Genomic and panproteomic analysis of the development of infant immune responses to antigenically-diverse pneumococci.

Streptococcus pneumoniae (pneumococcus) is a nasopharyngeal commensal and respiratory pathogen. This study characterises the immunoglobulin G (IgG) repertoire recognising pneumococci from birth to 24 months old (mo) in a prospectively-sampled cohort of 63 children using a panproteome array. IgG levels are highest at birth, due to transplacental transmission of maternal antibodies. The subsequent emergence of responses to individual antigens exhibit distinct kinetics across the cohort. Stable differences in the strength of individuals' responses, correlating with maternal IgG concentrations, are established by 6 mo. By 12 mo, children develop unique antibody profiles that are boosted by re-exposure. However, some proteins only stimulate substantial responses in adults. Integrating genomic data on nasopharyngeal colonisation demonstrates rare pneumococcal antigens can elicit strong IgG levels post-exposure. Quantifying such responses to the diverse core loci (DCL) proteins is complicated by cross-immunity between variants. In particular, the conserved N terminus of DCL protein zinc metalloprotease B provokes the strongest early IgG responses. DCL proteins' ability to inhibit mucosal immunity likely explains continued pneumococcal carriage despite hosts' polyvalent antibody repertoire. Yet higher IgG levels are associated with reduced incidence, and severity, of pneumonia, demonstrating the importance of the heterogeneity in response strength and kinetics across antigens and individuals.

A Prognostic Model for Critically Ill Children in Locations With Emerging Critical Care Capacity.

OBJECTIVES: To develop a clinical prediction model to risk stratify children admitted to PICUs in locations with limited resources, and compare performance of the model to nine existing pediatric severity scores. DESIGN: Retrospective, single-center, cohort study. SETTING: PICU of a pediatric hospital in Siem Reap, northern Cambodia. PATIENTS: Children between 28 days and 16 years old admitted nonelectively to the PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical and laboratory data recorded at the time of PICU admission were collected. The primary outcome was death during PICU admission. One thousand five hundred fifty consecutive nonelective PICU admissions were included, of which 97 died (6.3%). Most existing severity scores achieved comparable discrimination (area under the receiver operating characteristic curves [AUCs], 0.71-0.76) but only three scores demonstrated moderate diagnostic utility for triaging admissions into high- and low-risk groups (positive likelihood ratios [PLRs], 2.65-2.97 and negative likelihood ratios [NLRs], 0.40-0.46). The newly derived model outperformed all existing severity scores (AUC, 0.84; 95% CI, 0.80-0.88; p < 0.001). Using one particular threshold, the model classified 13.0% of admissions as high risk, among which probability of mortality was almost ten-fold greater than admissions triaged as low-risk (PLR, 5.75; 95% CI, 4.57-7.23 and NLR, 0.47; 95% CI, 0.37-0.59). Decision curve analyses indicated that the model would be superior to all existing severity scores and could provide utility across the range of clinically plausible decision thresholds. CONCLUSIONS: Existing pediatric severity scores have limited potential as risk stratification tools in resource-constrained PICUs. If validated, our prediction model would be a readily implementable mechanism to support triage of critically ill children at admission to PICU and could provide value across a variety of contexts where resource prioritization is important.

External validation of clinical severity scores to guide referral of paediatric acute respiratory infections in resource-limited primary care settings.

Accurate and reliable guidelines for referral of children from resource-limited primary care settings are lacking. We identified three practicable paediatric severity scores (the Liverpool quick Sequential Organ Failure Assessment (LqSOFA), the quick Pediatric Logistic Organ Dysfunction-2, and the modified Systemic Inflammatory Response Syndrome) and externally validated their performance in young children presenting with acute respiratory infections (ARIs) to a primary care clinic located within a refugee camp on the Thailand-Myanmar border. This secondary analysis of data from a longitudinal birth cohort study consisted of 3010 ARI presentations in children aged ≤ 24 months. The primary outcome was receipt of supplemental oxygen. We externally validated the discrimination, calibration, and net-benefit of the scores, and quantified gains in performance that might be expected if they were deployed as simple clinical prediction models, and updated to include nutritional status and respiratory distress. 104/3,010 (3.5%) presentations met the primary outcome. The LqSOFA score demonstrated the best discrimination (AUC 0.84; 95% CI 0.79-0.89) and achieved a sensitivity and specificity > 0.80. Converting the scores into clinical prediction models improved performance, resulting in ~ 20% fewer unnecessary referrals and ~ 30-50% fewer children incorrectly managed in the community. The LqSOFA score is a promising triage tool for young children presenting with ARIs in resource-limited primary care settings. Where feasible, deploying the score as a simple clinical prediction model might enable more accurate and nuanced risk stratification, increasing applicability across a wider range of contexts.

