Symptom experience before vs. after confirmed SARS-CoV-2 infection: a population and case control study using prospectively recorded symptom data. (preprint)

Background: Some individuals experience prolonged illness after acute COVID-19. We assessed whether pre-infection symptoms affected post-COVID illness duration. Methods Survival analysis was performed in adults (n=23,452) with community-managed SARC-CoV-2 infection prospectively self-logging data through the ZOE COVID Symptom Study app, at least weekly, from 8 weeks before to 12 weeks after COVID-19 onset, conditioned on presence vs. absence of baseline symptoms (4-8 weeks before COVID-19). A case-control study was performed in 1350 individuals with long illness ([≥]8 weeks, 906 [67.1%] with illness [≥]12 weeks), matched 1:1 (for age, sex, body mass index, testing week, prior infection, vaccination, smoking, index of multiple deprivation) with 1350 individuals with short illness (<4 weeks). Baseline symptoms were compared between the two groups; and against post-COVID symptoms. Findings: Individuals reporting baseline symptoms had longer post-COVID symptom duration (from 10 to 15 days) with baseline fatigue nearly doubling duration. Two-thirds (910 of 1350 [67.4%]) of individuals with long illness were asymptomatic beforehand. However, 440 (32.6%) had baseline symptoms, vs. 255 (18.9%) of 1350 individuals with short illness (p<0.0001). Baseline symptoms increased the odds ratio for long illness (2.14 [CI: 1.78; 2.57]). Prior comorbidities were more common in individuals with long vs. short illness. In individuals with long illness, baseline symptomatic (vs. asymptomatic) individuals were more likely to be female, younger, and have prior comorbidities; and baseline and post-acute symptoms and symptom burden correlated strongly. Interpretation: Individuals experiencing symptoms before COVID-19 have longer illness duration and increased odds of long illness. However, many individuals with long illness are well before SARS-CoV-2 infection.

Metabolomic and gut microbiome profiles across the spectrum of community-based COVID and non-COVID disease: A COVID-19 Biobank study (preprint)

Whilst many with SARS-CoV-2 infection have mild disease, managed in the community, individuals with cardiovascular risk factors experienced often more severe acute disease, requiring hospitalisation. Increasing concern has also developed over long symptom duration in many individuals, including the majority who managed acutely in the community. Risk factors for long symptom duration, including biological variables, are still poorly defined. We examine post-illness metabolomic and gut-microbiome profiles, in community-dwelling participants with SARS-CoV-2, ranging from asymptomatic illness to Post-COVID Syndrome, and participants with prolonged non-COVID-19 illnesses. We also assess a pre-established metabolomic biomarker score for its association with illness duration. We found an atherogenic-dyslipidaemic metabolic profile, and greater biomarker scores, associated with longer illness, both in individuals with and without SARS-CoV-2 infection. We found no association between illness duration and gut microbiome in convalescence. Findings: highlight the potential role of cardiometabolic dysfunction to the experience of long illness duration, including after COVID-19.

Vaccination against SARS-CoV-2 in UK school-aged children and young people decreases infection rates and reduces COVID-19 symptoms (preprint)

Background We aim to explore the effectiveness of one-dose BNT162b2 vaccination upon SARS-CoV-2 infection rates in children and young people (CYP) during Delta and Omicron variant predominance in the UK, and study its effect on COVID-19 presentation and post-vaccination symptoms. Methods In this prospective longitudinal cohort study, we analysed data from 115,775 CYP aged 12-17 years, proxy-reported through the Covid Symptom Study (CSS) smartphone application. We calculated post-vaccination infection risk after one dose of BNT162b2. We described the illness profile of CYP with post-vaccination SARS-CoV-2 infection, compared to unvaccinated CYP. Findings Between August 5, 2021 and February 14, 2022, 25,971 UK CYP aged 12-17 years received one dose of BNT162b2 vaccine. Vaccination reduced infection (reporting) risk (-80.4% and -53.7% at 14-30 days with Delta and Omicron variants respectively, and -61.5% and -63.7% after 61-90 days). The probability of remaining infection-free diverged after vaccination, and was more robust with prior infection. Vaccinated CYP who contracted SARS-CoV-2 during the Delta period had milder disease than unvaccinated CYP; however, during the Omicron period this was only evident in children aged 12-15 years, and overall disease profile was similar in both vaccinated and unvaccinated CYP. Post-vaccination local side-effects were common, systemic side-effects were uncommon, and both resolved quickly. Interpretation One dose of BNT162b2 vaccine reduced risk of SARS-CoV-2 infection for at least 90 days in CYP aged 12-17 years. Vaccine protection was modulated by SARS-CoV-2 variant type (lower for Omicron than Delta variant), and was enhanced by pre-vaccination SARS-CoV-2 infection. Severity of COVID-19 presentation after vaccination is generally milder, although unvaccinated CYP also have an uncomplicated course. Overall, vaccination was well-tolerated.

