Genetically predicted high IGF-1 levels showed protective effects on COVID-19 susceptibility and hospitalization: a Mendelian randomisation study with data from 60 studies across 25 countries.

Background: Epidemiological studies observed gender differences in COVID-19 outcomes, however, whether sex hormone plays a causal in COVID-19 risk remains unclear. This study aimed to examine associations of sex hormone, sex hormones-binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), and COVID-19 risk. Methods: Two-sample Mendelian randomization (TSMR) study was performed to explore the causal associations between testosterone, estrogen, SHBG, IGF-1, and the risk of COVID-19 (susceptibility, hospitalization, and severity) using genome-wide association study (GWAS) summary level data from the COVID-19 Host Genetics Initiative (N=1,348,701). Random-effects inverse variance weighted (IVW) MR approach was used as the primary MR method and the weighted median, MR-Egger, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test were conducted as sensitivity analyses. Results: Higher genetically predicted IGF-1 levels have nominally significant association with reduced risk of COVID-19 susceptibility and hospitalization. For one standard deviation increase in genetically predicted IGF-1 levels, the odds ratio was 0.77 (95% confidence interval [CI], 0.61-0.97, p=0.027) for COVID-19 susceptibility, 0.62 (95% CI: 0.25-0.51, p=0.018) for COVID-19 hospitalization, and 0.85 (95% CI: 0.52-1.38, p=0.513) for COVID-19 severity. There was no evidence that testosterone, estrogen, and SHBG are associated with the risk of COVID-19 susceptibility, hospitalization, and severity in either overall or sex-stratified TSMR analysis. Conclusions: Our study indicated that genetically predicted high IGF-1 levels were associated with decrease the risk of COVID-19 susceptibility and hospitalization, but these associations did not survive the Bonferroni correction of multiple testing. Further studies are needed to validate the findings and explore whether IGF-1 could be a potential intervention target to reduce COVID-19 risk. Funding: We acknowledge support from NSFC (LR22H260001), CRUK (C31250/A22804), SHLF (Hjärt-Lungfonden, 20210351), VR (Vetenskapsrådet, 2019-00977), and SCI (Cancerfonden).

Risk of serious COVID-19 outcomes among adults and children with moderate-to-severe asthma: a systematic review and meta-analysis.

BACKGROUND: The Joint Committee on Vaccination and Immunisation in the United Kingdom requested an evidence synthesis to investigate the relationship between asthma and coronavirus disease 2019 (COVID-19) outcomes. OBJECTIVE: We conducted a systematic review and meta-analysis to summarise evidence on the risk of severe COVID-19 outcomes in people with uncontrolled asthma or markers of asthma severity. METHODS: High-dose inhaled corticosteroids (ICS) or oral corticosteroids (OCS) were used as markers of asthma severity, following international or national asthma guidelines. Risk of bias was assessed using Joanna Briggs Institute tools. Adjusted point estimates were extracted for random-effects meta-analyses and subgroup analyses. RESULTS: After screening, 12 studies (11 in adults and one in children) met the eligibility criteria. Adults using high-dose ICS or OCS had a pooled adjusted hazard ratio (aHR) of 1.33 (95% CI 1.06-1.67, I2=0%) for hospitalisation and an aHR of 1.22 (95% CI 0.90-1.65, I2=70%) for mortality for COVID-19. We found insufficient evidence for associations between markers on COVID-19 mortality in the subgroup analyses. CONCLUSIONS: Adults with severe asthma are at increased risk of COVID-19 hospitalisation compared to nonusers. Our analysis highlighted the dearth of studies in children with asthma investigating serious COVID-19 outcomes.

To what extent is alcohol consumption in social gatherings associated with observance of COVID-19 restrictions? A rapid review.