Pneumococcal colonization and severity of pneumonia in hospitalized Cambodian children following introduction of the 13-valent pneumococcal conjugate vaccine.

Objectives: This study sought to characterize pneumococcal colonization and clinical/radiological features in Cambodian children admitted to hospital with an illness compatible with pneumonia following national introduction of the 13-valent pneumococcal conjugate vaccine (PCV13). Methods: Children aged 0-59 months admitted to Angkor Hospital for Children who met the World Health Organization (WHO) case definition for clinical pneumonia were enrolled over a 3-year period. Clinical, radiological and vaccination data were collected at enrolment. A nasopharyngeal swab was collected for detection of pneumococcal colonization using the WHO standard culture method. Results: Between 1 September 2015 and 31August 2018, 2209 analysable illness episodes were enrolled. Pneumococci were detected in 943/2209 (42.7%) children. PCV13 serotypes were detected less frequently in children who had been vaccinated appropriately for their age compared with undervaccinated children: 309/567 (53.6%) vs 216/342 (63.2%) (P=0.006). Age-appropriate PCV13 vaccination was negatively associated with hypoxic presentation [adjusted odds ratio (aOR) 0.72, 95% confidence interval (CI) 0.60-0.87; P=0.0006] and primary endpoint pneumonia on chest x ray (aOR 0.69, 95% CI 0.54-0.90; P=0.006). Conclusions: The introduction of PCV13 in Cambodia was associated with a decline in vaccine serotype nasopharyngeal colonization, and clinical and radiological severity in children hospitalized with clinical pneumonia.

Defining the role of host biomarkers in the diagnosis and prognosis of the severity of childhood pneumonia: a prospective cohort study.

Reliable tools to inform outpatient management of childhood pneumonia in resource-limited settings are needed. We investigated the value added by biomarkers of the host infection response to the performance of the Liverpool quick Sequential Organ Failure Assessment score (LqSOFA), for triage of children presenting with pneumonia to a primary care clinic in a refugee camp on the Thailand-Myanmar border. 900 consecutive presentations of children aged ≤ 24 months meeting WHO pneumonia criteria were included. The primary outcome was receipt of supplemental oxygen. We compared discrimination of a clinical risk score (LqSOFA) to markers of endothelial injury (Ang-1, Ang-2, sFlt-1), immune activation (CHI3L1, IP-10, IL-1ra, IL-6, IL-8, IL-10, sTNFR-1, sTREM-1), and inflammation (CRP, PCT), and quantified the net benefit of including biomarkers alongside LqSOFA. We evaluated the differential contribution of LqSOFA and host biomarkers to the diagnosis and prognosis of pneumonia severity. 49/900 (5.4%) presentations met the primary outcome. Discrimination of LqSOFA and Ang-2, the best performing biomarker, were comparable (AUC 0.82 [95% CI 0.76-0.88] and 0.81 [95% CI 0.74-0.87] respectively). Combining Ang-2 with LqSOFA improved discrimination (AUC 0.91; 95% CI 0.87-0.94; p < 0.001), and resulted in greater net benefit, with 10-30% fewer children who required oxygen supplementation incorrectly identified as safe for community-based management. Ang-2 had greater prognostic utility than LqSOFA to identify children requiring supplemental oxygen later in their illness course. Combining Ang-2 and LqSOFA could guide referrals of childhood pneumonia from resource-limited community settings. Further work on test development and integration into patient triage is required.

Born too soon in a resource-limited setting: A 10-year mixed methods review of a special care baby unit for refugees and migrants on the Myanmar-Thailand border.

