Interstitial lung diseases (ILDs) are a group of >200 disease entities characterized by diffuse parenchymal abnormalities. ILDs can be classified into two major groups: (1) diseases associated with predominant inflammation and fibrosis, and (2) diseases with predominantly granulomatous reaction in interstitial or vascular areas . ILDs are nonmalignant and noninfectious, and they are typically chronic. The differential diagnosis of ILDs often includes infections (e.g., atypical mycobacteria, fungi) and malignancy (e.g., bronchioloalveolar cell carcinoma, lymphangitic carcinomatosis). One of the most common ILDs associated with a granulomatous reaction, sarcoidosis, is discussed in Chap.. Many ILDs are of unknown etiology; however, some ILDs are known to be associated with specific environmental exposures including asbestos, radiation therapy, and organic dusts.
APPROACH TO THE PATIENT
History: Common presenting symptoms for pts with ILDs include dyspnea and nonproductive cough. Symptom onset and duration can assist in the differential diagnosis. Chronic symptoms (over months to years) are typically seen in most ILDs, including idiopathic pulmonary fibrosis (IPF), pneumoconioses, and pulmonary Langerhans cell histiocytosis (PLCH or eosinophilic granuloma). Subacute symptoms (over weeks to months) can also be observed in many ILDs, especially in sarcoidosis, drug-induced ILDs, cryptogenic organizing pneumonitis [COP, also known as bronchiolitis obliterans with organizing pneumonia (BOOP)], and alveolar hemorrhage syndromes. Acute presentations are uncommon for ILDs but are typically observed with acute interstitial pneumonia (AIP), and they can also occur with eosinophilic pneumonia and hypersensitivity pneumonitis. Sudden onset of dyspnea can indicate a pneumothorax, which occurs in PLCH and tuberous sclerosis/ lymphangioleiomyomatosis. Fatigue and weight loss are common in all ILDs. Episodic presentations also are unusual, but they are more typical for eosinophilic pneumonia, hypersensitivity pneumonitis, and COP. Age at presentation also can guide the differential diagnosis. IPF pts typically present at age >60, while sarcoidosis, PLCH, lymphangioleiomyomatosis (LAM), and connective tissue disease–related ILD often present between the ages of 20 and 40. LAM occurs exclusively in women, while ILD in rheumatoid arthritis (RA) typically occurs in men. Cigarette smoking is a risk factor for several ILDs including IPF, PLCH, Goodpasture’s syndrome, and respiratory bronchiolitis. Occupational exposures can be important risk factors for many types of hypersensitivity pneumonitis as well as pneumoconioses. Medical treatment with radiation and drugs also should be assessed. Physical examination: Tachypnea and bibasilar end-inspiratory crackles are commonly observed in inflammatory ILDs, but they are less frequent in granulomatous ILDs. Clubbing of the digits is observed in some pts with advanced ILD. Laboratory studies: Antinuclear antibodies and rheumatoid factor at low titers are observed in some IPF pts without a connective tissue disorder. Specific serum antibodies can confirm exposure to relevant antigens in hypersensitivity pneumonitis, but they do not prove causation. Chest imaging: Chest x-ray (CXR) does not typically provide a specific diagnosis but often raises the possibility of ILD by demonstrating a bibasilar reticular pattern. Upper-lung-zone predominance of nodular opacities is noted in several ILDs, including PLCH, sarcoidosis, chronic hypersensitivity pneumonitis, and silicosis. High-resolution chest CT scans provide improved sensitivity for the early detection of ILDs and may be sufficiently specific to allow a diagnosis to be made in ILDs such as IPF, PLCH, and asbestosis. Honeycombing is indicative of advanced fibrosis. Pulmonary function testing: Lung function measurements can assess the extent of pulmonary involvement in pts with ILD. Most ILDs produce a restrictive ventilatory defect with reduced total lung capacity. The forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) are typically reduced, but the ratio of FEV1/FVC is usually normal to increased. Reduction in the diffusing capacity of the lung for carbon monoxide (Dlco) is commonly observed. Cardiopulmonary exercise testing can be useful to detect exercise-induced hypoxemia. Tissue and cellular examination: In order to provide a specific diagnosis and assess disease activity, lung biopsy is often required. Bronchoscopy with transbronchial biopsies can be diagnostic in some ILDs, including sarcoidosis and eosinophilic pneumonia. In addition, bronchoscopy can assist by excluding chronic infections or lymphangitic carcinomatosis. However, the more extensive tissue samples provided by open lung biopsies, often obtained by video-assisted thoracic surgery, are often required to establish a specific diagnosis. Evidence for diffuse end-stage disease, such as widespread honeycombing, or other major operative risks are relative contraindications to lung biopsy procedures.
