Multisystem Inflammatory Syndrome in Children and SARS-CoV-2 Serology Steven L. Zeichner, MD, PhD,a Andrea T. Cruz, MD, MPHb

Coronavirus disease 2019 (COVID-19) processes.16–18 That the most effective is arguably the most socially and therapy to reduce mortality in adults economically disruptive pandemic with severe COVID-19 yet established is fl since the 1918 in uenza pandemic. an immune suppressant, Departments of aPediatrics and Microbiology, Immunology, 19 Although pediatric COVID-19 shares dexamethasone, reveals the and Cancer Biology, University of Virginia, Charlottesville, b features with the adult disease, there importance of inflammatory and Virginia; and Department of Pediatrics, Baylor College of Medicine, Houston, Texas are several differences. Children immune-mediated pathologies. produce virus in amounts at least equal Opinions expressed in these commentaries are Pediatrics, 20 to adults, if not higher,1 and can In this issue of Rostad et al those of the author and not necessarily those of the American Academy of Pediatrics or its Committees transmit the virus, just as adults can.2 showed that children hospitalized fi DOI: School-aged children are generally less- with MIS-C have signi cantly higher https://doi.org/10.1542/peds.2020-032888 severely affected than infants or adults, concentrations of antibodies against Accepted for publication Sep 22, 2020 the receptor-binding domain (RBD), but some children without significant Address correspondence to Steven Zeichner, MD, underlying disease become ill or die in a part of the severe acute respiratory PhD, Department of Pediatrics, University of Virginia, a disease process analogous to the one syndrome coronavirus 2 (SARS-CoV-2) Box 801349, Charlottesville, VA 22908. E-mail: [email protected] most commonly seen in adults: severe spike protein (S). RBD is the part of S pulmonary disease and respiratory mediating virus binding to its receptor, PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, – 1098-4275). failure.3 6 Children and adults appear angiotensin-converting enzyme 2, on fi to have different humoral immune host cells. This nding is reinforced by Copyright © 2020 by the American Academy of Pediatrics responses to COVID-19.7 other research, which showed that anti- RBD antibody concentrations were FINANCIAL DISCLOSURE: Drs Cruz and Zeichner are A small fraction of children higher in children with severe MIS-C associate editors for Pediatrics. with COVID-19 experience than in children with mild MIS-C or FUNDING: Dr Cruz reports no funding source for this a hyperinflammatory process,8–13 patients not meeting MIS-C definitions.1 work. Dr Zeichner receives funding through the termed multisystem inflammatory The children also had high SARS-CoV-2 McLemore Birdsong endowed chair, the Pendleton Pediatric Infectious Disease Laboratory, the Manning syndrome in children (MIS-C) in the neutralization titers, consistent with Fund for coronavirus disease 2019 research, the Ivy United States, with features distinct the observations that anti-RBD Foundation, and the Coulter Foundation. from Kawasaki disease.14 This case antibodies can effectively neutralize POTENTIAL CONFLICT OF INTEREST: Dr Zeichner fi $ 21 de nition includes 2 of these the virus. The patients with MIS-C discloses that the University of Virginia has filed 20 symptoms: rash, conjunctivitis, or described in Rostad et al also tended patent applications related to new technologies for mucocutaneous inflammation; to have higher antibody levels against the rapid production of vaccines and Dr Zeichner is hypotension; cardiac disease; the entire spike protein and the viral an inventor on those patent applications. Dr Zeichner’s laboratory at the University of Virginia is coagulopathy; or acute gastrointestinal nucleocapsid protein, which is not 15 working to employ those new technologies to problems. MIS-C, which is not exposed on the surface of the virion. develop candidate subunit coronavirus disease 2019 correlated with viral load levels, The anti-RBD antibody levels vaccines. The University of Virginia will own any typically appears some time after initial correlated with the erythrocyte intellectual property related to that work and the infection.13 MIS-C’s incidence is difficult sedimentation rate, suggesting that University has established intellectual property policies that could result in Dr Zeichner personally to determine, given the high rate of higher anti-RBD antibodies are fl 12 receiving money. Dr Cruz has no potential con icts of asymptomatic infection. associated with a more interest to disclose. proinflammatory state. Adults with COVID-19 also can experience inflammatory disorders: The finding that patients with MIS-C To cite: Zeichner SL and Cruz AT. Multisystem fl coagulopathies, vasculitis, have higher anti-RBD antibodies is In ammatory Syndrome in Children and SARS-CoV-2 Serology. Pediatrics. 2020;146(6):e2020032888 cardiomyositis, and neuroinflammatory interesting and potentially important

