Résumé

Objectif

Étudier les caractéristiques cliniques des enfants qui sont morts de maladies diarrhéiques dans des pays à revenu faible et intermédiaire, telles que la durée de la diarrhée, les conditions de comorbidité, le comportement en matière de sollicitation des soins et l'utilisation de thérapie de réhydratation orale.

Méthodes

L'étude a inclus les données des autopsies verbales sur des enfants décédés de maladies diarrhéiques entre 2000 et 2012 dans 7 sites du Bangladesh, de l'Éthiopie, du Ghana, de l'Inde, du Pakistan, de l'Ouganda et de la Tanzanie, respectivement. Les données provenaient des sites de surveillance démographique, des essais randomisés et d'une enquête démographique et sanitaire étendue. Les diarrhées ont été classées par type, en tant que diarrhée aqueuse aiguë, diarrhée sanglante aiguë ou diarrhée persistante, et les facteurs de risque ont été identifiés. Les décès chez les enfants âgés de 1 à 11 mois et de 1 à 4 ans ont été analysés séparément.

Résultats

Le pourcentage de la mortalité infantile liée aux maladies diarrhéiques varie considérablement entre les 7 sites, de moins de 3% à 30%. Chez les enfants âgés de 1 à 4 ans, les diarrhées aqueuses aiguës représentaient 31% à 69% des décès liés aux maladies diarrhéiques, les diarrhées sanglantes aiguës 12% à 28% et les diarrhées persistantes 12% à 56%. Chez les enfants âgés de 1  mois, les diarrhées persistantes représentaient plus de 30% des décès liés aux maladies diarrhéiques en Éthiopie, en Inde, en Ouganda et en Tanzanie. Dans la plupart des sites, plus de 40% des enfants qui sont morts de diarrhée persistante souffraient de malnutrition.

Conclusion

La diarrhée persistante reste une cause importante de décès liés aux maladies diarrhéiques chez les jeunes enfants dans les pays à revenu faible et intermédiaire. Il est nécessaire de mener des recherches sur la charge de la diarrhée persistante pour la santé publique et sur les pratiques actuelles de traitement afin de comprendre pourquoi des enfants meurent encore de cette maladie.

Resumen

Objetivo

Investigar las características clínicas de los niños que murieron de diarrea en países de ingresos medios y bajos, tales como la duración de la diarrea, las afecciones comórbidas, el comportamiento de búsqueda de atención y el uso de la terapia de rehidratación oral.

Métodos

El estudio incluyó datos verbales de autopsias de niños que murieron de diarrea entre los años 2000 y 2012 en siete emplazamientos en Bangladesh, Etiopía, Ghana, India, Pakistán, Uganda y la República Unida de Tanzanía, respectivamente. Los datos provinieron de centros de vigilancia demográfica, ensayos aleatorios y una encuesta demográfica y de salud ampliada. El tipo de diarrea se clasificó como acuosa aguda, sanguinolenta aguda o persistente, y se identificaron los factores de riesgo. Se analizaron por separado las muertes en niños de 1 a 11 meses y de 1 a 4 años.

Resultados

La proporción de muertes infantiles por diarrea varió considerablemente entre los siete emplazamientos, de menos del 3 % hasta el 30 %. Entre los niños de entre 1 y 4 años, la diarrea acuosa aguda representó del 31 % al 69 % de las muertes por diarrea, la diarrea sanguinolenta aguda, del 12 % al 28 %, y la diarrea persistente, del 12 % al 56 %. Entre los niños de 1 a 11 meses, la diarrea persistente supuso más del 30 % de las muertes por diarrea en Etiopía, India, Pakistán, Uganda y la República Unida de Tanzanía. En la mayoría de los emplazamientos, más del 40 % de los niños que murieron por diarrea persistente estaban malnutridos.

Conclusión

La diarrea persistente sigue siendo una causa importante de muerte diarreica en niños pequeños en países de ingresos medios y bajos. Es necesario realizar investigaciones sobre la carga de salud pública de la diarrea persistente y las prácticas de tratamiento actuales para entender por qué los niños siguen muriendo por esta afección.

ملخص

الغرض

تحري الخصائص السريرية للأطفال الذين لقوا حتفهم جراء الإصابة بالإسهال في البلدان المنخفضة والمتوسطة الدخل، مثل مدة الإسهال واعتلالات المراضة المشتركة وسلوك الحصول على الرعاية واستعمال المعالجة بالإمهاء الفموي.

الطريقة

شملت الدراسة بيانات التشريح الشفوي عن الأطفال الذين لقوا حتفهم جراء الإصابة بالإسهال بين عامي 2000 و2012 في سبعة مواقع في بنغلاديش وإثيوبيا وغانا والهند وباكستان وأوغندا وجمهورية تنزانيا المتحدة، على التوالي. وتم الحصول على البيانات من مواقع الترصد الديمغرافي والتجارب العشوائية ومن مسح ديمغرافي وصحي موسع. وتم تصنيف نوع الإسهال إلى إسهال مائي حاد أو إسهال دموي حاد أو إسهال مستمر وتم تحديد عوامل الاختطار. وتم تحليل الوفيات لدى الأطفال الذين تتراوح أعمارهم من شهر إلى 11 شهراً ومن سنة إلى 4 سنوات بشكل منفصل.

