Acute respiratory tract infections (ARI) and Vitamin A deficiency are important public health problems in many developing countries. Vitamin A deficiency is associated with impaired humoral and cellular immune function, keratinisation of the respiratory epithelium and decreased mucus secretion, which weaken barriers to infection (Ross 1996). Acute respiratory infection (ARI), mostly in the form of pneumonia, is the leading cause of death in children under five in developing countries. It is associated with or causes about 3.8 million childhood deaths annually, 30.3% of these are in children under the age of 5 years (Kirkwood 1995).
Community based clinical trials have been conducted in order to determine whether periodic high-dose vitamin A supplementation reduces the incidence and/or severity of acute respiratory infections in children. The association between vitamin A deficiency and child mortality was first observed in the 1930s when vitamin A supplementation significantly reduced mortality among measles patients (Ellison 1932). Two meta-analyses (Glasziou 1993 & Fawzi 1993) examined the relationship between vitamin A supplementation and infectious diseases. Glasziou (1993) reported that vitamin A reduced all-cause mortality in children in developing countries by one third. However the reduction in deaths from respiratory disease was seen only in the measles studies. Fawzi (1993) also reported that supplementation was protective against overall mortality in community based studies (OR=0.70) and highly protective against mortality in hospitalised measles patients (OR=0.39).
From the current evidence it appears that vitamin A supplementation reduces the severity of respiratory infection and other systemic complications of measles. However, the association between vitamin A and non-measles ARI is unclear. The WHO Programme for the Control of Acute Respiratory Infections published a meta-analysis to assess the impact of supplementation on pneumonia morbidity and mortality (VAPWG 1995). They reported no consistent overall protective or detrimental effect on pneumonia-specific mortality and no effect on the incidence or the prevalence of pneumonia.
Hospital-based clinical trials examining the effectiveness of high-dose vitamin A administered during an acute episode of non-measles ARI in reducing morbidity or mortality have been performed, however no meta-analyses have been carried out. Given the apparent effectiveness of vitmain A in reducing mortality in hospitalised measles patients and the inexpensiveness of the intervention, clarification of the association between vitamin A and non-measles ARI is of some importance.
The objective of this review is to assess the effectiveness and safety of vitamin A in children with diagnosed non-measles pneumonia.
Criteria for considering studies for this review
Types of studies
Only parallel-arm, randomised and quasi-randomised controlled trials in which children with diagnosed non-measles pneumonia are treated with vitamin A (at the time of confirmed disease) will be included in this review. Studies that examine the effectiveness of vitamin A in preventing episodes of non-measle pneumonia will not be considered. Studies including patients with measles will also not be considered.
Types of participants
Children with non-specific and RSV pneumonia (the definition of pneumonia used will be a clinical case definition or radiological confirmation or both) uncomplicated by measles
under the age of 15 of either gender.
Types of intervention
Vitamin A plus standard medical treatment versus standard medical treatment with or without placebo.
Types of outcome measures
All cause mortality, pneumonia-specific mortality, severity of pneumonia, duration of hospitalisation, duration of pneumonia signs (fever, tachypnoea, dyspnoea) - also the development of adverse events such as diarrhoea and toxicity signs (vomiting and desquamation).
