Publications by authors named "Harish Nair"

116 Publications

Global burden of influenza-associated lower respiratory tract infections and hospitalizations among adults: A systematic review and meta-analysis.

PLoS Med 2021 Mar 1;18(3):e1003550. Epub 2021 Mar 1.

Division of Global Health Protection, US Centers for Disease Control and Prevention, Nairobi, Kenya.

Background: Influenza illness burden is substantial, particularly among young children, older adults, and those with underlying conditions. Initiatives are underway to develop better global estimates for influenza-associated hospitalizations and deaths. Knowledge gaps remain regarding the role of influenza viruses in severe respiratory disease and hospitalizations among adults, particularly in lower-income settings.

Methods And Findings: We aggregated published data from a systematic review and unpublished data from surveillance platforms to generate global meta-analytic estimates for the proportion of acute respiratory hospitalizations associated with influenza viruses among adults. We searched 9 online databases (Medline, Embase, CINAHL, Cochrane Library, Scopus, Global Health, LILACS, WHOLIS, and CNKI; 1 January 1996-31 December 2016) to identify observational studies of influenza-associated hospitalizations in adults, and assessed eligible papers for bias using a simplified Newcastle-Ottawa scale for observational data. We applied meta-analytic proportions to global estimates of lower respiratory infections (LRIs) and hospitalizations from the Global Burden of Disease study in adults ≥20 years and by age groups (20-64 years and ≥65 years) to obtain the number of influenza-associated LRI episodes and hospitalizations for 2016. Data from 63 sources showed that influenza was associated with 14.1% (95% CI 12.1%-16.5%) of acute respiratory hospitalizations among all adults, with no significant differences by age group. The 63 data sources represent published observational studies (n = 28) and unpublished surveillance data (n = 35), from all World Health Organization regions (Africa, n = 8; Americas, n = 11; Eastern Mediterranean, n = 7; Europe, n = 8; Southeast Asia, n = 11; Western Pacific, n = 18). Data quality for published data sources was predominantly moderate or high (75%, n = 56/75). We estimate 32,126,000 (95% CI 20,484,000-46,129,000) influenza-associated LRI episodes and 5,678,000 (95% CI 3,205,000-9,432,000) LRI hospitalizations occur each year among adults. While adults <65 years contribute most influenza-associated LRI hospitalizations and episodes (3,464,000 [95% CI 1,885,000-5,978,000] LRI hospitalizations and 31,087,000 [95% CI 19,987,000-44,444,000] LRI episodes), hospitalization rates were highest in those ≥65 years (437/100,000 person-years [95% CI 265-612/100,000 person-years]). For this analysis, published articles were limited in their inclusion of stratified testing data by year and age group. Lack of information regarding influenza vaccination of the study population was also a limitation across both types of data sources.

Conclusions: In this meta-analysis, we estimated that influenza viruses are associated with over 5 million hospitalizations worldwide per year. Inclusion of both published and unpublished findings allowed for increased power to generate stratified estimates, and improved representation from lower-income countries. Together, the available data demonstrate the importance of influenza viruses as a cause of severe disease and hospitalizations in younger and older adults worldwide.
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http://dx.doi.org/10.1371/journal.pmed.1003550DOI Listing
March 2021

Risk factors for RSV associated acute lower respiratory infection poor outcome and mortality in young children: A systematic review and meta-analysis.

J Infect Dis 2021 Feb 12. Epub 2021 Feb 12.

Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, Scotland, United Kingdom.

Respiratory syncytial virus associated acute lower respiratory infection (RSV-ALRI) constitutes a substantial disease burden in young children. We aimed to identify all studies investigating the risk factors of RSV-ALRI poor outcome or mortality in young children.We carried out a systematic literature review across 7 databases with data from studies published from January 1995 to December 2019. We defined poor outcome as need for prolonged hospital stay, oxygen supplementation, mechanical ventilation or intensive care unit (ICU) admission. Quality of all eligible studies was assessed according to modified GRADE criteria. We conducted meta-analyses to estimate odds ratio (OR) with 95% confidence intervals (CI) for individual risk factors. We identified 27 eligible studies, which investigated 20 risk factors for RSV-ALRI poor outcome and/or mortality in children younger than 5 years old, in comparison to those with RSV-ALRI who did not have poor outcome or mortality. Among those risk factors, 6 had statistically significant associations with RSV-ALRI poor outcome: any comorbidity (OR 2.69 (95% CI 1.89-3.83)), congenital heart disease (3.40 (95% CI 2.14-5.40)), prematurity with gestational age (GA) <37 weeks (1.75 (95% CI 1.31-2.36)), prematurity with GA ≤32 weeks (2.68 (95% CI 1.43-5.04)), age <3 months (4.91 (95% CI 1.64-14.71)), age <6 months (2.02 (95% CI 1.73-2.35)). Apart from age <3 months, the meta-estimate ORs for all other risk factors were based on studies using multivariable analysis. For mortality, only prematurity with GA <37 weeks had a significant meta-estimate of OR 3.81 (95% CI 1.68-8.63) based on univariable analysis.This study represents a comprehensive report of the association between various risk factors and RSV-ALRI poor outcome and mortality in young children. More research should be carried out to elucidate risk factors associated with poor outcome and mortality using multivariable analysis.
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http://dx.doi.org/10.1093/infdis/jiaa751DOI Listing
February 2021

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

J Glob Health 2020 Dec;10(2):021102

Centre for Global Health, Usher Institute, University of Edinburgh, UK.

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.
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http://dx.doi.org/10.7189/jogh.10.021102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719353PMC
December 2020

Global burden of acute lower respiratory infection associated with human metapneumovirus in children under 5 years in 2018: a systematic review and modelling study.

Lancet Glob Health 2021 01 26;9(1):e33-e43. Epub 2020 Nov 26.

Centre for Global Health, Usher Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK. Electronic address:

Background: Human metapneumovirus is a common virus associated with acute lower respiratory infections (ALRIs) in children. No global burden estimates are available for ALRIs associated with human metapneumovirus in children, and no licensed vaccines or drugs exist for human metapneumovirus infections. We aimed to estimate the age-stratified human metapneumovirus-associated ALRI global incidence, hospital admissions, and mortality burden in children younger than 5 years.

Methods: We estimated the global burden of human metapneumovirus-associated ALRIs in children younger than 5 years from a systematic review of 119 studies published between Jan 1, 2001, and Dec 31, 2019, and a further 40 high quality unpublished studies. We assessed risk of bias using a modified Newcastle-Ottawa Scale. We estimated incidence, hospital admission rates, and in-hospital case-fatality ratios (hCFRs) of human metapneumovirus-associated ALRI using a generalised linear mixed model. We applied incidence and hospital admission rates of human metapneumovirus-associated ALRI to population estimates to yield the morbidity burden estimates by age bands and World Bank income levels. We also estimated human metapneumovirus-associated ALRI in-hospital deaths and overall human metapneumovirus-associated ALRI deaths (both in-hospital and non-hospital deaths). Additionally, we estimated human metapneumovirus-attributable ALRI cases, hospital admissions, and deaths by combining human metapneumovirus-associated burden estimates and attributable fractions of human metapneumovirus in laboratory-confirmed human metapneumovirus cases and deaths.

