Acute lower respiratory tract infections (LRTIs) refer to acute infections which affect the airways below the epiglottis. These includes 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). LRTIs affect adults as well as children. However, children with a poor nutritional status are more vulnerable. Signs and symptoms of LRTIs includes cough, increased amount of sputum, wheezing, increased respiratory rate, changes in lung X-ray, etc.
Acute respiratory tract infections (ARTIs), especially in the form of pneumonia and bronchiolitis, are the leading causes 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 and pertussis and neonatal deaths, was 2.1 million, which means about 20% of this age group die annually 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 ARI in 2000, 70% of them in Africa and Southeast Asia (Williams 2002). The incidence of clinical pneumonia in developing countries is suggested to be near 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, it is not directly comparable to that of developing countries, due to different definitions and research methods (Rudan 2004).
Currently, the most common methods to prevent the acute LRTIs include improved general hygiene (Walter 2001), administering immunostimulants (Gutierrez 2001), administering antibiotics (Bonten 2003), administering gamma globulins (Nydahl-Persson 1995), measles and pertussis immunization and administering nutritional supplements such as zinc (Bhandari 2002; Sazawal 1998), vitamin C (Hemila 2004), vitamin A etc.
Vitamin A deficiency is also a common public health problem, especially in developing countries. It is associated with impaired humoral and cellular immune function, keratinization of the respiratory epithelium and decreased mucus secretion, which weakens barriers to infection (Ross 1996). Therefore it seems that the administration of vitamin A can prevent respiratory tract infections. However, overdosage of vitamin A causes acute toxicosis (resulting in raised intracranial pressure, nausea, vomiting, etc) and chronic toxicosis (resulting in an enlarged liver, loss of appetite, etc).
Much research has been done to determine the relationship between vitamin A administration and acute LRTIs. However, the results are not consistent. 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 the context-specific distribution of 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 (such as dosage, duration, etc) of vitamin A.
A meta-analysis assessed the effect of vitamin A supplementation on childhood morbidity from respiratory tract infections and diarrhea (Grotto 2003). It indicated that vitamin A supplementation slightly increased the incidence of respiratory tract infections. High-dose vitamin A supplements are not recommended on a routine basis for all preschool children, and should be given only to those with a vitamin A deficiency.
Given this information, a systematic clarification between the administration of vitamin A and the prevention of acute LRTIs is clearly important. We aim to determine the benefit versus the harms from administration of vitamin A in children and adults. We also aim to determine whether or not acute LRTIs, in subgroups of age, weight and nutritional state etc, differ in response to vitamin A supplementation.
To assess the effectiveness and safety of vitamin A in the prevention of acute LRTIs in children and adults.
Criteria for considering studies for this review
Types of studies
We will include any randomized controlled trial (RCT) which examines the effect of vitamin A on preventing and treating acute LRTIs. Children with repeated LRTIs will be included in the review. Trials assessing the effect of vitamin A on hospitalized children with pneumonia (or other illnesses) and subsequent morbidity and mortality due to LRTIs, will also included.
Types of participants
Children and adults of all ages.
Types of intervention
Vitamin A (any dose) versus placebo or no vitamin A.
Types of outcome measures
1. Incidence of acute LRTI confirmed by doctors using the gold standard during the study period on the basis of strict pre-defined criteria - usually fever, tachypnea and recession +/- cough or chest signs or radiological signs. Indirect criteria for LRTI such as hospitalization, clinic attendance, death etc. will be evaluated if a gold standard criterion is not stated in a study. Acute LRTIs refer to acute infections which affect the airways below the epiglottis (Rudan 2004; WHO 2003).
1. Incidence of signs and symptoms of acute LRTIs such as cough (alone or associated with fever), increased respiratory rate, increased sputum development, specific X-ray changes of the lung etc.
2. Severity of acute respiratory infections such as number of infected days, hospitalization rate/days, death, etc.
3. Adverse events following the administration of vitamin A such as raised intracranial pressure, vomiting, nausea, enlargement of liver, etc.
Search methods for identification of studies
See: Cochrane Acute Respiratory Infections Group methods used in reviews.
We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue); MEDLINE (1966 to present); EMBASE (1974 to present ); LILACS (all years); CINAHL (all years); Biological Abstracts (1990 to present); Current Contents (1990 to present); and the Chinese Biomedicine Database (CBM) (1976 to present).
We will run the following search strategy on MEDLINE in combination with the highly sensitive search strategy developed by the Cochrane Collaboration for identifying RCTs (Dickersin 1994). The search strategy will be modified accordingly when searching CENTRAL, EMBASE, LILACS, CINAHL, Biological Abstracts, and CBM and Current Contents.
#1. exp vitamin A/
#2. vitamin A.mp.
#5. or 1-4
#6. lower respiratory tract infection$.mp.
#7. lower respiratory infection$.mp.
