Mortality in COVID-19 amongst women on Hormone Replacement Therapy or Combined Oral Contraception: A cohort study (preprint)

ObjectiveTo investigate the association between Hormone Replacement Therapy (HRT) or Combined Oral Contraception (COCP) use, and the likelihood of death in women with COVID-19. DesignA cohort study Setting465 general practices in England within the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) primary care database. Population1,863,478 women aged over 18 years MethodsWe identified a cohort of women with COVID-19 from the computerised medical records of the RCGP RSC database. Mixed-effects logistic regression models were used to quantify the association between HRT or COCP use, and all-cause mortality among women with COVID-19 in unadjusted and adjusted models. ResultsThere were 5451 COVID-19 cases within the cohort. HRT was associated with a significantly lower likelihood of all-cause mortality in COVID-19 (adjusted OR 0.22, 95%{square}CI 0.05 to 0.94). There were no reported events for all-cause mortality in women prescribed COCPs. This prevented further examination of the impact of COCP. ConclusionsWomen on HRT with COVID-19 had a lower likelihood of death. Further work is needed in larger cohorts to examine the association of COCP in COVID-19. Our findings support the current hypothesis that oestrogens may contribute a protective effect against COVID-19 severity. FundingThis study was funded by a School for Primary Care National Institute for Health Research grant (SPCR2014-10043).

Effectiveness of First Dose of COVID-19 Vaccines Against Hospital Admissions in Scotland: National Prospective Cohort Study of 5.4 Million People (preprint)

Background: The BNT162b2 mRNA (Pfizer-BioNTech) and ChAdOx1 (Oxford-AstraZeneca) COVID-19 vaccines have demonstrated high efficacy against infection in phase 3 clinical trials and are now being used in national vaccination programmes in the UK and several other countries. There is an urgent need to study the ‘real-world’ effects of these vaccines. The aim of our study was to estimate the effectiveness of the first dose of these COVID-19 vaccines in preventing hospital admissions.Methods: We conducted a prospective cohort study using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) database comprising of linked vaccination, primary care, Real-Time Polymerase Chain Reaction (RT-PCR) testing, hospitalisation and mortality records for 5.4 million people in Scotland (covering ~99% of population). A time-dependent Cox model and Poisson regression models were fitted to estimate effectiveness against COVID-19 related hospitalisation (defined as 1- Adjusted Hazard Ratio) following the first dose of vaccine.Findings: The first dose of the BNT162b2 vaccine was associated with a vaccine effect of 85% (95% confidence interval [CI] 76 to 91) for COVID-19 related hospitalisation at 28-34 days post-vaccination. Vaccine effect at the same time interval for the ChAdOx1 vaccine was 94% (95% CI 73 to 99). Results of combined vaccine effect for prevention of COVID-19 related hospitalisation were comparable when restricting the analysis to those aged ≥80 years (81%; 95% CI 65 to 90 at 28-34 days post-vaccination).Interpretation: A single dose of the BNT162b2 mRNA and ChAdOx1 vaccines resulted in substantial reductions in the risk of COVID-19 related hospitalisation in Scotland.Funding: UK Research and Innovation (Medical Research Council); Research and Innovation Industrial Strategy Challenge Fund; Health Data Research UK.Conflict of Interest: AS is a member of the Scottish Government Chief Medical Officer’s COVID-19Advisory Group and the New and Emerging Respiratory Virus Threats (NERVTAG) Risk Stratification Subgroup. CRS declares funding from the MRC, NIHR, CSO and New Zealand Ministry for Business, Innovation and Employment and Health Research Council during the conduct of this study. SVK is co-chair of the Scottish Government’s Expert Reference Group on COVID-19 and ethnicity, is a member of the Scientific Advisory Group on Emergencies (SAGE) subgroup on ethnicity and acknowledges funding from a NRS Senior Clinical Fellowship, MRC and CSO. All other authors report no conflicts of interest.Ethical Approval: Approvals were obtained from the National Research Ethics Service Committee, Southeast Scotland 02 (reference number: 12/SS/0201) and Public Benefit and Privacy Panel for Health and Social Care (reference number: 1920-0279).