Findings: In 2018, among children younger than 5 years globally, there were an estimated 14·2 million human metapneumovirus-associated ALRI cases (uncertainty range [UR] 10·2 million to 20·1 million), 643 000 human metapneumovirus-associated hospital admissions (UR 425 000 to 977 000), 7700 human metapneumovirus-associated in-hospital deaths (2600 to 48 800), and 16 100 overall (hospital and community) human metapneumovirus-associated ALRI deaths (5700 to 88 000). An estimated 11·1 million ALRI cases (UR 8·0 million to 15·7 million), 502 000 ALRI hospital admissions (UR 332 000 to 762 000), and 11 300 ALRI deaths (4000 to 61 600) could be causally attributed to human metapneumovirus in 2018. Around 58% of the hospital admissions were in infants under 12 months, and 64% of in-hospital deaths occurred in infants younger than 6 months, of which 79% occurred in low-income and lower-middle-income countries.

Interpretation: Infants younger than 1 year have disproportionately high risks of severe human metapneumovirus infections across all World Bank income regions and all child mortality settings, similar to respiratory syncytial virus and influenza virus. Infants younger than 6 months in low-income and lower-middle-income countries are at greater risk of death from human metapneumovirus-associated ALRI than older children and those in upper-middle-income and high-income countries. Our mortality estimates demonstrate the importance of intervention strategies for infants across all settings, and warrant continued efforts to improve the outcome of human metapneumovirus-associated ALRI among young infants in low-income and lower-middle-income countries.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S2214-109X(20)30393-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783516PMC
January 2021

National burden estimates of hospitalisations for acute lower respiratory infections due to respiratory syncytial virus in young children in 2019 among 58 countries: a modelling study.

Lancet Respir Med 2021 02 21;9(2):175-185. Epub 2020 Sep 21.

Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK; Respiratory Syncytial Virus Network (ReSViNET) Foundation, Zeist, Netherlands. Electronic address:

Background: Respiratory syncytial virus (RSV) is the predominant viral pathogen associated with acute lower respiratory infection (ALRI) in children who are younger than 5 years. Little is reported on the national estimates of RSV-associated ALRI hospitalisations in these children on the basis of robust epidemiological data. We aimed to generate national level estimates for RSV-associated ALRI hospitalisations in children aged younger than 5 years.

Methods: We included data for RSV and ALRI hospitalisation in children who were younger than 5 years from systematic literature reviews (including unpublished data) and from inpatient databases, representing 58 countries. We used two different methods, the rate-based method and the proportion-based method, to estimate national RSV-associated ALRI hospitalisations in children younger than 5 years in 2019. The rate-based method synthesised data for laboratory-confirmed RSV-associated ALRI hospitalisation rates using a spatiotemporal Gaussian process meta-regression (ST-GPR). The proportion-based method applied data for RSV positive proportions among ALRI to all-cause ALRI hospitalisation envelopes (ie, total disease burden of ALRI hospitalisations of any cause) using a Bayesian regularised trimmed meta-regression (MR-BRT). Where applicable, we reported estimates by both methods to provide a plausible range for each country.

Findings: A total of 334 studies and 1985 data points (defined as an individual estimate for one age group and 1 year for each study) were included in our analysis, accounting for 398 million (59%) of the 677 million children aged younger than 5 years worldwide representing 58 countries. We reported the number of annual national RSV-associated ALRI hospitalisations for 29 countries using the rate-based method, and for 42 countries using the proportion-based method. The median number of RSV-associated ALRI hospitalisations in children younger than 5 years was 8·25 thousand (IQR 1·97-48·01), and the median rate of RSV-associated ALRI hospitalisations was 514 (339-866) hospitalisations per thousand children younger than 5 years. Despite large variation among countries, a high proportion of the RSV-associated ALRI hospitalisations were in infants aged younger than 1 year in all countries (median proportion 45%, IQR 32-56). In 272 (76%) of the 358 years included in the analysis, the RSV-associated ALRI hospitalisation rate fluctuated between 0·8 and 1·2 times the country's median yearly rate. General agreement was observed between estimates by the rate-based method and proportion-based method, with the exceptions of India, Kenya, Norway, and Philippines.

Interpretation: By incorporating data from various sources, our study provides robust estimates on national level burden of RSV-associated ALRI hospitalisation in children aged younger than 5 years. These estimates are important for informing policy for the introduction of RSV immunisations and also serve as baseline data for the RSV disease burden in young children.

Funding: The Foundation for Influenza Epidemiology.
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http://dx.doi.org/10.1016/S2213-2600(20)30322-2DOI Listing
February 2021

National, regional, and state-level pneumonia and severe pneumonia morbidity in children in India: modelled estimates for 2000 and 2015.

Lancet Child Adolesc Health 2020 09;4(9):678-687

Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.

Background: The absolute number of pneumonia deaths in India has declined substantially since 2000. However, pneumonia remains a major cause of morbidity in children in the country. We used a risk factor-based model to estimate pneumonia and severe pneumonia morbidity in Indian states in 2000 and 2015.

Methods: In this modelling study, we estimated the burden of pneumonia and severe pneumonia in children younger than 5 years using a risk factor-based model. We did a systematic literature review to identify published data on the incidence of pneumonia from community-based longitudinal studies and calculated summary estimates. We estimated state-specific incidence rates for WHO-defined clinical pneumonia between 2000 and 2015 using Poisson regression and the prevalence of risk factors in each state was obtained from National Family Health Surveys. From clinical pneumonia studies, we identified studies reporting the proportion of clinical pneumonia cases with lower chest wall indrawing to estimate WHO-defined severe pneumonia cases. We used the estimate of the proportion of cases with lower chest wall indrawing to estimate WHO-defined severe pneumonia cases for each state.

Findings: Between 2000 and 2015, the estimated number of pneumonia cases in Indian HIV-uninfected children younger than 5 years decreased from 83·8 million cases (95% uncertainty interval [UI] 14·0-300·8) to 49·8 million cases (9·1-174·2), representing a 41% reduction in pneumonia cases. The incidence of pneumonia in children younger than 5 years in India was 657 cases per 1000 children (95% UI 110-2357) in 2000 and 403 cases per 1000 children (74-1408) in 2015. The estimated national pneumonia case fatality rate in 2015 was 0·38% (95% UI 0·11-2·10). In 2015, the estimated number of severe pneumonia cases was 8·4 million (95% UI 1·2-31·7), with an incidence of 68 cases per 1000 children (9-257) and a case fatality ratio of 2·26% (0·60-16·30). In 2015, the estimated number of pneumonia cases in HIV-uninfected children was highest in Uttar Pradesh (12·4 million [95% UI 2·1-45·0]), Bihar (7·3 million [1·3-26·1]), and Madhya Pradesh (4·6 million [0·7-17·0]). Between 2000 and 2015, the greatest reduction in pneumonia cases was observed in Kerala (82% reduction). In 2015, pneumonia incidence was greater than 500 cases per 1000 children in two states: Uttar Pradesh (565 cases per 1000 children [95% UI 94-2047]) and Madhya Pradesh (563 cases per 1000 children [88-2084]).

