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

  1. Hengxi Chen2,
  2. Qi Zhuo3,
  3. Wei Yuan3,
  4. Juan Wang3,
  5. Taixiang Wu1,*

Editorial Group: Cochrane Acute Respiratory Infections Group

Published Online: 17 FEB 2010

Assessed as up-to-date: 29 JUN 2010

DOI: 10.1002/14651858.CD006090.pub2

Database Title

Additional Information

How to Cite

Chen H, Zhuo Q, Yuan W, Wang J, Wu T. Vitamin A for preventing acute lower respiratory tract infections in children up to seven years of age. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD006090. DOI: 10.1002/14651858.CD006090.pub2.

Author Information

  1. 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

  2. 2

    West China Second University Hospital, West China Women's and Children's Hospital, Department of Obstetrics and Gynecology, Chengdu, Sichuan, China

  3. 3

    West China Hospital, Sichuan University, 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.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 17 FEB 2010

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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).

 FigureFigure 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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification.

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.

 FigureFigure 2. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
 FigureFigure 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.

 FigureFigure 4.
 FigureFigure 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).

 
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).

 

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.

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.

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).

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.

 

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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).

 FigureFigure 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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
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 trials3Incidence of ALRI (Random, 95% CI)Subtotals only
    1.1 Age <= 5
3Incidence of ALRI (Random, 95% CI)1.13 [0.88, 1.43]
    1.2 Mega dose
2Incidence of ALRI (Random, 95% CI)1.13 [0.80, 1.60]
    1.3 Low dosage
1Incidence of ALRI (Random, 95% CI)1.16 [0.77, 1.76]
    1.4 Under weight
1Incidence of ALRI (Random, 95% CI)0.38 [0.17, 0.85]
    1.5 Stunted
1Incidence of ALRI (Random, 95% CI)0.48 [0.21, 1.12]
    1.6 Normal
1Incidence of ALRI (Random, 95% CI)2.22 [1.25, 3.95]
 2 Prevalence of symptoms of acute LRTI1Prevalence (Random, 95% CI)Totals not selected
    2.1 Overall cough
1Prevalence (Random, 95% CI)Not estimable
    2.2 Cough with difficulty in breathing
1Prevalence (Random, 95% CI)Not estimable
    2.3 Cough with fever
1Prevalence (Random, 95% CI)Not estimable

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Last assessed as up-to-date: 29 June 2010.

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract摘要Résumé
  3. 1 Background
  4. 2 Objectives
  5. 3 Methods
  6. 4 Results
  7. 5 Discussion
  8. 6 Authors' conclusions
  9. 7 Acknowledgements
  10. 8 Data and analyses
  11. 9 Appendices
  12. 10 What's new
  13. 11 History
  14. 12 Contributions of authors
  15. 13 Declarations of interest
  16. 14 Sources of support
  17. 15 Differences between protocol and review
  18. 16 Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. Additional references
  23. References to other published versions of this review
Barreto 1994 {published data only}
  • Barreto ML, Santos LM, Assis AM, Araujo MP, Farenzena GG, Santos PA, et al. Effect of vitamin A supplementation on diarrhoea and acute lower-respiratory-tract infections in young children in Brazil. Lancet 1994;344(8917):228-31.
Bhandari 1994 {published data only}
  • Bhandari N, Bhan MK, Sazawal S. Impact of massive dose of vitamin A given to preschool children with acute diarrhoea on subsequent respiratory and diarrhoeal morbidity. BMJ 1994;309(6966):1404-7.
Dibley 1996 {published data only}
  • Dibley MJ, Sadjimin T, Kjolhede CL, Moulton LH. Vitamin A supplementation fails to reduce incidence of acute respiratory illness and diarrhea in preschool-age Indonesian children. Journal of Nutrition 1996;126(2):434-42.
Donnen 1998 {published data only}
  • Donnen P, Dramaix M, Brasseur D, Bitwe R, Vertongen F, Hennart P. Randomized placebo-controlled clinical trial of the effect of a single high dose or daily low doses of vitamin A on the morbidity of hospitalised, malnourished children. American Journal of Clinical Nutrition 1998;68(8):1254-60.
Long 2006 {published data only}
  • Long KZ, Montoya Y, Hertzmark E, Santos JI, Rosado JL. A double-blind, randomised, clinical trial of the effect of vitamin A and zinc supplementation on diarrheal disease and respiratory tract infections in children in Mexico City, Mexico. American Journal of Clinical Nutrition 2006;83(3):693-700.
Rahman 2001 {published data only}
  • Rahman MM, Vermund SH, Wahed MA, Fuchs GJ, Baqui AH, Alvarez JO. Simultaneous zinc and vitamin A supplementation in Bangladeshi children: randomised double blind controlled trial. BMJ 2001;323(7308):314-8.
Rahmathullah 1991 {published data only}
  • Rahmathullah L, Underwood BA, Thulasiraj RD, Milton RC. Diarrhea, respiratory infections, and growth are not affected by a weekly low-dose vitamin A supplement: a masked, controlled field trial in children in southern India. American Journal of Clinical Nutrition 1991;53(3):568-77.
Sempertegui 1999 {published data only}
  • Sempertegui F, Estrella B, Camaniero V, Betancourt V, Izurieta R, Ortiz W, et al. The beneficial effects of weekly low-dose vitamin A supplementation on acute lower respiratory infections and diarrhea in Ecuadorian children. Pediatrics 1999;104(1):e1.
Stansfield 1993 {published data only}
  • Stansfield SK, Pierre-Louis M, Lerebours G, Augustin A. Vitamin A supplementation and increased prevalence of childhood diarrhoea and acute respiratory infections. Lancet. 1993;342(8871):578-82.
VAST 1993 {published data only}

