Lack of association between HLA and asymptomatic SARS-CoV-2 infection (preprint)

Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B*15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B*15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the US (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B*15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified. These findings suggest that memory T-cell immunity to seasonal coronaviruses does not strongly influence the outcome of SARS-CoV-2 infection in unvaccinated individuals.

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with critical COVID-19 (preprint)

Background We previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and autoantibodies against type I IFN in another 15-20% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI:1.5-528.7, P=1.1x10-4), in analyses restricted to biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70 [95%CI:1.3-8.2], P=2.1x10-4). Adding the recently reported TYK2 COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4]; P=3.4x10-3). When these 14 loci and TLR7 were considered, all individuals hemizygous (n=20) or homozygous (n=5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0], P=4.7x10-7), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9], P=0.02). Finally, the patients 13 with pLOF or bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10-5). Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie lifethreatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

Cumulative Incidence of SARS-CoV-2 Infection and Associated Risk Factors Among Frontline Health Care Workers in Paris, France: The SEROCOV Prospective Cohort Study (preprint)

Objective: With the COVID-19 pandemic, documenting whether health care workers (HCWs) are at increased risk of SARS-CoV-2 contamination and identifying risk factors is of major concern. Methods In this multicenter prospective cohort study, HCWs from frontline departments were included in March and April 2020 and followed for 3 months. SARS-CoV-2 serology was performed at month 0 (M0), M1, and M3 and RT-PCR in case of symptoms. The primary outcome was laboratory-confirmed SARS-CoV-2 infection at M3. Risk factors of laboratory-confirmed SARS-CoV-2 infection at M3 were identified by multivariate logistic regression. Results Among 1,062 HCWs (median [interquartile range] age, 33 [28-42] years; 758 [71.4%] women; 321 [30.2%] physicians), the cumulative incidence of SARS-CoV-2 infection at M3 was 14.6% (95% confidence interval [CI] [12.5; 16.9]). Risk factors were the working department specialty, with increased risk for intensive care units (odds ratio 1.80, 95%CI [0.38; 8.58]), emergency departments (3.91 [0.83; 18.43]) and infectious diseases departments (4.22 [0.92; 18.28]); active smoking was associated with reduced risk (0.36 [0.21; 0.63]). Age, sex, professional category, number of years of experience in the job or department, and public transportation use were not significantly associated with laboratory-confirmed SARS-CoV-2 infection at M3. Conclusion The rate of SARS-CoV-2 infection in frontline HCWs was 14.6% at the end of the first COVID-19 wave in Paris and occurred mainly early. The study argues for an origin of professional in addition to private life contamination and therefore including HCWs in the first-line vaccination target population. It also highlights that smokers were at lower risk. Trial registration: The study has been registered on ClinicalTrials.gov: NCT04304690 first registered on 11/03/2020.

SARS-COV-2 VIRUS INFECTED PATIENT IDENTIFICATION THROUGH CANINE OLFACTIVE DETECTION ON AXILLARY SWEAT SAMPLES (preprint)

Facing the COVID-19 pandemic, testing individuals in order to promptly isolate positive people is one of the key actions. One approach to rapid testing might be to consider the olfactory capacities of trained detection dogs in order to develop a non-invasive, rapid and cheap mass detection approach, through the Volatile Organic Compounds (VOCs) signature of SARS-CoV-2 infection. The goal of this study is to determine the individual values of sensitivity and specificity of trained dogs when performing olfactory detection of COVID-19 on axillary sweat samples. A group of 7 dogs was tested on a total of 218 samples (62 positive and 156 negative), completely unknown to the dogs, following a randomised and double-blinded protocol carried out on olfaction cone line-ups. To ensure a wide olfactory range as close as possible to operational conditions, the samples were retrieved from 13 different sites. Sensitivities vary from 87 to 94p100 for 6 dogs, and are above 90p100 for 3 of them. Only one dog, whose sensitivity was 60p100, was not selected to continue the study and enter the operational stage. Sensitivity results vary from 78 to 92p100, with 6 dogs over 85p100 and 4 over 90p100. Thanks to these results, a virtual approach of Positive and Negative Predilection Values (PPV and NPV) was designed, based on an almost perfect diagnostic tool as reference and for increasing prevalence values of SARS-CoV-2 infection. The studies to come on olfactory detection of COVID-19 by dogs will still face several challenges, but the accumulation of positive and encouraging results suggest that it may play an important part in mass COVID-19 pre-testing situations.

