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Authors: Gruber et al. 

Journal/ Pre-Print: MedRxiv 

Tags; Immunology/Immunity, Clinical/ Diagnostics, Inflammation 

Research Highlights 

  1. Multisystem inflammatory syndrome in children (MIS-C) results in enhanced inflammatory (IL-6) and chemotactic markers (CCL3, CCL4), while peripheral blood immune cells migrate to sites of inflammation 

  1. Autoantibodies against known and novel antigens is described in MIS-C 

  1. MIS-C patients were successfully treated with tocilizumab and intravenous immunoglobulins 

Summary 

Gruber et al explore the immune landscape of MIS-C, following COVID-19. MIS-C patientswere analysed and compared with healthy controls and convalescent patients. In depth techniques were used including CyTOF. MIS-C patients have elevated IL-6, although this maybe exacerbated by tocilizumab treatment. Additionally, CCL3 and CCL4, involved in neutrophil and monocyte recruitment, were elevated in MIS-C, while enhanced CD64 expression confirmed general inflammation. Furthermore, CD16+ monocytes, pDCs, NK and T cells were reduced in MIS-C peripheral blood, likely due to migration to inflamed tissues. Strikingly, MIS-C patients had autoantibodies against various antigens, such as those found in cardiac or gastrointestinal tissue. All patients received tocilizumab and all but onereceived intravenous immunoglobulins, resulting in the resolution of disease.  

Impact for SARS-CoV2/COVID19 research efforts  

Understand the immune response to  SARS-CoV2/COVID19: this study investigates the immune response in COVID-19-related multisystem inflammatory syndrome in children. 

Study Type  

  • Clinical Cohort study (e.g. drug trials) 

  • Patient Case study 

Strengths and limitations of the paper 

Novelty: The study is novel in underlying the immune pathology of MIS-C. Along with Consiglio et al, MedRxiv, 2020 provide important descriptions of the phenotype of disease. 

Standing in the field: A severe inflammatory disease in children has been described in multiple geographic locations during the COVID-19 pandemic (Rowley, Nature Reviews Immunology, 2020). The high IL-6 levels reported in this study have also been found in severe COVID-19 patients (Lucas et al, MedRxiv, 2020). At the same time, the inflammatory and autoimmune-associated CD64 increase has been observed in mild, moderate and severe COVID-19 patients (Mann et al, MedRxiv, 2020). This study found cardiac tissue antigens being the targets of autoantibodies in MIS-C, similar to a different study, although the peptides identified are different (Consiglio et al, MedRxiv, 2020). Overall, this investigation agrees with previous reports and adds significant insights into the immunopathology of MIS-C. 

Appropriate statistics: Yes 

Viral model used: N/A 

Translatability: Limited. This is a descriptive phenotypic study but may provide useful targets for further investigation.  

Main limitations:  

  1. This is a small number of MIS-C patients studied, and it could be argued that a more interesting comparison would be with children with other autoimmune diseases. 

  1. Are there cell population changes before/after tocilizumab/IVIG treatment? 

  1. Since pSTAT3 is not present in all MIS-C patients, does enhanced pSTAT3 correlate with high IL-6 levels? 

  1. A discussion on different treatment options would be interesting, given that MIS-C has also been treated with IVIG and anakinra (Consiglio et al, MedRxiv, 2020).