References to studies excluded from this review

  1. Top of page
  2. Abstract摘要Résumé
  3. 1 Background
  4. 2 Objectives
  5. 3 Methods
  6. 4 Results
  7. 5 Discussion
  8. 6 Authors' conclusions
  9. 7 Acknowledgements
  10. 8 Data and analyses
  11. 9 Appendices
  12. 10 What's new
  13. 11 History
  14. 12 Contributions of authors
  15. 13 Declarations of interest
  16. 14 Sources of support
  17. 15 Differences between protocol and review
  18. 16 Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. Additional references
  23. References to other published versions of this review
An 2000 {published data only}
  • An HP, Zhang HM, Li FG. 55 case of vitamin A in preventing and treating repeated respiratory tract infections. Journal of Applied Clinical Pediatrics 2000;15(1):49.
Biswas 1994 {published data only}
  • Biswas R, Biswas AB, Manna B, Bhattacharya SK, Dey R, Sarkar S. Effect of vitamin A supplementation on diarrhoea and acute respiratory tract infection in children. A double blind placebo controlled trial in a Calcutta slum community. European Journal of Epidemiology 1994;10(1):57-61.
Chang 2006 {published data only}
  • Chang AB, Torzillo PJ, Boyce NC, White AV, Stewart PM, Wheaton GR, et al. Zinc and vitamin A supplementation in Indigenous Australian children hospitalised with lower respiratory tract infection: a randomised controlled trial. Medical Journal of Australia 2006;184(3):107-12.
Cherian 2001 {published data only}
  • Cherian T, Ranjini EK, Balasubramaniam KA, Raghupati P. Vitamin A supplementation in children with recurrent respiratory infections. Indian Pediatrics 2001;38(7):771-5.
Chowdhury 2002 {published data only}
  • Chowdhury S, Kumar R, Ganguly NK, Kumar L, Walia BN. Effect of vitamin A supplementation on childhood morbidity and mortality. Indian Journal of Medical Sciences 2002;56(6):259-64.
Coutsoudis 1991 {published data only}
  • Coutsoudis A, Broughton M, Coovadia HM. Vitamin A supplementation reduces measles morbidity in young African children: a randomised, placebo-controlled, double-blind trial. American Journal of Clinical Nutrition 1991;54(5):890-5.
Coutsoudis 1995 {published data only}
  • Coutsoudis A, Bobat RA, Coovadia HM, Kuhn L, Tsai WY, Stein ZA. The effects of vitamin A supplementation on the morbidity of children born to HIV-infected women. American Journal of Public Health 1995;85(8 pt 1):1076-82.
Coutsoudis 2000 {published data only}
  • Coutsoudis A, Adhikari M, Pillay K, Kuhn L, Coovadia HM. Effect of vitamin A supplementation on morbidity of low-birth-weight neonates. South African Medical Journal 2000;90(7):730-6.
Daulaire 1992 {published data only}
Dudley 1997 {published data only}
  • Dudley L, Hussey G, Huskissen J, Kessow G. Vitamin A status, other risk factors and acute respiratory infection morbidity in children. South African Medical Journal 1997;87(1):65-70.
Fawzi 1998 {published data only}
  • Fawzi WW, Mbise RL, Fataki MR, Herrera MG, Kawau F, Hertzmark E, et al. Vitamin A supplementation and severity of pneumonia in children admitted to the hospital in Dar es Salaam, Tanzania. American Journal of Clinical Nutrition 1998;68(1):187-92.
Fawzi 1999 {published data only}
  • Fawzi WW, Mbise RL, Hertzmark E, Fataki MR, Herrera MG, Ndossi G, et al. A randomized trial of vitamin A supplements in relation to mortality among human immunodeficiency virus-infected and uninfected children in Tanzania. Pediatric Infectious Disease Journal 1999;18(2):127-33.
Fawzi 2000 {published data only}
  • Fawzi WW, Mbise R, Spiegelman D, Fataki M, Hertzmark E, Ndossi G. Vitamin A supplements and diarrhea and respiratory tract infections among children in Dar es Salaam, Tanzania. Journal of Pediatrics 2000;137(5):660-6.
