Distinct cytokine profiles associated with COVID-19 severity and mortality - 03/06/21

Doi : 10.1016/j.jaci.2021.03.047

Karim Dorgham, PhD ^a,^{∗
These authors contributed equally to this work.}, Paul Quentric, MD, MSc ^a,^{∗
These authors contributed equally to this work.}, Mehmet Gökkaya, MSc ^b,^c,^{∗
These authors contributed equally to this work.}, Stéphane Marot, MD ^d, Christophe Parizot, MSc ^a,^e, Delphine Sauce, PhD ^a, Amélie Guihot, MD, PhD ^a,^e, Charles-Edouard Luyt, MD, PhD ^f,^g, Matthieu Schmidt, MD, PhD ^f,^g, Julien Mayaux, MD ^h, Alexandra Beurton, MD, PhD ^h,ⁱ, Loic Le Guennec, MD, PhD ^j, Sophie Demeret, MD ^j, Elyes Ben Salah, PharmD, MSc ^a,^e, Alexis Mathian, MD, PhD ^a,^k, Hans Yssel, PhD ^a, Béhazine Combadiere, PhD ^a, Christophe Combadiere, PhD ^a, Claudia Traidl-Hoffmann, MD, PhD ^b,^c,^l, Sonia Burrel, PharmD, PhD ^d, Anne-Geneviève Marcelin, PharmD, PhD ^d, Zahir Amoura, MD, PhD ^a,^k, Guillaume Voiriot, MD ^m, Avidan U. Neumann, PhD ^b,^c,^n,^{‡
These authors contributed equally to this work.}, Guy Gorochov, MD, PhD ^a,^e,^⁎,^{‡
These authors contributed equally to this work.}
^a Sorbonne Université, Inserm, Centre d’Immunologie et des Maladies Infectieuses, CIMI-Paris, Paris, France
^b Department of Environmental Medicine, Faculty of Medicine, University Hospital of Augsburg, Augsburg, Germany
^c Institute of Environmental Medicine (IEM), Technical University of Munich and Helmholtz Zentrum München, Augsburg, Germany
^d Sorbonne Université, Inserm, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Département de Virologie, Paris, France
^e AP-HP, Hôpital Pitié-Salpêtrière, Département d’Immunologie, Paris, France
^f AP-HP, Hôpital Pitié-Salpêtrière, Service de Médecine Intensive Réanimation, Institut de Cardiologie, Paris, France
^g Sorbonne Université, Inserm, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
^h AP-HP, Hôpital Pitié-Salpêtrière, Service de Pneumologie, Médecine Intensive - Réanimation, Paris, France
ⁱ Sorbonne Université, Inserm UMR S 1158, Neurophysiologie respiratoire expérimentale et clinique, Paris, France
^j Sorbonne Université, AP-HP, Hôpital Pitié-Salpêtrière, Département de Neurologie, Unité de Médecine Intensive et Réanimation Neurologique, Paris, France
^k AP-HP, Hôpital Pitié-Salpêtrière, Service de Médecine Interne 2, Institut E3M, Paris, France
^l Christine Kühne Center for Allergy Research and Education (CK-CARE), Davos, Switzerland
^m AP-HP, Hôpital Tenon, Service de Médecine Intensive Réanimation, Paris, France
ⁿ Institute of Experimental Medicine (IEM), Czech Academy of Sciences, Prague, Czech Republic

^∗Corresponding author: Guy Gorochov, MD, PhD, Département d’Immunologie, Hôpital Pitié-Salpêtrière, 83 bv. de l’Hôpital, 75013 Paris, France.Département d’ImmunologieHôpital Pitié-Salpêtrière83 bv. de l’HôpitalParis75013France

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Abstract

Background

Markedly elevated levels of proinflammatory cytokines and defective type-I interferon responses were reported in patients with coronavirus disease 2019 (COVID-19).

Objective

We sought to determine whether particular cytokine profiles are associated with COVID-19 severity and mortality.

Methods

Cytokine concentrations and severe acute respiratory syndrome coronavirus 2 antigen were measured at hospital admission in serum of symptomatic patients with COVID-19 (N = 115), classified at hospitalization into 3 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 proinflammatory response with elevated levels of TNF-α, 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 1 month was associated with higher levels of proinflammatory 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 < .0001). Severe acute respiratory syndrome coronavirus 2 antigen levels correlated with type-I interferon levels and were associated with mortality, but not with proinflammatory response or severity.

Conclusions

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.

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Graphical abstract

Le texte complet de cet article est disponible en PDF.

Key words : COVID-19, serum cytokines, type-I interferons, respiratory severity, mortality, principal-component analysis

Abbreviations used : COVID-19, f_CC, ECMO, MVS, PCA, SAPS-II, SARS-CoV-2

Plan

Methods

Patients and samples

Immunoassays

Statistical and bioinformatics analysis

Results

Patients’ severity and mortality

Distinct cytokine profiles associated with COVID-19 severity

COVID-19 mortality risk is associated with distinct cytokine profiles

High viral load associated with mortality in No-MVS and MVS, but not in ECMO, patients

Viral load is correlated with type-I interferon response but not with inflammatory cytokines

Association of cytokine levels and SARS-CoV-2 viral load with baseline conditions

Discussion

Conclusions

This study was supported by the Fondation de France, “Tous unis contre le virus” framework Alliance (Fondation de France, AP-HP, Institut Pasteur) in collaboration with Agence Nationale de la Recherche (ANR Flash COVID19 program), by the SARS-CoV-2 Program of the Faculty of Medicine from Sorbonne University ICOViD programs, by the Programme Hospitalier de Recherche Clinique PHRC-20-0375 COVID-19 (PI: G.G.), by the Christine Kühne - Center for Allergy Research and Education (M.G., C.T.-H., and A.U.N.), and by the Initiative and Networking Fund (Immunology & Inflammation) of the Helmholtz Association (M.G., C.T.-H., and A.U.N.).

Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Vol 147 - N° 6

P. 2098-2107 - juin 2021 Retour au numéro

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Distinct cytokine profiles associated with COVID-19 severity and mortality - 03/06/21

Abstract

Background

Objective

Methods

Results

Conclusions

Graphical abstract

Plan

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