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.
Exertional dyspnea, a nonproductive cough, and inspiratory crackles with or without digital clubbing may be present on physical examination. HRCT lung scans typically show patchy, predominantly basilar, subpleural reticular opacities, often associated with traction bronchiectasis and honeycombing (Fig. 315-2). A definite UIP pattern on HRCT is highly accurate for the presence of a UIP pattern on surgical lung biopsy. Atypical findings that should suggest an alternative diagnosis include extensive ground-glass abnormality, nodular opacities, upper or midzone 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.
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 usually is 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 frequently are 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 usual interstitial pneumonia is used for patients in whom the lesion is idiopathic and not associated with another condition.
TREATMENT Management Issues in Patients with IPF
Untreated patients with IPF show continued progression of their disease and have a high mortality rate. There is no effective therapy for IPF. Thalidomide appears to improve cough in patients with IPF. Chronic microaspiration secondary to gastroesophageal reflux may play a role in the pathogenesis and natural history of IPF. Gastroesophageal reflux (GER) therapy may be of benefit in IPF. In patients with IPF, treatment with the three-drug regimen of prednisone, azathioprine, and N-acetylcysteine (NAC) or warfarin (in IPF patients who lacked other indications for anticoagulation) has been shown to increase the risks of hospitalization and death.
Patients with IPF and coexisting emphysema (combined pulmonary fibrosis and emphysema [CPFE]) are more likely to require long-term oxygen therapy and develop pulmonary hypertension and may have a more dismal outcome than those without emphysema.
Patients with IPF may have acute deterioration secondary to infections, pulmonary embolism, or pneumothorax. Heart failure and ischemic heart disease are common problems in patients with IPF, accounting for nearly one-third of deaths. These patients also commonly experience 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 ground-glass abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with the UIP pattern; 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. No therapy has been found to be effective in the management of acute exacerbations of IPF. Often mechanical ventilation is required, but it is usually not successful, with a hospital mortality rate of up to three-fourths of patients. In those who survive, a recurrence of acute exacerbation is common and usually results in death at those times.
Patients should be referred early for lung transplant because of the unpredictability of disease progression (e.g., acute exacerbations) (Chap. 320e).
NONSPECIFIC INTERSTITIAL PNEUMONIA
This condition defines a subgroup of the idiopathic interstitial pneumonias that can be distinguished clinically and pathologically from UIP, DIP, AIP, and COP. Importantly, many cases with this histopathologic pattern occur in the context of an underlying disorder, such as a CTD, drug-induced ILD, or chronic hypersensitivity pneumonitis.
Patients with idiopathic NSIP have clinical, serologic, radiographic, and pathologic characteristics highly suggestive of autoimmune disease and meet the criteria for undifferentiated CTD. Idiopathic NSIP is a subacute restrictive process with a presentation similar to that of 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. 315-3). Patchy areas of airspace consolidation and reticular abnormalities may be present, but honeycombing is unusual.
Nonspecific interstitial pneumonia. High-resolution computed tomography 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.
The key histopathologic feature of NSIP is 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.
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 or mycophenolate mofetil.
ACUTE INTERSTITIAL PNEUMONIA (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. 322) 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 common manifestations at presentation. Diffuse, bilateral, air-space opacification is present on the chest radiograph. HRCT scans show bilateral, patchy, symmetric areas of ground-glass attenuation. Bilateral areas of air-space consolidation also may 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
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. Foci of organizing pneumonia are a nonspecific reaction to lung injury found adjacent to other pathologic processes or as a component of other primary pulmonary disorders (e.g., cryptococcosis, granulomatosis with polyangiitis [Wegener], 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.
Glucocorticoid therapy induces clinical recovery in two-thirds of patients. A few patients have rapidly progressive courses with fatal outcomes despite glucocorticoids.
ILD ASSOCIATED WITH CIGARETTE SMOKING
Desquamative Interstitial Pneumonia
DIP is a rare but distinct clinical and pathologic entity found almost 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.
A diffuse and uniform accumulation of macrophages in the alveolar spaces is the hallmark of DIP. The macrophages contain golden, brown, or black pigment of tobacco smoke. There may be mild thickening of the alveolar walls by fibrosis and scanty inflammatory cell infiltration.
Clinical recognition of DIP is important because the process is associated with a better prognosis (10-year survival rate is ~70%) in response to smoking cessation. There are no clear data showing that systemic glucocorticoids are effective in DIP.
