Systemic lupus erythematosus (SLE) is a multifactorial, specific autoimmune disease that is characterized by multiple autoantibodies and can involve almost any organ system throughout the body, including through autoimmune complexes. SLE can involve any part of the respiratory system including the pleura, lung parenchyma, pulmonary vasculature and respiratory muscles. The main manifestations are: pulmonary infections, pleurisy, acute lupus pneumonia, alveolar hemorrhage, acute reversible hypoxemia, chronic interstitial pneumonia (fibrosis), obstructive bronchitis with mechanized pneumonia, respiratory muscle weakness, pulmonary hypertension, pulmonary thromboembolism, obstructive lung disease, and upper airway dysfunction.
Pulmonary involvement in SLE can occur at any stage of the disease, and the incidence has been reported differently, with some suggesting up to 60%, while others have reported pleural involvement in 17% and pulmonary involvement in 3% of cases at the onset of SLE, and pleural involvement in up to 36% and pulmonary involvement in up to 7% throughout the course of the disease. The clinical and imaging manifestations and even histopathological manifestations of various pulmonary lesions in SLE may overlap, and some patients may have more than one pulmonary symptom throughout the course of the disease. pulmonary involvement in SLE suggests a poor prognosis, and the mortality rate is more than twice as high as that of patients without pulmonary involvement. In this article, we will review the pulmonary manifestations of SLE.
I. Pleural lesions
Pleural involvement is more common in SLE than in other connective tissue diseases, and pleurisy is also the most common pulmonary manifestation of SLE, with an incidence of 17-60%, and the incidence of autopsy-confirmed pleurisy or pleural effusion can be 50-93%. Pleurisy can be the first symptom of SLE, with 45-60% of patients presenting with chest pain, often accompanied by dyspnea, cough, and low-grade fever, with or without pleural effusion.
The pathology of pleurisy is characterized by lymphocytic and plasma cell infiltration, fibrosis, fibrinous pleurisy with varying degrees of mechanization, and rare hematoxylin bodies. Thoracoscopy reveals nodules overlying the dirty pleura, and immunofluorescence examination reveals immunoglobulin and complement deposits. The appearance of pleural effusion is usually yellow and clear or pale blood, usually non-bloody. All are exudate with increased protein and lactate dehydrogenase (LDH) levels. ANA (titer >1:320), anti-dsDNA and typical lupus cells can be detected in pleural effusions with relative specificity but not high sensitivity. complement C3 and C4 are decreased, immune complex levels are increased and rheumatoid factor is positive in SLE pleural effusions, but similar changes can be seen in rheumatoid arthritis (RA). Unlike the latter, GLU levels are higher in SLE pleural effusions (>56 mg/dl, RA <20 mg/dl); whereas LDH levels are higher in RA pleural effusions (>500 IU/L).
Pleural effusion can be detected by X-ray plain radiograph in 16-50% of SLE patients, but Fenlon et al [13] analyzed 34 cases of SLE and found only 21% had pleural effusion by high-resolution CT (HRCT). Pleural effusions are generally small to moderate in volume and distributed bilaterally or unilaterally (50% of each). Large pleural effusions should be noted in addition to other diseases. Diagnostic puncture must be performed for new pleural effusions. A small amount of pleural thickening often remains after the pleural effusion resolves. Patients with SLE with combined pleural, cardiac and/or pulmonary pathology are more likely to have recurrence or rapid exacerbation of pleural effusion than those with pleural involvement alone.
II. Acute Lupus Pneumonitis (ALP)
ALP is a sudden onset of non-infectious pneumonia, often accompanied by fever.ALP is mostly reported as an individual or a few cases, with an estimated incidence of 1-4%. The main manifestations are sudden onset of dyspnea, cough (with or without sputum production), chest pain, hypoxemia, fever and, in some cases, hemoptysis. ALP may be the first symptom of SLE or may appear at any stage of the disease. Because of its high mortality rate of 50%, a timely and decisive diagnosis is crucial. Young women, unexplained pulmonary infiltrates, and those with evidence of active lupus disease should be particularly alert for ALP. female patients are at high risk for ALP in the days to weeks after delivery.
