Prevalence of COVID-19-related risk factors and risk of severe influenza outcomes in cancer survivors: a matched cohort study using linked English electronic health records data

BackgroundPeople with active cancer are recognised as at risk of COVID-19 complications, but it is unclear whether the much larger population of cancer survivors is at elevated risk. We aimed to address this by comparing cancer survivors and cancer-free controls for (i) prevalence of comorbidities considered risk factors for COVID-19; and (ii) risk of severe influenza, as a marker of susceptibility to severe outcomes from epidemic respiratory viruses. MethodsWe included survivors ([≥]1 year) of the 20 most common cancers, and age, sex and general practice-matched cancer-free controls, derived from UK primary care data linked to cancer registrations, hospital admissions and death registrations. Comorbidity prevalences were calculated 1 and 5 years from cancer diagnosis. Risk of hospitalisation or death due to influenza was compared using Cox models adjusted for baseline demographics and comorbidities. Findings108,215 cancer survivors and 523,541 cancer-free controls were included. Cancer survivors had more asthma, other respiratory, cardiac, diabetes, neurological, renal, and liver disease, and less obesity, compared with controls, but there was variation by cancer site. There were 205 influenza hospitalisations/deaths, with cancer survivors at higher risk than controls (adjusted HR 2.78, 95% CI 2.04-3.80). Haematological cancer survivors had large elevated risks persisting for >10 years (HR overall 15.17, 7.84-29.35; HR >10 years from cancer diagnosis 10.06, 2.47-40.93). Survivors of other cancers had evidence of raised risk up to 5 years from cancer diagnosis only (HR 2.22, 1.31-3.74). InterpretationRisks of severe COVID-19 outcomes are likely to be elevated in cancer survivors. This should be taken into account in policies targeted at clinical risk groups, and vaccination for both influenza, and, when available, COVID-19, should be encouraged in cancer survivors. FundingWellcome Trust, Royal Society, NIHR. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSFew data are available to date on how COVID-19 affects cancer survivors. We searched PubMed with the keywords "influenza cancer survivors" to identify studies that compared severe influenza outcomes in cancer survivors and in a control group. No study was identified. Added value of this studyIn this matched cohort study of routinely collected electronic health records, we demonstrated raised risks of influenza hospitalisation or mortality in survivors from haematological malignancies for >10 years after diagnosis, and in survivors from solid cancers up to 5 years after diagnosis. Implications of all the available evidenceCancer survivorship appears to be an important risk factor for severe influenza outcomes, suggesting that cancer survivors may also be at raised risk of poor COVID-19 outcomes. This should be taken into account in public health policies targeted at protecting clinical risk groups. Influenza vaccination should be encouraged in this group, and may need to be extended to a wider population of medium- to long-term cancer survivors than currently recommended.

Early impact of the COVID-19 pandemic and social distancing measures on routine childhood vaccinations in England, January to April 2020

Electronic health records were used to assess the early impact of COVID-19 on routine childhood vaccination in England to 26 April 2020. MMR vaccination counts fell from February 2020, and in the three weeks after introduction of social distancing measures were 19.8% lower (95% CI -20.7 to -18.9%) than the same period in 2019, before improving in mid-April. A gradual decline in hexavalent vaccination counts throughout 2020 was not accentuated on introduction of social distancing.

UK prevalence of underlying conditions which increase the risk of severe COVID-19 disease: a point prevalence study using electronic health records

