The Multisystem Inflammatory Syndrome in Adults With SARS-CoV-2 Infection—Another Piece of an Expanding Puzzle | Infectious Diseases | JAMA Network Open | JAMA Network
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Invited Commentary
Infectious Diseases
May 19, 2021

The Multisystem Inflammatory Syndrome in Adults With SARS-CoV-2 Infection—Another Piece of an Expanding Puzzle

Author Affiliations
  • 1Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle
JAMA Netw Open. 2021;4(5):e2110344. doi:10.1001/jamanetworkopen.2021.10344

The COVID-19 pandemic has upended our societal status quo. SARS-CoV-2, the virus responsible for COVID-19, has led to a myriad of clinical presentations, many of which were different from the diseases caused by other respiratory viral infections. Among the manifestations were olfactory dysfunction and so-called COVID toes, leading to a constant change of what we understood as the spectrum of illness caused by SARS-CoV-2. To help understand this complex clinical picture, a framework for the spectrum of SARS-CoV-2 infection has been proposed.1 Now, more than a year after the initial discovery of COVID-19, that complete clinical picture continues to be evasive as new features of SARS-CoV-2 are described.

In April 2020, European colleagues were the first to report pediatric cases of a hyperinflammatory syndrome2 that shared clinical features of Kawasaki disease and toxic shock syndrome.3 Pediatricians who frequently encounter cases of these conditions identified children who presented to the hospital with fevers, rashes, gastrointestinal symptoms, and severely elevated inflammatory markers. Many patients arrived in shock, with diagnoses of myocarditis. Clinicians and public health officials recognized the temporal association of this syndrome with the initial European wave of the pandemic, with these pediatric cases occurring approximately 2 to 4 weeks after initial SARS-CoV-2 infection; many of these patients had developed positive SARS-CoV-2 serology. As a result, this novel syndrome was initially called pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Soon thereafter, US cases were reported in the state of New York, offering an opportunity to contribute to the growing science of this novel syndrome. State partners and a field team from the US Centers for Disease Control and Prevention summarized the data from these cases in New York State,4 which helped to establish an initial epidemiologic case definition5 as well as a new name: the multisystem inflammatory syndrome in children (MIS-C). In choosing this name, we wanted to be inclusive of adult patients, as we suspected that multisystem inflammatory syndrome in adults (MIS-A) existed but had not yet been described.

A new report published elsewhere in JAMA Network Open describes 15 adult patients with MIS-A,6 illustrating that the original hyperinflammation syndrome attributed to the pediatric population in fact spans the age range. While previous publications relied on case reports or case series to describe MIS-A,7 Davogustto et al6 used a systematic approach to identify cases of MIS-A among adults admitted to their institution who have had laboratory-confirmed SARS-CoV-2 infection. Compared with those classified as having acute COVID-19, patients with MIS-A were significantly younger and more likely to have detectable SARS-CoV-2 serology. Among the MIS-A group, 33.3% required intensive care unit admission and 20% were diagnosed with shock. Despite the morbidity associated with MIS-A, none of the 15 patients died in the hospital, similar to what was seen in cases of MIS-C. In adults, the overlapping symptoms of acute COVID-19 and MIS-A make differentiating the 2 diagnoses difficult. It is likely that among those diagnosed with severe or critical acute COVID-19, a proportion are cases of MIS-A. Unlike adult cases of acute COVID-19, most pediatric patients experience asymptomatic infection or mild COVID-19 symptoms, thus allowing a contrast between the diagnoses of acute COVID-19 and MIS-C. Underscoring this challenge, the authors6 found that 60.0% of their patients with MIS-A had overlapping acute COVID-19 symptoms. However, Davogustto et al6 laid the groundwork for future studies by offering an initial framework by which MIS-A cases could be identified systematically in future research studies (eMethods and eFigure 1 in the Supplement).

