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

BackgroundWe 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 auto-antibodies against type I IFN in another 15-20% of cases. MethodsWe 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. ResultsNo 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 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). ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening 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

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

Anal Dysplasia Among Patients With Multiple Human Papillomavirus Anal Lesions: Mosaic or Homogeneity?

Purpose@#Anal dysplasia is caused by chronic infection with the human papillomavirus and exposes to the risk of anal cancer. The aim of this study was to evaluate the distribution of dysplasia anal grade among patients operated on for multiple anal condylomas with no macroscopic differences. @*Methods@#This is a cross-sectional study of patients operated on for multiple anal condylomas including a mapping of dysplasia by performing systematically for each patient one biopsy on visible lesion from each of the 4 quadrants on anal margin and in anal canal. All biopsies were read independently by 2 different pathologists. @*Results@#Among 72 patients, 60 were men and 48 were human immunodeficiency virus (HIV)-infected with a median age of 37.5 years. The proportion of high-grade squamous intraepithelial lesion (HSIL) was higher in the anal canal (41.7%) compared to the margin (20.8%) (P = 0.004). HSIL frequency did not differ according to the quadrant (anterior, posterior, right, and left) of the 2 areas. HSIL on anal canal was not associated with HSIL on anal margin and vice versa (P = 0.390). Neither age nor sex was associated to HSIL but HIV positivity increased the risk of HSIL on the anal margin (P = 0.010). @*Conclusion@#Anal dysplasia is heterogeneously distributed in the anal canal as well as between anal canal and anal margin. The diagnostic of the grade of dysplasia for a person should require multiple biopsies on the canal and anal margin.

Anal Dysplasia Among Patients With Multiple Human Papillomavirus Anal Lesions: Mosaic or Homogeneity?

Purpose@#Anal dysplasia is caused by chronic infection with the human papillomavirus and exposes to the risk of anal cancer. The aim of this study was to evaluate the distribution of dysplasia anal grade among patients operated on for multiple anal condylomas with no macroscopic differences. @*Methods@#This is a cross-sectional study of patients operated on for multiple anal condylomas including a mapping of dysplasia by performing systematically for each patient one biopsy on visible lesion from each of the 4 quadrants on anal margin and in anal canal. All biopsies were read independently by 2 different pathologists. @*Results@#Among 72 patients, 60 were men and 48 were human immunodeficiency virus (HIV)-infected with a median age of 37.5 years. The proportion of high-grade squamous intraepithelial lesion (HSIL) was higher in the anal canal (41.7%) compared to the margin (20.8%) (P = 0.004). HSIL frequency did not differ according to the quadrant (anterior, posterior, right, and left) of the 2 areas. HSIL on anal canal was not associated with HSIL on anal margin and vice versa (P = 0.390). Neither age nor sex was associated to HSIL but HIV positivity increased the risk of HSIL on the anal margin (P = 0.010). @*Conclusion@#Anal dysplasia is heterogeneously distributed in the anal canal as well as between anal canal and anal margin. The diagnostic of the grade of dysplasia for a person should require multiple biopsies on the canal and anal margin.

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

BackgroundIdentification of prognostic factors in COVID-19 remains a global challenge. The role of smoking is still controversial. ObjectiveTo evaluate the rate of daily smokers in patients with COVID-19. MethodsCOVID-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. ResultsThe 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. ConclusionDaily smokers rate in patients with symptomatic COVID-19 is lower as compared to the general population