Respiratory Syncytial Virus Hospital-Based Burden of Disease in Children Younger Than 5 Years, 2015-2022.

Importance: Respiratory syncytial virus (RSV) resurgences have been noted following the COVID-19 pandemic in many countries. Recent findings suggest that the 2021 and 2022 RSV seasons were more severe than in past seasons, and age distribution may have shifted toward older children in the younger than 5 years age group. Objectives: To estimate age-specific changes in RSV hospital-based burden of disease before and after the COVID-19 pandemic and to compare incidence by Medicaid use. Design, Setting, and Participants: This retrospective cohort study included children younger than 5 years diagnosed with RSV and bronchiolitis at 50 US children's hospitals in 10 US geographic regions. The included participants had an encounter in intensive care, inpatient, emergency, or observational units, between June 1, 2015, and March 31, 2023. Exposures: Diagnosis of RSV, bronchiolitis, or both at encounter. Main Outcome and Measures: Incidence rate ratio of hospital use within each care unit before vs after the COVID-19 pandemic. It was hypothesized a priori that incidence of hospital use would increase overall in 2021 and 2022 compared with 2015 to 2019 and that the increase would be greater among children 12 months and older. Results: Of 924 061 study participants (median [IQR] age, 8 (5-16) months; 535 619 [58.0%] male), 348 077 (37.7%) were diagnosed with RSV. Of these, 187 850 (54.0%) were hospitalized. Incidence rate ratios of hospitalization increased for all ages in 2021 and 2022 compared with 2015 to 2019. Children aged 24 to 59 months were 4.86 (95% CI, 4.75-4.98) times as likely to be hospitalized in 2022 compared with 2015 to 2019, whereas infants aged 0 to 5 months were 1.77 (95% CI, 1.74-1.80) times as likely. Medicaid patients were more likely to be hospitalized than non-Medicaid patients regardless of year. Conclusions and Relevance: Hospitalizations for RSV and bronchiolitis demonstrated atypical seasonality in 2021 and 2022, with an overall increase in RSV encounters. Postpandemic RSV hospitalization increased for all ages, but especially among older children, whereas bronchiolitis hospitalization was decreased or unchanged compared with earlier seasons. These findings suggest some of the observed increase in RSV hospital use may be due to increased testing.

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.

The Long-Term Healthcare Utilization and Economic Burden of RSV Infection in Children ≤5 Years in Japan: Propensity Score Matched Cohort Study.

Background: The objective of this study was to estimate the long-term healthcare utilization and cost burden of RSV by chronological age of diagnosis (Year 1, Year 2 and Years 3-5 cohorts) as well as by gestational age at birth in Japan. Methods: The JMDC database was used to retrospectively identify RSV and control patients between February 1, 2011 and January 31, 2016 and follow them through December 31, 2017. Infants with RSV infection (n = 9028 in Year 1; n = 4929 in Year 2; n = 2004 in Years 3-5) were matched to controls (n = 17,886; n = 9351; n = 3655, respectively) based on gestational age and year and quarter of birth; controls were assigned the index date (ie, diagnosis) of their respective match. Covariate-balancing propensity score weights were employed adjusting for remaining imbalances between cohorts. The main outcomes were average cumulative rates for all-cause, asthma/wheezing, and respiratory-related hospitalizations, physician and urgent care/emergency visits and associated costs (reported as 2018 ¥JPY) over 36-months of follow-up since index. Results: Healthcare utilization was significantly higher among RSV cases for most comparisons. All-cause average differential cost burden was higher for RSV, compared to controls, among the following cohorts: Year 1 full-term (¥277,727); Year 2 preterm (¥530,302), late preterm (¥270,797), full-term (¥238,832); Years 3-5 preterm (¥110,057), late preterm (¥486,670), full-term (¥289,986). While all-cause costs were similar for preterm and late preterm children in the Year 1 cohort, respiratory- and asthma/wheezing-related attributable costs were substantially higher for RSV. Conclusion: RSV infection had a significant long-term health and economic burden among children infected during their first year of life and later in life. Study findings have import for prevention strategies, currently directed at maternal immunization and monoclonal antibodies for preventing primary RSV infections in the first six months of life and beyond but also for older age not targeted currently.

