Zinc supplementation for the prevention of pneumonia in children aged 2 months to 59 months

  • Review
  • Intervention

Authors


Abstract

Background

Pneumonia is a leading cause of morbidity and mortality in children younger than five years of age. Most deaths occur during infancy and in low-income countries. Daily regimens of zinc have been reported to prevent acute lower respiratory tract infection and reduce child mortality.

Objectives

To evaluate the effectiveness of zinc supplementation in the prevention of pneumonia in children aged two to 59 months.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 2), which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to January Week 2, 2010), EMBASE (1974 to January 2010) and LILACS (1985 to January 2010).

Selection criteria

Randomised controlled trials (RCTs) evaluating supplementation of zinc for the prevention of pneumonia in children aged 2 to 59 months of age.

Data collection and analysis

Two review authors independently assessed trial quality and extracted data.

Main results

We included six trials and 7850 participants in the meta-analysis. Analysis showed that zinc supplementation reduced the incidence of pneumonia by 13% (risk ratio (RR) 0.87; 95% confidence interval (CI) 0.81 to 0.94, fixed-effect, six studies) and prevalence of pneumonia by 41% (RR 0.59; 95% CI 0.35 to 0.99, random-effects, one study). On subgroup analysis, we found that zinc reduced the incidence of pneumonia defined by specific clinical criteria by 21% (i.e. confirmation by chest examination or chest radiograph) (RR 0.79; 95% CI 0.0.71 to 0.88, fixed-effect, four studies, n = 4591) but had no effect on lower specificity pneumonia case definition (i.e. age specific fast breathing with or without lower chest indrawing) (RR 0.95; 95% CI 0.86 to 1.06, fixed-effect, four studies, n = 3259).

Authors' conclusions

Zinc supplementation in children is associated with a reduction in the incidence and prevalence of pneumonia, the leading cause of death in children.

Resumen

Antecedentes

Suplementos de zinc para la prevención de la neumonía en niños de dos a 59 meses de vida

La neumonía es la causa principal de morbilidad y mortalidad en los niños menores de cinco años de edad. La mayoría de las muertes ocurren durante el período de lactancia y en países de bajos ingresos. Se ha informado que los regímenes diarios con zinc previenen la infección aguda de las vías respiratorias inferiores y reducen la mortalidad infantil.

Objetivos

Evaluar la efectividad de los suplementos de zinc en la prevención de la neumonía en niños de dos a 59 meses de vida.

Estrategia de búsqueda

Se hicieron búsquedas en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL) (The Cochrane Library 2010, número 2), que contiene el Registro Especializado del Grupo Cochrane de Infecciones Respiratorias Agudas (Acute Respiratory Infections [ARI]), MEDLINE (1966 hasta enero, semana 2, 2010), EMBASE (1974 hasta enero 2010) y en LILACS (1985 hasta enero 2010).

Criterios de selección

Ensayos controlados aleatorios (ECA) que evaluaran la administración de suplementos del zinc para la prevención de la neumonía en niños de dos a 59 meses de vida.

Obtención y análisis de los datos

Dos autores de la revisión evaluaron de forma independiente la calidad de los ensayos y extrajeron los datos.

Resultados principales

Se incluyeron seis ensayos y 7850 participantes en el metanálisis. El análisis demostró que la suplementos de zinc redujeron la incidencia de neumonía en un 13% (cociente de riesgos [CR] 0,87; intervalo de confianza [IC] del 95%: 0,81 a 0,94; efectos fijos, seis estudios) y la prevalencia de la neumonía en un 41% (CR 0,59; IC del 95%: 0,35 a 0,99; efectos aleatorios, un estudio). En el análisis de subgrupos, se halló que el zinc redujo la incidencia de neumonía definida por criterios clínicos específicos en un 21% (es decir, confirmada por examen torácico o radiografía del tórax) (CR 0,79; IC del 95%: 0,71 a 0,88; efectos fijos, cuatro estudios, n = 4591) pero no tuvo ningún efecto sobre la definición de caso de neumonía de especificidad inferior (es decir, respiración rápida específica de la edad con o sin tiraje torácico inferior) (CR 0,95; IC del 95%: 0,86 a 1,06; efectos fijos, cuatro estudios, n = 3259).

Conclusiones de los autores

Los suplementos de zinc en los niños se asocian con una reducción de la incidencia y la prevalencia de la neumonía, la principal causa de muerte en este grupo etario.

Traducción

Traducción realizada por el Centro Cochrane Iberoamericano

摘要

針對2個月至59個月的孩童為了預防肺炎補充鋅

研究背景

肺炎是5歲以下的兒童造成罹病和死亡的原因。大多數的死亡發生在嬰兒期及低所得的國家。曾經有報告每天補充鋅可預防急性下呼吸道感染以及降低兒童死亡率。

研究目的

為了評估補充鋅對2至59個月的兒童其肺炎預防的有效性。

检索策略

我們搜尋了the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010 第2期),其中包含了the Acute Respiratory Infections Group's Specialised Register、MEDLINE (1966年至2010年1月第2周)、EMBASE (1974年至2010年1月)和LILACS (1985年至2010年1月)。

标准/纳入排除标准

隨機對照試驗(RCTs)評估2個月至59個月大的孩童,補充鋅對於預防肺炎的效用。

数据收集与分析

兩位評價作者獨立評估試驗品質及擷取資料 。

主要结果

我們以統合分析方式納入了6個試驗及7850位參與者。分析顯示補充鋅可降低13%肺炎發生率 (risk ratio (RR) 0.87; 95%信賴區間(CI)0.81至0.94,固定效應 (fixedeffect),6個試驗)及肺炎盛行率41%(RR 0.59; 95% CI 0.35至0.99,隨機效應 (randomeffects),1個試驗)。在子群分析,我們發現在特定臨床規範中,鋅可明確降低肺炎發生率達21%。(如:以胸部檢查或以胸部放射影像來確立) (RR 0.79; 95% CI 0.0.71 至0.88,固定效應,4個試驗,n = 4591),但是在定義為低特異性肺炎的個案上則沒有影響(如:在特定年齡呼吸過快時,有或無伴隨胸部下緣內凹)(RR 0.95; 95% CI 0.86至1.06,固定效應,4個試驗,n = 3259)。

作者结论

補充鋅對孩童來說與降低肺炎發生率及盛行率有關,而這些都會導致孩童死亡。我們以統合分析方式納入了6個試驗及7850位參與者。分析顯示補充鋅可降低13%肺炎發生率 (risk ratio (RR) 0.87; 95%信賴區間(CI)0.81至0.94,固定效應 (fixedeffect),6個試驗)及肺炎盛行率41%(RR 0.59; 95% CI 0.35至0.99,隨機效應 (randomeffects),1個試驗)。在子群分析,我們發現在特定臨床規範中,鋅可明確降低肺炎發生率達21%。(如:以胸部檢查或以胸部放射影像來確立) (RR 0.79; 95% CI 0.0.71 至0.88,固定效應,4個試驗,n = 4591),但是在定義為低特異性肺炎的個案上則沒有影響(如:在特定年齡呼吸過快時,有或無伴隨胸部下緣內凹)(RR 0.95; 95% CI 0.86至1.06,固定效應,4個試驗,n = 3259)。

Résumé scientifique

Supplémentation en zinc pour la prévention de la pneumonie chez l'enfant âgé de 2 à 59 mois

Contexte

La pneumonie est l'une des premières causes de morbidité et de mortalité chez les enfants de moins de cinq ans. La plupart des décès se produisent pendant la petite enfance et dans des pays à faibles revenus. Il a été rapporté qu'une prise quotidienne de zinc prévenait l'infection aiguë des voies respiratoires inférieures et réduisait la mortalité infantile.

Objectifs

Évaluer l'efficacité d'une supplémentation en zinc dans la prévention de la pneumonie chez les enfants âgés de 2 à 59 mois.

Stratégie de recherche documentaire

Nous avons consulté le registre Cochrane des essais contrôlés (CENTRAL) (Bibliothèque Cochrane 2010, numéro 2), qui contient le registre spécialisé du groupe Cochrane sur les infections respiratoires aiguës, ainsi que MEDLINE (1966 à la 2ème semaine de janvier 2010), EMBASE (1974 à janvier 2010) et LILACS (1985 à janvier 2010).

