Patients with interstitial lung diseases (ILDs) come to medical attention mainly because of the onset of progressive exertional dyspnea or a persistent nonproductive cough. Hemoptysis, wheezing, and chest pain may be present. Often, the identification of interstitial opacities on chest x-ray focuses the diagnostic approach on one of the ILDs.
ILDs represent a large number of conditions that involve the parenchyma of the lung—the alveoli, the alveolar epithelium, the capillary endothelium, and the spaces between those structures—as well as the perivascular and lymphatic tissues. The disorders in this heterogeneous group are classified together because of similar clinical, roentgenographic, physiologic, or pathologic manifestations. These disorders often are associated with considerable rates of morbidity and mortality, and there is little consensus regarding the best management of most of them.
ILDs have been difficult to classify because >200 known individual diseases are characterized by diffuse parenchymal lung involvement, either as the primary condition or as a significant part of a multiorgan process, as may occur in the connective tissue diseases (CTDs). One useful approach to classification is to separate the ILDs into two groups based on the major underlying histopathology: (1) those associated with predominant inflammation and fibrosis and (2) those with a predominantly granulomatous reaction in interstitial or vascular areas (Table 261-1). Each of these groups can be subdivided further according to whether the cause is known or unknown. For each ILD there may be an acute phase, and there is usually a chronic one as well. Rarely, some are recurrent, with intervals of subclinical disease.
Sarcoidosis (Chap. 329), idiopathic pulmonary fibrosis (IPF), and pulmonary fibrosis associated with CTDs (Chaps. 319–326) are the most common ILDs of unknown etiology. Among the ILDs of known cause, the largest group includes occupational and environmental exposures, especially the inhalation of inorganic dusts, organic dusts, and various fumes or gases (Chaps. 255 and 256) (Table 261-2). A clinical diagnosis is possible for many forms of ILD, especially if an occupational and environmental history is pursued aggressively. High-resolution computed tomography (HRCT) scanning improves the diagnostic accuracy and may eliminate the need for tissue examination in many cases, especially in IPF. For other forms, tissue examination, usually obtained by thoracoscopic lung biopsy, is critical to confirmation of the diagnosis.
The ILDs are nonmalignant disorders and are not caused by identified infectious agents. The precise pathway(s) leading from injury to fibrosis is not known. Although there are multiple initiating agent(s) of injury, the immunopathogenic responses of lung tissue are limited, and the mechanisms of repair have common features (Fig. 261-1).
Proposed mechanism for the pathogenesis of pulmonary fibrosis. The lung is naturally exposed to repetitive injury from a variety of exogenous and endogenous stimuli. Several local and systemic factors (e.g., fibroblasts, circulating fibrocytes, chemokines, growth factors, and clotting factors) contribute to tissue healing and functional recovery. Dysregulation of this intricate network through genetic predisposition, autoimmune conditions, or superimposed diseases can lead to aberrant wound healing, with the result of pulmonary fibrosis. Alternatively, excessive injury to the lung may overwhelm even intact reparative mechanisms and lead to pulmonary fibrosis. (From S Garantziotis et al: J Clin Invest 114:319, 2004.)
As mentioned above, the two major histopathologic patterns are a granulomatous pattern and a pattern in which inflammation and fibrosis predominate.
Granulomatous Lung Disease
This process is characterized by an accumulation of T lymphocytes, macrophages, and epithelioid cells organized into discrete structures (granulomas) in the lung parenchyma. The granulomatous lesions can progress to fibrosis. Many patients with granulomatous lung disease remain free of severe impairment of lung function or, when symptomatic, improve after treatment. The main differential diagnosis is between sarcoidosis (Chap. 329) and hypersensitivity pneumonitis (Chap. 255).
Inflammation and Fibrosis
The initial insult is an injury to the epithelial surface that causes inflammation in the air spaces and alveolar walls (Fig. 261-2). If the disease becomes chronic, inflammation spreads to adjacent portions of the interstitium and vasculature and eventually causes interstitial fibrosis. Important histopathologic patterns found in the ILDs include usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia, respiratory bronchiolitis/desquamative interstitial pneumonia, organizing pneumonia, diffuse alveolar damage (acute or organizing), and lymphocytic interstitial pneumonia. The development of irreversible scarring (fibrosis) of alveolar walls, airways, or vasculature is the most feared outcome in all of these conditions because it is often progressive and leads to significant derangement of ventilatory function and gas exchange.
