Quantifying the indirect effects of key child survival interventions for pneumonia, diarrhoea, and measles.

To date many studies have measured the effect of key child survival interventions on the main cause of mortality while anecdotally reporting effects on all-cause mortality. We conducted a systematic literature review and abstracted cause-specific and all-cause mortality data from included studies. We then estimated the effect of the intervention on the disease of primary interest and calculated the additional deaths prevented (i.e. the indirect effect). We calculated that insecticide-treated nets have been shown to result in a 12% reduction [95% confidence interval (CI) 0·0-23] among non-malaria deaths. We found pneumonia case management to reduce non-pneumonia mortality by 20% (95% CI 8-22). For measles vaccine, seven of the 10 studies reporting an effect on all-cause mortality demonstrated an additional benefit of vaccine on all-cause mortality. These interventions may have benefits on causes of death beyond the specific cause of death they are targeted to prevent and this should be considered when evaluating the effects of implementation of interventions.

A population-based case-control study of 1250 stroke deaths in rural Bangladesh.

BACKGROUND AND PURPOSE: There are limited population-based studies to determine the risk factors for stroke in Bangladesh. METHODS: A health and demographic surveillance system has been maintained in Matlab, Bangladesh (population 223 886, 142 villages in 2008). All adult stroke and injury deaths (2005-2008) were monitored by verbal autopsy. Risk factors for stroke deaths were calculated using a multivariable logistic regression model with adult injury deaths as controls. RESULTS: A total of 1250 stroke deaths (51% women; mean age 72.3 years, range 20-101) occurred out of 4955 total deaths and were compared with 246 adult injury deaths (47% women, mean age 55.8 years, range 20-100). The population-attributable mortality of stroke was 25.2% based on the verbal autopsy instrument and 17.8% when accounting for the reported sensitivity and specificity of a similar verbal autopsy instrument that has been validated for stroke death. Risk of stroke death was significantly increased with hypertension (OR 7.94, 95% CI 4.44-15.54, P < 0.001), diabetes mellitus (OR 2.54, 1.21-6.21, P = 0.02), and betel consumption (OR 2.36, 1.45-3.80, P < 0.001) when adjusted for age and sex. An increased risk was not observed with heart disease (OR 1.37, 0.45-5.95, P = 0.62), cigarette smoking (OR 1.41, 0.82-2.45, P = 0.22), tobacco powder (OR 1.15, 0.30-7.64, P = 0.86), or cigar/hookah pipe smoking 0.94 (0.45-2.18, P = 0.88) when adjusted for age and sex. There were more strokes in winter (December-March) than summer (June-September) (P < 0.001). CONCLUSIONS: There is a high modifiable burden of risk factors for adult stroke deaths in rural Bangladesh, most notably including hypertension. Betel consumption may be an under-recognized risk factor for stroke death.

Can mothers recognize neonatal illness correctly? Comparison of maternal report and assessment by community health workers in rural Bangladesh.

OBJECTIVES: To validate maternal recognition of neonatal illnesses at home compared to assessment by community health workers (CHWs) during routine household surveillance for neonatal illness in rural Bangladesh. METHODS: Surveillance in the intervention arm of two cluster-randomized, controlled trials of newborn interventions conducted in Sylhet and Mirzapur districts of Bangladesh. CHWs promoted birth and newborn care preparedness during two prenatal visits, including recognition of neonatal illnesses. CHWs assessed 8472 neonates on post-natal days 0, 3, and 6 between 2004 and 2005 in Sylhet, and 7587 neonates on post-natal days 0, 2, 5, and 8 between 2004 and 2006 in Mirzapur. In both sites, CHW identified neonates with very severe disease (VSD), using clinical algorithms that included ascertainment of illness history reported by mother and observation of clinical signs of illness. We calculated sensitivity, specificity, positive predictive value and negative predictive value of maternal report of any illness sign compared to CHWs' assessments and classification of VSD. Analysis was restricted to mothers whose neonates were assessed by CHWs at home during the routine visit schedule. RESULTS: Maternal report of any signs had sensitivity of 24% and 20% and positive predictive value of 45% and 54% in Sylhet and Mirzapur, respectively. CONCLUSIONS: Maternal recognition of neonatal illnesses at home was poor in two rural areas in Bangladesh. Interventions need to be designed to improve maternal recognition, and routine post-natal assessment by CHWs at home may be an essential component of community-based newborn care to improve care-seeking for newborn illness.

