Ursodeoxycholic acid and severe COVID-19 outcomes in people with liver disease: a cohort study using the OpenSAFELY platform (preprint)

Biological evidence suggests ursodeoxycholic acid (UDCA) - a common treatment of cholestatic liver disease - may prevent severe COVID-19 outcomes. With the approval of NHS England, we conducted a population-based cohort study using primary care records, linked to death registration data and hospital records through the OpenSAFELY-TPP platform. We estimated the hazard of COVID-19 hospitalisation or death between 1 March 2020 and 31 December 2022, comparing UDCA treatment to no UDCA treatment in a population with indication. Of 11,320 eligible individuals, 642 were hospitalised or died with COVID-19 during follow-up, 402 (63%) events among UDCA users. After confounder adjustment, UDCA was associated with a 21% (95% CI 7%-33%) relative reduction in the hazard of COVID-19 hospitalisation or death, consistent with an absolute risk reduction of 1.3% (95% CI 1.0%-1.6%). Our findings support calls for clinical trials investigating UDCA as a preventative measure for severe COVID-19 outcomes.

A comparison of four self-controlled study designs in an analysis of COVID-19 vaccines and myocarditis using five European databases (preprint)

IntroductionThe aim of this study was to assess the possible extent of bias due to violation of a core assumption (event-dependent exposures) when using self-controlled designs to analyse the association between COVID-19 vaccines and myocarditis. MethodsWe used data from five European databases (Spain: BIFAP, FISABIO VID, and SIDIAP; Italy: ARS-Tuscany; England: CPRD Aurum) converted to the ConcePTION Common Data Model. Individuals who experienced both myocarditis and were vaccinated against COVID-19 between 1 September 2020 and the end of data availability in each country were included. We compared a self-controlled risk interval study (SCRI) using a pre-vaccination control window, an SCRI using a post-vaccination control window, a standard SCCS and an extension of the SCCS designed to handle violations of the assumption of event-dependent exposures. ResultsWe included 1,757 cases of myocarditis. In unadjusted analyses, agreement between study designs varied by vaccine brand. There was good agreement between all designs for AstraZeneca and Pfizer, but for Moderna we found harmful incidence rate ratios (IRR) using the standard and extended SCCS (standard SCCS: IRR = 3.12, 95%CI = 1.53 - 6.40; extended SCCS: IRR = 2.43, 95%CI = 1.11 - 5.33) compared with no association with the SCRIs (SCRI-pre: IRR = 0.60, 95%CI = 0.27 - 1.33; SCRI-post: IRR = 0.86, 95%CI = 0.34 - 2.19), although confidence intervals were wide. There was very good agreement between all designs for the unadjusted second dose analyses, confirming the known harmful association between the second dose of Moderna and Pfizer vaccines and myocarditis. ConclusionsIn the context of the known association between COVID-19 vaccines and myocarditis, we have demonstrated that two forms of SCRI and two forms of SCCS led to largely comparable results, possibly because of limited violation of the assumption of event-dependent exposures.

OpenSAFELY: Representativeness of Electronic Health Record platform OpenSAFELY-TPP data compared to the population of England. (preprint)

BackgroundSince its inception in March 2020, data from the OpenSAFELY-TPP electronic health record platform has been used for more than 50 studies relating to the global COVID-19 emergency. OpenSAFELY-TPP data is derived from practices in England using SystmOne software, and has been used for the majority of these studies. We set out to investigate the representativeness of OpenSAFELY-TPP data by comparing it to national population estimates. MethodsWith the approval of NHS England, we describe the age, sex, Index of Multiple Deprivation and ethnicity of the OpenSAFELY-TPP population compared to national estimates from the Office for National Statistics. The five leading causes of death occurring between the 1st January 2020 and the 31st December 2020 were also compared to deaths registered in England during the same period. ResultsDespite regional variations, TPP is largely representative of the general population of England in terms of IMD (all within 1.1 percentage points), age, sex (within 0.1 percentage points), ethnicity and causes of death. The proportion of the five leading causes of death is broadly similar to those reported by ONS (all within 1 percentage point). ConclusionsData made available via OpenSAFELY-TPP is broadly representative of the English population. SummaryUsers of OpenSAFELY must consider the issues of representativeness, generalisability and external validity associated with using TPP data for health research. Although the coverage of TPP practices varies regionally across England, TPP registered patients are generally representative of the English population as a whole in terms of key demographic characteristics. Key messagesO_LIThere is regional variability across England in terms of key population characteristics C_LIO_LIUsers of OpenSAFELY should carefully consider the issues of representativeness, generalisability and external validity associated with using TPP data for health research. C_LIO_LITPP registered patients are a representative sub-sample of the English population as a whole in terms of age, sex, IMD and ethnicity. C_LIO_LIThe proportions of the five leading causes of death in TPP in 2020 are broadly similar to those reported by ONS. C_LI

Effectiveness of BNT162b2 booster doses in England: an observational study in OpenSAFELY-TPP (preprint)

