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Lower respiratory tract infections, commonly caused by respiratory syncytial virus (RSV) or Streptococcus pneumoniae (pneumococcus), pose a substantial global health burden, especially in children younger than 5 years of age. A deeper understanding of the relationship between RSV and pneumococcus would aid the development of health-care approaches to disease prevention and management. We completed a systematic review to identify and assess evidence pertaining to the relationship between RSV and pneumococcus in the pathogenesis of childhood respiratory infections. We found mechanistic evidence for direct pathogen-pathogen interactions and for indirect interactions involving host modulation. We found a strong seasonal epidemiological association between these two pathogens, which was recently confirmed by a parallel decrease and a subsequent resurgence of both RSV and pneumococcus-associated disease during the COVID-19 pandemic. Importantly, we found that pneumococcal vaccination was associated with reduced RSV hospitalisations in infants, further supporting the relevance of their interaction in modulating severe disease. Overall evidence supports a broad biological and clinical interaction between pneumococcus and RSV in the pathogenesis of childhood respiratory infections. We hypothesise that the implementation of next-generation pneumococcal and RSV vaccines and monoclonal antibodies targeting RSV will act synergistically to reduce global morbidity and mortality related to childhood respiratory infections., Competing Interests: Declaration of interests LB and RD obtained a research grant from the Investigator-Initiated Studies Program of Merck Sharp & Dohme (MSD) to cover the costs of Violicom's searches and screening of the data. LB is the founding chairman of the Respiratory Syncytial Virus Foundation (ReSViNET Foundation); he has regular interactions with pharmaceutical and other industrial partners, but he has not received personal fees or other personal benefits. LB reports the following funding to his institution: funding for investigator-initiated studies from AbbVie, MedImmune, AstraZeneca, Sanofi, Janssen, Pfizer, MSD, and MeMed Diagnostics; funding for the RSV GOLD study from the Bill & Melinda Gates Foundation; funding as part of the Innovative Medicines Initiative-funded RESCEU and PROMISE projects with partners GSK, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi; funding for participation in clinical studies sponsored by MedImmune and Pfizer from Julius Clinical; and consulting fees and fees for invited lectures from AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, AstraZeneca, MSD, Sanofi, and Janssen. AM has received research grants to her institution from Janssen, Merck, and the US National Institutes of Health (NIH); fees for participation on advisory boards from Janssen, Sanofi Pasteur, Merck, Pfizer, and AstraZeneca; and fees for lectures from Sanofi Pasteur and AstraZeneca. OR has received research grants to his institution from Janssen, Merck, NIH, and the Bill & Melinda Gates Foundation; fees for participation on advisory boards from Sanofi Pasteur, Merck, and Pfizer; and fees for lectures from Pfizer, Sanofi Pasteur, and AstraZeneca. DMW is supported by a grant from the NIH National Institute of Allergy and Infectious Diseases (R01AI137093) and has received consulting fees from Pfizer, Merck, and GSK/Affinivax for work unrelated to this manuscript; he is the principal investigator on grants from Pfizer and Merck to his institution for work unrelated to this manuscript. RD has received grants to his institution from Pfizer, MSD, and MedImmune/AstraZeneca; consulting fees and fees for participation on advisory boards from Pfizer and MSD; payment for speakers bureaus from Pfizer, MSD, Sanofi Pasteur, and GSK; and payment for expert testimony from Pfizer. SBB and DB declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Competing Interests: NH declares grants or contracts from Merck (investigator-initiated) and has participated on an advisory board for CSL-Seqirus. LB declares interaction with pharmaceutical and other industrial partners, but has not received personal fees or other personal benefits; and is the founding chairman of the ReSViNET Foundation. University Medical Center Utrecht has received major funding for investigator initiated studies from AstraZeneca, Sanofi, Janssen, Pfizer, MSD, MeMed Diagnostics, and the Bill and Melinda Gates Foundation; has received major funding as part of the public–private partnership IMI-funded RESCEU and PROMISE projects with partners GlaxoSmithKline, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi; has received major funding by Julius Clinical for participating in clinical studies sponsored by AstraZeneca, Merck, and Pfizer; and has received minor funding for consultation, Data and Safety Monitoring Board membership, or invited lectures by Ablynx, Bavaria Nordic, GlaxoSmithKline, Novavax, Pfizer, Moderna, AstraZeneca, MSD, Sanofi, and Janssen.