Interpretation: The estimated number of pneumonia and severe pneumonia cases among children younger than 5 years in India decreased between 2000 and 2015. Improvements in socioeconomic indicators and specific government initiatives are likely to have contributed to declines in the prevalence of pneumonia risk factors in many states. However, pneumonia incidence in many states remains high. The introduction of new vaccines that target pneumonia pathogens and reduce risk factors will help further reduce the burden of pneumonia in the country.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S2352-4642(20)30129-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457699PMC
September 2020

Unveiling the Risk Period for Death After Respiratory Syncytial Virus Illness in Young Children Using a Self-Controlled Case Series Design.

J Infect Dis 2020 10;222(Suppl 7):S634-S639

Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.

Background: Respiratory syncytial virus (RSV)-related acute lower respiratory infection is an important cause of death in infants and young children. However, little is known about the risk period for RSV-related deaths after presentation to health services with an RSV illness.

Methods: Using the Scottish national mortality database, we identified deaths from respiratory/circulatory causes (hereafter "respiratory/circulatory deaths") in young children aged <5 years during 2009-2016, whose medical history and records of laboratory-confirmed RSV infections were obtained by linking the mortality database to the national surveillance data set and the Scottish Morbidity Record. We used a self-controlled case series (SCCS) design to evaluate the relative incidence of deaths with respiratory/circulatory deaths in the first year after an RSV episode. We defined the risk interval as the first year after the RSV episode, and the control interval as the period before and after the risk interval until 5 years after birth. Age-adjusted incidence ratio and attributable fraction were generated using the R software package SCCS.

Results: We included 162 respiratory/circulatory deaths, of which 36 occurred in children with a history of laboratory-confirmed RSV infection. We found that the mortality risk decreased with time after the RSV episode and that the risk was statistically significant for the month after RSV illness. More than 90% of respiratory/circulatory deaths occurring within 1 week after the RSV episode were attributable to RSV (attributable fraction, 93.9%; 95% confidence interval, 77.6%-98.4%), compared with about 80% of those occurring 1 week to 1 month after RSV illness (80.3%; 28.5%-94.6%).

Conclusions: We found an increased risk of death in the first month after an RSV illness episode leading to healthcare attendance. This provides a practical cutoff time window for community-based surveillance studies estimating RSV-related mortality risk. Further studies are warranted to assess the mortality risk beyond the first month after RSV illness episode.
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http://dx.doi.org/10.1093/infdis/jiaa309DOI Listing
October 2020

Presumed Risk Factors and Biomarkers for Severe Respiratory Syncytial Virus Disease and Related Sequelae: Protocol for an Observational Multicenter, Case-Control Study From the Respiratory Syncytial Virus Consortium in Europe (RESCEU).

J Infect Dis 2020 10;222(Suppl 7):S658-S665

Department of Paediatrics, Oxford Vaccine Group, Oxford, United Kingdom.

Respiratory syncytial virus (RSV) is the leading viral pathogen associated with acute lower respiratory tract infection and hospitalization in children < 5 years of age worldwide. While there are known clinical risk factors for severe RSV infection, the majority of those hospitalized are previously healthy infants. There is consequently an unmet need to identify biomarkers that predict host response, disease severity, and sequelae. The primary objective is to identify biomarkers of severe RSV acute respiratory tract infection (ARTI) in infants. Secondary objectives include establishing biomarkers associated with respiratory sequelae following RSV infection and characterizing the viral load, RSV whole-genome sequencing, host immune response, and transcriptomic, proteomic, metabolomic and epigenetic signatures associated with RSV disease severity. Six hundred thirty infants will be recruited across 3 European countries: the Netherlands, Spain, and the United Kingdom. Participants will be recruited into 2 groups: (1) infants with confirmed RSV ARTI (includes upper and lower respiratory tract infections), 500 without and 50 with comorbidities; and (2) 80 healthy controls. At baseline, participants will have nasopharyngeal, blood, buccal, stool, and urine samples collected, plus complete a questionnaire and 14-day symptom diary. At convalescence (7 weeks ± 1 week post-ARTI), specimen collection will be repeated. Laboratory measures will be correlated with symptom severity scores to identify corresponding biomarkers of disease severity.

Clinical Trials Registration: NCT03756766.
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http://dx.doi.org/10.1093/infdis/jiaa239DOI Listing
October 2020

Hospital Admission Trends for Bronchiolitis in Scotland, 2001-2016: A National Retrospective Observational Study.

J Infect Dis 2020 10;222(Suppl 7):S592-S598

Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh United Kingdom.

Background: Bronchiolitis is the commonest cause of respiratory related hospital admissions in young children. This study aimed to describe temporal trends in bronchiolitis admissions for children under 2 years of age in Scotland by patient characteristics, socioeconomic deprivation, and duration of admission.

Methods: The national hospital admissions database for Scotland was used to extract data on all bronchiolitis admissions (International Classification of Disease, Tenth Revision, code J21) in children <2 years of age from 2001 to 2016. Deprivation quintiles were classified using the 2011 Scottish Index of Multiple Deprivation.

Results: Over the 15-year study period, admission rates for children under 2 years old increased 2.20-fold (95% confidence interval [CI], 1.4-3.6-fold) from 17.2 (15.9-18.5) to 37.7 (37.4-38.1) admissions per 1000 children per year. Admissions peaked in infants aged 1 month, and in those born in the 3 months preceding the peak bronchiolitis month-September, October, and November. Admissions from the most-deprived quintile had the highest overall rate of admission, at 40.5 per 1000 children per year (95% CI, 39.5-41.5) compared with the least-deprived quintile, at 23.0 admissions per 1000 children per year (22.1-23.9). The most-deprived quintile had the greatest increase in admissions over time, whereas the least-deprived quintile had the lowest increase. Zero-day admissions, defined as admission and discharge within the same calendar date, increased 5.3-fold (5.1-5.5) over the study period, with the highest increase in patients in the most-deprived quintile.

Conclusions: This study provides baseline epidemiological data to aid policy makers in the strategic planning of preventative interventions. With the majority of bronchiolitis caused by respiratory syncytial virus (RSV), and several RSV vaccines and monoclonal antibodies currently in clinical trials, understanding national trends in bronchiolitis admissions is an important proxy for determining potential RSV vaccination strategies.
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http://dx.doi.org/10.1093/infdis/jiaa323DOI Listing
October 2020

An analysis of clinical predictive values for radiographic pneumonia in children.

BMJ Glob Health 2020 08;5(8)

Division of Emergency Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA

Introduction: Healthcare providers in resource-limited settings rely on the presence of tachypnoea and chest indrawing to establish a diagnosis of pneumonia in children. We aimed to determine the test characteristics of commonly assessed signs and symptoms for the radiographic diagnosis of pneumonia in children 0-59 months of age.

Methods: We conducted an analysis using patient-level pooled data from 41 shared datasets of paediatric pneumonia. We included hospital-based studies in which >80% of children had chest radiography performed. Primary endpoint pneumonia (presence of dense opacity occupying a portion or entire lobe of the lung or presence of pleural effusion on chest radiograph) was used as the reference criterion radiographic standard. We assessed the sensitivity, specificity, and likelihood ratios for clinical findings, and combinations of findings, for the diagnosis of primary endpoint pneumonia among children 0-59 months of age.

