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 toward 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 these structures, as well as the perivascular and lymphatic tissues. This heterogeneous group of disorders is classified together because of similar clinical, roentgenographic, physiologic, or pathologic manifestations. These disorders are often associated with considerable 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 255-1). Each of these groups can be further subdivided 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.
Table 255-1 Major Categories of Alveolar and Interstitial Inflammatory Lung Disease
Lung Response: Alveolitis, Interstitial Inflammation, and Fibrosis
Known Cause
Asbestos
Fumes, gases
Drugs (antibiotics, amiodarone, gold) and chemotherapy drugs
Radiation
Aspiration pneumonia
Residual of adult respiratory distress syndrome
Unknown Cause
Idiopathic interstitial pneumonias
Idiopathic pulmonary fibrosis (usual interstitial pneumonia)
Desquamative interstitial pneumonia
Respiratory bronchiolitis-associated interstitial lung disease
Acute interstitial pneumonia (diffuse alveolar damage)
Cryptogenic organizing pneumonia (bronchiolitis obliterans with organizing pneumonia)
Nonspecific interstitial pneumonia
Connective tissue diseases
Systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, systemic sclerosis, Sjögren's syndrome, polymyositis-dermatomyositis
Pulmonary hemorrhage syndromes
Goodpasture's syndrome, idiopathic pulmonary hemosiderosis, isolated pulmonary capillaritis
Pulmonary alveolar proteinosis
Lymphocytic infiltrative disorders (lymphocytic interstitial pneumonitis associated with connective tissue disease)
Eosinophilic pneumonias
Lymphangioleiomyomatosis
Amyloidosis
Inherited diseases
Tuberous sclerosis, neurofibromatosis, Niemann-Pick disease, Gaucher's disease, Hermansky-Pudlak syndrome
Gastrointestinal or liver diseases (Crohn's disease, primary biliary cirrhosis, chronic active hepatitis, ulcerative colitis)
Graft-vs.-host disease (bone marrow transplantation; solid organ transplantation)
Lung Response: Granulomatous
Known Cause
Hypersensitivity pneumonitis (organic dusts) Inorganic dusts: beryllium, silica
Unknown Cause
Sarcoidosis
Langerhans' cell granulomatosis (eosinophilic granuloma of the lung)
Granulomatous vasculitides
Wegener's granulomatosis, allergic granulomatosis of Churg-Strauss
Bronchocentric granulomatosis
Lymphomatoid granulomatosis
Sarcoidosis (Chap. 322), idiopathic pulmonary fibrosis (IPF), and pulmonary fibrosis associated with CTDs (Chaps. 313, 314, 315, 316, 317, 318, and 319) are the most common ILDs of unknown etiology. Among the ILDs of known cause, the largest group comprises occupational and environmental exposures, especially the inhalation of inorganic dusts, organic dusts, and various fumes or gases (Chaps. 249 and 250) (Table 255-2). A clinical diagnosis is possible for many forms of ILD, especially if an occupational and environmental history is aggressively pursued. For other forms, tissue examination, usually obtained by thoracoscopic lung biopsy, is critical to confirmation of the diagnosis. High-resolution computed tomography (HRCT) scanning improves diagnostic accuracy as experience with histologic-image correlation is perfected.
Table 255-2 Estimated Relative Frequency of the Interstitial Lung Diseases
Diagnosis Relative Frequency, %
Idiopathic interstitial pneumonias 40
Idiopathic pulmonary fibrosis 55
Nonspecific interstitial pneumonia 25
Respiratory bronchiolitis—ILD and desquamative interstitial pneumonia 15
Cryptogenic organizing pneumonia 3
Acute interstitial pneumonia <1
Occupational and environmental 26
Sarcoidosis 10
Connective tissue diseases 9
Drug and radiation 1
Pulmonary hemorrhage syndromes <1
Other 13
Source: From DB Coultas, R Hubbard, in JP Lynch III (ed): Lung Biology in Health and Disease. New York, Marcel Dekker, 2004; and S Garantziotis et al: J Clin Invest 114:319, 2004.
Pathogenesis
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. 255-1).
Figure 255-1
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, they improve after treatment. The main differential diagnosis is between sarcoidosis (Chap. 322) and hypersensitivity pneumonitis (Chap. 249).