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).

Risk Factors for Respiratory Syncytial Virus Lower Respiratory Tract Infections: Evidence from an Indonesian Cohort.

Although risk factors for hospitalization from a respiratory syncytial virus (RSV) are well known, RSV lower respiratory tract infections (LRIs) in the community are much less studied or understood, especially in developing countries. In a prospective, cohort study we studied factors predisposing Indonesian infants and children under 5 years of age to developing RSV LRIs. Subjects were enrolled in two cohorts: a birth cohort and a cross-sectional cohort of children <48 months of age. Subjects were visited weekly at home to identify any LRI, using the World Health Organization's criteria. RSV etiology was determined through analysis of nasal washings by enzyme immunoassay and polymerase chain reaction. Risk factors for the development of the first documented RSV LRI were identified by multivariate analysis using logistic regression and Cox proportional hazard modeling. Of the 2014 children studied, 999 were enrolled within 30 days of birth. There were 149 first episodes of an RSV. Risk factors for an RSV LRI were poverty (p < 0.01), use of kerosene as a cooking fuel (p < 0.05), and household ownership of rabbits and chickens (p < 0.01). Our findings suggested that in a middle-income country such as Indonesia, with a substantial burden of RSV morbidity and mortality, lower socioeconomic status, environmental air quality, and animal exposure are predisposing factors for developing an RSV LRI.

Population-based otoscopic and audiometric assessment of a birth cohort recruited for a pneumococcal vaccine trial 15-18 years earlier: a protocol.

INTRODUCTION: A cohort of 12 000 children in the Philippines who had enrolled in a 2000-2004 (current ages 16 to 20 years) Phase 3 11-valent pneumococcal conjugate vaccine for the prevention of radiographically confirmed pneumonia are now being asked to participate in a separate study (expected completion date September 2021) to assess the cohort's current long-term audiometric and otologic status. This new study would allow assessments of the utility of the pneumococcal vaccine in conferring its protective effects on the long-term sequelae of otitis media (OM), if any. Lack of trained local healthcare providers in otolaryngology/audiology and testing equipment in Bohol, Philippines, necessitates the development of a distinct methodology that would lead to meaningful data analysis. METHODS AND ANALYSIS: Reliable data collection and transfer are achieved by a US otolaryngologist/audiologist team training local nurses on all procedures in a didactic and hands-on process. An assortment of portable otolaryngologic and audiologic equipment suitable for field testing has been acquired, including an operating otoscope (Welch-Allyn), a video-otoscope (JedMed), a tympanometer with distortion product otoacoustic emission measurements (Path Sentiero) and a screening audiometer (HearScreen). Data will then be uploaded to a Research Electronic Data Capture database in the USA.Tympanometric and audiologic data will be codified through separate conventional algorithms. A team of paediatric otolaryngology advanced practice providers (APPs) have been trained and validated in interpreting video otoscopy. The protocol for classification of diagnostic outcome variables based on video otoscopy and tympanometry has been developed and is being used by APPs to evaluate all otoscopy data. ETHICS AND DISSEMINATION: The study was approved by the Research Institute of Tropical Medicine, Alabang, Manila, Philippines, and the institutional review board and the Colorado Multiple Institutional Review Board of the University of Colorado School of Medicine, Aurora, Colorado, USA.Research results will be made available to children and their caregivers with abnormal audiologic outcomes, the funders and other researchers. TRIAL REGISTRATION NUMBER: ISRCTN 62323832; Post-results.