Results: Ten studies met inclusion criteria comprising 15 029 children; 24.9% (n=3743) had radiographic pneumonia. The presence of age-based tachypnoea demonstrated a sensitivity of 0.92 and a specificity of 0.22 while lower chest indrawing revealed a sensitivity of 0.74 and specificity of 0.15 for the diagnosis of radiographic pneumonia. The sensitivity and specificity for oxygen saturation <90% was 0.40 and 0.67, respectively, and was 0.17 and 0.88 for oxygen saturation <85%. Specificity was improved when individual clinical factors such as tachypnoea, fever and hypoxaemia were combined, however, the sensitivity was lower.

Conclusions: No single sign or symptom was strongly associated with radiographic primary end point pneumonia in children. Performance characteristics were improved by combining individual signs and symptoms.
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http://dx.doi.org/10.1136/bmjgh-2020-002708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430338PMC
August 2020

Global Seasonality of Human Seasonal Coronaviruses: A Clue for Postpandemic Circulating Season of Severe Acute Respiratory Syndrome Coronavirus 2?

J Infect Dis 2020 09;222(7):1090-1097

Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.

Background: The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could recur as seasonal outbreaks, a circulating pattern observed among other preexisting human seasonal coronaviruses (sCoVs). However, little is known about seasonality of sCoVs on a global scale.

Methods: We conducted a systematic review of data on seasonality of sCoVs. We compared seasonality of sCoVs with influenza virus and respiratory syncytial virus. We modeled monthly activity of sCoVs using site-specific weather data.

Results: We included sCoV seasonality data in 40 sites from 21 countries. sCoVs were prevalent in winter months in most temperate sites except for China, whereas sCoVs tended to be less seasonal in China and in tropical sites. In temperate sites excluding China, 53.1% of annual sCoV cases (interquartile range [IQR], 34.6%-61.9%) occurred during influenza season and 49.6% (IQR, 30.2%-60.2%) of sCoV cases occurred during respiratory syncytial virus season. Low temperature combined with high relative humidity was associated with higher sCoV activity.

Conclusions: This is the first study that provides an overview of the global seasonality of sCoVs. Our findings offer clues to the possible postpandemic circulating season of SARS-CoV-2 and add to the knowledge pool necessary for postpandemic preparedness for SARS-CoV-2.
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http://dx.doi.org/10.1093/infdis/jiaa436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454715PMC
September 2020

The role of viral co-infections in the severity of acute respiratory infections among children infected with respiratory syncytial virus (RSV): A systematic review and meta-analysis.

J Glob Health 2020 Jun;10(1):010426

Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK.

Background: Respiratory syncytial virus (RSV) is the predominant viral cause of childhood pneumonia. Little is known about the role of viral-coinfections in the clinical severity in children infected with RSV.

Methods: We conducted a systematic literature review of publications comparing the clinical severity between RSV mono-infection and RSV co-infection with other viruses in children under five years (<5y). Clinical severity was measured using the following six clinical outcomes: hospitalisation, length of hospital stay, use of supplemental oxygen, intensive care unit (ICU) admission, mechanical ventilation and deaths. We summarised the findings by clinical outcome and conducted random-effect meta-analyses, where applicable, to quantitatively synthesize the association between RSV mono-infection/RSV co-infection and the clinical severity.

Results: Overall, no differences in the clinical severity were found between RSV mono-infection and RSV co-infection with any viruses, except for the RSV-human metapneumovirus (hMPV) co-infection. RSV-hMPV coinfection was found to be associated with a higher risk of ICU admission (odds ratio (OR) = 7.2, 95% confidence interval (CI) = 2.1-25.1; OR after removal of the most influential study was 3.7, 95% CI = 1.1-12.3). We also observed a trend from three studies that RSV-hMPV coinfections were likely to be associated with longer hospital stay.

Conclusion: Our findings suggest that RSV-hMPV coinfections might be associated with increased risk for ICU admission in children <5y compared with RSV mono-infection but such association does not imply causation. Our findings do not support the association between RSV coinfections with other viruses and clinical severity but further large-scale investigations are needed to confirm the findings.

Protocol Registration: PROSPERO CRD42019154761.
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http://dx.doi.org/10.7189/jogh.10.010426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295447PMC
June 2020

Validating a GPS-based approach to detect health facility visits against maternal response to prompted recall survey.

J Glob Health 2020 Jun;10(1):010602

KEM Hospital Research Centre, Sardar Moodliar Road, Rasta Peth, Pune, India.

Introduction: Common approaches to measure health behaviors rely on participant responses and are subject to bias. Technology-based alternatives, particularly using GPS, address these biases while opening new channels for research. This study describes the development and implementation of a GPS-based approach to detect health facility visits in rural Pune district, India.

Methods: Participants were mothers of under-five year old children within the Vadu Demographic Surveillance area. Participants received GPS-enabled smartphones pre-installed with a location-aware application to continuously record and transmit participant location data to a central server. Data were analyzed to identify health facility visits according to a parameter-based approach, optimal thresholds of which were calibrated through a simulation exercise. Lists of GPS-detected health facility visits were generated at each of six follow-up home visits and reviewed with participants through prompted recall survey, confirming visits which were correctly identified. Detected visits were analyzed using logistic regression to explore factors associated with the identification of false positive GPS-detected visits.

Results: We enrolled 200 participants and completed 1098 follow-up visits over the six-month study period. Prompted recall surveys were completed for 694 follow-up visits with one or more GPS-detected health facility visits. While the approach performed well during calibration (positive predictive value (PPV) 78%), performance was poor when applied to participant data. Only 440 of 22 251 detected visits were confirmed (PPV 2%). False positives increased as participants spent more time in areas of high health facility density (odds ratio (OR) = 2.29, 95% confidence interval (CI) = 1.62-3.25). Visits detected at facilities other than hospitals and clinics were also more likely to be false positives (OR = 2.78, 95% CI = 1.65-4.67) as were visits detected to facilities nearby participant homes, with the likelihood decreasing as distance increased (OR = 0.89, 95% CI = 0.82-0.97). Visit duration was not associated with confirmation status.

Conclusions: The optimal parameter combination for health facility visits simulated by field workers substantially overestimated health visits from participant GPS data. This study provides useful insights into the challenges in detecting health facility visits where providers are numerous, highly clustered within urban centers and located near residential areas of the population which they serve.
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http://dx.doi.org/10.7189/jogh.10.010602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211413PMC
June 2020

Respiratory Syncytial Virus-related Death in Children With Down Syndrome: The RSV GOLD Study.

Pediatr Infect Dis J 2020 08;39(8):665-670

From the Division of Infectious Diseases, Department of Pediatrics, University Medical Centre Utrecht, Utrecht, The Netherlands.

Background: Respiratory syncytial virus (RSV) is a major cause of mortality in children younger than 5 years worldwide. Systematic reviews have shown that Down syndrome (DS) is an independent risk factor for severe RSV infection. We aimed to describe demographic and clinical characteristics of children with DS who died with RSV infection.