Cumulative incidence of SARS-CoV-2 infection and associated risk factors among frontline health care workers in Paris, France: the SEROCOV prospective cohort study (preprint)

BackgroundWith the COVID-19 pandemic, documenting whether health care workers (HCWs) are at increased risk of SARS-CoV-2 contamination and identifying risk factors is of major concern. MethodsIn this multicenter prospective cohort study, HCWs from frontline departments were included in March and April 2020 and followed for 3 months. SARS-CoV-2 serology was performed at month 0 (M0), M1, and M3 and RT-PCR in case of symptoms. The primary outcome was laboratory-confirmed SARS-CoV-2 infection at M3. Risk factors of laboratory-confirmed SARS-CoV-2 infection at M3 were identified by multivariate logistic regression. ResultsAmong 1,062 HCWs (median [interquartile range] age, 33 [28-42] years; 758 [71.4%] women; 321 [30.2%] physicians), the cumulative incidence of SARS-CoV-2 infection at M3 was 14.6% (95% confidence interval [CI] [12.5; 16.9]). Risk factors were the working department specialty, with increased risk for intensive care units (odds ratio 1.80, 95%CI [0.38; 8.58]), emergency departments (3.91 [0.83; 18.43]) and infectious diseases departments (4.22 [0.92; 18.28]); active smoking was associated with reduced risk (0.36 [0.21; 0.63]). Age, sex, professional category, number of years of experience in the job or department, and public transportation use were not significantly associated with laboratory-confirmed SARS-CoV-2 infection at M3. ConclusionThe rate of SARS-CoV-2 infection in frontline HCWs was 14.6% at the end of the first COVID-19 wave in Paris and occurred mainly early. The study argues for an origin of professional in addition to private life contamination and therefore including HCWs in the first-line vaccination target population. It also highlights that smokers were at lower risk. Key messagesO_LIDuring the first epidemic wave, 14.6% of 1,062 first-line Health Care Workers had a positive serology and/or RT-PCR test for SARS-CoV-2. C_LIO_LIMost infections occurred early C_LIO_LIRisk was increased by working in infectious diseases (OR 4.22, 95% confidence interval [0.92; 18.28]), emergency (3.91 [0.83; 18.43]) and intensive care units (1.80, [0.38; 8.58]) C_LIO_LIBeing an active smoker was protective (0.36 [0.21; 0.3]). C_LI

Cumulative Incidence of SARS-CoV-2 Infection and Associated Risk Factors Among Frontline Health Care Workers in Paris, France: The SEROCOV Prospective Cohort Study (preprint)

Background: With the COVID-19 pandemic, documenting whether health care workers (HCWs) are at increased risk of SARS-CoV-2 contamination and identifying risk factors is of major concern.Methods: In this multicenter prospective cohort study, HCWs from COVID-19 frontline departments were included in March and April 2020 and followed for 3 months. SARS-CoV-2 serology was performed at month 0 (M0), M1, and M3 and RT-PCR in case of symptoms. The primary outcome was laboratory-confirmed SARS-CoV-2 infection (positive serology and/or positive RT-PCR result) at M3. Secondary outcomes were positive serology for SARS-CoV-2 at M0, M1 and M3. Risk factors of laboratory-confirmed SARS-CoV-2 infection at M3 were identified by multivariate logistic regression.Findings: Among 1,062 HCWs (median [interquartile range] age, 33 [28-42] years; 758 [71.4%] women; 321 [30.2%] physicians), the cumulative incidence of SARS-CoV-2 infection at M3 was 14.6% (95% confidence interval [CI] [12.5; 16.9]). Seroprevalence at M0, M1, and M3 was 5.9% [4.7; 7.5], 12.9% [10.9; 15.1] and 13.0% [11.1; 15.2], respectively. Risk factors were the working department specialty, with increased risk for intensive care units (odds ratio 1.80, 95%CI [0.38; 8.58]), emergency departments (3.91 [0.83; 18.43]) and infectious diseases departments (4.22 [0.92; 18.28]); active smoking was associated with reduced risk (0.36 [0.21; 0.63]). Age, sex, professional category, number of years of experience in the job or department, and public transportation use were not significantly associated with laboratory-confirmed SARS-CoV-2 infection at M3.Interpretation: The rate of SARS-CoV-2 infection in frontline HCWs was 14.6% at the end of the first COVID-19 wave in Paris and occurred mainly early. Seroprevalence in May was higher than in the general population. The study argues for an origin of professional in addition to private life contamination and therefore including HCWs in the first-line vaccination target population. It also highlights that smokers were at lower risk.Trial Registration: The study is registered on ClinicalTrials.gov: NCT04304690Funding Statement: The sponsor of the study was Assistance Publique-Hôpitaux de Paris (AP-HP), with study management by URC Pitié-Salpêtrière. This study was funded by the French Ministry of Health (Programme Hospitalier de Recherche Clinique) and the French Agency for Research (Fond d’amorçage de l’Agence National pour la Recherche).Declaration of Interests: None to declare. Ethics Approval Statement: The SEROCOV study was approved by the ethics committee (CPP Sud-Ouest et Outre-Mer I, approval no. 2-20-023 id7257) and all participants signed informed consent before inclusion.

