Multi-System Inflammatory Syndrome in Children (MIS-C): Comparison
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Please note this is a comparison between Version 2 by Mona Zou and Version 1 by Simon Parzen-Johnson.

Critical illness due to Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infection is rare in children, especially in those who were previously healthy. However, two post-infectious sequelae emerged during the pandemic that had significant impact on the morbidity associated with pediatric SARS-CoV-2 infections: Multi-System Inflammatory Syndrome in Children (MIS-C) and Post-Acute Sequelae of SARS-CoV-2 Infection (PASC or Long COVID). These two clinical entities are both temporally related to acute SARS-CoV-2 infection, yet they have drastically different natural histories and management strategies. 

  • PASC
  • COVID-19
  • pediatrics
  • MISC
  • PIM
  • ME/CFS

1. Pathophysiology and Identification

MIS-C is a uniquely severe presentation following SARS-CoV-2 infection, seen mainly in pediatric patients. It emerged as a clinical entity in early 2020, and although it has been described for over three years, the case definitions remain broad and diagnosis can be difficult. Initial reports described a syndrome of systemic inflammation resembling Kawasaki disease, with fever, variable rash, generalized extremity pain, and gastrointestinal symptoms including diarrhea, emesis, and abdominal pain about 4 weeks following acute COVID-19 infection [2][1]. In severe cases, patients had shock, multiple organ dysfunction, and sometimes pleural, pericardial, and ascitic effusions [2][1].
There are many hypotheses about the pathophysiology of systemic inflammation driving the clinical presentation of MIS-C. It is difficult to distinguish patients with severe COVID-19 infection and those with MIS-C. Shared characteristics include profound cytokine responses, decreased absolute T-cell numbers with increased activation, elevated markers of angiopathy, and increased plasmablast production [3][2]. When applying multi-omics to a cohort of children with severe COVID-19, MIS-C, and healthy controls, there are common HLA alleles seen in patients with MIS-C and severe COVID-19 that suggest an underlying genetic predilection to both serious conditions [4][3]. Beyond these findings, a recent study by Lee and colleagues performed whole-exome or whole-genome sequencing on 558 pediatric patients with MIS-C to identify potential monogenic variants that predicted the development of MIS-C over severe COVID-19 pneumonia. In their cohort, 1% of patients (significantly higher than in the general population) shared a common deficiency in genes related to OAS1, OAS2, or RNAse L. Because these genes are all involved in the innate immune response against viruses, their deficiency might explain the development of MIS-C in a few patients [5][4]. The researchers posit that if other such genes can be found to be lacking in patients who develop MIS-C, that this could explain, from a host perspective, why certain pediatric patients developed MIS-C after mild COVID-19 infection while others, even those within the same household exposed to the same viral variant, were spared.

2. Diagnosis

MIS-C has many mimickers and thus posed a diagnostic challenge. While initially confused with Kawasaki disease (KD) due to overlapping signs and symptoms, it is now easier to distinguish these two diseases [6][5]. The median age of patients with KD and shock is <3 years, while for those with MIS-C the median age is >9 years. Significant abdominal pain, lymphopenia, myocardial dysfunction, and extremely elevated levels of N-terminal pro B-type natriuretic peptide (>10,000 pg/mL) are rare in KD but common in MIS-C [7][6]. Additionally, viral upper respiratory tract symptoms 2–6 weeks prior to presentation are common in MIS-C, but not in KD.
A similar distinction can be made between MIS-C and severe COVID-19, because, in contrast to acute COVID-19, children with MIS-C have few respiratory symptoms [8][7]. Although some children with MIS-C require mechanical ventilation, this is for cardiovascular stabilization as opposed to respiratory decompensation, as seen in acute COVID-19 [2,8][1][7].
Both the World Health Organization (WHO) and the Centers for Disease Control (CDC) created case definitions to assist with diagnosis, management, and surveillance efforts of MIS-C.
CDC Case Definition [9][8]:
  • Patients less than 21 years of age with fever, laboratory evidence of inflammation, and clinically severe illness requiring hospitalization with multisystem organ involvement. No alternative plausible diagnosis. Current or recent SARS-CoV-2 infection within 4 weeks prior to onset of symptoms.
WHO Case Definition [10][9]:
  • Patients less than 19 years of age with fever for three or more days, clinical signs of multisystem involvement with elevated markers of inflammation, no microbial cause of inflammation, and evidence of SARS-CoV-2 infection or exposure to COVID-19.
With the utilization of these case definitions, large case series were published highlighting the variable presenting symptoms and severity of the disease. In 2023, new case definitions of MIS-C were released which included additional clinical (cardiac, mucocutaneous, GI, etc.) and laboratory (C-Reactive Protein > 3.0 mg/dL, Platelet < 150,000 cells/μL) features, but MIS-C remains a diagnosis of exclusion. In addition to fever, gastrointestinal symptoms emerged as the most common clinical finding, followed by rash, conjunctival injection, and oropharyngeal findings [11][10]. Neurologic symptoms are common and range in severity from headache to life-threatening manifestations including stroke, cerebral edema, and demyelination syndromes [12][11].
Establishing the temporal relationship with prior SARS-CoV-2 infection was variable among case series; some patients tested positive by polymerase chain reaction for SARS-CoV-2 on presentation, others had positive serologies, and some only had exposure histories [11][10]. Although patients have been reported to have MIS-C without laboratory evidence of prior SARS-CoV-2 infection, these patients may very well have a different diagnosis (i.e., Kawasaki disease, systemic juvenile idiopathic arthritis, systemic lupus erythematosus, etc.). Establishing the association of preceding SARS-CoV-2 infection has been complicated by vaccination and rising infection rates in the population because of the consequent need to now distinguish vaccine immunity (manifested by SARS-CoV-2 anti-spike protein antibody) and natural immunity (manifested by nucleocapsid antibody). Acknowledging limitations due to inconsistencies with diagnosis, outcomes are reassuring, with a mortality of less than 1.5% in children [8[7][10],11], and most patients have resolution of disease without significant long-term morbidity [13][12].

