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.

AP HP Hôpital Pitié Salpêtrière Service de Médecine Intensive Réanimation Institut de Cardiologie Paris France; Sorbonne Université Inserm Institute of Cardiometabolism and Nutrition Paris France

AP HP Hôpital Pitié Salpêtrière Service de Pneumologie Médecine Intensive Réanimation Paris France

AP HP Hôpital Pitié Salpêtrière Service de Pneumologie Médecine Intensive Réanimation Paris France; Sorbonne Université Inserm UMR S 1158 Neurophysiologie respiratoire expérimentale et clinique Paris France

AP HP Hôpital Tenon Service de Médecine Intensive Réanimation Paris France

Department of Environmental Medicine Faculty of Medicine University Hospital of Augsburg Augsburg Germany; Institute of Environmental Medicine Czech Academy of Sciences Prague Czech Republic

Department of Environmental Medicine Faculty of Medicine University Hospital of Augsburg Augsburg Germany; Institute of Environmental Medicine Davos Switzerland

Department of Environmental Medicine Faculty of Medicine University Hospital of Augsburg Augsburg Germany; Institute of Environmental Medicine Technical University of Munich and Helmholtz Zentrum München Augsburg Germany

Sorbonne Université AP HP Hôpital Pitié Salpêtrière Département de Neurologie Unité de Médecine Intensive et Réanimation Neurologique Paris France

Sorbonne Université Inserm Centre d'Immunologie et des Maladies Infectieuses CIMI Paris Paris France

Sorbonne Université Inserm Centre d'Immunologie et des Maladies Infectieuses CIMI Paris Paris France; AP HP Hôpital Pitié Salpêtrière Département d'Immunologie Paris France

Sorbonne Université Inserm Centre d'Immunologie et des Maladies Infectieuses CIMI Paris Paris France; AP HP Hôpital Pitié Salpêtrière Service de Médecine Interne 2 Institut E3M Paris France

Sorbonne Université Inserm Institut Pierre Louis d'Epidémiologie et de Santé Publique Hôpital Pitié Salpêtrière Département de Virologie Paris France

Zobrazit více v PubMed

Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet (London, England) 2020;395:497–506. PubMed PMC

Wang Q., Zhang Y., Wu L., Niu S., Song C., Zhang Z. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell. 2020;181:894–904.e9. PubMed PMC

Schmidt M., Hajage D., Lebreton G., Monsel A., Voiriot G., Levy D. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort study. Lancet Respir Med. 2020;8:1121–1131. PubMed PMC

Moore J.B., June C.H. Cytokine release syndrome in severe COVID-19. Science. 2020;368:473–474. PubMed

Chen J., Subbarao K. The immunobiology of SARS∗. Annu Rev Immunol. 2007;25:443–472. PubMed

The WHO Rapid Evidence Appraisal for COVID-19 Therapies Working Group Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. 2020;324:1330–1341. PubMed PMC

Le Gall J.R., Lemeshow S., Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA. 1993;270:2957–2963. PubMed

Hingrat QL, Visseaux B, Laouenan C, Tubiana S, Bouadma L, Yazdanpanah Y, et al. Detection of SARS-CoV-2 N-antigen in blood during acute COVID-19 provides a sensitive new marker and new testing alternatives [published online ahead of print December 8, 2020]. Clin Microbiol Infect. https://doi.org/10.1016/j.cmi.2020.11.025. PubMed DOI PMC

Jankovic D., Kullberg M.C., Feng C.G., Goldszmid R.S., Collazo C.M., Wilson M. Conventional T-bet(+)Foxp3(−) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J Exp Med. 2007;204:273–283. PubMed PMC

Puel A., Cypowyj S., Bustamante J., Wright J.F., Liu L., Lim H.K. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science. 2011;332:65–68. PubMed PMC

Liu B., Mori I., Hossain M.J., Dong L., Takeda K., Kimura Y. Interleukin-18 improves the early defence system against influenza virus infection by augmenting natural killer cell-mediated cytotoxicity. J Gen Virol. 2004;85:423–428. PubMed

