Global disease burden of and risk factors for acute lower respiratory infections caused by respiratory syncytial virus in preterm infants and young children in 2019: a systematic review and meta-analysis of aggregated and individual participant data.

BACKGROUND: Infants and young children born prematurely are at high risk of severe acute lower respiratory infection (ALRI) caused by respiratory syncytial virus (RSV). In this study, we aimed to assess the global disease burden of and risk factors for RSV-associated ALRI in infants and young children born before 37 weeks of gestation. METHODS: We conducted a systematic review and meta-analysis of aggregated data from studies published between Jan 1, 1995, and Dec 31, 2021, identified from MEDLINE, Embase, and Global Health, and individual participant data shared by the Respiratory Virus Global Epidemiology Network on respiratory infectious diseases. We estimated RSV-associated ALRI incidence in community, hospital admission, in-hospital mortality, and overall mortality among children younger than 2 years born prematurely. We conducted two-stage random-effects meta-regression analyses accounting for chronological age groups, gestational age bands (early preterm, <32 weeks gestational age [wGA], and late preterm, 32 to <37 wGA), and changes over 5-year intervals from 2000 to 2019. Using individual participant data, we assessed perinatal, sociodemographic, and household factors, and underlying medical conditions for RSV-associated ALRI incidence, hospital admission, and three severity outcome groups (longer hospital stay [>4 days], use of supplemental oxygen and mechanical ventilation, or intensive care unit admission) by estimating pooled odds ratios (ORs) through a two-stage meta-analysis (multivariate logistic regression and random-effects meta-analysis). This study is registered with PROSPERO, CRD42021269742. FINDINGS: We included 47 studies from the literature and 17 studies with individual participant-level data contributed by the participating investigators. We estimated that, in 2019, 1 650 000 (95% uncertainty range [UR] 1 350 000-1 990 000) RSV-associated ALRI episodes, 533 000 (385 000-730 000) RSV-associated hospital admissions, 3050 (1080-8620) RSV-associated in-hospital deaths, and 26 760 (11 190-46 240) RSV-attributable deaths occurred in preterm infants worldwide. Among early preterm infants, the RSV-associated ALRI incidence rate and hospitalisation rate were significantly higher (rate ratio [RR] ranging from 1·69 to 3·87 across different age groups and outcomes) than for all infants born at any gestational age. In the second year of life, early preterm infants and young children had a similar incidence rate but still a significantly higher hospitalisation rate (RR 2·26 [95% UR 1·27-3·98]) compared with all infants and young children. Although late preterm infants had RSV-associated ALRI incidence rates similar to that of all infants younger than 1 year, they had higher RSV-associated ALRI hospitalisation rate in the first 6 months (RR 1·93 [1·11-3·26]). Overall, preterm infants accounted for 25% (95% UR 16-37) of RSV-associated ALRI hospitalisations in all infants of any gestational age. RSV-associated ALRI in-hospital case fatality ratio in preterm infants was similar to all infants. The factors identified to be associated with RSV-associated ALRI incidence were mainly perinatal and sociodemographic characteristics, and factors associated with severe outcomes from infection were mainly underlying medical conditions including congenital heart disease, tracheostomy, bronchopulmonary dysplasia, chronic lung disease, or Down syndrome (with ORs ranging from 1·40 to 4·23). INTERPRETATION: Preterm infants face a disproportionately high burden of RSV-associated disease, accounting for 25% of RSV hospitalisation burden. Early preterm infants have a substantial RSV hospitalisation burden persisting into the second year of life. Preventive products for RSV can have a substantial public health impact by preventing RSV-associated ALRI and severe outcomes from infection in preterm infants. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe.

Respiratory Syncytial Virus-Associated Hospital Admissions by Deprivation Levels Among Children and Adults in Scotland.

