One year health outcomes associated with systemic corticosteroids for COVID-19: a longitudinal cohort study (preprint)

BackgroundIn patients with COVID-19 requiring supplemental oxygen, dexamethasone reduces acute severity and improves survival, but longer-term effects are unknown. We hypothesised that systemic corticosteroid administration during acute COVID-19 would be associated with improved health-related quality of life (HRQoL) one year after discharge. MethodsAdults admitted to hospital between February 2020 and March 2021 for COVID-19 and meeting current guideline recommendations for dexamethasone treatment were included using two prospective UK cohort studies. HRQoL, assessed by EQ-5D-5L utility index, pre-hospital and one year after discharge were compared between those receiving corticosteroids or not after propensity weighting for treatment. Secondary outcomes included patient reported recovery, physical and mental health status, and measures of organ impairment. Sensitivity analyses were undertaken to account for survival and selection bias. FindingsIn 1,888 participants included in the primary analysis, 1,149 received corticosteroids. There was no between-group difference in EQ-5D-5L utility index at one year (mean difference 0.004, 95% CI: -0.026 to 0.034, p = 0.77). A similar reduction in EQ-5D-5L was seen at one year between corticosteroid exposed and non-exposed groups (mean (SD) change -0.12 (0.22) vs -0.11 (0.22), p = 0.32). Overall, there were no differences in secondary outcome measures. After sensitivity analyses modelled using a larger cohort of 109,318 patients admitted to hospital with COVID-19, EQ-5D-5L utility index at one year remained similar between the two groups. InterpretationSystemic corticosteroids for acute COVID-19 have no impact on the large reduction in HRQoL one year after hospital discharge. Treatments to address this are urgently needed. Take home messageSystemic corticosteroids given for acute COVID-19 do not affect health-related quality of life or other patient reported outcomes, physical and mental health outcomes, and organ function one year after hospital discharge

Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease (preprint)

One in ten SARS-CoV-2 infections result in prolonged symptoms termed "long COVID", yet disease phenotypes and mechanisms are poorly understood. We studied the blood proteome of 719 adults, grouped by long COVID symptoms. Elevated markers of monocytic inflammation and complement activation were associated with increased likelihood of all symptoms. Elevated IL1R2, MATN2 and COLEC12 associated with cardiorespiratory symptoms, fatigue, and anxiety/depression, while elevated MATN2 and DPP10 associated with gastrointestinal (GI) symptoms, and elevated C1QA was associated with cognitive impairment (the proteome of those with cognitive impairment and GI symptoms being most distinct). Markers of neuroinflammation distinguished cognitive impairment whilst elevated SCG3, indicative of brain-gut axis disturbance, distinguished those with GI symptoms. Women had a higher incidence of long COVID and higher inflammatory markers. Symptoms did not associate with respiratory inflammation or persistent virus in sputum. Thus, persistent inflammation is evident in long COVID, distinct profiles being associated with specific symptoms.

Cohort Profile: Post-hospitalisation COVID-19 study (PHOSP-COVID) (preprint)

Abstract [bullet] PHOSP-COVID is a national UK multi-centre cohort study of patients who were hospitalised for COVID-19 and subsequently discharged. [bullet] PHOSP-COVID was established to investigate the medium- and long-term sequelae of severe COVID-19 requiring hospitalisation, understand the underlying mechanisms of these sequelae, evaluate the medium- and long-term effects of COVID-19 treatments, and to serve as a platform to enable future studies, including clinical trials. [bullet] Data collected covered a wide range of physical measures, biological samples, and Patient Reported Outcome Measures (PROMs). [bullet] Participants could join the cohort either in Tier 1 only with remote data collection using hospital records, a PROMs app and postal saliva sample for DNA, or in Tier 2 where they were invited to attend two specific research visits for further data collection and biological research sampling. These research visits occurred at five (range 2-7) months and 12 (range 10-14) months post-discharge. Participants could also participate in specific nested studies (Tier 3) at selected sites. [bullet] All participants were asked to consent to further follow-up for 25 years via linkage to their electronic healthcare records and to be re-contacted for further research. [bullet] In total, 7935 participants were recruited from 83 UK sites: 5238 to Tier 1 and 2697 to Tier 2, between August 2020 and March 2022. [bullet] Cohort data are held in a Trusted Research Environment and samples stored in a central biobank. Data and samples can be accessed upon request and subject to approvals.