Diarrhoea morbidity and mortality in older children, adolescents, and adults.

Diarrhoea is a leading cause of morbidity and mortality yet diarrhoea specific incidence and mortality rates for older children, adolescents, and adults have not been systematically calculated for many countries. We conducted a systematic literature review to generate regional incidence rates by age and to summarize diarrhoea specific mortality rates for regions of the world with inadequate vital registration data. Diarrhoea morbidity rates range from 29.9 episodes/100 person-years for adults in the South East Asian region to 88.4 episodes/100 person-years in older children in the Eastern Mediterranean region and have remained unchanged in the last 30 years. Diarrhoea mortality rates decline as the child ages and remain relatively constant during adulthood. These data are critical for improving estimates worldwide and further highlight the need for improved diarrhoea specific morbidity and mortality data in these age groups.

Vitamin D status and acute lower respiratory infection in early childhood in Sylhet, Bangladesh.

AIM: Acute lower respiratory tract infection (ALRI) is the most important global cause of childhood death. Micronutrient deficiencies may increase the risk of ALRI. A case-control study was conducted to assess the association between vitamin D status and ALRI in rural Bangladesh. METHODS: Children aged 1-18 months hospitalized with ALRI (cases) were individually matched to controls on age, sex, and village (N = 25 pairs). The mean serum 25-hydroxyvitamin D concentration [25(OH)D] in cases and controls was compared using paired t-test. The unadjusted and adjusted odds of ALRI were assessed by multivariate conditional logistic regression. RESULTS: Mean [25(OH)D] was significantly lower among ALRI cases than controls (29.1 nmol/L vs. 39.1 nmol/L; p = 0.015). The unadjusted odds of ALRI was halved for each 10 nmol/L increase in [25(OH)D] (OR 0.53, 95% CI 0.30-0.96). Adjustment for confounders increased the magnitude of the association. CONCLUSION: Vitamin D status was associated with early childhood ALRI in a matched case-control study in rural Bangladesh. Randomized trials may establish whether interventions to improve vitamin D status can reduce the burden of ALRI in early childhood.

Meeting Report: WHO Workshop on modelling global mortality and aetiology estimates of enteric pathogens in children under five. Cape Town, 28-29th November 2018.

Investment in vaccine product development should be guided by up-to-date and transparent global burden of disease estimates, which are also fundamental to policy recommendation and vaccine introduction decisions. For low- and middle-income countries (LMICs), vaccine prioritization is primarily driven by the number of deaths caused by different pathogens. Enteric diseases are known to be a major cause of death in LMICs. The two main modelling groups providing mortality estimates for enteric diseases are the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, Seattle and the Maternal Child Epidemiology Estimation (MCEE) group, led by Johns Hopkins Bloomberg School of Public Health. Whilst previous global diarrhoea mortality estimates for under five-year-olds from these two groups were closely aligned, more recent estimates for 2016 have diverged, particularly with respect to numbers of deaths attributable to different enteric pathogens. This has impacted prioritization and investment decisions for vaccines in the development pipeline. The mission of the Product Development for Vaccines Advisory Committee (PDVAC) at the World Health Organisation (WHO) is to accelerate product development of vaccines and technologies that are urgently needed and ensure they are appropriately targeted for use in LMICs. At their 2018 meeting, PDVAC recommended the formation of an independent working group of subject matter experts to explore the reasons for the difference between the IHME and MCEE estimates, and to assess the respective strengths and limitations of the estimation approaches adopted, including a review of the data on which the estimates are based. Here, we report on the proceedings and recommendations from a consultation with the working group of experts, the IHME and MCEE modelling groups, and other key stakeholders. We briefly review the methodological approaches of both groups and provide a series of proposals for investigating the drivers for the differences in enteric disease burden estimates.

Addition of isovitalex in chocolate agar for the isolation of Haemophilus influenzae.

