Cecilia M. Smith and Gordon L. Yung
SYSTEMIC LUPUS ERYTHEMATOSUS
Systemic lupus erythematosus (SLE) commonly affects the lungs and pleura. Manifestations of SLE that directly affect the respiratory system include (1) pleuritis with or without pleural effusions; (2) acute lupus pneumonitis; (3) chronic interstitial pneumonitis and interstitial fibrosis; (4) hemorrhagic alveolitis with or without hemoptysis; (5) bronchiolitis obliterans with organizing pneumonia (BOOP); (6) diaphragm–respiratory muscle dysfunction; (7) upper airway dysfunction; (8) pulmonary hypertension with or without thromboembolic disease; (9) less commonly, diffuse lung disease findings of organizing pneumonia (OP), diffuse alveolar damage (DAD), or acute fibrinous and organizing pneumonia (AFOP); and (10) risk for lung cancer. The indirect effects of SLE on the lungs arise from predisposition to infection; in fact, pneumonia is the most frequent cause of infiltrates in patients with lupus.
Pleuritis and accompanying pleuritic chest pain, with or without effusions, are the most common pulmonary manifestations of SLE, occurring in 50% to 75% of patients, with a slightly higher male predominance. It can occur at any time during the clinical course and is the initial manifestation in approximately one-third of cases. The effusions are generally small and bilateral, but can be massive, unilateral, or associated with a pericardial effusion. The exudative fluid can be clear or serosanguineous, and the pH can be high or low; however, the glucose is usually greater than 56 mg/dL, which is useful in distinguishing it from a rheumatoid effusion. Cell counts reveal predominantly polymorphonuclear cells. Total hemolytic complement and serum antinuclear antibody (ANA) titers can be variable, but pleural fluid ANA titers greater than 1:320 strongly support the diagnosis of SLE pleuritis. Lupus erythematosus cells in the pleural fluid are diagnostic. Although most pleural effusions resolve completely with steroid therapy, some residual pleural thickening can persist.
The incidence of interstitial pneumonitis in SLE is controversial, depending on whether clinical, pulmonary function testing, or histologic findings are used as the criteria for diagnosis. Histologic changes display a spectrum similar to idiopathic interstitial pneumonitis, ranging from interstitial mononuclear infiltration to extensive fibrosis. The presence of anti-Sm antibodies in the serum significantly correlates with lung fibrosis. Clinically, acute lupus pneumonitis often presents with the sudden appearance of fever (as high as 104°F) and a nonproductive cough, which can progress rapidly to frank respiratory failure. Histology reveals a florid mononuclear cell infiltrate, interstitial thickening, alveolitis, and vasculitis. Several series report findings of immune complexes and complement within the alveolar walls, the pulmonary arterioles, and small vessels.
In contrast to other collagen vascular diseases such as rheumatoid arthritis and scleroderma, chronic interstitial pneumonitis and interstitial fibrosis are uncommon in SLE. In one report, fibrosis was observed in fewer than 3% of patients with lupus. Patients with fibrosis tend to be older (45–50 years) and have had a prolonged duration of disease before the development of chronic lung disease. The histologic findings include evidence of (1) chronic or recurrent pneumonitis, (2) interstitial and alveolar fibrosis, and (3) immunoglobulin and complement deposition in the alveolar septae. The nail-fold capillary density is a useful physical finding, because it correlates with the extent of gas exchange deficiency. Both acute and chronic lupus pneumonitis may clear radiographically. However, they can also progress to advanced interstitial fibrosis and honeycomb lung. Even after improvement in symptoms and radiographic appearance, decreased diffusing capacity of lung for carbon monoxide (DLCO) and restrictive defects in pulmonary function often persist.
Pulmonary alveolar hemorrhage is a relatively rare presenting feature of SLE. It occurs predominantly in women and is associated with the presence of lupus nephritis. In the correct setting, the combination of anemia, dyspnea associated with hypoxemia, and new radiographic chest infiltrate may suggest its presence. Mortality approaches 50% and is even higher in patients who have required mechanical ventilation, have received cyclophosphamide (perhaps indicating more advanced disease), or have a nosocomial infection. Pathology usually shows a small vessel capillaritis, arteriolitis, and venulitis. Immune complex deposition in a granular pattern distinguishes the pathology of diffuse alveolar hemorrhage (DAH) in SLE from Goodpasture’s (linear distribution).
A relatively common histologic finding in open-lung biopsy specimens is cryptogenic organizing pneumonia (COP), which includes characteristic plugs of granulation tissue within small airways and alveolar ducts in conjunction with inflammatory changes of the bronchioles and pulmonary parenchyma. The usual associated clinical presentation is nonspecific, and patients may show a restrictive ventilatory defect. Diagnosis requires thoracoscopic or open-lung biopsy, and the pathologic changes tend to respond to steroid treatment.