النتائج

اختلفت نسبة وفيات الأطفال جراء الإصابة بالإسهال بشكل كبير بين المواقع السبعة من أقل من 3 % إلى 30 %. ومن بين الأطفال في سن 1-4 سنوات، تعزى نسبة 31 % إلى 69 % من الوفيات جراء الإسهال إلى الإسهال المائي الحاد ومن 12 % إلى 28 % إلى الإسهال الدموي الحاد ومن 12 % إلى 56 % إلى الإسهال المستمر. تجاوزت الوفيات جراء الإصابة بالإسهال 30 % في إثيوبيا والهند وباكستان وأوغندا وجمهورية تنزانيا المتحدة بين الرضع في سن 1-11 شهراً. وكان أكثر من 40 % من الأطفال الذين لقوا حتفهم جراء الإصابة بالإسهال المستمر يعانون من سوء التغذية في معظم المواقع.

الاستنتاج

يظل الإسهال المستمر سبباً مهماً للوفاة جراء الإسهال لدى صغار الأطفال في البلدان المنخفضة والبلدان المتوسطة الدخل. ويجب إجراء بحوث حول عبء الإسهال المستمر في الصحة العمومية وممارسات العلاج الحالية بغية فهم سبب استمرار وفاة الأطفال جراء الإصابة بهذا الاعتلال.

摘要

目的

调查中低收入国家死于腹泻的儿童临床特征，如腹泻时长、共患病情况、求医行为和口服补液疗法使用。

方法

研究包括在2000年到2012年之间在孟加拉国、埃塞俄比亚、加纳、印度、巴基斯坦、乌干达和坦桑尼亚联合共和国七个地点死于腹泻病的儿童的口头尸检数据。数据来自人口监测点、随机试验和扩展的人口统计和健康调查。腹泻的类型分为急性水样腹泻、急性出血或持续腹泻，并进行风险因素识别。对1至11个月和1到4岁的儿童死亡分别进行分析。

结果

七个地点死于腹泻儿童的比例差别很大，从低于3%到30%不等。在1到4岁的儿童腹泻死亡的原因中，急性水样腹泻占31%到69%、急性出血性腹泻占12%至28%，持续腹泻占12%到56%。在埃塞俄比亚、印度、巴基斯坦、乌干达和坦桑尼亚联合共和国，1到11个月婴儿中持续腹泻是30%以上腹泻死亡的原因。在大多数地点，超过40%死于持续腹泻的儿童营养不良。

结论

持续性腹泻仍然是中低收入国家幼儿腹泻死亡的一个重要原因。需要对持续腹泻的公共卫生负担和目前的治疗实践进行研究，从而理解儿童仍死于这种疾病的原因。

Резюме

Цель

Исследовать клинические характеристики детей, умерших от диареи, в странах с низким и средним уровнем дохода, такие как продолжительность диареи, сопутствующие заболевания, активное обращение за медицинской помощью и использование пероральной регидратационной терапии.

Методы

В ходе исследования были рассмотрены данные, полученные путем опроса очевидцев об обстоятельствах смерти детей от диареи за 2000-2012 гг. в семи странах: Бангладеше, Эфиопии, Гане, Индии, Пакистане, Уганде и Объединенной Республики Танзании соответственно. Данные поступали из мест проведения демографических наблюдений, рандомизированных исследований и расширенного Опроса, посвященного демографии и здравоохранению. По типу диарея была классифицирована как острая водянистая, острая геморрагическая или упорная. Также были выявлены факторы риска. Был проведен отдельный анализ смертности среди детей в возрасте от 1 до 11 месяцев и от 1 года до 4 лет.

Результаты

Соотношение детских смертей из-за диареи значительно отличалось в семи центрах и варьировались от менее 3% до 30%. Среди детей в возрасте от 1-го года до 4-х лет 31-69% смертей от диареи приходились на острую водянистую диарею, от 12% до 28% — на острую геморрагическую диарею и от 12% до 56% — на упорную диарею. Среди детей в возрасте от 1 до 11 месяцев на упорную диарею приходилось более 30% смертей от диареи в Эфиопии, Индии, Пакистане, Уганде и Объединенной Республике Танзании. В большинстве стран более 40% детей, умерших от упорной диареи, страдали от недоедания.

Вывод

Упорная диарея остается важной причиной смерти от диареи у детей младшего возраста в странах с низким и средним уровнем дохода. Чтобы понять, почему дети продолжают умирать от этого заболевания, необходимы исследования бремени упорной диареи для общественного здравоохранения и существующей практики лечения.