Critères de sélection

Les essais contrôlés randomisés (ECR) évaluant une supplémentation en zinc dans la prévention de la pneumonie chez des enfants âgés de 2 à 59 mois.

Recueil et analyse des données

Deux auteurs de revue ont évalué la qualité de l'essai individuellement et ont extrait les données.

Résultats principaux

Six essais portant sur 7 850 participants ont été inclus dans la méta-analyse. L'analyse montrait qu'une supplémentation en zinc réduisait de 13 % l'incidence de la pneumonie (risque relatif (RR) de 0,87 ; intervalle de confiance (IC) à 95 %, entre 0,81 à 0,94, effets fixes, six études) et de 41 % la prévalence de la pneumonie (RR de 0,59 ; IC à 95 %, entre 0,35 et 0,99, effets aléatoires, une étude). Dans l'analyse en sous groupe, nous avons observé que le zinc réduisait de 21 % l'incidence de la pneumonie définie sur la base de critères cliniques spécifiques (c'est-à-dire confirmée par exploration thoracique ou radiographie pulmonaire) (RR de 0,79 ; IC à 95 %, entre 0,71 et 0,88, effets fixes, quatre études, n = 4 591), mais n'avait aucun effet sur une pneumonie définie de manière moins spécifique (c'est-à-dire une polypnée liée à l'âge avec ou sans rétraction inspiratoire de la partie inférieure du thorax) (RR de 0,95 ; IC à 95 %, entre 0,86 et 1,06, effets fixes, quatre études, n = 3 259).

Conclusions des auteurs

La supplémentation en zinc chez l'enfant est associée à une réduction de l'incidence et de la prévalence de la pneumonie, la première cause de mortalité infantile.

Plain language summary

Zinc supplementation for the prevention of pneumonia in children aged two to 59 months

Zinc is an essential element for growth and development of children. Its deficiency is associated with increased risk of infection, particularly diarrhoea and pneumonia. Zinc supplementation in children has been reported to prevent pneumonia; however, its effect remains unclear. The aim of this review is to evaluate the role of zinc supplementation in the prevention of pneumonia in children of two to 59 months of age.

The review authors found six randomised controlled trials evaluating the impact of providing zinc supplementation for the prevention of pneumonia. The studies were conducted in Bangladesh, India, Peru, and South Africa. Children of two to 59 months of age were randomly assigned to receive zinc or a placebo. In two studies, the children were given vitamin A in both the groups. Analysis of the studies showed that zinc supplementation was significantly associated with reducing the incidence and prevalence of pneumonia among children of two to 59 months of age. Evidence provided so far from randomised controlled trials is sufficient to recommend zinc intake in deficient populations through supplementation, dietary improvements, or fortification, for enhancing child survival.

概要

針對2個月至59個月的孩童為了預防肺炎補充鋅。鋅是孩童成長和發展的必要元素,它的缺乏與增加感染風險有關,尤其是腹瀉和肺炎。曾經有報告孩童補充鋅可預防肺炎;然而,它的功效仍然不明。這篇回顧的目的是要評估2個月至59個月齡的孩童,補充鋅對預防肺炎所扮演的角色。 評估的作者找到6個隨機對照試驗,評估補充鋅對預防肺炎的影響。研究在孟加拉、印度、祕魯和南非進行。孩童年齡自2個月至59個月,隨機分配至補充鋅及安慰劑組。在2個研究中,2組中的孩童皆給予維他命A。分析這些研究顯示,補充鋅在年齡2個月至59個月中,與降低肺炎發生率及盛行率有顯著相關。到目前為止,證據來自隨機對照試驗,是足以建議在鋅攝取量不足的人口,透過補充、飲食改善、或防禦工作 (fortification),以提高兒童的生存。

翻译注解

Résumé simplifié

Supplémentation en zinc pour la prévention de la pneumonie chez l'enfant âgé de 2 à 59 mois

Le zinc est un élément essentiel à la croissance et au développement des enfants. Une déficience en zinc est associée à un risque accru d'infection, en particulier de diarrhée et de pneumonie. Il a été rapporté qu'une supplémentation en zinc pourrait prévenir la pneumonie chez l'enfant, mais ses effets demeurent incertains. L'objectif de cette revue est d'évaluer le rôle de la supplémentation en zinc dans la prévention de la pneumonie chez les enfants âgés de 2 à 59 mois.

Les auteurs de la revue ont identifié six essais contrôlés randomisés évaluant l'impact d'une supplémentation en zinc dans la prévention de la pneumonie. Ces études avaient été menées au Bangladesh, en Inde, au Pérou et en Afrique du Sud. Des enfants de 2 à 59 mois étaient randomisés pour recevoir du zinc ou un placebo. Dans deux études, les enfants des deux groupes recevaient de la vitamine A. L'analyse des études montrait que la supplémentation en zinc était significativement associée à une réduction de l'incidence et de la prévalence de la pneumonie chez les enfants âgés de 2 à 59 mois. Les preuves issues d'essais contrôlés randomisés disponibles à ce jour sont suffisantes pour recommander la prise de zinc sous forme de supplémentation, d'amélioration ou de renforcement du régime alimentaire en vue d'améliorer la survie des enfants présentant une déficience en zinc.

Notes de traduction

Traduit par: French Cochrane Centre 1st December, 2012
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

سلیس ترجمہ

دو 59 ماہ کی عمر کے بچوں میں نمونیا کی روک تھام کے لئے زنک supplementation کے

زنک بچوں کی ترقی اور ترقی کے لئے ایک لازمی عنصر ہے. اس کمی کے انفیکشن کا خطرہ بڑھ، خاص طور اسہال اور نمونیا کے ساتھ منسلک کیا جاتا ہے. بچوں میں جنک supplementation کے نمونیا کو روکنے کے لئے رپورٹ کیا گیا ہے؛ تاہم، اس کا اثر واضح نہیں رہتا. اس جائزے کا مقصد عمر کے دو سے 59 ماہ کے بچوں میں نمونیا کی روک تھام میں زنک supplementation کے کردار کا اندازہ کرنے کے لئے ہے.

جائزہ لینے کے مصنفین نمونیا کی روک تھام کے لئے زنک supplementation کے فراہم کرنے کے اثرات کا جائزہ لینے کے چھ randomized کنٹرول ٹرائلز پایا. مطالعہ بنگلہ دیش، بھارت، پیرو، اور جنوبی افریقہ میں منعقد کی گئی. عمر کے دو 59 ماہ کے بچوں تصادفی زنک یا ایک placebo حاصل کرنے کے لئے مقرر کئے گئے تھے. دو جائزوں میں، بچوں کے دونوں گروپوں میں وٹامن دی گئی. مطالعہ کے تجزیہ زنک supplementation کے نمایاں طور پر سال کی عمر کے دو 59 ماہ کے بچوں کے درمیان نمونیا کے واقعات اور کوریج کو کم کرنے کے ساتھ منسلک کیا گیا تھا ظاہر ہوا ہے کہ. کنٹرول randomized مقدمات سے اب تک فراہم کردہ ثبوت بچوں کی بقا کو بڑھانے کے لئے، اضافی، غذائی بہتری، یا کلبندی کے ذریعے کمی آبادی میں زنک کی مقدار سفارش کرنے کے لئے کافی ہے.

وضاحتیں

مترجم: فہد جاوید صدیقی⏎نظرِ ثانی: جاود عمر صدیقی؛ ⏎تعاون: Duke-NUS Grduate Medical School, Singapore⏎ اس ترجمہ سے متعلق رابطہ کے لئے:⏎fahad.siddiqui@duke-nus.edu.sg

Laički sažetak

Uzimanje dodataka cinka za sprječavanje upala pluća u djece dobi od dva do 59 mjeseci

Cink je esencijalni element za rast i razvoj djece. Njegov manjak je povezan s povećanim rizikom od infekcija, posebice proljeva i upale pluća. Opisano je kako dodatak cinka kod djece sprječava pojavu upale pluća; međutim, njegov učinak ostaje nejasan. Cilj ovog Cochrane sustavnog pregleda je ocijeniti ulogu dodataka cinka u sprječavanju upale pluća u djece starosti od dva do 59 mjeseci.