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 146, number 6, December 2020:e2020032888 COMMENTARY because, despite case definitions, correlated with inflammatory 2 neutralizing activity, preferentially MIS-C may be difficult to diagnose. If markers. avoid eliciting strong anti-RDB immune high levels of anti-RBD antibodies are responses. Another implication may be that if associated with MIS-C, quantitative How could aberrant immune assays for anti-RBD antibodies anti-RBD antibodies are associated with MIS-C, it might be desirable to responses promote MIS-C? might enable more-accurate MIS-C Hypothetical mechanisms include diagnosis or predict patients at higher screen convalescent sera for anti–SARS-CoV-2 neutralizing activity antibody-dependent enhancement, risk for MIS-C, potentially enabling direct cytotoxicity, immune early interventions. and anti-RBD activity, selecting units with good neutralizing activity but complexes, and macrophage hyperinflammatory responses,33 So far, authors of reports describing with lower anti-RBD activity. This perhaps enabled by substantial associations of high anti-RBD IgG with may also be a consideration for – differences in humoral responses.7 MIS-C have looked at anti-RBD IgG bulk anti SARS-CoV-2 therapeutic Another theoretical possibility would properties. However, all antibodies may monoclonal antibody development. be innate activities of anti-RBD not have equal activity to cause, or Some investigators have antibodies. Antibodies with catalytic equal propensities to be associated hypothesized that children may have activity (abzymes) have been with, MIS-C. Detailed study of the milder COVID-19 disease because of described and can be significant in antibodies, including mapping binding cross-reactive immunity to other autoimmune diseases.34,35 Antibodies siteswithinRBD,mayyieldimproved 24,25 coronaviruses, but it is also against proteins that bind enzymes understanding of pathogenesis. conceivable that such previous can themselves have weak catalytic Immune responses to COVID-19 are coronavirus exposures might have activity; an antibody against a protein heterogeneous. Neutralizing antibody increased risks of an inflammatory (RBD) that binds an enzyme concentrations vary widely; some response or worse disease, as seen (angiotensin-converting enzyme 2) patients do not develop detectable 26,27 with dengue hemorrhagic fever. could plausibly have catalytic activity, titers.22 Patients who recover exhibit with physiologic consequences.36 different antibody responses from With their findings, Rostad et al20 may those who die.23 It may be helpful to also have implications for vaccine MIS-C and COVID-19 inflammatory modulate immune responses to achieve development. Close attention to disorders in children are relatively ideal levels of activity generally, such as vaccines eliciting anti-RBD antibodies uncommon but can be serious. dexamethasone for severe disease, or may be advisable, if dysregulated or Better diagnostics and improved specifically, if anti-RBD immune aberrant responses against RBD or management will be important as responses prove problematic. parts of RBD contribute to more children are infected. Greater hyperinflammation. Many candidate understanding of MIS-C pathogenesis Beyond potential use in diagnosing vaccines aim to elicit responses against may help optimize convalescent MIS-C, the findings may have the entire S, including RBD. Some aim plasma therapy and inform vaccine implications for pathogenesis, to specifically elicit antibodies development. therapy, and vaccine development. against RBD.28 Although a COVID-19 In producing immune responses vaccine is urgently needed, ABBREVIATIONS against COVID-19, there may be leading vaccinologists have cautioned a response that optimally addresses against deploying vaccines without COVID-19: coronavirus disease threats posed by infection without thorough safety evaluations, recalling 2019 initiating harmful hyperactive unfortunate past tragedies involving MIS-C: multisystem inflammatory immune responses. The response candidate vaccines, with vaccination syndrome in children against RBD may reflect general yielding increased morbidity and RBD: receptor-binding domain characteristics of immune mortality when vaccine recipients were S: severe acute respiratory responses against SARS-CoV-2, or later infected with circulating syndrome coronavirus 2 – there may be something virus.29 32 If strong anti-RBD responses spike protein particularly problematic about are associated with an increased risk of SARS-Co-V-2: severe acute immune responses directed against inflammatory disorders, it may then be respiratory syndrome RBD, per se, an idea reinforced by advantageous to develop vaccines that, coronavirus 2 the finding that RBD antibodies are while eliciting excellent anti–SARS-CoV-

Downloaded from www.aappublications.org/news by guest on September 28, 2021 2 ZEICHNER and CRUZ COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/2020-018242.

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Downloaded from www.aappublications.org/news by guest on September 28, 2021 Multisystem Inflammatory Syndrome in Children and SARS-CoV-2 Serology Steven L. Zeichner and Andrea T. Cruz Pediatrics 2020;146; DOI: 10.1542/peds.2020-032888 originally published online September 24, 2020;

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