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 that of DIP. Crackles are often heard on chest examination and occur throughout inspiration; sometimes they continue into expiration. The process is best seen on HRCT lung scanning, which shows bronchial wall thickening, centrilobular nodules, ground-glass opacity, and emphysema with air trapping. There is a spectrum of CT features in asymptomatic smokers (and elderly asymptomatic individuals) that may not necessarily represent clinically relevant disease.
The histologic findings in RB-ILD include alveolar macrophage accumulation in respiratory bronchioles, with a variable chronic inflammatory cell infiltrate in bronchiolar and surrounding alveolar walls and occasional peribronchial alveolar septal fibrosis. The pulmonary parenchyma may show presence of smoking-related emphysema.
RB-ILD appears to resolve in most patients after smoking cessation alone.
Pulmonary Langerhans Cell Histiocytosis
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 common 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 advances, fibrosis progresses to involve adjacent lung tissue, leading to pericicatricial air space 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 experience 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 pain 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. For the majority of CTDs, with the exception of progressive system sclerosis, recommended initial treatment for ILD includes oral glucocorticoids often in association with an immunosuppressive agent (usually oral or intravenous cyclophosphamide or oral azathioprine) or mycophenolate mofetil.
Progressive Systemic Sclerosis (PSS)
(See also Chap. 382) 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. The HRCT features of lung disease in PSS range from predominant ground-glass attenuation to a predominant reticular pattern and are mostly similar to idiopathic NSIP.
NSIP is the histopathologic pattern in most patients (~75%); the UIP pattern is rare (<10%).
Therapy is similar to that in idiopathic NSIP. UIP in PSS has a better outcome than IPF. The most widely used initial treatment regimen is low-dose glucocorticoid therapy and an immunosuppressive agent, usually oral or pulse cyclophosphamide. There are no convincing data showing this regime to be efficacious, and there is concern that the risk of renal crisis rises substantially with corticosteroids. Pulmonary vascular disease alone or in association with pulmonary fibrosis, pleuritis, or recurrent aspiration pneumonitis is strikingly resistant to current modes of therapy.
(See also Chap. 380) 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 syndrome (rheumatoid pneumoconiosis), pulmonary hypertension secondary to rheumatoid pulmonary vasculitis, organized pneumonia, and upper airway obstruction due to cricoarytenoid arthritis.
There are two primary histopathologic patterns of ILD that are observed in patients with ILD associated with RA: NSIP pattern and UIP pattern.
Little data exist to support the management of ILD in RA. Initial treatment of rheumatoid ILD, if required, is typically with oral glucocorticoids, which should be tried for 1–3 months. The potential benefit of anti-tumor necrosis factor α (TNF-α) therapy has been clouded by concerns about the development of a rapid and occasionally fatal lung disease in patients with RA-associated ILD treated with anti-TNF-α therapy.
Systemic Lupus Erythematosus
(See also Chap. 378) 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 organized pneumonia. Acute lupus pneumonitis characterized by pulmonary capillaritis leading to alveolar hemorrhage is uncommon. Chronic, progressive ILD is uncommon (<10%). 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.
The most common pathologic patterns seen include NSIP, UIP, LIP, and, on occasion, organizing pneumonia and amyloidosis.
There have been no controlled trials of treatment for ILD in SLE. Treatment involves the use of a glucocorticoid, either alone or, more often, in combination with an additional immunomodulating agent.
Polymyositis and Dermatomyositis (PM/DM)
(See also Chap. 388) 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 (NSIP pattern). 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.
NSIP predominates over UIP, organizing pneumonia, or other patterns of interstitial pneumonia.
The optimal treatment is unknown. The most widely used initial treatment is oral glucocorticoids. Fulminant disease may require high-dose intravenous methylprednisolone (1.0 g/d) for 3–5 days.
(See also Chap. 383) General dryness and lack of airway secretion cause the major problems of hoarseness, cough, and bronchitis.
Lung biopsy is frequently required to establish a precise pulmonary diagnosis. Fibrotic NSIP is most common. Lymphocytic interstitial pneumonitis, lymphoma, pseudolymphoma, bronchiolitis, and bronchiolitis obliterans are associated with this condition.
Glucocorticoids have been used in the management of ILD associated with Sjögren syndrome with some degree of clinical success.
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, and 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.
The patterns of lung injury vary widely and depend on the agent.
