Distinct cytokine profiles associated with COVID-19 severity and mortality

Dorgham, Karim; Quentric, Paul; Gökkaya, Mehmet; Marot, Stéphane; Parizot, Christophe; Sauce, Delphine; Guihot, Amélie; Luyt, Charles-Edouard; Schmidt, Matthieu; Mayaux, Julien; Beurton, Alexandra; Le Guennec, Loic; Demeret, Sophie; Ben Salah, Elyes; Mathian, Alexis; Yssel, Hans; Combadiere, Béhazine; Combadiere, Christophe; Traidl-Hoffmann, Claudia; Burrel, Sonia; Marcelin, Anne-Geneviève; Amoura, Zahir; Voiriot, Guillaume; Neumann, Avidan U.; Gorochov, Guy

Background Markedly elevated levels of pro-inflammatory cytokines and defective type-I interferon responses were reported in COVID-19 patients. Objective This study aimed to determine whether particular cytokine profiles are associated with COVID-19 severity and mortality. Methods Cytokine concentrations and SARS-CoV-2 antigen were measured at hospital admission in serum of symptomatic COVID-19 patients (N=115), classified at hospitalization into three respiratory severity groups: no need for mechanical ventilatory support (No-MVS), intermediate severity requiring mechanical ventilatory support (MVS) and critical severity requiring extracorporeal membrane oxygenation (ECMO). Principal component analysis was used to characterize cytokine profiles associated with severity and mortality. The results were thereafter confirmed in an independent validation cohort (N=86). Results At time of hospitalization, ECMO patients presented a dominant pro-inflammatory response with elevated levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-8 and IL-10. In contrast, an elevated type-I interferon response involving IFN-α and IFN-β was characteristic of No-MVS patients, whereas MVS patients exhibited both profiles. Mortality at one month was associated with higher levels of pro-inflammatory cytokines in ECMO patients, higher levels of type-I interferons in No-MVS patients and their combination in MVS patients, resulting in a combined mortality prediction accuracy of 88.5% (Risk Ratio 24.3, p<0.0001). SARS-CoV-2 antigen levels correlated with type-I interferon levels and were associated with mortality, but not with pro-inflammatory response or severity. Conclusion Distinct cytokine profiles are observed in association with COVID-19 severity and are differentially predictive of mortality according to oxygen support modalities. These results warrant personalized treatment of COVID-19 patients based on cytokine profiling.