#10. exp respiratory tract infections/
#11. exp bronchiolitis/
#12. exp bronchitis/
#13. exp laryngitis/
#14. exp pneumonia/
#15. lung inflammation.mp.
#17. pulmonary inflammation.mp.
#18. exp tracheitis/
#20. 5 AND 19
We will also search the following ongoing database registers:
In addition, we will search publications from organizations such as the World Health Organization. Evidence on adverse effects will be searched from other sources such as UK Medicines Control Agency http://www.open.gov.uk/mca, MedWatch produced by the US Food and Drug Administration and the Australian Adverse Drug Reactions Bulletin http://www.health.gov.au/. We will also handsearch journals and monographs not found in electronic database searches and attempt to locate unpublished studies, for example, meetings papers and degree theses. There will be no language restrictions.
Methods of the review
Four authors (Chen, Wang, Zhuo, Yuan) will independently examine abstracts from the initial search in order to identify studies that meet the inclusion criteria. The full text of those studies thought to fulfill the inclusion criteria and those without abstracts will be retrieved. Chen will conduct telephone interviews or e-mail the original authors of Chinese articles to identify the randomization method and other methodological issues, to ensure the included studies were RCTs. If the required information is not available, the article will be added to the 'Awaiting assessment' reference section.
Two authors (Chen and Wu) will independently extract data from the included studies using a piloted data extraction form. Differences will be resolved by discussion among the review authors or by consulting the Cochrane Acute Respiratory Infections Group. Authors will be blinded to the articles' authors, their institutions, the source of funding and acknowledgments, in order to unbias the assessment.
We will assess the methodological quality of each trial in terms of generation of allocation sequence, allocation concealment, blinding, and loss to follow up; and classify them as 'adequate', 'inadequate', or 'unclear' according to the guidelines of Cochrane Reviewers' Handbook 4.2 (Higgins 2005). Sensitivity analyses will then be undertaken on the basis of whether those quality factors are adequate, inadequate, or unclear. Differences will be resolved by discussion among the review authors.
The following characteristics will be assessed.
Adequacy of the randomization process
A - adequate sequence generation is reported using one of following approaches: random number tables, computer-generated random numbers, coin tossing, or card shuffling
B - does not specify one of the adequate methods outlined in (A) but only mentioned 'random'
C - other methods of allocation that appear to be biased
Adequacy of the allocation concealment process
A - adequate measures to conceal allocations such as central randomization; serially numbered, opaque, sealed envelopes; or another description that contains convincing elements of concealment
B - unclearly concealed trials in which the author does not report an allocation concealment approach at all
C - inadequately concealed allocation that reports an approach that does not fall into one of the categories in (A)
D - does not conceal allocation
Potential for selection bias after allocation
A - trials where an intention-to-treat analysis is possible and few losses to follow up are noted
B - trials which report exclusions (as listed in (A) but exclusions were less than 10%)
C - no reporting on exclusions or exclusions of at least 10%, or wide differences in exclusions between groups
Level of masking
A - blinding of patients (yes/no/unclear)
B - blinding of caregivers (yes/no/unclear)
C - blinding of outcome assessment (yes/no/unclear)
We will analyze the data using Review Manager (version 4.2). We will compare outcome measures for binary data using relative risks. For continuous data, we will use the weighted mean difference. If continuous data have been reported using geometric means, we will combine the findings on a log scale and report on the original scale. We will report medians and ranges in tables only. We will assess heterogeneity amongst trials by inspecting the forest plots and using the chi-square test for heterogeneity with a 10% level and I-square with a 50% level of statistical significance.
Where it is appropriate to pool data and heterogeneity is detected, we will use the random-effects model. We do not intend to combine results of trials with different comparators. Potential bias will be tested for using a funnel plot or other corrective analytical methods, depending on the number of clinical trials included in the systematic review (Egger 1997).
We intend to explore the following potential sources of heterogeneity using subgroup analyses or meta-regression. Subgroup analyses may be based on the following:
1. Ages of participants;
2. Dosage or usage of vitamin A;
3. State of nutrition or weight of participants.
The outcome measures will be discussed according to the above subgroups.
We will explore reasons for heterogeneity in studies and, if necessary, use sensitivity analyses to examine the effects of excluding study subgroups, for example, those studies with lower methodological quality.
Potential conflict of interest
The authors wish to thank Liz Dooley (Review Group Co-ordinator) and Ruth Foxlee (Trials Search Co-ordinator) of the Cochrane ARI Group, Dr. Nick Brown, Dilip Mahalanabis, Nelcy, Janet Wale and Ludovic Reveiz for commenting on this protocol.
Sources of support
External sources of support
- Cochrane Acute Respiratory Infections Group AUSTRALIA
Internal sources of support
- Chinese Cochrane Centre, West China Medical Centre, Sichuan University CHINA
- China Medical Board of New York USA