Oldham R.R. Toxic effects of interferon. Science. 1983;219:902. PubMed

Teragawa H., Hondo T., Amano H., Hino F., Ohbayashi M. Adverse effects of interferon on the cardiovascular system in patients with chronic hepatitis C. Jpn Heart J. 1996;37:905–915. PubMed

Holly J.M.P., Biernacka K., Maskell N., Perks C.M. Obesity, diabetes and COVID-19: an infectious disease spreading from the east collides with the consequences of an unhealthy western lifestyle. Front Endocrinol (Lausanne) 2020;11 PubMed PMC

Blanco-Melo D., Nilsson-Payant B.E., Liu W.C., Uhl S., Hoagland D., Møller R. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell. 2020;181:1036–1045.e9. PubMed PMC

Trouillet-Assant S., Viel S., Gaymard A., Pons S., Richard J.C., Perret M. Type I IFN immunoprofiling in COVID-19 patients. J Allergy Clin Immunol. 2020;146:206–208.e2. PubMed PMC

Zhang Q., Bastard P., Liu Z., Pen J.L., Moncada-Velez M., Moncada-Velez M. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020;370 PubMed PMC

Bastard P., Rosen L.B., Zhang Q., Michailidis E., Hoffmann H.H., Zhang Y. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020;370:423. PubMed PMC

Hadjadj J., Yatim N., Barnabei L., Corneau A., Boussier J., Smith N. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science. 2020;369:718–724. PubMed PMC

Notarangelo L.D., Bacchetta R., Casanova J.L., Su H.C. Human inborn errors of immunity: an expanding universe. Sci Immunol. 2020;5 PubMed PMC

Ziegler C.G.K., Allon S.J., Nyquist S.K., Mbano I.M., Miao V.N., Tzouanas C.N. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell. 2020;181:1016–1035.e19. PubMed PMC

Channappanavar R., Fehr A.R., Vijay R., Mack M., Zhao J., Meyerholz D.K. Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell Host Microbe. 2016;19:181–193. PubMed PMC

De Luca G., Cavalli G., Campochiaro C., Della-Torre E., Angelillo P., Tomelleri A. GM-CSF blockade with mavrilimumab in severe COVID-19 pneumonia and systemic hyperinflammation: a single-centre, prospective cohort study. Lancet Rheumatol. 2020;2:e465–e473. PubMed PMC

Stone J.H., Frigault M.J., Serling-Boyd N.J., Fernandes A.D., Harvey L., Foulkes A.S. Efficacy of tocilizumab in patients hospitalized with Covid-19. N Engl J Med. 2020;383:2333–2344. PubMed PMC

The CORIMUNO-19 Collaborative group Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial. Lancet Respir Med. 2021;9:295–304. PubMed PMC

Del Valle D.M., Kim-Schulze S., Huang H.H., Beckmann N.D., Nirenberg S., Wang B. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med. 2020;26:1636–1643. PubMed PMC

RECOVERY Collaborative Group. Horby P., Lim W.S., Emberson J.R., Mafham M., Bell J.L., Linsell L. Dexamethasone in hospitalized patients with Covid-19—preliminary report. N Engl J Med. 2021;384:693–704. PubMed PMC

Bennett L., Palucka A.K., Arce E., Cantrell V., Borvak J., Banchereau J. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003;197:711–723. PubMed PMC

Dorgham K., Neumann A.U., Decavele M., Luyt C.-E., Yssel H., Gorochov G. Considering personalized interferon-β therapy for COVID-19. Antimicrob Agents Chemother. 2021;65 AAC.00065-21. PubMed PMC

Pairo-Castineira E., Clohisey S., Klaric L., Bretherick A.D., Rawlik K., Pasko D. Genetic mechanisms of critical illness in Covid-19. Nature. 2021;591:92–98. PubMed

Kwon YJ, Toussie D, Finkelstein M, Cedillo MA, Maron SZ, Manna S, et al. Combining initial radiographs and clinical variables improves deep learning prognostication of patients with COVID-19 from the emergency department [published online ahead of print December 16, 2020]. Radiol Artif Intell. https://doi.org/10.1148/ryai.2020200098. PubMed DOI PMC