Search strategy for identification of studies
See: Cochrane Acute Respiratory Infections Group search strategy
Searches of various electronic databases including CINAHL, Biological abstracts, Current Contents, Cochrane Controlled Trials Register and the LILACS database. Both Medical Subject Heading (MeSH) and text word searches will be conducted. The search strategy will be used in combination with the search strategy developed by the Cochrane Collaboration for identifying randomised controlled trials. As an electronic search of Medline, using Phases 1 and 2 of the Cochrane search strategy to identify Medline records not identified as randomised controlled trials or controlled clinical trials was completed for the years 1966-1999 and the result were included in Issue 2 2001, The Cochrane Library. Embase was similarily searched. The search strategy will be modified appropriately to search Medline from 2000 onwards and Embase from 1998 onwards. The Medline search will include the following terms:
1. exp vitamin A/
2. vitamin A.mp
4. exp dietary supplements/
6. exp pneumonia/
8. exp pneumonia, bacterial/
9. exp pneumonia, lipid/
10. exp pneumonia, mycoplasma/
11. exp pneumonia, pneumococcal/
12. exp pneumonia, rickettsial/
13. exp pneumonia, staphlococcal/
14. exp pneumonia, viral/
15. exp respiratory tract infections/
16. acute adj/respiratory.mp
17. respiratory adj/infection.mp
18. respiratory adj/disease.mp
20. 4 and 19
In addition to electronic databases, reference lists will be searched. Authors of trial reports published only as abstracts will be contacted and asked for full reports or data sets.
Methods of the review
SELECTION OF STUDIES
Study citations will be collated into a single library. The contact reviewer will exclude duplicates and articles unlikely to be relevant by scanning abstracts, citations with abstracts missing will be retrieved in full text. A second reviewer will independently review a sample of the selection process. Relevant articles will be retrieved in full text and inclusion criteria will be applied by two independent reviewers. Where disagreements occur the third reviewer will consider the article.
Included studies will be extracted independently by two authors using standardised forms. Primary authors will be contacted to provide information if missing data is encountered or if an intention to treat analysis is not performed. All differences will be resolved by discussion among the reviewers.
Study quality will be assessed using an adaptation of the method outlined in Schulz 1995. The following characteristics will be assessed:
Adequacy of the randomisation process:
A - Adequate sequence generation is reported using random number tables, computer random number generator, coin tossing, or shuffling;
B - Did not specify one of the adequate reported methods in (A) but mentioned randomisation method;
C - Other methods of allocation that appear to be unbiased.
Adequacy of the allocation concealment process:
A - Adequate measures to conceal allocations such as central randomisation; serially numbered, opaque, sealed envelopes; or other description that contained convincing elements of concealment;
B - Unclearly concealed trials in which the author either did not report an allocation concealment approach at all, or reported an approach that did not fall into one of the categories in (A);
C - Inadequately concealed trials in which method of allocation is not concealed such as alteration methods or use of case record numbers.
Potential for selection bias after allocation:
A - Trials where an intention to treat analysis is possible and few losses to follow-up are noted;
B - Trials which reported exclusions (as listed in (A) but exclusions were less than 10%);
C - No reporting on exclusions or exclusions greater than 19% or wide differences in exclusions between groups.
Level of masking:
A - Double or triple blind;
B - Single blind;
C - Non-blind.
A statistical summary of treatment effect will proceed only in the absence of significant clinical or statistical heterogeneity. Heterogeneity will be tested using the Cochrane Q statistic (Cochran 1954) with significance at p<0.10 (Boissel 1989; Fleiss 1986).
Dichotomous data will be expressed as relative risk (95% confidence interval) and if appropriate a number needed to treat will be derived to help clarify the degree of benefit. Continuous data will be converted to the weighted mean difference and an overall weighted mean difference will be calculated. Overall estimates will be based on the random effects model (DerSimonian 1986). Publication bias will be tested using funnel plots or other corrective analytical methods, depending on the number of clinical trials included in the systematic review.
Subgroup and investigations of heterogeneity
The meta-analysis will be stratified for the following factors if adequate data is available:
- non-specific pneumonia vs. RSV pnemonia
- infants (<5 yrs) vs. older children (>5 years to 15 years old)
- vitamin A dosage
- vitamin A deficient children vs well nourished children
- study design, RCTs vs quasi-RCTs
If significant heterogeneity is detected the following explanations will be considered:
- duration of therapy
- geographical differences
- aspects of study quality in particular allocation concealment and blinding
Potential conflict of interest
Sources of support
External sources of support
- No sources of support supplied
Internal sources of support
- No sources of support supplied