COVID-19–Related Multisystem Inflammatory Syndrome in Children

Abstract

Source: Whittaker E, Bamford A, Kenny J, et al. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA. 2020; 324(3): 259– 269; doi: 10.1001/jama.2020.10369Investigators at multiple institutions conducted a case series to describe the characteristics of children with pediatric inflammatory multisystem syndrome (PIMS), also termed multisystem inflammatory syndrome in Children (MIS-C). Children were eligible if they were hospitalized in England between March and May 2020 and met criteria for PIMS/MIS-C as defined by the Royal College of Pediatrics and Child Health, the World Health Organization, or the CDC. Investigators abstracted clinical and laboratory features of cases from the medical record.Cases were compared to patients with Kawasaki disease (KD) and KD shock syndrome, as well as patients with toxic shock syndrome (TSS). Patients with KD were seen between 2002 and 2019 at Rady Children’s Hospital in San Diego, CA. Patients with TSS were part of a European database of febrile children seen between 2012 and 2020.There were 58 children who met PIMS/MIS-C criteria. Overall, 45 (78%) had evidence of current or prior SARS-CoV-2 infection. The median age was 9 years (range: 3 months-17 years). All patients with PIMS/MIS-C presented with persistent fever for 3 to 19 days with variable combinations of sore throat (10%), headache (26%), abdominal pain (53%), erythematous rashes (52%), lymphadenopathy (16%), mucous membrane changes (29%), and swollen hands and feet (16%). Pediatric intensive care was required for 50%, and shock requiring inotropic support was present in 47%. All patients had marked elevation of inflammatory markers, including CRP (median 229 mg/L). Blood, surface, and other site cultures were negative. Three clinical patterns were evident among patients: (a) a persistent fever and elevated inflammatory marker pattern without evidence of organ failure or mucocutaneous features suggestive of KD or TSS (39%); (b) shock, often associated with left ventricular dysfunction (50%); and (c) development of diagnostic criteria for KD (11%).The comparison groups included 1,132 children with KD, 45 with KD shock syndrome, and 37 with TSS. Children with KD, KD shock, or TSS were younger (mean age of 2.7, 3.8, and 7.4 years, respectively) than children with PIMS/MIS-C. Children with PIMS/MIS-C also had higher CRP and white blood cell counts than children with KD or KD shock. Children with PIMS/MIS-C who met diagnostic criteria for KD also tended to be older and have higher CRP, ferritin, and troponin levels than children with KD.The authors conclude that PIMS/MIS-C appears to be distinct from other pediatric inflammatory diseases.Dr Higgins disclosed no financial relationship relevant to this commentary.MIS-C/PIMS recently has been described in children, most with evidence of COVID-19 infection, resulting in rapidly worsening illness. Numerous articles describing presentation, treatment, and outcomes of such patients have been published in the last several months.1Based on the current report and others, a portion of children with COVID-19 who develop MIS-C have signs and symptoms similar to those with TSS or KD, but the relationship of these syndromes has yet to be elucidated.2 Both TSS and KD are very familiar to primary care pediatricians, but another relevant disorder is less well known: macrophage activation syndrome (MAS), also known as secondary hemophagocytic lymphohistiocytosis. MAS is a severe, sometimes fatal, multisystem inflammatory syndrome that occurs in patients with rheumatic disease and less frequently in previously healthy children.3 Like KD,2 it is believed to be related to an infection.3 KD, MAS, and MIS-C may be members of a family of overly exuberant inflammatory responses to pathogens in genetically susceptible patients.3,4 Since pro-inflammatory cytokines are elevated in these disorders, including MIS-C, the overall description “cytokine storm syndromes” has been proposed.3,4Prompt identification of MIS-C in the context of the primary COVID-19 pneumonitis can be difficult. Cytokine levels are not routinely measured in clinical care and may be less informative in the setting of severe infection. Clinicians must rely primarily on a combination of physical signs and abnormal results of common laboratory tests, including lymphopenia and neutrophilia, hyperferritinemia, high CRP, evidence of coagulopathy, and markers of hepatic and/or cardiac injury, of which none is specific, as is also true for MAS.3 Children with COVID-19–associated MIS-C are optimally evaluated and managed in a tertiary care setting by a team of pediatric subspecialists in intensive care, infectious disease, pulmonology, cardiology, and rheumatology. The American College of Rheumatology recently has published detailed draft guidelines for evaluating and treating such children.5 Though optimal treatment of COVID-19–associated MIS has not been established, glucocorticoids, IV immunoglobulin, and specific inhibitors of cytokines such as IL-1 and IL-6 have been used successfully and are being investigated.MIS-C associated with COVID-19 is a serious hyper-inflammatory syndrome that resembles other disorders characterized by cytokine storm. It presents with a spectrum of signs, symptoms, and disease severity, including fever, myocardial injury, shock, and coronary artery aneurysms. (See AAP Grand Rounds. 2020;44[1]:5.6)