Vitamin A for preventing acute lower respiratory tract infections in children up to seven years of age

  • Review
  • Intervention

Authors

  • Hengxi Chen,

    1. West China Second University Hospital, West China Women's and Children's Hospital, Department of Obstetrics and Gynecology, Chengdu, Sichuan, China
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  • Qi Zhuo,

    1. West China Hospital, Sichuan University, Chengdu, Sichuan, China
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  • Wei Yuan,

    1. West China Hospital, Sichuan University, Chengdu, Sichuan, China
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  • Juan Wang,

    1. West China Hospital, Sichuan University, Chengdu, Sichuan, China
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  • Taixiang Wu

    Corresponding author
    1. West China Hospital, Sichuan University, Chinese Cochrane Centre, Chinese Clinical Trial Registry, Chinese Evidence-Based Medicine Centre, INCLEN Resource and Training Centre, Chengdu, Sichuan, China
    • Taixiang Wu, Chinese Cochrane Centre, Chinese Clinical Trial Registry, Chinese Evidence-Based Medicine Centre, INCLEN Resource and Training Centre, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan, 610041, China. txwutx@hotmail.com.

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Abstract

Background

Vitamin A supplements are effective for preventing diarrhoea. There are theoretical reasons why they may also be effective for acute lower respiratory tract infections (LRTIs), also very common in children, especially in low-income countries.

Objectives

To assess the effectiveness and safety of vitamin A for preventing acute LRTIs in children up to seven years of age.

Search methods

In this updated review we searched CENTRAL (2010, Issue 1), which contains the Cochrane Acute Respiratory Infection Group's Specialised Register, MEDLINE (1966 to February Week 4, 2010), EMBASE (1974 to March 2010) and the Chinese Databases CNKI and VIP (1976 to June 2010).

Selection criteria

Randomised controlled trials (RCTs) that assessed the effectiveness of vitamin A in the prevention of acute LRTI in children up to seven years of age.

Data collection and analysis

The review authors independently extracted data and assessed trial quality. We contacted study authors for additional information.

Main results

Ten studies including 33,179 participants were included in this review. Eight studies found no significant effect of vitamin A on the incidence of acute LRTI, or prevalence of symptoms of acute LRTI. Vitamin A caused an increased incidence of acute LRTI in one study; an increase in cough and fever; and increased symptoms of cough and rapid breathing in two other studies. Three reported no differences and no protective effect of vitamin A. Two studies reported that vitamin A significantly reduced the incidence of acute LRTI in children with poor nutritional status or weight, but increased the incidence in healthy children.

Authors' conclusions

This unexpected result is outside our current understanding of the use of vitamin A for preventing acute LRTIs. Accordingly, vitamin A should not be given to all children to prevent acute LRTIs. Despite its benefits in preventing diarrhoeal illnesses, vitamin A supplementation has only a limited effect in preventing acute LRTIs. Positive effects appear limited to populations with acute and chronic under nutrition. Low-dose vitamin A appears to have fewer side effects and at least equal benefit to a high dose of vitamin A.

摘要

背景

使用維生素A預防7歲以下兒童得到急性下呼吸道感染

補充維生素 A可有效預防腹瀉。在理論上它可能也可預防急性下呼吸道感染(LRTIs),急性下呼吸道感染常見於兒童,特別是在低收入國家。

目標

評估使用維生素A在預防7歲以下兒童得到急性下呼吸道感染的效果

搜尋策略

我們搜尋了Cochrane Central Register of Controlled Trials (CENTRAL)(The Cochrane Library 2007年第2期); MEDLINE (1966年到2007年7月); EMBASE (1974年到2007年7月); 及Chinese Biomedicine Database (CBM) (1976年2007年7月).

選擇標準

有評估使用維生素A在預防7歲以下兒童得到急性下呼吸道感染有無效果的隨機對照試驗(RCT).

資料收集與分析

作者們各自檢閱試驗的品質及摘錄資料;聯繫研究的作者以了解更多訊息。

主要結論

大多數的研究發現維生素A對急性下呼吸道感染的發生率或症狀發生並無顯著影響;一項試驗發現維生素會增加急性下呼吸道感染的發生率;增加咳嗽和發燒的比例;在二項其他研究中則發現會增加咳嗽和呼吸急促的症狀。有三項研宄則發現維生素A沒有保護作用也不會造成差異。兩項研究報告則指出,維生素A在營養狀況不佳或體重過輕的兒童可顯著減少急性下呼吸道感染的發病率,但在正常兒童中則會增加發病率。

作者結論

結果超出預期,與目前對使用維生素A在預防急性下呼吸道感染的理解不同。因此,維生素A不應該用在所有兒童中來預防急性下呼吸道感染。證據指出在血清中維生素A過低或營養狀況不佳的兒童中補充維生素A, 可以預防急性下呼吸道感染。

翻譯人

本摘要由臺灣大學附設醫院郭耀文翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

急性下呼吸道感染與維生素A缺乏症是7歲以下兒童常見的問題。急性下呼吸道感染中,特別是肺炎和支氣管炎,是造成5歲以下兒童死亡的主要原因。在全球疾病負荷2000年計劃估計5歲以下兒童的死亡人數,與急性呼吸道感染相關的有210萬人(不包括麻疹,百日咳,及新生兒死亡)。其他研究估計世界各地兒童因急性呼吸道感染而死亡的人數在2000年有190萬人,其中70%是在非洲和東南亞。維生素A缺乏症常見於低收入國家,且會削弱對感染的屏障。我們納入了9個試驗,試驗地點都是維生素 A缺乏症或營養不良盛行的區域,包含了33179位兒童(有31379位在社區,1800位在醫院)。因為不同的研究測量不同的項目(‘急性下呼吸道感染‘包含那些疾病;回憶症狀的時間), 而且同時可能包含其他的治療(特別是營養不良的兒童),這些都可能導致研究偏差。大多數研究顯示補充維生素A對於急性下呼吸道感染的發病率及症狀發生沒有顯著的助益。納入的研究中都沒大闡明維生素A的其他副作用。我們不建議給所有兒童補充維生素A來預防急性下呼吸道感染,因為少部份研究意外發現 維生素A會增加感染的機會或惡化症狀。 一些證據顯示給予血清中維生素A過低(或營養狀況不良)的兒童補充維生素A是有助益的。 表明維生素補充劑利益

Résumé scientifique

La vitamine A pour la prévention des infections aiguës des voies respiratoires inférieures chez les enfants de moins de sept ans

Contexte

La supplémentation en vitamine A est efficace pour la prévention de la diarrhée. Pour certaines raisons théoriques elle pourrait aussi être efficace contre les Infections Aiguës des Voies Respiratoires Inférieures (IAVRI), également très fréquentes chez les enfants, en particulier dans les pays à faible revenu.

Objectifs

Évaluer l'efficacité et l'innocuité de la vitamine A pour la prévention des IAVRI chez les enfants de moins de sept ans.

Stratégie de recherche documentaire

Pour cette mise à jour de la revue, nous avons effectué une recherche dans CENTRAL (2010, numéro 1), qui contient le registre spécialisé du groupe Cochrane sur les infections respiratoires aiguës, MEDLINE (de 1966 à la 4ème semaine de février 2010), EMBASE (de 1974 à mars 2010) et dans les bases de données chinoises CNKI et VIP (de 1976 à juin 2010).

Critères de sélection

Des essais contrôlés randomisés (ECR) ayant évalué l'efficacité de la vitamine A dans la prévention des IAVRI chez les enfants de moins de sept ans.

Recueil et analyse des données

Les auteurs de la revue ont, indépendamment, extrait les données et évalué la qualité des essais. Nous avons contacté des auteurs d'études afin d'obtenir des informations complémentaires.

Résultats principaux

Dix essais incluant 33 179 patients ont été inclus dans cette revue. Huit études n'avaient pas constaté d'effet significatif de la vitamine A sur l'incidence des IAVRI ou sur la prévalence des symptômes d'IAVRI. La vitamine A a causé une incidence accrue des IAVRI dans une étude et une augmentation de la toux et de la fièvre ainsi que des symptômes de toux et de l’augmentation du rythme respiratoire dans deux autres études. Trois n'ont pas signalé de différences ni d'effet protecteur de la vitamine A. Deux études ont rapporté que la vitamine A réduit significativement l'incidence des IAVRI chez les enfants en mauvais état nutritionnel ou de faible poids, mais augmente cette incidence chez les enfants en bonne santé.

Conclusions des auteurs

Ce résultat inattendu est en désaccord avec notre compréhension actuelle du rôle de la vitamine A dans la prévention des IAVRI. En conséquence, il ne faut pas donner de vitamine A à tous les enfants sous prétexte de prévenir les IAVRI. En dépit de son rôle sur la prévention des maladies diarrhéiques, la supplémentation en vitamine A n'a qu'un effet limité dans la prévention des IAVRI. Les effets positifs semblent limités aux populations dans lesquelles la sous-alimentation est aiguë et chronique. La vitamine A à faible dose semble avoir moins d'effets secondaires et être tout aussi bénéfique que des doses élevées.

Plain language summary

Vitamin A for preventing acute lower respiratory tract infections in children up to seven years of age

Acute lower respiratory tract infections (LRTIs), especially pneumonia and bronchiolitis, are leading causes of mortality in children up to five years of age. The Global Burden of Disease 2000 project estimated that the annual number of acute respiratory tract infection (ARTI)-related deaths in children up to five years of age was 2.1 million (excluding deaths caused by measles, whooping cough and neonatal deaths). Others estimate worldwide child deaths from ARTIs at 1.9 million in 2000, 70% of them in Africa and Southeast Asia. Vitamin A deficiency is common in low-income countries and weakens barriers to infection.

We included 10 trials (33,179 children) where vitamin A deficiency or malnutrition was prevalent (31,379 in the community and 1800 in a hospital setting). Studies measured different aspects (for example, what constituted 'acute LRTI', the time to symptom resolution, etc.). There may have been other treatments (especially of malnourished children) which could have led to bias. Most studies showed no significant benefit of vitamin A supplements on the incidence or prevalence of symptoms of acute LRTIs. Although no included studies addressed adverse effects of vitamin A, the use of vitamin A should be carefully monitored.