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

BACKGROUND: Human metapneumovirus is a common virus associated with acute lower respiratory infections (ALRIs) in children. No global burden estimates are available for ALRIs associated with human metapneumovirus in children, and no licensed vaccines or drugs exist for human metapneumovirus infections. We aimed to estimate the age-stratified human metapneumovirus-associated ALRI global incidence, hospital admissions, and mortality burden in children younger than 5 years. METHODS: We estimated the global burden of human metapneumovirus-associated ALRIs in children younger than 5 years from a systematic review of 119 studies published between Jan 1, 2001, and Dec 31, 2019, and a further 40 high quality unpublished studies. We assessed risk of bias using a modified Newcastle-Ottawa Scale. We estimated incidence, hospital admission rates, and in-hospital case-fatality ratios (hCFRs) of human metapneumovirus-associated ALRI using a generalised linear mixed model. We applied incidence and hospital admission rates of human metapneumovirus-associated ALRI to population estimates to yield the morbidity burden estimates by age bands and World Bank income levels. We also estimated human metapneumovirus-associated ALRI in-hospital deaths and overall human metapneumovirus-associated ALRI deaths (both in-hospital and non-hospital deaths). Additionally, we estimated human metapneumovirus-attributable ALRI cases, hospital admissions, and deaths by combining human metapneumovirus-associated burden estimates and attributable fractions of human metapneumovirus in laboratory-confirmed human metapneumovirus cases and deaths. FINDINGS: In 2018, among children younger than 5 years globally, there were an estimated 14·2 million human metapneumovirus-associated ALRI cases (uncertainty range [UR] 10·2 million to 20·1 million), 643 000 human metapneumovirus-associated hospital admissions (UR 425 000 to 977 000), 7700 human metapneumovirus-associated in-hospital deaths (2600 to 48 800), and 16 100 overall (hospital and community) human metapneumovirus-associated ALRI deaths (5700 to 88 000). An estimated 11·1 million ALRI cases (UR 8·0 million to 15·7 million), 502 000 ALRI hospital admissions (UR 332 000 to 762 000), and 11 300 ALRI deaths (4000 to 61 600) could be causally attributed to human metapneumovirus in 2018. Around 58% of the hospital admissions were in infants under 12 months, and 64% of in-hospital deaths occurred in infants younger than 6 months, of which 79% occurred in low-income and lower-middle-income countries. INTERPRETATION: Infants younger than 1 year have disproportionately high risks of severe human metapneumovirus infections across all World Bank income regions and all child mortality settings, similar to respiratory syncytial virus and influenza virus. Infants younger than 6 months in low-income and lower-middle-income countries are at greater risk of death from human metapneumovirus-associated ALRI than older children and those in upper-middle-income and high-income countries. Our mortality estimates demonstrate the importance of intervention strategies for infants across all settings, and warrant continued efforts to improve the outcome of human metapneumovirus-associated ALRI among young infants in low-income and lower-middle-income countries. FUNDING: Bill & Melinda Gates Foundation.

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

The World Health Organization (WHO) recently completed the first phase of a RSV surveillance pilot study in fourteen countries (two to three in each WHO region) building on the Global Influenza Surveillance and Response System (GISRS). This active surveillance strategy had several objectives including understanding RSV-related health burden in a variety of settings. A range of approaches can be used to estimate disease burden; most approaches could not be applied by participating countries in the WHO surveillance pilot. This article provides the recommendations made by WHO for strengthening and expanding the scope of the RSV surveillance in the next phase to enable burden estimation.

Long-term Assessment of Healthcare Utilization 5 Years After Respiratory Syncytial Virus Infection in US Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is the primary cause of respiratory tract infections in infants; however, current burden estimates report only the short-term effects of acute infection. METHODS: Infants with RSV infection and ≥24 months of continuous enrollment were retrospectively identified from the Truven MarketScan database (1 January 2004-30 September 2015). Exposed infants (n = 38 473) were propensity score matched to nonexposed controls (n = 76 825) by baseline characteristics and gestational age. Five-year cumulative all-cause, asthma/wheezing, and respiratory event-related hospitalization rates and physician and emergency department healthcare-resource utilization rates were assessed. RESULTS: During follow-up, RSV-infected cohorts had higher average all-cause cumulative hospitalization rates, compared with controls, with values of 79.9 hospitalizations/100 patient-years (95% confidence interval [CI], 41.7-118.2) for 213 early premature infants (P < .001), 18.2 hospitalizations/100 patient-years (95% CI, .8-35.7) for 397 premature infants (P = .04), 34.2 hospitalizations/100 patient-years (95% CI, 29.1-39.2) for 4446 late premature infants (P < .001), and 16.1 hospitalizations/100 patient-years (95% CI, 14.9-17.4) for 33 417 full-term infants (P < .001). Cumulative rates of physician and emergency department visits were also higher for RSV-infected infants. Asthma/wheezing accounted for 10%-18% of total 5-year physician visits. CONCLUSIONS: Infant RSV infection has a significant long-term healthcare-resource utilization impact across gestational ages for at least 5 years after infection, most of it in the first 2 years. Systematically collecting healthcare-resource utilization data will be important for cost-effectiveness evaluations of RSV interventions in planned or ongoing trials.