Inflammation and Fibrosis
The initial insult is an injury to the epithelial surface causing inflammation in the air spaces and alveolar walls (Fig. 255-2). 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, organizing pneumonia [bronchiolitis obliterans with organizing pneumonia (BOOP) pattern], diffuse alveolar damage (acute or organizing), desquamative interstitial pneumonia, 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.
Figure 255-2
Cellular bases 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-, transforming growth factor ; TIMPs, tissue inhibitors of metalloproteinases; TNF-, tumor necrosis factor ; VEGF, vascular endothelial growth factor. (From M Selman et al: Ann Intern Med 134:136, 2001; with permission.)
History
Duration of Illness
Acute presentation (days to weeks), while 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.
Age
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 50 years.
Gender
LAM and pulmonary involvement in tuberous sclerosis occur exclusively in premenopausal women. Also, 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. Because of occupational exposures, pneumoconioses also occur more frequently in men.
Family History
Family associations (with an autosomal dominant pattern) have been identified in tuberous sclerosis and neurofibromatosis. An autosomal recessive pattern of inheritance occurs in Niemann-Pick disease, Gaucher's disease, and the Hermansky-Pudlak syndrome. Familial clustering has been increasingly identified in sarcoidosis. Familial lung fibrosis has been associated with mutations in the surfactant protein C gene and is characterized by several patterns of interstitial pneumonia, including nonspecific interstitial pneumonia, desquamative interstitial pneumonia, and UIP.
Smoking History
Two-thirds to 75% of patients with IPF have a history of smoking. Patients with PLCH, desquamative interstitial pneumonia (DIP), Goodpasture's syndrome, respiratory bronchiolitis, and pulmonary alveolar proteinosis are almost always current or former smokers.
Occupation 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. 249-1), 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. 249). Symptoms may diminish or disappear after the patient leaves the site of exposure for several days; similarly, symptoms may reappear on returning 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 from all patients with ILD because several processes may occur at the time of initial presentation or during the clinical course, e.g., HIV infection, BOOP, AIP, lymphocytic interstitial pneumonitis, or 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.
Physical Examination
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 mid or late stages of the disease, when findings of pulmonary hypertension and cor pulmonale may become evident (Chap. 244). Cyanosis and clubbing of the digits occur in some patients with advanced disease.
Laboratory
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 angiotensin-converting enzyme level 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 dilatation and/or hypertrophy in the presence of pulmonary hypertension.
Chest Imaging Studies
Chest X-Ray
ILD may be first suspected based on an abnormal chest radiograph, which most commonly reveals a bibasilar reticular pattern. A nodular or mixed pattern of alveolar filling and increased reticular markings may also 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.
Computed Tomography
High-resolution computed tomography (HRCT) is superior to the plain chest x-ray for early detection and confirmation of suspected ILD (Fig. 255-3). Also, 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.
Figure 255-3
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. 246). 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, while common in tuberous sclerosis and LAM). Pulmonary function studies have proven to have prognostic value in patients with idiopathic interstitial pneumonias, particularly, IPF or nonspecific interstitial pneumonia (NSIP).
Diffusing Capacity
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 importantly, to mismatching of ventilation and perfusion (/). 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.
Arterial Blood Gas
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. 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 ratio (Chap. 246)], 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.
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 255-3). The role for 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 255-3 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 initiation of treatment. A definitive diagnosis avoids confusion and anxiety later in the clinical course if the patient does not respond to therapy or suffers 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, then 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, or other major operative risks, especially in the elderly.
Interstitial Lung Disease: Treatment
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 by supplemental oxygen. If cor pulmonale develops, diuretic therapy and phlebotomy may occasionally be required (Chaps. 227 and 244).
Drug Therapy
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, 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, 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 while on glucocorticoids, a second agent (see below) is often added and the prednisone dose is lowered to or maintained at 0.25 mg/kg per day.
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, 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. 260).
Idiopathic Pulmonary Fibrosis
IPF is the most common form of idiopathic interstitial pneumonia. Separating IPF from other forms of lung fibrosis is an important step in the evaluation of all patients presenting with ILD. IPF has a distinctly poor response to therapy and a bad prognosis.
Clinical Manifestations
Exertional dyspnea, a nonproductive cough, and inspiratory crackles with or without digital clubbing may be present on physical examination. The HRCT lung scans typically show patchy, predominantly basilar, subpleural reticular opacities, often associated with traction bronchiectasis and honeycombing (Fig. 255-3). Atypical findings that should suggest an alternative diagnosis include: extensive ground-glass abnormality, nodular opacities, upper or mid-zone predominance, and prominent hilar or mediastinal lymphadenopathy. Pulmonary function tests often reveal a restrictive pattern, a reduced DLCO, and arterial hypoxemia that is exaggerated or elicited by exercise.