PRINCIPLES OF MANAGEMENT
If a causative agent can be identified (e.g., thermophilic actinomyces in hypersensitivity pneumonitis), cessation of exposure to that agent is imperative. Because the response to treatment among different ILDs is so variable, identification of treatable causes is essential. Glucocorticoids can be highly effective for eosinophilic pneumonias, COP, hypersensitivity pneumonitis (HP), radiation pneumonitis, and drug-induced ILD. Prednisone at 0.5–1.0 mg/kg qd is commonly given for 4–12 weeks, followed by a gradual tapering dose. On the other hand, glucocorticoids are typically not beneficial in IPF. Smoking cessation is essential, especially for smoking-related ILDs such as PLCH and respiratory bronchiolitis. Supportive therapeutic measures include providing supplemental O2 for pts with significant hypoxemia (Pao2 <55 mmHg at rest and/or with exercise). Pulmonary rehabilitation may also be beneficial. For young pts with end-stage ILD, lung transplantation should be considered.
SELECTED INDIVIDUAL ILDS
Idiopathic Pulmonary Fibrosis
IPF, which is also known as usual interstitial pneumonia (UIP), is the most common idiopathic interstitial pneumonia. Cigarette smoking is a risk factor for IPF. Common respiratory symptoms include exertional dyspnea and a nonproductive cough. Physical examination is notable for inspiratory crackles at the lung bases. Clubbing may occur. High-resolution chest CT scans show subpleural reticular opacities predominantly in the lower lung fields, which are associated with honeycombing in advanced disease. Pulmonary function tests reveal a restrictive ventilatory defect with reduced Dlco. Surgical lung biopsy is usually required to confirm the diagnosis, although classic presentations may not require a biopsy. IPF can include acute exacerbations characterized by accelerated clinical deterioration over days to weeks. IPF is poorly responsive to available pharmacologic treatment.
Nonspecific Interstitial Pneumonia
Nonspecific interstitial pneumonia (NSIP) is a histologic pattern that can be observed in connective tissue disease, drug-induced ILD, and chronic HP. NSIP is a subacute restrictive process with similar presentation to IPF. High-resolution CT (HRCT) shows bilateral ground-glass opacities, and honeycombing is rare. Unlike IPF, NSIP pts have a good prognosis and typically respond well to systemic glucocorticoid treatment.
ILD Associated with Connective Tissue Disorders
Pulmonary manifestations may precede systemic manifestations of a connective tissue disorder. In addition to direct pulmonary involvement, it is necessary to consider complications of therapy (e.g., opportunistic infections), respiratory muscle weakness, esophageal dysfunction, and associated malignancies as contributors to pulmonary parenchymal abnormalities in pts with connective tissue disorders. Progressive systemic sclerosis (scleroderma) commonly includes ILD as well as pulmonary vascular disease. Lung involvement tends to be highly resistant to available treatment. In addition to pulmonary fibrosis (ILD), RA can involve a range of pulmonary complications, including pleural effusions, pulmonary nodules, and pulmonary vasculitis. ILD in RA pts is more common in men. Systemic lupus erythematosus (SLE) also can involve a range of pulmonary complications, including pleural effusions, pulmonary vascular disease, pulmonary hemorrhage, and BOOP. Chronic, progressive ILD is not commonly observed.
