Zinc supplementation in preventing pneumonia in children: a systematic review Research Proposal

Queensland University of Technology
HLN 707 Research Methods in Health
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Table of contents
I. Project title …………………………………………………………………………………………………………….. 2 II. Investigator(s) …………………………………………………………………………………………………………. 2 III. Summary …………………………………………………………………………………………………………..…. 2 IV. Background …………………………………………………………………………………………………………… 2 IV.1. Description of the condition ……………………………………………………………………………………. 2 IV.2. Description of the intervention ………………………………………………………………………………… 2 IV.3. How the intervention may work ……………………………………………………………………………….. 3 IV.4. Why it is important to do this review ………………………………………………………………………….. 3 IV.5.Purpose statement ………………………………………………………………………………………………. 5 V. Objectives …………………………………………………………………………………………………………….. 5 VI. Study methods ……………………………………………………………………………………………………….. 6 VI.1. Research design ………………………………………………………………………………………………… 6 VI.2.Criteria for considering studies for this systematic review ……………………………………………………… 6 VI.2.1.Types of studies ………………………………………………………………………………………… 6 VI.2.2. Types of participants …………………………………………………………………………………… 6 VI.2.3. The intervention ……………………………………………………………………………………….. 6 VI.2.4. The control ……………………………………………………………………………………………… 7 VI.2.5. The outcome …………………………………………………………………………………………… 7 VI.2.6. Inclusion and exclusion criteria ………………………………………………………………………… 8 VI.3. Search methods for the identification of studies ……………………………………………………………….. 8 VI.4. Data collection and analysis ……………………………………………………………………………………. 8 VI.4.1. Selection of studies …………………………………………………………………………………….. 8 VI.4.2. Data extraction and management ……………………………………………………………………… 9 VI.5. Data analysis …………………………………………………………………………………………………… 9 VI.5.1. Study strength and risk of bias ………………………………………………………………………… 9 VI.5.2. Intervention effects …………………………………………………………………………………….. 9 VII. Ethical implications …………………………………………………………………………………………………. 10 VIII. Project Planning ……………………………………………………………………………………………………. 10 VIII.1. Publication planning ………………………………………………………………………………………. 10 VIII.2. Resources ………………………………………………………………………………………………….. 10 VIII.3. Estimated costs …………………………………………………………………………………………….. 10 VIII.4. Roles and responsibilities ………………………………………………………………………………….. 11 VIII.5. Authorship …………………………………………………………………………………………………. 11 IX. Study significant ……………………………………………………………………………………………………… 11 X. References …………………………………………………………………………………………………………….. 12 XI. Appendixes …………………………………………………………………………………………………………… 14 Table 1. Search strategy for each database …………………………………………………………………………… 14 Table 2. Search results documentation ……………………………………………………………………………….. 15 Table 3. Excluded studies and reasons for exclusion ………………………………………………………………… 16 Table 4. The data extraction table for included studies ……………………………………………………………… 17 Table 5. The summary of the intervention and the control of included studies ……………………………………… 18 Table 6. The summary of the intervention effect of included studies ………………………………………………… 19 Table 7 The relative risk of pneumonia between the zinc and the control groups according to the study strength 20 and risk of bias ……………………………………………………………………………………………… Table 8 The relative risk of pneumonia between the zinc and the control groups, according to the dosage and 21 administration in strong studies with low risk of bias ………………………………………………………. Table 9 The relative risk of pneumonia between the zinc and the control groups, according to the dosage and 22 administration in moderate studies with low risk of bias …………………………………………………… Table 10 The relative risk of pneumonia between the zinc and the control groups, according to the dosage and 23 administration in weak studies with unclear or high risk of bias ………………………………………….. Table 11 The timeline the systematic review project ………………………………………………………………… 24 Table 12 The estimated costs of the systematic review project ……………………………………………………… 24 Figure 1. Article search and selection process flow diagram ………………………………………………………… 25 Figure 2. The example of the summary of risk of bias of included studies ………………………………………….. 26
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I. Project title The efficacy of continuous zinc supplementation in preventing pneumonia in children aged 6 months to 30 months in developing countries: a systematic review.
II. Investigator(s) xxxxxx
III. Summary The efficacy of zinc supplementation in preventing pneumonia is evident but remains inconclusive. One of possible reasons is that factors affecting the zinc efficacy were not accounted for in previous systematic reviews. In addition, the effective zinc dosage and administration, as well as the efficacy of zinc supplementation in children aged 6 to 30 months, the high risk group for zinc deficiency and pneumonia, have not been studied. For these reasons, this systematic review aims to refine previous approaches in determining zinc efficacy in preventing pneumonia with a focus on continuous zinc supplementation on children aged from 6 to 30 months in developing countries. This systematic review will also determine the effective zinc supplementation dosage and administration. The results will add more understanding about the efficacy of zinc supplementation to prevent pneumonia in children. In addition, the findings can also be used as evidence for clinicians and public health decision makers to reduce the burden of disease due to pneumonia in children.
IV. Background IV.1. Description of the condition Pneumonia is the leading cause of morbidity and mortality in children, especially in developing countries. Followed by diarrhoea and neonatal infections, pneumonia is the most common cause of death of under-five children.1 The incidence of pneumonia worldwide is 0.19 episodes per child-year, 60% of which occur in developing countries.2 The burden of disease due to pneumonia also varies with age and the incidence of pneumonia drops rapidly after the age of 30 months.2 Children younger than 24 months are at the highest risk of mortality due to pneumonia, which accounts for 81% of the deaths of children at that age.2 In addition, children younger than 24 months are also prone to restrictive and obstructive lung diseases as the long-term complications of pneumonia.3 Consequently, approaches to reduce the incidence of pneumonia in children aged 30 months or younger in developing countries are essential. IV.2. Description of the intervention The main aim of zinc supplementation in preventing pneumonia in children in developing countries is to correct zinc deficiency as a factor that increases the risk of infection. Zinc