PRINCIPLE trial demonstrates scope for in-pandemic improvement in primary care antibiotic stewardship (preprint)

Background The Platform Randomised trial of INterventions against COVID-19 In older peoPLE (PRINCIPLE) trial has provided in-pandemic evidence of what does not work in the early primary care management of coronavirus-2019 disease (COVID-19). PRINCIPLE’s first finding was that azithromycin and doxycycline were not effective. Aim To explore the extent to which azithromycin and doxycycline were being used in-pandemic, and the scope for trial findings impacting on practice. Design and Setting We compared crude rates of prescribing and respiratory tract infections (RTI) in 2020, the pandemic year, with 2019, using the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC). Methods We used a negative binomial model including age-band, gender, socioeconomic status, and NHS region to compare azithromycin and doxycycline lower respiratory tract infections (LRTI), upper respiratory tract infections (URTI), and influenza-like-illness (ILI) in 2020 with 2019; reporting incident rate ratios (IRR) between years and 95% confidence intervals (95%CI). Results Azithromycin prescriptions increased 7% in 2020 compared to 2019, whereas doxycycline decreased by 7%. Concurrently, LRTI and URTI incidence fell by over half (58.3% and 54.4% respectively) while ILI rose slightly (6.4%). The overall percentage of RTI prescribed azithromycin rose by 42.1% between 2019 and 2020, doxycycline increased by 33%. Our adjusted IRR showed azithromycin prescribing was 22% higher in 2020 (IRR=1.22, 95%CI:1.19-1.26, p<0.0001), for every unit rise in confirmed COVID there was an associated 3% rise in prescription (IRR=1.026, 95%CI 1.024-1.0285, p<0.0001); whereas these measures were static for doxycycline. Conclusion PRINCIPLE trial flags scope for improvement in antimicrobial stewardship.

Capital flows during the pandemic: lessons for a more resilient international financial architecture (preprint)

This paper explores how the sudden stop in capital flows to emerging market economies associated with the Covid-19 pandemic unfolded, the substantial policy responses that were needed to alleviate it, and the lessons we might draw from this episode. We identify four areas where further work could be undertaken to enhance the policy response to capital flow pressures in the future: (i) addressing data gaps — particularly gaps in the composition of portfolio flows, in flows to low income countries, and on the timeliness of macroprudential and capital flow management policy responses; (ii) improving the resilience of non-bank financial intermediation as a source of financing for emerging market economies; (iii) understanding the effectiveness of different policy mix responses; and (iv) ensuring the global financial safety net is sufficiently resilient to cope with future severe and sustained capital flow shocks.

The Impact of Primary Care Supported Shielding on the Risk of Mortality in People Vulnerable to COVID-19: English Sentinel Network Matched Cohort Study (preprint)

