Clinical features of multisystem inflammatory syndrome in children.

PURPOSE OF REVIEW: To review diagnosis, clinical characteristics and treatment of multisystem inflammatory syndrome in children (MIS-C) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RECENT FINDINGS: MIS-C emerged in spring 2020 as a hyperinflammatory syndrome following SARS-CoV-2 exposure in children. Despite growing awareness of MIS-C, diagnosis remains challenging due to the range of phenotypes and severity. Fever accompanied by shock, cardiac dysfunction, gastrointestinal symptoms, or mucocutaneous signs suggestive of Kawasaki disease, especially in the presence of known or suspected coronavirus disease 2019 exposure, should trigger consideration of MIS-C. However, clinical presentations are highly varied and may overlap with other infectious diseases. Clinicians must maintain a high index of suspicion for MIS-C and be aware that patients may develop coronary artery aneurysms and myocarditis even with few or no Kawasaki disease symptoms. More precise diagnostic criteria and specific biomarkers are needed to aid diagnosis. Intravenous immunoglobulin (IVIG) is first-line therapy, and steroids should be considered as initial adjunctive treatment for patients with severe manifestations or other risk factors. Prompt treatment is essential, as patients may worsen acutely, though overall prognosis is reassuring. SUMMARY: MIS-C associated with SARS-CoV-2 has varied clinical manifestations. Clinicians must be aware of the common presentation and potential for decompensation and cardiac sequalae to guide appropriate evaluation and treatment.

The Notch1/CD22 signaling axis disrupts Treg cell function in SARS-CoV2-associated multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C are destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variants impacting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Treg cells induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results establish a Notch1-CD22 signaling axis that disrupts Treg cell function in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.

SARS-CoV-2-specific T cell responses in patients with multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infections that occurs in the pediatric population. We sought to characterize T cell responses in MIS-C compared to COVID-19 and pediatric hyperinflammatory syndromes. MIS-C was distinct from COVID-19 and hyperinflammatory syndromes due to an expansion of T cells expressing TRBV11-2 that was not associated with HLA genotype. Children diagnosed with MIS-C, but who were negative for SARS-CoV-2 by PCR and serology, did not display Vß skewing. There was no difference in the proportion of T cells that became activated after stimulation with SARS-CoV-2 peptides in children with MIS-C compared to convalescent COVID-19. The frequency of SARS-CoV-2-specific TCRs and the antigens recognized by these TCRs were comparable in MIS-C and COVID-19. Expansion of Vß11-2⁺ T cells was a specific biomarker of MIS-C patients with laboratory confirmed SARS-CoV-2 infections. Children with MIS-C had robust antigen-specific T cell responses to SARS-CoV-2.

FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation.

SARS-CoV-2 can cause acute respiratory distress and death in some patients1. Although severe COVID-19 is linked to substantial inflammation, how SARS-CoV-2 triggers inflammation is not clear2. Monocytes and macrophages are sentinel cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D, leading to inflammatory death (pyroptosis) and the release of potent inflammatory mediators3. Here we show that about 6% of blood monocytes of patients with COVID-19 are infected with SARS-CoV-2. Monocyte infection depends on the uptake of antibody-opsonized virus by Fcγ receptors. The plasma of vaccine recipients does not promote antibody-dependent monocyte infection. SARS-CoV-2 begins to replicate in monocytes, but infection is aborted, and infectious virus is not detected in the supernatants of cultures of infected monocytes. Instead, infected cells undergo pyroptosis mediated by activation of NLRP3 and AIM2 inflammasomes, caspase-1 and gasdermin D. Moreover, tissue-resident macrophages, but not infected epithelial and endothelial cells, from lung autopsies from patients with COVID-19 have activated inflammasomes. Taken together, these findings suggest that antibody-mediated SARS-CoV-2 uptake by monocytes and macrophages triggers inflammatory cell death that aborts the production of infectious virus but causes systemic inflammation that contributes to COVID-19 pathogenesis.

American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 3.