We do not recommend giving vitamin A to all children to prevent acute LRTIs because a few studies unexpectedly found that vitamin A increased the chance of infections or worsened symptoms in otherwise healthy children. Some evidence shows benefit for vitamin supplements given to children with low serum retinol or with a poor nutritional status. Limitations of our review include trials conducted within very specific populations and poor methodological quality of some of the included trials.

Résumé simplifié

La vitamine A pour la prévention des infections aiguës des voies respiratoires inférieures chez les enfants de moins de sept ans

Les Infections Aiguës des Voies Respiratoires Inférieures (IAVRI), en particulier la pneumonie et la bronchiolite, sont les principales causes de mortalité chez les enfants de moins de cinq ans. Le projet Le rapport mondial sur la morbidité 2000 avait estimé que le nombre annuel des décès liés aux Infections Aiguës des Voies Respiratoires (IAVR) chez les enfants de moins de cinq ans était de 2,1 millions (non compris les décès causés par la rougeole et la coqueluche, et la mortalité néonatale). D'autres estiment à 1,9 million la mortalité infantile mondiale d'IAVR en 2000, dont 70 % en Afrique et en Asie du Sud-Est. La carence en vitamine A est répandue dans les pays à revenu faible où elle affaiblit la résistance aux infections.

Nous avons inclus 10 essais (soit 33 179 enfants) réalisés dans des contextes où l'avitaminose A ou la malnutrition sont très répandues (31 379 dans la communauté et 1 800 en milieu hospitalier). Les études mesuraient différents aspects (par exemple, en quoi consistait une IAVRI, le temps de résolution des symptômes, etc.). Il pouvait y avoir eu d'autres traitements (en particulier chez les enfants souffrant de malnutrition) ayant pu conduire à un biais. La plupart des études n'avaient pas constaté de bénéfice significatif de la supplémentation en vitamine A sur l'incidence ou la prévalence des symptômes d'IAVRI. Bien qu'aucune des études incluses ne se soit intéressée aux effets indésirables de la vitamine A, son utilisation doit être surveillée attentivement.

Nous ne recommandons pas de donner de la vitamine A à tous les enfants sous prétexte de prévenir les IAVRI, car quelques études ont découvert de manière inattendue que la vitamine A augmentait les risques d'infection ou aggravait les symptômes chez les enfants par ailleurs en bonne santé. Certains résultats montrent que la supplémentation vitaminique est bénéfique pour les enfants ayant un bas niveau de rétinol sérique ou un mauvais état nutritionnel. Les limitations de notre revue viennent des essais menés au sein de populations très spécifiques et d'une mauvaise qualité méthodologique de certains des essais inclus.

Notes de traduction

Traduit par: French Cochrane Centre 21st August, 2012
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

Background

Description of the condition

Acute lower respiratory tract infections (LRTIs) refer to acute infections which affect the airways below the epiglottis. These include acute laryngitis, tracheitis, bronchitis, bronchiolitis, acute manifestations of lung infections and any combination of the above; or any of these in addition to upper respiratory tract infections, including influenza (Rudan 2004; WHO 2003). The most important signs and symptoms of LRTIs include cough, increased amount of sputum, wheezing, increased respiratory rate and changes evident on chest X-rays.

Acute respiratory tract infections (ARTIs), especially in the form of pneumonia and bronchiolitis, are the leading cause of mortality in children younger than five years of age. The Global Burden of Disease 2000 project estimated that the annual number of ARTI-related deaths in children under five years of age, excluding deaths caused by measles, pertussis and neonatal deaths, was 2.1 million. This means that about 20% of deaths in this age group annually are from ARTI-related diseases (Murray 2001). Another analysis, Estimates of world-wide distribution of child deaths from acute respiratory infections, suggests that throughout the world 1.9 million (95% CI 1.6 to 2.2 million) children died from ARTIs in 2000, 70% of them in Africa and Southeast Asia (Williams 2002). The incidence of clinical pneumonia in low-income countries may be around 0.29 episodes per child per year, equating to an annual incidence of 150.7 million new cases, 11 to 20 million (7% to 13%) of which are severe enough to require hospitalization. The average incidence of community-acquired pneumonia among children less than five years of age, reported in four large population-based studies in the United States and Europe, was estimated to be approximately 0.026 episodes per child per year. However, this incidence is not directly comparable to that of low-income countries due to different definitions and research methods (Rudan 2004).

Description of the intervention

Currently, the most common methods to prevent acute LRTIs include improved general hygiene (Walter 2001), antibiotics (Bonten 2003), immunisation against measles and pertussis and administering nutritional supplements such as zinc (Bhandari 2002; Sazawal 1998), vitamin C (Hemila 2004) and vitamin A (Barreto 1994).

Vitamin A deficiency in children is a common public health problem, especially in low-income countries. Vitamin A deficiency weakens barriers to infections (Ross 1996) and it is possible that the administration of vitamin A could prevent respiratory tract infections.

How the intervention might work

The role of vitamin A in preventing acute LRTIs is based on experimental studies. Vitamin A was found to benefit the development of the epithelium mucosae of the respiratory tract. Conversely, vitamin A deficiency leads to problems with respiratory tract epithelium mucosae growth and tissue repair (Haq 1991; Tateya 2007) and increased susceptibility of the respiratory tract to infections. It improves humoral and cellular immunity by influencing synthesis of immunoglobulins (Bjersing 2002; Tokuyama 1996). Vitamin A can increase the IgG synthesis of peripheral blood B T-lymphocytes and synthesis of adenoid B T-lymphocytes IgM, IgG, and IgA (Ballow 1996). Vitamin A affects local respiratory tract immune reaction by regulating the production of dendritic cells. When levels of vitamin A fall, dendritic cells in the local mucosa increase, which in turn promotes an inflammatory reaction, leading to increased tissue damage (Matzinger 2002).

Why it is important to do this review

Much research has been done to determine the relationship between vitamin A administration and acute LRTIs. However, the results are inconsistent. Some studies found that the incidence of ARTIs in the vitamin A group was not significantly different to the control group (Chowdhury 2002; Donnen 1998). Other studies found benefits only among specific groups, for example, in underweight children (Sempertegui 1999) and people suffering from malnutrition (Dibley 1996). Other studies concluded that vitamin A supplementation increased the incidence of acute LRTIs within specific groups, for example, normal-weight children (Sempertegui 1999) and children with an adequate nutritional status (Dibley 1996). The apparent lack of an overall effect of vitamin A on the incidence of acute LRTIs could be attributed to conditions that affect both growth and the response to supplementation, for example, baseline vitamin A status, deficiency of other nutrients (fat, zinc) and the usage of vitamin A (such as dosage, duration, etc).

A meta-analysis assessed the effect of vitamin A supplementation on childhood morbidity from respiratory tract infections and diarrhoea (Grotto 2003). It found that vitamin A supplementation slightly increased the incidence of respiratory tract infections, leading to the recommendation that it not be used for all preschool children routinely, but instead only be given to those with a vitamin A deficiency.

Accordingly we set out to determine the benefits and harms of vitamin A administered to children up to seven years of age, including the importance of factors such as age, weight, dose of vitamin A and the nutritional status for preventing acute LRTIs.

Objectives

To assess the effectiveness and safety of vitamin A versus a placebo in the prevention of acute LRTIs in children up to seven years of age.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCT) which examined the effect of vitamin A in preventing acute LRTIs. Both hospital- and community-based trials were included. We excluded trials that included participants with HIV infections or measles-related pneumonia. We excluded quasi-RCTs.

Types of participants

Children up to seven years of age without HIV infections or measles-related pneumonia.

Types of interventions

Vitamin A (any dose) versus placebo or vitamin A plus standard supplements (for example, vitamin E to stabilise vitamin A) versus standard supplements.

Types of outcome measures

Primary outcomes
  1. Incidence or prevalence of acute LRTIs confirmed by doctors on the basis of strict, pre-defined criteria (usually fever, tachypnea, remission with or without cough, chest or radiological signs) during the study period.

Acute LRTIs refer to severe infections which affect the airways below the epiglottis (Rudan 2004; WHO 2003).

Secondary outcomes
  1. Incidence or prevalence of signs and symptoms of acute LRTIs, such as cough (alone or associated with fever), increased respiratory rate, increased sputum production, and specific X-ray changes of the lung.

  2. Adverse events following the administration of vitamin A, such as raised intracranial pressure, vomiting, nausea, enlargement of the liver.

Search methods for identification of studies

Electronic searches

For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2010, Issue 1), which contains the Acute Respiratory Infection Group's Specialised Register, MEDLINE (July 2007 to February Week 4, 2010), EMBASE (July 2007 to March 2010) and the Chinese Databases CNKI and VIP (1976 to July 2010). For details of previous searches see Appendix 1.

We used the following search strategy to search CENTRAL and MEDLINE. We combined the MEDLINE search strategy with the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity-maximising version (2008 revision); Ovid format (Lefebvre 2009). The search strategy was modified to search EMBASE (see Appendix 2) and Chinese databases include CNKI, VIP (see Figure 1).

Figure 1.

Search strategy in Chinese databases

MEDLINE (OVID)
1 exp Respiratory Tract Infections/
2 respiratory tract infection*.tw.
3 lower respiratory infection*.tw.
4 (lrti or alri).tw.
5 exp Bronchitis/
6 bronchit*.tw.
7 bronchiolit*.tw.
8 bronchopneumon*.tw.
9 tracheobronchit*.tw.
10 exp Laryngitis/
11 laryngit*.tw.
12 laryngotracheobronchit*.tw.
13 exp Pneumonia/
14 pneumon*.tw.
15 ((lung or pulmonary) adj3 (inflam* or infect*)).tw.
16 Tracheitis/
17 tracheit*.tw.
18 or/1-17
19 exp Vitamin A/
20 vitamin a.tw,nm.
21 retinol.tw,nm.
22 retinal.tw,nm.
23 or/19-22
24 18 and 23

Searching other resources

We also handsearched journals and monographs not found in electronic database searches and attempted to locate unpublished studies, for example, from meeting papers and academic theses. There were no language or publication restrictions.

