Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Comment
  • Published:

From hyperinflammation to recovery: serum immune biomarkers predict severity and track rapid inflammatory resolution in MIS-C

Pediatric Research (2026)Cite this article

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Plasma immune biomarkers across the course of MIS-C.

References

  1. Lee, P. I. & Hsueh, P. R. Multisystem inflammatory syndrome in children: A dysregulated autoimmune disorder following COVID-19. J. Microbiol. Immunol. Infect. 56, 236–245 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Jiang, L. et al. COVID-19 and multisystem inflammatory syndrome in children and adolescents. Lancet Infect. Dis. 20, e276–e288 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Santos, M. O. et al. Multisystem inflammatory syndrome (MIS-C): a systematic review and meta-analysis of clinical characteristics, treatment, and outcomes. J. Pediatr. (Rio J.) 98, 338–349 (2022).

    Article  PubMed  Google Scholar 

  4. Yousaf, A. R. et al. Notes from the field: Surveillance for multisystem inflammatory syndrome in children—United States, 2023. MMWR Morb. Mortal. Wkly. Rep. 73, 225–228 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Carzaniga, T. et al. Dynamics of multisystem inflammatory syndrome in children associated with COVID-19: steady severity despite declining cases and new SARS-CoV-2 variants-a single-center cohort study. Eur. J. Pediatr. 184, 327 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. La Torre, F. et al. Incidence and prevalence of multisystem inflammatory syndrome in children (MIS-C) in southern Italy. Children (Basel) 10, 766 (2023).

    PubMed  Google Scholar 

  7. Payne, A. B. et al. Incidence of multisystem inflammatory syndrome in children among US persons infected with SARS-CoV-2. JAMA Netw. Open 4, e2116420 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Avrusin, I. S. et al. Determination of risk factors for severe life-threatening course of multisystem inflammatory syndrome associated with COVID-19 in children. Children (Basel) 10, 1366 (2023).

    PubMed  Google Scholar 

  9. Tran, D. M. et al. Severity predictors for multisystem inflammatory syndrome in children after SARS-CoV-2 infection in Vietnam. Sci. Rep. 14, 15810 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wurm, J. et al. Clinical and laboratory biomarkers as predictors of severity in pediatric inflammatory multisystem syndrome-temporally associated with SARS-CoV-2: data from a prospective nationwide surveillance study in Switzerland. Pediatr. Infect. Dis. J. 43, 675–681 (2024).

    Article  PubMed  Google Scholar 

  11. Merckx, J. et al. Predictors of severe illness in children with multisystem inflammatory syndrome after SARS-CoV-2 infection: a multicentre cohort study. CMAJ 194, E513–E523 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yilmaz, D. et al. Evaluation of 601 children with multisystem inflammatory syndrome (Turk MISC study). Eur. J. Pediatr. 182, 5531–5542 (2023).

    Article  CAS  PubMed  Google Scholar 

  13. Coşkun, S. et al. The role of indices in predicting disease severity and outcomes of multisystem inflammatory syndrome in children. Pediatr. Int. 65, e15609 (2023).

    Article  PubMed  Google Scholar 

  14. Consiglio, C. R. et al. The immunology of multisystem inflammatory syndrome in children with COVID-19. Cell 183, 968–981.e7 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vella, L. A. et al. Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19. Sci. Immunol. 6, eabf7570 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Yeoh, S. et al. Plasma protein biomarkers distinguish multisystem inflammatory syndrome in children from other pediatric infectious and inflammatory diseases. Pediatr. Infect. Dis. J. 43, 444–453 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Loy, C. J. et al. Nucleic acid biomarkers of immune response and cell and tissue damage in children with COVID-19 and MIS-C. Cell Rep. Med. 4, 101034 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sacco, K. et al. Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19. Nat. Med. 28, 1050–1062 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ciortea, D. A. et al. Cardiac manifestations and emerging biomarkers in multisystem inflammatory syndrome in children (MIS-C): a systematic review and meta-analysis. Life (Basel) 15, 805 (2025).

    CAS  PubMed  Google Scholar 

  20. Zhao, Y. et al. The inflammatory markers of multisystem inflammatory syndrome in children (MIS-C) and adolescents associated with COVID-19: a meta-analysis. J. Med. Virol. 93, 4358–4369 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pidkova, T. et al. Tracking the soluble biomarkers of MIS-C and their association with clinical parameters and severity. Pediatr Res. https://doi.org/10.1038/s41390-025-04542-8 (2025).

    Article  PubMed  Google Scholar 

  22. Burkly, L. C. et al. TWEAKing tissue remodeling by a multifunctional cytokine: role of TWEAK/Fn14 pathway in health and disease. Cytokine 40, 1–16 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Josien, R. et al. TRANCE, a tumor necrosis factor family member, enhances the longevity and adjuvant properties of dendritic cells in vivo. J. Exp. Med. 191, 495–502 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jone, P. N. et al. SARS-CoV-2 infection and associated cardiovascular manifestations and complications in children and young adults: a scientific statement from the American Heart Association. Circulation 145, e1037–e1052 (2022).

    Article  CAS  PubMed  Google Scholar 

  25. Spolski, R., Li, P. & Leonard, W. J. Biology and regulation of IL-2: from molecular mechanisms to human therapy. Nat. Rev. Immunol. 18, 648–659 (2018).

