CD 006090

Vitamin A for preventing acute lower respiratory tract
infections in children up to seven years of age (Review)
Chen H, Zhuo Q, Yuan W, Wang J, Wu T
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2008, Issue 1
http://www.thecochranelibrary.com
Vitamin A for preventing acute lower respiratory tract infections in children up to seven years of age (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Analysis 1.1. Comparison 1 Vitamin A versus placebo, Outcome 1 Incidence of acute LRTI in community-based trials. 38
Analysis 1.2. Comparison 1 Vitamin A versus placebo, Outcome 2 Prevalence of symptoms of acute LRTI. . . . . 39
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 46
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Vitamin A for preventing acute lower respiratory tract infections in children up to seven years of age (Review) i
[Intervention Review]
Vitamin A for preventing acute lower respiratory tract

infections in children up to seven years of age
Hengxi Chen2 , Qi Zhuo3 , Wei Yuan3 , Juan Wang3 , Taixiang Wu1

1 Chinese Cochrane Centre, Chinese Clinical Trial Registry, Chinese Evidence-Based Medicine Centre, INCLEN Resource and Training
Centre, West China Hospital, Sichuan University, Chengdu, China. 2 Department of Obstetrics and Gynecology, West China Second
University Hospital, West China Women’s and Children’s Hospital, Chengdu, China. 3 West China Hospital, Sichuan University,
Chengdu, China
Contact address: 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.
Editorial group: Cochrane Acute Respiratory Infections Group.
Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 1, 2011.
Review content assessed as up-to-date: 29 June 2010.
Citation: 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.
ABSTRACT
Background
Vitamin A supplements are effective for preventing diarrhoea. There are theoretical reasons why they may also be effective for acute
lower respiratory tract infections (LRTIs), also very common in children, especially in low-income countries.
Objectives
To assess the effectiveness and safety of vitamin A for preventing acute LRTIs in children up to seven years of age.
Search methods
In this updated review we searched CENTRAL (2010, Issue 1), which contains the Cochrane Acute Respiratory Infection Group’s
Specialised Register, MEDLINE (1966 to February Week 4, 2010), EMBASE (1974 to March 2010) and the Chinese Databases CNKI
and VIP (1976 to June 2010).
Selection criteria
Randomised controlled trials (RCTs) that assessed the effectiveness of vitamin A in the prevention of acute LRTI in children up to
seven years of age.
Data collection and analysis
The review authors independently extracted data and assessed trial quality. We contacted study authors for additional information.
Main results
Ten studies including 33,179 participants were included in this review. Eight studies found no significant effect of vitamin A on the
incidence of acute LRTI, or prevalence of symptoms of acute LRTI. Vitamin A caused an increased incidence of acute LRTI in one
study; an increase in cough and fever; and increased symptoms of cough and rapid breathing in two other studies. Three reported no
differences and no protective effect of vitamin A. Two studies reported that vitamin A significantly reduced the incidence of acute LRTI
in children with poor nutritional status or weight, but increased the incidence in healthy children.
Vitamin A for preventing acute lower respiratory tract infections in children up to seven years of age (Review) 1
Authors’ conclusions
This unexpected result is outside our current understanding of the use of vitamin A for preventing acute LRTIs. Accordingly, vitamin
A should not be given to all children to prevent acute LRTIs. Despite its benefits in preventing diarrhoeal illnesses, vitamin A
supplementation has only a limited effect in preventing acute LRTIs. Positive effects appear limited to populations with acute and
chronic under nutrition. Low-dose vitamin A appears to have fewer side effects and at least equal benefit to a high dose of vitamin A.
PLAIN LANGUAGE SUMMARY
Vitamin A for preventing acute lower respiratory tract infections in children up to seven years of age
Acute lower respiratory tract infections (LRTIs), especially pneumonia and bronchiolitis, are leading causes of mortality in children up
to five years of age. The Global Burden of Disease 2000 project estimated that the annual number of acute respiratory tract infection
(ARTI)-related deaths in children up to five years of age was 2.1 million (excluding deaths caused by measles, whooping cough and
neonatal deaths). Others estimate worldwide child deaths from ARTIs at 1.9 million in 2000, 70% of them in Africa and Southeast
Asia. Vitamin A deficiency is common in low-income countries and weakens barriers to infection.
We included 10 trials (33,179 children) where vitamin A deficiency or malnutrition was prevalent (31,379 in the community and 1800
in a hospital setting). Studies measured different aspects (for example, what constituted ’acute LRTI’, the time to symptom resolution,
etc.). There may have been other treatments (especially of malnourished children) which could have led to bias. Most studies showed
no significant benefit of vitamin A supplements on the incidence or prevalence of symptoms of acute LRTIs. Although no included
studies addressed adverse effects of vitamin A, the use of vitamin A should be carefully monitored.
We do not recommend giving vitamin A to all children to prevent acute LRTIs because a few studies unexpectedly found that vitamin
A increased the chance of infections or worsened symptoms in otherwise healthy children. Some evidence shows benefit for vitamin
supplements given to children with low serum retinol or with a poor nutritional status. Limitations of our review include trials conducted
within very specific populations and poor methodological quality of some of the included trials.
BACKGROUND 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 res-
Description of the condition piratory infections, suggests that throughout the world 1.9 million
Acute lower respiratory tract infections (LRTIs) refer to acute in- (95% CI 1.6 to 2.2 million) children died from ARTIs in 2000,
fections which affect the airways below the epiglottis. These in- 70% of them in Africa and Southeast Asia (Williams 2002). The
clude acute laryngitis, tracheitis, bronchitis, bronchiolitis, acute incidence of clinical pneumonia in low-income countries may be
manifestations of lung infections and any combination of the around 0.29 episodes per child per year, equating to an annual in-
above; or any of these in addition to upper respiratory tract incidence of 150.7 million new cases, 11 to 20 million (7% to 13%)
fections, including influenza (Rudan 2004; WHO 2003). The of which are severe enough to require hospitalization. The aver-
most important signs and symptoms of LRTIs include cough, in- age incidence of community-acquired pneumonia among children
creased amount of sputum, wheezing, increased respiratory rate less than five years of age, reported in four large population-based
and changes evident on chest X-rays. studies in the United States and Europe, was estimated to be ap-
Acute respiratory tract infections (ARTIs), especially in the form proximately 0.026 episodes per child per year. However, this inci-
of pneumonia and bronchiolitis, are the leading cause of mortality dence is not directly comparable to that of low-income countries
in children younger than five years of age. The Global Burden of due to different definitions and research methods (Rudan 2004).
Disease 2000 project estimated that the annual number of ARTI-
related deaths in children under five years of age, excluding deaths
Description of the intervention A meta-analysis assessed the effect of vitamin A supplementation
on childhood morbidity from respiratory tract infections and di-
Currently, the most common methods to prevent acute LR-
arrhoea (Grotto 2003). It found that vitamin A supplementation
TIs include improved general hygiene (Walter 2001), antibiotics
slightly increased the incidence of respiratory tract infections, lead-
(Bonten 2003), immunisation against measles and pertussis and
ing to the recommendation that it not be used for all preschool
administering nutritional supplements such as zinc (Bhandari
children routinely, but instead only be given to those with a vita-
2002; Sazawal 1998), vitamin C (Hemila 2004) and vitamin A
min A deficiency.
(Barreto 1994).
Accordingly we set out to determine the benefits and harms of vi-
Vitamin A deficiency in children is a common public health prob-
tamin A administered to children up to seven years of age, includ-
lem, especially in low-income countries. Vitamin A deficiency
ing the importance of factors such as age, weight, dose of vitamin
weakens barriers to infections (Ross 1996) and it is possible that
A and the nutritional status for preventing acute LRTIs.
the administration of vitamin A could prevent respiratory tract
infections.
OBJECTIVES
How the intervention might work
To assess the effectiveness and safety of vitamin A versus a placebo
The role of vitamin A in preventing acute LRTIs is based on exper- in the prevention of acute LRTIs in children up to seven years of
imental studies. Vitamin A was found to benefit the development age.
of the epithelium mucosae of the respiratory tract. Conversely, vi-
tamin A deficiency leads to problems with respiratory tract epithe-
lium mucosae growth and tissue repair (Haq 1991; Tateya 2007)
and increased susceptibility of the respiratory tract to infections. It
METHODS
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-lym- Criteria for considering studies for this review
phocytes 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. Types of studies
When levels of vitamin A fall, dendritic cells in the local mucosa Randomised controlled trials (RCT) which examined the effect of
increase, which in turn promotes an inflammatory reaction, lead- vitamin A in preventing acute LRTIs. Both hospital- and commu-
ing to increased tissue damage (Matzinger 2002). nity-based trials were included. We excluded trials that included
participants with HIV infections or measles-related pneumonia.
We excluded quasi-RCTs.
Why it is important to do this review
Much research has been done to determine the relationship be- Types of participants
tween vitamin A administration and acute LRTIs. However, the Children up to seven years of age without HIV infections or
results are inconsistent. Some studies found that the incidence measles-related pneumonia.
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, Types of interventions
in underweight children (Sempertegui 1999) and people suffering Vitamin A (any dose) versus placebo or vitamin A plus standard
from malnutrition (Dibley 1996). Other studies concluded that supplements (for example, vitamin E to stabilise vitamin A) versus
vitamin A supplementation increased the incidence of acute LR- standard supplements.
TIs 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 vi- Types of outcome measures
tamin A on the incidence of acute LRTIs could be attributed to
conditions that affect both growth and the response to supplemen-
tation, for example, baseline vitamin A status, deficiency of other Primary outcomes
nutrients (fat, zinc) and the usage of vitamin A (such as dosage, 1. Incidence or prevalence of acute LRTIs confirmed by
duration, etc). doctors on the basis of strict, pre-defined criteria (usually fever,
tachypnea, remission with or without cough, chest or Electronic searches
radiological signs) during the study period.
Acute LRTIs refer to severe infections which affect the airways
below the epiglottis (Rudan 2004; WHO 2003).
For this update we searched the Cochrane Central Register of Con-
trolled Trials (CENTRAL) (2010, Issue 1), which contains the
Secondary outcomes Acute Respiratory Infection Group’s Specialised Register, MED-
1. Incidence or prevalence of signs and symptoms of acute LINE (July 2007 to February Week 4, 2010), EMBASE (July
LRTIs, such as cough (alone or associated with fever), increased 2007 to March 2010) and the Chinese Databases CNKI and VIP
respiratory rate, increased sputum production, and specific X-ray (1976 to July 2010). For details of previous searches see Appendix
changes of the lung. 1.
2. Adverse events following the administration of vitamin A, We used the following search strategy to search CENTRAL and
such as raised intracranial pressure, vomiting, nausea, MEDLINE. We combined the MEDLINE search strategy with
enlargement of the liver. 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
Search methods for identification of studies databases include CNKI, VIP (see Figure 1).
Figure 1. Search strategy in Chinese databases
MEDLINE (OVID)
1 exp Respiratory Tract Infections/ 13 exp Pneumonia/
2 respiratory tract infection*.tw. 14 pneumon*.tw.
3 lower respiratory infection*.tw. 15 ((lung or pulmonary) adj3 (inflam* or infect*)).tw.
4 (lrti or alri).tw. 16 Tracheitis/
5 exp Bronchitis/ 17 tracheit*.tw.
6 bronchit*.tw. 18 or/1-17
7 bronchiolit*.tw. 19 exp Vitamin A/
8 bronchopneumon*.tw. 20 vitamin a.tw,nm.
9 tracheobronchit*.tw. 21 retinol.tw,nm.
10 exp Laryngitis/ 22 retinal.tw,nm.
11 laryngit*.tw. 23 or/19-22
12 laryngotracheobronchit*.tw. 24 18 and 23
Searching other resources No - inadequately concealed allocation that reported an approach
We also handsearched journals and monographs not found in that does not fall into one of the categories in ’Adequate’.
electronic database searches and attempted to locate unpublished • Blinding:
studies, for example, from meeting papers and academic theses. Blinding of patients (yes, no or unclear).
There were no language or publication restrictions. Blinding of caregivers (yes, no or unclear).
We searched WHO ICTRP (http://www.who.int/ictrp/zh/) for Blinding of outcome assessment (yes, no or unclear).
ongoing studies. • Incomplete outcome data addressed:
Yes - described loss of participants to follow up at each data col-
lection point and exclusion of participants after randomisation.
Data collection and analysis Unclear - did not mention this domain.
No - not described.
• Free of selective reporting bias:
Selection of studies Yes - study is free of suggestions of selective reporting bias.
Two review authors (HC, WY) independently examined abstracts Unclear - not mentioned.
identified from the electronic searches in order to locate studies No - not described.
that met the inclusion criteria. We retrieved the full text of these • Free of other bias:
studies and those without abstracts. One review author (HC) in- Yes - the baselines were balanced.
terviewed the first authors of the Chinese articles, by telephone, Unclear - not mentioned.
to identify the randomisation method and other methodological No - the baselines were not balanced.
issues as a way of ensuring that the included studies were true
RCTs.
Measures of treatment effect
We analysed the data using Review Manager (RevMan 2008).
Data extraction and management
Because most of the data listed in the articles were counts (episodes
Two review authors (HC, WY) independently extracted data from of acute LRTI and person-time of follow up), we treated the data
the included studies using a piloted data extraction form. Differ- for combination analyses as generic inverse variance outcomes.
ences were resolved by discussion among the review authors. 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,
Assessment of risk of bias in included studies and we will present binary data as risk ratios with 95% confidence
Two review authors (HC, WY) independently assessed risk of bias intervals.
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, Unit of analysis issues
including sequence generation, allocation concealment, blinding,
incomplete outcome data addressed, free of selective reporting All of the participants were recruited and analysed individually.
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. Dealing with missing data
• Generation of allocation sequence: We tried to contact the original trial authors for missing data,
Yes - adequate sequence generation was reported using one of the however we did not receive any replies.
following approaches: random number tables, computer-gener-
ated random numbers, coin tossing or card shuffling.
Unclear - allocation sequence generation not mentioned.
No - other methods of allocation that appear to be biased. Assessment of heterogeneity
•Allocation concealment: We tested heterogeneity using the Cochrane Q statistic with sig-
Yes - adequate measures to conceal allocations such as central ran- nificance at a P value of less than 0.10. We used the I2 statistic to
domisation, serially numbered, opaque, sealed envelopes, or an- estimate of the percentage of heterogeneity between trials which
other description that contained convincing elements of conceal- could not be ascribed to sampling variation; 25% was considered
ment. as low level heterogeneity, 25% to 50% as moderate, and higher
Unclear - unclearly concealed trials in which the author did not than 50% as high. If there was evidence of substantial heterogene-
report an allocation concealment approach at all. ity, we investigated and reported the possible reasons for this.
Assessment of reporting biases All were community-based trials except for two (Bhandari 1994;
We did not test for reporting bias as only a small number of studies Donnen 1998) which were hospital-based.
were included in the review. All included studies focused on children between 0 to 83 months
of age. Participants in the two hospital-based trials either had diar-
rhoea (Bhandari 1994) or were referred to a hospital mainly deal-
Data synthesis ing with protein-energy malnutrition (Donnen 1998). A total of
We used the random-effects model for meta-analysis. 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
Subgroup analysis and investigation of heterogeneity 103,000 IU vitamin A (Dibley 1996) and six used 100,000 IU or
We performed subgroup analyses based on the ages of participants, 200,000 IU vitamin A (Barreto 1994; Bhandari 1994; Donnen
dosage or usage of vitamin A, nutritional status, development or 1998; Rahman 2001; Stansfield 1993; VAST 1993). Four studies
weight of participants. The outcome measures were discussed ac- were low-dose trials: one with daily 5000 IU vitamin A (Donnen
cording to the subgroups. We did not perform a sensitivity analysis 1998); one with weekly 10,000 IU vitamin A (Sempertegui 1999);
as there were insufficient studies in the subgroups. 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).
RESULTS Outcome measures

