung resections connected with DDS The aims for an adequate chest drainage system to be fulfilled are: •

remove fluid & air as promptly as possible

•

prevent drained air & fluid from returning to the pleural space, restore negative pressure in the pleural space to re-expand the lung.

Thus, a drainage device must: •

allow air and fluid to leave the chest

•

contain a one-way valve to prevent air & fluid returning to the chest

•

have design so that the device is below the level of the chest tube for gravity drainage.

An underwater seal chest drainage system is used to restore proper air pressure to the lungs, re-inflate a collapsed lung as well as remove blood and other fluids.8 The underwater seal drainage system acts as a one-way valve allowing fluid and air to leave the pleuralspace during expiration and coughing but preventing it from being sucked back in during inspiration.9

However, there are complications and risks associated with this type of drainage system. If patients have an effective cough combined with a functional underwater seal they may be able to reinflate the lung. However, if the lung does not reinflate or a persistent air leak prevents reinflation, high-volume, low-pressure thoracic suction in the range of 3-5kPa may be used.

The use of suction after thoracic surgery is controversial; some surgeons always use it while others feel it is hazardous.For example, a medical device alert was issued by Medicines and Healthcare products Regulatory Agency (MHRA)after a patient with a chest drain under active wall suction sustained a tension pneumothorax due to the incorrect use of suction systems with no reservoir in situ.10 Recently, several companies have manufactured and commercialized new pleural drainage units that incorporate electronic components for the digital quantification of air through chest tubes and, in some instances, pleural pressure assessment. The goal of these systems is to objectify this previously subjective bedside clinical parameter and allow for more objective, consistent

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YES

248

measurement of air leaks. The belief is this will lead to quicker and more accurate chest tube management. In addition, some systems feature portable suction devices.

These may afford earlier mobilization of patients because the pleural drainage chamber is attached to a batterypowered smart suction device.11

PULMONOLOGY

Digital drainage systems (DDS) (Figure 1)

All DDS are portable and powered by a rechargeable battery with a sufficiently long run time. They have alarms for various situations, including but not limited to tube occlusion, disconnection and suction failure. Being a completely closed system, the fluid has no contact with the outside environment, and provides improved biosafety for the health care team and patients themselves.

Furthermore these devices eliminate inter-observer variability with objective measurement of air leaks recorded in the system (mL/min) and displayed on a screen.12The most important advantage is the ability to apply regulated pressure in the pleural space independent of patient, tube and device position.

The digital thoracic drainage system has been found to be especially beneficial for outpatients undergoing pulmonary resection surgery.The withdrawal of thoracic drainage has been found to be comfortable, safe and well tolerated by patients; it helps to reduce or eliminate the cost of hospital stay, because, according to the different series published in recent months, it is possible to withdraw drainage sooner and thus discharge patients earlier.13

Contraindications

Anticoagulation, coagulopathy, or a bleeding diathesis are relative contraindications in a patient undergoing elective chest tube placement. Transudative pleural effusions due to liver failure are not generally managed with thoracostomy drainage.

Blind insertion of a chest tube is dangerous in a patient with pleural adhesions from infection, previous pleurodesis, or prior pulmonary surgery; guidance by ultrasound or computed tomography (CT) scan without contrast is preferred.

THORACOSCOPY

Thoracoscopy (or pleuroscopy) involves passage of an endoscope through the chest wall and offers the clinician a “window” for direct visualization and collection of samples from the pleura. It is a valuable diagnostic procedure and, in some cases, can also provide an opportunity for treatment.14

Indications14 •

Diagnosis of pleural effusion

•

Pleural biopsy

•

Spontaneous pneumothorax

•

Empyema (early stage)

• Bullectomy •

Chemical pleurodesis

•

Pulmonary biopsy (forceps)

• Sympatholysis •

Empyema (chronic stage)

•

Pulmonary biopsy (stapler)

Preprocedural Considerations15

Informed consent is obtained from the patient in preparation for the pleuroscopy. During the preprocedural assessment, the patient’s imaging is reviewed. A transthoracic ultrasound may be performed in the pleuroscopy position to ensure adequate fluid quantity and identify a safe location for entry into the pleural space.

Equipment

The standard setup for pleuroscopy includes skin preparation (chlorhexadine swabs), sterile drapes and towels, towel clips, sterile marking pen, local anesthesia (typically 30 mL of 1% lidocaine), hypodermic needles (25 gauge for the skin and 18 or 22 gauge to access pleural space), No. 11 blade scalpel, sterile gauze, Kelly forceps for blunt dissection, trocar port with obturator, pleuroscope (rigid or semirigid with 0° optic), flexible suction catheter (may use rigid suction if rigid pleuroscope used), sterile biopsy forceps, talc poudrage apparatus (if necessary), large-bore chest tube (24F), and needle driver and suture to close skin and secure the chest tube.

Personnel

A dedicated nurse trained in moderate sedation or anesthesia support is necessary for administration of sedation and monitoring of the patient throughout the procedure. A second nurse is required to circulate and assist the physician. One physician with an assistant performs the procedure. All members of the team must be familiar with the procedure, including specimen handling. Once the decision is made to proceed, IV access is obtained, and prophylactic antibiotics are provided to cover skin organisms (usually 1 g cefazolin, or 1 g vancomycin if patient has a penicillin allergy).

Method of anesthesia: Thoracoscopy can be performed under either local or general anesthesia, depending upon the purpose of the procedure.

Indications for thoracoscopy under local anesthesia are inspection of the pleural space, removal of pleural fluid, biopsy of pleura/lung, and talc pleurodesis. Thoracoscopy can be safely performed under local anesthesia in a fullyequipped endoscopy suite under strict sterile precautions.

Thoracoscopy can also be performed under general anesthesia with or without selective bronchial intubation.

Single lung ventilation is preferable when video assisted thoracic surgery (VATS) is performed, because selective contralateral lung ventilation permits complete ipsilateral lung deflation.

Procedure — Patients are prepped and sterilely draped in the lateral decubitus position. Monitoring of cardiac rhythm and cutaneous oxygen saturation is necessary.

After the initial preparation, a 10 mm incision is made above the superior rib margin. Simple dissection is performed with a hemostat through the intercostal muscles and parietal pleura. A blunt-tip trocar and cannula are then introduced carefully to avoid lung injury. The site of trocar insertion depends upon the anticipated location of the abnormality.

The mid-axillary line of the 4th or 5th intercostal space will usually allow complete inspection of the pleura.

●

A higher intercostal space is generally preferred for evaluation of spontaneous pneumothorax.

●

Metastatic tumor or mesothelioma is more commonly found in the costovertebral angles and on the diaphragmatic surface. These lesions may be more easily accessed through the lower intercostal spaces.

Ultrasound-guided selection of the entry point into the pleural cavity may optimize the chance for success by avoiding adhesions.16

Relative contraindications are uncontrolled cough and hypoxemia that is not due to the pleural effusions.

When a lung biopsy is being considered, an additional consideration is whether pulmonary hypertension, honeycomb lung, or a vascular tumor is present. As with any intervention, the clinician must routinely evaluate the risks and benefits of the procedure.

BRONCHOSCOPY (FIBEROPTIC AND RIGID)

Bronchoscopy is a procedure that is utilized to visualize the nasal passages, pharynx, larynx, vocal cords, and tracheal bronchial tree.

There are two types of bronchoscopy- flexible and rigid bronchoscopy.The flexible bronchoscope is used more often than the rigid bronchoscope because it usually does not require general anesthesia, is more comfortable for patients, and offers a better view of the smaller airways.

Rigid bronchoscopy is usually done with general anesthesia.

Exploration of the pleural cavity is accomplished by maneuvering the telescope in a circular manner. Biopsies of suspicious areas are obtained through either the working channel of the thoracoscope or a separate entry site. Adhesions, which may interfere with complete examination of the pleural cavity, can be lysed with either a blunt probe or cautery forceps, with caution to avoid vascularized adhesions. If the distance between the lung and the chest wall is small, air can be cautiously introduced to collapse the lung further and enlarge the pleural space.

The rigid bronchoscope allows evaluation, control, and therapeutic manipulation of the proximal tracheobronchial tree. Massive hemoptysis, foreign body removal, airway stenosis, laser resection, and pediatric bronchoscopy are the most common indications for the rigid bronchoscope.18

Although the single puncture technique is the most commonly employed method of diagnostic thoracoscopy, some physicians effectively use a double puncture method.

With this latter technique, the second site of entry is made under direct video guidance to simplify visualization of difficult to reach areas such as the costovertebral angle, mediastinal pleural surfaces, and the lung apex.

Diagnostic indications for FB20

A chest tube is inserted for removal of air and fluid at the completion of the thoracoscopic procedure. Extra holes may be placed in the chest tube to ease fluid drainage after pleurodesis. The chest tube can be removed within a few hours when thoracoscopy does not involve a lung biopsy or pleurodesis.

249

The flexible bronchoscope offers greater manoeuvrability than the rigid bronchoscope and may be done in conjunction with other procedures, such as bronchoalveolar lavage, transbronchial biopsy, endobronchial ultrasound, electrocautery or laser treatments.19 •

Suspected neoplasia: lung, tracheal, bronchial, metastatic

•

Early detection of lung cancer

•

Chest X-ray abnormalities

• Hemoptysis •

Diffuse lung disease/intersticial lung diseases

•

Diaphragmatic paralysis

•

Vocal cord paralysis, persistent hoarseness

•

Persistent cough in selected patients

This approach should lower the cost of the procedure. If thoracoscopy is done for pleurodesis, the chest tube should be left in place until the fluid drainage is less than 150 mL per day. Chest tubes should remain in place until any air leak has resolved. A daily chest radiograph is obtained to assess chest tube position and lung re-expansion.

•

Wheezing, stridor and dyspnea

•

Suspected pneumonia, lung abscess, study of cavitated lesions

•

Lung in filtrates in the immunocompromised patient

Contraindications: Major contraindications to thoracoscopy include the inability to enter the pleural space due to pleural adhesions, inability to lay supine, inability to tolerate a pneumothorax, severe cardiac

•

Chest trauma (assessment of tracheal or bronchial rupture)

•

Chemical and thermal burns of the airway, smoke inhalation

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●

disease, severe respiratory disease unrelated to the effusion, and severe coagulopathy.17

PULMONOLOGY

250

•

Suspected airway fi stula: trachealesophageal, bronchioesophageal, mediastinal, bronchopleural

•

Suspected tracheobronchio malacia

•

Suspected foreign body in the airway

•

Suspected obstruction of the airway

•

Evaluation of endotracheal tube positioning

•

Evaluation of post transplant patients (status of sutures, stenosis, transplant rejection)

•

Persistent lung collapse

•

Persistent atelectasis

•

Persistent pleural effusion

•

Mediastinal adenopathies or masses

• Suction •

Containers for samples, syringes

•

Supplemental oxygen

•

Pulse oximeter

• Sphygmomanometer

Therapeutic indications for FB20 •

Bronchial washing (broncholithiasis, bronchiectasis, infected lung suppuration, cystic fibrosis)

•

Lung lavage (alveolar proteinosis)

•

Hemoptysis (bronchial tamponade, placement of Fogarti’s catheter)

•

Foreign body removal

•

Laser, electrocoagulation, cryotherapy, plasma coagulation application

•

Photodynamic therapy

argon

• Brachytherapy

• Fluoroscopy •

Resuscitation equipment

Consent21 1.

Explain the procedure to the patient and allay anxieties. Patients may have heard about the distress associated with a rigid bronchoscope.

Explain that the fiberoptic bronchoscope has made the procedure much easier.

2.

Assure the patient that there is sufficient room for air to go through.

3.

Instruct the patient that he should not talk during the procedure to avoid the likelihood of injury to the vocal cord. However establish some mechanism of communication e.g. instruct to raise fist whenever uncomfortable. If a transbronchial biopsy is planned, cooperation will be required: to take a deep breath and expire slowly.

4.

Inform the patient not to expect the results immediately; normally takes two to three days before the histopathological exams are complete.

Pre-screening

• Thermoplasty

•

History of allergic reactions to local anaesthetic

•

Platelet count, coagulation profile:INR, PT and aPTT

Percutaneous dilatational tracheostomy

•

Urea and creatinine

•

Sealing of bronchopleural pneumothorax

•

Evidence of recent MI/ACS

•

•

Aspiration of bronchial, mediastinal, pericardial cysts

If there is a focal lesion present, reveiw all available imaginmake an assessment as the most probable segment

•

Diffi cult airway intubation

•

•

Intralesional injection

•

Gene therapy

If there is history of asthma, consider prepare the patient with steroids or administer bronchodilator by inhaler prior to topical anaesthesia.

•

If the patient has a history of chronic obstructive pulmonary disease, ascertain baseline O2 saturation and whether patient has CO2 retention. In certain cases, respiratory depressants to premedicate may have to avoided, and thus rely primarily on local anaesthesia.

•

Medicines: Check whether patient is on aspirin, clopidogrel, Warfarin, or low molecular weight heparin

•

Balloon dilatation of stenosis, strictures

•

Endobronchial lung volume reduction

•

fistula/persistent

Flexible Bronchoscopy can be performed in a bronchoscopy suit or in the operating room. It can also be performed at the bedside in the ICU or at the emergency room, according to patient location and clinical status.