Introduction

In the 1980s, five million children worldwide died every year because of diarrhoea, essentially because there was no readily available treatment.¹1 Snyder JD, Merson MH. The magnitude of the global problem of acute diarrhoeal disease: a review of active surveillance data. Bull World Health Organ. 1982;60(4):605–13. PMID: 6982783 In the intervening 30 years, improved management of diarrhoea, such as treatment with oral rehydration solutions, intravenous fluids and zinc,²2 Bhutta ZA, Das JK, Walker N, Rizvi A, Campbell H, Rudan I, et al.; Lancet Diarrhoea and Pneumonia Interventions Study Group. Interventions to address deaths from childhood pneumonia and diarrhoea equitably: what works and at what cost? Lancet. 2013;381(9875):1417–29. doi: http://dx.doi.org/10.1016/S0140-6736(13)60648-0 PMID: 23582723
https://doi.org/10.1016/S0140-6736(13)60... has led to a substantial reduction in mortality to approximately 614 000 deaths every year.³3 Global Health Observatory Data Repository [Internet]. Geneva: World Health Organization; 2012 . Available from: http://apps.who.int/gho/data/?theme=main [cited 2014 May 19].
http://apps.who.int/gho/data/?theme=main... ^,44 Level and trends in child mortality. Report 2013. New York: United Nations Children’s Fund; 2013. Available from: http://www.childinfo.org/files/Child_Mortality_Report_2013.pdf [cited 2014 May 29].
http://www.childinfo.org/files/Child_Mor... Nevertheless, diarrhoea remains a common cause of death in all children and is the second most common cause in those aged over 1 month.⁵5 Liu L, Johnson HL, Cousens S, Perin J, Scott S, Lawn JE, et al.; Child Health Epidemiology Reference Group of WHO and UNICEF. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet. 2012;379(9832):2151–61. doi: http://dx.doi.org/10.1016/S0140-6736(12)60560-1 PMID: 22579125
https://doi.org/10.1016/S0140-6736(12)60... ^,66 Global Health Observatory (GHO): Causes of child mortality, 2012 [Internet]. Geneva: World Health Organization; 2014. Available from: http://www.who.int/gho/child_health/mortality/causes/en/ [cited 2014 Jun 3].
http://www.who.int/gho/child_health/mort... It is worth asking why children continue to die from the condition.

Diarrhoeal diseases can be classified according to their clinical pattern as: (i) persistent diarrhoea (i.e. diarrhoea lasting 14 days or more); (ii) acute watery diarrhoea (i.e. diarrhoea without blood lasting less than 14 days); or (iii) acute bloody diarrhoea (i.e. diarrhoea with blood lasting less than 14 days).⁷7 Diarrhoea: why children are still dying and what can be done [Internet]. Geneva & New York: World Health Organization & United Nations Children’s Fund; 2009. Available from: http://www.who.int/maternal_child_adolescent/documents/9789241598415/en/ [cited 2014 Jun 3].
http://www.who.int/maternal_child_adoles... With acute diarrhoea, dehydration is the main contributor to mortality and treatment with oral rehydration solutions and zinc is effective. However, persistent diarrhoea is associated with malnutrition, delayed growth and development, vitamin A deficiency and systemic infections such as respiratory infections and urinary tract infection,⁸8 Shahid NS, Sack DA, Rahman M, Alam AN, Rahman N. Risk factors for persistent diarrhoea. BMJ. 1988;297(6655):1036–8. doi: http://dx.doi.org/10.1136/bmj.297.6655.1036 PMID: 3142603
https://doi.org/10.1136/bmj.297.6655.103... ^,99 Das SK, Faruque AS, Chisti MJ, Malek MA, Salam MA, Sack DA. Changing trend of persistent diarrhoea in young children over two decades: observations from a large diarrhoeal disease hospital in Bangladesh. Acta Paediatr. 2012;101(10):e452–7. doi: http://dx.doi.org/10.1111/j.1651-2227.2012.02761.x PMID: 22734659
https://doi.org/10.1111/j.1651-2227.2012... which makes treatment more complex.

Following the recent publication of the Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea,¹⁰10 Ending preventable child deaths from pneumonia and diarrhoea by 2025. The integrated Global Action Plan for Pneumonia and Diarrhoea (GAPPD). Geneva & New York: World Health Organization & United Nations Children’s Fund; 2013. Available from: http://apps.who.int/iris/bitstream/10665/79200/1/9789241505239_eng.pdf?ua=1 [cited 2014 Jun 3].
http://apps.who.int/iris/bitstream/10665... there was a renewed emphasis on the management of diarrhoea. In addition, diarrhoea is also a key feature of initiatives such as the United Nations Commission on Life-Saving Commodities for Women's and Children's Health and the Commission on Information and Accountability for Women's and Children's Health. These global strategies focus mainly on the treatment of acute diarrhoea using oral rehydration and zinc. Although these medications are key components in the treatment of diarrhoea, there is no mention of specific treatment for persistent diarrhoea. The aim of the current study was to identify: (i) conditions underlying childhood diarrhoea; (ii) gaps in the management of childhood diarrhoea; and (iii) associations between death due to childhood diarrhoea and clinical characteristics such as the type of diarrhoea, comorbid conditions, care-seeking behaviour and the use of oral rehydration therapy.

Methods

The study involved verbal autopsy data on children from low- and middle-income countries who died because of diarrhoea. All sites in the INDEPTH network were invited to participate and were asked if they were able to provide data on at least 50 diarrhoeal deaths in children less than 5 years of age during the period 2000 to 2012.¹¹11 INDEPTH network [Internet]. Kanda: INDEPTH network; 2014. Available from: http://www.indepth-network.org/ [cited 2014 Jun 3].
http://www.indepth-network.org/... Only population-based studies were included and both demographic surveillance and randomized cohort studies were eligible. Seven sites were able to provide sufficient verbal autopsy data: they were in Bangladesh, Ethiopia, Ghana, India, Pakistan, Uganda and the United Republic of Tanzania (Table 1).