Barreto 1994
Description of studies
Acute incidence of LRTIs
See: Characteristics of included studies; Characteristics of excluded 1. Acute LRTI-1 was defined as a respiratory rate >= 50/min to
studies; Characteristics of studies awaiting classification. 12 months of age, or >= 40/min for older children.
In this updated review, a study in the Characteristics of studies 2. Acute LRTI-2 was defined as a respiratory rate >= 50/min for
awaiting classification table of the original review was selected for any age.
inclusion (Rahman 2001). However, this did not change the results After consideration, we decided to use the acute LRTI-1 for anal-
of the review. ysis 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.
Results of the search
3. Mean daily prevalence of respiratory signs and symptoms:
After examining the titles, abstracts or full texts we identified 73 a. cough;
papers from the search results. Of these, 25 Chinese studies ap- b. cough plus fever;
peared to meet the inclusion criteria. We contacted the first au- c. cough plus instantaneous respiratory rate (IRR).
thors of these studies and found that although the studies claimed Rahmathullah 1991
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. Incidence of LRTIs
We did not find any ongoing studies. 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.
Included studies Rahman 2001
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 Incidence of LRTIs
1998), one in Mexico (Long 2006), one in the USA (Bhandari Acute lower respiratory infection was defined as the presence of
1994), one in Canada (Stansfield 1993) and one in Bangladesh cough, difficult or rapid breathing, and fever. Chest retraction
(Rahman 2001). was added to these symptoms to define severe lower respiratory
The included studies were mainly conducted in areas where mal- infection. Seven consecutive days free from disease were regarded
nutrition, vitamin A deficiency at a subclinical or clinical level, as resolution of previous respiratory illness.
or conditions that affected vitamin A absorption were prevalent. VAST 1993
Mean daily prevalence of signs of LRTIs 3. Cough and rapid respiratory rate.
1. Daytime cough. Stansfield 1993
2. Severe respiratory illness. Two-week prevalence of signs of respiratory tract infections: cold,
3. Difficulty in breathing. cough and rapid breathing.
4. Rapid breathing. Donnen 1998
Dibley 1996
Incidence of acute LRTI
1. Acute LRTI-1: defined as cough plus a respiratory rate >= 40
Incidence of acute LRTI breaths/min.
An episode of acute LRTI was defined as periods of two or more 2. Acute LRTI-2: cough plus a temperature > 38.5 °C at least once
consecutive days during which the child had cough and elevated in a 24-hour period.
respiratory rate. The data were transformed to dichotomous data.
Sempertegui 1999 Bhandari 1994

