Systemic Lupus Erythematosus
SLE is a multi-system autoimmune disorder characterized by generation of autoantibodies against cellular components and tissue damage from immune complex deposition. While SLE is more common in adults, approximately 20% of individuals present prior to the age of 18 [85], with female predominance in both age groups. The incidence and prevalence of childhood onset SLE (cSLE) varies between populations, with an incidence range of 0.28-0.48/100,000 and a prevalence rate of 6.3-24.0/100,000 [86]. Fever, fatigue, lymphadenopathy, nephritis, neuropsychiatric disease, cytopenia and mucocutaneous involvement (Malar, photosensitive, purpuric vasculitic rashes and oral/nasal mucosal ulcers) are more common in children at presentation than adults [85, 87]. Overall, cSLE is reported to have a more severe course [85].
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Pulmonary involvement in SLE can occur at onset of symptoms or any time during disease course, ranging from asymptomatic to severe and acutely life-threatening. Pulmonary complications in cSLE includes involvement of the upper airway, lung parenchyma, pulmonary vasculature, pleura and respiratory muscles, with prior reports of pneumonia (up to 90%), pleuritis (50-80%), acute pneumonitis (<10%), chronic ILD (3%), pulmonary hypertension (5-14%), diffuse alveolar hemorrhage (DAH) (<2%), shrinking lung syndrome (<1%) and thrombotic disease [52, 88, 89].
Pleuritis can be unilateral or bilateral and may be associated with a pleural effusion. Patients can present asymptomatically or with debilitating dyspnea, pain, and fever. Pleuritis can be treated with NSAIDs, although may require escalation of immune suppression.
Diffuse alveolar hemorrhage (DAH) in SLE is associated with significant morbidity and mortality. Patients may present with dyspnea, hemoptysis, fatigue, anemia, and respiratory failure. It can be difficult to distinguish DAH from infection as both can present with diffuse alveolar opacities. Flexible bronchoscopy, and in some cases lung biopsy, may aid in diagnosis. Infections have been identified at the onset of DAH, so simultaneous treatment of both may be required. Two studies have systematically examined DAH in pediatric SLE cohorts with an incidence of 1.7-2.2% of cSLE patients [90, 91]. Mortality varied widely in these cohorts, close to 50% in one cohort, whereas the second was 14%. In both cohorts, patients often required transfusions and mechanical ventilation [90, 91]. While there are no controlled trials, for critically ill patients, prompt initiation of high dose steroid with an additional agent like cyclophosphamide is often pursued. Rituximab may also be helpful but has a slower time to effect [92-94]. Immunomodulatory dosing of intravenous immunoglobulin (IVIG) and plasmapheresis can be considered in refractory cases.
ILD is a rare pulmonary manifestation in adult SLE, is rarer still in cSLE, and can present as acute pneumonitis or chronic ILD. In a twenty-year retrospective cohort of 157 cSLE patients, lupus pneumonitis/ILD was diagnosed in 3.8% at diagnosis and in 12.1% during disease course. Acute lupus pneumonitis is associated with significant morbidity and mortality [95] and is characterized pathologically by alveolitis, interstitial inflammation and edema. Findings associated with capillaritis and pleuritis can also be seen concurrently [96, 97]. Chronic ILD in cSLE can occur following acute lupus pneumonitis or develop in isolation, with pathologic findings including cellular interstitial pneumonia, interstitial fibrosis, lymphocytic interstitial pneumonitis, fibrinous pleuritis, organizing pneumonia, desquamative interstitial pneumonitis, nonspecific interstitial pneumonitis, bronchiolitis and peribronchiolitis [98, 99]. ILD with pathologic findings consistent with organizing pneumonia has been described in patients meeting criteria for SLE including a pediatric patient [96]. ILD in SLE has been associated with >10 years duration of disease, Raynaud phenomenon, anti-(U1) RNP anti-bodies, sclerodactyly, and abnormal nailfold capillary loops [97, 100]. Given the rarity of ILD in SLE, drug reaction and other rheumatologic diagnoses such as mixed connective tissue disease should be considered.
Acute lupus pneumonitis warrants aggressive treatment given poor prognosis. The ideal treatment of chronic ILD in pediatric patients with SLE is unknown due to lack of controlled trials in children or adults. As it can be very difficult to determine if it is lupus pneumonitis vs. infection vs. DAH or co-existence of multiple complications, empiric treatment with broad spectrum antimicrobials and extensive infectious disease and DAH evaluation is warranted. Systemic steroids are often employed, given the significance of steroid toxicity, steroid sparing agents such as azathioprine, mycophenolate, cyclophosphamide, and rituximab should be considered [94, 101-103]. Antifibrotic treatment should be considered if there is evidence of fibrosis or progression.
Pulmonary hypertension in pediatric SLE can occur secondary to ILD or without associated ILD, with other potential causes including pulmonary vasculitis, pulmonary thromboembolism (especially with coexisting antiphospholipid antibodies), and cardiac dysfunction [104]. Pulmonary hypertension in SLE can occur at any point during disease course and may be present in asymptomatic patients or patients with fatigue, weakness, shortness of breath, exercise intolerance, presyncope, syncope, hemoptysis, or respiratory failure. Early identification is important [105, 106] as the presence of pulmonary hypertension in SLE negatively affects survival overall [107].
Shrinking lung syndrome (SLS) is a rare complication of pediatric SLE where patients experience dyspnea and pleuritic chest pain, with PFT evidence of restrictive lung disease and reduced maximal respiratory pressures and sometimes radiographic signs of reduced lung volumes and atelectasis. These patients generally do not have evidence of ILD [108, 109]. The pathophysiology of SLS is unclear, but may be related to myositis, myopathy, phrenic nerve dysfunction, and/or parenchymal reorganization impairing lung compliance [109]. Treatment includes immunosuppressive medications and, in our experience, exercise/pulmonary rehabilitation may be beneficial due to improvements in diaphragmatic mobility and lung compliance.
Pediatric SLE patients may be asymptomatic from a respiratory standpoint but have PFT and chest CT abnormalities predating pulmonary symptoms. Abnormalities in spirometry, plethysmography and diffusion have been described, with restrictive defect potentially secondary to parenchymal involvement or respiratory muscle dysfunction and DLCO reduction secondary to parenchymal disease or pulmonary hypertension. Disease duration is a risk factor for development of PFT abnormalities and DLCO may improve with treatment [110, 111].