Prognostic peripheral blood biomarkers at ICU admission predict COVID-19 clinical outcomes.

The COVID-19 pandemic continues to challenge the capacities of hospital ICUs which currently lack the ability to identify prospectively those patients who may require extended management. In this study of 90 ICU COVID-19 patients, we evaluated serum levels of four cytokines (IL-1ß, IL-6, IL-10 and TNFα) as well as standard clinical and laboratory measurements. On 42 of these patients (binned into Initial and Replication Cohorts), we further performed CyTOF-based deep immunophenotyping of peripheral blood mononuclear cells with a panel of 38 antibodies. All measurements and patient samples were taken at time of ICU admission and retrospectively linked to patient clinical outcomes through statistical approaches. These analyses resulted in the definition of a new measure of patient clinical outcome: patients who will recover after short ICU stays (< 6 days) and those who will subsequently die or recover after long ICU stays (≥6 days). Based on these clinical outcome categories, we identified blood prognostic biomarkers that, at time of ICU admission, prospectively distinguish, with 91% sensitivity and 91% specificity (positive likelihood ratio 10.1), patients in the two clinical outcome groups. This is achieved through a tiered evaluation of serum IL-10 and targeted immunophenotyping of monocyte subsets, specifically, CD11clow classical monocytes. Both immune biomarkers were consistently elevated ( ≥15 pg/ml and ≥2.7 x107/L for serum IL-10 and CD11clow classical monocytes, respectively) in those patients who will subsequently die or recover after long ICU stays. This highly sensitive and specific prognostic test could prove useful in guiding clinical resource allocation.

Prognostic peripheral blood biomarkers at ICU admission predict COVID-19 clinical outcomes

The COVID-19 pandemic continues to challenge the capacities of hospital ICUs which currently lack the ability to identify prospectively those patients who may require extended management. In this study of 90 ICU COVID-19 patients, we evaluated serum levels of four cytokines (IL-1β, IL-6, IL-10 and TNFα) as well as standard clinical and laboratory measurements. On 42 of these patients (binned into Initial and Replication Cohorts), we further performed CyTOF-based deep immunophenotyping of peripheral blood mononuclear cells with a panel of 38 antibodies. All measurements and patient samples were taken at time of ICU admission and retrospectively linked to patient clinical outcomes through statistical approaches. These analyses resulted in the definition of a new measure of patient clinical outcome: patients who will recover after short ICU stays (< 6 days) and those who will subsequently die or recover after long ICU stays (≥6 days). Based on these clinical outcome categories, we identified blood prognostic biomarkers that, at time of ICU admission, prospectively distinguish, with 91% sensitivity and 91% specificity (positive likelihood ratio 10.1), patients in the two clinical outcome groups. This is achieved through a tiered evaluation of serum IL-10 and targeted immunophenotyping of monocyte subsets, specifically, CD11clow classical monocytes. Both immune biomarkers were consistently elevated ( ≥15 pg/ml and ≥2.7 x107/L for serum IL-10 and CD11clow classical monocytes, respectively) in those patients who will subsequently die or recover after long ICU stays. This highly sensitive and specific prognostic test could prove useful in guiding clinical resource allocation.

Physical Activity during the COVID-19 Pandemic in the UK: A Qualitative Analysis of Free-Text Survey Data.

BACKGROUND: Several quantitative studies have found a decline in physical activity in response to COVID-19 pandemic restrictions. The aim of the present study was to use large-scale free text survey data to qualitatively gain a more in-depth understanding of the impact of the COVID-19 pandemic on physical activity, then map barriers and facilitators to the Capability, Opportunity, Motivation, and Behaviour (COM-B) Model of Behaviour to aid future intervention development. METHODS: 17,082 participants provided a response to the free text module, and data from those who mentioned a physical activity related word in any context were included. Data were analysed using thematic analysis and key themes identified. RESULTS: 5396 participants provided 7490 quotes related to physical activity. The sample were predominately female (84%), white (British/Irish/Other) (97%) and aged <60 years (57%). Seven key themes were identified: the importance of outdoor space, changes in daily routine, COVID-19 restrictions prevented participation, perceived risks or threats to participation, the importance of physical health, the importance of physical activity for mental health and the use of technology. CONCLUSION: Future physical activity interventions could encourage people to walk outdoors, which is low cost, flexible, and accessible to many. Developing online resources to promote and support physical activity provides a flexible way to deliver quality content to a large audience.

