INTRODUCTION

Systemic lupus erythematosus (SLE) can affect all parts of the respiratory system, including airways (upper and lower), lung parenchyma, pleura, pulmonary vasculature, and respiratory muscles (Table 33.1). The lungs and the pleura are commonly affected in SLE with 50 to 70% of patients developing pleuropulmonary manifestations during the course of their disease.¹^–³ It may be asymptomatic and is frequently not associated with significant morbidity; however, life-threatening disease can occur. Patients can develop more than one pulmonary manifestation over the course of the disease. Pulmonary involvement diagnosed within the first year of disease is reported to be associated with increased mortality at 10 years.⁴

TABLE 33.1 PULMONARY MANIFESTATIONS OF SYSTEMIC LUPUS ERYTHEMATOSUS

	Primary
Pleural	Pleuritis Pleural effusion Pleural thickening
Diffuse lung disease	Acute pneumonitis Diffuse alveolar hemorrhage Usual interstitial pneumonia Nonspecific interstitial pneumonia Lymphocytic interstitial pneumonia Organizing pneumonia
Small airways disease	Bronchiolitis obliterans
Vascular	Pulmonary hypertension Vasculitis Thromboembolism with or without antiphospholipid syndrome Acute reversible hypoxemic syndrome

	Secondary
Respiratory muscle weakness	Shrinking lung syndrome
Pneumonia
Drug-induced lupus
Pulmonary edema (renal/cardiac)

PLEURAL DISEASE

Pleuritis is present in 45 to 60% of patients, and is the most common thoracic manifestation of SLE.^1,⁵ It tends to be painful and can be a presenting feature in 20%,⁶ but occurs more commonly (50%) during a disease exacerbation. Pleural abnormalities are found at autopsy in 50 to 100% of patients.⁷

Pleuritis is associated with a pleural effusion in 50% of patients.^1,⁸ Effusions are commonly small or moderate in size, bilateral more often than unilateral, and equally distributed between right and left hemithoraces (Fig. 33.1).⁹ Pleural fluid is commonly exudative, serosanguinous, and neutrophilic during acute attacks, and lymphocytic in chronic effusions. It often contains antinuclear antibodies, although this is not tested routinely unless the diagnosis is unclear.¹⁰ Pleural effusions can occur in lupus secondary to cardiac or renal involvement but tend not to be painful.

Fig. 33.1 Pleural effusion. Chest radiograph shows blunting of both costophrenic angles, compatible with small pleural effusions.

Pleural effusions can resolve spontaneously and small asymptomatic effusions may require no specific treatment. Symptomatic pleurisy may require nonsteroidal anti-inflammatory drugs (NSAIDS). Moderate effusions may require introducing corticosteroids or stepping up their dosage.³ Long-term treatment may require immunosuppressive drugs or hydroxychloroquine. Pleurodesis or chest drain insertion is rarely required.

ACUTE PNEUMONITIS

Acute lupus pneumonitis occurs in up to 4% of patients.^1,¹¹ Rarely it can be a presenting feature of lupus. It presents abruptly with fever, cough, dyspnea, pleuritic chest pain, hypoxia, and occasionally hemoptysis. Chest radiography typically shows patchy unilateral or bilateral pneumonic-like infiltrates, usually at the bases, commonly associated with pleural effusions. These features are seen more graphically via computed tomography (CT).

Histopathologic findings include diffuse alveolar damage and necrosis, edema, inflammatory cell infiltrate, hemorrhage, and hyaline membrane formation.¹² Alveolar damage is immune complex mediated. Immunofluorescence studies have shown granular deposits of IgG and C3 along the alveolar walls.¹³ Symptoms mimic bacterial infection or alveolar hemorrhage, and these should be excluded using bronchoalveolar lavage. Patients require corticosteroids,² and in some cases require cyclophosphamide in addition.³ Plasmapheresis is also useful.¹¹ This acute presentation carries a mortality of 50%.^11,¹² In survivors, more chronic disease is characterized by persistent radiographic shadowing and a restrictive ventilatory defect and reduced gas transfer for carbon monoxide (DLCO).

