Neurodevelopmental outcomes following possible serious bacterial infection in early infancy in Karachi, Pakistan: a prospective cohort study.

BACKGROUND: Pakistan reports a significant burden of neonatal mortality, with infections as one of the major causes. We aim to assess the long-term impact of early infancy infections on neurodevelopmental outcomes during later childhood. METHODS: We conducted a prospective follow-up study of the cohort enrolled at the Karachi site of the Aetiology of Neonatal Infection in South Asia (ANISA) during 2019-2020. Children with a possible serious bacterial infection (based on the WHO IMCI algorithm) at early infancy were assessed for neurodevelopment at 6-9 years of age and compared with healthy controls. The Ten Questions (TQS) questionnaire, Strengths and Difficulties Questionnaire (SDQ), and Parent's Evaluation of Developmental Stage Assessment Level (PEDS: DM-AL) neurodevelopmental assessment tools, were administered and scored by the research staff who were blinded to the child's exposure status. Generalized Structural Equation Modelling (GSEM) was employed to verify relationships and associations among developmental milestones, anthropometry, and sociodemographic variables. RESULTS: A total of 398 children (241 cases and 157 controls) completed neurodevelopmental and growth assessments. Cases had a significantly higher rate of abnormal TQS scores (54.5% vs. 35.0%, p-value 0.001), greater delays in motor milestones (21.2% vs. 12.1%, p-value 0.02), lower fine motor skills (78.4 ± 1.4 vs. 83.2 ± 1.5, p-value 0.02). The receptive language skills were well-developed in both groups. According to the logistic regression model, exposure to infection during the first 59 days of life was associated with delayed TQS milestones (ß = -0.6, 95% CI -1.2,-0.04), TQS hearing domain (ß = -0.3, 95% CI: -1.2 to 0.7), PEDS: DM-AL fine motor domain (ß = -1.3, 95% CI: -4.4 to 1.7), PEDS: DM-AL receptive language development (ß = -1.1, 95% CI: -3.7 to 1.4) and child anthropometric measurements such as weight and height (ß = -0.2, 95% CI: -0.4 to 0.01 and ß = -0.2, 95% CI: -0.4 to -0.01, respectively). Early pSBI exposure was positively associated with PEDS: DM-AL self-help domain (ß = 0.6, 95% CI: -1.2 to 2.4) and SDQ-P overall score (ß = 0.02, 95% CI: -0.3 to 0.3). CONCLUSION: Children exposed to PSBI during early infancy have higher rates of abnormal development, motor delays, and lower fine motor skills during later childhood in Pakistan. Socioeconomic challenges and limited healthcare access contribute to these challenges, highlighting the need for long-term follow-ups with integrated neurodevelopment assessments.

Implementation research to increase treatment coverage of possible serious bacterial infections in young infants when a referral is not feasible: lessons learnt.

BACKGROUND: The objective was to achieve high coverage of possible serious bacterial infections (PSBI) treatment using the World Health Organization (WHO) guideline for managing it on an outpatient basis when referral to a hospital is not feasible. METHODS: We implemented this guideline in the programme settings at 10 Basic Health Units (BHU) in two rural districts of Sindh in Pakistan using implementation research. A Technical Support Unit supported the programme to operationalize guidelines, built capacity of health workers through training, monitored their clinical skills, mentored them and assured quality. The community-based health workers visited households to identify sick infants and referred them to the nearest BHU for further management. The research team collected data. RESULTS: Of 17 600 identified livebirths, 1860 young infants with any sign of PSBI sought care at BHUs and 1113 (59.8%) were brought by families. We achieved treatment coverage of 95%, assuming an estimated 10% incidence of PSBI in the first 2 months of life and that 10% of young infants came from outside the study catchment area. All 923 infants (49%; 923/1860) 7-59 days old with only fast breathing (pneumonia) treated with outpatient oral amoxicillin were cured. Hospital referral was refused by 83.4% (781/937) families who accepted outpatient treatment; 92.2% (720/781) were cured and 0.8% (6/781) died. Twelve (7.6%; 12/156) died among those treated in a hospital. CONCLUSION: It is feasible to achieve high coverage by implementing WHO PSBI management guidelines in a programmatic setting when a referral is not feasible.

Prospective cohort study of referred Malawian children and their survival by hypoxaemia and hypoglycaemia status.

Objective: To investigate survival in children referred from primary care in Malawi, with a focus on hypoglycaemia and hypoxaemia progression. Methods: The study involved a prospective cohort of children aged 12 years or under referred from primary health-care facilities in Mchinji district, Malawi in 2019 and 2020. Peripheral blood oxygen saturation (SpO2) and blood glucose were measured at recruitment and on arrival at a subsequent health-care facility (i.e. four hospitals and 14 primary health-care facilities). Children were followed up 2 weeks after discharge or their last clinical visit. The primary study outcome was the case fatality ratio at 2 weeks. Associations between SpO2 and blood glucose levels and death were evaluated using Cox proportional hazards models and the treatment effect of hospitalization was assessed using propensity score matching. Findings: Of 826 children recruited, 784 (94.9%) completed follow-up. At presentation, hypoxaemia was moderate (SpO2: 90-93%) in 13.1% (108/826) and severe (SpO2: < 90%) in 8.6% (71/826) and hypoglycaemia was moderate (blood glucose: 2.5-4.0 mmol/L) in 9.0% (74/826) and severe (blood glucose: < 2.5 mmol/L) in 2.3% (19/826). The case fatality ratio was 3.7% (29/784) overall but 26.3% (5/19) in severely hypoglycaemic children and 12.7% (9/71) in severely hypoxaemic children. Neither moderate hypoglycaemia nor moderate hypoxaemia was associated with mortality. Conclusion: Presumptive pre-referral glucose treatment and better management of hypoglycaemia could reduce the high case fatality ratio observed in children with severe hypoglycaemia. The morbidity and mortality burden of severe hypoxaemia was high; ways of improving hypoxaemia identification and management are needed.

