Childhood growth during recovery from acute illness in Africa and South Asia: a secondary analysis of the childhood acute illness and nutrition (CHAIN) prospective cohort.

Background: Growth faltering is well-recognized during acute childhood illness and growth acceleration during convalescence, with or without nutritional therapy, may occur. However, there are limited recent data on growth after hospitalization in low- and middle-income countries. Methods: We evaluated growth following hospitalization among children aged 2-23 months in sub-Saharan Africa and South Asia. Between November 2016 and January 2019, children were recruited at hospital admission and classified as: not-wasted (NW), moderately-wasted (MW), severely-wasted (SW), or having nutritional oedema (NO). We describe earlier (discharge to 45-days) and later (45- to 180-days) changes in length-for-age [LAZ], weight-for-age [WAZ], mid-upper arm circumference [MUACZ], weight-for-length [WLZ] z-scores, and clinical, nutritional, and socioeconomic correlates. Findings: We included 2472 children who survived to 180-days post-discharge: NW, 960 (39%); MW, 572 (23%); SW, 682 (28%); and NO, 258 (10%). During 180-days, LAZ decreased in NW (-0.27 [-0.36, -0.19]) and MW (-0.23 [-0.34, -0.11]). However, all groups increased WAZ (NW, 0.21 [95% CI: 0.11, 0.32]; MW, 0.57 [0.44, 0.71]; SW, 1.0 [0.88, 1.1] and NO, 1.3 [1.1, 1.5]) with greatest gains in the first 45-days. Of children underweight (<-2 WAZ) at discharge, 66% remained underweight at 180-days. Lower WAZ post-discharge was associated with age-inappropriate nutrition, adverse caregiver characteristics, small size at birth, severe or moderate anaemia, and chronic conditions, while lower LAZ was additionally associated with household-level exposures but not with chronic medical conditions. Interpretation: Underweight and poor linear growth mostly persisted after an acute illness. Beyond short-term nutritional supplementation, improving linear growth post-discharge may require broader individual and family support. Funding: Bill & Melinda Gates FoundationOPP1131320; National Institute for Health ResearchNIHR201813.

Stunting in the first year of life: Pathway analysis of a birth cohort.

Malnutrition among infants aged below 6 months has been largely overlooked creating gaps in our understanding of factors underlying stunting in early infancy. Recent evidence suggests that pre-natal and early childhood factors may contribute more to driving childhood stunting than previously appreciated. The study was set up to examine pathways including parental and household characteristics, birth size and gestation, and illness in infancy with stunting at birth and months 3, 6 and 12 using an a priori hypothesized framework. It was a secondary analysis of a birth cohort of 1017 infants recruited from four health facilities in Burkina Faso and followed up for one year. Structural equation models (SEM) were generated to explore pathways to stunting at birth and months 3, 6 and 12. The prevalence of being stunted at birth and months 3, 6 and 12 was 7.4%, 23%, 20% and 18% respectively. The fractions of month 12 stunting attributable to being stunted at birth, months 3 and 6 were 11% (95%CI 5.0‒16%), 32% (95%CI 22‒41%) and 40% (95%CI 31‒49%) respectively. In the structural equation model, male sex and maternal characteristics had direct effects on stunting at birth and at 3 months, but not subsequently. Premature birth, twin birth and being stunted at a previous time point were directly associated with stunting at months 3, 6 and 12. Both maternal and paternal characteristics were directly associated with preterm birth. Non-exclusive breastfeeding had borderline positive direct effect on stunting at month 6 but not at month 12. The direct and indirect pathways identified in this study highlight the complex interlinks between child, maternal, paternal and household characteristics. Interventions tackling preterm birth, in utero growth, exclusive breastfeeding and maternal wellbeing may reduce stunting in the first year of life.

Drivers determining tuberculosis disease screening yield in four European screening programmes: a comparative analysis.

