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Viktor Chirikov,1 Marc Botteman,1 Eric AF Simões2 1OPEN Health, Evidence & Access, Bethesda, MD, USA; 2Department of Pediatrics, University of Colorado School of Medicine, Department of Epidemiology, Center for Global Health, Colorado School of Public Health, and Section of Infectious Disease, Children’s Hospital Colorado, Aurora, CO, USACorrespondence: Viktor Chirikov, OPEN Health Evidence & Access, Bethesda, MD, 20814, USA, Tel +1 240 821 9662, Email ViktorChirikov@openhealthgroup.comBackground: 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.Keywords: respiratory syncytial virus, long-term follow-up, lower respiratory tract infection, prematurity

Background: A model to predict hospitalization due to respiratory syncytial virus (RSV) of infants born at 33- 35 weeks' gestation was developed using seven risk factors from the Spanish FLIP study 'birth ±10 weeks from the beginning of the RSV season', 'birth weight', 'breast fed <=2 months', 'number of siblings >=2 years', 'number of family members with atopy', 'number of family members with wheezing', and 'gender'. The aim of this study was to validate the model using French data. Methods: The FLIP model [predictive accuracy 71%, receiver operating characteristic (ROC) 0.791] was tested against the French data (77 hospitalized infants with RSV born at 33-35 weeks and 154 age-matched controls) using discriminatory function analysis by applying the FLIP coefficients to the French data and by generating the seven variable model from the French data. Results: Applying the FLIP coefficients to the French dataset, the model correctly classified 69% of cases (ROC 0.627). The predictive power increased to 73% (ROC 0.654) when 'number of siblings >=2 years' was substituted for 'number of children at school'. The number needed to treat (NNT) in order to prevent 70% of hospitalizations was 18. The model derived using French data could correctly classify 62% of cases in the French data (ROC 0.658). Conclusions: The model was successfully validated and may potentially optimize immunoprophylaxis in French infants born at 33-35 week's gestation. [ABSTRACT FROM AUTHOR]

Objective:To determine the bacterial etiology, clinical presentation and risk factors for outcome of serious community-acquired infections in young infants.Study Design:Infants younger than 60 days, admitted for severe pneumonia or suspected sepsis/meningitis were prospectively evaluated using complete blood count, blood culture, chest radiograph, cerebrospinal fluid (CSF) culture in suspected meningitis. chi (2) or Fisher's exact test and stepwise logistic regression were used for analysis.Results:Thirty-four of 767 enrolled infants had a positive blood or CSF culture. Gram-negative bacteria were more frequent than Gram positive: overall (P=0.004), in those below 7 days of age (P=0.002) and among home deliveries (P=0.012). Case fatality rates were higher among infants below 1 week old (OR 4.14, P<0.001), those with dense (OR 2.92, P<0.001) or diffuse radiographic infiltrates (OR 2.79, P=0.003).Conclusions:Gram-negative enteric bacteria are the predominant causes of community-acquired infections in Filipino infants below 2 months old. Age below 7 days and radiographic pneumonia predicted death. [ABSTRACT FROM AUTHOR]

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. Copyright © 2003 World Health Organization [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess the burden of respiratory syncytial virus (RSV)-associated lower respiratory infections (LRI) in children in four developing countries. METHODS: A WHO protocol for prospective population-based surveillance of acute respiratory infections in children aged less than 5 years was used at sites in Indonesia, Mozambique, Nigeria and South Africa. RSV antigen was identified by enzyme-linked immunosorbent assay performed on nasopharyngeal specimens from children meeting clinical case definitions. FINDINGS: Among children aged < 5 years, the incidence of RSV-associated LRI per 1000 child-years was 34 in Indonesia and 94 in Nigeria. The incidence of RSV-associated severe LRI per 1000 child-years was 5 in Mozambique, 10 in Indonesia, and 9 in South Africa. At all study sites, the majority of RSV cases occurred in infants. CONCLUSION: These studies demonstrate that RSV contributes to a substantial but quite variable burden of LRI in children aged < 5 years in four developing countries. The possible explanations for this variation include social factors, such as family size and patterns of seeking health care; the proportion of children infected by human immunodeficiency syndrome (HIV); and differences in clinical definitions used for obtaining samples. The age distribution of cases indicates the need for an RSV vaccine that can protect children early in life. [ABSTRACT FROM AUTHOR]