Basic equipment for flexible bronchoscopy • Bronchoscope •

Light source

•

Cytology brushes

•

Biopsy forceps

•

Needle aspiration catheters

Premedication

• Sedation: - Midazolam

- Fentanyl - Alfentanyl

Preparation •

Pre-Procedure Screening: NBM -The patient should abstain from food and liquids since midnight if the procedure is planned for the morning or after a light breakfast if planned for the afternoon. The stomach should be empty during the procedure to prevent aspiration. As a general rule, food and liquids should be withheld five to six hours prior to the bronchoscopy.

Assess the need for fluoroscopy: In general, all of the peripheral lesions and transbronchial lung biopsies require fluoro guidance and should be planned for.

•

Plan ahead for tests: Anticipate your needs and gather all of the necessary material ahead of time i.e. forceps, specimen bottles, TBNA needle, brush, flumazenil, ice saline, adrenaline etc.

•

Oxygenation and monitors: Start the patient on 1-2 liters of oxygen by nasal cannulation as there is an approximate drop of 10-20 mg Hg PO2 during the procedure. Providing supplemental oxygen prevents hypoxemia during the procedure and the patient’s oxygenation status should be monitored by cutaneous oximetry.

•

The knob of the handle controls the position of the tip of the scope: flexion and extension

•

There is a channel for suction controlled by a button that is depressed.

•

The channel on the side facilitates instillation of anaesthetic or saline and passage of biopsy forceps and instruments.

Routes of Intubation

There are many ways the fiberoptic bronchoscope can be introduced. An awareness of these alternatives is important. Each method has its own unique advantage.

The anesthetic procedure will vary depending on the method you have selected.

Transnasal: The transnasal method allows a more stable, aesthetic method, and allows the patients to swallow secretions more easily. The disadvantage is the difficulty beginners seem to have in introduction of the scope and nose bleeding may occur due to injury.

Transoral •

With a mouth bite protects accidental injury to the bronchoscope and is tolerated well by the patient.

•

Transoral with soft ET tube: The soft endotracheal tube is slipped over the bronchoscope as a sleeve.

The scope is then introduced directly into the trachea. The endotracheal tube is slipped into the trachea. The bronchoscope is withdrawn and a mouth bite is placed about the endotracheal tube for protection. This permits removal and re-insertion of the scope conveniently. This is especially useful in certain interventional procedures.

•

Through a rigid bronchoscope: The fiberoptic bronchoscope is introduced after insertion of a rigid bronchoscope. This method used to be practiced by thoracic surgeons in the early days.

With increasing familiarity and experience with fiberoptic scope, this method of introduction of the fiberoptic bronchoscope is now rarely done.

Conscious Sedation

Consider starting an IV line and titrate midazolam 1mg at a time, watching the patient’s response. Older patients are very sensitive. Therefore, 1 or 2 mg total may suffice.

Midazolam also provides amnesia but an excessive dose can induce respiratory depression. Reversal agents Flumazenil must be available.

Monitoring

The occurrence of endoscopically induced arrhythmias and ischemic changes is well documented in both gastroscopy and colonoscopy. However, fiberoptic bronchoscopy, with the additional factor of airway intubation only has a small risk of inducing an arrhythmia. The avoidance of hypoxemia by routine use of supplemental oxygen and the use of topical lignocaine may be of importance. Close monitoring of oxygen saturations, BP and pulse, and level of consciousness in all situations where conscious sedation is done for the procedure is essential.

Transtracheal •

Via endotracheal tube: When patients are on a ventilator, one can perform a bronchoscopy through an adapter or T-piece. The adapter permits insertion of a bronchoscope and performance of the procedure without the interruption of continuous mechanical ventilation.

•

Via tracheostomy: It is easy to introduce the bronchoscope through the tracheostomy stoma or through the tracheostomy tube via an adapter.

Instill local anesthetic through the stoma and proceed with bronchoscopy.

Administration of Oxygen 1.

Nasal cannula

2.

A mask with a hole made to permit passage of the bronchoscope

3.

Single cushioned naal prong

Instrument •

The bronchoscope consists of a handle and fiberoptic bundle. The light passes from the light source through the fiberoptic bundle to illuminate

251

The size of the bronchoscope and the endotracheal tube are important considerations. A size 8 tube and larger is required when using a bronchoscope 5.5 mm in diameter.

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•

the bronchus. Newer scopes avail video processing technology

252

With smaller tubes, the peak pressures developed by the ventilator become excessive and the risk of pneumothorax becomes higher.

Diffuse interstitial fibrosis

-

Opportunistic infections

For patients on the ventilator, prior to bronchoscopy increase the oxygen concentration to 100% and increase the tidal volume to account for a leak.

Lavage returns and more frequently with the middle lobe and anterior segments. Wedge the bronchoscope into the selected segment. Slowly instill 20 cc’s of saline and apply suction intermittently to collect the secretions.

BRONCHIAL ANATOMY

•

Transbronchial Lung Biopsy: For peripheral lesions and diffuse lung disease, a transbronchial biopsy is indicated, and under fluoroscopic guidance where appropriate. The following lists the value of fluoroscope:

-

It is absolutely necessary for placement of the forceps into peripheral lesions that are not visible endobronchially.

-

It ensures that the forceps are open.

-

It minimizes the risk of a pneumothorax.

It is essential to familiarize onerself with the segmental anatomy and get a three dimensional feel for the tracheobronchial tree.

PULMONOLOGY

-

1.

Starting in the trachea, the C-shaped tracheal rings with the posterior membranous portion normally bulging in during expiration and cough.

2.

Preferably inspect the the side opposite to the known abnormal lung.

3.

Right bronchial tree: The right main stem bronchus is in line with the trachea and is short. The right upper lobe bronchus branches immediately beyond the carina along the lateral wall. The right intermediate bronchus continues to three orifices. Along the medial wall, is the RML, RLL straight down and the superior segment of the RLL opposite to the RML. The medial basal segment of the RLL will branch off first along the medial side.

At the end you will see the posterior, anterior and lateral basal segments (three musketeers) clustered together. Withdraw the scope and a gentle turn of the bronchoscope tip towards the lateral sided will bring the RUL orifice into view with posterior, anterior and apical segments.

4.

Left bronchial tree: The left main stem bronchus is at an angulation and longer. Recognize the cardiac pulsation along the inferomedial aspect. At the orifice of the LLL, the superior segment branches off posteriorly. Upon entering the LL, the three basal segments can be seen. The left upper orifice divides into the LUL and lingular. The lingual has superior and inferior segments, the LUL has apical, posterior and anterior segments.

Endobronchial Procedures •

•

•

Brushing: The cytology brush can be passed through the bronchoscope to the desired site and the lesion can be brushed. The brush resides inside a protective sheath. Retract the brush into the sheath after brushing. This procedure will avoid the loss of the specimen during withdrawal of the brush.

Biopsy: Advance the biopsy forceps to the abnormal site. Familiarize yourself with opening and closing the forceps. Moving the handle forward opens the forceps. Under direct vision, advance the opened forceps to the selected site and close it to take a bite of the lesion.

Lavage: The indications for diagnostic lavage are:

- Sarcoidosis

For diffuse lung diseases, lateral segment of the right lower lobe is preferred site.

Place the bronchoscope in the lower lobe bronchus and identify the lateral basal segment. Advance the forceps into the segment to about 3 cms near the rib cage. Open the forceps and instruct the patient to take a deep breath while simultaneously advancing the forceps. Advance the forceps until either it wedges, is close to the chest wall or the patient develops pleuritic pain. If the patient complains of pleuritic pain, withdraw the forceps slightly until there is no pain. Ask the patient to expire slowly.

Close the forceps at the completion of expiration. Gently withdraw the forceps. You will note a tug on the lung.

Advancement during inspiration enables the forceps to go as far as possible into the lung. The end expiration will provide you with the most lung tissue for the biopsy.

Multiple biopsies (5-6) are recommended if there is no significant bleeding. Depending on the indication, the specimen should be sent for the following: -

Histology in formalin

-

AFB and fungal cultures in saline

-

Immunofluorescent stains in saline immediately

•

Transbronchial Needle Aspiration: The indications for transbronchial needle aspiration are:

-

Transcarinal: For purposes of lung cancer staging or for undiagnosed mediastinal nodes.

-

For peripheral pulmonary nodules.

-

At times, even for endobronchial lesions, it is particularly useful for a submucosal process where the standard biopsy forceps may fail to provide adequate tissue.

•

Triple Lumen Catheter:The development of the plugged, double sheathed, telescoping microbiology brush catheter offers a satisfactory method of sampling lower respiratory tract secretions without contamination from the inner

253

Table 1: Comparison of the two types of EBUS26

Radial probe EBUS Rotating mechanical transducer

View

360° to the long axis of scope

Frequency Tissue penetration Image quality

20 MHz (12, 30 also available) 4–5 cm Very good. Allows airway layers to be identified Not possible Not possible

Real time TBNA Doppler to indentify blood vessels

channel of the bronchoscope. The bronchoscope should be positioned in the orifice of the affected pneumonic segmental bronchus. Under direct vision, the sterile catheter is advanced 1-2 cm beyond the tip of the bronchoscope. The inner telescoping cannula containing the sterile brush is advanced, thereby ejection the polyethylene glyco plug. The brush is further advanced beyond the inner cannula to enable sampling of secretions. It is then withdrawn into the inner cannula, prior to removing the catheter from the bronchoscope. The distal portion is then clipped with sterile scissors into the culture medium.

Post Procedure Management

•

Linear probe EBUS Fixed array of electronic transducer aligned in a curvilinear pattern 60° parallel to the long axis of the scope 5–12 MHz 5 cm Currently not possible to identify airway layers Possible Possible

Inability to adequately oxygenate the patient during the procedure.

ENDOBRONCHIAL ULTRASOUND (EBUS)

Endobronchial ultrasound (EBUS) is a bronchoscopic technique that uses ultrasound to visualize structures within the airway wall, lung, and mediastinum.22Originally, it was developed for the staging and diagnosis of lung cancer, but its use rapidly expanded to other malignancies and even benign disease.23Extending the view beyond the airway wall, EBUS provides evaluation of tumor involvement of tracheobronchial wall and mediastinum and plays an essential role as a guidance technique for peripheral pulmonary diseases.24

•

Observation period: Post bronchoscopy management is mainly followed to screen for complications. The complications of routine bronchoscopy are negligible but is strongly recommended to observe the patient for 90120 minutes following the bronchoscopy. If a transbronchial lung biopsy was done, the period of observation should be two hours and it is important to get a chest x-ray following a transbronchial biopsy to rule out pneumothorax.

•

Instructions to the patient

-

Not to eat or drink for another two hours. The gag reflex should return before he can resume oral consumption.

EBUS technology is currently available in two forms: radial and linear transducer probes (Table 1). Ultrasound images are generated when high frequency sound energy is emitted by a transducer, reflected off a tissue interface, then received by the same transducer and finally processed. The challenge of ultrasonography of the lungs is related to the acoustic properties of air, which reflects ultrasound waves and permits no transmission. This results in images with multiple artefacts and obscures structures within the thorax that are not air-filled. By miniaturizing transducer probes such that they can be inserted via flexible bronchoscopy, these limitations are overcome because mediastinal and peri-bronchial structures can be visualized without intervening alveoli obscuring the view.25

-

An attendant to drive the patient home.

Indications27

-

Anticipate a sore throat and take a throat lozenge.

-

Call if a fever, shortness of breath or chest pain develops.

-

Anticipate mild haemoptysis.

Absolute Contraindications20 •

Lack of informed consent

•

Lack of an experienced bronchoscopist to perform or closely supervise the procedure

•

Lack of adequate facilities and personnel to care for emergencies that can occur, such as cardiopulmonary arrest, pneumothorax or bleeding

EBUS has become the standard of care and has rapidly attained a key status in the diagnosis and staging of various lung cancers, but in addition is also aiding and helping manage other pulmonary pathologies such as sarcoidosis, lymphoma, and in situ endobronchial lesions.

The ability of EBUS to help perform mediastinal and transbronchial biopsies less invasively and with better sensitivity and specificity makes it more favorable than mediastinoscopy.

Contraindications28

Contraindications to EBUS are similar to those of bronchoscopy in general. Recent myocardial infarction or ischemia, poorly controlled heart failure, significant hemodynamic instability, chronic obstructive pulmonary disease or asthma exacerbations, or life-threatening

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Transducer

254

cardiac dysrhythmias should delay an endobronchial procedure. Contraindications particular to EBUS-TBNA are related to coagulopathies (medication induced or inherent). The recommendation is to hold antiplatelet and anticoagulation agents prior to endoscopy to reduce bleeding risk.

PULMONOLOGY

Technique27

EBUS may be performed under conscious sedation or general anesthesia depending on the anticipated length of the procedure. Local anesthetic may be administered to minimize cough, and the flexible bronchoscope is advanced for an initial airway exam. Bronchial segments and subsegments are identified, secretions are suctioned, and 1% to 2% lidocaine is administered to further minimize cough.

After initial airway examination, the flexible bronchoscope is removed and the EBUS bronchoscope is advanced. While EBUS is performed, the bronchoscopist simultaneously visualizes the ultrasonic and bronchoscopic views on display. EBUS can help differentiate normal parenchyma from malignant tissue by its sonographic appearance.

The sonographic visualization of normal alveolar tissue is described as a â&#x20AC;&#x153;snowstormâ&#x20AC;? appearance.