Methods: We performed a retrospective case series in which data were shared by individual researchers, research networks and physicians worldwide as part of the RSV Global Online Database study. We included children with DS who died when younger than 5 years of age with laboratory-confirmed RSV infection.

Results: We included 53 children with DS and RSV-related mortality from 20 countries in 5 continents. Five (9.4%) children were from low-income or lower-middle-income countries. Median age at time of death was 6.0 months [interquartile range (IQR): 3.00-12.0]. Thirteen (24.5%) children were born term and had no other risk factors for severe RSV disease. In total, 36 (67.9%) children had congenital heart disease, 8 (15.1%) had chronic lung disease and 1 (1.9%) had congenital immunodeficiency. Duration of hospitalization was significantly longer for children with DS compared with children without DS [median length of stay, 13 days (IQR: 6.8-21.0) vs. 8 days (IQR: 3.0-18.5), P=0.005].

Conclusions: One-fourth of children with DS and RSV-confirmed death did not have risk factors for severe RSV disease, indicating that DS is an important risk factor for RSV-related mortality. Age distribution at time of death demonstrates that maternal vaccination would not be sufficient to protect children with DS against RSV-related mortality.
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http://dx.doi.org/10.1097/INF.0000000000002666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360096PMC
August 2020

An evidence-based framework for priority clinical research questions for COVID-19.

J Glob Health 2020 Jun;10(1):011001

Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK.

Background: On 31 December, 2019, the World Health Organization China Country Office was informed of cases of pneumonia of unknown aetiology. Since then, there have been over 75 000 cases globally of the 2019 novel coronavirus (COVID-19), 2000 deaths, and over 14 000 cases recovered. Outbreaks of novel agents represent opportunities for clinical research to inform real-time public health action. In 2018, we conducted a systematic review to identify priority research questions for Severe Acute Respiratory Syndrome-related coronavirus (SARS-CoV) and Middle East Respiratory Syndrome-related coronavirus (MERS-CoV). Here, we review information available on COVID-19 and provide an evidenced-based framework for priority clinical research in the current outbreak.

Methods: Three bibliographic databases were searched to identify clinical studies published on SARS-CoV and MERS-CoV in the outbreak setting. Studies were grouped thematically according to clinical research questions addressed. In February 2020, available information on COVID19 was reviewed and compared to the results of the SARS-CoV and MERS-CoV systematic review.

Results: From the research objectives for SARS-CoV and MERS-CoV, ten themes in the literature were identified: Clinical characterisation, prognosis, diagnosis, clinical management, viral pathogenesis, epidemiological characterisation, infection prevention and control/transmission, susceptibility, psychosocial, and aetiology. For COVID19, some information on clinical presentation, diagnostic testing, and aetiology is available but many clinical research gaps have yet to be filled.

Conclusions: Based on a systematic review of other severe coronaviruses, we summarise the state of clinical research for COVID-19, highlight the research gaps, and provide recommendations for the implementation of standardised protocols. Data based on internationally standardised protocols will inform clinical practice real-time.
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http://dx.doi.org/10.7189/jogh.10-011001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125419PMC
June 2020

Cost of Respiratory Syncytial Virus-Associated Acute Lower Respiratory Infection Management in Young Children at the Regional and Global Level: A Systematic Review and Meta-Analysis.

J Infect Dis 2020 10;222(Suppl 7):S680-S687

Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.

Background: Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory infection (ALRI) in young children aged <5 years.

Methods: We aimed to identify the global inpatient and outpatient cost of management of RSV-ALRI in young children to assist health policy makers in making decisions related to resource allocation for interventions to reduce severe morbidity and mortality from RSV in this age group. We searched 3 electronic databases including Global Health, Medline, and EMBASE for studies reporting cost data on RSV management in children under 60 months from 2000 to 2017. Unpublished data on the management cost of RSV episodes were collected through collaboration with an international working group (RSV GEN) and claim databases.

Results: We identified 41 studies reporting data from year 1987 to 2017, mainly from Europe, North America, and Australia, covering the management of a total of 365 828 RSV disease episodes. The average cost per episode was €3452 (95% confidence interval [CI], 3265-3639) and €299 (95% CI, 295-303) for inpatient and outpatient management without follow-up, and it increased to €8591(95% CI, 8489-8692) and €2191 (95% CI, 2190-2192), respectively, with follow-up to 2 years after the initial event.

Conclusions: Known risk factors (early and late preterm birth, congenital heart disease, chronic lung disease, intensive care unit admission, and ventilator use) were associated with €4160 (95% CI, 3237-5082) increased cost of hospitalization. The global cost of inpatient and outpatient RSV ALRI management in young children in 2017 was estimated to be approximately €4.82 billion (95% CI, 3.47-7.93), 65% of these in developing countries and 55% of global costs accounted for by hospitalization. We have demonstrated that RSV imposed a substantial economic burden on health systems, governments, and the society.
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http://dx.doi.org/10.1093/infdis/jiz683DOI Listing
October 2020

Global burden of respiratory infections associated with seasonal influenza in children under 5 years in 2018: a systematic review and modelling study.

Lancet Glob Health 2020 04 20;8(4):e497-e510. Epub 2020 Feb 20.

Centre for Global Health, Usher Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK. Electronic address:

Background: Seasonal influenza virus is a common cause of acute lower respiratory infection (ALRI) in young children. In 2008, we estimated that 20 million influenza-virus-associated ALRI and 1 million influenza-virus-associated severe ALRI occurred in children under 5 years globally. Despite this substantial burden, only a few low-income and middle-income countries have adopted routine influenza vaccination policies for children and, where present, these have achieved only low or unknown levels of vaccine uptake. Moreover, the influenza burden might have changed due to the emergence and circulation of influenza A/H1N1pdm09. We aimed to incorporate new data to update estimates of the global number of cases, hospital admissions, and mortality from influenza-virus-associated respiratory infections in children under 5 years in 2018.

Methods: We estimated the regional and global burden of influenza-associated respiratory infections in children under 5 years from a systematic review of 100 studies published between Jan 1, 1995, and Dec 31, 2018, and a further 57 high-quality unpublished studies. We adapted the Newcastle-Ottawa Scale to assess the risk of bias. We estimated incidence and hospitalisation rates of influenza-virus-associated respiratory infections by severity, case ascertainment, region, and age. We estimated in-hospital deaths from influenza virus ALRI by combining hospital admissions and in-hospital case-fatality ratios of influenza virus ALRI. We estimated the upper bound of influenza virus-associated ALRI deaths based on the number of in-hospital deaths, US paediatric influenza-associated death data, and population-based childhood all-cause pneumonia mortality data in six sites in low-income and lower-middle-income countries.

Findings: In 2018, among children under 5 years globally, there were an estimated 109·5 million influenza virus episodes (uncertainty range [UR] 63·1-190·6), 10·1 million influenza-virus-associated ALRI cases (6·8-15·1); 870 000 influenza-virus-associated ALRI hospital admissions (543 000-1 415 000), 15 300 in-hospital deaths (5800-43 800), and up to 34 800 (13 200-97 200) overall influenza-virus-associated ALRI deaths. Influenza virus accounted for 7% of ALRI cases, 5% of ALRI hospital admissions, and 4% of ALRI deaths in children under 5 years. About 23% of the hospital admissions and 36% of the in-hospital deaths were in infants under 6 months. About 82% of the in-hospital deaths occurred in low-income and lower-middle-income countries.