Histologic Findings
Confirmation of the presence of the UIP pattern on histologic examination is essential to confirm this diagnosis. Transbronchial biopsies are not helpful in making the diagnosis of UIP, and surgical biopsy is usually required. The histologic hallmark and chief diagnostic criterion of UIP is a heterogeneous appearance at low magnification with alternating areas of normal lung, interstitial inflammation, foci of proliferating fibroblasts, dense collagen fibrosis, and honeycomb changes. These histologic changes affect the peripheral, subpleural parenchyma most severely. The interstitial inflammation is usually patchy and consists of a lymphoplasmacytic infiltrate in the alveolar septa, associated with hyperplasia of type 2 pneumocytes. The fibrotic zones are composed mainly of dense collagen, although scattered foci of proliferating fibroblasts are a consistent finding. The extent of fibroblastic proliferation is predictive of disease progression. Areas of honeycomb change are composed of cystic fibrotic air spaces that are frequently lined by bronchiolar epithelium and filled with mucin. Smooth-muscle hyperplasia is commonly seen in areas of fibrosis and honeycomb change. A fibrotic pattern with some features similar to UIP may be found in the chronic stage of several specific disorders such as: pneumoconioses (e.g., asbestosis), radiation injury, certain drug-induced lung diseases (e.g., nitrofurantoin), chronic aspiration, sarcoidosis, chronic hypersensitivity pneumonitis, organized chronic eosinophilic pneumonia, and PLCH. Commonly, other histopathologic features are present in these situations thus allowing separation of these lesions from the UIP-like pattern. Consequently, the term UIP is used for those patients in whom the lesion is idiopathic and not associated with another condition.
Patients with IPF may suffer acute deterioration secondary to infections, pulmonary embolism, pneumothorax, or heart failure. These patients also commonly suffer an accelerated phase of rapid clinical decline that is associated with a poor prognosis (so-called acute exacerbations of IPF). These acute exacerbations are defined by: worsening of dyspnea within a few days to 4 weeks; newly developing diffuse radiographic opacities; worsening hypoxemia; and absence of infectious pneumonia, heart failure, and sepsis. The rate of these acute exacerbations ranges from 10–57%, apparently depending on the length of follow-up. During these episodes, the histopathologic pattern of diffuse alveolar damage is often found on the background of UIP.
Idiopathic Pulmonary Fibrosis: Treatment
No therapy has been found to be effective in the management of acute exacerbations of IPF. Often mechanical ventilation is required but is usually not successful, with a hospital mortality rate of up to three-fourths of the patients. In those that survive, a recurrence of acute exacerbation is common and usually results in death at those times.
Lung transplantation should be considered for those patients who experience progressive deterioration despite optimal medical management and who meet the established criteria (Chap. 260).
Nonspecific Interstitial Pneumonia (NSIP)
This condition defines a subgroup of the idiopathic interstitial pneumonias that can be distinguished clinically and pathologically from UIP, desquamative interstitial pneumonia (DIP), AIP, and idiopathic BOOP. Importantly, many cases with this histopathologic pattern occur in the context of an underlying disorder, such as a connective tissue disease, drug-induced ILD, or chronic hypersensitivity pneumonitis. Idiopathic NSIP is a subacute restrictive process with a presentation similar to IPF but usually at a younger age, most commonly in women who have never smoked. It is often associated with a febrile illness. HRCT shows bilateral, subpleural ground-glass opacities, often associated with lower lobe volume loss (Fig. 255-4). Patchy areas of airspace consolidation and reticular abnormalities may be present, but honeycombing is unusual. The key histopathologic features of NSIP are the uniformity of interstitial involvement across the biopsy section, and this may be predominantly cellular or fibrosing. There is less temporal and spatial heterogeneity than in UIP and little or no honeycombing is found. The cellular variant is rare. Unlike patients with IPF (UIP), the majority of patients with NSIP have a good prognosis (5-year mortality rate estimated at <15%) with most showing improvement after treatment with glucocorticoids, often used in combination with azathioprine.