Fawzi 2003 {published data only}
  • Fawzi WW, Msamanga GI, Wei R, Spiegelman D, Antelman G, Villamor E, et al. Effect of providing vitamin supplements to human immunodeficiency virus-infected, lactating mothers on the child's morbidity and CD4+ cell counts. Clinical Infectious Diseases 2003;36(8):1053-62.
Hussey 1990 {published data only}
Jiang 2009a {published data only}
  • Jiang W, Fang CX, Qu P, Liu X, Chen K, Huang HM, et al. Oral supplementation of vitamin A and E, zinc, selenite for neonates with pneumonia: a randomised placebo-controlled clinical trial of 150 cases. Acta Academiae Medicinae Militaris Tertiae 2009;31(5):450-3.
Jiang 2009b {published data only}
  • Jiang CX, Chen ZQ, Wang H, Jin JM. Study of micro-ecological preparations for preventing diarrhea secondary to pneumonia in children. Modern Journal of Integrated Traditional Chinese and Western Medicine 2009;18(20):2370-5.
Jin 2003 {published data only}
  • Jin H, Zhao TQ. Observation of the effect of Zn and vitamin A in preventing and treating recurrent respiratory tract infections in infants and children. Chinese Medical Journal of Metallurgical Industry 2003;20(4):308-9.
Julien 1999 {published data only}
  • Julien MR, Gomes A, Varandas L, Rodrigues P, Malveiro F, Aguiar P, et al. A randomized, double-blind, placebo-controlled clinical trial of vitamin A in Mozambican children hospitalized with nonmeasles acute lower respiratory tract infections. Tropical Medicine & International Health 1999;4(12):794-800.
    Direct Link:
Kao 1996 {published data only}
  • Kao Y, Yu XL, Li ZY. Observation of the effect of vitamin A as a complementary supplement for treating pneumonia in children. Zhejiang Journal of Preventive Medicine 1996;8(6):39-40.
Kartasasmita 1995 {published data only}
  • Kartasasmita C, Rosmayudi O, Demedts M, The Respiratory Diseases Working Group. Plasma retinol level, vitamin A supplementation and acute respiratory infections in children of 1-5 years old in a developing country. Tubercle and Lung Disease 1995;76(6):563-9.
Kjolhede 1995 {published data only}
Li 2005 {published data only}
  • Li YH. Evaluation of the effect of vitamin A in preventing and treating recurrent respiratory tract infections. Journal of Zhonghua Modern Paediatics 2005;2(6):541-2.
Liang 2005 {published data only}
  • Liang SY. Observation of the effect of vitamin A in preventing and treating recurrent respiratory tract infections in children. Zhonghua Clinic Medicine Research Magazine 2005;10(102):3245-6.
Liu 2003 {published data only}
  • Liu BX, Wen HY, Cao LW. 30 case of vitamin A for preventing and treating recurrent respiratory tract infections in children. Chinese Medicine of Factory and Mines 2003;16(3):207-8.
Liu 2004 {published data only}
  • Liu YL, Yang XQ, Wang LJ, Jiang LP. Clinical study on bacille calmette-guerin alone or combined with interferon gamma and vitamin A in preventing asthma children after bronchiolitis. Journal of Applied Clinical Pediatrics 2004;19(6):441-3.
Lu 2000 {published data only}
  • Lu ZX, Yang CX. Analysis of the effect of levamisol vitamin AD and vitamin E in preventing the recurrent respiratory tract infections. Journal of Huaihai Medicine 2000;18(3):230-1.
Ma 1998 {published data only}
  • Ma TF, Yang JC. Prevention of repeated infantile respiratory infection with vitamin A and zinc gluconate. Medical Journal of National Defending Forces in Southwest China 1998;8(2):92-3.
Ma 2003 {published data only}
  • Ma LZ, He ZQ. Observation of the effect of thymosin and vitamin A in preventing and treating the recurrent respiratory tract infections. Guangdong Medicine 2003;24(10):1128-9.