Background The UK COVID-19 vaccination programme delivered its first "booster" doses in September 2021, initially in groups at high risk of severe disease then across the adult population. The BNT162b2 Pfizer-BioNTech vaccine was used initially, with Moderna mRNA-1273 subsequently also used. Methods We used the OpenSAFELY-TPP database, covering 40% of English primary care practices and linked to national coronavirus surveillance, hospital episodes, and death registry data, to estimate the effectiveness of boosting with BNT162b2 compared with no boosting in eligible adults who had received two primary course vaccine doses between 16 September and 16 December 2021 when the Delta variant of SARS-CoV-2 was dominant. Follow up was for up to 10 weeks. Each booster recipient was matched with an unboosted control on factors relating to booster priority status and prior immunisation. Additional factors were adjusted for in Cox models estimating hazard ratios (HRs). Outcomes were positive SARS-CoV-2 test, COVID-19 hospitalisation, COVID-19 death and non-COVID-9 death. Booster vaccine effectiveness was defined as 1-HR. Results Among 4,352,417 BNT162b2 booster recipients matched with unboosted controls, estimated effectiveness of a booster dose compared with two doses only was 50.7% (95% CI 50.1-51.3) for positive SARS-CoV-2 test, 80.1% (78.3-81.8) for COVID-19 hospitalisation, 88.5% (85.0-91.1) for COVID-19 death, and 80.3% (79.0-81.5) for non-COVID-19 death. Estimated effectiveness was similar among those who had received a BNT162b2 or ChAdOx1-S two-dose primary vaccination course, but effectiveness against severe COVID-19 was slightly lower in those classified as clinically extremely vulnerable (76.3% (73.1-79.1) for COVID-19 hospitalisation, and 85.1% (79.6-89.1) for COVID-19 death). Estimated effectiveness against each outcome was lower in those aged 18-65 years than in those aged 65 and over. Conclusion Our findings are consistent with strong protection of BNT162b2 boosting against positive SARS-CoV-2 test, COVID-19 hospitalisation, and COVID-19 death.

Comparative effectiveness of sotrovimab and molnupiravir for prevention of severe COVID-19 outcomes in non-hospitalised patients: an observational cohort study using the OpenSAFELY platform (preprint)

Objective: To compare the effectiveness of sotrovimab (a neutralising monoclonal antibody) vs. molnupiravir (an antiviral) in preventing severe COVID-19 outcomes in non-hospitalised high-risk COVID-19 adult patients. Design: With the approval of NHS England, we conducted a real-world cohort study using the OpenSAFELY-TPP platform. Setting: Patient-level electronic health record data were obtained from 24 million people registered with a general practice in England that uses TPP software. The primary care data were securely linked with data on COVID-19 infection and therapeutics, hospital admission and death within the OpenSAFELY-TPP platform, covering a period where both medications were frequently prescribed in community settings. Participants: Non-hospitalised adult COVID-19 patients at high-risk of severe outcomes treated with sotrovimab or molnupiravir between December 16, 2021 and February 10, 2022. Interventions: Sotrovimab or molnupiravir administered in the community by COVID-19 Medicine Delivery Units. Main outcome measure: COVID-19 related hospitalisation or COVID-19 related death within 28 days after treatment initiation. Results: Patients treated with sotrovimab (n=3288) and molnupiravir (n=2663) were similar with respect to most baseline characteristics. The mean age of all 5951 patients was 52 (SD=16) years; 59% were female, 89% White and 87% had three or more COVID-19 vaccinations. Within 28 days after treatment initiation, 84 (1.4%) COVID-19 related hospitalisations/deaths were observed (31 treated with sotrovimab and 53 with molnupiravir). Cox proportional hazards models stratified by area showed that after adjusting for demographics, high-risk cohort categories, vaccination status, calendar time, body mass index and other comorbidities, treatment with sotrovimab was associated with a substantially lower risk than treatment with molnupiravir (hazard ratio, HR=0.53, 95% CI: 0.32-0.88; P=0.014). Consistent results were obtained from propensity score weighted Cox models (HR=0.51, 95% CI: 0.31-0.83; P=0.007) and when restricted to fully vaccinated people (HR=0.52, 95% CI: 0.30-0.90; P=0.020). No substantial effect modifications by other characteristics were detected (all P values for interaction>0.10). Conclusion: In routine care of non-hospitalised high-risk adult patients with COVID-19 in England, those who received sotrovimab were at lower risk of severe COVID-19 outcomes than those receiving molnupiravir.

Accident and emergency (AE) attendance in England following infection with SARS-CoV-2 Omicron or Delta (preprint)

The SARS-CoV-2 Omicron variant is increasing in prevalence around the world. Accurate estimation of disease severity associated with Omicron is critical for pandemic planning. We found lower risk of accident and emergency (AE) attendance following SARS-CoV-2 infection with Omicron compared to Delta (HR: 0.39 (95% CI: 0.30 - 0.51; P<.0001). For AE attendances that lead to hospital admission, Omicron was associated with an 85% lower hazard compared with Delta (HR: 0.14 (95% CI: 0.09 - 0.24; P<.0001)). Conflicts of InterestsNothing to declare. Funding statementThis work was supported by the Medical Research Council MR/V015737/1. TPP provided technical expertise and infrastructure within their data centre pro bono in the context of a national emergency. Rosalind Eggo is funded by HDR UK (grant: MR/S003975/1), MRC (grant: MC_PC 19065), NIHR (grant: NIHR200908).

