Community-based asthma assessment in young children: adaptations for a multicentre longitudinal study in South Asia.

Background: Systematic assessment of childhood asthma is challenging in low- and middle-income country (LMIC) settings due to the lack of standardised and validated methodologies. We describe the contextual challenges and adaptation strategies in the implementation of a community-based asthma assessment in four resource-constrained settings in Bangladesh, India, and Pakistan. Method: We followed a group of children of age 6-8 years for 12 months to record their respiratory health outcomes. The study participants were enrolled at four study sites of the 'Aetiology of Neonatal Infection in South Asia (ANISA)' study. We standardised the research methods for the sites, trained field staff for uniform data collection and provided a 'Child Card' to the caregiver to record the illness history of the participants. We visited the children on three different occasions to collect data on respiratory-related illnesses. The lung function of the children was assessed in the outreach clinics using portable spirometers before and after 6-minute exercise, and capillary blood was examined under light microscopes to determine eosinophil levels. Results: We enrolled 1512 children, 95.5% (1476/1512) of them completed the follow-up, and 81.5% (1232/1512) participants attended the lung function assessment tests. Pre- and post-exercise spirometry was performed successfully in 88.6% (1091/1232) and 85.7% (1056/1232) of children who attempted these tests. Limited access to health care services, shortage of skilled human resources, and cultural diversity were the main challenges in adopting uniform procedures across all sites. Designing the study implementation plan based on the local contexts and providing extensive training of the healthcare workers helped us to overcome these challenges. Conclusion: This study can be seen as a large-scale feasibility assessment of applying spirometry and exercise challenge tests in community settings of LMICs and provides confidence to build capacity to evaluate children's respiratory outcomes in future translational research studies.

Age-Specific Estimates of Respiratory Syncytial Virus-Associated Hospitalizations in 6 European Countries: A Time Series Analysis.

BACKGROUND: Knowledge on age-specific hospitalizations associated with RSV infection is limited due to limited testing, especially in older children and adults in whom RSV infections are not expected to be severe. Burden estimates based on RSV coding of hospital admissions are known to underestimate the burden of RSV. We aimed to provide robust and reliable age-specific burden estimates of RSV-associated hospital admissions based on data on respiratory infections from national health registers and laboratory-confirmed cases of RSV. METHODS: We conducted multiseason regression analysis of weekly hospitalizations with respiratory infection and weekly laboratory-confirmed cases of RSV and influenza as covariates, based on national health registers and laboratory databases across 6 European countries. The burden of RSV-associated hospitalizations was estimated by age group, clinical diagnosis, and presence of underlying medical conditions. RESULTS: Across the 6 European countries, hospitalizations of children with respiratory infections were clearly associated with RSV, with associated proportions ranging from 28% to 60% in children younger than 3 months and we found substantial proportions of admissions to hospital with respiratory infections associated with RSV in children younger than 3 years. Associated proportions were highest among hospitalizations with ICD-10 codes of "bronchitis and bronchiolitis." In all 6 countries, annual incidence of RSV-associated hospitalizations was >40 per 1000 persons in the age group 0-2 months. In age group 1-2 years the incidence rate ranged from 1.3 to 10.5 hospitalizations per 1000. Adults older than 85 years had hospitalizations with respiratory infection associated to RSV in all 6 countries although incidence rates were low. CONCLUSIONS: Our findings highlight the substantial proportion of RSV infections among hospital admissions across different ages and may help public health professionals and policy makers when planning prevention and control strategies. In addition, our findings provide valuable insights for health care professionals attending to both children and adults presenting with symptoms of viral respiratory infections.

Global, regional, and national prevalence of asthma in 2019: a systematic analysis and modelling study.