Interpretation: A large proportion of the influenza-associated burden occurs among young infants and in low-income and lower middle-income countries. Our findings provide new and important evidence for maternal and paediatric influenza immunisation, and should inform future immunisation policy particularly in low-income and middle-income countries.

Funding: WHO; Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S2214-109X(19)30545-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083228PMC
April 2020

Determinants and patterns of care-seeking for childhood illness in rural Pune District, India.

J Glob Health 2020 Jun;10(1):010601

Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, UK.

Background: An estimated 1.2 million children under five years of age die each year in India, with pneumonia and diarrhea among the leading causes. Increasing care-seeking is important to reduce mortality and morbidity from these causes. This paper explores the determinants and patterns of care-seeking for childhood illness in rural Pune district, India.

Methods: Mothers having at least one child <5 years from the study area of the Vadu Health and Demographic Surveillance System were enrolled in a prospective cohort study. Household sociodemographic information was collected through a baseline questionnaire administered at enrollment. Participants were visited up to six times between July 2015 and February 2016 to collect information on recent childhood acute illness and associated care-seeking behavior. Multivariate logistic regression explored the associations between care-seeking and child, participant, and household characteristics.

Results: We enrolled 743 mothers with 1066 eligible children, completing 2585 follow-up interviews (90% completion). Overall acute illness prevalence in children was 26% with care sought from a health facility during 71% of episodes. Multivariable logistic regression showed care-seeking was associated with the number of reported symptoms (Odds ratio (OR) = 2.4, 95% confidence interval (CI) = 1.5-3.9) and household insurance coverage (OR = 2.2, 95% CI = 1.1-4.3). We observed an interaction between the associations of illness severity and maternal employment on care-seeking. Somewhat-to-very severe illness was associated with increased care-seeking among both employed (OR = 5.0, 95% CI = 2.2-11.1) and currently unemployed mothers (OR = 7.0, 95% CI = 3.9-12.6). Maternal employment was associated with reduced care-seeking for non-severe illness (OR = 0.3, 95% CI = 0.1-0.7), but not associated with care-seeking for somewhat-to-very severe illness. Child sex was not associated with care-seeking.

Conclusions: This study demonstrates the importance of illness characteristics in determining facility-based care-seeking while also suggesting that maternal employment resulted in decreased care-seeking among non-severe illness episodes. The nature of the association between maternal employment and care-seeking is unclear and should be explored through additional studies. Similarly, the absence of male bias in care-seeking should be examined to assess for potential bias at other stages in the management of childhood illness.
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http://dx.doi.org/10.7189/jogh.10.010601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020658PMC
June 2020

Does respiratory syncytial virus lower respiratory illness in early life cause recurrent wheeze of early childhood and asthma? Critical review of the evidence and guidance for future studies from a World Health Organization-sponsored meeting.

Vaccine 2020 03 20;38(11):2435-2448. Epub 2020 Jan 20.

Department of Immunizations, Vaccines and Biologicals, World Health Organization, 20 Avenue Appia, Geneva, Switzerland.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI) and hospitalization in infants and children globally. Many observational studies have found an association between RSV LRTI in early life and subsequent respiratory morbidity, including recurrent wheeze of early childhood (RWEC) and asthma. Conversely, two randomized placebo-controlled trials of efficacious anti-RSV monoclonal antibodies (mAbs) in heterogenous infant populations found no difference in physician-diagnosed RWEC or asthma by treatment group. If a causal association exists and RSV vaccines and mAbs can prevent a substantial fraction of RWEC/asthma, the full public health value of these interventions would markedly increase. The primary alternative interpretation of the observational data is that RSV LRTI in early life is a marker of an underlying predisposition for the development of RWEC and asthma. If this is the case, RSV vaccines and mAbs would not necessarily be expected to impact these outcomes. To evaluate whether the available evidence supports a causal association between RSV LRTI and RWEC/asthma and to provide guidance for future studies, the World Health Organization convened a meeting of subject matter experts on February 12-13, 2019 in Geneva, Switzerland. After discussing relevant background information and reviewing the current epidemiologic evidence, the group determined that: (i) the evidence is inconclusive in establishing a causal association between RSV LRTI and RWEC/asthma, (ii) the evidence does not establish that RSV mAbs (and, by extension, future vaccines) will have a substantial effect on these outcomes and (iii) regardless of the association with long-term childhood respiratory morbidity, severe acute RSV disease in young children poses a substantial public health burden and should continue to be the primary consideration for policy-setting bodies deliberating on RSV vaccine and mAb recommendations. Nonetheless, the group recognized the public health importance of resolving this question and suggested good practice guidelines for future studies.
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http://dx.doi.org/10.1016/j.vaccine.2020.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049900PMC
March 2020

Respiratory Syncytial Virus-Associated Acute Lower Respiratory Infections in Children With Bronchopulmonary Dysplasia: Systematic Review and Meta-Analysis.

J Infect Dis 2020 10;222(Suppl 7):S620-S627

Centre for Global Health, Usher Institute, the University of Edinburgh, Medical School, Teviot Place, Edinburgh, United Kingdom.

Background: Respiratory syncytial virus (RSV) is among the most important causes of acute lower respiratory tract infection (ALRI) in young children. We assessed the severity of RSV-ALRI in children less than 5 years old with bronchopulmonary dysplasia (BPD).

Methods: We searched for studies using EMBASE, Global Health, and MEDLINE. We assessed hospitalization risk, intensive care unit (ICU) admission, need for oxygen supplementation and mechanical ventilation, and in-hospital case fatality (hCFR) among children with BPD compared with those without (non-BPD). We compared the (1) length of hospital stay (LOS) and (2) duration of oxygen supplementation and mechanical ventilation between the groups.

Results: Twenty-nine studies fulfilled our inclusion criteria. The case definition for BPD varied substantially in the included studies. Risks were higher among children with BPD compared with non-BPD: RSV hospitalization (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.7-4.2; P < .001), ICU admission (OR, 2.9; 95% CI, 2.3-3.5; P < .001), need for oxygen supplementation (OR, 4.2; 95% CI, .5-33.7; P = .175) and mechanical ventilation (OR, 8.2; 95% CI, 7.6-8.9; P < .001), and hCFR (OR, 12.8; 95% CI, 9.4-17.3; P < .001). Median LOS (range) was 7.2 days (4-23) (BPD) compared with 2.5 days (1-30) (non-BPD). Median duration of oxygen supplementation (range) was 5.5 days (0-21) (BPD) compared with 2.0 days (0-26) (non-BPD). The duration of mechanical ventilation was more often longer (>6 days) in those with BPD compared with non-BPD (OR, 11.9; 95% CI, 1.4-100; P = .02).