We searched WHO ICTRP (http://www.who.int/ictrp/zh/) for ongoing studies.

Data collection and analysis

Selection of studies

Two review authors (HC, WY) independently examined abstracts identified from the electronic searches in order to locate studies that met the inclusion criteria. We retrieved the full text of these studies and those without abstracts. One review author (HC) interviewed the first authors of the Chinese articles, by telephone, to identify the randomisation method and other methodological issues as a way of ensuring that the included studies were true RCTs.

Data extraction and management

Two review authors (HC, WY) independently extracted data from the included studies using a piloted data extraction form. Differences were resolved by discussion among the review authors.

Assessment of risk of bias in included studies

Two review authors (HC, WY) independently assessed risk of bias and reported the findings in the 'Risk of bias' table according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009). The 'Risk of bias' table consists of six domains, including sequence generation, allocation concealment, blinding, incomplete outcome data addressed, free of selective reporting bias, and free of other bias, with a judgement of 'Yes' indicating low risk of bias, 'No' indicating high risk of bias and 'Unclear' indicating unclear or unknown risk of bias.

• Generation of allocation sequence:
Yes - adequate sequence generation was reported using one of the following approaches: random number tables, computer-generated random numbers, coin tossing or card shuffling.
Unclear - allocation sequence generation not mentioned.
No - other methods of allocation that appear to be biased.

•Allocation concealment:
Yes - adequate measures to conceal allocations such as central randomisation, serially numbered, opaque, sealed envelopes, or another description that contained convincing elements of concealment.
Unclear - unclearly concealed trials in which the author did not report an allocation concealment approach at all.
No - inadequately concealed allocation that reported an approach that does not fall into one of the categories in 'Adequate'.

• Blinding:
Blinding of patients (yes, no or unclear).
Blinding of caregivers (yes, no or unclear).
Blinding of outcome assessment (yes, no or unclear).

• Incomplete outcome data addressed:
Yes - described loss of participants to follow up at each data collection point and exclusion of participants after randomisation.
Unclear - did not mention this domain.
No - not described.

• Free of selective reporting bias:
Yes - study is free of suggestions of selective reporting bias.
Unclear - not mentioned.
No - not described.

• Free of other bias:
Yes - the baselines were balanced.
Unclear - not mentioned.
No - the baselines were not balanced.

Measures of treatment effect

We analysed the data using Review Manager (RevMan 2008). Because most of the data listed in the articles were counts (episodes of acute LRTI and person-time of follow up), we treated the data for combination analyses as generic inverse variance outcomes. Other types of data are listed in the 'Additional tables' section. For future updates, we will use the mean difference if outcomes are measured in the same way as continuous data between trials, and we will present binary data as risk ratios with 95% confidence intervals.

Unit of analysis issues

All of the participants were recruited and analysed individually.

Dealing with missing data

We tried to contact the original trial authors for missing data, however we did not receive any replies.

Assessment of heterogeneity

We tested heterogeneity using the Cochrane Q statistic with significance at a P value of less than 0.10. We used the I2 statistic to estimate of the percentage of heterogeneity between trials which could not be ascribed to sampling variation; 25% was considered as low level heterogeneity, 25% to 50% as moderate, and higher than 50% as high. If there was evidence of substantial heterogeneity, we investigated and reported the possible reasons for this.

Assessment of reporting biases

We did not test for reporting bias as only a small number of studies were included in the review.

Data synthesis

We used the random-effects model for meta-analysis.

Subgroup analysis and investigation of heterogeneity

We performed subgroup analyses based on the ages of participants, dosage or usage of vitamin A, nutritional status, development or weight of participants. The outcome measures were discussed according to the subgroups. We did not perform a sensitivity analysis as there were insufficient studies in the subgroups.

Results

Description of studies

In this updated review, a study in the Characteristics of studies awaiting classification table of the original review was selected for inclusion (Rahman 2001). However, this did not change the results of the review.

Results of the search

After examining the titles, abstracts or full texts we identified 73 papers from the search results. Of these, 25 Chinese studies appeared to meet the inclusion criteria. We contacted the first authors of these studies and found that although the studies claimed to be randomized, this was not true. Three studies are listed in the Characteristics of studies awaiting classification table (Donnen 2007; Long 2007; Swami 2007). Finally we included 10 studies. We did not find any ongoing studies.

Included studies

One trial was conducted in Brazil (Barreto 1994), two in Indonesia (Dibley 1996; Sempertegui 1999), one in India (Rahmathullah 1991), one in Ghana (VAST 1993), one in the Congo (Donnen 1998), one in Mexico (Long 2006), one in the USA (Bhandari 1994), one in Canada (Stansfield 1993) and one in Bangladesh (Rahman 2001).
The included studies were mainly conducted in areas where malnutrition, vitamin A deficiency at a subclinical or clinical level, or conditions that affected vitamin A absorption were prevalent. All were community-based trials except for two (Bhandari 1994; Donnen 1998) which were hospital-based.

All included studies focused on children between 0 to 83 months of age. Participants in the two hospital-based trials either had diarrhoea (Bhandari 1994) or were referred to a hospital mainly dealing with protein-energy malnutrition (Donnen 1998). A total of 33,979 children were included: 32,179 children in community-based trials and 1800 children in hospital-based trials.

Seven studies were mega-dose trials: one used 206,000 IU or 103,000 IU vitamin A (Dibley 1996) and six used 100,000 IU or 200,000 IU vitamin A (Barreto 1994; Bhandari 1994; Donnen 1998; Rahman 2001; Stansfield 1993; VAST 1993). Four studies were low-dose trials: one with daily 5000 IU vitamin A (Donnen 1998); one with weekly 10,000 IU vitamin A (Sempertegui 1999); one with weekly 8333 IU vitamin A (Rahmathullah 1991); and one using 45,000 or 20,000 IU vitamin A every two months (Long 2006).

Outcome measures

Barreto 1994

Acute incidence of LRTIs

1. Acute LRTI-1 was defined as a respiratory rate >= 50/min to 12 months of age, or >= 40/min for older children.
2. Acute LRTI-2 was defined as a respiratory rate >= 50/min for any age.
After consideration, we decided to use the acute LRTI-1 for analysis in order to be comparable to other studies. Irrespective of the definition, there were no significant differences in the rate ratio of incidence of acute LRTI.
3. Mean daily prevalence of respiratory signs and symptoms:
a. cough;
b. cough plus fever;
c. cough plus instantaneous respiratory rate (IRR).

Rahmathullah 1991

Incidence of LRTIs

An episode of LRI was defined as >= three days in which the required symptoms (the combination of cough, cold and fever with lung involvement) were reported.

Rahman 2001

Incidence of LRTIs

Acute lower respiratory infection was defined as the presence of cough, difficult or rapid breathing, and fever. Chest retraction was added to these symptoms to define severe lower respiratory infection. Seven consecutive days free from disease were regarded as resolution of previous respiratory illness.

VAST 1993

Mean daily prevalence of signs of LRTIs

1. Daytime cough.
2. Severe respiratory illness.
3. Difficulty in breathing.
4. Rapid breathing.

Dibley 1996

Incidence of acute LRTI

An episode of acute LRTI was defined as periods of two or more consecutive days during which the child had cough and elevated respiratory rate.

Sempertegui 1999

Incidence of acute LRTI

An episode was defined as tachypnea (respiratory rate 40/min) or lower respiratory tract secretions (alveolar or bronchoalveolar) assessed by thoracic auscultation, or both, with one or more of the following symptoms: cough, fever and chest retractions.

Long 2006

Prevalence of respiratory tract infections

1. Cough alone.
2. Cough and fever.
3. Cough and rapid respiratory rate.

Stansfield 1993
Two-week prevalence of signs of respiratory tract infections: cold, cough and rapid breathing.

Donnen 1998

Incidence of acute LRTI

1. Acute LRTI-1: defined as cough plus a respiratory rate >= 40 breaths/min.
2. Acute LRTI-2: cough plus a temperature > 38.5 °C at least once in a 24-hour period.
The data were transformed to dichotomous data.

Bhandari 1994

Incidence of acute LRTI

An episode of acute LRTI was defined as cough, elevated respiratory rate >= 40 min, or lower chest indrawing.

Excluded studies

We excluded 59 articles. For details see Characteristics of excluded studies table.

Risk of bias in included studies

See Figure 2 and Figure 3.

Figure 2.

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

Figure 3.

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

Allocation

All included studies were randomized trials. Four described the methods of randomisation (Bhandari 1994; Dibley 1996; Long 2006; Sempertegui 1999). One study used a cluster-sampling design (Rahmathullah 1991). Five studies described allocation concealment (Barreto 1994; Bhandari 1994; Rahman 2001; Sempertegui 1999; VAST 1993).

Blinding

All included studies were blinded, with six double-blinded (Barreto 1994; Donnen 1998; Long 2006; Rahman 2001; Sempertegui 1999; Stansfield 1993) and two triple-blinded (Dibley 1996; VAST 1993).

Incomplete outcome data

The total rate of loss to follow up in Barreto 1994 was 10.3%. The numbers of loss were equal in both arms. Fifty-eight participants were excluded after allocation to the Bhandari 1994 study. In Dibley 1996, less than 2% of the daily morbidity records were missing. No participants were lost to follow up in Donnen 1998. In Rahman 2001, 135 (17%) were excluded or dropped out. The total number of exclusions for analysis was 4561 (29.6%) in Rahmathullah 1991. Fifty-nine (12.9%) participants were excluded in Sempertegui 1999. Fourteen participants (1.0%) developed measles, four (0.3%) withdrew consent and 119 (8.2%) were lost to follow up in the VAST 1993 study. Stansfield 1993 did address incomplete outcome data.