Background: Asthma has a significant impact on people of all ages, particularly children. A lack of universally accepted case definition and confirmatory tests and a poor understanding of major risks interfere with a global response. We aimed to provide global estimates of asthma prevalence and cases in 2019 across four main epidemiological case definitions - current wheezing, ever wheezing, current asthma, and ever asthma. We further investigated major associated factors to determine regional and national distributions of prevalence and cases for current wheezing and ever asthma. Methods: We identified relevant population-based studies published between January 1, 1990, and December 31, 2019. Using a multilevel multivariable mixed-effects meta-regression model, we assessed the age- and sex-adjusted associations of asthma with study-level variables, including year, setting, region and socio-demographic index (SDI). Using a random-effects meta-analysis, we then identified risk factors for current wheezing and asthma. From a "risk factor-based model", which included current smoking, and biomass exposure for current wheezing, and rural setting, current smoking, biomass exposure, and SDI for ever asthma, we estimated case numbers and prevalence across regions and 201 countries and territories in 2019. Results: 220 population-based studies conducted in 88 countries were retained. In 2019, the global prevalence estimates of asthma in people aged 5-69 years by various definitions, namely current wheezing, ever wheezing, current asthma, and ever asthma were 11.5% (95% confidence interval (CI) = 9.1-14.3), 17.9% (95% CI = 14.2-22.3), 5.4% (95% CI = 3.2-9.0) and 9.8% (95% CI = 7.8-12.2), respectively. These translated to 754.6 million (95% CI = 599. 7-943.4), 1181.3 million (95% CI = 938.0-1,471.0), 357.4 million (95% CI = 213.0-590.8), 645.2 million (95% CI = 513.1-806.2) cases, respectively. The overall prevalence of current wheezing among people aged 5-69 years was the highest in the African Region at 13.2% (95% CI = 10.5-16.5), and the lowest in the Americas Region at 10.0% (95% CI = 8.0-12.5). For ever asthma, the estimated prevalence in those aged 5-69 years was also the highest in the African Region at 11.3% (95% CI = 9.0-14.1), but the lowest in South-East Asia Region (8.8, 95% CI = 7.0-11.0). Conclusions: Although varying approaches to case identification in different settings make epidemiological estimates of asthma very difficult, this analysis reaffirms asthma as a common global respiratory condition before the COVID-19 pandemic in 2019, with higher prevalence than previously reported in many world settings.

Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0-60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0-60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development. METHODS: In this systematic analysis, we expanded our global RSV disease burden dataset by obtaining new data from an updated search for papers published between Jan 1, 2017, and Dec 31, 2020, from MEDLINE, Embase, Global Health, CINAHL, Web of Science, LILACS, OpenGrey, CNKI, Wanfang, and ChongqingVIP. We also included unpublished data from RSV GEN collaborators. Eligible studies reported data for children aged 0-60 months with RSV as primary infection with acute lower respiratory infection in community settings, or acute lower respiratory infection necessitating hospital admission; reported data for at least 12 consecutive months, except for in-hospital case fatality ratio (CFR) or for where RSV seasonality is well-defined; and reported incidence rate, hospital admission rate, RSV positive proportion in acute lower respiratory infection hospital admission, or in-hospital CFR. Studies were excluded if case definition was not clearly defined or not consistently applied, RSV infection was not laboratory confirmed or based on serology alone, or if the report included fewer than 50 cases of acute lower respiratory infection. We applied a generalised linear mixed-effects model (GLMM) to estimate RSV-associated acute lower respiratory infection incidence, hospital admission, and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. We estimated country-level RSV-associated acute lower respiratory infection incidence through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality. This review was registered in PROSPERO (CRD42021252400). FINDINGS: In addition to 317 studies included in our previous review, we identified and included 113 new eligible studies and unpublished data from 51 studies, for a total of 481 studies. We estimated that globally in 2019, there were 33·0 million RSV-associated acute lower respiratory infection episodes (uncertainty range [UR] 25·4-44·6 million), 3·6 million RSV-associated acute lower respiratory infection hospital admissions (2·9-4·6 million), 26 300 RSV-associated acute lower respiratory infection in-hospital deaths (15 100-49 100), and 101 400 RSV-attributable overall deaths (84 500-125 200) in children aged 0-60 months. In infants aged 0-6 months, we estimated that there were 6·6 million RSV-associated acute lower respiratory infection episodes (4·6-9·7 million), 1·4 million RSV-associated acute lower respiratory infection hospital admissions (1·0-2·0 million), 13 300 RSV-associated acute lower respiratory infection in-hospital deaths (6800-28 100), and 45 700 RSV-attributable overall deaths (38 400-55 900). 2·0% of deaths in children aged 0-60 months (UR 1·6-2·4) and 3·6% of deaths in children aged 28 days to 6 months (3·0-4·4) were attributable to RSV. More than 95% of RSV-associated acute lower respiratory infection episodes and more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries (LMICs). INTERPRETATION: RSV contributes substantially to morbidity and mortality burden globally in children aged 0-60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0-60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).

