Christopher R. Sudfeld

Effectiveness of measles vaccination and vitamin A treatment

Background The current strategy utilized by WHO/United Nations Childrens Fund (UNICEF) to reach the Global Immunization Vision and Strategy 2010 measles reduction goal includes increasing coverage of measles vaccine, vitamin A treatment and supplementation in addition to offering two doses of vaccine to all children. Methods We conducted a systematic review of published randomized controlled trials (RCTs) and quasi-experimental (QE) studies in order to determine effect estimates of measles vaccine and vitamin A treatment for the Lives Saved Tool (LiST). We utilized a standardized abstraction and grading format in order to determine effect estimates for measles mortality employing the standard Child Health Epidemiology Research Group Rules for Evidence Review. Results We identified three measles vaccine RCTs and two QE studies with data on prevention of measles disease. A meta-analysis of these studies found that vaccination was 85% [95% confidence interval (CI) 83–87] effective in preventing measles disease, which will be used as a proxy for measles mortality in LiST for countries vaccinating before one year of age. The literature also suggests that a conservative 95% effect estimate is reasonable to employ when vaccinating at 1 year or later and 98% for two doses of vaccine based on serology reviews. We included six high-quality RCTs in the meta-analysis of vitamin A treatment of measles which found no significant reduction in measles morality. However, when stratifying by vitamin A treatment dose, at least two doses were found to reduce measles mortality by 62% (95% CI 19–82). Conclusion Measles vaccine and vitamin A treatment are effective interventions to prevent measles mortality in children.

Impact of vitamin A supplementation on infant and childhood mortality

IntroductionVitamin A is important for the integrity and regeneration of respiratory and gastrointestinal epithelia and is involved in regulating human immune function. It has been shown previously that vitamin A has a preventive effect on all-cause and disease specific mortality in children under five. The purpose of this paper was to get a point estimate of efficacy of vitamin A supplementation in reducing cause specific mortality by using Child Health Epidemiology Reference Group (CHERG) guidelines.MethodsA literature search was done on PubMed, Cochrane Library and WHO regional data bases using various free and Mesh terms for vitamin A and mortality. Data were abstracted into standardized forms and quality of studies was assessed according to standardized guidelines. Pooled estimates were generated for preventive effect of vitamin A supplementation on all-cause and disease specific mortality of diarrhea, measles, pneumonia, meningitis and sepsis. We did a subgroup analysis for vitamin A supplementation in neonates, infants 1-6 months and children aged 6-59 months. In this paper we have focused on estimation of efficacy of vitamin A supplementation in children 6-59 months of age. Results for neonatal vitamin A supplementation have been presented, however no recommendations are made as more evidence on it would be available soon.ResultsThere were 21 studies evaluating preventive effect of vitamin A supplementation in community settings which reported all-cause mortality. Twelve of these also reported cause specific mortality for diarrhea and pneumonia and six reported measles specific mortality. Combined results from six studies showed that neonatal vitamin A supplementation reduced all-cause mortality by 12 % [Relative risk (RR) 0.88; 95 % confidence interval (CI) 0.79-0.98]. There was no effect of vitamin A supplementation in reducing all-cause mortality in infants 1-6 months of age [RR 1.05; 95 % CI 0.88-1.26]. Pooled results for preventive vitamin A supplementation showed that it reduced all-cause mortality by 25% [RR 0.75; 95 % CI 0.64-0.88] in children 6-59 months of age. Vitamin A supplementation also reduced diarrhea specific mortality by 30% [RR 0.70; 95 % CI 0.58-0.86] in children 6-59 months. This effect has been recommended for inclusion in the Lives Saved Tool. Vitamin A supplementation had no effect on measles [RR 0.71, 95% CI: 0.43-1.16], meningitis [RR 0.73, 95% CI: 0.22-2.48] and pneumonia [RR 0.94, 95% CI: 0.67-1.30] specific mortality.ConclusionPreventive vitamin A supplementation reduces all-cause and diarrhea specific mortality in children 6-59 months of age in community settings in developing countries.

