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Table of Contents
Year : 2020  |  Volume : 17  |  Issue : 3  |  Page : 166-169

Pediatric inflammatory multisystem syndrome-temporally associated with SARS-CoV-2

1 Department of Pediatric Critical Care, Indraprastha Apollo Hospitals, New Delhi, India
2 Department of Pediatric Critical Care and Pulmonology, Indraprastha Apollo Hospitals, New Delhi, India

Date of Submission30-Jun-2020
Date of Acceptance30-Jul-2020
Date of Web Publication07-Aug-2020

Correspondence Address:
Nameet Jerath
Pediatric OPD, Room No. 1238, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi - 110 076
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/am.am_73_20

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Covid-19 is generally a mild disease in children. Coinciding with the peak of the pandemic many children have been reported with a severe disease syndrome comprising fevers, shock with hyper-inflammation, and multiorgan dysfunction, now named pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2-(CoV-2). Although initially thought to be a spurt in cases of Kawasaki Disease (KD) the clinical manifestations differ from KD in being more common in older children with more severe derangements of inflammatory markers and cardiac dysfunction. Gastrointestinal symptoms are prominent. This is likely a postinfection hyper-inflammatory response as almost 90% test positive for antibodies against CoV-2 with significantly raised inflammatory markers and cytokine levels. Most children require cardiovascular and respiratory support and vasoactive therapy in intensive care units. Extracorporeal support is occasionally needed. Intravenous immunoglobulin, aspirin, and steroids are the cornerstones of therapy, though some refractory cases require immune-modulating agents. With adequate treatment, most have shown a favorable outcome.

Keywords: Children, Covid, multisystem inflammatory syndrome in children, pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2

How to cite this article:
Oberoi T, Jerath N. Pediatric inflammatory multisystem syndrome-temporally associated with SARS-CoV-2. Apollo Med 2020;17:166-9

How to cite this URL:
Oberoi T, Jerath N. Pediatric inflammatory multisystem syndrome-temporally associated with SARS-CoV-2. Apollo Med [serial online] 2020 [cited 2021 Jan 21];17:166-9. Available from: https://www.apollomedicine.org/text.asp?2020/17/3/166/291736

  Introduction Top

Children in the severe acute respiratory syndrome coronavirus 2 pandemic (SARS-CoV-2, Covid-19) have been less affected for reasons still not entirely clear, accounting for about 1%–5% of all cases. Most have mild disease with severe disease in about 5% and critical illness in <1%.[1]

During the peak of this pandemic, a cluster of children have been reported features resembling Kawasaki Disease (KD) of fevers, raised markers of inflammation and cardiac dysfunction. Soon, it became clear that this set of severe symptoms with fevers, severe inflammation and associated multiorgan dysfunction is a related but separate entity with many features distinct from KD. This surge in cases has been reported with a lag of a few weeks following the peak. There is a temporal and consistent relationship in the rise of these cases with the rise in Covid-19 cases in the community.[2],[3],[4] Most of these children test negative for SARS-CoV-2 by reverse transcription-polymerase chain reaction (RT-PCR) while many show a positive anti-CoV-2 antibody response speculating this syndrome to be a postinfective inflammatory response. These children present with high-grade fevers, multiorgan dysfunction often with shock requiring intensive care management and with features overlapping KD, KD shock syndrome, toxic shock syndrome and macrophage activation syndrome.[5]

  Case Definition Top

This syndrome has been given many names such as pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and multisystem inflammatory syndrome in children (MIS-C). PIMS-TS/MIS-C case definition criteria have been defined by the WHO, RCPCH, and CDC with minor differences amongst each other.[5]

In general, PIMS-TS is defined in children or adolescents of age 0–21 years presenting with:

  1. Fever >72 h

  2. and

  3. Laboratory evidence of inflammation (raised erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], Procalcitonin, Ferritin, D-dimer, interleukin [IL]-6)

  4. and

  5. Evidence of multiorgan dysfunction involving two or more organ systems:

    1. Hypotension and shock
    2. Cardiac: clinical, echocardiographic, and laboratory evidence of myocardial injury, pericarditis, valvulitis, or coronary abnormalities.
    3. Gastrointestinal: diarrhea, vomiting, and abdominal pain
    4. Coagulopathy: deranged international normalized ratio, activated partial thromboplastin time, d-Dimers
    5. Mucocutaneous manifestations such as rash and nonpurulent conjunctivitis
    6. Neurological manifestations such as headaches, irritability and aseptic meningitis.


  6. No alternative plausible diagnosis; exclude staphylococcal, streptococcal shock syndromes, or any other microbial cause.

