Comparative safety and effectiveness of Pfizer BA.4-5 versus Sanofi during the spring 2023 COVID-19 booster vaccination programme in England: a matched cohort study in OpenSAFELY-TPP (preprint)

Introduction: The spring 2023 COVID-19 booster vaccination programme in England used both Pfizer BA.4-5 and Sanofi vaccines. All people aged 75 years or over and the clinically vulnerable were eligible to receive a booster dose. Direct comparisons of the effectiveness of these two vaccines in boosting protection against severe COVID-19 events have not been made in trials or observational data. Methods With the approval of NHS England, we used the OpenSAFELY-TPP database to compare effectiveness of the Pfizer BA.4-5 and Sanofi vaccines during the spring 2023 booster programme, between 1 April and 30 June 2023. We investigated two cohorts separately: those aged 75 or over (75+); and those aged 50 or over and clinically vulnerable (CV). In each cohort, vaccine recipients were matched on date of vaccination, COVID-19 vaccine history, age, and other characteristics. Effectiveness outcomes were COVID-19 hospital admission, COVID-19 critical care admission, and COVID-19 death up to 16 weeks after vaccination. Safety outcomes were pericarditis and myocarditis up to 4 weeks after vaccination. We report the cumulative incidence of each outcome, and compare safety and effectiveness using risk differences (RD), relative risks (RR), and incidence rate ratios (IRRs). Results 492,642 people were 1-1 matched in the CV cohort, and 673,926 in the 75+ cohort, contributing a total of 7,423,251 and 10,173,230 person-weeks of follow-up, respectively. The incidence of COVID-19 hospital admission was higher for Sanofi than for Pfizer BA.4-5. In the CV cohort, 16-week risks per 10,000 people were 22.3 (95%CI 20.4 to 24.3) for Pfizer BA.4-5 and 26.4 (24.4 to 28.7) for Sanofi, with an IRR of 1.19 (95%CI 1.06 to 1.34). In the 75+ cohort, these were 17.5 (16.1 to 19.1) for Pfizer BA.4-5 and 20.4 (18.9 to 22.1) for Sanofi, with an IRR of 1.18 (1.05-1.32). These findings were similar across all pre-specified subgroups. More severe COVID-19 related outcomes (critical care admission and death), and safety outcomes at 4 weeks, were rare in both vaccines so we could not reliably compare effectiveness of the two vaccines. Conclusion This observational study comparing effectiveness of Pfizer BA.4-5 and Sanofi vaccine during the spring 2023 programme in England in the two main eligible cohorts - people aged 75 and over and in clinically vulnerable people - found some evidence of superior effectiveness against COVID-19 hospital admission for Pfizer BA.4-5 compared with Sanofi within 16 weeks after vaccination.

Quantifying and adjusting for confounding from health-seeking behaviour and healthcare access in observational research. (preprint)

Objective: To assess the feasibility and effect of using proxy markers of health-seeking behaviour and healthcare access to quantify and adjust for confounding in observational studies of influenza and COVID-19 vaccine effectiveness (VE). Design: Cohort study for influenza VE in the 2019/2020 influenza season and for early COVID-19 VE (December 2020 to March 2021). Setting: Primary care data pre-linked to secondary care and death data in England. Participants: Individuals aged ≥66 years on 1 September 2019. Interventions: Vaccination with any influenza vaccination in the 2019/2020 season or with either a BNT162b2 or ChAdOx1-S vaccination from 08/12/2020 to 31/03/2021. Main outcome measures: Influenza or COVID-19 specific infections, hospitalisation and death. VE was estimated with sequential adjustment for demographics, underlying health conditions, and 14 markers reflecting uptake of public health interventions (screenings, vaccinations and NHS health checks), active healthcare access/use (prostate antigen testing, bone density scans, GP practice visits, low value procedures and blood pressure measurements) and lack of access/underuse (hospital visits for ambulatory care sensitive conditions and did not attend primary care visits). Influenza vaccination in the 2019/2020 season was also considered as a negative exposure intervention against the first wave of COVID-19. Results: We included 1,991,284, 1,796,667, and 1,946,943 individuals in the influenza, COVID-19 and negative exposure VE populations, respectively. Vaccinated individuals were more likely to display active health-seeking behaviour, including participation in UK national screening programmes, compared with unvaccinated individuals. In the 2019/2020 influenza season, adjusting for health-seeking markers increased VE against infection from -1.5% (95%CI: -3.2,0.1) to 7.1% (95%CI: 5.4,8.7), but this trend was less apparent for more severe outcomes. For COVID-19 during early vaccine roll out, adjusting for health-seeking markers in addition to demographics and underlying health conditions did not change VE estimates against infection or severe disease (e.g., two doses of BNT162b2 against infection: from 82.8% [95%CI: 78.4,86.3] to 83.1% [95%CI: 78.7,86.5]). Adjusting for health-seeking markers removed bias in the negative exposure analysis of influenza vaccination against SARS-CoV-2 infection (-7.5% [95%CI: -10.6,-4.5] vs -2.1% [95%CI: -6.0,1.7] before vs after adjusting for health-seeking markers). Conclusions: Markers of health-seeking behaviour and healthcare access can be identified in electronic health records, are associated with vaccination uptake, and can be used to quantify and account for confounding in observational studies.