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., Competing Interests: Declaration of interests YM and ES were affiliated with the University of Edinburgh when this work was conducted. YM is currently affiliated to the School of Public Health, Wuhan University, Wuhan, China and ES is employed by University College Hospital, University College Hospitals NHS Foundation Trust, London, UK. XW reports grants from GSK to their institution and personal fees from Pfizer, outside the submitted work. YL reports grants from Wellcome Trust, WHO, and GSK paid to their institution, and personal fees from Pfizer, outside the submitted work. TS reports grants from Royal Society of Edinburgh outside the submitted work. LJB reports regular interactions with AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, AstraZeneca, MSD, Sanofi, Genzyme, MeMed Diagnostics, and Janssen but has not received personal fees or other personal benefits; being the founding chairman of the ReSViNET Foundation; their affiliation (University Medical Centre Utrecht) has received major funding (>€100 000 per industrial partner) for investigator-initiated studies from AbbVie, MedImmune, AstraZeneca, Sanofi, Janssen, Pfizer, MSD, and MeMed Diagnostics; major funding for the RSV GOLD study from the Bill & Melinda Gates Foundation; major funding as part of the public private partnership IMI-funded RESCEU and PROMISE projects with partners GSK, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi; major funding by Julius Clinical for participating in clinical studies sponsored by MedImmune and Pfizer; and minor funding (€1000–€25 000 per industrial partner) for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, AstraZeneca, MSD, Sanofi, and Janssen. HYC reports consulting for Ellume, Pfizer, and the Gates Foundation; serving on advisory boards for Vir, Merck, and AbbVie; conducting continuing medical education teaching with Medscape, Vindico, Cataylst CME, and Clinical Care Options; research funding from Gates Ventures; and receiving support and reagents from Ellume and Cepheid, all outside of the submitted work. HJZ reports grants from the Gates Foundation, AstraZeneca, MSD, and Pfizer paid to their institution outside the submitted work, and serving on advisory boards for MSD. TH reports personal fees from Janssen, Sanofi, Enanta, MSD, and Moderna, all outside of the submitted work. MHJ reports personal fees from AstraZeneca, OM-Pharma, Chiesi, GSK, and Boehringer Ingelheim, outside the submitted work. MCN reports grants from the Gates Foundation, European & Developing Countries Clinical Trials Partnership, Pfizer, AstraZeneca, and Sanofi; and serving on advisory boards for Sanofi, all outside the submitted work. BR received honoraria due to lectures from AbbVie, Germania, Sanofi, AstraZeneca, Milupa, Nestle, and Fresenius, outside the submitted work; and travel support from AbbVie, Chiesi, AstraZeneca, Sanofi, and Nestle. HN reports grants from the Innovative Medicines Initiative related to the submitted work; grants from WHO, the National Institute for Health Research, Pfizer, and Icosavax; and personal fees from the Gates Foundation, Pfizer, ReViral, GSK, Merck, Icosavax, Sanofi, Novavax, and AbbVie, outside the submitted work. CFY reports grants from National Medical Research Council Singapore and Wellcome Trust, and funding to attend conferences and honorarium from Sanofi, Pfizer, and Takeda, outside the submitted work. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: LJB has regular interaction with pharmaceutical and other industrial partners and has not received personal fees or other personal benefits; the University Medical Center Utrecht has received funding for investigator-initiated studies from AbbVie, MedImmune, AstraZeneca, Sanofi, Janssen, Pfizer, MSD, and MeMed Diagnostics; major funding for the RSV GOLD study from the Bill & Melinda Gates Foundation; major funding as part of the public–private partnership IMI-funded RESCEU and PROMISE projects with partners GSK, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi; major funding by Julius Clinical for participating in clinical studies sponsored by MedImmune and Pfizer; and funding for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, Astrazeneca, MSD, Sanofi, Genzyme, and Janssen. LJB is the founding Chair of the ReSViNET Foundation. M-NB declares no competing interests.