Association between household composition and severe COVID-19 outcomes in older people by ethnicity: an observational cohort study using the OpenSAFELY platform (preprint)

Background Ethnic differences in the risk of severe COVID-19 may be linked to household composition. We quantified the association between household composition and risk of severe COVID-19 by ethnicity for older individuals. Methods With the approval of NHS England, we analysed ethnic differences in the association between household composition and severe COVID-19 in people aged 67 or over in England. We defined households by number of generations living together, and used multivariable Cox regression stratified by location and wave of the pandemic and accounted for age, sex, comorbidities, smoking, obesity, housing density and deprivation. We included 2 692 223 people over 67 years in wave 1 (01/02/2020-31/08/2020) and 2 731 427 in wave 2 (01/09/2020-31/01/2021). Findings Multigenerational living was associated with increased risk of severe COVID-19 for White and South Asian older people in both waves (e.g. wave 2, 67+ living with 3 other generations vs 67+ year olds only: White HR 1.61 95% CI 1.38-1.87, South Asian HR 1.76 95% CI 1.48-2.10), with a trend for increased risks of severe COVID-19 with increasing generations in wave 2. Interpretation Multigenerational living was associated with severe COVID-19 in older adults. Older South Asian people are over-represented within multigenerational households in England, especially in the most deprived settings. The number of generations in a household, number of occupants, ethnicity and deprivation status are important considerations in the continued roll-out of COVID-19 vaccination and targeting of interventions for future pandemics. Funding This research was funded in part, by the Wellcome Trust. For the purpose of open access, the author has applied a CC-BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

Describing the population experiencing COVID-19 vaccine breakthrough following second vaccination in England: A cohort study from OpenSAFELY (preprint)

Background While the vaccines against COVID-19 are considered to be highly effective, COVID-19 vaccine breakthrough is likely and a small number of people will still fall ill, be hospitalised, or die from COVID-19, despite being fully vaccinated. With the continued increase in numbers of positive SARS-CoV-2 tests, describing the characters of individuals who have experienced a COVID-19 vaccine breakthrough could be hugely important in helping to determine who may be at greatest risk. Method We conducted a retrospective cohort study using routine clinical data from the OpenSAFELY TPP database of fully vaccinated individuals, linked to secondary care and death registry data, and described the characteristics of those experiencing a COVID-19 vaccine breakthrough. Results As of 30th June 2021, a total of 10,782,870 individuals were identified as being fully vaccinated against COVID-19, with a median follow-up time of 43 days (IQR: 23-64). From within this population, a total of 16,815 (0.1%) individuals reported a positive SARS-CoV-2 test. For every 1000 years of patient follow-up time, the corresponding incidence rate was 12.33 (95% CI 12.14-12.51). There were 955 COVID-19 hospital admissions and 145 COVID-19-related deaths; corresponding incidence rates of 0.70 (95% CI 0.65-0.74) and 0.12 (95% CI 0.1-0.14), respectively. When broken down by the initial priority group, higher rates of hospitalisation and death were seen in those in care homes. Comorbidities with the highest rates of breakthrough COVID-19 included renal replacement therapy, organ transplant, haematological malignancy, and immunocompromised. Conclusion The majority of COVID-19 vaccine breakthrough cases in England were mild with relatively few fully vaccinated individuals being hospitalised or dying as a result. However, some concerning differences in rates of breakthrough cases were identified in several clinical and demographic groups, The continued increase in numbers of positive SARS-CoV-2 tests are concerning and, as numbers of fully vaccinated individuals increases and follow-up time lengthens, so too will the number of COVID-19 breakthrough cases. Additional analyses, aimed at identifying individuals at higher risk, are therefore required.

Comparative effectiveness of ChAdOx1 versus BNT162b2 COVID-19 vaccines in Health and Social Care workers in England: a cohort study using OpenSAFELY (preprint)