Figure 255-4
Nonspecific interstitial pneumonia. High-resolution CT through the lower lung shows volume loss with extensive ground-glass abnormality, reticular abnormality and traction bronchiectasis. There is sparing on the lung immediately adjacent to the pleura. Histology showed a combination of inflammation and mild fibrosis.
Acute Interstitial Pneumonia (AIP, Hamman-Rich Syndrome)
AIP is a rare, fulminant form of lung injury characterized histologically by diffuse alveolar damage on lung biopsy. Most patients are older than 40 years. AIP is similar in presentation to the acute respiratory distress syndrome (ARDS) (Chap. 262) and probably corresponds to the subset of cases of idiopathic ARDS. The onset is usually abrupt in a previously healthy individual. A prodromal illness, usually lasting 7–14 days before presentation, is common. Fever, cough, and dyspnea are frequent manifestations at presentation. Diffuse, bilateral, air-space opacification is present on chest radiograph. HRCT scans show bilateral, patchy, symmetric areas of ground-glass attenuation. Bilateral areas of air-space consolidation may also be present. A predominantly subpleural distribution may be seen. The diagnosis of AIP requires the presence of a clinical syndrome of idiopathic ARDS and pathologic confirmation of organizing diffuse alveolar damage. Therefore, lung biopsy is required to confirm the diagnosis. Most patients have moderate to severe hypoxemia and develop respiratory failure. Mechanical ventilation is often required. The mortality rate is high (>60%), with most patients dying within 6 months of presentation. Recurrences have been reported. However, those who recover often have substantial improvement in lung function. The main treatment is supportive. It is not clear that glucocorticoid therapy is effective.
Cryptogenic Organizing Pneumonia
Also known as idiopathic BOOP, COP is a clinicopathologic syndrome of unknown etiology. The onset is usually in the fifth and sixth decades. The presentation may be of a flulike illness with cough, fever, malaise, fatigue, and weight loss. Inspiratory crackles are frequently present on examination. Pulmonary function is usually impaired, with a restrictive defect and arterial hypoxemia being most common. The roentgenographic manifestations are distinctive, revealing bilateral, patchy, or diffuse alveolar opacities in the presence of normal lung volume. Recurrent and migratory pulmonary opacities are common. HRCT shows areas of air-space consolidation, ground-glass opacities, small nodular opacities, and bronchial wall thickening and dilation. These changes occur more frequently in the periphery of the lung and in the lower lung zone. Lung biopsy shows granulation tissue within small airways, alveolar ducts, and airspaces, with chronic inflammation in the surrounding alveoli. Glucocorticoid therapy induces clinical recovery in two-thirds of patients. A few patients have rapidly progressive courses with fatal outcomes despite glucocorticoids.
Foci of organizing pneumonia (i.e., a "BOOP pattern") is a nonspecific reaction to lung injury found adjacent to other pathologic processes or as a component of other primary pulmonary disorders (e.g., cryptococcosis, Wegener's granulomatosis, lymphoma, hypersensitivity pneumonitis, and eosinophilic pneumonia). Consequently, the clinician must carefully reevaluate any patient found to have this histopathologic lesion to rule out these possibilities.
ILD Associated with Cigarette Smoking
Desquamative Interstitial Pneumonia
DIP is a rare but distinct clinical and pathologic entity found exclusively in cigarette smokers. The histologic hallmark is the extensive accumulation of macrophages in intraalveolar spaces with minimal interstitial fibrosis. The peak incidence is in the fourth and fifth decades. Most patients present with dyspnea and cough. Lung function testing shows a restrictive pattern with reduced DLCO and arterial hypoxemia. The chest x-ray and HRCT scans usually show diffuse hazy opacities. Clinical recognition of DIP is important because the process is associated with a better prognosis (10-year survival rate is ~70%) and a better response to smoking cessation and systemic glucocorticoids than IPF.
Respiratory Bronchiolitis–Associated ILD
Respiratory bronchiolitis–associated ILD (RB-ILD) is considered to be a subset of DIP and is characterized by the accumulation of macrophages in peribronchial alveoli. The clinical presentation is similar to DIP. Rales are often heard on chest examination and occur throughout inspiration; sometimes they continue into expiration. The process is seen best on HRCT lung scanning which shows bronchial wall thickening, centrilobular nodules, ground-glass opacity, and emphysema with air trapping. RB-ILD appears to resolve in most patients following smoking cessation alone.