The pathology of ALP is nonspecific and is characterized by alveolar wall damage and necrosis, inflammatory cell infiltration, hemorrhage, edema, and hyaline membrane formation. Hematoxylin bodies and lupus cells are occasionally seen and are considered to be highly specific for the diagnosis of SLE. Immunoglobulin and complement deposits may be seen. Vasculitic changes in the large vessels are rare, and microangiitis involving capillaries, fibrinoid thrombosis with interstitial pneumonia, and necrotizing neutrophil infiltration in small vessels are sometimes seen, but are uncommon. The mechanism by which these tissue changes occur is controversial.
Chest radiographs show bilateral or unilateral, patchy solid shadows, predominantly at the base of the lung, focal pulmonary atelectasis, and septal muscle elevation. Most of them are associated with pleural effusion.
Diffuse Alveolar Hemorrhage (DAH)
DAH is rare, with an incidence of approximately 2% of SLE, 1.5-3.7% of SLE hospitalizations, and 22% of SLE hospitalizations for pulmonary lesions. DAH is a potentially critical complication of SLE with a mortality rate of more than 50%, which has decreased in recent years, with Badsha et al. reporting 36% and Santos-Ocampo et al. observing a group of 7 patients with a 100% survival rate, but most reports still report a mortality rate of 50%. around. Poor prognosis is associated with mechanical ventilation, co-infection (especially nosocomial infections), and cyclophosphamide treatment at presentation.
DAH is most common in young women and presents with hemoptysis, dyspnea, hypoxemia, cough, and anemia, and more than half of the patients must be mechanically ventilated. Some of the major symptoms such as hemoptysis and hypoxemia may be absent at presentation (approximately 42-66%), and many severe alveolar hemorrhages may even remain completely absent of hemoptysis. These atypical and nonspecific clinical manifestations make the diagnosis difficult. Decreased hemoglobin and decreased erythropoietic pressure are characteristic signs of alveolar hemorrhage and are an important clue, especially in patients without hemoptysis; Zamora et al. reported an average decrease in erythropoietic pressure of 7.1%, with the most severe decrease of 18%. A higher rate of antiphospholipid antibody (ACL) positivity has been reported in SLE combined with DAH than in usual SLE patients, but Zamora et al. did not reach the same conclusion in their report.
DAH usually occurs in patients with established SLE and often has high titers of positive anti-dsDNA antibodies as well as extra-pulmonary activity. DAH is often combined with lupus nephritis, but the latter is not a factor in the poor prognosis of alveolar hemorrhage. Nearly one-third of patients with DAH may have coexisting pulmonary infections, such as cytomegalovirus, herpes simplex virus, Aspergillus, Staphylococcus, and Legionella.
The pathological changes of DAH are mostly nonspecific and include interstitial pneumonia, hyaline membrane, alveolar necrosis and edema, and microvascular thrombosis. Overt vasculitis or necrosis is rare, and diffuse damage to the pulmonary microvasculature, called “capillaritis” or “endotheliitis,” is seen in 80% of patients. 50% of patients have alveolar wall deposits of IgG, C3, or immune complex particles. The pathogenesis of DAH is unknown, and factors such as immune complex-mediated injury, microvascular or capillary vasculitis, diffuse alveolar injury associated with infection or other factors may be involved.
The radiographic presentation is a bilateral diffuse, indistinct patchy shadow with poorly defined borders predominantly in the lower band of the lung fields. The lung shadows are usually bilaterally symmetrical, but may be asymmetrical or even unilateral. In the early stage of CT, the lung shadowing may appear as scattered nodular shadows of uniform size with a diameter of 1-3 mm, and when the disease progresses to acute alveolar hemorrhage, the CT may reveal hairy glass-like blurred shadows that obscure the original nodular shadows and sometimes solid shadows containing bronchial air phase. The chronic phase changes are mainly thickening of the lobular septa, which may be a manifestation of early stromal fibrosis.