The impact of Long COVID on Health-Related Quality-of-life using OpenPROMPT (preprint)

Background: Long COVID is a major problem affecting patient health, the health service, and the workforce. To optimise the design of future interventions against COVID-19, and to better plan and allocate health resources, it is critical to quantify the health and economic burden of this novel condition. Methods With the approval of NHS England, we developed OpenPROMPT, a UK cohort study measuring the impact of long COVID on health-related quality-of-life (HRQoL). OpenPROMPT invited responses to Patient Reported Outcome Measures (PROMs) using a smartphone application and recruited between November 2022 and October 2023. We used the validated EuroQol EQ-5D questionnaire with the UK Value Set to develop disutility scores (1-utility) for respondents with and without Long COVID using linear mixed models, and we calculated subsequent Quality-Adjusted Life-Months (QALMs) for long COVID. Results We used data from 6,070 participants where 24.7% self-reported long COVID. In multivariable regressions, long COVID had a consistent impact on HRQoL, showing a high probability of reporting loss in quality-of-life (OR: 22, 95% CI:12.35-39.29) compared with people who did not report long COVID. Reporting a disability was the largest predictor of losses of HRQoL (OR: 60.2, 95% CI: 27.79-130.57) across survey responses. Self-reported long COVID was associated with an 0.37 QALM loss. Conclusions We found substantial impacts on quality-of-life due to long COVID, representing a major burden on patients and the health service. We highlight the need for continued support and research for long COVID, as HRQoL scores compared unfavourably to patients with conditions such as multiple sclerosis, heart failure, and renal disease.

Clinical coding of long COVID in primary care 2020-2023 in a cohort of 19 million adults: an OpenSAFELY analysis (preprint)

Background Long COVID is the patient-coined term for the persistent symptoms of COVID-19 illness for weeks, months or years following the acute infection. There is a large burden of long COVID globally from self-reported data, but the epidemiology, causes and treatments remain poorly understood. Primary care is used to help identify and treat patients with long COVID and therefore Electronic Health Records (EHRs) of past COVID-19 patients could be used to help fill these knowledge gaps. We aimed to describe those with long COVID in primary care records in England. Methods With the approval of NHS England we used routine clinical data from over 19 million adults in England linked to SARS-COV-2 test result, hospitalisation and vaccination data to describe trends in the recording of 16 clinical codes related to long COVID between November 2020 and January 2023. We calculated rates per 100,000 person-years and plotted how these changed over time. We compared crude and minimally adjusted rates of recorded long COVID in patient records between different key demographic and vaccination characteristics using negative binomial models. Findings We identified a total of 55,465 people recorded to have long COVID over the study period, with incidence of new long COVID records increasing steadily over 2021, and declining over 2022. The overall rate per 100,000 person-years was 177.5 cases in women (95% CI: 175.5-179) and 100.5 men (99.5-102). In terms of vaccination against COVID-19, the lowest rates were observed in those with 3+ vaccine doses (103.5 [95% CI: 101.5-105]). Finally, the majority of those with a long COVID record did not have a recorded positive SARS-COV-2 test 12 weeks before the long COVID record. Interpretation EHR recorded long COVID remains very low compared and incident records of long COVID declined over 2022. We found the lowest rates of recorded long COVID in people with 3 or more vaccine doses. We summarised several sources of possible bias for researchers using EHRs to study long COVID. Funding This research was supported by the National Institute for Health and Care Research (NIHR) (OpenPROMPT: COV-LT2-0073))