COVID-19 vaccine hesitancy in rural South Africa: Deepening understanding to increase uptake and access.

Background: To date, COVID-19 vaccine coverage in the African region falls far too short of global goals. Increasing vaccination rates requires understanding barriers to vaccination so that effective interventions that sensitively and effectively address barriers to vaccination can be implemented. Methods: To assess COVID-19 vaccination levels and identify major barriers to vaccine uptake we conducted a population-based, cross-sectional survey among 1662 adults 18 and older from August 25 to October 29 2021 in the Agincourt Health and Socio-Demographic Surveillance System (AHDSS) area, Mpumalanga, South Africa. Results: Half of participants reported receiving a COVID-19 vaccine (50.4%) with 41.1% being fully vaccinated and 9.3% being partially vaccinated; 49.6% were unvaccinated. More women than men were vaccinated (55.5% vs 42.8%, P < 0.001), and older age groups were more likely to be vaccinated than younger age groups (P < 0.001). Among the unvaccinated, 69.0% planned to get vaccinated as soon as possible, while 14.7% reported definitely not wanting the vaccine. Major barriers to vaccination included lacking information on eligibility (12.3%) or where to get vaccinated (13.0%), concerns about side effects (12.5%), and inconvenient hours and locations for vaccination (11.0%). Confidence in the safety and efficacy of COVID-19 vaccines was higher among those vaccinated than unvaccinated (75.3% vs 51.2%, 75.8% vs 51.0%, both P < 0.001, respectively). Conclusions: Increasing vaccination in South Africa beyond current levels will require a concerted effort to address concerns around vaccine safety and increase confidence in vaccine efficacy. Clarifying eligibility and ensuring access to vaccines at times and places that are convenient to younger populations, men, and other vulnerable groups is necessary.

Introducing pulse oximetry in routine IMCI services in Bangladesh: A context-driven approach to influence policy and programme through stakeholder engagement.