BackgroundThis study aimed to describe the population at risk of severe COVID-19 due to underlying health conditions across the United Kingdom in 2019. MethodsWe used anonymised electronic health records from the Clinical Practice Research Datalink GOLD to describe the point prevalence on 5 March 2019 of the at-risk population following national guidance. Prevalence for any risk condition and for each individual condition is given overall and stratified by age and region. We repeated the analysis on 5 March 2014 for full regional representation and to describe prevalence of underlying health conditions in pregnancy. We additionally described the population of cancer survivors, and assessed the value of linked secondary care records for ascertaining COVID-19 at-risk status. FindingsOn 5 March 2019, 24{middle dot}4% of the UK population were at risk due to a record of at least one underlying health condition, including 8{middle dot}3% of school-aged children, 19{middle dot}6% of working-aged adults, and 66{middle dot}2% of individuals aged 70 years or more. 7{middle dot}1% of the population had multimorbidity. The size of the at-risk population was stable over time comparing 2014 to 2019, despite increases in chronic liver disease and diabetes and decreases in chronic kidney disease and current asthma. Separately, 1{middle dot}6% of the population had a new diagnosis of cancer in the past five years. InterpretationThe population at risk of severe COVID-19 (aged [≥]70 years, or with an underlying health condition) comprises 18.5 million individuals in the UK, including a considerable proportion of school-aged and working-aged individuals. FundingNIHR HPRU in Immunisation Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched Pubmed for peer-reviewed articles, preprints, and research reports on the size and distribution of the population at risk of severe COVID. We used the terms (1) risk factor or co-morbidity or similar (2) COVID or SARS or similar and (3) prevalence to search for studies aiming to quantify the COVID-19 at-risk UK population published in the previous year to 19 July 2020, with no language restrictions. We found one study which modelled prevalence of risk factors based on the Global Burden of Disease (which included the UK) and one study which estimated that 8.4 million individuals aged [≥]30 years in the UK were at risk based on prevalence of a subset of relevant conditions in England. There were no studies which described the complete COVID-19 at-risk population across the UK. Added value of this studyWe used a large, nationally-representative dataset based on electronic health records to estimate prevalence of increased risk of severe COVID-19 across the United Kingdom, including all conditions in national guidance. We stratified by age, sex and region to enable regionally-tailored prediction of COVID-19-related healthcare burden and interventions to reduce transmission of infection, and planning and modelling of vaccination of the at-risk population. We also quantified the value of linked secondary care records to supplement primary care records. Implications of all the available evidenceIndividuals at moderate or high risk of severe COVID-19 according to current national guidance (aged [≥]70 years, or with a specified underlying health condition) comprise 18{middle dot}5 million individuals in the United Kingdom, rather than the 8.43 million previously estimated. The 8{middle dot}3% of school-aged children and 19{middle dot}6% of working-aged adults considered at-risk according to national guidance emphasises the need to consider younger at-risk individuals in shielding policies and when re-opening schools and workplaces, but also supports prioritising vaccination based on age and condition-specific mortality risk, rather than targeting all individuals with underlying conditions, who form a large population even among younger age groups. Among individuals aged [≥]70 years, 66{middle dot}2% had at least one underlying health condition, suggesting an age-targeted approach to vaccination may efficiently target individuals at risk of severe COVID-19. These national estimates broadly support the use of Global Burden of Disease modelled estimates and age-targeted vaccination strategies in other countries.

HIV infection and COVID-19 death: population-based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform

BackgroundIt is unclear whether HIV infection is associated with risk of COVID-19 death. We aimed to investigate this in a large-scale population-based study in England. MethodsWorking on behalf of NHS England, we used the OpenSAFELY platform to analyse routinely collected electronic primary care data linked to national death registrations. People with a primary care record for HIV infection were compared to people without HIV. COVID-19 death was defined by ICD-10 codes U07.1 or U07.2 anywhere on the death certificate. Cox regression models were used to estimate the association between HIV infection and COVID-19 death, initially adjusted for age and sex, then adding adjustment for index of multiple deprivation and ethnicity, and finally for a broad range of comorbidities. Interaction terms were added to assess effect modification by age, sex, ethnicity, comorbidities and calendar time. Results17.3 million adults were included, of whom 27,480 (0.16%) had HIV recorded. People living with HIV were more likely to be male, of black ethnicity, and from a more deprived geographical area than the general population. There were 14,882 COVID-19 deaths during the study period, with 25 among people with HIV. People living with HIV had nearly three-fold higher risk of COVID-19 death than those without HIV after adjusting for age and sex (HR=2.90, 95% CI 1.96-4.30). The association was attenuated but risk remained substantially raised, after adjustment for deprivation and ethnicity (adjusted HR=2.52, 1.70-3.73) and further adjustment for comorbidities (HR=2.30, 1.55-3.41). There was some evidence that the association was larger among people of black ethnicity (HR = 3.80, 2.15-6.74, compared to 1.64, 0.92-2.90 in non-black individuals, p-interaction=0.045) InterpretationHIV infection was associated with a markedly raised risk of COVID-19 death in a country with high levels of antiretroviral therapy coverage and viral suppression; the association was larger in people of black ethnicity.