  7. With or without

  8. Evidence of Covid-19 (directly by RT-PCR, antigen test, or by serology positivity) or history of close contact with Covid-19 patient.

  Epidemiology Top

PIMS-TS/MIS-C has been reported in clusters with the peak of Covid-19 and just after from many centers around the world. The temporal association with the rise in Covid-19 cases seen consistently prompted search for a causal association. In most centers, PIMS-TS has been described predominantly in children of black, Asian and minority ethnic descent, 70%–80% in two case series.[2],[4] Surprisingly, most of the Asian countries that were first affected by the pandemic have not reported such cases.[6] These countries have a higher incidence of KD in general.

There is an increasing number of reports of PIMS-TS coming in from across India.

  Clinical Features Top

PIMS-TS/MIS-C has features overlapping KD with fevers and raised inflammatory markers being the most consistent features. Other features are of the various organ systems involved. Markers of inflammation are severely deranged suggesting that a hyperinflammatory response or cytokine storm.

Fever has been the most consistent feature, seen in almost all the patients. The syndrome should be suspected in unrelenting fevers lasting more than 72 h.

Gastrointestinal symptoms of vomiting, diarrhea, and pain abdomen have been reported in 50%–80% of the patients. These symptoms are not commonly ascribed to KD. Some patients have presented as acute abdomen even ending up having emergency surgeries which did not reveal any surgical cause.[4],[7]

Significant cardiovascular involvement is another significant feature. It has been described in 3/4th of the patients with varying degrees of cardiac dysfunction. Valvular regurgitation, reduced ejection fraction (EF) and cardiac function, arrhythmias, heart block and shock requiring vasoactive support have all been reported. Coronary involvement, including aneurysmal dilation, has also been seen. The cardiac enzymes-Troponins, pro-BNP, and CPK-MB are elevated as markers of myocardial inflammation.[8],[9]

Mucocutaneous involvement is often seen, including erythema, maculopapular rashes, toxic erythroderma, desquamation and nonpurulent conjunctivitis. Most of these features are characteristic of KD. Diffuse myositis has also been described.

Predominant respiratory symptoms are surprisingly not that common in this respiratory virus disease. Many patients did require ventilator support as a part of the management of shock. Neurologic symptoms of headaches, confusion and irritability have also been seen.

Three patterns of clinical features have been described:[7]

  1. Fevers with raised inflammatory markers and no features of multiorgan failure or shock
  2. Inflammation with shock
  3. Consistent with KD with fevers, inflammation, and cardiac/coronary involvement.

  Investigations Top

The various laboratory investigations are targeted towards the identification of a hyperinflammatory response and ruling out other alternative diagnoses.

Blood tests

  • Blood counts: lymphopenia
  • Raised inflammatory markers – CRP, ESR, ferritin, lactate dehydrogenase, IL-6 and procalcitonin
  • Cardiac markers – Troponin I, CPK and Pro-BNP
  • Cultures – blood, urine, body fluids and swabs to rule out any other probable diagnosis.


Chest X-ray: can show pleural effusion/consolidation/cardiomegaly.

Cardiac investigations

Twelve lead electrocardiogram to assess heart blocks, rhythm disorders.

Two-dimensional echo to assess:

  • Coronary arteries: for prominence, dilatation and aneurysms
  • Ventricular functions: by measuring fractional shortening, EF, MAPSE and TAPSE
  • Atrioventricular valve regurgitation.

Tests for Covid

RT-PCR for CoV-2 using a nasopharyngeal and oropharyngeal swab and antibodies against SARS-CoV-2. These tests may or may not be positive. The RT-PCR has been found to be positive in 25%–40% of the cases while the IgG antibody against CoV-2 is positive in 90% of the cases.[2],[7] This has prompted the explanation that the syndrome is possibly a postinfectious phenomenon. This together with the temporal relationship with the pandemic suggests a causal relationship.

  Kawasaki Disease and Pediatric Inflammatory Multisystem Syndrome Temporally Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Top

PIMS-TS has features which are similar to those in KD such as fevers, multiorgan inflammation, rash, lymphadenopathy and cardiac involvement. In fact, this increase in KD cases was thought to be triggered by CoV-2 viral infection. In spite of the similarities, there are some significant differences. KD is a disease of younger children, usually <5 years of age. The patients of PIMS-TS were older in age, the average age being 10 years.[8] Coronary involvement is the characteristics of KD. Most children with PIMS-TS have ventricular dysfunction and only a small percentage showed coronary abnormalities. In many series these coronary abnormalities have resolved much earlier as compared to classic KD. These patients also have higher white cell counts, neutrophil counts and CRP and lower hemoglobin and platelet counts compared to KD.[3],[7] Moreover, this syndrome has not been reported in Asian countries which normally have a higher reported incidence of KD.

