Management of MIS-C (Multi-system Inflammatory Syndrome in Children): Decision-making regarding a new condition in the absence of clinical trial data.

Multisystem inflammatory syndrome in children (MIS-C) is a new illness that evolved during the COVID-19 pandemic with initial reports of severe disease including use of extracorporeal membrane oxygenation and death. Institutions rapidly assembled task forces to develop treatment algorithms. At the national/international levels, collaboratives and associations assembled consensus writing groups to draft guidelines. These guidelines and algorithms were initially based on expert opinion and small case series. Some groups utilized the Delphi approach, and the resultant guidelines often mimicked those for other conditions that resembled MIS-C, like Kawasaki disease (KD). For instance, intravenous immunoglobulin (IVIG), a known effective treatment in KD, was recommended for MIS-C. Early in the pandemic many favored IVIG over steroids as first line therapy. As evidence evolved so did some guidelines which now endorse the dual use of IVIG plus steroids as first line therapy. In contrast, withholding immunotherapy became an option for some MIS-C patients with mild symptoms. Here, we review guidelines and discuss the evidence informing early recommendations, how this has evolved, the role and limitations of expert opinion and observational data, and the importance of leveraging existing research infrastructures, such as the intensive care unit collaborative (Overcoming COVID-19 surveillance registry), and the International KD Registry. Finally, we discuss strategies to rapidly develop, deploy and adapt clinical trials evaluating the treatment of such rare conditions in children, which may include alternatives to conventional clinical trial design. The emergence of MIS-C during the COVID-19 pandemic has highlighted unmet needs regarding research of a new condition.