OpenSAFELY: factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients.

BackgroundEstablishing who is at risk from a novel rapidly arising cause of death, and why, requires a new approach to epidemiological research with very large datasets and timely data. Working on behalf of NHS England we therefore set out to deliver a secure and pseudonymised analytics platform inside the data centre of a major primary care electronic health records vendor establishing coverage across detailed primary care records for a substantial proportion of all patients in England. The following results are preliminary. Data sourcesPrimary care electronic health records managed by the electronic health record vendor TPP, pseudonymously linked to patient-level data from the COVID-19 Patient Notification System (CPNS) for death of hospital inpatients with confirmed COVID-19, using the new OpenSAFELY platform. Population17,425,445 adults. Time period1st Feb 2020 to 25th April 2020. Primary outcomeDeath in hospital among people with confirmed COVID-19. MethodsCohort study analysed by Cox-regression to generate hazard ratios: age and sex adjusted, and multiply adjusted for co-variates selected prospectively on the basis of clinical interest and prior findings. ResultsThere were 5683 deaths attributed to COVID-19. In summary after full adjustment, death from COVID-19 was strongly associated with: being male (hazard ratio 1.99, 95%CI 1.88-2.10); older age and deprivation (both with a strong gradient); uncontrolled diabetes (HR 2.36 95% CI 2.18-2.56); severe asthma (HR 1.25 CI 1.08-1.44); and various other prior medical conditions. Compared to people with ethnicity recorded as white, black people were at higher risk of death, with only partial attenuation in hazard ratios from the fully adjusted model (age-sex adjusted HR 2.17 95% CI 1.84-2.57; fully adjusted HR 1.71 95% CI 1.44-2.02); with similar findings for Asian people (age-sex adjusted HR 1.95 95% CI 1.73-2.18; fully adjusted HR 1.62 95% CI 1.431.82). ConclusionsWe have quantified a range of clinical risk factors for death from COVID-19, some of which were not previously well characterised, in the largest cohort study conducted by any country to date. People from Asian and black groups are at markedly increased risk of in-hospital death from COVID-19, and contrary to some prior speculation this is only partially attributable to pre-existing clinical risk factors or deprivation; further research into the drivers of this association is therefore urgently required. Deprivation is also a major risk factor with, again, little of the excess risk explained by co-morbidity or other risk factors. The findings for clinical risk factors are concordant with policies in the UK for protecting those at highest risk. Our OpenSAFELY platform is rapidly adding further NHS patients records; we will update and extend these results regularly.

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

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).

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

BackgroundThere 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 FindingsWorking 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. ConclusionsPeople 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.

Association between oral anticoagulants and COVID-19 related outcomes: two cohort studies