Background: Pneumonia is the leading cause of under-five child deaths globally and in Bangladesh. Hypoxaemia or low (<90%) oxygen concentration in the arterial blood is one of the strongest predictors of child mortality from pneumonia and other acute respiratory infections. Since 2014, the World Health Organization recommends using pulse oximetry devices in Integrated Management of Childhood Illness (IMCI) services (outpatient child health services), but it was not routinely used in most health facilities in Bangladesh until 2018. This paper describes the stakeholder engagement process embedded in an implementation research study to influence national policy and programmes to introduce pulse oximetry in routine IMCI services in Bangladesh. Methods: Based on literature review and expert consultations, we developed a conceptual framework, which guided the planning and implementation of a 4-step stakeholder engagement process. Desk review, key informant interviews, consultative workshops and onsite demonstration were the key methods to involve and engage a wide range of stakeholders. In the first step, a comprehensive desk review and key informant interviews were conducted to identify stakeholder organisations and scored them based on their power and interest levels regarding IMCI implementation in Bangladesh. In the second step, two national level, two district level and five sub-district level sensitisation workshops were organised to orient all stakeholder organisations having high power or high interest regarding the importance of using pulse oximetry for pneumonia assessment and classification. In the third step, national and district level high power-high interest stakeholder organisations were involved in developing a joint action plan for introducing pulse oximetry in routine IMCI services. In the fourth step, led by a formal working group under the leadership of the Ministry of Health, we updated the national IMCI implementation package, including all guidelines, training manuals, services registers and referral forms in English and Bangla. Subsequently, we demonstrated its use in real-life settings involving various levels of (national, district and sub-district) stakeholders and worked alongside the government leaders towards carefully resuming activities despite the COVID-19 pandemic. Results: Our engagement process contributed to the national decision to introduce pulse oximetry in routine child health services and update the national IMCI implementation package demonstrating country ownership, government leadership and multi-partner involvement, which are steppingstones towards scalability and sustainability. However, our experience clearly delineates that stakeholder engagement is a context-driven, time-consuming, resource-intensive, iterative, mercurial process that demands meticulous planning, prioritisation, inclusiveness, and adaptability. It is also influenced by the expertise, experience and positionality of the facilitating organization. Conclusions: Our experience has demonstrated the value and potential of the approach that we adopted for stakeholder engagement. However, the approach needs to be conceptualised coupled with the allocation of adequate resources and time commitment to implement it effectively.

Research priorities to reduce the impact of COVID-19 in low- and middle-income countries

Background The COVID-19 pandemic has caused disruptions to the functioning of societies and their health systems. Prior to the pandemic, health systems in low- and middle-income countries (LMIC) were particularly stretched and vulnerable. The International Society of Global Health (ISoGH) sought to systematically identify priorities for health research that would have the potential to reduce the impact of the COVID-19 pandemic in LMICs. Methods The Child Health and Nutrition Research Initiative (CHNRI) method was used to identify COVID-19-related research priorities. All ISoGH members were invited to participate. Seventy-nine experts in clinical, translational, and population research contributed 192 research questions for consideration. Fifty-two experts then scored those questions based on five pre-defined criteria that were selected for this exercise: 1) feasibility and answerability;2) potential for burden reduction;3) potential for a paradigm shift;4) potential for translation and implementation;and 5) impact on equity. Results Among the top 10 research priorities, research questions related to vaccination were prominent: health care system access barriers to equitable uptake of COVID-19 vaccination (ranked 1st), determinants of vaccine hesitancy (4th), development and evaluation of effective interventions to decrease vaccine hesitancy (5th), and vaccination impacts on vulnerable population/s (6th). Health care delivery questions also ranked highly, including: effective strategies to manage COVID-19 globally and in LMICs (2nd) and integrating health care for COVID-19 with other essential health services in LMICs (3rd). Additionally, the assessment of COVID-19 patients’ needs in rural areas of LMICs was ranked 7th, and studying the leading socioeconomic determinants and consequences of the COVID-19 pandemic in LMICs using multi-faceted approaches was ranked 8th. The remaining questions in the top 10 were: clarifying paediatric case-fatality rates (CFR) in LMICs and identifying effective strategies for community engagement against COVID-19 in different LMIC contexts. Interpretation Health policy and systems research to inform COVID-19 vaccine uptake and equitable access to care are urgently needed, especially for rural, vulnerable, and/or marginalised populations. This research should occur in parallel with studies that will identify approaches to minimise vaccine hesitancy and effectively integrate care for COVID-19 with other essential health services in LMICs. ISoGH calls on the funders of health research in LMICs to consider the urgency and priority of this research during the COVID-19 pandemic and support studies that could make a positive difference for the populations of LMICs.