Economic-Burden Trajectories in Commercially Insured US Infants With Respiratory Syncytial Virus Infection.

BACKGROUND: This study evaluates the long-term respiratory syncytial virus (RSV) burden among preterm and full-term infants in the United States. METHODS: Infants with birth hospitalization claims and ≥24 months of continuous enrollment were retrospectively identified in the Truven MarketScan Commercial Claims and Encounters database for the period 1 January 2004-30 September 2015. Infants with RSV infection in the first year of life (n = 38 473) were matched to controls (n = 76 825), and remaining imbalances in the number of individuals in each group were adjusted using propensity score methods. All-cause, respiratory-related, and asthma/wheezing-related 5-year average cumulative costs were measured. RESULTS: Early premature (n = 213), premature (n = 397), late premature (n = 4446), and full-term (n = 33 417) RSV-infected infants were matched to 424, 791, 8875, and 66 735 controls, respectively. After 2 years since RSV diagnosis, all-cause cumulative costs for RSV-infected infants as compared to those for controls increased by $22 081 (95% confidence interval [CI], -$5800-$42 543) for early premature infants, by $14 034 (95% CI, $5095- $22 973) for premature infants, by $10 164 (95% CI, $8835-$11 493) for late premature infants, and by $5404 (95% CI, $5110-$5698) for full-term infants. The 5-year RSV burden increased to $39 490 (95% CI, $18 217-$60 764), $23 160 (95% CI, $13 002-$33 317),$13 755 (95% CI, $12 097-$15 414), and $6631 (95% CI, $6060-$7202), respectively. The RSV burden was higher when stratified by inpatient and outpatient setting and respiratory-related and asthma/wheezing-related costs. CONCLUSIONS: The RSV burden extends across cost domains and prematurity, with the greatest burden incurred by the second year of follow-up. Findings are useful in determining the cost-effectiveness of RSV therapies in development.

Lay Field-worker-Led School Health Program for Primary Schools in Low- and Middle-Income Countries.

BACKGROUND AND OBJECTIVES: School health programs are frequently attempted in low- and/or middle-income countries; however, programmatic scope and reach is limited by human resource constraints. We sought to determine if trained community members could implement a school health program that improved outcomes in rural primary schools in India. METHODS: This was a mixed-methods, stepped-wedge, cluster-controlled study of schools pragmatically assigned to receive a multicomponent, comprehensive school health program delivered by lay field-workers. RESULTS: All students in 22 primary schools (9 government schools and 13 low-cost private schools) participated in this study. A total of 3033 student-years were included in the analysis (2100 student-years in the intervention period and 933 student-years in the control period). Qualitative feedback was collected from 38 teachers, 49 parents, and 4 field-workers. In low-cost private schools, the diarrhea incidence was lower in students receiving the intervention (incidence rate ratio 0.58; 95% confidence interval [CI] 0.47 to 0.71; P < .001). There was no difference in diarrhea incidence for students in government schools (incidence rate ratio 0.87; 95% CI 0.68 to 1.12; P = .29). Health-knowledge acquisition was higher in intervention schools (mean difference 12.6%; 95% CI 8.8 to 16.4; P < .001) and similar in both school types. Intervention coverage rates were high (mean 93.9%; SD 2.0%), and performance assessment scores indicated fidelity (mean 3.45; SD 0.69). Stakeholders revealed favorable perceptions of the field-workers and high levels of perceived impact. CONCLUSIONS: Lay field-worker-led school health programs offer a promising alternative for improving school health delivery in resource-constrained settings.