Antibiotics needed to treat multidrug-resistant infections in neonates.

Infections remain a leading cause of death in neonates. The sparse antibiotic development pipeline and challenges in conducting neonatal research have resulted in few effective antibiotics being adequately studied to treat multidrug-resistant (MDR) infections in neonates, despite the increasing global mortality burden caused by antimicrobial resistance. Of 40 antibiotics approved for use in adults since 2000, only four have included dosing information for neonates in their labelling. Currently, 43 adult antibiotic clinical trials are recruiting patients, compared with only six trials recruiting neonates. We review the World Health Organization (WHO) priority pathogens list relevant to neonatal sepsis and propose a WHO multiexpert stakeholder meeting to promote the development of a neonatal priority antibiotic development list. The goal is to develop international, interdisciplinary consensus for an accelerated neonatal antibiotic development programme. This programme would enable focused research on identified priority antibiotics for neonates to reduce the excess morbidity and mortality caused by MDR infections in this vulnerable population.

Les infections demeurent l'une des principales causes de décès chez les nouveau-nés. Les rares projets de développement d'antibiotiques et les défis posés par la recherche néonatale ont entraîné une pénurie d'antibiotiques efficaces spécialement étudiés pour traiter les infections multirésistantes (MR) chez les nouveau-nés, en dépit d'une mortalité galopante due à une résistance accrue aux antimicrobiens. Sur 40 antibiotiques autorisés pour les adultes depuis 2000, quatre à peine sont munis d'un étiquetage indiquant la posologie adaptée aux nouveau-nés. Actuellement, 43 essais cliniques portant sur des antibiotiques recrutent des patients du côté des adultes, contre six seulement du côté des nouveau-nés. Dans le présent document, nous passons en revue la liste prioritaire d'agents pathogènes établie par l'Organisation mondiale de la Santé (OMS) pour soigner la septicémie néonatale et proposons de réunir, sous l'égide de l'OMS, des parties prenantes issues de plusieurs domaines d'expertise afin de promouvoir la création d'une liste prioritaire de développement d'antibiotiques destinés aux nouveau-nés. Objectif: parvenir à un consensus international et interdisciplinaire visant à accélérer le programme de mise au point d'antibiotiques à usage néonatal. Ce programme permettrait d'orienter les recherches vers des antibiotiques identifiés comme prioritaires pour les nouveau-nés, en vue de faire baisser les taux de morbidité et de mortalité excessifs qu'engendrent les infections MR au sein de cette population vulnérable.

Las infecciones siguen siendo una de las principales causas de muerte en los recién nacidos. Debido al escaso desarrollo de los antibióticos y a las dificultades para llevar a cabo la investigación neonatal, son pocos los antibióticos eficaces que se estudian de manera adecuada para tratar las infecciones multirresistentes (MR) en los recién nacidos, a pesar de la creciente carga de mortalidad mundial causada por la resistencia a los antimicrobianos. De los 40 antibióticos aprobados para su uso en adultos desde el 2000, solo cuatro han incluido información sobre la dosis para recién nacidos en su etiquetado. En la actualidad, 43 ensayos clínicos con antibióticos para adultos están reclutando pacientes, en comparación con solo seis ensayos que reclutan recién nacidos. Se revisa la lista de patógenos prioritarios de la Organización Mundial de la Salud (OMS) relevantes para la sepsis neonatal y se propone una reunión de la OMS con múltiples expertos para promover el desarrollo de una lista de antibióticos prioritarios para los recién nacidos. El objetivo es desarrollar un consenso internacional e interdisciplinario para establecer un programa acelerado de desarrollo de antibióticos neonatales. Este programa permitiría centrar la investigación en los antibióticos prioritarios identificados para los recién nacidos con el fin de reducir el exceso de morbilidad y mortalidad causado por las infecciones MR en esta población vulnerable.

Antibiotic use for inpatient newborn care with suspected infection: EN-BIRTH multi-country validation study.