COVID-19 due to the B.1.617.2 (Delta) variant compared to B.1.1.7 (Alpha) variant of SARS-CoV-2: two prospective observational cohort studies (preprint)

Background The Delta (B.1.617.2) variant became the predominant UK circulating SARS-CoV-2 strain in May 2021. How Delta infection compares with previous variants is unknown. Methods This prospective observational cohort study assessed symptomatic adults participating in the app-based COVID Symptom Study who tested positive for SARS-CoV-2 from May 26 to July 1, 2021 (Delta overwhelmingly predominant circulating UK variant), compared (1:1, age- and sex-matched) with individuals presenting from December 28, 2020 to May 6, 2021 (Alpha (B.1.1.7) predominant variant). We assessed illness (symptoms, duration, presentation to hospital) during Alpha- and Delta-predominant timeframes; and transmission, reinfection, and vaccine effectiveness during the Delta-predominant period. Findings 3,581 individuals (aged 18 to 100 years) from each timeframe were assessed. The seven most frequent symptoms were common to both variants. Within the first 28 days of illness, some symptoms were more common with Delta vs. Alpha infection (including fever, sore throat and headache) and vice versa (dyspnoea). Symptom burden in the first week was higher with Delta vs. Alpha infection; however, the odds of any given symptom lasting [≥]7 days was either lower or unchanged. Illness duration [≥]28 days was lower with Delta vs. Alpha infection, though unchanged in unvaccinated individuals. Hospitalisation for COVID-19 was unchanged. The Delta variant appeared more (1.47) transmissible than Alpha. Re-infections were low in all UK regions. Vaccination markedly (69-84%) reduced risk of Delta infection. Interpretation COVID-19 from Delta or Alpha infections is clinically similar. The Delta variant is more transmissible than Alpha; however, current vaccines show good efficacy against disease. Funding UK Government Department of Health and Social Care, Wellcome Trust, UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging & Artificial Intelligence Centre for Value Based Healthcare, UK National Institute for Health Research, UK Medical Research Council, British Heart Foundation, Alzheimer's Society, and ZOE Limited.

Illness characteristics of COVID-19 in children infected with the SARS-CoV-2 Delta variant (preprint)

Background The Delta (B.1.617.2) SARSCoV2 variant became the predominant UK circulating strain in May 2021. Whether COVID19 from Delta infection differs to infection with other variants in children is unknown. Methods Through the prospective COVID Symptom Study, 109,626 UK school-aged children were proxy-reported between December 28, 2020 and July 8, 2021. We selected all symptomatic children who tested positive for SARS-CoV-2 and were proxy-reported at least weekly, within two timeframes: December 28, 2020 to May 6, 2021 (Alpha (B.1.1.7) the main UK circulating variant); and May 26 to July 8, 2021 (Delta the main UK circulating variant). We assessed illness profiles (symptom prevalence, duration, and burden), hospital presentation, and presence of long (>28 day) illness; and calculated odds ratios for symptoms presenting within the first 28 days of illness. Findings 694 (276 younger [5 11 years], 418 older [12 17 years]) symptomatic children tested positive for SARS-CoV-2 with Alpha infection and 706 (227 younger and 479 older) children with Delta infection. Median illness duration was short with either variant (overall cohort: 5 days (IQR 2 9.75) with Alpha, 5 days (IQR 2 9) with Delta). The seven most prevalent symptoms were common to both variants. Symptom burden over the first 28 days was slightly greater with Delta compared with Alpha infection (in younger children, 3 (IQR 2 5) with Alpha, 4 (IQR 2 7) with Delta; in older children 5 (IQR 3 8) with Alpha and 6 (IQR 3 9) with Delta infection in older children). The odds of several symptoms were higher with Delta than Alpha infection, including headache and fever. Few children presented to hospital, and long illness duration was uncommon, with either variant. Interpretation COVID-19 in UK school-aged children due to SARSCoV2 Delta strain B.1.617.2 resembles illness due to the Alpha variant B.1.1.7., with short duration and similar symptom burden.