Autori sustavnog pregleda su pronašli šest randomiziranih kontroliranih ispitivanja koja su procijenila učinak dodataka cinka na sprječavanje upale pluća. Istraživanja su bila provedena u Bangladešu, Indiji, Peruu i Južnoafričkoj Republici. Nasumičnim odabirom je djeci u dobi od dva do 59 mjeseci davan cink ili placebo. U dvama istraživanjima, u obje skupine djece davan je i vitamin A. Analiza istraživanja pokazuje kako je dodatak cinka značajno povezan sa smanjenjem incidencije i prevalencije upala pluća među djecom od dva do 59 mjeseci starosti. Dokazi iz do sada provedenih randomiziranih kontroliranih ispitivanja su dovoljni za preporuku uzimanja cinka u populacijama s njegovim nedostatkom, i to unosom dodataka, poboljšanjem ili obogaćivanjem prehrane, kako bi se povećalo preživljavanje djece .

Bilješke prijevoda

Hrvatski Cochrane
Preveo: Mato Lakić
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Background

Description of the condition

Zinc deficiency is common amongst children in low-income countries, as defined by the World Bank (World Bank 2008) due to a variety of factors such as low food intake, particularly from animal sources; limited zinc bioavailability from local diets; and loss of zinc during recurrent diarrhoeal illnesses (Bhutta 1999; Black 1998). Zinc deficiency is associated with decreased immunocompetence (Shankar 1998) and increased rates of serious infectious diseases (Bahl 1998; Black 1998). The deficiency is widely recognised as contributing to limited growth of children in both low-income and high-income countries (Ploysangam 1997).

Acute lower respiratory tract infections (LRTIs) are among the leading causes of mortality in children under five years of age (Bryce 2005; Rudan 2008) and account for nearly two million deaths annually, the majority of which occur in low-income countries. Pneumonia is the largest cause of mortality, accounting for 19% of all childhood deaths in low-income countries (Bryce 2005; Rudan 2008). Interventions that affect mortality due to pneumonia are thus of great importance in any effort to improve childhood survival.

Description of the intervention

The effect of zinc supplementation on infections remains unclear. It is reported to prevent pneumonia (Bhutta 1999) and has also been found to be beneficial in reducing the duration and severity of diarrhoeal episodes in children with acute and persistent diarrhoea (Bhandari 1994; Zinc Group 2000). Trials of zinc supplementation vary with regard to the magnitude of the effect demonstrated and the presence of a differential effect according to sex, age, nutritional status or baseline plasma zinc concentration.

How the intervention might work

Zinc plays an important role in maintaining a normal immune function. Studies have suggested that zinc deficiency impairs cell regeneration, epithelial barrier functions and linear growth (Shankar 1998). Zinc deficiency also impairs immunocompetence with reduced cell-mediated immune responses, decreased T-lymphocytes, abnormal T-helper and/or suppressor functions, impaired macrophage function and reduced killer cells and antibody-dependent cytotoxicity (Ibs 2003; Ravaglia 2000). Zinc supplementation in children causes an increase in the levels of complement in the blood that modulate the function of monocytes, macrophages and neutrophils polymorphs. It also helps in the development and activation of T-lymphocytes. When zinc supplements are given to individuals with low levels of zinc, the numbers of T-cell lymphocytes circulating in the blood increase and the ability of lymphocytes to fight against infection improves (Fraker 1993). Because zinc is not stored in the body, adequate zinc supplementations are required.

Why it is important to do this review

A previously published review in 1999 (Bhutta 1999) has shown that continuous zinc supplementation was associated with decreased rates of pneumonia. Since then, additional studies have been published that were larger in size and scope. In a review published in 2007 (Aggarwal 2007), recent studies were added, but they included children aged between 0 and 59 months who were given zinc supplements for at least a few months. Recently, Roth 2010 also assessed this topic and calculated the effect size by case definition of pneumonia. However, they also included studies that gave supplements to children aged between 0 and 59 months with zinc. We realised the need for a systematic review of children aged from two to 59 months and therefore conducted a meta-analysis of trials investigating supplemented zinc for at least three months.

Objectives

To evaluate the effectiveness of zinc supplementation in the prevention of pneumonia in children aged two to 59 months.

Methods

Criteria for considering studies for this review

Types of studies

We included RCTs evaluating supplementation of zinc for the prevention of pneumonia in children aged two to 59 months. We included studies that define an episode of pneumonia in the following ways.

  1. Reported cough or difficulty in breathing with a respiratory rate above the WHO-defined age-specific values (respiratory rate of 50 breaths per minute or more for children aged two to 11 months, or respiratory rate of 40 breaths per minute or more for children aged 12 to 59 months), and either documented fever of above 38oC or chest in-drawing (WHO 1990).

  2. A diagnosis of pneumonia based on chest examination by a physician.

  3. A diagnosis of pneumonia based on a chest radiograph.

We included trials published in languages other than English. We excluded quasi-RCTs.

Types of participants

Children aged from two to 59 months.

Types of interventions

Oral supplement containing at least the United States' recommended daily allowance (RDA) of zinc versus either an oral supplement without zinc or placebo. Supplementation of zinc was the only difference between the intervention and the control group. We excluded trials in which individuals were given additional supplements unless the co-interventions other than zinc was the same in both groups. The RDA for infants is 5 mg of elemental zinc per day and for children aged from one to five years, it is 10 mg per day (RDA 1989). We included trials in which supplements were administered for at least three months and outcome surveillance was carried out for at least four weeks.

Types of outcome measures

Outcome measures included the number of new episodes of pneumonia and the prevalence (number of days of illness per total days of observation) of pneumonia in children aged two to 59 months.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, issue 2), which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to January Week 2, 2010), EMBASE (1974 to January 2010) and LILACS (1985 to January 2010).

We used the following search strategy to search MEDLINE and CENTRAL. The search strategy incorporates the search strategy devised by Boluyt 2008 to identify child studies. Due to the small number of search results we chose not to use a search filter to identify randomised trials. We adapted the search strategy to search EMBASE (see Appendix 1) and LILACS (see Appendix 2).

1 exp Pneumonia/
2 pneumon*.tw.
3 lower respiratory tract infection*.tw.
4 lower respiratory infection*.tw.
5 lrti.tw.
6 or/1-5
7 Zinc/
8 (zinc or zn).tw,nm.
9 or/7-8
10 exp Infant/
11 (infant* or infancy or newborn* or baby* or babies or neonat* or preterm* or prematur*).tw.
12 exp Child/
13 (child* or schoolchild* or school age* or preschool* or kid or kids or toddler*).tw.
14 Adolescent/
15 (adoles* or teen* or boy* or girl*).tw.
16 Minors/
17 Puberty/
18 (minor* or pubert* or pubescen*).tw.
19 exp Pediatrics/
20 (pediatric* or pediatric*).tw.
21 exp Schools/
22 (nursery school* or kindergar* or primary school* or secondary school* or elementary school* or high school* or highschool*).tw.
23 or/10-22
24 6 and 9 and 23

Searching other resources

We imposed no language or publication restrictions. We also searched related conference proceedings for relevant abstracts. We contacted organisations and researchers in the field and pharmaceutical companies for information on unpublished and ongoing trials. We also checked the reference lists of all trials identified by the above methods.

Data collection and analysis

Selection of studies

Two review authors (ZSL, BAH) independently assessed for inclusion all the potential studies we identified as a result of the search strategy. We resolved any disagreement through discussion and, if required, we consulted the third review author (ZAB).

Data extraction and management

We designed a data extraction form. Two review authors (ZSL, BAH) extracted the data using the agreed form. We resolved discrepancies through discussion and, if required, we consulted the third review author (ZAB). We entered data into Review Manager software (RevMan 2008) and checked for accuracy.

Assessment of risk of bias in included studies

Two review authors (ZSL, BAH) independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). We resolved any disagreement by discussion with the third review author (ZAB).

(1) Sequence generation (checking for possible selection bias)

We described for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups. We assessed the method as:

  • adequate (any truly random process, for example, random number table; computer random number generator);

  • inadequate (any non random process, for example, odd or even date of birth; hospital or clinic record number); or

  • unclear.   