BACKGROUND: An estimated 30 million neonates require inpatient care annually, many with life-threatening infections. Appropriate antibiotic management is crucial, yet there is no routine measurement of coverage. The Every Newborn Birth Indicators Research Tracking in Hospitals (EN-BIRTH) study aimed to validate maternal and newborn indicators to inform measurement of coverage and quality of care. This paper reports validation of reported antibiotic coverage by exit survey of mothers for hospitalized newborns with clinically-defined infections, including sepsis, meningitis, and pneumonia. METHODS: EN-BIRTH study was conducted in five hospitals in Bangladesh, Nepal, and Tanzania (July 2017-July 2018). Neonates were included based on case definitions to focus on term/near-term, clinically-defined infection syndromes (sepsis, meningitis, and pneumonia), excluding major congenital abnormalities. Clinical management was abstracted from hospital inpatient case notes (verification) which was considered as the gold standard against which to validate accuracy of women's report. Exit surveys were conducted using questions similar to The Demographic and Health Surveys (DHS) approach for coverage of childhood pneumonia treatment. We compared survey-report to case note verified, pooled across the five sites using random effects meta-analysis. RESULTS: A total of 1015 inpatient neonates admitted in the five hospitals met inclusion criteria with clinically-defined infection syndromes. According to case note verification, 96.7% received an injectable antibiotic, although only 14.5% of them received the recommended course of at least 7 days. Among women surveyed (n = 910), 98.8% (95% CI: 97.8-99.5%) correctly reported their baby was admitted to a neonatal ward. Only 47.1% (30.1-64.5%) reported their baby's diagnosis in terms of sepsis, meningitis, or pneumonia. Around three-quarters of women reported their baby received an injection whilst in hospital, but 12.3% reported the correct antibiotic name. Only 10.6% of the babies had a blood culture and less than 1% had a lumbar puncture. CONCLUSIONS: Women's report during exit survey consistently underestimated the denominator (reporting the baby had an infection), and even more so the numerator (reporting known injectable antibiotics). Admission to the neonatal ward was accurately reported and may have potential as a contact point indicator for use in household surveys, similar to institutional births. Strengthening capacity and use of laboratory diagnostics including blood culture are essential to promote appropriate use of antibiotics. To track quality of neonatal infection management, we recommend using inpatient records to measure specifics, requiring more research on standardised inpatient records.

Predictive value of pulse oximetry for mortality in infants and children presenting to primary care with clinical pneumonia in rural Malawi: A data linkage study.

BACKGROUND: The mortality impact of pulse oximetry use during infant and childhood pneumonia management at the primary healthcare level in low-income countries is unknown. We sought to determine mortality outcomes of infants and children diagnosed and referred using clinical guidelines with or without pulse oximetry in Malawi. METHODS AND FINDINGS: We conducted a data linkage study of prospective health facility and community case and mortality data. We matched prospectively collected community health worker (CHW) and health centre (HC) outpatient data to prospectively collected hospital and community-based mortality surveillance outcome data, including episodes followed up to and deaths within 30 days of pneumonia diagnosis amongst children 0-59 months old. All data were collected in Lilongwe and Mchinji districts, Malawi, from January 2012 to June 2014. We determined differences in mortality rates using <90% and <93% oxygen saturation (SpO2) thresholds and World Health Organization (WHO) and Malawi clinical guidelines for referral. We used unadjusted and adjusted (for age, sex, respiratory rate, and, in analyses of HC data only, Weight for Age Z-score [WAZ]) regression to account for interaction between SpO2 threshold (pulse oximetry) and clinical guidelines, clustering by child, and CHW or HC catchment area. We matched CHW and HC outpatient data to hospital inpatient records to explore roles of pulse oximetry and clinical guidelines on hospital attendance after referral. From 7,358 CHW and 6,546 HC pneumonia episodes, we linked 417 CHW and 695 HC pneumonia episodes to 30-day mortality outcomes: 16 (3.8%) CHW and 13 (1.9%) HC patients died. SpO2 thresholds of <90% and <93% identified 1 (6%) of the 16 CHW deaths that were unidentified by integrated community case management (iCCM) WHO referral protocol and 3 (23%) and 4 (31%) of the 13 HC deaths, respectively, that were unidentified by the integrated management of childhood illness (IMCI) WHO protocol. Malawi IMCI referral protocol, which differs from WHO protocol at the HC level and includes chest indrawing, identified all but one of these deaths. SpO2 < 90% predicted death independently of WHO danger signs compared with SpO2 ≥ 90%: HC Risk Ratio (RR), 9.37 (95% CI: 2.17-40.4, p = 0.003); CHW RR, 6.85 (1.15-40.9, p = 0.035). SpO2 < 93% was also predictive versus SpO2 ≥ 93% at HC level: RR, 6.68 (1.52-29.4, p = 0.012). Hospital referrals and outpatient episodes with referral decision indications were associated with mortality. A substantial proportion of those referred were not found admitted in the inpatients within 7 days of referral advice. All 12 deaths in 73 hospitalised children occurred within 24 hours of arrival in the hospital, which highlights delay in appropriate care seeking. The main limitation of our study was our ability to only match 6% of CHW episodes and 11% of HC episodes to mortality outcome data. CONCLUSIONS: Pulse oximetry identified fatal pneumonia episodes at HCs in Malawi that would otherwise have been missed by WHO referral guidelines alone. Our findings suggest that pulse oximetry could be beneficial in supplementing clinical signs to identify children with pneumonia at high risk of mortality in the outpatient setting in health centres for referral to a hospital for appropriate management.

Safety of azithromycin in pediatrics: a systematic review and meta-analysis.