Perceived Social Support and Sustained Physical Activity During the COVID-19 Pandemic.

BACKGROUND: COVID-19 lockdown introduced substantial barriers to physical activity, providing a unique 'natural experiment' to understand the social factors associated with sustained physical activity. The objectives of this study were to identify the proportion of people who successfully sustained physical activity during lockdown and to explore whether social support, loneliness and social isolation were associated with maintenance of physical activity during COVID-19 lockdown. METHOD: Longitudinal data from 16,980 participants, mean age 51.3 years (SD = 14.3) from the COVID-19 Social Study was used to identify a sample of participants who maintained their physical activity despite lockdown. RESULTS: Seventeen percent were consistently active whilst 42% were completely inactive. After adjustment for multiple confounders, high social support was associated with a 64% (95% CI 50-80%) increased odds of sustaining physical activity and medium social support was associated with 32% (95% CI 20-44%) increased odds. Associations between physical activity and loneliness and social isolation were not found. CONCLUSION: This study supports previous research showing the importance of social support for the long-term maintenance of physical activity behaviour but shows that such effects extend to contexts of social restrictions.

Lifestyle risk factors, inflammatory mechanisms, and COVID-19 hospitalization: A community-based cohort study of 387,109 adults in UK.

We conducted the first large-scale general population study on lifestyle risk factors (smoking, physical inactivity, obesity, and excessive alcohol intake) for COVID-19 using prospective cohort data with national registry linkage to hospitalisation. Participants were 387,109 men and women (56.4 ± 8.8 yr; 55.1% women) residing in England from UK Biobank study. Physical activity, smoking, and alcohol intake, were assessed by questionnaire at baseline (2006-2010). Body mass index, from measured height and weight, was used as an indicator of overall obesity. Outcome was cases of COVID-19 serious enough to warrant a hospital admission from 16-March-2020 to 26-April-2020. There were 760 COVID-19 cases. After adjustment for age, sex and mutually for each lifestyle factor, physical inactivity (Relative risk, 1.32, 95% confidence interval, 1.10, 1.58), smoking (1.42;1.12, 1.79) and obesity (2.05 ;1.68, 2.49) but not heavy alcohol consumption (1.12; 0.93, 1.35) were all related to COVID-19. We also found a dose-dependent increase in risk of COVID-19 with less favourable lifestyle scores, such that participants in the most adverse category had 4-fold higher risk (4.41; 2.52-7.71) compared to people with the most optimal lifestyle. C-reactive protein levels were associated with elevated risk of COVID-19 in a dose-dependent manner, and partly (10-16%) explained associations between adverse lifestyle and COVID-19. Based on UK risk factor prevalence estimates, unhealthy behaviours in combination accounted for up to 51% of the population attributable fraction of severe COVID-19. Our findings suggest that an unhealthy lifestyle synonymous with an elevated risk of non-communicable disease is also a risk factor for COVID-19 hospital admission, which might be partly explained by low grade inflammation. Adopting simple lifestyle changes could lower the risk of severe infection.

Alcohol intake and mortality risk of COVID-19, pneumonia, and other infectious diseases: An analysis of 437191 UK biobank participants.

This study aims to investigate the association between alcohol consumption and COVID-19, infectious diseases, and pneumonia mortality. This is a prospective analysis of 437,191 UK Biobank participants (age 56.3 years, 54% female). The main exposure was self-reported alcohol consumption. In addition to never and previous drinkers, we applied quartiles-based and UK guidelines-based criteria to divide current drinkers by weekly consumption into four groups. Outcomes included COVID-19, infectious diseases, and pneumonia mortality, obtained from the national death registries until May 2020. After an 11-year follow-up, compared to never drinkers, previous drinkers had higher mortality risks of infectious diseases and pneumonia (adjusted HR: 1.29 [95% CI 1.06-1.57] and 1.35 [1.07-1.70], respectively), but not COVID-19. There was a curvilinear association of alcohol consumption with infectious diseases and pneumonia mortality. Drinking within-guidelines (<14 UK units/wk) and amounts up to double the recommendation (14 to < 28 UK units/wk) was associated with the lowest mortality risks of infectious diseases (0.70 [0.59-0.83] and 0.70 [0.59-0.83], respectively) and pneumonia (0.71 [0.58-0.87] and 0.72 [0.58-0.88], respectively). Alcohol consumption was associated with lower risks of COVID-19 mortality (e.g., drinking within-guidelines: 0.53 [0.33-0.86]). Drinkers reporting multiples of the recommended alcohol drinking amounts did not have higher mortality risks of COVID-19 and other infectious diseases than never drinkers. Despite the well-established unfavorable effects on general health, we found no deleterious associations between alcohol consumption and the risk of infectious diseases, including COVID-19. Future research with other study designs is needed to confirm the causality.