BACKGROUND & OBJECTIVE: The reason for lack of data on burden of Haemophilus influenzae type b (Hib) in developing countries was mainly failure of detection of this fastidious organism in laboratories. Use of isovitalex (IVX) was suggested as an essential supplement for growing this organism. This study was carried out to investigate the impact of IVX supplementation to chocolate agar for detection of Hib. METHODS: Chocolate agar with and without supplementation of IVX was prepared. Clinical samples as well as reference strains of Hib were simultaneously cultured on both the media. RESULTS: H. influenzae isolates (N=194) were simultaneously grown on chocolate agar (CA) with and without isovitalex (IVX). Average colony size of H. influenzae on CA with IVX (CA-IVX) was larger only by 0.10 cm (range 0.05 to 0.16 cm) compared to CA alone. Addition of IVX to CA increased the cost of media by 2.1-fold. INTERPRETATION & CONCLUSION: Isovitalex is not essential for the isolation and growth of H. influenzae almost halving the cost.

[Conclusions and recommendations of a WHO expert consultation meeting on iron supplementation for infants and young children in malaria endemic areas]. / Conclusions et recommandations à l'issue de la consultation de l'OMS sur la lutte contre la carence martiale chez le nourrisson et le jeune enfant dans les pays d'endémie palustre.

This article presents the results of an expert consultation meeting aimed at evaluating the safety and public health implications of administering supplemental iron to infants and young children in malaria-endemic areas. Participants at this meeting that took place in Lyon, France on June 12-14, 2006 reached consensus on several important issues related to iron supplementation for infants and young children in malaria-endemic areas. The conclusions in this report apply specifically to regions where malaria is endemic.

Zinc for diarrhoea management in Sub-Saharan Africa: a review.

OBJECTIVES: To review the evidence supporting the inclusion of zinc for diarrhoea management specifically in sub-Saharan Africa where diarrhoea remains a leading cause of morbidity and mortality. DATA SOURCES: We searched PubMed for studies assessing the efficacy and effectiveness of zinc for the treatment and prevention of common childhood morbidities. STUDY SELECTION: We included only studies conducted in sub-Saharan Africa. DATA SYNTHESIS: Details of studies conducted in sub-Saharan Africa are presented in the context of the global evidence supporting the use of zinc for diarrhoea management. CONCLUSIONS: There is a significant body of evidence to support the use of zinc for diarrhoea management in sub-Saharan Africa. The accelerated introduction of zinc into routine community-based diarrhoea treatment is critical for the reduction of diarrhoea morbidity and mortality.

Effect of community-based newborn care on cause-specific neonatal mortality in Sylhet district, Bangladesh: findings of a cluster-randomized controlled trial.

OBJECTIVES: Community-based maternal and newborn intervention packages have been shown to reduce neonatal mortality in resource-constrained settings. This analysis uses data from a large community-based cluster-randomized trial to assess the impact of a community-based package on cause-specific neonatal mortality and draws programmatic and policy implications. In addition, the study shows that cause-specific mortality estimates vary substantially based on the hierarchy used in assigning cause of death, which also has important implications for program planning. Therefore, understanding the methods of assigning causes of deaths is important, as is the development of new methodologies that account for multiple causes of death. The objective of this study was to estimate the effect of two service delivery strategies (home care and community care) for a community-based package of maternal and neonatal health interventions on cause-specific neonatal mortality rates in a rural district of Bangladesh. STUDY DESIGN: Within the general community of the Sylhet district in rural northeast Bangladesh. Pregnancy histories were collected from a sample of women in the study area during the year preceding the study (2002) and from all women who reported a pregnancy outcome during the intervention in years 2004 to 2005. All families that reported a neonatal death during these time periods were asked to complete a verbal autopsy interview. Expert algorithms with two different hierarchies were used to assign causes of neonatal death, varying in placement of the preterm/low birth weight category within the hierarchy (either third or last). The main outcome measure was cause-specific neonatal mortality. RESULT: Deaths because of serious infections in the home-care arm declined from 13.6 deaths per 1000 live births during the baseline period to 7.2 during the intervention period according to the first hierarchy (preterm placed third) and from 23.6 to 10.6 according to the second hierarchy (preterm placed last). CONCLUSION: This study confirms the high burden of neonatal deaths because of infection in low resource rural settings like Bangladesh, where most births occur at home in the absence of skilled birth attendance and care seeking for newborn illnesses is low. The study demonstrates that a package of community-based neonatal health interventions, focusing primarily on infection prevention and management, can substantially reduce infection-related neonatal mortality.

