Which patients will develop a severe form of Covid-19? This is a key question that needs to be answered to improve the individual management and prognosis of patients. In a study published in Science on July 13, teams from AP-HP, Inserm, Université of Paris, Institut Pasteur and Institut Imagine describe a unique and unexpected immunological phenotype in severe and critical patients, consisting of a severely impaired response of interferon (IFN) type I, associated with a persistent blood viral load and an excessive inflammatory response. These data suggest that IFN type I deficiency in the blood could be a hallmark of severe forms of Covid-19. It also supports the potential value of therapeutic approaches that combine early administration of IFN, with appropriate anti-inflammatory therapy targeting IL-6 or TNF-α, in patients preventing severe disease forms.
Approximately 5% of people with Covid-19 progress to a severe or critical form, including the development of severe pneumonia that progresses to acute respiratory distress syndrome. While these forms sometimes occur early in the course of the disease, clinical observations generally describe a two-stage progression of the disease, beginning with a mild to moderate form, followed by respiratory aggravation 9 to 12 days after the onset of the first symptoms. This sudden progression suggests deregulation of the host inflammatory response. A growing number of indications suggest that this aggravation is caused by a large increase in cytokines. This runaway inflammatory response is correlated with massive infiltration in the lungs of innate immune cells, namely neutrophils and monocytes, creating lung damage and acute respiratory distress syndrome.
By analogy with a genetic disease leading to a similar pulmonary pathology identified at Institut Imagine by the team of Inserm researcher Frédéric Rieux-Laucat, the initial hypothesis assumed excessive production of interferon (IFN) type I, a marker of the response to infections. However, in seriously ill patients, the teams of Darragh Duffy (Dendritic Cell Immunobiology Unit, Institut Pasteur/Inserm), Frédéric Rieux-Laucat (Laboratory of Immunogenetics of Pediatric Autoimmune Diseases at Institut Imagine - Inserm/Université de Paris), Solen Kernéis (Mobile Infectiology Team, AP-HP. Centre - Université of Paris) and Benjamin Terrier (Department of Internal Medicine, AP-HP. Centre - Université of Paris) show that the production and activity of type-I IFN are strongly reduced in the most severe forms of Covid-19. In addition, there is a persistent blood viral load, indicating poor control of viral replication by the patient's immune system which leads to an ineffective and pathological inflammatory response. The inflammation, caused by the transcription factor NF-kB, also leads to increased production and signaling of tumor necrosis factor (TNF)-alpha and the pro-inflammatory cytokine interleukin IL-6.
Distinct type-I IFN responses may be characteristic of each stage of the disease
This low signature of type-I IFN differs from the response induced by other respiratory viruses such as human respiratory syncytial virus (RSV) or influenza A virus, both of which are characterized by high production of type-I IFN.
The study also showed that low levels of type-I IFN in plasma precede clinical worsening and transfer to intensive care. Levels of circulating Type 1 IFN could even characterize each stage of disease, with the lowest levels observed in the most severe patients. These results suggest that in SARS-CoV-2 infection, the production of type-I IFN is inhibited in the infected host, which could explain the more frequent severe forms in individuals with low production of this cytokine, such as the elderly or those with co-morbidities.
Therefore, type-I IFN deficiency could be a signature of severe forms of COVID-19 and could identify a high-risk population.
These results further suggest that the administration of IFN-alpha/Beta combined with anti-inflammatory therapy targeting IL-6 or TNF-α, or corticosteroids such as dexamethasone, in the most severe patients could be a therapeutic avenue to be evaluated for severe forms of COVID-19.
Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients, Science, 13 juillet 2020
Jérôme Hadjadj1,2,*, Nader Yatim2,3,*, Laura Barnabei1, Aurélien Corneau4, Jeremy Boussier3, Nikaïa Smith3, Hélène Péré5,6, Bruno Charbit7, Vincent Bondet3, Camille Chenevier-Gobeaux8, Paul Breillat2, Nicolas Carlier9, Rémy Gauzit10, Caroline Morbieu2, Frédéric Pène11, Nathalie Marin11, Nicolas Roche9, Tali-Anne Szwebel2, Sarah H Merkling12, Jean-Marc Treluyer13, David Veyer5, Luc Mouthon2, Catherine Blanc4, Pierre-Louis Tharaux6, Flore Rozenberg14, Alain Fischer1,15,16, Darragh Duffy3,7,†, Frédéric Rieux-Laucat1,†, Solen Kernéis10,17,†, Benjamin Terrier2,6,†,‡
1 Imagine institute, laboratory of Immunogenetics of Pediatric Autoimmune Diseases, INSERM UMR 1163, Université de Paris, F-75015, Paris.
2 Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Assistance Publique Hôpitaux de Paris-Centre (APHP-CUP), Université de Paris, F-75014, Paris.
3 Laboratory of Dendritic Cell Immunobiology, Inserm U1223, Department of Immunology, Institut Pasteur, F-75015, Paris.
4 Sorbonne Université, Faculté de médecine, UMS037, PASS, Plateforme de cytométrie de la Pitié-Salpêtrière CyPS, F-75013, Paris.
5 Department of Virology, APHP-CUP, Université de Paris, F-75015, Paris.
6 PARCC, INSERM U970, Paris.
7 Cytometry and Biomarkers UTechS, CRT, Institut Pasteur, F-75015, Paris.
8 Department of Automated Diagnostic Biology, APHP-CUP, F-75014, Paris.
9 Department of Pulmonology, APHP-CUP, Institut Cochin, UMR 1016, Université de Paris, F-75014, Paris.
10 Equipe Mobile d’Infectiologie, APHP-CUP, Université de Paris, F-75014, Paris.
11 Medical intensive care unit, APHP-CUP, Institut Cochin, INSERM U1016, CNRS UMR 8104, Université de Paris, F-75014, Paris.
12 Insect-Virus Interactions Unit, Institut Pasteur, UMR2000, CNRS, Paris.
13 Centre Régional de Pharmacovigilance, APHP-CUP, Université de Paris, F-75014, Paris.
14 Department of Virology, APHP-CUP, Université de Paris, F-75014, Paris.
15 Unité d’immunologie hématologie et rhumatologie pédiatriques, APHP-CUP, Université de Paris, F-75015, Paris.
16 Collège de France, Paris.
17 Epidémiologie et modélisation de la résistance aux antimicrobiens, Institut Pasteur, F-75015, Paris, France.