(2) Allocation concealment (checking for possible selection bias)

We described for each included study the method used to conceal the allocation sequence in sufficient detail and determine whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment. We assessed the methods as:

  • adequate (for example, telephone or central randomisation; consecutively numbered sealed opaque envelopes);

  • inadequate (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth); or

  • unclear.   

(3) Blinding (checking for possible performance bias)

We described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We judged studies at low risk of bias if they were blinded, or if we judged that the lack of blinding could not have affected the results. We assessed blinding separately for different outcomes or classes of outcomes. We assessed the methods as:

  • adequate, inadequate or unclear for participants;

  • adequate, inadequate or unclear for personnel; and

  • adequate, inadequate or unclear for outcome assessors.

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

We described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported, or could be supplied by the trial authors, we re-included missing data in the analyses which we undertook. We assessed methods as:

  • adequate;

  • inadequate; or

  • unclear.

(5) Selective reporting bias

We described for each included study how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the methods as:

  • adequate (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);

  • inadequate (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported); or

  • unclear.

(6) Other sources of bias

We described for each included study any important concerns we have about other possible sources of bias. We assessed whether each study was free of other problems that could put it at risk of bias:

  • yes;

  • no; or

  • unclear.

(7) Overall risk of bias

We made explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We also explored the impact of the level of bias through undertaking sensitivity analyses. 

Measures of treatment effect

For dichotomous outcomes, we extracted the total number of participants for each group and the number of participants experiencing an event. We used the risk ratio (RR) and 95% confidence intervals (CIs).

Unit of analysis issues

We carried out statistical analysis using the Review Manager software (RevMan 2008). Initially, we used fixed-effect inverse variance meta-analysis for combining data where trials were examining the same intervention, and the trials’ populations and methods were judged sufficiently similar. Where we suspected clinical or methodological heterogeneity between studies sufficient to suggest that treatment effects may differ between trials, we used random-effects meta-analysis. When we identified substantial heterogeneity in a fixed-effect meta-analysis, we noted this and repeated the analysis using a random-effects method.

Dealing with missing data

For included studies, we noted levels of attrition. For all outcomes, we carried out analyses, as far as possible, on an intention to treat (ITT) basis, i.e. we attempted to include all participants randomised to each group in the analyses.

Assessment of heterogeneity

We measured heterogeneity among the trials by calculating the I2 statistic, Chi2 P value and by visual inspection of the forest plots. If I2 statistic exceeds 50%, Chi2 P value is less than 0.1, and visual inspection of the forest plots is indicative, then we considered heterogeneity to be substantial. We did not find any heterogeneity; therefore, we did not attempt to undertake subgroup analyses based on differences in zinc dosage, age, supplementation in healthy children against that of children recovering from an episode of illness, and pre-intervention zinc levels. However, we attempted to look for the differential effect of zinc supplementation on the case definition of ALRI.

Results

Description of studies

See Characteristics of included studies, Table 1 and Characteristics of excluded studies tables.

Table 1. Zinc supplement schedule and duration
StudySupplementScheduleDurationSurveillance
ZincControl

Bhandari 2002a

Bhandari 2002b

Zinc gluconate

10 mg

Both groups vitamin ADaily4 monthsOnce weekly
Bobat 2005

Zinc sulphate

10 mg

PlaceboDaily6 monthsEvery 2 weeks
Brooks 2005

Zinc acetate 35 mg to infants

70 mg to children > 12 months

PlaceboWeekly12 monthsOnce weekly
Luabeya 2007

Zinc gluconate

10 mg

Both groups vitamin ADaily(Continued until 24 months of age)Once weekly
Penny 2004

Zinc gluconate

10 mg

PlaceboDaily6 monthsOnce weekly

Sazawal 1998a

Sazawal 1998b

Zinc gluconate

10 mg

PlaceboDaily4 monthsEvery 5th day

Results of the search

Through the search strategy we identified six trials that fulfilled the eligibility criteria of inclusion.

Included studies

We included six trials in the pooled analysis. However, we included Sazawal and Bhandari twice in the analysis, because the investigators in the trials reported ALRI in two different ways.

The trial from Lima, Peru, Penny 2004, was a randomised, double-masked, placebo-controlled community-based trial. Children aged six to 36 months with diarrhoea for more than 14 days were randomly assigned and were given zinc daily for two weeks. Characteristics of the children at baseline was similar except for sex and length-for-age Z scores.

Brooks 2005 was also conducted in a poor population in an urban setting of Dhaka, Bangladesh. The study included 1665 children aged 60 days to 12 months who were randomly allocated to the zinc (70 mg) or placebo orally once weekly group. In this study, children were assessed every week by field research assistants at their homes. On finding children with suggestive respiratory disease or diarrhoea, children were referred to clinics where medical officers and nurses were involved in their assessment and diagnosis was made based on the WHO criteria. At the outset, no significant demographic differences were found between the two groups, except for a slightly higher proportion of boys in the zinc group.

The trial from the urban slums of New Delhi, India (Bhandari 2002a; Bhandari 2002b) included 2482 children aged six to 30 months. These children were given daily elemental zinc, 10 mg to infants and 20 mg to older children, or placebo for four months. Both these groups also received a single massive dose of vitamin A (100,000 IU for infants and 200,000 IU for older children) at enrolment. Both these groups were comparable in age, anthropometry, child feeding practices, morbidity in the previous 24 hours, socioeconomic characteristics, and plasma zinc concentration.

The trial from the KwaZulu-Natal Province of South Africa by Luabeya 2007 included children four to six months of age and was divided into two intervention arms and one control arm. In the control arm, children were given vitamin A alone; in the first intervention arm they were given vitamin A plus zinc; and in the second intervention arm they were given vitamin A, zinc and multiple micronutrients. Children in this study were given supplements until 24 months of age, thus each child was given with supplement for the period of 18 to 20 months. In the study sample 32 children were born with HIV positive status, while 154 were born without HIV infection to HIV positive mothers. Baseline characteristics of the treatment groups in the three cohorts did not significantly differ with the exception of weight-for-length.

The trial conducted by Sazwal et al (Sazawal 1998a; Sazawal 1998b) was in a low socioeconomic population of urban India. It was a double-blind controlled trial in which 609 children (zinc, n = 298; control, n = 311) aged six to 35 months were recruited and assigned to supplementation and placebo groups. The treatment group received 10 mg elemental zinc and the placebo group a substance similar in colour and taste. The fixed dose of 5 mL per child was given daily for six months to the all enrolled children, while it was increased to 10 mL in the case of diarrhoeal illnesses. The baseline characteristics of children included into the two groups were similar for age, sex, nutritional status, and baseline plasma zinc.

The trial from South Africa by Bobat et al (Bobat 2005) was a randomised, double-blind placebo-controlled equivalence trial of zinc supplementation at Grey's Hospital in Pietermaritzburg. In this trial 96 children aged from six to 60 months with HIV 1 infection were randomly assigned to receive 10 mg of elemental zinc as sulphate or placebo daily for six months. Baseline characteristics of included children assigned into the two treatment groups were similar.

Please refer to the Characteristics of included studies table for more details.

Excluded studies

We excluded 19 studies as they did not satisfy the inclusion criteria for this review. Five studies included children outside the age limits of our review criteria (Lira 1998; Osendarp 2002; Sur 2003; Taneja 2009; Tielsch 2007). We excluded another five studies as they supplemented their participants for less than three months (Baqui 2002; Castillo-Duran 1987; Rahman 2001; Roy 1999; Sempértegui 1996). We found eight studies that had a case definition for ALRI/pneumonia which was different from what we had reported (Baqui 2003; Long 2006; Lind 2004; Ninh 1996; Reul 1997; Richard 2006; Rosado 1997; Umeta 2000). We excluded one study because the investigators supplemented children by using a fortified drink (Bates 1993).

Please refer to the Characteristics of excluded studies table for more details.

Risk of bias in included studies

Figure 1 and Figure 2 provide a graphical summary of the results of risk of bias for the six included studies.

Figure 1.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

Figure 2.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Allocation

All included studies, except one (Penny 2004), have adequate sequence generation (Bhandari 2002a; Bhandari 2002b; Bobat 2005; Brooks 2005; Luabeya 2007; Sazawal 1998a; Sazawal 1998b). Allocation concealment was also adequate in all, except for Bobat 2005, Brooks 2005 and Penny 2004 which had insufficient information to permit judgement.

