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Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C).

ABSTRACT: Initially, the global outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spared children from severe disease. However, after the initial wave of infections, clusters of a novel hyperinflammatory disease have been reported in regions with ongoing SARS-CoV-2 epidemics. While the characteristic clinical features are becoming clear, the pathophysiology remains unknown. Herein, we report on the immune profiles of eight Multisystem Inflammatory Syndrome in Children (MIS-C) cases. We document that all MIS-C patients had evidence of prior SARS-CoV-2 exposure, mounting an antibody response with normal isotype-switching and neutralization capability. We further profiled the secreted immune response by high-dimensional cytokine assays, which identified elevated signatures of inflammation (IL-18 and IL-6), lymphocytic and myeloid chemotaxis and activation (CCL3, CCL4, and CDCP1) and mucosal immune dysregulation (IL-17A, CCL20, CCL28). Mass cytometry immunophenotyping of peripheral blood revealed reductions of mDC1 and non-classical monocytes, as well as both NK- and T- lymphocytes, suggesting extravasation to affected tissues. Markers of activated myeloid function were also evident, including upregulation of ICAM1 and FcR1 in neutrophil and non-classical monocytes, well-documented markers in autoinflammation and autoimmunity that indicate enhanced antigen presentation and Fc-mediated responses. Finally, to assess the role for autoimmunity secondary to infection, we profiled the auto-antigen reactivity of MIS-C plasma, which revealed both known disease-associated autoantibodies (anti-La) and novel candidates that recognize endothelial, gastrointestinal and immune-cell antigens. All patients were treated with anti- IL6R antibody or IVIG, which led to rapid disease resolution tracking with normalization of inflammatory markers.

SUBMITTER: Gruber C

PROVIDER: S-EPMC7359537 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C).

Gruber Conor C Patel Roosheel R Trachman Rebecca R Lepow Lauren L Amanat Fatima F Krammer Florian F Wilson Karen M KM Onel Kenan K Geanon Daniel D Tuballes Kevin K Patel Manishkumar M Mouskas Konstantinos K Simons Nicole N Barcessat Vanessa V Valle Diane Del DD Udondem Samantha S Kang Gurpawan G Gangadharan Sandeep S Ofori-Amanfo George G Rahman Adeeb A Kim-Schulze Seunghee S Charney Alexander A Gnjatic Sacha S Gelb Bruce D BD Merad Miriam M Bogunovic Dusan D

medRxiv : the preprint server for health sciences 20200706

Initially, the global outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spared children from severe disease. However, after the initial wave of infections, clusters of a novel hyperinflammatory disease have been reported in regions with ongoing SARS-CoV-2 epidemics. While the characteristic clinical features are becoming clear, the pathophysiology remains unknown. Herein, we report on the immune profiles of eight Multisystem Inflammatory Syndrome in Chil ...[more]

PMID: 32676612

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Project description:Background: Most children and adolescents infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop a mild coronavirus disease 2019 (COVID-19) that usually does not require medical intervention. However, a small proportion of pediatric patients develop a severe clinical condition, Multisystem Inflammatory Syndrome in Children (MIS-C). The involvement of epigenetics in the control of the immune response and viral activity prompted us to carry out an epigenomic study to uncover target loci regulated by DNA methylation that could be altered upon the appearance of MIS-C. Methods: Peripheral blood samples were recruited from 43 confirmed MIS-C patients with a median age of 7.7 years, most of whom were of West-Eurasian origin. Four or more organ systems were involved in the majority of patients. 69 non-COVID-19 pediatric samples and 15 COVID-19 pediatric samples without MIS-C were used as controls. The cases in the two groups were mixed and divided into discovery (MIS-C = 29 and non-MIS-C = 56) and validation (MIS-C = 14 and non-MIS-C = 28) cohorts, and balanced for age, gender and ethnic background. We interrogated 850,000 CpG sites of the human genome for DNA methylation variants. Findings: The DNA methylation content of 33 CpG loci was linked with the presence of MIS-C. Of these sites, 18 (54.5%) were located in described genes. The top candidate gene was the immune T-cell mediator ZEB2; and others highly ranked candidates included the regulator of natural killer cell functional competence SH2D1B; VWA8, which contains a domain of the Von Willebrand factor A involved in the pediatric hemostasis disease; and human leukocyte antigen complex member HLA-DRB1; in addition to pro-inflammatory genes such as CUL2 and AIM2. The identified loci were used to construct a DNA methylation profile (EPIMISC) that was associated with MIS-C in both cohorts. The EPIMISC signature was also overrepresented in Kawasaki disease patients, a childhood pathology with also a possible viral trigger, that shares many of the clinical features of MIS-C. Interpretation: We have characterized DNA methylation loci that are associated with the onset of MIS-C. The identified genes are likely contributors to the characteristic exaggerated host inflammatory response observed in these patients. The described epigenetic signature could also provide new targets for more specific therapies for the disorder.