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supplementation is given orally as syrup,4 food sprinkles,5 or dispersed tablets.6 The dosage used in current studies ranges from 5 mg5 to 20 mg4 per day.
IV.3. How the intervention might work Zinc supplementation has potential to prevent pneumonia by addressing zinc deficiency. Zinc deficiency decreases interferon gamma and causes a T-helper1 and T-helper2 imbalance; all of these led to cell-mediated immune system impairment,7 which increases children’s vulnerability to infections. Therefore, by correcting zinc deficiency, the risk of contracting infectious diseases, including pneumonia, can be reduced. Furthermore, the benefit of zinc supplementation in controlling diarrhoea has been documented.8,9 Consequently, the success of zinc supplementation in controlling diarrhoea brings a promising future of zinc supplementation in preventing pneumonia in children. Zinc supplementation is beneficial for children in developing countries, in which zinc deficiency is prevalent.10,11 In this population, zinc deficiency is a result of the consumption of staple food containing less absorbable zinc, lower zinc status at birth due to low birth weight and mother under-nutrition, diarrhoea, excessive zinc loss due to perspiration and skin exfoliation, especially in countries where the weather is hot and humid.12 In addition, infants older than 6 months are prone to zinc deficiency due to the introduction and the consumption of solid food containing less absorbable zinc and significant reduction in the consumption of breast-milk, the source of absorbable zinc.12,13 Through zinc supplementation, these factors can be addressed and the impact of zinc deficiency on immune system can be prevented.
IV.4. Why it is important to do this review Many studies have been done to determine zinc preventive effect on pneumonia in under-five children; however, the results have not been conclusive. From previous studies, three single randomised controlled trials (RCTs) 4,14, 15 show that zinc supplementation was effective in preventing pneumonia but not in three other RCTs.5,6,16 Moreover, two single RCTs reported that the incidence of pneumonia was higher in the zinc group compared to the control group.17,18 Meanwhile, three systematic reviews found that zinc was effective and the risk of having pneumonia ranged from 0.51 to 0.87 times lower in children who had zinc supplementation compare to those who did not.19,20,21 However, two other systematic reviews22,23 revealed that zinc was not effective. Therefore, a further study is needed to ascertain the efficacy of zinc supplementation in preventing pneumonia. Another reason why it is important to do this systematic review is that in previous studies factors that affecting the efficacy of zinc supplementation in preventing pneumonia were not completely accounted for. First, the duration of zinc supplementation that should cover the pneumonia surveillance period was not fully considered in previous systematic reviews.19-23 In some RCTs the incidence of pneumonia was still measured until 4 months4,15 and 6 months6,16,18 after the cessation of zinc supplementation. As zinc cannot be accumulated and zinc plasma levels drop significantly after
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the cessation of zinc supplementation,16 zinc should be given continuously along the duration of pneumonia surveillance in order to prove zinc efficacy in preventing pneumonia. Consequently, continuous zinc supplementation in preventing pneumonia in children needs further study. In addition, the methods of zinc administration were not fully assessed in previous studies. Zinc administration whether with or without food was not considered in sub-group analysis in some systematic reviews.19,20,22,23 In previous RCTs, the zinc administration method varied greatly whether zinc was given without food,16 with food5,17 breast-milk,6 or not specified.4,14,15,18 Not considering zinc supplementation given with or without food may cause zinc inefficacy in preventing pneumonia in previous studies since food containing phytate, dietary fibre, and calcium will decrease zinc absorption and efficacy.12 Therefore, a systematic review in which zinc given with or without food is accounted for is necessary to determine the efficacy of zinc supplementation in preventing childhood pneumonia. Another reason why this systematic review is valuable is that the intervention coverage of zinc supplementation was not considered in previous studies. Intervention coverage should be assessed since it affects the efficacy of zinc supplementation. As zinc supplementation coverage has not been assessed in previous systematic reviews,19-23 intervention coverage should be further studied in assessing the efficacy of zinc supplementation in preventing childhood pneumonia. Moreover, the optimal dosage of zinc supplementation has not been completely determined. Three RCTs6,14,15 extrapolated the dosage from the dosage for diarrhoea treatment, which is 10 mg per day for children younger than 1 year and 20 mg for older children.9 This dosage is twice as high as the recommended dietary allowance (RDA), which is 5 mg per day for infants and 10 mg per day for preadolescent children.24 Many studies used a dosage of 5 mg,5 10 mg,15-17 and 20 mg4 per day without considering the age of the children. Zinc supplementation according to RDA can be a potential effective dosage since a dosage lower than RDA was not effective.5 Zinc supplementation higher than RDA is not necessary as a small amount of zinc is more efficiently absorbed than a larger amount, especially in a zinc deficiency status.24 However, only one systematic review assessed the zinc dosage.23 As the duration of zinc supplementation that should cover the duration of pneumonia surveillance was not clearly determined in the previous systematic review,23 the optimal dosage of zinc supplementation in preventing pneumonia needs further study. Another factor that contributes to inconsistency of zinc’s preventive effect on pneumonia across studies is non-specific pneumonia case definitions. The efficacy of zinc supplementation in preventing pneumonia was not detected if the case definition of pneumonia is not specific, based on reported respiratory symptoms but not chest examinations.20 The efficacy of zinc in preventing pneumonia was documented in reviewed studies using more specific pneumonia case definitions.14,15,19,20 In studies not using specific pneumonia case definitions; however, the preventive effect of zinc supplementation on pneumonia was not detected.6,16-18, 22,23 Therefore, specific