After sonographic confirmation of the biopsy site, the transbronchial needle aspiration (TBNA) needle is advanced through a 2.2 mm working channel on the bronchoscope. This needle may be 21 or 22 gauge and can be advanced up to 40 mm. A stylet or wire is present in the needle at the time of insertion to clear tissue that may have collected while crossing the bronchial or tracheal wall. The distal end of the needle is grooved, rendering it hyperechoic and improving ultrasound visualization.

After the lymph node or tumor is punctured, the needle is connected to suction and excursions are made in the lymph node. Multiple punctures have been recommended to decrease sampling error.

The samples obtained can either be analyzed on site by the use of rapid on-site evaluation (ROSE) or collected in saline or cell culture media. The application of ROSE has been shown to significantly lower the need for additional bronchoscopic procedures and puncture number. ROSE is particularly beneficial when performing EBUS in the operating room with an expected need for further invasive exploration or surgical resection. Procedure length varies by the number of lymph node stations sampled. When EBUS is performed in the outpatient setting, patients can be discharged home after they regain their gag reflex.

Complications29

EBUS and EBUS-TBNA are usually safe procedures. No serious complications were found on a systematic review of effectiveness and safety of CP-EBUS-TBNA of regional lymph nodes.Reported complications are agitation, cough, hypoxia, laryngeal injury, fever, bacteremia and infection, bleeding, pneumothorax, and broken equipment becoming stuck in the airway. Complications related to upper airway local anesthesia are laryngospasm, laryngeal edema, bronchospasm, methemoglobinemia, and cardiac arrhythmias.Complications attributable to procedural sedation are respiratory depression, cardiovascular instability, vomiting, and aspiration.

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Porcel JM. Tuberculous pleural effusion. Lung 2009; 187:263-70.

4. Cantey EP, Walter JM, Corbridge T, Barsuk JH. Complications of thoracentesis: incidence, risk factors, and strategies for prevention. Curr Opin Pulm Med 2016; 22:37885.

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Perazzo A, Gatto P, Barlascini C, Ferrari-Bravo M, Nicolini A. Can ultrasound guidance reduce the risk of pneumothorax following thoracentesis? J Bras Pneumol 2014; 40:6-12.

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George RS, Papagiannopoulos K. Advances in chest drain management in thoracic disease. J Thorac Dis 2016; 8:S5564.

7.

Klopp M, Hoffmann H, Dienemann H. How to do - the chest tube drainage. Dtsch Med Wochenschr 2015; 140:33942.

8. Zisis C, Tsirgogianni K, Lazaridis G, Lampaki S, Baka S, Mpoukovinas I, Karavasilis V, Kioumis I, Pitsiou G, Katsikogiannis N, Tsakiridis K, Rapti A, Trakada G, Karapantzos I, Karapantzou C, Zissimopoulos A, Zarogoulidis K, Zarogoulidis P. Chest drainage systems in use. Ann Transl Med 2015; 3:43.

9.

Allibone L. Principles for inserting and managing chest drains. Nurs Times 2005; 101:45-9.

10. Medicines and Healthcare products Regulatory Agency (2010) Medical Device Alert: All Chest Drains When Used with High-flow, Low-vacuum Suction Systems (Wall Mounted) (MDA/2010/040). London.

The anatomical lymph node stations that are accessible via EBUS are 2R, 2L, 3P, 4R, 4L and 7. A unique advantage of EBUS is the accessibility of stations 10R, 10L, 11R, and 11L, which are inaccessible by other invasive techniques.

11. Cerfolio RJ, Varela G, Brunelli A. Digital and smart chest drainage systems to monitor air leaks: the birth of a new era? Thorac Surg Clin 2010; 20:413-20.

Endoscopic ultrasound (EUS) also provides access to 7, but in addition lymph node stations 8 and 9 can be accessed. EBUS may be performed safely in a single session alongside EUS. EBUS is preferred as a primary procedure when EUS is performed in the same session.

13. Mier JM, Fibla JJ, Molins L. The benefits of digital thoracic drainage system for outpatients undergoing pulmonary resection surgery. Rev Port Pneumol 2011; 17:225-7.

12. George RS, Papagiannopoulos K. Advances in chest drain management in thoracic disease. J Thorac Dis 2016; 8:S55-64.

14. Rodriguez-Panadero F, Janssen JP, Astoul P. Thoracoscopy: general overview and place in the diagnosis and

management of pleural effusion. Eur Respir J 2006; 28:40922.

22. Hürter T, Hanrath P. Endobronchial sonography: feasibility and preliminary results. Thorax 1992; 47:565-7.

15. Hersh CP, Feller-Kopman D, Wahidi M, Garland R, Herth F, Ernst A. Ultrasound guidance for medical thoracoscopy: a novel approach. Respiration 2003; 703:299-301.

23. Palamidas AF, Rosendahl U, Shah PL. Endobronchial Ultrasound Bronchoscopy to the Heart of the Matter.

Respiration 2016; 92:127-30.

16. Medford AR, Agrawal S, Bennett JA, Free CM, Entwisle JJ. Thoracic ultrasound prior to medical thoracoscopy improves pleural access and predicts fibrous septation.

Respirology 2010; 15:804-8.

24. Gompelmann D, Eberhardt R, Herth FJ. Endobronchial ultrasound. Endosc Ultrasound 2012; 1:69-74.

17. Michaud G, Berkowitz DM, Ernst A. Pleuroscopy for diagnosis and therapy for pleural effusions. Chest 2010; 138:1242-6.

26. T B, F J H. Endobronchial ultrasound: A new innovation in bronchoscopy. Lung India 2009; 26:17-21.

19. Yonker LM, Fracchia MS. Flexible bronchoscopy. Adv Otorhinolaryngol. 2012;73:12-8.

20. Rodriguez AN. Flexible Bronchoscopy. InInterventions in Pulmonary Medicine 2013 (pp. 13-34). Springer New York.

21. Available from http://www.fordoctorsbydoctors. co.uk/home/bronchoscopy-training-day/learn-aboutbronchoscopy/step-by-step-bronchoscopy. Accessed on 12th September 2016.

25. Anantham D, Koh MS, Ernst A. Endobronchial ultrasound.

Respir Med 2009; 103:1406-14.

27. Jalil BA, Yasufuku K, Khan AM. Uses, limitations, and complications of endobronchial ultrasound. Proc (Bayl Univ Med Cent). 2015; 28:325-30.

28. Ernst A, Eberhardt R, Wahidi M, Becker HD, Herth FJ. Effect of routine clopidogrel use on bleeding complications after transbronchial biopsy in humans. Chest 2006; 129:734-7.

29. Available from http://emedicine.medscape.com/ article/1970392. Accessed on 12th September 2016.

CHAPTER 55

18. Wain JC. Rigid bronchoscopy: the value of a venerable procedure. Chest Surg Clin N Am 2001; 11:691-9.

255

C H A P T E R

56

High Altitude and Respiratory System BNBM Prasad

“The Himalaya is a great deva-atma, a great spiritual presence, stretching from the west to the eastern sea like a measuring rod to gauge the world’s greatness.”

Kalidasa.

INTRODUCTION

Mankind has been fascinated by mountainous regions of the world from the time immemorial. More than 400 million people permanently reside at elevations above 1500 meters above the sea level1 while an estimated 40 million people travel and stay temporarily for leisure, sports, adventure, mining, scientific studies and for many other reasons including religion.2 Many of Indian yogis have made Himalayas their permanent abode and live there with nature without any special protection.

India has a large border with her neighbours stretching across the Himalayan and Karakoram ranges and Indian troops stay there for many months in extreme hostile conditions as prevalent in higher regions of Ladakh such as Siachen glacier which is considered as the highest battle field in the world. Indian subcontinent has some of the highest mountains in the world namely: Mount Everest (8,848 meters, 29029 feet), K2(Godwin Austen8,611 meters,28251 feet ), Kangchenjunga (8,586 meters, 28169 feet) and Nanga Parbat (8126 meters, 26660 feet).

These mountains have been climbed several times and continues to be formidable and risky to many who continue to venture to these heights.

Andes (6962)

Ethiopia (4620) Himalayas(8848)

Fig. 1: Arrows Altitude regions -1: Arrows depicting Highdepicting Altitude High regions of the worldof the world

HIGH ALTITUDE

High altitude is defined as regions above 2400 meters above the sea level (8000 feet). It is further divided in to very high altitude-3500 meters to 5500 meters (11,500– 18,000 feet) and extreme high altitude- more than 5500 meters (>18,000 feet). More than 140 million people, almost 2% of world’s population dwell in high altitude regions of the world.3 High altitude regions are found across continents in Himalayan mountains and Tibetan plateau of Asia, high lands of Ethiopia and Andean mountains of South America (Figure 1).4 Exposure to high altitude is a physiological stress due to prevailing extreme environmental conditions there and therefore, human survival becomes possible by physiological adaptations to such conditions. Permanent human habitation is difficult beyond 5500 metres.

Respiratory system plays a significant role in determining survival and undergoes series of adaptive changes to compensate for hypobaric hypoxia and optimise tissue delivery and utilisation of oxygen. In the event of failure of adaptation, there is an imminent risk of developing altitude related sickness that can affect the one globally but lungs are commonly affected.

Conditions special to high altitude: Unlike at sea level, high altitude has a unique environment characterised by hypoxia, hypobaria and low temperatures. At sea level the barometric pressure is 760 mm of Hg with a partial pressure of inspired oxygen of 159 mm of Hg (FIO2 of 20%) while the barometric pressure is 253 mm of Hg with

Table 1: Altitude, Barometric Pressure and Inspired Partial Pressure of Oxygen Altitude (meters)

Altitude (feet)

Barometric Pressure (mm Hg)

Inspired PO2 (mm Hg)

0

0

760

159

1000

3280

674

141

2000

6560

596

125

3000

9840

526

110

4000

13,120

463

97

5000

16,400

405

85

6000

19,680

354

79

8000

26,240

268

56

88848

29,028

253

43

after abrupt initial drop on acute high altitude exposure (Figure 3).

Oxygen Cascade at sea level and 4450 m 160

257

Saturation(red) and PaO2 (blue) at altitude

140

120

120

100

100

80

80 60

60

40

40

20 0

20 Inspired

Alveolar

Arterial

Capillary

Venous

0

Sea level

Day 1

Day 2

Day 3

Weeks

CHAPTER 56

Fig. 2: Oxygen cascade at both sea level and 4450 meters

Fig. 3: Arterial saturation(blue) and arterial oxygen partial pressure of inspired oxygen of 43 mm of Hg (FIO2 Fig-3: Arterial saturation(blue) and arterial oxygen tension(red) before at sea level and duringtension(red) sudden high altitude exposure. before at sea level and during sudden high 8%) on the summit of Mount Everest (Table 1). altitude This sustained hyperventilation despiteexposure hypocapnea is considered to be due to relative This decline in partial pressure of oxygen in the air, as one gains height results in lower partial pressure of oxygen(PO2) at every step in the oxygen transport chain as oxygen moves from atmosphere to tissue as to result in less availability of oxygen for oxidative phosphorylation in the mitochondria of the cell. Oxygen cascade both at sea level and high altitude are depicted in the Figure 2.

RESPIRATOTY SYSTEM IN HIGH ALTITUDE

Respiration both external and internal leads to delivery of oxygen to tissue from atmosphere. In high altitude due to prevailing hypobaric hypoxic conditions, subjects who are exposed such an environment have to undergo series of adaptations in various steps of oxygen transportation to overcome tissue hypoxia as a result of less availability of oxygen for gas exchange, oxygenation of blood and cellular oxidative phosphorylation. These adaptations are complementary and are acute (immediate to 5 days), subacute (over weeks), chronic (months to years) or lifelong depending on the duration of high altitude exposure.

Ventilation

On rapid ascent to a height of more than 1500 meters, there is a marked increase in ventilation within few hours of exposure due to hypoxia induced respiratory stimulation via carotid body to minimise fall in alveolar PO2 (PAO2) as a result of fall in barometric pressure.5 This hypoxic ventilator response (HVR) results in decrease in alveolar PCO2 in order to increase PAO2 for compensating lower partial pressure of oxygen in the blood (PaO2). At Mount Everest with barometric pressure of 253 mm of Hg and partial pressure of oxygen in the atmosphere of just 43 mm of Hg, PAO2 is maintained around 34 mm of Hg due to hyperventilation when alveolar PCO2 falls to 13 mm of Hg.6 HVR is related to degree of hypoxia and greater response is expected when arterial PO2 (PaO2) is below 60 mm of Hg.7,8 Hyperventilation at a given altitude persists over a period of weeks and tends to normalise after few weeks of deinduction to a lower altitude.9 Over a period of days to weeks of stay in high altitude, oxygen saturation of blood improves due to sustained hyper ventilation after abrupt initial drop on acute high altitude exposure (Figure 3).

metabolic and CSF acidosis following bicarbonate loss in the urine for compensating This sustained hyperventilation despite hypocapnea respiratory alkalosis. However, this classic explanation attributing metabolic acidosis for sustained altitude related hyperventilation is being questioned sinceand PH ofCSF both blood and is considered to be due to relative metabolic CSF remains alkaline so also that of interstitial fluid and intracellular fluid of the brain acidosis following bicarbonate loss in the urine for after dedespite alkaline urine. Further PH of both blood and CSF normalises soon induction yet hyperventilation persistsalkalosis. for few weeks.