Primary care coding activity related to the use of online consultation systems or remote consulting: an analysis of 53 million peoples' health records using OpenSAFELY (preprint)

Objective: We aimed to explore general practice coding activity associated with the use of online consultation systems in terms of trends, COVID-19 effect, variation and quality. The pandemic accelerated work by the NHS in England to enable and stimulate use of online consultation systems across all practices, for improved access to primary care. Methods: With the approval of NHS England, OpenSAFELY-TPP and OpenSAFELY-EMIS were used to query and analyse in situ records of electronic health record systems of over 53 million patients in over 6,400 practices, mainly in 2019-2020. SNOMED CT codes relevant to online consultation systems and written online consultations were identified. Coded events were described by volumes, practice coverage, trends pre- and post-COVID-19 and inter-practice and sociodemographic variation. Results: 3,550,762 relevant coding events were found in TPP practices, with code eConsultation detected in 84% of practices. Coding activity related to digital forms of interaction increased rapidly from March 2020 at the onset of the COVID-19 pandemic, though we found large variation in coding instance rates among practices in England. Code instances were more commonly found among females, those aged 18-40, those least deprived or white. eConsultation coded activity was more commonly found recorded among patients with a history of asthma or depression. Conclusions: We successfully queried general practice coding activity relevant to the use of online consultation systems, showing increased adoption as well as key areas of variation during the COVID-19 pandemic. The work can be expanded to support monitoring of coding quality and underlying activity. In future, large-scale impact evaluation studies can be implemented within the platform, namely looking at resource utilisation and patient outcomes.

The impact of the COVID-19 pandemic on Antipsychotic Prescribing in individuals with autism, dementia, learning disability, serious mental illness or living in a care home: A federated analysis of 59 million patients primary care records in situ using OpenSAFELY (preprint)

Background: The COVID-19 pandemic significantly affected health and social care services. We aimed to explore whether this impacted the prescribing rates of antipsychotics within at-risk populations. Methods With the approval of NHS England, we completed a retrospective cohort study, using the OpenSAFELY platform to explore primary care data of 59 million patients. We identified patients in five at-risk groups: autism, dementia, learning disability, serious mental illness and care home residents. We then calculated the monthly prevalence of antipsychotic prescribing in the population, as well as the incidence of new prescriptions in each month over the study period (Jan 2019-Dec 2021). Results The average monthly rate of antipsychotic prescribing increased in dementia from 82.75 patients prescribed an antipsychotic per 1000 patients (95% CI 82.30-83.19) in Q1 2019 to 90.1 (95% CI 89.68-90.60) in Q4 2021 and from 154.61 (95% CI 153.79-155.43) in Q1 2019 to 166.95 (95% CI 166.23-167.67) in Q4 2021 in care homes . There were notable spikes in the rate of new prescriptions issued to patients with dementia and in care homes. In learning disability and autism groups, the average monthly rate of prescribing per 1000 decreased from 122.97 (95% CI 122.29-123.66) in Q1 2019 to 119.29 (95% CI 118.68-119.91) in Q4 2021, and from 54.91 (95% CI 54.52-55.29) in Q1 2019 to 51.04 (95% CI 50.74-51.35) in Q4 2021 respectively. Conclusions During each of the lockdowns in 2020, we observed a significant spike in antipsychotic prescribing in the dementia and care home groups. We have shown that these peaks are likely due to prescribing of antipsychotics for palliative care purposes and may have been linked to pre-emptive prescribing, when on-site medical visits would have been restricted. Over the study period, we observed gradual increases in antipsychotic use in patients with dementia and in care homes and a decrease in their use in patients with learning disability or autism.

Eleven key measures for monitoring general practice clinical activity during COVID-19 using federated analytics on 48 million adults' primary care records through OpenSAFELY (preprint)