Cellular basis for the pathogenesis of interstitial lung disease. Multiple microinjuries damage and activate alveolar epithelial cells (top left), which in turn induce an antifibrinolytic environment in the alveolar spaces, enhancing wound clot formation. Alveolar epithelial cells secrete growth factors and induce migration and proliferation of fibroblasts and differentiation into myofibroblasts (bottom left). Subepithelial myofibroblasts and alveolar epithelial cells produce gelatinases that may increase basement membrane disruption and allow fibroblast–myofibroblast migration (bottom right). Angiogenic factors induce neovascularization. Both intraalveolar and interstitial myofibroblasts secrete extracellular matrix proteins, mainly collagens. An imbalance between interstitial collagenases and tissue inhibitors of metalloproteinases provokes the progressive deposit of extracellular matrix (top right). Signals responsible for myofibroblast apoptosis seem to be absent or delayed in usual interstitial pneumonia, increasing cell survival. Myofibroblasts produce angiotensinogen that, as angiotensin II, provokes alveolar epithelial cell death, further impairing reepithelialization. Abbreviations: FGF-2, fibroblast growth factor 2; MMPs, metalloproteinases; PAI-1, PAI-2, plasminogen activator inhibitor 1, 2; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor β; TIMPs, tissue inhibitors of metalloproteinases; TNF-α, tumor necrosis factor α; VEGF, vascular endothelial growth factor. (From M Selman et al: Ann Intern Med 134:136, 2001, with permission.)
Acute presentation (days to weeks), although unusual, occurs with allergy (drugs, fungi, helminths), acute interstitial pneumonia (AIP), eosinophilic pneumonia, and hypersensitivity pneumonitis. These conditions may be confused with atypical pneumonias because of diffuse alveolar opacities on chest x-ray. Subacute presentation (weeks to months) may occur in all ILDs but is seen especially in sarcoidosis, drug-induced ILDs, the alveolar hemorrhage syndromes, cryptogenic organizing pneumonia (COP), and the acute immunologic pneumonia that complicates systemic lupus erythematosus (SLE) or polymyositis. In most ILDs the symptoms and signs form a chronic presentation (months to years). Examples include IPF, sarcoidosis, pulmonary Langerhans cell histiocytosis (PLCH) (also known as Langerhans cell granulomatosis, eosinophilic granuloma, or histiocytosis X), pneumoconioses, and CTDs. Episodic presentations are unusual and include eosinophilic pneumonia, hypersensitivity pneumonitis, COP, vasculitides, pulmonary hemorrhage, and Churg-Strauss syndrome.
Most patients with sarcoidosis, ILD associated with CTD, lymphangioleiomyomatosis (LAM), PLCH, and inherited forms of ILD (familial IPF, Gaucher's disease, Hermansky-Pudlak syndrome) present between the ages of 20 and 40 years. Most patients with IPF are older than 60 years.
LAM and pulmonary involvement in tuberous sclerosis occur exclusively in premenopausal women. In addition, ILD in Hermansky-Pudlak syndrome and in the CTDs is more common in women; an exception is ILD in rheumatoid arthritis (RA), which is more common in men. IPF is more common in men. Because of occupational exposures, pneumoconioses also occur more frequently in men.
Familial lung fibrosis has been associated with mutations in three genes: the surfactant protein Cgene, the surfactant protein A2 gene, and the ATP-binding cassette transporter A3 gene. Familial lung fibrosis is characterized by several patterns of interstitial pneumonia, including nonspecific interstitial pneumonia, desquamative interstitial pneumonia, and UIP. Older age, male sex, and a history of cigarette smoking have been identified as risk factors for familial lung fibrosis. Family associations (with an autosomal dominant pattern) have been identified in tuberous sclerosis and neurofibromatosis. Familial clustering has been identified increasingly in sarcoidosis. The genes responsible for several rare ILDs have been identified, i.e., alveolar microlithiasis, Gaucher's disease, Hermansky-Pudlak syndrome, and Niemann-Pick disease, along with the genes for surfactant homeostasis in pulmonary alveolar proteinosis and for control of cell growth and differentiation in LAM.
Two-thirds to 75% of patients with IPF and familial lung fibrosis have a history of smoking. Patients with PLCH, respiratory bronchiolitis/desquamative interstitial pneumonia (DIP), Goodpasture's syndrome, respiratory bronchiolitis, and pulmonary alveolar proteinosis are usually current or former smokers.
Occupational and Environmental History
A strict chronologic listing of the patient's lifelong employment must be sought, including specific duties and known exposures. In hypersensitivity pneumonitis (see Fig. 255-1), respiratory symptoms, fever, chills, and an abnormal chest roentgenogram are often temporally related to a hobby (pigeon breeder's disease) or to the workplace (farmer's lung) (Chap. 255). Symptoms may diminish or disappear after the patient leaves the site of exposure for several days; similarly, symptoms may reappear when the patient returns to the exposure site.
