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 Table of Contents  
Year : 2021  |  Volume : 8  |  Issue : 6  |  Page : 263-265

COVID-19-associated multi-system inflammatory syndrome in children: Not “MIS-Cing” the wood for the trees!

1 Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
2 Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia; Department of Anesthesiology, Critical Care and Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States

Date of Submission10-Oct-2021
Date of Acceptance21-Oct-2021
Date of Web Publication19-Nov-2021

Correspondence Address:
Dr. Vijay Srinivasan
Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA 19104
United States
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpcc.jpcc_87_21

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How to cite this article:
Loscalzo S, Srinivasan V. COVID-19-associated multi-system inflammatory syndrome in children: Not “MIS-Cing” the wood for the trees!. J Pediatr Crit Care 2021;8:263-5

How to cite this URL:
Loscalzo S, Srinivasan V. COVID-19-associated multi-system inflammatory syndrome in children: Not “MIS-Cing” the wood for the trees!. J Pediatr Crit Care [serial online] 2021 [cited 2022 Aug 16];8:263-5. Available from: http://www.jpcc.org.in/text.asp?2021/8/6/263/330733

The coronavirus disease 2019 (COVID-19) pandemic has caused catastrophic disease worldwide. Although children have been relatively spared from severe acute respiratory illness,[1] the emergence of an associated novel disease process - Multisystem Inflammatory Syndrome in Children (MIS-C) - has posed a unique threat to pediatric populations. In April of 2020, clinicians in the United Kingdom published a case series on a small cluster of previously healthy children presenting with cardiovascular shock, fever, and hyperinflammation.[2] Subsequent case series and a proposed temporal association with coronavirus infections prompted public health officials to establish a case definition for MIS-C to characterize disease prevalence, guide treatment strategies, and study outcomes and long-term sequelae. The MIS-C case definition, provided by the Centers for Disease Control and Prevention, includes six criteria: serious illness leading to hospitalization, an age of <21 years, fever that lasted for at least 24 h, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or exposure to persons with COVID-19 in the past month.[3]

The incidence of MIS-C intriguingly increases 4–6 weeks following peak COVID-19 infections in affected populations. Although a causal link has yet to be identified, an exaggerated activation of the innate immune system during the adaptive immune response to SARS-CoV-2 has been proposed.[4] The median age of presentation is approximately 8 years old with higher incidences among African American and Hispanic/Latino populations.[5] The clinical features of MIS-C can vary but do overlap with other pediatric inflammatory conditions including Kawasaki disease (KD). However, there appear to be distinct MIS-C phenotypes that may impact prognosis and therapeutic decisions.[4] An early large cohort study of 186 patients from the United States observed gastrointestinal, cardiac, hematologic, and mucocutaneous symptoms in affected children. The authors reported clinically significant coronary artery aneurysms in 8% of patients with nearly half of the patients requiring support with vasoactive infusions for hemodynamic instability, especially in older children and adolescents.[6]

Treatment for MIS-C largely includes appropriate supportive care – supplementation with oxygen, crystalloid fluids, antipyretic agents, and if required, early referral for appropriate additional evaluation and monitoring depending on the severity of presentation. First-line treatments have included various therapeutic combinations of anticoagulation agents, steroids, intravenous immunoglobulins (IVIG), and occasionally select immunomodulating agents. The National Health Service led a comprehensive Delphi process to construct an expert informed clinical guideline for the United Kingdom physicians given the differing clinical phenotypes and variable severity in MIS-C (referred to as Paediatric Inflammatory Multisystem Syndrome temporally associated with COVID-19 or). The authors distinguished two primary phenotypes: a KD-like presentation (complete and incomplete), and a nonspecific presentation. A stepwise treatment algorithm, depending on disease severity and responsiveness, broadly included IVIG (2 g/kg) as first-line, high-dose methylprednisolone (10–30 mg/kg) as second line, and suggested the consideration of biologic immunomodulators (tocilizumab, anakinra, and infliximab) for children refractory to first- and second-line therapies. All affected children are recommended to receive antiplatelet therapy with low-dose aspirin and anticoagulation if indicated.[7]

As evidence for the most effective therapies for MIS-C continues to emerge, attention is now increasingly shifting to determining treatment efficacy and responsiveness based on disease severity and phenotype at the time of presentation. A retrospective cohort study from the United States found that patients treated with a combination of IVIG and methylprednisolone experienced a more favorable fever course and required fewer biologic immunomodulators compared to therapy with IVIG alone.[8] Importantly, this study emphasized the importance of characterizing specific phenotypes and determined that selected therapies administered based on a given phenotype impacted critical outcomes beyond mortality such as hospital days, intensive care unit (ICU)-days, and associated ICU-level therapies. However, this study was limited by its observational design and the use of the broad case definition of MIS-C could have potentially also included other patients with alternative diagnoses.