PURPOSE: To evaluate the toxicity of azithromycin in neonates, infants, and children. METHODS: A systematic review was performed for relevant studies using Medline (Ovid), PubMed, Cochrane Central Register of Controlled Trials, EMBASE, CINAHL, and International Pharmaceutical Abstracts. We calculated the pooled incidence of adverse drug reactions (ADRs) associated with azithromycin based on prospective studies (RCTs and prospective cohort studies) and analyzed the risk difference (RD) of ADRs between azithromycin and placebo or other antibiotics using meta-analysis of RCTs. RESULTS: We included 133 studies with 4243 ADRs reported in 197,675 neonates, infants, and children who received azithromycin. The safety of azithromycin as MDA in pediatrics was poorly monitored. The main ADRs were diarrhea and vomiting. In prospective non-MDA studies, the most common toxicity was gastrointestinal ADRs (938/1967; 47.7%). The most serious toxicities were cardiac (prolonged QT or irregular heart beat) and idiopathic hypertrophic pyloric stenosis (IHPS). Compared with placebo, azithromycin did not show increased risk ADRs based on RCTs (risk difference - 0.17 to 0.07). The incidence of QT prolonged was higher in the medium-dosage group (10-30 mg/kg/day) than that of low-dosage group (≤ 10 mg/kg/day) (82.0% vs 1.2%). CONCLUSION: The safety of azithromycin as MDA needs further evaluation. The most common ADRs are diarrhea and vomiting. The risk of the most serious uncommon ADRs (cardiac-prolonged QT and IHPS) is unknown.

Comparison of 3 Days Amoxicillin Versus 5 Days Co-Trimoxazole for Treatment of Fast-breathing Pneumonia by Community Health Workers in Children Aged 2-59 Months in Pakistan: A Cluster-randomized Trial.

BACKGROUND: Globally, most deaths due to childhood pneumonia occur at the community level. Some countries are still using oral co-trimoxazole, despite a World Health Organization recommendation of oral amoxicillin for the treatment of fast-breathing pneumonia in children at the community level. METHODS: We conducted an unblinded, cluster-randomized, controlled-equivalency trial in Haripur District, Pakistan. Children 2-59 months of age with fast-breathing pneumonia were treated with oral amoxicillin suspension (50 mg/kg/day) for 3 days in 14 intervention clusters and oral co-trimoxazole suspension (8 mg trimethoprim/kg and 40 mg sulfamethoxazole/kg/day) for 5 days in 14 control clusters by lady health workers (LHW). The primary outcome was treatment failure by day 4 for intervention clusters and by day 6 for control clusters. The analysis was per protocol. RESULTS: Out of the 15 749 cases enrolled in the study, 9153 cases in intervention and 6509 cases in control clusters were included in the analysis. Treatment failure rates were 3.6% (326) in intervention clusters and 9.1% (592) in control clusters. After adjusting for clustering, the risk of treatment failure was lower in intervention clusters (risk difference [RD] -5.5%, 95% confidence interval [CI] -7.4--3.7%) than in control clusters. Children with incomplete adherence had a small increase in treatment failure versus those with complete adherence (RD 2.9%, 95% CI 1.6-4.1%). No deaths or serious adverse events occurred. CONCLUSIONS: A 3-day course of oral amoxicillin, administered by LHWs, is an effective and safe treatment for fast-breathing pneumonia in children 2-59 months of age. A shorter course of amoxicillin improves adherence to therapy, is low in cost, and puts less pressure on antimicrobial resistance. CLINICAL TRIALS REGISTRATION: ISRCTN10618300.

mHealth intervention "ImTeCHO" to improve delivery of maternal, neonatal, and child care services-A cluster-randomized trial in tribal areas of Gujarat, India.

BACKGROUND: The coverage of community-based maternal, neonatal, and child health (MNCH) services remains low, especially in hard-to-reach areas. We evaluated the effectiveness of a mobile-phone-and web-based application, Innovative Mobile-phone Technology for Community Health Operations (ImTeCHO), as a job aid to the government's Accredited Social Health Activists (ASHAs) and Primary Health Center (PHC) staff to improve coverage of MNCH services in rural tribal communities of Gujarat, India. METHODS AND FINDINGS: This open cluster-randomized trial was conducted in 22 PHCs in six tribal blocks of Bharuch and Narmada districts in India. The ImTeCHO mobile-phone-and web-based application included various technology-based job aids to facilitate scheduling of home visits, screening for complications, counseling during home visits, and supportive supervision by PHC staff. Primary outcome indicators were a composite index calculated based on coverage of important MNCH services and coverage of at least two home visitations by ASHA within the first week of birth. Primary analysis was intention to treat (ITT). Generalized Estimating Equation (GEE) was used to account for clustering. Eleven PHCs each were randomly allocated to the intervention (280 ASHAs, population: 234,134) and control (281 ASHAs, population: 242,809) arms. The intervention was implemented from February, 2016 to January, 2017. At the end of the implementation, 6,493 mothers were surveyed. Most of the surveyed women were tribal (5,571, 85.8%), and reported having a government-issued certificate for living below poverty line (4,916, 75.7%). The coverage of at least two home visits within first week of birth was 32.4% in the intervention clusters compared to 22.9% in the control clusters (adjusted effect size 10.2 [95% CI: 6.4, 14.0], p < 0.001). Mean number of home visits within first week of birth was 1.11 and 0.80 for intervention and control clusters, respectively (adjusted effect size 0.34 [95% CI: 0.23, 0.45], p < 0.001). The composite coverage index was 43.0% in the intervention clusters compared to 38.5% (adjusted effect size 4.9 [95% CI: 0.2, 9.5], p = 0.03) in the control clusters. There were substantial improvements in coverage home visits by ASHAs during antenatal period (adjusted effect size 15.7 [95% CI: 11.0, 20.4], p < 0.001), postnatal period (adjusted effect size 6.4, [95% CI: 3.2, 9.6], p <0.001), early initiation of breastfeeding (adjusted effect size 7.8 [95% CI: 4.2, 11.4], p < 0.001), and exclusive breastfeeding (adjusted effect size 13.4 [95% CI: 8.9, 17.9], p < 0.001). Number of infant and neonatal deaths was similar in the two arms in the ITT analysis. The limitations of the study include potential risk of inaccuracies in reporting events that occurred during pregnancy by the mothers and the duration of intervention being 12 months, which might be considered short. CONCLUSIONS: In this study, we found that use of ImTeCHO mobile- and web-based application as a job aid by government ASHAs and PHC staff improved coverage and quality of MNCH services in hard-to-reach areas. Supportive supervision, change management, and timely resolution of technology-related issues were critical implementation considerations to ensure adherence to the intervention. TRIAL REGISTRATION: Study was registered at the Clinical Trial Registry of India (www.ctri.nic.in). Trial number: CTRI/2015/06/005847. The trial was registered (prospective) on 3 June, 2015. First enrollment was done on 26 August, 2015.