Risk of cardiovascular events following COVID-19 in people with and without pre-existing chronic respiratory disease (preprint)

Background COVID-19 is associated with a higher risk of cardiovascular outcomes in the general population. People with chronic respiratory disease have a higher risk of cardiovascular disease than the general population therefore, we investigated the association between pre-existing chronic respiratory disease and risk of cardiovascular events following COVID-19 using routinely collected data from 56 million people in England. Methods Primary and secondary care data from the English National Health Service and COVID-19-specific linked data were used to define a population of adults with COVID-19 between 01/01/2020-30/11/2021. Start of follow-up was from first COVID-19 diagnosis. Pre-existing chronic respiratory disease included asthma, chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, or pulmonary fibrosis prior to COVID-19 diagnosis. Adjusted Cox Proportional Hazard regression was used to investigate the association between pre-existing chronic respiratory disease and risk of cardiovascular events. Secondary objectives investigated the impact of COVID-19 hospitalisation and vaccine dose on risk of cardiovascular outcomes. Findings A total of 3,670,455 people were included. People with pre-existing respiratory disease had a higher risk of cardiovascular events (adjusted HR 1.11, 95% confidence intervals 1.07-1.14), heart failure (1.15, 1.09-1.21), and pulmonary embolism (1.20, 1.11-1.30) compared with those without pre-existing respiratory disease. Regardless of pre-existing respiratory disease, the risk of cardiovascular events was lower with increasing COVID-19 vaccine dose. Interpretation People with chronic respiratory disease have a higher risk of some cardiovascular outcomes but the risk might be explained by the underlying respiratory condition. Risk of cardiovascular events was lower with increasing COVID-19 vaccine doses regardless of pre-existing chronic respiratory disease. Funding This work was funded by the British Heart Foundation Data Science Centre.

Nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination. (preprint)

Background Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. Methods Plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. Findings Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months. Nasal and plasma anti-S IgG remained elevated for at least 12 months with high plasma neutralising titres against all variants. Of 180 with complete data, 160 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal. Samples 12 months after admission showed no association between nasal IgA and plasma IgG responses, indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. Interpretation The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity.

Device-assessed sleep and physical activity in individuals recovering from a hospital admission for COVID-19: a prospective, multicentre study (preprint)

ObjectivesTo describe physical behaviours following hospital admission for COVID-19 including associations with acute illness severity and ongoing symptoms. Methods1077 patients with COVID-19 discharged from hospital between March and November 2020 were recruited. Using a 14-day wear protocol, wrist-worn accelerometers were sent to participants after a five-month follow-up assessment. Acute illness severity was assessed by the WHO clinical progression scale, and the severity of ongoing symptoms was assessed using four previously reported data-driven clinical recovery clusters. Two existing control populations of office workers and type 2 diabetes were comparators. ResultsValid accelerometer data from 253 women and 462 men were included. Women engaged in a mean{+/-}SD of 14.9{+/-}14.7 minutes/day of moderate-to-vigorous physical activity (MVPA), with 725.6{+/-}104.9 minutes/day spent inactive and 7.22{+/-}1.08 hours/day asleep. The values for men were 21.0{+/-}22.3 and 755.5{+/-}102.8 minutes/day and 6.94{+/-}1.14 hours/day, respectively. Over 60% of women and men did not have any days containing a 30-minute bout of MVPA. Variability in sleep timing was approximately 2 hours in men and women. More severe acute illness was associated with lower total activity and MVPA in recovery. The very severe recovery cluster was associated with fewer days/week containing continuous bouts of MVPA, longer sleep duration, and higher variability in sleep timing. Patients post-hospitalisation with COVID-19 had lower levels of physical activity, greater sleep variability, and lower sleep efficiency than a similarly aged cohort of office workers or those with type 2 diabetes. ConclusionsPhysical activity and regulating sleep patterns are potential treatable traits for COVID-19 recovery programmes.