The study included data on all children aged 1 to 59 months in every household covered by the sites in Bangladesh, Ethiopia, Pakistan, Uganda and the United Republic of Tanzania. For Ghana, data were available on all infants aged 1 to 11 months who were enrolled in a vitamin A trial.¹²12 Hurt L, ten Asbroek A, Amenga-Etego S, Zandoh C, Danso S, Edmond K, et al. Effect of vitamin A supplementation on cause-specific mortality in women of reproductive age in Ghana: a secondary analysis from the ObaapaVitA trial. Bull World Health Organ. 2013;91(1):19–27. doi: http://dx.doi.org/10.2471/BLT.11.100412 PMID: 23397347
https://doi.org/10.2471/BLT.11.100412... For India, only infants aged 1 to 11 months from the control arm of the Integrated Management of Neonatal and Childhood Illness trial were included because the trial intervention could have affected the risk of death due to diarrhoea.¹³13 Bhandari N, Mazumder S, Taneja S, Sommerfelt H, Strand TA; IMNCI Evaluation Study Group. Effect of implementation of Integrated Management of Neonatal and Childhood Illness (IMNCI) programme on neonatal and infant mortality: cluster randomised controlled trial. BMJ. 2012;344:e1634. doi: http://dx.doi.org/10.1136/bmj.e1634 PMID: 22438367
https://doi.org/10.1136/bmj.e1634... Neonates were not included because their clinical presentation was different and limited data were available. All sites used a common framework and a standardized questionnaire for conducting verbal autopsies;¹⁴14 International standard verbal autopsy questionnaires. In: Verbal autopsy standards. Geneva: World Health Organization; 2012. pp. 5–34. Available from: http://www.who.int/healthinfo/statistics/verbal_autopsy_standards2.pdf [cited 2014 Jun 3].
http://www.who.int/healthinfo/statistics... the cause of death was assigned by two independent physicians and, if there was a disagreement, a third physician carried out a review. A data collection template was developed to standardize the variables extracted from verbal autopsy data across the different sites. The variables selected for each child were: age; gender; duration and type of diarrhoea; the presence of blood in stool; malnutrition (i.e. the child was either wasted or very thin or had swollen ankles or yellowish hair); treatment with oral rehydration solutions or intravenous fluids; and the caregiver seeking health care at a facility. Also variables on the prevalence of human immunodeficiency virus (HIV) infection, treatment with zinc or other medicines and the duration of diarrhoea before treatment was started were selected.

In Bangladesh, data came from the rural subdistrict of Matlab where information on child deaths was registered by a health and demographic surveillance system established by the International Centre for Diarrhoeal Disease Research in Bangladesh between 2003 and 2011.¹⁵15 Matlab [Internet]. Dhaka: icddr,b; 2014. Available from: http://www.icddrb.org/how-we-do-it/our-field-sites/matlab [cited 3013 Nov 15].
http://www.icddrb.org/how-we-do-it/our-f... In 2003 and 2004, only one of the two reviewers was a trained physician but from 2005 onwards the cause of death was assigned by a physician. In Ethiopia, data were collected between 2003 and 2012, at a demographic surveillance site established by the Butajira Rural Health Programme in nine rural and one urban kebele (i.e. administrative unit) in the former Meskan and Mareko district.¹⁶16 Butajira HDSS. Ethiopia. Kanda: INDEPTH network; 2013. Available from: http://www.indepth-network.org/Profiles/butajira_hdss_2013.pdf [cited 2014 Jun 3].
http://www.indepth-network.org/Profiles/... Data on vital status and migration were registered quarterly and verbal autopsies have been conducted since 2003. In Ghana, part of the cohort data came from a cluster-randomized, double-blind, placebo-controlled vitamin A trial that ran between 2000 and 2008. Verbal autopsy data were available for child deaths between 2003 and 2008. The trial was performed in seven predominantly rural districts to assess the effect of weekly, low-dose, vitamin A supplementation in women and found that supplementation did not affect all-cause or diarrhoeal mortality in women or their children. Households were visited every 4 weeks and the single most important cause of death was assigned by physicians.¹²12 Hurt L, ten Asbroek A, Amenga-Etego S, Zandoh C, Danso S, Edmond K, et al. Effect of vitamin A supplementation on cause-specific mortality in women of reproductive age in Ghana: a secondary analysis from the ObaapaVitA trial. Bull World Health Organ. 2013;91(1):19–27. doi: http://dx.doi.org/10.2471/BLT.11.100412 PMID: 23397347
https://doi.org/10.2471/BLT.11.100412...