Linear Growth and Child Development in Low- and Middle-Income Countries: A Meta-Analysis

BACKGROUND AND OBJECTIVE: The initial years of life are critical for physical growth and broader cognitive, motor, and socioemotional development, but the magnitude of the link between these processes remains unclear. Our objective was to produce quantitative estimates of the cross-sectional and prospective association of height-for-age z score (HAZ) with child development. METHODS: Observational studies conducted in low- and middle-income countries (LMICs) presenting data on the relationship of linear growth with any measure of child development among children <12 years of age were identified from a systematic search of PubMed, Embase, and PsycINFO. Two reviewers then extracted these data by using a standardized form. RESULTS: A total of 68 published studies conducted in 29 LMICs were included in the final database. The pooled adjusted standardized mean difference in cross-sectional cognitive ability per unit increase in HAZ for children ≤2 years old was +0.24 (95% confidence interval [CI], 0.14–0.33; I2 = 53%) and +0.09 for children >2 years old (95% CI, 0.05–0.12; I2 = 78%). Prospectively, each unit increase in HAZ for children ≤2 years old was associated with a +0.22-SD increase in cognition at 5 to 11 years after multivariate adjustment (95% CI, 0.17–0.27; I2 = 0%). HAZ was also significantly associated with earlier walking age and better motor scores (P < .05). CONCLUSIONS: Observational evidence suggests a robust positive association between linear growth during the first 2 years of life with cognitive and motor development. Effective interventions that reduce linear growth restriction may improve developmental outcomes; however, integration with environmental, educational, and stimulation interventions may produce larger positive effects.

PREVALENCE AND RISK FACTORS FOR RECOVERY OF FILAMENTOUS FUNGI IN INDIVIDUALS WITH CYSTIC FIBROSIS

BACKGROUND Filamentous fungi are frequently recovered from respiratory cultures of individuals with CF. METHODS A CF cohort database was utilized to determine filamentous fungal prevalence and risk factors. RESULTS The prevalence of filamentous fungal isolation increased from 2.0% in 1997 to 28.7% in 2007. The odds of isolating filamentous fungi during a quarter was greater in CF adults [p<0.001], during chronic oral antibiotic use [p=0.002] and increased with each 10% drop in FEV(1) percent predicted [p=0.005], while inhaled corticosteroids surprisingly decreased the likelihood [p=0.012]. The direction of these effects persisted after excluding individuals with ABPA. A sub-analysis determined older age [p=0.019] and use of inhaled antibiotics [p=0.011] were independent risk factors for onset of fungal colonization. CONCLUSIONS This study suggests that isolation of filamentous fungi in CF at JHH has increased and risk factors include older age, decreased lung function, and chronic oral antibiotics.

Early Childhood Developmental Status in Low- and Middle-Income Countries: National, Regional, and Global Prevalence Estimates Using Predictive Modeling

Background The development of cognitive and socioemotional skills early in life influences later health and well-being. Existing estimates of unmet developmental potential in low- and middle-income countries (LMICs) are based on either measures of physical growth or proxy measures such as poverty. In this paper we aim to directly estimate the number of children in LMICs who would be reported by their caregivers to show low cognitive and/or socioemotional development. Methods and Findings The present paper uses Early Childhood Development Index (ECDI) data collected between 2005 and 2015 from 99,222 3- and 4-y-old children living in 35 LMICs as part of the Multiple Indicator Cluster Survey (MICS) and Demographic and Health Surveys (DHS) programs. First, we estimate the prevalence of low cognitive and/or socioemotional ECDI scores within our MICS/DHS sample. Next, we test a series of ordinary least squares regression models predicting low ECDI scores across our MICS/DHS sample countries based on country-level data from the Human Development Index (HDI) and the Nutrition Impact Model Study. We use cross-validation to select the model with the best predictive validity. We then apply this model to all LMICs to generate country-level estimates of the prevalence of low ECDI scores globally, as well as confidence intervals around these estimates. In the pooled MICS and DHS sample, 14.6% of children had low ECDI scores in the cognitive domain, 26.2% had low socioemotional scores, and 36.8% performed poorly in either or both domains. Country-level prevalence of low cognitive and/or socioemotional scores on the ECDI was best represented by a model using the HDI as a predictor. Applying this model to all LMICs, we estimate that 80.8 million children ages 3 and 4 y (95% CI 48.1 million, 113.6 million) in LMICs experienced low cognitive and/or socioemotional development in 2010, with the largest number of affected children in sub-Saharan Africa (29.4.1 million; 43.8% of children ages 3 and 4 y), followed by South Asia (27.7 million; 37.7%) and the East Asia and Pacific region (15.1 million; 25.9%). Positive associations were found between low development scores and stunting, poverty, male sex, rural residence, and lack of cognitive stimulation. Additional research using more detailed developmental assessments across a larger number of LMICs is needed to address the limitations of the present study. Conclusions The number of children globally failing to reach their developmental potential remains large. Additional research is needed to identify the specific causes of poor developmental outcomes in diverse settings, as well as potential context-specific interventions that might promote children’s early cognitive and socioemotional well-being.

