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 Table of Contents  
Year : 2021  |  Volume : 16  |  Issue : 1  |  Page : 73-78

Hyperinflammatory syndrome in children related to Covid-19

Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Submission16-Jun-2020
Date of Acceptance29-Jun-2020
Date of Web Publication23-Mar-2021

Correspondence Address:
Dr. Latika Gupta
Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_151_20

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The coronavirus disease 2019 (Covid-19) has been implicated in a Cytokine Release Syndrome (CRS) in adults. Initial reports of Covid-19 suggested a milder disease course and better prognosis in children. However, a new inflammatory syndrome, reminiscent of Kawasaki Disease (KD) is associated with covid-19 in a proportion of children. This has been variously referred to as Kawasaki-like disease, multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome, temporally associated with SARS-CoV2 (PIMS-TS). Similar to KD, these patients have frequent cardiac involvement and are responsive to steroids and intravenous immunoglobulins (IVIG). But there are important distinctions in that, they are older, often have gastrointestinal manifestations, and more profound lymphopenia, and acute phase response. In this review, we underline the important takeaways from various published case series, and describe clinical characteristics, speculated pathogenetic mechanisms, implications for treatment and future directions for this novel syndrome.

Keywords: Coronavirus disease 2019, hyperinflammatory syndrome, Kawasaki-like disease, pediatric multisystem inflammatory syndrome

How to cite this article:
Sundaram T G, Gupta L. Hyperinflammatory syndrome in children related to Covid-19. Indian J Rheumatol 2021;16:73-8

How to cite this URL:
Sundaram T G, Gupta L. Hyperinflammatory syndrome in children related to Covid-19. Indian J Rheumatol [serial online] 2021 [cited 2021 Dec 2];16:73-8. Available from:

  Introduction Top

The coronavirus disease 2019 (COVID-19) has been implicated in a cytokine release syndrome (CRS) in adults.[1] CRSs are associated with various infections, malignancies, auto-immune, and auto-inflammatory diseases. Three months into the pandemic, numerous reports, and a systematic review have shown that children with COVID-19 have a milder disease course and better prognosis compared to adults, with deaths being extremely rare.[2] However, recent descriptions of a new inflammatory syndrome reminiscent of Kawasaki Disease (KD) in a proportion of children with COVID-19, has led to heightened concerns among pediatricians, intensivists, and rheumatologists. Many of these are manifest in adolescents and older children, who are likely to receive transitional care from adult rheumatologists. This hyperinflammatory state has been referred to as Kawasaki-like disease,[3] multisystem inflammatory syndrome in children (MIS-C)[4] or pediatric inflammatory multisystem syndrome, temporally associated with SARS-CoV2 (PIMS-TS).[5]

  Initial Reports Top

On April 7, 2020, a month after the World Health Organization (WHO) had declared COVID-19 as a pandemic, pediatricians from Palo Alto, California, reported the first case of PIMS-TS.[4] This was followed by an official statement of 85 similar cases from New York.[5] Since then, case series have been published from Italy,[3] France,[6] and the UK,[7],[8] apart from media reports from Canada[9] and Switzerland,[10] among others. Notably, the surge in cases was reported a fortnight after the peak of the epidemic in each of these countries. With a delayed peaking of cases in India, Africa, and South America, epidemiologic estimates suggest that rheumatologists may expect a surge in cases.

To identify suspected PIMS-TS, the WHO [Table 1] has published a case definition for its diagnosis,[11] and similar ones have been proposed by the Royal College of Pediatrics[12] and Child Health and the Centers for Disease Control and Prevention (CDC)[13] [Supplementary Table 1]. The CDC definition includes all cases below 21 years, while the former two are limited to those below 19 years of age.
Table 1: World Health Organization case definition for pediatric inflammatory multisystem syndrome, temporally associated with SARS-CoV2

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  Clinical Profile Top

The largest case series yet, described 58 children from the UK,[5] with a mean age of 9 years (5.7–14). All children presented with fever and nonspecific symptoms, including vomiting (26/58 [45%]), abdominal pain (31/58 [53%]), and diarrhea (30/58 [52%]). Three provisional clinical patterns were observed in this study and are described in [Figure 1]. Nearly three-quarters (78%, 45) of them had evidence of the current of prior SARS-CoV-2 infection; most of them were positive on serology.
Figure 1: Clinical phenotypes of PIMS-TS; Drawn roughly to scale; KDKawasaki Disease

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Compared to the conventional KD, patients of PIMS-TS have an increased prevalence of gastrointestinal (GI) symptoms such as diarrhea, nausea, and vomiting.[5],[14] This fact has been recognized in the WHO case definition too, with GI manifestations being included as a clinical criterion. The French study by Belhadjer et al.[4] described 35 patients with acute heart failure associated with MIS-C; 80% of whom had cardiogenic shock. In this study too, GI symptoms were prominent with 80% children experiencing them. Curiously, none of these patients fulfilled the American Heart Association criteria for KD[15] and all patients survived with intravenous immunoglobulins (IVIG), adjunctive steroids, and extra-corporeal membrane oxygenation (ECMO).