    Article  CAS  PubMed  Google Scholar 

  26. Hoyer, K. K., Dooms, H., Barron, L. & Abbas, A. K. Interleukin-2 in the development and control of inflammatory disease. Immunol. Rev. 226, 19–28 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Molofsky, A. B., Savage, A. K. & Locksley, R. M. Interleukin-33 in tissue homeostasis, injury, and inflammation. Immunity 42, 1005–1019 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sun, L. et al. Advances in understanding the roles of CD244 (SLAMF4) in immune regulation and associated diseases. Front. Immunol. 12, 648182 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Edgar, J. M., Michaels, Y. S. & Zandstra, P. W. Multi-objective optimization reveals time- and dose-dependent inflammatory cytokine-mediated regulation of human stem-cell-derived T-cell development. NPJ Regen. Med. 7, 11 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhao, P. et al. Clinical and functional characterization of a novel TNFRSF9 variant causing immune dysregulation with predisposition to EBV-driven lymphomagenesis. Front. Immunol. 16, 1605221 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Koh, C. H. et al. CD8 T-cell subsets: heterogeneity, functions, and therapeutic potential. Exp. Mol. Med. 55, 2287–2299 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Beckmann, N. D. et al. Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children. Nat. Commun. 12, 4854 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Fröhlich, A. et al. Comprehensive analysis of tumor necrosis factor receptor TNFRSF9 (4-1BB) DNA methylation with regard to molecular and clinicopathological features, immune infiltrates, and response prediction to immunotherapy in melanoma. EBioMedicine 52, 102647 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Reiter, A. et al. Proteomic mapping identifies serum marker signatures associated with MIS-C-specific hyperinflammation and cardiovascular manifestation. Clin. Immunol. 264, 110237 (2024).

    Article  CAS  PubMed  Google Scholar 

  35. Mizuta, M. et al. Clinical significance of serum CXCL9 levels as a biomarker for systemic juvenile idiopathic arthritis associated macrophage activation syndrome. Cytokine 119, 182–187 (2019).

    Article  CAS  PubMed  Google Scholar 

  36. Rodriguez-Smith, J. J. et al. Inflammatory biomarkers in COVID-19-associated multisystem inflammatory syndrome in children, Kawasaki disease, and macrophage activation syndrome: a cohort study. Lancet Rheumatol 3, e574–e584 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Esteve-Sole, A. et al. Similarities and differences between the immunopathogenesis of COVID-19-related pediatric multisystem inflammatory syndrome and Kawasaki disease. J. Clin. Invest. 131, e144554 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Caldarale, F. et al. Plasmacytoid dendritic cell depletion and elevation of IFN-γ-dependent chemokines CXCL9 and CXCL10 in children with multisystem inflammatory syndrome. Front. Immunol. 12, 654587 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bracaglia, C. et al. Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterize patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Ann. Rheum. Dis. 76, 166–172 (2017).

    Article  CAS  PubMed  Google Scholar 

  40. Tschoeke, S. K., Oberholzer, A. & Moldawer, L. L. Interleukin-18: a novel prognostic cytokine in bacteria-induced sepsis. Crit. Care Med. 34, 1225–1233 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Krei, J. M., Møller, H. J. & Larsen, J. B. The role of interleukin-18 in the diagnosis and monitoring of hemophagocytic lymphohistiocytosis/macrophage activation syndrome—a systematic review. Clin. Exp. Immunol. 203, 174–182 (2021).

    Article  CAS  PubMed  Google Scholar 

  42. Shan, N. N. et al. Interleukin-18 and interleukin-18-binding protein in patients with idiopathic thrombocytopenic purpura. Br. J. Haematol. 144, 755–761 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Belay, E. D. et al. Trends in geographic and temporal distribution of US children with multisystem inflammatory syndrome during the COVID-19 pandemic. JAMA Pediatr 175, 837–845 (2021).

    Article  PubMed  Google Scholar 

  44. Miller, A. D. et al. Multisystem inflammatory syndrome in children—United States, February 2020–July 2021. Clin. Infect. Dis. 75, e1165–e1175 (2022).

    Article  PubMed  Google Scholar 

  45. Martin, B. et al. Characteristics, outcomes, and severity risk factors associated with SARS-CoV-2 infection among children in the US National COVID Cohort Collaborative. JAMA Netw. Open 5, e2143151 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Preston, L. E. et al. Characteristics and disease severity of US children and adolescents diagnosed with COVID-19. JAMA Netw. Open 4, e215298 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Penner, J. et al. Six-month multidisciplinary follow-up and outcomes of patients with pediatric inflammatory multisystem syndrome (PIMS-TS) at a UK tertiary pediatric hospital: a retrospective cohort study. Lancet Child Adolesc. Health 5, 473–482 (2021).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors received no financial support for this article.

Author information

Authors and Affiliations

  1. Children’s National Research Institute, Washington, D.C., USA

    Nora Wolff & Ioannis Koutroulis

  2. Children’s National Hospital, Division of Emergency Medicine, Washington, D.C., USA

    Ioannis Koutroulis

  3. The George Washington University School of Medicine and Health Sciences, Washington, D.C., USA

    Ioannis Koutroulis

Authors
  1. Nora Wolff
    View author publications

    Search author on:PubMed Google Scholar

  2. Ioannis Koutroulis
    View author publications

    Search author on:PubMed Google Scholar

Contributions

N.W. contributed to the critical discussion of the reviewed article and relevant literature, and manuscript drafting. I.K. provided conceptual guidance, critically revised the manuscript for important intellectual content, and prepared the final version for submission.

Corresponding author

Correspondence to Ioannis Koutroulis.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wolff, N., Koutroulis, I. From hyperinflammation to recovery: serum immune biomarkers predict severity and track rapid inflammatory resolution in MIS-C. Pediatr Res (2026). https://doi.org/10.1038/s41390-025-04745-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41390-025-04745-z

Search

Advanced search

Quick links