Physiologic studies include the importance of diaphragmatic and respiratory muscle weakness as a cause of dyspnea and a restrictive ventilatory defect in some patients with SLE. A condition known as shrinking lung syndrome consists of dyspnea with chest radiograph findings of small lung volumes, elevated hemidiaphragms, and basilar atelectasis. Maximal inspiratory pressure and maximal expiratory pressure measurements demonstrate inspiratory and expiratory respiratory muscle weakness as the basis for the restrictive ventilatory defects. Comparing the movement of the two hemidiaphragms by fluoroscopy is not useful because both tend to be affected. Transdiaphragmatic pressure during active breathing, measured by esophageal and gastric balloons, confirms the presence of diaphragmatic weakness. Most patients do not have diffuse muscle weakness; therefore, random muscle biopsy is of little utility. The pathogenesis remains unclear and the optimal therapy for this syndrome has not been established. This is also associated with pleurisy. Pleurisy with pleuritic chest pain was present at the time of evaluation in 65% of 77 patients reported.
Although upper airway involvement is uncommon in SLE, hypopharyngeal ulceration, laryngeal inflammation, epiglottitis, and subglottic stenosis have been reported. These manifestations of SLE may result in complications following endotracheal intubation.
Pulmonary hypertension with cor pulmonale, which can be seen with or without associated pulmonary emboli, is significantly correlated with the antiphospholipid syndrome. In one series of 24 patients who had pulmonary hypertension, 68% had a lupus anticoagulant or anticardiolipin antibody. The cause of pulmonary hypertension in SLE can vary among patients. Possible causes include (1) small vessel arteriopathy, (2) chronic large vessel thromboembolic disease, and (3) secondary hypertension caused by end-stage parenchymal fibrosis. In many patients, the pathologic findings in the pulmonary vascular bed are indistinguishable from primary pulmonary hypertension. Raynaud phenomenon is almost uniformly seen in cases not associated with parenchymal lung disease. Vasculitis and immune deposits are seen in SLE with or without the development of pulmonary hypertension. On the other hand, thromboembolism occurs in up to 25% of patients with SLE and is a major cause of death. Most patients with thromboembolism are treated with life-long anticoagulation. Thromboendarterectomy for chronic pulmonary thromboembolic disease has been successful in lupus patients.
Less common to rare manifestations include OP and DAD. AFOP has histopathology features of intra-alveolar fibrin deposition associated with OP. There are overlap features with DAD, OP, and AFOP. Thoracoscopic or open-lung biopsy is required to differentiate these histopathologic findings.
Acute reversible hypoxemia has been described in patients with lupus associated with normal chest radiographs and widened A–a oxygen gradients. Patients generally present with pleuritic chest pain, dyspnea, and chest discomfort. Vital capacity and DLCO are significantly reduced. The syndrome appears to respond to corticosteroids, which improve oxygenation. The cause may be related to transient, complement-mediated aggregation, and neutrophil activation within the pulmonary vasculature.
There is a link between SLE and an increased risk of lung cancer. In one review of 30 cases, 75% were female with a median age of 61 (range 21–91) years. The histologic distribution of the cell types of lung cancers from SLE patients was similar to that of lung cancer patients in the general population. In this group, 71% were smokers and only 20% were exposed to immunosuppressive therapies.
Pulmonary function abnormalities are common, occurring in 70% to 80% of patients with SLE-associated lung disease even in the absence of symptoms and radiographic abnormalities. The most common abnormalities are decreased DLCO and reduced lung volumes. Airway obstruction is unusual. Hypoxemia at rest or with exercise is present frequently. Concomitant renal dysfunction is seen frequently with lupus-associated pulmonary disease.
The management of pulmonary involvement in SLE is generally supportive. Corticosteroids appear to be the most useful drugs, with other agents such as cyclophosphamide, azathioprine, or mycophenolate mofetil added according to the severity of organ involvement. Therapies focusing on B- and T-cell functions by rituximab (anti-CD20 monoclonal antibody) or infliximab (tumor necrosis factor-α blockade) are also being evaluated in ongoing studies. Even if the patient responds to therapy, pulmonary involvement is a poor prognostic sign; respiratory syndromes in SLE have been associated with a 2-fold increased risk of death at 1 year. Pulmonary hypertension associated with SLE is responsive to each type of pulmonary vasodilator therapy as reported in the literature. For patients with pulmonary hypertension associated with pulmonary thromboemboli, treatment is directed for pulmonary embolic disease, acute or chronic.