Background: Respiratory syncytial virus (RSV) is a major cause of hospitalisation in infants. The burden of RSV infection in healthy term infants has not yet been established. Accurate health-care burden data in healthy infants are necessary to determine RSV immunisation policy when RSV immunisation becomes available., Methods: We performed a multicentre, prospective, observational birth cohort study in healthy term-born infants (≥37 weeks of gestation) in five sites located in different European countries to determine the health-care burden of RSV. The incidence of RSV-associated hospitalisations in the first year of life was determined by parental questionnaires and hospital chart reviews. We performed active RSV surveillance in a nested cohort to determine the incidence of medically attended RSV infections. The study is registered with ClinicalTrials.gov, NCT03627572., Findings: In total, 9154 infants born between July 1, 2017, and April 1, 2020, were followed up during the first year of life and 993 participated in the nested active surveillance cohort. The incidence of RSV-associated hospitalisations in the total cohort was 1·8% (95% CI 1·6-2·1). There were eight paediatric intensive care unit admissions, corresponding to 5·5% of 145 RSV-associated hospitalisations and 0·09% of the total cohort. Incidence of RSV infection in the active surveillance cohort confirmed by any diagnostic assay was 26·2% (24·0-28·6) and that of medically attended RSV infection was 14·1% (12·3-16·0)., Interpretation: RSV-associated acute respiratory infection causes substantial morbidity, leading to the hospitalisation of one in every 56 healthy term-born infants in high-income settings. Immunisation of pregnant women or healthy term-born infants during their first winter season could have a major effect on the health-care burden caused by RSV infections., Funding: Innovative Medicines Initiative 2 Joint Undertaking, with support from the EU's Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations., Competing Interests: Declaration of interests LJB has regular interaction with pharmaceutical and other industrial partners. He has not received personal fees or other personal benefits. UMCU has received major funding (>€100 000 per industrial partner) for investigator initiated studies from AbbVie, MedImmune, AstraZeneca, Sanofi, Janssen, Pfizer, MSD, and MeMed Diagnostics. UMCU has received major funding for the RSV GOLD study from the Bill & Melinda Gates Foundation. UMCU has received major funding as part of the public private partnership IMI-funded RESCEU and PROMISE projects with partners GSK, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi. UMCU has received major funding by Julius Clinical for participating in clinical studies sponsored by MedImmune and Pfizer. UMCU received minor funding (€1000–25 000 per industrial partner) for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, Astrazeneca, MSD, Sanofi, Genzyme, and Janssen. LJB is the founding chairman of the ReSViNET Foundation. SC has provided consultancy or investigator roles in relation to product development for Ablynx, Janssen, MedImmune, AstraZeneca, Pfizer, GSK, Vertex, AbbVie, Valneva, Fibrogen, and Boehringer Ingelheim, with fees paid to the University of Edinburgh. FM-T reports honoraria from GSK group, Pfizer, Sanofi Pasteur, MSD, Seqirus, Biofabri, and Janssen for taking part in advisory boards and expert meetings and for acting as a speaker in congresses, outside the submitted work; and principal investigator-role in randomised controlled trials for GSK, Pfizer, Sanofi Pasteur, MSD, Seqirus, Biofabri, Janssen, Ablynx, Gilead, Regeneron, Roche, Abbott, Novavax, and MedImmune, with honoraria paid to his institution. MDS acts as an investigator on behalf of the University of Oxford on research studies funded by vaccine manufacturers including GSK, Janssen, MCM vaccines, Novavax, AtraZeneca, and Pfizer. MDS was an National Institute for Heath and Care Research (NIHR) Senior Investigator and received salary support from the NIHR Oxford Biomedical Research Centre during the course of this work. MDS is currently an employee of Moderna. SBD had received honoraria from MSD and Sanofi Pasteur for taking part in advisory boards and has provided consultancy or investigator roles in relation to product development for Janssen, AstraZeneca, Pfizer, Valneva, MSD, and Sanofi Pasteur with fees paid to St George's University of London. TH has received honoraria for lectures or participation in advisory boards or data monitoring committees from Janssen, Sanofi Pasteur, Enanta, and MSD. BR is a full-time employee of the GSK group and holds shares and restricted shares in the GSK group as part of their employee remuneration. AJP is currently Chair of the Department of Health Social Cares Joint Committee on Vaccination and Immunisation and was previously a member of WHO Scientific Advisory Group for Emergencies and chair of the European Medicine's Agency Scientific Advisory Group on Vaccines. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: Year-to-year variation in respiratory viruses may result in lower attack rates than expected. We aimed to illustrate the impact of year-to-year variation in attack rates on the likelihood of demonstrating vaccine efficacy (VE)., Study Design and Setting: We considered an individually randomized maternal vaccine trial against respiratory syncytial virus (RSV)-associated hospitalizations. For 10 RSV-associated hospitalizations per 1,000 infants, sample size to have 80% power for true VE of 50% and 70% was 9,846 and 4,424 participants. We reported power to show VE for varying attack rates, selected to reflect realistic year-to-year variation using observational studies. Eight scenarios including varying number of countries and seasons were developed to assess the influence of these trial parameters., Results: Including up to three seasons decreased the width of the interquartile range for power. Including more seasons concentrated statistical power closer to 80%. Least powered trials had higher statistical power with more seasons. In all scenarios, at least half of the trials had <80% power. For three-season trials, increasing the sample size by 10% reduced the percentage of underpowered trials to less than one-quarter of trials., Conclusion: Year-to-year variation in RSV attack rates should be accounted for during trial design. Mitigation strategies include recruiting over more seasons, or adaptive trial designs., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: We declare no competing interests. We thank Stephane Leteurtre, the Groupe Francophone de Réanimation et d’Urgences pédiatriques, and the Dutch Pediatric Intensive Care Evaluation study group for previously collected data.