BACKGROUND: The World Health Organization End TB Strategy emphasises screening for early diagnosis of tuberculosis (TB) in high-risk groups, including migrants. We analysed key drivers of TB yield differences in four large migrant TB screening programmes to inform TB control planning and feasibility of a European approach. METHODS: We pooled individual TB screening episode data from Italy, the Netherlands, Sweden and the UK, and analysed predictors and interactions for TB case yield using multivariable logistic regression models. RESULTS: Between 2005 and 2018 in 2 302 260 screening episodes among 2 107 016 migrants to four countries, the programmes identified 1658 TB cases (yield 72.0 (95% CI 68.6-75.6) per 100 000). In logistic regression analysis, we found associations between TB screening yield and age (≥55 years: OR 2.91 (95% CI 2.24-3.78)), being an asylum seeker (OR 3.19 (95% CI 1.03-9.83)) or on a settlement visa (OR 1.78 (95% CI 1.57-2.01)), close TB contact (OR 12.25 (95% CI 11.73-12.79)) and higher TB incidence in the country of origin. We demonstrated interactions between migrant typology and age, as well as country of origin. For asylum seekers, the elevated TB risk remained similar above country of origin incidence thresholds of 100 per 100 000. CONCLUSIONS: Key determinants of TB yield included close contact, increasing age, incidence in country of origin and specific migrant groups, including asylum seekers and refugees. For most migrants such as UK students and workers, TB yield significantly increased with levels of incidence in the country of origin. The high, country of origin-independent TB risk in asylum seekers above a 100 per 100 000 threshold could reflect higher transmission and re-activation risk of migration routes, with implications for selecting populations for TB screening.

Influence of Sex and Sex-Based Disparities on Prevalent Tuberculosis, Vietnam, 2017-2018.

To assess sex disparities in tuberculosis in Vietnam, we conducted a nested, case-control study based on a 2017 tuberculosis prevalence survey. We defined the case group as all survey participants with laboratory-confirmed tuberculosis and the control group as a randomly selected group of participants with no tuberculosis. We used structural equation modeling to describe pathways from sex to tuberculosis according to an a priori conceptual framework. Our analysis included 1,319 participants, of whom 250 were case-patients. We found that sex was directly associated with tuberculosis prevalence (adjusted odds ratio for men compared with women 3.0 [95% CI 1.7-5.0]) and indirectly associated through other domains. The strong sex difference in tuberculosis prevalence is explained by a complex interplay of factors relating to behavioral and environmental risks, access to healthcare, and clinical manifestations. However, after controlling for all those factors, a direct sex effect remains that might be caused by biological factors.

Predicting Clinical Deterioration and Mortality at Differing Stages During Hospitalization: A Systematic Review of Risk Prediction Models in Children in Low- and Middle-Income Countries.

OBJECTIVE: To determine which risk prediction model best predicts clinical deterioration in children at different stages of hospital admission in low- and middle-income countries. METHODS: For this systematic review, Embase and MEDLINE databases were searched, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. The key search terms were "development or validation study with risk-prediction model" AND "deterioration or mortality" AND "age 0-18 years" AND "hospital-setting: emergency department (ED), pediatric ward (PW), or pediatric intensive care unit (PICU)" AND "low- and middle-income countries." The Prediction Model Risk of Bias Assessment Tool was used by two independent authors. Forest plots were used to plot area under the curve according to hospital setting. Risk prediction models used in two or more studies were included in a meta-analysis. RESULTS: We screened 9486 articles and selected 78 publications, including 67 unique predictive models comprising 1.5 million children. The best performing models individually were signs of inflammation in children that can kill (SICK) (ED), pediatric early warning signs resource limited settings (PEWS-RL) (PW), and Pediatric Index of Mortality (PIM) 3 as well as pediatric sequential organ failure assessment (pSOFA) (PICU). Best performing models after meta-analysis were SICK (ED), pSOFA and Pediatric Early Death Index for Africa (PEDIA)-immediate score (PW), and pediatric logistic organ dysfunction (PELOD) (PICU). There was a high risk of bias in all studies. CONCLUSIONS: We identified risk prediction models that best estimate deterioration, although these risk prediction models are not routinely used in low- and middle-income countries. Future studies should focus on large scale external validation with strict methodological criteria of multiple risk prediction models as well as study the barriers in the way of implementation. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews: Prospero ID: CRD42021210489.

