ABSTRACT
SARS-CoV-2 infection fatality rate (IFR) doubles with every five years of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ~20% of deceased patients across age groups. In the general population, they are found in ~1% of individuals aged 20-70 years and in >4% of those >70 years old. With a sample of 1,261 deceased patients and 34,159 uninfected individuals, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to non-carriers. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRD was 17.0[95% CI:11.7-24.7] for individuals under 70 years old and 5.8[4.5-7.4] for individuals aged 70 and over, whereas, for autoantibodies neutralizing both molecules, the RRD was 188.3[44.8-774.4] and 7.2[5.0-10.3], respectively. IFRs increased with age, from 0.17%[0.12-0.31] for individuals <40 years old to 26.7%[20.3-35.2] for those ≥80 years old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84%[0.31-8.28] to 40.5%[27.82-61.20] for the same two age groups, for autoantibodies neutralizing both molecules. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, particularly those neutralizing both IFN-α2 and -ω. Remarkably, IFR increases with age, whereas RRD decreases with age. Autoimmunity to type I IFNs appears to be second only to age among common predictors of COVID-19 death.
Subject(s)
COVID-19ABSTRACT
Background: Severe coronavirus disease 2019 (Covid-19) is characterized by inflammation and coagulation in the presence of complement activation. Methods: We conducted an explorative phase 2 randomized, open label first part of an adaptive phase 2/3 trial of intravenous IFX-1, a monoclonal antibody selectively blocking the anaphylatoxin C5a, in adults with severe Covid-19. Patients were randomized between IFX-1 plus best supportive care (BSC) or BSC only. Results: 30 patients underwent randomization: 15 assigned to IFX-1 and 15 to BSC. PaO2/FiO2 ratio improvement on day 5, chosen as primary outcome parameter, did not show significant differences between groups. However, IFX-1 treatment was associated with consistent trends of improvement as evidenced by lower mortality rate, reduction in renal impairment, normalization of lymphocyte counts, and lowering of plasma lactate dehydrogenase concentrations. Kaplan-Meier estimates of mortality by 28 days were 13% for IFX-1 and 27% for BSC (HR for death, 0.56; 95%CI 0.09-3.74). Serious adverse events rates were comparable between groups but the rate of pulmonary embolisms was three-fold lower in the IFX-1 group (13%) compared to BSC group (40%). IFX-1 treatment was associated with significant increase of D-dimer levels suggesting a potential pro-fibrinolytic activity of anti-C5a treatment. Conclusion: In this exploratory part of the study, C5a inhibition with IFX-1 was shown to be safe in severe Covid-19. PaO2/FiO2 ratio at day five was comparable between groups, but consistent signals of benefit including a lower 28-day all-cause mortality rate, lower rate in impaired kidney function and a lower rate of pulmonary embolism warrant investigating C5a-inhibition with IFX-1 within a phase 3 trial.Trial Registration: This trial has been registered with the NIH, U.S. National Library of Medicine at ClinicalTrials.gov (NCT04333420). Funding Statement: The trial is funded by InflaRx GmbH.Declaration of Interests: NR and RG are founders, active officers and executive directors of InflaRx (InflaRx GmbH, InflaRx Pharmaceuticals Inc. and InflaRx N.V.) and hold shares and stock options in InflaRx. KP is Global Head of Clinical Development of InflaRx and holds stock options in InflaRx. SR is employee at Metronomia, a contracted statistical service provider for InflaRx. MW is supported by grants from the German Research Foundation, SFB-TR84 C6 and C9 and by the German Ministry of Education and Research in the framework of the CAPSyS (01ZX1304B) and the PROVID project (FKZ 01KI20160A). DvdB reports receiving departmental honoraria for serving on a scientific advisory board for InflaRx in 2017, paid to Amsterdam UMC. All other authors have no Conflict of Interest. Ethics Approval Statement: The study protocol was approved by the institutional review board of the Academic Medical Center, part of Amsterdam UMC, Amsterdam, the Netherlands (IRB: 2020_067#B2020179). If direct informed consent of patients was not feasible, patients could be included with a deferred consent procedure. All patients or their legally authorized representatives gave written informed consent for the study.