Respiration 12 Interstitial Lung Diseases

Interstitial Lung Disease Diffuse Parenchymal lung disease

Introduction Interstitial lung disease, or diffuse parenchymal lung disease, comprises a heterogeneous group of disorders that share a common response of the lung to injury: • Alveolitis, or inflammation • Fibrosis of the inter-alveolar septum

• The term "interstitial" is misleading since the pathologic process usually begins with injury to the alveolar epithelial or capillary endothelial cells • Persistent alveolitis may lead to obliteration of alveolar capillaries and reorganization of the lung parenchyma, accompanied by irreversible fibrosis • The process does not affect the airways proximal to the respiratory bronchioles • At least 180 disease entities may present as interstitial lung diseases

Differential diagnosis of interstitial lung disease. Drug-related   

• Antiarrhythmic agents (amiodarone)   • Antibacterial agents (nitrofurantoin, sulfonamides)   • Antineoplastic agents (bleomycin, cyclophosphamide, methotrexate, nitrosoureas)   • Antirheumatic agents (gold salts, penicillamine)   • Phenytoin

Environmental and occupational (inhalation exposures)   

• Dust, inorganic (asbestos, silica, hard metals, beryllium)   • Dust, organic (thermophilic actinomycetes, avian antigens, Aspergillus species) • Gases, fumes, and vapors (chlorine, isocyanates, paraquat, sulfur dioxide)   • Ionizing radiation   • Talc (injection drug users)

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Infections    Fungus, disseminated (Coccidioides immitis, Blastomyces dermatitidis, Histoplasma capsulatum)    Mycobacteria, disseminated  Pneumocystis jiroveci    Viruses Primary pulmonary disorders    Cryptogenic organizing pneumonitis (COP)   Idiopathic fibrosing interstitial pneumonia,Acute interstitial pneumonitis, desquamative interstitial pneumonitis, nonspecific interstitial pneumonitis, usual interstitial pneumonitis, respiratory bronchiolitisassociated interstitial lung disease   Pulmonary alveolar proteinosis

Systemic disorders    • Acute respiratory distress syndrome   • Amyloidosis  Ankylosing spondylitis  ` • Autoimmune disease: Dermatomyositis, polymyositis, rheumatoid arthritis, systemic sclerosis (scleroderma), systemic lupus erythematosus   • Chronic eosinophilic pneumonia   • Goodpasture's syndrome  •  Idiopathic pulmonary hemosiderosis   • Inflammatory bowel disease   • Langerhans cell histiocytosis (eosinophilic granuloma)   • Lymphangitic spread of cancer (lymphangitic carcinomatosis)   • Lymphangioleiomyomatosis   • Pulmonary edema   • Pulmonary venous hypertension, chronic  •  Sarcoidosis   • Wegener's granulomatosis

Etiology • In most patients, no specific cause can be identified • In the remainder, drugs and a variety of organic and inorganic dusts are the principal causes

Clinical Features • The clinical consequence of widespread lung fibrosis is diminished lung compliance, which presents as restrictive lung disease • Patients usually describe an insidious onset of exertional dyspnea and cough • Sputum production is minimal

• The history—particularly the occupational and medication history —may provide evidence of a specific cause • Chest examination reveals fine, late inspiratory crackles at the lung bases • Digital clubbing

Digital clubbing

Investigations • Pulmonary function testing: It shows a loss of lung volume with normal to increased airflow rates The diffusing capacity for carbon monoxide is decreased

• Arterial Blood Gases: Hypoxemia with exercise is common In advanced cases, resting hypoxemia may be present

Chest radiograph: • The chest radiograph is normal in some patients on presentation • More typically, it shows patchy distribution of ground-glass, reticular, or reticulonodular infiltratess • In advanced disease there are multiple small, thick-walled cystic spaces in the lung periphery ("honeycomb" lung) • Honeycombing indicates the presence of locally advanced fibrosis with destruction of normal lung architecture

CT: Conventional CT and high-resolution CT imaging reveal in greater detail the findings described on chest radiograph. In some cases, high-resolution CT may be strongly suggestive of a specific pathologic process.