Conclusions: The risk of severe RSV disease is considerably higher among children with BPD. There is an urgent need to establish standardized BPD case definitions, review the RSV prophylaxis guidelines, and encourage more specific studies on RSV infection in BPD patients, including vaccine development and RSV-specific treatment.
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http://dx.doi.org/10.1093/infdis/jiz492DOI Listing
October 2020

Acute Lower Respiratory Infections Associated With Respiratory Syncytial Virus in Children With Underlying Congenital Heart Disease: Systematic Review and Meta-analysis.

J Infect Dis 2020 10;222(Suppl 7):S613-S619

Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh Medical School, Edinburgh, United Kingdom.

Background: Respiratory syncytial virus (RSV) is the most common viral pathogen associated with acute lower respiratory infections (ALRIs), with significant childhood morbidity and mortality worldwide. Estimates reporting RSV-associated ALRI (RSV-ALRI) severity in children with congenital heart disease (CHD) are lacking, thus warranting the need to summarize the available data. We identified relevant studies to summarize the findings and conducted a meta-analysis of available data on RSV-associated ALRI hospitalizations in children aged <5 years, comparing those with underlying CHD to those without CHD.

Methods: We conducted a systematic search of existing relevant literature and identified studies reporting hospitalization of children aged <5 years with RSV-ALRI with underlying or no CHD. We summarized the data and conducted (where possible) a random-effects meta-analysis to compare the 2 groups.

Results: We included 18 studies that met our strict eligibility criteria. The risk of severe RSV-ALRI (odds ratio, 2.2; 95% confidence interval [CI], 1.6-2.8), the rate of hospitalization (incidence rate ratio, 2.8; 95% CI, 1.9-4.1), and the case-fatality ratio (risk ratio [RR], 16.5; 95% CI, 13.7-19.8) associated with RSV-ALRI was higher among children with underlying CHD as compared to those without no CHD. The risk of admission to the intensive care unit (RR, 3.9; 95% CI, 3.4-4.5), need for supplemental oxygen therapy (RR, 3.4; 95% CI, .5-21.1), and need for mechanical ventilation (RR, 4.1; 95% CI, 2.1-8.0) was also higher among children with underlying CHD.

Conclusion: This is the most detailed review to show more-severe RSV-ALRI among children aged <5 years with underlying CHD, especially hemodynamically significant underlying CHD, as compared those without CHD, supporting a need for improved RSV prophylactics and treatments that also have efficacy in children older than 1 year.
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http://dx.doi.org/10.1093/infdis/jiz150DOI Listing
October 2020

Approaches to use the WHO respiratory syncytial virus surveillance platform to estimate disease burden.

Influenza Other Respir Viruses 2020 11 8;14(6):615-621. Epub 2019 Oct 8.

Global Influenza Program, World Health Organization, Geneva, Switzerland.

The World Health Organization (WHO) recently completed the first phase of a RSV surveillance pilot study in fourteen countries (two to three in each WHO region) building on the Global Influenza Surveillance and Response System (GISRS). This active surveillance strategy had several objectives including understanding RSV-related health burden in a variety of settings. A range of approaches can be used to estimate disease burden; most approaches could not be applied by participating countries in the WHO surveillance pilot. This article provides the recommendations made by WHO for strengthening and expanding the scope of the RSV surveillance in the next phase to enable burden estimation.
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http://dx.doi.org/10.1111/irv.12667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578280PMC
November 2020

A Systematic Review of Clinical Practice Guidelines for the Diagnosis and Management of Bronchiolitis.

J Infect Dis 2020 10;222(Suppl 7):S672-S679

Usher Institute of Population Health Sciences and Informatics, Edinburgh.

Background: Bronchiolitis is the leading cause of hospital admission for respiratory disease among infants aged <1 year. Clinical practice guidelines can benefit patients by reducing the performance of unnecessary tests, hospital admissions, and treatment with lack of a supportive evidence base. This review aimed to identify current clinical practice guidelines worldwide, appraise their methodological quality, and discuss variability across guidelines for the diagnosis and management of bronchiolitis.

Methods: A systematic literature review of electronic databases EMBASE, Global Health, and Medline was performed. Manual searches of the gray literature, national pediatric society websites, and guideline-focused databases were performed, and select international experts were contacted to identify additional guidelines. The Appraisal of Guidelines for Research and Evaluation assessment tool was used by 2 independent reviewers to appraise each guideline.

Results: Thirty-two clinical practice guidelines met the selection criteria. Quality assessment revealed significant shortcomings in a number of guidelines, including lack of systematic processes in formulating guidelines, failure to state conflicts of interest, and lack of consultation with families of affected children. There was widespread agreement about a number of aspects, such as avoidance of the use of unnecessary diagnostic tests, risk factors for severe disease, indicators for hospital admission, discharge criteria, and nosocomial infection control. However, there was variability, even within areas of consensus, over specific recommendations, such as variable thresholds for oxygen therapy. Guidelines showed significant variability in recommendations for the pharmacological management of bronchiolitis, with conflicting recommendations over whether use of nebulized epinephrine, hypertonic saline, or bronchodilators should be routinely trialled.

Conclusions: Future guidelines should aim to be compliant with international standards for clinical guidelines to improve their quality and clarity and to promote their adoption into practice. Variable recommendations between guidelines may reflect the evolving evidence base for bronchiolitis management, and platforms should be created to understand this variability and promote evidence-based recommendations.
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http://dx.doi.org/10.1093/infdis/jiz240DOI Listing
October 2020

Leveraging the Global Influenza Surveillance and Response System for global respiratory syncytial virus surveillance-opportunities and challenges.

Influenza Other Respir Viruses 2020 11 24;14(6):622-629. Epub 2019 Aug 24.

Global Influenza Program, Influenza Preparedness and Response, World Health Organization, Geneva, Switzerland.

Background: Respiratory syncytial virus (RSV)-associated acute lower respiratory infection is a common cause for hospitalization and hospital deaths in young children globally. There is urgent need to generate evidence to inform immunization policies when RSV vaccines become available. The WHO piloted a RSV surveillance strategy that leverages the existing capacities of the Global Influenza Surveillance and Response System (GISRS) to better understand RSV seasonality, high-risk groups, validate case definitions, and develop laboratory and surveillance standards for RSV.

Methods: The RSV sentinel surveillance strategy was piloted in 14 countries. Patients across all age groups presenting to sentinel hospitals and clinics were screened all year-round using extended severe acute respiratory infection (SARI) and acute respiratory infection (ARI) case definitions for hospital and primary care settings, respectively. Respiratory specimens were tested for RSV at the National Influenza Centre (NIC) using standardized molecular diagnostics that had been validated by an External Quality Assurance program. The WHO FluMart data platform was adapted to receive case-based RSV data and visualize interactive visualization outputs.

Results: Laboratory standards for detecting RSV by RT-PCR were developed. A review assessed the feasibility and the low incremental costs for RSV surveillance. Several challenges were addressed related to case definitions, sampling strategies, the need to focus surveillance on young children, and the data required for burden estimation.

Conclusions: There was no evidence of any significant adverse impact on the functioning of GISRS which is primarily intended for virologic and epidemiological surveillance of influenza.
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http://dx.doi.org/10.1111/irv.12672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578328PMC
November 2020

Association Between Respiratory Syncytial Virus-Associated Acute Lower Respiratory Infection in Early Life and Recurrent Wheeze and Asthma in Later Childhood.