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pneumonia case definitions should be considered in evaluating the efficacy of zinc supplementation on pneumonia. Lastly, zinc efficacy in preventing pneumonia in children aged 6 to 30 months in developing countries has not been studied. Most of previous systematic review focused on children aged from 2 month to 59 months.19-21,23 Meanwhile, children aged 6 to 30 months are the most benefited from the interventions since pneumonia and zinc deficiency are prevalent in that population.2,12,13 For this reason, a systematic review focusing on that population is necessary.
IV.5. Purpose statement Based on the gaps in the current evidence of the efficacy of zinc supplementation in preventing pneumonia in children, it is essential to conduct a systematic review to determine the efficacy of continuous zinc supplementation in preventing pneumonia in children aged of 6 to 30 months in developing countries. This systematic review will verify the efficacy of continuous zinc supplementation in preventing pneumonia in children. In addition, through this systematic review the most effective dosage and administration of zinc supplementation will also be determined.
V. Objectives This systematic review is intended to answer the following research questions: 1. Is the relative risk of pneumonia in children aged 6 to 30 months who received continuous zinc supplementation significantly different compared to those who did not?” 2. Is the relative risk of pneumonia between children aged 6 to 30 months who received continuous zinc supplementation and those who did not different according to the dosage? 3. Is the relative risk of pneumonia between children aged 6 to 30 months who received continuous zinc supplementation and those who did not different according to the administration method?
The hypotheses of this systematic review are: 1. The relative risk of pneumonia in children aged 6 to 30 months receiving continuous zinc supplementation is lower than the risk of pneumonia in those who did not. 2. The relative risk of pneumonia between children aged 6 to 30 months who received continuous zinc supplementation and those who did not is different according to the dosage. 3. The relative risk of pneumonia between children aged 6 to 30 months who received continuous zinc supplementation and those who did not is different according to the administration method.
The aims of this systematic review are: 1. To determine the relative risk of having pneumonia in children aged 6 to 30 months who received continuous zinc supplementation compared to those who did not.
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2. To determine the relative risk of pneumonia between children aged 6 to 30 months who received continuous zinc supplementation and those who did not according to the dosage. 3. To determine the relative risk of pneumonia between children aged 6 to 30 months who received continuous zinc supplementation and those who did not according to the administration method.
VI. Study methods
VI.1. Research design The design of this study is systematic review of RCTs since it is the best design to determine the efficacy of intervention.25,26
VI.2. Criteria for considering studies for this systematic review VI.2.1. Types of studies This systematic review focuses on single and cluster randomised controlled trials comparing zinc supplementation versus placebo in preventing pneumonia in children with intention to treat analysis. All RCTs should have parallel designs. Cross-over RCT will not be included as this design will affect the validity of intention to treat analysis.26 VI.2.2. Types of participants The target population in this systematic review of RCTs is children aged 6 to 30 months in developing countries since children younger than 30 months have the highest burden of disease due to pneumonia2,3 and children with an age of 6 month or older are at risk of zinc deficiency.12,13 In addition zinc deficiency and pneumonia are prevalent in developing countries.2,11,12 Therefore, zinc supplementation in preventing pneumonia in this population will be beneficial. Studies focusing zinc supplementation to prevent pneumonia in children with severe malnutrition, serious illnesses, congenital heart diseases, human immunodeficiency virus infection, will be excluded, because these populations have a higher risk of pneumonia compared to the general population at the same age.2 In addition, RCTs of which the study populations are children with chronic infections, recurrent diarrhoea, and malabsorption will be excluded since zinc requirements in this population are higher than the average population.11 Consequently, the comparability across individual studies in this systematic review can be ensured.
VI.2.3. The intervention Studies using zinc supplementation as additional treatment for pneumonia will not be included since this systematic review focuses on zinc preventive effect. Zinc preparations included in this systematic review are dispersed tablets, powders, or syrup. Studies using syrup containing iron or calcium will be excluded because iron and calcium impair zinc absorption.11,27 In addition, food
