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 Table of Contents  
Year : 2020  |  Volume : 7  |  Issue : 5  |  Page : 271-275

Pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 – An emerging problem of PICU: A case series

1 Department of Pediatrics, INHS Kalyani, Visakhapatnam, Andhra Pradesh, India
2 Department of Pediatrics, Military Hospital, Jammu and Kashmir, India
3 Department of Pediatrics, Wockhardt Hospital, Ahmedabad, Gujarat, India
4 Department of Pediatrics, Research and Referral Hospital, New Delhi, India

Date of Submission06-Aug-2020
Date of Decision16-Aug-2020
Date of Acceptance21-Aug-2020
Date of Web Publication14-Sep-2020

Correspondence Address:
Dr. Ashutosh Kumar
Department of Pediatrics, Research and Referral Hospital, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JPCC.JPCC_120_20

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Among rising number of coronavirus disease 2019 cases in children, there has been a rapid rise in cases of pediatric multisystem inflammatory syndrome associated with severe acute respiratory syndrome coronavirus 2 (PIMS-TS) with clinical features either simulating Kawasaki disease or toxic shock syndrome. We report three children who initially presented with fever, multisystem involvement, and features of hyperinflammation satisfying the World Health Organization criteria for PIMS-TS clinically and on laboratory investigations. All patients were treated with immune modulation by intravenous immunoglobulin and/or methylprednisolone and recovered to discharge.

Keywords: Coronavirus disease 2019, inflammatory markers, intravenous immunoglobulin, Kawasaki disease, pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2, World Health Organization

How to cite this article:
Mukund B, Sharma M, Mehta A, Kumar A, Bhat V. Pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 – An emerging problem of PICU: A case series. J Pediatr Crit Care 2020;7:271-5

How to cite this URL:
Mukund B, Sharma M, Mehta A, Kumar A, Bhat V. Pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 – An emerging problem of PICU: A case series. J Pediatr Crit Care [serial online] 2020 [cited 2021 Jan 20];7:271-5. Available from: http://www.jpcc.org.in/text.asp?2020/7/5/271/295013

  Introduction Top

Coronavirus disease 2019 (COVID-19) triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to around 16 million infections and approximately 6.5 lakhs deaths world over as of July 26, 2020.[1] In adults, it has manifested with severe hypoxemia in acute-phase and profound inflammatory response with cytokine storm leading to multi-organ dysfunction syndrome contributing to high mortality in symptomatic patients. Fortunately, the risk of infection and acute disease in children has been consistently low. On May 1, 2020, the Royal College of Paediatrics and Child Health (RCPCH) published clinical management guidelines for children with presentation of pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) infection and proposed a case definition.[2] These guidelines were formulated because health authorities at the UK reported a number of seriously ill children with clinical signs of circulatory shock and/or hyperinflammatory states with features consistent with diagnosis of Kawasaki disease (KD) or toxic shock syndrome. The same syndrome has been called multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. Among these children, some tested positive for SARS-CoV-2 infection or had exposure to them from a positive contact. Similarly, on April 7, 2020, a classic case of KD with COVID-19 was reported from the USA.[3] In France, on May 12, 125 suspected cases were reported, 65 cases were provisionally diagnosed as PIMS-TS, and additionally, 15 were noted to have probable links with COVID-19.[4] From India, Rauf et al. were first to report a similar case from South India on May 28, 2020.[5]

A causal association between SARS-CoV-2 infection and PIMS-TS has not yet been proven. It is, however, hypothesized that it probably reflects a dysregulation of immune response to this virus and may hence occur as a late reaction to SARS-CoV-2 infection. It is also not known why only a subset of children manifest with PIMS-TS among large number of positive/exposed cases among children and adolescents. Probably, the inflammatory reaction is also influenced by the genetic background of the individuals resulting in rarity of this condition. One possible mechanism that causes KD or PIMS-TS in children could be antibody-dependent enhancement (ADE) where the presence of antibodies can be detrimental when their levels are too low to provide protection but high enough to enable the virus an abode for spread and immunomodulate. ADE has been demonstrated in SARS-CoV-2 in vitro, where antibodies to spike protein improve the ability of novel strains of the virus to enter host cells.[6],[7] In order to establish the causality of SARS-CoV-2 infection in PIMS, Bradford Hill's nine causality criteria were applied, where it was found that these criteria partially met (i.e., 2+) in consistency and temporality and minimally met (1+) in strength, coherence, and plausibility and not met (−/±) in specificity, biological gradient, experiment, or analogy as per the European Centre for Disease Prevention and Control report dated May 15, 2020. The report also said that the onset of symptoms of PIMS-TS was estimated to be 2–4 weeks after COVID-19 infection.[8] The World Health Organization (WHO) in its scientific brief report dated May 15, 2020, proposed diagnostic criteria for PIMS-TS in children and the Centers for Disease Control and Prevention (CDC) published similar criteria on May 14, 2020 [Table 1].[9],[10]
Table 1: WHO and CDC criteria for PIMS-TS/Multisystem Inflammatory Syndrome in children (MIS-C)

