Dysregulated Innate and Adaptive Immune Responses Discriminate Disease Severity in COVID-19

Nico A.F. Janssen, Inge Grondman, Aline H. De Nooijer, Collins K. Boahen, Valerie A.C.M. Koeken, Vasiliki Matzaraki, Vinod Kumar, Xuehui He, Matthijs Kox, Hans J.P.M. Koenen, Ruben L. Smeets, Irma Joosten, Roger J.M. Brüggemann, Ilse J.E. Kouijzer, Hans G. Van Der Hoeven, Jeroen A. Schouten, Tim Frenzel, Monique H.E. Reijers, Wouter Hoefsloot, Anton S.M. DofferhoffMarjan J. Van Apeldoorn, Marc J.T. Blaauw, Karin Veerman, Coen Maas, Arjan H. Schoneveld, Imo E. Hoefer, Lennie P.G. Derde, Marcel Van Deuren, Jos W.M. Van Der Meer, Reinout Van Crevel, Evangelos J. Giamarellos-Bourboulis, Leo A.B. Joosten, Michel M. Van Den Heuvel, Jacobien Hoogerwerf, Quirijn De Mast, Peter Pickkers, Mihai G. Netea, Frank L. Van De Veerdonk

Research output: Contribution to journalArticlepeer-review

37 Citations (Scopus)


The clinical spectrum of COVID-19 varies and the differences in host response characterizing this variation have not been fully elucidated. COVID-19 disease severity correlates with an excessive proinflammatory immune response and profound lymphopenia. Inflammatory responses according to disease severity were explored by plasma cytokine measurements and proteomics analysis in 147 COVID-19 patients. Furthermore, peripheral blood mononuclear cell cytokine production assays and whole blood flow cytometry were performed. Results confirm a hyperinflammatory innate immune state, while highlighting hepatocyte growth factor and stem cell factor as potential biomarkers for disease severity. Clustering analysis revealed no specific inflammatory endotypes in COVID-19 patients. Functional assays revealed abrogated adaptive cytokine production (interferon-γ, interleukin-17, and interleukin-22) and prominent T-cell exhaustion in critically ill patients, whereas innate immune responses were intact or hyperresponsive. Collectively, this extensive analysis provides a comprehensive insight into the pathobiology of severe to critical COVID-19 and highlights potential biomarkers of disease severity.

Original languageEnglish
Pages (from-to)1322-1333
Number of pages12
JournalThe Journal of infectious diseases
Issue number8
Publication statusPublished - 15 Apr 2021
Externally publishedYes


  • adaptive immunity
  • biomarkers
  • COVID-19
  • cytokines
  • disease severity
  • exhaustion markers
  • flow cytometry
  • innate immunity
  • proteomics


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