ALP and DAH are almost identical in terms of clinical symptoms, imaging or pathologic features and natural course. Both are likely to be two manifestations of the same disease spectrum of acute alveolar-capillary injury leading to pulmonary lesions. They are also difficult to distinguish from other common pulmonary complications of SLE, such as infection, pulmonary embolism, heart failure, and uremic syndrome. However, the identification of these etiologies is critical, especially in patients on hormonal and immunosuppressive therapy, where various bacterial or opportunistic infections are more common. Therefore, blood culture, sputum culture, bronchoscopy or open lung biopsy must be actively performed to exclude other causes of pulmonary lesions.
Chronic Interstitial Pneumonia (CIP)
The incidence of chronic interstitial pneumonia in patients with SLE is low compared to other connective tissue diseases such as RA and scleroderma, about 3-13%, but the incidence may be higher in those with asymptomatic involvement, with up to two-thirds of SLE patients reported to have abnormal pulmonary function tests.
SLE combined with CIP can present at any stage of the disease, but pulmonary symptoms are often the initial, most dominant manifestation of the disease. The clinical symptoms, imaging and pathological features are very similar to those of idiopathic interstitial pulmonary fibrosis (IPF), but the former tends to be milder and progresses more slowly, with rapid and critical progression rare. the average age of onset of CIP is 46 years, and clinical features include progressive dyspnea and dry cough. The clinical features include progressive dyspnea and dry cough. On examination, fever, cyanosis, pestle fingers, and popping sounds at the base of both lungs are seen. Pulmonary function tests are characterized by decreased tidal volume, total lung volume, and diffusion volume.
The pathological features of CIP and IPF are similar. Early manifestations of the disease are alveolitis, with large numbers of activated immune and inflammatory cells visible in the alveolar wall and alveolar lumen, peribronchial lymph-like hyperplasia, and type II alveolar cell hyperplasia. Repeated inflammation resulted in structural destruction and deformation of the alveoli. Fibroblast proliferation and the production of large amounts of collagen and extracellular matrix lead to dense scar formation. The lesion progresses heterogeneously, with inflammatory activity coexisting with dense fibrosis. Large numbers of inflammatory cells, immunoglobulins, immune complexes, cytokines and growth factors are seen in the alveolar lavage fluid.
Abnormal imaging findings (6-24%) may be slightly more prevalent than clinical symptoms of CIP. Early in the course of the disease, X-rays may show no abnormal changes even in those who are symptomatic or who already have abnormal lung function. As the disease progresses, X-rays show irregular linear blurred images and hairy glass-like changes in the lung bases bilaterally. HRCT mainly shows irregular linear blurring of the lung bases, hairy glass-like changes, honeycomb changes, and traction atelectasis. Scattered nodular shadows and lobular septal thickening were less common. Mild enlargement of mediastinal lymph nodes is also common. Although the role of HRCT in the diagnosis of SLE combined with pulmonary fibrosis needs to be further investigated, HRCT is indeed a respected non-invasive test for understanding the extent of pulmonary foveal changes or inflammation.
V. Pulmonary vascular lesions
1. Acute reversible hypoxemia
Acute reversible hypoxemia has recently been reported to be more common in critically ill patients. Clinical manifestations include chest pain or chest discomfort, dyspnea, hypoxemia, diffusion dysfunction due to obstructive vascular disease, and widening of the alveolar-arterial oxygen concentration difference. It is not associated with diffuse parenchymal lung lesions. The possible pathogenesis is the stasis of neutrophils in the pulmonary vasculature due to proliferating endothelial cells and activation of complement, with a role for vascular cell adhesion factor (VCAM) and intercellular adhesion factor (ICAM). Most patients respond better to high-dose hormone therapy. The combination of low-dose hormones and high-dose aspirin helps to improve pulmonary symptoms, but is not sufficient to control systemic disease activity.