Prevalence of hypoxaemia in children with pneumonia in low-income and middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Pneumonia accounts for around 15% of all deaths of children younger than 5 years globally. Most happen in resource-constrained settings and are potentially preventable. Hypoxaemia is one of the strongest predictors of these deaths. We present an updated estimate of hypoxaemia prevalence among children with pneumonia in low-income and middle-income countries. METHODS: We conducted a systematic review using the following key concepts "children under five years of age" AND "pneumonia" AND "hypoxaemia" AND "low- and middle-income countries" by searching in 11 bibliographic databases and citation indices. We included all articles published between Nov 1, 2008, and Oct 8, 2021, based on observational studies and control arms of randomised and non-randomised controlled trials. We excluded protocol papers, articles reporting hypoxaemia prevalence based on less than 100 pneumonia cases, and articles published before 2008 from the review. Quality appraisal was done with the Joanna Briggs Institute tools. We reported pooled prevalence of hypoxaemia (SpO2 <90%) by classification of clinical severity and by clinical settings by use of the random-effects meta-analysis models. We combined our estimate of the pooled prevalence of pneumonia with a previously published estimate of the number of children admitted to hospital due to pneumonia annually to calculate the total annual number of children admitted to hospital with hypoxaemic pneumonia. FINDINGS: We identified 2825 unique records from the databases, of which 57 studies met the eligibility criteria: 26 from Africa, 23 from Asia, five from South America, and four from multiple continents. The prevalence of hypoxaemia was 31% (95% CI 26-36; 101 775 children) among all children with WHO-classified pneumonia, 41% (33-49; 30 483 children) among those with very severe or severe pneumonia, and 8% (3-16; 2395 children) among those with non-severe pneumonia. The prevalence was much higher in studies conducted in emergency and inpatient settings than in studies conducted in outpatient settings. In 2019, we estimated that over 7 million children (95% CI 5-8 million) were admitted to hospital with hypoxaemic pneumonia. The studies included in this systematic review had high τ2 (ie, 0·17), indicating a high level of heterogeneity between studies, and a high I2 value (ie, 99·6%), indicating that the heterogeneity was not due to chance. This study is registered with PROSPERO, CRD42019126207. INTERPRETATION: The high prevalence of hypoxaemia among children with severe pneumonia, particularly among children who have been admitted to hospital, emphasises the importance of overall oxygen security within the health systems of low-income and middle-income countries, particularly in the context of the COVID-19 pandemic. Even among children with non-severe pneumonia that is managed in outpatient and community settings, the high prevalence emphasises the importance of rapid identification of hypoxaemia at the first point of contact and referral for appropriate oxygen therapy. FUNDING: UK National Institute for Health Research (Global Health Research Unit on Respiratory Health [RESPIRE]; 16/136/109).

Global hospital admissions and in-hospital mortality associated with all-cause and virus-specific acute lower respiratory infections in children and adolescents aged 5-19 years between 1995 and 2019: a systematic review and modelling study.

INTRODUCTION: The burden of acute lower respiratory infections (ALRI), and common viral ALRI aetiologies among 5-19 years are less well understood. We conducted a systematic review to estimate global burden of all-cause and virus-specific ALRI in 5-19 years. METHODS: We searched eight databases and Google for studies published between 1995 and 2019 and reporting data on burden of all-cause ALRI or ALRI associated with influenza virus, respiratory syncytial virus, human metapneumovirus and human parainfluenza virus. We assessed risk of bias using a modified Newcastle-Ottawa Scale. We developed an analytical framework to report burden by age, country and region when there were sufficient data (all-cause and influenza-associated ALRI hospital admissions). We estimated all-cause ALRI in-hospital deaths and hospital admissions for ALRI associated with respiratory syncytial virus, human metapneumovirus and human parainfluenza virus by region. RESULTS: Globally, an estimated 5.5 million (UR 4.0-7.8) all-cause ALRI hospital admissions occurred annually between 1995 and 2019 in 5-19 year olds, causing 87 900 (UR 40 300-180 600) in-hospital deaths annually. Influenza virus and respiratory syncytial virus were associated with 1 078 600 (UR 4 56 500-2 650 200) and 231 800 (UR 142 700-3 73 200) ALRI hospital admissions in 5-19 years. Human metapneumovirus and human parainfluenza virus were associated with 105 500 (UR 57 200-181 700) and 124 800 (UR 67 300-228 500) ALRI hospital admissions in 5-14 years. About 55% of all-cause ALRI hospital admissions and 63% of influenza-associated ALRI hospital admissions occurred in those 5-9 years globally. All-cause and influenza-associated ALRI hospital admission rates were highest in upper-middle income countries, Asia-Pacific region and the Latin America and Caribbean region. CONCLUSION: Incidence and mortality data for all-cause and virus-specific ALRI in 5-19 year olds are scarce. The lack of data in low-income countries and Eastern Europe and Central Asia, South Asia, and West and Central Africa warrants efforts to improve the development and access to healthcare services, diagnostic capacity, and data reporting.