It is likely that compensating respiratory However, thisaugmented classic sensitivity of carotid chemoreceptors to hypoxia and mediators such as erythropoietin and hypoxiaexplanation attributing metabolic acidosis for sustained inducible transcription factor1 alpha(HIF-1Îą) are some of the contributing factors for this altitudeacclimatization(10,11).It related hyperventilation questioned ventilatory may be notedisthatbeing at higher ventilator rates as one ascends higher, oxygen demand and for breathing increases alkaline and net gain oxygenation by since PH of both blood CSF remains soinalso compensatory ventilatory response is traded off by the increased cost of breathing. that of pattern interstitial intracellular fluid of central the brain Breathing changesfluid in highand altitude due to response of both and peripheral chemoreceptors to dynamic changes and oscillatory patternblood of oxygen andCSF carbon dioxide despite alkaline urine.

Further PH of both and levels in the blood (12). Hyperventilation leads to carbon dioxide wash out with spells of normalises soon after de-induction yet hyperventilation apneas due to fall in partial pressure of carbon dioxide in the blood(PCO2) below the thresh hold that to stimulateItcentral chemoreceptors.

Periodic breathing with persists foris required few weeks. is likely that augmented recurrent episodes of apnea and hyperpnea is a feature among healthy people at high sensitivity of carotid chemoreceptors to hypoxia and altitude that can occur at a modest height of 2500 meters during both wakefulness and

mediators such as erythropoietin and hypoxia-inducible transcription factor1 alpha(HIF-1Îą) are some of the contributing factors for this ventilatory acclimatization.10,11 It may be noted that at higher ventilator rates as one ascends higher, oxygen demand for breathing increases and net gain in oxygenation by compensatory ventilatory response is traded off by the increased cost of breathing.

Breathing pattern changes in high altitude due to response of both central and peripheral chemoreceptors to dynamic changes and oscillatory pattern of oxygen and carbon dioxide levels in the blood.12 Hyperventilation leads to carbon dioxide wash out with spells of apneas due to fall in partial pressure of carbon dioxide in the blood (PCO2) below the thresh hold that is required to stimulate central chemoreceptors. Periodic breathing with recurrent episodes of apnea and hyperpnea is a feature among healthy people at high altitude that can occur at a modest height of 2500 meters during both wakefulness and different stages of sleep.13,14 At extreme high altitude above 5500 meters, periodic breathing disappears due to high frequency of breathing.15,16 Central sleep apnea is a feature in both highlanders and sojourners resulting in steep fall in oxygen saturation during apneas and arousals during hyperpneas. It is a contributing factor for severe hypoxemia that leads to altitude related illnesses.17 Lung functions in high altitude subjects show reduced gas exchange, fall in vital capacity, increase in residual volume, peak expiratory flow and total lung capacity. Lowlanders exposed to high altitude have lower vital capacity due to changes in pulmonary mechanics due to hypoxia and

258

hypocapnia. There is air way narrowing, increase in interstitial fluid, hypoxic pulmonary vasoconstriction, VQ mismatch and decreased muscle strength. On the other hand, highlanders have lower minute ventilation compared to lowlanders at high altitude under similar atmospheric conditions due to carotid body hypertrophy and blunted chemoreceptor response to hypoxia. They have advantage of higher vital capacity, reduced cost of breathing and increased exercise capacity.18,19,20

PULMONOLOGY

Perfusion

Lung perfusion is inhomogeneous in both health and disease. Alveolar hypoxia causes hypoxic pulmonary vasoconstriction to facilitate redistribution of blood in various zones of lung to match ventilation and optimise diffusion of oxygen from alveoli to blood.21

Diffusion

pulmonary artery pressure and do not exhibit the vascular changes of the Andean highlanders.25

Cardiac Output

Ascent to altitude augments cardiac output by increasing the heart rate without any concomitant increase in the stroke volume. In-fact, there is decrease in the stroke volume due to decreased plasma volume as a result of alkaline diuresis, natriuresis and respiratory fluid loss due to hyperventilation.26 Myocardial depression that can occur with severe hypoxia is not the usual cause for low stroke volume. Upon acute exposure to altitude there is elevation of systemic blood pressure and increase in vascular resistance due to augmented sympathetic activity. Prolonged stay in high altitude is likely to reduce peripheral vascular resistance due to vasodilatory effect of hypoxia on peripheral circulation.

Decreases with high altitude due to decrease in pressure gradient across alveolar capillary membrane that cannot be compensated even with a resting transit time of 0.75 seconds. Diffusion further decreases with shortened transit time following exercise.22 As a result, PaO2 is lowered and is in the range that falls in to the steep portion of the oxygen dissociation curve. This results in marked decrease in oxygen content of the pulmonary capillary blood even with a small decrease in PaO2.Long term residents of high altitude have less alveolar arterial oxygen difference, better diffusing capacity and higher mean PaO2 compared to low landers exposed to high altitude.

Oxygen transport On exposure to high altitude PaO2 levels are found in the steep portion of oxygen dissociation curve to cause substantial decrease in the oxygen content of haemoglobin(Hb) even with a slight fall in PaO2. In order to improve oxygen uptake in the lung, oxygen dissociation curve that determine the oxygen content of the blood shifts to left due to respiratory alkalosis caused by hypoxia induced hyperventilation. At the tissue level oxygen dissociation curve shifts to right to facilitate oxygen release from Hb. This rightward shift is due to renal compensation for respiratory alkalosis and increase in level of 2, 3-diphosphoglycerate (2,3-DPG) concentration.27

Pulmonary circulation

Erythropoiesis

The pulmonary circulation is a high-flow, low-pressure system.23 At altitude the entire lung is hypoxic and hypocapnic. Vasomotor tone of pulmonary vasculature is largely due to the local effects of oxygen and carbon dioxide. Hypoxia causes acute pulmonary vasoconstriction that can be reversed by oxygen inhalation. Hypoxic pulmonary vasoconstriction has substantial inter-individual variability and results in acute elevation of pulmonary pressures that becomes substantial when PAO2 falls below 70 mm of Hg.24 It may be noted that acute effects of high altitude are due to dramatic changes in pulmonary hemodynamics without appreciable changes in pulmonary mechanics.

Chronic hypoxia in high altitude residents brings out structural changes-intimal fibrosis, smooth muscle hypertrophy and collagen proliferation with remodelling of pulmonary vasculature that cannot be reversed by correcting hypoxia. As a result, there is sustained increase in resting pulmonary arterial pressure and pulmonary vascular resistance. It takes several weeks to months after return to sea level for normalisation of right ventricular hypertrophy and pulmonary vascular pressures in such cases.21 Andean highlanders have high pulmonary artery pressures and descent to sea level or normal oxygen tension does not restore pulmonary artery pressure or right ventricular hypertrophy to normal levels. In contrast, Tibetan highlanders have minimal elevation of

Hemoconcentration occurs on exposure to high altitude.

Within few days of high altitude stay, Hb level increases due to increased erythropoiesis due hypoxia mediated erythropoietin release from the kidney.28 Increased oxygen content of the blood improves oxygen delivery. Variability in the degree of high altitude induced erythropoiesis is observed in different highland population. Environmental and genetic factors have been implicated for the same.

Colorado residents and Andean highlanders exhibit significant erythrocytosis while Tibetan highlanders have minimal or no erythrocytosis.29,30 Presence of excessive cobalt as well as genetic factors have been attributed for this difference among Andean highlanders. Polycythemia with hematocrit beyond 60% has deleterious effect on cardiac output and microcirculation due to increased viscosity of the blood. Hypercoagulability with prothrombotic state due to high altitude has been implicated in the pathogenies of high altitude pulmonary edema and thromboembolism.

Tissue Changes

In the face of decreasing driving pressures observed in high altitude dwellers, many structural and metabolic changes occur to improve oxygen delivery and its utilization. These changes include: levels of myoglobin, cytoglobin, erythropoietin, neuroglobin and enzymes involved in oxidative phosphorylation.31

BENEFITS OF HIGH ALTITUDE

•

Increased ventilation rate

•

increased red cell mass and hematocrit

•

Increased red cell mass and hematocrit

•

Muscles extract more oxygen

•

Increased cardiac output

•

Decreased cardiovascular mortality

•

Increased basal metabolic rate

•

Decreased conditions

•

Better bronchial asthma control

•

Reduced appetite

•

Weight loss – reduced levels of obesity

•

Better glucose metabolism

•

Lower free radical injury at cellular level

•

Delayed aging

•

Increased longevity

air

pollution

and

hypoallergenic

ILL EFFECTS OF HIGH ALTITUDE

Sudden ascent to high altitude and stay there without adaptation is risky with high susceptibility to high altitude associated illnesses such as Acute Mountain Sickness(AMS), High Altitude Cerebral Edema(HACE) and High Altitude Pulmonary Edema(HAPE).21,35 Their frequency increases with increasing altitude. Thus height of stay matters so also rate of ascent, physical conditioning and associated morbidity, besides individual susceptibility. Young, obese and old are vulnerable. There are no specific markers to predict susceptibility but those with poor hypoxic ventilatory response(HVR) are at greater risk.

Acute high altitude illnesses respond to oxygen and descent to lower altitude. These conditions have several overlapping features. They can be prevented by avoiding undue physical exertion, gradual ascent, acclimatization and drug prophylaxis. Incidence varies from 9% to 70% among different population such as trekkers, skiers and Armed Forces personnel. Altitude-related exposure to cold may also contribute to illness. High altitude illnesses,

259

High Altitude Headache

High Altitude Headache (HAH) is very commonly reported among those who are inducted to high altitude and is attributed to increased water loss with hyperventilation, overexertion and insufficient energy intake. Hypercapnia may also contribute by cerebral vasodilation.39 Treatment consists of adequate hydration and analgesics for symptomatic relief.

Acute Mountain Sickness (AMS)

AMS is the commonest altitude sickness characterised by frontal headache, fatigue or weakness, dizziness or light headedness, nausea or vomiting, anorexia and difficulty in sleeping, occurring 4 hours to 36 hours of altitude exposure. Symptoms frequently occur on the first day and are severe in the morning after the first night stay at high altitude.

Incidence of AMS is altitude and time dependent affecting 22% to 70% of sojourners.40 Rapid ascent to higher altitude affect the most.21 The exact pathogenesis is not clear.

Cerebral vasodilatation, cerebral edema, changes in brain volume, raised intracranial pressure and hypoventilation have been implicated in the pathogenesis of AMS.41,42 Symptoms are nonspecific and AMS can be mistaken for viral illness, poor sleep, intense exercise, jet lag, alcohol intake, carbon monoxide poisoning, dehydration and dyselectrolemia. There are no specific clinical findings.

Few crackles over lungs, peripheral edema and low oxygen saturation in some cases have been observed.

Mental status as well as neurological examination is normal in AMS and the presence of abnormal mental status and or neurological finding suggests HACE which is a serious condition. Severity of AMS can be assessed by the Lake Louise Symptom Score Questionnaire (Table 2).43 AMS is a self-limiting illness and recovery from it is expected after three days. In serious cases recovery takes longer. Treatment consists of supplemental oxygen through nasal prongs or face mask, rest and analgesics for relief of headache. Acetazolamide, a carbonic anhydrase inhibitor is widely used in the dosage of 250 mg twice day for three days in the treatment of progressive and severe AMS.44 Dexamethasone can be used in a remote location in severe cases where rapid evacuation is not possible and descent is undertaken by keeping the subject ambulatory. Descent to lower altitude is required in few severe cases having progressive symptoms. A descent of about 300 meters can improve symptoms. Treatment inside a portable hyperbaric chamber is recommended in severe cases and in those cases where descent is not possible nor oxygen is available for therapy (Figure 4).45

CHAPTER 56

In the ancient text- ‘Kumarasambhava’ by the famous poet Kalidas, Himalayan mountains are described as a treasure house of innumerable precious stones, minerals, important herbs, trees, plants, creepers with delightful flowers; as the abode of the Siddhas, Ascetics, Yakshas, Kinnaras, Kiratas and various types of animals and birds; as the source of the Ganga and several other rivers. Undoubtedly Himalayan ranges have been a great treasure of knowledge and strength. Long term residents of Tibetan plateau have adapted very well to high altitude by exhibiting many beneficial physiological responses.

Some of the beneficial effects of high altitude residence are enumerated below:32-34

often pose serious challenges to health care system since prompt therapy is difficult to arrange due to lack of adequate medical facilities at the location of occurrence and hurdles in evacuating such cases to lower altitude where treatment facilities are available. Among altitude related acute illnesses, HAPE and HACE are serious conditions and can be fatal with mortality approaching 30%.36-38

260

Table 2: Lake Louise Symptom Score Self Report Questionnaire. For assessing severity of AMS Symptom Headache

PULMONOLOGY

Gastrointestinal

Fatigue or weakness

Dizziness/light headedness

Difficulty of sleeping

Severity

Point

No headache

0

Mild headache

1

Moderate headache

2

Severe headache

3

No gastrointestinal symptoms

0

Poor appetite or nausea

1

Moderate nausea or vomiting

2

Incapacitating

3

Not tired ore weakness

0

Mild fatigue/weakness

1

Moderate fatigue / weakness

2

Incapacitating

3

Not dizzy

0

Mild dizziness

1

Moderate dizziness

2

Severe dizziness, incapacitating

3

Slept as well as usual

0

Did not sleep as well as usual

1

Woke up many times, poor nightâ&#x20AC;&#x2122;s sleep

2

Treatment consists of oxygen supplementation, hyperbaric therapy, descent to lower altitude of more than 1000 meters and use of dexamethasone. Oxygen should be given and it produces beneficial effect equivalent to 300 meters descent for every 1% increase in inspired oxygen above 21%. Hyperbaric therapy using portable chamber is a temporizing measure awaiting descent to lower altitude and the beneficial effects of hyperbaric therapy are slow to develop (Figure 4).37,45 Keeping the patient in hyperbaric chambers is useful as it improves symptoms and buys time for arranging descent. Emergency therapy with intramuscular administration of dexamethasone (4-8mg) is recommended in severe cases to reduce cerebral edema.