Explaining Ethnic Differentials in COVID-19 Mortality: A Cohort Study.

Ethnic inequalities in coronavirus disease 2019 (COVID-19) hospitalizations and mortality have been widely reported, but there is scant understanding of how they are embodied. The UK Biobank prospective cohort study comprises approximately half a million people who were aged 40-69 years at study induction, between 2006 and 2010, when information on ethnic background and potential explanatory factors was captured. Study members were prospectively linked to a national mortality registry. In an analytical sample of 448,664 individuals (248,820 women), 705 deaths were ascribed to COVID-19 between March 5, 2020, and January 24, 2021. In age- and sex-adjusted analyses, relative to White participants, Black study members experienced approximately 5 times the risk of COVID-19 mortality (odds ratio (OR) = 4.81, 95% confidence interval (CI): 3.28, 7.05), while there was a doubling in the South Asian group (OR = 2.05, 95% CI: 1.30, 3.25). Controlling for baseline comorbidities, social factors (including socioeconomic circumstances), and lifestyle indices attenuated this risk differential by 34% in Black study members (OR = 2.84, 95% CI: 1.91, 4.23) and 37% in South Asian individuals (OR = 1.57, 95% CI: 0.97, 2.55). The residual risk of COVID-19 deaths in ethnic minority groups may be ascribed to a range of unmeasured characteristics and requires further exploration.

Estimating changes in physical behavior during lockdowns using accelerometry-based simulations in a large UK cohort.

To contain the recent COVID-19 outbreak, restrictions have been imposed, which has limited outdoor activity. These physical behavior changes can have serious health implications, but there is little objective information quantifying these changes. This study aimed to estimate the change in physical behavior levels during full lockdown conditions using objective data collected from a thigh-worn activity monitor. Data used were from 6492 individuals in the 1970 British Cohort Study, collected between 2016 and 2018. Using walking bout characteristics, days were classified as either "indoor only" (n = 861), "indoor and exercise" (n = 167), and "outdoor active" (n = 31 934). When compared to "outdoor active" days, "indoor only" days had 6590 fewer steps per day (2320 vs 8876, p < 0.001), a longer sedentary time (1.5 h, p < 0.001), longer lying time (1.4 h, p < 0.001) and shorter standing (1.9 h, p < 0.001) and stepping (1.3 h, p < 0.001) times. The "indoor and exercise" days had a smaller number of steps compared to "outdoor active" (7932 vs 8876, p < 0.05). There is a strong relationship between reduced daily stepping, and increased sedentary time, with a range of poor health outcomes. This has important implications for public health policy and messaging during pandemics.

Association of pre-pandemic high-density lipoprotein cholesterol with risk of COVID-19 hospitalisation and death: The UK Biobank cohort study.

There is growing evidence of, and biological plausibility for, elevated levels of high-density lipoprotein cholesterol (HDL-C) being related to lower rates of respiratory disease. We tested whether pre-pandemic HDL-C within the normal range is associated with subsequent COVID-19 hospitalisations and death. We analysed data on participants from UK Biobank, a prospective cohort study, baseline data for which were collected between 2006 and 2010. Follow-up for COVID-19 was via hospitalisation records (1845 events in 317,306 individuals) and a national mortality registry (458 deaths in 317,833 individuals). After controlling for a series of confounding factors which included health behaviours, inflammatory markers, and socio-economic status, higher levels of HDL-C were related to a lower risk of later hospitalisation. The effect was linear (p-value for trend 0.001), whereby a 0.2 mmol/L increase in HDL-C was associated with a 7% lower risk (odds ratio; 95% confidence interval: 0.93; 0.90, 0.96). Corresponding relationships for mortality were markedly weaker, such that statistical significance at conventional levels were not apparent for both the linear trend (p-value 0.25) and the odds ratio per 0.2 mmol/L increase (0.98; 0.91, 1.05). While our finding for HDL-C and hospitalisations for COVID-19 raise the possibility that favourable modification of this cholesterol fraction via lifestyle changes or drug intervention may impact upon the risk of the disease, it warrants testing in other studies.