Background: Respiratory syncytial virus (RSV) infection during infancy is suggested to cause long-term wheeze. In turn, wheeze has been associated with bacterial dysbiosis of the respiratory tract. We investigated the effects of RSV prophylaxis with palivizumab in otherwise healthy preterm infants on respiratory microbiota composition at 1 year and 6 years of age., Methods: In a multicentre, single-blind, randomised, placebo-controlled trial (the MAKI trial), infants born between 32-35 weeks of gestation, in one university and in 15 regional hospitals in the the Netherlands, were randomly assigned (1:1) to receive palivizumab or placebo during the RSV season of their first year of life. Intramuscular injections of palivizumab 15 mg/kg or placebo were given during one RSV season: either from Oct 1, or from discharge from the neonatal unit until March 10 (minimun of 2 and maximum of 5 injections were given). Children were 6 months old or younger at the start of the RSV season; exclusion criteria included congenital heart disease, bronchopulmonary dysplasia, Down's syndrome, or other serious congenital disorders, use of mechanical ventilation at birth, treatment with surfactant, or physician-diagnosed wheeze before the start of the RSV season. Children were followed up for clinical symptoms until 6 years of age. For this subanalysis, we obtained nasopharyngeal swabs from children aged 1 year and 6 years and analysed them using 16S-rRNA sequencing. At 6 years we also measured reversible airway obstruction. The primary outcome was the effect of palivizumab during infancy on the respiratory microbiota composition at age 1 year and 6 years (intention-to-treat analysis). The trial is registered in the ISRCTN registry, number ISRCTN73641710., Findings: From April 1, 2008, to Dec 31, 2010, 429 infants were enrolled in the MAKI trial (n=214 to the palivizumab group; n=215 to the placebo group). At 1 year, we collected swabs and sequenced DNA from 170 (40%) of 429 children, of which 145 (85%) samples had high-quality DNA. The overall microbiota composition was significantly different (R 2 1·3%; p=0·0185) between the palivizumab group and the placebo group at 1 year of life; children in the palivizumab group had a significantly lower abundance of the Staphylococcus-dominated cluster (odds ratio 0·28 [95% CI 0·11-0·68]; p=0·00394), an increased abundance of biomarker species, such as Klebsiella, and a more diverse set of oral taxa, including Streptococcus spp, compared with children in the placebo group. At 6 years, we collected swabs and sequenced DNA from 349 (88%) of 395 children who completed follow-up, of which 342 (98%) samples had high-quality DNA. The overall microbiota composition was not significantly different between groups at 6 years (R 2 0·6%; p=0·0575); however, children in the palivizumab group had a significantly increased abundance of Haemophilus spp and lower abundance of Moraxella and Neisseriaceae spp compared with children in the placebo group. Absence of PCR-confirmed RSV infection at 1 year was significantly associated with a higher abundance of Haemophilus spp at age 6 years and a significantly lower abundance of Moraxella and Neisseriaceae than children with RSV infection at 1 year. Reversible airway obstruction at 6 years was also positively associated with Haemophilus abundance and negatively associated with the abundance of health-associated taxa, such as Moraxella, Corynebacterium, Dolosigranulum, and Staphylococcus, even after correction for RSV immunoprophylaxis (all: p<0·05). Additionally, reversible airway instruction was associated with significantly higher Streptococcus pneumoniae abundance., Interpretation: Palivizumab in infancy in otherwise healthy preterm infants is associated with persistent effects on the abundance of specific, potentially pathogenic, microbial taxa in the respiratory tract. Several of the palivizumab-associated biomarker species were associated with reversible airway obstruction at age 6 years. These results warrant further studies to establish the long-term ecological effects and health consequences of palivizumab in infancy., Funding: MedImmune., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Although a positive association has been established, it is unclear whether lower respiratory tract infections (LRTIs) with respiratory syncytial virus (RSV) cause chronic wheezing illnesses. If RSV-LRTI were causal, we would expect RSV-LRTI prevention to reduce the incidence of chronic wheezing illnesses in addition to reducing acute disease. We aimed to evaluate the strength of evidence for a causal effect of RSV-LRTI on subsequent