The Burden of Respiratory Syncytial Virus in Children Under 2 Years of Age in a Rural Community in Maharashtra, India.

BACKGROUND: Globally, respiratory syncytial virus (RSV) is a common cause of acute lower tract infection (LRTI) in children younger than 2 years of age, but there are scant population-based studies on the burden of RSV illness in rural communities and no community studies in preterm infants. METHODS: Active surveillance of LRTI was performed in the community and hospital setting for the population of 93 tribal villages in Melghat, Central India, over 4 respiratory seasons. A nasopharyngeal swab was obtained from cases presenting as a severe LRTI for molecular analysis of respiratory pathogens including RSVA and B. RESULTS: High rates of RSV-associated LRTI were found in preterm and term infants beyond 6 months of age, extending into the second year of life. Community severe RSV LRTI rates for 0-11 months of age was 22.4 (18.6-27.0)/1000 child-years (CY) and the hospital-associated rate was 14.1 (11.1-17.8)/1000 CY. For preterm infants, these rates were 26.2 (17.8-38.5)/1000 CY and 12.6 (7.2-22.0)/1000 CY. Comparable rates in the first 6 months were 15.9 (11.8-21.4)/1000 CY and 12.9 (9.3-18.0)/1000 CY in term infants and 26.3 (15.4-45.0)/1000 CY and 10.1 (4.2-24.2)/1000 CY for preterms. The single RSV B season had higher incidences of RSV LRTI in every age group than the 2 RSV A seasons in both preterm and term infants. There were 11 deaths, all term infants. CONCLUSIONS: Studies restricted to the healthcare settings significantly underestimate the burden of RSV LRTI and preterm and term infants have comparable burdens of disease in this rural community.

Mortality From Respiratory Syncytial Virus in Children Under 2 Years of Age: A Prospective Community Cohort Study in Rural Maharashtra, India.

BACKGROUND: Although respiratory syncytial virus (RSV) is the most important viral cause of lower respiratory tract infection deaths in infants, there are few data on infant community deaths caused by RSV. METHODS: This was an active surveillance of children younger than 2 years of age in 93 villages, 5 primary health centers, and 3 hospitals serving these villages. Village health workers and counselors at the health facilities monitored all lower respiratory tract infections (LRTIs) in consented subjects. Children with severe, or very severe LRTIs and all who died, had nasopharyngeal swabs collected for detection of RSV by molecular methods. RESULTS: In the 12 134 subjects, there were 2064 episodes of severe LRTIs and 1732 of very severe LRTIs, of which 271 and 195, respectively, had RSV. Fifteen of 16 (94%) children with RSV died of LRTIs, 14 in the community and 1 in the hospital. The case fatality ratios for severe RSV LRTIs in the first 6 months of life were 3/52 (7.1%) and 1/36 (2.8%) in the community and hospital, respectively. Of those with very severe LRTIs in the community, 17.6% died. There were no very severe RSV LRTI hospital deaths. The adjusted RSV LRTI mortality rates ranged from 1.0 to 3.0/1000 child-years (CY) overall, and 2.0 to 6.1/1000 CY, accounting for 20% of the LRTI deaths and 10% of the postneonatal infant mortality. CONCLUSIONS: Community deaths from RSV account for the majority of RSV LRTI deaths, and efforts at prevention should be preferentially directed at populations where access to care is limited.

Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study.

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.

Intravenous acyclovir and renal dysfunction in children: a matched case control study.

OBJECTIVES: A cluster of children receiving intravenous (IV) acyclovir for meningoencephalitis developed acute renal failure in April-May 2008, which prompted a retrospective case-control study to determine the rate of and risk factors for acute nephrotoxicity during IV acyclovir treatment in children. STUDY DESIGN: The percentage decrease in glomerular filtration rate in children receiving IV acyclovir who had ≥ 1 creatinine measurement after acyclovir initiation from October 2006 to January 2009 was classified as renal risk, injury, or failure according to modified Pediatric Risk Injury, Failure, Loss, End-Stage Renal Disease criteria. Univariate and multivariate matched analyses were conducted to identify risk factors contributing to nephrotoxicity. RESULTS: In the selected study group, renal dysfunction was seen in 131 of 373 (35%) treatment courses studied: 81 of 373 (22%) risk, 36 of 373 (9.7%) injury, and 14 of 373 (3.8%) failure. Most renal dysfunction occurred within 48 hours of the initiation of acyclovir. Renal function returned to the normal range but not to baseline in most cases during the follow-up period. Risk factors for renal dysfunction included acyclovir dose >15 mg/kg (OR 3.81, 95% CI 1.55-9.37) for risk; cumulative exposure greater than calculated cumulative exposure based on 500 mg/m(2)/dose (OR 6.00, 95% CI 1.95-18.46) for injury; and age >8 years (OR 21.5, 95% CI 2.2, >1000) and ceftriaxone coadministration (OR 19.3, 95% CI 1.8, >1000) for failure. CONCLUSIONS: Nephrotoxicity associated with IV acyclovir is common and necessitates renal function monitoring. Risk factors include greater dose, older age, and concomitant ceftriaxone administration. Outside the neonatal period, renal dysfunction may be minimized by dosing IV acyclovir below thresholds associated with nephrotoxicity (ie, ≤ 500 mg/m(2)/dose or ≤ 15 mg/kg/dose), particularly in older patients.