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sprinkles will also be excluded since the absorption of zinc can be interfered by phytate, dietary fibre, and calcium in food.12 Otherwise, zinc preventive effect cannot be assessed objectively. Based on the dosage frequently used in the previous studies, the dosage of zinc supplementation in this systematic review will be grouped into: 1. 5 mg for all children5 2. 5 mg for children younger than 1 year and 10 mg for older children23 3. 10 mg for all children15-18 4. 10 mg for children younger than 1 year and 20 mg and older children6,14 5. 20 mg for all children.4 To ensure comparability across RCTs, other zinc supplementation intervals except once daily will be excluded. In addition, the intervention coverage will be considered in evaluating individual studies since it influences the effectiveness of this intervention. Through these approaches, the most effective zinc supplementation dosage can be ascertained. The duration of zinc supplementation should cover pneumonia surveillance since zinc cannot be accumulated and zinc reduces significantly after the cessation of zinc supplementation.16 Therefore, studies that still measured pneumonia incidence after zinc supplementation being stopped will be excluded.
VI.2.4. The control The control of this systematic review is placebo or iron-free and calcium-free micronutrient supplementation which is also given to the zinc group. The duration of the control should be identical to the duration of zinc supplementation to ensure comparability.
VI.2.5. The outcome The outcome reviewed in this systematic review is the incidence pneumonia. The incidence of pneumonia in the zinc group and the placebo group will be compared as a relative risk.26 If the relative risk is significant, a number needed to treat will also be calculated.26 The case definition of pneumonia will be based on UNICEF/WHO criteria1 of rapid breathing (respiratory rate more than 50 times per minute for children younger than 1 year or a respiratory rate more than 40 times per minute for children aged 1 to 5 years), and chest wall indrawing or stridor, confirmed with chest examination by physicians or chest radiological imaging to ensure specific case definition.19,20 The efficacy of zinc supplementation in preventing pneumonia was not detected if case the case definition of pneumonia is not specific, based on reported respiratory symptoms.20 Therefore, studies using pneumonia definition based on reported respiratory symptoms will be excluded. The duration of pneumonia surveillance should be at least two months since every year children have an average of six episodes of common cold, which usually precedes
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pneumonia.28 Therefore, a minimum of two month periods of pneumonia surveillance potentially enables the detection of pneumonia.
VI.2.6. Inclusion and exclusion criteria All those inclusion methods are summarised in the following inclusion and exclusion criteria. Inclusion criteria include: 1. Randomised controlled trials or cluster randomised controlled trial with parallel designs. 2. The study populations include children aged 6 months to 30 months in developing countries 3. The study intervention is zinc supplementation given with a dosage from 5 mg to 20 mg per day as syrup, powders, or dispersed tablets 4. The control groups received placebo or other supplements that also given to the zinc group 5. The pneumonia case definition was constructed based on the WHO criteria confirmed with physical examination by physicians or chest x-ray examination. 6. Zinc is given continuously along pneumonia surveillance 7. The duration of pneumonia surveillance is minimum 2 months
Exclusion criteria include: 1. Study populations that include children with severe malnutrition, serious illnesses, congenital heart diseases, human immunodeficiency virus infection, chronic infections, recurrent diarrhoea, and malabsorption. 2. Co-supplementation containing iron or calcium 3. Zinc supplementation duration less than the duration of pneumonia surveillance
VI.3. Search methods for the identification of studies In order to prevent publication bias, eligible studies will be searched electronically through various sources, including health databases (Medline, Central, Embase), citation index (Web of Science), dissertation database (ProQuest Dissertation & Theses Database), and ongoing studies through a RCT registry (International Clinical Trials Registry Platform). The reference lists of relevant studies will be obtained through hand-searching. Studies from all languages and all year publication will be included. The search strategies are described in Table 1 (Appendix) and search process results will be documented in Table 2 (Appendix).
VI.4. Data collection and analysis VI.4.1. Selection of studies Studies will be independently selected by two reviewers. First, duplicated articles will be excluded through using the EndNote X7 reference manager29. Next, the titles and the abstracts of the studies are assessed according to relevance. Finally, the relevant studies are selected against inclusion
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and exclusion criteria above. Excluded studies and reasons for exclusion are summarised in Table 3 (Appendix). All the discrepancies between two reviewers will be solved with a consultation with a third reviewer. The selection process will be described using the PRISMA 2009 Flow Diagram.30 The selection flow of this systematic review is described in Figure 1 (Appendix).
VI.4.2. Data extraction and management Data from reviewed studies will be extracted by the first and the second authors independently into a data extractions table, described as Table 4 (Appendix). The extracted data include the name of the study, the authors, the journal and the year of publication, the subjects, the interventions, the outcomes, and study strength and risks of bias, which will be explained in the following section. The extracted data will be stored and managed using the RevMan.5.3.31 The intervention and the control of included studies will be described in Table 5 (Appendix). To deal with missing data, the authors of the reviewed studies will be contacted. The discrepancies between two reviewers in data extraction will be solved with a consultation with a third reviewer.