Physical activity and mental well-being under COVID-19 lockdown: a cross-sectional multination study.

BACKGROUND: COVID-19 lockdowns have reduced opportunities for physical activity (PA) and encouraged more sedentary lifestyles. A concomitant of sedentariness is compromised mental health. We investigated the effects of COVID-19 lockdown on PA, sedentary behavior, and mental health across four Western nations (USA, UK, France, and Australia). METHODS: An online survey was administered in the second quarter of 2020 (N = 2541). We measured planned and unplanned dimensions of PA using the Brunel Lifestyle Physical Activity Questionnaire and mental health using the 12-item General Health Questionnaire. Steps per day were recorded only from participants who used an electronic device for this purpose, and sedentary behavior was reported in hours per day (sitting and screen time). RESULTS: In the USA and Australia samples, there was a significant decline in planned PA from pre- to during lockdown. Among young adults, Australians exhibited the lowest planned PA scores, while in middle-aged groups, the UK recorded the highest. Young adults exhibited the largest reduction in unplanned PA. Across nations, there was a reduction of ~ 2000 steps per day. Large increases in sedentary behavior emerged during lockdown, which were most acute in young adults. Lockdown was associated with a decline in mental health that was more pronounced in women. CONCLUSIONS: The findings illustrate the deleterious effects of lockdown on PA, sedentary behavior, and mental health across four Western nations. Australian young and lower middle-aged adults appeared to fare particularly badly in terms of planned PA. The reduction in steps per day is equivalent to the non-expenditure of ~ 100 kcal. Declines in mental health show how harmful lockdowns can be for women in particular.

Lifestyle risk factors and infectious disease mortality, including COVID-19, among middle aged and older adults: Evidence from a community-based cohort study in the United Kingdom.

In this community-based cohort study, we investigated the relationship between combinations of modifiable lifestyle risk factors and infectious disease mortality. Participants were 468,569 men and women (56.5 ± 8.1, 54.6% women) residing in the United Kingdom. Lifestyle indexes included traditional and emerging lifestyle risk factors based on health guidelines and best practice recommendations for: physical activity, sedentary behaviour, sleep quality, diet quality, alcohol consumption, and smoking status. The main outcome was mortality from infectious diseases, including pneumonia, and coronavirus disease 2019 (COVID-19). Meeting public health guidelines or best practice recommendations among combinations of lifestyle risk factors was inversely associated with mortality. Hazard ratios ranged between 0.26 (0.23-0.30) to 0.69 (0.60-0.79) for infectious disease and pneumonia. Among participants with pre-existing cardiovascular disease or cancer, hazard ratios ranged between 0.30 (0.25-0.34) to 0.73 (0.60-0.89). COVID-19 mortality risk ranged between 0.42 (0.28-0.63) to 0.75 (0.49-1.13). We found a beneficial dose-response association with a higher lifestyle index against mortality that was consistent across sex, age, BMI, and socioeconomic status. There was limited evidence of synergistic interactions between most lifestyle behaviour pairs, suggesting that the dose-response relationship among different lifestyle behaviours is not greater than the sum of the risk induced by each behaviour. Improvements in lifestyle risk factors and meeting public health guidelines or best practice recommendations could be used as an ancillary measure to ameliorate infectious disease mortality.

Effects of Regular Physical Activity on the Immune System, Vaccination and Risk of Community-Acquired Infectious Disease in the General Population: Systematic Review and Meta-Analysis.