OBJECTIVE: To provide guidance on the management of Multisystem Inflammatory Syndrome in Children (MIS-C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of SARS-CoV-2 infection. Recommendations are also provided for children with hyperinflammation during COVID-19, the acute, infectious phase of SARS-CoV-2 infection. METHODS: The Task Force is composed of 9 pediatric rheumatologists and 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS-C and hyperinflammation in COVID-19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved anonymous voting and webinar discussion. A 9-point scale was used to determine the appropriateness of each statement (median scores of 1-3 for inappropriate, 4-6 for uncertain, and 7-9 for appropriate). Consensus was rated as low, moderate, or high based on dispersion of the votes. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, which were prespecified before voting. RESULTS: The guidance was approved in June 2020 and updated in November 2020 and October 2021, and consists of 41 final guidance statements accompanied by flow diagrams depicting the diagnostic pathway for MIS-C and recommendations for initial immunomodulatory treatment of MIS-C. CONCLUSION: Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. This guidance document reflects currently available evidence coupled with expert opinion, and will be revised as further evidence becomes available.

Coagulation profiles and viscoelastic testing in multisystem inflammatory syndrome in children.

OBJECTIVE: To characterize viscoelastic testing profiles of children with multisystem inflammatory syndrome in children (MIS-C). METHODS: This single-center retrospective review included 30 patients diagnosed with MIS-C from March 1 to September 1, 2020. Thromboelastography (TEG) with platelet mapping was performed in 19 (63%) patients and compared to age- and sex-matched controls prior to cardiac surgery. Relationships between TEG parameters and inflammatory markers were assessed using correlation. RESULTS: Patients with MIS-C had abnormal TEG results compared to controls, including decreased kinetic (K) time (1.1 vs. 1.7 minutes, p < .01), increased alpha angle (75.0° vs. 65.7°, p < .01), increased maximum amplitude (70.8 vs. 58.3 mm, p < .01), and decreased lysis in 30 minutes (Ly30) (1.1% vs. 3.7%, p = .03); consistent with increased clot formation rate and strength, and reduced fibrinolysis. TEG maximum amplitude was moderately correlated with erythrocyte sedimentation rate (ESR) (r = 0.60, p = .02), initial platelet count (r = 0.67, p < .01), and peak platelet count (r = 0.51, p = .03). TEG alpha angle was moderately correlated with peak platelet count (r = 0.54, p = .02). Seventeen (57%) patients received aspirin (ASA) and anticoagulation, five (17%) received only ASA, and three (10%) received only anticoagulation. No patients had a symptomatic thrombotic event. Six (20%) patients had a bleeding event, none of which was major. CONCLUSIONS: Patients with MIS-C had evidence of hypercoagulability on TEG. Increased ESR and platelets were associated with higher clot strength. Patients were prophylactically treated with ASA or anticoagulation with no symptomatic thrombosis or major bleeding. Further multicenter study is required to characterize the rate of thrombosis and optimal thromboprophylaxis algorithm in this patient population.

Socioeconomic and Racial and/or Ethnic Disparities in Multisystem Inflammatory Syndrome.

OBJECTIVES: To characterize the socioeconomic and racial and/or ethnic disparities impacting the diagnosis and outcomes of multisystem inflammatory syndrome in children (MIS-C). METHODS: This multicenter retrospective case-control study was conducted at 3 academic centers from January 1 to September 1, 2020. Children with MIS-C were compared with 5 control groups: children with coronavirus disease 2019, children evaluated for MIS-C who did not meet case patient criteria, children hospitalized with febrile illness, children with Kawasaki disease, and children in Massachusetts based on US census data. Neighborhood socioeconomic status (SES) and social vulnerability index (SVI) were measured via a census-based scoring system. Multivariable logistic regression was used to examine associations between SES, SVI, race and ethnicity, and MIS-C diagnosis and clinical severity as outcomes. RESULTS: Among 43 patients with MIS-C, 19 (44%) were Hispanic, 11 (26%) were Black, and 12 (28%) were white; 22 (51%) were in the lowest quartile SES, and 23 (53%) were in the highest quartile SVI. SES and SVI were similar between patients with MIS-C and coronavirus disease 2019. In multivariable analysis, lowest SES quartile (odds ratio 2.2 [95% confidence interval 1.1-4.4]), highest SVI quartile (odds ratio 2.8 [95% confidence interval 1.5-5.1]), and racial and/or ethnic minority background were associated with MIS-C diagnosis. Neither SES, SVI, race, nor ethnicity were associated with disease severity. CONCLUSIONS: Lower SES or higher SVI, Hispanic ethnicity, and Black race independently increased risk for MIS-C. Additional studies are required to target interventions to improve health equity for children.