Emergency calls are early indicators of ICU bed requirement during the COVID-19 epidemic A retrospective study in Ile-de-France region, France (preprint)

Background: The aim of our retrospective study was to evaluate the earliest COVID19-related signal to anticipate requirements of intensive care unit (ICU) beds. Although the number of ICU beds is crucial during the COVID-19 epidemic, there is no recognized early indicator to anticipate it. Methods: In the Ile-de-France region, from February 20 to May 5, 2020, emergency medical service (EMS) calls and the response provided (ambulances) together the percentage of positive reverse transcriptase polymerase chain reaction (RT-PCR) tests, general practitioner (GP) and emergency department (ED) visits, and hospital admissions of COVID-19 patients were recorded daily and compared to the number of ICU patients. Correlation curve analysis was performed to determine the best correlation coefficient, depending on the number of days the indicator has been shifted. Primary endpoint was the number of ICU patients. Results: EMS calls, percentage of positive RT-PCR tests, ambulances used, ED and GP visits of COVID-19 patients were strongly associated with COVID-19 ICU patients with an anticipation delay of 23, 15, 14, 13, and 12 days respectively. Hospitalization did not anticipate ICU bed requirement. Conclusion: The daily number of COVID19-related telephone calls received by the EMS and corresponding dispatch ambulances, and the proportion of positive RT-PCR tests were the earliest indicators of the number of COVID19 patients requiring ICU care during the epidemic crisis, rapidly followed by ED and GP visits. This information may help health authorities to anticipate a future epidemic, including a second wave of COVID19 or decide additional social measures.

Low rate of daily smokers in patients with symptomatic COVID-19 (preprint)

Background: Identification of prognostic factors in COVID-19 remains a global challenge. The role of smoking is still controversial. Objective: To evaluate the rate of daily smokers in patients with COVID-19. Methods: COVID-19 in-and outpatients from a large French university hospital were systematically interviewed for their smoking status, use of e-cigarette and nicotinic substitutes. The rates of daily smokers in in-and outpatients were compared to those in the 2019 French general population, after standardization for sex and age. Results: The inpatient group was composed of 340 patients, median age 66 years: 203 men (59.7%) and 137 women (40.3%), median age for both 66 years, with a daily smokers rate of 4.1 % CI95% [2.3-6.9] (5.4% of men, 2.2% of women). The outpatient group was composed of 139 patients, median age 44 years: 62 men (44.6%, median age 43 years), and 77 women (55.4%, median age 44 years). The daily smoker rate was 6.1 % CI 95% [2.7-11.6] (5.1% of men, 6.8% of women). In the 2019 French population, the daily smoker rate was 24.0% (27.5% of men, 20.7% of women). Among inpatients, daily smokers represented 2.2% and 3.4% of the 45 dead patients and of the 29 patients transferred to ICU, respectively. The rate of daily smokers was significantly lower in COVID-19 patients, as compared to that in the French general population after standardization by age and sex, with Standardized Incidence Ratios of 0.24 [0.12-0.48] for outpatients and 0.24 [0.14-0.40] for inpatients. Conclusion: Daily smokers rate in patients with symptomatic COVID-19 is lower as compared to the general population