Mahalanabis 2002 {published data only}
  • Mahalanabis D, Chowdhury A, Jana S, Bhattacharya MK, Chakrabarti MK, Wahed MA, et al. Zinc supplementation as adjunct therapy in children with measles accompanied by pneumonia: a double-blind, randomised controlled trial. American Journal of Clinical Nutrition 2002;76(3):604-7.
Mahalanabis 2004 {published data only}
  • Mahalanabis D, Lahiri M, Paul D, Gupta S, Gupta A, Wahed MA, et al. Randomized, double-blind, placebo-controlled clinical trial of the efficacy of treatment with zinc or vitamin A in infants and young children with severe acute lower respiratory infection. American Journal of Clinical Nutrition 2004;79(3):430-6.
Nacul 1997 {published data only}
  • Nacul LC, Kirkwood BR, Arthur P, Morris SS, Magalhaes M, Fink MC. Randomised, double blind, placebo controlled clinical trial of efficacy of vitamin A treatment in non-measles childhood pneumonia. BMJ 1997;315(7107):505-10.
Nacul 1998 {published data only}
  • Nacul LC, Arthur P, Kirkwood BR, Morris SS, Cameiro AC, Benjamin AF. The impact of vitamin A supplementation given during a pneumonia episode on the subsequent morbidity of children. Tropical Medicine & International Health 1998;3(8):661-6.
    Direct Link:
Ogaro 1993 {published data only}
  • Ogaro FO, Orinda VA, Onyango FE, Black RE. Effect of vitamin A on diarrhoeal and respiratory complications of measles. Tropical and Geographical Medicine 1993;45(6):283-6.
Quinlan 1996 {published data only}
Rahman 1996 {published data only}
  • Rahman MM, Mahalanabis D, Alvarez JO, Wahed MA, Islam MA, Habte D, et al. Acute respiratory infections prevent improvement of vitamin A status in young infants supplemented with vitamin A. Journal of Nutrition 1996;126(3):628-33.
Rodriguez 2005 {published data only}
  • Rodriguez A, Hamer DH, Rivera J, Acosta M, Salgado G, Gordillo M, et al. Effects of moderate doses of vitamin A as an adjunct to the treatment of pneumonia in underweight and normal-weight children: a randomised, double-blind, placebo-controlled trial. American Journal of Clinical Nutrition 2005;82(5):1090-6.
Rosales 1994 {published data only}
  • Rosales FJ, Kjolhede C. A single 210-mumol oral dose of retinol does not enhance the immune response in children with measles. Journal of Nutrition 1994;124(9):1604-14.
Rosales 1996 {published data only}
  • Rosales FJ, Kjolhede C, Goodman S. Efficacy of a single oral dose of 200,000 IU of oil-soluble vitamin A in measles-associated morbidity. American Journal of Epidemiology 1996;143(5):413-22.
Rosales 2002 {published data only}
  • Rosales FJ. Vitamin A supplementation of vitamin a deficient measles patients lowers the risk of measles-related pneumonia in Zambian children. Journal of Nutrition 2002;132(12):3700-3.
Si 1997 {published data only}
  • Si NV, Grytter C, Vy NN, Hue NB, Pedersen FK. High dose vitamin A supplementation in the course of pneumonia in Vietnamese children. Archives of Pediatrics 1997;86(10):1052-5.
Song 2000 {published data only}
  • Song JH, Zhao AP. 50 case of Zingaite with vitamin A in preventing the respiratory tract infections. Guiding Journal of Medicine 2000;19(2):161.
Stephensen 1998 {published data only}
  • Stephensen CB, Franchi LM, Hernandez H, Campos M, Gilman RH, Alvarez JO. Adverse effects of high-dose vitamin A supplements in children hospitalized with pneumonia. Pediatrics 1998;101(5):e3.
Tan 2002 {published data only}
  • Tan CW, Wu GC, Zhou XY, Sun JP, Jiang JX, Pan H, et al. Vitamin A of prevention and assist treatment to children with diarrhea and pneumonia. Journal of Applied Clinical Pediatrics 2002;17(1):54-5.
