Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection

Carter, Michael J.; Fish, Matthew; Jennings, A.R.; Doores, Katie J.; Wellman, Paul; Seow, Jeffrey; Acors, Sam; Graham, Carl; Timms, Emma; Kenny, Julia; Neil, Stuart J. D.; Malim, Michael H.; Tibby, Shane M.; Shankar-Hari, Manu

doi:10.1038/s41591-020-1054-6

Cited by 340 publications

(470 citation statements)

References 45 publications

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“…1 B). However, there are now clinical, microbiological and immunological data describing PIMS-TS as a novel immunopathogenic illness [5,9,10]. Similarities between PIMS-TS and KD include ubiquity of fever and high prevalence of oral mucositis, conjunctivitis and rash.…”

Section: What Are the Differential Diagnoses Of Pims-ts?mentioning

confidence: 99%

“…Approximately 45% of children with PIMS-TS have a positive PCR test for SARS-CoV-2 infection. In addition, the high proportion (75%) with class-switched antibody to viral antigens, indicate that most, if not all, cases of PIMS-TS are a result of prior, or uncleared, infection with SARS-CoV-2 [9]. However, with no accurate test for the diagnosis of PIMS-TS, vigilance for alternative diagnoses must be maintained.…”

Section: What Are the Differential Diagnoses Of Pims-ts?mentioning

confidence: 99%

“…1C) [8]. Certainly, children with PIMS-TS have greatly elevated serum concentrations of pro-inflammatory interleukins (IL-1 beta, IL-17, IL-6 and IL-8), accompanied by activation of neutrophils and monocytes [9]. However, we have few data on the role of anti-viral interferons (alpha, beta and lambda) in viral clearance.…”

Section: What Is the Pathobiology Of Pims-ts?mentioning

confidence: 99%

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Paediatric Inflammatory Multisystem Syndrome Temporally-Associated with SARS-CoV-2 Infection: An Overview

2020

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In spring 2020 paediatricians working across Europe and the USA [1] alerted colleagues to clusters of previously healthy children presenting with unremitting fever, multisystem inflammation and pancarditis. This syndrome, initially termed Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 infection (PIMS-TS), or by its US variation Multisystem Inflammatory Syndrome in Children (MIS-C; Table 1), appears to be a rare complication of (largely) asymptomatic SARS-CoV-2 infection in children [8]. However, the overlap with other paediatric inflammatory syndromes such as Kawasaki disease (KD) and optimum treatments remain unknown. We provide a narrative overview of PIMS-TS and highlight important knowledge gaps.

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Section: What Are the Differential Diagnoses Of Pims-ts?mentioning

confidence: 99%

Section: What Are the Differential Diagnoses Of Pims-ts?mentioning

confidence: 99%

Section: What Is the Pathobiology Of Pims-ts?mentioning

confidence: 99%

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Paediatric Inflammatory Multisystem Syndrome Temporally-Associated with SARS-CoV-2 Infection: An Overview

2020

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“…The inflammatory illness in children is consistent with the vascular cell target of SARS-CoV2 (50). SARS2-CoV2 infection in children results in autoimmune and autoinflammatory responses that are termed as pediatric inflammatory multisystem syndrome (PIMS) or multisystem inflammatory syndrome in children (MISC-C) (45,51,52). The immune and inflammatory cells as well as inflammatory cytokine profile has resulted in the phrase "cytokine storm" in the severe disease.…”

Section: Socs1/3 Antagonist and Severe Covid-19mentioning

confidence: 87%

SOCS, Intrinsic Virulence Factors, and Treatment of COVID-19

2020

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The suppressor of cytokine signaling (SOCS) family of intracellular checkpoint inhibitors has received little recognition compared to other checkpoint inhibitors. Two members of this family, SOCS1 and SOCS3, are indispensable, since SOCS1 knockout in mice results in neonatal death due to interferon gamma (IFNg) induced inflammatory disease, and SOCS3 knockout leads to embryonic lethality. We have shown that SOCS1 and SOCS3 (SOCS1/3) function as virus induced intrinsic virulence factors for influenza A virus, EMC virus, herpes simplex virus 1 (HSV-1), and vaccinia virus infections. Other viruses such as pathogenic pig enteric coronavirus and coronavirus induced severe acute respiratory syndrome (SARS) spike protein also induce SOCS virus intrinsic virulence factors. SOCS1/3 exert their viral virulence effect via inhibition of type I and type II interferon (IFN) function. Specifically, the SOCS bind to the activation loop of receptor-associated tyrosine kinases JAK2 and TYK2 through the SOCS kinase inhibitory region (KIR), which inhibits STAT transcription factor activation by the kinases. Activated STATs are required for IFN function. We have developed a small peptide antagonist of SOCS1/3 that blocks SOCS1/3 inhibitory activity and prevents virus pathogenesis. The antagonist, pJAK2 (1001-1013), is comprised of the JAK2 activation loop, phosphorylated at tyrosine 1007 with a palmitate for cell penetration. The remarkable thing about SOCS1/3 is that it serves as a broad, simple tool of perhaps most pathogenic viruses to avoid innate host IFN defense. We suggest in this Perspective that SOCS1/3 antagonist is a simple counter measure to SOCS1/3 and should be an effective mechanism as a prophylactic and/or therapeutic against the COVID-19 pandemic that is caused by coronavirus SARS-CoV2.

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“…Our assessment highlights (at least) 4 areas of thriving translational research: (1) 'delivering and adapting the clinical service'-caring for COVID-19 patients on an infectious diseases ward whilst providing a consult and infection prevention and control service across the hospitals. This gave visibility of core and rapidly changing clinical needs; (2) 'developing laboratory diagnostic capability'-setting up a new COVID-19 diagnostic expansion laboratory embedded within academic research facilities at Guy's Hospital introducing novel accredited pipelines; technologies; PCR or serological tests; and COVID-19 or metagenomic sequencing for clinical service, infection control, and public health asymptomatic screening [5][6][7][8] (we named this new laboratory in recognition of June Almeida who discovered coronaviruses by electron microscopy at St Thomas' Hospital in 1966 [9]); (3) 'conducting fundamental research'-comprehensive immunophenotyping to understand correlates of disease/protection and to inform novel therapies; virus culture to dissect viral replication and support preclinical drug discovery; and viral sequencing to inform transmission networks, immune escape, and persistence [10][11][12]; (4) 'supporting therapeutics and vaccine research'-recruiting patients into nationally coordinated clinical trials of new therapies (e.g., convalescent serum, vaccines, and biologics) and participating in cohort-based and population studies to explore, inter alia, rates of infection, disease severity risk factors, and renewed or persistent COVID-19 infection [13].…”

Section: What Progress Has Been Made In the First 4 Months?mentioning

confidence: 99%