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.
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.
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
- 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.
- 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.
- 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
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|
1 exp Respiratory Tract Infections/
2 respiratory tract infection*.tw.
3 lower respiratory infection*.tw.
4 (lrti or alri).tw.
5 exp Bronchitis/
10 exp Laryngitis/
13 exp Pneumonia/
15 ((lung or pulmonary) adj3 (inflam* or infect*)).tw.
19 exp Vitamin A/
20 vitamin a.tw,nm.
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.
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 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 I
Assessment of reporting biases
We did not test for reporting bias as only a small number of studies were included in the review.
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.
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.
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).
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:
b. cough plus fever;
c. cough plus instantaneous respiratory rate (IRR).
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.
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.
Mean daily prevalence of signs of LRTIs
1. Daytime cough.
2. Severe respiratory illness.
3. Difficulty in breathing.
4. Rapid breathing.
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.
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.
Prevalence of respiratory tract infections
1. Cough alone.
2. Cough and fever.
3. Cough and rapid respiratory rate.
Two-week prevalence of signs of respiratory tract infections: cold, cough and rapid breathing.
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.
Incidence of acute LRTI
An episode of acute LRTI was defined as cough, elevated respiratory rate >= 40 min, or lower chest indrawing.
We excluded 59 articles. For details see Characteristics of excluded studies table.
Risk of bias in included studies
|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.|
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).
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.
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.
1. Primary outcome: incidence of acute LRTI
Subgroup: by dosage
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).
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.
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.
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.
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.
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
- Top of page
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Differences between protocol and review
- 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.
1 exp vitamin A/
2 vitamin A.mp.
6 lower respiratory tract infection$.mp.
7 lower respiratory infection$.mp.
10 exp respiratory tract infections/
11 exp bronchiolitis/
13 exp bronchitis/
15 exp laryngitis/
17 exp pneumonia/
19 (lung adj inflammation).mp.
21 (pulmonary adj inflammation).mp.
22 exp tracheitis/
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
#12. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11
#9. ((lung OR pulmonary) NEAR/3 (inflam* OR infect*)):ab,ti
#6. laryngit*:ab,ti OR laryngotracheobronchit*:ab,ti
#4. bronchit*:ab,ti OR bronchiolit*:ab,ti OR bronchopneumon*:ab,ti OR tracheobronchit*:ab,ti
#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
Last assessed as up-to-date: 29 June 2010.
Protocol first published: Issue 3, 2006
Review first published: Issue 1, 2008
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
Sources of support
- Chinese Cochrane Centre, West China Medical Centre, Sichuan University, China.
- 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.
Medical Subject Headings (MeSH)
Acute Disease; Child Nutrition Disorders [complications; drug therapy]; Cough [drug therapy; etiology]; Infant, Newborn; Randomized Controlled Trials as Topic; Respiration Disorders [etiology]; Respiratory Tract Infections [*drug therapy; etiology]; Vitamin A [adverse effects; *therapeutic use]; Vitamin A Deficiency [complications; drug therapy]; Vitamins [adverse effects; *therapeutic use]
MeSH check words
Child; Child, Preschool; Humans; Infant
* Indicates the major publication for the study