Cryptogenic Organizing Pneumonia
When the BOOP pathologic pattern occurs without another primary pulmonary disorder, the term cryptogenic organizing pneumonia (COP) is used. COP may present with a flulike illness. Recurrent and migratory pulmonary opacities are common. Glucocorticoid therapy is often effective.
Desquamative Interstitial Pneumonia and Respiratory BronchiolitisAssociated ILD
Desquamative interstitial pneumonia (DIP) includes extensive macrophage accumulation in intraalveolar spaces with minimal fibrosis. It is seen almost exclusively in cigarette smokers and improves with smoking cessation. Respiratory bronchiolitis-associated ILD is a subset of DIP that includes bronchial wall thickening, ground-glass opacities, and air trapping on HRCT; it also resolves in most pts after smoking cessation.
Pulmonary Alveolar Proteinosis
Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease, with a male predominance, that involves the accumulation of lipoproteinaceous material in the distal airspaces, rather than a classic ILD. More common in males, PAP usually presents insidiously, with dyspnea, fatigue, weight loss, cough, and low-grade fever. Whole-lung lavage is often of therapeutic benefit.
Pulmonary Infiltrates with Eosinophilia
Several disorders are characterized by pulmonary infiltrates and peripheral blood eosinophilia. Tropical eosinophilia relates to parasitic infection; druginduced eosinophilic pneumonias are more common in the United States. Löffler’s syndrome typically includes migratory pulmonary infiltrates and minimal clinical symptoms. Acute eosinophilic pneumonia involves pulmonary infiltrates with severe hypoxemia. Chronic eosinophilic pneumonia is often in the differential diagnosis with other ILDs; it includes fever, cough, and weight loss, with a CXR notable for peripheral infiltrates. Eosinophilic pneumonias tend to be rapidly responsive to glucocorticoid therapy.
Alveolar Hemorrhage Syndromes
A variety of diseases can cause diffuse alveolar hemorrhage, including systemic vasculitic syndromes [e.g., granulomatosis with polyangiitis (Wegener’s)], connective tissue diseases (e.g., SLE), and Goodpasture’s syndrome. Although typically an acute process, recurrent episodes can lead to pulmonary fibrosis. Hemoptysis may not occur initially in one-third of cases. CXR typically shows patchy or diffuse alveolar opacities. The Dlco may be increased. High doses of IV methylprednisolone are typically required, followed by gradual tapering of systemic steroid doses. Plasmapheresis may be effective for Goodpasture’s syndrome.
Pulmonary Langerhans Cell Histiocytosis
PLCH is a smoking-related diffuse lung disease that typically affects men 20 to 40 years of age. Presenting symptoms often include cough, dyspnea, chest pain, weight loss, and fever. Pneumothorax occurs in 25% of pts. High-resolution chest CT scan reveals upper-zone-predominant nodular opacities and thin-walled cysts, which are virtually diagnostic of this disorder. Smoking cessation is the key therapeutic intervention.
Hypersensitivity Pneumonitis
HP is an inflammatory lung disorder caused by repeated inhalation of an organic agent in a susceptible individual. Many organic agents have been implicated. Clinical presentations can be acute, with cough, fever, malaise, and dyspnea developing within 6–8 h after exposure; subacute, with cough and dyspnea that can become progressively worse over weeks; and chronic, which can appear similar to IPF. Peripheral blood eosinophilia is not observed. Serum precipitins can be measured as an indicator of an environmental exposure. Although helpful in implicating specific agents, the presence of a specific serum precipitin is not diagnostic since many exposed individuals without HP will have such precipitins; false-negative results can also occur. Diagnosis is made based on symptoms, physical findings, pulmonary function tests (restrictive or obstructive pattern), and radiographic studies (chest CT scans typically show ground-glass opacification in acute and subacute forms) that are consistent with HP; history of exposure to a recognized antigen; and presence of an antibody to that antigen. In some cases, lung biopsy (transbronchial or open lung) may be required to confirm the diagnosis. Treatment involves avoiding exposure to the causative antigen; systemic corticosteroids may be required in subacute or chronic HP.
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