Chapter 9 Diseases of Altered Immunologic Activity
Several pulmonary disorders are associated with systemic or local bronchopulmonary immunologic alterations. Some of these disorders primarily involve the lung, and in others, the pulmonary manifestations result from disease arising elsewhere. The choice of diseases included in this chapter is somewhat arbitrary. For example, asthma is addressed elsewhere with chronic obstructive pulmonary disease. Some of the infiltrative lung diseases such as sarcoidosis and occupational lung diseases such as silicosis and asbestosis are associated with multiple immunologic aberrations, but they are also discussed elsewhere.
There are four basic types of immunologic reaction, all of which may be responsible for diseases in the lung. These reactions are not mutually exclusive, and the development of one type may be accompanied by the simultaneous or subsequent development of another (Box 9-1).
Box 9-1 Types of Immune Reactions
Goodpasture’s syndrome (Box 9-2) is a disorder of unknown origin that is characterized by repeated episodes of pulmonary hemorrhage, iron deficiency anemia, and glomerulonephritis. It is often rapidly progressive. The immunopathologic nature of the disease is apparent because of the linear deposits of immunoglobulins, which can be demonstrated in the glomerular basement membrane and alveolar septa.
Box 9-2 Goodpasture’s Syndrome
Goodpasture’s syndrome is an autoimmune disease in which the renal and pulmonary lesions are mediated by an anti-glomerular basement membrane (anti-GBM) antibody that cross-reacts with lung basement membrane. Most patients with Goodpasture’s syndrome have circulating anti-GBM antibodies.
The syndrome is classically a disease of young men. The initial and most common symptom is hemoptysis. Iron deficiency anemia is invariably present. Pulmonary hemorrhage commonly antedates the clinical manifestations of renal disease. Anti-GBM antibodies can be identified in the sera of patients with the disease.
The classic radiographic appearance of Goodpasture’s syndrome consists of diffuse, homogeneous consolidation or alveolar opacities distributed fairly uniformly throughout all lung zones (Fig. 9-1). These changes are characteristic of the early stages of the disease and the development of acute pulmonary hemorrhage. Although the radiographic pattern is similar to that of cardiogenic pulmonary edema, conspicuously absent features are cardiomegaly, Kerley B lines, and pleural effusions. In the later stages, the changes depend on the time sequence and the number of hemorrhages that have occurred in the past. The alveolar consolidation seen during the acute episode may resolve in 2 to 3 days. Irregular or linear opacities often persist for an extended period. If bleeding is continuous or repetitive, these linear and occasionally nodular opacities become permanent as increasing amounts of hemosiderin are deposited within the interstitial tissue. Goodpasture’s syndrome must be differentiated from pulmonary hemorrhage due to other causes, such as idiopathic pulmonary hemorrhage (i.e., hemosiderosis) and numerous causes of vasculitis. Hemorrhage may occur rarely in patients receiving systemic anticoagulants.
The connective tissue or collagen vascular diseases are a group of immunologically mediated disorders characterized by inflammation of joints, serosal membranes, connective tissue, and blood vessels in various organs. Pathologically, alterations occur in the connective tissue ground substance, which contains elastin, collagen, and reticulin. Edema, fibrinoid degeneration, and vascular lesions are characteristic.
Rheumatoid arthritis is a subacute or chronic disease that primarily affects the joints with a symmetric inflammatory arthritis. Constitutional symptoms are common, and laboratory abnormalities include an elevated erythrocyte sedimentation rate and a high level of rheumatoid factor. Occasionally, rheumatoid arthritis may involve other organs and tissues, including the lungs and pleura.
Six pleuropulmonary abnormalities are associated with rheumatoid disease: pleurisy with or without effusion; diffuse interstitial pneumonitis or fibrosis; pulmonary (necrobiotic) nodules; Caplan’s syndrome (i.e., pneumoconiotic nodules); pulmonary hypertension resulting from rheumatoid vasculitis, and airways disease (i.e., bronchiectasis, obliterative bronchiolitis, and follicular bronchiolitis).