ObjectivesWe investigated the role of routinely prescribed oral anticoagulants (OACs) in COVID-19 outcomes, comparing current OAC use versus non-use in Study 1; and warfarin versus direct oral anticoagulants (DOACs) in Study 2. DesignTwo cohort studies, on behalf of NHS England. SettingPrimary care data and pseudonymously-linked SARS-CoV-2 antigen testing data, hospital admissions, and death records from England. ParticipantsStudy 1: 70,464 people with atrial fibrillation (AF) and CHA{square}DS{square}-VASc score of 2. Study 2: 372,746 people with non-valvular AF. Main outcome measuresTime to test for SARS-CoV-2, testing positive for SARS-CoV-2, COVID-19 related hospital admission, COVID-19 deaths or non-COVID-19 deaths in Cox regression. ResultsIn Study 1, we included 52,416 current OAC users and 18,048 non-users. We observed no difference in risk of being tested for SARS-CoV-2 associated with current use (adjusted HR, 1.01, 95%CI, 0.96 to 1.05) versus non-use. We observed a lower risk of testing positive for SARS-CoV-2 (adjusted HR, 0.73, 95%CI, 0.60 to 0.90), and COVID-19 deaths (adjusted HR, 0.69, 95%CI, 0.49 to 0.97) associated with current use versus non-use. In Study 2, we included 92,339 warfarin users and 280,407 DOAC users. We observed a lower risk of COVID-19 deaths (adjusted HR, 0.79, 95%CI, 0.76 to 0.83) associated with warfarin versus DOACs. Similar associations were found for all other outcomes. ConclusionsAmong people with AF and a CHA{square}DS{square}-VASc score of 2, those receiving OACs had a lower risk of receiving a positive COVID-19 test and severe COVID-19 outcomes than non-users; this might be explained by a causal effect of OACs in preventing severe COVID-19 outcomes or more cautious behaviours leading to reduced infection risk. There was no evidence of a higher risk of severe COVID-19 outcomes associated with warfarin versus DOACs in people with non-valvular AF regardless of CHA{square}DS{square}-VASc score. Key pointsO_ST_ABSWhat is already known on this topicC_ST_ABSO_LICurrent studies suggest that prophylactic or therapeutic anticoagulant use, particularly low molecular weight heparin, lower the risk of pulmonary embolism and mortality during hospitalisation among patients with COVID-19. C_LIO_LIReduced vitamin K status has been reported to be correlated with severity of COVID-19. This could mean that warfarin, as a vitamin K antagonist, is associated with more severe COVID-19 disease than non-vitamin K anticoagulants. C_LI What this study addsO_LIIn 70,464 people with atrial fibrillation, at the threshold of being treated with an OAC based on risk of stroke, we observed a lower risk of testing positive for SARS-CoV-2 and COVID-19 related deaths associated with routinely prescribed OACs, relative to non-use. C_LIO_LIThis might be explained by OACs preventing severe COVID-19 outcomes, or more cautious behaviours and environmental factors reducing the risk of SARS-CoV-2 infection in those taking OACs. C_LIO_LIIn 372,746 people with non-valvular atrial fibrillation, there was no evidence of a higher risk of severe COVID-19 outcomes associated with warfarin compared with DOACs. C_LI

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

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<.0001). Absolute risk of death by 28-days increased with age and comorbidities. VOC has potential to spread faster with higher mortality than the pandemic to date.

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

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.

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

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

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

Factors associated with deaths due to COVID-19 versus other causes: population-based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform

BackgroundMortality from COVID-19 shows a strong relationship with age and pre-existing medical conditions, as does mortality from other causes. However it is unclear how specific factors are differentially associated with COVID-19 mortality as compared to mortality from other causes. MethodsWorking on behalf of NHS England, we carried out a cohort study within the OpenSAFELY platform. Primary care data from England were linked to national death registrations. We included all adults (aged [≥]18 years) in the database on 1st February 2020 and with >1 year of continuous prior registration, the cut-off date for deaths was 9th November 2020. Associations between individual-level characteristics and COVID-19 and non-COVID deaths were estimated by fitting age- and sex-adjusted logistic models for these two outcomes. Results17,456,515 individuals were included. 17,063 died from COVID-19 and 134,316 from other causes. Most factors associated with COVID-19 death were similarly associated with non-COVID death, but the magnitudes of association differed. Older age was more strongly associated with COVID-19 death than non-COVID death (e.g. ORs 40.7 [95% CI 37.7-43.8] and 29.6 [28.9-30.3] respectively for [≥]80 vs 50-59 years), as was male sex, deprivation, obesity, and some comorbidities. Smoking, history of cancer and chronic liver disease had stronger associations with non-COVID than COVID-19 death. All non-white ethnic groups had higher odds than white of COVID-19 death (OR for Black: 2.20 [1.96-2.47], South Asian: 2.33 [2.16-2.52]), but lower odds than white of non-COVID death (Black: 0.88 [0.83-0.94], South Asian: 0.78 [0.75-0.81]). InterpretationSimilar associations of most individual-level factors with COVID-19 and non-COVID death suggest that COVID-19 largely multiplies existing risks faced by patients, with some notable exceptions. Identifying the unique factors contributing to the excess COVID-19 mortality risk among non-white groups is a priority to inform efforts to reduce deaths from COVID-19. FundingWellcome, Royal Society, National Institute for Health Research, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, Health Data Research UK.