Oxygen systems to improve clinical care and outcomes for children and neonates: A stepped-wedge cluster-randomised trial in Nigeria.

BACKGROUND: Improving oxygen systems may improve clinical outcomes for hospitalised children with acute lower respiratory infection (ALRI). This paper reports the effects of an improved oxygen system on mortality and clinical practices in 12 general, paediatric, and maternity hospitals in southwest Nigeria. METHODS AND FINDINGS: We conducted an unblinded stepped-wedge cluster-randomised trial comparing three study periods: baseline (usual care), pulse oximetry introduction, and stepped introduction of a multifaceted oxygen system. We collected data from clinical records of all admitted neonates (<28 days old) and children (28 days to 14 years old). Primary analysis compared the full oxygen system period to the pulse oximetry period and evaluated odds of death for children, children with ALRI, neonates, and preterm neonates using mixed-effects logistic regression. Secondary analyses included the baseline period (enabling evaluation of pulse oximetry introduction) and evaluated mortality and practice outcomes on additional subgroups. Three hospitals received the oxygen system intervention at 4-month intervals. Primary analysis included 7,716 neonates and 17,143 children admitted during the 2-year stepped crossover period (November 2015 to October 2017). Compared to the pulse oximetry period, the full oxygen system had no association with death for children (adjusted odds ratio [aOR] 1.06; 95% confidence interval [CI] 0.77-1.46; p = 0.721) or children with ALRI (aOR 1.09; 95% CI 0.50-2.41; p = 0.824) and was associated with an increased risk of death for neonates overall (aOR 1.45; 95% CI 1.04-2.00; p = 0.026) but not preterm/low-birth-weight neonates (aOR 1.30; 95% CI 0.76-2.23; p = 0.366). Secondary analyses suggested that the introduction of pulse oximetry improved oxygen practices prior to implementation of the full oxygen system and was associated with lower odds of death for children with ALRI (aOR 0.33; 95% CI 0.12-0.92; p = 0.035) but not for children, preterm neonates, or neonates overall (aOR 0.97, 95% CI 0.60-1.58, p = 0.913; aOR 1.12, 95% CI 0.56-2.26, p = 0.762; aOR 0.90, 95% CI 0.57-1.43, p = 0.651). Limitations of our study are a lower-than-anticipated power to detect change in mortality outcomes (low event rates, low participant numbers, high intracluster correlation) and major contextual changes related to the 2016-2017 Nigerian economic recession that influenced care-seeking and hospital function during the study period, potentially confounding mortality outcomes. CONCLUSIONS: We observed no mortality benefit for children and a possible higher risk of neonatal death following the introduction of a multifaceted oxygen system compared to introducing pulse oximetry alone. Where some oxygen is available, pulse oximetry may improve oxygen usage and clinical outcomes for children with ALRI. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12617000341325.

Causes and incidence of community-acquired serious infections among young children in south Asia (ANISA): an observational cohort study.