In India, the study site was taking part in a cluster-randomized cohort study in which the package of interventions that formed part of the Integrated Management of Neonatal and Childhood Illness strategy was compared with no intervention. The study was conducted between 2008 and 2010 and included infants less than 1 year of age. All households were visited by field workers every month to identify new pregnancies and to inquire about the outcome of previously identified pregnancies. Households where a live birth had taken place were visited 29 days after the birth and, subsequently, every quarter to document the vital status of the infant and to conduct a verbal autopsy if appropriate.¹³13 Bhandari N, Mazumder S, Taneja S, Sommerfelt H, Strand TA; IMNCI Evaluation Study Group. Effect of implementation of Integrated Management of Neonatal and Childhood Illness (IMNCI) programme on neonatal and infant mortality: cluster randomised controlled trial. BMJ. 2012;344:e1634. doi: http://dx.doi.org/10.1136/bmj.e1634 PMID: 22438367
https://doi.org/10.1136/bmj.e1634... In Pakistan, data were collected, and verbal autopsies on child deaths were carried out, in an extended Demographic and Health Survey.¹⁷17 Pakistan Demographic and Health Survey 2006-07. Islamabad & Calverton: National Institute of Population Studies & Macro International Inc.; 2008. Available from: http://dhsprogram.com/pubs/pdf/FR200/FR200.pdf [cited 2014 Jun 3].
http://dhsprogram.com/pubs/pdf/FR200/FR2... For this analysis, data came from the Pakistan Demographic and Health Survey for 2006 to 2007. In the United Republic of Tanzania, the Ifakara Health Institute has been implementing a health and demographic surveillance system at two sentinel sites.¹⁸18 Ifakara HDSS. Tanzania. Kanda: INDEPTH network; 2011. Available from: http://www.indepth-network.org/Profiles/Ifakara%20HDSS.pdf [cited 2014 Jun 3].
http://www.indepth-network.org/Profiles/... Households are visited three times a year to carry out health surveillance and verbal autopsies and data were obtained between 2000 and 2011. In Uganda, the Iganga–Mayuge Health and Demographic Surveillance Site comprised 65 villages drawn from Iganga and Mayuge districts and every household was visited twice a year.¹⁹19 Iganga–Mayuge health and demographic surveillance site. Kanda: INDEPTH network; 2013. Available from: http://www.indepth-network.org/Profiles/iganga_mayuge_hdss_2013.pdf [cited 2014 Jun 3].
http://www.indepth-network.org/Profiles/... Village scouts reported all births and deaths in their villages and trained interviewers conducted verbal autopsies. Data were obtained between 2007 and 2010.

Our analysis included only deaths for which the underlying or single cause of death was diarrhoea. Information from verbal autopsies was used to identify risk factors for death and to classify the type of diarrhoea as either: (i) persistent; (ii) acute watery; or (iii) acute bloody diarrhoea. In addition, deaths in two age groups were studied: postneonatal infants aged 1 to 11 months and children aged 1 to 4 years at death. For each study site, the proportion of diarrhoeal deaths due to each type of diarrhoea was calculated and the presence of the following risk factors was determined from information provided by caregivers: malnourishment; receipt of oral rehydration solutions or intravenous fluids during the final illness; seeking health care outside the home during the final illness; and the sex of the child for whom care was sought. Insufficient information was available to determine whether the type of diarrhoea varied according to either the prevalence of HIV infection, treatment with zinc or other medicines or the duration of diarrhoea before treatment was started.

Results

The study included data on childhood deaths collected between 2000 and 2012. The population covered at the seven study sites ranged from approximately 60 000 to 600 000, except for Pakistan where the Demographic and Health Survey covered the country’s total population of 160 493 000 (Table 1). The overall infant mortality rate reported by the World Health Organization (WHO) and our estimates of mortality rates in our two age groups were comparable across the seven sites (Table 2);²⁰20 World health statistics 2010. Geneva: World Health Organization; 2010. Available from: http://www.who.int/whosis/whostat/EN_WHS10_Full.pdf?ua=1 [cited 2014 May 29].
http://www.who.int/whosis/whostat/EN_WHS... rates were highest in Ethiopia and Pakistan. However, there was a considerable difference in the rate of use of oral rehydration reported in demographic and health surveys: from 26.0% in India to 77.6% in Bangladesh.¹²12 Hurt L, ten Asbroek A, Amenga-Etego S, Zandoh C, Danso S, Edmond K, et al. Effect of vitamin A supplementation on cause-specific mortality in women of reproductive age in Ghana: a secondary analysis from the ObaapaVitA trial. Bull World Health Organ. 2013;91(1):19–27. doi: http://dx.doi.org/10.2471/BLT.11.100412 PMID: 23397347
https://doi.org/10.2471/BLT.11.100412... ^,1313 Bhandari N, Mazumder S, Taneja S, Sommerfelt H, Strand TA; IMNCI Evaluation Study Group. Effect of implementation of Integrated Management of Neonatal and Childhood Illness (IMNCI) programme on neonatal and infant mortality: cluster randomised controlled trial. BMJ. 2012;344:e1634. doi: http://dx.doi.org/10.1136/bmj.e1634 PMID: 22438367
https://doi.org/10.1136/bmj.e1634... ^,1515 Matlab [Internet]. Dhaka: icddr,b; 2014. Available from: http://www.icddrb.org/how-we-do-it/our-field-sites/matlab [cited 3013 Nov 15].
http://www.icddrb.org/how-we-do-it/our-f... ^–1919 Iganga–Mayuge health and demographic surveillance site. Kanda: INDEPTH network; 2013. Available from: http://www.indepth-network.org/Profiles/iganga_mayuge_hdss_2013.pdf [cited 2014 Jun 3].
http://www.indepth-network.org/Profiles/... ^,2121 National Family Health Survey (NFHS-3), 2005-06, India: key findings. Mumbai & Calverton: International Institute for Population Sciences (IIPS) & Macro International Inc.; 2007.