Selective reporting

We were unable to address selective reporting in the included studies.

Other potential sources of bias

There were no significant differences between groups in the included studies.

Effects of interventions

As most of the data listed in the articles were counts (episodes of acute LRTI and person-time of follow up), we extracted them as generic inverse variance outcomes (see Figure 4, Figure 5). Other types of data are presented in the 'Additional tables'. We did not combine data due to heterogeneity.

Figure 4.
Figure 5.

1. Primary outcome: incidence of acute LRTI

Subgroup: by dosage
Mega doses

Seven studies belonged to this subgroup. In the five community-based trials (Barreto 1994; Dibley 1996; Rahman 2001; Stansfield 1993; VAST 1993), two did not contain data about the incidence of acute LRTI (Stansfield 1993; VAST 1993), and one (Rahman 2001) provided data in a different format, so we combined the two other studies (Barreto 1994; Dibley 1996) in a meta-analysis. One trial (Dibley 1996) showed an elevated incidence of acute LRTI in the vitamin A group (RR 1.39, 95% CI 1.03 to 1.88). The other trial (Barreto 1994) showed no difference in acute LRTI between the two groups (RR 0.97, 95% CI 0.87 to 1.10). The total effect of vitamin A in these two studies showed no protective effect on acute LRTI (RR 1.13, 95% CI 0.80 to 1.60) (Figure 4; Table 1). In the hospital-based studies, one trial (Bhandari 1994) showed no protective effect of vitamin A on the incidence of acute LRTI (RR 1.07, 95% CI 0.92 to 1.26). The other two studies came to the same conclusion that administration of vitamin A had not reduced the incidence of acute LRTI (Donnen 1998; Rahman 2001) (Table 2; Table 3).

Table 1. Incidence of acute lower respiratory infections of community-based trials (original data)
StudyVitamin A groupPlacebo groupRR
Barreto 1994Incidence: 0.002686 per child-daysIncidence: 0.002757 per child-days0.97 (0.86 to 1.09)
Dibley 1996Incidence: 0.0002668 per child-daysIncidence: 0.0003712 per child-days1.39 (1.003 to 1.931)
Sempertegui 1999 (underweight)Incidence: 8.5 per 1000 child-weeksIncidence: 22.3 per 1000 child-weeks0.38 (0.17 to 0.85)
Sempertegui 1999 (stunted)Incidence: 4.7 per 1000 child-weeksIncidence: 9.8 per 1000 child-weeks0.48 (0.21 to 1.12)
Sempertegui 1999 (normal)Incidence: 9.8 per 1000 child-weeksIncidence: 4.4 per 1000 child-weeks2.21 (1.24 to 3.39)
Table 2. Donnen 1998: morbidity during hospitalisation related to respiratory tract infections
  1. ALRI = acute lower respiratory infection

SymptomsHigh-doseLow-dosePlacebo
ALRI1   
Never99.3%98.6%98.6%
>= 1 episodes0.7%1.4%1.4%
ALRI2   
Never98.6%99.0%99.3%
>= 1 episodes1.4%1.0%0.7%
Fever   
Never90.6%92.7%92.1%
>= 1 episodes9.4%7.3%7.9%
Table 3. Rahman 2001: incidence and prevalence of acute lower respiratory infections
 IncidencePrevalence
GroupEpisodes ALRIPerson-years at risk infectionIncidence

Rate ratio

(95%CI)

Days with

illness

Person-yearsPrevalence

Rate ratio

(95% CI)

Acute lower respiratory infection

Zinc

(n = 345)

17255.0031.14

1.62

(1.16 to 2.25)

78756.3225.10

2.07

(1.76 to 2.44)

Vitamin A

(n = 334)

13753.7620.93

1.06

(0.74 to 1.53)

58054.7273.87

1.20

(0.99 to 1.45)

Placebo

(n = 161)

5625.8360.791.021126.2152.941.0
Interaction of zinc and vitamin A   

0.75

(0.46 to 1.20)

   

0.58

(0.46 to 0.73)

Severe acute lower respiratory infection

Zinc

(n = 345)

17255.0031.14

1.62

(1.16 to 2.25)

78756.3225.10

2.07

1.76 to 2.44)

Vitamin A

(n = 334)

13753/7620.93

1.06

(0.74 to 1.53)

58054.7273.87

1.20

(0.99 to 1.45)

Placebo

(n = 161)

5625.8360.791.021126.2152.941.0
Interaction of zinc and vitamin A   

0.66

(0.33 to 1.31)

   

0.56

(0.39 to 0.80)

Low doses

Four studies belong to this subgroup. In the three community-based trials, one (Sempertegui 1999) showed no protective effect of vitamin A on the incidence of acute LRTI, with a RR of 1.16 (95% CI 0.77 to 1.76) (see Figure 4). One trial (Rahmathullah 1991) stated that the age-adjusted RR was 1.01 (95% CI 0.73 to 1.40), which showed no protective effect of vitamin A on the incidence of acute LRTI; one study (Long 2006) did not state the incidence of acute LRTI. One hospital-based trial (Donnen 1998) showed no protective effect of vitamin A on the incidence of acute LRTI (Table 2).

Subgroup: by state of nutrition, development or weight of participants

One trial (Rahmathullah 1991) only listed the percentage of children with LRTIs according to their nutritional state, and showed no significant differences between the two groups. One trial (Sempertegui 1999) showed that vitamin A had a significant protective effect on the incidence of acute LRTI in underweight children (RR 0.38, 95% CI 0.17 to 0.85), while it significantly elevated the incidence of acute LRTI in normal-weight children (RR 2.22, 95% 1.25 to 3.95) (see Figure 4). One trial (Dibley 1996) showed a significant increase in the incidence of acute LRTIs in normal-sized children (RR 1.83, 95% CI 1.257 to 2.669) but did not show an increase in the incidence for nutritionally stunted children (RR 0.48; 95% CI 0.21 to 1.12) (Figure 4; Table 1).

Subgroup: by age

One trial (Rahmathullah 1991) only listed the percentage of children with LRTIs according to their age, and showed no significant differences between the two groups (Table 4). One trial (Bhandari 1994) listed the incidence of acute LRTIs by age group (age <= 23 months and > 23 months) (Table 5). The meta-analysis we conducted on children aged five years or younger showed that there was no protective effect of vitamin A on the incidence of acute LRTIs (Figure 4).

Table 4. Rahmathullah 1991: number of episodes of acute lower respiratory infections/number of children
AgeVitamin APlaceboRate ratio95% CI
<= 11 mo0.0060.061.010.58 to 1.76
12 to 35 mo0.050.050.980.58 to 1.66
>= 36 mo0.040.041.050.55 to 2.00
Table 5. Bhandari 1994: incidence of acute lower respiratory infections over 90 days
AgeVitamin APlaceboRelative risk
All children0.440.411.07 (0.92 to 1.26)
Age <= 23 months0.590.491.19 (0.99 to 1.43)
Age > 23 months0.330.340.98 (0.75 to 1.26)

2. Secondary outcome: prevalence of symptoms of acute LRTI

Four studies discussed the prevalence of symptoms of acute LRTI.

Barreto 1994 (Table 6; Table 1)
Mean daily prevalence of:
a. cough with the prevalence in the vitamin A group, control group; rate ratio, and P value being 0.24, 0.24, 0.99, 0.57 respectively;
b. cough plus fever being 0.03, 0.03, 0.99, 0.90 respectively;
c. cough plus instantaneous respiratory rate (IRR) being 0.01, 0.01, 0.96, 0.74 respectively.

Table 6. Barreto 1994: mean daily prevalence of respiratory symptoms
  1. IRR = instantaneous respiratory rate

SymptomsVitamin APlaceboRate ratioP
Cough0.24290.23880.990.57
Cough + fever0.02890.02820.990.90
Cough + IRR0.01240.01290.960.74

Clearly there were no significant differences in the mean daily prevalence of respiratory signs and symptoms.

VAST 1993 (Table 7)
Mean daily prevalence of:
a. daytime cough, 13.2% for the vitamin A group and 13% for the control group; prevalence ratio 1.02, P = 0.67;
b. 'tired ribs' (severe respiratory illness), 1.1% for the vitamin A group and 1.1% for the control group; prevalence ratio 0.98, P = 0.86;
c. difficulty in breathing, 1.2% for the vitamin A group and 1.2% for the control group; prevalence ratio 0.96, P = 0.70;
d. rapid breathing, 1.1% for the vitamin A group and 1.3% for the control group; prevalence ratio 0.81, P = 0.11.

Table 7. VAST 1993: mean daily prevalence of signs or symptoms
SymptomsVitamin APlaceboPrevalence ratioP
Daytime cough13.2%13.0%1.020.67
"Tied ribs" (severe respiratory illness)1.1%1.1%0.980.86
Difficulty breathing1.2%1.2%0.960.70
Rapid breathing1.1%1.3%0.810.11

There were no significant differences between the vitamin A group and the control group in the mean daily prevalence of acute LRTI symptoms.

Stansfield 1993 (Table 8, Table 9)
Two-week prevalence of:
a. cough, 48% for the vitamin A group and 45% for the placebo group; rate ratio 1.18 (95% CI 1.09 to 1.27);
b. rapid breathing, 18% for the vitamin A group and 15% for the placebo group; rate ratio 1.18 (95% CI 1.09 to 1.27).