OpenSAFELY NHS Service Restoration Observatory 1: describing trends and variation in primary care clinical activity for 23.3 million patients in England during the first wave of COVID-19

BackgroundThe COVID-19 pandemic has disrupted healthcare activity globally. The NHS in England stopped most non-urgent work by March 2020, but later recommended that services should be restored to near-normal levels before winter where possible. The authors are developing the OpenSAFELY NHS Service Restoration Observatory, using data to describe changes in service activity during COVID-19, and reviewing signals for action with commissioners, researchers and clinicians. Here we report phase one: generating, managing, and describing the data. ObjectiveTo describe the volume and variation of coded clinical activity in English primary care across 23.8 million patients records, taking respiratory disease and laboratory procedures as key examples. MethodsWorking on behalf of NHS England we developed an open source software framework for data management and analysis to describe trends and variation in clinical activity across primary care EHR data on 23.8 million patients; and conducted a population cohort-based study to describe activity using CTV3 coding hierarchy and keyword searches from January 2019-September 2020. ResultsMuch activity recorded in general practice declined to some extent during the pandemic, but largely recovered by September 2020, with some exceptions. There was a large drop in coded activity for commonly used laboratory tests, with broad recovery to pre-pandemic levels by September. One exception was blood coagulation tests such as International Normalised Ratio (INR), with a smaller reduction (median tests per 1000 patients in 2020: February 8.0; April 6.2; September 7.0). The overall pattern of recording for respiratory symptoms was less affected, following an expected seasonal pattern and classified as "no change" from the previous year. Respiratory tract infections exhibited a sustained drop compared with pre-pandemic levels, not returning to pre-pandemic levels by September 2020. Various COVID-19 codes increased through the period. We observed a small decline associated with high level codes for long-term respiratory conditions such as chronic obstructive pulmonary disease (COPD) and asthma. Asthma annual reviews experienced a small drop but since recovered, while COPD annual reviews remain below baseline. ConclusionsWe successfully delivered an open source software framework to describe trends and variation in clinical activity across an unprecedented scale of primary care data. The COVD-19 pandemic led to a substantial change in healthcare activity. Most laboratory tests showed substantial reduction, largely recovering to near-normal levels by September 2020, with some important tests less affected. Records of respiratory infections decreased with the exception of codes related to COVID-19, whilst activity of other respiratory disease codes was mixed. We are expanding the NHS Service Restoration Observatory in collaboration with clinicians, commissioners and researchers and welcome feedback.