Plasma lipids and growth faltering: A longitudinal cohort study in rural Gambian children.

Growth faltering in children arises from metabolic and endocrine dysfunction driven by complex interactions between poor diet, persistent infections, and immunopathology. Here, we determined the progression of the plasma lipidome among Gambian children (n = 409) and assessed its association with growth faltering during the first 2 years of life using the panel vector autoregression method. We further investigated temporal associations among lipid clusters. We observed that measures of stunting, wasting, and underweight are dynamically associated with each other and that lipid groups containing polyunsaturated fatty acids (PUFAs) and phosphatidylcholines consistently predict future growth outcomes. Linear growth was dynamically associated with the majority of lipids, indicating a higher nutritional demand to improve height compared to weight among growth-restricted children. Our results indicate a critical role for PUFAs and choline in early life dietary interventions to combat the child growth faltering still so prevalent in low-income settings.

Predicting the risk of mortality during hospitalization in sick severely malnourished children using daily evaluation of key clinical warning signs.

BACKGROUND: Despite adherence to WHO guidelines, inpatient mortality among sick children admitted to hospital with complicated severe acute malnutrition (SAM) remains unacceptably high. Several studies have examined risk factors present at admission for mortality. However, risks may evolve during admission with medical and nutritional treatment or deterioration. Currently, no specific guidance exists for assessing daily treatment response. This study aimed to determine the prognostic value of monitoring clinical signs on a daily basis for assessing mortality risk during hospitalization in children with SAM. METHODS: This is a secondary analysis of data from a randomized trial (NCT02246296) among 843 hospitalized children with SAM. Daily clinical signs were prospectively collected during ward rounds. Multivariable extended Cox regression using backward feature selection was performed to identify daily clinical warning signs (CWS) associated with time to death within the first 21 days of hospitalization. Predictive models were subsequently developed, and their prognostic performance evaluated using Harrell's concordance index (C-index) and time-dependent area under the curve (tAUC). RESULTS: Inpatient case fatality ratio was 16.3% (n=127). The presence of the following CWS during daily assessment were found to be independent predictors of inpatient mortality: symptomatic hypoglycemia, reduced consciousness, chest indrawing, not able to complete feeds, nutritional edema, diarrhea, and fever. Daily risk scores computed using these 7 CWS together with MUAC<10.5cm at admission as additional CWS predict survival outcome of children with SAM with a C-index of 0.81 (95% CI 0.77-0.86). Moreover, counting signs among the top 5 CWS (reduced consciousness, symptomatic hypoglycemia, chest indrawing, not able to complete foods, and MUAC<10.5cm) provided a simpler tool with similar prognostic performance (C-index of 0.79; 95% CI 0.74-0.84). Having 1 or 2 of these CWS on any day during hospitalization was associated with a 3 or 11-fold increased mortality risk compared with no signs, respectively. CONCLUSIONS: This study provides evidence for structured monitoring of daily CWS as recommended clinical practice as it improves prediction of inpatient mortality among sick children with complicated SAM. We propose a simple counting-tool to guide healthcare workers to assess treatment response for these children. TRIAL REGISTRATION: NCT02246296.

The clinical use of longitudinal bio-electrical impedance vector analysis in assessing stabilization of children with severe acute malnutrition.