3. Treatment, Epidemiology, and Outcomes

Treatment for MISC is focused on the treatment of systemic inflammation with medications like intravenous immunoglobulin (IVIG) and steroids. When first described, therapy was modeled on that used for KD, and IVIG was typically administered, with apparent benefit. Many clinicians noted improved clinical outcomes when corticosteroids were added to IVIG, and retrospective studies demonstrated improvements in myocardial function when dual therapy was administered compared with IVIG alone [14,15][13][14]. However, these findings are not universal [16,17][15][16]. Son et al. (2021) found that IVIG with glucocorticoids was associated with a decreased risk of starting vasopressors, an increased need for immunomodulatory therapy, and cardiovascular dysfunction when compared to IVIG alone [15][14]. McArdle et al. (2021) found a similar decreased risk of progression to the need for increased immunomodulatory therapy, but they found no significant difference in clinical progression (needing inotropic support or mechanical ventilation) or death when comparing IVIG and glucocorticoids to either therapy alone; however, they included patients that did not meet any of the strict case definitions of MIS-C [17][16]. A meta-analysis by Ouldali et al. (2023) found improved cardiovascular outcomes associated with IVIG plus glucocorticoids when compared to either medication alone. Combination therapy was also associated with the faster resolution of fever and decreased need for secondary therapies when compared to glucocorticoids alone [18][17]. Potential reasons for the reported differences in response to therapy in different series, besides different case definitions, include the different SARS-CoV-2 variants and the vaccination status of the children affected [19,20][18][19].
Individual centers have developed unique diagnostic and treatment protocols, although most involve IVIG and steroids. These variations illustrate the continued need for rigorous studies on the diagnosis and treatment of MIS-C [21][20], although this will be challenging due to continued waning case volumes [22][21].
Through various national reporting databases, epidemiologic studies showed that MIS-C occurred disproportionately in Black and Hispanic patients [23][22]. This was initially postulated to be secondary to the increased incidence of SARS-CoV-2 infections among these groups. However, as surveillance data and modeling improved it was found that when controlling for rates of SARS-CoV-2 infection, Black and Hispanic patients were still more likely to develop MIS-C [24][23]; whether this is due to genetic or environmental factors (or both) is still unknown.
Interestingly, there appeared to be shifting epidemiology of the disease itself over the course of the COVID-19 pandemic. Initial surveillance data linked spikes in incidence of MIS-C to spikes in SARS-CoV-2 infection, with MIS-C increases occurring approximately 4 weeks after the largest initial SARS-CoV-2 outbreaks [2][1]. However, as the pandemic continued, this relationship became less pronounced. In the summer and winter of 2021, increases in SARS-CoV-2 caseloads did not lead to proportioned peaks of MIS-C in the weeks following [22][21]. Likely, this was due to differences in the viral variant causing the acute infection; markedly fewer and less severe MIS-C cases were reported when the delta and omicron variants were the predominant circulating strain than when the alpha variant predominated [25,26][24][25]. Viral variants could differ in cellular tropism, the ability to persist, severity, or other factors that may influence the likelihood of developing MIS-C. Vaccination rates also increased during 2021, and the risk of MIS-C was lower following vaccination in children [27][26], although immunizations for school-aged children were not authorized in the United States until after the delta variant peaked. Hopefully, with the high levels of population immunity and vaccination, along with decreasing pathogenicity, as SARS-CoV-2 continues to evolve, severe COVID-19 epidemics will be mainly a thing of the past and MIS-C will seldom be seen.