The association of community mobility with the time-varying reproduction number (R) of SARS-CoV-2: a modelling study across 330 local UK authorities.

BACKGROUND: Community mobility data have been used to assess adherence to non-pharmaceutical interventions and its impact on SARS-CoV-2 transmission. We assessed the association between location-specific community mobility and the reproduction number (R) of SARS-CoV-2 across UK local authorities. METHODS: In this modelling study, we linked data on community mobility from Google with data on R from 330 UK local authorities, for the period June 1, 2020, to Feb 13, 2021. Six mobility metrics are available in the Google community mobility dataset: visits to retail and recreation places, visits to grocery and pharmacy stores, visits to transit stations, visits to parks, visits to workplaces, and length of stay in residential places. For each local authority, we modelled the weekly change in R (the R ratio) per a rescaled weekly percentage change in each location-specific mobility metric relative to a pre-pandemic baseline period (Jan 3-Feb 6, 2020), with results synthesised across local authorities using a random-effects meta-analysis. FINDINGS: On a weekly basis, increased visits to retail and recreation places were associated with a substantial increase in R (R ratio 1·053 [99·2% CI 1·041-1·065] per 15% weekly increase compared with baseline visits) as were increased visits to workplaces (R ratio 1·060 [1·046-1·074] per 10% increase compared with baseline visits). By comparison, increased visits to grocery and pharmacy stores were associated with a small but still statistically significant increase in R (R ratio 1·011 [1·005-1·017] per 5% weekly increase compared with baseline visits). Increased visits to parks were associated with a decreased R (R ratio 0·972 [0·965-0·980]), as were longer stays at residential areas (R ratio 0·952 [0·928-0·976]). Increased visits to transit stations were not associated with R nationally, but were associated with a substantial increase in R in cities. An increasing trend was observed for the first 6 weeks of 2021 in the effect of visits to retail and recreation places and workplaces on R. INTERPRETATION: Increased visits to retail and recreation places, workplaces, and transit stations in cities are important drivers of increased SARS-CoV-2 transmission; the increasing trend in the effects of these drivers in the first 6 weeks of 2021 was possibly associated with the emerging alpha (B.1.1.7) variant. These findings provide important evidence for the management of current and future mobility restrictions. FUNDING: Wellcome Trust and Data-Driven Innovation initiative.

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.

RSV genomic diversity and the development of a globally effective RSV intervention.

Respiratory syncytial virus (RSV) is the most common cause of serious lower respiratory tract illness in infants and children and causes significant disease in the elderly and immunocompromised. Recently there has been an acceleration in the development of candidate RSV vaccines, monoclonal antibodies and therapeutics. However, the effects of RSV genomic variability on the implementation of vaccines and therapeutics remain poorly understood. To address this knowledge gap, the National Institute of Allergy and Infectious Diseases and the Fogarty International Center held a workshop to summarize what is known about the global burden and transmission of RSV disease, the phylogeographic dynamics and genomics of the virus, and the networks that exist to improve the understanding of RSV disease. Discussion at the workshop focused on the implications of viral evolution and genomic variability for vaccine and therapeutics development in the context of various immunization strategies. This paper summarizes the meeting, highlights research gaps and future priorities, and outlines what has been achieved since the meeting took place. It concludes with an examination of what the RSV community can learn from our understanding of SARS-CoV-2 genomics and what insights over sixty years of RSV research can offer the rapidly evolving field of COVID-19 vaccines.