J Infect Dis 2020 10;222(Suppl 7):S628-S633

Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics.

Background: Recurrent wheeze and asthma in childhood are commons causes of chronic respiratory morbidity globally. We aimed to explore the association between respiratory syncytial virus (RSV) infection in early life and subsequent respiratory sequelae up to age 12 years.

Methods: We estimated the strength of association by 3 control groups and 3 follow-up age groups, with data from studies published between January 1995 and May 2018. We also estimated associations by diagnostic criteria, age at infection, and high-risk population.

Results: Overall, we included 41 studies. A statistically significant association was observed between early life RSV infection and subsequent childhood recurrent wheeze, in comparison to those who were healthy or those without respiratory symptoms: OR 3.05 (95% confidence interval [CI], 2.50-3.71) for 0 to <36 months follow-up age; OR 2.60 (95% CI, 1.67-4.04) for 36-72 months; and OR 2.14 (95% CI, 1.33-3.45) for 73-144 months. For the subsequent development of asthma, a statistically significant association was observed only in relation to those aged 73-144 months at follow-up: OR 2.95 (95% CI, 1.96-4.46).

Conclusions: Further studies using standardized definitions and from diverse settings are needed to elucidate the role of confounders and provide more robust estimates.
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http://dx.doi.org/10.1093/infdis/jiz311DOI Listing
October 2020

Global patterns in monthly activity of influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus: a systematic analysis.

Lancet Glob Health 2019 08;7(8):e1031-e1045

Centre for Global Health Research, University of Edinburgh, Edinburgh, UK. Electronic address:

Background: Influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus are the most common viruses associated with acute lower respiratory infections in young children (<5 years) and older people (≥65 years). A global report of the monthly activity of these viruses is needed to inform public health strategies and programmes for their control.

Methods: In this systematic analysis, we compiled data from a systematic literature review of studies published between Jan 1, 2000, and Dec 31, 2017; online datasets; and unpublished research data. Studies were eligible for inclusion if they reported laboratory-confirmed incidence data of human infection of influenza virus, respiratory syncytial virus, parainfluenza virus, or metapneumovirus, or a combination of these, for at least 12 consecutive months (or 52 weeks equivalent); stable testing practice throughout all years reported; virus results among residents in well-defined geographical locations; and aggregated virus results at least on a monthly basis. Data were extracted through a three-stage process, from which we calculated monthly annual average percentage (AAP) as the relative strength of virus activity. We defined duration of epidemics as the minimum number of months to account for 75% of annual positive samples, with each component month defined as an epidemic month. Furthermore, we modelled monthly AAP of influenza virus and respiratory syncytial virus using site-specific temperature and relative humidity for the prediction of local average epidemic months. We also predicted global epidemic months of influenza virus and respiratory syncytial virus on a 5° by 5° grid. The systematic review in this study is registered with PROSPERO, number CRD42018091628.

Findings: We initally identified 37 335 eligible studies. Of 21 065 studies remaining after exclusion of duplicates, 1081 full-text articles were assessed for eligibility, of which 185 were identified as eligible. We included 246 sites for influenza virus, 183 sites for respiratory syncytial virus, 83 sites for parainfluenza virus, and 65 sites for metapneumovirus. Influenza virus had clear seasonal epidemics in winter months in most temperate sites but timing of epidemics was more variable and less seasonal with decreasing distance from the equator. Unlike influenza virus, respiratory syncytial virus had clear seasonal epidemics in both temperate and tropical regions, starting in late summer months in the tropics of each hemisphere, reaching most temperate sites in winter months. In most temperate sites, influenza virus epidemics occurred later than respiratory syncytial virus (by 0·3 months [95% CI -0·3 to 0·9]) while no clear temporal order was observed in the tropics. Parainfluenza virus epidemics were found mostly in spring and early summer months in each hemisphere. Metapneumovirus epidemics occurred in late winter and spring in most temperate sites but the timing of epidemics was more diverse in the tropics. Influenza virus epidemics had shorter duration (3·8 months [3·6 to 4·0]) in temperate sites and longer duration (5·2 months [4·9 to 5·5]) in the tropics. Duration of epidemics was similar across all sites for respiratory syncytial virus (4·6 months [4·3 to 4·8]), as it was for metapneumovirus (4·8 months [4·4 to 5·1]). By comparison, parainfluenza virus had longer duration of epidemics (6·3 months [6·0 to 6·7]). Our model had good predictability in the average epidemic months of influenza virus in temperate regions and respiratory syncytial virus in both temperate and tropical regions. Through leave-one-out cross validation, the overall prediction error in the onset of epidemics was within 1 month (influenza virus -0·2 months [-0·6 to 0·1]; respiratory syncytial virus 0·1 months [-0·2 to 0·4]).

Interpretation: This study is the first to provide global representations of month-by-month activity of influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus. Our model is helpful in predicting the local onset month of influenza virus and respiratory syncytial virus epidemics. The seasonality information has important implications for health services planning, the timing of respiratory syncytial virus passive prophylaxis, and the strategy of influenza virus and future respiratory syncytial virus vaccination.

Funding: European Union Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).
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http://dx.doi.org/10.1016/S2214-109X(19)30264-5DOI Listing
August 2019

A landscape review of the published research output relating to respiratory syncytial virus (RSV) in North & Central America and Europe between 2011-2015.

J Glob Health 2019 Jun;9(1):010425

Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland, UK.

Background: The high disease burden of respiratory syncytial virus (RSV) infection and renewed focus on developing a vaccine has led to sustained interest in published RSV-related research. The majority of this research comes from Europe and North/Central America and this landscape review aimed to identify and characterize RSV-related research published during 2011-2015 in these geographical areas.

Methods: We conducted a literature review on electronic databases Scopus and Web of Science to identify published studies investigating RSV throughout Europe and North/Central America. We stratified RSV-related publications between 2011-2015 by study type, country, research institution and funding body.

Results: The annual published output of RSV-related research has increased by 29% over the period 2011-2015. Eighty seven percent (13/15) of the most highly cited papers on RSV during this period were from North America. US universities with the highest number of RSV-related publications included Emory (n = 23), Vanderbilt (n = 23), University of Michigan (n = 21) and Ohio State (n = 20). The UK (n = 125), Netherlands (n = 97) and Spain (n = 76) were major European contributors to RSV-related publications. University Medical Centre Utrecht (n = 40) and Imperial College London (n = 28) were the European universities with the largest number of RSV-related publications. The National Institutes of Health provided funding for one quarter of all RSV-related publications. However, few countries in Eastern Europe, Central America and the Caribbean published RSV-related research. Few epidemiological studies focused on adult populations over 18 years old (n = 28, 7%) with only five publications specifically investigating elderly populations over 65.

Conclusions: This review identifies key regions and research institutions which contributed to RSV-related research during 2011-2015 as well as the donor agencies which supported this research. Further research investment is required in a number of countries. More research in the elderly and in high-risk adults is required given the lack of studies pertaining to these populations. Researchers and those commissioning research can use the data from this review to identify productive research institutions and geographical gaps in RSV research.
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http://dx.doi.org/10.7189/jogh.09.010425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513410PMC
June 2019