The Italian study that compared KD pre and post the outbreak, reported that those affected by Kawasaki-like disease associated with COVID-19, had a higher mean age (7.5 vs. 3.0 years) and were more prone to have cardiac involvement[4] (in the form of coronary aneurysm, myocarditis, pericarditis, and valvulitis), KD Shock Syndrome, macrophage activation syndrome and increased need for adjunctive treatment with steroids, in addition to IVIG.[3]

Compared to those with other inflammatory diseases such as KD and toxic shock syndrome, children with PIMS-TS tend to have higher white blood cell count, neutrophil count, C-reactive protein (CRP), fibrinogen and troponin levels, as well as more profound lymphopenia, anemia, and lower platelet counts.[5]

Most of these patients respond to IVIG and adjunctive steroids. In resistant cases of circulatory failure, ECMO has been effective.[4] In patients with refractory systemic inflammation, tocilizumab, anakinra, and infliximab have been useful in a selected patients in various case series.[4],[5],[16],[17] A summary of published case series on this syndrome is provided in [Table 2].
Table 2: Published case series on pediatric inflammatory multisystem syndrome, temporally associated with SARS-CoV2

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  Putative Mechanisms Top

KD is usually preceded by a prodrome of upper respiratory tract or GI infection. Viruses such as Enterovirus, Adenovirus, Rhinovirus, and Coronavirus have been found to be associated with KD.[18] It is likely that SARS-CoV-2 has also triggered a Kawasaki-like disease, with some important differences such as lymphopenia, thrombocytopenia, and relatively higher levels of acute phase reactants.

Antibodies of two kinds are produced against the surface proteins of SARS-CoV-2.[19] Neutralizing antibodies, which are produced against Angiotensin Converting Enzyme-2 (ACE-2) receptor binding regions-receptor binding domain and HR2 region of S protein, are protective. Nonneutralizing antibodies, which are produced against the nucleocapsid and other epitopes on the S-protein, could potentially be harmful. Nonneutralizing antibodies against viral proteins such as the spike protein, mediate antibody-dependent enhancement (ADE) by binding to the FcR on immune cells, FcγRlla, and potentiating viral entry. This causes endosomal release of virions, which can activate toll-like receptors and cytosolic RNA sensors like RIG-1 like receptors, ultimately triggering release of pro-inflammatory cytokines like Type 1 Interferons.[20] It is likely that these antibodies are of the IgA isotype, as anti-IgA antibodies to the spike protein have been shown to be associated with a poor clinical outcome.[21] This phenomenon is known as ADE [Figure 2].
Figure 2: Proposed mechanism of antibody-dependent enhancement in the pathogenesis of coronavirus disease 2019 associated inflammation

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Apart from neutralization and blocked binding to the ACE receptor, antibody-mediated effector responses can be mediated by Fc engagement with cytotoxic cells (Antibody-dependent cellular cytotoxicity), phagocytes (Antibody-dependent cellular phagocytosis), or complements (Complement dependent cytotoxicity). Although the evidence base for these pathways is demonstrated for Coronaviruses, the exact role in PIMS-TS is only speculated. Other putative mechanisms include super-antigen like function, activation of endogenous retroviruses, and direct infection of the immune cells. However, the temporality of antibody production and the absence of active viral shedding from phagocytes makes the latter less plausible. A summary of the various possible mechanisms involved in the pathogenesis of PIMS-TS is summarized in [Table 3].[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33]
Table 3: Putative mechanisms in the pathogenesis of pediatric inflammatory multisystem syndrome, temporally associated with SARS-CoV2

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  Implications for Treatment Top

Hyperinflammation in COVID-19 is mediated by cytokines such as interleukin (IL)-6, Interferon-γ, IL-1 β and IL-18, and is associated with biomarkers of CRS such as raised CRP, ferritin, fibrinogen, procalcitonin, and d-dimers.[1] Multiple trials are underway, which have been designed to target the hyperinflammation in COVID-19, with glucocorticoids (GCs) (ChiCTR2000029386), IL-6 inhibitors (NCT04324073, NCT04315298), IL-1 inhibitors (NCT04324021), and Janus Kinase (JAK) inhibitors (NCT04320277, NCT04321993). These drugs could similarly be tried in PIMS-TS too.

In a recent series,[5] SARS-CoV-2 polymerase chain reaction positivity was present in 26%, while SARS-CoV-2 IgG positivity was seen in 87% children. This raises doubts of whether antibodies against SARS-CoV-2 are harmful. Previously, immunization against feline infectious peritonitis virus (a virulent form of feline coronavirus), has been known to increase disease severity paradoxically.[34] This has implications in vaccine development, as a vaccine that generates humoral immunity against Spike (S) protein can potentially trigger a hyperinflammatory state in the event of an infection, making it more harmful than beneficial.[35]

  Future Directions Top

The key to successful treatment of PIMS-TS lies in understanding the immune origins of this condition. IVIG is beneficial in multiple ways such as providing antivirus, anti-lymphocyte, and anti-cytokine antibodies. They may also help by downregulating B cells through acting on the inhibitory receptor, FcγRllb, development of T regulatory cells, and stimulation of immunosuppressive cytokines like Il-10. However, the effects are short lived, and cost may be a concern. Anti-cytokine monoclonal antibodies have shown some promise in COVID-19-CRS, but have not been described in PIMS-TS yet. Tocilizumab, infliximab, and anakinra are all possible options that could be tried in future trials of PIMS-TS. Besides, anti-complement therapies may potentially hold promise if the role of CDC is demonstrated. It is important to gather follow-up data on this condition, to understand the damage caused, risk for recurrence as well as long-term implications like the risk for autoimmune disease later in life.

  Conclusion Top

Through this brief report, we intend to highlight a novel inflammatory syndrome associated with COVID-19, PIMS-TS, which has many features similar to KD.[36] It is associated with cardiac complications, shock and multi-organ failure, leading to poor patient outcomes. Hence, it is essential to recognize this condition early and treat it promptly with IVIG, GCs and if need be, IL-6/IL-1 β/JAK inhibitors. The exact pathogenesis of this disease is still not clear. There is a need for increased awareness among pediatricians, cardiologists, rheumatologists, and intensivists regarding this disease and collaborative efforts need to be undertaken to better understand its nature for effective management.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3]


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