Clinical phenotypes and outcomes associated with SARS-CoV-2 variant Omicron, sublineages BA.1, BA.1.1, BA.2 and impact of mutational patterns in critically ill French patients with COVID-19 (preprint)

Infection with SARS-CoV-2 variant Omicron is considered to be less severe than infection with variant Delta, with a rarer occurrence of severe disease requiring intensive care. However, a substantial number of patients infected with variant Omicron still experienced severe COVID-19. Little information is available on comorbid factors, clinical conditions and specific viral mutational patterns associated with the severity of variant Omicron infection. In this multicenter prospective cohort study, patients consecutively admitted for severe COVID-19 in 20 participating intensive care units in France between December 7th 2021 and May 1st 2022 were included. Among 259 patients for whom SARS-CoV-2 variant lineage was determined, we show that the clinical phenotype of patients infected with variant Omicron (n = 148) was different from that in those infected with variant Delta (n = 111). We observed no significant relationship between Delta and Omicron variant lineages/sublineages and 28-day mortality (adjusted odds ratio [95% confidence interval] = 0.68 [0.35–1.32]; p = 0.253). Among Omicron-infected patients, 43.2% were immunocompromised, most of whom had received two doses of vaccine or more (85.9%) but displayed a poor humoral response to vaccination (mean difference in serum anti-spike IgG antibody titers between vaccinated and non-vaccinated immunocompromised patients: 1078 BAU/mL [-319.4; 2475.0]; p = 0.160). The mortality rate of immunocompromised patients infected with variant Omicron was significantly higher than that of non-immunocompromised patients (46.9% vs 26.2%; p = 0.009). In patients infected with variant Omicron, there was no association between specific sublineages (BA.1/BA.1.1 (n = 109) and BA.2 (n = 21)) or any viral genome polymorphisms or mutational profile and the 28-day mortality.

The risk of COVID-19 death is much greater and age-dependent with type I IFN autoantibodies (preprint)

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.

The 501Y.V2 SARS-CoV-2 variant has an intermediate viral load between the 501Y.V1 and the historical variants in nasopharyngeal samples from newly diagnosed COVID-19 patients (preprint)

The 501Y.V2 and the 501Y.V1 SARS-CoV-2 variants emerged and spread rapidly into the world. We analysed the RT-PCR cycle threshold values of 643 nasopharyngeal samples of COVID-19 patients at diagnosis and found that the 501Y.V2 variant presented an intermediate viral load between the 501Y.V1 and the historical variants.

SARS-CoV-2 variants of concern are associated with lower RT-PCR amplification cycles between January and March 2021 in France (preprint)

SARS-CoV-2 variants raise concern regarding the mortality caused by COVID-19 epidemics. We analyse 88,375 cycle amplification (Ct) values from variant-specific RT-PCR tests performed between January 26 and March 13, 2021. We estimate that on March 12, nearly 85% of the infections were caused by the V1 variant and that its transmission advantage over wild type strains was between 38 and 44%. We also find that tests positive for V1 and V2/V3 variants exhibit significantly lower cycle threshold (Ct) values.

Epidemiological and clinical insights from SARS-CoV-2 RT-PCR cycle amplification values (preprint)

The SARS-CoV-2 pandemic has led to an unprecedented daily use of molecular RT-PCR tests. These tests are interpreted qualitatively for diagnosis, and the relevance of the test result intensity, i.e. the number of amplification cycles (Ct), is debated because of strong potential biases. We analyze a national database of tests performed on more than 2 million individuals between January and November 2020. Although we find Ct values to vary depending on the testing laboratory or the assay used, we detect strong significant trends with patient age, number of days after symptoms onset, or the state of the epidemic (the temporal reproduction number) at the time of the test. These results suggest that Ct values can be used to improve short-term predictions for epidemic surveillance.

Pre-COVID-19 humoral immunity to common coronaviruses does not confer cross-protection against SARS-CoV-2 (preprint)

It is currently unknown whether acquired immunity to common alpha- and beta-coronaviruses provides cross-protection against SARS-CoV-2. In this study, we found that certain patient sera and intravenous immunoglobulins (IVIG) collected prior to the COVID-19 outbreak were cross-reactive to SARS-CoV-2 full-length Spike, S2 domain, and nucleoprotein. However, their presence did not translate into neutralizing activity against SARS-CoV-2 in vitro. Importantly, we detected serum IgG reactivity to common coronaviruses in the early sera of patients with severe COVID-19 before the appearance of anti-SARS-CoV-2 antibodies. Collectively, the results of our study indicate that pre-existing immunity to common coronaviruses does not confer cross-protection against SARS-CoV-2 in vivo.

Ventilator-Associated Pneumonia in Patients with SARS-CoV-2–Associated Acute Respiratory Failure Requiring Mechanical Ventilation: A Retrospective Cohort Study (preprint)

Background: Data on incidence, clinical presentation and outcomes of ventilator-associated pneumonia (VAP) in patients with severe coronavirus disease 2019 (COVID-19) pneumonia requiring mechanical ventilation (MV) are limited. Methods: . Case series of patients with COVID-19 pneumonia admitted to a single ICU in France. All consecutive patients requiring MV with RT-PCR–confirmed SARS-CoV-2 infection between March 12th and April 24 th , 2020 were included. Frequency, clinical characteristics, responsible pathogens and outcomes of VAP were assessed, and compared to an historical cohort of patients with severe influenza-associated pneumonia requiring MV admitted to the same ICU during the preceding three winter seasons. Results: : Among 54 consecutive patients with Covid-19–associated acute respiratory failure requiring MV included (median (IQR) age 48 (42-58) years; 74% male; 93% requiring venovenous-extracorporeal membrane oxygenation), 46 (85%) developed VAP (median (IQR) MV duration before the first episode, 11 (8-16) days). VAP-causative pathogens were predominantly Enterobacteriaceae (72%), particularly inducible AmpC-cephalosporinase producers (41%), followed by Pseudomonas aeruginosa (35%). VAP recurred in 46 (85%) patients and 17 (31%) died. Most recurrences were relapses (ie, infection with the same pathogen), with a high percentage occurring on adequate antimicrobial treatment. Despite a high P. aeruginosa -VAP rate in patients with influenza-associated ARDS, the pulmonary infection recurrence rate was significantly lower than in Covid-19 patients. Overall mortality was similar for the two groups. Conclusions: : Patients with severe Covid-19–associated acute respiratory failure requiring MV had a very high late-onset VAP rate. Inducible AmpC-cephalosporinase–producing Enterobacteriaceae and Pseudomonas aeruginosa frequently caused VAP, with multiple recurrences and difficulties eradicating the pathogen from the lung.

Early phylodynamics analysis of the COVID-19 epidemics in France (preprint)

France was one of the first countries to be reached by the COVID-19 pandemic. Here, we analyse 196 SARS-Cov-2 genomes collected between Jan 24 and Mar 24 2020, and perform a phylodynamics analysis. In particular, we analyse the doubling time, reproduction number (Rt) and infection duration associated with the epidemic wave that was detected in incidence data starting from Feb 27. Different models suggest a slowing down of the epidemic in Mar, which would be consistent with the implementation of the national lock-down on Mar 17. The inferred distributions for the effective infection duration and Rt are in line with those estimated from contact tracing data. Finally, based on the available sequence data, we estimate that the French epidemic wave originated between mid-Jan and early Feb. Overall, this analysis shows the potential to use sequence genomic data to inform public health decisions in an epidemic crisis context and calls for further analyses with denser sampling.