Background: The UK COVID-19 vaccination programme delivered both the BNT162b2 mRNA (Pfizer-BioNTech) and the ChAdOx1 (Oxford-AstraZeneca) vaccines during overlapping periods, providing a rare opportunity to emulate a trial that directly compares both vaccines using routinely-collected NHS data. Frontline Health and Social Care workers comprise a useful population to assess comparative effectiveness due to early vaccine eligibility and relatively high post-vaccination transmission risk due to occupational exposure. Methods: With the approval of NHS England we used the OpenSAFELY-TPP database, covering 40% of GP practices in England and linked to national coronavirus surveillance, hospital episodes, and death registry data, to compare the effectiveness of ChAdOx1 versus BNT162b2 in 1/3 million health and social care workers vaccinated between 4 January and 28 February 2021. Recipients were followed-up for 20 weeks. Second-dose effects were estimated under an intention-to-treat strategy. Primary outcomes were recorded SARS-CoV-2 infection, COVID-19-related accident and emergency attendance, and COVID-19-related hospital admission. Results: The cumulative incidence of each outcome was similar for both vaccines during the first 20 weeks post-vaccination. The cumulative incidence of recorded SARS-CoV-2 infection 6 weeks after vaccination with BNT162b2 was 19.2 per 1000 people (95%CI 18.6 to 19.7) and with ChAdOx1 was 18.9 (95%CI 17.6 to 20.3), representing a difference of -0.24 per 1000 people (95%CI -1.71 to 1.22). The difference in the cumulative incidence of COVID-19 accident and emergency attendance at 6 weeks was 0.01 per 1000 people (95%CI -0.27 to 0.28). For COVID-19 hospital admission, this difference was 0.03 per 1000 people (95%CI -0.22 to 0.27). Conclusion: In this cohort of healthcare workers where we would not anticipate vaccine type to be related to health status, we found no substantial differences in the incidence of SARS-CoV-2 infection or COVID-19 disease up to 20 weeks after vaccination. Incidence dropped sharply after 3-4 weeks and there were very few COVID-19 hospital attendance and admission events after this period. This is in line with expected onset of vaccine-induced immunity, and suggests strong protection against COVID-19 disease for both vaccines.

Risk of severe COVID-19 outcomes associated with immune-mediated inflammatory diseases and immune modifying therapies: a nationwide cohort study in the OpenSAFELY platform (preprint)

BackgroundIt is unclear if people with immune-mediated inflammatory diseases (IMIDs) (joint, bowel and skin) and on immune modifying therapy have increased risk of serious COVID-19 outcomes. MethodsWith the approval of NHS England we conducted a cohort study, using OpenSAFELY, analysing routinely-collected primary care data linked to hospital admission, death and previously unavailable hospital prescription data. We used Cox regression (adjusting for confounders) to estimate hazard ratios (HR) comparing risk of COVID-19-death, death/critical care admission, and hospitalisation (March to September 2020) in: 1) people with IMIDs compared to the general population; and 2) people with IMIDs on targeted immune modifying drugs (e.g., biologics) compared to standard systemic treatment (e.g., methotrexate). FindingsWe identified 17,672,065 adults; of 1,163,438 (7%) with IMIDs, 19,119 people received targeted immune modifying drugs, and 200,813 received standard systemics. We saw evidence of increased COVID-19-death (HR 1.23, 95%CI 1.20, 1.27), and COVID-19 hospitalisation (HR 1.32, 95%CI 1.29, 1.35) in individuals with IMIDs overall compared to individuals without IMIDs of the same age, sex, deprivation and smoking status. We saw no evidence of increased COVID-19 deaths with targeted compared to standard systemic treatments (HR 1.03, 95%CI 0.80, 1.33). There was no evidence of increased COVID-19-related death in those prescribed TNF inhibitors, IL-12/23, IL7, IL-6 or JAK inhibitors compared to standard systemics. Rituximab was associated with increased COVID-19 death (HR 1.68, 95%CI 1.11, 2.56); however, this finding may relate to confounding. InterpretationCOVID-19 death and hospitalisation was higher in people with IMIDs. We saw no increased risk of adverse COVID-19 outcomes in those on most targeted immune modifying drugs for IMIDs compared to standard systemics. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed on May 19th, 2021, using the terms "COVID-19", "SARS-CoV-2" and "rheumatoid arthritis", "psoriatic arthritis" "ankylosing spondylitis", "Crohns disease" "ulcerative colitis" "hidradenitis suppurativa" and "psoriasis", to identify primary research articles examining severe COVID-19 outcome risk in individuals with immune-mediated inflammatory diseases (IMIDs) and those on immune modifying therapy. The studies identified (including matched cohort studies and studies in disease-specific registries) were limited by small sample sizes and number of outcomes. Most studies did not show a signal of increased adverse COVID-19 outcomes in those on targeted therapies, with the exception of rituximab. Additionally, disease- specific registries are subject to selection bias and lack denominator populations. Added value of the studyIn our large population-based study of 17 million individuals, including 1 million people with IMIDs and just under 200,000 receiving immune modifying medications, we saw evidence that people with IMIDs had an increased risk of COVID-19-related death compared to the general population after adjusting for potential confounders (age, sex, deprivation, smoking status) (HR 1.23, 95%CI 1.20, 1.27). We saw differences by IMID type, with COVID-19-related death being increased by the most in people with inflammatory joint disease (HR 1.47, 95%CI 1.40, 1.54). We also saw some evidence that those with IMIDs were more likely, compared to the general population, to have COVID-19-related critical care admission/death (HR 1.24, 95%CI 1.21, 1.28) and hospitalisation (HR 1.32, 95%CI 1.29, 1.35). Compared to people with IMIDs taking standard systemics, we saw no evidence of differences in severe COVID-19-related outcomes with TNF inhibitors, IL-17 inhibitors, IL-12/23 inhibitors, IL-6 inhibitors and JAK inhibitors. However, there was some evidence that rituximab was associated with an increased risk of COVID-19-related death (HR 1.68, 95%CI 1.11, 2.56) and death/critical care admission (HR 1.92, 95%CI 1.31, 2.81). We also saw evidence of an increase in COVID-19-related hospital admissions in people prescribed rituximab (HR 1.59, 95%CI 1.16, 2.18) or JAK inhibition (HR 1.81, 95%CI 1.09, 3.01) compared to those on standard systemics, although this could be related to worse underlying health rather than the drugs themselves, and numbers of events were small. This is the first study to our knowledge to use high-cost drug data on medicines supplied by hospitals at a national scale in England (to identify targeted therapies). The availability of these data fills an important gap in the medication record of those with more specialist conditions treated by hospitals creating an important opportunity to generate insights to these conditions and these medications Implications of all of the available evidenceOur study offers insights into future risk mitigation strategies and SARS-CoV-2 vaccination priorities for individuals with IMIDs, as it highlights that those with IMIDs and those taking rituximab may be at risk of severe COVID-19 outcomes. Critically, our study does not show a link between most targeted immune modifying medications compared to standard systemics and severe COVID-19 outcomes. However, the increased risk of adverse COVID-19 outcomes that we saw in people with IMIDs and those treated with rituximab merits further study.