BACKGROUND: Socioeconomic deprivation may predispose individuals to respiratory tract infections. We estimated RSV-associated hospitalizations by socioeconomic deprivation in Scotland. METHODS: Using national routine health care records and virological surveillance from 2010 to 2016, we used a time-series linear regression model and a direct measurement based on ICD-10 coded diagnoses to estimate RSV-associated hospitalizations by Scottish Index of Multiple Deprivation (SIMD) quintile and age in comparison to influenza-associated hospitalizations. RESULTS: We estimated an annual average rate per 1000 people of 0.76 (95% CI: 0.43-0.90) in the least deprived group to 1.51 (1.03-1.79) for the most deprived group using model-based approach. The rate ratio (RR) was 1.96 (1.23-3.25), 1.60 (1.0-2.66), 1.35 (0.85-2.25), and 1.12 (0.7-1.85) in the 1st to 4th quintile versus the least deprived group. The pattern of RSV-associated hospitalization rates variation with SIMD was most pronounced in children 0-2y. The ICD-10 approach provided much lower rates than the model-based approach but yielded similar RR estimates between SIMD. Influenza-associated hospitalization rate generally increased with higher deprivation levels among individuals 1y+. CONCLUSIONS: Higher RSV and influenza hospitalization rates are related to higher deprivation levels. Differences between deprivation levels are most pronounced in infants and young children for RSV, and are more apparent among individuals 1y+ for influenza.

Validity of Clinical Severity Scores for Respiratory Syncytial Virus: A Systematic Review.

BACKGROUND: Respiratory syncytial virus (RSV) is a widespread respiratory pathogen, and RSV-related acute lower respiratory tract infections are the most common cause of respiratory hospitalization in children <2 years of age. Over the last 2 decades, a number of severity scores have been proposed to quantify disease severity for RSV in children, yet there remains no overall consensus on the most clinically useful score. METHODS: We conducted a systematic review of English-language publications in peer-reviewed journals published since January 2000 assessing the validity of severity scores for children (≤24 months of age) with RSV and/or bronchiolitis, and identified the most promising scores. For included articles, (1) validity data were extracted, (2) quality of reporting was assessed using the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis checklist (TRIPOD), and (3) quality was assessed using the Prediction Model Risk Of Bias Assessment Tool (PROBAST). To guide the assessment of the validity data, standardized cutoffs were employed, and an explicit definition of what we required to determine a score was sufficiently validated. RESULTS: Our searches identified 8541 results, of which 1779 were excluded as duplicates. After title and abstract screening, 6670 references were excluded. Following full-text screening and snowballing, 32 articles, including 31 scores, were included. The most frequently assessed scores were the modified Tal score and the Wang Bronchiolitis Severity Score; none of the scores were found to be sufficiently validated according to our definition. The reporting and/or design of all the included studies was poor. The best validated score was the Bronchiolitis Score of Sant Joan de Déu, and a number of other promising scores were identified. CONCLUSIONS: No scores were found to be sufficiently validated. Further work is warranted to validate the existing scores, ideally in much larger datasets.

Impact of Subgroup Distribution on Seasonality of Human Respiratory Syncytial Virus: A Global Systematic Analysis.

BACKGROUND: Previous studies reported inconsistent findings regarding the association between respiratory syncytial virus (RSV) subgroup distribution and timing of RSV season. We aimed to further understand the association by conducting a global-level systematic analysis. METHODS: We compiled published data on RSV seasonality through a systematic literature review, and unpublished data shared by international collaborators. Using annual cumulative proportion (ACP) of RSV-positive cases, we defined RSV season onset and offset as ACP reaching 10% and 90%, respectively. Linear regression models accounting for meteorological factors were constructed to analyze the association of proportion of RSV-A with the corresponding RSV season onset and offset. RESULTS: We included 36 study sites from 20 countries, providing data for 179 study-years in 1995-2019. Globally, RSV subgroup distribution was not significantly associated with RSV season onset or offset globally, except for RSV season offset in the tropics in 1 model, possibly by chance. Models that included RSV subgroup distribution and meteorological factors explained only 2%-4% of the variations in timing of RSV season. CONCLUSIONS: Year-on-year variations in RSV season onset and offset are not well explained by RSV subgroup distribution or meteorological factors. Factors including population susceptibility, mobility, and viral interference should be examined in future studies.