Background The COVID-19 pandemic has had a significant impact on delivery of NHS care. We have developed the OpenSAFELY Service Restoration Observatory (SRO) to describe this impact on primary care activity and monitor its recovery. Objectives To develop key measures of primary care activity and describe the trends in these measures throughout the COVID-19 pandemic. Methods With the approval 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 electronic health record (EHR) data on 48 million adults. We developed SNOMED-CT codelists for key measures of primary care clinical activity selected by a expert clinical advisory group and conducted a population cohort-based study to describe trends and variation in these measures January 2019-December 2021, and pragmatically classified their level of recovery one year into the pandemic using the percentage change in the median practice level rate. Results We produced 11 measures reflective of clinical activity in general practice. A substantial drop in activity was observed in all measures at the outset of the COVID-19 pandemic. By April 2021, the median rate had recovered to within 15% of the median rate in April 2019 in six measures. The remaining measures showed a sustained drop, ranging from a 18.5% reduction in medication reviews to a 42.0% reduction in blood pressure monitoring. Three measures continued to show a sustained drop by December 2021. Conclusions The COVID-19 pandemic was associated with a substantial change in primary care activity across the measures we developed, with recovery in most measures. We delivered an open source software framework to describe trends and variation in clinical activity across an unprecedented scale of primary care data. We will continue to expand the set of key measures to be routinely monitored using our publicly available NHS OpenSAFELY SRO dashboards with near real-time data.

Changes in English medication safety indicators throughout the COVID-19 pandemic: a federated analysis of 57 million patients' primary care records in situ using OpenSAFELY (preprint)

Objective: To describe the impact of the COVID-19 pandemic on safe prescribing, using the PINCER prescribing indicators; to implement complex prescribing indicators at national scale using GP data. Design: Population based cohort study, with the approval of NHS England using the OpenSAFELY platform. Setting: Electronic health record data from 56.8 million NHS patients' general practice records. Participants: All NHS patients registered at a GP practice using TPP or EMIS computer systems and recorded as at risk of at least one potentially hazardous PINCER indicator between September 2019 and September 2021. Main outcome measure: Monthly trends and between-practice variation for compliance with 13 PINCER measures between September 2019 and September 2021. Results: The indicators were successfully implemented across GP data in OpenSAFELY. Hazardous prescribing remained largely unchanged during the COVID-19 pandemic, with only small reductions in achievement of the PINCER indicators. There were transient delays in blood test monitoring for some medications, particularly ACE inhibitors. All indicators exhibited substantial recovery by September 2021. We identified 1,813,058 patients at risk of at least one hazardous prescribing event. Conclusion: Good performance was maintained during the COVID-19 pandemic across a diverse range of widely evaluated measures of safe prescribing.

Waning effectiveness of BNT162b2 and ChAdOx1 COVID-19 vaccines over six months since second dose: a cohort study using linked electronic health records (preprint)

Summary Background The rate at which COVID-19 vaccine effectiveness wanes over time is crucial for vaccination policies, but is incompletely understood with conflicting results from different studies. Methods This cohort study, using the OpenSAFELY-TPP database and approved by NHS England, included individuals without prior SARS-CoV-2 infection assigned to vaccines priority groups 2-12 defined by the UK Joint Committee on Vaccination and Immunisation. We compared individuals who had received two doses of BNT162b2 or ChAdOx1 with unvaccinated individuals during six 4-week comparison periods, separately for subgroups aged 65+ years; 16-64 years and clinically vulnerable; 40-64 years and 18-39 years. We used Cox regression, stratified by first dose eligibility and geographical region and controlled for calendar time, to estimate adjusted hazard ratios (aHRs) comparing vaccinated with unvaccinated individuals, and quantified waning vaccine effectiveness as ratios of aHRs per-4-week period. The outcomes were COVID-19 hospitalisation, COVID-19 death, positive SARS-CoV-2 test, and non-COVID-19 death. Findings The BNT162b2, ChAdOx1 and unvaccinated groups comprised 1,773,970, 2,961,011 and 2,433,988 individuals, respectively. Waning of vaccine effectiveness was similar across outcomes and vaccine brands: e.g. in the 65+ years subgroup ratios of aHRs versus unvaccinated for COVID-19 hospitalisation, COVID-19 death and positive SARS-CoV-2 test ranged from 1.23 (95% CI 1.15-1.32) to 1.27 (1.20-1.34) for BNT162b2 and 1.16 (0.98-1.37) to 1.20 (1.14-1.27) for ChAdOx1. Despite waning, rates of COVID-19 hospitalisation and COVID-19 death were substantially lower among vaccinated individuals compared to unvaccinated individuals up to 26 weeks after second dose, with estimated aHRs <0.20 (>80% vaccine effectiveness) for BNT162b2, and <0.26 (>74%) for ChAdOx1. By weeks 23-26, rates of SARS-CoV-2 infection in fully vaccinated individuals were similar to or higher than those in unvaccinated individuals: aHRs ranged from 0.85 (0.78-0.92) to 1.53 (1.07-2.18) for BNT162b2, and 1.21 (1.13-1.30) to 1.99 (1.94-2.05) for ChAdOx1. Interpretation The rate at which estimated vaccine effectiveness waned was strikingly consistent for COVID-19 hospitalisation, COVID-19 death and positive SARS-CoV-2 test, and similar across subgroups defined by age and clinical vulnerability. If sustained to outcomes of infection with the Omicron variant and to booster vaccination, these findings will facilitate scheduling of booster vaccination doses.