Anxiety and depression symptoms after COVID-19 infection: results from the COVID Symptom Study app (preprint)

Background: Mental health issues have been reported after SARS-CoV-2 infection. However, comparison to prevalence in uninfected individuals and contribution from common risk factors (e.g., obesity, comorbidities) have not been examined. We identified how COVID-19 relates to mental health in the large community-based COVID Symptom Study. Methods: We assessed anxiety and depression symptoms using two validated questionnaires in 413,148 individuals between February and April 2021; 26,998 had tested positive for SARS-CoV-2. We adjusted for physical and mental pre-pandemic comorbidities, BMI, age, and sex. Findings: Overall, 26.4% of participants met screening criteria for general anxiety and depression. Anxiety and depression were slightly more prevalent in previously SARS-CoV-2 positive (30.4%) vs. negative (26.1%) individuals. This association was small compared to the effect of an unhealthy BMI and the presence of other comorbidities, and not evident in younger participants ([≤]40 years). Findings were robust to multiple sensitivity analyses. Association between SARS-CoV-2 infection and anxiety and depression was stronger in individuals with recent (<30 days) vs. more distant (>120 days) infection, suggesting a short-term effect. Interpretation: A small association was identified between SARS-CoV-2 infection and anxiety and depression symptoms. The proportion meeting criteria for self-reported anxiety and depression disorders is only slightly higher than pre-pandemic.

Diet quality and risk and severity of COVID-19: a prospective cohort study (preprint)

Objective: Poor metabolic health and certain lifestyle factors have been associated with risk and severity of coronavirus disease 2019 (COVID-19), but data for diet are lacking. We aimed to investigate the association of diet quality with risk and severity of COVID-19 and its intersection with socioeconomic deprivation. Design: We used data from 592,571 participants of the smartphone-based COVID Symptom Study. Diet quality was assessed using a healthful plant-based diet score, which emphasizes healthy plant foods such as fruits or vegetables. Multivariable Cox models were fitted to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for COVID-19 risk and severity defined using a validated symptom-based algorithm or hospitalization with oxygen support, respectively. Results: Over 3,886,274 person-months of follow-up, 31,815 COVID-19 cases were documented. Compared with individuals in the lowest quartile of the diet score, high diet quality was associated with lower risk of COVID-19 (HR, 0.91; 95% CI, 0.88-0.94) and severe COVID-19 (HR, 0.59; 95% CI, 0.47-0.74). The joint association of low diet quality and increased deprivation on COVID-19 risk was higher than the sum of the risk associated with each factor alone (Pinteraction=0.005). The corresponding absolute excess rate for lowest vs highest quartile of diet score was 22.5 (95% CI, 18.8-26.3) and 40.8 (95% CI, 31.7-49.8; 10,000 person-months) among persons living in areas with low and high deprivation, respectively. Conclusions: A dietary pattern characterized by healthy plant-based foods was associated with lower risk and severity of COVID-19. These association may be particularly evident among individuals living in areas with higher socioeconomic deprivation.

App-based COVID-19 surveillance and prediction: The COVID Symptom Study Sweden (preprint)

