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© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. 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.

Background Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants. Early detection of RSV can optimize clinical management and minimize use of antibiotics. BinaxNOW RSV (BN) is a rapid antigen detection test that is widely used. We aimed to validate the sensitivity of BN in hospitalized and nonhospitalized infants against the gold standard of molecular diagnosis. Methods We evaluated the performance of BN in infants with acute respiratory tract infections with different degrees of disease severity. Diagnostic accuracy of BN test results were compared with molecular diagnosis as reference standard. Results One hundred sixty-two respiratory samples from 148 children from October 2017 to February 2019 were studied. Sixty-six (40.7%) samples tested positive for RSV (30 hospitalizations, 31 medically attended episodes not requiring hospitalization, and 5 nonmedically attended episodes). Five of these samples tested positive with BN, leading to an overall sensitivity of BN of 7.6% (95% confidence interval [CI], 3.3%–16.5%) and a specificity of 100% (95% CI, 96.2%–100%). Sensitivity was low in all subgroups. Conclusions We found a low sensitivity of BN for point-of-care detection of RSV infection. BinaxNOW RSV should be used and interpreted with caution.

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 Methods We conducted a systematic search of existing relevant literature and identified studies reporting hospitalization of children aged 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

BACKGROUND: Influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus are the most common viruses associated with acute lower respiratory infections in young children (

BackgroundRecurrent 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.MethodsWe 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.ResultsOverall, 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 ConclusionsFurther studies using standardized definitions and from diverse settings are needed to elucidate the role of confounders and provide more robust estimates.

Pneumonia constitutes a substantial disease burden among adults overall and those who are elderly. We aimed to identify all studies investigating the disease burden among older adults (age, ≥65 years) admitted to the hospital with pneumonia. We estimated the hospital admission rate and in-hospital case-fatality ratio (CFR) of pneumonia in older adults, stratified by age and economic status (industrialized vs developing), with data from a systematic review of studies published from 1996 through 2017 and from 8 unpublished population-based studies. We applied these rate estimates to population estimates for 2015 to calculate the global and regional burden in older adults who would have been admitted to the hospital with pneumonia that year. We estimated the number of in-hospital pneumonia deaths by combining in-hospital CFRs with hospital admission estimates from hospital-based studies. We identified 109 eligible studies; 73 used clinical pneumonia as the case definition, and 36 used radiologically confirmed pneumonia as the case definition. We estimated that, in 2015, 6.8 million episodes (uncertainty range [UR], 5.8–8.0 episodes) of clinical pneumonia resulted in hospital admissions of older adults worldwide. The hospital admission rate increased with advancing age and was higher in men. The total disease burden was likely underestimated when using the definition of radiologically confirmed pneumonia. Based on data from 52 hospital studies reporting data on pneumonia mortality, we estimated that about 1.1 million in-hospital deaths (UR, 0.9–1.4 in-hospital deaths) occurred among older adults. The burden of pneumonia requiring hospitalization among older adults is substantial. Appropriate prevention and management strategies should be developed to reduce its impact.

Respiratory syncytial virus–associated acute respiratory infection (RSV-ARI) constitutes a substantial disease burden in older adults aged ≥65 years. We aimed to identify all studies worldwide investigating the disease burden of RSV-ARI in this population. We estimated the community incidence, hospitalization rate, and in-hospital case-fatality ratio (hCFR) of RSV-ARI in older adults, stratified by industrialized and developing regions, using data from a systematic review of studies published between January 1996 and April 2018 and 8 unpublished population-based studies. We applied these rate estimates to population estimates for 2015 to calculate the global and regional burdens in older adults with RSV-ARI in the community and in hospitals for that year. We estimated the number of in-hospital deaths due to RSV-ARI by combining hCFR data with hospital admission estimates from hospital-based studies. In 2015, there were about 1.5 million episodes (95% confidence interval [CI], .3 million–6.9 million) of RSV-ARI in older adults in industrialized countries (data for developing countries were missing), and of these, approximately 14.5% (214 000 episodes; 95% CI, 100 000–459 000) were admitted to hospitals. The global number of hospital admissions for RSV-ARI in older adults was estimated at 336 000 hospitalizations (uncertainty range [UR], 186 000–614 000). We further estimated about 14 000 in-hospital deaths (UR, 5000–50 000) related to RSV-ARI globally. The hospital admission rate and hCFR were higher for those aged ≥65 years than for those aged 50–64 years. The disease burden of RSV-ARI among older adults is substantial, with limited data from developing countries. Appropriate prevention and management strategies are needed to reduce this burden.