An episode of acute LRTI was defined as cough, elevated respira-
An episode was defined as tachypnea (respiratory rate 40/min) tory rate >= 40 min, or lower chest indrawing.
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. Excluded studies
Long 2006 We excluded 59 articles. For details see Characteristics of excluded
studies table.
Prevalence of respiratory tract infections

1. Cough alone.
Risk of bias in included studies
2. Cough and fever. See Figure 2 and Figure 3.
Figure 2. Methodological quality graph: review authors’ judgements about each methodological quality
item presented as percentages across all included studies.
Figure 3. Methodological quality summary: review authors’ judgements about each methodological quality
item for each included study.
Allocation
The total number of exclusions for analysis was 4561 (29.6%)
All included studies were randomized trials. Four described the in Rahmathullah 1991. Fifty-nine (12.9%) participants were ex-
methods of randomisation (Bhandari 1994; Dibley 1996; Long cluded in Sempertegui 1999. Fourteen participants (1.0%) devel-
2006; Sempertegui 1999). One study used a cluster-sampling oped measles, four (0.3%) withdrew consent and 119 (8.2%) were
design (Rahmathullah 1991). Five studies described allocation lost to follow up in the VAST 1993 study. Stansfield 1993 did
concealment (Barreto 1994; Bhandari 1994; Rahman 2001; address incomplete outcome data.
Sempertegui 1999; VAST 1993).
Selective reporting
Blinding We were unable to address selective reporting in the included stud-
All included studies were blinded, with six double-blinded ies.
(Barreto 1994; Donnen 1998; Long 2006; Rahman 2001;
Sempertegui 1999; Stansfield 1993) and two triple-blinded (
Other potential sources of bias
Dibley 1996; VAST 1993).
There were no significant differences between groups in the in-
cluded studies.
Incomplete outcome data
The total rate of loss to follow up in Barreto 1994 was 10.3%.
Effects of interventions
The numbers of loss were equal in both arms. Fifty-eight partici- As most of the data listed in the articles were counts (episodes of
pants were excluded after allocation to the Bhandari 1994 study. acute LRTI and person-time of follow up), we extracted them as
In Dibley 1996, less than 2% of the daily morbidity records were generic inverse variance outcomes (see Figure 4, Figure 5). Other
missing. No participants were lost to follow up in Donnen 1998. types of data are presented in the ’Additional tables’. We did not
In Rahman 2001, 135 (17%) were excluded or dropped out. combine data due to heterogeneity.
Figure 4.
Figure 5.
1. Primary outcome: incidence of acute LRTI

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
Subgroup: by dosage
not reduced the incidence of acute LRTI (Donnen 1998; Rahman
2001) (Table 2; Table 3).
Mega doses
Seven studies belonged to this subgroup. In the five community-
based trials (Barreto 1994; Dibley 1996; Rahman 2001; Stansfield Low doses
1993; VAST 1993), two did not contain data about the incidence
of acute LRTI (Stansfield 1993; VAST 1993), and one (Rahman Four studies belong to this subgroup. In the three community-
2001) provided data in a different format, so we combined the based trials, one (Sempertegui 1999) showed no protective effect
two other studies (Barreto 1994; Dibley 1996) in a meta-analysis. of vitamin A on the incidence of acute LRTI, with a RR of 1.16
One trial (Dibley 1996) showed an elevated incidence of acute (95% CI 0.77 to 1.76) (see Figure 4). One trial (Rahmathullah
LRTI in the vitamin A group (RR 1.39, 95% CI 1.03 to 1.88). 1991) stated that the age-adjusted RR was 1.01 (95% CI 0.73
The other trial (Barreto 1994) showed no difference in acute LRTI to 1.40), which showed no protective effect of vitamin A on the
between the two groups (RR 0.97, 95% CI 0.87 to 1.10). The incidence of acute LRTI; one study (Long 2006) did not state the
total effect of vitamin A in these two studies showed no protective incidence of acute LRTI. One hospital-based trial (Donnen 1998)
effect on acute LRTI (RR 1.13, 95% CI 0.80 to 1.60) (Figure 4; showed no protective effect of vitamin A on the incidence of acute
Table 1). In the hospital-based studies, one trial (Bhandari 1994) LRTI (Table 2).
Subgroup: by state of nutrition, development or weight of There were no significant differences between the vitamin A group
participants and the control group in the mean daily prevalence of acute LRTI
One trial (Rahmathullah 1991) only listed the percentage of symptoms.
children with LRTIs according to their nutritional state, and Stansfield 1993 (Table 8, Table 9)
showed no significant differences between the two groups. One Two-week prevalence of:
trial (Sempertegui 1999) showed that vitamin A had a significant a. cough, 48% for the vitamin A group and 45% for the placebo
protective effect on the incidence of acute LRTI in underweight group; rate ratio 1.18 (95% CI 1.09 to 1.27);
children (RR 0.38, 95% CI 0.17 to 0.85), while it significantly b. rapid breathing, 18% for the vitamin A group and 15% for the
elevated the incidence of acute LRTI in normal-weight children placebo group; rate ratio 1.18 (95% CI 1.09 to 1.27).
(RR 2.22, 95% 1.25 to 3.95) (see Figure 4). One trial (Dibley This showed that vitamin A increased the risk of symptoms such
1996) showed a significant increase in the incidence of acute LR- as cough and rapid breathing. This study also showed that there
TIs in normal-sized children (RR 1.83, 95% CI 1.257 to 2.669) was no clear correlation between risk and age.
but did not show an increase in the incidence for nutritionally Long 2006 (Figure 5; Table 10)
stunted children (RR 0.48; 95% CI 0.21 to 1.12) (Figure 4; Table There were no differences in the prevalence of overall cough, cough
1). with fever, or cough with rapid respiratory rate between the two
groups.
Subgroup: by age 3. Adverse effect of vitamin A