Table 8. Stansfield 1993: risk ratio for 2-week prevalence of morbidity by age group
Age group (months)ColdCoughRapid breathing
<11 (817; 660)0.99 (0.93 to 1.06)1.00 (0.90 to 1.12)1.18 (0.97 to 1.45)
12-23 (1206; 1001)1.05 (1.00 to 1.11)1.07 (0.98 to 1.18)1.25 (1.04 to 1.50)
24-35 (1210; 966)1.10 (1.05 to 1.16)1.15 (1.05 to 1.26)1.05 (0.88 to 1.26)
36-47 (1181; 930)1.00 (0.95 to 1.06)1.02 (0.93 to 1.12)1.23 (1.00 to 1.51)
48-59 (1069; 921)1.09 (1.02 to 1.15)1.13 (1.03 to 1.25)1.20 (0.97 to 1.47)
60-71 (896; 809)0.98 (0.92 to 1.04)1.02 (0.92 to 1.14)1.19 (0.94 to 1.50)
72-83 (711; 540)1.05 (0.98 to 1.12)1.06 (0.93 to 1.20)1.03 (0.79 to 1.34)
Table 9. Stansfield 1993: 2-week prevalence of morbidity
SymptomVitamin APlaceboRate ratio
Cough48%45%1.18 (1.09 to 1.27)
Rapid breathing18%15%1.18 (1.09 to 1.27)

This showed that vitamin A increased the risk of symptoms such as cough and rapid breathing. This study also showed that there was no clear correlation between risk and age.

Long 2006 (Figure 5; Table 10)
There were no differences in the prevalence of overall cough, cough with fever, or cough with rapid respiratory rate between the two groups.

Table 10. Prevalence of symptoms of acute lower respiratory infections (original data)
StudyVitamin A groupPlacebo groupRR
Long 2006 (overall cough)Prevalence: 481/153.9 per child-yearsPrevalence: 539/155.1 per child-years0.90
Long 2006 (cough with difficulty breathing)Prevalence: 5/153.9 per child-yearsPrevalence: 10/155.1 per child-years0.50
Long 2006 (cough with fever)Prevalence: 146/153.9 per child-yearsPrevalence: 142/155.1 per child-years1.04

3. Adverse effect of vitamin A

No studies discussed the adverse effects of vitamin A, such as raised intracranial pressure, vomiting, nausea, enlargement of the liver, etc.

Discussion

Summary of main results

The majority of studies showed that there was no significant effect on the incidence or prevalence of acute LRTI symptoms with vitamin A supplementation (Barreto 1994; Bhandari 1994; Donnen 1998; Rahman 2001; Rahmathullah 1991; VAST 1993). One study (Dibley 1996) showed an elevated incidence of acute LRTIs in the vitamin A group; one study (Long 2006) showed an elevated prevalence of cough and fever; and one study (Stansfield 1993) showed that vitamin A increased the risk of symptoms such as cough and rapid breathing. Two studies (Rahmathullah 1991; Sempertegui 1999) showed that there was no difference and no protective effect of vitamin A on the incidence of acute LRTIs in age subgroups; and one study (Stansfield 1993) concluded that there was no clear relationship between vitamin A and age. Two studies (Dibley 1996; Sempertegui 1999) concluded that the effect of vitamin A on the incidence of acute LRTIs was significantly associated with nutritional status or the child's weight, with an increase in acute LRTI episodes in 'normal' children.

The actual dosage of vitamin A supplement is an important element when considering the outcome, especially adverse effects. Over-dosage of vitamin A can causes acute toxicosis (resulting in raised intracranial pressure, nausea, vomiting, etc) and chronic toxicosis (resulting in an enlarged liver, loss of appetite, etc). Acute toxicosis could be induced by one single dose of 1,000,000 IU for adults and 300,000 IU for children, while chronic toxicosis could be induced by daily administration of 10,000 IU of vitamin A for several months. However, adverse effect usually disappear within one or two weeks after stopping the supplementation (Maurice 2006). Only one study (Donnen 1998) discussed both the high-dose and low-dose effects of vitamin A supplementation. There were no significant differences in the duration and incidence of acute LRTIs, but the number of participants was small. No studies discussed the adverse effects of vitamin A.

Vitamin A deficiency up-regulates the Th1-mediated immune response while vitamin A supplement up-regulates the Th2 response and down-regulates the Th1 response, which protects individuals against infections such as the respiratory syncytial virus. Further studies on the protective value of vitamin A supplementation on specific acute LRTIs should be conducted to clarify whether vitamin A supplementation increases the incidence of acute LRTIs or not.

Overall completeness and applicability of evidence

Five studies (Barreto 1994; Bhandari 1994; Long 2006; Rahman 2001; Sempertegui 1999) described the sample size calculations (1240; 900; 336; 400, respectively). Five studies (Dibley 1996; Donnen 1998; Rahmathullah 1991; Stansfield 1993; VAST 1993) did not state the methods they employed to estimate sample sizes, but they were large (1405; 900; 15,419; 11; 124; 1455, respectively).

Quality of the evidence

Vitamin A deficiency is associated with impaired humoral and cellular immune function, keratinisation of the respiratory epithelium and decreased mucous secretion, which weakens barriers to infection (Ross 1996). Vitamin A deficiency usually occurs in those with a poor nutritional status or who are underweight. These people seem to benefit from vitamin A supplementation, which could explain the results of one study (Sempertegui 1999) that concluded that vitamin A supplementation decreases the incidence of acute LRTIs in underweight children. However, children with a poor nutritional status usually experience multi-nutrient deficits, including vitamin A deficiency, or have conditions which may affect the immune response or the effect of vitamin A. It is often difficult to identify the effect of vitamin A deficiency and this may partly account for inconsistencies between the studies. These inconsistencies could also be related to different definitions of acute LRTIs. One meta-analysis based on age showed there was a slight protective response to vitamin A given to children older than 11 months, but this may have been due to the fact that the nutritional status can worsen after weaning. We could not get a clear picture of the relationship between the effect of vitamin A and age. We hypothesise that the inconsistent results in the different age subgroups could be due to more complex factors such as nutritional status, serum retinol, etc.

One study (Dibley 1996) showed an elevated incidence of acute LRTIs in the vitamin A group and two studies (Long 2006; Stansfield 1993) showed that vitamin A increased the risk of symptoms of acute LRTI. Two studies (Dibley 1996; Sempertegui 1999) concluded that the effect of vitamin A on the incidence of acute LRTIs was significantly associated with the nutritional status or weight of the children, with an increase in acute LRTI episodes in 'normal' children. Some researchers hypothesise that vitamin A supplementation given to children with adequate vitamin A stores might cause a temporary immune dysregulation and lead to increased susceptibility to infectious diseases (Grotto 2003). Vitamin A supplementation in animal studies showed that, when there is a chronic excess of vitamin A, it may depress immune responses, including humoral and cellular responses (Friedman 1989; Friedman 1991). This may explain why children with normal serum retinol levels sometimes experience more episodes of acute LRTI when given vitamin A supplements.

The quality of the evidence ranged from moderate to very low (Figure 6).

Figure 6.

Summary findings table

Potential biases in the review process

This review has some limitations. The included studies differed in some important aspects of design, namely the definitions of acute respiratory tract infections and the recall period for assessing morbidity symptoms, which could lead to biases of information and misclassification. The included studies did not mention whether underweight children or children with poor nutritional status received any concomitant intervention, such as an improved diet, during trials. If so, this could also introduce bias.

Agreements and disagreements with other studies or reviews

A Cochrane systematic review (Brian 2007) found that supplementation of vitamin A for very low birthweight infants reduced death or oxygen requirements at one month of age. There is also a trend towards reduction in oxygen requirement in survivors at one month of age and mortality. These results are similar to our own findings, i.e. that supplementation should only be given to children who lack vitamin A.

Authors' conclusions

Implications for practice

Despite its benefits in preventing diarrhoeal illnesses, vitamin A supplementation has only limited efficacy in preventing acute LRTIs. There is some beneficial evidence limited to populations with acute and chronic under nutrition. Low-dose vitamin A schedules appear to have fewer side effects and at least equal benefit to high-dose vitamin A schedules.

Implications for research

Large RCTs should be conducted to clarify the relationship between the dosage of vitamin A and the incidence of acute LRTIs, especially to clarify the adverse effects of different doses of vitamin A. We also suggest that further studies on the protective effect of vitamin A supplementation on specific acute LRTIs should be conducted in order to clarify whether vitamin A supplementation increases or decreases the incidence of specific infections. Finally, further studies are needed to address the mode of vitamin A delivery and combination with improving general nutritional status, both in children and ante-natally.

Acknowledgements

The authors wish to thank Liz Dooley (Managing Editor) and Sarah Thorning (Trials Search Co-ordinator) of the Cochrane ARI Group, Dr. Nick Brown, Dilip Mahalanabis, Nelcy Rodriguez, Janet Wale and Ludovic Reveiz for commenting on the protocol. We thank the following people for commenting on the draft review: Ann Fonfa, Naseem Qureshi, Dilip Mahalanabis, Nick Brown, Terry Neeman and Ludovic Reveiz. Finally we acknowledge the following people for commenting on the updated review: Angel Magar, Ann Fonfa, Nick Brown, Mark Griffin and Ludovic Reveiz.

Data and analyses

Download statistical data

Comparison 1. Vitamin A versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of acute LRTI in community-based trials3 Incidence of ALRI (Random, 95% CI)Subtotals only
1.1 Age <= 53 Incidence of ALRI (Random, 95% CI)1.13 [0.88, 1.43]
1.2 Mega dose2 Incidence of ALRI (Random, 95% CI)1.13 [0.80, 1.60]
1.3 Low dosage1 Incidence of ALRI (Random, 95% CI)1.16 [0.77, 1.76]
1.4 Under weight1 Incidence of ALRI (Random, 95% CI)0.38 [0.17, 0.85]
1.5 Stunted1 Incidence of ALRI (Random, 95% CI)0.48 [0.21, 1.12]
1.6 Normal1 Incidence of ALRI (Random, 95% CI)2.22 [1.25, 3.95]
2 Prevalence of symptoms of acute LRTI1 Prevalence (Random, 95% CI)Totals not selected
2.1 Overall cough1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
2.2 Cough with difficulty in breathing1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
2.3 Cough with fever1 Prevalence (Random, 95% CI)0.0 [0.0, 0.0]
Analysis 1.1.