Background Clinical manifestations of respiratory syncytial virus (RSV) infection vary widely from mild, self-limiting illness to severe life-threatening disease. There are gaps in knowledge of biomarkers to objectively define severe disease and predict clinical outcomes. Methods A systematic search was performed, 1945–March 2019 in databases Ovid Medline, Embase, Global health, Scopus, and Web of Science. Risk of bias was assessed using the Cochrane tool. Results A total of 25 132 abstracts were screened and studies were assessed for quality, risk of bias, and extracted data; 111 studies met the inclusion criteria. RSV severity was correlated with antibody titers, reduced T and B cells, dysregulated innate immunity, neutrophil mobilization to the lungs and blood, decreased Th1 response, and Th2 weighted shift. Microbial exposures in respiratory tract may contribute to neutrophil mobilization to the lungs of the infants with severe RSV compared with mild RSV disease. Conclusions Although a wide range of biomarkers have been associated with RSV disease severity, robust validated biomarkers are lacking. This review illustrates the broad heterogeneity of study designs and high variability in the definition of severe RSV disease. Prospective studies are required to validate biomarkers. Additional research investigating epigenetics, metabolomics, and microbiome holds promise for novel biomarkers.

BackgroundRespiratory syncytial virus (RSV) is the most common cause of bronchiolitis in young infants. However, it is also a significant pathogen in older adults. Validated biomarkers of RSV disease severity would benefit diagnostics, treatment decisions, and prophylactic interventions. This review summarizes knowledge of biomarkers for RSV disease in adults.MethodsA literature review was performed using Ovid Medline, Embase, Global health, Scopus, and Web of Science for articles published 1946–October 2016. Nine articles were identified plus 9 from other sources.ResultsFrom observational studies of natural infection and challenge studies in volunteers, biomarkers of RSV susceptibility or disease severity in adults were: (1) lower anti-RSV neutralizing antibodies, where neutralizing antibody (and local IgA) may be a correlate of susceptibility/severity; (2) RSV-specific CD8+ T cells in bronchoalveolar lavage fluid preinfection (subjects with higher levels had less severe illness); and (3) elevated interleukin-6 (IL-6), IL-8, and myeloperoxidase levels in the airway are indicative of severe infection.ConclusionsFactors determining susceptibility to and severity of RSV disease in adults have not been well defined. Respiratory mucosal antibodies and CD8+ T cells appear to contribute to preventing infection and modulation of disease severity. Studies of RSV pathogenesis in at-risk populations are needed.

Targeted metagenomics using strand-specific libraries with target enrichment is a sensitive, generalized approach to pathogen sequencing and transcriptome profiling. Using this method, we recovered 13 (76%) complete human respiratory syncytial virus (RSV) genomes from 17 clinical respiratory samples, reconstructed the phylogeny of the infecting viruses, and detected differential gene expression between 2 RSV subgroups, specifically, a lower expression of the P gene and a higher expression of the M2 gene in RSV-A than in RSV-B. This methodology can help to relate viral genetics to clinical phenotype and facilitate ongoing population-level RSV surveillance and vaccine development. Clinical Trials Registration. NCT03627572 and NCT03756766.

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 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.

Background Respiratory syncytial virus (RSV) is a leading cause of respiratory tract illness in young children and a major cause of hospital admissions globally. Methods Here we fit age-structured transmission models with immunity propagation to data from the Netherlands (2012–2017). Data included nationwide hospitalizations with confirmed RSV, general practitioner (GP) data on attendance for care from acute respiratory infection, and virological testing of acute respiratory infections at the GP. The transmission models, equipped with key parameter estimates, were used to predict the impact of maternal and pediatric vaccination. Results Estimates of the basic reproduction number were generally high (R0 > 10 in scenarios with high statistical support), while susceptibility was estimated to be low in nonelderly adults ( Conclusions Pediatric vaccination is expected to reduce the incidence of infection in infants and young children (0–5 years), slightly increase incidence in 5 to 9-year-old children, and have minor indirect benefits.

BackgroundRespiratory syncytial virus (RSV) causes significant morbidity and mortality in infants worldwide. Although prematurity and cardiopulmonary disease are risk factors for severe disease, the majority of infants hospitalized with RSV are previously healthy. Various vaccines and therapeutics are under development and expected to be available in the near future. To inform the use of these new vaccines and therapeutics, it is necessary to determine the burden of RSV disease in Europe. We will prospectively follow-up a birth cohort to obtain incidence data on RSV acute respiratory tract infection (ARTI).MethodsMulticenter prospective study of a birth cohort consisting of 10 000 healthy infants, recruited during 3 consecutive years. RSV associated hospitalization in the first year of life will be determined by questionnaires and hospital chart reviews. A nested cohort of 1000 infants will be actively followed. In case of ARTI, a respiratory sample will be collected for RSV molecular diagnosis.ResultsThe primary outcome is the incidence rate of RSV-associated hospitalization in the first year of life. In the active cohort the primary outcome is RSV associated ARTI and MA-ARTI.ConclusionsWe will provide key information to fill the gaps in knowledge about the burden of RSV disease in healthy infants.Clinical Trials RegistrationNCT03627572.

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

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.