Background The response of the Swedish authorities to the COVID-19 pandemic was less restrictive than in most countries during the first year, with infection and death rates substantially higher than in neighbouring Nordic countries. Because access to PCR testing was limited during the first wave (February to June 2020) and regional data were reported with delay, adequate monitoring of community disease spread was hampered. The app-based COVID Symptom Study was launched in Sweden to disseminate real-time estimates of disease spread and to collect prospective data for research. The aim of this study was to describe the research project, develop models for estimation of COVID-19 prevalence and to evaluate it for prediction of hospital admissions for COVID-19. Methods We enrolled 143 531 study participants ([≥]18 years) throughout Sweden, who contributed 10.6 million daily symptom reports between April 29, 2020 and February 10, 2021. Data from 19 161 self-reported PCR tests were used to create a symptom-based algorithm to estimate daily prevalence of symptomatic COVID-19. The prediction model was validated using external datasets. We further utilized the model estimates to forecast subsequent new hospital admissions. Findings A prediction model for symptomatic COVID-19 based on 17 symptoms, age, and sex yielded an area under the ROC curve of 0.78 (95% CI 0.74-0.83) in an external validation dataset of 943 PCR-tested symptomatic individuals. App-based surveillance proved particularly useful for predicting hospital trends in times of insufficient testing capacity and registration delays. During the first wave, our prediction model estimates demonstrated a lower mean error (0.38 average new daily hospitalizations per 100 000 inhabitants per week (95% CI 0.32, 0.45)) for subsequent hospitalizations in the ten most populated counties, than a model based on confirmed case data (0.72 (0.64, 0.81)). The model further correctly identified on average three out of five counties (95% CI 2.3, 3.7) with the highest rates of hospitalizations the following week during the first wave and four out of five (3.0, 4.6) during the second wave. Interpretation The experience of the COVID Symptom Study highlights the important role citizens can play in real-time monitoring of infectious diseases, and how app-based data collection may be used for data-driven rapid responses to public health challenges.

Post-vaccination SARS-CoV-2 infection: risk factors and illness profile in a prospective, observational community-based case-control study (preprint)

Background: Both BNT162b2 and ChAdOx1 vaccines show good efficacy in clinical trials and real-world data. However, some still contract SARS-CoV-2 post-vaccination. This study identifies risk factors associated with SARS-CoV-2 infection at least 14 days after first vaccination and describes characteristics of post-vaccination illness. Methods: Cases were UK adults reporting post-vaccination SARS-CoV-2 infection between 8th December 2020 and 1st May 2021, reporting on the COVID Symptom Study app. We assessed the associations of age, frailty, comorbidity, area-level deprivation and lifestyle factors with infection (vaccinated cases vs. negative-vaccinated controls); and vaccination with illness profile (vaccinated cases vs positive-unvaccinated controls). Findings: Post-vaccination infection risk was substantially higher in older adults with frailty (OR= 2.78, 95% CI [1.98-3.89], p-value<0.0001) and in individuals living in most deprived areas (OR vs. intermediate group=1.22, 95%CI [1.04-1.43], p-value=0.01). Risk was lower in individuals with a healthier diet (OR=0.73, 95%CI [0.62-0.86], p-value<0.0001) and without obesity (OR=0.6, 95% CI [0.44-0.82], p-value=0.001). Vaccination was associated with reduced odds of hospitalisation (OR=0.36, 95%CI [0.28-0.46], p-value<0.0001), and high acute-symptom burden (OR=0.51, 95%CI [0.42-0.61], p-value<0.0001). In the 60+ age group, risk of >28 days illness was lower following vaccination (OR=0.72 , 95%CI [0.51-1.00], p-value=0.05). Most symptoms were reported less in positive-vaccinated vs. positive-unvaccinated individuals, except sneezing, which was more common post-vaccination (OR=1.24, 95%CI [1.05-1.46], p-value=0.01). Interpretation: Our findings highlight reduced symptom burden and duration in those infected post-vaccination. Whilst reassuring, our data should prompt efforts to boost vaccine effectiveness in at-risk populations; moreover, targeted infection control measures will still be appropriate to minimise SARS-CoV-2 infection.

Aspirin and NSAID use and the risk of COVID-19 (preprint)

Early reports raised concern that use of non-steroidal anti-inflammatory drugs (NSAIDs) may increase risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19). Users of the COVID Symptom Study smartphone application reported use of aspirin and other NSAIDs between March 24 and May 8, 2020. Users were queried daily about symptoms, COVID-19 testing, and healthcare seeking behavior. Cox proportional hazards regression was used to determine the risk of COVID-19 among according to aspirin or non-aspirin NSAID users. Among 2,736,091 individuals in the U.S., U.K., and Sweden, we documented 8,966 incident reports of a positive COVID-19 test over 60,817,043 person-days of follow-up. Compared to non-users and after stratifying by age, sex, country, day of study entry, and race/ethnicity, non-aspirin NSAID use was associated with a modest risk for testing COVID-19 positive (HR 1.23 [1.09, 1.32]), but no significant association was observed among aspirin users (HR 1.13 [0.92, 1.38]). After adjustment for lifestyle factors, comorbidities and baseline symptoms, any NSAID use was not associated with risk (HR 1.02 [0.94, 1.10]). Results were similar for those seeking healthcare for COVID-19 and were not substantially different according to lifestyle and sociodemographic factors or after accounting for propensity to receive testing. Our results do not support an association of NSAID use, including aspirin, with COVID-19 infection. Previous reports of a potential association may be due to higher rates of comorbidities or use of NSAIDs to treat symptoms associated with COVID-19. One Sentence Summary NSAID use is not associated with COVID-19 risk.