VI.5. Data analysis VI.5.1. Study strength and risk of bias The risks of bias of individual studies will be assessed according to the Cochrane handbook of systematic review of interventions.25 In addition, the strength of the reviewed studies will also be rated using the Effective Public Health Practice Project (EPHPP) quality assessment tool32 in order to ensure assessment objectivity. Through the EPHHP tool, study strength according to intervention coverage can also be ascertained.32 The study strengths and risk of bias for each study are documented in the data extraction table. In addition, risk of bias for each study will be summarised in a pictorial record according to the Cochrane handbook of systematic review,25 described in Figure 2 (Appendix). The discrepancies between two reviewers in the analysis of study strength and risk of bias will be solved with a consultation with a third reviewer.
VI.5.2. Intervention effects The intervention effects are expressed as relative risks complemented with 95% confidence intervals (CIs).26 In addition, a number needed to treat (NNT)26 will also be expressed for the risk ratios that are significant. The intervention effects will be summarised in Table 6 (Appendix). The relative risk of pneumonia between the zinc and the control group will be narratively described according to study strength and risk of bias and summarised in the Table 7 (Appendix). A sub-group analysis according to the dosage and administration will be performed in strong studies with low risk of bias, moderate studies with low risk of bias, and weak studies with high/unclear risk of bias and
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will be summarised in Table 8, Table 9, and Table 10 (Appendix) respectively. The level of significance is expressed as p-value <0.05 and 95% confidence interval not crossing 1 value.
VII. Ethical implications This is a systematic review using individual RCTs reports; therefore, there will be limited ethical implications.
VIII. Project Planning The purpose of this project is to perform systematic review of within budget and time frame. The scope of this project includes from ethical application to the publication of this systematic review. Time needed to complete this project is 12 months. The timeline of this project is described in Table 11 (Appendix).
VIII.1. Publication planning This systematic review is intended to be published in at least in one relevant peer review journals, including Pediatrics, Bulletin of the World Health Organization, Journal of Epidemiology and Community Health, the Lancet Infectious Diseases, Respiratory Research, Medical Decision Making, International Journal of Epidemiology, and the Journal of Nutrition.
VIII.2. Resources Resources required for this project include access to data bases and articles, and human resources. The estimated human resources requirements include: 1. Three reviewers 2. Translators Through a project trial, it was found there were articles written in Russian, French, Norwegian, and Danish. Therefore, translators for articles written in Russian, French, Danish, and Norwegian may be required. For anticipatory reason, translators for articles written in Arabic, Spanish, and Chinese, are potentially required since those languages are the most common spoken languages worldwide after English. The translation service can be outsourced through translation services from embassies. From the trial, it is estimated that there will be 18 articles need translation. 3. One proof reader The proof reader can be outsourced from the local universities.
VIII.3. Estimated costs The estimated cost of this project is AUD 2,596. Most of the expenses are translation and proofreading services. The estimated project costs are summarised in Table 12 (Appendix).
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VIII.4. Roles and responsibilities 1. The first reviewer will perform ethical application. 2. The first reviewer together with the second reviewer will perform the searching process, followed by study selection process, data collection, and data analysis. 3. The first reviewer and the second reviewers should consult the third reviewer if there is any discrepancy from the selection process to data analysis. 4. The first reviewer should contact the authors of reviewed study for further information if necessary. 5. The second reviewer should contact the translators if necessary. 6. The first reviewer will write the systematic review and the second reviewer together with the third reviewer will review and endorse the systematic review written by the first reviewer. 7. The first reviewer will ask the proof reader to assess any language and typographic errors. 8. The first reviewer will contact the journal for publication and perform corrections asked by the journal for publication. 9. All the corrections made before the publication should be reviewed and endorsed by the second and the third reviewers.
VIII.5. Authorship The three reviewers have the right of authorship. If the journal published, the sequence of author names written starts with the first author, followed by the second and the third authors. The agreements about the roles and the responsibilities as well as the authorship should be signed at the beginning of the project.
IX. Study significant The results of this study will add current knowledge about the efficacy of zinc supplementation in preventing pneumonia in children. In addition, this systematic review will also provide evidence to clinicians and public health decision makers to reduce the burden of disease and health inequity due to childhood pneumonia in developing countries. Another benefit of the determination of zinc efficacy in preventing pneumonia is that it can prevent unnecessary interventions. Consequently, unnecessary health expenses and potential adverse effects due to zinc supplementation can be prevented.