Recording of 'COVID-19 vaccine declined' among vaccination priority groups: a cohort study on 57.9 million NHS patients' primary care records in situ using OpenSAFELY (preprint)

BackgroundAll patients in England within vaccine priority groups were offered a COVID-19 vaccine by mid-April 2021. Clinical record systems contain codes to denote when such an offer has been declined by a patient (although these can in some cases be entered for a variety of other reasons including vaccination delay, or other administrative issues). We set out to describe the patterns of usage of codes for COVID-19 vaccines being declined. MethodsWith the approval of NHS England and using the full pseudonymised primary care records for 57.9 million NHS patients, we identified all patients in key vaccine priority groups: aged over 50, or over 16 and at increased risk from COVID-19 (Clinically Extremely Vulnerable [CEV] or otherwise "at risk"). We describe the proportion of patients recorded as declining a COVID-19 vaccination for each priority group, and by other clinical and demographic factors; whether patients recorded as "declined" subsequently went on to receive a vaccination; and the distribution of code usage across GP practices. ResultsOf 24.5 million patients in priority groups as of May 25th 2021, 89.2% had received a vaccine, 8.8% had neither a vaccination nor a decline recorded, and 663,033 (2.7%) had a decline code recorded. Of patients with a recorded decline, 125,587 (18.9%) were subsequently vaccinated. Subsequent vaccination was slightly more common in the South Asian population than other ethnicities (e.g. 32.3% vs 22.8%, over 65s). The proportion of declining-unvaccinated patients varied strongly with ethnicity (Black 15.3%, South Asian 5.6%, White 1.5% in over 80s); and was higher in patients from more deprived areas. COVID-19 vaccine decline codes were present in almost all practices (98.8%), but with wide variation between practices in rates of usage. Among all priority groups, declining-unvaccinated status was most common in CEV (3.3%). ConclusionsClinical codes indicative of COVID-19 vaccinations being declined are widely used in English general practice. They are substantially more common among Black and South Asian patients, and patients from more deprived areas. There is a need for more detailed survey and/or qualitative research with patients and clinicians to determine the most common reasons for these recorded declines.

Overall and cause-specific hospitalisation and death after COVID-19 hospitalisation in England: cohort study in OpenSAFELY using linked primary care, secondary care and death registration data (preprint)

Background: There is concern about medium to long-term adverse outcomes following acute COVID-19, but little relevant evidence exists. We aimed to investigate whether risks of hospital admission and death, overall and by specific cause, are raised following discharge from a COVID-19 hospitalisation. Methods and Findings: Working on behalf of NHS-England, we used linked primary care and hospital data in OpenSAFELY to compare risks of hospital admission and death, overall and by specific cause, between people discharged from COVID-19 hospitalisation (February-December 2020), and (i) demographically-matched controls from the 2019 general population; (ii) people discharged from influenza hospitalisation in 2017-19. We used Cox regression adjusted for personal and clinical characteristics. 24,673 post-discharge COVID-19 patients, 123,362 general population controls, and 16,058 influenza controls were followed for [≤]315 days. Overall risk of hospitalisation or death (30968 events) was higher in the COVID-19 group than general population controls (adjusted-HR 2.23, 2.14-2.31) but similar to the influenza group (adjusted-HR 0.94, 0.91-0.98). All-cause mortality (7439 events) was highest in the COVID-19 group (adjusted-HR 4.97, 4.58-5.40 vs general population controls and 1.73, 1.60-1.87 vs influenza controls). Risks for cause-specific outcomes were higher in COVID-19 survivors than general population controls, and largely comparable between COVID-19 and influenza patients. However, COVID-19 patients were more likely than influenza patients to be readmitted/die due to their initial infection/other lower respiratory tract infection (adjusted-HR 1.37, 1.22-1.54), and to experience mental health or cognitive-related admission/death (adjusted-HR 1.36, 1.01-2.83); in particular, COVID-19 survivors with pre-existing dementia had higher risk of dementia death. One limitation of our study is that reasons for hospitalisation/death may have been misclassified in some cases due to inconsistent use of codes. Conclusions: People discharged from a COVID-19 hospital admission had markedly higher risks for rehospitalisation and death than the general population, suggesting a substantial extra burden on healthcare. Most risks were similar to those observed after influenza hospitalisations; but COVID-19 patients had higher risks of all-cause mortality, readmissions/death due to the initial infection, and dementia death, highlighting the importance of post-discharge monitoring.