Association between the acquired immunodeficiency syndrome and infection with Salmonella typhi or Salmonella paratyphi in an endemic typhoid area.

Eight cases of typhoid and paratyphoid fever were identified during a 4-year period in a cohort of 117 patients who were positive for human immunodeficiency virus in Lima, Peru. Asymptomatic patients with human immunodeficiency virus infection and patients with the lymphadenopathy syndrome had a typical clinical presentation and response to therapy. Patients with the acquired immunodeficiency syndrome who were culture positive for Salmonella typhi or Salmonella paratyphi presented with fulminant diarrhea and/or colitis; the two patients for whom at least 2 months of follow-up were available relapsed. In our cohort there were 0.06 cases of typhoid or paratyphoid per patient year of observation; this rate is approximately 60 times that in the general population in Lima, and 25 times that in the 15- to 35-year-old age group. Our data indicate that patients who are positive for human immunodeficiency virus are at significantly increased risk for infection with S typhi and S paratyphi, and suggest that the clinical presentation of these diseases in patients with the acquired immunodeficiency syndrome differs from that seen immunocompetent hosts.

Counting children with tuberculosis: why numbers matter.

In the last 5 years, childhood tuberculosis (TB) has received increasing attention from international organisations, national TB programmes and academics. For the first time, a number of different groups are developing techniques to estimate the burden of childhood TB. We review the challenges in diagnosing TB in children and the reasons why cases in children can go unreported. We discuss the importance of an accurate understanding of burden for identifying problems in programme delivery, targeting interventions, monitoring trends, setting targets, allocating resources appropriately and providing strong advocacy. We briefly review the estimates produced by new analytical methods, and outline the reasons for recent improvements in our understanding and potential future directions. We conclude that while innovation, collaboration and better data have improved our understanding of the childhood TB burden, it remains substantially incomplete.

Therapeutic and preventive effects of zinc on serious childhood infectious diseases in developing countries.

In children in developing countries, zinc deficiency may be common and associated with immune impairment and increased risk of serious infectious diseases such as diarrhea, pneumonia, and malaria. Studies have evaluated the therapeutic effects of zinc supplementation during acute or persistent diarrhea. In studies of acute diarrhea, the illness duration has been found to be 9-23% shorter in zinc-supplemented than in control children. Diarrhea was also less severe in zinc-supplemented children. In studies of persistent diarrhea, the effect sizes were similar but were often not statistically significant, perhaps because of the small number of children participating in these studies. Trials that provided continuous daily zinc supplementation for 5-15 mo evaluated effects on the incidence of diarrhea and in some studies acute lower respiratory infections and malaria. The reduction in the incidence of diarrhea in the zinc-supplemented group in these studies ranged from 8% to 45%. A study that gave 2 wk of zinc supplementation found preventive effects against diarrhea for the 3 mo of surveillance. More limited data also suggest that the incidence of acute lower respiratory infection and clinical attacks of malaria may also be reduced by zinc supplementation. If these results are confirmed by meta-analysis of the existing trials and additional research, improvement of zinc nutriture should become a priority intervention to reduce the high burden of serious infectious disease in children in developing countries.

Relative effects of diarrhea, fever, and dietary energy intake on weight gain in rural Bangladeshi children.

Quantitative studies of morbidity, food intake, and somatic growth were done prospectively during 14 mo for 70 children aged 5-18 mo in two Bangladeshi villages. When random-effect regression models were used, monthly changes in weight were inversely related to proportions of days in the month with fever and diarrhea and positively related to energy intake per kilogram body weight. Interestingly, weight changes did not vary with age in this interval. Estimates indicate that increasing energy intakes to the recommended World Health Organization level would have a significantly greater effect on weight gain than would the elimination of diarrhea and fever. With energy at recommended intake and diarrhea and fever prevalence as found in US children, weight gain is predicted to be near that of the international reference population. Therefore, interventions aimed at improving dietary intake may be as important as infection-control programs for improving growth of children in poor developing nations.