Patient symptoms and experience following COVID-19: results from a UK wide survey (preprint)

Objectives To investigate the experience of people who continue to be unwell after acute COVID-19, often referred to as 'Long-COVID', both in terms of their symptoms and their interactions with healthcare. Design We conducted a mixed-methods analysis (quantitative and qualitative) of responses to a survey accessed through a UK online post-COVID support and information hub between April 2020 and December 2020 about people's experiences after having acute COVID-19. Participants Of 3290 respondents, 78% were female, median age range 45-54 years, 92.1% reported white ethnicity; 12.7% had been hospitalised. 494 respondents (16.5%) completed the survey between 4 and 8 weeks of the onset of their symptoms, 641 (21.4%) between 8 and 12 weeks and 1865 (62.1%) more than 12 weeks after. Results The ongoing symptoms most frequently reported were; breathing problems (92.1%), fatigue (83.3%), muscle weakness or joint stiffness (50.6%), sleep disturbances (46.2%), problems with mental abilities (45.9%) changes in mood, including anxiety and depression (43.1%) and cough (42.3%). Symptoms did not appear to be related to the severity of the acute illness or to the presence of pre-existing medical conditions. Analysis of free text responses revealed three main themes (1) Experience of living with COVID-19 - physical and psychological symptoms that fluctuate unpredictably; (2) Interactions with healthcare; (3) Implications for the future - their own condition, society and the healthcare system and the need for research Conclusion People living with persistent problems after the acute phase of COVID-19 report multiple and varying symptoms that are not necessarily associated with initial disease severity or the presence of pre-existing health conditions. Many have substantial unmet needs and experience barriers to accessing healthcare. Consideration of patient perspective and experiences will assist in the planning of services to address this.

Post-acute COVID-19 sequelae in cases managed in the community or hospital in the UK: a population based study (preprint)

Objective To compare post-COVID-19 sequelae between hospitalised and non-hospitalised individuals Design Population-based cohort study Setting 1,383 general practices in England contributing to Clinical Practice Research Database Aurum Participants 46,687 COVID-19 cases diagnosed between 1st August to 17th October 2020 (45.4% male; mean age 40), either hospitalised within two weeks of diagnosis or non-hospitalised, and followed-up for a maximum of three months. Main outcome measures Event rates of new symptoms, diseases, prescriptions and healthcare utilisation in hospitalised and non-hospitalised individuals, with between-group comparison using Cox regression. Outcomes compared at 6 and 12 months prior to index date, equating to first UK wave and pre-pandemic. Non-hospitalised group outcomes stratified by age and sex. Results 45,272 of 46,687 people were non-hospitalised; 1,415 hospitalised. Hospitalised patients had higher rates of 13/26 symptoms and 11/19 diseases post-COVID-19 than the community group, received more prescriptions and utilised more healthcare. The largest differences were noted for rates per 100,000 person-weeks [95%CI] of breathlessness: 536 [432 to 663] v. 85 [77 to 93]; joint pain: 295 [221 to 392] v. 168 [158 to 179]; diabetes: 303 [225 to 416] v. 36 [32 to 42], hypertension: 244 [178 to 344] v. 47 [41 to 53]. Although low, rates of chest tightness, tinnitus and lung fibrosis were higher in the community group. 4.2% (1882/45,272) of the community group had a post-acute burden, most frequently reporting anxiety, breathlessness, chest pain and fatigue. In those non-hospitalised, age and sex differences existed in outcome rates. Healthcare utilisation in the community group increased 28.5% post-COVID-19 relative to pre-pandemic. Conclusions Post-COVID-19 sequelae differ between hospitalised and non-hospitalised individuals, with age and sex-specific differences in those non-hospitalised. Most COVID-19 cases managed in the community do not report ongoing issues to healthcare professionals. Post-COVID-19 follow-up and management strategies need to be tailored to specific groups.

Increasing but inadequate intention to receive Covid-19 vaccination over the first 50 days of impact of the more infectious variant and roll-out of vaccination in UK: indicators for public health messaging (preprint)