Blinding

Blinding of participants, study personnel and outcome assessors was achieved in all seven included studies. Blinding of participants, study personnel and outcome assessors was achieved in one study (Sazawal 1998a; Sazawal 1998b), whereas in Bhandari (Bhandari 2002a; Bhandari 2002b), participants and outcome assessors were blinded to the assignment but we are unsure of the blinding of study personnel. In Brooks 2005 participants and study personnel were blinded to the assignment but we are unsure of the blinding of outcome assessors.

Incomplete outcome data

Attrition and exclusions were the reasons described in all except Sazawal (Sazawal 1998a; Sazawal 1998b ).

Selective reporting

All the included studies appeared to be free of reporting bias.

Effects of interventions

Incidence of pneumonia

Administration of zinc supplementation showed a statistically significant impact on reducing the incidence of pneumonia by 13% (RR 0.87; 95% CI 0.81 to 0.94, fixed-effect model, six studies, n = 7850), and there was no heterogeneity (I2 statistic = 28% and Chi2 test P value = 0.20) (Analysis 1.1; Figure 3). We then separately pooled studies using a similar case definition. Studies that used clinical definitions of age-specific fast-breathing with or without lower chest indrawing did not find any impact of zinc supplementation on reducing the incidence of pneumonia (RR 0.95; 95% CI 0.86 to1.06, fixed-effect model, four studies, n = 3259) and there was no heterogeneity (I2 statistic = 0% and Chi2 test P value = 0.74). On the other hand, studies that used the above-mentioned case definitions with chest examination or chest radiograph found a significant impact of zinc supplementation on reducing incidence pf pneumonia by 21% (RR 0.79; 95% CI 0.0.71 to 0.88, fixed-effect model, four studies, n = 4591) and there was no heterogeneity (I2 statistic = 0% and Chi2 test P value = 0.44).

Figure 3.

Forest plot of comparison: 1 Zinc supplementation versus placebo, outcome: 1.1 Pneumonia incidence. (LCI = lower chest indrawing)

Prevalence of pneumonia

Administration of zinc supplementation showed a statistically significant impact on reducing the prevalence of pneumonia among children aged two to 59 months by 41% (RR 0.59; 95% CI 0.35 to 0.99, fixed-effect model, one study, n = 3296) (Analysis 1.2; Figure 4).

Figure 4.

Forest plot of comparison: 1 Zinc supplementation vs placebo, outcome: 1.5 Pneumonia Prevalence.

Discussion

Summary of main results

We found six RCTs evaluating the impact of zinc supplementation in children aged two to 59 months. Our meta-analysis indicated that zinc supplementation for children between two to 59 months of age led to reductions in the incidence of pneumonia by 13% and pneumonia prevalence by 41%. The reason for the greater overall reduction of pneumonia prevalence is probably because the prevalence data originated from one study.

Regarding subgroup analysis, we found that zinc reduced the incidence of pneumonia (defined by specific clinical criteria) by 21% (i.e. confirmation by chest examination or chest radiograph) compared to no effect on lower specificity pneumonia case definition (i.e. age-specific fast-breathing with or without lower chest indrawing). We found an expected association of ALRI case definition with an effect size (P = 0.02) since it has been known that low specificity takes the biases towards the null as poor specificity leads to high false positive diagnoses in outcome ascertainment (non-differential error) (White 1986). We found benefits of zinc supplementation when the ALRI case was diagnosed, for example, clinical examination or chest radiograph that suggested infection.

The reduction of pneumonia incidence by 21% would support the use of zinc supplements among children two to 59 months of age. Because zinc, unlike vitamin A, is not stored in the body after a large oral dose, it has been thought that adequate zinc must be available in the daily diet (Sanstead 1995). Therefore, children, particularly those from low-income countries who have an inadequate intake of foods that contain zinc (mainly foods of animal origin) should be given supplements to recover this deficiency.

Overall completeness and applicability of evidence

Participants in the majority of the included studies were from urban slums of low-income countries like Bangladesh, India and South Africa. In two selected studies, either children or their mothers had HIV positive status (Bobat 2005; Luabeya 2007). In most of the studies children were excluded if they had other co-morbidities like tuberculosis, congenital heart diseases, < 60% median weight-for-age Z score, and nutritional oedema, while in Penny 2004 children were selected based on their breastfeeding status. The use of strict definitions of pneumonia, with emphasis on clinical documentation of key sign or radiographic diagnosis, avoids misclassification and leads to greater confidence in the findings.

Quality of the evidence

In order to combine studies it is important that the outcome measures are comparable to avoid measurement bias. Of note, half of the trials included in this analysis reported pneumonia by using the WHO definition (WHO 1990), while the other half included clinical examination and chest radiographs. We therefore looked for the differential effect on outcome estimates with respect to case definition and reported their impacts separately. Adequate allocation concealment, on the other hand, can avoid selection bias in controlled trials and there is evidence that inadequate allocation concealment leads to an overestimation of the treatment effect. In our included trials, allocation concealment was adequately described in all except for Penny 2004, which supports the evidence of lower risk of bias from selective reporting. All included studies were deemed to be adequately blinded for treatment assignment. Completion rates were greater than 90% in all but one study in which it was 16% (Penny 2004) and one study did not report the numbers of participants who dropped out (Sazawal 1998a). Due to the low levels of missing data, we did not choose to look for its impact on the overall estimates as it was not expected to cause a significant bias in the study results.

Potential biases in the review process

We undertook a systematic, thorough search of the literature to identify all studies meeting the inclusion criteria for this review and we are confident that all trials meeting the inclusion criteria are included in this review. Study selection and data extraction were done in duplicate and independently and we reached consensus by discussing any discrepancies.

Agreements and disagreements with other studies or reviews

Over the past two decades, we have found strong evidence from multiple RCTs, in both high-income and low-income countries, showing an effect of zinc in decreasing morbidity and mortality in children due to gastrointestinal and respiratory infections (Hambidge 1999; Sazawal 1998a; Sazawal 1998b). This effect of zinc against infectious diseases is therapeutic as well as preventive. Consistent findings were drawn from previous reviews by the Zinc Investigators’ Collaborative Group in 1999 (Bhutta 1999) and  by Aggarwal 2007 that have studied the effect of zinc supplementation on diarrhoeal and respiratory morbidity. In the review by the Zinc Investigators' Collaborative Group (Bhutta 1999) the zinc supplemented children had an odds ratio (OR) of 0.59 (95% CI 0.41 to 0.83) for pneumonia. Moreover, that review included trials which administered zinc supplementation with a therapeutic intent which might have led to an overestimation of the potential preventive effects of zinc. Aggarwal 2007 included trials that recruited children aged from 0 to 59 months and provided zinc supplementation for at least three months, and showed a 20% decreased incidence of respiratory illness among children supplemented with zinc compared to a placebo. Similar findings were also reported by Roth 2010, who also assessed specific case definitions for impact evaluation on children between zero and five years of age. They reported that zinc reduced the incidence of ALRI defined by specific clinical criteria (IRR 0.65, 95% CI: 0.52 to 0.82), compared to no effect on lower-specificity ALRI case definitions based on the caregiver reports (IRR 1.01; 95% CI: 0.91 to 1.12) or World Health Organization ‘non-severe pneumonia’ (IRR 0.96; 95% CI: 0.86 to 1.08).

Authors' conclusions

Implications for practice

Evidence to date is sufficient to recommend the use of zinc supplementation for children aged two to 59 months of age for the prevention of pneumonia. To conclude, our analysis supports the inclusion of preventive zinc supplementation in public health programmes to improve child health.

Implications for research

More well-designed, large-scale RCTs are needed to establish the benefit of zinc supplementation for the prevention of pneumonia among children aged two to 59 months. The development of effective and feasible interventions to improve the zinc status in children is essential. Enhancement of bioavailable zinc in foods by genetic engineering and plant breeding and period supplementation are other possible intervention strategies that should be evaluated.

Given the rising burden of child mortality due to respiratory infections, particularly pneumonia, and considering its decreasing impact with zinc supplementation, further reviews should be considered in the near future in which effectiveness of zinc supplementation should be assessed for severe pneumonia provided cases are well-defined by strict clinical criteria.