Background: Pre-pandemic research found a connection between alcohol consumption and reduced physical distancing among strangers. Understanding the association between alcohol consumption at social gatherings and observance of COVID-19 restrictions can help inform policy related to the safe operation of public spaces where alcohol is typically consumed, as well as guidance related to the safe conduct of social events in private spaces. Methods: We conducted a rapid review using adapted systematic review methods to explore the association between alcohol consumption in social gatherings and compliance with COVID-19 public health measures and produced a narrative synthesis of our findings. We ran searches in eleven health-related databases (MEDLINE, PubMed, CINAHL, Scopus, Embase (Ovid), ProQuest Public Health, ProQuest Coronavirus, Global Health (Ovid), WHO COVID-19 literature database, PsycInfo (Ovid) and ASSIA) between July 9, 2021, and July 31, 2021. We assessed methodological quality using the relevant Joanna Briggs Institute (JBI) checklists. This review was conducted and reported in accordance with PRISMA-P guidelines. Results: We identified 7936 studies from the searches. After title, abstract and full-text review, three cross-sectional studies were eligible for inclusion. One study found that people who adhered strongly to physical distancing rules were engaged in about 40% fewer weekly drinks and 60% fewer heavy episodic drinking occasions in a week than people who adhered poorly to physical distancing rules (P < 0.01). One study found that people who reported low-risk alcohol consumption patterns had a higher chance of adhering to hand hygiene measures than those who reported high-risk alcohol consumption (odds ratio (OR) = 4.24, 95% confidence interval (CI) = 1.08-16.64). No other statistically significant results on patterns of alcohol consumption and compliance with individual public health measures or with non-pharmaceutical interventions (NPIs) were found. The direction of effect between alcohol consumption and non-adherence to NPIs and the effect of confounding factors has not been established. The quality of studies found was low to moderate, with risk of recall bias and selection bias due to study design; and the extent to which those studies can be generalised beyond their original settings may be limited. Conclusions: Despite existing evidence suggesting an association between alcohol consumption, reduced physical distancing, and increased social interaction, we found few studies of variable quality exploring the relationship between alcohol consumption and compliance with public health measures. A possible association between higher-risk alcohol behaviours and lower compliance with certain NPIs was suggested, but the direction of effect is unknown, and further studies are required to confirm this finding.

Clinical features of COVID-19 for integration of COVID-19 into influenza surveillance: A systematic review.

Background: In November 2020, the World Health Organization (WHO) created interim guidance on how to integrate testing for SARS-CoV-2 into existing influenza surveillance systems. Influenza-like illness (ILI) and severe acute respiratory illness (SARI) case definitions have been used to specify the case definition of COVID-19 for surveillance purposes. This review aims to assess whether the common clinical features of COVID-19 have changed to the point that the criteria used to identify both COVID-19 and influenza in surveillance programs needs to be altered. Methods: A systematic review of reviews following PRISMA-P guidelines was conducted using the "COVID-19 evidence review" database from August 19, 2020, to August 19, 2021. Reviews providing pooled estimates of the prevalence of clinical features of COVID-19 within the general population, diagnosed by polymerase chain reaction or rapid diagnostic test, were included. These were critically appraised and sensitivity analysis was undertaken to examine potential causes of bias. Results: Fourteen reviews were identified, including three on adults only and three on children only. For all reviews, combined fever (median prevalence = 73.0%, IQR = 58.3-78.7) and cough (45.1%, IQR = 28.9-54.0) were the most common features. These were followed by loss of taste or smell (45.1%, IQR = 28.9-54.0), hypoxemia (33%, one review), fatigue (26.4%, IQR = 9.0-39.4) and expectoration (23.9%, IQR = 23.3-25.5). Fever and cough continued to be the most prevalent features for adults and children, with subsequent symptoms being similar for adults only. However, the pattern differed for children, with headache (34.3%, IQR = 18-50.7) and nasal congestion (20%, one review) being the third and fourth commonest symptoms. Conclusions: The prevalent features found in this recent review were the same as the ones identified at the beginning of the pandemic. Therefore, the current approach of using the ILI and SARI criteria which incorporate fever and cough will identify COVID-19 cases in addition to influenza. Interestingly, children may present with different features, as headaches and nasal congestion were more common in this group. Future research could examine this further and investigate whether symptomology changes with new variants of COVID-19.

SARS-CoV-2 transmission in schools: An updated living systematic review (version 2;November 2020)

Background Better understanding of SARS-CoV-2 transmission risks is needed to support decision-making around mitigation measures for COVID-19 in schools. Methods We updated a living systematic review and meta-analysis to investigate the extent of SARS-CoV-2 transmission in schools. In this update we modified our inclusion criteria to include: 1) cohort studies;2) cross-sectional studies that investigated and cross-assessed SARS-COV-2 positivity rates in schools and communities;and 3) pre-post studies. We performed risk of bias evaluation for all included studies using the Newcastle-Ottawa Scale (NOS). Results 6270 articles were retrieved and six new studies were added in this update. In total from the two updates and using the new inclusion criteria, we identified 11 cohort studies (1st update: n = 5;2nd update: n = 6) and one cross-sectional study (1st update: n = 1;2nd update: n = 0). We performed a meta-analysis on nine of the 11 cohort studies investigating IAR in schools. Nine cohort studies reported a total of 91 student and 52 staff index cases that exposed 5698 contacts with 101 secondary infections (overall infection attack rate (IAR) = 1.45%, 95% CI = 0.31%-3.26%). IARs for students and school staff were 1.66% (95% CI = 0.08%-4.78%) and 1.18% (95% CI = 0.00%-4.43%) respectively. The risk of bias was found to be high for most studies identified, limiting the confidence in results. Conclusions There is limited high-quality evidence available to quantify the extent of SARS-CoV-2 transmission in schools or to compare it to community transmission. Emerging evidence suggests the overall IAR and SARS-CoV-2 positivity rate in school settings are low. Higher IAR were found in students, compared to staff. Note This article is a living systematic review that will be updated to reflect emerging evidence. This is the second version of the original article published on 23 December 2020 (J Glob Health 2020;11:021104), and previous versions can be found as data supplements. When citing this paper please consider adding the version number and date of access for clarity.