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[17] Owusu-Agyei S, Newton S, Mahama E, et al. Impact of vitamin A with zinc supplementation on malaria morbidity in Ghana. Nutrition Journal [Internet]. 2013 [cited 2015 Apr 28]; 12: [about 9 p.]. Available from: http://www.nutritionj.com/content/12/1/131. DOI: 10.1186/1475-2891-12-131. [18] Soofi S, Cousens S, Iqbal SP, et al. Effect of provision of daily zinc and iron with several micronutrients on growth and morbidity among young children in Pakistan: a cluster-randomised trial. Lancet [Internet]. 2013 [cited 2015 Apr 28]; 382: [about 12 p.]. Available from http://dx.doi.org/10.1016/S0140-6736(13)60437-7. [19] Lassi ZS, Haider BA, Bhutta ZA. Zinc supplementation for the prevention of pneumonia in children aged 2 months to 59 months. 2010 [cited 2015 Apr 28]. In: the Cochrane Database of Systematic Reviews [Internet]. [Place unknown]: John Wiley & Sons. Available from http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD005978.pub2/pdf. DOI: 10.1002/14651858.CD005978.pub2. [20] Roth DE, Richard SA, Black RE. Zinc supplementation for the prevention of acute lower respiratory infection in children in developing countries: meta-analysis and meta-regression of randomized trials. International Journal of Epidemiology [Internet]. 2010 [cited 2015 Apr 28]; 39: [about 7 p.]. Available from: http://ije.oxfordjournals.org/content/39/3/795.full.pdf+html. DOI:10.1093/ije/dyp391. [21] Yakoob MY, Theodoratou E, Jabeen A, et al. Preventive zinc supplementation in developing countries: impact on mortality and morbidity due to diarrhea, pneumonia and malaria. BioMed Central Public Health [Internet]. 2011 [cited 2015 Apr 28]; 11(Suppl3): [about 10 p.]. Available from: http://www.biomedcentral.com/1471-2458/11/S3/S23. [22] Mayo-Wilson E, Junior JA, Imdad A, et al. Preventive zinc supplementation for children, and the effect of additional iron: a systematic review and meta-analysis. British Medical Journal Open [Internet]. 2014 [cited 2015 Apr 28]; 4: [about 13 p.]. Available from: http://bmjopen.bmj.com/content/4/6/e004647.full.pdf+html. DOI:10.1136/bmjopen-2013-004647. [23] Mayo-Wilson E, Junior JA, Imdad A, et al. Zinc supplementation for preventing mortality, morbidity, and growth failure in children aged 6 months to 12 years of age. 2014 [cited 2015 Apr 28]. In: the Cochrane Database of Systematic Reviews [Internet]. [Place unknown]: John Wiley & Sons. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009384.pub2/pdf. DOI: 10.1002/14651858.CD009384.pub2. [24] National Research Council (US) Subcommittee on the Tenth Edition of the RDAs, National Institutes of Health (US), & National Research Council (US) Committee on Dietary Allowances, Recommended Dietary Allowances. Recommended dietary allowances (10th ed.) [Internet]. Washington, DC: National Academy Press; 1989 [cited 2015 May 5]. Available from: http://www.nap.edu/openbook.php?record_id=1349&page=R1. [25] Higgins J PT, Green S. Cochrane handbook of systematic reviews of interventions, version 5.1.0 [Internet]. [Place unknown]: The Cochrane Collaboration; 2011[cited 2015 May 5]. Available from: http://handbook.cochrane.org. [26] Gordis L. Epidemiology. 5th ed. Philadelphia (PA): Elsevier Saunders; 2014. 392 p. [27] O’Brien KO, Zavaleta N, Caulfield LE, et al. Prenatal iron supplements impair zinc absorption in pregnant Peruvian women. Journal of Nutrition [Internet]. 2000 [cited 2015 May 9]; 130: [about 5p.]. Available from: http://jn.nutrition.org/content/130/9/2251.full.pdf+html. [28] Turner RB, Hayden, GF. The common cold. In: Behrman RE, Kliegman, RM, Jenson, HB (Eds.). Nelson textbook of paediatrics (17th ed.). Philadelphia: Saunders; 2004. P. 1389-1391. [29] Thomson Reuters Endnote. Online user guide [Internet]. [Place unknown]: Thomson Reuters; 2014 [cited 2015 Jun 20]. Available from: http://endnote.com/support/online-user-manual/x7. [30] Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Medicine [Internet]. 2009 [cited 2015 Jun 8]; 6(7): [about 6p.]. Available from: http://www.plosmedicine.org/article/fetchObject.action?uri=info:doi/10.1371/journal.pmed.1000097&representation= PDF. DOI:10.1371/journal.pmed.1000097. [31] The Cochrane Collaboration. Review Manager (RevMan) [Computer program], version 5.3 [Internet]. [Copenhagen]: The Nordic Cochrane Centre; 2014 [cited 2015 Jun 20]. Available from http://tech.cochrane.org/revman/about-revman-5. [32] Thomson Reuters Endnote. Online user guide [Internet]. [Place unknown]: Thomson Reuters; 2014 [cited 2015 Jun 20]. Available from: http://endnote.com/support/online-user-manual/x7.
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XI. Appendixes Table 1. Search strategy for each database
Source Research strategy Medline Advance search: 1. pneumonia OR “respiratory tract infection” OR bronchopneumonia OR “lower respiratory infection” OR “lung infection” 2. zinc OR “zinc supplementation” 3. children OR infant* OR paediatric OR pediatric OR toddler* OR baby OR babies OR “day care” OR preschool 4. #1 AND #2 AND #3 Central Advance search: 1. pneumonia OR “respiratory tract infection” OR bronchopneumonia OR “lower respiratory infection” OR “lung infection” 2. zinc OR “zinc supplementation” 3. children OR infant* OR paediatric OR pediatric OR toddler* OR baby OR babies OR “day care” OR preschool 4. #1 AND #2 AND #3 Embase Advance search: 1. pneumonia OR ‘respiratory tract infection’ OR bronchopneumonia OR ‘lower respiratory infection’ OR ‘lung infection’ 2. zinc OR ‘zinc supplementation’ 3. children OR infant* OR paediatric OR pediatric OR toddler* OR baby OR babies OR ‘day care’ OR preschool 4. #1 AND #2 AND #3 Web of Science (Web of Science Core collection database) Advance search: 1. TS= (pneumonia OR respiratory tract infection OR bronchopneumonia OR lower respiratory infection OR lung infection) 2. TS= (zinc OR zinc supplementation) 3. TS= (children OR infant* OR paediatric OR pediatric OR toddler* OR baby OR babies OR “day care” OR preschool) 4. #1 AND #2 AND #3 ProQuest Dissertations and Theses Global Advance search: ab(zinc OR “zinc supplementation”) AND (pneumonia OR “respiratory tract infection” OR bronchopneumonia OR “lower respiratory infection” OR “lung infection”) AND (children OR infant* OR paediatric OR pediatric OR toddler* OR baby OR babies OR “day care” OR preschool) International Clinical Trials Registry Platform Advance search: In the title: children OR infant* OR paediatric OR pediatric OR toddler OR baby OR babies OR day care OR preschool In the condition: pneumonia OR respiratory tract infection OR bronchopneumonia OR lower respiratory infection OR lung infection In the intervention: zinc OR zinc supplementation
15
Table 2. Search results documentation
Search date Database Key words Numbers of articles found

