The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19
clinical diagnostics drug discovery/repurposing immunology/immunity inflammation
Authors: Consiglio et al.
Link to paper: https://doi.org/10.1101/2020.07.08.20148353
Journal/ Pre-Print: MedRxiv
Tags: Immunology/Immunity, Clinical/ Diagnostics, Inflammation, Drug discovery/ Drug repurposing
1. Profiling of peripheral blood from children with multisystem inflammatory syndrome (MIS-C) compared with Kawasaki pre-pandemic disease samples, children with mild COVID-19, healthy children, and adults with severe Covid-19 (data taken from literature). The authors also investigated T cell subsets in the cohort groups.
2. Consiglio et al use their data to identify contrasting treatments for Kawasaki disease and MIS-C. This was in agreement with treatments which have been successful in a handful of MIS-C children.
3. The authors identified endoglin, an endothelial glycoprotein, as a top target for autoantibodies.
Consiglio et al established a cohort of 44 Children with COVID-19, of which 4 children subsequently developed MIS-C, and pre-pandemic samples from 28 children with Kawasaki disease and 12 healthy paediatric controls. Hyperinflammation in MIS-C and Kawasaki disease and severe Covid-19 in adults (from literature) were found to have distinct cytokine profiles. This was similar for T cell subsets (severe Covid-19 adults weren’t compared). Multiomic analysis identified sets of features which may discriminate between these diseases and have potential use in diagnostics. The authors identified antigens on Endoglin and RBPJ to be the most common targets of autoantibodies, describing their expression in the different cohort groups.
Impact for SARS-CoV2/COVID19 research efforts
Understand the immune response to SARS-CoV2/COVID19
Clinical symptoms and pathogenesis of SARS-Cov2/COVID19
Treatment of SARS-CoV2/COVID19 positive individuals - The authors measure cytokine profiles in the different disease groups and antigen targets of autoantibodies, providing insights into which treatments may be more or less effective compared to severe Covid-19 in adults. Consiglio et al state their results correlate well with clinical information and support this with references. Although there are very few MIS-C patients, the authors thoroughly profile their T cell subsets and cytokines and most importantly, compared them with Kawasaki disease, an autoimmune disease which has been reported to have clinical features in common with MIS-C, as well as children with mild Covid-19. Together with Gruber et al. Medrxiv 2020, the data may highlight useful therapeutic targets.
· Clinical Cohort study (e.g. drug trials)
Strengths and limitations of the paper
Cytokine profiles for MIS-C compared to mild Covid-19 in children, healthy children, and Kawasaki disease, and adults with severe Covid-19 (citing other papers)
Study of different T cell subsets by flow cytometry across MIS-C, mild Covid-19 in children, healthy children and Kawasaki disease
Use of gene enrichment analysis to find the most prevalent autoantibody antigens of 9341 measured and compared autoantibodies targeting these in different groups.
Standing in the field: Good use of statistics, if not always clearly explained and good rationale for the different experiments the authors performed. Consiglio et al identified the immunology behind their results and cited papers when stating that the results of their experiments agreed with clinical observations and outcomes.
Appropriate statistics: Statistics were appropriate and accurate, but would have been good to have included more p-values even when data seemed to not be statistically significant.
Viral model used: Clinical SARS-CoV-2 patients in Italy.
Translatability: The authors suggest further work could assess the usefulness of some of the markers they have identified for diagnosis and prognosis of children with Covid-19. Comparison of cytokine storm data in MIS-C with severe Covid-19 in adults, suggests some treatments successful in adults may not be successful in MIS-C and suggest some of those with apparent success to treat MIS-C correlated well with their data (e.g. IL-1RA, IVIG, corticosteroids).
Although MIS-C is relatively rare and therefore the analyses were done on just four MIS-C patients, and should therefore be interpreted with care.
Would have been helpful to have included a healthy control profile in the PCA analysis.
Difficult to see half of the MIS-C points in the Figure 2A PCA plot.
Figure 5E has two measurements of CD4 Tcm loading weight for Factor 5 with different results, and no explanation.
Autoantibody measurements only seemed to include three children with mild Covid-19.