chronic wheezing illness to inform public health expectations for RSV vaccines., Methods: We did a systematic review and meta-analysis of observational studies evaluating the association between RSV-LRTI and subsequent wheezing illness (exposure studies) and studies evaluating the association between RSV immunoprophylaxis and subsequent wheezing illness (immunoprophylaxis studies). Exposure studies were included if the exposure group members had an LRTI with laboratory-confirmed RSV and if the exposure ascertainment period began before 2 years of age and ended before 5 years of age. We required a wash-out period of more than 30 days between the index RSV-LRTI and the outcome measurement to allow for resolution of the acute illness. Comparisons between RSV-LRTI and non-RSV-LRTI were not included. Immunoprophylaxis studies were included if they measured the association with subsequent wheezing illness relative to a control group, either in a randomised controlled trial (RCT) or an observational design. For the immunoprophylaxis drugs in question, we required evidence of efficacy in targeting RSV-LRTI from at least one RCT to ensure biological plausibility. All variations of wheezing illness were combined into a single outcome that refers broadly to asthma or any other respiratory illness with wheezing symptoms. Ovid MEDLINE and Embase databases were searched from inception up to Aug 28, 2018. We evaluated whether data from exposure studies could provide evidence against the most viable non-causal theory that RSV-LRTI is a marker of respiratory illness susceptibility rather than a causal factor. Additionally, we tested whether RSV immunoprophylaxis reduces the odds of subsequent wheezing illnesses. We used a random-effects modelling framework and, to accommodate studies providing multiple correlated estimates, robust variance estimation meta-regressions. Meta-regression coefficients (b) quantify differences between exposure and comparator groups on the log e odds ratio (log e OR) scale., Findings: From 14 235 records we identified 57 eligible articles that described 42 studies and provided 153 effect estimates. 35 studies estimated the direct effect of RSV-LRTI on wheezing illnesses (exposure studies) and eight evaluated the effect of RSV immunoprophylaxis (immunoprophylaxis studies). Exposure studies that adjusted for genetic influences yielded a smaller mean adjusted OR estimate (aOR + 2·45, 95% CI 1·23-4·88) compared with those that did not (4·17, 2·36-7·37), a significant difference (b 0·53, 95% CI 0·04-1·02). Infants who were not protected with RSV immunoprophylaxis tended to have higher odds of subsequent wheezing illness, as we would expect if RSV-LRTI were causal, but the effect was not significant (OR + 1·21, 95% CI 0·73-1·99). There was generally a high threat of confounding bias in the observational studies. Additionally, in both the observational studies and immunoprophylaxis RCTs, there was high risk of bias due to missing outcome data., Interpretation: Our findings, limited to exposure and immunoprophylaxis studies, do not support basing policy decisions on an assumption that prevention of RSV-LRTI will reduce recurrent chronic wheezing illnesses., Funding: Bill & Melinda Gates Foundation., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Rubella infection during pregnancy may cause foetal death or congenital rubella syndrome. In South Africa, the national public immunization programme does not include rubella vaccination. The aim of this study was to evaluate rubella sero-epidemiology in pregnant South African women living with and without HIV., Methods: Serum samples obtained from women living with HIV (n=552) and without HIV (n=552) were tested for rubella immunoglobulin G antibodies using an ELISA. The proportions of women with seronegative titres (<8IU/ml) and seropositive titres (≥11IU/ml), and geometric mean titres (GMT) were compared by age group and HIV status., Results: The overall proportion of rubella seropositivity was 97.8%. The proportion of seropositive women increased with age group (18-25 years: 97.0%; 26-32 years: 97.7%; 33-40 years: 99.3%; p=0.047 after adjusting for HIV status). Similar proportions of women living with and without HIV were seropositive., Conclusions: Rubella immunity was high among South African pregnant women living with and without HIV in the absence of rubella vaccination in the public immunization programme. However, a lower percentage of younger women had seropositive titres, indicating the need for routine rubella vaccination after an increase in vaccine coverage rates., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: