Adverse events of special interest for COVID-19 vaccines - background incidences vary by sex, age and time period and are affected by the pandemic (preprint)

Background With large-scale COVID-19 vaccination implemented world-wide, safety signals needing rapid evaluation will emerge. We report population-based, age- and-sex-specific background incidence rates of conditions representing potential vaccine adverse events of special interest (AESI) for the Swedish general population using register data. Methods We studied an age/sex-stratified random 10% sample of the Swedish population on 1 Jan 2020, followed for AESI outcomes during 1 year, as the COVID-19 pandemic emerged and developed, before the start of vaccinations. We selected and defined the following outcomes based on information from regulatory authorities, large-scale adverse events initiatives and previous studies: aseptic meningitis, febrile seizure, Kawasaki syndrome, MISC, post-infectious arthritis, arthritis, myocarditis, ARDS, myocardial infarction, stroke, ischemic stroke, hemorrhagic stroke, venous thromboembolism, pulmonary embolism, kidney failure, liver failure, erythema multiforme, disseminated intravascular coagulation, autoimmune thyroiditis, and appendicitis. We calculated incidence rates stratified by age, sex and time period (quarters of 2020), and classified them using Council of International Organizations of Medical Sciences (CIOMS) categories: very common, common, uncommon, rare, or very rare. Results We included 972,723 study subjects, representing the Swedish national population on 1 Jan 2020. We found that AESI incidence rates vary greatly by age and in some cases sex. Several common AESIs showed expected increase with age, while some (e.g. appendicitis, aseptic meningitis, autoimmune thyroiditis, Kawasaki syndrome and MISC) were more common in young people, and others exhibited a flatter age pattern (e.g. myocarditis, DIC and erythema multiforme). Consequently, the CIOMS classification for AESIs varied widely according to age. Considerable variability was suggested for some AESI rates across the 4 quarters of 2020, potentially related to pandemic waves, seasonal variation, healthcare system overload or other healthcare delivery effects. Conclusion Age, sex, and timing of rates are important to consider when background AESI rates are compared to corresponding rates observed with COVID-19 vaccines.

Risk factors for COVID-19-related death, hospitalization and intensive care: A population-wide study of all inhabitants in Stockholm (preprint)

Since the beginning of the Covid-19 pandemic, the scientific community has explored determinants of Covid 19 disease severity. However, the majority of studies are based on in-hospital patients with high risk of collider- or selection bias. The present investigation details risk factors associated with overall mortality, hospitalization and intensive care unit (ICU) admission in Covid-19 infections, with complete population coverage and high-resolution data on patient characteristics and comorbid conditions. Methods: This population-based observational study comprises all residents 18 years and older in Stockholm Region – 1.8 million inhabitants - using the real-time Covid-19 monitoring framework. The observation period lasted between March 1 to December 31, 2020. Hazard ratios (HR) for risk factors of Covid-19 disease severity were assessed using Cox proportional hazard models. Results: In total, 3,322 deaths, 11,508 hospitalizations and 1,423 ICU-admissions related to Covid-19 occurred during the study period. Kidney failure, diabetes and obesity increased risk of mortality and so did heart failure and ischemic heart disease. However, atrial fibrillation and hypertension did not. Risk of hospitalization follow a similar pattern, whereas admission to intensive care differs; triage processes where clearly present as certain co-morbid conditions were associated with lower ICU-admission. Conclusions: Observed differences in risk of mortality and hospitalization among patients with Covid 19 raise important questions about potentially protective co-medication which will be further addressed using the real-time Covid-19 monitoring framework.

Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19 (preprint)

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.