2. Vascular disease (including pulmonary hypertension)
SLE pulmonary parenchymal lesions may be combined with pulmonary vascular involvement, but vasculitis is not the underlying damage in most pulmonary parenchymal lesions. The mechanism of SLE combined with pulmonary hypertension is unknown, but possible mechanisms include interstitial pneumonia, small pulmonary artery vasculitis, in situ thrombosis or pulmonary thromboembolism, and pulmonary vasoconstriction. the incidence of SLE combined with pulmonary hypertension is about 10%, and its clinical manifestations are similar to those of primary pulmonary hypertension. The clinical manifestations are similar to those of primary pulmonary hypertension. The main manifestations are progressive dyspnea, decreased activity tolerance, right heart insufficiency, and eventual progression to pulmonary heart disease. 75% of the cases are combined with Raynaud’s phenomenon, and the ACL positivity rate is 60-68%. Patients with peripheral edema, especially bilateral lower extremity edema, often suggest pulmonary heart disease, and SLE combined with pulmonary hypertension suggests a poor prognosis, with a two-year survival rate of no more than 50%.
Pulmonary vascular involvement is often present in SLE, and nearly 50% of patients have pulmonary vascular pathology, although the incidence varies among reports. Acute damage is characterized by fibrinoid necrosis and vasculitis. Chronic damage is characterized by intimal or peri-arterial fibrosis, mid-layer hypertrophy, and elastic lamina rupture. Usually only small vessels are involved, but myenteric arteries are the most common and most severe. There may also be varying degrees of smooth muscle (middle layer) hypertrophy and hyperplasia, intimal fibrosis, inflammatory cell infiltration of small pulmonary arteries, destruction of the elastic lamina, and in situ thrombosis.
X-rays may be normal in the early stages of the disease. The progressive stage shows enlarged right ventricle, dilated central pulmonary artery, and stumpy distal arteries due to vascular obstruction. Pulmonary ventilation/flow imaging and pulmonary angiography may exclude pulmonary embolism. Cardiac ultrasound can measure right ventricular and pulmonary artery pressure, the internal diameter of each atrium, and can exclude intracardiac shunts with high sensitivity.
3. Pulmonary embolism
Positive lupus anticoagulant in SLE patients is a risk factor for intravascular thrombosis. Acute and chronic pulmonary embolism is associated with antiphospholipid antibodies (ACL). A study of 842 SLE patients showed that ACL-positive individuals had 24% and 13% of IgG and IgM subtypes, respectively, with a significantly higher incidence of pulmonary embolism compared to ACL-negative individuals (30% and 9%, respectively). Another analysis of 390 SLE patients found a 47% ACL positivity rate, but no correlation with pulmonary embolism. It is therefore possible that only a certain subtype of ACL is associated with pulmonary embolism.
Patients with recurrent thromboembolism should be anticoagulated for life. In addition, aggressive hormonal and immunosuppressive therapy should be given concomitantly to control the thrombus.
Respiratory myopathy
Patients with SLE often have an elevated diaphragm and progressive lung volume reduction with progressive dyspnea on chest radiographs, which is called shrinking lung syndrome. Primary diaphragmatic myopathy may be a cause, especially in the most severe cases of restrictive dyspnea. Diminished diaphragmatic motion may also be associated with pleural adhesions. The main manifestation is dyspnea, but chest pain, fever, and a small amount of pleural effusion may also be present. Fever and pleurisy mostly improve with hormonal therapy, but dyspnea does not improve significantly, especially in patients who have developed significant diaphragmatic elevation. The overall prognosis of diaphragmatic dysfunction is good, despite the symptoms of restricted breathing and dyspnea at the onset. After years of follow-up, many patients do not experience a further decrease in tidal volume.