Effectiveness of public health measures in reducing the incidence of covid-19, SARS-CoV-2 transmission, and covid-19 mortality: systematic review and meta-analysis.

OBJECTIVE: To review the evidence on the effectiveness of public health measures in reducing the incidence of covid-19, SARS-CoV-2 transmission, and covid-19 mortality. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, CINAHL, Biosis, Joanna Briggs, Global Health, and World Health Organization COVID-19 database (preprints). ELIGIBILITY CRITERIA FOR STUDY SELECTION: Observational and interventional studies that assessed the effectiveness of public health measures in reducing the incidence of covid-19, SARS-CoV-2 transmission, and covid-19 mortality. MAIN OUTCOME MEASURES: The main outcome measure was incidence of covid-19. Secondary outcomes included SARS-CoV-2 transmission and covid-19 mortality. DATA SYNTHESIS: DerSimonian Laird random effects meta-analysis was performed to investigate the effect of mask wearing, handwashing, and physical distancing measures on incidence of covid-19. Pooled effect estimates with corresponding 95% confidence intervals were computed, and heterogeneity among studies was assessed using Cochran's Q test and the I2 metrics, with two tailed P values. RESULTS: 72 studies met the inclusion criteria, of which 35 evaluated individual public health measures and 37 assessed multiple public health measures as a "package of interventions." Eight of 35 studies were included in the meta-analysis, which indicated a reduction in incidence of covid-19 associated with handwashing (relative risk 0.47, 95% confidence interval 0.19 to 1.12, I2=12%), mask wearing (0.47, 0.29 to 0.75, I2=84%), and physical distancing (0.75, 0.59 to 0.95, I2=87%). Owing to heterogeneity of the studies, meta-analysis was not possible for the outcomes of quarantine and isolation, universal lockdowns, and closures of borders, schools, and workplaces. The effects of these interventions were synthesised descriptively. CONCLUSIONS: This systematic review and meta-analysis suggests that several personal protective and social measures, including handwashing, mask wearing, and physical distancing are associated with reductions in the incidence covid-19. Public health efforts to implement public health measures should consider community health and sociocultural needs, and future research is needed to better understand the effectiveness of public health measures in the context of covid-19 vaccination. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020178692.

An observational and Mendelian randomisation study on vitamin D and COVID-19 risk in UK Biobank.

A growing body of evidence suggests that vitamin D deficiency has been associated with an increased susceptibility to viral and bacterial respiratory infections. In this study, we aimed to examine the association between vitamin D and COVID-19 risk and outcomes. We used logistic regression to identify associations between vitamin D variables and COVID-19 (risk of infection, hospitalisation and death) in 417,342 participants from UK Biobank. We subsequently performed a Mendelian Randomisation (MR) study to look for evidence of a causal effect. In total, 1746 COVID-19 cases (399 deaths) were registered between March and June 2020. We found no significant associations between COVID-19 infection risk and measured 25-OHD levels after adjusted for covariates, but this finding is limited by the fact that the vitamin D levels were measured on average 11 years before the pandemic. Ambient UVB was strongly and inversely associated with COVID-19 hospitalization and death overall and consistently after stratification by BMI and ethnicity. We also observed an interaction that suggested greater protective effect of genetically-predicted vitamin D levels when ambient UVB radiation is stronger. The main MR analysis did not show that genetically-predicted vitamin D levels are causally associated with COVID-19 risk (OR = 0.77, 95% CI 0.55-1.11, P = 0.160), but MR sensitivity analyses indicated a potential causal effect (weighted mode MR: OR = 0.72, 95% CI 0.55-0.95, P = 0.021; weighted median MR: OR = 0.61, 95% CI 0.42-0.92, P = 0.016). Analysis of MR-PRESSO did not find outliers for any instrumental variables and suggested a potential causal effect (OR = 0.80, 95% CI 0.66-0.98, p-val = 0.030). In conclusion, the effect of vitamin D levels on the risk or severity of COVID-19 remains controversial, further studies are needed to validate vitamin D supplementation as a means of protecting against worsened COVID-19.

