True prevalence of long-COVID in a nationwide, population cohort study.

Long-COVID prevalence estimates vary widely and should take account of symptoms that would have occurred anyway. Here we determine the prevalence of symptoms attributable to SARS-CoV-2 infection, taking account of background rates and confounding, in a nationwide population cohort study of 198,096 Scottish adults. 98,666 (49.8%) had symptomatic laboratory-confirmed SARS-CoV-2 infections and 99,430 (50.2%) were age-, sex-, and socioeconomically-matched and never-infected. While 41,775 (64.5%) reported at least one symptom 6 months following SARS-CoV-2 infection, this was also true of 34,600 (50.8%) of those never-infected. The crude prevalence of one or more symptom attributable to SARS-CoV-2 infection was 13.8% (13.2%,14.3%), 12.8% (11.9%,13.6%), and 16.3% (14.4%,18.2%) at 6, 12, and 18 months respectively. Following adjustment for potential confounders, these figures were 6.6% (6.3%, 6.9%), 6.5% (6.0%, 6.9%) and 10.4% (9.1%, 11.6%) respectively. Long-COVID is characterised by a wide range of symptoms that, apart from altered taste and smell, are non-specific. Care should be taken in attributing symptoms to previous SARS-CoV-2 infection.

Natural history of long-COVID in a nationwide, population cohort study.

Previous studies on the natural history of long-COVID have been few and selective. Without comparison groups, disease progression cannot be differentiated from symptoms originating from other causes. The Long-COVID in Scotland Study (Long-CISS) is a Scotland-wide, general population cohort of adults who had laboratory-confirmed SARS-CoV-2 infection matched to PCR-negative adults. Serial, self-completed, online questionnaires collected information on pre-existing health conditions and current health six, 12 and 18 months after index test. Of those with previous symptomatic infection, 35% reported persistent incomplete/no recovery, 12% improvement and 12% deterioration. At six and 12 months, one or more symptom was reported by 71.5% and 70.7% respectively of those previously infected, compared with 53.5% and 56.5% of those never infected. Altered taste, smell and confusion improved over time compared to the never infected group and adjusted for confounders. Conversely, late onset dry and productive cough, and hearing problems were more likely following SARS-CoV-2 infection.

Chronic pain and COVID-19 hospitalisation and mortality: a UK Biobank cohort study.

ABSTRACT: The risk of COVID-19 in those with chronic pain is unknown. We investigated whether self-reported chronic pain was associated with COVID-19 hospitalisation or mortality. UK Biobank recruited 502,624 participants aged 37 to 73 years between 2006 and 2010. Baseline exposure data, including chronic pain (>3 months, in at least 1 of 7 prespecified body sites) and chronic widespread pain (>3 months, all over body), were linked to COVID-19 hospitalisations or mortality. Univariable or multivariable Poisson regression analyses were performed on the association between chronic pain and COVID-19 hospitalisation and Cox regression analyses of the associations with COVID-19 mortality. Multivariable analyses adjusted incrementally for sociodemographic confounders, then lifestyle risk factors, and finally long-term condition count. Of 441,403 UK Biobank participants with complete data, 3180 (0.7%) were hospitalised for COVID-19 and 1040 (0.2%) died from COVID-19. Chronic pain was associated with hospital admission for COVID-19 even after adjustment for all covariates (incidence rate ratio 1.16; 95% confidence interval [CI] 1.08-1.24; P < 0.001), as was chronic widespread pain (incidence rate ratio 1.33; 95% CI 1.06-1.66; P = 0.012). There was clear evidence of a dose-response relationship with number of pain sites (fully adjusted global P -value < 0.001). After adjustment for all covariates, there was no association between chronic pain (HR 1.01; 95% CI 0.89-1.15; P = 0.834) but attenuated association with chronic widespread pain (HR 1.50, 95% CI 1.04-2.16, P -value = 0.032) and COVID-19 mortality. Chronic pain is associated with higher risk of hospitalisation for COVID-19, but the association with mortality is unclear. Future research is required to investigate these findings further and determine whether pain is associated with long COVID.

Outcomes among confirmed cases and a matched comparison group in the Long-COVID in Scotland study.