Respiratory Syncytial Virus-Associated Hospitalization in Adults With Comorbidities in 2 European Countries: A Modeling Study.

BACKGROUND: Individuals with comorbidities are at increased risk of severe respiratory syncytial virus (RSV) infection. We estimated RSV-associated respiratory hospitalization among adults aged ≥45 years with comorbidities in Denmark and Scotland. METHODS: By analyzing national hospital and virologic data, we estimated annual RSV-associated hospitalizations by 7 selected comorbidities and ages between 2010 and 2018. We estimated rate ratios of RSV-associated hospitalization for adults with comorbidity than the overall population. RESULTS: In Denmark, annual RSV-associated hospitalization rates per 1000 adults ranged from 3.1 for asthma to 19.4 for chronic kidney disease (CKD). In Scotland, rates ranged from 2.4 for chronic liver disease to 9.0 for chronic obstructive pulmonary disease (COPD). In both countries, we found a 2- to 4-fold increased risk of RSV hospitalization for adults with COPD, ischemic heart disease, stroke, and diabetes; a 1.5- to 3-fold increased risk for asthma; and a 3- to 7-fold increased risk for CKD. RSV hospitalization rates among adults aged 45 to 64 years with COPD, asthma, ischemic heart disease, or CKD were higher than the overall population. CONCLUSIONS: This study provides important evidence for identifying risk groups and assisting health authorities in RSV vaccination policy making.

External Validation of the Discriminative Validity of the ReSVinet Score and Development of Simplified ReSVinet Scores in Secondary Care.

BACKGROUND: There is no consensus on how to best quantify disease severity in infants with respiratory syncytial virus (RSV) and/or bronchiolitis; this lack of a sufficiently validated score complicates the provision of clinical care and, the evaluation of trials of therapeutics and vaccines. The ReSVinet score appears to be one of the most promising; however, it is too time consuming to be incorporated into routine clinical care. We aimed to develop and externally validate simplified versions of this score. METHODS: Data from a multinational (the Netherlands, Spain, and United Kingdom) multicenter case-control study of infants with RSV were used to develop simplified versions of the ReSVinet score by conducting a grid search to determine the best combination of equally weighted parameters to maximize for the discriminative ability (measured by area under the receiver operating characteristic curve [AUROC]) across a range of outcomes (hospitalization, intensive care unit admission, ventilation requirement). Subsequently discriminative validity of the score for a range of secondary care outcomes was externally validated by secondary analysis of datasets from Rwanda and Colombia. RESULTS: Three candidate simplified scores were identified using the development dataset; they were excellent (AUROC >0.9) at discriminating for a range of outcomes, and their performance was not significantly different from the original ReSVinet score despite having fewer parameters. In the external validation datasets, the simplified scores were moderate to excellent (AUROC, 0.7-1) across a range of outcomes. In all outcomes, except in a single dataset for predicting admission to the high-dependency unit, they performed at least as well as the original ReSVinet score. CONCLUSIONS: The candidate simplified scores developed require further external validation in larger datasets, ideally from resource-limited settings before any recommendation regarding their use.

Burden of Respiratory Syncytial Virus-Associated Acute Respiratory Infections During Pregnancy.