Background: Preterm birth is a major public health concern with the largest burden of morbidity and mortality falling within low- and middle-income countries (LMIC). Materials and methods: This sequential explanatory mixed methods study was conducted in special care baby units (SCBUs) serving migrants and refugees along the Myanmar-Thailand border. It included a retrospective medical records review, qualitative interviews with mothers receiving care within SCBUs, and focus group discussions with health workers. Changes in neonatal mortality and four clinical outcomes were described. A mix of ethnographic phenomenology and implementation frameworks focused on cultural aspects, the lived experience of participants, and implementation outcomes related to SCBU care. Results: From 2008-2017, mortality was reduced by 68% and 53% in very (EGA 28-32 weeks) and moderate (EGA 33-36 weeks) preterm neonates, respectively. Median SCBU stay was longer in very compared to moderate preterm neonates: 35 (IQR 22, 48 days) vs. 10 days (IQR 5, 16). Duration of treatments was also longer in very preterm neonates: nasogastric feeding lasted 82% (IQR 74, 89) vs. 61% (IQR 40, 76) of the stay, and oxygen therapy was used a median of 14 (IQR 7, 27) vs. 2 (IQR 1, 6) days respectively. Nine interviews were conducted with mothers currently receiving care in the SCBU and four focus group discussions with a total of 27 local SCBU staff. Analysis corroborated quantitative analysis of newborn care services in this setting and incorporated pertinent implementation constructs including coverage, acceptability, appropriateness, feasibility, and fidelity. Coverage, acceptability, and appropriateness were often overlapping outcomes of interest highlighting financial issues prior to or while admitted to the SCBU and social issues and support systems adversely impacting SCBU stays. Interview and FGD findings highlight the barriers in this resource-limited setting as they impact the feasibility and fidelity of providing evidence-based SCBU care that often required adaptation to fit the financial and environmental constraints imposed by this setting. Discussion: This study provides an in-depth look at the nature of providing preterm neonatal interventions in a SCBU for a vulnerable population in a resource-limited setting. These findings support implementation of basic evidence-based interventions for preterm and newborn care globally, particularly in LMICs.

In-hospital mortality risk stratification in children aged under 5 years with pneumonia with or without pulse oximetry: A secondary analysis of the Pneumonia REsearch Partnership to Assess WHO REcommendations (PREPARE) dataset.

OBJECTIVES: We determined the pulse oximetry benefit in pediatric pneumonia mortality risk stratification and chest-indrawing pneumonia in-hospital mortality risk factors. METHODS: We report the characteristics and in-hospital pneumonia-related mortality of children aged 2-59 months who were included in the Pneumonia Research Partnership to Assess WHO Recommendations dataset. We developed multivariable logistic regression models of chest-indrawing pneumonia to identify mortality risk factors. RESULTS: Among 285,839 children, 164,244 (57.5%) from hospital-based studies were included. Pneumonia case fatality risk (CFR) without pulse oximetry measurement was higher than with measurement (5.8%, 95% confidence interval [CI] 5.6-5.9% vs 2.1%, 95% CI 1.9-2.4%). One in five children with chest-indrawing pneumonia was hypoxemic (19.7%, 95% CI 19.0-20.4%), and the hypoxemic CFR was 10.3% (95% CI 9.1-11.5%). Other mortality risk factors were younger age (either 2-5 months [adjusted odds ratio (aOR) 9.94, 95% CI 6.67-14.84] or 6-11 months [aOR 2.67, 95% CI 1.71-4.16]), moderate malnutrition (aOR 2.41, 95% CI 1.87-3.09), and female sex (aOR 1.82, 95% CI 1.43-2.32). CONCLUSION: Children with a pulse oximetry measurement had a lower CFR. Many children hospitalized with chest-indrawing pneumonia were hypoxemic and one in 10 died. Young age and moderate malnutrition were risk factors for in-hospital chest-indrawing pneumonia-related mortality. Pulse oximetry should be integrated in pneumonia hospital care for children under 5 years.

Pneumococcal within-host diversity during colonization, transmission and treatment.

Characterizing the genetic diversity of pathogens within the host promises to greatly improve surveillance and reconstruction of transmission chains. For bacteria, it also informs our understanding of inter-strain competition and how this shapes the distribution of resistant and sensitive bacteria. Here we study the genetic diversity of Streptococcus pneumoniae within 468 infants and 145 of their mothers by deep sequencing whole pneumococcal populations from 3,761 longitudinal nasopharyngeal samples. We demonstrate that deep sequencing has unsurpassed sensitivity for detecting multiple colonization, doubling the rate at which highly invasive serotype 1 bacteria were detected in carriage compared with gold-standard methods. The greater resolution identified an elevated rate of transmission from mothers to their children in the first year of the child's life. Comprehensive treatment data demonstrated that infants were at an elevated risk of both the acquisition and persistent colonization of a multidrug-resistant bacterium following antimicrobial treatment. Some alleles were enriched after antimicrobial treatment, suggesting that they aided persistence, but generally purifying selection dominated within-host evolution. Rates of co-colonization imply that in the absence of treatment, susceptible lineages outcompeted resistant lineages within the host. These results demonstrate the many benefits of deep sequencing for the genomic surveillance of bacterial pathogens.