Vitamin D and HIV Progression among Tanzanian Adults Initiating Antiretroviral Therapy

Background There is growing evidence of an association between low vitamin D and HIV disease progression; however, no prospective studies have been conducted among adults receiving antiretroviral therapy (ART) in sub-Saharan Africa. Methods Serum 25-hydroxyvitamin D (25(OH)D) levels were assessed at ART initiation for a randomly selected cohort of HIV-infected adults enrolled in a trial of multivitamins (not including vitamin D) in Tanzania during 2006–2010. Participants were prospectively followed at monthly clinic visits for a median of 20.6 months. CD4 T-cell measurements were obtained every 4 months. Proportional hazard models were utilized for mortality analyses while generalized estimating equations were used for CD4 T-cell counts. Results Serum 25(OH)D was measured in 1103 adults 9.2% were classified as vitamin D deficient (<20 ng/ml), 43.6% insufficient (20–30 ng/mL), and 47.2% as sufficient (>30 ng/mL). After multivariate adjustment, vitamin D deficiency was significantly associated with increased mortality as compared to vitamin D sufficiency (HR: 2.00; 95% CI: 1.19–3.37; p = 0.009), whereas no significant association was found for vitamin D insufficiency (HR: 1.24; 95% CI: 0.87–1.78; p = 0.24). No effect modification by ART regimen or change in the associations over time was detected. Vitamin D status was not associated with change in CD4 T-cell count after ART initiation. Conclusions Deficient vitamin D levels may lead to increased mortality in individuals receiving ART and this relationship does not appear to be due to impaired CD4 T-cell reconstitution. Randomized controlled trials are needed to determine the safety and efficacy of vitamin D supplementation for individuals receiving ART.

Vitamin D Status and Incidence of Pulmonary Tuberculosis, Opportunistic Infections, and Wasting Among HIV-Infected Tanzanian Adults Initiating Antiretroviral Therapy

BACKGROUND Maintaining vitamin D sufficiency may decrease the incidence of pulmonary tuberculosis and other infectious diseases. We present the first prospective study of vitamin D among human immunodeficiency virus (HIV)-infected adults receiving antiretrovirals in sub-Saharan Africa. METHODS Serum 25-hydroxyvitamin D (25(OH)D) level was assessed at antiretroviral therapy (ART) initiation for 1103 HIV-infected adults enrolled in a trial of multivitamins (not including vitamin D) in Tanzania. Participants were prospectively followed at monthly visits at which trained physicians performed a clinical examination and nurses took anthropometric measurements and assessed self-reported symptoms. Cox proportional hazards models estimated hazard ratios (HRs) of morbidity outcomes. RESULTS After multivariate adjustment, vitamin D deficiency (defined as a concentration of <20 ng/mL) had a significantly greater association with incident pulmonary tuberculosis, compared with vitamin D sufficiency (HR, 2.89; 95% confidence interval [CI], 1.31-7.41; P = .027), but no association was found for vitamin D insufficiency (defined as a concentration of 20-30 ng/mL; P = .687). Deficiency was also significantly associated with incident oral thrush (HR, 1.96; 95% CI, 1.01-3.81; P = .046), wasting (HR, 3.10; 95% CI, 1.33-7.24; P = .009), and >10% weight loss (HR, 2.10; 95% CI, 1.13-3.91; P = .019). Wasting results were robust to exclusion of individuals experiencing pulmonary tuberculosis. Vitamin D status was not associated with incident malaria, pneumonia, or anemia. CONCLUSIONS Vitamin D supplementation trials for adults receiving ART appear to be warranted.

Risk Factors for Childhood Stunting in 137 Developing Countries: A Comparative Risk Assessment Analysis at Global, Regional, and Country Levels.