BACKGROUND: With the licensure of maternal respiratory syncytial virus (RSV) vaccines in Europe and the United States, data are needed to better characterize the burden of RSV-associated acute respiratory infections (ARI) in pregnancy. The current study aimed to determine among pregnant individuals the proportion of ARI testing positive for RSV and the RSV incidence rate, RSV-associated hospitalizations, deaths, and perinatal outcomes. METHODS: We conducted a systematic review, following PRISMA 2020 guidelines, using 5 databases (Medline, Embase, Global Health, Web of Science, and Global Index Medicus), and including additional unpublished data. Pregnant individuals with ARI who had respiratory samples tested for RSV were included. We used a random-effects meta-analysis to generate overall proportions and rate estimates across studies. RESULTS: Eleven studies with pregnant individuals recruited between 2010 and 2022 were identified, most of which recruited pregnant individuals in community, inpatient and outpatient settings. Among 8126 pregnant individuals, the proportion with ARI that tested positive for RSV ranged from 0.9% to 10.7%, with a meta-estimate of 3.4% (95% confidence interval [CI], 1.9%-54%). The pooled incidence rate of RSV among pregnant individuals was 26.0 (95% CI, 15.8-36.2) per 1000 person-years. RSV hospitalization rates reported in 2 studies were 2.4 and 3.0 per 1000 person-years. In 5 studies that ascertained RSV-associated deaths among 4708 pregnant individuals, no deaths were reported. Three studies comparing RSV-positive and RSV-negative pregnant individuals found no difference in the odds of miscarriage, stillbirth, low birth weight, and small size for gestational age. RSV-positive pregnant individuals had higher odds of preterm delivery (odds ratio, 3.6 [95% CI, 1.3-10.3]). CONCLUSIONS: Data on RSV-associated hospitalization rates are limited, but available estimates are lower than those reported in older adults and young children. As countries debate whether to include RSV vaccines in maternal vaccination programs, which are primarily intended to protect infants, this information could be useful in shaping vaccine policy decisions.

The disease burden of respiratory syncytial virus in older adults.

PURPOSE OF REVIEW: To highlight the respiratory syncytial virus (RSV) disease burden and the current developments and challenges in RSV prevention for older adults ≥60 years through analysis of RSV epidemiology and the effectiveness of emerging vaccines. RECENT FINDINGS: In industrialized countries, RSV incidence rates and hospitalization rates among older adults are estimated to be 600.7 cases per 100 000 person-years and 157 hospitalizations per 100 000 person-years, respectively. Yet, accurately determining RSV morbidity and mortality in older adults is challenging, thus resulting in substantially under-estimating the disease burden. The in-hospital fatality rates vary substantially with age and geographies, and can be as high as 9.1% in developing countries. Two promising RSV vaccines for the elderly have been approved, demonstrating efficacies of up to 94.1%, signifying considerable advancement in RSV prevention. However, concerns over potential side effects remain. SUMMARY: RSV is associated with a significant burden in older adults. While the landscape of RSV prevention in older adults is promising with the licensure of vaccines from two companies, current trial data underscore the need for additional studies. Addressing the real-world effectiveness of these vaccines, understanding potential rare side effects, and ensuring broad inclusivity in future trials are crucial steps to maximize their potential benefits.

Pediatric Respiratory Syncytial Virus Diagnostic Testing Performance: A Systematic Review and Meta-analysis.

BACKGROUND: Adding additional specimen types (eg, serology or sputum) to nasopharyngeal swab (NPS) reverse transcription polymerase chain reaction (RT-PCR) increases respiratory syncytial virus (RSV) detection among adults. We assessed if a similar increase occurs in children and quantified underascertainment associated with diagnostic testing. METHODS: We searched databases for studies involving RSV detection in persons <18 years using ≥2 specimen types or tests. We assessed study quality using a validated checklist. We pooled detection rates by specimen and diagnostic tests and quantified performance. RESULTS: We included 157 studies. Added testing of additional specimens to NP aspirate (NPA), NPS, and/or nasal swab (NS) RT-PCR resulted in statistically nonsignificant increases in RSV detection. Adding paired serology testing increased RSV detection by 10%, NS by 8%, oropharyngeal swabs by 5%, and NPS by 1%. Compared to RT-PCR, direct fluorescence antibody tests, viral culture, and rapid antigen tests were 87%, 76%, and 74% sensitive, respectively (pooled specificities all ≥98%). Pooled sensitivity of multiplex versus singleplex RT-PCR was 96%. CONCLUSIONS: RT-PCR was the most sensitive pediatric RSV diagnostic test. Adding multiple specimens did not substantially increase RSV detection, but even small proportional increases could result in meaningful changes in burden estimates. The synergistic effect of adding multiple specimens should be evaluated.

Underascertainment of Respiratory Syncytial Virus Infection in Adults Due to Diagnostic Testing Limitations: A Systematic Literature Review and Meta-analysis.