Saving babies' lives (SBL) - a programme to reduce neonatal mortality in rural Cambodia: study protocol for a stepped-wedge cluster-randomised trial.

BACKGROUND: Neonatal mortality remains unacceptably high. Many studies successful at reducing neonatal mortality have failed to realise similar gains at scale. Effective implementation and scale-up of interventions designed to tackle neonatal mortality is a global health priority. Multifaceted programmes targeting the continuum of neonatal care, with sustainability and scalability built into the design, can provide practical insights to solve this challenge. Cambodia has amongst the highest neonatal mortality rates in South-East Asia, with rural areas particularly affected. The primary objective of this study is the design, implementation, and assessment of the Saving Babies' Lives programme, a package of interventions designed to reduce neonatal mortality in rural Cambodia. METHODS: This study is a five-year stepped-wedge cluster-randomised trial conducted in a rural Cambodian province with an estimated annual delivery rate of 6615. The study is designed to implement and evaluate the Saving Babies' Lives programme, which is the intervention. The Saving Babies' Lives programme is an iterative package of neonatal interventions spanning the continuum of care and integrating into the existing health system. The Saving Babies' Lives programme comprises two major components: participatory learning and action with community health workers, and capacity building of primary care facilities involving facility-based mentorship. Standard government service continues in control arms. Data collection covering the whole study area includes surveillance of all pregnancies, verbal and social autopsies, and quality of care surveys. Mixed methods data collection supports iteration of the complex intervention, and facilitates impact, outcome, process and economic evaluation. DISCUSSION: Our study uses a robust study design to evaluate and develop a holistic, innovative, contextually relevant and sustainable programme that can be scaled-up to reduce neonatal mortality. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04663620 . Registered on 11th December 2020, retrospectively registered.

A mixed methods evaluation of Advanced Life Support in Obstetrics (ALSO) and Basic Life Support in Obstetrics (BLSO) in a resource-limited setting on the Thailand-Myanmar border.

Background: Short emergency obstetric care (EmOC) courses have demonstrated improved provider confidence, knowledge and skills but impact on indicators such as maternal mortality and stillbirth is less substantial. This manuscript evaluates Advanced Life Support in Obstetrics (ALSO) and Basic Life Support (BLSO) as an adult education tool, in a protracted, post-conflict and resource-limited setting. Methods: A mixed methods evaluation was used. Basic characteristics of ALSO and BLSO participants and their course results were summarized. Kirkpatrick's framework for assessment of education effectiveness included: qualitative data on participants' reactions to training (level 1); and quantitative health indicator data on change in the availability and quality of EmOC and in maternal and/or neonatal health outcomes (level 4), by evaluation of the post-partum haemorrhage (PPH) related maternal mortality ratio (MMR) and stillbirth rate in the eight years prior and following implementation of ALSO and BLSO. Results: 561 Thailand-Myanmar border health workers participated in ALSO (n=355) and BLSO (n=206) courses 2008-2020. Pass rates on skills exceeded 90% for both courses while 50% passed the written ALSO test. Perceived confidence significantly improved for all items assessed. In the eight-year block preceding the implementation of ALSO and BLSO (2000-07) the PPH related MMR per 100,000 live births was 57.0 (95%CI 30.06-108.3)(9/15797) compared to 25.4 (95%CI 11.6-55.4)(6/23620) eight years following (2009-16), p=0.109. After adjustment, PPH related maternal mortality was associated with birth before ALSO/BLSO implementation aOR 3.825 (95%CI 1.1233-11.870), migrant (not refugee) status aOR 3.814 (95%CI 1.241-11.718) and attending ≤four antenatal consultations aOR 3.648 (95%CI 1.189-11.191). Stillbirth rate per 1,000 total births was 18.2 (95%CI 16.2-20.4)(291/16016) before the courses, and 11.1 (95%CI 9.8-12.5)(264/23884) after, p=0.038. Birth before ALSO/ BLSO implementation was associated with stillbirth aoR 1.235 (95%CI 1.018-1.500). Conclusions: This evaluation suggests ALSO and BLSO are sustainable, beneficial, EmOC trainings for adult education in protracted, post-conflict, resource-limited settings.