Treatment consists of discontinuation of any possible offending drug and supportive care.
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. PAP is an autoimmune disease with a neutralizing antibody of immunoglobulin G isotype against granulocyte-macrophage colony-stimulating factor (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 frameshift 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 is 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 common. Markedly elevated serum levels of lung surfactant proteins A and D have been found in PAP. In the absence of any known secondary cause of PAP, an elevated serum anti-GM-CSF titer is highly sensitive and specific for the diagnosis of acquired PAP. BAL fluid levels of anti-GM-CSF antibodies correlate better with the severity of PAP than do serum titers. Radiographically, bilateral symmetric alveolar opacities located centrally in middle and lower lung zones result in a “bat-wing” distribution. HRCT shows a ground-glass opacification and thickened intralobular structures and interlobular septa.
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.
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 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. Whites are affected much more commonly than are 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.
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.
Progression is common, with a median survival of 8–10 years from diagnosis. No therapy is of proven benefit in LAM. Sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), appears to be an active agent for LAM. After 12 months, it stabilized lung function (FVC, FEV1, and functional residual capacity) and was associated with a reduction in symptoms and improvement in quality of life. Adverse effects (e.g., mucositis, diarrhea, nausea, hypercholesterolemia, acneiform rash, peripheral edema) were more common in the sirolimus group, but serious adverse effects were not increased. Subjects were followed off sirolimus for an additional 12 months, during which time pulmonary function declined at the same rate as in the placebo group. Progesterone 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
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 common. Evidence for impaired renal function caused by focal segmental necrotizing glomerulonephritis, usually with crescent formation, also may be present. Varying degrees of hypoxemia may occur and are often severe enough to require ventilatory support. DlCO may be increased, resulting from the increased hemoglobin within the alveoli compartment.
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) also may occur.
Evaluation of either lung or renal tissue by immunofluorescent techniques indicates an absence of immune complexes (pauci-immune) in granulomatosis with polyangiitis (Wegener), 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 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 syndrome, and isolated pulmonary capillaritis is IV methylprednisolone, 0.5–2 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, because 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.
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 cases, 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 diseases include the phakomatoses, tuberous sclerosis and neurofibromatosis (Chap. 118), and the lysosomal storage diseases, Niemann-Pick disease and Gaucher disease (Chap. 432e). 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 315-1) that are discussed in Chaps. 310 and 311. Sarcoidosis (Chap. 390) is prominent among granulomatous diseases of unknown cause in which ILD is an important feature.
(See also Chap. 385) 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. Granulomatosis with polyangiitis (Wegener) and Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) 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 is 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 syndrome and HIV infection.
Pulmonary lymphomatoid granulomatosis generally presents predominantly in men between the ages of 30 and 50, although patients can be affected at any age. The effects of race and geography on disease incidence are not known, although a higher diagnosis rate is reported in Western countries. Although it may affect virtually any organ, it is most frequently characterized by pulmonary (>90%), skin, and central nervous system involvement. The most common presenting symptoms and signs include cough, fever, rash/nodules, malaise, weight loss, neurologic abnormalities, dyspnea, and chest pain.
This multisystem disorder of unknown etiology is an angiocentric malignant (T cell) lymphoma characterized by a polymorphic lymphoid infiltrate, an angiitis, and granulomatosis.
The clinical course of lymphomatoid granulomatosis ranges from remission without treatment to death from malignant lymphoma within 2 years. The choice of a treatment strategy should be based upon the presence of symptoms, history of using an inciting medication, extent of extrapulmonary involvement, and careful assessment of the histopathologic grade of the lesion. Referral to a hematology oncology specialist for consultation is recommended.
Rather than a specific clinical entity, bronchocentric granulomatosis (BG) is a descriptive histologic term that is applied to 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 one-half of the patients described have had 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.
Bronchocentric granulomatosis is characterized by peribronchial and peribronchiolar necrotizing granulomatous inflammation. Destruction of airway walls and adjacent parenchyma leads to granulomatous replacement of mucosa and submucosa by palisading, epithelioid, and multinucleated histiocytes. Bronchocentric granulomatosis does not typically involve the pulmonary arteries.
Glucocorticoids are the treatment of choice, often with an excellent outcome, although recurrences may occur as therapy is tapered or stopped.
Limited epidemiologic data exist describing the prevalence or incidence of ILD in the general population. With a few exceptions, e.g., sarcoidosis and 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 (Chap. 390).