BACKGROUND: Most observational population-based studies identify respiratory syncytial virus (RSV) by nasal/nasopharyngeal swab reverse transcriptase real-time PCR (RT-PCR) only. We conducted a systematic review and meta-analyses to quantify specimen and diagnostic testing-based underascertainment of adult RSV infection. METHODS: EMBASE, PubMed, and Web of Science were searched (January 2000-December 2021) for studies including adults using/comparing >1 RSV testing approach. We quantified test performance and RSV detection increase associated with using multiple specimen types. RESULTS: Among 8066 references identified, 154 met inclusion. Compared to RT-PCR, other methods were less sensitive: rapid antigen detection test (RADT; pooled sensitivity, 64%), direct fluorescent antibody (DFA; 83%), and viral culture (86%). Compared to singleplex PCR, multiplex PCR's sensitivity was lower (93%). Compared to nasal/nasopharyngeal swab RT-PCR alone, adding another specimen type increased detection: sputum RT-PCR, 52%; 4-fold rise in paired serology, 44%; and oropharyngeal swab RT-PCR, 28%. Sensitivity was lower in estimates limited to only adults (for RADT, DFA, and viral culture), and detection rate increases were largely comparable. CONCLUSIONS: RT-PCR, particularly singleplex testing, is the most sensitive RSV diagnostic test in adults. Adding additional specimen types to nasopharyngeal swab RT-PCR testing increased RSV detection. Synergistic effects of using ≥3 specimen types should be assessed, as this approach may improve the accuracy of adult RSV burden estimates.

Respiratory syncytial virus (RSV) is an important cause of illness and death among older adults. Most studies of how frequent RSV infection is among older adults use only nasal swab testing to identify RSV infection. These nasal swabs are checked for genetic material from the virus, known as polymerase chain reaction (PCR) testing. We examined published studies from January 2000 to December 2021 to estimate how many RSV infections would be missed by using only this approach to RSV testing. We found 154 studies had information to answer our question. Compared to PCR testing of nasal swab alone, adding sputum specimen PCR testing (ie, testing cough mucus or phlegm for RSV genetic material) increased RSV infections found by 52%. Adding blood testing increased RSV infections found by 44%. Adding mouth/throat swab PCR testing, increased RSV infections by 28%. In summary, adding additional specimen types to nasal swab PCR testing increased RSV detection. Impact of using 3 or more specimen types at the same time should be assessed, as this approach may further improve accuracy.

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).

Understanding the age spectrum of respiratory syncytial virus associated hospitalisation and mortality burden based on statistical modelling methods: a systematic analysis.

BACKGROUND: Statistical modelling studies based on excess morbidity and mortality are important for understanding RSV disease burden for age groups that are less frequently tested for RSV. We aimed to understand the full age spectrum of RSV morbidity and mortality burden based on statistical modelling studies, as well as the value of modelling studies in RSV disease burden estimation. METHODS: The databases Medline, Embase and Global Health were searched to identify studies published between January 1, 1995, and December 31, 2021, reporting RSV-associated excess hospitalisation or mortality rates of any case definitions using a modelling approach. All reported rates were summarised using median, IQR (Interquartile range) and range by age group, outcome and country income group; where applicable, a random-effects meta-analysis was conducted to combine the reported rates. We further estimated the proportion of RSV hospitalisations that could be captured in clinical databases. RESULTS: A total of 32 studies were included, with 26 studies from high-income countries. RSV-associated hospitalisation and mortality rates both showed a U-shape age pattern. Lowest and highest RSV acute respiratory infection (ARI) hospitalisation rates were found in 5-17 years (median: 1.6/100,000 population, IQR: 1.3-18.5) and < 1 year (2235.7/100,000 population, 1779.1-3552.5), respectively. Lowest and highest RSV mortality rates were found in 18-49 years (0.1/100,000 population, 0.06-0.2) and ≥ 75 years (80.0/100,000 population, 70.0-90.0) for high-income countries, respectively, and in 18-49 years (0.3/100,000 population, 0.1-2.4) and < 1 year (143.4/100,000 population, 143.4-143.4) for upper-middle income countries. More than 70% of RSV hospitalisations in children < 5 years could be captured in clinical databases whereas less than 10% of RSV hospitalisations could be captured in adults, especially for adults ≥ 50 years. Using pneumonia and influenza (P&I) mortality could potentially capture half of all RSV mortality in older adults but only 10-30% of RSV mortality in children. CONCLUSIONS: Our study provides insights into the age spectrum of RSV hospitalisation and mortality. RSV disease burden using laboratory records alone could be substantially severely underreported for age groups ≥ 5 years. Our findings confirm infants and older adults should be prioritised for RSV immunisation programmes. TRIAL REGISTRATION: PROSPERO CRD42020173430.