SYSTEMIC SCLEROSIS
Systemic scleroderma (SSc) is one form of scleroderma that involves internal organs as well as the characteristic skin disorder, which typically undergoes serial changes from the edematous phase to induration and skin thickening and tightness. Eventually, pitting scars and acrosclerosis can also occur in the fingers. The other form of this disease is localized to skin and adjacent tissues (morphea, linear scleroderma). Systemic sclerosis is further categorized into five subsets based on the extent and distribution of the skin involvement, plus the pattern of internal organs involved: diffuse cutaneous, limited cutaneous, sine scleroderma, environmentally induced scleroderma, and overlap syndrome with other collagen vascular diseases.
The two most common subsets of SSc are diffuse cutaneous and limited cutaneous. The disease is considered to be either diffuse or limited based on the extent and distribution of skin involvement plus internal organs affected.
Diffuse cutaneous systemic sclerosis (dcSSc) is associated with diffuse, often rapidly progressive, skin involvement of the chest, abdomen, shoulders and upper arms, and internal organ injuries due to fibrosis and/or ischemic vascular disease. Raynaud phenomenon generally is followed rapidly by the onset of skin and other systemic changes. Internal organ involvement with renal disease, interstitial pulmonary fibrosis, GI (esophageal dysmotility), and myocardial disease can occur early and be significant, and overall prognosis is generally poor.
Limited cutaneous systemic sclerosis (lcSSc) differs from dcSSc in that the skin involvement is generally limited to the hands and distal forearms as well as the face and neck, and there is often prolonged delay in the appearance of internal organ manifestations. Limited cutaneous SSc is associated with vascular manifestations such as telangiectasia and calcinosis; in its full form, it is often associated with the CREST syndrome. The CREST syndrome consists of (1) calcinosis cutis, (2) Raynaud phenomenon, (3) presence or absence of esophageal dysfunction, (4) sclerodactyly, and (5) telangiectasias. Raynaud phenomenon may be present for an extensive period of time before diagnosis.
The other subsets of SSc include sine scleroderma, which is a rare form with the presence of internal organ disease without skin involvement; environmentally induced scleroderma, with the manifestations of scleroderma precipitated by exposure to a chemical agent (e.g., vinyl chloride or pesticides); and overlap syndrome including features of scleroderma as well as manifestations of other collagen vascular diseases.
Systemic sclerosis commonly affects the lung. Lung pathology is second in frequency to esophageal disease, and pulmonary complications are the most frequent cause of death, making early detection of lung involvement an important predictor of survival. Pulmonary pathology is found in approximately 90% of patients at autopsy.
The most common lung abnormalities include interstitial lung disease and pulmonary arterial hypertension (PAH). The most common pattern of diffuse lung disease is nonspecific interstitial pneumonitis (NSIP). This pattern is seen in up to 75% of patients with SSc-associated interstitial lung disease. It is more frequent in dcSSc (approximately 40%) than in lcSSc (approximately 35%). A small subset of these patients evolves to end-stage pulmonary fibrosis, with histopathology consistent with findings of usual interstitial pneumonia (UIP).
PAH occurs in up to 40% of patients with systemic sclerosis. PAH occurs in both diffuse and limited forms of disease but is seen 10 times more commonly in the limited cutaneous form of systemic sclerosis. PAH can occur with or without interstitial pulmonary fibrosis. When PAH develops, it can lead to cor pulmonale and right-sided heart failure.
Other pulmonary conditions associated with systemic sclerosis include aspiration pneumonitis associated with esophageal dysmotility, airway disease, hypoventilation due to neuromuscular weakness, extrinsic pulmonary restrictive physiology due to chest wall involvement of cutaneous skin disease, pleural effusions, pneumothorax, and lung cancer.
Patients with scleroderma have significantly higher risk for lung cancer than the general population. Scleroderma patients who smoke have a 7-fold higher risk as compared to nonsmoking scleroderma patients, and nonsmoking scleroderma patients have a 5-fold higher risk for developing lung cancer as compared to age- and gender-matched subsets of the general population. This appears to be similar for both diffuse cutaneous as well as limited cutaneous forms of systemic sclerosis.
Although the lung is commonly affected, respiratory symptoms are rarely the presenting complaint. Dyspnea on exertion is the most common pulmonary symptom, followed by a nonproductive or minimally productive cough. Pleuritic chest pain and pleural effusions are rare. Lung examination reveals basilar inspiratory crackles. Signs of pulmonary hypertension may be present, depending on the severity of the disease. The finding of digital ulcers is associated with interstitial lung disease but not PAH.
Pulmonary function studies are abnormal in most patients; decreased DLCO is the most common finding, followed by reduced lung volumes and airway obstruction. Chest roentgenograms reveal interstitial infiltrates in approximately one-third of patients. The echocardiogram with estimated pulmonary arterial pressures can screen for the development of PAH. However, if abnormal, a right-heart catheterization is required to diagnose PAH. An exercise echocardiogram may need to be performed to elicit abnormal elevation in pulmonary artery pressure.
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