Objectives To inform critical public health messaging by determining how changes in Covid-19 vaccine hesitancy, attitudes to the priorities for administration, the emergence of new variants and availability of vaccines may affect the trajectory and achievement of herd immunity. Methods >9,000 respondents in an ongoing cross-sectional participatory longitudinal epidemiology study (LoC-19, n=18,581) completed a questionnaire within their personal electronic health record in the week reporting first effective Covid-19 vaccines, and then again after widespread publicity of the increased transmissibility of a new variant (November 13th and December 31st 2020 respectively). Questions covered willingness to receive Covid-19 vaccination and attitudes to prioritisation. Descriptive statistics, unadjusted and adjusted odds ratios (ORs) and natural language processing of free-text responses are reported, and how changes over the first 50 days of both vaccination roll-out and new-variant impact modelling of anticipated transmission rates and the likelihood and time to herd immunity. Findings Compared with the week reporting the first efficacious vaccine there was a 15% increase in acceptance of Covid-19 vaccination, attributable in one third to the impact of the new variant, with 75% of respondents "shielding" -- staying at home and not leaving unless essential -- regardless of health status or tier rules. 12.5% of respondents plan to change their behaviour two weeks after completing vaccination compared with 45% intending to do so only when cases have reduced to a low level. Despite the increase from 71% to 86% over this critical 50-day period, modelling of planned uptake of vaccination remains below that required for rapid effective herd immunity -- now estimated to be 90 percent in the presence of a new variant escalating R0 to levels requiring further lockdowns. To inform the public messaging essential therefore to improve uptake, age and female gender were, respectively, strongly positively and negatively associated with wanting a vaccine. 22.7% disagreed with the prioritisation list, though 70.3% were against being able to expedite vaccination through payment. Teachers (988, 12.6%) and Black, Asian and Minority Ethnic (BAME) (837, 10.7%) groups were most cited by respondents for prioritisation. Interpretation In this sample, the growing impact of personal choice among the increasingly informed public highlights a decrease in Covid-19 vaccine hesitancy over time, with news of a new variant motivating increased willingness for vaccination but at levels below what may be required for effective herd immunity. We identify public preferences for next-in-line priorities, headed by teachers and BAME groups, consideration of which will help build trust and community engagement critical for maximising compliance with not only the vaccination programme but also all other public health measures.

Inadequate intention to receive Covid-19 vaccination: indicators for public health messaging needed to improve uptake in UK (preprint)

Data promising effective Covid-19 vaccines have accelerated the UKs mass vaccination programme. The UK publics attitudes to the governments prioritisation list are unknown, and achieving critical population immunity will require the remaining majority to accept both vaccination and the delay in access of up to a year or more. This cross-sectional observational study sent an online questionnaire to registrants of the UK National Health Services largest personal health record. Question items covered willingness for Covid-19 vaccine uptake and attitudes to prioritisation. Among 9,122 responses, 71.5% indicated wanting a vaccine, below what previous modelling indicated as critical levels for progressing towards herd immunity. 22.7% disagreed with the prioritisation list, though 70.3% were against being able to expedite vaccination through payment. Age and female gender were, respectively, strongly positively and negatively associated with wanting a vaccine. Teachers and Black, Asian and Minority Ethnic (BAME) groups were most cited by respondents for prioritisation. This study identifies factors to inform the public health messaging critical to improving uptake.

The Impact of the Covid-19 Pandemic on Uptake of Influenza Vaccine: A UK-Wide Observational Study (preprint)

ObjectivesThe objective of this study was to measure the impact of the Covid-19 pandemic on acceptance of flu vaccination in the 2020-21 season, including for those newly eligible for the UK National Health Service (NHS) free vaccination programme, extended this year to include an estimated 32.4 million (48.8%) of the UK population. Knowing intended uptake is essential to inform supply and steer public health messaging to maximise vaccination given the combined threats of both flu and Covid-19 -- the unknown impact of which on both attitudes and the need for mass uptake yet again create the threat of ill-informed planning resulting in failure to meet necessary public health demand. MethodsAn online questionnaire posing question items on influenza vaccination was administered to registrants of the Care Information Exchange (CIE), the NHSs largest patient electronic personal health record. This was part of a longitudinal study initiated during the Covid-19 pandemic lockdown. This analysis was limited to those who, in line with established NHS criteria, were previously or newly eligible but had not routinely received seasonal influenza vaccination in the past. Groups were stratified by response (yes/no) to intending to receive flu vaccination in 2020-21: Group 1.) Previously eligible now responding yes, 2.) Previously eligible still responding no, 3.) Newly eligible responding yes, and 4.) Newly eligible responding no. Within these groups, response by health worker status and each groups inclination to vaccinate school age children was also measured. Summary statistics were reported alongside univariate and multivariable regression. Lastly, a network analysis visualised the frequency and co-occurrence of reasons qualifying response for or against influenza vaccination in 2020/21. FindingsAmong 6,641 respondents, 4,040 (61.1%) had previously routinely received the flu vaccination. 1,624 (24.5%) had been either previously eligible but not vaccinated (945, 58.2%) or newly eligible (679, 41.8%). Among the previously eligible participants who had not routinely received influenza vaccination 536 (56.7%) responded they would in 2020-21, increasing the vaccination rate in the entire previously eligible cohort from 79.6% to 91.2%, and 466 (68.6%) in the newly eligible. Multivariable logistic regression resulted in few substantial changes to effect estimates, with the exception of age, for which all estimates showed a stronger association with intention to receive the flu vaccine. In those who became newly eligible to receive the flu vaccine, there was an association between intention to receive the flu vaccine and increased age (OR = 1.07, 95% CI 1.03 to 1.12), IMD quintile, and considering oneself at high risk from Covid-19 (OR = 1.80, 95% CI 1.22 to 2.70). Network analysis showed the most frequent themes for previously eligible unvaccinated and newly eligible participants accepting vaccination in 2020/21 were: precaution for myself (41.2% and 46.1%) and Covid-19 (27.4% and 27.1%), where the former was qualified by the latter in 36% and 29.1% of responses. Among the previously and newly eligible not intending to receive vaccination in 2020/21, misinformed themes of makes me unwell, gives me flu and vaccine doesnt work were present across 37.4% and 21.9% of responses, respectively. Among participants with school age children, of those previously eligible who now intend to be vaccinated themselves, 82.5% also intend to vaccinate their children in 2020/21 compared to 25.8% of those who would not accept the influenza vaccine for themselves. Among the newly eligible respondents this was 82.1% and 43.5%, respectively. 49.9% of the previously unvaccinated healthcare workers would continue to decline the vaccine in 2020/21. InterpretationIn this UK-wide observational study, Covid-19 has increased acceptance of flu vaccination in 2020/21 from 79.6% to 91.2% in those previously eligible, and for the 69% of those newly eligible. This high anticipated vaccination rate (to 26 million (80%) of the UK population) requires appropriate planning, but can be further increased with effective messaging campaigns to address negative misconceptions about flu vaccination, which may also help in preparation for future Covid-19 vaccination. It remains of concern that 50% of healthcare professionals who refused it previously still do not intend to have the flu vaccine.