Acknowledgements

The authors wish to thank Ammad Saeed, who assisted in the development of protocol and Ms Sarah Thorning for her assistance with the literature search.The review authors would like to thank the following people for commenting on the draft review: Abdullah Brooks, Robert Black, Teenah Handiside and Jiaan-Der Wang, Mark Griffin, and John Holden.

Data and analyses

Download statistical data

Comparison 1. Zinc supplementation vs placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Pneumonia incidence87850Risk Ratio (Fixed, 95% CI)0.87 [0.81, 0.94]
1.1 Diagnosis based on age-specific fast breathing with or without lower chest indrawing43259Risk Ratio (Fixed, 95% CI)0.95 [0.86, 1.06]
1.2 Diagnosis based age-specific fast breathing AND confirmed by chest examination or chest radiograph44591Risk Ratio (Fixed, 95% CI)0.79 [0.71, 0.88]
2 Pneumonia prevalence13296Risk Ratio (Fixed, 95% CI)0.59 [0.35, 0.99]
Analysis 1.1.

Comparison 1 Zinc supplementation vs placebo, Outcome 1 Pneumonia incidence.

Analysis 1.2.

Comparison 1 Zinc supplementation vs placebo, Outcome 2 Pneumonia prevalence.

Appendices

Appendix 1. Embase.com search strategy

14. #5 AND #9 AND #13
13. #10 OR #11 OR #12
12. child*:ab,ti OR schoolchild*:ab,ti OR preschool*:ab,ti OR kid:ab,ti OR kids:ab,ti OR toddler*:ab,ti OR pediatric*:ab,ti OR paediatric*:ab,ti OR kindergar*:ab,ti OR (school* NEAR/2 (nursery OR primary OR elementary OR age*)):ab,ti
11. infant*:ab,ti OR infancy:ab,ti OR newborn*:ab,ti OR baby*:ab,ti OR babies:ab,ti OR neonat*:ab,ti
OR preterm*:ab,ti OR prematur*:ab,ti
10. 'infant'/exp OR 'child'/exp OR 'pediatrics'/exp OR 'school'/exp
9. #6 OR #7 OR #8
8. zinc:ab,ti OR zn:ab,ti
7. 'gluconate zinc'/exp
6. 'zinc'/exp
5. #1 OR #2 OR #3 OR #4
4. 'lower respiratory tract infection':ab,ti OR 'lower respiratory tract infections':ab,ti OR
'lower respiratory infection':ab,ti OR 'lower respiratory infections':ab,ti OR lrti:ab,ti
3. 'lower respiratory tract infection'/de
2. pneumon*:ab,ti
1. 'pneumonia'/exp

Appendix 2. LILACS search strategy

pneumon$ or namonia or pulmonia or neumonia [Words] and zinc$ or cinc [Words]

"PNEUMONIA" [Subject descriptor] and "ZINC" [Subject descriptor]

Feedback

Feedback comment by Joseph L. Mathew, 10 February 2011

Summary

Please note the following feedback. 

1. The forest plot in Analysis 1.1 shows that participants in the trial by Bhandari et al, have been split to present two different outcomes. Half the participants in each arm are included for the outcome "Diagnosis based on age-specific fast breathing with or without lower chest indrawing" and half for the outcome "Diagnosis based age-specific fast breathing AND confirmed by chest examination or chest radiograph". Both outcomes have been presented as subgroup analysis in the same forest plot; although the trial report mentions that both outcomes were evaluated in all participants. Please confirm whether the procedure adopted in this review is standard practice; and the purpose of doing this.

2. A similar adjustment seems to have been made with the participants in the trial by Sazawal et al.

3. The reference section mentions three citations under Sazawal 1998a; and one under Sazawal 1998b. The third citation in Sazawal 1998a is the same as Sazawal 1998b. Further, none of the citations reports 3300 participants in the trial; whereas this is the number included in the meta-analysis. Sazawal's 1995 publication in the New England Journal of Medicine mention s937 participants; while the 1998 publication in Pediatrics reported 609 participants. Please confirm the basis for using the numbers in the meta-analysis.

4. The meta-analysis has pooled data from children with HIV infection, along with otherwise healthy children. While it seems reasonable to pool children with unknown HIV status with otherwise healthy children, it would be better to analyse HIV infected children separately since pneumonia in immuno-compromised children could be quite different from otherwise healthy children.

Submitter agrees with default conflict of interest statement:
I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.

Reply

We thank Dr Mathew for these comments and will take them into account in our update planned for this year i.e. 2012.

Contributors

Joseph L. Mathew

What's new

DateEventDescription
10 February 2012AmendedAuthors replied to Feedback comment

History

Protocol first published: Issue 2, 2006
Review first published: Issue 12, 2010

DateEventDescription
8 August 2011Feedback has been incorporatedFeedback added to review.

Contributions of authors

Zohra S Lassi (ZSL) entered the data, created the comparisons, did the analysis and wrote the text of the review under the guidance of Dr Zulfiqar A Bhutta (ZAB).
The draft protocol was written by Dr Batool A Haider (BAH) who also designed the eligibility and the data extraction forms.
BAH also took part in the initial stages of the review and assisted in data extraction.

Declarations of interest

Dr Bhutta has been involved in previous studies of zinc supplementation in diarrhoea and was part of the Zinc Investigators Collaborative Group that produced the initial meta-analysis of the preventive and therapeutic benefits of zinc. However, Dr Bhutta has not been involved in any studies of zinc supplementation in acute respiratory infections.

Sources of support

Internal sources

  • The Aga Khan University, Pakistan.

External sources

  • No sources of support supplied

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Bhandari 2002a

MethodsRCT in which the children were individually randomised by a computer generated simple randomisation scheme in blocks of 8. Zinc or placebo bottles were labelled with a unique child identification number according to the randomisation scheme. 6 bottles, one for each month and 2 extra, for each child were produced and labelled before enrolment commenced. The supplies for each child were kept separately in labelled plastic bags. The zinc and placebo syrups were similar in appearance, taste, and packaging. Masking was maintained during analyses by coding the groups as A or B
ParticipantsThe study included children aged 6 to 30 months. There were 1241 children in each group and after drop outs the number reduced to 1093 in the zinc and 1133 in the placebo group. Children were excluded if consent was refused, were likely to move out of the study area within the next four months, needed urgent admission to hospital on the enrolment day or had received a massive dose of vitamin A (100,000 IU for infants and 200,000 IU for older children) within the two months before enrolment
InterventionsDoses of elemental zinc were 10 mg for infants and 20 mg for older children (twice the recommended daily dosage) as zinc gluconate. Zinc or placebo was taken daily for four months. Both groups received single massive doses of vitamin A (100,000 IU for infants and 200,000 IU for older children) at enrolment. Immunisations and treatment for acute illnesses were provided as per World Health Organization (WHO) guidelines. Children with acute lower respiratory tract infections received co­trimoxazole. Amoxicillin was substituted if the child did not respond within three days. Children were sent to hospital if they had signs and symptoms that warranted referral according to WHO guidelines
OutcomesNumber of incidence of ALRI. ALRIs were defined by cough and fast-breathing or lower chest indrawing as assessed by the physician; other clinical signs were not taken into account. Fast breathing was defined as 2 counts of > 50 breaths/min for infants and > 40 breaths/min for older children
NotesThe study took place in the urban slum of Dakshinpuri in New Delhi, India. For episodes to be counted as individual, there had to be at least 14 intervening days. The children in the two groups were comparable for age, anthropometry, child feeding practices, morbidity in the previous 24 hours, socioeconomic characteristics and plasma zinc concentration
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "children were individually randomised by a simple randomisation scheme in blocks of eight. The randomisation scheme was generated by a statistician at Statens Serum Institut, not otherwise involved with this study, using the SAS software"

Comment: adequately done

Allocation concealment (selection bias)Low risk

Quote: "zinc or placebo syrups were prepared and packaged in unbreakable bottles by GK Pharma ApS Koge, Denmark, who also labelled bottles with a unique child identification number according to the randomisation scheme. The supplies of each child were kept separately in labelled plastic bags. The Zinc and placebo were similar in appearances, taste and packaging. Masking was maintained during the analysis by coding the groups as A and B"