End-stage pulmonary fibrosis of unknown origin, taken from an autopsy

The findings of interstitial disease include not only that the process has the localized increased density but also radiating linear findings consistent with air bronchograms indicating filled the distal alveoli while retaining the capacity for aeration

Diffuse interstitial infiltrates bilaterally, somewhat more central than peripheral. No pleural effusions. No cardiomegaly

Pronounced reticulonodular pattern in the lower lobes

Pronounced reticulonodular pattern in the lower lobes

CT scan of the chest demonstrates recurrent nodular interstitial lung disease, with more extensive involvement

Interlobular septal thickening is commonly seen in patients with interstitial lung disease. On HRCT, numerous clearly visible septal lines usually indicates the presence of some interstitial abnormality

• Serologic tests for antinuclear antibodies and rheumatoid factor are positive in 20–40% of patients but are rarely diagnostic

• Antineutrophil cytoplasmic antibodies (ANCAs) may be diagnostic in some clinical settings

• Invasive diagnostic testing • Three diagnostic techniques are in common use • Bronchoalveolar lavage • Transbronchial biopsy • Surgical lung biopsy • Bronchoalveolar lavage may provide a specific diagnosis in cases of infection, particularly with P jiroveci or mycobacteria, or when cytologic examination reveals the presence of malignant cells. • Transbronchial biopsy through the flexible bronchoscope can make a definitive diagnosis of sarcoidosis, lymphangitic spread of carcinoma, pulmonary alveolar proteinosis, miliary tuberculosis, and Langerhans cell histiocytosis.

• Surgical lung biopsy is the standard for diagnosis of interstitial lung disease • Two or three biopsies taken from multiple sites in the same lung, including apparently normal tissue, may yield a specific diagnosis as well as prognostic information regarding the extent of fibrosis versus active inflammation • Patients under age 60 without a specific diagnosis generally should undergo surgical lung biopsy • In older and sicker patients, the risks and benefits must be weighed carefully

Idiopathic Fibrosing Interstitial Pneumonia (Formerly: Idiopathic Pulmonary Fibrosis)

The most common diagnosis among patients presenting with interstitial lung disease is idiopathic pulmonary fibrosis

Patients with idiopathic fibrosing interstitial pneumonia may present with any of the histologic patterns • Usual interstitial pneumonia (UIP)  • Respiratory bronchiolitis- associated interstitial lung disease (RB-ILD) • Acute interstitial pneumonitis (AIP)  • Nonspecific interstitial pneumonitis (NSIP)  • Cryptogenic organizing pneumonitis (formerly bronchiolitis obliterans organizing pneumonia [BOOP]) 

Evaluation • The first step in evaluation is to identify patients whose disease is truly idiopathic as most identifiable causes of interstitial lung disease are infectious, drug-related, or environmental or occupational agents • Apart from acute interstitial pneumonia, the clinical presentations of the idiopathic interstitial pneumonias are sufficiently similar to preclude a specific diagnosis

Clinical Presentation • Progressive exertional dyspnea • Persistent dry cough • Gross clubbing of fingers and toes • Chest examination: Chest expansion is poor • Numerous bilateral end-expiratory crackles

Laboratory findings • Pulmonary function tests show restrictive pattern • Abnormal gas exchange is the hallmark of the disease • Chest X-ray: Diffuse pulmonary opacities • Advanced disease shows honeycomb lung: diffuse pulmonary shadowing is interspersed with small cystic translucencies • High-resolution CT scans are occasionally diagnostic even in early disease

• Patients with apparently idiopathic disease require surgical lung biopsy to make a definitive diagnosis • Accurate diagnosis allows the clinician to provide accurate information about the cause and natural history of the illness and also helps distinguish patients most likely to benefit from therapy • Surgical lung biopsy may spare these patients from treatment with potentially morbid therapies

Criteria for Diagnosis Definitie Diagnosis • Surgical Biopsy showing Usual interstitial pneumonia UIP • Exclusion of other causes of interstitial lung disease e.g. drug toxicities, environmental exposure and collagen vascular diseases • ↓ FEV1/FVC • ↑ A-a DO2 and ↓ DL • Chest X-ray and CT changes

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Clinical Diagnosis

In the absence of surgical biopsy clinical diagnosis includes all of the major criteria and at least 3 of the 4 minor criteria

• Major criteria: 1. Exclusion of other causes 2. Pulmonary function with restrictice pattern, ↓diffusing capacities, and ↑ A-a gradient 3. Bibasilar reticular abnormalities with ground glass opacities on CT 4. Tranbronchial biopsies or Bronchialveolar lavage