MMGB/SA Consensus Estimate of the Binding Free Energy Between the Novel Coronavirus Spike Protein to the Human ACE2 Receptor (preprint)

The ability to estimate protein-protein binding free energy in a computationally efficient via a physics-based approach is beneficial to research focused on the mechanism of viruses binding to their target proteins. Implicit solvation methodology may be particularly useful in the early stages of such research, as it can offer valuable insights into the binding process, quickly. Here we evaluate the potential of the related molecular mechanics generalized Born surface area (MMGB/SA) approach to estimate the binding free energy {Delta}Gbind between the SARS-CoV-2 spike receptor-binding domain and the human ACE2 receptor. The calculations are based on a recent flavor of the generalized Born model, GBNSR6. Two estimates of {Delta}Gbind are performed: one based on standard bondi radii, and the other based on a newly developed set of atomic radii (OPT1), optimized specifically for protein-ligand binding. We take the average of the resulting two {Delta}Gbind values as the consensus estimate. For the well-studied Ras-Raf protein-protein complex, which has similar binding free energy to that of the SARS-CoV-2/ACE2 complex, the consensus {Delta}Gbind = -11.8 {+/-} 1 kcal/mol, vs. experimental -9.7 {+/-} 0.2 kcal/mol. The consensus estimates for the SARS-CoV-2/ACE2 complex is {Delta}Gbind = -9.4 {+/-} 1.5 kcal/mol, which is in near quantitative agreement with experiment (-10.6 kcal/mol). The availability of a conceptually simple MMGB/SA-based protocol for analysis of the SARS-CoV-2 /ACE2 binding may be beneficial in light of the need to move forward fast.

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

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.

Belief of Previous COVID-19 Infection and Unclear Government Policy are Associated with Reduced Willingness to Participate in App-Based Contact Tracing: A UK-Wide Observational Study of 13,000 Patients (preprint)