BACKGROUND: Regular physical activity is the prime modality for the prevention of numerous non-communicable diseases and has also been advocated for resilience against COVID-19 and other infectious diseases. However, there is currently no systematic and quantitative evidence synthesis of the association between physical activity and the strength of the immune system. OBJECTIVE: To examine the association between habitual physical activity and (1) the risk of community-acquired infectious disease, (2) laboratory-assessed immune parameters, and (3) immune response to vaccination. METHODS: We conducted a systemic review and meta-analysis according to PRISMA guidelines. We searched seven databases (MEDLINE, Embase, Cochrane CENTRAL, Web of Science, CINAHL, PsycINFO, and SportDiscus) up to April 2020 for randomised controlled trials and prospective observational studies were included if they compared groups of adults with different levels of physical activity and reported immune system cell count, the concentration of antibody, risk of clinically diagnosed infections, risk of hospitalisation and mortality due to infectious disease. Studies involving elite athletes were excluded. The quality of the selected studies was critically examined following the Cochrane guidelines using ROB2 and ROBINS_E. Data were pooled using an inverse variance random-effects model. RESULTS: Higher level of habitual physical activity is associated with a 31% risk reduction (hazard ratio 0.69, 95% CI 0.61-0.78, 6 studies, N = 557,487 individuals) of community-acquired infectious disease and 37% risk reduction (hazard ratio 0.64, 95% CI 0.59-0.70, 4 studies, N = 422,813 individuals) of infectious disease mortality. Physical activity interventions resulted in increased CD4 cell counts (32 cells/µL, 95% CI 7-56 cells/µL, 24 studies, N = 1112 individuals) and salivary immunoglobulin IgA concentration (standardised mean difference 0.756, 95% CI 0.146-1.365, 7 studies, N = 435 individuals) and decreased neutrophil counts (704 cells/µL, 95% CI 68-1340, 6 studies, N = 704 individuals) compared to controls. Antibody concentration after vaccination is higher with an adjunct physical activity programme (standardised mean difference 0.142, 95% CI 0.021-0.262, 6 studies, N = 497 individuals). CONCLUSION: Regular, moderate to vigorous physical activity is associated with reduced risk of community-acquired infectious diseases and infectious disease mortality, enhances the first line of defence of the immune system, and increases the potency of vaccination. PROTOCOL REGISTRATION: The original protocol was prospectively registered with PROSPERO (CRD42020178825).

Relationships among behavioural regulations, physical activity, and mental health pre- and during COVID-19 UK lockdown.

A nationwide survey was conducted during the first UK lockdown to further understanding of the degree to which motives for exercise were associated with physical activity (PA) behaviours and, in turn, how PA behaviours were associated with mental health. A cross-sectional design was employed and data were collected by use of a one-off online survey (N = 392; 18-85 years; M BMI = 25.48; SD BMI = 5.05; 314 women). Exercise motives, PA, and mental health were measured by use of the Behavioural Regulations in Exercise Questionnaire-3, Brunel Lifestyle Physical Activity Questionnaire, and General Health Questionnaire-12, respectively. Participants were also asked to specify their average step count per day, if they used a mobile device for this purpose (n = 190). Analyses comprised hierarchical regressions and partial correlations. Results indicated that behavioural regulations were more strongly associated with planned PA pre-lockdown, compared to during lockdown. There were no differences observed in explained variance between pre- and during lockdown for unplanned PA and steps per day. Planned and unplanned PA were significant explanatory variables for mental health both pre- and during lockdown, but sedentary behaviour was not. Partial correlations, with BMI and age partialled out, showed that steps per day were not correlated with mental health either pre- or during lockdown. The range of variables used to explain planned and unplanned PA and mental health suggest that people's motives to exercise were tempered by lockdown. For those who routinely measured their steps per day, the step count was unrelated to their mental health scores both pre- and during lockdown. It appears that engagement in regular PA confers some minor benefits for mental health.

Diabetes, glycaemic control, and risk of COVID-19 hospitalisation: Population-based, prospective cohort study.