Pleural involvement is the most common thoracic manifestation of rheumatoid disease (Box 9-3). Clinical evidence of rheumatoid pleurisy appears in about 20% of patients, but only 5% have radiologic evidence of effusions. In contrast, pleural involvement may be found in 50% of autopsy series. Pleural disease occurs much more frequently in men than in women with rheumatoid disease. Rheumatoid pleurisy usually occurs in the sixth decade of life and is associated with moderate to severe arthritis. Rheumatoid factor is present in the serum and the pleural fluid in high titers. The pleural fluid is exudative and characterized by a low glucose concentration and low pH.
Box 9-3 Rheumatoid Pleurisy
The chest radiograph usually shows a small- to medium-sized pleural effusion. It is typically unilateral, with a slight predominance on the right. Rheumatoid effusions tend to remain unchanged for many months or even years. Other manifestations of rheumatoid lung disease, such as interstitial fibrosis, are usually absent. The effusions may be recurrent and occasionally result in a diffusely thickened pleura or fibrothorax (Fig. 9-2).
Figure 9-2 Rheumatoid lung is a pleuropulmonary disease. The posteroanterior chest radiograph shows linear opacities diffusely distributed in both lungs, indicating interstitial fibrosis. There is bilateral pleural thickening (arrows) with blunting of both costophrenic angles. The patient had recurrent bilateral rheumatoid pleurisy with effusions.
Interstitial lung disease (Box 9-4) may be seen in a variety of collagen vascular diseases. Histopathologically, the abnormalities may take the form of any of the various idiopathic interstitial pneumonias, including usual interstitial pneumonitis (UIP), nonspecific interstitial pneumonitis (NSIP), cryptogenic organizing pneumonia (COP), and lymphocytic interstitial pneumonia (LIP). Whereas NSIP is the most common histopathologic pattern in most collagen vascular disorders, UIP predominates in patients with rheumatoid arthritis. The prevalence may be as high as 30%. Immunologically mediated injury most likely plays a central role in this interstitial pneumonitis, and immune complexes (i.e., type III reaction) containing rheumatoid factor have been identified in alveolar walls and pulmonary capillaries by immunofluorescence.
The interstitial lung disease may occur before, after, or with the onset of arthritis. The classic symptom is progressive dyspnea, and pulmonary function tests show evidence of restrictive ventilatory impairment.
The radiologic features of rheumatoid interstitial disease are usually identical to those seen in UIP (Fig. 9-3) and NSIP. In the early stages, a pattern of fine linear or irregular opacities can be identified predominantly in the bases, which may progress to coarse reticulation with end-stage cystic changes and honeycombing. CT findings include reticular opacities located predominantly in the subpleural regions in the lung bases; ground-glass attenuation (especially in NSIP) (Fig. 9-4); irregular pleural and mediastinal interfaces; thickened interlobular septa; and honeycomb cysts (especially in UIP). Progressive loss of volume (“shrinking lungs”) may be observed on serial studies. Pleural effusion or thickening may be present. Occasionally, other features of rheumatoid disease may be observed in the bony thorax, including typical arthritic changes in the shoulder, joints, and tapering of the distal clavicles.
The intrapulmonary rheumatoid or necrobiotic nodule is pathologically identical to the subcutaneous nodule in rheumatoid arthritis. It may occur in the pleura and pericardium in addition to the lung parenchyma. It is an uncommon manifestation of pulmonary rheumatoid disease, and it is usually associated with the presence of advanced arthritis and subcutaneous nodules.
Radiographically, these lesions appear as multiple, well-circumscribed pulmonary nodules that are usually located in the periphery of the lungs (Fig. 9-5). Cavitation is common, and the walls are usually thick and smooth. Changes in the size of nodules may be observed; these correlate with the activity and treatment status of the disease. Although nodules usually cause no symptoms, they may rarely lead to complications, including pleural effusion, pneumothorax, bronchopleural fistula, hemoptysis, and infection.