OpenSAFELY: impact of national guidance on switching from warfarin to direct oral anticoagulants (DOACs) in early phase of COVID-19 pandemic in England

BackgroundEarly in the COVID-19 pandemic the NHS recommended that appropriate patients anticoagulated with warfarin should be switched to direct acting oral anticoagulants (DOACs), requiring less frequent blood testing. Subsequently, a national safety alert was issued regarding patients being inappropriately co-prescribed two anticoagulants following a medication change, and associated monitoring. ObjectiveTo describe which people were switched from warfarin to DOACs; identify potentially unsafe co-prescribing of anticoagulants; and assess whether abnormal clotting results have become more frequent during the pandemic. MethodsWorking on behalf of NHS England we conducted a population cohort based study using routine clinical data from >17 million adults in England. Results20,000 of 164,000 warfarin patients (12.2%) switched to DOACs between March and May 2020, most commonly to edoxaban and apixaban. Factors associated with switching included: older age, recent renal function test, higher number of recent INR tests recorded, atrial fibrillation diagnosis and care home residency. There was a sharp rise in co-prescribing of warfarin and DOACs from typically 50-100 per month to 246 in April 2020, 0.06% of all people receiving a DOAC or warfarin. INR testing fell by 14% to 506.8 patients tested per 1000 warfarin patients each month. We observed a very small increase in elevated INRs (n=470) during April compared with January (n=420). ConclusionsIncreased switching of anticoagulants from warfarin to DOACs was observed at the outset of the COVID-19 pandemic in England following national guidance. There was a small but substantial number of people co-prescribed warfarin and DOACs during this period. Despite a national safety alert on the issue, a widespread rise in elevated INR test results was not found. Primary care has responded rapidly to changes in patient care during the COVID-19 pandemic.

Association between living with children and outcomes from COVID-19: an OpenSAFELY cohort study of 12 million adults in England

BackgroundClose contact with children may provide cross-reactive immunity to SARs-CoV-2 due to more frequent prior coryzal infections from seasonal coronaviruses. Alternatively, close contact with children may increase risk of SARs-CoV-2 infection. We investigated whether risk of infection with SARs-CoV-2 and severe outcomes differed between adults living with and without children. MethodsWorking on behalf of NHS England, we conducted a population-based cohort study using primary care data and pseudonymously-linked hospital and intensive care admissions, and death records, from patients registered in general practices representing 40% of England. Using multivariable Cox regression, we calculated fully-adjusted hazard ratios (HR) of outcomes from 1st February-3rd August 2020 comparing adults living with and without children in the household. FindingsAmong 9,157,814 adults [≤]65 years, living with children 0-11 years was not associated with increased risks of recorded SARS-CoV-2 infection, COVID-19 related hospital or ICU admission but was associated with reduced risk of COVID-19 death (HR 0.75, 95%CI 0.62-0.92). Living with children aged 12-18 years was associated with a small increased risk of recorded SARS-CoV-2 infection (HR 1.08, 95%CI 1.03-1.13), but not associated with other COVID-19 outcomes. Living with children of any age was also associated with lower risk of dying from non-COVID-19 causes. Among 2,567,671 adults >65 years there was no association between living with children and outcomes related to SARS-CoV-2. We observed no consistent changes in risk following school closure. InterpretationFor adults living with children there is no evidence of an increased risk of severe COVID-19 outcomes. These findings have implications for determining the benefit-harm balance of children attending school in the COVID-19 pandemic. FundingThis work was supported by the Medical Research Council MR/V015737/1. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched MEDLINE on 19th October 2020 for population-based epidemiological studies comparing the risk of SARS-CoV-2 infection and COVID-19 disease in people living with and without children. We searched for articles published in 2020, with abstracts available, and terms "(children or parents or dependants) AND (COVID or SARS-CoV-2 or coronavirus) AND (rate or hazard or odds or risk), in the title, abstract or keywords. 244 papers were identified for screening but none were relevant. One additional study in preprint was identified on medRxiv and found a reduced risk of hospitalisation for COVID-19 and a positive SARS-CoV-2 infection among adult healthcare workers living with children. Added value of this studyThis is the first population-based study to investigate whether the risk of recorded SARS-CoV-2 infection and severe outcomes from COVID-19 differ between adults living in households with and without school-aged children during the UK pandemic. Our findings show that for adults living with children there is no evidence of an increased risk of severe COVID-19 outcomes although there may be a slightly increased risk of recorded SARS-CoV-2 infection for working-age adults living with children aged 12 to 18 years. Working-age adults living with children 0 to 11 years have a lower risk of death from COVID-19 compared to adults living without children, with the effect size being comparable to their lower risk of death from any cause. We observed no consistent changes in risk of recorded SARS-CoV-2 infection and severe outcomes from COVID-19 comparing periods before and after school closure. Implications of all the available evidenceOur results demonstrate no evidence of serious harms from COVID-19 to adults in close contact with children, compared to those living in households without children. This has implications for determining the benefit-harm balance of children attending school in the COVID-19 pandemic.