BACKGROUND & AIMS: Severe Acute Malnutrition (SAM) in children is determined using anthropometry. However, bio-electrical impedance (BI) analysis could improve the estimation of altered body composition linked to edema and/or loss of lean body mass in children with SAM. We aimed to assess: 1) the changes in BI parameters during clinical stabilization and 2) whether BI parameters add prognostic value for clinical outcome beyond the use of anthropometry. METHODS: This prospective observational study enrolled children, aged 6-60 months, that were admitted at Queen Elizabeth Central Hospital in Blantyre, Malawi, for complicated SAM (i.e., having either severe wasting or edematous SAM with a complicating illness). Height, weight, mid-upper arm circumference (MUAC), and BI were measured on admission and after clinical stabilization. BI measures were derived from height-adjusted indices of resistance (R/H), reactance (Xc/H), and phase angle (PA) and considered to reflect body fluids and soft tissue in BI vector analysis (BIVA). RESULTS: We studied 183 children with SAM (55% edematous; age 23.0 ± 12.0 months; 54% male) and 42 community participants (age 20.1 ± 12.3 months; male 62%). Compared to community participants, the BIVA of children with edematous SAM were short with low PA and positioned low on the hydration axis which reflects severe fluid retention. In contrast, children with severe wasting had elongated vectors with a PA that was higher than children with edematous SAM but lower than community participants. Their BIVA position fell within the top right quadrant linked to leanness and dehydration. BIVA from severely wasted and edematous SAM patients differed between groups and from community children both at admission and after stabilization (p < 0.001). Vector position shifted during treatment only in children with edematous SAM (p < 0.001) and showed a upward translation suggestive of fluid loss. While PA was lower in children with SAM, PA did not contribute more than anthropometry alone towards explaining mortality, length of stay, or time-to-discharge or time-to-mortality. The variability and heterogeneity in BI measures was high and their overall added predictive value for prognosis of individual children was low. CONCLUSIONS: BIVA did not add prognostic value over using anthropometry alone to predict clinical outcome. Several implementation challenges need to be optimized. Thus, in low-resource settings, the routine use of BI in the management of pediatric malnutrition is questionable without improved implementation.

Prediction of mortality in severe acute malnutrition in hospitalized children by faecal volatile organic compound analysis: proof of concept.

Children with severe acute malnutrition (SAM) display immature, altered gut microbiota and have a high mortality risk. Faecal volatile organic compounds (VOCs) reflect the microbiota composition and may provide insight into metabolic dysfunction that occurs in SAM. Here we determine whether analysis of faecal VOCs could identify children with SAM with increased risk of mortality. VOC profiles from children who died within six days following admission were compared to those who were discharged alive using machine learning algorithms. VOC profiles of children who died could be separated from those who were discharged with fair accuracy (AUC) = 0.71; 95% CI 0.59-0.87; P = 0.004). We present the first study showing differences in faecal VOC profiles between children with SAM who survived and those who died. VOC analysis holds potential to help discover metabolic pathways within the intestinal microbiome with causal association with mortality and target treatments in children with SAM.Trial Registration: The F75 study is registered at clinicaltrials.gov/ct2/show/NCT02246296.

The prominent role of informal medicine vendors despite health insurance: a weekly diaries study in rural Nigeria.

In sub-Saharan Africa, accessibility to affordable quality care is often poor and health expenditures are mostly paid out of pocket. Health insurance, protecting individuals from out-of-pocket health expenses, has been put forward as a means of enhancing universal health coverage. We explored the utilization of different types of healthcare providers and the factors associated with provider choice by insurance status in rural Nigeria. We analysed year-long weekly health diaries on illnesses and injuries (health episodes) for a sample of 920 individuals with access to a private subsidized health insurance programme. The weekly diaries capture not only catastrophic events but also less severe events that are likely underreported in surveys with longer recall periods. Individuals had insurance coverage during 34% of the 1761 reported health episodes, and they consulted a healthcare provider in 90% of the episodes. Multivariable multinomial logistic regression analyses showed that insurance coverage was associated with significantly higher utilization of formal health care: individuals consulted upgraded insurance programme facilities in 20% of insured episodes compared with 3% of uninsured episodes. Nonetheless, regardless of insurance status, most consultations involved an informal provider visit, with informal providers encompassing 73 and 78% of all consultations among insured and uninsured episodes, respectively, and individuals spending 54% of total annual out-of-pocket health expenditures at such providers. Given the high frequency at which individuals consult informal providers, their position within both the primary healthcare system and health insurance schemes should be reconsidered to reach universal health coverage.

Impact of the community healthcare plan and the free maternity services programme on maternal and child healthcare utilisation in rural Kenya: a dairy farmer population-based study.