DIFFUSE ALVEOLAR HEMORRHAGE

Alveolar hemorrhage is rare and occurs in 2% of lupus patients,¹ but accounts for 20% of SLE hospital admissions.¹⁴ Alveolar hemorrhage can be the presenting feature in 20% of SLE patients and carries a mortality of 50 to 60%.^14,¹⁵ The typical presentation is of acute severe dyspnea with fever, and crepitations are heard on auscultation. Hemoptysis occurs in up to two-thirds of patients.¹⁶ Chest radiographs can show widespread pulmonary infiltrates, ground-glass opacities, and areas of consolidation, usually bilateral with a lower zone predominance that clear within a few days either spontaneously or with treatment.¹⁷ CT confirms widespread patchy ground-glass attenuation with or without consolidation (Fig. 33.2). Arterial hypoxemia is common, and many patients need ventilatory support. Bronchoscopy and bronchoalveolar lavage are required to exclude a site of bleeding, concurrent infection, and other causes of acute respiratory failure. Blood in the large airways, serosanguinous lavage with incremental amounts of blood from serial aliquots, hemosiderin-laden macrophages, and lack of purulent sputum support the diagnosis, especially when hemoptysis is not present.¹⁸ A decrease in hemoglobin, seen in the first 1 to 2 days, is a characteristic feature, and is a useful clue in patients who do not have hemoptysis. Alveolar hemorrhage usually occurs in patients with active extra-pulmonary disease, commonly arthropathy and renal disease, and high levels of dsDNA antibodies.^1,¹⁵ Alveolar hemorrhage is often associated with glomerulonephritis in lupus patients.^19,²⁰ Lupus nephritis is normally a pre-existing condition rather than an acute co-presentation with alveolar hemorrhage.^15,¹⁶ Histopathologic features include polymorphonuclear and mononuclear cell interstitial inflammation, alveolar necrosis, hemosiderin-laden macrophages, and an acute necrotizing capillaritis.²¹ Immune complexes IgG and C3 are found in 50% of cases. Alveolar hemorrhage can have a fatal outcome with mortality rates reported of 40 to 90%.^14,¹⁶ Patients who have a fatal course usually die rapidly within the first few days. There are no randomized controlled trials regarding treatment. The treatment of choice is high-dose corticosteroids with cyclophosphamide.¹⁵ Plasmapheresis should be used for patients with severe alveolar hemorrhage.^16,²²

Fig. 33.2 Diffuse alveolar haemorrhage. CT shows patchy ground glass attenuation in a bronchocentric distribution, consistent with intra-alveolar blood.

CHRONIC INTERSTITIAL LUNG DISEASE

Chronic interstitial lung disease (ILD) is a rare manifestation of SLE. Most cases are asymptomatic. In some studies, up to two-thirds of patients have abnormalities of pulmonary function tests,^1,²³ and in one series, a third of patients was found to have chronic interstitial infiltrate at autopsy.²⁴ Clinically significant pulmonary fibrosis is found in 3 to 13% of patients.^25,²⁶ In some cases, pulmonary fibrosis is preceded by acute pneumonitis, and is said to show radiologically the organizing phase of diffuse alveolar damage that has an interstitial pattern.¹¹

Chronic ILD is characterized by progressive dyspnea, cough, bibasal crackles, diffuse interstitial infiltrates, and a restrictive lung defect. Bronchoalveolar lavage (BAL) reveals an increased lymphocyte count and slight increase in neutrophils and occasional eosinophils.²⁷ Chest radiographs usually show bilateral pulmonary infiltrates affecting the lower lobes.²⁸ Parenchymal opacities and interstitial abnormalities have been described. A prospective study by Fenlon and colleagues²⁹ assessed high-resolution chest tomography (HRCT) in 34 patients with SLE, of whom 23% had respiratory symptoms. The most common features were thickened interlobular septa, parenchymal bands, subpleural bands, pleural tags, and thickening. Only 6% had ground-glass opacities, consolidation, and honeycombing. In 21% of patients, there was bronchiectasis and bronchial wall thickening. Pleural thickening was noted in 15% of patients. A lung biopsy will help to confirm diagnosis, and the site of biopsy should be chosen after review of HRCT scans to select the most optimal sites in discussion with the thoracic surgeon.