With increasing numbers infected by SARS-CoV-2, understanding long-COVID is essential to inform health and social care support. A Scottish population cohort of 33,281 laboratory-confirmed SARS-CoV-2 infections and 62,957 never-infected individuals were followed-up via 6, 12 and 18-month questionnaires and linkage to hospitalization and death records. Of the 31,486 symptomatic infections,1,856 (6%) had not recovered and 13,350 (42%) only partially. No recovery was associated with hospitalized infection, age, female sex, deprivation, respiratory disease, depression and multimorbidity. Previous symptomatic infection was associated with poorer quality of life, impairment across all daily activities and 24 persistent symptoms including breathlessness (OR 3.43, 95% CI 3.29-3.58), palpitations (OR 2.51, OR 2.36-2.66), chest pain (OR 2.09, 95% CI 1.96-2.23), and confusion (OR 2.92, 95% CI 2.78-3.07). Asymptomatic infection was not associated with adverse outcomes. Vaccination was associated with reduced risk of seven symptoms. Here we describe the nature of long-COVID and the factors associated with it.

The association between a lifestyle score, socioeconomic status, and COVID-19 outcomes within the UK Biobank cohort.

BACKGROUND: Infection with SARS-CoV-2 virus (COVID-19) impacts disadvantaged groups most. Lifestyle factors are also associated with adverse COVID-19 outcomes. To inform COVID-19 policy and interventions, we explored effect modification of socioeconomic-status (SES) on associations between lifestyle and COVID-19 outcomes. METHODS: Using data from UK-Biobank, a large prospective cohort of 502,536 participants aged 37-73 years recruited between 2006 and 2010, we assigned participants a lifestyle score comprising nine factors. Poisson regression models with penalised splines were used to analyse associations between lifestyle score, deprivation (Townsend), and COVID-19 mortality and severe COVID-19. Associations between each exposure and outcome were examined independently before participants were dichotomised by deprivation to examine exposures jointly. Models were adjusted for sociodemographic/health factors. RESULTS: Of 343,850 participants (mean age > 60 years) with complete data, 707 (0.21%) died from COVID-19 and 2506 (0.76%) had severe COVID-19. There was evidence of a nonlinear association between lifestyle score and COVID-19 mortality but limited evidence for nonlinearity between lifestyle score and severe COVID-19 and between deprivation and COVID-19 outcomes. Compared with low deprivation, participants in the high deprivation group had higher risk of COVID-19 outcomes across the lifestyle score. There was evidence for an additive interaction between lifestyle score and deprivation. Compared with participants with the healthiest lifestyle score in the low deprivation group, COVID-19 mortality risk ratios (95% CIs) for those with less healthy scores in low versus high deprivation groups were 5.09 (1.39-25.20) and 9.60 (4.70-21.44), respectively. Equivalent figures for severe COVID-19 were 5.17 (2.46-12.01) and 6.02 (4.72-7.71). Alternative SES measures produced similar results. CONCLUSIONS: Unhealthy lifestyles are associated with higher risk of adverse COVID-19, but risks are highest in the most disadvantaged, suggesting an additive influence between SES and lifestyle. COVID-19 policy and interventions should consider both lifestyle and SES. The greatest public health benefit from lifestyle focussed COVID-19 policy and interventions is likely to be seen when greatest support for healthy living is provided to the most disadvantaged groups.

Family history of diabetes and risk of SARS-COV-2 in UK Biobank: A prospective cohort study.

INTRODUCTION: The aim of this study was to determine risk of being SARS-CoV-2 positive and severe infection (associated with hospitalization/mortality) in those with family history of diabetes. METHODS: We used UK Biobank, an observational cohort recruited between 2006 and 2010. We compared the risk of being SARS-CoV-2 positive and severe infection for those with family history of diabetes (mother/father/sibling) against those without. RESULTS: Of 401,268 participants in total, 13,331 tested positive for SARS-CoV-2 and 2282 had severe infection by end of January 2021. In unadjusted models, participants with ≥2 family members with diabetes were more likely to be SARS-CoV-2 positive (risk ratio-RR 1.35; 95% confidence interval-CI 1.24-1.47) and severe infection (RR 1.30; 95% CI 1.04-1.59), compared to those without. The excess risk of being tested positive for SARS-CoV-2 was attenuated but significant after adjusting for demographics, lifestyle factors, multimorbidity and presence of cardiometabolic conditions. The excess risk for severe infection was no longer significant after adjusting for demographics, lifestyle factors, multimorbidity and presence of cardiometabolic conditions, and was absent when excluding incident diabetes. CONCLUSION: The totality of the results suggests that good lifestyle and not developing incident diabetes may lessen risks of severe infections in people with a strong family of diabetes.

Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol.

