Life-threatening macrophage activation syndrome with fulminant myocarditis successfully rescued by high dose intravenous Anakinra

ABSTRACT

Introduction: Macrophage activation syndrome (MAS) is a rare, potentially life-threatening complication of some rheumatologic diseases1. Objectives: We report the case of a child with systemic onset Juvenile Idiopathic Arthritis (sJIA) complicated by severe MAS and acute myocarditis, needing veno-arterial Extracorporeal Membrane Oxygenation (VA-ECMO), successfully rescued by high dose intravenous Anakinra (HDIV-ANA). Methods: Case report's description Results: A two-year-old boy presented with one month history of fever associated with limping gait, cervical lymphadenopathy and skin rash. Laboratory tests showed elevation of inflammatory markers and ferritin. By exclusion criteria, sJIA was diagnosed and steroid therapy started. After a soft tissue bacterial infection, fever relapsed and laboratory tests were consistent with MAS (day 1) Hb 8.5 g/dL, PLT 44000/mm3;FDP 1522 ug/L, CRP 100 mg/L, ferritin 2200 ug/L. High doses intravenous metilprednisolone and oral Cyclosporin A (CSA) were started. On day 2 he presented a Systemic Capillary Leak Syndrome and acute myocarditis. He was admitted into the pediatric intensive care unit (PICU) where intravenous immunoglobulin and subcutaneous Anakinra (ANA) were added. On day 4, due to an episode of cardiac arrest, VA-ECMO was started and we tried high dose intravenous ANA (HDIV-ANA, 8 mg/Kg/day q6h). This treatment brought immediate benefit echocardiography showed progressive resolution of myocarditis so that VA-ECMO was definitely weaned off in six days. Laboratory test showed isolated neutropenia (PMNs 0-100/mm3). Suspecting a iatrogenic cause, HDIV-ANA was gradually reduced to the maintenance dose without benefit. On day 22, ANA was stopped and neutropenia resolved. Analysis of PRF1 gene revealed a mutation (c.[272C>T] p.[Ala91Val]) in heterozygosis. 49 days after admission he was discharged on oral prednisone and CSA. Neither neurological nor other organ consequences related to MAS were reported. A few months later, on tapering down of therapy, he relapsed. ANA was restarted with rapid improvement and no side effects, including neutropenia. Currently, after 12 months, the disease is in clinical remission on medication. Conclusion: MAS is a rare life-threatening complication of sJIA, triggered by infections in up to one-third of the patients 2. It is the result of a cytokine storm that lead to a dysregulated inflammatory activation of the immune system, with rapid progression to multiorgan failure. Treatment usually includes high dose corticosteroids and immunosuppressive agents. Recently, the use of selective cytokine inhibitors has been suggested. No standardized guidelines are available to date, but the use of ANA has been already reported, pointing out the need for a higher doses regimen in refractory cases. MAS in our patient appeared after a soft tissue infection which could have act as triggering factor in a patient with sJIA and genetic predisposing pattern. The choice of intravenous administration of ANA was partly due to the generalized edema and partly to the severe discoaugulopathy. Considering the higher doses needed for rapidly suppressing the cytokine storm and ANA pharmacokinetics, we split the daily dose into four administrations. No major adverse events were reported, except for a transient neutropenia, already reported 6. Based on our experience, HDIV-ANA is a safe and effective treatment for refractory life-threatening sJIA-related MAS. This therapeutic approach may be also considered in the current pandemic COVID-19 emergency where recent evidence showed IL1-driven MAS-like complication triggered by SARS-COV-2 virus as predictor of bad outcome7.