BACKGROUND: More than 500 000 neonatal deaths per year result from possible serious bacterial infections (pSBIs), but the causes are largely unknown. We investigated the incidence of community-acquired infections caused by specific organisms among neonates in south Asia. METHODS: From 2011 to 2014, we identified babies through population-based pregnancy surveillance at five sites in Bangladesh, India, and Pakistan. Babies were visited at home by community health workers up to ten times from age 0 to 59 days. Illness meeting the WHO definition of pSBI and randomly selected healthy babies were referred to study physicians. The primary objective was to estimate proportions of specific infectious causes by blood culture and Custom TaqMan Array Cards molecular assay (Thermo Fisher, Bartlesville, OK, USA) of blood and respiratory samples. FINDINGS: 6022 pSBI episodes were identified among 63 114 babies (95·4 per 1000 livebirths). Causes were attributed in 28% of episodes (16% bacterial and 12% viral). Mean incidence of bacterial infections was 13·2 (95% credible interval [CrI] 11·2-15·6) per 1000 livebirths and of viral infections was 10·1 (9·4-11·6) per 1000 livebirths. The leading pathogen was respiratory syncytial virus (5·4, 95% CrI 4·8-6·3 episodes per 1000 livebirths), followed by Ureaplasma spp (2·4, 1·6-3·2 episodes per 1000 livebirths). Among babies who died, causes were attributed to 46% of pSBI episodes, among which 92% were bacterial. 85 (83%) of 102 blood culture isolates were susceptible to penicillin, ampicillin, gentamicin, or a combination of these drugs. INTERPRETATION: Non-attribution of a cause in a high proportion of patients suggests that a substantial proportion of pSBI episodes might not have been due to infection. The predominance of bacterial causes among babies who died, however, indicates that appropriate prevention measures and management could substantially affect neonatal mortality. Susceptibility of bacterial isolates to first-line antibiotics emphasises the need for prudent and limited use of newer-generation antibiotics. Furthermore, the predominance of atypical bacteria we found and high incidence of respiratory syncytial virus indicated that changes in management strategies for treatment and prevention are needed. Given the burden of disease, prevention of respiratory syncytial virus would have a notable effect on the overall health system and achievement of Sustainable Development Goal. FUNDING: Bill & Melinda Gates Foundation.

Improving community health worker performance through supportive supervision: a randomised controlled implementation trial in Pakistan.

AIM: To assess the effect of enhanced supportive supervision of lady health workers (LHWs) by lady health supervisors on integrated community case management of childhood pneumonia and diarrhoea. METHODS: A total of thirty-four supervisors were randomly assigned to intervention and comparison arms. The intervention included enhanced training of supervisors on supervisory skills and written feedback to LHWs by supervisors. The performance of both cadres was assessed three times. Household surveys judged caregiver practices. RESULTS: Intervention arm LHWs performed better than those in the comparison arm in assessing dehydration (92% [n = 25] vs 64% [n = 25]) and in classifying diarrhoea correctly (68% [n = 25] vs 40% [n = 25]). The two arms differed little in correct disease classification for pneumonia (44% [n = 25] vs 40% [n = 25]). Supervisory performance of intervention arm supervisors was better than that in the comparison arm in correcting the workers' clinical examination skills (64% [n = 25] vs 40% [n = 25]) and more frequent feedback. In the household survey, only 18% (n = 2182) intervention and 23% (n = 2197) comparison arm caregivers considered LHWs capable of providing diarrhoea and pneumonia care. Commodities for integrated community case management were not regularly available to workers. CONCLUSION: Supportive supervision can improve community case management performance. Support through refresher training, logistics and commodities is essential.

Using the RE-AIM framework to evaluate the implementation of integrated community case management in Kenya.

AIM: To evaluate an integrated community case management programme for sick children aged 2 to 59 months in western Kenya using the Research, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework. METHODS: This was a prospective observational research project conducted between December 2013 and February 2016. Outcome variables were measured before, during and at end of implementation using a series of surveys as well as by looking at routine service statistics. RESULTS: A total of 2604 community health workers were trained in 245 community units. The average post-training knowledge level (73.5%) and retention rates (89.7) of trained community health workers was high. At the end of study, there was an increase in the proportion of children who received appropriate treatment for diarrhoea (49.2%), pneumonia (19.5%), malaria (16.4%) and vitamin A (51.5%) from baseline. Community health workers were able to assess, classify and treat sick children with a similar quality as that provided by facility-based healthcare workers (>85% concordance). CONCLUSION: Based on the RE-AIM metrics, our results demonstrate promising practical approaches and outcomes of a large-scale implementation of integrated community case management in western Kenya. The findings have important implications for future design and expansion of the programme in Kenya.

Community case management of lower chest indrawing pneumonia with oral amoxicillin in children in Kenya.

AIM: To determine the accuracy and effectiveness of community health workers (CHWs) when compared to trained nurses for management of pneumonia in Kenyan children. METHODS: In Homabay County in western Kenya, children 2-59 months of age with lower chest indrawing pneumonia were identified, classified and treated by CHWs with oral amoxicillin (90 mg/kg per day) for five days at home. Trained nurses visited the child within 24 hours to verify diagnosis; and on day 4 and 14 to assess treatment outcomes. RESULTS: CHWs identified 1906 children with lower chest indrawing pneumonia. There was an 88.7% concordance in classification and treatment for lower chest indrawing pneumonia by CHWs compared to nurses. Children with moderate malnutrition (OR 1.68; 95% CI: 1.22-2.30), comorbidities such as diarrhoea or malaria (OR 1.55; 95% CI: 1.32-1.81) or an additional day of delay in care seeking (OR 1.06; 95% CI: 1.02-1.10) were more likely to have an incorrect classification of lower chest indrawing by the CHW. Comorbidity (OR 1.66; 95% CI: 1.12-2.48) and fast breathing (OR 4.66; 95% CI: 1.26-17.27) were significantly associated with treatment failure on day 14. CONCLUSION: CHWs can correctly manage lower chest indrawing pneumonia even in high-mortality settings, such as western Kenya, in sub-Saharan Africa.

