Multisystem Inflammatory Syndrome in Children Associated with COVID-19 Infection: A Comprehensive Review

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Objectives: The Multisystem Inflammatory Syndrome in Children (MIS-C) is a post-infectious syndrome associated with COVID-19 disease in children. The aim of this study is to conduct a thorough review to assist healthcare professionals in diagnosis and management of this complication of COVID-19 disease in children Material and Methods: A thorough systematic review was conducted through an on-line search based on MIS-C with the primary focus on epidemiology, clinical characteristics, diagnosis, pathophysiology, management and long-term follow-up. Results: This syndrome is characterized by an exaggerated and uncontrolled release of pro-inflammatory cytokines involving dysfunction of both innate and adaptive immunity. In this review, a summary of observational studies and case reports was conducted, in which we found that MIS-C generates multiple-organ failure frequently presenting with hemodynamic instability further characterized by Kawasaki-like symptoms (such as persistent high fever, polymorphic rash and bilateral conjunctivitis) and predominance of gastrointestinal and cardiovascular signs and symptoms. Keys to effective management involve early diagnosis, timely treatment and re-evaluation following hospital discharge. Diagnosis is marked by significant elevation of inflammatory biomarkers, laboratory evidence of COVID-19 infection or history of recent exposure, and absence of any other plausible explanation for the associated signs, symptoms and presentation. Management includes hemodynamic stabilization, empiric antibiotic therapy (de-escalation if cultures and PCR studies indicate no bacterial co-infection) immunomodulatory therapy (methylprednisolone, IVIG, anakinra, tocilizumab, siltuximab, Janus kinase inhibitors, TNF-α inhibitors), antivirals (remdesivir) and, anticoagulation (acetylsalicylic acid, unfractionated or low molecular weight heparin or new oral anticoagulants). In addition, we identified poor prognostic risk factors to include concurrent comorbidities, blood component consumption and marrow suppression (lymphopenia, thrombocytopenia), depletion of homeostatic components (hypoalbuminemia) and, marked evidence of a hyperinflammatory response to include elevated values of ferritin, CRP, and D-dimer. Conclusions: MIS-C constitutes a post-infectious syndrome characterized by a marked cytokine storm, characterized by fever, bilateral conjunctivitis and multiple organ dysfunction. Promoting future research and long-term follow-up will be essential for the development of guidelines and recommendations leading to effective identification and management of MIS-C.

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