Grandparent caregiving in Cambodian skip-generation households: Roles and impact on child nutrition.

This study aims to understand nutrition-related roles, responsibilities and ethical issues of grandparents caring for their grandchildren in skip-generation households in rural Cambodia. Over the past decade, Cambodia has experienced a rise in economic migration of working age populations. This has resulted in increasing numbers of 'skip-generation' households, in which grandparents and grandchildren co-reside without parents, reflecting potential household vulnerability. This qualitative study involved in-depth interviews and focus group discussions with Cambodian grandparents who were primary caregivers to grandchildren for six months or longer. A total of 39 grandparents were recruited at two sites in north-west Cambodia. Interviews and focus group discussions were conducted in Khmer and were recorded, transcribed and translated into English. Data were analysed using thematic analysis. Grandparents in this study looked after an average of three children, aged between two months and 18 years old. Overall, 40% were sole caregivers. Analysis showed that grandparents, particularly grandmothers, played a central role in their grandchildren's health and nutrition. Although grandchildren's health and nutrition were a major priority to grandparents, they reported facing significant challenges to safeguard their grandchildren's and their own nutritional needs. As a result, grandparents frequently faced difficult ethical trade-offs and prioritised their grandchildren's health and nutrition over their own. This study highlights that in order to improve child nutrition, policies and interventions need to be designed in ways that support and enable grandparent caregivers to meet their grandchildren's health and nutritional needs without neglecting their own.

A randomized controlled trial of dihydroartemisinin-piperaquine, artesunate-mefloquine and extended artemether-lumefantrine treatments for malaria in pregnancy on the Thailand-Myanmar border.

BACKGROUND: Artemisinin and artemisinin-based combination therapy (ACT) partner drug resistance in Plasmodium falciparum have spread across the Greater Mekong Subregion compromising antimalarial treatment. The current 3-day artemether-lumefantrine regimen has been associated with high treatment failure rates in pregnant women. Although ACTs are recommended for treating Plasmodium vivax malaria, no clinical trials in pregnancy have been reported. METHODS: Pregnant women with uncomplicated malaria on the Thailand-Myanmar border participated in an open-label randomized controlled trial comparing dihydroartemisinin-piperaquine (DP), artesunate-mefloquine (ASMQ) and a 4-day artemether-lumefantrine regimen (AL+). The primary endpoint for P. falciparum infections was the PCR-corrected cure rate and for P. vivax infections was recurrent parasitaemia, before delivery or day 63, whichever was longer, assessed by Kaplan-Meier estimate. RESULTS: Between February 2010 and August 2016, 511 pregnant women with malaria (353 P. vivax, 142 P. falciparum, 15 co-infections, 1 Plasmodium malariae) were randomized to either DP (n=170), ASMQ (n=169) or AL+ (n=172) treatments. Successful malaria elimination efforts in the region resulted in premature termination of the trial. The majority of women had recurrent malaria (mainly P. vivax relapses, which are not prevented by these treatments). Recurrence-free proportions (95% confidence interval [95% CI]) for vivax malaria were 20.6% (5.1-43.4) for DP (n=125), 46.0% (30.9-60.0) for ASMQ (n=117) and 28.7% (10.0-50.8) for AL+ (n=126). DP and ASMQ provided longer recurrence-free intervals. PCR-corrected cure rates (95% CI) for falciparum malaria were 93.7% (81.6-97.9) for DP (n=49), 79.6% (66.1-88.1) for AMSQ (n=55) and 87.5% (74.3-94.2) for AL+ (n=50). Overall 65% (85/130) of P. falciparum infections had Pfkelch13 propeller mutations which increased over time and recrudescence occurred almost exclusively in them; risk ratio 9.42 (95% CI 1.30-68.29). Among the women with falciparum malaria, 24.0% (95% CI 16.8-33.6) had P. vivax parasitaemia within 4 months. Nausea, vomiting, dizziness and sleep disturbance were more frequent with ASMQ. Miscarriage, small-for-gestational-age and preterm birth did not differ significantly among the treatment groups, including first trimester exposures (n=46). CONCLUSIONS: DP was well tolerated and safe, and was the only drug providing satisfactory efficacy for P. falciparum-infected pregnant woman in this area of widespread artemisinin resistance. Vivax malaria recurrences are very common and warrant chloroquine prophylaxis after antimalarial treatment in this area. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01054248 , registered on 22 January 2010.