Figure 9-5 Rheumatoid necrobiotic nodules. A and B, Radiographs obtained 4 years apart show multiple nodules that are slowly increasing in size. Some of the nodules are cavitated (arrows). An open lung biopsy was performed for a nodule in the left upper lobe.
On pathologic examination, these lesions are identical to the subcutaneous rheumatoid nodule, and they contain a central zone of fibrinoid necrosis surrounded by a zone of palisading fibroblasts oriented at right angles to the zone of necrosis. External to the palisade is a zone of cellular granulation tissue.
In rare cases, pulmonary vasculitis may cause pulmonary hypertension in rheumatoid arthritis; more commonly, pulmonary hypertension is caused by end-stage fibrosis. The radiographic features consist of enlargement of the right side of the heart and dilation of central pulmonary arteries, with rapid tapering of peripheral branches.
Bronchiectasis has been reported in up to 30% of patients with rheumatoid arthritis. In most cases, it is not clinically significant. Obliterative bronchiolitis may be caused by rheumatoid arthritis or several drugs used to treat this condition, including d-penicillamine, gold, and sulfasalazine. This disorder is discussed separately in Chapter 13. Patients with rheumatoid arthritis may also develop follicular bronchiolitis, a benign condition characterized by lymphoid hyperplasia of bronchus-associated lymphoid tissue (BALT). This entity is discussed separately at the end of this chapter.
Progressive systemic sclerosis or scleroderma (Box 9-5) is a connective tissue disease characterized by fibrosis and atrophy of the skin, lungs, gastrointestinal tract, heart, and kidneys. Patients are usually affected in the fourth to sixth decade of life, and the disease is three times more common in women than in men.
After the esophagus, the lung is the second most frequently involved visceral organ. Chest radiographic abnormalities have been reported in up to 25% of cases. The pulmonary manifestations of scleroderma may take one of three forms; interstitial fibrosis is the most common, but pulmonary vascular disease and pleural changes may also occur. Although the pathogenesis of interstitial lung disease is unknown, an immunologic mechanism is likely. Vascular disease involving the arterioles and capillary bed frequently occurs in the lungs of scleroderma patients. These changes appear to be unrelated to the interstitial fibrosis and may occur independently. Pulmonary hypertension may develop as a consequence of these lesions.
Clinical symptoms include dyspnea and nonproductive cough. Pulmonary function abnormalities consist of restrictive pattern with a diminished diffusing capacity. Signs of cor pulmonale may occur at a later stage. Pulmonary hypertension is a frequent complication of scleroderma, and it appears to be independent of the duration of the disease or the severity of the interstitial fibrosis. It results from primary lesions in the small- and medium-sized pulmonary arteries that are characterized by intimal proliferation with myxomatous changes. In contrast to interstitial lung disease, pulmonary hypertension usually is a late complication of systemic sclerosis. Severe pulmonary hypertension is also found in patients with the CREST syndrome (i.e., calcinosis cutis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia). It is a benign variant of scleroderma. Pulmonary symptoms may also occur as a result of recurrent aspiration pneumonia because of disturbances of esophageal motility and distal esophageal strictures.
The radiographic pattern is usually identical to that seen in NSIP or UIP and may be indistinguishable from rheumatoid lung. NSIP is the most common histopathologic pattern in patients with systemic sclerosis. A fine linear pattern of small, irregular opacities can be identified, with predominant involvement at the bases and often accompanied by ground-glass attenuation. As the disease progresses, the opacities become coarser, and eventually, traction bronchiectasis and honeycomb cysts develop. The latter pattern is a typical feature of UIP. Progressive loss of volume occurs over several years. Pleural involvement, however, is uncommon. On high-resolution CT (Fig. 9-6), findings are similar to those described in rheumatoid lung disease. In patients with systemic sclerosis, interstitial lung disease is frequently accompanied by thoracic lymphadenopathy, which tends to increase as the profusion of lung disease worsens.