Background: Contact tracing and lockdown are health policies being used worldwide to combat the coronavirus (COVID-19). While easing lockdown, the UK National Health Service (NHS) launched its Track and Trace Service at the end of May 2020, and aims by end of June 2020 also to include app-based notification and advice to self-isolate for those who have been in contact with a person known to have COVID-19. To be successful, such an app will require high uptake, the determinants and willingness for which are unclear but essential to understand for effective public health benefit. Objectives: To measure the determinants of willingness to participate in an NHS app-based contact tracing programme using a questionnaire within the Care Information Exchange (CIE) - the largest patient-facing electronic health record in the NHS. Methods: Observational study of 47,708 registered NHS users of the CIE, 27% of whom completed a novel questionnaire asking about willingness to participate in app-based contact tracing, understanding of government advice, mental and physical wellbeing and their healthcare utilisation -- related or not to COVID-19. Descriptive statistics are reported alongside univariate and multivariable logistic regression models, with positive or negative responses to a question on app-based contact tracing as the dependent variable. Results: 26.1% of all CIE participants were included in the analysis (N = 12,434, 43.0% male, mean age 55.2). 60.3% of respondents were willing to participate in app-based contact tracing. Out of those who responded "no", 67.2% stated that this was due to privacy concerns. In univariate analysis, worsening mood, fear and anxiety in relation to changes in government rules around lockdown were associated with lower willingness to participate. Multivariable analysis showed that difficulty understanding government rules was associated with a decreased inclination to download the app, with those scoring 1-2 and 3-4 in their understanding of the new government rules being 45% and 27% less inclined to download the contact tracing app, respectively; when compared to those who rated their understanding as 5-6/10 (OR for 1-2/10 = 0.57 [CI 0.48 - 0.67]; OR for 3-4/10 = 0.744 [CI 0.64 - 0.87]), whereas scores of 7-8 and 9-10 showed a 43% and 31% respective increase. Those reporting an unconfirmed belief of having previously had and recovered from COVID-19 were 27% less likely to be willing to download the app; belief of previous recovery from COVID-19 infection OR 0.727 [0.585 - 0.908]). Conclusions: In this large UK-wide questionnaire of wellbeing in lockdown, a willingness for app-based contact tracing is 60% - close to the estimated 56% population uptake, and substantially less than the smartphone-user uptake considered necessary for an app-based contact-tracing to be an effective intervention to help suppress an epidemic. Given this marginal level of support over an appropriate age range, the impacts of difficulty comprehending government advice and a policy of not testing to confirm self-reported COVID-19 infection during lockdown indicate that uncertainty in communication and diagnosis in adopted public health policies will negatively impact the effectiveness of a government contact tracing app.

Current tobacco smoking and risk from COVID-19: results from a population symptom app in over 2.4 million people (preprint)

BackgroundThe association between current tobacco smoking, the risk of developing COVID-19 and the severity of illness is an important information gap. MethodsUK users of the COVID Symptom Study app provided baseline data including demographics, anthropometrics, smoking status and medical conditions, were asked to log symptoms daily from 24th March 2020 to 23rd April 2020. Participants reporting that they did not feel physically normal were taken through a series of questions, including 14 potential COVID-19 symptoms and any hospital attendance. The main study outcome was the association between current smoking and the development of "classic" symptoms of COVID-19 during the pandemic defined as fever, new persistent cough and breathlessness. The number of concurrent COVID-19 symptoms was used as a proxy for severity. In addition, association of subcutaneous adipose tissue expression of ACE2, both the receptor for SARS-CoV-2 and a potential mediator of disease severity, with smoking status was assessed in a subset of 541 twins from the TwinsUK cohort. ResultsData were available on 2,401,982 participants, mean(SD) age 43.6(15.1) years, 63.3% female, overall smoking prevalence 11.0%. 834,437 (35%) participants reported being unwell and entered one or more symptoms. Current smokers were more likely to develop symptoms suggesting a diagnosis of COVID-19; classic symptoms adjusted OR[95%CI] 1.14[1.10 to 1.18]; >5 symptoms 1.29[1.26 to 1.31]; >10 symptoms 1.50[1.42 to 1.58]. Smoking was associated with reduced ACE2 expression in adipose tissue (Beta(SE)=-0.395(0.149); p=7.01x10-3). InterpretationThese data are consistent with smokers having an increased risk from COVID-19. FundingZoe provided in kind support for all aspects of building, running and supporting the app and service to all users worldwide. The study was also supported by grants from the Wellcome Trust, UK Research and Innovation and British Heart Foundation. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSThe interaction between current smoking and COVID-19 is unclear. Smoking is known to increase susceptibility to viral infections and appears to be associated with worse outcomes in people admitted to hospital with COVID-19. However, case series have reported relatively low levels of current smoking among individuals admitted to hospital with the condition, raising the possibility that smoking has a protective effect against the disease. Added value of this studyData from a large UK population who are users of a symptom reporting app during the pandemic supports the hypothesis that smokers are more likely to develop symptoms consistent with COVID-19 and that they have an increased symptom burden. Implications of all the available evidenceThese population data, combined with evidence of a worse outcome in smokers hospitalised with the condition, support the contention that smoking increases individual risk from COVID-19. Support to help people to quit smoking should therefore form part of efforts to deal with the pandemic.