One trial (Rahmathullah 1991) only listed the percentage of chil- No studies discussed the adverse effects of vitamin A, such as raised
dren with LRTIs according to their age, and showed no significant intracranial pressure, vomiting, nausea, enlargement of the liver,
differences between the two groups (Table 4). One trial (Bhandari etc.
1994) listed the incidence of acute LRTIs by age group (age <= 23
months and > 23 months) (Table 5). The meta-analysis we con-
ducted on children aged five years or younger showed that there
was no protective effect of vitamin A on the incidence of acute DISCUSSION
LRTIs (Figure 4).
Summary of main results
The majority of studies showed that there was no significant effect
2. Secondary outcome: prevalence of symptoms of on the incidence or prevalence of acute LRTI symptoms with vita-
acute LRTI min A supplementation (Barreto 1994; Bhandari 1994; Donnen
Four studies discussed the prevalence of symptoms of acute LRTI. 1998; Rahman 2001; Rahmathullah 1991; VAST 1993). One
Barreto 1994 (Table 6; Table 1) study (Dibley 1996) showed an elevated incidence of acute LR-
Mean daily prevalence of: TIs in the vitamin A group; one study (Long 2006) showed an
a. cough with the prevalence in the vitamin A group, control group; elevated prevalence of cough and fever; and one study (Stansfield
rate ratio, and P value being 0.24, 0.24, 0.99, 0.57 respectively; 1993) showed that vitamin A increased the risk of symptoms such
b. cough plus fever being 0.03, 0.03, 0.99, 0.90 respectively; as cough and rapid breathing. Two studies (Rahmathullah 1991;
c. cough plus instantaneous respiratory rate (IRR) being 0.01, Sempertegui 1999) showed that there was no difference and no
0.01, 0.96, 0.74 respectively. protective effect of vitamin A on the incidence of acute LRTIs in
Clearly there were no significant differences in the mean daily age subgroups; and one study (Stansfield 1993) concluded that
prevalence of respiratory signs and symptoms. there was no clear relationship between vitamin A and age. Two
VAST 1993 (Table 7) studies (Dibley 1996; Sempertegui 1999) concluded that the ef-
Mean daily prevalence of: fect of vitamin A on the incidence of acute LRTIs was significantly
a. daytime cough, 13.2% for the vitamin A group and 13% for associated with nutritional status or the child’s weight, with an
the control group; prevalence ratio 1.02, P = 0.67; increase in acute LRTI episodes in ’normal’ children.
b. ’tired ribs’ (severe respiratory illness), 1.1% for the vitamin A The actual dosage of vitamin A supplement is an important el-
group and 1.1% for the control group; prevalence ratio 0.98, P = ement when considering the outcome, especially adverse effects.
0.86; Over-dosage of vitamin A can causes acute toxicosis (resulting in
c. difficulty in breathing, 1.2% for the vitamin A group and 1.2% raised intracranial pressure, nausea, vomiting, etc) and chronic
for the control group; prevalence ratio 0.96, P = 0.70; toxicosis (resulting in an enlarged liver, loss of appetite, etc). Acute
d. rapid breathing, 1.1% for the vitamin A group and 1.3% for toxicosis could be induced by one single dose of 1,000,000 IU for
the control group; prevalence ratio 0.81, P = 0.11. adults and 300,000 IU for children, while chronic toxicosis could
be induced by daily administration of 10,000 IU of vitamin A for which could explain the results of one study (Sempertegui 1999)
several months. However, adverse effect usually disappear within that concluded that vitamin A supplementation decreases the inci-
one or two weeks after stopping the supplementation (Maurice dence of acute LRTIs in underweight children. However, children
2006). Only one study (Donnen 1998) discussed both the high- with a poor nutritional status usually experience multi-nutrient
dose and low-dose effects of vitamin A supplementation. There deficits, including vitamin A deficiency, or have conditions which
were no significant differences in the duration and incidence of may affect the immune response or the effect of vitamin A. It is
acute LRTIs, but the number of participants was small. No studies often difficult to identify the effect of vitamin A deficiency and
discussed the adverse effects of vitamin A. this may partly account for inconsistencies between the studies.
Vitamin A deficiency up-regulates the Th1-mediated immune re- These inconsistencies could also be related to different definitions
sponse while vitamin A supplement up-regulates the Th2 response of acute LRTIs. One meta-analysis based on age showed there was
and down-regulates the Th1 response, which protects individuals a slight protective response to vitamin A given to children older
against infections such as the respiratory syncytial virus. Further than 11 months, but this may have been due to the fact that the
studies on the protective value of vitamin A supplementation on nutritional status can worsen after weaning. We could not get a
specific acute LRTIs should be conducted to clarify whether vita- clear picture of the relationship between the effect of vitamin A
min A supplementation increases the incidence of acute LRTIs or and age. We hypothesise that the inconsistent results in the differ-
not. ent 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
Overall completeness and applicability of LRTIs in the vitamin A group and two studies (Long 2006;
evidence Stansfield 1993) showed that vitamin A increased the risk of symp-
toms of acute LRTI. Two studies (Dibley 1996; Sempertegui 1999)
Five studies (Barreto 1994; Bhandari 1994; Long 2006; Rahman concluded that the effect of vitamin A on the incidence of acute
2001; Sempertegui 1999) described the sample size calculations LRTIs was significantly associated with the nutritional status or
(1240; 900; 336; 400, respectively). Five studies (Dibley 1996; weight of the children, with an increase in acute LRTI episodes
Donnen 1998; Rahmathullah 1991; Stansfield 1993; VAST 1993) in ’normal’ children. Some researchers hypothesise that vitamin
did not state the methods they employed to estimate sample sizes, A supplementation given to children with adequate vitamin A
but they were large (1405; 900; 15,419; 11; 124; 1455, respec- stores might cause a temporary immune dysregulation and lead
tively). 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
Quality of the evidence responses, including humoral and cellular responses (Friedman
Vitamin A deficiency is associated with impaired humoral and 1989; Friedman 1991). This may explain why children with nor-
cellular immune function, keratinisation of the respiratory ep- mal serum retinol levels sometimes experience more episodes of
ithelium and decreased mucous secretion, which weakens barri- acute LRTI when given vitamin A supplements.
ers to infection (Ross 1996). Vitamin A deficiency usually occurs The quality of the evidence ranged from moderate to very low
in those with a poor nutritional status or who are underweight. (Figure 6).
These people seem to benefit from vitamin A supplementation,
Figure 6. Summary findings table
Potential biases in the review process acute and chronic under nutrition. Low-dose vitamin A schedules
This review has some limitations. The included studies differed in appear to have fewer side effects and at least equal benefit to high-
some important aspects of design, namely the definitions of acute dose vitamin A schedules.
respiratory tract infections and the recall period for assessing mor-
bidity symptoms, which could lead to biases of information and Implications for research
misclassification. The included studies did not mention whether Large RCTs should be conducted to clarify the relationship be-
underweight children or children with poor nutritional status re- tween the dosage of vitamin A and the incidence of acute LRTIs,
ceived any concomitant intervention, such as an improved diet, especially to clarify the adverse effects of different doses of vitamin
during trials. If so, this could also introduce bias. A. We also suggest that further studies on the protective effect
of vitamin A supplementation on specific acute LRTIs should be
Agreements and disagreements with other conducted in order to clarify whether vitamin A supplementation
studies or reviews increases or decreases the incidence of specific infections. Finally,
further studies are needed to address the mode of vitamin A de-
A Cochrane systematic review (Brian 2007) found that supple- livery and combination with improving general nutritional status,
mentation of vitamin A for very low birthweight infants reduced both in children and ante-natally.
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. ACKNOWLEDGEMENTS
The authors wish to thank Liz Dooley (Managing Editor) and
Sarah Thorning (Trials Search Co-ordinator) of the Cochrane ARI
Group, Dr. Nick Brown, Dilip Mahalanabis, Nelcy Rodriguez,
Janet Wale and Ludovic Reveiz for commenting on the proto-
AUTHORS’ CONCLUSIONS
col. We thank the following people for commenting on the draft
review: Ann Fonfa, Naseem Qureshi, Dilip Mahalanabis, Nick
Implications for practice Brown, Terry Neeman and Ludovic Reveiz. Finally we acknowl-
Despite its benefits in preventing diarrhoeal illnesses, vitamin A edge the following people for commenting on the updated review:
supplementation has only limited efficacy in preventing acute LR- Angel Magar, Ann Fonfa, Nick Brown, Mark Griffin and Ludovic
TIs. There is some beneficial evidence limited to populations with Reveiz.
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Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Barreto 1994
Methods Randomised, double-blind, placebo-controlled clinical trial
Participants 1240 children aged 6 to 48 months. The baseline was comparable. The inclusion criteria:
children between 6 and 48 months. The exclusion criteria: active xerophthalmia, measles
within the previous 30 days, high-dose vitamin A supplementation in the previous 6
months, weight-for-age less than 60% of the statistical median
Interventions Vitamin A group received 100,000 IU every 4 months for 1 year for children younger
than 12 months and 200,000 IU for the older children. The placebo group only received
placebo
Outcomes 1. ALRI incidence

2. Mean daily prevalence of respiratory signs and symptoms
Notes This study was conducted in Serrinha, capital of the state of Bahia, where the climate is
hot and dry. The pubic health services there are inadequate. The biochemical deficiency
(serum vitamin A concentration < 0.35 mmol/L) rate in children is 7.4%, shown in an
earlier survey. According to WHO criteria, vitamin A deficiency should be considered a
pubic health problem in this area. Children were visited 3 times per week for 1 year, so
the recall period was 48 to 72 hours. The person-time of the vitamin A group and the
control group were 203,252 child-days and 201,656 child-days, respectively. The total
loss in follow-up time was 10.3%, equally distributed between the control and vitamin
A group. Migration away from the area was the main reason for loss to follow up. The
sample size of 1240 was estimated to give a power of 90% to detect a 15% reduction in
the incidence of diarrhoea
Risk of bias
Item Authors’ judgement Description
Adequate sequence generation? Unclear Only mentioned “randomly assigned”
Allocation concealment? Yes Only an external investigator had the codes

for the individually wrapped and num-
bered capsules
Blinding? Yes Double-blind

All outcomes
Incomplete outcome data addressed? No 9 children excluded from the trial because
All outcomes of severe weight loss
Free of selective reporting? No Not all the pre-specified outcomes were re-
ported
Barreto 1994 (Continued)
Free of other bias? Yes There were no significant differences be-

tween groups
Bhandari 1994
Methods Randomised, double-blind, placebo-controlled clinical trial. The randomisation method

was simple randomisation scheme drawn up by the WHO
Participants 900 children aged 12 to 60 months who resided in the slum area attending the govern-
ment clinic with diarrhoea duration 7 days or less and weight for height 70% or more of
the median were included. Exclusion criteria: presence of signs of vitamin A deficiency,
had received a large dose of vitamin A in the past 6 months, had the likelihood to migrate
out of the slum area, had associated illness, had been enrolled in the study within the
past 6 months and refused consent. The baseline line of two group were comparable
Interventions The vitamin A group received 200,000 IU vitamin A; the placebo group received only
placebo. They were followed up 90 days after recovery
Outcomes Incidence of ALRI
Notes This study was conducted at Govindpuri, an urban slum area in south Delhi where
vitamin A had not been given to people in the preceding 3 years. The sample size estimate
was 358 children per group based on detecting 25% reduction in the prevalence of acute
LRTIs with 90% power and 5% significance. The researchers increased the sample size
by 25% to allow for attrition. Children were visited every 3 days until 90 days after they
recovered from the diarrhoea. The final results were data according to 842 children, 422
in vitamin A group. 5 were for withdrawing consent, 46 for being unavailable for more
than 30 days, and 7 for fast breathing related to tuberculosis, cardiac disease or severe
anaemia. The child 90-day of follow up for vitamin A group and placebo group was 410
and 409
Risk of bias
Adequate sequence generation? Yes The randomisation was done using a sim-
ple randomisation scheme
Allocation concealment? Unclear Not mentioned