BACKGROUND: Access to and utilisation of quality maternal and child healthcare services is generally recognized as the best way to reduce maternal and child mortality. OBJECTIVES: We evaluated whether the introduction of a voluntary family health insurance programme, combined with quality improvement of healthcare facilities [The Community Health Plan (TCHP)], and the introduction of free access to delivery services in all public facilities [Free Maternity Services programme (FMS)] increased antenatal care utilisation and use of facility deliveries among pregnant women in rural Kenya. METHODS: TCHP was introduced in 2011, whilst the FMS programme was launched in 2013. To measure the impact of TCHP, percentage points (PP) changes in antenatal care utilisation and facility deliveries from the pre-TCHP to the post-TCHP period between the TCHP programme area and a control area were compared in multivariable difference-in-differences analysis. To measure the impact of the FMS programme, PP changes in antenatal care utilisation and facility deliveries from the pre-FMS to the post-FMS period in the pooled TCHP programme and control areas was assessed in multivariable logistic regression analysis. Data was collected through household surveys in 2011 and 2104. Households (n=549) were randomly selected from the member lists of 2 dairy companies, and all full-term pregnancies in the 3.5 years preceding the baseline and follow-up survey among women aged 15-49 at the time of pregnancy were eligible for this study (n=295). RESULTS: Because only 4.1% of eligible women were insured through TCHP during pregnancy, any increase in utilisation attributable to the TCHP programme could only have come about as a result of the quality improvements in TCHP facilities. Antenatal care utilisation significantly increased after TCHP was introduced (14.4 PP; 95% CI: 4.5-24.3; P=0.004), whereas no effect was observed of the programme on facility deliveries (8.8 PP; 95% CI: -14.1 to +31.7; P=0.450). Facility deliveries significantly increased after the introduction of the FMS programme (27.9 PP; 95% CI: 11.8-44.1; P=0.001), but antenatal care utilisation did not change significantly (4.0 PP; 95% CI: -0.6 to +8.5; P=0.088). CONCLUSION: Access to the FMS programme increased facility deliveries substantially and may contribute to improved maternal and new-born health and survival if the quality of delivery services is sustained or further improved. Despite low up-take, TCHP had a positive effect on antenatal care utilisation among uninsured women by improving the quality of existing healthcare facilities. An alignment of the two programmes could potentially lead to optimal results. FUNDING: The study was funded by the Health Insurance Fund (http://www.hifund.org/), through a grant from the Dutch Ministry of Foreign Affairs.

The effect of health insurance and health facility-upgrades on hospital deliveries in rural Nigeria: a controlled interrupted time-series study.

BACKGROUND: Access to quality obstetric care is considered essential to reducing maternal and new-born mortality. We evaluated the effect of the introduction of a multifaceted voluntary health insurance programme on hospital deliveries in rural Nigeria. METHODS: We used an interrupted time-series design, including a control group. The intervention consisted of providing voluntary health insurance covering primary and secondary healthcare, including antenatal and obstetric care, combined with improving the quality of healthcare facilities. We compared changes in hospital deliveries from 1 May 2005 to 30 April 2013 between the programme area and control area in a difference-in-differences analysis with multiple time periods, adjusting for observed confounders. Data were collected through household surveys. Eligible households ( n = 1500) were selected from a stratified probability sample of enumeration areas. All deliveries during the 4-year baseline period ( n = 460) and 4-year follow-up period ( n = 380) were included. FINDINGS: Insurance coverage increased from 0% before the insurance was introduced to 70.2% in April 2013 in the programme area. In the control area insurance coverage remained 0% between May 2005 and April 2013. Although hospital deliveries followed a common stable trend over the 4 pre-programme years ( P = 0.89), the increase in hospital deliveries during the 4-year follow-up period in the programme area was 29.3 percentage points (95% CI: 16.1 to 42.6; P < 0.001) greater than the change in the control area (intention-to-treat impact), corresponding to a relative increase in hospital deliveries of 62%. Women who did not enroll in health insurance but who could make use of the upgraded care delivered significantly more often in a hospital during the follow-up period than women living in the control area ( P = 0.04). CONCLUSIONS: Voluntary health insurance combined with quality healthcare services is highly effective in increasing hospital deliveries in rural Nigeria, by improving access to healthcare for insured and uninsured women in the programme area.