Hydroxychloroquine for prevention of COVID-19 mortality: a population-based cohort study

BackgroundHydroxychloroquine has been shown to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, but early clinical studies found no benefit treating patients with coronavirus disease 2019 (COVID-19). We set out to evaluate the effectiveness of hydroxychloroquine for prevention, as opposed to treatment, of COVID-19 mortality. MethodsWe pre-specified and conducted an observational, population-based cohort study using national primary care data and linked death registrations in the OpenSAFELY platform, representing 40% of the general population in England. We used Cox regression to estimate the association between ongoing routine hydroxychloroquine use prior to the COVID-19 outbreak in England and risk of COVID-19 mortality among people with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Model adjustment was informed by a directed acyclic graph. ResultsOf 194,637 patients with RA or SLE, 30,569 (15.7%) received [≥] 2 prescriptions of hydroxychloroquine in the six months prior to 1 March 2020. Between 1 March 2020 and 13 July 2020, there were 547 COVID-19 deaths, 70 among hydroxychloroquine users. Estimated standardised cumulative COVID-19 mortality was 0.23% (95% CI 0.18-0.29) among users and 0.22% (95% CI 0.20-0.25) among non-users; an absolute difference of 0.008% (95% CI -0.051-0.066). After accounting for age, sex, ethnicity, use of other immunuosuppressives, and geographic region, no association with COVID-19 mortality was observed (HR 1.03, 95% CI 0.80-1.33). We found no evidence of interactions with age or other immunosuppressives. Quantitative bias analyses indicated observed associations were robust to missing information regarding additional biologic treatments for rheumatological disease. We observed similar associations with the negative control outcome of non-COVID-19 mortality. ConclusionWe found no evidence of a difference in COVID-19 mortality among patients who received hydroxychloroquine for treatment of rheumatological disease prior to the COVID-19 outbreak in England. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPublished trials and observational studies to date have shown no evidence of benefit of hydroxychloroquine as a treatment for hospitalised patients who already have COVID-19. A separate question remains: whether routine ongoing use of hydroxychloroquine in people without COVID-19 protects against new infections or severe outcomes. We searched MEDLINE/PubMed for pharmacoepidemiological studies evaluating hydroxychloroquine for prevention of severe COVID-19 outcomes. The keywords "hydroxychloroquine AND (COVID OR coronavirus OR SARS-CoV-2) AND (prophyl* OR prevent*) AND (rate OR hazard OR odds OR risk)" were used and results were filtered to articles from the last year with abstracts available. 109 papers were identified for screening; none investigated pre-exposure prophylactic use of hydroxychloroquine for prevention of severe COVID-19 outcomes. Clinical trials of prophylactic use of hydroxychloroquine are ongoing; however, the largest trial does not expect to meet recruitment targets due to "...unjustified extrapolation and exaggerated safety concerns together with intense politicisation and negative publicity." In the absence of reported clinical trials, evidence can be generated from real-world data to support the need for randomised clinical trials. Added value of this studyIn this cohort study representing 40% of the population of England, we investigated whether routine use of hydroxychloroquine prior to the COVID-19 outbreak prevented COVID-19 mortality. Using robust pharmacoepidemiological methods, we found no evidence to support a substantial benefit of hydroxychloroquine in preventing COVID-19 mortality. At the same time, we have shown no significant harm, and this generates the equipoise to justify continuing randomised trials. We have demonstrated in this study that it is feasible to address specific hypotheses about medicines in a rapid and transparent manner to inform interim clinical decision making and support the need for large-scale, randomised trial data. Implications of all the available evidenceThis is the first study to investigate the ongoing routine use of hydroxychloroquine and risk of COVID-19 mortality in a general population. While we found no evidence of any protective benefit, due to the observational nature of the study, residual confounding remains a possibility. Completion of trials for prevention of severe outcomes is warranted, but prior to the completion of these, we found no evidence to support the use of hydroxychloroquine for prevention of COVID-19 mortality.