Background Stunting affects one-third of children under 5 y old in developing countries, and 14% of childhood deaths are attributable to it. A large number of risk factors for stunting have been identified in epidemiological studies. However, the relative contribution of these risk factors to stunting has not been examined across countries. We estimated the number of stunting cases among children aged 24–35 mo (i.e., at the end of the 1,000 days’ period of vulnerability) that are attributable to 18 risk factors in 137 developing countries. Methods and Findings We classified risk factors into five clusters: maternal nutrition and infection, teenage motherhood and short birth intervals, fetal growth restriction (FGR) and preterm birth, child nutrition and infection, and environmental factors. We combined published estimates and individual-level data from population-based surveys to derive risk factor prevalence in each country in 2010 and identified the most recent meta-analysis or conducted de novo reviews to derive effect sizes. We estimated the prevalence of stunting and the number of stunting cases that were attributable to each risk factor and cluster of risk factors by country and region. The leading risk worldwide was FGR, defined as being term and small for gestational age, and 10.8 million cases (95% CI 9.1 million–12.6 million) of stunting (out of 44.1 million) were attributable to it, followed by unimproved sanitation, with 7.2 million (95% CI 6.3 million–8.2 million), and diarrhea with 5.8 million (95% CI 2.4 million–9.2 million). FGR and preterm birth was the leading risk factor cluster in all regions. Environmental risks had the second largest estimated impact on stunting globally and in the South Asia, sub-Saharan Africa, and East Asia and Pacific regions, whereas child nutrition and infection was the second leading cluster of risk factors in other regions. Although extensive, our analysis is limited to risk factors for which effect sizes and country-level exposure data were available. The global nature of the study required approximations (e.g., using exposures estimated among women of reproductive age as a proxy for maternal exposures, or estimating the impact of risk factors on stunting through a mediator rather than directly on stunting). Finally, as is standard in global risk factor analyses, we used the effect size of risk factors on stunting from meta-analyses of epidemiological studies and assumed that proportional effects were fairly similar across countries. Conclusions FGR and unimproved sanitation are the leading risk factors for stunting in developing countries. Reducing the burden of stunting requires a paradigm shift from interventions focusing solely on children and infants to those that reach mothers and families and improve their living environment and nutrition.

Peer Support and Exclusive Breastfeeding Duration in Low and Middle-Income Countries: A Systematic Review and Meta-Analysis

Objective To examine the effect of peer support on duration of exclusive breastfeeding (EBF) in low and middle-income countries (LMICs). Data Sources Medline, EMBASE, and Cochrane Central Register for Controlled Trials were searched from inception to April 2012. Methods Two authors independently searched, reviewed, and assessed the quality of randomized controlled trials utilizing peer support in LMICs. Meta-analysis and metaregression techniques were used to produce pooled relative risks and investigate sources of heterogeneity in the estimates. Results Eleven randomized controlled trials conducted at 13 study sites met the inclusion criteria for systematic review. We noted significant differences in study populations, peer counselor training methods, peer visit schedule, and outcome ascertainment methods. Peer support significantly decreased the risk of discontinuing EBF as compared to control (RR: 0.71; 95% CI: 0.61–0.82; I2 = 92%). The effect of peer support was significantly reduced in settings with >10% community prevalence of formula feeding as compared to settings with <10% prevalence (p = 0.048). There was no evidence of effect modification by inclusion of low birth weight infants (p = 0.367) and no difference in the effect of peer support on EBF at 4 versus 6 months postpartum (p = 0.398). Conclusions Peer support increases the duration of EBF in LMICs; however, the effect appears to be reduced in formula feeding cultures. Future studies are needed to determine the optimal timing of peer visits, how to best integrate peer support into packaged intervention strategies, and the effectiveness of supplemental interventions to peer support in formula feeding cultures.

Association of Serum Albumin Concentration With Mortality, Morbidity, CD4 T-cell Reconstitution Among Tanzanians Initiating Antiretroviral Therapy

BACKGROUND Prospective studies of serum albumin concentration measurement as a low-cost predictor of human immunodeficiency virus (HIV) disease progression are needed for individuals initiating antiretroviral therapy (ART) in resource-limited settings. METHODS Serum albumin concentration was measured at ART initiation for 2145 adults in Tanzania who were enrolled in a trial examining the effect of multivitamins on HIV disease progression. Participants were prospectively followed for mortality, morbidity, and anthropometric outcomes at monthly visits (median follow-up duration, 21.2 months). Proportional hazard models were used to analyze mortality, morbidity, and nutritional outcomes, while generalized estimating equations were used to analyze CD4(+) T-cell counts. RESULTS Individuals with hypoalbuminemia (defined as a serum albumin concentration of <35 g/L) at ART initiation had a hazard of death that was 4.52 times (95% confidence interval, 3.37-6.07; P < .001) that of individuals with serum albumin concentrations of ≥ 35 g/L, after multivariate adjustment. Hypoalbuminemia was also independently associated with the incidence of pulmonary tuberculosis (P < .001), severe anemia (P < .001), wasting (P = .002), and >10% weight loss (P = .012). Secondary analyses suggested that serum albumin concentrations of <38 g/L were associated with increased mortality and incident pulmonary tuberculosis. There was no association between serum albumin concentration and changes in CD4(+) T-cell counts (P = .121). CONCLUSIONS Serum albumin concentrations can identify adults initiating ART who are at high risk for mortality and selected morbidities. Future research is needed to identify and manage conditions that reduce the serum albumin concentration.