Pulmonary Langerhans Cell Histiocytosis (PLCH)
This is a rare, smoking-related, diffuse lung disease that primarily affects men between the ages of 20 and 40 years. The clinical presentation varies from an asymptomatic state to a rapidly progressive condition. The most common clinical manifestations at presentation are cough, dyspnea, chest pain, weight loss, and fever. Pneumothorax occurs in ~25% of patients. Hemoptysis and diabetes insipidus are rare manifestations. The radiographic features vary with the stage of the disease. The combination of ill-defined or stellate nodules (2–10 mm in diameter), reticular or nodular opacities, bizarre-shaped upper zone cysts, preservation of lung volume, and sparing of the costophrenic angles are characteristics of PLCH. HRCT that reveals a combination of nodules and thin-walled cysts is virtually diagnostic of PLCH. The most frequent pulmonary function abnormality is a markedly reduced DLCO, although varying degrees of restrictive disease, airflow limitation, and diminished exercise capacity may occur. The characteristic histopathologic finding in PLCH is the presence of nodular sclerosing lesions that contain Langerhans' cells accompanied by mixed cellular infiltrates. The nodular lesions are poorly defined and are distributed in a bronchiolocentric fashion with intervening normal lung parenchyma. As the disease progresses, fibrosis progresses to involve adjacent lung tissue leading to pericicatricial airspace enlargement, which accounts for the concomitant cystic changes. Discontinuance of smoking is the key treatment, resulting in clinical improvement in one-third of patients. Most patients with PLCH suffer persistent or progressive disease. Death due to respiratory failure occurs in ~10% of patients.
ILD Associated with Connective Tissue Disorders
Clinical findings suggestive of a CTD (musculoskeletal pain, weakness, fatigue, fever, joint pains or swelling, photosensitivity, Raynaud's phenomenon, pleuritis, dry eyes, dry mouth) should be sought in any patient with ILD. The CTDs may be difficult to rule out since the pulmonary manifestations occasionally precede the more typical systemic manifestations by months or years. The most common form of pulmonary involvement is the nonspecific interstitial pneumonia histopathologic pattern. However, determining the precise nature of lung involvement in most of the CTDs is difficult due to the high incidence of lung involvement caused by disease-associated complications of esophageal dysfunction (predisposing to aspiration and secondary infections), respiratory muscle weakness (atelectasis and secondary infections), complications of therapy (opportunistic infections), and associated malignancies.
Progressive Systemic Sclerosis (PSS)
(See also Chap. 316) Clinical evidence of ILD is present in about one-half of patients with PSS, and pathologic evidence in three-quarters. Pulmonary function tests show a restrictive pattern and impaired diffusing capacity, often before any clinical or radiographic evidence of lung disease appears. Pulmonary vascular disease alone or in association with pulmonary fibrosis, pleuritis, or recurrent aspiration pneumonitis is strikingly resistant to current modes of therapy.
Rheumatoid Arthritis (RA)
(See also Chap. 314) ILD associated with RA is more common in men. Pulmonary manifestations of RA include pleurisy with or without effusion, ILD in up to 20% of cases, necrobiotic nodules (nonpneumoconiotic intrapulmonary rheumatoid nodules) with or without cavities, Caplan's syndrome (rheumatoid pneumoconiosis), pulmonary hypertension secondary to rheumatoid pulmonary vasculitis, BOOP, and upper airway obstruction due to crico-arytenoid arthritis.
Systemic Lupus Erythematosus (SLE)
(See also Chap. 313) Lung disease is a common complication in SLE. Pleuritis with or without effusion is the most common pulmonary manifestation. Other lung manifestations include the following: atelectasis, diaphragmatic dysfunction with loss of lung volumes, pulmonary vascular disease, pulmonary hemorrhage, uremic pulmonary edema, infectious pneumonia, and BOOP. Acute lupus pneumonitis characterized by pulmonary capillaritis leading to alveolar hemorrhage is uncommon. Chronic, progressive ILD is uncommon. It is important to exclude pulmonary infection. Although pleuropulmonary involvement may not be evident clinically, pulmonary function testing, particularly DLCO, reveals abnormalities in many patients with SLE.
Polymyositis and Dermatomyositis (PM/DM)
(See also Chap. 383) ILD occurs in ~10% of patients with PM/DM. Diffuse reticular or nodular opacities with or without an alveolar component occur radiographically, with a predilection for the lung bases. ILD occurs more commonly in the subgroup of patients with an anti-Jo-1 antibody that is directed to histidyl tRNA synthetase. Weakness of respiratory muscles contributing to aspiration pneumonia may be present. A rapidly progressive illness characterized by diffuse alveolar damage may cause respiratory failure.