Background: Rectovaginal group B Streptococcus (GBS) colonisation in pregnant individuals at the time of labour is a major risk factor for invasive GBS disease by age 7 days (early-onset disease). We aimed to investigate the prevalence of rectovaginal GBS colonisation at the time of labour among pregnant women and vertical transmission to their newborns across selected low-income and middle-income African and south Asian countries., Methods: This prospective, observational study was undertaken at 11 maternity and obstetric care facilities based in Ethiopia, Kenya, Mozambique, Nigeria, Mali, South Africa, Bangladesh, India, and Bhutan. HIV-negative pregnant women aged 18-45 years who were in the early stages of labour and at least 37 weeks' gestation were eligible for inclusion. Lower vaginal and rectal swabs and urine were collected from the women, and swabs of the umbilicus, outer ear, axillary fold, rectum, and throat were obtained from their newborns, for GBS culture. Standardised sampling and culture using direct plating and selective media broth for detection of GBS colonisation was undertaken at the sites. Serotyping of GBS isolates was done in South Africa. The primary outcome was the prevalence of rectovaginal GBS among pregnant women, analysed in participants with available data. This study is registered with the South African National Clinical Trials Register, number DOH-27-0418-4989., Findings: 6922 pregnant women were enrolled from Jan 10, 2016, to Dec 11, 2018, of whom 6514 (94·1%; 759-892 per country) were included in the analysis; data from Bhutan were not included in the study due to issues with specimen collection and processing. Overall, the prevalence of maternal GBS colonisation was 24·1% (95% CI 23·1-25·2; 1572 of 6514); it was highest in Mali (41·1% [37·7-44·6]; 314 of 764) and lowest in Ethiopia (11·6% [9·5-14·1]; 88 of 759). The overall rate of vertical transmission of GBS from women with rectovaginal GBS colonisation was 72·3% (70·0-74·4; 1132 of 1566); it was highest in Mozambique (79·2% [73·3-84·2]; 168 of 212) and lowest in Bangladesh (55·8%, 47·5-63·8; 77 of 138). The five most common GBS colonising serotypes were Ia (37·3% [34·9-39·7]; 586 of 1572), V (28·5% [26·3-30·8]; 448 of 1572), III (25·1% [23·0-27·3]; 394 of 1572), II (9·2% [7·8-10·7]; 144 of 1572), and Ib (6·5% [5·4-7·8]; 102 of 1572). There was geographical variability in serotype proportion distribution; serotype VII was the third most common serotype in India (8·6% [5·3-13·7]; 15 of 174) and serotype VI was mainly identified in Bangladesh (5·8% [3·0-11·0]; eight of 138) and India (5·7% [3·2-10·3]; ten of 174)., Interpretation: Our study reported a high prevalence of GBS colonisation in most settings, with some geographical variability even within African countries. Our findings suggest that serotypes not included in current multivalent capsular-polysaccharide GBS vaccines prevail in some regions, so vaccine efficacy and post-licensure effectiveness studies should assess the effect of vaccination on maternal GBS colonisation given the potential for replacement by non-vaccine serotypes., Funding: Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests SAM declares grant funding to his institution for research on GBS, separate from this study, from Pfizer, GlaxoSmithKline, and Minervax. GK declares grant funding to his institution for research on GBS from the Bill & Melinda Gates Foundation and PATH. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aim: To examine and compare the medical burden of measles, influenza and COVID-19 outbreaks in the city of Bnei Brak, Israel., Methods: The study was conducted during 2018-2021. The numbers of hospitalisations for these infections and their complications were recorded. Hospitalisation rates were determined by using the number of children residing in Bnei Brak and hospitalised with these infections during the study period as the numerators. The denominators were the estimated paediatric cases of measles, influenza and COVID-19 in Bnei Brak and were calculated under both pragmatic and conservative assumptions., Results: A total of 247, 65 and 32 children were hospitalised with influenza, COVID-19 and measles respectively. Complication rates were higher following measles than after influenza and SARS-CoV-2 infections. Hospitalisation rates were 10% for measles, 0.6%-1.2% for influenza and 0.15% - 0.25% for COVID-19 infections. Relative risks (RR) with 95% confidence intervals (CI) for hospitalisation following measles compared with COVID-19 ranged from 42 (26.3-67.3) to 70.1 (43.8-112.1), while the relative risks for influenza hospitalisation ranged from 2.5 (1.83-3.41) to 8.2 (6.0-11.2), compared with COVID-19 infection., Conclusion: Hospitalisation rates and direct medical burdens of measles and influenza were significantly higher than those of COVID-19 infection in children., (©2021 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Limited data exist on the burden of respiratory syncytial virus (RSV) illness among pregnant women, to determine their potential benefit from RSV vaccination. We evaluated the incidence of RSV illness from midpregnancy until 24 weeks postpartum in human immunodeficiency virus (HIV)-uninfected and HIV-infected women and their infants., Methods: Mother-infant dyads were enrolled in maternal influenza vaccine efficacy trials. These included 1060 and 1056 HIV-uninfected pregnant women in 2011 and 2012, respectively, 194 HIV-infected pregnant women in 2011, and their infants. Upper respiratory tract samples obtained at illness visits were tested for RSV., Results: The incidence (per 1000 person-months) of RSV illness (n = 43 overall) among HIV-uninfected women was lower in 2011 (1.2; 95% confidence interval [CI], .6-2.2) than in 2012 (4.0; 95% CI, 2.8-5.6). The incidence of RSV illness (n = 5) in HIV-infected women was 3.4 (95% CI, 1.4-8.1). Maternal RSV infection was associated with respiratory symptoms including cough (72.1%), rhinorrhea (39.5%), sore throat (37.2%), and headache (42%), but fever was absent. RSV infection during pregnancy was not associated with adverse pregnancy outcomes. Postpartum, RSV infection in mothers (n = 27) was associated with concurrent infection among 51.9% of their infants and, conversely, 29.8% of mothers investigated within 7 days of their infants having an RSV illness also tested positive for RSV., Conclusions: RSV infection is associated with respiratory illness during pregnancy and postpartum. Vaccination of pregnant women against RSV could benefit the mother, albeit primarily against nonfebrile illness, and her infant., Clinical Trial Registration: NCT01306669 and NCT01306682.