Other Important Past History
Parasitic infections may cause pulmonary eosinophilia, and therefore a travel history should be taken in patients with known or suspected ILD. History of risk factors for HIV infection should be elicited because several processes may occur at the time of initial presentation or during the clinical course, e.g., HIV infection, organizing pneumonia, AIP, lymphocytic interstitial pneumonitis, and diffuse alveolar hemorrhage.
Respiratory Symptoms and Signs
Dyspnea is a common and prominent complaint in patients with ILD, especially the idiopathic interstitial pneumonias, hypersensitivity pneumonitis, COP, sarcoidosis, eosinophilic pneumonias, and PLCH. Some patients, especially patients with sarcoidosis, silicosis, PLCH, hypersensitivity pneumonitis, lipoid pneumonia, or lymphangitis carcinomatosis, may have extensive parenchymal lung disease on chest x-ray without significant dyspnea, especially early in the course of the illness. Wheezing is an uncommon manifestation of ILD but has been described in patients with chronic eosinophilic pneumonia, Churg-Strauss syndrome, respiratory bronchiolitis, and sarcoidosis. Clinically significant chest pain is uncommon in most ILDs. However, substernal discomfort is common in sarcoidosis. Sudden worsening of dyspnea, especially if associated with acute chest pain, may indicate a spontaneous pneumothorax, which occurs in PLCH, tuberous sclerosis, LAM, and neurofibromatosis. Frank hemoptysis and blood-streaked sputum are rarely presenting manifestations of ILD but can be seen in the diffuse alveolar hemorrhage (DAH) syndromes, LAM, tuberous sclerosis, and the granulomatous vasculitides. Fatigue and weight loss are common in all ILDs.
The findings are usually not specific. Most commonly, physical examination reveals tachypnea and bibasilar end-inspiratory dry crackles, which are common in most forms of ILD associated with inflammation but are less likely to be heard in the granulomatous lung diseases. Crackles may be present in the absence of radiographic abnormalities on the chest radiograph. Scattered late inspiratory high-pitched rhonchi—so-called inspiratory squeaks—are heard in patients with bronchiolitis. The cardiac examination is usually normal except in the middle or late stages of the disease, when findings of pulmonary hypertension and cor pulmonale may become evident (Chap. 250). Cyanosis and clubbing of the digits occur in some patients with advanced disease.
Antinuclear antibodies and anti-immunoglobulin antibodies (rheumatoid factors) are identified in some patients, even in the absence of a defined CTD. A raised lactate dehydrogenase (LDH) level is a nonspecific finding common to ILDs. Elevation of the serum level of angiotensin-converting enzyme is common in sarcoidosis. Serum precipitins confirm exposure when hypersensitivity pneumonitis is suspected, although they are not diagnostic of the process. Antineutrophil cytoplasmic or anti-basement membrane antibodies are useful if vasculitis is suspected. The electrocardiogram is usually normal unless pulmonary hypertension is present; then it demonstrates right-axis deviation, right ventricular hypertrophy, or right atrial enlargement or hypertrophy. Echocardiography also reveals right ventricular dilation and/or hypertrophy in the presence of pulmonary hypertension.
ILD may be first suspected on the basis of an abnormal chest radiograph, which most commonly reveals a bibasilar reticular pattern. A nodular or mixed pattern of alveolar filling and increased reticular markings also may be present. A subgroup of ILDs exhibit nodular opacities with a predilection for the upper lung zones [sarcoidosis, PLCH, chronic hypersensitivity pneumonitis, silicosis, berylliosis, RA (necrobiotic nodular form), ankylosing spondylitis]. The chest x-ray correlates poorly with the clinical or histopathologic stage of the disease. The radiographic finding of honeycombing correlates with pathologic findings of small cystic spaces and progressive fibrosis; when present, it portends a poor prognosis. In most cases, the chest radiograph is nonspecific and usually does not allow a specific diagnosis.
High-resolution computed tomography is superior to the plain chest x-ray for early detection and confirmation of suspected ILD (Fig. 261-3). In addition, HRCT allows better assessment of the extent and distribution of disease, and it is especially useful in the investigation of patients with a normal chest radiograph. Coexisting disease is often best recognized on HRCT scanning, e.g., mediastinal adenopathy, carcinoma, or emphysema. In the appropriate clinical setting HRCT may be sufficiently characteristic to preclude the need for lung biopsy in IPF, sarcoidosis, hypersensitivity pneumonitis, asbestosis, lymphangitic carcinoma, and PLCH. When a lung biopsy is required, HRCT scanning is useful for determining the most appropriate area from which biopsy samples should be taken.
