Indirect impact of the COVID-19 pandemic on emergency department presentations and hospital admissions for urgent early pregnancy conditions: a population-based retrospective cohort study (preprint)

Objective: To compare emergency department (ED) presentations and hospital admissions for urgent early pregnancy conditions in Victoria before and after the onset of COVID-19 lockdown on 31 March 2020. Design: Population-based retrospective cohort study Setting: Australian state of Victoria Population: Pregnant women presenting to emergency departments or admitted to hospital Methods: We obtained state-wide hospital separation data from the Victorian Emergency Minimum Dataset and the Victorian Admitted Episodes Dataset from January 1, 2018, to October 31, 2020. A linear prediction model based on the pre-COVID period was used to identify the impact of COVID restrictions. Main outcome measures: Monthly ED presentations for miscarriage and ectopic pregnancy, hospital admissions for termination of pregnancy, with subgroup analysis by region, socioeconomic status, disease acuity, hospital type. Results: There was an overall decline in monthly ED presentations and hospital admissions for early pregnancy conditions in metropolitan areas where lockdown restrictions were most stringent. Monthly ED presentations for miscarriage during the COVID period were consistently below predicted, with the nadir in April 2020 (790 observed vs 985 predicted, 95% CI 835-1135). Monthly admissions for termination of pregnancy were also below predicted throughout lockdown, with the nadir in August 2020 (893 observed vs 1116 predicted, 95% CI 905-1326). There was no increase in ED presentations for complications following abortion, ectopic or molar pregnancy during the COVID period. Conclusions: Fewer women in metropolitan Victoria utilized hospital-based care for early pregnancy conditions during the first seven months of the pandemic, without any observable increase in maternal morbidity.

Whole genome sequencing identifies multiple loci for critical illness caused by COVID-19 (preprint)

Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care1 or hospitalisation2;3;4 following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study is designed to compare genetic variants in critically-ill cases with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease. We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.

Genetic mechanisms of critical illness in Covid-19 (preprint)

The subset of patients who develop critical illness in Covid-19 have extensive inflammation affecting the lungs and are strikingly different from other patients: immunosuppressive therapy benefits critically-ill patients, but may harm some non-critical cases. Since susceptibility to life-threatening infections and immune-mediated diseases are both strongly heritable traits, we reasoned that host genetic variation may identify mechanistic targets for therapeutic development in Covid-19. GenOMICC (Genetics Of Mortality In Critical Care, genomicc.org) is a global collaborative study to understand the genetic basis of critical illness. Here we report the results of a genome-wide association study (GWAS) in 2790 critically-ill Covid-19 patients from 208 UK intensive care units (ICUs), representing >95% of all ICU beds. Random controls were drawn from three distinct UK population studies. We identify and replicate several novel genome-wide significant associations including variants chr19p13.3 (rs2109069, P = 3.98 x 10-12), within the gene encoding dipeptidyl peptidase 9 (DPP9), and at chr21q22.1 (rs2236757, P = 4.99 x 10-8) in the interferon receptor IFNAR2. Consistent with our focus on extreme disease in younger patients with less comorbidity, we detect a stronger signal at the known 3p21.31 locus than previous studies (rs73064425, P = 1.2 x 10-27). We identify potential targets for repurposing of existing licensed medications. Using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease. Transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. We detected genome-wide significant gene-level associations for genes with central roles in viral restriction (OAS1, OAS2, OAS3). These results identify specific loci associated with life-threatening disease, and potential targets for host-directed therapies. Randomised clinical trials will be necessary before any change to clinical practice.