Current COVID-19 treatments: Rapid review of the literature.

BACKGROUND: As SARS-CoV-2 continues to spread worldwide, it has already resulted in over 110 million cases and 2.5 million deaths. Currently, there are no effective COVID-19 treatments, although numerous studies are under way. SARS-CoV-2, however, is not the first coronavirus to cause serious outbreaks. COVID-19 can be compared with previous human coronavirus diseases, such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), to better understand the development of treatments. METHODS: Databases Medline, Embase and WHO COVID-19 was systematically searched on 9 February 2021 for studies reporting on therapeutic effect of COVID-19 treatments. Clinical trials, case reports, observational studies and systematic reviews in the English language were eligible. RESULTS: 1416 studies were identified and 40 studies were included in this review. Therapies included are: remdesivir, convalescent plasma, hydroxychloroquine, lopinavir/ ritonavir, interferon, corticosteroids, cytokine storm inhibitors and monoclonal antibodies. Remdesivir, convalescent plasma and interferon seems to provide some clinical benefits such as faster recovery time and reduced mortality, but these effects are not clinically significant. Some corticosteroids are effective in reducing mortality in severe COVID-19 patients. Hydroxychloroquine do not convey any beneficial, and therapies such as cytokine storm inhibitors and monoclonal antibodies were also not effective and require further investigation. CONCLUSIONS: There is no single therapy effective against COVID-19. However, a combination of therapies administered at different stages of infection may provide some benefit. This conclusion is reflected in the limited effects of these treatments in previous human coronaviruses.

What is the evidence for transmission of COVID-19 by children in schools? A living systematic review.

BACKGROUND: It is of paramount importance to understand the transmission of SARS-CoV-2 in schools, which could support the decision-making about educational facilities closure or re-opening with effective prevention and control measures in place. METHODS: We conducted a systematic review and meta-analysis to investigate the extent of SARS-CoV-2 transmission in schools. We performed risk of bias evaluation of all included studies using the Newcastle-Ottawa Scale (NOS). RESULTS: 2178 articles were retrieved and 11 studies were included. Five cohort studies reported a combined 22 student and 21 staff index cases that exposed 3345 contacts with 18 transmissions (overall infection attack rate (IAR): 0.08%, 95% confidence interval (CI) = 0.00%-0.86%). IARs for students and school staff were 0.15% (95% CI = 0.00%-0.93%) and 0.70% (95% CI = 0.00%-3.56%) respectively. Six cross-sectional studies reported 639 SARS-CoV-2 positive cases in 6682 study participants tested [overall SARS-CoV-2 positivity rate: 8.00% (95% CI = 2.17%-16.95%). SARS-CoV-2 positivity rate was estimated to be 8.74% (95% CI = 2.34%-18.53%) among students, compared to 13.68% (95% CI = 1.68%-33.89%) among school staff. Gender differences were not found for secondary infection (OR = 1.44, 95% CI = 0.50-4.14, P = 0.49) and SARS-CoV-2 positivity (OR = 0.90, 95% CI = 0.72-1.13, P = 0.36) in schools. Fever, cough, dyspnea, ageusia, anosmia, rhinitis, sore throat, headache, myalgia, asthenia, and diarrhoea were all associated with the detection of SARS-CoV-2 antibodies (based on two studies). Overall, study quality was judged to be poor with risk of performance and attrition bias, limiting the confidence in the results. CONCLUSIONS: There is limited high-quality evidence available to quantify the extent of SARS-CoV-2 transmission in schools or to compare it to community transmission. Emerging evidence suggests lower IAR and SARS-CoV-2 positivity rate in students compared to school staff. Future prospective and adequately controlled cohort studies are necessary to confirm this finding.

The role of children in the transmission of SARS-CoV2: updated rapid review.