In the previous SARS-CoV-1 epidemic, it was noted that antibodies accentuate disease either by facilitating viral entry or replication which is also seen in dengue or by triggering a host inflammatory response. The triggered host response could be through the formation of immune complexes or direct cellular activation. It is possible that PIMS-TS arises from an unusual acquired immune response to SARS-CoV-2 either antibody or cell-mediated or both.[7]

KD, KDSS, systemic-onset juvenile idiopathic arthritis, TSS and HLH are all characterized by massive inflammatory surge leading to a state of cytokine storm and multiorgan dysfunction. PIMS-TS too is a disease of cytokine storm with a similar surge in cytokines observed such as IL-1 β, IL-6, IL-18 and interferon-γ. Evidence has shown that tissue damage in Covid-19 is mediated by the host innate immunity.[10] All these are on the spectrum of IL-1 β hyperinflammatory diseases and PIMS-TS may very well be on the same spectrum.

  Treatment Top

The treatment is targeted at dousing the inflammation and supportive care for the organ systems involved. These patients are best managed in an intensive care unit with close monitoring. Some patients with milder symptoms and no evidence of shock could be managed in the rooms.

Most of these patients require antibiotics while infectious etiologies are ruled out.

With the presentation resembling KD most treatment regimes have initiated intravenous immunoglobulins (IVIg, 2 g/kg) and aspirin (30–50 mg/kg/day) with or without steroids. IVIg was given in 75%–100% of the patients in various case series with concomitant steroids in 30%–60% in children at higher risk.[2],[3],[7],[9] Steroids, in low and high pulse doses, repeat doses of IVIg, and immune-modulating agents such as anakinra (IL-1 receptor antagonist), infliximab (monoclonal anti-TNF-α antibody), and tocilizumab (IL-6 receptor antagonist) have been tried in resistant or nonresponding cases. 15%–25% of the children required the second dose of IVIg.[2],[9] Three patients (out of 58) were given anakinra and infliximab was given to eight patients in a series.[7]

Most children with PIMS-TS also have cardiac involvement with or without shock and require appropriate hemodynamic and respiratory support. Extracorporeal life support might be needed in resistant states of shock. In a series 80% of children had cardiogenic shock requiring vasoactive medications, 66% needed mechanical ventilation and 28% required VA-ECMO support. All patients, including the ones requiring extracorporeal support survived.[8]

  Summary Top

PIMS-TS is a hyperinflammatory syndrome associated with SARS-CoV-2 in children and adolescents with fevers, shock and multiorgan dysfunction. IVIg with or without steroids and aspirin is the first line of management. Refractory cases may need repeat doses of IVIg, steroids or immune-modulating drugs. With appropriate care, most have a favorable outcome.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Ludvigsson JF. Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr 2020;109:1088-95.  Back to cited text no. 1
Toubiana J, Poirault C, Corsia A, Bajolle F, Fourgeaud J, Angoulvant F, et al. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: Prospective observational study. BMJ 2020;369:m2094.  Back to cited text no. 2
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. 3
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. 4
Guidance, Paediatric Multisystem Inflammatory Syndrome Temporally Associated with COVID-19 (PIMS). RCPCH; 2020. Available from: https://www.rcpch.ac.uk/resources/guidance-paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19-pims. [Last accessed on 2020 Jun 29].  Back to cited text no. 5
Lu X, Zhang L, Du H, Zhang J, Li YY, Qu J, et al. SARS-CoV-2 infection in children. N Engl J Med 2020;382:1663-5.  Back to cited text no. 6
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.  Back to cited text no. 7
Belhadjer Zahra, Méot Mathilde, Bajolle Fanny, Khraiche Diala, Legendre Antoine, Abakka Samya, et al. Acute Heart Failure in Multisystem Inflammatory Syndrome in Children (MIS-C) in the Context of Global SARS-CoV-2 Pandemic. Circulation; 2020. Available from: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.048360. [Last accessed on 2020 Jun 28].  Back to cited text no. 8
Ramcharan T, Nolan O, Lai CY, Prabhu N, Krishnamurthy R, Richter AG, et al. Paediatric inflammatory multisystem syndrome: Temporally associated with SARS-CoV-2 (PIMS-TS): Cardiac features, management and short-term outcomes at a UK tertiary paediatric hospital. Pediatr Cardiol 2020. Ahead of print.  Back to cited text no. 9
Henderson LA, Canna SW, Schulert GS, Volpi S, Lee PY, Kernan KF, et al. On the alert for cytokine storm: Immunopathology in COVID-19. Arthritis Rheumatol 2020;72:1059-63.  Back to cited text no. 10


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