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.

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.

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.

Maternal and neonatal colonization in Bangladesh: prevalences, etiologies and risk factors.

OBJECTIVE: To estimate the prevalence of maternal colonizers in South Asia and their potential to colonize the umbilicus, an important precondition causing neonatal sepsis. STUDY DESIGN: We conducted a cross-sectional study at a maternity center in Dhaka with 1219 pregnant women and a subset of 152 newborns from 15 January to 31 October 2011. During labor, study paramedics collected vaginal swabs for bacterial culture and rectal swabs for Group B Streptococcus (GBS) testing. Community health workers collected neonatal umbilical swabs. Log-binomial regression models were used to estimate risk ratios. RESULT: In all, 454 women (37.2%, 95% confidence interval (CI) 34.5 to 40.0%) were colonized. The most common organisms isolated were Staphylococcus aureus, Non-GBS and GBS. A total of 94 women (7.7%, 95% CI 6.2 to 9.2%) were colonized with GBS. The risk of GBS umbilical colonization was higher (RR=12.98, 95% CI 3.97 to 42.64) among newborns of mothers with GBS colonization. CONCLUSION: Newborns of mothers colonized with GBS are at higher risk of developing umbilical colonization.

Preterm birth and neonatal mortality in a rural Bangladeshi cohort: implications for health programs.

OBJECTIVE: To estimate the burden of prematurity, determine gestational age (GA)-specific neonatal mortality rates and provide recommendations for country programs. STUDY DESIGN: Prospective data on pregnancy, childbirth, GA and newborn mortality collected by trained community health workers from 10 585 mother-newborn pairs in a community-based study. RESULT: A total of 19.4% of newborn infants were preterm; 13.5% were late preterm (born between 34 and 36 weeks of gestation), 3.3% were moderate preterm (born at 32 to 33 weeks) and 2.6% were extremely preterm (born at 28 to 31 weeks of gestation). Preterm babies experienced 46% of all neonatal deaths; 40% of preterm deaths were in late preterm, 20% in moderate preterm and 40% in very preterm infants. The population attributable fraction of neonatal mortality in premature babies was 0.16 for very preterm, 0.07 for moderately preterm and 0.10 for late preterm. CONCLUSION: In settings where the majority of births and newborn deaths occur at home and successful referral is a challenge, moderate and late preterm babies may be an important target group for home-based or first-level facility-based management.

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.

Supplementing iron and zinc: double blind, randomized evaluation of separate or combined delivery.

BACKGROUND/OBJECTIVES: Many children have diets deficient in both iron and zinc, but there has been some evidence of negative interactions when they are supplemented together. The optimal delivery approach would maximize clinical benefits of both nutrients. We studied the effectiveness of different iron and zinc supplement delivery approaches to improve diarrhea and anemia in a rural Bangladesh population. STUDY DESIGN: Randomized, double blind, placebo-controlled factorial community trial. RESULTS: Iron supplementation alone increased diarrhea, but adding zinc, separately or together, attenuated these harmful effects. Combined zinc and iron was as effective as iron alone for iron outcomes. All supplements were vomited <1% of the time, but combined iron and zinc were vomited significantly more than any of the other supplements. Children receiving zinc and iron (together or separately) had fewer hospitalizations. Separating delivery of iron and zinc may have some additional benefit in stunted children. CONCLUSIONS: Separate and combined administration of iron and zinc are equally effective for reducing diarrhea, hospitalizations and improving iron outcomes. There may be some benefit in separate administration in stunted children.

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.

Global and regional child mortality and burden of disease attributable to zinc deficiency.

BACKGROUND/OBJECTIVES: Zinc is an essential micronutrient and deficiency can lead to an increased risk for infectious diseases and growth retardation among children under 5 years of age. We aimed to estimate disease-specific and all-cause mortality attributable to zinc deficiency. SUBJECT/METHODS: We estimated the prevalence of zinc deficiency in Latin America, Africa and Asia, where based on zinc availability in the diet and childhood stunting rates, zinc deficiency is widespread. The relative risks of death among zinc-deficient children for diarrhea, malaria and pneumonia were estimated from randomized controlled trials. We used the comparative risk assessment methods to calculate deaths and burden of disease (measured in disability-adjusted life years, DALYs) from each of these three diseases attributable to zinc deficiency in these regions. RESULTS: Zinc deficiency was responsible for 453,207 deaths (4.4% of childhood deaths), and 1.2% of the burden of disease (3.8% among children between 6 months and 5 years) in these three regions in 2004. Of these deaths, 260,502 were in Africa, 182,546 in Asia and 10,159 in Latin America. Zinc deficiency accounted for 14.4% of diarrhea deaths, 10.4% of malaria deaths and 6.7% of pneumonia deaths among children between 6 months and 5 years of age. CONCLUSIONS: Zinc deficiency contributes to substantial morbidity and mortality, especially from diarrhea. Zinc supplementation provided as an adjunct treatment for diarrhea may be the best way to target children most at risk of deficiency.

Low-dose weekly supplementation of iron and/or zinc does not affect growth among Bangladeshi infants.