BACKGROUND: This study sought to establish the long-term effects of Covid-19 following hospitalisation. METHODS: 327 hospitalised participants, with SARS-CoV-2 infection were recruited into a prospective multicentre cohort study at least 3 months post-discharge. The primary outcome was self-reported recovery at least ninety days after initial Covid-19 symptom onset. Secondary outcomes included new symptoms, disability (Washington group short scale), breathlessness (MRC Dyspnoea scale) and quality of life (EQ5D-5L). FINDINGS: 55% of participants reported not feeling fully recovered. 93% reported persistent symptoms, with fatigue the most common (83%), followed by breathlessness (54%). 47% reported an increase in MRC dyspnoea scale of at least one grade. New or worse disability was reported by 24% of participants. The EQ5D-5L summary index was significantly worse following acute illness (median difference 0.1 points on a scale of 0 to 1, IQR: -0.2 to 0.0). Females under the age of 50 years were five times less likely to report feeling recovered (adjusted OR 5.09, 95% CI 1.64 to 15.74), were more likely to have greater disability (adjusted OR 4.22, 95% CI 1.12 to 15.94), twice as likely to report worse fatigue (adjusted OR 2.06, 95% CI 0.81 to 3.31) and seven times more likely to become more breathless (adjusted OR 7.15, 95% CI 2.24 to 22.83) than men of the same age. INTERPRETATION: Survivors of Covid-19 experienced long-term symptoms, new disability, increased breathlessness, and reduced quality of life. These findings were present in young, previously healthy working age adults, and were most common in younger females. FUNDING: National Institute for Health Research, UK Medical Research Council, Wellcome Trust, Department for International Development and the Bill and Melinda Gates Foundation.

Remote history of VTE is associated with severe COVID-19 in middle and older age: UK Biobank cohort study.

BACKGROUND: Venous thromboembolism (VTE) is a common, life-threatening complication of COVID-19 infection. COVID-19 risk-prediction models include a history of VTE. However, it is unclear whether remote history (>9 years previously) of VTE also confers increased risk of COVID-19. OBJECTIVES: To investigate possible association between VTE and COVID-19 severity, independent of other risk factors. METHODS: Cohort study of UK Biobank participants recruited between 2006 and 2010. Baseline data, including history of VTE, were linked to COVID-19 test results, COVID-19-related hospital admissions, and COVID-19 deaths. The risk of COVID-19 hospitalization or death was compared for participants with a remote history VTE versus without. Poisson regression models were run univariately then adjusted stepwise for sociodemographic, lifestyle, and comorbid covariates. RESULTS: After adjustment for sociodemographic and lifestyle confounders and comorbid conditions, remote history of VTE was associated with nonfatal community (RR 1.61, 95% CI 1.02-2.54, p = .039), nonfatal hospitalized (RR 1.52, 95% CI 1.06-2.17, p = .024) and severe (hospitalized or fatal) (RR 1.40, 95% CI 1.04-1.89, p = .025) COVID-19. Associations with remote history of VTE were stronger among men (severe COVID-19: RR 1.68, 95% CI 1.14-2.42, p = .009) than for women (severe COVID-19: RR 1.07, 95% CI 0.66-1.74, p = .786). CONCLUSION: Our findings support inclusion of remote history of VTE in COVID-19 risk-prediction scores, and consideration of sex-specific risk scores.

Antenatal Exposure to UV-B Radiation and Preeclampsia: A Retrospective Cohort Study.

Background Risk of preeclampsia varies by month of delivery. We tested whether this seasonal patterning may be mediated through maternal vitamin D concentration using antenatal exposure to UV-B radiation as an instrumental variable. Methods and Results Scottish maternity records were linked to antenatal UV-B exposure derived from satellites between 2000 and 2010. Logistic regression analyses were used to explore the association between UV-B and preeclampsia, adjusting for the potential confounding effects of month of conception, child's sex, gestation, parity, and mean monthly temperature. Of the 522 896 eligible singleton deliveries, 8689 (1.66%) mothers developed preeclampsia. Total antenatal UV-B exposure ranged from 43.18 to 101.11 kJ/m2 and was associated with reduced risk of preeclampsia with evidence of a dose-response relationship (highest quintile of exposure: adjusted odds ratio, 0.57; 95% CI, 0.44-0.72; P<0.001). Associations were demonstrated for UV-B exposure in all 3 trimesters. Conclusions The seasonal patterning of preeclampsia may be mediated through low maternal vitamin D concentration in winter resulting from low UV-B radiation. Interventional studies are required to determine whether vitamin D supplements or UV-B-emitting light boxes can reduce the seasonal patterning of preeclampsia.