16
Table 3. Excluded studies and reasons for exclusion
Study Reasons for exclusion Note
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Table 4. The data extraction table for included studies
The name of the study
Publication details
Methods
Participants
The number of participants
Demographic characteristics
Setting
Interventions
Control
Outcomes
Notes
Study strength (overall)
Selection bias
Design
Confounders
Data collection method
Withdrawal
Risk of bias
Random sequence generation (selection bias)

Allocation concealment (selection bias)
Blinding (performance and detection bias)
Incomplete outcome data (attrition bias)
Selective reporting (reporting bias)
18
Table 5. The summary of the intervention and the control of included studies
Study Age Intervention
Dosage
Control
Administration
Duration

19
Table 6. The summary of the intervention effect of included studies
Study The number of participants
Dosage Administration Duration The incidence of pneumonia
RR (95% CI)
pvalue
NNT
Zinc Placebo

20
Table 7 The relative risk (RR) of pneumonia between the zinc and the control groups according to the study strength and risk of bias.
The study strength
The incidence of pneumonia
RR (95% confidence interval)
p-value NNT
Zinc Control
Strong studies, low risk of bias

Moderate studies, low risk of bias Weak studies, unclear or high risk of bias
21
Table 8 The relative risk of pneumonia between the zinc and the control group, according to the dosage and administration in strong studies with low risk of bias.
Studies Zinc dosage and administration
The incidence of pneumonia
RR (95% confidence interval)
p-value NNT
Zinc Control
5 mg for all children
Without food
With food
Unknown