Comparison 1 Vitamin A versus placebo, Outcome 1 Incidence of acute LRTI in community-based trials.

Analysis 1.2.

Comparison 1 Vitamin A versus placebo, Outcome 2 Prevalence of symptoms of acute LRTI.

Appendices

Appendix 1. Previous search

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 2), which contains the Cochrane Acute Respiratory Infection Group's Specialised Register; MEDLINE (1966 to July 2010); EMBASE (1974 to July 2010); and the Chinese Biomedicine Database (CBM) (1976 to July 2010).

We ran the following search strategy over CENTRAL and MEDLINE in combination with the highly sensitive search strategy developed by The Cochrane Collaboration for identifying RCTs (Dickersin 1994). The search strategy was modified to search the EMBASE and CBM databases.

MEDLINE (OVID)
1 exp vitamin A/
2 vitamin A.mp.
3 retinal.mp.
4 retinol.mp.
5 or/1-4
6 lower respiratory tract infection$.mp.
7 lower respiratory infection$.mp.
8 LRTI$.mp.
9 ALRI$.mp.
10 exp respiratory tract infections/
11 exp bronchiolitis/
12 bronchiolitis.mp.
13 exp bronchitis/
14 bronchitis.mp.
15 exp laryngitis/
16 laryngitis.mp.
17 exp pneumonia/
18 pneumonia.mp.
19 (lung adj inflammation).mp.
20 pneumonitis.mp.
21 (pulmonary adj inflammation).mp.
22 exp tracheitis/
23 tracheitis.mp.
24 or/6-23
25 5 and 24

We also searched (July 2007) the following ongoing trials registers: www.controlled-trials.com/; www.clinicaltrials.gov; www.trialscentral.org/ and ctr.glaxowellcome.co.uk/welcome.asp. In addition, we searched publications from organisations such as the World Health Organization. We searched for evidence on adverse effects from other sources, such as the UK Medicines Control Agency www.open.gov.uk/mca; MedWatch produced by the US Food and Drug Administration; and the Australian Adverse Drug Reactions Bulletin www.health.gov.au/.

Appendix 2. Embase.com search strategy

#20. #16 AND #19
#19. #17 OR #18
#18. random*:ab,ti OR placebo*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR 'cross-over':ab,ti OR allocat*:ab,ti OR
assign*:ab,ti OR volunteer*:ab,ti OR factorial*:ab,ti OR ((singl* OR doubl*) NEAR/2 (blind* OR mask*)):ab,ti
#17. 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp
#16. #12 AND #15
#15. #13 OR #14
#14. 'vitamin a':ab,ti OR retinol:ab,ti OR retinal:ab,ti
#13. 'retinol'/exp
#12. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11
#11. tracheit*:ab,ti
#10. 'tracheitis'/exp
#9. ((lung OR pulmonary) NEAR/3 (inflam* OR infect*)):ab,ti
#8. pneumon*:ab,ti
#7. 'pneumonia'/exp
#6. laryngit*:ab,ti OR laryngotracheobronchit*:ab,ti
#5. 'laryngitis'/exp
#4. bronchit*:ab,ti OR bronchiolit*:ab,ti OR bronchopneumon*:ab,ti OR tracheobronchit*:ab,ti
#3. 'bronchitis'/exp
#2. 'respiratory tract infection':ab,ti OR 'respiratory tract infections':ab,ti OR 'lower respiratory infections':ab,ti OR 'lower
respiratory infection':ab,ti OR lrti:ab,ti OR alri:ab,ti
#1. 'respiratory tract infection'/exp

What's new

DateEventDescription
10 March 2010New search has been performedSearches conducted. In this updated review, one new study was included (Rahman 2001) and two new studies were excluded (Jiang 2009a; Jiang 2009b) but the conclusions remain unchanged. Two new studies are awaiting classification (Donnen 2007; Long 2007). This update also includes the GRADE tool for assessing trial quality.

History

Protocol first published: Issue 3, 2006
Review first published: Issue 1, 2008

DateEventDescription
23 June 2008AmendedConverted to new review format.
14 September 2007AmendedAs a result of comments from an external peer referee, the review authors changed the focus of this review to children up to seven years of age.
20 July 2007New search has been performedSearches conducted.

Contributions of authors

Hengxi Chen (HC) was responsible for developing the protocol, searching for trials, quality assessment of trials, data extraction, data analysis and review development.
Taixiang Wu (TW) was responsible for data extraction, drafting the review, editing, commenting and amending the updated review.
Qi Zhuo (QZ), Wei Yuan (WY) and Juan Wang (JW) were responsible for telephone interviewing the first authors of the Chinese trials.

Declarations of interest

None known.

Sources of support

Internal sources

  • Chinese Cochrane Centre, West China Medical Centre, Sichuan University, China.

External sources

  • Cochrane Acute Respiratory Infections Group, Australia.

Differences between protocol and review

1. We used new methods to assess the risk of bias according to the new version of the Cochrane Handbook for Systematic Reviews of Interventions.
2. We used GRADEprofiler to assess the quality of evidence.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Barreto 1994

MethodsRandomised, double-blind, placebo-controlled clinical trial
Participants1240 children aged 6 to 48 months. The baseline was comparable. The inclusion criteria: children between 6 and 48 months. The exclusion criteria: active xerophthalmia, measles within the previous 30 days, high-dose vitamin A supplementation in the previous 6 months, weight-for-age less than 60% of the statistical median
InterventionsVitamin A group received 100,000 IU every 4 months for 1 year for children younger than 12 months and 200,000 IU for the older children. The placebo group only received placebo
Outcomes1. ALRI incidence
2. Mean daily prevalence of respiratory signs and symptoms
NotesThis study was conducted in Serrinha, capital of the state of Bahia, where the climate is hot and dry. The pubic health services there are inadequate. The biochemical deficiency (serum vitamin A concentration < 0.35 mmol/L) rate in children is 7.4%, shown in an earlier survey. According to WHO criteria, vitamin A deficiency should be considered a pubic health problem in this area. Children were visited 3 times per week for 1 year, so the recall period was 48 to 72 hours. The person-time of the vitamin A group and the control group were 203,252 child-days and 201,656 child-days, respectively. The total loss in follow-up time was 10.3%, equally distributed between the control and vitamin A group. Migration away from the area was the main reason for loss to follow up. The sample size of 1240 was estimated to give a power of 90% to detect a 15% reduction in the incidence of diarrhoea.
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Unclear riskOnly mentioned "randomly assigned"
Allocation concealment?Low riskOnly an external investigator had the codes for the individually wrapped and numbered capsules
Blinding?
All outcomes
Low riskDouble-blind
Incomplete outcome data addressed?
All outcomes
High risk9 children excluded from the trial because of severe weight loss.
Free of selective reporting?High riskNot all the pre-specified outcomes were reported
Free of other bias?Low riskThere were no significant differences between groups

Bhandari 1994

MethodsRandomised, double-blind, placebo-controlled clinical trial. The randomisation method was simple randomisation scheme drawn up by the WHO
Participants900 children aged 12 to 60 months who resided in the slum area attending the government clinic with diarrhoea duration 7 days or less and weight for height 70% or more of the median were included. Exclusion criteria: presence of signs of vitamin A deficiency, had received a large dose of vitamin A in the past 6 months, had the likelihood to migrate out of the slum area, had associated illness, had been enrolled in the study within the past 6 months and refused consent. The baseline line of two group were comparable
InterventionsThe vitamin A group received 200,000 IU vitamin A; the placebo group received only placebo. They were followed up 90 days after recovery
OutcomesIncidence of ALRI
NotesThis study was conducted at Govindpuri, an urban slum area in south Delhi where vitamin A had not been given to people in the preceding 3 years. The sample size estimate was 358 children per group based on detecting 25% reduction in the prevalence of acute LRTIs with 90% power and 5% significance. The researchers increased the sample size by 25% to allow for attrition. Children were visited every 3 days until 90 days after they recovered from the diarrhoea. The final results were data according to 842 children, 422 in vitamin A group. 5 were for withdrawing consent, 46 for being unavailable for more than 30 days, and 7 for fast breathing related to tuberculosis, cardiac disease or severe anaemia. The child 90-day of follow up for vitamin A group and placebo group was 410 and 409
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Low riskThe randomisation was done using a simple randomisation scheme
Allocation concealment?Unclear riskNot mentioned
Blinding?
All outcomes
Low riskDouble-blind
Incomplete outcome data addressed?
All outcomes
High risk58 participants were excluded. 5 withdrew consent, 46 were unavailable for more than 30 study days, 7 for persistent fast breathing due to tuberculosis.
Free of selective reporting?High riskNot all the pre-specified outcomes were reported
Free of other bias?Low riskThere were no significant differences between groups

Dibley 1996

MethodsRandomised, double-blind, placebo-controlled trial. Randomisation was done with 1:1 allocation ratio in blocks of 8 based on a table of random permutations of integers. Treatments were given once every 4 months for 6 treatment cycles
Participants1405 children aged 6 to 47 months. The inclusion criteria: children between 6 to 47 months. Exclusion criteria: those with cerebral palsy, epilepsy, flaccid paralysis, mental retardation, congenital or rheumatic heart disease were permanently excluded. Those with weight-for-height more than 3.00 SD below the WHO growth reference mean or acute xerophthalmia were excluded for one cycle and treated with high-dose vitamin A and then included. Demographic, clinical and nutritional characteristics at the baseline were the same, and the groups remained balance at the start of each of the other 5 cycles. Compliance was equally high in both group, on average, 89% of the age-eligible children received a treatment
InterventionsVitamin A group: 206,000 IU of retinyl ester plus 37 IU vitamin E or 103,000 IU retinyl ester plus 17 IU vitamin E if less than 12 months of age; the control group: placebo that contained 17 or 37 IU vitamin E on the age of the subject
OutcomesIncidence of ALRI
NotesThis study was conducted in 34 rural villages located on the southern coast of Central Java in Indonesia, with high prevalence of subclinical vitamin A deficiency. 4.6% migrated and 3.5% withdrew before the end of the treatment cycle. Morbidity surveillance was 96% and 97% in placebo and vitamin A group respectively. Less than 2% of the daily morbidity records were missing. Children were visited every other day for 6 cycles. The longest recall period allowed was 4 days. Observed child-days of ALRI of vitamin A group and control group were 280,186 and 273,630
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Unclear riskRandomisation procedure was described as "based on a table of random permutations of integers"
Allocation concealment?Unclear riskNot mentioned
Blinding?
All outcomes
Low riskAll investigator, field and laboratory staff, and participants were masked to the treatment code
Incomplete outcome data addressed?
All outcomes
High riskLess than 2% of the daily morbidity records were missing
Free of selective reporting?High riskNot all the pre-specified outcomes were reported
Free of other bias?Low riskThere were no significant differences between groups