The temporal association of introducing and lifting non-pharmaceutical interventions with the time-varying reproduction number (R) of SARS-CoV-2: a modelling study across 131 countries.

BACKGROUND: Non-pharmaceutical interventions (NPIs) were implemented by many countries to reduce the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of COVID-19. A resurgence in COVID-19 cases has been reported in some countries that lifted some of these NPIs. We aimed to understand the association of introducing and lifting NPIs with the level of transmission of SARS-CoV-2, as measured by the time-varying reproduction number (R), from a broad perspective across 131 countries. METHODS: In this modelling study, we linked data on daily country-level estimates of R from the London School of Hygiene & Tropical Medicine (London, UK) with data on country-specific policies on NPIs from the Oxford COVID-19 Government Response Tracker, available between Jan 1 and July 20, 2020. We defined a phase as a time period when all NPIs remained the same, and we divided the timeline of each country into individual phases based on the status of NPIs. We calculated the R ratio as the ratio between the daily R of each phase and the R from the last day of the previous phase (ie, before the NPI status changed) as a measure of the association between NPI status and transmission of SARS-CoV-2. We then modelled the R ratio using a log-linear regression with introduction and relaxation of each NPI as independent variables for each day of the first 28 days after the change in the corresponding NPI. In an ad-hoc analysis, we estimated the effect of reintroducing multiple NPIs with the greatest effects, and in the observed sequence, to tackle the possible resurgence of SARS-CoV-2. FINDINGS: 790 phases from 131 countries were included in the analysis. A decreasing trend over time in the R ratio was found following the introduction of school closure, workplace closure, public events ban, requirements to stay at home, and internal movement limits; the reduction in R ranged from 3% to 24% on day 28 following the introduction compared with the last day before introduction, although the reduction was significant only for public events ban (R ratio 0·76, 95% CI 0·58-1·00); for all other NPIs, the upper bound of the 95% CI was above 1. An increasing trend over time in the R ratio was found following the relaxation of school closure, bans on public events, bans on public gatherings of more than ten people, requirements to stay at home, and internal movement limits; the increase in R ranged from 11% to 25% on day 28 following the relaxation compared with the last day before relaxation, although the increase was significant only for school reopening (R ratio 1·24, 95% CI 1·00-1·52) and lifting bans on public gatherings of more than ten people (1·25, 1·03-1·51); for all other NPIs, the lower bound of the 95% CI was below 1. It took a median of 8 days (IQR 6-9) following the introduction of an NPI to observe 60% of the maximum reduction in R and even longer (17 days [14-20]) following relaxation to observe 60% of the maximum increase in R. In response to a possible resurgence of COVID-19, a control strategy of banning public events and public gatherings of more than ten people was estimated to reduce R, with an R ratio of 0·71 (95% CI 0·55-0·93) on day 28, decreasing to 0·62 (0·47-0·82) on day 28 if measures to close workplaces were added, 0·58 (0·41-0·81) if measures to close workplaces and internal movement restrictions were added, and 0·48 (0·32-0·71) if measures to close workplaces, internal movement restrictions, and requirements to stay at home were added. INTERPRETATION: Individual NPIs, including school closure, workplace closure, public events ban, ban on gatherings of more than ten people, requirements to stay at home, and internal movement limits, are associated with reduced transmission of SARS-CoV-2, but the effect of introducing and lifting these NPIs is delayed by 1-3 weeks, with this delay being longer when lifting NPIs. These findings provide additional evidence that can inform policy-maker decisions on the timing of introducing and lifting different NPIs, although R should be interpreted in the context of its known limitations. FUNDING: Wellcome Trust Institutional Strategic Support Fund and Data-Driven Innovation initiative.

Influenza vaccination strategies for 2020-21 in the context of COVID-19.