American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 2.

OBJECTIVE: To provide guidance on the management of Multisystem Inflammatory Syndrome in Children (MIS-C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Recommendations are also provided for children with hyperinflammation during coronavirus disease 2019 (COVID-19), the acute, infectious phase of SARS-CoV-2 infection. METHODS: The Task Force was composed of 9 pediatric rheumatologists and 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS-C and hyperinflammation in COVID-19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved anonymous voting and webinar discussion. A 9-point scale was used to determine the appropriateness of each statement (median scores of 1-3 for inappropriate, 4-6 for uncertain, and 7-9 for appropriate). Consensus was rated as low, moderate, or high based on dispersion of the votes. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, which were prespecified before voting. RESULTS: The first version of the guidance was approved in June 2020, and consisted of 40 final guidance statements accompanied by a flow diagram depicting the diagnostic pathway for MIS-C. The document was revised in November 2020, and a new flow diagram with recommendations for initial immunomodulatory treatment of MIS-C was added. CONCLUSION: Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. This guidance document reflects currently available evidence coupled with expert opinion, and will be revised as further evidence becomes available.

American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 1.

OBJECTIVE: To provide guidance on the management of multisystem inflammatory syndrome in children (MIS-C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and to provide recommendations for children with hyperinflammation during coronavirus disease 2019 (COVID-19), the acute, infectious phase of SARS-CoV-2 infection. METHODS: A multidisciplinary task force was convened by the American College of Rheumatology (ACR) to provide guidance on the management of MIS-C associated with SARS-CoV-2 and hyperinflammation in COVID-19. The task force was composed of 9 pediatric rheumatologists, 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS-C and hyperinflammation in COVID-19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved 2 rounds of anonymous voting and 2 webinars. A 9-point scale was used to determine the appropriateness of each statement (median scores of 1-3 for inappropriate, 4-6 for uncertain, and 7-9 for appropriate), and consensus was rated as low, moderate, or high based on dispersion of the votes along the numeric scale. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, as prespecified prior to voting. RESULTS: The ACR task force approved a total of 128 guidance statements addressing the management of MIS-C and hyperinflammation in pediatric COVID-19. These statements were refined into 40 final clinical guidance statements, accompanied by a flow diagram depicting the diagnostic pathway for MIS-C. CONCLUSION: Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. The guidance provided in this "living document" reflects currently available evidence, coupled with expert opinion, and will be revised as further evidence becomes available.

Distinct clinical and immunological features of SARS-CoV-2-induced multisystem inflammatory syndrome in children.

BACKGROUNDPediatric SARS-CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail.METHODSWe retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies, and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS).RESULTSTwenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range: 1 month to 17 years); 50% of patients had preexisting conditions. All patients had laboratory confirmation of SARS-CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) who required inotrope support. Seven patients (25%) met criteria for complete or incomplete KD, and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6, and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to patients with MIS-C included intravenous immune globulin (IVIG) (71%), corticosteroids (61%), and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort.CONCLUSIONMIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from KD and MAS.FUNDINGThis work was supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; Rheumatology Research Foundation Investigator Awards and Medical Education Award; Boston Children's Hospital Faculty Career Development Awards; the McCance Family Foundation; and the Samara Jan Turkel Center.

On the Alert for Cytokine Storm: Immunopathology in COVID-19.

Poor outcomes in COVID-19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID-19.