Risk Factors for Poor Outcome or Death in Young Children With Respiratory Syncytial Virus-Associated Acute Lower Respiratory Tract Infection: A Systematic Review and Meta-Analysis.

BACKGROUND: Respiratory syncytial virus (RSV)-associated acute lower respiratory tract infection (RSV-ALRTI) constitutes a substantial disease burden in young children. We aimed to identify all studies investigating the risk factors for RSV-ALRTI poor outcome or death in young children. METHODS: 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 admission. The quality of all eligible studies was assessed according to modified Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria. We conducted meta-analyses to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for individual risk factors. RESULTS: We identified 27 eligible studies, which investigated 20 risk factors for RSV-ALRTI poor outcome and/or death in children <5 years old, compared with children with RSV-ALRTI who did not have poor outcome or who did not die. Among the risk factors, 6 were significantly associated with RSV-ALRTI poor outcome: any comorbid condition (OR, 2.69; 95% CI, 1.89-3.83), congenital heart disease (3.40; 2.14-5.40), prematurity with gestational age (GA) <37 weeks (1.75 (1.31-2.36), prematurity with GA ≤32 weeks (2.68; 1.43-5.04), age <3 months (4.91; 1.64-14.71), and age <6 months (2.02; 1.73-2.35). The meta-estimate ORs for all risk factors other than age <3 months were based on studies using multivariable analysis. For death, only prematurity with GA <37 weeks had a significant meta-estimated OR-3.81 (95% CI, 1.68-8.63)-based on univariable analysis. CONCLUSIONS: This study represents a comprehensive report of the association between various risk factors and RSV-ALRTI poor outcome or death in young children. More research should be carried out to elucidate risk factors associated with poor outcome or death using multivariable analysis.

Time-Varying Association Between Severe Respiratory Syncytial Virus Infections and Subsequent Severe Asthma and Wheeze and Influences of Age at the Infection.

BACKGROUND: Early-life severe respiratory syncytial virus (RSV) infection has been associated with subsequent risk of asthma and recurrent wheeze. However, changes in the association over time and the interaction effect of the age at first RSV infection are less well understood. We aimed to assess the time-varying association between RSV and subsequent asthma and wheeze admission and explore how the association was affected by the age at RSV infection. METHODS: We retrospectively followed up a cohort of 23 365 children for a median of 6.9 years using Scottish health databases. Children who were born between 2001 and 2013 and had RSV-associated respiratory tract infection (RTI) admissions under 2 years were in the exposed group; those with unintentional accident admissions under 2 years comprised the control group. The Cox proportional-hazards model was used to report adjusted hazard ratios (HRs) of RSV admissions on subsequent asthma and wheeze admissions. We did subgroup analyses by follow-up years. We also explored how this association was affected by the age at first RSV admission. RESULTS: The association was strongest in the first 2 years of follow-up and decreased over time. The association persisted for 6 years in children whose first RSV-RTI admission occurred at 6-23 months of age, with an adjusted HR of 3.9 (95% confidence interval [CI], 3.1-4.9) for the first 2 years, 2.3 (95% CI, 1.6-3.2) for 2 to <4 years, and 1.9 (95% CI, 1.2-2.9) for 4 to <6 years of follow-up. In contrast, the association was only significant for the first 2 years after first RSV-RTI admissions occurring at 0-5 months. CONCLUSIONS: We found a more persistent association for subsequent asthma and wheeze in children whose first severe RSV infection occurred at 6-23 months compared to those whose first severe RSV infection occurred at 0-6 months. This provides new evidence for further assessment of the association and RSV intervention programs.