Malnutrition is a determining factor in diarrheal duration, but not incidence, among young children in a longitudinal study in rural Bangladesh.

Diarrhea and malnutrition are common in young children in developing countries and a reciprocal relationship has been postulated with diarrhea leading to malnutrition and malnutrition predisposing to diarrhea. To investigate the importance of malnutrition as a determining factor in diarrheal illnesses, data were analyzed from a longitudinal community-based study done in rural Bangladesh. Children classified by nutritional status according to a variety of anthropometric indicators were prospectively evaluated for incidence, duration, and etiology of diarrhea. Children with low weight for length had longer durations of diarrhea than better nourished children; however, children of differing nutritional status had similar diarrheal incidences. The duration of diarrhea, including that associated with enterotoxigenic Escherichia coli and Shigella, increased progressively as nutritional status indicators worsened. These results suggest that nutritional interventions alone are unlikely to reduce the high incidence of diarrhea, but that efforts to improve nutritional status may have a beneficial effect on the duration of diarrhea and its unfavorable nutritional consequences.

Seasonal changes in nutritional status and the prevalence of malnutrition in a longitudinal study of young children in rural Bangladesh.

During longitudinal field studies of the growth, dietary intake, and morbidity from infectious diseases of children between 6 and 60 months of age in two rural villages of Bangladesh, seasonal fluctuations in growth, nutritional status, and the prevalence of malnutrition were observed. The weight, length, arm circumference, and triceps skinfold thickness of 197 children were measured monthly for 15 months and compared with sex-specific local village norms and international reference populations. The percentages of expected weight for length, arm circumference for age, triceps skinfold thickness for age, and the percentages of expected monthly increments of weight and length for age were the indicators most sensitive to seasonal changes. The percentages of expected weight for age and length for age also changed significantly by month of year, but were less responsive to seasonal variation. The periods of greatest nutritional deficit depended on which anthrometric indicator was used to define nutritional status, but generally occurred during the monsoon and persisted until the subsequent harvest period. However, the fall in mean percentage of expected length for age and the increase in the prevalence of stunting occurred several months after the periods of greatest malnutrition identified by the other measurements. The importance of selecting the appropriate anthropometric techniques to detect seasonal changes and the implications of such changes are discussed.

PIP: During longitudinal field studies of the growth, dietary intake, and morbidity from infectious diseases of children between 6 and 60 months of age in 2 villages of rural Bangladesh, seasonal fluctuations in growth, nutritional status, and the prevalence of malnutrition were observed. The weight, length, arm circumference, and triceps skinfold thickness of 197 children were measured monthly for 15 months and compared with sex specific local village norms and international reference populations. The percentages of expected weight for length, arm circumference for age, triceps skinfold thickness for age, and the percentages of expected monthly increments of weight and length for age were the indicators most sensitive to seasonal changes. The percentages of expected weight for age and length for age also changed significantly by month of year, but were less responsive to seasonal variation. The periods of greatest nutritional deficit depended on which anthropometric indicator was used to define nutritional status, but generally occurred during the monsoon and persisted until the subsequent harvest period. However, the fall in mean percentage of expected length for age and the increase in prevalence of stunting occurred several months after the periods of greatest malnutrition identified by the other measurements. The importance of selecting the appropriate anthropometric techniques to detect seasonal changes and the implications of such changes are discussed.

Patterns of physical growth in a longitudinal study of young children in rural Bangladesh.

Longitudinal field studies of the physical growth of 197 children between 6 and 60 months of age have been completed in two rural villages of Bangladesh. The distribution of weights by age indicated that 90% of the village girls and boyd weighed less than the National Center for Health Statistics 5th percentile by 8 and 15 months of age, respectively. Of the children 90% were shorter than the reference population 10th percentile length by age by 10 to 13 months of age. Since the children's patterns of growth differed from those of the reference populations from North America and Europe, internal standards were created for the village girls and boys by fitting curves to their data for weight by age, length by age, arm circumference by age, triceps skinfold thickness by age, and weight by length. The village references enabled age-independent comparisons of children within the study population by relating their actual anthropometric status to the village norms. Comparisons of the village standards with the international reference data showed the period of poorest nutritional status of the village children persisted from shortly after birth to approximately 2 yr of age.