In this issue of the Journal of Pediatric Critical Care, Mehta et al., attempt to address these important gaps and questions that remain, and report their experiences with clinical and laboratory features, therapeutics, and short-term outcomes in children with MIS-C associated with SARS-CoV-2 infection from 11 pediatric ICUs in two cities (Mumbai and Pune) in India between February 2020 and December 2020.[9] The authors retrospectively stratified their cohort of 234 patients into three distinct phenotype groups - fever/hyperinflammatory syndrome, shock with/without MODS, and KD. Treatments were grouped as steroids and intravenous immunoglobulin (IVIG) or combinations or lack thereof. While there were no differences in ICU length of stay across treatment groups (primary outcome), there was a modest reduction of hospital length of stay both in the entire cohort of MIS-C as well as the phenotype of shock with/without MODS in the group that received both steroids and IVIG compared to the other treatment groups. This is a valuable study of a medium-size cohort of children with MIS-C that characterizes clinical phenotypes as well as differences in clinical responses to treatment with implications for short-term outcomes. Importantly, the authors attempt to draw comparisons between the clinical phenotypes, their biochemical and clinical features, and responsiveness to interventions - adding additional supportive evidence to the more widely accepted utilization of the combination of both steroids and IVIG for critically ill patients with MIS-C. Steroids are readily available in many clinical settings. IVIG, however, might be a more limited resource. Further analysis to understand which phenotypes of MIS-C benefit the most from IVIG can help health systems and clinicians allocate resources more appropriately and equitably.

The main limitations of this study are two-fold – one, patients were not randomized and two, the phenotypes were characterized retrospectively with possible classification bias. The differences in outcomes - particularly the duration of ICU stay and hospital stay - could be attributable to the variability of care between the two institutions as well as differences in patient-specific characteristics. An additional important confounding variable, not included in the analysis, may result from differences in the proportion of fluid overload after clinical presentation or decompensation. Existing evidence suggests that fluid overload among PICU survivors of critical illness correlates with increased PICU length of stay and mechanical ventilator days.[10] The time to initiate interventions following diagnosis of MIS-C is also not captured in the current study with the possibility that as the pandemic has progressed, recognition of MIS-C has improved considerably with earlier initiation of targeted therapies. Future analyses should focus on how treatments and related outcomes from MIS-C have evolved over time during the COVID-19 pandemic.

MIS-C is a novel disease that was recognized through massive collective efforts across multiple continents in real-time and has now been characterized as a largely treatable inflammatory condition in children with low mortality. The long-term sequelae of those children severely affected by MIS-C are still undetermined and are currently the focus of studies such as the “Long-terM Outcomes after Multisystem Inflammatory Syndrome in Children: MUSIC” study. In the ever-changing landscape of the pandemic with the emergence of newer variants and roll-out of pediatric vaccinations against COVID-19, it is certain that there will be many more questions that will arise. In the meantime, we must continue to diagnose and care for children with MIS-C with great vigilance and make every effort to not “MIS-C” the wood for the trees.

  References Top

WHO Coronavirus (COVID-19) Dashboard. Available from: https://covid19.who.int. [Last accessed on 2021 Oct 14].  Back to cited text no. 1
Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet 2020;395:1607-8.  Back to cited text no. 2
Emergency Preparedness and Response: Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19). CDCHAN-00432; May 14, 2020. Available from: https://emergency.cdc.gov/han/2020/han00432.asp. [Last accessed on 2021 Oct 14].  Back to cited text no. 3
Jiang L, Tang K, Levin M, Irfan O, Morris SK, Wilson K, et al. COVID-19 and multisystem inflammatory syndrome in children and adolescents. Lancet Infect Dis 2020;20:e276-88.  Back to cited text no. 4
Soma VL, Shust GF, Ratner AJ. Multisystem inflammatory syndrome in children. Curr Opin Pediatr 2021;33:152-8.  Back to cited text no. 5
Feldstein LR, Rose EB, Horwitz SM, Collins JP, Newhams MM, Son MB, et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med 2020;383:334-46.  Back to cited text no. 6
Harwood R, Allin B, Jones CE, Whittaker E, Ramnarayan P, Ramanan AV, et al. A national consensus management pathway for paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS): Results of a national Delphi process. Lancet Child Adolesc Health 2021;5:133-41.  Back to cited text no. 7
Ouldali N, Toubiana J, Antona D, Javouhey E, Madhi F, Lorrot M, et al. Association of intravenous immunoglobulins plus methylprednisolone vs immunoglobulins alone with course of fever in multisystem inflammatory syndrome in children. JAMA 2021;325:855-64.  Back to cited text no. 8
Mehta R, Joshi P, Bhondave A, Otiv M, Udani S, Mohite M, et al. A multicentre study of clinical and biochemical profiles, treatments and short term outcomes in children with multisystem inflammatory syndrome (MIS-C) associated with SARS CoV-2 infection from Western India. J Pediatr Crit Care 2021;8:30.  Back to cited text no. 9
Diaz F, Benfield M, Brown L, Hayes L. Fluid overload and outcomes in critically ill children: A single center prospective cohort study. J Crit Care 2017;39:209-13.  Back to cited text no. 10


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