Figure 9-6 Progressive systemic sclerosis. A, High-resolution CT shows extensive, basilar ground-glass attenuation, intralobular and interlobular thickening, and traction bronchiectasis, as well as a dilated esophagus. B, Coronal reformation image demonstrates subpleural and basilar distribution.
Other nonpulmonary manifestations of scleroderma may be identified on the chest radiograph. Calcinosis may be present in the skin and subcutaneous tissue of the thorax, particularly about the shoulders. Atrophy and atony of the esophagus that results in absent peristalsis may also lead to dilation of the esophagus. On chest radiography and CT, this is manifested by the presence of gas without an air-fluid level in a distended esophagus, the so-called air esophagram (see Fig. 9-6). Dilation of the central pulmonary arteries with rapid tapering of peripheral vessels is characteristic of pulmonary arterial hypertension (Fig. 9-7).
SLE is a chronic disease of unknown origin that affects the components of connective tissue of many organs, including the lungs. The vascular system, the epidermis, and serous and synovial membranes are the most commonly involved sites. The diagnosis of SLE is established by clinical and laboratory phenomena, including a positive antinuclear antibody test result and the lupus cell (i.e., LE cell phenomenon). SLE is the prototype of disease caused by a type III immunologic reaction.
Young women are affected four times as often as men. Renal and central nervous system involvement and various infections are common determinants of survival. The lungs and pleura are involved more frequently in SLE than in any other collagen vascular disease, with the prevalence ranging from 30% to 70% in several series.
The clinical manifestations of pleural pulmonary lupus vary. Symptoms include pleuritis and cough with or without dyspnea. Pleuritis occurs in 35% to 40% of patients and is often painful and accompanied by fever. Patients occasionally have hemoptysis associated with pulmonary hemorrhage. The radiographic manifestations may be classified in six categories (Box 9-6), and patient may have more than one of these entities.
Box 9-6 Systemic Lupus Erythematosus
Separately or combined, pleuritis and effusion are the most common pleuropulmonary abnormalities in SLE. Pleuritis is often an early manifestation of disease and may have exacerbations. The effusions are commonly bilateral and small, although they may be massive. Pericardial effusions may also be present (Fig. 9-8). The fluid is an exudate with a high protein content and normal glucose concentration.
Atelectasis, usually of the subsegmental variety, can be identified on chest radiographs in patients with SLE. These areas appear as horizontal-line opacities usually occurring at the bases. They may be migratory and fleeting. These areas are often associated with pleural effusion or diaphragmatic dysfunction.
Uremic pulmonary edema is seen in the presence of severe renal failure in patients with SLE. The chest radiograph reveals evidence of cardiac enlargement and central alveolar opacities in a classic butterfly or bat’s wing distribution.
Acute lupus pneumonitis is an uncommon but well-recognized manifestation of SLE. It is characterized by severe dyspnea, nonproductive cough, fever, and hypoxia. The radiographic features (Fig. 9-9) consist of poorly defined focal areas of increased opacity at the bases or widespread, extensive, unilateral or bilateral consolidation. These pulmonary opacities usually respond to steroids or cytotoxic drugs. The pathogenesis of this disorder is unclear, but histologic alterations include vasculitis and hemorrhage.
Unlike other collagen vascular diseases, chronic interstitial lung disease in SLE is distinctly uncommon. Estimates of prevalence vary from 1% to 6%. Clinical symptoms and pulmonary function tests are identical to those found in other collagen vascular diseases with interstitial fibrosis. The radiographic changes are identical to other causes of UIP or NSIP.
Diaphragmatic dysfunction with loss of lung volume is related to a diffuse myopathy affecting the diaphragmatic muscles. The chest radiograph shows evidence of elevated hemidiaphragms and loss of lung volume. On fluoroscopic examination, diaphragmatic movement is sluggish.
Pleural effusions and pulmonary disease may be seen in cases of drug-induced lupus-like syndromes. Unlike cases of idiopathic SLE, the prognosis is excellent after the offending agent is discontinued.