Minor Criteria 1. Patient older than 50 years 2. Insidious onset of otherwise unexplained dyspnea upon exertion 3. Duration of illness more than 30 days 4. Bibasilarr inspiratory crackles

Treatment Therapeutic goal: • To supress the alveolitis • To prevent fibrosis • Prevent continued destruction of lung parenchyma

• Corticosteroids:

They are the drug of choice Response is favorable if alveolitis is predominant and less beneficial in advanced honeycombing

• Immunosuppressive agents:

They suppress B cells and T-cells function. Used alone or in combination with steroids

• Antiviral Cytokines

Interferon gamma and interferon beta may be used to inhibit proliferation of fibroblasts and suppress connective tissue protein

• Antifibrotic agents

Pirfenidone inhibits Transforming growth factor beta stimulated collagen synthesis, blocks fibroblast proliferation and decrease extracellular matrix

Sarcoidosis It is a multisystem granulomatous disease of unknown origin characterized by activation of T lymphocytes and mononuclear phagocytes at the site of disease

Etiology and Pathogenesis It can affect any organ but lungs and Intra• thoracic lymph nodes are more commonly affected

• Cause is Unknown • Current theory suggests that sarcoidosis develops in genetically predisposed individuals who are exposed to certain environmental agents that trigger an exaggerated inflammatory immune response leading to granuloma formation

Pathology Pathological hallmark is presence of discrete, non-caseating, epithelioid cell granulomas

Histopathology of cutaneous sarcoidosis, demonstrating the presence of ill-defined noncaseating granulomas

Clinical features • Patients may present with malaise, fever, and dyspnea of insidious onset • Symptoms referable to the skin, eyes, peripheral nerves, liver, kidney, or heart may also cause the patient to seek care • Some individuals are asymptomatic and come to medical attention after abnormal findings (typically bilateral hilar and right paratracheal lymphadenopathy) on chest radiographs

Erythema nodosum of the lower legs

Plaque of sarcoidosis on the face

Skin manifestations in patients with sarcoidosis

Multiple plaques of sarcoidosis on the trunk

Punched-out choroidoretinal lesions in a patient with sarcoidosis

Conjunctival nodules in a patient with sarcoidosis

• Physical findings are atypical of interstitial lung disease: crackles are uncommon on chest examination • Other findings may include erythema nodosum, parotid gland enlargement, hepatosplenomegaly, and lymphadenopathy

Laboratory Findings • Laboratory tests may show leukopenia, an elevated erythrocyte sedimentation rate, and hypercalcemia or hypercalciuria. (Sarcoidosis patients manufacture the 1,25-D hormone within the inflammatory granuloma, under the influence of Angiotensin II and Interferon-gamma, so most Sarcoidosis patients possess high levels of 1,25-D in their blood leading to hypercalcemia)

• Pulmonary function testing may reveal evidence of airflow obstruction, but restrictive changes with decreased lung volumes and diffusing capacity are more common • Skin test anergy is present in 70% • ECG may show conduction disturbances and dysrhythmias

Imaging • Radiographic findings include bilateral hilar adenopathy, and parenchymal involvement • Parenchymal involvement is usually manifested radiographically by diffuse reticular infiltrates but focal infiltrates, acinar shadows, nodules, and, rarely, cavitation may be seen • Pleural effusion is noted in fewer than 10% of patients

Bilateral symmetrical hilar lymphadenopathy and lung infiltration

Chest xray showing sarcoidosis

Sarcoidosis - hilar adenopathy

Special Examinations • The diagnosis of sarcoidosis generally requires histologic demonstration of noncaseating granulomas in biopsies • Biopsy of easily accessible sites (eg, palpable lymph nodes, skin lesions, or salivary glands) is likely to be positive • Transbronchial lung biopsy is positive, especially in patients with radiographic evidence of parenchymal involvement • Bronchoalveolar lavage fluid in sarcoidosis is usually characterized by an increase in lymphocytes and a high CD4/CD8 cell ratio • Bronchoalveolar lavage does not establish a diagnosis but may be useful in following the activity of sarcoidosis in selected patients • All patients require a complete ophthalmologic evaluation.

Treatment • Oral corticosteroids (prednisone, 0.5– 1.0 mg/kg/d) • Long-term therapy is usually required over months to years. • Immunosuppressive drugs and cyclosporine have been tried, primarily when corticosteroid therapy has been exhausted, but experience with these drugs is limited