Knowledge barriers in the symptomatic-COVID-19 testing programme in the UK: an observational study (preprint)

Background Symptomatic testing programmes are crucial to the COVID-19 pandemic response. We sought to examine United Kingdom (UK) testing rates amongst individuals with test-qualifying symptoms, and factors associated with not testing. Methods We analysed a cohort of untested symptomatic app users (N=1,237), nested in the Zoe COVID Symptom Study (Zoe, N= 4,394,948); and symptomatic survey respondents who wanted, but did not have a test (N=1,956), drawn from the University of Maryland-Facebook Covid-19 Symptom Survey (UMD-Facebook, N=775,746). Findings The proportion tested among individuals with incident test-qualifying symptoms rose from ~20% to ~75% from April to December 2020 in Zoe. Testing was lower with one vs more symptoms (73.0% vs 85.0%), or short vs long symptom duration (72.6% vs 87.8%). 40.4% of survey respondents did not identify all three test-qualifying symptoms. Symptom identification decreased for every decade older (OR=0.908 [95% CI 0.883-0.933]). Amongst symptomatic UMD-Facebook respondents who wanted but did not have a test, not knowing where to go was the most cited factor (32.4%); this increased for each decade older (OR=1.207 [1.129-1.292]) and for every 4-years fewer in education (OR=0.685 [0.599-0.783]). Interpretation Despite current UK messaging on COVID-19 testing, there is a knowledge gap about when and where to test, and this may be contributing to the ~25% testing gap. Risk factors, including older age and less education, highlight potential opportunities to tailor public health messages.

Vaccine after Effects and Post-Vaccine Infection in a Real World Setting: Results from the COVID Symptom Study App (preprint)

Background: The Pfizer-BioNTech (BNT162b2) and the Oxford/AstraZeneca (ChAdOx1 nCoV-19) COVID-19 vaccines have shown excellent safety and efficacy in Phase III trials. Here we report results from a real world setting on the two most administered vaccines in the UK.Methods: We investigated self-reported systemic and local effects within eight days of vaccination in 387,471 individuals from the COVID Symptom Study app who received one (n=209,251) or two (n=13,478) doses of the BNT162b2 vaccine, or one dose of ChAdOx1 nCoV-19 vaccine (n=178,220) between December 8 and February 15 2021. A subset of individuals subsequently tested for SARS-CoV-2 were studied for infection rates from PCR or lateral flow test results post-vaccination (59,639 vaccinated vs 277,599 controls).Findings: Systemic side effects were reported in 11.8% of participants after the first BNT162b2 dose, 20.3% after the second BNT162b2 dose, and 29.4% after the first ChAdOx1 nCoV-19 dose. Systemic effects were more prevalent among individuals with pre-existing COVID-19 infection (BNT162b2:34.1%; ChAdOx1 nCoV-19:51.6%) than among individuals without known prior infection (BNT162b2:10.6%; ChAdOx1 nCoV-19:28.6%) and among those aged <55 years (BNT162b2:19.9%; ChAdOx1 nCoV-19:45.3%) compared to those aged >55 years (BNT162b2:9.2%, ChAdOx1 nCoV-19: 26.9%). We observed significant reduction in infection risk 12-21 days after the first dose (BNT162b2:-57% [-71%, -38%], ChAdOx1 nCoV-19:-42% [-71%, -17%]). Interpretation: This phase IV-type study assessing both BNT162b2 and ChAdOx1 nCoV-19 vaccines identifies mild systemic side effects affecting 11-30% of individuals post-vaccination, lower than in published Phase III trials. Our data on infection post-vaccine were also reassuring.Funding: Zoe, NIHR, CDRF, NIH, MRCDeclaration of Interests: TDS and AMV are consultants to Zoe Global Ltd (“Zoe”). JW, AM, LP and JC are employees of Zoe Global Limited. ALG is a regional PI on the COV002 trial and the Novavax COVID-19 vaccine trial and as such her organisation has received grants from Novavax. Other authors have no conflict of interest to declare.Ethics Approval Statement: Ethical approval for use of the app for research purposes in the UK was obtained from King’s College London Ethics Committee (review reference LRS-19/20-18210), and all users provided consent for non-commercial use.