All outcomes
Incomplete outcome data addressed? No 58 participants were excluded. 5 withdrew

All outcomes consent, 46 were unavailable for more than
30 study days, 7 for persistent fast breathing
due to tuberculosis
Bhandari 1994 (Continued)
ported

tween groups
Dibley 1996
Methods Randomised, double-blind, placebo-controlled trial. Randomisation was done with 1:

1 allocation ratio in blocks of 8 based on a table of random permutations of integers.
Treatments were given once every 4 months for 6 treatment cycles
Participants 1405 children aged 6 to 47 months. The inclusion criteria: children between 6 to 47
months. Exclusion criteria: those with cerebral palsy, epilepsy, flaccid paralysis, mental
retardation, congenital or rheumatic heart disease were permanently excluded. Those
with weight-for-height more than 3.00 SD below the WHO growth reference mean or
acute xerophthalmia were excluded for one cycle and treated with high-dose vitamin A
and then included. Demographic, clinical and nutritional characteristics at the baseline
were the same, and the groups remained balance at the start of each of the other 5 cycles.
Compliance was equally high in both group, on average, 89% of the age-eligible children
received a treatment
Interventions Vitamin A group: 206,000 IU of retinyl ester plus 37 IU vitamin E or 103,000 IU retinyl
ester plus 17 IU vitamin E if less than 12 months of age; the control group: placebo that
contained 17 or 37 IU vitamin E on the age of the subject
Notes This study was conducted in 34 rural villages located on the southern coast of Central Java
in Indonesia, with high prevalence of subclinical vitamin A deficiency. 4.6% migrated
and 3.5% withdrew before the end of the treatment cycle. Morbidity surveillance was
96% and 97% in placebo and vitamin A group respectively. Less than 2% of the daily
morbidity records were missing. Children were visited every other day for 6 cycles. The
longest recall period allowed was 4 days. Observed child-days of ALRI of vitamin A
group and control group were 280,186 and 273,630
Risk of bias
Adequate sequence generation? Unclear Randomisation procedure was described as

“based on a table of random permutations
of integers”
Dibley 1996 (Continued)
Blinding? Yes All investigator, field and laboratory staff,

All outcomes and participants were masked to the treat-
ment code
Incomplete outcome data addressed? No Less than 2% of the daily morbidity records
All outcomes were missing
ported

tween groups
Donnen 1998
Methods Randomised, double-blind, placebo-controlled clinical trial
Participants 900 children aged 0 to 72 months hospitalized in the Lwiro Pediatric Hospital for protein-
energy malnutrition. Children were not eligible for inclusion in the study if they had
been admitted to the hospital in a coma, if their parents or legal guardians had refused
their participation, or if they had taken vitamin A capsules within the previous 4 months.
Consecutively in the Lwiro Pediatric Hospital were included in the trial. The baselines
of the 2 groups were comparable
Interventions 1) The high-dose treatment group received 200,000 IU vitamin A (100,000 IU if aged
< 12 months) orally on the day of admission and a placebo on every subsequent day
during hospitalization
2) The low-dose treatment group received 5,000 IU vitamin A every day until discharge
3) The placebo group received a placebo every day during hospitalization
Notes This study was conducted in the health district of Katana, province of South Kivu in
Congo, with population mainly poor farmers. Children were visited every day until they
were discharged from the hospital. Protein-energy malnutrition reduces the absorption
of vitamin A and synthesis and release of retinol binding protein, it always coexists with
vitamin A deficiency. 73.9% to 78.5% of the study sample at baseline were found to
have deficient serum retinol concentrations (< 0.35 mmol/L)
Risk of bias
Adequate sequence generation? Unclear Only mentioned “randomly assigned”
Donnen 1998 (Continued)
Blinding? Yes “Double-blind”. Paediatrician was the only

All outcomes one with access to the allocation list
Incomplete outcome data addressed? Yes No participants lost to follow up

All outcomes
ported

tween groups
Long 2006
Methods Randomised, double-blind, placebo-controlled clinical trial. The randomisation se-

quence was generated by using a random-number table by project personnel. It was
stratified allocation
Participants 736 children aged 6 to 15 months living in a peri-urban area of Mexico City. 336 children
were in vitamin A group and placebo group. The baseline of the participants was not
significantly different between the 4 groups. Those who had diseases causing immuno-
suppression, had digestive disease that alter the absorption of micronutrients and those
who were taking vitamin supplements were excluded
Interventions They were assigned to 1 of 4 groups:

1) Vitamin A group that received 20,000 IU retinol every 2 months for children aged
<= 1 year or 45,000 IU for children aged > 1 year
2) Zn group that received a daily dose equivalent to 20 mg elemental Zn as zinc methio-
nine
3) A group that received both the zinc supplement and the vitamin A as above
4) A placebo group
Outcomes Prevalence of respiratory tract infections:

1) Cough alone
2) Cough and fever
3) Cough and rapid respiratory rate
Notes This study was conducted in La Magdalena Atlicpac, Mexico. About 12% of the children
there were classified as having a height-for-age z score below -2. Children were visited
twice a week for 1 year. 93 children were lost to follow up or were excluded, 736 children
were followed for 12 months (181 in the zinc group, 192 in the vitamin A + zinc group,
180 in the vitamin A group, and 183 in the placebo group). Child-year of follow up
in vitamin A group and placebo group were 153.9 and 155.1. The loss to follow up in
the vitamin A group and control group was 20 (10%) and 17 (8.5%) respectively. The
sample size of 200 per children per group was estimated by assuming that the diarrhoeal
disease rate was 3 episodes per child per year with a power of 80% and 95% significance
level and an expected loss to follow up of 20%
Long 2006 (Continued)
Risk of bias
Adequate sequence generation? Unclear Only mentioned “randomized trial”

All outcomes
Incomplete outcome data addressed? No The loss to follow up in the vitamin A group
All outcomes and control group were 20 (10%) and 17
(8.5%), respectively
ported

tween the groups
Rahman 2001
Methods Randomised, parallel groups design, double-blind
Participants 800 children aged 12 to 35 months
Interventions Children were randomized to receive 1 of 4 treatments: zinc, vitamin A, both zinc and
vitamin A, or placebo
The zinc group received 5 ml zinc syrup (20 mg elemental zinc) daily for 14 days and a
placebo capsule on day 14
The vitamin A group received 5 ml placebo syrup daily for 14 days and a 200,000 IU
(60 mg) vitamin A capsule on day 14
The zinc plus vitamin A group received 5 ml zinc syrup daily for 14 days and a 200,000
IU vitamin A capsule on day 14
The placebo group received 5 ml placebo syrup daily for 14 days and a placebo capsule
on day 14
Outcomes Incidence and prevalence of acute lower respiratory infection and diarrhoea
Notes There were no significant differences between groups
Risk of bias
Rahman 2001 (Continued)
Adequate sequence generation? Unclear There was no description about the method
of randomisation for generating the alloca-
tion sequence
Allocation concealment? Yes The randomisation code was kept sealed

until the completion of the study

All outcomes
Incomplete outcome data addressed? No 135 (17%) were excluded from the study
All outcomes or dropped out. Of these 135 children, 85
(11% of total) were excluded because they
had received vitamin A after enrolment
during the “National vitamin A week” cam-
paign in Bangladesh.
49 (6%) children were lost to follow up
or had fewer than 90 days of observation
period, and one child was excluded owing
to a complicated illness
ported
Free of other bias? Unclear There were no significant differences be-

tween the groups
Rahmathullah 1991
Methods The article stated it was a randomized, controlled, masked clinical trial. Due to varied
population density in the area where this study took place, the researchers used a cluster-
sampling design. 206 clusters were formed, and the majority of them consisted of 50
to 100 children 6 to 60 month of age. The article did not state clearly how the clusters
were randomly assigned to the control or vitamin A group
Participants 15,419 children 6 to 60 months of age were included in the study. The baseline of the 2
groups was comparable on the following characteristics: age and sex, 1-month history of
diarrhoea and respiratory disease, anthropometric indexes of nutritional status, xeroph-
thalmia status, 5-year retrospective history of mortality of children under 5, household
economic, household hygienic status, and serum retinol levels. Exclusion for analysis:
receiving a high-dose supplement of vitamin A because of xerophthalmia at baseline,
midterm, or final examination (n = 2687); missing receiving the supplement for > 7
consecutive weeks or for > 4 weeks on four occasions (n = 1874)
Interventions Half the children received weekly doses of 8333 IU vitamin A and 20 mg vitamin E
(treated) and 20 mg vitamin E the other half (control). Any children diagnosed with
xerophthalmia at baseline, midterm, or final examination was given a high-dose (60,000
ug) supplement of vitamin A and continued in their study
Rahmathullah 1991 (Continued)
Outcomes Incidence of lower respiratory tract infections
Notes Setting: the study was carried out in 3 drought-prone Panchayat Unions, which are poor
in economy and environment, of the Trichy district of Tamil Nadu in southern India.
Children were visited once a week for 52 weeks. All morbidity data were analysed both
without exclusion (N = 15,419, intention-to treat analysis) and with exclusion (N =
10858). The article stated that no significant changes in RR occurred when each of the
exclusions was applied. The data presented in the article were based on an intention-
to-treat analysis. On average > 90% of the children were contacted each week, and the
lowest coverage in any single week was 88%. 11% had clinical evidence of xerophthalmia
while about 38% had serum retinol concentrations <= 0.35 mmol/L at baseline
Risk of bias
Adequate sequence generation? Unclear Only mentioned “randomized”
Blinding? Yes Only mentioned “masked”