Correction: Multimorbidity, polypharmacy, and COVID-19 infection within the UK Biobank cohort.

[This corrects the article DOI: 10.1371/journal.pone.0238091.].

Vitamin D and COVID-19 infection and mortality in UK Biobank.

PURPOSE: Low blood 25-hydroxyvitamin D (25(OH)D) concentration has been proposed as a potential causal factor in COVID-19 risk. We aimed to establish whether baseline serum 25(OH)D concentration was associated with COVID-19 mortality, and inpatient confirmed COVID-19 infection, in UK Biobank participants. METHODS: UK Biobank recruited 502,624 participants aged 37-73 years between 2006 and 2010. Baseline exposure data, including serum 25(OH)D concentration, were linked to COVID-19 mortality. Univariable and multivariable Cox proportional hazards regression analyses were performed for the association between 25(OH)D and COVID-19 death, and Poisson regression analyses for the association between 25(OH)D and severe COVID-19 infection. RESULTS: Complete data were available for 341,484 UK Biobank participants, of which 656 had inpatient confirmed COVID-19 infection and 203 died of COVID-19 infection. 25(OH)D concentration was associated with severe COVID-19 infection and mortality univariably (mortality per 10 nmol/L 25(OH)D HR 0.92; 95% CI 0.86-0.98; p = 0.016), but not after adjustment for confounders (mortality per 10 nmol/L 25(OH)D HR 0.98; 95% CI = 0.91-1.06; p = 0.696). Vitamin D insufficiency or deficiency was also not independently associated with either COVID-19 infection or linked mortality. CONCLUSIONS: Our findings do not support a potential link between 25(OH)D concentrations and risk of severe COVID-19 infection and mortality. Randomised trials are needed to prove a beneficial role for vitamin D in the prevention of severe COVID-19 reactions or death.

Is older age associated with COVID-19 mortality in the absence of other risk factors? General population cohort study of 470,034 participants.

INTRODUCTION: Older people have been reported to be at higher risk of COVID-19 mortality. This study explored the factors mediating this association and whether older age was associated with increased mortality risk in the absence of other risk factors. METHODS: In UK Biobank, a population cohort study, baseline data were linked to COVID-19 deaths. Poisson regression was used to study the association between current age and COVID-19 mortality. RESULTS: Among eligible participants, 438 (0.09%) died of COVID-19. Current age was associated exponentially with COVID-19 mortality. Overall, participants aged ≥75 years were at 13-fold (95% CI 9.13-17.85) mortality risk compared with those <65 years. Low forced expiratory volume in 1 second, high systolic blood pressure, low handgrip strength, and multiple long-term conditions were significant mediators, and collectively explained 39.3% of their excess risk. The associations between these risk factors and COVID-19 mortality were stronger among older participants. Participants aged ≥75 without additional risk factors were at 4-fold risk (95% CI 1.57-9.96, P = 0.004) compared with all participants aged <65 years. CONCLUSIONS: Higher COVID-19 mortality among older adults was partially explained by other risk factors. 'Healthy' older adults were at much lower risk. Nonetheless, older age was an independent risk factor for COVID-19 mortality.

Multimorbidity, polypharmacy, and COVID-19 infection within the UK Biobank cohort.