Donnen 1998

MethodsRandomised, double-blind, placebo-controlled clinical trial
Participants900 children aged 0 to 72 months hospitalized in the Lwiro Pediatric Hospital for protein-energy malnutrition. Children were not eligible for inclusion in the study if they had been admitted to the hospital in a coma, if their parents or legal guardians had refused their participation, or if they had taken vitamin A capsules within the previous 4 months. Consecutively in the Lwiro Pediatric Hospital were included in the trial. The baselines of the 2 groups were comparable
Interventions1) The high-dose treatment group received 200,000 IU vitamin A (100,000 IU if aged < 12 months) orally on the day of admission and a placebo on every subsequent day during hospitalization
2) The low-dose treatment group received 5,000 IU vitamin A every day until discharge
3) The placebo group received a placebo every day during hospitalization
OutcomesIncidence of ALRI
NotesThis study was conducted in the health district of Katana, province of South Kivu in Congo, with population mainly poor farmers. Children were visited every day until they were discharged from the hospital. Protein-energy malnutrition reduces the absorption of vitamin A and synthesis and release of retinol binding protein, it always coexists with vitamin A deficiency. 73.9% to 78.5% of the study sample at baseline were found to have deficient serum retinol concentrations (< 0.35 mmol/L)
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Unclear riskOnly mentioned "randomly assigned"
Allocation concealment?Unclear riskNot mentioned
Blinding?
All outcomes
Low risk"Double-blind". Paediatrician was the only one with access to the allocation list
Incomplete outcome data addressed?
All outcomes
Low riskNo participants lost to follow up
Free of selective reporting?High riskNot all the pre-specified outcomes were reported
Free of other bias?Low riskThere were no significant differences between groups

Long 2006

MethodsRandomised, double-blind, placebo-controlled clinical trial. The randomisation sequence was generated by using a random-number table by project personnel. It was stratified allocation
Participants736 children aged 6 to 15 months living in a peri-urban area of Mexico City. 336 children were in vitamin A group and placebo group. The baseline of the participants was not significantly different between the 4 groups. Those who had diseases causing immuno-suppression, had digestive disease that alter the absorption of micronutrients and those who were taking vitamin supplements were excluded
InterventionsThey were assigned to 1 of 4 groups:
1) Vitamin A group that received 20,000 IU retinol every 2 months for children aged <= 1 year or 45,000 IU for children aged > 1 year
2) Zn group that received a daily dose equivalent to 20 mg elemental Zn as zinc methionine
3) A group that received both the zinc supplement and the vitamin A as above
4) A placebo group
OutcomesPrevalence of respiratory tract infections:
1) Cough alone
2) Cough and fever
3) Cough and rapid respiratory rate
NotesThis study was conducted in La Magdalena Atlicpac, Mexico. About 12% of the children there were classified as having a height-for-age z score below -2. Children were visited twice a week for 1 year. 93 children were lost to follow up or were excluded, 736 children were followed for 12 months (181 in the zinc group, 192 in the vitamin A + zinc group, 180 in the vitamin A group, and 183 in the placebo group). Child-year of follow up in vitamin A group and placebo group were 153.9 and 155.1. The loss to follow up in the vitamin A group and control group was 20 (10%) and 17 (8.5%) respectively. The sample size of 200 per children per group was estimated by assuming that the diarrhoeal disease rate was 3 episodes per child per year with a power of 80% and 95% significance level and an expected loss to follow up of 20%
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Unclear riskOnly mentioned "randomized trial"
Allocation concealment?Unclear riskNot mentioned
Blinding?
All outcomes
Low riskDouble-blind
Incomplete outcome data addressed?
All outcomes
High riskThe loss to follow up in the vitamin A group and control group were 20 (10%) and 17 (8.5%), respectively
Free of selective reporting?High riskNot all the pre-specified outcomes were reported
Free of other bias?Low riskThere were no significant differences between the groups

Rahman 2001

MethodsRandomised, parallel groups design, double-blind
Participants800 children aged 12 to 35 months
InterventionsChildren were randomized to receive 1 of 4 treatments: zinc, vitamin A, both zinc and vitamin A, or placebo
The zinc group received 5 ml zinc syrup (20 mg elemental zinc) daily for 14 days and a placebo capsule on day 14
The vitamin A group received 5 ml placebo syrup daily for 14 days and a 200,000 IU (60 mg) vitamin A capsule on day 14
The zinc plus vitamin A group received 5 ml zinc syrup daily for 14 days and a 200,000 IU vitamin A capsule on day 14
The placebo group received 5 ml placebo syrup daily for 14 days and a placebo capsule on day 14
OutcomesIncidence and prevalence of acute lower respiratory infection and diarrhoea
NotesThere were no significant differences between groups
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Unclear riskThere was no description about the method of randomisation for generating the allocation sequence
Allocation concealment?Low riskThe randomisation code was kept sealed until the completion of the study
Blinding?
All outcomes
Low riskDouble-blind
Incomplete outcome data addressed?
All outcomes
High risk135 (17%) were excluded from the study or dropped out. Of these 135 children, 85 (11% of total) were excluded because they had received vitamin A after enrolment during the “National vitamin A week” campaign in Bangladesh.
49 (6%) children were lost to follow up or had fewer than 90 days of observation period, and one child was excluded owing to a complicated illness
Free of selective reporting?High riskNot all the pre-specified outcomes were reported
Free of other bias?Unclear riskThere were no significant differences between the groups

Rahmathullah 1991

MethodsThe article stated it was a randomized, controlled, masked clinical trial. Due to varied population density in the area where this study took place, the researchers used a cluster-sampling design. 206 clusters were formed, and the majority of them consisted of 50 to 100 children 6 to 60 month of age. The article did not state clearly how the clusters were randomly assigned to the control or vitamin A group
Participants15,419 children 6 to 60 months of age were included in the study. The baseline of the 2 groups was comparable on the following characteristics: age and sex, 1-month history of diarrhoea and respiratory disease, anthropometric indexes of nutritional status, xerophthalmia status, 5-year retrospective history of mortality of children under 5, household economic, household hygienic status, and serum retinol levels. Exclusion for analysis: receiving a high-dose supplement of vitamin A because of xerophthalmia at baseline, midterm, or final examination (n = 2687); missing receiving the supplement for > 7 consecutive weeks or for > 4 weeks on four occasions (n = 1874).
InterventionsHalf the children received weekly doses of 8333 IU vitamin A and 20 mg vitamin E (treated) and 20 mg vitamin E the other half (control). Any children diagnosed with xerophthalmia at baseline, midterm, or final examination was given a high-dose (60,000 ug) supplement of vitamin A and continued in their study
OutcomesIncidence of lower respiratory tract infections
NotesSetting: the study was carried out in 3 drought-prone Panchayat Unions, which are poor in economy and environment, of the Trichy district of Tamil Nadu in southern India. Children were visited once a week for 52 weeks. All morbidity data were analysed both without exclusion (N = 15,419, intention-to treat analysis) and with exclusion (N = 10858). The article stated that no significant changes in RR occurred when each of the exclusions was applied. The data presented in the article were based on an intention-to-treat analysis. On average > 90% of the children were contacted each week, and the lowest coverage in any single week was 88%. 11% had clinical evidence of xerophthalmia while about 38% had serum retinol concentrations <= 0.35 mmol/L at baseline
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Unclear riskOnly mentioned "randomized"
Allocation concealment?Unclear riskNot mentioned
Blinding?
All outcomes
Low riskOnly mentioned "masked"
Incomplete outcome data addressed?
All outcomes
High riskOn average > 90% of the children were contacted each week, and the lowest coverage in any single week was 88%
Free of selective reporting?High riskNot all the pre-specified outcomes were reported
Free of other bias?Low riskThere were no significant differences between groups