Polymyositis and dermatomyositis (Box 9-7) include a group of autoimmune disorders characterized by diffuse inflammatory and degenerative changes in striated muscle. Fewer cases are associated with underlying malignancy. Symptoms include dyspnea on exertion and nonproductive cough. There is evidence of restriction on pulmonary function testing, and there may be a profound weakness of the muscles of respiration. The cause is unknown, and unlike other collagen vascular diseases, there are no circulating immune complexes.
Box 9-7 Polymyositis or Dermatomyositis
Three types of pulmonary disease can be identified in this disorder: chronic interstitial pneumonitis, aspiration pneumonia due to a hypotonic esophagus, and hypostatic pneumonia due to chest wall involvement with resultant hypoventilation. The prevalence of interstitial pneumonitis is low, estimated to be about 5%.
The radiologic features consist of diffuse linear opacities of varied coarseness that predominate at the bases, similar to other collagen vascular diseases, and correlate histopathologically to UIP or NSIP. However, many patients may have normal chest radiographs. CT findings may include multifocal areas of patchy, subpleural consolidation accompanied by parenchymal bands and bronchovascular thickening. Areas of peripheral consolidation correlate histopathologically with COP. These findings are potentially reversible after treatment with corticosteroids or other immunosuppressant therapy, or both.
When polymyositis involves the muscles of respiration, diaphragmatic elevation with small lung volumes and areas of subsegmental atelectasis are apparent. Unilateral or bilateral aspiration pneumonia may result when pharyngeal muscle paralysis is a feature. Diffuse soft tissue calcification may be identified on the chest radiograph, a finding more often seen in children than in adults.
Mixed connective tissue disease is a rheumatic disease syndrome that overlaps features of SLE, polymyositis, and scleroderma. It is distinguished from other collagen vascular diseases by the presence of a specific antibody to an extractable nuclear antigen (ENA) in the serum. Many patients with this disorder have had interstitial lung disease. The pulmonary involvement may be mild and responsive to steroids, but rapidly progressive fibrosis and pulmonary hypertension occasionally develop.
Involvement of the thoracic spine is common in ankylosing spondylitis. Between 1% and 2% of patients also may develop pleuropulmonary manifestations, most commonly in the form of upper lobe fibrotic and bullous disease (Fig. 9-10). Although it is rare, ankylosing spondylitis should be considered in the differential diagnosis of chronic infiltrative lung disorders that cause upper lobe scarring and fibrosis.
Figure 9-10 Ankylosing spondylitis. A, The posteroanterior radiograph demonstrates marked upper lobe fibrosis and retraction with bullae and pleural thickening. B, The lateral chest radiograph shows the typical features of ankylosing spondylitis of the thoracic spine. Notice the calcification of the anterior longitudinal ligament.
Any disease characterized pathologically by an inflammatory response within blood vessels may be considered a vasculitis. If the inflammation produces destruction of vessel walls, the process is called a necrotizing vasculitis. Most vascular diseases are systemic, although there often is a target organ. The lungs commonly are involved by several types of vasculitis. Box 9-8 provides a classification that divides these disorders into four groups. This section deals with diseases in category 1, those that histopathologically have a granulomatous appearance and have been characterized by Liebow as pulmonary angiitis and granulomatosis. In all these diseases, the lung is the major site of involvement. These granulomatous vasculitides include classic and limited Wegener’s granulomatosis, lymphomatoid granulomatosis, allergic granulomatosis (i.e., Churg-Strauss syndrome), necrotizing sarcoid angiitis and granulomatosis, and bronchocentric granulomatosis.
From Dreisin RB: Pulmonary vasculitis. Clin Chest Med 3:607–618, 1982.
Wegener’s granulomatosis (Box 9-9) usually consists of a disease triad of necrotizing vasculitis that involves the upper respiratory tract, lungs, and glomeruli of the kidneys. However, the limited form of Wegener’s is confined to the lungs.
Box 9-9 Wegener’s Granulomatosis