All outcomes
Incomplete outcome data addressed? No On average > 90% of the children were con-
All outcomes tacted each week, and the lowest coverage
in any single week was 88%
ported

tween groups
Sempertegui 1999
Methods A randomized, placebo-controlled, double-blind trial. Identical flasks containing vita-

min A or placebo were numbered from 1 to 400 by members of the study team in
Boston, Massachusetts. The local Ethical Committee of the Ecuadorian Biotechnology
Corporation in Quito did not know the identity of the active or placebo flasks, because
they did not have the code. Then, this committee assigned each flask to a specific child
from a random list by using a table of random numbers. After randomisation, the ethical
committee received the confidential code from Boston and kept it for the remainder of
the study, when it was revealed
Participants All study participants were children 6 to 36 months of age living in the neighbourhood.
All children (N = 613) between 6 to 36 months of age were considered eligible. Age was
verified through birth certificates. To decrease the drop-out rate, the researchers selected
those children who reliably stayed at home or at day care centres during weekdays (N =
Sempertegui 1999 (Continued)
525), and then they excluded children whose families had lived in the neighbourhood
for < 1 year (N = 60). Children who had been given multivitamins in the last 3 months
also were excluded (N = 6). A total of 459 children were available for entry into the study.
These children were examined by an ophthalmologist for signs of xerophthalmia. No cases
of xerophthalmia were found. Finally, 400 children completing the basal anthropometric
test were included. The baselines of the 2wo groups were comparable
Interventions Children in the supplement-treated group received a weekly dose of 10,000 IU of vitamin
A (3000 mg of retinol) for 40 weeks, and children in the non-supplement group received
a weekly placebo for the same period
Outcomes The incidence of ALRI: defined as tachypnea (respiratory rate 40 /min) and/ or lower
respiratory tract secretions (alveolar or bronchoalveolar) assessed by thoracic auscultation
with 1 or more of the following symptoms: cough, fever and chest retractions
Notes This study was conducted in the northwestern region of the Quito, Ecuador, which
represented most Ecuadorian high Andean slums with substantial rates of malnutrition
and subclinical vitamin A deficiency. Children were visited weekly. The total person-
time of follow up of vitamin A group and control group was 5719 child-weeks and 5707
child-weeks. The researchers assumed that the incidence of diarrhoeal disease in this area
was 46 episodes per 1000 child-weeks. The sample sizes of 200 children per group were
based on detecting a 25% reduction in the incidence of diarrhoea with 80% power and
2-tailed 0.05 significance, and it allowed for 30% annual drop-out. The reported yearly
incidence of acute respiratory tract infections is similar to that of acute diarrhoeal, so the
researchers inferred that this sample sizes of 200 children in each group were likely to be
sufficient
Risk of bias
Adequate sequence generation? Yes Allocation sequence was generated by using

a random number table
Allocation concealment? Yes The ethics committee received the confi-

dential code and kept it for the remainder
of the study until it was revealed

All outcomes
Incomplete outcome data addressed? No 50 children from the supplement-treated

All outcomes group and 44 from the non-supplement
group were lost to follow up
ported
Sempertegui 1999 (Continued)

tween groups
Stansfield 1993
Methods A randomized, placebo-controlled, double-blind trial
Participants 11,124 children aged 6 to 83 months. Those with corneal changes consistent with
vitamin A deficiency, with measles and those had received vitamin A within the past 4
months were excluded. The baseline of the 2 groups was comparable
Interventions The vitamin A group received 100,000 IU supplements every 4 months for 3 distribution
cycle for those 6 to 11 months and 200,000 IU for the older, while the other group only
received placebo
Outcomes 2 week prevalence of signs of respiratory tract infections: cold, cough and rapid breathing
Notes This study was conducted at north west of Haiti with a high prevalence of malnutrition
and xerophthalmia. 72% (7958) of total 11,124 participants received at least 2 doses,
and 38% (4178) received 3 doses. Children were visited every 2 weeks for 12 months
Risk of bias
Adequate sequence generation? Unclear Only mentioned “random”

All outcomes
Incomplete outcome data addressed? Unclear Not mentioned

All outcomes
ported

tween groups
VAST 1993
Methods Randomised double-blind controlled trial. Randomisation was by individuals in the

Health Study
Participants The Health Study included 1455 children aged 6 to 59 months. Inclusion: children 6
to 59 months. Children born from 1986 were included in the Health Study. Excluded:
children with active xerophthalmia or measles were excluded from the trial as soon as
they were confirmed
Interventions Children were randomly assigned either 200,000 IU retinol equivalent (100,000 IU
under 12 months) or placebo every 4 months
Outcomes Mean daily prevalence of sighs of lower respiratory tract infections:

1) daytime cough
2) tired ribs (severe respiratory illness)
3) difficulty in breathing
4) rapid breathing
Notes This study was conducted in guinea savannah area of Ghana with a sub-Sahelian climate.
The study populations were rural and their main staple foods are deficient in carotenoids
and vitamin A. Vitamin A deficiency and xerophthalmia were recognised as problems
locally. Children were visited weekly for 1 year. 1455 children in the Health Study were
followed up for 1185 child-years (596 for vitamin A group and 589 for control group),
of whom, 1287 (88.5%) survived, 26 (1.8%) died, 14 (1.0%) developed measles, 4 (0.
3%) withdrew consent, and 119 (8.2%) were lost to follow up
Risk of bias
Adequate sequence generation? Unclear Randomisation was carried out by an inde-

pendent statistician
Allocation concealment? Yes The randomisation code was kept by an

independent statistician
Blinding? Yes Triple-blinded

All outcomes
Incomplete outcome data addressed? Yes 14 (1.0%) developed measles, 4 (0.3%)

All outcomes withdrew consent, and 119 (8.2%) were
lost to follow up
ported

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

ALRI: acute lower respiratory tract infection
LRTI: lower respiratory tract infection
Characteristics of studies awaiting assessment [ordered by study ID]
Donnen 2007
Methods Randomised, double-blind controlled trial
Participants 604 and 610 Senegalese hospitalized children
Interventions A high-dose vitamin A supplement (200,000 IU) on admission, the second a daily low-dose vitamin A supplement
(5000 IU daily) during hospitalization
Outcomes Survival, incidence of respiratory disease, duration of respiratory infection, duration and incidence of diarrhoea,
mortality
Notes
Long 2007
Methods Randomised controlled trial
Participants A total of 188 children, aged 6 to 15 months, from peri-urban, marginalised communities of Mexico City
Interventions Vitamin A or placebo
Outcomes The incidence and duration of respiratory tract infections
Notes
Swami 2007
Methods Randomised controlled trial
Participants 27,642 (98.7%) and 31,762 (88.0%) children were included respectively in Chandigarh. A random sample of 276
children from the intervention area and 252 children from control area in the age group of 1 to 5 years were followed
Interventions Mass supplementation of vitamin A solution
Outcomes The average annual episodes of ARI
Notes
ARI: acute respiratory infection

IU: international units
DATA AND ANALYSES
Comparison 1. Vitamin A versus placebo
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Incidence of acute LRTI in 3 Incidence of ALRI (Random, 95% CI) Subtotals only
community-based trials
1.1 Age <= 5 3 Incidence of ALRI (Random, 95% CI) 1.13 [0.88, 1.43]
1.2 Mega dose 2 Incidence of ALRI (Random, 95% CI) 1.13 [0.80, 1.60]
1.3 Low dosage 1 Incidence of ALRI (Random, 95% CI) 1.16 [0.77, 1.76]
1.4 Under weight 1 Incidence of ALRI (Random, 95% CI) 0.38 [0.17, 0.85]
1.5 Stunted 1 Incidence of ALRI (Random, 95% CI) 0.48 [0.21, 1.12]
1.6 Normal 1 Incidence of ALRI (Random, 95% CI) 2.22 [1.25, 3.95]
2 Prevalence of symptoms of acute 1 Prevalence (Random, 95% CI) Totals not selected
LRTI
2.1 Overall cough 1 Prevalence (Random, 95% CI) Not estimable
2.2 Cough with difficulty in 1 Prevalence (Random, 95% CI) Not estimable
breathing
2.3 Cough with fever 1 Prevalence (Random, 95% CI) Not estimable
Analysis 1.1. Comparison 1 Vitamin A versus placebo, Outcome 1 Incidence of acute LRTI in community-
based trials.
Review: Vitamin A for preventing acute lower respiratory tract infections in children up to seven years of age
Comparison: 1 Vitamin A versus placebo
Outcome: 1 Incidence of acute LRTI in community-based trials
log
[Incidence Incidence of Incidence of
Study or subgroup of ALRI] ALRI Weight ALRI
(SE) IV,Random,95% CI IV,Random,95% CI
1 Age <= 5
Barreto 1994 -0.0261 (0.0602) 48.8 % 0.97 [ 0.87, 1.10 ]
Dibley 1996 0.3301 (0.1526) 29.9 % 1.39 [ 1.03, 1.88 ]
Sempertegui 1999 0.152 (0.2102) 21.2 % 1.16 [ 0.77, 1.76 ]
Subtotal (95% CI) 100.0 % 1.13 [ 0.88, 1.43 ]