BACKGROUND: It is now well recognised that the risk of severe COVID-19 increases with some long-term conditions (LTCs). However, prior research primarily focuses on individual LTCs and there is a lack of data on the influence of multimorbidity (≥2 LTCs) on the risk of COVID-19. Given the high prevalence of multimorbidity, more detailed understanding of the associations with multimorbidity and COVID-19 would improve risk stratification and help protect those most vulnerable to severe COVID-19. Here we examine the relationships between multimorbidity, polypharmacy (a proxy of multimorbidity), and COVID-19; and how these differ by sociodemographic, lifestyle, and physiological prognostic factors. METHODS AND FINDINGS: We studied data from UK Biobank (428,199 participants; aged 37-73; recruited 2006-2010) on self-reported LTCs, medications, sociodemographic, lifestyle, and physiological measures which were linked to COVID-19 test data. Poisson regression models examined risk of COVID-19 by multimorbidity/polypharmacy and effect modification by COVID-19 prognostic factors (age/sex/ethnicity/socioeconomic status/smoking/physical activity/BMI/systolic blood pressure/renal function). 4,498 (1.05%) participants were tested; 1,324 (0.31%) tested positive for COVID-19. Compared with no LTCs, relative risk (RR) of COVID-19 in those with 1 LTC was no higher (RR 1.12 (CI 0.96-1.30)), whereas those with ≥2 LTCs had 48% higher risk; RR 1.48 (1.28-1.71). Compared with no cardiometabolic LTCs, having 1 and ≥2 cardiometabolic LTCs had a higher risk of COVID-19; RR 1.28 (1.12-1.46) and 1.77 (1.46-2.15), respectively. Polypharmacy was associated with a dose response higher risk of COVID-19. All prognostic factors were associated with a higher risk of COVID-19 infection in multimorbidity; being non-white, most socioeconomically deprived, BMI ≥40 kg/m2, and reduced renal function were associated with the highest risk of COVID-19 infection: RR 2.81 (2.09-3.78); 2.79 (2.00-3.90); 2.66 (1.88-3.76); 2.13 (1.46-3.12), respectively. No multiplicative interaction between multimorbidity and prognostic factors was identified. Important limitations include the low proportion of UK Biobank participants with COVID-19 test data (1.05%) and UK Biobank participants being more affluent, healthier and less ethnically diverse than the general population. CONCLUSIONS: Increasing multimorbidity, especially cardiometabolic multimorbidity, and polypharmacy are associated with a higher risk of developing COVID-19. Those with multimorbidity and additional factors, such as non-white ethnicity, are at heightened risk of COVID-19.

Vitamin D concentrations and COVID-19 infection in UK Biobank.

BACKGROUND AND AIMS: COVID-19 and low levels of vitamin D appear to disproportionately affect black and minority ethnic individuals. We aimed to establish whether blood 25-hydroxyvitamin D (25(OH)D) concentration was associated with COVID-19 risk, and whether it explained the higher incidence of COVID-19 in black and South Asian people. METHODS: UK Biobank recruited 502,624 participants aged 37-73 years between 2006 and 2010. Baseline exposure data, including 25(OH)D concentration and ethnicity, were linked to COVID-19 test results. Univariable and multivariable logistic regression analyses were performed for the association between 25(OH)D and confirmed COVID-19, and the association between ethnicity and both 25(OH)D and COVID-19. RESULTS: Complete data were available for 348,598 UK Biobank participants. Of these, 449 had confirmed COVID-19 infection. Vitamin D was associated with COVID-19 infection univariably (OR = 0.99; 95% CI 0.99-0.999; p = 0.013), but not after adjustment for confounders (OR = 1.00; 95% CI = 0.998-1.01; p = 0.208). Ethnicity was associated with COVID-19 infection univariably (blacks versus whites OR = 5.32, 95% CI = 3.68-7.70, p-value<0.001; South Asians versus whites OR = 2.65, 95% CI = 1.65-4.25, p-value<0.001). Adjustment for 25(OH)D concentration made little difference to the magnitude of the association. CONCLUSIONS: Our findings do not support a potential link between vitamin D concentrations and risk of COVID-19 infection, nor that vitamin D concentration may explain ethnic differences in COVID-19 infection.

UVA and Seasonal Patterning of 56 370 Myocardial Infarctions Across Scotland, 2000-2011.

Background Myocardial infarction exhibits seasonal patterning, with higher amplitude at increased latitude. Epidemiological evidence suggests that sunlight is protective against cardiovascular disease, independent of ambient temperature, but ultraviolet B-mediated vitamin D production has been discounted as causal. We aimed to determine whether ultraviolet A is associated with the seasonal patterning of myocardial infarction. Methods and Results Routine hospitalization data were used to determine monthly incidence of myocardial infarction in Scotland between 2000 and 2011. Small-area-level aggregated data were obtained on ambient temperature from the Meteorological Office and ultraviolet A and ultraviolet B irradiance from NASA satellites. Autoregressive distributed lag models were run for ultraviolet A and myocardial infarction, including adjustment for ambient temperature and ultraviolet B. Monthly incidence of myocardial infarction displayed winter peaks and summer troughs superimposed on the underlying trend, with a mean amplitude of 0.31 (95% CI: 0.21, 0.41) myocardial infarctions per 100 000 population per month. Ultraviolet A exposure was inversely associated with myocardial infarction independent of ambient temperature (coefficient, -0.05; 95% CI, -0.09, -0.01; P=0.015) and ultraviolet B UVB (coefficient, -0.05; 95% CI, -0.09, -0.02; P=0.004). Conclusions Further research is required to explore whether an ultraviolet-mediated mechanism different to vitamin D, such as nitric oxide-mediated vasodilatation, may play a causal role in the seasonal and geographical patterning of myocardial infarction.