The Importance of Differentiating MIS-C From Other Hyperinflammatory Conditions

Identification of multisystem inflammatory syndrome in children (MIS-C) cases with enough specificity to allow for the development of management guidelines and meaningful clinical outcome prognostication has been a priority since the first clinical cases emerged after the onset of the coronavirus disease 2019 pandemic. Because of significant overlap with several infectious and postinfectious inflammatory syndromes, identifying patients with MIS-C has challenged clinicians and investigators. In this issue of Pediatrics, the REKAMLATINA-3 MIS-C Study Group Investigators present data from a large cohort of patients across 84 Latin American centers in 16 countries to identify the overlapping clinical and laboratory characteristics and outcomes between children diagnosed with MIS-C and concurrent macrophage activation syndrome (MAS) to those without MAS.1 Dating back to 2013, the REKAMLATINA network (Red de Enfermedad de Kawasaki en América Latina) was created to collect data on and begin to study Kawasaki disease in 20 Latin American countries. REKAMLATINA is the world's largest multinational international network with the largest number of countries integrated for research into the epidemiology of Kawasaki disease in children.2 In August 2020, the REKAMLATINA network started the REKAMLATINA-3 study, a multinational study focused on MIS-C in Latin American children and adolescents. Data were initially collected between January 2020 and June 2022. The authors note that gastrointestinal and neurologic findings were more frequent in cases where MAS complicated MIS-C and that the mortality rate was higher in patients with MIS-C complicated by MAS compared with those without it. Given the intersection between MIS-C and other inflammatory syndromes, the data presented by Gámez-González et al exemplify the challenges with clinical research on MIS-C and the critical need for a standardized, reproducible case definition.Although intentionally broad, the first US Centers for Disease Control and Prevention case definition for MIS-C from 2020 ensured those at-risk patients were identified quickly and referred for medical care appropriately.3 The Centers for Disease Control and Prevention noted that the prioritization was focused on sensitivity, not specificity, because of the limited data from early case series. The initial case definition led to extreme heterogeneity in subsequent MIS-C study populations as a direct result of the intentionally broad definition. Recent literature highlights the overlap between cases of MIS-C and other disorders of systemic inflammation, including acute infection with severe acute respiratory syndrome coronavirus 2 virus, Kawasaki disease (KD), and toxic shock syndrome.4–7 This overlap can lead to an inaccurate and incomplete understanding of the natural history of these conditions for affected children and skew population-based studies aimed at providing clinical management guidance or those studies that describe the natural course and outcomes of patients with MIS-C.Given the considerable risk of morbidity and mortality in patients with MIS-C, and the available treatment options for other inflammatory conditions that may mimic or overlap with MIS-C, a clear case definition for MIS-C is crucial for both clinical care and research. In 2023, the Council of State and Territorial Epidemiologists revised the MIS-C case definition to better distinguish MIS-C from similar disorders.8 Misclassification of MIS-C with other hyperinflammatory vasculopathies has implications for clinical care and outcomes, especially in patients with KD, where pharmaceutical management differs, and mismanagement may result in harmful, long-term complications. KD and MIS-C have several key differences, including epidemiologic, pathophysiologic, clinical, and immunologic features.9–11 These differences highlight that hyperinflammatory syndromes with overlapping characteristics belong on a spectrum; however, they remain distinct pathologies requiring targeted investigation and management.Unfortunately, the clinical application of the results and conclusions stemming from early MIS-C studies remains problematic and is limited by small heterogenous study cohorts, retrospective design, variations in data collection methods and content, and inconsistencies with the MIS-C case definitions. This heterogeneity makes it challenging to draw definitive conclusions about the specific characteristics and outcomes of MIS-C, especially in patients with other concurrent or distinct systemic inflammatory diagnoses. As the definition of MIS-C has evolved, so should the general research strategy and considerations regarding MIS-C case definitions that do not allow for discrimination between MIS-C and other hyperinflammation syndromes. Using retrospective data is often necessary, given that MIS-C is a relatively new and infrequent clinical syndrome. However, to adequately move forward the understanding of this distinct clinical entity, a reanalysis of previously collected data and MIS-C data sets with the newer case definitions may be warranted because conclusions are likely to change. The data from children described early in the evolution of MIS-C, if accurately identified, may provide important clues into longer-term outcomes and prognosis because of this novel hyperinflammatory syndrome. Until diagnostic biomarkers or a highly specific test is developed to positively identify MIS-C patients, a uniform and consistently applied case definition for MIS-C, without confounding overlap to other inflammatory syndromes, should be a prerequisite for future research publications.