Background Coronavirus disease 2019 (Covid-19) is a major global threat that has already caused more than 100,000 deaths worldwide. It is characterized by distinct patterns of disease progression implying a diverse host immune response. However, the immunological features and molecular mechanisms involved in Covid-19 severity remain so far poorly known.

Methods We performed an integrated immune analysis that included in-depth phenotypical profiling of immune cells, whole-blood transcriptomic and cytokine quantification on a cohort of fifty Covid19 patients with a spectrum of disease severity. All patient were tested 8 to 12 days following first symptoms and in absence of anti-inflammatory therapy.

Results A unique phenotype in severe and critically ill patients was identified. It consists in a profoundly impaired interferon (IFN) type I response characterized by a low interferon production and activity, with consequent downregulation of interferon-stimulated genes. This was associated with a persistent blood virus load and an exacerbated inflammatory response that was partially driven by the transcriptional factor NF?B. It was also characterized by increased tumor necrosis factor (TNF)-? and interleukin (IL)-6 production and signaling as well as increased innate immune chemokines.

Conclusion We propose that type-I IFN deficiency in the blood is a hallmark of severe Covid-19 and could identify and define a high-risk population. Our study provides a rationale for testing IFN administration combined with adapted anti-inflammatory therapy targeting IL-6 or TNF-? in most severe patients. These data also raise concern for utilization of drugs that interfere with the IFN pathway.

### Competing Interest Statement

The authors have declared no competing interest.

### Funding Statement

This study was supported by the Fonds IMMUNOV, for Innovation in Immunopathology. The study was also supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), by a government grant managed by the Agence National de la Recherche as part of the “Investment for the Future” program (ANR-10-IAHU-01), and by a grant from the Agence National de la Recherche (ANR-flash Covid19 “AIROCovid” to FRL). J.H. is a recipient of an Institut Imagine MD-PhD fellowship program supported by the Fondation Bettencourt Schueller. L.B. is supported by the EUR G.E.N.E. (reference #ANR-17-EURE-0013) program of the Université de Paris IdEx #ANR-18-IDEX-0001 funded by the French Government through its “Investments for the Future” program

### Author Declarations

All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.

Yes

All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

All the microarray data (nanostring) are being processed for upload on GEO database. All the data published are available upon request to the corresponding author.

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