Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5x10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10−22 and p = 8.1x10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7x10−8) and ARHGAP33 (p = 1.3x10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

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One of the critical elements of antimicrobial stewardship programs is the ability to measure the quality of antibiotic prescriptions. The aims of the present study were to evaluate the performance properties of a set of previously developed quality indicators (QIs) and to identify the potential room for improvement in antibiotic use in our setting. A monthly cross-sectional point prevalence survey was conducted in a 400-bed acute care teaching hospital, from June to November 2015. All adult patients treated for ≥24 hours with antibiotic therapy for a suspected hospital- or community-acquired bacterial infection were included. Performance scores (adherence, room for improvement, interobserver reliability, and applicability) were calculated for 8 QIs. A total of 362 patients were evaluated. Adherence to the whole set of QIs was accomplished for 14.1% of evaluable patients. The QIs with greater room for improvement were adequate request for blood cultures (60.6%), therapeutic drug monitoring (TDM) (59.1%), sequential antibiotic therapy within 72 hours (48.2%), and empirical antibiotic therapy according to local guidelines (30.4%). The percentage of patients receiving unnecessary antibiotic treatment in the absence of clinical or microbiological evidence of infection after 5 days was 12.2%. All indicators scored kappa values of ≥0.6, suggesting good interobserver reliability. Low applicability (6.1% of reviewed patients) was found only for the TDM QI. The QIs analyzed were found to be applicable, showed good interobserver reliability, and were useful tools to identify areas with potential room for improvement in antibiotic use.