Heterogeneity: Tau2 = 0.03; Chi2 = 5.07, df = 2 (P = 0.08); I2 =61%
Test for overall effect: Z = 0.96 (P = 0.34)
2 Mega dose
Barreto 1994 -0.0261 (0.0602) 57.7 % 0.97 [ 0.87, 1.10 ]
Dibley 1996 0.3301 (0.1526) 42.3 % 1.39 [ 1.03, 1.88 ]
Subtotal (95% CI) 100.0 % 1.13 [ 0.80, 1.60 ]

Heterogeneity: Tau2 = 0.05; Chi2 = 4.71, df = 1 (P = 0.03); I2 =79%
3 Low dosage
Sempertegui 1999 0.152 (0.2102) 100.0 % 1.16 [ 0.77, 1.76 ]
Subtotal (95% CI) 100.0 % 1.16 [ 0.77, 1.76 ]

Heterogeneity: not applicable
4 Under weight
Sempertegui 1999 -0.9612 (0.4082) 100.0 % 0.38 [ 0.17, 0.85 ]
Subtotal (95% CI) 100.0 % 0.38 [ 0.17, 0.85 ]

5 Stunted
Sempertegui 1999 -0.7339 (0.433) 100.0 % 0.48 [ 0.21, 1.12 ]
Subtotal (95% CI) 100.0 % 0.48 [ 0.21, 1.12 ]

6 Normal
Sempertegui 1999 0.7983 (0.2942) 100.0 % 2.22 [ 1.25, 3.95 ]
Subtotal (95% CI) 100.0 % 2.22 [ 1.25, 3.95 ]

0.2 0.5 1 2 5
Favours treatment Favours control
Analysis 1.2. Comparison 1 Vitamin A versus placebo, Outcome 2 Prevalence of symptoms of acute LRTI.
Review: Vitamin A for preventing acute lower respiratory tract infections in children up to seven years of age
Comparison: 1 Vitamin A versus placebo
Outcome: 2 Prevalence of symptoms of acute LRTI
Study or subgroup log [Prevalence] Prevalence Prevalence

(SE) IV,Random,95% CI IV,Random,95% CI
1 Overall cough
Long 2006 -0.1061 (0.0627) 0.90 [ 0.80, 1.02 ]
2 Cough with difficulty in breathing

Long 2006 -0.6855 (0.5477) 0.50 [ 0.17, 1.47 ]
3 Cough with fever

Long 2006 0.0354 (0.1178) 1.04 [ 0.82, 1.31 ]
0.2 0.5 1 2 5
Favours treatment Favours control
ADDITIONAL TABLES
Table 1. Incidence of acute lower respiratory infections of community-based trials (original data)
Study Vitamin A group Placebo group RR
Barreto 1994 Incidence: 0.002686 per child- Incidence: 0.002757 per child- 0.97 (0.86 to 1.09)
days days
Dibley 1996 Incidence: 0.0002668 per Incidence: 0.0003712 per 1.39 (1.003 to 1.931)
child-days child-days
Sempertegui 1999 Incidence: 8.5 per 1000 child- Incidence: 22.3 per 1000 child- 0.38 (0.17 to 0.85)
(underweight) weeks weeks
Sempertegui 1999 (stunted) Incidence: 4.7 per 1000 child- Incidence: 9.8 per 1000 child- 0.48 (0.21 to 1.12)
weeks weeks
Table 1. Incidence of acute lower respiratory infections of community-based trials (original data) (Continued)
Sempertegui 1999 (normal) Incidence: 9.8 per 1000 child- Incidence: 4.4 per 1000 child- 2.21 (1.24 to 3.39)
weeks weeks
Table 2. Donnen 1998: morbidity during hospitalisation related to respiratory tract infections
Symptoms High-dose Low-dose Placebo
ALRI1
Never 99.3% 98.6% 98.6%
>= 1 episodes 0.7% 1.4% 1.4%
ALRI2
Never 98.6% 99.0% 99.3%
>= 1 episodes 1.4% 1.0% 0.7%
Fever
Never 90.6% 92.7% 92.1%
>= 1 episodes 9.4% 7.3% 7.9%
ALRI = acute lower respiratory infection
Table 3. Rahman 2001: incidence and prevalence of acute lower respiratory infections
Incidence Prevalence
Group Episodes Person-years Incidence Rate ratio Days with Person-years Prevalence Rate ratio
ALRI at risk infec- (95%CI) illness (95% CI)
tion
Acute lower respiratory infection
Zinc 172 55.003 1.14 1.62 787 56.322 5.10 2.07

(n = 345) (1.16 to 2. (1.76 to 2.44)
25)
Vitamin A 137 53.762 0.93 1.06 580 54.727 3.87 1.20

(n = 334) (0.74 to 1. (0.99 to 1.45)
53)
Table 3. Rahman 2001: incidence and prevalence of acute lower respiratory infections (Continued)
Placebo 56 25.836 0.79 1.0 211 26.215 2.94 1.0

(n = 161)
Interac- 0.75 0.58

tion of zinc (0.46 to 1. (0.46 to 0.73)
and vitamin 20)
A
Severe acute lower respiratory infection
Zinc 172 55.003 1.14 1.62 787 56.322 5.10 2.07

(n = 345) (1.16 to 2. 1.76 to 2.44)
25)
Vitamin A 137 53/762 0.93 1.06 580 54.727 3.87 1.20

(n = 334) (0.74 to 1. (0.99 to 1.45)
53)
Placebo 56 25.836 0.79 1.0 211 26.215 2.94 1.0

(n = 161)
Interac- 0.66 0.56

tion of zinc (0.33 to 1. (0.39 to 0.80)
and vitamin 31)
A
Table 4. Rahmathullah 1991: number of episodes of acute lower respiratory infections/number of children
Age Vitamin A Placebo Rate ratio 95% CI
<= 11 mo 0.006 0.06 1.01 0.58 to 1.76
12 to 35 mo 0.05 0.05 0.98 0.58 to 1.66
>= 36 mo 0.04 0.04 1.05 0.55 to 2.00
Table 5. Bhandari 1994: incidence of acute lower respiratory infections over 90 days
Age Vitamin A Placebo Relative risk
All children 0.44 0.41 1.07 (0.92 to 1.26)
Age <= 23 months 0.59 0.49 1.19 (0.99 to 1.43)
Age > 23 months 0.33 0.34 0.98 (0.75 to 1.26)
Table 6. Barreto 1994: mean daily prevalence of respiratory symptoms
Symptoms Vitamin A Placebo Rate ratio P
Cough 0.2429 0.2388 0.99 0.57
Cough + fever 0.0289 0.0282 0.99 0.90
Cough + IRR 0.0124 0.0129 0.96 0.74
IRR = instantaneous respiratory rate
Table 7. VAST 1993: mean daily prevalence of signs or symptoms
Symptoms Vitamin A Placebo Prevalence ratio P
Daytime cough 13.2% 13.0% 1.02 0.67
“Tied ribs” (severe respi- 1.1% 1.1% 0.98 0.86

