Résilience - COVID-19 - Résilience - Coronavirus disease 2019

Pronostic value of type I ANTi-Interferon antibodies in patients with COVID-19 acute respiratory failure: a multicenter observational study – ANTICOV

Auto-antibodies against type I interferons in critically ill COVID-19 patients: a prospective multicentre study

SARS-CoV-2 infection leads to a broad spectrum of symptoms with a large inter-individual variability. Impaired interferon (IFN) type I response seems to be involved in patients with severe SARS-CoV-2 infection. Auto-antibodies (auto-Abs) neutralizing type I IFN-a2 and IFN-? were found in 10% of severe COVID-19 cases . Dertermining whether auto-Abs neutralizing type I IFNs are associated with outcomes in critically ill patients with COVID-19 could lead to specific therapeutic interventions.

We conducted a prospective multicentre study including 11 intensive care units (ICU). Patients hospitalized in ICU with proven SARS-CoV-2 infection and acute respiratory failure requiring oxygen or mechanical ventilation support were included. Our objectives were to compare the mortality of patients with versus without auto-Abs neutralizing type I IFNs, assess the rate of positivity of auto-Abs and the factors associated with their positivity.

Human anti-IFN-a detection was performed using ELISA.
The functional evaluation of anti-cytokine auto-Abs was performed as follows: the blocking activity of anti-IFN-a2 and anti-IFN-? auto-Abs was determined with a reporter luciferase activity.

925 critically ill COVID-19 patients were included in the study between March 2020 and May 2021. Auto-Abs neutralizing type I IFN were found in 96 patients (10.3%): partitioned as follows: 78.3% had auto-Abs against IFN-a2, 74% against IFN-? and 12.5% against IFN-ß.
Baseline characteristics did not differ between patients with and without auto-Abs (Table 1). At ICU admission, positive patients required a higher FiO2 (100% (70-100) vs 90% (60-100), p=0.01), and more frequently met the diagnosis criteria for the acute respiratory distress syndrome (92.7% vs 77.6%, p=0.0005). Mortality at day 28 was not different between groups (18.7% vs 23.7%, p=0.279). In multivariate multivariable analysis, variables associated with 28-days mortality were age (adjusted odds ratio (aOR)=1.06 [1.04-1.08], p< 0.001), SOFA score (aOR=1.18 [1.12-1.23, p<0.001) and immunosuppression (aOR=1.82 [1.1-3.0], p = 0.02) were associated with 28-days mortality, but auto-Abs positivity was not (aOR=0.69 [0.38-1.26], p=0.23).
There was a non-significant trend towards a higher proportion of men among positive patients (78.1 vs 69.6%) contrasting with previous studies the reporting previous finding that auto-Abs were in almost uniquely detected in men (94%)1. Compared to women without auto-Abs, positive women were significantly younger (45 (24-62) vs 60 years (45.5-67.5)) and more frequently displayed an auto-immune background with more frequent positive anti-nuclear antibody (27.8% vs 4%, p=0.003). They required more frequent invasive mechanical ventilation (71.4% vs 46.8%, p = 0.04) at ICU admission but 28-days mortality was not different. A higher rate of auto-Abs against IFN-ß (33.3%) was found than in men.

In ICU patients, auto-Abs against type I IFNs are present in 10% of patients but are not associated with worse outcomeshigher 28_days mortality. Positive women seem to have an auto-immune background and more frequently required mechanical ventilation.

An abstract has been submitted to the 2022 meeting of the French Intensive Care Society.

Severe SARS-CoV-2 infections are frequently associated with the acute respiratory distress syndrome (ARDS), which leads to a mortality of 30-40%. An altered type I interferon (IFN) response has been demonstrated in patients with severe COVID-19, together with a high viral load. A recent study revealed that 10% of patients admitted in the intensive care unit (ICU) for severe COVID-19 had positive type I anti-IFN antibodies. Such finding has potentially important therapeutic implications, as patients having positive anti-IFN antibodies could benefit from targeted interventions, including plasmapheresis.
The primary objectives of the current work are, in a large cohort of patients with severe COVID-19 admitted in the ICU, to determine the prevalence of patients with positive anti-IFN antibodies and to determine their outcome, as compared to patients having negative anti-IFN antibodies.
Secondary objectives include the study of the association between type I anti-IFN antibody positivity and other auto-antibodies (e.g., anti-cardiolipin, anti-nuclear antibody, anti-neutrophil cytoplasmic antibody (ANCA), rhumatoid factor, anti-smooth muscle antibody, anti-cytokine antibodies).
A biobanking will be performed in the Immunology Laboratory, Henri Mondor Hospital, Créteil, France, under the responsibility of Pr Sophie Hüe, who will be in charge of assaying anti-IFN antibodies and other auto-immunity tests using ELISA. Positive sera for anti-IFN antibodies will be shipped at the GHMI Laboratory (Institut Imagine, Paris, France) under the responsibility of Dr Paul Bastard and Pr Casanova and reanalysed using a reference method (Bastard et al. Science 2020).
This is a multicenter (13 participating centers) retro-prospective cohort study including critically-ill COVID-19 patients admitted in the intensive care unit. The study has been approved by the Centre de Protection des Personnes Nord Ouest IV on November 5th 2020 (# EudraCT : 2020-A03009-30) and has been registered on Clinical trials.gov (NCT 04733105). The minimal number of patients to be included is 530 and the follow-up duration is 28 days. Inclusions of COVID-19 patients have started on November 19th 2020. By March 1st 2021, more than 650 patients have been included in the cohort.
The ANTICOV study will provide large scale granular data and allow for assessing whether anti-IFN auto-antibodies are independently associated with day 28 mortality, after adjusting on major outcome confounders. Additionally, other anti-cytokines antibodies and auto-immunity tests will also be performed to explore the underlying auto-immunity of patients having IFN auto-antibodies or not, thus allowing to explore the role of extrafollicular B cell activation in these patients, and eventually, delineate the most suitable therapeutic approach.

Project coordination

Nicolas De Prost (DMU APHP.Mondor : MEDECINE)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.



Help of the ANR 67,200 euros
Beginning and duration of the scientific project: April 2021 - 12 Months

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