If a gold standard is lacking in a diagnostic test accuracy study, expert diagnosis is frequently used as reference standard. However, interobserver and intraobserver agreements are imperfect. The aim of this study was to quantify the reproducibility of a panel diagnosis for pediatric infectious diseases., Study Design and Setting: Pediatricians from six countries adjudicated a diagnosis (i.e., bacterial infection, viral infection, or indeterminate) for febrile children. Diagnosis was reached when the majority of panel members came to the same diagnosis, leaving others inconclusive. We evaluated intraobserver and intrapanel agreement with 6 weeks and 3 years' time intervals. We calculated the proportion of inconclusive diagnosis for a three-, five-, and seven-expert panel., Results: For both time intervals (i.e., 6 weeks and 3 years), intrapanel agreement was higher (kappa 0.88, 95%CI: 0.81-0.94 and 0.80, 95%CI: NA) compared to intraobserver agreement (kappa 0.77, 95%CI: 0.71-0.83 and 0.65, 95%CI: 0.52-0.78). After expanding the three-expert panel to five or seven experts, the proportion of inconclusive diagnoses (11%) remained the same., Conclusion: A panel consisting of three experts provides more reproducible diagnoses than an individual expert in children with lower respiratory tract infection or fever without source. Increasing the size of a panel beyond three experts has no major advantage for diagnosis reproducibility., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Respiratory syncytial virus (RSV) infection is associated with subsequent wheeze and asthma. We previously reported on the causal relationship between prevention of RSV infection during infancy and reduced frequency of subsequent wheeze using a double-blind, randomised, placebo-controlled trial (MAKI). We continued follow-up and analysed the effect of RSV prevention during infancy on asthma and lung function at age 6 years., Methods: We studied 429 infants born at 32-35 weeks of gestation between 2008-10 who had randomly received either palivizumab for RSV immunoprophylaxis or placebo during the RSV season of their first year of life. After the first year of follow-up, single, assessor-blind follow-up of children continued until they were aged 6 years. Primary outcomes were parent-reported current asthma and forced expiratory volume in 0·5 s (FEV 0·5 ). The trial is registered in the ISRCTN registry, number ISRCTN73641710., Findings: 395 (92%) of 429 participants completed this 6-year follow-up study. Parent-reported current asthma was reported in 28 (14·1%) of 199 children in the RSV prevention group and 47 (24·0%) of 196 children in the placebo group (absolute risk reduction [ARR] 9·9%, 95% CI 2·2 to 17·6). The difference in current asthma, which was a composite endpoint, was due to a difference in infrequent wheeze (one to three episodes in the past year; 12 [6·0%] of 199 vs 26 [13·4%] of 194, ARR 7·4%, 95% CI 1·5 to 13·2). FEV 0·5 percentage predicted values were similar between the RSV prevention group (89·1% [SD 10·6]) and placebo group (90·1% [11·1]), with a mean difference of 1·0 (95% CI -1·3 to 3·3). The proportion of children with current physician-diagnosed asthma was similar between the RSV prevention group (19 [10·3%] of 185) and placebo group (18 [9·9%] of 182), with an ARR of -0·4 (95% CI -6·5 to 5·8)., Interpretation: In otherwise healthy preterm infants, this single-blind, randomised, placebo-controlled trial showed that RSV prevention did not have a major effect on current asthma or lung function at age 6 years. Future research will inform on the effect of RSV prevention on asthma at school age in the general population., Funding: AbbVie., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: We have previously estimated that respiratory syncytial virus (RSV) was associated with 22% of all episodes of (severe) acute lower respiratory infection (ALRI) resulting in 55 000 to 199 000 deaths in children younger than 5 years in 2005. In the past 5 years, major research activity on RSV has yielded substantial new data from developing countries. With a considerably expanded dataset from a large international collaboration, we aimed to estimate the global incidence, hospital admission rate, and mortality from RSV-ALRI episodes in young children in 2015., Methods: We estimated the incidence and hospital admission rate of RSV-associated ALRI (RSV-ALRI) in children younger than 5 years stratified by age and World Bank income regions from a systematic review of studies published between Jan 1, 1995, and Dec 31, 2016, and unpublished data from 76 high quality population-based studies. We estimated