Venkatarao 1996 {published data only}
  • Venkatarao T, Ramakrishnan R, Nair NG, Radhakrishnan S, Sundaramoorthy L, Koya PK, et al. Effect of vitamin A supplementation to mother and infant on morbidity in infancy. Indian Pediatrics 1996;33(4):279-86.
Vijayaraghavan 1990 {published data only}
Villamor 2002 {published data only}
  • Villamor E, Mbise R, Spiegelman D, Hertzmark E, Fataki M, Peterson KE. Vitamin A supplements ameliorate the adverse effect of HIV-1, malaria, and diarrheal infections on child growth. Pediatrics 2002;109(1):e6.
Villamor 2005 {published data only}
  • Villamor E, Saathoff E, Manji K, Msamanga G, Hunter DJ, Fawzi WW. Vitamin supplements, socioeconomic status, and morbidity events as predictors of wasting in HIV-infected women from Tanzania. American Journal of Clinical Nutrition 2005;82(4):857-65.
Wang 1993 {published data only}
  • Wang ZY. Observation of the effect of vitamin A in preventing the recurrent respiratory tract infections in children. Journal of Changzhi Medical College 1993;7(4):443-4.
Wang 1995 {published data only}
  • Wang ZY, Qin XQ, Zhang LL. Observation of effect of vitamin A in preventing recurrent respiratory tract infections. Journal of Clinical Pediatrics 1995;13(1):68-9.
Wang 1997 {published data only}
  • Wang L, Ruan LL. Observation of the effect of vitamin A in preventing and treating repeated respiratory tract infections in children. Zejiang Medicine 1997;19(1):53.
Wang 1999 {published data only}
  • Wang ZX, Jiang XY. Observation of the effect of vitamin A in preventing the recurrent respiratory tract infections in 60 case. Journal of Linyi Medical College 1999;21(3):239-40.
Yan 1992 {published data only}
  • Yan HC. Evaluation of effect of vitamin A supplement in preventing diarrhea and respiratory tract infectious disease in children. Health Research 1992;21(6):308-10.
Yang 1995 {published data only}
  • Yang P, Li XY. Discuss of the effect of oral small dosage of vitamin A in preventing respiratory tract infections in children. Hebei Journal of Integrated Chinese Traditional and Western Medicine 1995;4(2):15.
Yang 2003 {published data only}
  • Yang LL, Wu GY, Li DK. Observation of the effect of thymosin and vitamin A in preventing the recurrent respiratory tract infections. Journal of Chinese Physician 2003;5(9):1281-2.
Yang 2005 {published data only}
  • Yang LQ. Observation of the effect of vitamin A in preventing recurrent respiratory tract infections in children. Shiyong Pharmacy and Clinical Remedies 2005;8(4):39-40.
Zar 2003 {published data only}
  • Zar HJ. Prevention of HIV-associated respiratory illness in children in developing countries: potential benefits. International Journal of Tuberculosis and Lung Disease 2003;7(9):820-7.
Zhang 1997 {published data only}
  • Zhang JH, Qian YQ, Zhen DY. The study of the effects of massive dose vitamin A intervention to recurrent respiratory infection. Acta Nutrimenta Sinica 1997;19(3):283-6.
Zhang 1999 {published data only}
  • Zhang WX. Traditional Chinese Medicine and Western Medicine in preventing recurrent respiratory tract infections in children. Journal of Bengbu Medical College 1999;24(6):465-6.
Zhang 2000 {published data only}
  • Zhang J, Zhang M. Clinical study on preventing recurrent respiratory tract infections (RRTI) with both vitamin A and 21-SUPER-VITA. Journal of International Zhonghua Clinic Medicine 2000;1(2):92-3.
Zhang 2002 {published data only}
  • Zhang HT, Sun ZZ. Observation of 46 case of vitamin AD for preventing respiratory tract infections in children. Chinese Journal of Coal Industry Medicine 2002;5(9):948-9.