Exploring health care seeking knowledge, perceptions and practices for childhood diarrhea and pneumonia and their context in a rural Pakistani community.

BACKGROUND: Where access to facilities for childhood diarrhea and pneumonia is inadequate, community case management (CCM) is an effective way of improving access to care. In Pakistan, utilization of CCM for these diseases through the Lady Health Worker Program remains low. Challenges of access to facilities persist leading to delayed care and poor outcomes. Estimating caregiver knowledge, understanding their perceptions and practices, and recognizing how these are related to care seeking decisions about childhood diarrhea and pneumonia is crucial to bring about coherence between supply and demand-side practices. METHODS: Data was collected from family caregivers to explore their knowledge, perceptions and practices regarding childhood diarrhea and pneumonia. Data from a household survey with 7025 caregivers, seven focus group discussion (FGDs), seven in-depth interviews (IDIs), and 20 detailed narrative interviews are used to explore caregiver knowledge, perceptions and practices. RESULTS: Household survey shows that most family caregivers recognize main signs and symptoms of diarrhea such as loose stools (76%). Fewer recognize signs and symptoms of pneumonia such as breathing problems (21%). Few caregivers (18%) have confidence in lady health workers' (LHWs) ability to treat childhood diarrhea and pneumonia. Care seeking from LHWs remains negligible (< 1%). Caregivers overwhelmingly prefer to seek care from doctors (97%). Seventy-five percent caregivers sought care from private providers and 45% from public providers. FGDs, IDIs, and narrative interviews show that care mostly begins with home remedies and sometimes self-prescribed medicines. Treatment delays occur because of caregiver inability to recognize disease, use of home remedies, financial constraints, and low utilization of community based LHW services. Caregivers do not seek care from LHWs because of lack of trust and LHWs' inability to provide medicines. If finances allow, private doctors, who caregivers perceive as more responsive, are preferred over public sector doctors. Financial resources, availability of time, support for household chores by family and community determine whether, when, and from whom caregivers seek care. CONCLUSIONS: Many children do not receive recommended diarrhea and pneumonia treatment on time. Taking into consideration caregiver concerns, adequate supply of medicines to LHWs, improved facility level care could improve care seeking practices and child health outcomes. TRIAL REGISTRATION: The trial is registered with 'Australian New Zealand Clinical Trials Registry'. Registration Number: ACTRN12613001261707 . Registered 18 November 2013.

Improving quality of care for perinatal and newborn care at district and subdistrict hospitals in Haryana, India: Implementation research protocol.

AIM: This implementation research aims to improve quality of care for mothers and newborns in three districts of Haryana, India at different public health facilities. BACKGROUND: The decline in key maternal and newborn health indicators in India is relatively slower than expected and missed the millennium development goals. The multifold rise in institutional delivery in last decade has limited impact on neonatal and maternal mortality. Despite investments in infrastructure, equipment, supplies, monitoring tools, and also manpower, suboptimal gains in indicators point towards potential challenge in quality of care. DESIGN: This study adopts pre-post, quasi-experimental study design with repeated observations using mixed research methods to document the impact of the plan-do-study-act implementation cycles. METHODS: The quality improvement interventions shall be implemented at three district hospitals and six-first referral unit hospitals in three districts of Haryana targeting the antenatal, delivery, newborn care services with nurses as the key partners. Formative research, situational analysis, and root-cause analysis shall inform the contextualization, prioritization of interventions. Incremental plan-do-study-act cycles over 15 months shall be implemented. The changes in adherence to protocols, appropriate documentation, reduction in delays, and client satisfaction shall be documented for 16 indicators across delivery, antenatal, and sick newborn care domains. DISCUSSION: The successful implementation of the quality improvement processes has the potential of improving the pregnancy outcomes in terms of stillbirths, maternal, and newborn mortality and sick newborn outcomes. The feasibility and learning of coimplementation in the public health system shall inform integration into standards and scaling up.

Providing oxygen to children in hospitals: a realist review.

OBJECTIVE: To identify and describe interventions to improve oxygen therapy in hospitals in low-resource settings, and to determine the factors that contribute to success and failure in different contexts. METHODS: Using realist review methods, we scanned the literature and contacted experts in the field to identify possible mechanistic theories of how interventions to improve oxygen therapy systems might work. Then we systematically searched online databases for evaluations of improved oxygen systems in hospitals in low- or middle-income countries. We extracted data on the effectiveness, processes and underlying theory of selected projects, and used these data to test the candidate theories and identify the features of successful projects. FINDINGS: We included 20 improved oxygen therapy projects (45 papers) from 15 countries. These used various approaches to improving oxygen therapy, and reported clinical, quality of care and technical outcomes. Four effectiveness studies demonstrated positive clinical outcomes for childhood pneumonia, with large variation between programmes and hospitals. We identified factors that help or hinder success, and proposed a practical framework depicting the key requirements for hospitals to effectively provide oxygen therapy to children. To improve clinical outcomes, oxygen improvement programmes must achieve good access to oxygen and good use of oxygen, which should be facilitated by a broad quality improvement capacity, by a strong managerial and policy support and multidisciplinary teamwork. CONCLUSION: Our findings can inform practitioners and policy-makers about how to improve oxygen therapy in low-resource settings, and may be relevant for other interventions involving the introduction of health technologies.