OBJECTIVES: To determine the effect of low-dose weekly supplementation with iron, zinc or both on growth of infants from 6 to 12 months of age. SUBJECTS/METHODS: A total of 645 breastfed infants age 6 months who were not severely anemic (Hb> or = 90 g l(-1)) or severely malnourished (weight-for-age > or = 60% median) were randomized to receive 20 mg iron and 1 mg riboflavin; 20 mg zinc and 1 mg riboflavin; 20 mg iron, 20 mg zinc and 1 mg riboflavin; or riboflavin alone (control) weekly for 6 months. RESULTS: Baseline characteristics were similar among the four supplementation groups. Weight, length and mid-upper arm circumference were assessed at baseline, 8, 10 and 12 months of age. There was no interaction of iron and zinc when given in a combined supplement on either weight or length (P>0.05). There were no effects of either iron or zinc on the rate of length or weight gain for all infants or when stratified by baseline Hb concentration. CONCLUSIONS: Weekly supplementation of 20 mg Fe, 20 mg Zn, or both does not benefit growth among infants 6-12 months of age in rural Bangladesh, a region with high rates of anemia and zinc deficiency.

[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.

An established extracorporeal membrane oxygenation protocol promotes survival in extreme hypothermia.

BACKGROUND: Historical reports indicate that active rewarming with extracorporeal membrane oxygenation (ECMO) can salvage a patient after hypothermic cardiac arrest. We created a protocol that includes ECMO for extreme hypothermia to guide rewarming of the hypothermic patient. METHODS: A retrospective review of the ECMO rewarming protocol (2004-2006) was conducted. RESULTS: The active rewarming protocol is a flowchart that is available on our hospital intranet and can be accessed in the trauma bay. A severely hypothermic patient triggers the activation of a TRAUMA ONE-OP ECMO response. During the 2-year period, there were 5 activations of the system and 4 children were placed on ECMO. Two of the 4 were dramatically salvaged and eventually discharged neurologically intact. All 5 children were found pulseless at the scene before transport. The average time from the injury occurrence to arrival was 94 minutes (range, 41-181 minutes). Mean cardiopulmonary resuscitation time was 78.2 minutes (range, 37-152 minutes). The mean core temperature on arrival was 25.4 degrees C (range, 20.4 degrees C-28.6 degrees C). The average time from arrival to ECMO cannulation was 25.5 minutes (range, 16-37 minutes). CONCLUSION: A preemptive strategy for the severely hypothermic patient provides an organized approach and prompt response. Expeditious rewarming can make the difference in an opportunity for survival.

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.

Newborn care in rural Uttar Pradesh.

OBJECTIVES: To describe selected newborn care practices related to cord care, thermal care and breastfeeding in rural Uttar Pradesh and to identify socio-demographic, antenatal and delivery care factors that are associated with these practices. METHODS: A cross-sectional survey in rural Uttar Pradesh included 13,167 women who had a livebirth at home during the two years preceding data collection. Logistic regression was used to identify socio-demographic, antenatal and delivery care factors that were associated with the three care practices. RESULTS: Use of antenatal care and skilled attendance at delivery were significantly associated with clean cord care and early breastfeeding, but not with thermal care. Antenatal home visits by a community-based worker were associated only with clean cord care. Women who received counseling from health workers or other sources on each of the newborn care practices during pregnancy were more likely to report the respective care practices, although levels of counseling were low. CONCLUSION: The association between newborn care practices and antenatal care, counseling and skilled delivery attendance suggest that evidence-based newborn care practices can be promoted through improved coverage with existing health services.

Rates, timing and causes of neonatal deaths in rural India: implications for neonatal health programmes.

OBJECTIVE: To assess the rates, timing and causes of neonatal deaths and the burden of stillbirths in rural Uttar Pradesh, India. We discuss the implications of our findings for neonatal interventions. METHODS: We used verbal autopsy interviews to investigate 1048 neonatal deaths and stillbirths. FINDINGS: There were 430 stillbirths reported, comprising 41% of all deaths in the sample. Of the 618 live births, 32% deaths were on the day of birth, 50% occurred during the first 3 days of life and 71% were during the first week. The primary causes of death on the first day of life (i.e. day 0) were birth asphyxia or injury (31%) and preterm birth (26%). During days 1-6, the most frequent causes of death were preterm birth (30%) and sepsis or pneumonia (25%). Half of all deaths caused by sepsis or pneumonia occurred during the first week of life. The proportion of deaths attributed to sepsis or pneumonia increased to 45% and 36% during days 7-13 and 14-27, respectively. CONCLUSION: Stillbirths and deaths on the day of birth represent a large proportion of perinatal and neonatal deaths, highlighting an urgent need to improve coverage with skilled birth attendants and to ensure access to emergency obstetric care. Health interventions to improve essential neonatal care and care-seeking behavior are also needed, particularly for preterm neonates in the early postnatal period.

Prevalence of sputum smear-positive tuberculosis in a rural area in Bangladesh.

The objective of the study was to determine the prevalence of smear-positive tuberculosis (TB) in a rural area in Bangladesh at Matlab. A TB surveillance system was established among 106,000 people in rural Bangladesh at Matlab. Trained field workers interviewed all persons aged > or = 15 years to detect suspected cases of TB (cough > 21 days) and sputum specimens of suspected cases were examined for acid-fast bacilli (AFB). Of 59,395 persons interviewed, 4235 (7.1%) had a cough for > 21 days. Sputum specimens were examined for AFB from 3834 persons, 52 (1.4%) of them were positive for AFB. The prevalence of chronic cough and sputum positivity were significantly higher among males compared to females (P < 0.001). The population-based prevalence rate of smear-positive TB cases was 95/100,000 among persons aged > or = 15 years. Cases of TB clustered geographically (relative risk 5.53, 95% CI 3.19-9.59). The high burden of TB among rural population warrants appropriate measures to control TB in Bangladesh. The higher prevalence of persistent cough and AFB-positive sputum among males need further exploration. Factors responsible for higher prevalence of TB in clusters should be investigated.