In Bangladesh, the study site covered a population of 225 202 and verbal autopsies were carried out between 2003 and 2011 on 2138 deaths in children aged 1 to 59 months (Table 3). Diarrhoea was a direct cause of death in 59 cases: 41 in children aged 1 to 11 months and 18 in those aged 1 to 4 years. In Ethiopia, the population covered was 62 178 and 681 children aged 1 to 59 months died between 2003 and 2012, including 60 who died because of diarrhoea: 28 aged 1 to 11 months and 32 aged 1 to 4 years. In Ghana, the study population was 600 000 and 153 of 1790 deaths in children aged 1 to 11 months enrolled in the trial were due to diarrhoea. Complete data, which enabled the type of diarrhoea to be classified, were available for only 145 of these deaths. In India, 197 deaths due to diarrhoea were recorded among 809 deaths in infants aged 1 to 11 months in the control arm of the randomized study. In Pakistan, data were available from the Demographic and Health Survey for 2006 to 2007 on 1426 deaths among children aged 1 to 59 months, of which 318 were due to diarrhoea: 220 in infants aged 1 to 11 months and 98 in children aged 1 to 4 years. In Uganda, the surveillance site covered a population of 69 243 and 631 deaths were recorded in children less than 5 years of age between 2007 and 2010: diarrhoea was the cause of death in 115 cases. Due to a lack of information on disease duration, the analysis included only 77 of the 115: 28 out of 46 infants (1–11 months) and 49 out of 115 children (1– 4 years). In the United Republic of Tanzania, the site covered a population of 222 958 and 3774 deaths were registered among children less than 5 years of age between 2000 and 2011, of which 80 were due to diarrhoea: 39 in infants aged 1 to 11 months and 41 in children aged 1 to 4 years.

The proportion of all deaths in infants aged 1 to 11 months that were due to diarrhoea varied considerably across the seven countries: from less than 3% in Bangladesh and the United Republic of Tanzania to between 24% and 30% in Ethiopia, India and Pakistan (Table 3). At most sites, the proportion of deaths due to diarrhoea was similar in infants aged 1 to 11 months and in children aged 1 to 4 years. The exception was Ethiopia where diarrhoea accounted for 29.5% (28/95) of deaths among infants aged 1 to 11 months but only 8.8% (60/681) among children aged 1 to 4 years.

The type of diarrhoea involved also varied greatly between countries (Table 4). Among infants aged 1 to 11 months, persistent diarrhoea accounted for 30% or more of diarrhoeal deaths in Ethiopia, India, Pakistan, Uganda and the United Republic of Tanzania and for more than 35% in three of these countries. Among children aged 1 to 4 years, persistent diarrhoea accounted for more than 25% of diarrhoeal deaths in Bangladesh, Ethiopia and Uganda. The highest proportion of diarrhoeal deaths due to acute bloody diarrhoea was observed in Bangladesh: 27.8% (5/18) in children aged 1 to 4 years. The proportion in the United Republic of Tanzania was also high: 15.4% (6/39) in infants aged 1 to 11 months and 17.1% (7/41) in children aged 1 to 4 years. At all other sites, bloody diarrhoea accounted for less than 15% of diarrhoeal deaths in infants aged 1 to 11 months and less than 10% in children aged 1 to 4 years. Acute watery diarrhoea was the commonest cause of diarrhoeal deaths at several sites: among infants aged 1 to 11 months, it accounted for 85.4% (35/41) of deaths in Bangladesh and 78.6% (114/145) in Ghana; among children aged 1 to 4 years, it accounted for 70.7% (29/41) in the United Republic of Tanzania and 69.4% (68/98) in Pakistan.

Over 40% of children who died from persistent diarrhoea were severely malnourished in all countries except the United Republic of Tanzania: among infants aged 1 to 11 months, 90.6% (77/85) in India and 85.7% (18/21) in Ghana were malnourished; among children aged 1 to 59 months, 55.6% (5/9) in Bangladesh and 71.0% (22/31) in Uganda were malnourished (Table 5). In our analysis we found that, at the majority of surveillance sites, more than half the children who died from persistent diarrhoea had received oral rehydration solutions or intravenous fluids. The rate was slightly lower for acute diarrhoea. Rates were considerably lower in Ethiopia, where only 5.7% (2/35) of children who died from persistent diarrhoea and 15.8% (3/19) who died from acute diarrhoea had received fluids (Table 5). The proportion of caretakers who reported seeking care for their child with persistent diarrhoea ranged from 70% to 100% in all countries except Pakistan, where it was 42.9% (36/84). In addition, over 75% sought care for acute diarrhoea at five of the seven sites. There was no substantial difference in the proportion who sought care for boys or girls.