This drug can be repeated once in every 6 hours.35,41

Unable to sleep

3

High Altitude Pulmonary Edema(HAPE)

*Score of > 4 AMS ** Score >10 severe AMS requiring immediate intervention

Inside these hyperbaric chambers, a pressure up to 2 psi and FIO2 of 0.21% with low CO2 can be maintained by ensuring sufficient gas flow by using a foot pump to simulate benefits of 2000 feet to 5000 feet descent.46

High Altitude Cerebral Edema(HACE)

It is serious condition, potentially fatal having features of altered mental status or ataxia in a person with features of acute mountain sickness.41 In cases of HACE, there is gross cerebral edema (unlike mild edema seen in AMS), markedly elevated Intracranial pressure and micro haemorrhages in the brain. Ataxia can be demonstrated by heel to toe walking on a straight line or by positive Romberg sign.47,48 AMS is incapacitating and may be associated with global neurological dysfunctions such papilledema, visual changes, aphasia, cranial nerve palsy, hallucinations, seizures, paraesthesia, clonus, bladder dysfunction.49 It mimics many other causes of encephalopathy and gradual onset with global neurological dysfunction in a case of AMS prompts the

Fig. 4: Portable hyperbaric chamber with foot pump diagnosis of HACE. Presence of somnolence, stupor and changes in pupillary responsiveness indicate severe disease with poor outcome. Some cases may have pulmonary edema.

High Altitude Pulmonary Edema is a form of noncardiogenic pulmonary edema affecting people after ascent to altitude usually above 2700 meters.50 It can occur at altitudes as low as 2200 meters. Generally, it develops 2 days to 4 days after arrival at high altitude in other wise young and healthy individual who has climbed too fast or exerted on arrival.51 The incidence is from 0.25 % to 15 %, depending upon the altitude being inducted to and speed of ascent.21,35 Late onset HAPE is a new entity documented in Ladakh with manifestations of HAPE occurring 7 days to 65 days after the induction to high altitude.

The incidence of HAPE increases with increase in altitude and rate of ascent. Induction to high altitude by air than by road predisposes to higher risk especially if altitude is greater than 11,000 feet. Individual susceptibility varies and occurrence of recurrent attacks has been reported in the susceptible individuals. Pre-existing common cold and respiratory tract infection as well as unaccustomed physical exertion are risk factors. Re-inductees with previous history of HAPE are at a greater risk of recurrence. Some develop HAPE at a particular altitude on repeated ascents to that altitude only but not at a lower

altitude. Highlanders who descend to sea level and return back are also vulnerable.

Patients of HAPE may have symptoms of AMS initially before becoming breathless. They may have cough which is initially dry later becoming productive and frothy and pink. Examination reveals tachycardia, tachypnea, central cyanosis and inspiratory crackles over lung fields. As severity of HAPE increases, there is worsening of breathlessness and tachycardia and the inspiratory crackles become diffuse and bilateral with development of accentuated pulmonary component of 2nd heart

Fig. 5: Alveolar opacities BMZ & BUZ of lung fields

Fig. 6: CT Chest: Patchy alveolar opacities over right lung

Table 3: Medications for the Prevention and Treatment of Altitude Illness Drug

Indication

Dose

Contraindication

Acetazolamide

Prevention of AMS

125 mg twice daily

Liver disease

Treatment of AMS

250 mg BD

Avoid in CKD with GFR less than 10 ml/minute

Prevention of HAPE

20-30 mg sustained release(SR) BD

Treatment of HAPE

20-30 mg SR BD

Caution when in use with other antihypertensives; sudden drop in BP when used sublingually.

2mgQID/4mg BD

Avoid in peptic ulcer,Diabetetes.

Nifedipine

Dexamethasone Prevention of AMS Tadalafil

Sidenafil

Salmetrol

Treatment of HACE

8mg followed by 4 mg 6 hourly

Prevention of HAPE

10 mg BD

Liver disese Childâ&#x20AC;&#x2122;s class C

Treatment of HAPE

Role not established

Dose adjustment in CKD with GFR less than 50ml/minute

Prevention of HAPE

50 mg 8 hourly

Liver disese Childâ&#x20AC;&#x2122;s class C

Treatment of HAPE

Role not established

Dose adjustment in CKD with GFR less than 50ml/minute

Prevention of HAPE

125 microgram BD

Treatment HAPE

Role not established

Avoid concurrent use of beta blockers and in CAD

261

CHAPTER 56

Pathogenesis of HAPE is attributed to hypoxia induced exaggerated uneven pulmonary vasoconstrictor response.35 This results in hypo-perfusion of constricted vessels while permitting hyper-perfusion of less constricted pulmonary vessels. This augmented pulmonary pressure and flow cause stress failure of capillary endothelium leading to leaky membrane and extravasation of fluid in to pulmonary interstitium and alveoli.52 Thus the events leading to HAPE are exaggerated non-homogenous pulmonary vasoconstriction, over perfusion of some regions of the pulmonary vascular bed, increased pulmonary capillary pressure, stress failure of pulmonary capillaries and leakage of alveolar fluid across capillary endothelium. Augmented sympathetic activity, increased levels of endothelin-1 and decreased levels of nitric oxide (NO) have been implicate in the pathogenesis. HAPE is also considered as a form of neurogenic pulmonary

edema due to sympathetic mediated venous constriction.

Role of nitric oxide(NO) is supported by the beneficial clinical response to phosphodiesterase-5 inhibitors.

Role of Inflammation in the pathogenesis is ssuggested by the pre-existing cold and upper respiratory infection seen in large number of patients with increased levels of C-reactive proteins and other inflammatory markers.

In addition, various kinins have been identified in the edema fluid that are likely to increase permeability and recruit leukocytes.53

PULMONOLOGY

262

sound and features of right heart failure. HAPE may be unilateral in early or mild HAPE, usually involving right middle lobe. Pulse oximetry is a useful tool to document hypoxia and to monitor response to therapy. Oxygen saturation is inappropriately reduced and is much lower in severe cases. In a study of HAPO patients at an altitude of 4559 meters, observed values for SaO2 was 48± 8% and for PaO2 23± 3 mm Hg as against healthy control values of 78±7% and 40±5mm of Hg respectively.54 X-ray chest and computed tomography reveal patchy alveolar opacities (Figures 5 & 6). Echocardiography reveals evidence of pulmonary hypertension. In HAPE both pulmonary wedge pressure and cardiac size are normal.55

Prevention

Drug Prophylaxis - in those who have experienced HAPE before, use of nifedipine prophylactically (slow-release formulation 20 mg twice daily prior to ascent, then three times daily) reduces the incidence of HAPE.56 Nifedipine is a pulmonary vasodilator that causes smooth muscle relaxation with fall in pulmonary pressures. The drug appears to be ineffective in preventing AMS. Prophylactic use of an inhaled β-agonist may reduce the risk of HAPE.57 Medications for the prevention and treatment of Altitude Illnesses are shown in the Table 3.35,41,44,56-59

Acclimatization

High altitude illness can be prevented by acclimatization by means of gradual ascent and physical activity after initial rest on induction to high altitude(60,61).

It is recommended to ascend 300-350 meters per day at altitudes above 2700 meters (sleeping altitude).

Acclimatization schedules followed in high altitude areas are as under:

Stage I: 9000-12000 feet •

Day 1 & 2: Rest

•

Day 3 & 4: Walk 1.5-3 km, avoid steep climbs

•

Day 5: Walk up to 5 km

•

Day 6: Walk up to 5 km. Climb 300m

Stage II: 12000-15000 feet •

Day 1 & 2: Walk up to 1.5-3 km, avoid steep climbs

•

Day 3: Walk up to 3 km, climb up to 300m

•

Day 4:Climb 300m without equipment.

Stage III: 15000-18000 feet •

Day 1 & 2: Walk up to 1.5-3 km, avoid steep climbs

•

Day 3: Walk up to 3 km, climb up to 300m

•

Day 4: Climb 300m without equipment

Absence from high altitude(Re-inductees) •

Less than ten days acclimatization not required

•

More than 28 days: Complete acclimatization

10 to 28 days •

Day 1 & 2: Rest except short walk

•

Day 3: Walk at slow pace 1-2 km, avoid steep climb

•

Day 4: Walk for 1-2 km, climb up to 300m.

Treatment

Apart from rest and supplemental oxygen immediate descent to lower altitude is vital for a better outcome and an early recovery. Patient should be evacuated to lower altitude as soon as possible since an immediate descent of 500 meters to 1000 meters can hasten recovery. Oxygen therapy is the mainstay of therapy. High flow rates of oxygen through face mask/ nasal prongs to ensure FIO2 of 40% is given to keep arterial oxygen saturation of greater than 90% and oxygen therapy is continued till one becomes asymptomatic and pulse rate normalises. In remote locations where descent is not possible, therapy with 10 mg nifedipine per orally can be initiated with careful monitoring for hypotension and if no significant hypotension occurs, then the drug can be repeated after 30 minutes. Though many pulmonary vasodilators have been tried, nifedipine remains the drug of choice.The use of hyperbaric chamber especially portable that simulates conditions of lower altitudes is recommended and is quite effective in managing HAPE when urgent descent is not possible. Keeping the patient inside a portable hyperbaric chamber achieves the benefits of simulated descent of 1500 meters to 1800 meters. In a hospital setting, larger stationary hyperbaric chambers are used. The use of CPAP can improve oxygenation.

Sub-Acute Mountain Sickness(SAMS)

This condition has been described among Indian soldiers who stayed for more than 10 weeks in high altitude between 5800 to 6700 meters and presenting with features of pulmonary hypertension and right heart failure due to exaggerated hypoxic pulmonary vasoconstriction.62 Treatment is evacuation to lower altitude and supportive therapy.

Chronic Mountain Sickness(CMS)

This condition also known as Monge disease was described in 1920s by Carlos Monge in high-altitude residents of the Andes who presented with polycythemia.63 It is characterized by a triad of polycythemia, hypoxemia and impaired mental function among long term residents (> 1 year). These cases have extreme polycythemia, with Hb and haematocrit values as high as 23 g/dL and 83% respectively. They have lower oxygen saturation and hypoxic ventilatory response with relative hypercapnia.

They develop pulmonary hypertension and right ventricular enlargement. Features include headache, dizziness, somnolence fatigue, irritability, impaired concentration, loss of mental acuity, depression and even hallucinations.64 They have poor exercise tolerance; though exertional breathlessness is uncommon.65 They also have clubbing and cyanosis.

Treatment consists of descent and stay at lower altitude, periodic phlebotomy, diuretics and respiratory stimulants.64 Descent to sea level is the definitive treatment. However, for those who wish to remain at altitude, phlebotomy and administration of supplemental oxygen are beneficial. Phlebotomy improves many of the

neuropsychological symptoms, and in some patients, pulmonary gas exchange and exercise performance have also improved. ACE inhibition has been found to be effective and safe to ameliorate altitude polycythaemia while also in reducing proteinuria.66 Role of drugs such as medroxyprogesterone, acetazolamide and sildenafil have not been established. Acetazolamide may be useful in improving oxygen saturation during sleep.

Medroxyprogesterone has been tried with some success.

High Altitude Pulmonary Hypertension

HIGH ALTITUDE ILLNESSES UNRELATED TO ACCLIMATIZATION

There are several respiratory conditions that are influenced by high altitude exposure but their occurrence

Chronic Obstructive Pulmonary Disease(COPD)

Incidence of COPD is lower in high altitude. Those with pre-existing COPD become more hypoxemic at high altitude.32 These cases should undergo detailed evaluation before induction to high altitude and to be assed for therapy with O2 supplementation.69 If PaO2 is found to be < 50-55 mm Hg, travel to high altitude if deemed necessary can be undertaken with adjusted supplemental O2 therapy and pulse oximetry monitoring. Pneumothorax becomes worse at high altitude and those with bullae and emphysema should not travel to high altitude. All cases of COPD should be evaluated for the same before they are advised for travelling to high altitude.68

Bronchial Asthma

High altitude stay has been found to be beneficial to asthma patients due to lower ambient temperature, humidity, allergen load and air density. Decreased airway resistance improves airflow and asthma control.70 Ultraviolet radiation exposure at high altitude has an immunomodulatory effect. However, severe hypoxia, hypocapnea and cold air prevalent in high altitude can have adverse impact on asthma control by aggravating bronchial hyper-responsiveness.

Well controlled asthmatics can travel up to altitude of 5000 meters provided they continue baseline medications and carry ample rescue medications and steroids. Those with severe asthma are advised against travel to high altitude.