Mortality among Care Home Residents in England during the first and second waves of the COVID-19 pandemic: an analysis of 4.3 million adults over the age of 65 (preprint)

Background: Residents in care homes have been severely impacted by the COVID-19 pandemic. We describe trends in risk of mortality among care home residents compared to residents in private homes in England. Methods: On behalf of NHS England, we used OpenSAFELY-TPP, an analytics platform running across the linked electronic health records of approximately a third of the English population, to calculate monthly age-standardised risks of death due to all causes and COVID-19 among adults aged >=65 years between 1/2/2019 and 31/03/2021. Care home residents were identified using linkage to the Care and Quality Commission. Findings: We included 4,329,078 people aged 65 years or older on the 1st of February 2019, 2.2% of whom were classified as residing in a care or nursing home. Age-standardised mortality risks were approximately 10 times higher among care home residents compared to non-residents in February 2019 residents (CMF = 10.59, 95%CI = 9.51, 11.81 among women, CMF = 10.82, 95%CI = 9.89, 11.84 among men). This increased to more than 17 times in April 2020 (CMF = 17.52, 95%CI = 16.38, 18.74 among women, CMF = 18.12, 95%CI = 17.17, 19.12 among men) before returning to pre-pandemic levels in June 2020. CMFs did not increase during the second wave, despite a rise in the absolute age-standardised COVID-19 mortality risks. Interpretation: The first COVID-19 wave had a disproportionate impact on care home residents in England compared to older private home residents. A degree of immunity, improved protective measures or changes in the underlying frailty of the populations may explain the lack of an increase in the relative mortality risks during the second wave. The care home population should be prioritised for measures aimed at controlling the spread of COVID-19.

Clinical coding of long COVID in English primary care: a federated analysis of 58 million patient records in situ using OpenSAFELY (preprint)

BackgroundLong COVID is a term to describe new or persistent symptoms at least four weeks after onset of acute COVID-19. Clinical codes to describe this phenomenon were released in November 2020 in the UK, but it is not known how these codes have been used in practice. MethodsWorking on behalf of NHS England, we used OpenSAFELY data encompassing 96% of the English population. We measured the proportion of people with a recorded code for long COVID, overall and by demographic factors, electronic health record software system, and week. We also measured variation in recording amongst practices. ResultsLong COVID was recorded for 23,273 people. Coding was unevenly distributed amongst practices, with 26.7% of practices having not used the codes at all. Regional variation was high, ranging between 20.3 per 100,000 people for East of England (95% confidence interval 19.3-21.4) and 55.6 in London (95% CI 54.1-57.1). The rate was higher amongst women (52.1, 95% CI 51.3-52.9) compared to men (28.1, 95% CI 27.5-28.7), and higher amongst practices using EMIS software (53.7, 95% CI 52.9-54.4) compared to TPP software (20.9, 95% CI 20.3-21.4). ConclusionsLong COVID coding in primary care is low compared with early reports of long COVID prevalence. This may reflect under-coding, sub-optimal communication of clinical terms, under-diagnosis, a true low prevalence of long COVID diagnosed by clinicians, or a combination of factors. We recommend increased awareness of diagnostic codes, to facilitate research and planning of services; and surveys of clinicians experiences, to complement ongoing patient surveys.

OpenSAFELY: Risks of COVID-19 hospital admission and death for people with learning disabilities - a cohort study. (preprint)

ObjectivesTo assess the association between learning disability and risk of hospitalisation and mortality from COVID-19 in England among adults and children. DesignWorking on behalf of NHS England, two cohort studies using patient-level data for >17 million people from primary care electronic health records were linked with death data from the Office for National Statistics and hospitalization data from NHS Secondary Uses Service using the OpenSAFELY platform. SettingGeneral practices in England which use TPP software. ParticipantsParticipants were males and females, aged up to 105 years, from two cohorts: (1) wave 1, registered with a TPP practice as of 1st March 2020 and followed until 31st August, 2020; (2) wave 2 registered 1st September 2020 and followed until 31st December 2020 (for admissions) or 8th February 2021 (for deaths). The main exposure group was people included on a general practice learning disability register (LDR), with a subgroup of people classified as having profound or severe learning disability. We also identified patients with Down syndrome and cerebral palsy (whether or not on the learning disability register). Main outcome measures(i) COVID-19 related death, (ii) COVID-19 related hospitalisation. Non-COVID-19 related death was also explored. ResultsIn wave 1, of 14,301,415 included individuals aged 16 and over, 90,095 (0.63%) were identified as being on the LDR. 30,173 COVID-related hospital admissions, 13,919 COVID-19 related deaths and 69,803 non-COVID deaths occurred; of which 538 (1.8%), 221 (1.6%) and 596 (0.85%) were among individuals on the LDR, respectively. In wave 2, 27,611 COVID-related hospital admissions, 17,933 COVID-19 related deaths and 54,171 non-COVID deaths occurred; of which 383 (1.4%), 260 (1.4%) and 470 (0.87%) were among individuals on the LDR. Wave 1 hazard ratios for individuals on the LDR, adjusted for age, sex, ethnicity and geographical location, were 5.3 (95% confidence interval (CI) 4.9, 5.8) for COVID-19 related hospital admissions and 8.2 (95% CI: 7.1, 9.4) for COVID-19 related death. Wave 2 produced similar estimates. Associations were stronger among those classed as severe-profound and among those in residential care. Down syndrome and cerebral palsy were associated with increased hazard of both events in both waves; Down syndrome to a much greater extent. Hazards of non-COVID-19 related death followed similar patterns with weaker associations. ConclusionsPeople with learning disabilities have markedly increased risks of hospitalisation and mortality from COVID-19. This raised risk is over and above that seen for non-COVID causes of death. Ensuring prompt access to Covid-19 testing and health care and consideration of prioritisation for COVID-19 vaccination and other targeted preventive measures are warranted.