Identifying Gaps in Respiratory Syncytial Virus Disease Epidemiology in the United States Prior to the Introduction of Vaccines.

Respiratory syncytial virus (RSV) causes lower respiratory tract illness frequently. No effective antivirals or vaccines for RSV are approved for use in the United States; however, there are at least 50 vaccines and monoclonal antibody products in development, with those targeting older adults and pregnant women (to protect young infants) in phase 2 and 3 clinical trials. Unanswered questions regarding RSV epidemiology need to be identified and addressed prior to RSV vaccine introduction to guide the measurement of impact and future recommendations. The Centers for Disease Control and Prevention (CDC) convened a technical consultation to gather input from external subject matter experts on their individual perspectives regarding evidence gaps in current RSV epidemiology in the United States, potential studies and surveillance platforms needed to fill these gaps, and prioritizing efforts. Participants articulated their individual views, and CDC staff synthesized individuals' input into this report.

SENTINEL1: An Observational Study of Respiratory Syncytial Virus Hospitalizations among U.S. Infants Born at 29 to 35 Weeks' Gestational Age Not Receiving Immunoprophylaxis.

Objective SENTINEL1 characterized U.S. preterm infants 29 to 35 weeks' gestational age (wGA) < 12 months old hospitalized for laboratory-confirmed respiratory syncytial virus (RSV) disease and not receiving RSV immunoprophylaxis during the 2014 to 2015 RSV season. Study Design This is a noninterventional, observational, cohort study. Results A total of 702 infants were hospitalized with community-acquired RSV disease, of whom an estimated 42% were admitted to the intensive care unit (ICU) and 20% required invasive mechanical ventilation (IMV). Earlier gestational age and younger chronologic age were associated with an increased frequency of RSV-confirmed hospitalization (RSVH), ICU admission, and IMV. Among infants 29 to 32 wGA and < 3 months of age, 68% required ICU admission and 44% required IMV. One death occurred of an infant 29 wGA. Among the 212 infants enrolled for in-depth analysis of health care resource utilization, mean and median RSVH charges were $55,551 and $27,461, respectively, which varied by intensity of care required. Outpatient visits were common, with 63% and 62% of infants requiring visits before and within 1 month following the RSVH, respectively. Conclusion Preterm infants 29 to 35 wGA are at high risk for severe RSV disease, which imposes a substantial health burden, particularly in the first months of life.

Clinical Endpoints for Respiratory Syncytial Virus Prophylaxis Trials in Infants and Children in High-income and Middle-income Countries.

Respiratory syncytial virus (RSV) continues to cause significant clinical and economic burden around the world. Historically, RSV-associated hospitalization was used as a primary endpoint for RSV prophylaxis trials in infants. However, because of the changing epidemiology and healthcare system landscape, this endpoint has become a critical bottleneck on the pathway to licensure for new therapeutics. A panel of 7 RSV experts was convened (Chicago, IL, May 22, 2014) to evaluate the challenges of defining RSV prevention endpoints for clinical trials and to develop endpoints that are clinically meaningful while minimizing subjectivity and bias to achieve sufficient consistency of response for regulatory approval. Particular consideration was given to the ability to collect data systematically and consistently in countries with different healthcare practices and systems, while capturing the greatest proportion of disease impact. The group consensus was that a clinically meaningful primary endpoint could include medically attended RSV illness in settings beyond RSV-associated hospitalizations alone, in particular, a composite reduction in hospitalization, emergency room or urgent care center visits because of an RSV respiratory infection. Relevant secondary endpoints included reductions in RSV lower respiratory tract infection, RSV-related intensive care unit rates, subsequent recurrent wheezing or asthma and direct and indirect costs.

