Immunometabolic signatures predict risk of progression to sepsis in COVID-19

PLoS One. 2021 Aug 30;16(8):e0256784. doi: 10.1371/journal.pone.0256784. eCollection 2021.


Viral sepsis has been proposed as an accurate term to describe all multisystemic dysregulations and clinical findings in severe and critically ill COVID-19 patients. The adoption of this term may help the implementation of more accurate strategies of early diagnosis, prognosis, and in-hospital treatment. We accurately quantified 110 metabolites using targeted metabolomics, and 13 cytokines/chemokines in plasma samples of 121 COVID-19 patients with different levels of severity, and 37 non-COVID-19 individuals. Analyses revealed an integrated host-dependent dysregulation of inflammatory cytokines, neutrophil activation chemokines, glycolysis, mitochondrial metabolism, amino acid metabolism, polyamine synthesis, and lipid metabolism typical of sepsis processes distinctive of a mild disease. Dysregulated metabolites and cytokines/chemokines showed differential correlation patterns in mild and critically ill patients, indicating a crosstalk between metabolism and hyperinflammation. Using multivariate analysis, powerful models for diagnosis and prognosis of COVID-19 induced sepsis were generated, as well as for mortality prediction among septic patients. A metabolite panel made of kynurenine/tryptophan ratio, IL-6, LysoPC a C18:2, and phenylalanine discriminated non-COVID-19 from sepsis patients with an area under the curve (AUC (95%CI)) of 0.991 (0.986-0.995), with sensitivity of 0.978 (0.963-0.992) and specificity of 0.920 (0.890-0.949). The panel that included C10:2, IL-6, NLR, and C5 discriminated mild patients from sepsis patients with an AUC (95%CI) of 0.965 (0.952-0.977), with sensitivity of 0.993(0.984-1.000) and specificity of 0.851 (0.815-0.887). The panel with citric acid, LysoPC a C28:1, neutrophil-lymphocyte ratio (NLR) and kynurenine/tryptophan ratio discriminated severe patients from sepsis patients with an AUC (95%CI) of 0.829 (0.800-0.858), with sensitivity of 0.738 (0.695-0.781) and specificity of 0.781 (0.735-0.827). Septic patients who survived were different from those that did not survive with a model consisting of hippuric acid, along with the presence of Type II diabetes, with an AUC (95%CI) of 0.831 (0.788-0.874), with sensitivity of 0.765 (0.697-0.832) and specificity of 0.817 (0.770-0.865).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Area Under Curve
  • COVID-19 / complications
  • COVID-19 / pathology*
  • COVID-19 / virology
  • Chemokines / blood
  • Cytokines / blood
  • Female
  • Humans
  • Kynurenine / blood
  • Lymphocytes / cytology
  • Male
  • Metabolomics*
  • Middle Aged
  • Neutrophils / cytology
  • ROC Curve
  • Retrospective Studies
  • Risk Factors
  • SARS-CoV-2 / isolation & purification
  • Sepsis / diagnosis*
  • Sepsis / etiology
  • Severity of Illness Index
  • Tryptophan / blood


  • Chemokines
  • Cytokines
  • Kynurenine
  • Tryptophan

Grants and funding

CONACyT grant number 311880 was awarded to Yamile Lopez Hernandez. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.