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Clinical management of PIMS-TS has been supportive. On suspicion, efforts should be made to exclude bacterial sepsis and viral infections such as Epstein–Barr virus, in addition to investigation of household members for COVID-19 infection. Treatment with intravenous immunoglobulin (IVIG) has been a predominant management option. Methylprednisolone, heparin, and anti-inflammatory agents like tocilizumab have also been tried. A few children with PIMS-TS have required inotropic support, mechanical ventilation, and extracorporeal membrane oxygenation. There is a need for continuous surveillance and additional data from the Indian subcontinent so that a better understanding of the complications and ideal modality of treatment can be recommended. Till mid-May, 5 fatalities have been documented with PIMS-TS, 3 in the USA, and 1 each in France and the UK. Since most of these children present with myocardial involvement or coronary abnormalities, a long-term follow-up is required.[11] Case details of the three cases are enumerated below [Table 2].[Figure 1], [Figure 2], [Figure 3], [Figure 4]
Table 2: Case details

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Figure 1: Chest X-ray depicting bilateral opacities and cardiomegaly

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Figure 2: Computed tomography chest showing bilateral ground-glass opacities and consolidation

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Figure 3: Periungual excoriation

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Figure 4: Generalized body rash

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  Discussion Top

There are a growing number of media reports and publications from around the world including India that a SARS-CoV-2-related inflammatory syndrome is emerging. Although PIMS-TS or MIS-C has been compared with KD, there are some differences such as an older age at presentation in former (mean age: 7 vs. 3 years in KD) with high incidence of shock and myocardial involvement, similar to that seen in our series.[12] Our patient's age profile matched PIMS-TS profile reported so far. Initial clusters were reported from the UK and Europe. However, it is increasingly reported with fever, features of hyperinflammation, and multi-organ dysfunction with laboratory evidence of COVID-19 positivity or with definite exposure to the virus from positive cases. Our cases had similar features of multi-organ involvement including all three of them depicting involvement of heart either with echo evidence as in all three, and biochemical evidence in two (markedly raised NT Pron BNP).[13] [Table 2] depicts clinical features, investigations, and treatment summary of our patients. PIMS-TS generally has higher inflammatory markers, elevated NT-proBNP/BNP, and lymphopenia. All our patients in the series had raised inflammatory markers. In accordance with the RCPCH, WHO, and CDC guidelines, common bacterial sepsis and EBV infections were excluded. In all our patients, all cultures and common tropical infection mimics such as enteric fever, scrub typhus, and dengue were excluded. Most of the published literature had either reverse transcriptase–polymerase chain reaction positivity to COVID-19 virus or IgG antibody positivity or definite exposure to a positive case. Fortunately, the approach of early recognition, prompt investigation, and appropriate therapy with treatments often used for KD have worked in PIMS-TS as well with high rate of recovery. Nonetheless, the ideal and optimum treatment for PIMS-TS remains uncertain. The majority of patients in literature have been treated with immunomodulatory therapy with IVIG, steroids, and fewer with anakinra, infliximab, or tocilizumab.[14],[15] Patients with cardiac involvement require aggressive therapy with ICU admission and early immunomodulation, as has been observed by Belhadjer et al.[16] We managed all our patients with steroids and IVIG, and all children recovered satisfactorily. A well-randomized controlled trial is required before IVIG or steroid can be recommended in PIMS-TS. The first reported child with possible PIMS-TS from India required steroid pulses in addition to IVIG. However, none of our children required steroid pulses.[5] None of our patients required tocilizumab. With the COVID-19 pandemic still progressing in India, more such cases will be reported in the future; hence, general pediatricians should be aware of this entity and should refer them to higher centers with PICU facilities for optimum management. Mortality is rare with early treatment, and in a recently published study by Feldstein et al. from the USA, out of 186 patients, only 24 died.[17] Further research is needed to understand immunobiology, spectrum, best therapy, and follow-up of such patients, particularly those involving the heart, and for this, multiple registries have been started by the WHO, RCPCH, and others.