References

  1. Riphagen, S.; Gomez, X.; Gonzalez-Martinez, C.; Wilkinson, N.; Theocharis, P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet 2020, 395, 1607–1608.
  2. Vella, L.A.; Rowley, A.H. Current Insights into the Pathophysiology of Multisystem Inflammatory Syndrome in Children. Curr. Pediatr. Rep. 2021, 9, 83–92.
  3. Sacco, K.; Castagnoli, R.; Vakkilainen, S.; Liu, C.; Delmonte, O.M.; Oguz, C.; Kaplan, I.M.; Alehashemi, S.; Burbelo, P.D.; Bhuyan, F.; et al. Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19. Nat. Med. 2022, 28, 1050–1062.
  4. Lee, D.; Le Pen, J.; Yatim, A.; Dong, B.; Aquino, Y.; Ogishi, M.; Pescarmona, R.; Talouarn, E.; Rinchai, D.; Zhang, P.; et al. Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children. Science 2023, 379, eabo3627.
  5. Consiglio, C.R.; Cotugno, N.; Sardh, F.; Pou, C.; Amodio, D.; Rodriguez, L.; Tan, Z.; Zicari, S.; Ruggiero, A.; Pascucci, G.R.; et al. The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19. Cell 2020, 183, 968–981.e7.
  6. Rowley, A.H. Multisystem Inflammatory Syndrome in Children and Kawasaki Disease: Two Different Illnesses with Overlapping Clinical Features. J. Pediatr. 2020, 224, 129–132.
  7. Feldstein, L.R.; Tenforde, M.W.; Friedman, K.G.; Newhams, M.; Rose, E.B.; Dapul, H.; Soma, V.L.; Maddux, A.B.; Mourani, P.M.; Bowens, C.; et al. Characteristics and Outcomes of US Children and Adolescents with Multisystem Inflammatory Syndrome in Children (MIS-C) Compared with Severe Acute COVID-19. JAMA 2021, 325, 1074–1087.
  8. CDC. Information for Healthcare Providers about Multisystem Inflammatory Syndrome in Children (mis-C); CDC: Atlanta, GA, USA, 2023. Available online: https://www.cdc.gov/mis/mis-c/hcp/index.html (accessed on 1 August 2023).
  9. WHO. Multisystem Inflammatory Syndrome in Children and Adolescents with COVID-19: Scientific Brief; WHO: Geneva, Switzerland, 2020; Available online: https://www.who.int/publications-detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19 (accessed on 1 August 2023).
  10. Aronoff, S.C.; Hall, A.; Del Vecchio, M.T. The Natural History of Severe Acute Respiratory Syndrome Coronavirus 2-Related Multisystem Inflammatory Syndrome in Children: A Systematic Review. J. Pediatr. Infect. Dis. Soc. 2020, 9, 746–751.
  11. LaRovere, K.L.; Riggs, B.J.; Poussaint, T.Y.; Young, C.C.; Newhams, M.M.; Maamari, M.; Walker, T.C.; Singh, A.R.; Dapul, H.; Hobbs, C.V.; et al. Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome. JAMA Neurol. 2021, 78, 536–547.
  12. Zuccotti, G.; Calcaterra, V.; Mannarino, S.; D’auria, E.; Bova, S.M.; Fiori, L.; Verduci, E.; Milanese, A.; Marano, G.; Garbin, M.; et al. Six-month multidisciplinary follow-up in multisystem inflammatory syndrome in children: An Italian single-center experience. Front. Pediatr. 2022, 10, 1080654.
  13. Belhadjer, Z.; Auriau, J.; Méot, M.; Oualha, M.; Renolleau, S.; Houyel, L.; Bonnet, D. Addition of Corticosteroids to Immunoglobulins Is Associated with Recovery of Cardiac Function in Multi-Inflammatory Syndrome in Children. Circulation 2020, 142, 2282–2284.