Idiopathic pulmonary fibrosis. High-resolution CT image shows bibasal, peripheral predominant reticular abnormality with traction bronchiectasis and honeycombing. The lung biopsy showed the typical features of usual interstitial pneumonia.
Pulmonary Function Testing
Spirometry and Lung Volumes
Measurement of lung function is important in assessing the extent of pulmonary involvement in patients with ILD. Most forms of ILD produce a restrictive defect with reduced total lung capacity (TLC), functional residual capacity, and residual volume (Chap. 252). Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) are reduced, but these changes are related to the decreased TLC. The FEV1/FVC ratio is usually normal or increased. Lung volumes decrease as lung stiffness worsens with disease progression. A few disorders produce interstitial opacities on chest x-ray and obstructive airflow limitation on lung function testing (uncommon in sarcoidosis and hypersensitivity pneumonitis but common in tuberous sclerosis and LAM). Pulmonary function studies have been proved to have prognostic value in patients with idiopathic interstitial pneumonias, particularly IPF and nonspecific interstitial pneumonia (NSIP).
A reduction in the diffusing capacity of the lung for carbon monoxide (DlCO) is a common but nonspecific finding in most ILDs. This decrease is due in part to effacement of the alveolar capillary units but, more important, to mismatching of ventilation and perfusion (V./Q.). Lung regions with reduced compliance due to either fibrosis or cellular infiltration may be poorly ventilated but may still maintain adequate blood flow, and the ventilation-perfusion mismatch in these regions acts like true venous admixture. The severity of the reduction in DlCO does not correlate with disease stage.
The resting arterial blood gas may be normal or reveal hypoxemia (secondary to a mismatching of ventilation to perfusion) and respiratory alkalosis. A normal arterial O2 tension (or saturation by oximetry) at rest does not rule out significant hypoxemia during exercise or sleep. Carbon dioxide (CO2) retention is rare and is usually a manifestation of end-stage disease.
Cardiopulmonary Exercise Testing
Because hypoxemia at rest is not always present and because severe exercise-induced hypoxemia may go undetected, it is useful to perform exercise testing with measurement of arterial blood gases to detect abnormalities of gas exchange. Arterial oxygen desaturation, a failure to decrease dead space appropriately with exercise [i.e., a high Vd/Vt (dead space/tidal volume) ratio (Chap. 252)], and an excessive increase in respiratory rate with a lower than expected recruitment of tidal volume provide useful information about physiologic abnormalities and extent of disease. Serial assessment of resting and exercise gas exchange is an excellent method for following disease activity and responsiveness to treatment, especially in patients with IPF. Increasingly, the 6-min walk test is used to obtain a global evaluation of submaximal exercise capacity in patients with ILD. The walk distance and level of oxygen desaturation tend to correlate with the patient's baseline lung function and mirror the patient's clinical course.
Fiberoptic Bronchoscopy and Bronchoalveolar Lavage (BAL)
In selected diseases (e.g., sarcoidosis, hypersensitivity pneumonitis, DAH syndrome, cancer, pulmonary alveolar proteinosis), cellular analysis of BAL fluid may be useful in narrowing the differential diagnostic possibilities among various types of ILD (Table 261-3). The role of BAL in defining the stage of disease and assessment of disease progression or response to therapy remains poorly understood, and the usefulness of BAL in the clinical assessment and management remains to be established.