BACKGROUND: Understanding carriage and transmission potential of SARS-CoV-2 in children is of paramount importance to understand the spread of virus in school and community settings. METHODS: We performed an updated rapid review to investigate the role of children in the transmission of SARS-CoV-2. We synthesized evidence for five categories and results are reported narratively. RESULTS: A total of 33 new studies were included for this review. We did not identify additional studies that reported documented cases of SARS-CoV-2 transmission by children. We identified 15 new studies that demonstrate children's susceptibility and transmission risk of SARS-CoV-2 with evidence provided on the chance of being index or secondary cases, the potential of faecal-oral transmission, and the possibility of asymptomatic transmission. There is little data on the transmission of SARS-CoV-2 in schools. There were three studies reporting COVID-19 school outbreaks in France (Oise), Australia (New South Wales) and Israel. The remaining four studies found that all reported cases did not infect any other pupils or staff. With data from seven studies and governmental websites, the proportion of children among all confirmed COVID-19 patients was estimated for 29 countries, varying from 0.3% (lowest in Spain) up to 13.8% (highest in Argentina). Lastly, we identified seven studies reporting on PIMS-TS linked to COVID-19 among paediatric patients. CONCLUSIONS: There is somewhat limited evidence available for quantifying the extent to which children may contribute to overall transmission, but the balance of evidence so far suggests that children and schools play only a limited role in overall transmission.

Physical activity and COVID-19: an observational and Mendelian randomisation study.

BACKGROUND: Physical activity (PA) is known to be a protective lifestyle factor against several non-communicable diseases while its impact on infectious diseases, including Coronavirus Disease 2019 (COVID-19) is not as clear. METHODS: We performed univariate and multivariate logistic regression to identify associations between both objectively and subjectively measured PA collected prospectively and COVID-19 related outcomes (overall COVID-19, inpatient COVID-19, outpatient COVID-19, and COVID-19 death) in the UK Biobank cohort. Subsequently, we tested causality by using Mendelian randomisation (MR) analyses. RESULTS: In the multivariable model, the increased acceleration vector magnitude PA (AMPA) is associated with a decreased probability of overall and outpatient COVID-19 with an odds ratio (OR) and 95% confidence interval (CI) of 0.80 (0.69, 0.93) and 0.74 (0.58, 0.95), respectively. No association is found between self-reported moderate-to-vigorous PA (MVPA) and COVID-19 related outcomes. No association is found by MR analyses. CONCLUSIONS: Our results indicate a protective effect of objectively measured PA and COVID-19 outcomes (outpatient COVID-19 and overall COVID-19) independent of age, sex, measures of obesity, and smoking status. Although the MR analyses do not support a causal association, that may be due to limited power. We conclude that policies to encourage and facilitate exercise at a population level during the pandemic should be considered.

The role of children in transmission of SARS-CoV-2: A rapid review.

BACKGROUND: Understanding the role of children in the transmission of SARS-CoV-2 is urgently required given its policy implications in relation to the reopening of schools and intergenerational contacts. METHODS: We conducted a rapid review of studies that investigated the role of children in the transmission of SARS-CoV-2. We synthesized evidence for four categories: 1) studies reporting documented cases of SARS-CoV-2 transmission by infected children; 2) studies presenting indirect evidence on the potential of SARS-CoV-2 transmission by (both symptomatic and asymptomatic) children; 3) studies reporting cluster outbreaks of COVID-19 in schools; 4) studies estimating the proportions of children infected by SARS-CoV-2, and reported results narratively. RESULTS: A total of 16 unique studies were included for narrative synthesis. There is limited evidence detailing transmission of SARS-CoV-2 from infected children. We found two studies that reported a 3-month-old whose parents developed symptomatic COVID-19 seven days after caring for the infant and two children who may have contracted COVID-19 from the initial cases at a school in New South Wales. In addition, we identified six studies presenting indirect evidence on the potential for SARS-CoV-2 transmission by children, three of which found prolonged virus shedding in stools. There is little data on the transmission of SARS-CoV-2 in schools. We identified only two studies reporting outbreaks of COVID-19 in school settings and one case report of a child attending classes but not infecting any other pupils or staff. Lastly, we identified six studies estimating the proportion of children infected; data from population-based studies in Iceland, Italy, South Korea, Netherlands, California and a hospital-based study in the UK suggest children may be less likely to be infected. CONCLUSIONS: Preliminary results from population-based and school-based studies suggest that children may be less frequently infected or infect others, however current evidence is limited. Prolonged faecal shedding observed in studies highlights the potentially increased risk of faeco-oral transmission in children. Further seroprevalence studies (powered adequately for the paediatric population) are urgently required to establish whether children are in fact less likely to be infected compared to adults. NOTE: We plan to update this rapid review as new data becomes available. These updates are available at https://www.ed.ac.uk/usher/uncover/completed-uncover-reviews.