Prediction of disease severity in young children presenting with acute febrile illness in resource-limited settings: a protocol for a prospective observational study.

INTRODUCTION: In rural and difficult-to-access settings, early and accurate recognition of febrile children at risk of progressing to serious illness could contribute to improved patient outcomes and better resource allocation. This study aims to develop a prognostic clinical prediction tool to assist community healthcare providers identify febrile children who might benefit from referral or admission for facility-based medical care. METHODS AND ANALYSIS: This prospective observational study will recruit at least 4900 paediatric inpatients and outpatients under the age of 5 years presenting with an acute febrile illness to seven hospitals in six countries across Asia. A venous blood sample and nasopharyngeal swab is collected from each participant and detailed clinical data recorded at presentation, and each day for the first 48 hours of admission for inpatients. Multianalyte assays are performed at reference laboratories to measure a panel of host biomarkers, as well as targeted aetiological investigations for common bacterial and viral pathogens. Clinical outcome is ascertained on day 2 and day 28.Presenting syndromes, clinical outcomes and aetiology of acute febrile illness will be described and compared across sites. Following the latest guidance in prediction model building, a prognostic clinical prediction model, combining simple clinical features and measurements of host biomarkers, will be derived and geographically externally validated. The performance of the model will be evaluated in specific presenting clinical syndromes and fever aetiologies. ETHICS AND DISSEMINATION: The study has received approval from all relevant international, national and institutional ethics committees. Written informed consent is provided by the caretaker of all participants. Results will be shared with local and national stakeholders, and disseminated via peer-reviewed open-access journals and scientific meetings. TRIAL REGISTRATION NUMBER: NCT04285021.

An analysis of clinical predictive values for radiographic pneumonia in children.

INTRODUCTION: Healthcare providers in resource-limited settings rely on the presence of tachypnoea and chest indrawing to establish a diagnosis of pneumonia in children. We aimed to determine the test characteristics of commonly assessed signs and symptoms for the radiographic diagnosis of pneumonia in children 0-59 months of age. METHODS: We conducted an analysis using patient-level pooled data from 41 shared datasets of paediatric pneumonia. We included hospital-based studies in which >80% of children had chest radiography performed. Primary endpoint pneumonia (presence of dense opacity occupying a portion or entire lobe of the lung or presence of pleural effusion on chest radiograph) was used as the reference criterion radiographic standard. We assessed the sensitivity, specificity, and likelihood ratios for clinical findings, and combinations of findings, for the diagnosis of primary endpoint pneumonia among children 0-59 months of age. RESULTS: Ten studies met inclusion criteria comprising 15 029 children; 24.9% (n=3743) had radiographic pneumonia. The presence of age-based tachypnoea demonstrated a sensitivity of 0.92 and a specificity of 0.22 while lower chest indrawing revealed a sensitivity of 0.74 and specificity of 0.15 for the diagnosis of radiographic pneumonia. The sensitivity and specificity for oxygen saturation <90% was 0.40 and 0.67, respectively, and was 0.17 and 0.88 for oxygen saturation <85%. Specificity was improved when individual clinical factors such as tachypnoea, fever and hypoxaemia were combined, however, the sensitivity was lower. CONCLUSIONS: No single sign or symptom was strongly associated with radiographic primary end point pneumonia in children. Performance characteristics were improved by combining individual signs and symptoms.

Barriers and facilitators to neonatal health and care-seeking behaviours in rural Cambodia: a qualitative study.

OBJECTIVES: Neonatal mortality remains persistently high in low-income and middle-income countries. In Cambodia, there is a paucity of data on the perception of neonatal health and care-seeking behaviours at the community level. This study aimed to identify influencers of neonatal health and healthcare-seeking behaviour in a rural Cambodian province. DESIGN: A qualitative study using focus group discussions and thematic content analysis. SETTING: Four health centres in a rural province of Northern Cambodia. PARTICIPANTS: Twenty-four focus group discussions were conducted with 85 community health workers in 2019. RESULTS: Community health workers recognised an improvement in neonatal health over time. Key influencers to neonatal health were identified as knowledge, sociocultural behaviours, finances and transport, provision of care and healthcare engagement. Most influencers acted as both barriers and facilitators, with the exception of finances and transport that only acted as a barrier, and healthcare engagement that acted as a facilitator. CONCLUSION: Understanding health influencers and care-seeking behaviours is recognised to facilitate appropriate community health programmes. Key influencers and care-seeking behaviours have been identified from rural Cambodia adding to the current literature. Where facilitators have already been established, they should be used as building blocks for continued change.