Many questions about MIS remain. First, the underlying etiopathogenesis remains unknown, but because cases occur in the post–acute COVID-19 period, an antibody-mediated process or dysregulated immune response is suspected. Second, the incidence of MIS-A is not known, but it is likely to be an uncommon complication of SARS-CoV-2 infection among adults, as it is in children. From March 1 through March 10, 2020, the incidence of MIS-C in New York State among people younger than 21 years was 2 per 100 000 individuals vs 322 per 100 000 individuals with laboratory-confirmed SARS-CoV-2 infection.4 Third, there may be a diversity of phenotypes of MIS not only between individual cases but across age groups. In MIS-C, mucocutaneous manifestations were more common in the younger cohort, while myocarditis and gastrointestinal symptoms were more frequently reported in older children.4 In fact, in the adult cases of MIS identified by Davogustto et al,6 12 of 15 patients with MIS-A (80.0%) had gastrointestinal complications. As we learn more about MIS-A, we are likely to uncover additional aspects of its spectrum. Lastly, evidence for an optimal treatment strategy for MIS-A is lacking, and for now therapy may depend on supportive medical management. In children, MIS-C therapy frequently includes intravenous immunoglobulins and glucocorticoids, which are extrapolated from the management strategies of Kawasaki disease. Further research will be needed to decide whether these same treatments can be applied to adult cases.

Although MIS-A is a rare entity, the study by Davogustto et al6 offers an initial description of this clinically significant condition. Not only does MIS have important implications for our understanding of SARS-CoV-2 pathology, but it also has the potential to offer new insights in how our immune system functions and its role in hyperinflammation. MIS-A is yet another important piece to the ever-expanding SARS-CoV-2 puzzle.

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Article Information

Published: May 19, 2021. doi:10.1001/jamanetworkopen.2021.10344

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Chow EJ. JAMA Network Open.

Corresponding Author: Eric J. Chow, MD, MS, MPH, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 1959 NE Pacific St, PO Box 356423, Seattle, WA 98195 (

Conflict of Interest Disclosures: None reported.

Datta  SD, Talwar  A, Lee  JT.  A proposed framework and timeline of the spectrum of disease due to SARS-CoV-2 infection: illness beyond acute infection and public health implications.   JAMA. 2020;324(22):2251-2252. doi:10.1001/jama.2020.22717PubMedGoogle ScholarCrossref
Whittaker  E, Bamford  A, Kenny  J,  et al; PIMS-TS Study Group and EUCLIDS and PERFORM Consortia.  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.2020.10369PubMedGoogle ScholarCrossref
Riphagen  S, Gomez  X, Gonzalez-Martinez  C, Wilkinson  N, Theocharis  P.  Hyperinflammatory shock in children during COVID-19 pandemic.   Lancet. 2020;395(10237):1607-1608. doi:10.1016/S0140-6736(20)31094-1PubMedGoogle ScholarCrossref
Dufort  EM, Koumans  EH, Chow  EJ,  et al; New York State and Centers for Disease Control and Prevention Multisystem Inflammatory Syndrome in Children Investigation Team.  Multisystem inflammatory syndrome in children in New York State.   N Engl J Med. 2020;383(4):347-358. doi:10.1056/NEJMoa2021756PubMedGoogle ScholarCrossref
US Centers for Disease Control and Prevention. Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19). Reviewed March 27, 2020. Accessed February 28, 2021.
Davogustto  GE, Clark  DE, Hardison  E,  et al.  Characteristics associated with multisystem inflammatory syndrome among adults with SARS-CoV-2 infection.   JAMA Netw Open. 2021;4(5):e2110323. doi:10.1001/jamanetworkopen.2021.10323Google Scholar
Morris  SB, Schwartz  NG, Patel  P,  et al.  Case series of multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection—United Kingdom and United States, March-August 2020.   MMWR Morb Mortal Wkly Rep. 2020;69(40):1450-1456. doi:10.15585/mmwr.mm6940e1PubMedGoogle ScholarCrossref
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