However, some uncontrolled and refractory cases can benefit from high altitude sojourn undertaken with proper medication and supervision due to aforementioned beneficial effects of high altitude on asthma control.

Interstitial Lung Disease: Exposure to high altitude worsens dyspnea, hypoxemia and pre-existing pulmonary hypertension.71 These cases have poor exercise tolerance.

Treatment is essentially supportive and supplemental oxygenation if PaO2 < 50-55 mm Hg.

Fig. 7: X-ray chest showing wedge opacity RLZ with blunting of CP angle and elevated diaphragm

263

Pulmonary Thromboembolism & thrombosis: High altitude is a prothrombotic state with increased risk of thrombosis and pulmonary thromboembolism.68 These

Figs. 8 & 9: CT Angio: thrombus in right lower pulmonary artery with pleural based consolidation

CHAPTER 56

In this condition there is pulmonary hypertension (mean pulmonary artery pressure>30 mm of Hg and systolic pulmonary artery pressure > 50 mm of Hg) with cor pulmonale without excessive erythrocytosis (Hb <21 g/ dl in men and <19 gm/dl in women) among long term residents of high altitude.67 They have overlapping features of subacute mountain sickness and CMS. Treatment of this condition is descent to lower altitudes and supportive.

is unrelated to acclimatization.68 These conditions include: Chronic Obstructive Pulmonary Diseases(COPD), Bronchial Asthma, Interstitial Lung Disease (ILD), Sleep Apnea, Pulmonary Hypertension and Pulmonary Thromboembolism.

PULMONOLOGY

264

cases should be evacuated to lower altitude and managed on standard lines. Figures 7, 8 & 9 show thrombus in the pulmonary artery with pulmonary infarct in a high altitude inductee.

Pulmonary hypertension: Those with pre-existing pulmonary hypertension are at increased risk of HAPO, right heart failure and subacute mountain sickness.

These cases should avoid travel in to high altitude. If travel becomes unavoidable then supplemental O2 and nifedipine SR at 20 mg BD should be given during their stay in high altitude. Sildenafil/dexamethasone as an alternative to nifedipine can be given.

Obesity Hypoventilation Syndrome: Obstructive sleep apnea improves but central sleep apnea worsens on exposure to high altitude.72 The beneficial effect of lower incidence of obstructive apneas is offset by increase in central apneas. Those who travel to high altitude should use Continuous Positive Airway Pressure (CPAP) ventilation. Due to hypobaric conditions, set CPAP is not delivered by the portable CPAP machine in the absence of pressure compensating features. In this situation higher pressure is needed to deliver set pressure by the CPAP machine to produce relief from symptoms.

CONCLUSIONS

High altitude regions in the world are increasingly being explored and have become permanent abode for about 2% of worldâ&#x20AC;&#x2122;s population. High altitude is an alien environment of extreme hypoxia and hypothermia with low barometric pressure and intense exposure to ultraviolet radiation. Respiratory system vital for oxygenation of tissue plays an important role in adaptation to high altitude. Maladjustment to high altitude conditions leads to various illnesses that are acute, subacute and chronic in nature. Majority of them affect respiratory system. Treatment of these conditions is essentially the management of high altitude related hypoxia that can be best achieved by evacuating them to normobaric normoxic condition. Prophylactic medication and strict adherence to acclimatization schedule significantly reduce risks of altitude related acute illnesses occurring among low landers who ascend to high altitude.

Those long term residents who acclimatize and adapt well are sure to harvest several physiological benefits. In the human evolution, higher regions of the world have inspired many to conquer nature by reaching to greater heights. High altitude regions of the world not only pose physiological challenges but also provide the milieu for the mankind to evolve to higher levels.

Maladies are the tragedies of time Affecting one who is lame In this evolutionary game Conquer time to be in infinite frame Are mountains really tall From the star looks very small In inverted space a narrow pit

They are big for tiny a lot To become the master through their hat.

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C H A P T E R

57

Since times immemorial mountains have fascinated human beings tempting them to come, explore and conquer them. The magnitude of these explorations was limited but still one comes across many writings and its extent especially in Alps and Andes. In 20th Century with opening of these areas for economic activities, tourism and as battle ground in Indo-China war and Indi-Pak war at Siachin, the real extent of manifestations were noticed.

Air travel has also compounded the problem by enabling unacclimatised travelers to reach high altitude. The exact incidence of Acute Mountain Sickness is unknown as mild symptoms are not reported and ignored as travel related exertion.

Acute Mountain Sickness Rajiv Raina, Sanjay K Mahajan

gained acclimatization he can develop acute high altitude illnesses. The factors contributing significantly in the process are the environmental factors, genetic factors and changes induced in cardiovascular, respiratory and oxygen transport/delivery systems.

ENVIRONMENTAL FACTORS

The environmental factors responsible are: 1.

Decreased partial arterial pressure of oxygen (PaO2). It falls further due to hypoventilation in sleep leading to tissue hypoxia.

2.

Cold temperature, high wind velocities and resultant drop in humidity of air. All these lead to dehydration due to increased insensible loss of water from body.

3.

Increased ionizing and non ionizing radiations.

4.

Lowered bariatric pressure which is directly proportional to high altitude is a major factor responsible for acclimatization and development of acute mountain sickness.

INTRODUCTION

It is estimated that about 150 million people reside permanently at an altitude of 2500 meters or above and about 50 million people enter these areas every year.

These new entrants to high altitude areas comprise mainly tourists, trekkers, mountaineers, pilgrims, porters, workers, soldiers etc. The entry of these un-acclimatized individuals along with native highlanders who reenter high altitudes after moving down or ascending up further from native heights renders them liable to Acute Mountain Sickness (AMS) at high altitude (HA) ranging from Benign Acute Mountain Sickness to life threatening or fatal disorders like acute High Altitude Pulmonary Oedema (HAPO) or High Altitude Cerebral Oedema (HACO).

There is no consensus of the altitude at which high altitude illness can occur but 2500 meters altitude is taken as high altitude by most. Altitudes over 5400 meters are taken as extremely high altitudes as at this level permanent acclimatization is not possible. However, occasionally high altitudes illnesses are known to occur even at moderate altitudes of 2000 meters to 2700 meters.

As a person ascends from altitude of 2000 meters one becomes susceptible to high altitude illnesses. The probability of developing symptoms depends mainly on altitude reached, speed of ascent, physical activities carried out after attaining that altitude and other variables like age, sex, obesity, prior history, hydration status etc.

At present however, there is no consensus yet of the, association of these variable with high altitude illnesses.

Arrival in high altitude results in certain physiological adjustments enabling the person to survive in that environment. If a person fails to acclimatise or loses the

PATHO PHYSIOLOGY OF HIGH ALTITUDE ILLNESSES

At HA due to hypobaric hypoxia ventilation increases resulting in reduced oxygen gradient from inspired air to alveoli. This response in seen within few hours of ascent and increases in next few days and is mediated by peripheral chemoreceptors in carotid and aortic bodies and results in increased respiratory rate and tidal volume.

The resultant respiratory alkalosis is slowly compensated by renal excretion of bicarbonate. If an individual is unable to provide this chemoreceptor mediated ventilator response, acclimatization is impaired leading to high incidence of high altitude related disorder. At high altitude a small drop of oxygen tension results in significant drop in SaO2. The difference in Arterial O2 tension and alveolar O2 tension is called A-a difference. This A-a difference is also reduced in high altitude. Thus due to hypoxia induced pulmonary vasoconstrictions there is increase in pulmonary artery pressure leading to more uniform perfusion of lungs and is seen in all acclimatized lowlanders However despite this hyperventilation and reduction in A-a gradient arterial oxygen tension is still lower than at sea level. It is compensated by increase in hemoglobin.

This transient increase in low-landers depends on extent, rate and duration of ascent and returns to normal within 3 weeks of descent.

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268

Initially this rise in hemoglobin is due to increase hemoconcentration due to diuresis resulting in decrease in plasma volume by 15-20% but after few days it is due to increase release of erythropoietin. The hyperventilation, reduction of A-a gradient and increase in haemoglobin and haematocrit help in bringing oxygen level in blood to near normal. However to decrease the affinity of hemoglobin with oxygen there is increase in partial pressure of oxygen at HA which reduces the affinity of hemoglobin to oxygen and shifts the hemoglobin oxygen dissociation curve to right. This shift to right favours offloading of oxygen from hemoglobin.

At HA in spite of tachycardia there is fall in cardiac output due to drop in stroke volume by about 20-25%. This drop in stroke volume is due to decrease in venous return and hypoxia induced myocardial depression. Plasma volume also normally decreases on ascent due to alkaline diuresis.

This reduction in plasma volume is sustained along with subsequent increase in total blood volume.

The hypoxic ventilator response (HVR) is a basic response to hypoxia via the chemoreceptors and is foundation for successful acclimatization. A subnormal HVR would lead to alveolar hypoventilation, lower alveolar O2 tension causing pulmonary vasoconstriction leading to cerebral vasodilatation due to high CO2 in blood.

The likely pathogenesis of benign AMS and HACO is different from other HA illnesses. The basic abnormality between Benign AMS and HACO is cerebral oedema, the common underlying unifying factor with HAPO is probably pulmonary arterial hypertension. The increase in pulmonary blood flow and pulmonary artery pressure leads to “stress failure” of the pulmonary capillaries leading to leakage of fluid in to interstitial and alveolar spaces resulting in pulmonary oedema. Exercise further increases the PA pressures and can therefore precipitate HAPO. The key determinant of HA illness, risk and severity include both individual susceptibility factors and altitudinal factors (rapid rate & height) of ascent and total change in altitude.

Individual factors contributing to AMS include underlying disease like cardiac and pulmonary disease, pre existing blood disorders and other chronic medical diseases. Those with symptomatic cardiac or pulmonary diseases are more likely to develop AMS & should avoid high altitude.

CLINICAL FEATURES

Benign Acute Mountain Sickness

Of all types of mountain sicknesses Benign Acute Mountain Sickness is commonest. The exact incidence is not known but it usually develops within 6-96 hours of stay at altitude. The presentation of AMS commonly starts with headache which is frontal in location, throbbing in character and is bilateral. It increases in morning on waking up, on exertion and straining. It may be accompanied by lightheadedness, malaise, nausea, vomiting, sleep disturbance and shortness of breath. In

many cases the headache can be the only symptom and it usually respond to analgesics but in few it becomes severer with progression of disease failing to respond to analgesic. It may be associated with decreased urinary output also.

The physical examination may not yield any characteristic findings. These symptoms will have a benign and self limiting course and will tend to disappear in a week.

The relationship of AMS with history of ascent to higher altitude is characteristic. AMS may have to be differentiated from common viral illnesses, effects of alcohol and from a dangerous syndrome of HACO. Karinen et al noted that it was possible to predict and diagnose AMS at an early stage by measuring oxygen saturation by pulse oxymeter at rest and after moderate exercise. They concluded that lowering of SaO2 predicts the impending AMS. The Lake Louis Consensus group derived Lake Louis Scoring System is gold standard for AMS (Table1) which is based on clinical and subjective symptoms. A score 3 or more signifies AMS and a score >5 indicate severe mountain sickness.

High Altitude Pulmonary Oedema (HAPO)

Of all altitude related illnesses HAPO is commonest and in a large study it contributed about half of all high altitude related illnesses. It has been associated with altitude as low as 2500-3000 meters.

The first symptoms of HAPO occur within 1-3 days after arrival at altitude. In adults, these symptoms commonly occur after exercise and consist of cough, shortness of breath, chest tightness, and fatigue. In approximately half the cases, these symptoms are associated with the typical symptoms of AMS. Initially, the cough is nonproductive, but thin, clear, or yellowish sputum is later produced.

In some cases, the sputum is tinged with blood. Fatigue may be the first symptom, occurring even before dyspnea develops and manifest as the inability of the affected individual to maintain the pace of the group. In a study of 417 cases by Rao et al the majority of cases occurred in those who ascended rapidly especially by air travel, and in those who re-entered HA. The onset of symptoms occurred within a week and in majority it occurred within first three days of arrival at HA. In about 50% of cases symptom appeared within 12 hours and occurrence was rare after one week. The onset was earlier among reinducted individuals when compared with fresh arrivals. Five patients in the study developed symptoms immediately on arrival at HA. Physical findings in HAPO include cyanosis, temperature as high as 101°F (38.5°C, a higher fever creates suspicion of pneumonia), flat neck veins, and crackles over the mid chest. Heart and respiratory rates are increased. In a large study conducted on soldiers of Indian Army posted at HA, cough (96%), breathlessness ((94%), headache (94%), fever (65%), expectoration (60%), chest pain (59%), bodyaches (48%), haemoptysis (37%), vomiting (34%), dizziness (30%) and anorexia (25%) were main features noted. Majority of patients complained of disturbed sleep

Table 1: Lake Louise Score of Acute Mountain Sickness A. Questionnaire 1. Headache 0. No headache 1. Mild headache 2. Moderate headache 3. Severe headache 2. Gastrointestinal Symptoms 1. Poor appetite or nausea 2. Moderate nausea and vomiting 3. Severe nausea or vomiting, incapacitating 3. Fatigue and/or weakness 0. Not tired or weak 1. Mild fatigue/ weakness 2. Severe fatigue/ weakness incapacitating 4. Dizziness/ Lightheadedness 0. Not dizzy 1. Mild dizziness 2. Moderate dizziness 3. Severe dizziness, incapacitating 5. Difficulty sleeping 0. Slept as well as usual

B. Clinical assessment

Mild

Moderate

Severe

<120

120-140

>140

-

Âą

Âą

6. Change in mental status

Pulse (bmp)

0. No change in mental status

Respiratory rate (/min)

<40

40-50

>50

Conscious

Yes

Yes

Yes/No

<1/2 lung field

>1/2 lung field

>1/2 lung field

1. Lethargy/lassitude 2. Disoriented/confused 3. Stupor/confused 4. Coma 7. Ataxia (heel to toe walking) 0. No ataxia 1. Maneuvers to maintain balance 2. Steps offline 3. Falls down 4. Cannot stand 8. Peripheral Oedema 0. No peripheral oedema 1. Peripheral oedema at one location 2. Peripheral oedema at two or more location C. Functional score Overall if you had any symptoms how did they affect your activities?