The effect of malnutrition on the risk of diarrheal and respiratory mortality in children < 2 y of age in Cebu, Philippines.

The effects of nutritional status on diarrheal and acute lower respiratory infection (ALRI) mortality in children < 2 y of age were examined by using data from a 1988-1991 longitudinal study of 9942 children in Metro Cebu, Philippines. Cox regression methods were used to study the strengths of the associations, possible interactions with birth weight and breast-feeding status, and the effect of additional confounding factors. Nutritional status as measured by weight-for-age was a significant risk factor for both ALRI and diarrheal mortality in the first 2 y of life. Poor nutritional status resulted in a 1.6-fold increased risk of diarrheal mortality for each one-unit decrease in weight-for-age Z score. For ALRI mortality, a one-unit decrease in weight-for-age Z score resulted in a 1.7-fold increase in risk, and for mortality associated with ALRI and diarrhea combined, the relative risk was 2.0. This study provides further evidence that malnutrition is a major determinant of mortality in very young children and it is one of the first longitudinal studies to estimate the magnitude of the effect on cause-specific mortality associated with nutritional status.

Effects of season and illness on the dietary intake of weanlings during longitudinal studies in rural Bangladesh.

Longitudinal, quantitative studies of the dietary intake of 70 weanlings between five and 30 months of age from two Bangladeshi villages have been analyzed to determine the effects of season and illness on dietary intake. During 1014 days of observation, all foods consumed by the children were weighed by a field worker present in the home; 24-hour breast milk intake was estimated from 12-hour test weighings. Inter-individual differences explained 29% to 50% of the variance in consumption of selected nutrients and foods during 632 studies conducted when children were free from diarrhea and fever. Multiple linear regressions controlling for inter-individual differences indicated that 60-day seasonal periods explained a significant proportion of the variation in intake. Average energy consumption (kcal/kg/d) was approximately one-third greater during the post-harvest periods than during the pre-harvest monsoon period. Breast milk intake varied similarly even after controlling for age-related decreases. Consumption of rice and wheat, the major non-breast milk sources of energy and protein, had distinct seasonal patterns, thus limiting the overall seasonal variability in cereal intake. Older children, particularly boys, benefited more from the post-harvest relative abundance of food. The intake of most nutrients was significantly depressed by approximately 10% during febrile illnesses. Minor decreases in intake with other illnesses were not statistically significant.

Efficacy of zinc supplementation in reducing the incidence and prevalence of acute diarrhea--a community-based, double-blind, controlled trial.

A community-based, double-blind, randomized trial was conducted in a population of low socioeconomic status in urban India to determine whether daily zinc supplementation reduces the incidence and prevalence of acute diarrhea, especially in those with zinc deficiency. Children 6-35 mo of age were randomly assigned to zinc (n = 286) and control (n = 293) groups and received a supplement daily for 6 mo. Zinc gluconate (10 mg elemental Zn) was given, with both zinc and control groups also receiving multivitamins. The primary outcome measures determined by home visits every fifth day and physician examinations were the number of acute diarrheal episodes (incidence) and total diarrheal days (prevalence). Zinc supplementation had no effect in children 6-11 mo old. In children aged > 11 mo there was significantly less diarrhea in the zinc group. In boys > 11 mo old, supplementation resulted in a 26% (95% CI: 13%, 38%) lower diarrheal incidence and a 35% (95% CI: 20%, 50%) lower prevalence. In zinc-supplemented girls > 11 mo of age, the incidence was 17% (95% CI: 2%, 30%) lower and the prevalence was 19% (95% CI: 4%, 47%) lower. Overall, zinc supplementation resulted in a 17% (95% CI: 1%, 30%) lower diarrheal incidence in children with plasma zinc concentrations < 9.18 mumol/L at enrollment and a 33% (95% CI: 6%, 52%) lower incidence in children with concentrations < 50 mumol/L. In conclusion, zinc supplementation had a significant effect on acute diarrheal morbidity in children > 11 mo old and in children with low plasma zinc concentrations.