Racial and ethnic differences in COVID-19 vaccine hesitancy and uptake (preprint)

Background Racial and ethnic minorities have been disproportionately impacted by COVID-19. In the initial phase of population-based vaccination in the United States (U.S.) and United Kingdom (U.K.), vaccine hesitancy and limited access may result in disparities in uptake. Methods We performed a cohort study among U.S. and U.K. participants in the smartphone-based COVID Symptom Study (March 24, 2020-February 16, 2021). We used logistic regression to estimate odds ratios (ORs) of COVID-19 vaccine hesitancy (unsure/not willing) and receipt. Results In the U.S. ( n =87,388), compared to White non-Hispanic participants, the multivariable ORs of vaccine hesitancy were 3.15 (95% CI: 2.86 to 3.47) for Black participants, 1.42 (1.28 to 1.58) for Hispanic participants, 1.34 (1.18 to 1.52) for Asian participants, and 2.02 (1.70 to 2.39) for participants reporting more than one race/other. In the U.K. ( n =1,254,294), racial and ethnic minorities had similarly elevated hesitancy: compared to White participants, their corresponding ORs were 2.84 (95% CI: 2.69 to 2.99) for Black participants, 1.66 (1.57 to 1.76) for South Asian participants, 1.84 (1.70 to 1.98) for Middle East/East Asian participants, and 1.48 (1.39 to 1.57) for participants reporting more than one race/other. Among U.S. participants, the OR of vaccine receipt was 0.71 (0.64 to 0.79) for Black participants, a disparity that persisted among individuals who specifically endorsed a willingness to obtain a vaccine. In contrast, disparities in uptake were not observed in the U.K. Conclusions COVID-19 vaccine hesitancy was greater among racial and ethnic minorities, and Black participants living in the U.S. were less likely to receive a vaccine than White participants. Lower uptake among Black participants in the U.S. during the initial vaccine rollout is attributable to both hesitancy and disparities in access.

The effect of SARS-CoV-2 variant B.1.1.7 on symptomatology, re-infection and transmissibility (preprint)

The new SARS-CoV-2 variant B.1.1.7 was identified in December 2020 in the South-East of England, and rapidly increased in frequency and geographic spread. While there is some evidence for increased transmissibility of this variant, it is not known if the new variant presents with variation in symptoms or disease course, or if previously infected individuals may become reinfected with the new variant. Using longitudinal symptom and test reports of 36,920 users of the Covid Symptom Study app testing positive for COVID-19 between 28 September and 27 December 2020, we examined the association between the regional proportion of B.1.1.7 and reported symptoms, disease course, rates of reinfection, and transmissibility. We found no evidence for changes in reported symptoms, disease severity and disease duration associated with B.1.1.7. We found a likely reinfection rate of around 0.7% (95% CI 0.6-0.8), but no evidence that this was higher compared to older strains. We found an increase in R(t) by a factor of 1.35 (95% CI 1.02-1.69). Despite this, we found that regional and national lockdowns have reduced R(t) below 1 in regions with very high proportions of B.1.1.7.

Impact of COVID-19 on health behaviours and body weight: A prospective observational study in a cohort of 1.1 million UK and US individuals (preprint)

Evidence regarding the impact of COVID-19 on health behaviours is limited. In this prospective study including 1.1 million UK and US participants we collected diet and lifestyle data ‘pre-’ and ‘peri-’ pandemic, and computed a bi-directional health behaviour disruption index. We show that disruption was higher in the younger, female and socioeconomically deprived (p<0.001). A loss in body weight (-0.57kg) was greater in highly disrupted individuals compared to those with low disruption (0.01kg). There were large inter-individual changes observed in all 46 health and diet behaviors measured peri-pandemic versus pre-pandemic, but no mean change in the total population. Individuals most adherent to unhealthy pre-pandemic health behaviours improved their diet quality (0.93units) and weight (-0.79kg) compared with those reporting healthy pre-pandemic behaviours (0.08units and 0.04kg respectively), irrespective of relative deprivation. For a proportion of the population, the pandemic may have provided an impetus to improve health behaviours.