Case fatality risk of the SARS-CoV-2 variant of concern B.1.1.7 in England (preprint)

The B.1.1.7 variant of concern (VOC) is increasing in prevalence across Europe. Accurate estimation of disease severity associated with this VOC is critical for pandemic planning. We found increased risk of death for VOC compared with non-VOC cases in England (HR: 1.67 (95% CI: 1.34 - 2.09; P

Predicting COVID-19 related death using the OpenSAFELY platform (preprint)

Objectives To compare approaches for obtaining relative and absolute estimates of risk of 28-day COVID-19 mortality for adults in the general population of England in the context of changing levels of circulating infection. Design Three designs were compared. (A) case-cohort which does not explicitly account for the time-changing prevalence of COVID-19 infection, (B) 28-day landmarking, a series of sequential overlapping sub-studies incorporating time-updating proxy measures of the prevalence of infection, and (C) daily landmarking. Regression models were fitted to predict 28-day COVID-19 mortality. Setting Working on behalf of NHS England, we used clinical data from adult patients from all regions of England held in the TPP SystmOne electronic health record system, linked to Office for National Statistics (ONS) mortality data, using the OpenSAFELY platform. Participants Eligible participants were adults aged 18 or over, registered at a general practice using TPP software on 1st March 2020 with recorded sex, postcode and ethnicity. 11,972,947 individuals were included, and 7,999 participants experienced a COVID-19 related death. The study period lasted 100 days, ending 8th June 2020. Predictors A range of demographic characteristics and comorbidities were used as potential predictors. Local infection prevalence was estimated with three proxies: modelled based on local prevalence and other key factors; rate of A&E COVID-19 related attendances; and rate of suspected COVID-19 cases in primary care. Main outcome measures COVID-19 related death. Results All models discriminated well between patients who did and did not experience COVID-19 related death, with C-statistics ranging from 0.92-0.94. Accurate estimates of absolute risk required data on local infection prevalence, with modelled estimates providing the best performance. Conclusions Reliable estimates of absolute risk need to incorporate changing local prevalence of infection. Simple models can provide very good discrimination and may simplify implementation of risk prediction tools in practice.

Changes in the rate of cardiometabolic and pulmonary events during the COVID-19 pandemic (preprint)

BackgroundThere has been extensive speculation about the relationship between COVID-19 and various cardiometabolic and pulmonary conditions. This a complex question: COVID-19 may cause a cardiometabolic or respiratory event; admission for a clinical event may result in hospital-acquired SARS-CoV-2 infection; both may contribute to a patient surpassing the threshold for presenting to services; and the presence of a pandemic may change whether patients present to services at all. To inform analysis of these questions, we set out to describe the overall rate of various key clinical events over time, and their relationship with COVID-19. MethodsWorking on behalf of NHS England, we used data from the OpenSAFELY platform containing data from approximately 40% of the population of England. We selected the whole adult population of 17m patients and within this identified two further mutually exclusive groups: patients who tested positive for SARS-CoV-2 in the community; and patients hospitalised with COVID-19. We report counts of death, DVT, PE, ischaemic stroke, MI, heart failure, AKI and diabetic ketoacidosis in each month between February 2019 and October 2020 within each of: the general population, community SARS-CoV-2 cases, and hospitalised patients with COVID-19. Outcome events were defined using hospitalisations, GP records and cause of death data. ResultsFor all outcomes except death there was a lower count of events in April 2020 compared to April 2019. For most outcomes the minimum count of events was in April 2020, where the decrease compared to April 2019 in events ranged from 5.9% (PE) to 40.0% (heart failure). Despite hospitalised COVID-19 patients making up just 0.14% of the population in April 2020, these patients accounted for an extremely high proportion of cardiometabolic and respiratory events in that month (range of proportions 10.3% (DVT) to 33.5% (AKI)). InterpretationWe observed a substantial drop in the incidence of cardiometabolic and pulmonary events in the non-COVID-19 general population, but high occurrence of COVID-19 among patients with these events. Shortcomings in routine NHS secondary care data, especially around the timing and order of events, make causal interpretations challenging. We caution that the intermediate findings reported here should be used to inform the design and interpretation of any studies using a general population comparator to evaluate the relationship between COVID-19 and other clinical events.