the RSV-ALRI incidence for 132 developing countries using a risk factor-based model and 2015 population estimates. We estimated the in-hospital RSV-ALRI mortality by combining in-hospital case fatality ratios with hospital admission estimates from hospital-based (published and unpublished) studies. We also estimated overall RSV-ALRI mortality by identifying studies reporting monthly data for ALRI mortality in the community and RSV activity., Findings: We estimated that globally in 2015, 33·1 million (uncertainty range [UR] 21·6-50·3) episodes of RSV-ALRI, resulted in about 3·2 million (2·7-3·8) hospital admissions, and 59 600 (48 000-74 500) in-hospital deaths in children younger than 5 years. In children younger than 6 months, 1·4 million (UR 1·2-1·7) hospital admissions, and 27 300 (UR 20 700-36 200) in-hospital deaths were due to RSV-ALRI. We also estimated that the overall RSV-ALRI mortality could be as high as 118 200 (UR 94 600-149 400). Incidence and mortality varied substantially from year to year in any given population., Interpretation: Globally, RSV is a common cause of childhood ALRI and a major cause of hospital admissions in young children, resulting in a substantial burden on health-care services. About 45% of hospital admissions and in-hospital deaths due to RSV-ALRI occur in children younger than 6 months. An effective maternal RSV vaccine or monoclonal antibody could have a substantial effect on disease burden in this age group., Funding: The Bill & Melinda Gates Foundation., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: New vaccines and RSV therapeutics have been developed in the past decade. With approval of these new pharmaceuticals on the horizon, new challenges lie ahead in selecting the appropriate target population. We aimed to improve a previously published prediction model for prediction of RSV-hospitalization within the first year of life., Methods: Two consecutive prospective multicenter birth cohort studies were performed from June 2008 until February 2015. The first cohort (RISK-I, n=2524, 2008-2011) was used to update the existing model. The updated model was subsequently validated in the RISK-II cohort (n=1564, 2011-2015). We used the TRIPOD criteria for transparent reporting., Results: 181 infants (n=127 in RISK-I, n=54 in RISK-II) were hospitalized for RSV within their first year of life. The updated model included the following predictors; day care attendance and/or siblings (OR: 5.3; 95% CI 2.8-10.1), birth between Aug. 14th and Dec. 1st (OR: 2.4; 1.8-3.2), neonatal respiratory support (OR 2.2; 1.6-3.0), breastfeeding ≤4 months (OR 1.6; 1.2-2.2) and maternal atopic constitution (OR 1.5; 1.1-2.1). The updated models' discrimination was superior to the original model in the RISK-II cohort (AUROC 0.72 95% CI 0.65-0.78 versus AUROC 0.66, 95% CI 0.60-0.73, respectively). The updated model was translated into a simple nomogram to be able to distinguish infants with high versus low risk of RSV-hospitalization., Conclusion: We developed and validated a clinical prediction model to be able to predict RSV-hospitalization in preterm infants born within 32-35 weeks gestational age. A simple nomogram was developed to target RSV therapeutics to those children who will benefit the most., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infection during early childhood and is associated with a great burden on patients, parents, and society. While no treatment is yet available, results from recent phase 2 clinical trials of cell-entry inhibitors and RSV vaccines are promising. To prepare for introduction of these novel therapeutics, good understanding of its molecular epidemiology and continuous RSV surveillance data are necessary. This paper provides an overview of RSV prevalence and genotype distribution in Iran from 1996 to 2013. This meta-analysis includes 21 published studies. In total, 775 (18.7%) of 4140 respiratory specimens were positive for RSV infection. The male-female ratio of RSV-positive patients was 1.5:1. Significant peaks of RSV infection were detected during the cold season (November-March). RSV infection was mainly observed in patients <2 years of age. Phylogenetic studies showed that genotypes GA1, GA2, GA5, and BA co-circulated in Iran in 2007-2013. This review highlights the necessity of introducing standard molecular surveillance programs to inform the epidemiological, clinical, and pathological characteristics of various RSV genotypes. Improved understanding of the molecular epidemiology will be useful for development of novel RSV therapeutics., (Copyright © 2015 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.)