The authors acknowledge cardiologists and staff nurses in PICU for optimum management of case.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Available from: https://coronavirus.jhu.edu/map.html 20. [Last accessed on 2020 Jul 26].  Back to cited text no. 1
Royal College of Paediatrics and Child Health, editor. Guidance: Paediatric Multisystem Inflammatory Syndrome Temporally Associated with COVID-19. UK: Royal College of Paediatrics and Child Health; 2020.  Back to cited text no. 2
Jones VG, Mills M, Suarez D, Hogan CA, Yeh D, Segal JB, et al. COVID-19 and Kawasaki Disease: Novel Virus and Novel Case. Hosp Pediatr 2020;10:537-40.  Back to cited text no. 3
Santé Publique France. COVID-19 chez l'enfant: état des connaissances en amont de la réouverture des écoles. Paris: Santé publique France; 2020. Available from: https://www.santepubliquefrance.fr/les-actualites/2020/covid-19-chez-l-enfant-etat-des-connaissances-enamont-de-la-reouverture-des-ecoles. [Last accessed on 2020 May 10].  Back to cited text no. 4
Rauf A, Vijayan A, John ST, Krishnan R, Latheef A. Multisystem Inflammatory Syndrome with Features of Atypical Kawasaki Disease during COVID-19 Pandemic. Indian J Pediatr 2020;87:745-7.  Back to cited text no. 5
Gronvall G, Connell N, Kobokovich A, West R, Warmbrod KL, Shearer MP, et al. Developing a National Strategy for Serology (Antibody Testing) in the United States. Baltimore: 2020.  Back to cited text no. 6
Eubank S, Eckstrand I, Lewis B, Venkatramanan S, Marathe M, Barrett CL. Commentary on Ferguson, et al. “impact of non-pharmaceutical interventions (NPIs) to Reduce COVID-19 mortality and healthcare demand”. Bull Math Biol 2020;82:52.  Back to cited text no. 7
Morand A, Urbina D, Fabre A. COVID-19 and Kawasaki Like Disease: The Known-Known, the Unknown-Known and the Unknown-Unknown. Preprints; 2020.  Back to cited text no. 8
World Health Organization. Multisystem inflammatory syndrome in children and adolescents with COVID-19. World Health Organization; 2020. Available from: https://www.who.int/publications-detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19. [Last accessed on 2020 Jul 20].  Back to cited text no. 9
Centers for Disease Control and Prevention. Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019 (COVID-19); 2020. Available from: https://emergency.cdc.gov/han/2020/han00432.asp. 20. [Last accessed on 2020 Jul 20].  Back to cited text no. 10
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. 11
Verdoni L, Mazza A, Gervasoni A, Martelli L, Ruggeri M, Ciuffreda M, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: An observational cohort study. Lancet 2020;395:1771-8.  Back to cited text no. 12
Guidance- COVID-19 paediatric multisystem inflammatory syndrome. Royal College of Paediatrics and Child Health. Available from: https://www.rcpch.ac.uk/resources/guidance-paediatricmultisystem-inflammatory-syndrome-temporally-associatedcovid-19. 20. [Last accessed on 2020 Jul 20].  Back to cited text no. 13
Cheung EW, Zachariah P, Gorelik M, Boneparth A, Kernie SG, Orange JS, et al. Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City [published online ahead of print, 2020 Jun 8]. JAMA. 2020;e2010374. doi:10.1001/jama.2020.10374.  Back to cited text no. 14
Whittaker E, Bamford A, Kenny J, Kaforou M, Jones CE, Shah P, et al. Clinical Characteristics of 58 Children with a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2. JAMA. 2020;324:259–69. doi:10.1001/jama.2020.10369.  Back to cited text no. 15
Belhadjer Z, Méot M, Bajolle F, Khraiche D, Legendre A, Abakka S, et al. Acute Heart Failure in Multisystem Inflammatory Syndrome in Children in the Context of Global SARS-CoV-2 Pandemic. Circulation. 2020;142:429-36.  Back to cited text no. 16
Feldstein LR, Rose EB, Horwitz SM, Collins JP, Newhams MM, Son MBF, et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med 2020;383:334-46.  Back to cited text no. 17


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2]

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