Short report: Ethnicity and COVID-19 death in the early part of the COVID-19 second wave in England: an analysis of OpenSAFELY data from 1st September to 9th November 2020 (preprint)

Black and minority ethnic groups were at raised risk of dying from COVID-19 during the first few months of the COVID-19 epidemic in England. We aimed to investigate whether ethnic inequalities in COVID-19 deaths were similar in the more recent "second wave" of the epidemic. Working on behalf of NHS England, we used primary care and linked ONS mortality data within the OpenSAFELY platform. All adults in the database at 1st September 2020 and with at least 1 year of prior follow-up and a record of ethnicity were included. The outcome was COVID-19-related death (death with COVID-19 listed as a cause of death on the death certificate). Follow-up was to 9th November 2020. Hazard ratios for ethnicity were calculated using Cox regression models adjusted for age and sex, and then further adjusted for deprivation. 13,223,154 people were included. During the study period, people of South Asian ethnicity were at higher risk of death due to COVID-19 than white people after adjusting for age and sex (HR = 3.47, 95% CI 2.99-4.03); the association attenuated somewhat on further adjustment for index of multiple deprivation (HR = 2.86, 2.46-3.33, Table 2). In contrast with the first wave of the epidemic, we found little evidence of a raised risk in black or other ethnic groups compared to white (HR for black vs white = 1.28, 0.87-1.88 adjusted for age and sex; and 1.01, 0.69-1.49 further adjusted for deprivation). Our findings suggest that ethnic inequalities in the risk of dying COVID-19-related death have changed between the first and early second wave of the epidemic in England. O_TBL View this table: org.highwire.dtl.DTLVardef@987a5org.highwire.dtl.DTLVardef@1a8a141org.highwire.dtl.DTLVardef@1f2de56org.highwire.dtl.DTLVardef@1e2f9b8org.highwire.dtl.DTLVardef@78bfcc_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable 2:C_FLOATNO O_TABLECAPTIONAssociation between ethnicity and COVID-19 death 1st Sept - 9th Nov 2020 C_TABLECAPTION C_TBL

Trends, regional variation, and clinical characteristics of COVID-19 vaccine recipients: a retrospective cohort study in 23.4 million patients using OpenSAFELY. (preprint)

Background On December 8th 2020, NHS England administered the first COVID-19 vaccination as part of an ambitious vaccination programme during a global health emergency. Aims To develop a framework for detailed near-real-time monitoring of COVID-19 vaccine roll-out; to describe trends and variation in coverage by geographic area, and between key clinical and demographic patient groups. Methods Working on behalf of NHS England we used routine clinical data from 23.4 million adults to conduct a retrospective cohort study of comprehensive electronic health record data in NHS England, using the OpenSAFELY-TPP platform which covers approximately 40% of the general population in England with weekly data updates. We developed algorithms to identify key demographic and clinical sub-groups within this population and generated descriptive statistics on proportion of eligible patients receiving the vaccine among key Joint Committee on Vaccination and Immunisation (JCVI) target groups. Results Between December 8th and January 13th 961,580 people out of 23.4m in our dataset received a COVID-19 vaccine. Of 1,160,062 patients aged 80 or over and not living in a care home (currently targeted by JCVI) 476,375 had been vaccinated in total (41.1%). We observed a substantial divergence in vaccination by ethnicity within this group (White 42.5% vaccinated, Black 20.5%) and across rankings of deprivation (least deprived 44.7%, most deprived 37.9%). Patients with pre-existing medical conditions were equally likely, or more likely, to have received a vaccine across most co-morbidity groups with two exceptions: severe mental illness (30.3% vaccinated) and learning disability (28.1%). We identify substantial variation in vaccination among the over-80s between Sustainability and Transformation Partnerships (STPs; Range 12%-74%); lower vaccination rates among ethnic minority and deprived groups was observed in most but not all STPs. In the 70-79 age cohort 74,108 people (3.6%) had been vaccinated. 378,921 vaccine recipients under 70 and not identifiably resident in a care home were presumed to be health or social care workers; 32,174 recipients were identified as older aged care home residents (33.2% coverage). Of all those vaccinated, 169,472 had received a second dose (17.6%). Conclusions The NHS in England has rapidly delivered mass vaccination. We were able to deploy a data monitoring framework across small clinical subgroups using linked patient-level NHS data on 23.4 million people with very short delays from vaccine administration to completed analysis. Targeted activity may be needed to address lower vaccination rates observed among certain key groups: ethnic minorities, people living in areas of higher deprivation, and those with severe mental illness or learning disabilities. However we note that this data is only from the first preliminary weeks of the vaccination programme. Variation in vaccination coverage between groups and regions will have many complex drivers, the figures presented in this manuscript require thoughtful interpretation to support a rapidly evolving NHS vaccination campaign; we are sharing local level data with national and regional NHS teams on request. Keywords: Vaccination, COVID-19, SARS-CoV-2, NHS England