Background & Objectives: Human parvovirus B19V (B19V) is known to be associated with erythema infectiosum commonly in children, aplastic crisis, especially in persons with underlying haemolytic disorders, hydrops fetalis in pregnancies and arthritis. This cross-sectional study was aimed to determine the presence of B19V infection in childhood febrile illnesses, association of B19V with arthropathies and in adult patients with end-stage renal disease (ESRD) on dialysis. The genetic diversity among the sequences was also analysed., Methods: A nested polymerase chain reaction (nPCR) assay was used for B19V DNA targeting VP1/VP2 region and used for testing 618 patients and 100 healthy controls. Phylogenetic analysis on nucleotide and amino acid sequences was carried out to compare our sequences with other Indian strains and global strains., Results: Among 618 samples tested, seven (1.13%) were found positive. The phylogenetic analysis revealed that all the seven sequences belonged to genotype 1 and showed low genetic diversity. The clustering pattern of seven sequences was similar both by nucleotide and by predicted amino acid sequences. The fixed effects likelihood analysis showed no positive or negatively selected sites., Interpretation & Conclusions: Seven samples (4 from non-traumatic arthropathies, 2 from patients with ESRD and 1 from febrile illness patient) were found positive by nPCR. When our seven sequences were compared with global strains, the closest neighbour was other Indian strains followed by the Tunisian strains., Competing Interests: None

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.)

The pathology of respiratory syncytial virus (RSV) disease in bonnet monkeys parallels findings with human RSV disease. RSV-infected animals pre-immunized with a formalin-inactivated (FI) RSV vaccine develop inflammation in peribronchiolar, perivascular, interstitial and intra-alveolar sites with lung inflammation scores significantly higher than animals with a primary RSV infection and those pre-immunized with an FI-Vero cell control vaccine (P=0.05). Animals previously infected and re-exposed to RSV had significantly lower alveolar, interstitial and total lung inflammation scores than in primary infection (P=0.05). Immunization with two intra-muscular doses of 0.5 ml of the FI-RSV vaccine administered 21 days apart resulted in little serum-neutralizing and ELISA antibody, low levels of secretory IgA and a low lymphocyte proliferative response that was significantly lower than the response observed in animals that were previously infected with live RSV. Higher RSV virus titres were detected in the lungs and lung lavage fluid of monkeys immunized with the FI-RSV vaccine than in those with a primary infection (P=0.001). RSV was detected by in situ hybridization in pulmonary inflammatory infiltrates, where the single most abundant infiltrating cellular species was macrophages, so it may be these cells that support the enhanced virus replication that contributes to the enhanced pulmonary pathology of FI-RSV immunization.

Vaccine-associated paralytic poliomyelitis is a serious concern while using the live attenuated oral polio vaccine for the eradication of poliomyelitis. The bonnet monkey model of poliovirus central nervous system (CNS) infection following experimental inoculation into the ulnar nerve allows the comparative study of wild-type and attenuated poliovirus invasiveness. Dosages >/=10(4) TCID(50) of Mahoney strain of poliovirus type 1 [PV1(M)] result in paralysis. In contrast, even with 10(7) TCID(50) of Sabin attenuated strain of poliovirus type 1 (LSc/2ab), no paralysis occurs, but virus spreads into the CNS where viral RNA is found in spinal cord neurons. While wild-type PV1(M) viral RNA replicates in neurons (and possibly in glial cells) and in cells around vessel walls, which may be mononuclear or endothelial cells, attenuated viral RNA is detected only in neurons. Systemic viraemia and gastrointestinal virus shedding occurs only in PV1(M)-infected animals. While a systemic serologic response is detected in both groups of animals, cerebrospinal fluid antibodies are detected only in animals infected with PV1(M). Both the PV1(M) and LSc/2ab strains spread to the cervical spinal cord and then to the lumbar spinal cord following ulnar nerve inoculation. Neuronophagia and neuronal loss are only seen in PV1(M)-infected monkeys in whom clinical paralysis is observed. Infection with LSc/2ab does not result in neuronophagia, neuronal loss or clinical paralysis. Spread of attenuated poliovirus in spinal cord neurons without causing paralysis following inoculation into the ulnar nerve is an important finding.