Understanding the Potential Drivers for Respiratory Syncytial Virus Rebound During the Coronavirus Disease 2019 Pandemic.

Nonpharmaceutical interventions (NPIs) were widely introduced to combat the coronavirus disease 2019 (COVID-19) pandemic. These interventions also likely led to substantially reduced activity of respiratory syncytial virus (RSV). From late 2020, some countries observed out-of-season RSV epidemics. Here, we analyzed the role of NPIs, population mobility, climate, and severe acute respiratory syndrome coronavirus 2 circulation in RSV rebound through a time-to-event analysis across 18 countries. Full (re)opening of schools was associated with an increased risk for RSV rebound (hazard ratio [HR], 23.29 [95% confidence interval {CI}, 1.09-495.84]); every 5°C increase in temperature was associated with a decreased risk (HR, 0.63 [95% CI, .40-.99]). There was an increasing trend in the risk for RSV rebound over time, highlighting the role of increased population susceptibility. No other factors were found to be statistically significant. Further analysis suggests that increasing population susceptibility and full (re)opening of schools could both override the countereffect of high temperatures, which explains the out-of-season RSV epidemics during the COVID-19 pandemic.

Disease Burden Estimates of Respiratory Syncytial Virus related Acute Respiratory Infections in Adults With Comorbidity: A Systematic Review and Meta-Analysis.

BACKGROUND: Respiratory syncytial virus related acute respiratory infection (RSV-ARI) constitutes a substantial disease burden in adults with comorbidities. We aimed to identify all studies investigating the disease burden of RSV-ARI in this group. METHODS: We estimated the incidence, hospitalization rate, and in-hospital case fatality ratio (hCFR) of RSV-ARI in adults with comorbidities based on a systematic review of studies published between January 1996 and March 2020. We also investigated the association between RSV-ARI and any comorbidity in adults. Meta-analyses based on random effects model were carried out. RESULTS: Overall, 20 studies were included. The annual incidence rate of RSV-ARI in adults with any comorbidity was 37.6 (95% confidence interval [CI], 20.1-70.3) per 1000 persons per year in industrialized countries and the seasonal incidence rate was 28.4 (11.4-70.9) per 1000 persons per season. The hCFR in industrialized countries was 11.7% (5.8%-23.4%). There were no studies in developing countries. There were insufficient data to generate the meta-estimate of hospitalization rate. The likelihood of experiencing RSV-ARI for those with any comorbidity compared to those without was estimated to be 4.1 (odds ratio [OR], 1.6-10.4) and 1.1 (OR, 0.6-1.8) from studies using univariable and multivariable analysis respectively. CONCLUSION: The disease burden of RSV-ARI among adults with comorbidity is substantial with limited data available.

Global Disease Burden of Respiratory Syncytial Virus in Preterm Children in 2019: A Systematic Review and Individual Participant Data Meta-Analysis Protocol.

Existing guidelines on respiratory syncytial virus (RSV) prophylaxis differ greatly by gestational age (GA) and other underlying risk factors, highlighting the data gaps in RSV disease burden among preterm infants. We will conduct a systematic review and individual participant data (IPD) meta-analysis of RSV global disease burden among preterm-born children. Three databases, Medline, Embase, and Global Health, will be searched for relevant studies on RSV disease burden for 2019 or before in preterm-born children published between 1 January 1995 and 31 December 2021. IPD will be sought by contacting the investigators identified from published literature and from existing collaboration networks. One-stage and 2-stage random-effects meta-analyses will be used to combine information from IPD and non-IPD studies to produce summary RSV burden estimates of incidence rate, hospital admission rate, and in-hospital case fatality ratio. The framework will be extended to examine subgroup(s) with the most substantial RSV disease burden.