Sustained effect of health insurance and facility quality improvement on blood pressure in adults with hypertension in Nigeria: A population-based study.

BACKGROUND: Hypertension is a leading risk factor for death in sub-Saharan Africa. Quality treatment is often not available nor affordable. We assessed the effect of a voluntary health insurance program, including quality improvement of healthcare facilities, on blood pressure (BP) in hypertensive adults in rural Nigeria. METHODS: We compared changes in outcomes from baseline (2009) to midline (2011) and endline (2013) between non-pregnant hypertensive adults in the insurance program area (PA) and a control area (CA), through household surveys. The primary outcome was the difference between the PA and CA in change in BP, using difference-in-differences analysis. RESULTS: Of 1500 eligible households, 1450 (96.7%) participated, including 559 (20.8%) hypertensive individuals, of which 332 (59.4%) had follow-up data. Insurance coverage increased from 0% at baseline to 41.8% at endline in the PA and remained under 1% in the CA. The PA showed a 4.97 mm Hg (95% CI: -0.76 to +10.71 mm Hg) greater decrease in systolic BP and a 1.81 mm Hg (-1.06 to +4.68 mm Hg) greater decrease in diastolic BP from baseline to endline compared to the CA. Respondents with stage 2 hypertension showed an 11.43 mm Hg (95% CI: 1.62 to 21.23 mm Hg) greater reduction in systolic BP and 3.15 mm Hg (-1.22 to +7.53 mm Hg) greater reduction in diastolic BP in the PA compared to the CA. Attrition did not affect the results. CONCLUSION: Access to improved quality healthcare through an insurance program in rural Nigeria was associated with a significant longer-term reduction in systolic BP in subjects with moderate or severe hypertension.

Improving Maternal Care through a State-Wide Health Insurance Program: A Cost and Cost-Effectiveness Study in Rural Nigeria.

BACKGROUND: While the Nigerian government has made progress towards the Millennium Development Goals, further investments are needed to achieve the targets of post-2015 Sustainable Development Goals, including Universal Health Coverage. Economic evaluations of innovative interventions can help inform investment decisions in resource-constrained settings. We aim to assess the cost and cost-effectiveness of maternal care provided within the new Kwara State Health Insurance program (KSHI) in rural Nigeria. METHODS AND FINDINGS: We used a decision analytic model to simulate a cohort of pregnant women. The primary outcome is the incremental cost effectiveness ratio (ICER) of the KSHI scenario compared to the current standard of care. Intervention cost from a healthcare provider perspective included service delivery costs and above-service level costs; these were evaluated in a participating hospital and using financial records from the managing organisations, respectively. Standard of care costs from a provider perspective were derived from the literature using an ingredient approach. We generated 95% credibility intervals around the primary outcome through probabilistic sensitivity analysis (PSA) based on a Monte Carlo simulation. We conducted one-way sensitivity analyses across key model parameters and assessed the sensitivity of our results to the performance of the base case separately through a scenario analysis. Finally, we assessed the sustainability and feasibility of this program's scale up within the State's healthcare financing structure through a budget impact analysis. The KSHI scenario results in a health benefit to patients at a higher cost compared to the base case. The mean ICER (US$46.4/disability-adjusted life year averted) is considered very cost-effective compared to a willingness-to-pay threshold of one gross domestic product per capita (Nigeria, US$ 2012, 2,730). Our conclusion was robust to uncertainty in parameters estimates (PSA: median US$49.1, 95% credible interval 21.9-152.3), during one-way sensitivity analyses, and when cost, quality, cost and utilization parameters of the base case scenario were changed. The sustainability of this program's scale up by the State is dependent on further investments in healthcare. CONCLUSIONS: This study provides evidence that the investment made by the KSHI program in rural Nigeria is likely to have been cost-effective; however, further healthcare investments are needed for this program to be successfully expanded within Kwara State. Policy makers should consider supporting financial initiatives to reduce maternal mortality tackling both supply and demand issues in the access to care.