0. Not at all 1. Mild reduction 2. Moderate reduction 3. Severe reduction

1. Did not sleep as well as usual 2. Woke many times, poor sleep 3. Could not sleep and decreased urinary output was also reported after onset of symptoms. Rao et al classified HAPO in to three grades of severity on clinical criteria (Table 2).

On examination, patient is sick looking with tachyponea and tachycardia. The presence of altered sensorium may indicate underlying cerebral oedema and presence of cyanosis also indicate severe disease. On auscultation of chest, the extent of crepitation will depend on severity of the disease. Fine crepitations at bases of lung are audible in early part and resolving disease. The presence of fine crepitations in the interscapular area has been reported as earliest auscultatory clinical finding of HAPO. Signs of pulmonary arterial hypertension can also be present with

Cyanosis

Crepitations

loud pulmonary component of second heart sound.

Lake Louis Consensus on definition of altitude illness defines HAPO as (in the presence of recent gain in altitude) the presence of at least 2 of 4 symptoms (dyspnoea at rest, cough, weakness or decreased exercise performance, and chest tightness or congestion) and any 2 of 4 signs (crackles/wheezing in at least one lung field, central cyanosis, tachypnoea and tachycardia).

Investigations may reveal mild to moderate polymorphonuclear leucocytosis. It ranges from 700028000 and may not be related to severity of HAPO. The mean pH, PO2 and oxygen saturation may be 7.4, 34 mm Hg and 63% respectively and respiratory alkalosis.

The ECG shows sinus tachycardia, right axis deviation, right atrial enlargement and T wave inversion in right precordial leads. Echocardiography may show dilatation of right ventricle and pulmonary artery and diastolic dysfunction of left ventricle.

The diagnosis of HAPO is based on history, clinical features and is confirmed by performing X-ray chest. X-ray chest can reveal bilateral soft fluffy, non-homogenous shadows which can be asymmetric. The involvement of right side of lung is more common, and mid and lower zones are also more commonly involved than upper zone. Main pulmonary trunk and right pulmonary artery are prominent. Lichtenstein et al reported the utility of Ultrasound Comet Tail Sign (UCTS) for detection of interstitial pulmonary edema resembling a comet with tail. Performing ultrasonography of chest routinely at HA has been able to diagnose subclinical HAPO by UCTS and correlates inversely with oxygen saturation. It is a useful in diagnosis of HAPO in early stage.

High Altitude Cerebral Dedema (HACO)

It is least common but most dangerous high altitude illness and is also called malignant acute mountain sickness. HACO in isolation is not common but it occurs usually in combination with HAPO. It should be suspected in patients of AMS with altered sensorium.

The onset of ataxia is earliest. Dimmunition of vision, dizziness, drowsiness progressing to confusion and coma are other features noted. Psychiatric symptoms like mood changes and hallucinations have been noted. Seizures, incontinence or retention of urine have also been reported.

The onset of HACO in AMS can occur in 1-3 days in untreated cases and alteration in level of consciousness is most important sign. It may be associated with VI and

CHAPTER 57

0. No GI symptom

269

Table 2: Severity of High Altitude Pulmonary Oedema

PULMONOLOGY

270

Relief valves

Windows

Tie-down strops

Zipper

Optional Intake Valve (for air compressor) Intake Valve (for foot pump)

Sphygmomanometer

Fig. 1: Hyperbaric (Gamow) Bag VII cranial nerve palsies, hemiparesis and changes in muscle tone. Ophthalmological examination can reveal venous engorgement, blurred margins of optic disc and papillioedema. The presence of papillioedema is specific to HACO. HACO usually occur at isolated places often as an emergency where investigations are not available. The diagnosis is made on clinical picture and if available, x-ray chest may show co-existing HAPO.

TREATMENT

Benign Acute Mountain Sickness

In mild cases, rest, analgesics and cessation of ascent are sufficient and patient is asked to acclimatize at same altitude. Ibuprofen is helpful for HA headache, intramuscular prochlorperazine or promethazine orally are helpful for vomiting. However in severe cases or in those with progression of symptoms, descent is recommended and if not possible then hyperbaric bag should be used. Actazolamide 250 mg twice or thrice a day for 2-3 days is helpful; it is reported to be of use in insomnia also. Sedation and alcohol should be avoided.

Low flow oxygen therapy at night is useful in treatment of mild AMS.

High Altitude Pulmonary Oedema

The evacuation of patient to lower altitude is the ideal treatment if it is not possible, oxygen therapy remains mainstay of treatment. In mild to moderate cases oxygen is delivered at high flow rate with face mask. It is continued till patient improves which is apparent within 1-2 hours of therapy and pulse rate is a sensitive indicator of response to therapy. The use of positive pressure masks have been shown to be beneficial also. Nifedipine (10 mg) orally every 4-6 hours or 20 mg sustain release every 12 hours reduces pulmonary artery pressure and is useful.

A portable lightweight, fabric hyperbaric bag called Gamow bag (American) or Certec bag (French) is available commercially for the emergency treatment of

malignant HA illness (Figure 1). The patient is placed in the bag which is inflated with a foot pump. The pressure inside bag is raised above ambient atmospheric pressure which simulates descent. The exact descent simulated is directly related to the altitude of patient. At an altitude of 3000 m, the altitude simulated in bag is 1555 m whereas at 4500 m the altitude reached in bag is 2787 m. Hyperbaric chamber is also used for treatment of HAPO in which more than one patient can be placed and pressure inside is built up to sea level. In a study inhaled NO increased PaO2 significantly and lead to faster clinical and radiological recovery. A combination of inhaled NO and O2 was better than either alone. Ghofrani et al conducted a double blind randomized controlled trial which demonstrated the efficacy of oral sildenafil in reducing pulmonary artery systolic pressure at rest and during exercise at HA and it enhanced exercise capacity. Inhaled Beta-agonists have been found useful in prevention of HAPO by improving dynamics of oedema fluid removal from alveolar spaces, tightening of alveolar-capillary barrier and decreased vasoconstriction to hypoxia. The mortality due to HAPO was 2% in a series by Rao et al.

High Altitude Cerebral Oedema

High flow oxygen and rapid descent are indicated and if evacuation to lower altitude is not feasible, use of hyperbaric bag is life saving. Parenteral dexamethasone 8 mg stat followed by 4 mg every 6 hours is indicated. Other cerebral decongestants like parenteral mannitol, low dose furosemide and oral glycerol have been used even in the absence of evidence of their efficacy. Endotracheal intubation with ventilation is needed in patients in comma. Rao et al observed the mortality rate of 25% due to HACO even with adequate treatment.

High Altitude Retiopathy

The eye involvement is common at HA. Asymptomatic retinal hemorrhages can be seen in about one third cases and are related directly to altitude. The pathogenesis has been related to increased retinal flow that occurs with

and venous congestion are very common. Papilloedema is usually associated with HACO.

Table 3: Summary of the Wilderness Altitude Illness Guidelines 2010 Prevention of AMS/ HAPO

Prevention of HACO

Recommendation Grade Recommendation Grade Gradual ascent

Gradual ascent

1B

Nifedipine 60 mg SR 1A (Divided doses)

Acetazolamide 125 mg BD

1A

Salmetrol 125 ug BD 2B

Dexamethasone

Tadalafil 10 mg BD

1C

• 2mg 6h or 4 mg 12h

Dexamethasone 16 mg (Divided doses)

1C

• Duration not more than 10 days 1A

Acetazolamide

2C

Ginko biloba

2C

Cocoa leaves

NR

Forced hydration

NR

PREVENTION OF ACUTE MOUNTAIN SICKNESS

The Wilderness Altitude Illness Guidelines 2010 described the prophylactic measures for prevention of AMS. Table 3 and Table 4 describes the acclimatization procedure for prevention of AMS.

REFERENCES

1.

West JB High life: a history of high altitude physiology and medicine. Oxford Univ Press. New York 1998.

2.

Mason NP. The physiology of high altitude an introduction to the cardiorespiratory changes occurring on ascent to altitude. Current Anaethesia and Critical Care 2000; 11:34-41.

3. Winslow RM, Samaja M, West JB et al Red cell function at extreme altitude ay Mount Everest. J of App Physiol 1984; 56:109

Table 4: Acclimatisation Procedure

4. Penaloza D, Arias-Stella J. The heart and pulmonary circulation at high altitude: healthy highlanders and chronic mountain sickness Circulation 2007; 115:1132-46.

First stage

5.

BartchP, Vock P, Moggiorini M et al Respiratory symptoms, radiographic and physiologic correlation at high altitude In Sutton JR, Houston CS, Remmers JE eds. Hypoxia: the adaptations. Toronto BC Deckers. 1990: 241-45

6.

Rao KS. High altitude syndromes and their management. In Text Book of Environmental Medicine. 2nd edi. Nair V (Edi.) Pune Wolter Kluwer Health. 2014; 1.3:17-36.

For > 2700 m up to 3600 m. Acclimatisation period up to 6 days • 1st & 2nd day: Rest except short walk, not involving climb • 3rd & 4th day: Walking at slow pace for 1 ½ -3 Km, avoid steep climbs • 5 & 6 day: Can walk up to 5 Km and climb up to 300 m at slow pace th

th

Second stage For > 3600 m up to 4500 m. Acclimatisation period up to 4 days • 1st & 2nd day: Slow walk of 1 ½ -3 Km, avoid steep climbs • 3 day: Slow walk and climb up to 300 m rd

• 34th day: Climb up to 300 m Third stage For > 4500 m. lasting for 4 days and is same as second stage Reentry For those who left HA for > 10 days, require acclimatization again • Those who were away > 4 weeks, require full acclimatization • Those who were away > 10 days but < 4 weeks, require acclimatization for 4 days at each step - 1 & 2 day: Rest except short walk st

nd

- 3rd day: Walking at slow pace for 1 -2 Km, avoid steep climbs • 4th day: Walk 1-2 Km and climb up to 300 m increased cerebral flow associated with acclimatization and are more commonly noted in fresh entrants. These usually disappear after descent. Hyperaemia of optic disc

7. Karinen HM, Paltonen JE, Kahonen H et al. Prediction of acute mountain sickness by monitoring arterial oxygen saturation during ascent. High Alt Med Biol Winter 2010; 11:325-32.

8.

Roach RC, Bartsch P, Hackett PH et al The Lake Louis acute mountain sickness scoring system. In Sutton JR, Houston CS, Coates G eds. Hypoxia and Molecular Medicines, Burlington,VT; Queens City Press 1993; 272-74.

9.

Kale RM. Altitude-Related Disorders. emedicine J 2015; @ www.emedicine.com.

10. Rao KS, Narayanan K, Garg MK. High altitude pulmonary oedema. In Medicine Update-2. Proceedings of the Scientific Session of APICON-2, ed Mukherjee S. The Association of Physicians of India.

11. Menon ND. High altitude pulmonary oedema. New Engl J Med 1965; 273:66-74.

12. Sutton JR, Houston CS, Coates G eds. Lake Louis Consensus on definition and quantification of altitude illness. In Hypoxia and Molecular Medicines; Queens City Press, Burlington,Vermont 1992.

13. Rao KS, Narayanan K, Apte CV et al Echocardiography of right ventricle at high altitude. Indian Heart J 1991; 43:256.

14. Lichtenstein D, MeziereG, Biderman P et al The comettail artefact. An ultrasound sign of alveolar-interstitial syndrome. Am J Crit Care Med 1997; 156:1640-46.

15. Pratali L, Cavana M, Sicari R et al Frequent subclinical high altitude pulmonary oedema detected by chest sonography as ultrasoung lung comet in recreational climbers. Crit Care Med 2010; 38:1818-23.

16. Schoene RB, Roach RC, Hackewtt PH et al High altitude pulmonary oedema and exercise at 4400 m on Mount McKinley. Effect of expiratory positive airway pressure.

Chest 1985; 87:330-33.

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1C

271

272

17. Oelz O, Noti C, Ritter M et al Nifedipine for high altitude pulmonary oedema. Lancet 1989; ii: 1241-44.

18. Archer SL, Huang JMC, Reev HL et al Differential distribution of electrophysiologically distinct myocytes in conduit and resistance arteries determines their response to nitric oxide and hypoxia. Circ Res 1996; 78:431-42.