A Systematic Review and Meta-analysis of Animal Studies Investigating the Relationship Between Serum Antibody, T Lymphocytes, and Respiratory Syncytial Virus Disease.

BACKGROUND: Respiratory syncytial virus (RSV) infections occur in human populations around the globe, causing disease of variable severity, disproportionately affecting infants and older adults (>65 years of age). Immune responses can be protective but also contribute to disease. Experimental studies in animals enable detailed investigation of immune responses, provide insights into clinical questions, and accelerate the development of passive and active vaccination. We aimed to review the role of antibody and T-cell responses in relation to RSV disease severity in animals. METHODS: Systematic review and meta-analysis of animal studies examining the association between T-cell responses/phenotype or antibody titers and severity of RSV disease. The PubMed, Zoological Record, and Embase databases were screened from January 1980 to May 2018 to identify animal studies of RSV infection that assessed serum antibody titer or T lymphocytes with disease severity as an outcome. Sixty-three studies were included in the final review. RESULTS: RSV-specific antibody appears to protect from disease in mice, but such an effect was less evident in bovine RSV. Strong T-cell, Th1, Th2, Th17, CD4/CD8 responses, and weak Treg responses accompany severe disease in mice. CONCLUSIONS: Murine studies suggest that measures of T-lymphocyte activity (particularly CD4 and CD8 T cells) may be predictive biomarkers of severity. Further inquiry is merited to validate these results and assess relevance as biomarkers for human disease.

Clinical and Viral Factors Associated With Disease Severity and Subsequent Wheezing in Infants With Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in infants and young children worldwide. Here we evaluated host demographic and viral factors associated with RSV disease severity in 325 RSV-infected infants under 1 year of age from 3 European countries during 2017-2020. Younger infants had a higher clinical severity (ReSViNET) score and were more likely to require hospitalization, intensive care, respiratory support, and/or mechanical ventilation than older infants (<3 months vs 3 to <6 months and 3 to <6 months vs ≥6 months). Older age (≥6 months vs <3 months), higher viral load, and RSV-A were associated with a greater probability of fever. RSV-A and RSV-B caused similar disease severity and had similar viral dynamics. Infants with a more severe RSV infection, demonstrated by having a higher ReSViNET score, fever, and requiring hospitalization and intensive care, were more likely to have developed subsequent wheezing at 1 year of age. CLINICAL TRIALS REGISTRATION: NCT03756766.

Seasonality of respiratory syncytial virus and its association with meteorological factors in 13 European countries, week 40 2010 to week 39 2019.

BackgroundRespiratory syncytial virus (RSV) is the predominant cause of clinical pneumonia among infants and young children, often peaking during the winter months in temperate regions.AimTo describe RSV seasonality in 13 European countries and examine its association with meteorological factors.MethodsWe included weekly RSV seasonality data from 13 European countries between week 40 2010 and week 39 2019. Using local weighted regression method, we modelled weekly RSV activity with meteorological factors using data from the 2010/11 to the 2017/18 season. We predicted the weekly RSV activity of the 2018/19 season across 41 European countries and validated our prediction using empirical data.ResultsAll countries had annual wintertime RSV seasons with a longitudinal gradient in RSV onset (Pearson's correlation coefficient, r = 0.71, 95% CI: 0.60 to 0.80). The RSV season started 3.8 weeks later (95% CI: -0.5 to 8.0) in countries in the eastern vs western parts of Europe, and the duration ranged from 8-18 weeks across seasons and countries. Lower temperature and higher relative humidity were associated with higher RSV activity, with a 14-day lag time. Through external validation, the prediction error in RSV season onset was -2.4 ± 3.2 weeks. Similar longitudinal gradients in RSV onset were predicted by our model for the 2018/19 season (r = 0.45, 95% CI: 0.16 to 0.66).ConclusionMeteorological factors, such as temperature and relative humidity, could be used for early warning of RSV season onset. Our findings may inform healthcare services planning and optimisation of RSV immunisation strategies in Europe.