Distinguishing immune activation and inflammatory signatures of multisystem inflammatory syndrome in children (MIS-C) versus hemophagocytic lymphohistiocytosis (HLH)

• Type of Material: Article
• Authors: Deepak Kumar, Emory University; Christina Rostad, Emory University; Preeti Jaggi, Emory University; D. Sofia Villacis Nunez, Emory University; Chengyu Prince, Emory University; Austin Lu, Emory University; Laila Hussaini, Emory University; Thinh H. Nguyen, Emory University; Sakshi Malik, Emory University; Lori A. Ponder, Children's Healthcare of Atlanta; Sreekala P. V. Shenoy, Emory University; Evan Anderson, Emory University; Michael Briones, Emory University; Ignacio Sanz, Emory University; Sampath Prahalad, Emory University; Shanmuganathan Chandrakasan, Emory University
• Language: English
• Date: 2022-05-01
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2022 American Academy of Allergy, Asthma & Immunology.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jaci.2022.02.028
• Title of Journal or Parent Work: Journal of Allergy and Clinical Immunology
• Volume: 149
• Issue: 5
• Start Page: 1592
• End Page: 1606.e16
• Grant/Funding Information: This work was supported by the National Heart, Lung, and Blood Institute (grant no. 1K08HL141635-01A1), Atlanta Pediatric Scholars Program K12 Scholar (grant nos. K12HD072245 and U54AI082973 to S.C.), and the National Institute of Allergy and Infectious Diseases 3U19AI110483-07S1 to I.S. (PI) and S.C. (Co-I) and S.P. (Co-I). S.P. is supported in part by the Marcus Foundation, Inc, Atlanta.; Disclosure of potential conflict of interest: S. Chandrakasan serves on the advisory committee for SOBI. S. Prahalad serves on a macrophage activation syndrome adjudication committee for Novartis Pharmaceuticals and is an Op-Med fellow for Doximity for 2021-2022. E. J. Anderson has consulted for Pfizer, Sanofi-Pasteur, Janssen, and Medscape, and his institution receives funds to conduct clinical research unrelated to this manuscript from MedImmune, Regeneron, PaxVax, Pfizer, GlaxoSmithKline (GSK), Merck, Sanofi-Pasteur, Janssen, and Micron. He also serves on a safety monitoring board for Kentucky BioProcessing, Inc, and Sanofi-Pasteur. His institution has also received funding from the National Institutes of Health to conduct clinical trials of Moderna and Janssen coronavirus disease 2019 vaccines. C. A. Rostad’s institution has received funds to conduct clinical research unrelated to this manuscript from BioFire, Inc, GSK, MedImmune, Micron, Janssen, Merck, Moderna, Novavax, PaxVax, Pfizer, Regeneron, and Sanofi-Pasteur. The rest of the authors declare that they have no relevant conflicts of interest.
• Keywords: COVID-19; Systemic Inflammatory Response Syndrome; Child; cardiac dysfunction; MIS-C; Humans; Lymphohistiocytosis, Hemophagocytic; Cytokines; Ligands; HLH; T-cell activation; Vascular Endothelial Growth Factor A; hyperinflammation
• Research Categories: Health Sciences, Immunology; Biology, Cell; Health Sciences, Public Health; Biology, Virology

Abstract

Background: Multisystem inflammatory syndrome in children (MIS-C) is a potentially life-threatening sequela of severe acute respiratory syndrome coronavirus 2 infection characterized by hyperinflammation and multiorgan dysfunction. Although hyperinflammation is a prominent manifestation of MIS-C, there is limited understanding of how the inflammatory state of MIS-C differs from that of well-characterized hyperinflammatory syndromes such as hemophagocytic lymphohistiocytosis (HLH). Objectives: We sought to compare the qualitative and quantitative inflammatory profile differences between patients with MIS-C, coronavirus disease 2019, and HLH. Methods: Clinical data abstraction from patient charts, T-cell immunophenotyping, and multiplex cytokine and chemokine profiling were performed for patients with MIS-C, patients with coronavirus disease 2019, and patients with HLH. Results: We found that both patients with MIS-C and patients with HLH showed robust T-cell activation, markers of senescence, and exhaustion along with elevated TH1 and proinflammatory cytokines such as IFN-γ, C-X-C motif chemokine ligand 9, and C-X-C motif chemokine ligand 10. In comparison, the amplitude of T-cell activation and the levels of cytokines/chemokines were higher in patients with HLH when compared with patients with MIS-C. Distinguishing inflammatory features of MIS-C included elevation in TH2 inflammatory cytokines such as IL-4 and IL-13 and cytokine mediators of angiogenesis, vascular injury, and tissue repair such as vascular endothelial growth factor A and platelet-derived growth factor. Immune activation and hypercytokinemia in MIS-C resolved at follow-up. In addition, when these immune parameters were correlated with clinical parameters, CD8+ T-cell activation correlated with cardiac dysfunction parameters such as B-type natriuretic peptide and troponin and inversely correlated with platelet count. Conclusions: Overall, this study characterizes unique and overlapping immunologic features that help to define the hyperinflammation associated with MIS-C versus HLH.