An evaluation of the emerging interventions against Respiratory Syncytial Virus (RSV)-associated acute lower respiratory infections in children.

BACKGROUND: Respiratory Syncytial Virus (RSV) is the leading cause of acute lower respiratory infections (ALRI) in children. It is estimated to cause approximately 33.8 million new episodes of ALRI in children annually, 96% of these occurring in developing countries. It is also estimated to result in about 53,000 to 199,000 deaths annually in young children. Currently there are several vaccine and immunoprophylaxis candidates against RSV in the developmental phase targeting active and passive immunization. METHODS: We used a modified CHNRI methodology for setting priorities in health research investments. This was done in two stages. In Stage I, we systematically reviewed the literature related to emerging vaccines against RSV relevant to 12 criteria of interest. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies). The policy makers and industry representatives accepted our invitation on the condition of anonymity, due to the sensitive nature of their involvement in such exercises. They answered questions from the CHNRI framework and their "collective optimism" towards each criterion was documented on a scale from 0 to 100%. RESULTS: In the case of candidate vaccines for active immunization of infants against RSV, the experts expressed very low levels of optimism for low product cost, affordability and low cost of development; moderate levels of optimism regarding the criteria of answerability, likelihood of efficacy, deliverability, sustainability and acceptance to end users for the interventions; and high levels of optimism regarding impact on equity and acceptance to health workers. While considering the candidate vaccines targeting pregnant women, the panel expressed low levels of optimism for low product cost, affordability, answerability and low development cost; moderate levels of optimism for likelihood of efficacy, deliverability, sustainability and impact on equity; high levels of optimism regarding acceptance to end users and health workers. The group also evaluated immunoprophylaxis against RSV using monoclonal antibodies and expressed no optimism towards low product cost; very low levels of optimism regarding deliverability, affordability, sustainability, low implementation cost and impact on equity; moderate levels of optimism against the criteria of answerability, likelihood of efficacy, acceptance to end-users and health workers; and high levels of optimism regarding low development cost. They felt that either of these vaccines would have a high impact on reducing burden of childhood ALRI due to RSV and reduce the overall childhood ALRI burden by a maximum of about 10%. CONCLUSION: Although monoclonal antibodies have proven to be effective in providing protection to high-risk infants, their introduction in resource poor settings might be limited by high cost associated with them. Candidate vaccines for active immunization of infants against RSV hold greatest promise. Introduction of a low cost vaccine against RSV would reduce the inequitable distribution of burden due to childhood ALRI and will most likely have a high impact on morbidity and mortality due to severe ALRI.

Management of severely ill children at first-level health facilities in sub-Saharan Africa when referral is difficult.

OBJECTIVES: To quantify the main reasons for referral of infants and children from first-level health facilities to referral hospitals in sub-Saharan Africa and to determine what further supplies, equipment, and legal empowerment might be needed to manage such children when referral is difficult. METHODS: In an observational study at first-level health facilities in Uganda, the United Republic of Tanzania, and Niger, over 3-5 months, we prospectively documented the diagnoses and severity of diseases in children using the standardized Integrated Management of Childhood Illness (IMCI) guidelines. We reviewed the facilities for supplies and equipment and examined the legal constraints of health personnel working at these facilities. FINDINGS: We studied 7195 children aged 2-59 months, of whom 691 (9.6%) were classified under a severe IMCI classification that required urgent referral to a hospital. Overall, 226 children had general danger signs, 292 had severe pneumonia or very severe disease, 104 were severely dehydrated, 31 had severe persistent diarrhoea, 207 were severely malnourished, and 98 had severe anaemia. Considerably more ill were 415 young infants aged one week to two months: nearly three-quarters of these required referral. Legal constraints and a lack of simple equipment (suction pumps, nebulizers, and oxygen concentrators) and supplies (nasogastric tubes and 50% glucose) could prevent health workers from dealing more appropriately with sick children when referral was not possible. CONCLUSION: When referral is difficult or impossible, some additional supplies and equipment, as well as provision of simple guidelines, may improve management of seriously ill infants and children.