Inhaled corticosteroid use and risk COVID-19 related death among 966,461 patients with COPD or asthma: an OpenSAFELY analysis

BackgroundEarly descriptions of the coronavirus outbreak showed a lower prevalence of asthma and COPD than was expected for people diagnosed with COVID-19, leading to speculation that inhaled corticosteroids (ICS) may protect against infection with SARS-CoV-2, and development of serious sequelae. We evaluated the association between ICS and COVID-19 related death using linked electronic health records in the UK. MethodsWe conducted cohort studies on two groups of people (COPD and asthma) using the OpenSAFELY platform to analyse data from primary care practices linked to national death registrations. People receiving an ICS were compared to those receiving alternative respiratory medications. Our primary outcome was COVID-19 related death. FindingsWe identified 148,588 people with COPD and 817,973 people with asthma receiving relevant respiratory medications in the four months prior to 01 March 2020. People with COPD receiving ICS were at a greater risk of COVID-19 related death compared to those receiving a long-acting beta agonist (LABA) and a long-acting muscarinic antagonist (LAMA) (adjusted HR = 1.38, 95% CI = 1.08 - 1.75). People with asthma receiving high dose ICS were at an increased risk of death compared to those receiving a short-acting beta agonist (SABA) only (adjusted HR = 1.52, 95%CI = 1.08 - 2.14); the adjusted HR for those receiving low-medium dose ICS was 1.10 (95% CI = 0.82 - 1.49). Quantitative bias analyses indicated that an unmeasured confounder of only moderate strength of association with exposure and outcome could explain the observed associations in both populations. InterpretationThese results do not support a major role of ICS in protecting against COVID-19 related deaths. Observed increased risks of COVID-19 related death among people with COPD and asthma receiving ICS can be plausibly explained by unmeasured confounding due to disease severity. FundingThis work was supported by the Medical Research Council MR/V015737/1.

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

BackgroundThe 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. MethodsWe 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. ResultsAmong 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. ConclusionOur findings are consistent with strong protection of BNT162b2 boosting against positive SARS-CoV-2 test, COVID-19 hospitalisation, and COVID-19 death.

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

BackgroundWhile 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. MethodWith the approval of NHS England 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. ResultsAs of 01st November 2021, a total of 15,436,455 individuals were identified as being fully vaccinated against COVID-19, with a median follow-up time of 149 days (IQR: 107-179). From within this population, a total of 577245 (<4%) individuals reported a positive SARS-CoV-2 test. For every 1000 years of patient follow-up time, the corresponding incidence rate was 98.02 (95% CI 97.9-98.15). There were 16,120 COVID-19-related hospital admissions, 1,100 COVID-19 critical care admission patients and 3,925 COVID-19-related deaths; corresponding incidence rates of 2.72 (95% C 2.7-2.74), 0.19 (95% C 0.18-0.19) and 0.66 (95% C 0.65-0.67), respectively. When broken down by the initial priority group, higher rates of hospitalisation and death were seen in those in care homes and those over 80 years of age. Comorbidities with the highest rates of breakthrough COVID-19 included chronic kidney disease, dialysis, transplant, haematological malignancy, and immunocompromised. ConclusionThe 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. While it is important to note that these findings are simply descriptive and cannot be used to answer why certain groups have higher rates of COVID-19 breakthrough than others, the emergence of the Omicron variant of COVID-19 coupled with the continued increase in numbers of positive SARS-CoV-2 tests are concerning. 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.