5mg (<1year old) & 10 mg per day (≥1 year old)
Without food
With food
Unknown

10 mg for all children
Without food
With food
Unknown

10 mg (<1year old) & 20 mg (≥1 year old)
Without food
With food
Unknown

20 mg for all children
Without food
With food
Unknown

22
Table 9 The relative risk of pneumonia between the zinc and the control group, according to the dosage and administration in moderate studies with low risk of bias.
Studies Zinc dosage and administration
The incidence of pneumonia
RR (95% confidence interval)
p-value NNT
Zinc Control
5 mg for all children
Without food
With food
Unknown

5mg (<1year old) & 10 mg per day (≥1 year old)
Without food
With food
Unknown

10 mg for all children
Without food
With food
Unknown

10 mg (<1year old) & 20 mg (≥1 year old)
Without food
With food
Unknown

20 mg for all children
Without food
With food
Unknown

23
Table 10 The relative risk of pneumonia between the zinc and the control group, according to the dosage and administration in weak studies with unclear or high risk of bias.
Studies Zinc dosage and administration
The incidence of pneumonia
RR (95% confidence interval)
p-value NNT
Zinc Control
5 mg for all children
Without food
With food
Unknown

5mg (<1year old) & 10 mg per day (≥1 year old)
Without food
With food
Unknown

10 mg for all children
Without food
With food
Unknown

10 mg (<1year old) & 20 mg (≥1 year old)
Without food
With food
Unknown

20 mg for all children
Without food
With food
Unknown

24
Table 11 The timeline the systematic review project
Activities Jul Aug Sept Oct Nov Dec Jan Feb Mar Apr May Jun Ethic application and approval Literature searching Selecting the studies Data collection Data analysis Writing the systematic review Evaluation and endorsement Proof reading Publication process
Table 12 The estimated costs of the systematic review project Expenses Costs Estimated costs Translators AUD 40 per hour, approximately 3 hours per article AUD 2,160 Proof readers AUD 50 per hour AUD 200 Unexpected costs Estimated increases in fees (10%) AUD 236 Total costs AUD 2,596
25
Figure 1 Article search and selection process flow diagram30
26
Figure 2. The example of the summary of risk of bias of included studies25
Note: Low risk of bias Unclear risk of bias High risk of bias

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