Discussion

Our study showed that 49–85% of diarrhoeal deaths in infants aged 1 to 11 months were due to acute watery diarrhoea at six of the seven study sites, whereas 5–15% of diarrhoeal deaths at all sites were due to acute bloody diarrhoea and 10–61% at all sites were due to persistent diarrhoea (Table 4). These rates were similar to those reported in 1993, which showed that acute diarrhoea accounted for 28% of diarrhoeal deaths among infants and that persistent diarrhoea accounted for 62% in infants less than 11 months of age in Brazil.²²22 Victora CG, Huttly SR, Fuchs SC, Barros FC, Garenne M, Leroy O, et al. International differences in clinical patterns of diarrhoeal deaths: a comparison of children from Brazil, Senegal, Bangladesh, and India. J Diarrhoeal Dis Res. 1993;11(1):25–9. PMID: 8315250 Moreover, persistent diarrhoea accounted for more than 30% of diarrhoeal deaths in infants aged 1–11 months at five of the seven sites and more than 25% of deaths in children aged 1–4 years at three of the five sites where data were available. While there is evidence that persistent childhood diarrhoea has decreased, our data shows that in some countries it is a major contributor to diarrhoeal deaths.⁹9 Das SK, Faruque AS, Chisti MJ, Malek MA, Salam MA, Sack DA. Changing trend of persistent diarrhoea in young children over two decades: observations from a large diarrhoeal disease hospital in Bangladesh. Acta Paediatr. 2012;101(10):e452–7. doi: http://dx.doi.org/10.1111/j.1651-2227.2012.02761.x PMID: 22734659
https://doi.org/10.1111/j.1651-2227.2012...

In agreement with previous reports,²³23 Lima AA, Guerrant RL. Persistent diarrhea in children: epidemiology, risk factors, pathophysiology, nutritional impact, and management. Epidemiol Rev. 1992;14:222–42. PMID: 1289113^–2525 Umamaheswari B, Biswal N, Adhisivam B, Parija SC, Srinivasan S. Persistent diarrhea: risk factors and outcome. Indian J Pediatr. 2010;77(8):885–8. doi: http://dx.doi.org/10.1007/s12098-010-0125-y PMID: 20799078
https://doi.org/10.1007/s12098-010-0125-... we found that more than 50% of children who died from persistent diarrhoea were malnourished at four of the seven study sites; the proportion was over 70% at three sites. However, the relationship between diarrhoea, particularly persistent diarrhoea, and malnutrition is bidirectional and it is not possible to determine the extent to which malnutrition may be due to persistent diarrhoea.²⁶26 Amadi B, Mwiya M, Chomba E, Thomson M, Chintu C, Kelly P, et al. Improved nutritional recovery on an elemental diet in Zambian children with persistent diarrhoea and malnutrition. J Trop Pediatr. 2005;51(1):5–10. doi: http://dx.doi.org/10.1093/tropej/fmh064 PMID: 15601655
https://doi.org/10.1093/tropej/fmh064... ^,2727 Nel ED. Diarrhoea and malnutrition. S Afr J Clin Nutr. 2010;23(1) Suppl:S15–8.

Surprisingly, at six of the seven sites, 70–100% of children with persistent diarrhoea who died had been seen in a health-care facility. Although the cause of death was probably multifactorial, this finding raises questions about the quality of the care provided. Mortality could be reduced by improving the quality of care and by increasing awareness of the need for immediate treatment. Further research is needed on how best to manage persistent diarrhoea in low- and middle-income countries. Furthermore, at most sites we found that more than half of children with persistent diarrhoea who died had received oral rehydration solutions or intravenous fluids, though we had no data on the volume of fluids administered or the duration of treatment. The rate of fluid use was lower for acute diarrhoea than for persistent diarrhoea, perhaps because of the shorter disease duration. Previous studies have shown that the correct use of oral rehydration solutions is uncommon in cases of acute diarrhoea.²⁸28 Barros FC, Victora CG, Forsberg B, Maranhão AG, Stegeman M, Gonzalez-Richmond A, et al. Management of childhood diarrhoea at the household level: a population-based survey in north-east Brazil. Bull World Health Organ. 1991;69(1):59–65. PMID: 2054921^,2929 Blum LS, Oria PA, Olson CK, Breiman RF, Ram PK. Examining the use of oral rehydration salts and other oral rehydration therapy for childhood diarrhea in Kenya. Am J Trop Med Hyg. 2011;85(6):1126–33. doi: http://dx.doi.org/10.4269/ajtmh.2011.11-0171 PMID: 22144457
https://doi.org/10.4269/ajtmh.2011.11-01... In addition, data from demographic and health surveys have shown that the use of oral rehydration solutions or zinc is low in many countries, though there is a great variation.¹²12 Hurt L, ten Asbroek A, Amenga-Etego S, Zandoh C, Danso S, Edmond K, et al. Effect of vitamin A supplementation on cause-specific mortality in women of reproductive age in Ghana: a secondary analysis from the ObaapaVitA trial. Bull World Health Organ. 2013;91(1):19–27. doi: http://dx.doi.org/10.2471/BLT.11.100412 PMID: 23397347
https://doi.org/10.2471/BLT.11.100412... ^,1313 Bhandari N, Mazumder S, Taneja S, Sommerfelt H, Strand TA; IMNCI Evaluation Study Group. Effect of implementation of Integrated Management of Neonatal and Childhood Illness (IMNCI) programme on neonatal and infant mortality: cluster randomised controlled trial. BMJ. 2012;344:e1634. doi: http://dx.doi.org/10.1136/bmj.e1634 PMID: 22438367
https://doi.org/10.1136/bmj.e1634... ^,1515 Matlab [Internet]. Dhaka: icddr,b; 2014. Available from: http://www.icddrb.org/how-we-do-it/our-field-sites/matlab [cited 3013 Nov 15].
http://www.icddrb.org/how-we-do-it/our-f... ^–1919 Iganga–Mayuge health and demographic surveillance site. Kanda: INDEPTH network; 2013. Available from: http://www.indepth-network.org/Profiles/iganga_mayuge_hdss_2013.pdf [cited 2014 Jun 3].
http://www.indepth-network.org/Profiles/... Although the use of oral rehydration, zinc and antibiotics for bloody diarrhoea needs to be scaled up,³⁰30 Munos MK, Walker CL, Black RE. The effect of oral rehydration solution and recommended home fluids on diarrhoea mortality. Int J Epidemiol. 2010;39 Suppl 1:i75–87. doi: http://dx.doi.org/10.1093/ije/dyq025 PMID: 20348131
https://doi.org/10.1093/ije/dyq025... doing so might not be sufficient to reduce diarrhoeal deaths and achieve the target set by the Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea,¹⁰10 Ending preventable child deaths from pneumonia and diarrhoea by 2025. The integrated Global Action Plan for Pneumonia and Diarrhoea (GAPPD). Geneva & New York: World Health Organization & United Nations Children’s Fund; 2013. Available from: http://apps.who.int/iris/bitstream/10665/79200/1/9789241505239_eng.pdf?ua=1 [cited 2014 Jun 3].
http://apps.who.int/iris/bitstream/10665... which is that mortality from diarrhoea in children aged less than 5 years of age should be less than 1 per 1000 live births.