Extreme neonatal hyperbilirubinaemia in refugee and migrant populations: retrospective cohort.

OBJECTIVE: To describe neonatal survival and long-term neurological outcome in neonatal hyperbilirubinaemia (NH) with extreme serum bilirubin (SBR) values. DESIGN: Retrospective chart review, a one-off neurodevelopmental evaluation. SETTING: Special care baby unit in a refugee camp and clinics for migrant populations at the Thailand-Myanmar border with phototherapy facilities but limited access to exchange transfusion (ET). PATIENTS: Neonates ≥28 weeks of gestational age with extreme SBR values and/or acute neurological symptoms, neurodevelopment evaluation conducted at 23-97 months of age. MAIN OUTCOME MEASURES: Neonatal mortality rate, prevalence of acute bilirubin encephalopathy (ABE) signs, prevalence of delayed development scores based on the Griffiths Mental Development Scale (GMDS). RESULTS: From 2009 to 2014, 1946 neonates were diagnosed with jaundice; 129 (6.6%) had extreme SBR values during NH (extreme NH). In this group, the median peak SBR was 430 (IQR 371-487) µmol/L and the prevalence of ABE was 28.2%. Extreme NH-related mortality was 10.9% (14/129). Median percentile GMDS general score of 37 survivors of extreme NH was poor: 11 (2-42). 'Performance', 'practical reasoning' and 'hearing and language' domains were most affected. Four (10.8%) extreme NH survivors had normal development scores (≥50th centile). Two (5.4%) developed the most severe form of kernicterus spectrum disorders. CONCLUSION: In this limited-resource setting, poor neonatal survival and neurodevelopmental outcomes, after extreme NH, were high. Early identification and adequate treatment of NH where ET is not readily available are key to minimising the risk of extreme SBR values or neurological symptoms.

Impact of 13-Valent Pneumococcal Conjugate Vaccine on Colonization and Invasive Disease in Cambodian Children.

BACKGROUND: Cambodia introduced the 13-valent pneumococcal conjugate vaccine (PCV13) in January 2015 using a 3 + 0 dosing schedule and no catch-up campaign. We investigated the effects of this introduction on pneumococcal colonization and invasive disease in children aged <5 years. METHODS: There were 6 colonization surveys done between January 2014 and January 2018 in children attending the outpatient department of a nongovernmental pediatric hospital in Siem Reap. Nasopharyngeal swabs were analyzed by phenotypic and genotypic methods to detect pneumococcal serotypes and antimicrobial resistance. Invasive pneumococcal disease (IPD) data for January 2012-December 2018 were retrieved from hospital databases. Pre-PCV IPD data and pre-/post-PCV colonization data were modelled to estimate vaccine effectiveness (VE). RESULTS: Comparing 2014 with 2016-2018, and using adjusted prevalence ratios, VE estimates for colonization were 16.6% (95% confidence interval [CI] 10.6-21.8) for all pneumococci and 39.2% (95% CI 26.7-46.1) for vaccine serotype (VT) pneumococci. There was a 26.0% (95% CI 17.7-33.0) decrease in multidrug-resistant pneumococcal colonization. The IPD incidence was estimated to have declined by 26.4% (95% CI 14.4-35.8) by 2018, with a decrease of 36.3% (95% CI 23.8-46.9) for VT IPD and an increase of 101.4% (95% CI 62.0-145.4) for non-VT IPD. CONCLUSIONS: Following PCV13 introduction into the Cambodian immunization schedule, there have been declines in VT pneumococcal colonization and disease in children aged <5 years. Modelling of dominant serotype colonization data produced plausible VE estimates.

Transmission dynamics and control of multidrug-resistant Klebsiella pneumoniae in neonates in a developing country.