Otitis media sequelae and hearing in adolescence after administration of an 11-valent conjugate pneumococcal vaccine in infancy: a prospective cohort study with long-term follow-up of the ARIVAC trial.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) have been shown in randomised controlled trials and epidemiological studies to prevent acute otitis media caused by vaccine serotype pneumococci, although their role in preventing complications of acute otitis media is less clear. We hypothesised that the 11-valent PCV would reduce the long-term sequelae of acute otitis media, including moderate-to-severe ear disease and hearing loss. METHODS: This prospective cohort study, referred to as 11PCV study, included follow-up after 16-20 years of children previously enrolled in 2000-04, at age 6 weeks to 6 months, in the randomised, placebo-controlled, ARIVAC trial of 11-valent PCV for the prevention of radiographical pneumonia. The ARIVAC trial and this 11PCV study were conducted at six study centres in Bohol, Philippines. Ear disease was classified using video-otoscopy review and observations derived from the ear exam. The final classification of the worst ear disease was mild (ie, acute otitis media, otitis media with effusion, healed perforation, or tympanosclerosis), moderate (ie, dry perforation or adhesive otitis media), or severe (chronic suppurative otitis media). Hearing loss was assessed following a standard schema and classified according to the worst ear as mild (>15 to 30 dB puretone average) or moderate-to-profound (>30 dB pure tone average). We calculated the relative and absolute risk reduction in the primary outcome of moderate-to-severe ear disease and the secondary outcomes of mild or moderate-to-profound hearing loss in adolescents who previously received the 11-valent PCV compared with those who received placebo during infancy in ARIVAC. FINDINGS: Of the 15 593 children assessed for eligibility in ARIVAC, 12 194 were randomly assigned and 8926 were alive and could be located for enrolment in this 11PCV study between Sept 19, 2016, and Dec 13, 2019. 8321 (4188 in the vaccine group and 4133 in the placebo group) completed follow-up of the 11PCV study by March 30, 2020, and had sufficient data to classify ear disease and be included in the primary outcome analysis. The primary outcome of the absolute risk reduction in moderate-to-severe ear disease in the vaccine group (310 [7·4%] of 4188) versus those in the placebo group (356 [8·6%] of 4133) was 1·2% (95% CI 0·0-2·4; p=0·046) and the relative risk reduction was 14·1% (0·0 to 26·0). There were no differences in secondary outcomes of mild hearing loss or moderate-to-profound hearing loss between the vaccine and placebo groups. INTERPRETATION: The absolute risk reduction for moderate-to-severe ear disease in adolescence of 1·2% (12 per 1000 children) was almost three times higher than the 0·45% reduction (4·5 per 1000 children) in radiographical pneumonia in the first 2 years of life shown in ARIVAC. Administration of 11-valent PCV in infancy was associated with absolute and relative risk reductions in the sequelae of acute otitis media 16-20 years after the original ARIVAC trial. FUNDING: Bill & Melinda Gates Foundation.

Pathogen chip for respiratory tract infections.

Determining the viral etiology of respiratory tract infections (RTI) has been limited for the most part to specific primer PCR-based methods due to their increased sensitivity and specificity compared to other methods, such as tissue culture. However, specific primer approaches have limited the ability to fully understand the diversity of infecting pathogens. A pathogen chip system (PathChip), developed at the Genome Institute of Singapore (GIS), using a random-tagged PCR coupled to a chip with over 170,000 probes, has the potential to recognize all known human viral pathogens. We tested 290 nasal wash specimens from Filipino children <2 years of age with respiratory tract infections using culture and 3 PCR methods-EraGen, Luminex, and the GIS PathChip. The PathChip had good diagnostic accuracy, ranging from 85.9% (95% confidence interval [CI], 81.3 to 89.7%) for rhinovirus/enteroviruses to 98.6% (95% CI, 96.5 to 99.6%) for PIV 2, compared to the other methods and additionally identified a number of viruses not detected by these methods.

Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis.