References to studies awaiting assessment

  1. Top of page
  2. Abstract摘要Résumé
  3. 1 Background
  4. 2 Objectives
  5. 3 Methods
  6. 4 Results
  7. 5 Discussion
  8. 6 Authors' conclusions
  9. 7 Acknowledgements
  10. 8 Data and analyses
  11. 9 Appendices
  12. 10 What's new
  13. 11 History
  14. 12 Contributions of authors
  15. 13 Declarations of interest
  16. 14 Sources of support
  17. 15 Differences between protocol and review
  18. 16 Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. Additional references
  23. References to other published versions of this review
Donnen 2007 {published data only}
  • Donnen P, Sylla A, Dramaix M, Sall G, Kuakuvi N, Hennart P. Effect of daily low dose of vitamin A compared with single high dose on morbidity and mortality of hospitalised mainly malnourished children in Senegal: a randomised controlled clinical trial. European Journal of Clinical Nutrition 2007;61(12):1393-9.
Long 2007 {published data only}
  • Long KZ, Rosado JL, DuPont HL, Hertzmark E, Santos JI. Supplementation with vitamin A reduces watery diarrhoea and respiratory infections in Mexican children. British Journal of Nutrition 2007;97(2):337-43.
Swami 2007 {published data only}

Additional references

  1. Top of page
  2. Abstract摘要Résumé
  3. 1 Background
  4. 2 Objectives
  5. 3 Methods
  6. 4 Results
  7. 5 Discussion
  8. 6 Authors' conclusions
  9. 7 Acknowledgements
  10. 8 Data and analyses
  11. 9 Appendices
  12. 10 What's new
  13. 11 History
  14. 12 Contributions of authors
  15. 13 Declarations of interest
  16. 14 Sources of support
  17. 15 Differences between protocol and review
  18. 16 Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. References to studies awaiting assessment
  22. Additional references
  23. References to other published versions of this review
Ballow 1996
Bhandari 2002
  • Bhandari N, Bahl R, Taneja S, Strand T, Molbak K, Ulvik RJ, et al. Effect of routine zinc supplementation on pneumonia in children aged 6 months to 3 years: randomised controlled trial in an urban slum. BMJ 2002;324(7350):1358.
Bjersing 2002
Bonten 2003
Brian 2007
  • Darlow BA, Graham PJ. Vitamin A supplementation to prevent mortality and short and long-term morbidity in very low birthweight infants. Cochrane Database of Systematic Reviews 2007, Issue 4. [DOI: ]
Dickersin 1994
Friedman 1989
Friedman 1991
  • Friedman A, Meidovsky A, Leitner G, Sklan D. Decreased resistance and immune response to Escherichia coli infection in chicks with low or high intakes of vitamin A. Journal of Nutrition 1991;121:395-400.
Grotto 2003
  • Grotto I, Mimouni M, Gdalevich M, Mimouni D. Vitamin A supplementation and childhood morbidity from diarrhea and respiratory infections: a meta-analysis. Journal of Pediatrics 2003;142(3):297-304.
Haq 1991
  • Haq R, Haiti M, Chytil F. Retinoic acid affects the expression of nuclear retinoic acid receptors in tissues of retinol-deficient rats. Proceedings of the National Academy of Sciences of the United States of America 1991;88(18):8272-6.
Hemila 2004
Higgins 2009
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Lefebvre 2009
  • Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions. Chichester, UK: Wiley-Blackwell, 2009.
Matzinger 2002
Maurice 2006
  • Maurice ES, Moshe S, Ross AC, Benjamin C, Robert JC. Modern Nutrition in Health and Disease. 10th Edition. Lippincott Williams and Wilkins, 2006.
Murray 2001
  • World Health Organization: Murray CLJ, Lopez AD, Mathers CD, Stein C. The global burden of disease 2000 project: aims, methods and data sources. http://www.who.int/healthinfo/global_burden_disease/data_sources_methods/en/ 2001.
RevMan 2008
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Ross 1996
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Rudan 2004
  • Rudan I, Tomaskovic L, Boschi-Pinto C, Campbell H (on behalf of WHO Child Health Epidemiology Reference). Global estimate of the incidence of clinical pneumonia among children under five years of age. Bulletin of the World Health Organization 2004; Vol. 82:12.
Sazawal 1998
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Tateya 2007
  • Tateya I, Tateya T, Surles RL, Tanumihardjo S, Bless DM. Prenatal vitamin A deficiency causes laryngeal malformation in rats. Annals of Otology, Rhinology, and Laryngology 2007;16(10):785-92.
Tokuyama 1996
  • Tokuyama Y, Tokuyama H. Retinoids as Ig isotype-switch modulators. The role of retinoids in directing isotype switching to IgA and IgG1 (IgE) in association with IL-4 and IL-5. Cell Immunology 1996;170(2):230-4.
Walter 2001
  • Walter R, Merle A. Current diagnosis and treatment in infectious diseases. New York: McGraw-Hill, 2001.
WHO 2003
  • WHO. International Statistical Classification of Diseases and Related Health Problems. ICD-10. 10th Edition. Oxford: Oxford University Press, 2003.
Williams 2002
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