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.

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

Objectives: We 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. Design: Two cohort studies, on behalf of NHS England. Setting: Primary care data and pseudonymously-linked SARS-CoV-2 antigen testing data, hospital admissions, and death records from England. Participants: Study 1: 70,464 people with atrial fibrillation (AF) and CHA2DS2-VASc score of 2. Study 2: 372,746 people with non-valvular AF. Main outcome measures: Time 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. Results: In 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. Conclusions: Among people with AF and a CHA2DS2-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 CHA2DS2-VASc score.

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

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.

Quality of life and depressive symptoms among Peruvian university students during the COVID-19 pandemic (preprint)

ObjectivesCharacterize the quality of life and depressive symptoms of university students in Peru during the COVID-19 pandemic and to determine the associated factors. MethodsMulti-centre study in 1634 university students recruited by convenience sampling. Quality of life (QoL) was assessed with the European Quality of Life-5 Dimensions at three levels (EQ-5D-3L) and depressive symptoms with the Patient Health Questionarie-9 (PHQ-9). To evaluate factors associated with QoL and depressive symptoms, linear and adjusted regressions were used, with robust variance reporting coefficients ({beta}). ResultsThe percentage of participants most affected by QoL dimension was: anxiety/depression (47.2%) and pain/discomfort (35.6%). Regarding the Visual Analog Scale (EQ-VAS) of QoL, the score was 76.0 + 25.6. Those who had family economic decline during quarantine ({beta}=-3.4, IC95%=-6.5 to -0.3) or family with chronic diseases ({beta}=-3.7, IC95%=-6.1 to -1.4) presented significantly lower scores in their QoL. Regarding depressive symptomatology, the university students reported a moderate to severe level (28.9%). A higher risk of depressive symptoms was found in residents of Ayacucho ({beta}=0.8, IC95%=0.1 to 1.5), those who were released from quarantine ({beta}=0.7, IC95%=0.2 to 1.2) and those who had a family member with chronic disease ({beta}=1.5, IC95%=1.0 to 2.1). ConclusionsAlmost half and one third of participants reported anxiety/depression, and pain/discomfort in their QoL respectively. Nearly a third presented moderate and severe depressive symptoms. The deterioration of QoL was worse in those who had a decrease in income and a family member with chronic illness. The presence of depressive symptoms was found in students in Ayacucho, those who left home during quarantine and those who had a family member with chronic diseases.

First-described recently discovered non-toxic vegetal-derived furocoumarin preclinical efficacy against SARS-CoV-2: a promising antiviral herbal drug. (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiology of coronavirus disease 2019 (COVID19) pandemic. ICEP4 purified compound (ICEP4) is a recently discovered furocoumarin-related purified compound derived from the roots and seeds of Angelica archangelica (herbal drug). ICEP4-related herbal preparations have been extensively used as active herbal ingredients in traditional medicine treatments in several European countries. Extraction method of patent pending ICEP4 (patent application no. GB2017123.7) has previously shown strong manufacturing robustness, long-lasting stability, and repeated chemical consistency. Here we show that ICEP4 presents a significant in vitro cytoprotective effect in highly virulent-SARS-CoV-2 challenged Vero E6 cellular cultures, using doses of 34.5 and 69 M. No dose-related ICEP4 toxicity was observed in Vero E6 cells, M0 macrophages, B, CD4+ T and CD8+ T lymphocytes, Natural Killer (NK) or Natural Killer T (NKT) cells. No dose-related ICEP4 inflammatory response was observed in M0 macrophages quantified by IL6 and TNF release in cell supernatant. No decrease in survival rate was observed after either 24 hr acute or 21-day chronic exposure in in vivo toxicity studies performed in C. elegans. Therefore, ICEP4 toxicological profile has demonstrated marked differences compared to others vegetal furocoumarins. Successful ICEP4 doses against SARS-CoV-2-challenged cells are within the maximum threshold of toxicity concern (TTC) of furocoumarins as herbal preparation, stated by European Medicines Agency (EMA). The characteristic chemical compounding of ICEP4, along with its safe TTC, allow us to assume that the first-observation of a natural antiviral compound has occurred. The potential druggability of a new synthetic ICEP4-related compound remains to be elucidated. However, well-established historical use of ICEP4-related compounds as herbal preparations may point towards an already-safe, widely extended remedy, which may be ready-to-go for large-scale clinical trials under the EMA emergency regulatory pathway. To the best of the authors knowledge, ICEP4-related herbal drug can be postulated as a promising therapeutic treatment for COVID19.