Table 261-3 Diagnostic Value of Bronchoalveolar Lavage in Interstitial Lung Disease
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Table 261-3 Diagnostic Value of Bronchoalveolar Lavage in Interstitial Lung Disease
|Condition||Bronchoalveolar Lavage Finding|
|Sarcoidosis||Lymphocytosis; CD4:CD8 ratio >3.5 most specific of diagnosis|
|Hypersensitivity pneumonitis||Marked lymphocytosis (>50%)|
|Organizing pneumonia||Foamy macrophages; mixed pattern of increased cells characteristic; decreased CD4:CD8 ratio|
|Eosinophilic lung disease||Eosinophils >25%|
|Diffuse alveolar bleeding||Hemosiderin-laden macrophages, red blood cells|
|Diffuse alveolar damage, drug toxicity||Atypical hyperplastic type II pneumocytes|
|Opportunistic infections||Pneumocystis carinii, fungi, cytomegalovirus-transformed cells|
|Lymphangitic carcinomatosis, alveolar cell carcinoma, pulmonary lymphoma||Malignant cells|
|Alveolar proteinosis||Milky effluent, foamy macrophages and lipoproteinaceous intraalveolar material (periodic acid–Schiff stain–positive)|
|Lipoid pneumonia||Fat globules in macrophages|
|Pulmonary Langerhans cell histiocytosis||Increased CD1+ Langerhans cells, electron microscopy demonstrating Birbeck granule in lavaged macrophage (expensive and difficult to perform)|
|Asbestos-related pulmonary disease||Dust particles, ferruginous bodies|
|Berylliosis||Positive lymphocyte transformation test to beryllium|
|Silicosis||Dust particles by polarized light microscopy|
|Lipoidosis||Accumulation of specific lipopigment in alveolar macrophages|
Tissue and Cellular Examination
Lung biopsy is the most effective method for confirming the diagnosis and assessing disease activity. The findings may identify a more treatable process than originally suspected, particularly chronic hypersensitivity pneumonitis, COP, respiratory bronchiolitis–associated ILD, or sarcoidosis. Biopsy should be obtained before the initiation of treatment. A definitive diagnosis avoids confusion and anxiety later in the clinical course if the patient does not respond to therapy or experiences serious side effects from it.
Fiberoptic bronchoscopy with multiple transbronchial lung biopsies (four to eight biopsy samples) is often the initial procedure of choice, especially when sarcoidosis, lymphangitic carcinomatosis, eosinophilic pneumonia, Goodpasture's syndrome, or infection is suspected. If a specific diagnosis is not made by transbronchial biopsy, surgical lung biopsy by video-assisted thoracic surgery or open thoracotomy is indicated. Adequate-sized biopsies from multiple sites, usually from two lobes, should be obtained. Relative contraindications to lung biopsy include serious cardiovascular disease, honeycombing and other roentgenographic evidence of diffuse end-stage disease, severe pulmonary dysfunction, and other major operative risks, especially in the elderly.
Treatment: Interstitial Lung Disease
Although the course of ILD is variable, progression is common and often insidious. All treatable possibilities should be carefully considered. Since therapy does not reverse fibrosis, the major goals of treatment are permanent removal of the offending agent, when known, and early identification and aggressive suppression of the acute and chronic inflammatory process, thereby reducing further lung damage. Hypoxemia (PaO2 <55 mmHg) at rest and/or with exercise should be managed with supplemental oxygen. Management of cor pulmonale may be required as the disease progresses (Chaps. 234 and 250). Pulmonary rehabilitation has been shown to improve the quality of life in patients with ILD.
Glucocorticoids are the mainstay of therapy for suppression of the alveolitis present in ILD, but the success rate is low. There have been no placebo-controlled trials of glucocorticoids in ILD, and so there is no direct evidence that steroids improve survival in many of the diseases for which they are commonly used. Glucocorticoid therapy is recommended for symptomatic ILD patients with eosinophilic pneumonias, COP, CTD, sarcoidosis, hypersensitivity pneumonitis, acute inorganic dust exposures, acute radiation pneumonitis, DAH, and drug-induced ILD. In organic dust disease, glucocorticoids are recommended for both the acute and chronic stages.
The optimal dose and proper length of therapy with glucocorticoids in the treatment of most ILDs are not known. A common starting dose is prednisone, 0.5–1 mg/kg in a once-daily oral dose (based on the patient's lean body weight). This dose is continued for 4–12 weeks, at which time the patient is reevaluated. If the patient is stable or improved, the dose is tapered to 0.25–0.5 mg/kg and is maintained at this level for an additional 4–12 weeks, depending on the course. Rapid tapering or a shortened course of glucocorticoid treatment can result in recurrence. If the patient's condition continues to decline on glucocorticoids, a second agent (see below) often is added and the prednisone dose is lowered to or maintained at 0.25 mg/kg per d.
Cyclophosphamide and azathioprine (1–2 mg/kg lean body weight per day), with or without glucocorticoids, have been tried with variable success in IPF, vasculitis, progressive systemic sclerosis, and other ILDs. An objective response usually requires at least 8–12 weeks to occur. In situations in which these drugs have failed or could not be tolerated, other agents, including methotrexate, colchicine, penicillamine, and cyclosporine, have been tried. However, their role in the treatment of ILDs remains to be determined.
Many cases of ILD are chronic and irreversible despite the therapy discussed above, and lung transplantation may then be considered (Chap. 266).