BACKGROUND: The global burden of disease attributable to seasonal influenza virus in children is unknown. We aimed to estimate the global incidence of and mortality from lower respiratory infections associated with influenza in children younger than 5 years. METHODS: We estimated the incidence of influenza episodes, influenza-associated acute lower respiratory infections (ALRI), and influenza-associated severe ALRI in children younger than 5 years, stratified by age, with data from a systematic review of studies published between Jan 1, 1995, and Oct 31, 2010, and 16 unpublished population-based studies. We applied these incidence estimates to global population estimates for 2008 to calculate estimates for that year. We estimated possible bounds for influenza-associated ALRI mortality by combining incidence estimates with case fatality ratios from hospital-based reports and identifying studies with population-based data for influenza seasonality and monthly ALRI mortality. FINDINGS: We identified 43 suitable studies, with data for around 8 million children. We estimated that, in 2008, 90 million (95% CI 49-162 million) new cases of influenza (data from nine studies), 20 million (13-32 million) cases of influenza-associated ALRI (13% of all cases of paediatric ALRI; data from six studies), and 1 million (1-2 million) cases of influenza-associated severe ALRI (7% of cases of all severe paediatric ALRI; data from 39 studies) occurred worldwide in children younger than 5 years. We estimated there were 28,000-111,500 deaths in children younger than 5 years attributable to influenza-associated ALRI in 2008, with 99% of these deaths occurring in developing countries. Incidence and mortality varied substantially from year to year in any one setting. INTERPRETATION: Influenza is a common pathogen identified in children with ALRI and results in a substantial burden on health services worldwide. Sufficient data to precisely estimate the role of influenza in childhood mortality from ALRI are not available. FUNDING: WHO; Bill & Melinda Gates Foundation.

Using the Phenogen website for 'in silico' analysis of morphine-induced analgesia: identifying candidate genes.

The identification of genes that contribute to polygenic (complex) behavioral phenotypes is a key goal of current genetic research. One approach to this goal is to combine gene expression information with genetic information, i.e. to map chromosomal regions that regulate gene expression levels. This approach has been termed 'genetical genomics', and, when used in conjunction with the identification of genomic regions (QTLs) that regulate the complex physiological trait under investigation, provides a strong basis for candidate gene discovery. In this paper, we describe the implementation of the genetical genomic/phenotypic approach to identify candidate genes for sensitivity to the analgesic effect of morphine in BXD recombinant inbred mice. Our analysis was performed 'in silico', using an online interactive resource called PhenoGen (http://phenogen.ucdenver.edu). We describe in detail the use of this resource, which identified a set of candidate genes, some of whose products regulate the cellular localization and activity of the mu opiate receptor. The results demonstrate how PhenoGen can be used to identify a novel set of genes that can be further investigated for their potential role in pain, morphine analgesia and/or morphine tolerance.

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.

Trivalent influenza vaccination randomized control trial of pregnant women and adverse fetal outcomes.

INTRODUCTION: The purpose of this study was to evaluate the association of influenza vaccine during pregnancy and adverse fetal outcomes. Preventing fetal death, low birth weight, small for gestational age birth and preterm birth are important potential effects of antenatal maternal influenza immunization for which there are conflicting data. MATERIALS AND METHODS: A double-blind, randomized, placebo-controlled clinical trial of trivalent inactivated influenza vaccine was conducted in South Africa from March 2011 until after the 2012 influenza season when the infants born had reached the age of 24 weeks. Mothers were administered the vaccine or placebo during pregnancy at a gestation of 20 to 36 weeks. A comparison of rates of fetal death, low birth weight, small for gestational age birth, and preterm birth, between vaccinated and placebo groups was made. Fetal outcome differences between the groups were measured using Student's t-tests, vaccine efficacy with 95% confidence intervals, and Poisson regression for incidence rates. All analyses except fetal death excluded mothers who were administered vaccine or placebo after 34 weeks gestational age. RESULTS: There were 2116 HIV-uninfected pregnant women age 18 to 38 years in the trial; 2005 infants were born to mothers where vaccine or placebo had been administered ≥ 14 days prior to delivery, and there were 6 miscarriages and 23 stillbirths. There was no significant vaccine efficacy (with [95% confidence interval]) on fetal death (-21.2% [-150.8, 41.4]), low birth weight (-11.1% [-42.3, 12.5]), small for gestational age birth (-9.9% [-35.6, 11.0]), or preterm birth (-21.3% [-60.5, 8.3]). Neither was vaccine efficacy demonstrated when the analysis was restricted to infants of mothers who were exposed to an influenza season (1832 outcomes available). CONCLUSION: We did not find a beneficial effect of trivalent inactivated influenza vaccine during pregnancy on adverse fetal outcomes.