PULMONOLOGY

19. Ghofrani HA, Reichenberger F, Kohsgtall MG et al Sildenafil increased exercise capacity during hypoxia at low altitude and at Mount Everest base camp. A randomised, double blind, placebo controlled trial. Annals Intern Med 2004; 141:169-77.

20. Sartori C, Allemann Y, Duplain H et al Salmetrol for the prevention of high altitude pulmonary oedema. New Engl J Med 2002; 346:1631-36.

21. Dawson CA. Role of pulmonary vasomotion in physiology of lung. Physiol Rev 1984; 64:599-616.

22. Barthelms D, Bosch MM, Merz TM et al Delayed appearance of high altitude retinal haemorrhage. PLoS ONE 2011; 6e:1532.

23. Goswami BL. High altitude retinal haemorrhages. Ind J Ophthal 1984; 32:321-24.

C H A P T E R

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INTRODUCTION

Pulmonary hypertension connoting high blood pressure in arteries of the lung, has been labeled an orphan disease earlier for affecting few individuals and being overlooked by medical profession. It is complex ailment with relentless course especially if untreated, heading to right heart failure and death. It is now in limelight due to exciting discoveries in understanding the disease and introduction of new pharmacotherapies. The field has moved so rapidly that it has witnessed two major guidelines in last two years. i.e., CHEST guidelines (2014) and ESC/ ERS guidelines (2015). The morbidity and mortality ascribed to it has considerably declined by virtue of current management strategies.

DEFINITION

Pulmonary hypertension (PH) broadly refers to mean pulmonary artery pressure of 25mm Hg or greater. The definition of Group 1 of PH also referred to as pulmonary artery hypertension (PAH) requires that left sided cardiac filling pressure (PAWP), Left ventricular end-diastolic pressure (LVEDP) or left atrial pressure (LAP) be 15mm Hg or less and calculated pulmonary vascular resistance (PVR) be Wood units ≥3.

CLASSIFICATION

Diverse clinical groups of PH are classified into 5 groups based on pathological characteristics:

Table 1: Classification of Pulmonary Artery Hypertension (Group 1) Idiopathic(IPAH) Heritable BMPR 2 mutation etc.

Drugs/ Toxin Anorexigens (Fenfluramine) Rapeseed Associated with Connective tissue disease(systematic sclerosis) HIV infection

Pulmonary Hypertension Hope & Challenges Sudhir Varma, Samman Verma Group1: Pulmonary artery hypertension (PAH) predominantly affecting distal pulmonary arteries (<500 μm). The most frequent etiologies of group 1 are enlisted in table 1. It is further classified into: Group 1: Pulmonary veno-occlussive disease Group 1: Persistent pulmonary hypertension of the newborn Group 2: Due to left heart disease Group 3: Due to lung disease Group 4: Due to chronic thromboembolic pulmonary hypertension (CTEPH) Group 5: Due to unclear multifactorial mechanism

EPEDIMIOLOGY

PH secondary to left heart disease especially rheumatic valvular disease constitutes a major burden of PH in India and other developing countries. However, the most common etiology of PH in western world is idiopathic (iPAH) followed by associated (aPAH).

According to REVEAL Registry the prevalence of PAH in US was 12.4 cases per million and shown to affect more women than men (3.6:1) with a mean age of 47 years. In 1980’s 5 year survival of PAH was 37 % but it seems to be 60% now.

CLINICAL PRESENTATION

A thorough history and examination is essential for screening, diagnosis, management and prognostication.

Early in course of disease patients are asymptomatic but later they present with dysponea, chest pain, syncope and cough. Clinical examination may reveal accentuated pulmonary component of second heart sound (S2) with narrow spilt, holosystolic murmur of tricuspid regurgitation and diastolic murmur of pulmonary regurgitation. Signs of congestive heart failure are noted in late stage.

DIAGNOSTIC WORKUP

a.

PH/ PAH risk factors and clinical picture

b.

Echocardiography, Skigram, ECG, pulmonary function tests, diffusion capacity of lungs for carbon monoxide(DLCO), HRCT, V/ Q scan and arterial blood gases

c.

Right heart catheterization

d.

Specific Diagnostic tests for PAH associated diseases

Portal hypertension Congential Heart Disease Schistosomiasis BMPR2=Bonemarrow protein Receptor2, HIV = Human Immunodeficiency syndrome; Adapted from 2015 ESC/ERS guidelines

PULMONOLOGY

274

Table 2. World Health Organization Functional Classification of Patients with Pulmonary Hypertension Classification

Physical Activity

Symptoms Dysponea, fatigue, chest pain syncope

Class I

No limitation

None upon ordinary physical activity

Class II

Slight limitation

Symptoms appear upon less than ordinary activity

Class III

Marked limitation

Symptoms appear upon less than ordinary activity

Class IV

Severe limitation

Symptoms appear upon any physical activity or may be present at rest; signs of right heart failure present

Adapted from CHEST guidelines and expert panel Report (2015)

e.

with advanced disease or in whom worsening continue to occur despite other drugs. In PAH prostacyclin levels are reduced owing to downregulation of prostacyclin synthetase and prostacyclin analogues stimulate this pathway.

Available agents are intravenous(epoprostenol and trepostinil), subcutaneous and oral(eprostinil) and inhaled(ilaprost). Limitations in India are high cost and non-availability. Side effects include flushing, headache , jaw pain and diarrhea. Selexipeg is a potent orally available selective prostacyclin PGI2 receptor agonist. The high selectivity offers improved tolerability. In the double blind placebocontrolled, multicentric GRIPHON study on 1150 patients, the addition of oral selexipeg led on to morbidity/ mortality events reduction by 39% as compared to placebo.

Biomarkers like BNP and NT-Pro BNP

FUNCTIONAL CLASSIFICATION

WHO Functional Classification (table 2) is the commonest tool used to assess impact of disease and efficacy of treatment. WHO functional class (FC) III and IV have a poorer prognosis. 6 minute walk distance (6MWD) also is a useful parameter to identify high risk subject and treatment benefits.

RISK STRATIFICATION

It is vital to plan treatment options and categorize patients to low, moderate and intermediate risk categories. Patient with right heart failure, rapid symptom progression, recurrent syncope, FC IV and 6 min walk distance <165 meters fall in high risk category. Cardiopulmonary exercise testing, serum markers BNP (>300ng/L) and NT –proBNP(>1400ng/L) echocardiography (RA >26cm, pericardial effusion), hemodynamics (RAP> 14mm Hg, cardiac Index < 2.L/min/m2) and mixed venous oxygen saturation ≤60% predict severe form of disease.

c.

Nitric oxide (NO)Pathway

Endothelium derived NO induces vasodilation in pulmonary vasculature, smooth muscle cells and inhibits proliferation and acts through secondary messenger (cyclic Guanosine Monophosphate).

The drugs in this category include:

Phosphodiesterase-5 Inhibitors

Sildenafil (20mg TDS) or tadalafil(20-40mg/day) are available in India. Their use as mono- and combination therapy has been substantiated.

Vardenafil (5-10mg/day) also belongs to this category. Common side effects are headache, flushing, nasal congestion & hypotension when used with nitrates.

Riociguat is a unique drug in this category as it acts on soluble Guanyl Cyclase and it is a sensitizer to endogenous NO. It can be added to improve Functional Class and in treatment of CTEPH, when the case is inoperable or with failed surgical thromboendarctectomy. Efficacy and safety of riociguat (2.5mg) is proven with sustained improvement in exercise capacity upto 1 year.

Rarely hemoptysis occurs with its use.

TREATMENT STRATIGIES

Timely treatment of left heart disease, congenital heart disease, respiratory ailments and avoiding offending drugs can prevent development of PH. Oxygen therapy is a pulmonary vasodilator and hence useful especially in hypoxemic. Role of anticoagulation is controversial as conclusive randomized data is lacking.

Exercise rehabilitation and vaccination to prevention respiratory infection are needed.

Vascular directed therapies

They are the corner stone of treatment of PAH today and have established their role in last few decades. There are four different categories based on separate mechanisms & targets. a.

Calcium channel blockers(CCBs)

Previously widely accepted as a vasodilator therapy in 1980’s, now the only use is in patients who show vasoreactivity during right heart catheterization and hemodynamic lowering of pulmonary arterial pressure by ≥ 10mm Hg

b.

Prostacyclin Pathway (Prostanoids)

d.

Endothelin receptor antagonists (ERA)

They are the mainstay of therapy for those

They nullify the effect of endothelin in causing vasoconstriction and proliferation of smooth

NOVEL DRUG TARGETS

Other drugs under investigation include tyrosine kinase inhibitor Imatinib (400mg/day) to suppress platelet derived growth factor(PDGF), serotinin pathway inhibitors (terguride), Rho-kinase inhibitors and vasoactive intestinal peptide also hold some promise.

drugs is there. Advanced PAH targeted therapy has shown to improve survival in Eisenmenger’s syndrome both as monotherapy and as combination therapy.

CONCLUSION

Deeper insight into mechanism of PAH, vascular directed therapies, evidence-based guidelines and other recent advances have been able to convert a “potential killer” to a “chronic disesae”. Early screening, accurate diagnosis, prognostication and optimised treatment is instrumental for this change. Treatment options of PH with chronic heart and parenchymal lung disease need to be addressed.

Upfront combination therapy is emerging as a sound option in selected cases FC II or III but its superiority to monothearpy followed by stepped up care is not fully established. Low/intermediate risk patients deserve special attention considering the cost and side effects of multiple drugs. All the controversial issues and gaps can only be addressed to by quality clinical trials in the future.

REFERENCES

1.

UPFRONT COMBINATION THERAPY

Currently the understanding is that the more aggressive use of combination therapy initially in FC II & III rather than monotherapy may benefit patients. AMBITION trial on 500 patients has suggested that the combination of tadafil and ambrisentan is superior to monotherapy in reducing clinical failure events in this category. Triple combination therapy with intravenous epoprostenol, bosentan and sidenifil in FC III or IV patients has been shown to improve 6 MWD and hemodynamics. ESC/ ERC 2015 guidelines have strongly recommended combination therapy in FC II or III whereas it was not so in earlier guidelines.

Stem cell therapy and gene modulation of (BMPR 2) mutation is being investigated.

Heart lung transplant continues to be the option in patients not responding to other measures with 5 year survival of 47%.

SPECIFIC SITUATIONS

In PH due to left heart disease, there is need to address to associated co-morbidities. A special situation mimicking PAH is heart failure with preserved ejection fraction but here the role of PAH specific drugs is not validated.

PH secondary to pulmonary disease is usually slowly progressive and mostly mortatality is due to respiratory pathology. Whether pulmonary hypertension treatment changes outcome in these patients is a matter of debate and it should be considered only in those with severe PH or a circulatory impairment. In pregnancy the best option in PAH patients is to avoid it as it carries very high mortality and only anecdotal experience with specific

Taichman DB, Ornelas J, Chung L, et al. Pharmacologic therapy for pulmonary arterial hypertension in adults: CHEST guideline and expert panel report. Chest 2014; 146:449-75.

2. Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016; 37:67-119.

3.

Frost AE, Badesch DB, Barst RJ, et al. The changing picture of patients with pulmonary arterial hypertension in the United States: how REVEAL differs from historic and nonUS Contemporary Registries. Chest 2011; 139:128-37.

4.

Yaun JX, Morrell NW, Harikrishnan S, et al. The world of Pulmonary vascular disease, Pulm Circ 2011; 1:303-4

5.

Galie N, Barbera JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med 2015; 373:834-44.

6.

Dimpolous K , Inzuka R, Goletto S, et al. Improved survival among patients with Eisnmenger syndrome receiving advanced therapy for pulmonary arterial hypertension Circulation 2010; 121:20-5

7.

McLaughlin VV, Channick R, Chin K, et al. Effect on morbidity /morality in pulmonary arterial hypertension results of the GRIPHON study. J Am Coll Cardiol 2015; 65

OTHER TREATMENT MODALITIES

Pulmonary thromboendarctectomy is emerging as treatment of choice in CTEPH patients but it is not effective if distal vasailopathy is there. Pulmonary artery vascular interventions and denervation continue to be therapeutic target in selected patients.

275

8. Pulido T, Adzerikho I, Channick RN, et al. Mactentan and morbidity and mortality in pulmonary arterial hypertension. N Eng J Med 2013; 369:809-18 9.

Rubin LJ, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2). Eur Respir J. 2015; 45:1303-13

10. Noordegraaf A V, Groeneveldt J A., Bogaard H J et al., Pulmonary hypertension European Respiratory Review 2016; 25:4-11 11. Hill N S., MD; Cawley MJ., RRT PD, , and Heggen-Peay C L., et al. New Therapeutic Paradigms and Guidelines in the Management of Pulmonary Arterial Hypertension; JMCP 22, (S2 Suppl. 3-a) S3-S19

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muscles. Bosentan binds to A and B endothelin receptors. Initially 62.5mg b.i.d is given for a month followed by 125mg b.i.d. Hepotoxicity can lead to discontinuation. Fluid retension, anemia and oligospermia can also occur rarely. Ambrisenran, is first nonsulfonamide ERA. 5-10mg single dose is given after titration. Both these drugs areavailable in India can improve Functional Class. Macitentan, the new oral ERA has shown superior efficacy as compared to bosentan and ambrisentan. The phase III SERAPHIN study has shown reduction in morbidity and mortality over 3.5 years.( thus not focusing only on functional end-points alone for other drugs.)