BACKGROUND: Influenza vaccination prevents people from influenza-related diseases and thereby mitigates the burden on national health systems when COVID-19 circulates and public health measures controlling respiratory viral infections are relaxed. However, it is challenging to maintain influenza vaccine services as the COVID-19 pandemic has the potential to disrupt vaccination programmes in many countries during the 2020/21 winter. We summarise available recommendations and strategies on influenza vaccination, specifically the changes in the context of the COVID-19 pandemic. METHODS: We searched websites and databases of national and international public health agencies (focusing on Europe, North and South America, Australia, New Zealand, and South Africa). We also contacted key influenza immunization focal points and experts in respective countries and organizations including WHO and ECDC. RESULTS: Available global and regional guidance emphasises the control of COVID-19 infection in immunisation settings by implementing multiple measures, such as physical distancing, hand hygiene practice, appropriate use of personal protective equipment by health care workers and establishing separate vaccination sessions for medically vulnerable people. The guidance also emphasises using alternative models or settings (eg, outdoor areas and pharmacies) for vaccine delivery, communication strategies and developing registry and catch-up programmes to achieve high coverage. Several novel national strategies have been adopted, such as combining influenza vaccination with other medical visits and setting up outdoor and drive through vaccination clinics. Several Southern Hemisphere countries have increased influenza vaccine coverage substantially for the 2020 influenza season. Most of the countries included in our review have planned a universal or near universal influenza vaccination for health care workers, or have made influenza vaccination for health care workers mandatory. Australia has requested that all workers and visitors in long term care facilities receive influenza vaccine. The UK has planned to expand the influenza programme to provide free influenza vaccine for the first time to all adults 50-64 years of age, people on the shielded patient list and their household members and children in the first year of secondary school. South Africa has additionally prioritised people with hypertension for influenza vaccination. CONCLUSIONS: This review of influenza vaccination guidance and strategies should support strategy development on influenza vaccination in the context of COVID-19.

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 Etiological Role of Common Respiratory Viruses in Acute Respiratory Infections in Older Adults: A Systematic Review and Meta-analysis.

Acute respiratory tract infections (ARI) constitute a substantial disease burden in adults and elderly individuals. We aimed to identify all case-control studies investigating the potential role of respiratory viruses in the etiology of ARI in older adults aged ≥65 years. We conducted a systematic literature review (across 7 databases) of case-control studies published from 1996 to 2017 that investigated the viral profile of older adults with and those without ARI. We then computed a pooled odds ratio (OR) with a 95% confidence interval and virus-specific attributable fraction among the exposed (AFE) for 8 common viruses: respiratory syncytial virus (RSV), influenza virus (Flu), parainfluenza virus (PIV), human metapneumovirus (HMPV), adenovirus (AdV), rhinovirus (RV), bocavirus (BoV), and coronavirus (CoV). From the 16 studies included, there was strong evidence of possible causal attribution for RSV (OR, 8.5 [95% CI, 3.9-18.5]; AFE, 88%), Flu (OR, 8.3 [95% CI, 4.4-15.9]; AFE, 88%), PIV (OR, not available; AFE, approximately 100%), HMPV (OR, 9.8 [95% CI, 2.3-41.0]; AFE, 90%), AdV (OR, not available; AFE, approximately 100%), RV (OR, 7.1 [95% CI, 3.7-13.6]; AFE, 86%) and CoV (OR, 2.8 [95% CI, 2.0-4.1]; AFE, 65%) in older adults presenting with ARI, compared with those without respiratory symptoms (ie, asymptomatic individuals) or healthy older adults. However, there was no significant difference in the detection of BoV in cases and controls. This review supports RSV, Flu, PIV, HMPV, AdV, RV, and CoV as important causes of ARI in older adults and provides quantitative estimates of the absolute proportion of virus-associated ARI cases to which a viral cause can be attributed. Disease burden estimates should take into account the appropriate AFE estimates (for older adults) that we report.