Individual factors underlie temperature variation in sickness and in health: influence of age, BMI and genetic factors in a multi-cohort study (preprint)

IntroductionAgeing affects immune function resulting in aberrant fever response to infection. We assess the effects of biological variables on basal temperature and temperature in COVID-19 infection, proposing an updated temperature threshold for older adults. MethodsParticipants: O_LIUnaffected twin volunteers: 1089 adult TwinsUK participants. C_LIO_LILondon hospitalised COVID-19+: 520 adults with emergency admission. C_LIO_LIBirmingham hospitalised COVID-19+: 757 adults with emergency admission. C_LIO_LICommunity-based COVID-19+: 3972 adults self-reporting a positive test using the COVID Symptom Study mobile application. C_LI AnalysisHeritability assessed using saturated and univariate ACE models; Linear mixed-effect and multivariable linear regression analysing associations between temperature, age, sex and BMI; multivariable logistic regression analysing associations between fever ([≥]37.8{degrees}C) and age; receiver operating characteristic (ROC) analysis to identify temperature threshold for adults [≥] 65 years. ResultsAmong unaffected volunteers, lower BMI (p=0.001), and older age (p<0.001) associated with lower basal temperature. Basal temperature showed a heritability of 47% (95% Confidence Interval 18-57%). In COVID-19+ participants, increasing age associated with lower temperatures in cohorts (c) and (d) (p<0.001). For each additional year of age, participants were 1% less likely to demonstrate a fever (OR 0.99; p<0.001). Combining healthy and COVID-19+ participants, a temperature of 37.4{degrees}C in adults [≥]65 years had similar sensitivity and specificity to 37.8{degrees}C in adults <65 years for discriminating fever in COVID-19. ConclusionsAgeing affects temperature in health and acute infection. Significant heritability indicates biological factors contribute to temperature regulation. Our observations indicate a lower threshold (37.4{degrees}C) should be considered for assessing fever in older adults. Key PointsO_LIOlder adults, particularly those with lower BMI, have a lower basal temperature and a lower temperature in response to infection C_LIO_LIBasal temperature is heritable, suggesting biological factors underlying temperature regulation C_LIO_LIOur findings support a lower temperature threshold of 37.4{degrees}C for identifying possible COVID-19 infection in older adults C_LIO_LIThis has implications for case detection, surveillance and isolation and could be incorporated into observation assessment C_LI

Anosmia and other SARS-CoV-2 positive test-associated symptoms, across three national, digital surveillance platforms as the COVID-19 pandemic and response unfolded: an observation study (preprint)

Background: Multiple participatory surveillance platforms were developed across the world in response to the COVID-19 pandemic, providing a real-time understanding of community-wide COVID-19 epidemiology. During this time, testing criteria broadened and healthcare policies matured. We sought to test whether there were consistent associations of symptoms with SARS-CoV-2 test status across three national surveillance platforms, during periods of testing and policy changes, and whether inconsistencies could better inform our understanding and future studies as the COVID-19 pandemic progresses. Methods: Four months (1st April 2020 to 31st July 2020) of observation through three volunteer COVID-19 digital surveillance platforms targeting communities in three countries (Israel, United Kingdom, and United States). Logistic regression of self-reported symptom on self-reported SARS-CoV-2 test status (or test access), adjusted for age and sex, in each of the study cohorts. Odds ratios over time were compared to known changes in testing policies and fluctuations in COVID-19 incidence. Findings: Anosmia/ageusia was the strongest, most consistent symptom associated with a positive COVID-19 test, based on 658325 tests (5% positive) from over 10 million respondents in three digital surveillance platforms using longitudinal and cross-sectional survey methodologies. During higher-incidence periods with broader testing criteria, core COVID-19 symptoms were more strongly associated with test status. Lower incidence periods had, overall, larger confidence intervals. Interpretation: The strong association of anosmia/ageusia with self-reported SARS-CoV-2 test positivity is omnipresent, supporting its validity as a reliable COVID-19 signal, regardless of the participatory surveillance platform or testing policy. This analysis highlights that precise effect estimates, as well as an understanding of test access patterns to interpret differences, are best done only when incidence is high. These findings strongly support the need for testing access to be as open as possible both for real-time epidemiologic investigation and public health utility.