  14. Ouldali, N.; Toubiana, J.; Antona, D.; Javouhey, E.; Madhi, F.; Lorrot, M.; Léger, P.-L.; Galeotti, C.; Claude, C.; Wiedemann, A.; et al. Association of Intravenous Immunoglobulins Plus Methylprednisolone vs Immunoglobulins Alone with Course of Fever in Multisystem Inflammatory Syndrome in Children. JAMA 2021, 325, 855–864.
  15. Son, M.B.F.; Murray, N.; Friedman, K.; Young, C.C.; Newhams, M.M.; Feldstein, L.R.; Loftis, L.L.; Tarquinio, K.M.; Singh, A.R.; Heidemann, S.M.; et al. Multisystem Inflammatory Syndrome in Children—Initial Therapy and Outcomes. N. Engl. J. Med. 2021, 385, 23–34.
  16. McArdle, A.J.; Vito, O.; Patel, H.; Seaby, E.G.; Shah, P.; Wilson, C.; Broderick, C.; Nijman, R.; Tremoulet, A.H.; Munblit, D.; et al. Treatment of Multisystem Inflammatory Syndrome in Children. N. Engl. J. Med. 2021, 385, 11–22.
  17. Ouldali, N.; Son, M.B.F.; McArdle, A.J.; Vito, O.; Vaugon, E.; Belot, A.; Leblanc, C.; Murray, N.L.; Patel, M.M.; Levin, M.; et al. Immunomodulatory Therapy for MIS-C. Pediatrics 2023, 152, e2022061173.
  18. DeBiasi, R.L. Immunotherapy for MIS-C—IVIG, Glucocorticoids, and Biologics. N. Engl. J. Med. 2021, 385, 74–75.
  19. Borch, L.; Holm, M.; Knudsen, M.; Ellermann-Eriksen, S.; Hagstroem, S. Long COVID symptoms and duration in SARS-CoV-2 positive children—A nationwide cohort study. Eur. J. Pediatr. 2022, 181, 1597–1607.
  20. Dove, M.L.; Jaggi, P.; Kelleman, M.; Abuali, M.; Ang, J.Y.; Ballan, W.; Basu, S.K.; Campbell, M.J.; Chikkabyrappa, S.M.; Choueiter, N.F.; et al. Multisystem Inflammatory Syndrome in Children: Survey of Protocols for Early Hospital Evaluation and Management. J. Pediatr. 2021, 229, 33–40.
  21. CDC. Health Department-Reported Cases of Multisystem Inflammatory Syndrome in Children (MIS-C) in the United States; CDC: Atlanta, GA, USA, 2021. Available online: https://covid.cdc.gov/covid-data-tracker/#mis-national-surveillance (accessed on 11 August 2023).
  22. Abrams, J.Y.; Godfred-Cato, S.E.; Oster, M.E.; Chow, E.J.; Koumans, E.H.; Bryant, B.; Leung, J.W.; Belay, E.D. Multisystem Inflammatory Syndrome in Children Associated with Severe Acute Respiratory Syndrome Coronavirus 2: A Systematic Review. J. Pediatr. 2020, 226, 45–54.e1.
  23. Payne, A.B.; Gilani, Z.; Godfred-Cato, S.; Belay, E.D.; Feldstein, L.R.; Patel, M.M.; Randolph, A.G.; Newhams, M.; Thomas, D.; Magleby, R.; et al. Incidence of Multisystem Inflammatory Syndrome in Children Among US Persons Infected With SARS-CoV-2. JAMA Netw. Open 2021, 4, e2116420.
  24. Levy, N.; Koppel, J.H.; Kaplan, O.; Yechiam, H.; Shahar-Nissan, K.; Cohen, N.K.; Shavit, I. Severity and Incidence of Multisystem Inflammatory Syndrome in Children During 3 SARS-CoV-2 Pandemic Waves in Israel. JAMA 2022, 327, 2452–2454.
  25. Cohen, J.M.; Carter, M.J.; Cheung, C.R.; Ladhani, S. Lower Risk of Multisystem Inflammatory Syndrome in Children with the Delta and Omicron Variants of Severe Acute Respiratory Syndrome Coronavirus 2. Clin. Infect. Dis. 2023, 76, e518–e521.
  26. Holm, M.; Espenhain, L.; Glenthøj, J.; Schmidt, L.S.; Nordly, S.B.; Hartling, U.B.; Nygaard, U. Risk and Phenotype of Multisystem Inflammatory Syndrome in Vaccinated and Unvaccinated Danish Children Before and During the Omicron Wave. JAMA Pediatr. 2022, 176, 821–823.
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