Sjögren's Syndrome
(See also Chap. 317) General dryness and lack of airways secretion cause the major problems of hoarseness, cough, and bronchitis. Lymphocytic interstitial pneumonitis, lymphoma, pseudolymphoma, bronchiolitis, and bronchiolitis obliterans are associated with this condition. Lung biopsy is frequently required to establish a precise pulmonary diagnosis. Glucocorticoids have been used in the management of ILD associated with Sjögren's syndrome with some degree of clinical success.
Drug-Induced ILD
Many classes of drugs have the potential to induce diffuse ILD, which is manifest most commonly as exertional dyspnea and nonproductive cough. A detailed history of the medications taken by the patient is needed to identify drug-induced disease, including over-the-counter medications, oily nose drops, or petroleum products (mineral oil). In most cases, the pathogenesis is unknown, although a combination of direct toxic effects of the drug (or its metabolite) and indirect inflammatory and immunologic events are likely. The onset of the illness may be abrupt and fulminant, or it may be insidious, extending over weeks to months. The drug may have been taken for several years before a reaction develops (e.g., amiodarone), or the lung disease may occur weeks to years after the drug has been discontinued (e.g., carmustine). The extent and severity of disease are usually dose-related. Treatment consists of discontinuation of any possible offending drug and supportive care.
Eosinophilic Pneumonia
(See Chap. 249)
Pulmonary Alveolar Proteinosis (PAP)
Although not strictly an ILD, PAP resembles and is therefore considered with these conditions. It has been proposed that a defect in macrophage function, more specifically an impaired ability to process surfactant, may play a role in the pathogenesis of PAP. This diffuse disease is characterized by the accumulation of an amorphous, periodic acid–Schiff-positive lipoproteinaceous material in the distal air spaces. There is little or no lung inflammation, and the underlying lung architecture is preserved. Mutant mice lacking the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF) have a similar accumulation of surfactant and surfactant apoprotein in the alveolar spaces. Moreover, reconstitution of the respiratory epithelium of GM-CSF knockout mice with the GM-CSF gene completely corrects the alveolar proteinosis. Data from BAL studies in patients suggest that PAP is an autoimmune disease with neutralizing antibody of immunoglobulin G isotype against GM-CSF. These findings suggest that neutralization of GM-CSF bioactivity by the antibody causes dysfunction of alveolar macrophages, which results in reduced surfactant clearance. There are three distinct classes of PAP: acquired (>90% of all cases), congenital, and secondary. Congenital PAP is transmitted in an autosomal recessive manner and is caused by homozygosity for a frame shift mutation (121ins2) in the SP-B gene, which leads to an unstable SP-B mRNA, reduced protein levels, and secondary disturbances of SP-C processing. Secondary PAP is rare among adults and is caused by lysinuric protein intolerance, acute silicosis and other inhalational syndromes, immunodeficiency disorders, and malignancies (almost exclusively of hematopoietic origin) and hematopoietic disorders.
The typical age of presentation is 30–50 years, and males predominate. The clinical presentation is usually insidious and manifested by progressive exertional dyspnea, fatigue, weight loss, and low-grade fever. A nonproductive cough is common, but occasionally expectoration of "chunky" gelatinous material may occur. Polycythemia, hypergammaglobulinemia, and increased LDH levels are frequent. Markedly elevated serum levels of lung surfactant proteins A and D have been found in PAP. Radiographically, bilateral symmetric alveolar opacities located centrally in mid and lower lung zones result in a "bat-wing" distribution. HRCT shows a ground-glass opacification and thickened intralobular structures and interlobular septa. Whole-lung lavage(s) through a double-lumen endotracheal tube provides relief to many patients with dyspnea or progressive hypoxemia and also may provide long-term benefit.