OBJECTIVE: We aimed to examine the prospective association of diabetes and glycaemic control with COVID-19 hospitalisation in a large community-based cohort study. METHODS AND STUDY DESIGN: Participants (N = 337,802, aged 56.4 ±â€¯8.1 yr; 55.1% women) underwent biomedical assessments at baseline as part of the UK Biobank prospective cohort study. The outcome was cases of COVID-19 serious enough to warrant a hospital admission from 16-March-2020 to 26-April-2020. RESULTS: At follow up, 649 cases COVID-19 were recorded. In multivariable adjusted analyses, risk of COVID-19 was elevated in people with undiagnosed diabetes at baseline (A1C ≥ 6.5%) (risk ratio = 2.68; 95% confidence interval: 1.66, 4.33) and poorly controlled (A1C ≥ 8.6%) diagnosed diabetes (1.91;1.04, 3.52). There was a dose-dependent increase in risk of COVID-19 with increasing A1C, that persisted in multivariable adjusted models (per SD [0.9%]: 1.07; 1.03, 1.11; p[trend] < 0.001). CONCLUSION: In this large community-based sample, higher levels of A1C within the normal range were a risk factor for COVID-19. Glucose regulation may play a key role in immune responses to this infection. Undiagnosed cases of diabetes in the general community may present a particularly high risk.

Overweight, obesity, and risk of hospitalization for COVID-19: A community-based cohort study of adults in the United Kingdom.

The role of obesity and overweight in occurrence of COVID-19 is unknown. We conducted a large-scale general population study using data from a community-dwelling sample in England (n = 334,329; 56.4 ±8.1 y; 54.5% women) with prospective linkage to national registry on hospitalization for COVID-19. Body mass index (BMI, from measured height and weight) was used as an indicator of overall obesity, and waist-hip ratio for central obesity. Main outcome was cases of COVID-19 serious enough to warrant a hospital admission from 16 March 2020 to 26 April 2020. Around 0.2% (n = 640) of the sample were hospitalized for COVID-19. There was an upward linear trend in the likelihood of COVID-19 hospitalization with increasing BMI, that was evident in the overweight (odds ratio, 1.39; 95% CI 1.13 to 1.71; crude incidence 19.1 per 10,000) and obese stage I (1.70;1.34 to 2.16; 23.3 per 10,000) and stage II (3.38; 2.60 to 4.40; 42.7 per 10,000) compared to normal weight (12.5 per 10,000). This gradient was little affected after adjustment for a wide range of covariates; however, controlling for biomarkers, particularly high-density lipoprotein cholesterol and glycated hemoglobin, led to a greater degree of attenuation. A similar pattern of association emerged for waist-hip ratio. In summary, overall and central obesity are risk factors for COVID-19 hospital admission. Elevated risk was apparent even at modest weight gain. The mechanisms may involve impaired glucose and lipid metabolism.

Ethnic disparities in hospitalisation for COVID-19 in England: The role of socioeconomic factors, mental health, and inflammatory and pro-inflammatory factors in a community-based cohort study.

BACKGROUND: Differentials in COVID-19 hospitalisations and mortality according to ethnicity have been reported but their origin is uncertain. We examined the role of socioeconomic, mental health, and pro-inflammatory factors in a community-based sample. METHODS: We used data on 340,966 men and women (mean age 56.2 years) from the UK Biobank study, a prospective cohort study with linkage to hospitalisation for COVID-19. Logistic regression models were used to estimate associations between ethnicity and hospitalisation for COVID-19. RESULTS: There were 640 COVID-19 cases (571/324,306 White, 31/4,485 Black, 21/5,732 Asian, 17/5,803 Other). Compared to the White study members and after adjusting for age and sex, Black individuals had over a 4-fold increased risk of COVID-19 infection (odds ratio; 95% confidence interval: 4.32; 3.00-6.23), and there was a doubling of risk in the Asian group (2.12; 1.37, 3.28) and the 'other' non-white group (1.84; 1.13, 2.99). After controlling for potential explanatory factors which included neighbourhood deprivation, household crowding, smoking, body size, inflammation, glycated haemoglobin, and mental illness, these effect estimates were attenuated by 33% for Blacks, 52% for Asians and 43% for Other, but remained raised for Blacks (2.66; 1.82, 3.91), Asian (1.43; 0.91, 2.26) and other non-white groups (1.41; 0.87, 2.31). CONCLUSIONS: There were clear ethnic differences in risk of COVID-19 hospitalisation and these do not appear to be fully explained by measured factors. If replicated, our results have implications for health policy, including the targeting of prevention advice and vaccination coverage.