Histopathologically, the pattern is of interstitial pneumonia, either nonspecific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP). The NSIP pattern is more common,²⁹ and encompasses a wide morphologic spectrum with varying degrees of alveolar septal inflammation and fibrosis. The more cellular pattern features mild to moderate alveolar mononuclear cell infiltrate, with involvement of the peribronchial region, interlobular septa, and visceral pleura. Lung architecture is preserved without associated fibrosis. Organizing pneumonia may be present. Fibrotic variants are characterized by alveolar septal fibrosis, with less cellularity and little or no honeycombing present (Fig. 33.3). Less commonly in lupus, a patchy temporal and spatial distribution denotes the presence of the usual interstitial pneumonia pattern of histopathology.

Fig. 33.3 Nonspecific interstitial pneumonia (NSIP). CT scan at the lung bases shows widespread ground glass opacification with traction bronchiectasis compatible with a fibrotic NSIP histopathologic pattern. Note the absence of honeycombing.

Normally interstitial lung disease in lupus runs a slow course. Rarely, it can be severe with rapidly progressive disease. This tends to occur in patients who have overlap syndromes, especially with scleroderma.³⁰ Treatment involves corticosteroids in low doses together with immunosuppressive agents, generally azathioprine as the first choice.

Lymphocytic interstitial pneumonia is rarely associated with SLE.³¹^–³³ It is a relatively more benign lymphoinfiltrative disorder characterized by interstitial widening due to increased numbers of small lymphocytes and plasma cells with additional infiltration of bronchovascular bundles, interlobular septa, and pleura. It is associated with hypergammaglobulinemia.³⁴ Symptoms include cough, chest pain, fatigue, low-grade fever, and weight loss. Chest radiographs commonly show diffuse ground-glass, and reticular and nodular opacities with lower-zone predominance³⁵ and occasional nodular collections. HRCT findings include diffuse ground-glass attenuation, septal thickening, ill-defined centrilobular nodules (1 to 2 cm), and scattered thin-walled cysts. Mediastinal lymphadenopathy is seen. In advanced cases, architectural distortion and honeycombing occur.³⁶ Treatment includes corticosteroids and immunosuppression.

AIRWAYS DISEASE

Upper airway involvement is uncommon in SLE. Occasionally, hypopharyngeal ulceration, laryngeal inflammation, epiglotitis, and subglottic stenosis occur.^37,³⁸

Small Airways Disease

Abnormalities in pulmonary function tests are present in up to 70% of SLE patients with normal chest radiographs.³⁰ Reductions in the FEV₁/FVC ratio, characteristic of expiratory airflow obstruction, occurs in less than 10% of patients.^39,⁴⁰ However, in many of these studies, smoking status was not taken into account. A study by Andonopoulos and colleagues⁴¹ excluded smokers and compared SLE patients to controls. They found no significant difference in the prevalence of airflow obstruction between the two groups.

Several case reports of severe airways obstruction have been reported.⁴²^–⁴⁴ In these cases, there was no improvement with bronchodilators, but in one case there was response to oral corticosteroids. In one case, histopathology showed focal bronchiolitis, with complement and immunoglobulin deposition.⁴⁴ Intraluminal organizing pneumonia with inflammation in the terminal bronchioles extending into the alveoli has been described in several cases.^11,^45,⁴⁶ Organizing pneumonia in SLE is probably underdiagnosed due to lack of lung biopsies in symptomatic patients. The clinical symptoms include fever, cough, and dyspnea, and can mimic infection. Chest radiography shows nonspecific diffuse interstitial infiltrates with a restrictive lung defect on lung function testing. A surgical lung biopsy, usually thoracoscopic, is normally required to make the diagnosis and to exclude other causes of consolidation, including alveolar cell carcinoma. Histopathology shows inflammation of the lung parenchyma and bronchioles, which is associated with plugging of small airways and alveolar ducts with granulation tissue. Treatment includes high-dose corticosteroids, and in some more refractory cases, cyclophosphamide.

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