Elevation of the diaphragm on both sides is common on chest plain radiographs in patients with SLE, along with diminished movement of the diaphragm. Subsegmental pulmonary atelectasis may also be seen above the diaphragm, with occasional faint patchy shadows with poorly defined borders.
VII. Respiratory tract lesions
1. Upper respiratory tract lesions
Compared to rheumatoid arthritis, Wegener’s granulomatosis, and recurrent polychondritis, upper respiratory tract lesions are uncommon in SLE. SLE has been reported to be complicated by subpharyngeal ulcers, laryngeal inflammation, epiglottitis, subglottic stenosis, and vocal cord paralysis. Active SLE is particularly prone to upper airway complications after tracheal intubation.
2. Lower airway lesions
Bronchiolitis Obliterans Organizing Pneumonia (BOOP) is a pathology characterized by granulation tissue plugs in the small airways and alveolar ducts, often in combination with inflammation of the small bronchi and lung parenchyma. A variety of diseases. BOOP may be acute or subacute in onset, with non-specific clinical manifestations, mainly fever, cough, dyspnea, hypoxemia, and patchy or diffuse interstitial infiltrates. Pulmonary function tests typically suggest restrictive ventilatory impairment. Definitive diagnosis often requires lung biopsy, and hormonal therapy is effective. The overall prognosis is good, with one-third of patients resolving spontaneously.
The pathology of BOOP is characterized by fibrous obstruction of the respiratory bronchi and alveolar ducts by immature fibroblasts and Masson bodies, with inflammatory changes in the bronchi and surrounding interstitium.
The typical imaging of BOOP is a bilateral scattered hairy glassy shadow or air-containing solid shadow, and all lung bands can be involved. The most common CT change is a bilateral air-containing solid shadow. 50-60% are clearly distributed along the pleura. Bronchiectasis, glassy changes and scattered central lobular nodules are seen. Mediastinal lymph node enlargement and pleural effusion each account for one-third of the cases.
BOOP, as a separate clinicopathological type, has clinical and imaging similarities with other pulmonary lesions in SLE, and therefore is underdiagnosed. As the rate of lung biopsy in patients with SLE combined with acute or subacute lung damage increases, the understanding of SLE combined with BOOP will become more advanced.
VIII. Pulmonary infections
Respiratory infections are highly prevalent in SLE patients based on the following reasons: first, immune dysfunction and low antibacterial activity of alveolar macrophages in SLE patients; second, the use of hormones and other immunosuppressive agents; and third, pulmonary edema, respiratory muscle weakness, and other factors that aggravate the infection. Respiratory tract infections are an important cause of morbidity and mortality in SLE, second only to sepsis and renal failure. Therefore, any new pulmonary infiltrates in SLE patients must first focus on excluding pulmonary infections, especially in those treated with hormones and immunosuppressive agents.
Opportunistic infections in patients with SLE include Aspergillosis, Cryptococcosis, Pneumocystis carinii infection, cytomegalovirus infection, and S. syringae infection. Nocardia infections usually progress rapidly and have a high mortality rate if left untreated. Most patients improve with early diagnosis and aggressive treatment. Chest radiographs often show multiple patchy shadows or nodular masses, with some forming cavities.
Some studies have shown that the incidence of tuberculosis in SLE patients is 5%, but due to delayed diagnosis, there is a higher incidence of cornified tuberculosis and extrapulmonary tuberculosis. Because symptoms such as wasting and fever caused by TB may also be the first symptoms of SLE, the initial diagnosis of TB is often not timely enough to allow progression of the disease and a poor prognosis. Tuberculosis is a direct cause of death in SLE, and untimely diagnosis is one of the reasons for its high mortality rate.
IX. Summary
More than half of SLE patients develop pleural or pulmonary parenchymal involvement either early or late in the course of their disease. Since pulmonary lesions are one of the main clinical manifestations of SLE and often predict regression, clinicians must improve their understanding of the clinical symptoms and imaging manifestations of pulmonary involvement in SLE in order to diagnose early and give proper treatment early.