Background: There was excess mortality from the first wave of coronavirus 2019 infection (COVID-19), which mainly affected older people. To mitigate risk, the UK government recommended ‘shielding’ of vulnerable people through self-isolation for 12 weeks. We investigated the impact of primary care-reinforced shielding advice on all-cause mortality.Methods: We conducted a retrospective cohort study using a nationally representative English primary care database. We compare people aged >=40years who were recorded as being advised to shield using a fixed ratio of 1:1, matching (a mixture of exact and propensity score matching) to people with the same diagnoses not advised to shield (n=77,360 per group). Time-to-death was compared using Cox regression, reporting the hazard ratio (HR) of mortality between groups. A sensitivity analysis compared exact matched cohorts (n=24,752 shielded, n=61,566 exact matches). Findings: Over the follow-up period, we found a time-varying HR of mortality between groups. In the first 21 days, the mortality risk in people shielding was half those not (HR=0.50, 95%CI:0.41-0.59. p<0.0001). Over the remaining nine weeks, mortality risk was 54% higher in the shielded group (HR=1.54, 95%CI:1.41-1.70, p<0.0001). Beyond the shielding period, mortality risk was over two-and-a-half times higher in the shielded group (HR=2.61, 95%CI:2.38-2.87, p<0.0001).Interpretation: General practitioner-reinforced advice to shield halved the risk of mortality for 21 days compared to those who were not. Mortality risk became higher across the remainder of the shielding period, rising to two-and-a-half times greater post-shielding. Shielding may be beneficial in the next wave of COVID-19.Funding Statement: NIHR School of Primary Care, Public Health EnglandDeclaration of Interests: SdeL is the director of RCGP RSC. He has unrelated projects funded by GSK, Seqirus and has been a member of Global Advisory Boards for Seqirus and Sanofi. FDRH reports personal fees from Novartis and Boehringer Ingelheim and grants from Pfizer. All other authors declare no competing interests.Ethics Approval Statement: The RCGP RSC’s work concerning SARS-CoV-2 has been approved by Public Health England’s Caldicott Guardian Committee as fitting under Regulation 3 of the Health Service Control Patient Information Regulations 2002. The study was approved by RCGP.

Association of Age, Gender, Deprivation, Urbanicity, Ethnicity, and Smoking with a Positive Test for COVID-19 in an English Primary Care Surveillance Network: Cross Sectional Study of the First 500 Cases (preprint)

Background: There are few epidemiological studies of community cases in the current coronavirus-2019 (COVID-19) pandemic. We report on the first 500 COVID-19 cases identified through United Kingdom primary care surveillance and describe risk factors for testing COVID-19 positive. Methods: The Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC), is a nationally representative primary care sentinel network sharing pseudonymised data, including virological test data for COVID-19. We used multivariable logistic regression models with multiple imputation to identify risk factors for positive COVID-19 tests within this surveillance programme. Findings: We identified 3,802 COVID-19 results between 28/01/20 and 04/04/2020, 587 were positive. Greater odds of testing COVID-19 positive included: working-age people (40-64years) and older age, (≥75 years) versus 0-17 year olds (adjusted odds ratio [aOR] 5.26, 95%CI:3.26-8.49 and 5.17,95%CI:2.99-8.92, respectively); male gender (aOR 1.56, 95%CI:1.28-1.90); black and mixed ethnicity compared with white (aOR 4.55, 95%CI:2.55-8.10 and 1.84 95%CO:1.1-3.14, respectively)); urban compared with rural areas (aOR 4.58, 95%CI:3.57-5.88); people with chronic kidney disease (CKD) (aOR 1.88, 95%CI:1.29-2.75) and increasing body mass index (aOR 1.02, 95%CI:1.00-1.03). People in the least deprived deprivation quintile had lower odds of a positive test (aOR 0.49 95%CI:0.36-0.65) as did current smokers (aOR 0.53, 95%CI:0.38-0.74). Interpretation: A positive COVID-19 test result in primary care was associated with similar risk factors for severe outcomes seen in hospital settings, with the exception of smoking. We provide early evidence of potential sociodemographic factors associated with a positive test, including ethnicity, deprivation, population density, and CKD. Funding Statement: Public Health England provides the core funding for RCGP RSC, no specific funding was provided for this analysis.Declaration of Interests: The authors have no competing interests. SdeL is the Director of the Oxford RCGP RSC, RB, JS, FF, EK and GH are part funded by PHE; and CO and AC by a Wellcome Biomedical resources grant (212763/Z/18/Z). JD is funded by Wellcome Trust (216421/Z/19/Z).Ethics Approval Statement: This study was approved by the RCGP RSC study approval committee and was classified as a study of “usual practice”. Therefore, no further ethical approval was required.