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].
\soutPulmonary 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].