ratory illness)
Difficulty breathing 1.2% 1.2% 0.96 0.70
Rapid breathing 1.1% 1.3% 0.81 0.11
Table 8. Stansfield 1993: risk ratio for 2-week prevalence of morbidity by age group
Age group (months) Cold Cough Rapid breathing
<11 (817; 660) 0.99 (0.93 to 1.06) 1.00 (0.90 to 1.12) 1.18 (0.97 to 1.45)
12-23 (1206; 1001) 1.05 (1.00 to 1.11) 1.07 (0.98 to 1.18) 1.25 (1.04 to 1.50)
24-35 (1210; 966) 1.10 (1.05 to 1.16) 1.15 (1.05 to 1.26) 1.05 (0.88 to 1.26)
36-47 (1181; 930) 1.00 (0.95 to 1.06) 1.02 (0.93 to 1.12) 1.23 (1.00 to 1.51)
48-59 (1069; 921) 1.09 (1.02 to 1.15) 1.13 (1.03 to 1.25) 1.20 (0.97 to 1.47)
60-71 (896; 809) 0.98 (0.92 to 1.04) 1.02 (0.92 to 1.14) 1.19 (0.94 to 1.50)
72-83 (711; 540) 1.05 (0.98 to 1.12) 1.06 (0.93 to 1.20) 1.03 (0.79 to 1.34)
Table 9. Stansfield 1993: 2-week prevalence of morbidity
Symptom Vitamin A Placebo Rate ratio
Cough 48% 45% 1.18 (1.09 to 1.27)
Rapid breathing 18% 15% 1.18 (1.09 to 1.27)
Table 10. Prevalence of symptoms of acute lower respiratory infections (original data)
Study Vitamin A group Placebo group RR
Long 2006 (overall cough) Prevalence: 481/153.9 per Prevalence: 539/155.1 per 0.90
child-years child-years
Long 2006 (cough with diffi- Prevalence: 5/153.9 per child- Prevalence: 10/155.1 per child- 0.50
culty breathing) years years
Long 2006 (cough with fever) Prevalence: 146/153.9 per Prevalence: 142/155.1 per 1.04
child-years child-years
APPENDICES
Appendix 1. Previous search
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 2), which contains the
Cochrane Acute Respiratory Infection Group’s Specialised Register; MEDLINE (1966 to July 2010); EMBASE (1974 to July 2010);
and the Chinese Biomedicine Database (CBM) (1976 to July 2010).
We ran the following search strategy over CENTRAL and MEDLINE in combination with the highly sensitive search strategy developed
by The Cochrane Collaboration for identifying RCTs (Dickersin 1994). The search strategy was modified to search the EMBASE and
CBM databases.
MEDLINE (OVID)
1 exp vitamin A/
2 vitamin A.mp.
3 retinal.mp.
4 retinol.mp.
5 or/1-4
6 lower respiratory tract infection$.mp.
7 lower respiratory infection$.mp.
8 LRTI$.mp.
9 ALRI$.mp.
10 exp respiratory tract infections/
11 exp bronchiolitis/
12 bronchiolitis.mp.
13 exp bronchitis/
14 bronchitis.mp.
15 exp laryngitis/
16 laryngitis.mp.
17 exp pneumonia/
18 pneumonia.mp.
19 (lung adj inflammation).mp.
20 pneumonitis.mp.
21 (pulmonary adj inflammation).mp.
22 exp tracheitis/
23 tracheitis.mp.
24 or/6-23
25 5 and 24
We also searched (July 2007) the following ongoing trials registers: www.controlled-trials.com/; www.clinicaltrials.gov;
www.trialscentral.org/ and ctr.glaxowellcome.co.uk/welcome.asp. In addition, we searched publications from organisations such as the
World Health Organization. We searched for evidence on adverse effects from other sources, such as the UK Medicines Control Agency
www.open.gov.uk/mca; MedWatch produced by the US Food and Drug Administration; and the Australian Adverse Drug Reactions
Bulletin www.health.gov.au/.
Appendix 2. Embase.com search strategy

#20. #16 AND #19
#19. #17 OR #18
#18. random*:ab,ti OR placebo*:ab,ti OR crossover*:ab,ti OR ’cross over’:ab,ti OR ’cross-over’:ab,ti OR allocat*:ab,ti OR
assign*:ab,ti OR volunteer*:ab,ti OR factorial*:ab,ti OR ((singl* OR doubl*) NEAR/2 (blind* OR mask*)):ab,ti
#17. ’randomized controlled trial’/exp OR ’single blind procedure’/exp OR ’double blind procedure’/exp OR ’crossover procedure’/exp
#16. #12 AND #15
#15. #13 OR #14
#14. ’vitamin a’:ab,ti OR retinol:ab,ti OR retinal:ab,ti
#13. ’retinol’/exp
#12. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11
#11. tracheit*:ab,ti
#10. ’tracheitis’/exp
#9. ((lung OR pulmonary) NEAR/3 (inflam* OR infect*)):ab,ti
#8. pneumon*:ab,ti
#7. ’pneumonia’/exp
#6. laryngit*:ab,ti OR laryngotracheobronchit*:ab,ti
#5. ’laryngitis’/exp
#4. bronchit*:ab,ti OR bronchiolit*:ab,ti OR bronchopneumon*:ab,ti OR tracheobronchit*:ab,ti
#3. ’bronchitis’/exp
#2. ’respiratory tract infection’:ab,ti OR ’respiratory tract infections’:ab,ti OR ’lower respiratory infections’:ab,ti OR ’lower
respiratory infection’:ab,ti OR lrti:ab,ti OR alri:ab,ti
#1. ’respiratory tract infection’/exp
WHAT’S NEW
Last assessed as up-to-date: 29 June 2010.
Date Event Description
10 March 2010 New search has been performed Searches 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 classifica-
tion (Donnen 2007; Long 2007). This update also includes the GRADE tool
for assessing trial quality
HISTORY
Protocol first published: Issue 3, 2006
Review first published: Issue 1, 2008
Date Event Description
23 June 2008 Amended Converted to new review format.
14 September 2007 Amended As 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 2007 New search has been performed Searches conducted.
CONTRIBUTIONS OF AUTHORS
Hengxi Chen (HC) was responsible for developing the protocol, searching for trials, quality assessment of trials, data extraction, data
analysis and review development.
Taixiang Wu (TW) was responsible for data extraction, drafting the review, editing, commenting and amending the updated review.
Qi Zhuo (QZ), Wei Yuan (WY) and Juan Wang (JW) were responsible for telephone interviewing the first authors of the Chinese
trials.
DECLARATIONS OF INTEREST
None known.
SOURCES OF SUPPORT
Internal sources
• Chinese Cochrane Centre, West China Medical Centre, Sichuan University, China.
External sources
• Cochrane Acute Respiratory Infections Group, Australia.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

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

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Vitamin A for preventing acute lower respiratory tract

infections in children up to seven years of age (Review)

Chen H, Zhuo Q, Yuan W, Wang J, Wu T

Vitamin A for preventing acute lower respiratory tract

Hengxi Chen2 , Qi Zhuo3 , Wei Yuan3 , Juan Wang3 , Taixiang Wu1

PLAIN LANGUAGE SUMMARY

Figure 1. Search strategy in Chinese databases

RESULTS Outcome measures

Incidence of acute LRTI

Prevalence of respiratory tract infections

1. Primary outcome: incidence of acute LRTI

Subgroup: by age 3. Adverse effect of vitamin A

Characteristics of included studies [ordered by study ID]

Methods Randomised, double-blind, placebo-controlled clinical trial

Outcomes 1. ALRI incidence

Item Authors’ judgement Description

Adequate sequence generation? Unclear Only mentioned “randomly assigned”

Allocation concealment? Yes Only an external investigator had the codes

Blinding? Yes Double-blind

Free of other bias? Yes There were no significant differences be-

Methods Randomised, double-blind, placebo-controlled clinical trial. The randomisation method

Outcomes Incidence of ALRI

Item Authors’ judgement Description

Allocation concealment? Unclear Not mentioned

Blinding? Yes Double-blind

Incomplete outcome data addressed? No 58 participants were excluded. 5 withdrew

Free of other bias? Yes There were no significant differences be-

Methods Randomised, double-blind, placebo-controlled trial. Randomisation was done with 1:

Outcomes Incidence of ALRI

Item Authors’ judgement Description

Adequate sequence generation? Unclear Randomisation procedure was described as

Allocation concealment? Unclear Not mentioned

Blinding? Yes All investigator, field and laboratory staff,

Free of other bias? Yes There were no significant differences be-

Methods Randomised, double-blind, placebo-controlled clinical trial

Outcomes Incidence of ALRI

Item Authors’ judgement Description

Adequate sequence generation? Unclear Only mentioned “randomly assigned”

Allocation concealment? Unclear Not mentioned

Blinding? Yes “Double-blind”. Paediatrician was the only

Incomplete outcome data addressed? Yes No participants lost to follow up

Free of other bias? Yes There were no significant differences be-

Methods Randomised, double-blind, placebo-controlled clinical trial. The randomisation se-

Interventions They were assigned to 1 of 4 groups:

Outcomes Prevalence of respiratory tract infections:

Item Authors’ judgement Description

Adequate sequence generation? Unclear Only mentioned “randomized trial”

Allocation concealment? Unclear Not mentioned

Blinding? Yes Double-blind

Free of other bias? Yes There were no significant differences be-

Methods Randomised, parallel groups design, double-blind

Participants 800 children aged 12 to 35 months

Notes There were no significant differences between groups

Item Authors’ judgement Description

Allocation concealment? Yes The randomisation code was kept sealed

Blinding? Yes Double-blind

Free of other bias? Unclear There were no significant differences be-

Outcomes Incidence of lower respiratory tract infections

Item Authors’ judgement Description

Adequate sequence generation? Unclear Only mentioned “randomized”

Allocation concealment? Unclear Not mentioned

Blinding? Yes Only mentioned “masked”

Free of other bias? Yes There were no significant differences be-

Methods A randomized, placebo-controlled, double-blind trial. Identical flasks containing vita-