Respiratory syncytial virus (RSV) is a major worldwide cause of morbidity and mortality in children under five years of age. Evidence-based management guidelines suggest that there is no effective treatment for RSV lower respiratory tract infection (LRTI) and that supportive care, ie, hydration and oxygenation, remains the cornerstone of clinical management. However, RSV treatments in development in the past decade include 10 vaccines and 11 therapeutic agents in active clinical trials. Maternal vaccination is particularly relevant because the most severe disease occurs within the first 6 months of life, when children are unlikely to benefit from active immunisation. We must optimise the implementation of novel RSV therapeutics by understanding the target populations, showing safety, and striving for acceptable pricing in the context of this worldwide health problem. In this Review, we outline the limitations of RSV LRTI management, the drugs in development, and the remaining challenges related to study design, regulatory approval, and implementation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

IL-17 and T-helper (Th)17 cells contribute to viral airway pathology in human newborns. Because umbilical cord blood T cells fail to differentiate toward the Th17 lineage in the presence of autologous antigen-presenting cells, we asked whether Th17 cells are present in young infants that experience respiratory viral infection. To this end, we analyzed tracheal aspirate samples from infant patients suffering from acute respiratory syncytial virus (RSV) infection and healthy infant controls. Acute RSV infection associates with elevated IL-17 and accumulation of CD161(+) T cells in acute RSV infected lungs. Correspondingly, local Th17 polarizing cytokines were increased. In peripheral blood, we show that Th17 cells are absent in healthy 1-month-old infants, but are present in acute RSV patients. The triggering of pathogen-associated pattern receptors TLR4 and TLR7 promotes the generation of a Th17-polarizing cytokine environment by 1-month-old infant dendritic cell (DC). We thus conclude that although Th17 cells are absent in healthy newborns, Th17 cells are present in peripheral blood and the airways of infants that experience viral infection, thereby contributing to airway immunopathology., (Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

More than 1 in 10 babies are born prematurely and most of them are born after gestational age 32 weeks. Mortality and morbidity are more common in these moderate-to-late preterm infants than in full-term children. In this review, mechanisms and epidemiology of long-term airway morbidity in moderate-to-late preterm infants will be discussed. We discuss the potential of viral respiratory infections to further aggravate abnormal lung function associated with preterm birth., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) is the most frequent cause of bronchiolitis during infancy. Long-term airway morbidity with recurrent post bronchiolitis wheezing (PBW) episodes, which are probably associated with respiratory infections, occurs in 30 to 70% of infants that were hospitalised with RSV LRTI., Methods: We set up a multicenter, placebo-controlled double-blind randomized clinical trial in healthy preterm infants born between 33 and 35 weeks gestational age (WGA). The children received either one-monthly intramuscular palivizumab or placebo injection during the RSV season with a minimum of 2 injections., Results: The primary objective was to determine the preventive effect of RSV immunoprophylaxis (palivizumab) on the development of recurrent wheezing during the first year of life. The primary outcome measure was the number of wheezing days during the first year of life as obtained by daily logs. As a secondary outcome nasal swabs were taken for viral analysis in case of respiratory symptoms. We will also examine wheezing at age 1, 3 and 6 years both reported by the parents and the general practitioner and quality of life as secondary outcomes. This trial is possible because RSV immunoprophylaxis, although effective in this population, is not completely used in the Netherlands due to its high costs., Conclusion: The Institutional review board (IRB) concluded the study has high clinical relevance because the benefit of 50% chance of protection by palivizumab outweighs the risk of side adverse events due to intramuscular administration of placebo., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Down syndrome (DS) is the most common chromosomal abnormality among live-born infants. Respiratory tract infections are the most important cause of mortality in individuals with DS at all ages. In recent decades several studies have been performed to elucidate abnormalities of the immune system in DS. However, the influence of the immune system on the occurrence of respiratory tract infections in these children has never been reviewed., (Copyright © 2010 Institut Pasteur. Published by Elsevier SAS. All rights reserved.)