Multidrug-resistant Klebsiella pneumoniae is an increasing cause of infant mortality in developing countries. We aimed to develop a quantitative understanding of the drivers of this epidemic by estimating the effects of antibiotics on nosocomial transmission risk, comparing competing hypotheses about mechanisms of spread, and quantifying the impact of potential interventions. Using a sequence of dynamic models, we analysed data from a one-year prospective carriage study in a Cambodian neonatal intensive care unit with hyperendemic third-generation cephalosporin-resistant K. pneumoniae. All widely-used antibiotics except imipenem were associated with an increased daily acquisition risk, with an odds ratio for the most common combination (ampicillin + gentamicin) of 1.96 (95% CrI 1.18, 3.36). Models incorporating genomic data found that colonisation pressure was associated with a higher transmission risk, indicated sequence type heterogeneity in transmissibility, and showed that within-ward transmission was insufficient to maintain endemicity. Simulations indicated that increasing the nurse-patient ratio could be an effective intervention.

Evaluation of a treatment protocol for anaemia in pregnancy nested in routine antenatal care in a limited-resource setting.

Background: Anaemia in pregnancy is typically due to iron deficiency (IDA) but remains a complex and pervasive problem, particularly in low resource settings. At clinics on the Myanmar-Thailand border, a protocol was developed to guide treatment by health workers in antenatal care (ANC). Objective: To evaluate the clinical use of a protocol to treat anaemia in pregnancy. Methods: The design was a descriptive retrospective analysis of antenatal data obtained during the use of a standard anaemia treatment protocol. Two consecutive haematocrits (HCT) <30% prompted a change from routine prophylaxis to treatment doses of haematinics. Endpoints were anaemia at delivery (most recent HCT before delivery <30%) and timeliness of treatment initiation. Women whose HCT failed to respond to the treatment were investigated. Results: From August 2007 to July 2012, a median [IQR] of five [4-11] HCT measurements per woman resulted in the treatment of anaemia in 20.7% (2,246/10,886) of pregnancies. Anaemia at delivery was present in 22.8% (511/2,246) of treated women and 1.4% (123/8,640) who remained on prophylaxis. Human error resulted in a failure to start treatment in 97 anaemic women (4.1%, denominator 2,343 (2,246 + 97)). Fluctuation of HCT around the cut-point of 30% was the major problem with the protocol accounting for half of the cases where treatment was delayed greater than 4 weeks. Delay in treatment was associated with a 1.5 fold higher odds of anaemia at delivery (95% CI 1.18, 1.97). Conclusion: There was high compliance to the protocol by the health workers. An important outcome of this evaluation was that the clinical definition of anaemia was changed to diminish missed opportunities for initiating treatment. Reduction of anaemia in pregnancy requires early ANC attendance, prompt treatment at the first HCT <30%, and support for health workers.

Chloroquine Versus Dihydroartemisinin-Piperaquine With Standard High-dose Primaquine Given Either for 7 Days or 14 Days in Plasmodium vivax Malaria.

BACKGROUND: Primaquine is necessary for the radical cure of Plasmodium vivax malaria, but the optimum duration of treatment and best partner drug are uncertain. A randomized controlled trial was performed to compare the tolerability and radical curative efficacy of 7-day versus 14-day high-dose primaquine regimens (total dose 7mg/kg) with either chloroquine or dihydroartemisinin-piperaquine. METHODS: Patients with uncomplicated P. vivax malaria on the Thailand-Myanmar border were randomized to either chloroquine (25mg base/kg) or dihydroartemisinin-piperaquine (dihydroartemisinin 7mg/kg and piperaquine 55mg/kg) plus primaquine, either 0.5 mg/kg/day for 14 days or 1 mg/kg/day for 7 days. Adverse events within 42 days and 1-year recurrence rates were compared and their relationship with day 6 drug concentrations assessed. RESULTS: Between February 2012 and July 2014, 680 patients were enrolled. P. vivax recurrences (all after day 35) occurred in 80/654 (12%) patients; there was no difference between treatments. Compared to the 7-day primaquine groups the pooled relative risk of recurrence in the 14-day groups was 1.15 (95% confidence interval 0.7 to 1.8). Hematocrit reductions were clinically insignificant except in G6PD female heterozygotes, 2 of whom had hematocrit reductions to <23% requiring blood transfusion. CONCLUSION: Radical cure should be deployed more widely. The radical curative efficacy in vivax malaria of 7-day high-dose primaquine is similar to the standard 14-day high-dose regimen. Chloroquine and dihydroartemisinin-piperaquine are both highly effective treatments of the blood stage infection. Quantitative point of care G6PD testing would ensure safe use of the 7-day high-dose primaquine regimen in G6PD heterozygous females. CLINICAL TRIALS REGISTRATION: NCT01640574.