Dietary supplements during the COVID-19 pandemic: insights from 1.4M users of the COVID Symptom Study app - a longitudinal app-based community survey (preprint)

Objectives: Dietary supplements may provide nutrients of relevance to ameliorate SARS-CoV-2 infection, although scientific evidence to support a role is lacking. We investigate whether the regular use of dietary supplements can reduce the risk of testing positive for SARS-CoV-2 infection in around 1.4M users of the COVID Symptom Study App who completed a supplement use questionnaire. Design: Longitudinal app-based community survey and nested case control study. Setting: Subscribers to an app that was launched to enable self-reported information related to SARS-CoV-2 infection for use in the general population in three countries. Main Exposure: Self-reported regular dietary supplement usage since the beginning of the pandemic. Main Outcome Measures: SARS-CoV-2 infection confirmed by viral RNA polymerase chain reaction test (RT-PCR) or serology test. A secondary outcome was new-onset anosmia. Results: In an analysis including 327,720 UK participants, the use of probiotics, omega-3 fatty acids, multivitamins or vitamin D was associated with a lower risk of SARS-CoV-2 infection by 14%(95%CI: [8%,19%]), 12%(95%CI: [8%,16%]), 13%(95%CI: [10%,16%]) and 9%(95%CI: [6%,12%]), respectively, after adjusting for potential confounders. No effect was observed for vitamin C, zinc or garlic supplements. When analyses were stratified by sex, age and body mass index (BMI), the protective associations for probiotics, omega-3 fatty acids, multivitamins and vitamin D were observed in females across all ages and BMI groups, but were not seen in men. The same overall pattern of association was observed in both the US and Swedish cohorts. Results were further confirmed in a sub-analysis of 993,365 regular app users who were not tested for SARS-CoV-2 with cases (n= 126,556) defined as those with new onset anosmia (the strongest COVID-19 predictor). Conclusion: We observed a modest but significant association between use of probiotics, omega-3 fatty acid, multivitamin or vitamin D supplements and lower risk of testing positive for SARS-CoV-2 in women. No clear benefits for men were observed nor any effect of vitamin C, garlic or zinc for men or women. Randomised controlled trials of selected supplements would be required to confirm these observational findings before any therapeutic recommendations can be made.

Identifying optimal combinations of symptoms to trigger diagnostic work-up of suspected COVID-19 cases in vaccine trials: analysis from a community-based, prospective, observational cohort (preprint)

Background: Several COVID-19 vaccine efficacy trials are ongoing with others predicted to start soon. Diagnostic work-up of trial participants following any COVID-19 associated symptom will lead to extensive testing, potentially overwhelming laboratory capacity whilst primarily yielding negative results. We aimed to identify an efficient symptom combination to capture most cases using the lowest possible number of tests. Methods: UK and US users of the COVID-19 Symptom Study app who reported new-onset symptoms between March-September 2020 and an RT-PCR test within seven days of symptom onset were included. Sensitivity, specificity, and number of RT-PCR tests needed to identify one RT-PCR positive case were calculated for individual symptoms and symptom combinations. A multi-objective evolutionary algorithm was applied to generate symptom combinations with good trade-offs between sensitivity and specificity. Findings: The UK dataset included 122,305 individuals (1,202 RT-PCR positive). Findings were replicated in a US dataset including 3,162 individuals (79 RT-PCR positive). Within three days of symptom onset, the COVID-19 specific symptom combination (cough, dyspnoea, fever, anosmia/ageusia) identified 69% of cases requiring 47 RT-PCR tests per positive case. The symptom combination with the highest sensitivity was fatigue, anosmia, cough, diarrhoea, headache, and sore throat, identifying 96% of cases and requiring 96 tests. Interpretation: We confirm the significance of COVID-19 specific symptoms widely recommended for triggering RT-PCR. By using the data-driven optimization technique we identified additional symptoms (fatigue, sore throat, headache, diarrhoea) that enabled many more positive cases to be captured efficiently. By providing a set of solutions with optimal trade-offs between sensitivity and specificity, we produced a selection of symptom subsets that maximise the capture of cases given different laboratory capacities. The methodology may be of particular use for COVID-19 vaccine developers across a range of resource settings and have more far-reaching public health implications for detection of symptomatic SARS CoV2 infection.