Comment: adequately done

Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "the supplies for each child were kept separately in labelled plastic bags". "Masking was maintained during analyses by coding the groups as A or B"

Comment: participants and outcome assessors were blinded to the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskExclusion (35%) with their reasons documented. Attrition was 12% in the zinc group and 8.7% in the control group
Selective reporting (reporting bias)Low riskThe study appears to be free of selective reporting

Bhandari 2002b

MethodsSame as Bhandari 2002a
ParticipantsSame as Bhandari 2002a
InterventionsSame as Bhandari 2002a
OutcomesPneumonia was diagnosed either by a combination of cough with crepitations or bronchial breathing by auscultation or as an episode of acute lower respiratory tract infection associated with at least one of lower chest indrawing, convulsions, not able to drink or feed, extreme lethargy, restlessness or irritability, nasal flaring, or abnormal sleepiness
NotesSame as Bhandari 2002a
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "children were individually randomised by a simple randomisation scheme in blocks of eight. the randomisation scheme was generated by a statistician at Statens Serum Institut, not otherwise involved with this study, using the SAS software"

Comment: adequately done

Allocation concealment (selection bias)Low risk

Quote: "zinc or placebo syrups were prepared and packaged in unbreakable bottles by GK Pharma ApS Koge, Denmark, who also labelled bottles with a unique child identification number according to the randomisation scheme. The supplies of each child were kept separately in labelled plastic bags. The Zinc and placebo were similar in appearances, taste and packaging. Masking was maintained during the analysis by coding the groups as A and B

Comment: adequately done

Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "the supplies for each child were kept separately in labelled plastic bags". "Masking was maintained during analyses by coding the groups as A or B"

Comment: participants and outcome assessors were blinded to the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskExclusion (35%) with their reasons documented. Attrition was 12% in the zinc group and 8.7% in the control group
Selective reporting (reporting bias)Low riskThe study appears to be free of selective reporting

Bobat 2005

MethodsThis was a randomised, double-blind controlled placebo controlled trial conducted in Grey's Hospital in Pietermaritxburg, South Africa. Baseline measurements of plasma HIV-1 viral load and the percentage of CD4T lymphocytes were established at two study visits before randomisation, and measurements were repeated 3, 6, and 9 months after the start of supplementation
Participants96 children with HIV-1 infection between the ages of 6 months to 60 months, being cared for as outpatients at Grey’s Hospital, and not receiving anti-retroviral therapy were recruited. Pneumonia was diagnosed by history and physical examination, including chest auscultation, and confirmed by chest radiograph
InterventionsChildren either received 10 mg of elemental zinc as sulphate or placebo every day for 6 months. The child’s parent or guardian was given 1 packet at the first 2 visits and two packets at each monthly follow-up visit thereafter, and was instructed on how to give the tablet
OutcomesThe primary outcome measure was plasma HIV-1 viral load
NotesOutpatient management of children with HIV-1 infection is provided by a team of paediatricians, medical officers, and nurses who care for about 20 to 30 children per week. After starting zinc or placebo, children were assessed at Grey’s Hospital every 2 weeks for the first month, monthly for 5 months, and a final visit 9 months after zinc or placebo supplementation started. Pneumonia was diagnosed by history and physical examination, including chest auscultation, and confirmed by chest radiograph
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "Children were block–randomised in three age strata (6 to 23, 24 to 41, and 42 to 60 months)"; "Randomisation lists were computer generated at the WHO in a fixed block size of eight"

Comment: adequately done

Allocation concealment (selection bias)Unclear risk

Quote: "Tablets of zinc sulphate or placebo were produced by the same manufacturer (Nutriset, Bierne, France) and supplied in blister packets of 14 dispersible tablets"; "An investigator at Grey’s Hospital assigned children to the treatment groups. The investigators were unaware of the treatment allocation until follow up was completed"

Comment: insufficient information to permit judgement

Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "double-blind"; tablets of zinc sulphate or placebo were produced by the same manufacturer (Nutriset, Bierne, France) and supplied in blister packets of 14 dispersible tablets." An investigator at Grey’s Hospital assigned children to the treatment groups. The investigators were unaware of the treatment allocation until follow up was completed."

Comment: participants and the care givers were blinded to the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low risk9/105 (8.6%) were excluded. 2/46 (4.4%) and 9/50 (18%) did not complete trial in zinc and placebo groups, respectively. The reasons for lost to follow-up were given
Selective reporting (reporting bias)Low riskThe study appears to be free of selective reporting

Brooks 2005

MethodsIt is a randomised controlled trial in which random assignment to zinc or placebo was done with permuted blocks of variable length between 2 and 8. Placebo was designed to be identical to the zinc syrup in colour, odour, and taste
ParticipantsChildren aged 60 days to 12 months at the time of enrolment and excluded those with known or suspected tuberculosis, chronic respiratory or congenital heart disease, or severe malnutrition requiring hospital admission. Pneumonia was diagnosed if crepitations were heard on inspiration with a respiratory rate greater than 50 breaths per minute; severe pneumonia was diagnosed if there was also chest indrawing, or at least one other danger sign. Children with wheezing or rhonchi with crepitations were also diagnosed with pneumonia. 809 children were randomly assigned to zinc and 812 to placebo. There were no significant differences between groups at baseline, except for a slightly higher proportion of boys in the zinc group. There was no difference between the groups in serum zinc values at baseline
InterventionsZinc was given orally as a syrup (35 mg zinc acetate per 5 mL). The placebo was non-nutritious and vitamin-free. Compliance required intake of two teaspoons of syrup (10 mL). Children with pneumonia were treated with co-trimoxazole (10 mg/kg trimethoprim, twice daily for 5 days) for pneumonia. Children on antibiotics were assessed within 72 hours of starting treatment; those who did not improve (i.e., the respiratory rate did not change by more than 5 breaths/min from baseline) were switched to treatment with amoxicillin (40 mg/kg, three times daily for 5 days). If oral treatment failed, or if they had severe pneumonia, children were referred to hospital for parenteral treatment (ceftriaxone 75 mg/kg intramuscularly per day). Children with only expiratory wheezes or rhonchi were managed with salbutamol syrup (0·3 mg/kg, three times daily), or referred to hospital for danger signs
OutcomesThe main outcome was to find out the incidence of pneumonia in both groups. Other outcomes included frequency of other illnesses and mortality
NotesThe study was conducted at Kamalapur, southeastern Dhaka, Bangladesh. The medical officer diagnosed pneumonia if crepitations were heard on inspiration with a respiratory rate greater than 50 breaths per minute; severe pneumonia was diagnosed if there was also chest indrawing, or at least one other danger sign
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "Random assignment to zinc or placebo was done with permuted blocks of variable length between two and eight"

Comment: adequately done

Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement
Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "ACME Laboratories (Dhaka) prepared, labelled and masked the identity of both preparations. Both placebo and treatment were designed to be identical in colour, odour, and taste"; "identity of both the preparations were masked"

Comment: participants and care givers were blinded to the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe loss to follow up was 9.1% for the whole study
Selective reporting (reporting bias)Low riskThe study appears to be free of selective reporting

Luabeya 2007

MethodsThe study was conducted in northern KwaZulu-Natal Province, South Africa. Children were enrolled into the study by nurses at five government primary health care clinics
ParticipantsChildren eligible for study were 4 to 6 months old. Children were excluded from the study if they were: less than 60% of median weight-for-age using United States National Center for Health Statistics standards; had nutritional oedema; had received vitamin or micronutrient supplements in the previous month; had diarrhoea for more than seven days at the time of study enrolment; or were enrolled in another study of a clinical intervention. Confirmed pneumonia was defined as an elevated respiratory rate at rest measured by the fieldworker using WHO/UNICEF Integrated Management of Childhood Illness guidelines
InterventionsThe 3 treatment arms were: vitamin A alone; vitamin A plus zinc; and vitamin A, zinc and multiple micronutrients. All supplements were given daily at home from entry into the study until 24 months of age
OutcomesDiarrhoea, pneumonia
NotesPneumonia by maternal report was considered to have occurred if there was a history of either fast breathing or chest in-drawing. Confirmed pneumonia was defined as an elevated respiratory rate at rest measured by the fieldworker using WHO/UNICEF Integrated Management of Childhood Illness guidelines
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "An allocation list was prepared using computer-generated random numbers and a block size of six"; assignment to the three treatment arms was done separately for three cohorts of children stratified by HIV status of child and mother: HIV-infected children and mothers; HIV-uninfected children of HIV-infected mothers; and HIV-uninfected children of HIV-uninfected mothers