Pulmonary Lymphangioleiomyomatosis
Pulmonary LAM is a rare condition that afflicts premenopausal women and should be suspected in young women with "emphysema," recurrent pneumothorax, or chylous pleural effusion. It is often misdiagnosed as asthma or chronic obstructive pulmonary disease. Pathologically, LAM is characterized by the proliferation of atypical pulmonary interstitial smooth muscle and cyst formation. The immature-appearing smooth-muscle cells react with monoclonal antibody HMB45, which recognizes a 100-kDa glycoprotein (gp100) originally found in human melanoma cells. Caucasians are affected much more commonly than members of other racial groups. The disease accelerates during pregnancy and abates after oophorectomy. Common complaints at presentation are dyspnea, cough, and chest pain. Hemoptysis may be life threatening. Spontaneous pneumothorax occurs in 50% of patients; it may be bilateral and necessitate pleurodesis. Meningioma and renal angiomyolipomas (hamartomas), characteristic findings in the genetic disorder tuberous sclerosis, are also common in patients with LAM. Chylothorax, chyloperitoneum (chylous ascites), chyluria, and chylopericardium are other complications. Pulmonary function testing usually reveals an obstructive or mixed obstructive-restrictive pattern, and gas exchange is often abnormal. HRCT shows thin-walled cysts surrounded by normal lung without zonal predominance. Progression is common, with a median survival of 8–10 years from diagnosis. Progesterone (10 mg/d) and luteinizing hormone–releasing hormone analogues have been used. Oophorectomy is no longer recommended and estrogen-containing drugs should be discontinued. Lung transplantation offers the only hope for cure despite reports of recurrent disease in the transplanted lung.
Syndromes of ILD with Diffuse Alveolar Hemorrhage
Injury to arterioles, venules, and the alveolar septal (alveolar wall or interstitial) capillaries can result in hemoptysis secondary to disruption of the alveolar-capillary basement membrane. This results in bleeding into the alveolar spaces, which characterizes DAH. Pulmonary capillaritis, characterized by a neutrophilic infiltration of the alveolar septae, may lead to necrosis of these structures, loss of capillary structural integrity, and the pouring of red blood cells into the alveolar space. Fibrinoid necrosis of the interstitium and red blood cells within the interstitial space are sometimes seen. Bland pulmonary hemorrhage (i.e., DAH without inflammation of the alveolar structures) may also occur.
The clinical onset is often abrupt, with cough, fever, and dyspnea. Severe respiratory distress requiring ventilatory support may be evident at initial presentation. Although hemoptysis is expected, it can be absent at the time of presentation in one-third of the cases. For patients without hemoptysis, new alveolar opacities, a falling hemoglobin level, and hemorrhagic BAL fluid point to the diagnosis. The chest radiograph is nonspecific and most commonly shows new patchy or diffuse alveolar opacities. Recurrent episodes of DAH may lead to pulmonary fibrosis, resulting in interstitial opacities on the chest radiograph. An elevated white blood cell count and falling hematocrit are frequent. Evidence for impaired renal function caused by focal segmental necrotizing glomerulonephritis, usually with crescent formation, may also be present.
Varying degrees of hypoxemia may occur and are often severe enough to require ventilatory support. The DLCO may be increased, resulting from the increased hemoglobin within the alveoli compartment. Evaluation of either lung or renal tissue by immunofluorescent techniques indicates an absence of immune complexes (pauci-immune) in Wegener's granulomatosis, microscopic polyangiitis pauci-immune glomerulonephritis, and isolated pulmonary capillaritis. A granular pattern is found in the CTDs, particularly SLE, and a characteristic linear deposition is found in Goodpasture's syndrome. Granular deposition of IgA-containing immune complexes is present in Henoch-Schönlein purpura.
The mainstay of therapy for the DAH associated with systemic vasculitis, CTD, Goodpasture's syndrome, and isolated pulmonary capillaritis is IV methylprednisolone, 0.5–2.0 g daily in divided doses for up to 5 days, followed by a gradual tapering, and then maintenance on an oral preparation. Prompt initiation of therapy is important, particularly in the face of renal insufficiency, since early initiation of therapy has the best chance of preserving renal function. The decision to start other immunosuppressive therapy (cyclophosphamide or azathioprine) acutely depends on the severity of illness.
Goodpasture's Syndrome
Pulmonary hemorrhage and glomerulonephritis are features in most patients with this disease. Autoantibodies to renal glomerular and lung alveolar basement membranes are present. This syndrome can present and recur as DAH without an associated glomerulonephritis. In such case, circulating anti-basement membrane antibody is often absent, and the only way to establish the diagnosis is by demonstrating linear immunofluorescence in lung tissue. The underlying histology may be bland hemorrhage or DAH associated with capillaritis. Plasmapheresis has been recommended as adjunctive treatment.