Project description:BackgroundAlthough the radiographic features of coronavirus disease 2019 (COVID-19) in children have been described, the distinguishing features of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 are not well characterized.ObjectiveWe compared the chest radiographic findings of MIS-C with those of COVID-19 and described other distinguishing imaging features of MIS-C.Materials and methodsWe performed a retrospective case series review of children ages 0 to 18 years who were hospitalized at Children's Healthcare of Atlanta from March to May 2020 and who either met the Centers for Disease Control and Prevention (CDC) case definition for MIS-C (n=11) or who had symptomatic, laboratory-confirmed COVID-19 (n=16). Two radiologists reviewed the most severe chest radiographs for each patient. The type and distribution of pulmonary opacities and presence or absence of pleural effusions were recorded. The chest radiographs were categorized based on potential COVID-19 imaging findings as typical, indeterminate, atypical or negative. An imaging severity score was also assigned using a simplified version of the Radiographic Assessment of Lung Edema Score. Findings were statistically compared between patients with MIS-C and those with COVID-19. Additional imaging findings of MIS-C were also described.ResultsRadiographic features of MIS-C included pleural effusions (82% [9/11]), pulmonary consolidations (73% [8/11]) and ground glass opacities (91% [10/11]). All of the lung opacities (100% [10/10]) were bilateral, and the majority of the pleural effusions (67% [6/9]) were bilateral. Compared to children with COVID-19, children with MIS-C were significantly more likely to develop pleural effusions on chest radiograph (82% [9/11] vs. 0% [0/0], P-value <0.01) and a lower zone predominance of pulmonary opacifications (100% [10/10] vs. 38% [5/13], P-value <0.01). Children with MIS-C who also had abdominal imaging had intra-abdominal inflammatory changes.ConclusionKey chest radiographic features of MIS-C versus those of COVID-19 were pleural effusions and lower zone pulmonary opacifications as well as intra-abdominal inflammation. Elucidating the distinguishing radiographic features of MIS-C may help refine the case definition and expedite diagnosis and treatment.

Project description:Background: Following the spread of the coronavirus disease 2019 (COVID-19) pandemic a new disease entity emerged, defined as Pediatric Inflammatory Multisystem Syndrome temporally associated with COVID-19 (PIMS-TS), or Multisystem Inflammatory Syndrome in Children (MIS-C). In the absence of trials, evidence for treatment remains scarce. Purpose: To develop best practice recommendations for the diagnosis and treatment of children with PIMS-TS in Switzerland. It is acknowledged that the field is changing rapidly, and regular revisions in the coming months are pre-planned as evidence is increasing. Methods: Consensus guidelines for best practice were established by a multidisciplinary group of Swiss pediatric clinicians with expertise in intensive care, immunology/rheumatology, infectious diseases, hematology, and cardiology. Subsequent to literature review, four working groups established draft recommendations which were subsequently adapted in a modified Delphi process. Recommendations had to reach >80% agreement for acceptance. Results: The group achieved agreement on 26 recommendations, which specify diagnostic approaches and interventions across anti-inflammatory, anti-infectious, and support therapies, and follow-up for children with suspected PIMS-TS. A management algorithm was derived to guide treatment depending on the phenotype of presentation, categorized into PIMS-TS with (a) shock, (b) Kawasaki-disease like, and (c) undifferentiated inflammatory presentation. Conclusion: Available literature on PIMS-TS is limited to retrospective or prospective observational studies. Informed by these cohort studies and indirect evidence from other inflammatory conditions in children and adults, as well as guidelines from international health authorities, the Swiss PIMS-TS recommendations represent best practice guidelines based on currently available knowledge to standardize treatment of children with suspected PIMS-TS. Given the absence of high-grade evidence, regular updates of the recommendations will be warranted, and participation of patients in trials should be encouraged.

Dataset Information

Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C).

Publications

Mapping Systemic Inflammation and Antibody Responses in Multisystem Inflammatory Syndrome in Children (MIS-C).

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