Comment: adequately done

Allocation concealment (selection bias)Low risk

Quote: "The manufacturer prepared numbered packs of tablets corresponding to the allocation list. Children enrolled in the study were assigned by a study physician to one of the three study cohorts after results of the HIV tests became available. The physician then allocated the next pack of tablets from the blocks assigned to that cohort to the participant"

Comment: adequately done

Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "Investigators, study staff and participants were blind to the treatment assignments"

Comment: participants, care givers and outcome assessors were blinded to the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low riskExclusion (12.7%) and attrition (8.1% in vitamin A + zinc and 8.9% in vitamin A group) data were reported along with their reasons
Selective reporting (reporting bias)Low riskThe study appears to be free of selective reporting

Penny 2004

MethodsThis randomised, double-masked, placebo-controlled, community-based trial was carried out in Canto Grande, a shanty town on the outskirts of Lima, Peru. The study was carried out in 2 phases. During the first phase they evaluated the effect of zinc or multiple micronutrient supplementation on the recovery from persistent diarrhoea. During the second phase they assessed the effect of continued supplementation on morbidity from new infections during the following 6 months
Participants412 children aged 6 to 36 months with diarrhoea for 14 days were randomly assigned, after being stratified for breastfeeding status, to receive 2 weeks of daily supplementation with 1 of 3 indistinguishable supplements: placebo; 20 mg Zn/d as zinc gluconate (Zn group); or 20 mg Zn/d as zinc gluconate plus a mixture of other micronutrients, i.e., vitamins and minerals (ZnVM group). A subset of children consisting of the first 246 children enrolled who intended to remain in the study area subsequently received the same assigned supplement at one-half the initial daily dose (10 mgZn/d) and continued under observation for a total of 6 months
InterventionsThe supplements were supplied as individual doses of a dry micronutrient mixture with added sugar, colorings, and flavouring agents, which were dissolved in clean water in the participants’ homes and provided as a liquid beverage under the supervision of study personnel on Monday through Friday and by parents or other caregivers during the weekends. There were two intervention arms, zinc plus vitamins and minerals who were given 10 mg of zinc supplementation along with different combinations of mineral and vitamins. Another interventional arm was given zinc 10 mg and the control group was not given any supplementation
OutcomesChanges in plasma zinc, hematocrit, hemoglobin, plasma ferritin. Children with dysentery, diarrhoea and pneumonia
NotesIn this review, groups with zinc and placebo are included for analysis. Examination always included assessment of hydration status, measurement of rectal temperature and monitoring of respiratory rate, which was counted for 1 min and repeated if the rate was greater than age-specific upper limits (50/min for children aged 6 to 11 mo and 40/min for children
aged 11 mo). Children were referred to the study physician for diagnosis and treatment when the fieldworker or caregiver was concerned about the child’s health status or if the child had any one of several predefined signs of illness, including fever, presentation or worsening of cough with elevated respiratory rate (i.e., fieldworker-defined acute lower respiratory infection), persistent diarrhoea, diarrhoea with signs of dehydration, or vomiting or skin conditions requiring diagnosis
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskInsufficient information to permit judgement
Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement
Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "double-masked"

Comment: participants and treatment assigners were blinded to the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Low risk14/81 (17.3%) in zinc and 13/83 (15.7%) placebo groups lost to follow-up with reasons reported
Selective reporting (reporting bias)Low riskThe study appears to be free of selective reporting

Sazawal 1998a

MethodsIt is a double-blind RCT in which the loss of follow up was less than 2%
ParticipantsChildren, 6 to 35 months of age, presenting to a community based clinic for acute diarrhoea and before enrolment, a parent of the child was given an explanation of the study and written informed consent was obtained. The baseline characteristics for the child-periods included in the analysis were similar between the two groups. The zinc group had 298 participants and the placebo one had 311
InterventionsChildren were randomised to receive either zinc or placebo in a liquid preparation containing vitamins A (800 units), B1 (0.6 mg), B2 (0.5 mg), B6 (0.5 mg), D3 (100 IU), and E (3 mg) and niacinamide (10 mg); the zinc preparation contained zinc gluconate (10 mg elemental zinc). The liquid preparation 5 ml was given daily for 6 months to all enrolled children; during diarrhoeal illness this was increased to 10 mL to provide for excess zinc losses
OutcomesIncidence and prevalence of ALRI. ALRI was diagnosed as using WHO criteria for respiratory disease episodes based on fast breathing alone
NotesThe study was conducted in a low socioeconomic population of urban India
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "Randomisation schedules with permuted blocks of 10 were used for children"

Comment: adequately done

Allocation concealment (selection bias)Low risk

Quote: "Supplements were prepared and coded by Sandoz India Ltd (Mumbai). Both formulation were liquid preparations, similar in colour and taste"

Comment: adequately done

Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "double-blind"; "The Code, which was kept by WHO personnel, was not available to the investigator until the end of the study; "both formulation were liquid preparations, similar in colour and taste"

Comment: participants, care givers and outcome assessors were blinded to the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskExclusion and attrition rates with their reasons were not described in the study
Selective reporting (reporting bias)Low riskThe study appears to be free of selective reporting

Sazawal 1998b

  1. a

    ALRI: acute lower respiratory infection
    LCI: lower chest indrawing

MethodsSame as Sazawal 1998a
ParticipantsSame as Sazawal 1998a
InterventionsSame as Sazawal 1998a
OutcomesALRI defined as child having cough and at least one assessment documenting: a) an elevated respiratory rate more than the age-specific value on both 1-minute estimations; and b) a recorded temperature of more than 101°F or lower chest indrawing (LCI)
NotesSame as Sazawal 1998a
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "Randomisations schedules with permuted blocks of 10 were used for children"

Comment: adequately done

Allocation concealment (selection bias)Low risk

Quote: "Supplements were prepared and coded by Sandoz India Ltd (Mumbai). Both formulation were liquid preparations, similar in colour and taste"

Comment: adequately done

Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "double-blind"; "The Code, which was kept by WHO personnel, was not available to the investigator until the end of the study"

Comment: participants, care givers and outcome assessors were blinded to the treatment assignment

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskExclusion and attrition rates with their reasons were not described in the study
Selective reporting (reporting bias)Low riskThe study appears to be free of selective reporting

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    ALRI: acute lower respiratory infection
    d: days
    mo: months
    wk: week

Baqui 2002Zinc supplementation was given for 2 weeks
Baqui 2003ALRI was diagnosed if the child had reported symptoms of cough or difficulty in breathing with rapid breathing with or without chest indrawing
Bates 1993Zinc supplement was delivered in a fortified drink form
Castillo-Duran 1987Zinc supplementation period too short (60 d); did not study effects on diarrhoea or respiratory illnesses
Lind 2004Considered ‘cough and fever’ as ALRI outcome
Lira 1998Infants were recruited and supplemented from birth; short-course supplementation was provided; only cough was reported
Long 2006Respiratory tract infection outcomes were defined as the occurrence of cough alone, cough and fever, or cough and rapid respiratory rate as reported by the mother
Ninh 1996Respiratory outcome was cough and fever
Osendarp 2002Infants were recruited and supplemented from 4 weeks of age
Rahman 2001Supplementation was given for 2 weeks only
Reul 1997Respiratory infections were defined as the presence of at least two of the following symptoms: runny nose, cough, wheezing, difficulty breathing, or fever
Richard 2006An ALRI was parent defined by the presence of cough and rapid respiration
Rosado 1997Their respiratory illness was presence of runny nose, common cold, sore throat or cough
Roy 1999Zinc supplementation period was 2 weeks
Sempértegui 1996Zinc supplementation period was 60 days
Sur 2003Infants were recruited and supplemented from within 7 days of birth
Taneja 2009Zinc supplementation was given to infants between 2 to 4 wk and 12 mo of age
Tielsch 2007Trial was on children aged 1 to 35 months
Umeta 2000Cough was only reported respiratory outcome

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