Inherited Disorders Associated with ILD
Pulmonary opacities and respiratory symptoms typical of ILD can develop in related family members and in several inherited diseases. These include the phakomatoses, tuberous sclerosis and neurofibromatosis (Chap. 374), and the lysosomal storage diseases, Niemann-Pick disease and Gaucher's disease (Chap. 355). The Hermansky-Pudlak syndrome is an autosomal recessive disorder in which granulomatous colitis and ILD may occur. It is characterized by oculocutaneous albinism, bleeding diathesis secondary to platelet dysfunction, and the accumulation of a chromolipid, lipofuscin material in cells of the reticuloendothelial system. A fibrotic pattern is found on lung biopsy, but the alveolar macrophages may contain cytoplasmic ceroid-like inclusions.
ILD with a Granulomatous Response in Lung Tissue or Vascular Structures
Inhalation of organic dusts, which cause hypersensitivity pneumonitis, or of inorganic dust, such as silica, which elicits a granulomatous inflammatory reaction leading to ILD, produces diseases of known etiology (Table 255-1) that are discussed in Chaps. 249 and 250. Sarcoidosis (Chap. 322) is prominent among granulomatous diseases of unknown cause in which ILD is an important feature.
Granulomatous Vasculitides
(See also Chap. 319) The granulomatous vasculitides are characterized by pulmonary angiitis (i.e., inflammation and necrosis of blood vessels) with associated granuloma formation (i.e., infiltrates of lymphocytes, plasma cells, epithelioid cells, or histiocytes, with or without the presence of multinucleated giant cells, sometimes with tissue necrosis). The lungs are almost always involved, although any organ system may be affected. Wegener's granulomatosis and allergic angiitis and granulomatosis (Churg-Strauss syndrome) primarily affect the lung but are associated with a systemic vasculitis as well. The granulomatous vasculitides generally limited to the lung include necrotizing sarcoid granulomatosis and benign lymphocytic angiitis and granulomatosis. Granulomatous infection and pulmonary angiitis due to irritating embolic material (e.g., talc) are important known causes of pulmonary vasculitis.
Lymphocytic Infiltrative Disorders
This group of disorders features lymphocyte and plasma cell infiltration of the lung parenchyma. The disorders either are benign or can behave as low-grade lymphomas. Included are angioimmunoblastic lymphadenopathy with dysproteinemia, a rare lymphoproliferative disorder characterized by diffuse lymphadenopathy, fever, hepatosplenomegaly, and hemolytic anemia, with ILD in some cases.
Lymphocytic Interstitial Pneumonitis
This rare form of ILD occurs in adults, some of whom have an autoimmune disease or dysproteinemia. It has been reported in patients with Sjögren's syndrome and HIV infection.
Lymphomatoid Granulomatosis
This multisystem disorder of unknown etiology is an angiocentric malignant (T cell) lymphoma characterized by a polymorphic lymphoid infiltrate, an angiitis, and granulomatosis. Although it may affect virtually any organ, it is most frequently characterized by pulmonary, skin, and central nervous system involvement.
Bronchocentric Granulomatosis
Rather than a specific clinical entity, bronchocentric granulomatosis (BG) is a descriptive histologic term that describes an uncommon and nonspecific pathologic response to a variety of airway injuries. There is evidence that BG is caused by a hypersensitivity reaction to Aspergillus or other fungi in patients with asthma. About half of the patients described have chronic asthma with severe wheezing and peripheral blood eosinophilia. In patients with asthma, BG probably represents one pathologic manifestation of allergic bronchopulmonary aspergillosis or another allergic mycosis. In patients without asthma, BG has been associated with RA and a variety of infections, including tuberculosis, echinococcosis, histoplasmosis, coccidioidomycosis, and nocardiosis. The chest roentgenogram reveals irregularly shaped nodular or mass lesions with ill-defined margins, which are usually unilateral and solitary, with upper-lobe predominance. Glucocorticoids are the treatment of choice, often with excellent outcome, although recurrences may occur as therapy is tapered or stopped.
Global Considerations
Limited epidemiologic data exists describing the prevalence or incidence of ILD in the general population. With a few exceptions, e.g., sarcoidosis, certain occupational and environmental exposures, there appear to be no significant differences in the prevalence or incidence of ILD among various populations. For sarcoidosis, there are important environmental, racial, and genetic differences
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