Sempertegui 1999

MethodsA randomized, placebo-controlled, double-blind trial. Identical flasks containing vitamin A or placebo were numbered from 1 to 400 by members of the study team in Boston, Massachusetts. The local Ethical Committee of the Ecuadorian Biotechnology Corporation in Quito did not know the identity of the active or placebo flasks, because they did not have the code. Then, this committee assigned each flask to a specific child from a random list by using a table of random numbers. After randomisation, the ethical committee received the confidential code from Boston and kept it for the remainder of the study, when it was revealed
ParticipantsAll study participants were children 6 to 36 months of age living in the neighbourhood. All children (N = 613) between 6 to 36 months of age were considered eligible. Age was verified through birth certificates. To decrease the drop-out rate, the researchers selected those children who reliably stayed at home or at day care centres during weekdays (N = 525), and then they excluded children whose families had lived in the neighbourhood for < 1 year (N = 60). Children who had been given multivitamins in the last 3 months also were excluded (N = 6). A total of 459 children were available for entry into the study. These children were examined by an ophthalmologist for signs of xerophthalmia. No cases of xerophthalmia were found. Finally, 400 children completing the basal anthropometric test were included. The baselines of the 2wo groups were comparable
InterventionsChildren in the supplement-treated group received a weekly dose of 10,000 IU of vitamin A (3000 mg of retinol) for 40 weeks, and children in the non-supplement group received a weekly placebo for the same period
OutcomesThe incidence of ALRI: defined as tachypnea (respiratory rate 40 /min) and/ or lower respiratory tract secretions (alveolar or bronchoalveolar) assessed by thoracic auscultation with 1 or more of the following symptoms: cough, fever and chest retractions
NotesThis study was conducted in the northwestern region of the Quito, Ecuador, which represented most Ecuadorian high Andean slums with substantial rates of malnutrition and subclinical vitamin A deficiency. Children were visited weekly. The total person-time of follow up of vitamin A group and control group was 5719 child-weeks and 5707 child-weeks. The researchers assumed that the incidence of diarrhoeal disease in this area was 46 episodes per 1000 child-weeks. The sample sizes of 200 children per group were based on detecting a 25% reduction in the incidence of diarrhoea with 80% power and 2-tailed 0.05 significance, and it allowed for 30% annual drop-out. The reported yearly incidence of acute respiratory tract infections is similar to that of acute diarrhoeal, so the researchers inferred that this sample sizes of 200 children in each group were likely to be sufficient
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Low riskAllocation sequence was generated by using a random number table
Allocation concealment?Low riskThe ethics committee received the confidential code and kept it for the remainder of the study until it was revealed
Blinding?
All outcomes
Low riskDouble-blind
Incomplete outcome data addressed?
All outcomes
High risk50 children from the supplement-treated group and 44 from the non-supplement group were lost to follow up
Free of selective reporting?High riskNot all the pre-specified outcomes were reported
Free of other bias?Low riskThere were no significant differences between groups

Stansfield 1993

MethodsA randomized, placebo-controlled, double-blind trial
Participants11,124 children aged 6 to 83 months. Those with corneal changes consistent with vitamin A deficiency, with measles and those had received vitamin A within the past 4 months were excluded. The baseline of the 2 groups was comparable
InterventionsThe vitamin A group received 100,000 IU supplements every 4 months for 3 distribution cycle for those 6 to 11 months and 200,000 IU for the older, while the other group only received placebo
Outcomes2 week prevalence of signs of respiratory tract infections: cold, cough and rapid breathing
NotesThis study was conducted at north west of Haiti with a high prevalence of malnutrition and xerophthalmia. 72% (7958) of total 11,124 participants received at least 2 doses, and 38% (4178) received 3 doses. Children were visited every 2 weeks for 12 months
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Unclear riskOnly mentioned "random"
Allocation concealment?Unclear riskNot mentioned
Blinding?
All outcomes
Low riskDouble-blind
Incomplete outcome data addressed?
All outcomes
Unclear riskNot mentioned
Free of selective reporting?High riskNot all the pre-specified outcomes were reported
Free of other bias?Low riskThere were no significant differences between groups

VAST 1993

  1. a

    ALRI: acute lower respiratory infection
    IU: international units
    SD: standard deviation
    WHO: World Health Organization

MethodsRandomised double-blind controlled trial. Randomisation was by individuals in the Health Study
ParticipantsThe Health Study included 1455 children aged 6 to 59 months. Inclusion: children 6 to 59 months. Children born from 1986 were included in the Health Study. Excluded: children with active xerophthalmia or measles were excluded from the trial as soon as they were confirmed
InterventionsChildren were randomly assigned either 200,000 IU retinol equivalent (100,000 IU under 12 months) or placebo every 4 months
OutcomesMean daily prevalence of sighs of lower respiratory tract infections:
1) daytime cough
2) tired ribs (severe respiratory illness)
3) difficulty in breathing
4) rapid breathing
NotesThis study was conducted in guinea savannah area of Ghana with a sub-Sahelian climate. The study populations were rural and their main staple foods are deficient in carotenoids and vitamin A. Vitamin A deficiency and xerophthalmia were recognised as problems locally. Children were visited weekly for 1 year. 1455 children in the Health Study were followed up for 1185 child-years (596 for vitamin A group and 589 for control group), of whom, 1287 (88.5%) survived, 26 (1.8%) died, 14 (1.0%) developed measles, 4 (0.3%) withdrew consent, and 119 (8.2%) were lost to follow up
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Unclear riskRandomisation was carried out by an independent statistician
Allocation concealment?Low riskThe randomisation code was kept by an independent statistician
Blinding?
All outcomes
Low riskTriple-blinded
Incomplete outcome data addressed?
All outcomes
Low risk14 (1.0%) developed measles, 4 (0.3%) withdrew consent, and 119 (8.2%) were lost to follow up
Free of selective reporting?High riskNot all the pre-specified outcomes were reported
Free of other bias?Low riskThere were no significant differences between groups

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    ARI: acute respiratory tract infection
    ALRI: acute lower respiratory tract infection
    LRTI: lower respiratory tract infection

An 2000Random allocation mentioned, but trial authors allocated participants
Biswas 1994Discussed the prevention of ARI but not LRTIs
Chang 2006Included children aged < 11 years hospitalized with 215 ALRI episodes
Cherian 2001The trial focused on recurrent respiratory infections, not preventing ALRI
Chowdhury 2002Included children aged < 10 years
Coutsoudis 1991The participants had measles-related pneumonia
Coutsoudis 1995The participants were HIV positive
Coutsoudis 2000This study focused on low birth weight neonates, and should be included in another Cochrane Review (Brian 2007)
Daulaire 1992Did not discuss the preventative effect of vitamin A on LRTIs
Dudley 1997Did not discuss the preventative effect of vitamin A on LRTIs
Fawzi 1998Did not discuss the preventative effect of vitamin A on LRTIs
Fawzi 1999The participants involved had HIV infection
Fawzi 2000The participants involved had HIV infection
Fawzi 2003The participants involved had HIV infection
Hussey 1990The participants had measles-related pneumonia
Jiang 2009aDiscussed the treatment but not prevention
Jiang 2009bDiscussed the prevention of diarrhoea following pneumonia
Jin 2003The inventions used were vitamin A with other supplementation versus placebo
Julien 1999Discussed the prevention of ARIs but not LRTIs
Kao 1996Random allocation mentioned, but trial authors allocated participants
Kartasasmita 1995Discussed the prevention of ARI but not LRTIs
Kjolhede 1995The research was not about LRTIs
Li 2005Random allocation mentioned, but trial authors allocated participants
Liang 2005Random allocation mentioned, but trial authors allocated participants
Liu 2003Random allocation mentioned, but trial authors allocated participants
Liu 2004Interventions included vitamin A with other supplementation but not vitamin A alone
Lu 2000Interventions included vitamin A with other supplementation but not vitamin A alone
Ma 1998Interventions included vitamin A with other supplementation but not vitamin A alone
Ma 2003Interventions included vitamin A with other supplementation but not vitamin A alone
Mahalanabis 2002Involved treatment not prevention of LRTIs
Mahalanabis 2004Involved treatment not prevention of LRTIs
Nacul 1997Prevention of LRTIs with vitamin A not discussed
Nacul 1998The study dealt with vitamin A supplementation for ARI and subsequent follow up in terms of recurrence of symptoms
Ogaro 1993Participants involved complicated with measles infection
Quinlan 1996Prevention of LRTIs with vitamin A not discussed
Rahman 1996Discussed the prevention of ARI but not LRTIs
Rodriguez 2005Discussed treatment, not preventing LRTIs
Rosales 1994Prevention of LRTIs with vitamin A not discussed
Rosales 1996The participants had measles-related pneumonia
Rosales 2002The participants had measles-related pneumonia
Si 1997Prevention of LRTIs with vitamin A not discussed
Song 2000The interventions included vitamin A with other supplementation but not vitamin A alone
Stephensen 1998Prevention of LRTIs with vitamin A not discussed
Tan 2002Random allocation mentioned, but participants actually allocated optionally by the authors (confirmed by telephoning the author)
Venkatarao 1996Discussed the prevention of ARI but not LRTIs
Vijayaraghavan 1990Discussed the prevention of ARI but not LRTIs
Villamor 2002Participants involved also had HIV infections
Villamor 2005Participants involved also had HIV infections
Wang 1993Random allocation mentioned, but trial authors allocated participants
Wang 1995Random allocation mentioned, but trial authors allocated participants
Wang 1997Not blinded
Wang 1999Random allocation mentioned, but trial authors allocated participants
Yan 1992Random allocation mentioned, but trial authors allocated participants
Yang 1995Random allocation mentioned, but trial authors allocated participants
Yang 2003The interventions included vitamin A with other supplementation but not vitamin A alone
Yang 2005Random allocation mentioned, but trial authors allocated participants
Zar 2003Participants with HIV infection were included
Zhang 1997Random allocation mentioned, but trial authors allocated participants
Zhang 1999Discussed the combined effect of vitamin A with other supplementation
Zhang 2000Interventions included vitamin A with other supplementation but not vitamin A alone
Zhang 2002Interventions included vitamin A with other supplementation but not vitamin A alone

Characteristics of studies awaiting assessment [ordered by study ID]

Donnen 2007

MethodsRandomised, double-blind controlled trial
Participants604 and 610 Senegalese hospitalized children
InterventionsA high-dose vitamin A supplement (200,000 IU) on admission, the second a daily low-dose vitamin A supplement (5000 IU daily) during hospitalization
OutcomesSurvival, incidence of respiratory disease, duration of respiratory infection, duration and incidence of diarrhoea, mortality
Notes 

Long 2007

MethodsRandomised controlled trial
ParticipantsA total of 188 children, aged 6 to 15 months, from peri-urban, marginalised communities of Mexico City
InterventionsVitamin A or placebo
OutcomesThe incidence and duration of respiratory tract infections
Notes 

Swami 2007

  1. a

    ARI: acute respiratory infection
    IU: international units

MethodsRandomised controlled trial
Participants27,642 (98.7%) and 31,762 (88.0%) children were included respectively in Chandigarh. A random sample of 276 children from the intervention area and 252 children from control area in the age group of 1 to 5 years were followed
InterventionsMass supplementation of vitamin A solution
OutcomesThe average annual episodes of ARI
Notes 

Ancillary