Longitudinal analyses reveal immunological misfiring in severe COVID-19

Nature. 2020 Aug;584(7821):463-469. doi: 10.1038/s41586-020-2588-y. Epub 2020 Jul 27.


Recent studies have provided insights into the pathogenesis of coronavirus disease 2019 (COVID-19)1-4. However, the longitudinal immunological correlates of disease outcome remain unclear. Here we serially analysed immune responses in 113 patients with moderate or severe COVID-19. Immune profiling revealed an overall increase in innate cell lineages, with a concomitant reduction in T cell number. An early elevation in cytokine levels was associated with worse disease outcomes. Following an early increase in cytokines, patients with moderate COVID-19 displayed a progressive reduction in type 1 (antiviral) and type 3 (antifungal) responses. By contrast, patients with severe COVID-19 maintained these elevated responses throughout the course of the disease. Moreover, severe COVID-19 was accompanied by an increase in multiple type 2 (anti-helminths) effectors, including interleukin-5 (IL-5), IL-13, immunoglobulin E and eosinophils. Unsupervised clustering analysis identified four immune signatures, representing growth factors (A), type-2/3 cytokines (B), mixed type-1/2/3 cytokines (C), and chemokines (D) that correlated with three distinct disease trajectories. The immune profiles of patients who recovered from moderate COVID-19 were enriched in tissue reparative growth factor signature A, whereas the profiles of those with who developed severe disease had elevated levels of all four signatures. Thus, we have identified a maladapted immune response profile associated with severe COVID-19 and poor clinical outcome, as well as early immune signatures that correlate with divergent disease trajectories.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • COVID-19
  • Cluster Analysis
  • Coronavirus Infections / immunology*
  • Coronavirus Infections / physiopathology*
  • Cytokines / analysis*
  • Cytokines / immunology
  • Eosinophils / immunology
  • Female
  • Humans
  • Immunoglobulin E / analysis
  • Immunoglobulin E / immunology
  • Interleukin-13 / analysis
  • Interleukin-13 / immunology
  • Interleukin-5 / analysis
  • Interleukin-5 / immunology
  • Male
  • Middle Aged
  • Pandemics
  • Pneumonia, Viral / immunology*
  • Pneumonia, Viral / physiopathology*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • Viral Load
  • Young Adult


  • Cytokines
  • Interleukin-13
  • Interleukin-5
  • Immunoglobulin E