Limitations

We used data on diarrhoeal mortality collected at the seven sites by verbal autopsy, in which the cause of a child’s death, or the sequence of causes that led to death, is determined from information obtained by interviewing the next of kin or other caregivers using a standardized questionnaire.¹⁴14 International standard verbal autopsy questionnaires. In: Verbal autopsy standards. Geneva: World Health Organization; 2012. pp. 5–34. Available from: http://www.who.int/healthinfo/statistics/verbal_autopsy_standards2.pdf [cited 2014 Jun 3].
http://www.who.int/healthinfo/statistics... Although this approach is frequently used in public health research for collecting mortality data at a community or population level, it may not be an accurate way of attributing the cause of death in individuals. However, since our data came from population-based cohorts, they provide more information on the pattern of deaths in the general population than hospital data. Nevertheless, the small size of the study population at some sites may have influenced interpretation of the findings at those sites. In addition, even though we restricted the analysis to the time period between 2000 and 2012, there was still some variability in the age of the data among sites, which may have affected our interpretation of the clinical patterns observed. We were not able to investigate the effect of potentially important variables such as HIV infection as most sites did not collect the information needed. Finally, given the variability between sites in the data collected, we were not able to compare sites.

Our findings indicate that a greater focus on the treatment of persistent diarrhoea is needed. In particular, if most children with persistent diarrhoea are moderately or severely malnourished, treatment might have to include therapeutic foods. Nearly two decades ago, an International Working Group on Persistent Diarrhoea developed a treatment algorithm based on the findings of a multicentre cohort study.³¹31 International Working Group on Persistent Diarrhoea. Evaluation of an algorithm for the treatment of persistent diarrhoea: a multicentre study. Bull World Health Organ. 1996;74(5):479–89. PMID: 9002328 Although use of the algorithm was recommended internationally, a recent consultation on diarrhoea by WHO concluded that it had been implemented in very few places and that there was a need for a policy to promote its wider use in treatment and research.³²32 Report of an informal expert meeting on management of diarrhoea including persistent diarrhoea. Geneva: World Health Organization; 2014.

In conclusion, we found that persistent diarrhoea accounted for a substantial proportion of diarrhoeal deaths in young children in low- and middle-income countries. However, many global and national strategies and initiatives for the prevention and treatment of diarrhoea in children do not mention persistent diarrhoea. Moreover, little research on the condition has been carried out over the last two decades. If the Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea target for reducing mortality from diarrhoea is to be achieved,¹⁰10 Ending preventable child deaths from pneumonia and diarrhoea by 2025. The integrated Global Action Plan for Pneumonia and Diarrhoea (GAPPD). Geneva & New York: World Health Organization & United Nations Children’s Fund; 2013. Available from: http://apps.who.int/iris/bitstream/10665/79200/1/9789241505239_eng.pdf?ua=1 [cited 2014 Jun 3].
http://apps.who.int/iris/bitstream/10665... public health policies must be changed to include the management of persistent diarrhoea. In addition, research is needed into the public health burden of persistent diarrhoea and barriers to the implementation of recommended treatment to understand why children are still dying from the condition.

Acknowledgements

The Persistent Diarrhoea Research Group includes Seeba Amenga-Etego, Bilal Avan, Nita Bhandari, Kiran Bhatia, Oona Campbell, Samuel Danso, Brinda Dube, Karen Edmond, Shams El Arifeen, Justin Fenty, Olivier Fontaine, Edward Galiwango, Zelee Hill, Chris Hurt, Judith Kaija, Jasmine Kaur, Jose Martines, Seth Owusu-Agyei, Elizeus Rutebemberwa, Peter Kim Streatfield, Sunita Taneja, Charlotte Tawiah, Worku Tefera, Guus ten Asbroek, Etsehiwot Tilahun, Musa Waibi and Charles Zandoh.

The authors thank Nadia Pillai and all staff and residents at the study sites, including the Iganga–Mayuge health and demographic surveillance site in Uganda.

References

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