Elevated temperature inhibits SARS-CoV-2 replication in respiratory epithelium independently of the induction of IFN-mediated innate immune defences (preprint)

The pandemic spread of SARS-CoV-2, the etiological agent of COVID-19, represents a significant and ongoing international health crisis. A key symptom of SARS-CoV-2 infection is the onset of fever, with a hyperthermic temperature range of 38 to 41{degrees}C. Fever is an evolutionarily conserved host response to microbial infection and inflammation that can influence the outcome of viral pathogenicity and regulation of host innate and adaptive immune responses. However, it remains to be determined what effect elevated temperature has on SARS-CoV-2 tropism and replication. Utilizing a 3D air-liquid interface (ALI) model that closely mimics the natural tissue physiology and cellular tropism of SARS-CoV-2 infection in the respiratory airway, we identify tissue temperature to play an important role in the regulation of SARS-CoV-2 infection. We show that temperature elevation induces wide-spread transcriptome changes that impact upon the regulation of multiple pathways, including epigenetic regulation and lncRNA expression, without disruption of general cellular transcription or the induction of interferon (IFN)-mediated antiviral immune defences. Respiratory tissue incubated at temperatures >37{degrees}C remained permissive to SARS-CoV-2 infection but severely restricted the initiation of viral transcription, leading to significantly reduced levels of intraepithelial viral RNA accumulation and apical shedding of infectious virus. To our knowledge, we present the first evidence that febrile temperatures associated with COVID-19 inhibit SARS-CoV-2 replication. Our data identify an important role for temperature elevation in the epithelial restriction of SARS-CoV-2 that occurs independently of the induction of canonical IFN-mediated antiviral immune defences and interferon-stimulated gene (ISG) expression.

OpenSAFELY: Do adults prescribed Non-steroidal anti-inflammatory drugs have an increased risk of death from COVID-19? (preprint)

Importance: There has been speculation that non-steroidal anti-inflammatory drugs (NSAIDs) may negatively affect coronavirus disease 2019 (COVID-19) outcomes, yet clinical evidence is limited. Objective: To assess the association between NSAID use and deaths from COVID-19 using OpenSAFELY, a secure analytical platform. Design: Two cohort studies (1st March-14th June 2020). Setting: Working on behalf of NHS England, we used routine clinical data from >17 million patients in England linked to death data from the Office for National Statistics. Participants: Study 1: General population (people with an NSAID prescription in the last three years). Study 2: people with rheumatoid arthritis/osteoarthritis. Exposures: Current NSAID prescription within the 4 months before 1st March 2020. Main Outcome and Measure: We used Cox regression to estimate hazard ratios (HRs) for COVID-19 related death in people currently prescribed NSAIDs, compared with those not currently prescribed NSAIDs, adjusting for age, sex, comorbidities and other medications. Results: In Study 1, we included 535,519 current NSAID users and 1,924,095 non-users in the general population. The crude HR for current use was 1.25 (95% CI, 1.07-1.46), versus non-use. We observed no evidence of difference in risk of COVID-19 related death associated with current use (HR, 0.95, 95% CI, 0.80-1.13) in the fully adjusted model. In Study 2, we included 1,711,052 people with rheumatoid arthritis/osteoarthritis, of whom 175,631 (10%) were current NSAID users. The crude HR for current use was 0.43 (95% CI, 0.36-0.52), versus non-use. In the fully adjusted model, we observed a lower risk of COVID-19 related death (HR, 0.78, 95% CI, 0.65-0.94) associated with current use of NSAID versus non-use. Conclusion and Relevance: We found no evidence of a harmful effect of NSAIDs on COVID-19 related deaths. Risks from COVID-19 do not need to influence decisions about therapeutic use of NSAIDs.

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

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.