Research priorities in Maternal, Newborn, & Child Health & Nutrition for India: An Indian Council of Medical Research-INCLEN Initiative.

In India, research prioritization in Maternal, Newborn, and Child Health and Nutrition (MNCHN) themes has traditionally involved only a handful of experts mostly from major cities. The Indian Council of Medical Research (ICMR)-INCLEN collaboration undertook a nationwide exercise engaging faculty from 256 institutions to identify top research priorities in the MNCHN themes for 2016-2025. The Child Health and Nutrition Research Initiative method of priority setting was adapted. The context of the exercise was defined by a National Steering Group (NSG) and guided by four Thematic Research Subcommittees. Research ideas were pooled from 498 experts located in different parts of India, iteratively consolidated into research options, scored by 893 experts against five pre-defined criteria (answerability, relevance, equity, investment and innovation) and weighed by a larger reference group. Ranked lists of priorities were generated for each of the four themes at national and three subnational (regional) levels [Empowered Action Group & North-Eastern States, Southern and Western States, & Northern States (including West Bengal)]. Research priorities differed between regions and from overall national priorities. Delivery domain of research which included implementation research constituted about 70 per cent of the top ten research options under all four themes. The results were endorsed in the NSG meeting. There was unanimity that the research priorities should be considered by different governmental and non-governmental agencies for investment with prioritization on implementation research and issues cutting across themes.

Health workers' perspectives, knowledge and skills regarding community case management of childhood diarrhoea and pneumonia: a qualitative inquiry for an implementation research project "Nigraan" in District Badin, Sindh, Pakistan.

BACKGROUND: Pakistan's Lady Health Worker Programme aims to provide care to children sick with pneumonia and diarrhoea, which continues to cause 27 % under-five mortality in Pakistan. The quality of supervision received by Lady Health Workers (LHWs) in the programme influence their knowledge and skills, in turn impacting their ability to provide care. METHODS: This study is part of an implementation research project titled "Nigraan" (an Urdu word meaning supervisor), and explores LHW and Lady Health Supervisor (LHS) perspectives regarding the role of supervision in improving LHWs performance and motivation in district Badin, Sindh, Pakistan. Their knowledge and skills regarding integrated community case management (iCCM) of diarrhoea and pneumonia were also assessed. Fourteen focus group discussions and 20 in-depth interviews were conducted as part of this qualitative inquiry. Analysis was done using QSR NVivo version 10. RESULTS: Most LHWs and LHSs identified pneumonia and diarrhoea as two major causes of death among children under-five. Poverty, illiteracy, poor hygiene and lack of clean drinking water were mentioned as underlying causes of high mortality due to diarrhoea and pneumonia. LHWs and LHSs gaps in knowledge included classification of dehydration, correctly preparing ORS and prescribing correct antibiotics in pneumonia. Lack of training, delayed salaries and insufficient medicines and other supplies were identified as major factors impeding appropriate knowledge and skill development for iCCM of childhood diarrhoea and pneumonia. LHWs considered adequate supervision and the presence of LHSs during household visits as a factor facilitating their performance. LHWs did not have a preference for written or verbal feedback, but LHSs considered written individual feedback to LHWs to be more useful than group and verbal feedback. CONCLUSION: LHWs have knowledge and skill gaps that prevent them from providing effective care for diarrhoea and pneumonia. Enhanced supportive feedback from LHSs could improve LHWs skills and performance.

Stunting is associated with poor outcomes in childhood pneumonia.

OBJECTIVE: Stunting affects 26.7% of children worldwide, and little is known about its effects on the outcomes of childhood pneumonia. We evaluated the effect of stunting on the outcomes of pneumonia among children enrolled in two large clinical trials. METHODS: We analysed data from two WHO and USAID-sponsored inpatient treatment trials, the Severe Pneumonia Evaluation Antimicrobial Research study (n = 958) and the Amoxicillin Penicillin Pneumonia International Study (n = 1702), which enrolled children aged 2-59 months across 16 sites in LMICs. We assessed the effect of stunting (height-for-age Z score < -2) on treatment outcome and time to resolution of hypoxaemic pneumonia. RESULTS: Among 2542 (96%) children with valid data for height, 28% were stunted and 12.8% failed treatment by 5 days. The failure rate among stunted patients was 16.0% vs. 11.5% among non-stunted patients [unadjusted RR = 1.24 (95% CI 1.08, 1.41); adjusted RR = 1.28 (95% CI 1.10, 1.48)]. An inverse relationship was observed between height and failure rates, even among non-stunted children. Among 845 patients with hypoxaemic pneumonia, stunting was associated with a lower probability of normalisation of respiratory rate [HR = 0.63 (95% CI 0.52, 0.75)] and oxygen saturation [HR = 0.74 (95% CI 0.61, 0.89)]. CONCLUSIONS: Stunting increases the risk of treatment failure and is associated with a longer course of recovery in children with pneumonia. Strategies to decrease stunting may decrease the burden of adverse outcomes in childhood pneumonia in low-resource settings.