Zinc supplementation as an adjunct to antibiotics in the treatment of pneumonia in children 2 to 59 months of age
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To evaluate the role of zinc supplementation, as an adjunct to antibiotics, in the treatment of pneumonia in children aged 2 months to 59 months.
Background
Description of the condition
Zinc is a trace element and an essential mineral. It participates in all major biochemical pathways and plays multiple roles in the perpetuation of genetic material and cellular division. Zinc is present in all tissues, fluids, and secretions in the body and is critical to cellular metabolism, physical growth, immunocompetence, reproductive functions, integrity of intestinal mucosa and neuro‐behavioral development (Aggett 1995; Bhatangar 2004). Zinc deficiency is associated with decreased immunocompetence (Golden 1995; Sazawal 1997; Shankar 1998), high rates of serious infectious disease, such as skin infections, diarrhea, respiratory infections, malaria (Black 2001; Lopez 1989; Murray 1996), and delayed wound healing (Bahl 1998; Black 1998; Prasad 1985). Zinc deficiency may be an underlying cause of increased infant mortality in malnourished children in low income countries (Castillo‐Duran 2001).
Description of the intervention
The daily requirement of zinc varies with age, with the recommended dietary allowance (RDA) for infants and children aged one to five years being 5 mg and 10 mg per day, respectively (RDA 1989). Manifestations of zinc deficiency also vary with age (Hambidge 1986). Diarrhea, neuro‐behavioral problems and learning impairment are prominent symptoms of zinc deficiency in infancy (Penland 2000), and skin problems, hair loss, growth retardation, and recurrent infections are common findings in school‐aged children (Van Wouwe 1989). Zinc deficiency has at least five general causes: inadequate intake from foods (particularly from animal sources), increased requirements, malabsorption, increased losses during recurrent diarrheal illnesses (Bhutta 1999; Black 1998), and impaired metabolic utilization (Solomons 1984).
How the intervention might work
Diarrheal disorders and acute respiratory infections (ARI), especially pneumonia, are the two most common causes of death in low income countries (Bryce 2005). The annual estimated incidence of pneumonia is 151 million new cases per year (Rudan 2004), of which two million die annually. It is the largest killer, accounting for 18% of all child deaths in low income countries (WHO 2003). With the inclusion of neonatal pneumonia, recent estimates indicate that it accounts for 28% to 34% of deaths globally in children below five years of age (Wardlaw 2006).
It is assumed that preventive zinc supplementation may correct any deficiency leading to immunodeficiency, and indeed some evidence suggests that preventive zinc supplementation may reduce child mortality and morbidity from infectious diseases, particularly diarrhea and pneumonia (Bhutta 1999; Jones 2003).
Why it is important to do this review
Current evidence on zinc supplementation as a preventative measure has shown beneficial effects by reducing the incidence of diarrhea and pneumonia in children (Aggarwal 2007; Bhutta 1999; Bhutta 2008; Brooks 2005). The preventative aspect of zinc in reducing pneumonia is also being evaluated in another Cochrane review (Haider 2006). Established evidence of the benefit of zinc supplementation in the management of children with diarrhea, along with oral rehydration solution, is available and has formed the basis of the Joint WHO/UNICEF recommendation (WHO 2004). Studies evaluating the impact of zinc supplementation as an adjunct in the management of pneumonia are limited and have shown variable results. The study by Brooks et al shows a reduction in pneumonia and mortality in young children when zinc is administered along with an antimicrobial therapy (Brooks 2005). However, Bose et al failed to show a benefit of zinc supplementation in the management of pneumonia (Bose 2006). To reduce deaths due to pneumonia, it is important to evaluate the role of zinc supplementation as an adjunct to antibiotics, in the treatment of pneumonia in children aged 2 months to 59 months.
Objectives
To evaluate the role of zinc supplementation, as an adjunct to antibiotics, in the treatment of pneumonia in children aged 2 months to 59 months.
Methods
Criteria for considering studies for this review
Types of studies
We will include all randomized control trials (RCTs), irrespective of publication status and language, evaluating supplementation of zinc as an adjunct to antibiotics for pneumonia in children aged 2 months to 59 months in this review. We will include both individual and cluster RCTs. We will exclude non‐RCTs (quasi‐randomized studies).
Types of participants
Children aged 2 months to 59 months suffering from pneumonia. We will consider for inclusion studies of children suffering from an episode of pneumonia and diagnosed in the following ways:
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reported cough or difficult breathing with a respiratory rate above the WHO defined age‐specific values (respiratory rate ≧ 50 breaths per minute for children aged 2 to 11 months, or respiratory rate ≧ 40 breaths per minute for children aged 12 to 59 months) (WHO 1990), and either documented fever of > 101oF or chest in‐drawing;
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a diagnosis of pneumonia based on chest examination by a physician; or
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a diagnosis of pneumonia based on a chest radiograph.
We will exclude from the review studies including children suffering from other debilitating diseases.
Types of interventions
Oral supplements containing zinc versus oral supplements without zinc or a placebo. All participants should receive standard antibiotic therapy. Supplementation of zinc should be the only difference between the intervention and control group.
Types of outcome measures
Primary outcomes
Time to clinical recovery, defined as recovery from tachypnoea, fever, and chest in‐drawing for at least 24 hours.
Secondary outcomes
Duration (in hours) of hospital stay (time from randomization to discharge).
Re‐admission/re‐diagnosis with pneumonia within three months, starting from the last day of current episode.
Mortality within 10 days of randomization.
Mortality within one month of randomization.
Search methods for identification of studies
Electronic searches
We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue), which contains the Cochrane Acute Respiratory Infection (ARI) Group and the Cochrane Infectious Diseases Group Specialized Registers; MEDLINE (1966 to present); EMBASE (1974 to present); and LILACS (all years) for relevant trials. The search terms will be combined with the highly sensitive search strategy devised by Dickersin (Dickersin 1994) and run through MEDLINE and CENTRAL. The terms will be adapted to search EMBASE and LILACS. The search terms are as follows.
MEDLINE
((exp Pneumonia/) OR pneumonia OR lower respiratory tract
infection$ OR LRTI OR lower respiratory infection$)
AND
(exp Zinc/ OR zinc)
AND
(exp Child/ OR child OR children exp Infant/ OR infant OR
infants OR paediatric OR pediatric) OR Child, Preschool/ OR toddler OR preschool*
Searching other resources
There will be no language or publication restrictions. We will also search the related conference proceedings for relevant abstracts. We will contact organizations, researchers in the field, and pharmaceutical companies for information on unpublished and ongoing trials. We will also check the reference lists of all trials identified by the above methods.
Data collection and analysis
Selection of studies
Two review authors (BAH, QH) will independently assess trial eligibility and will screen all available titles and abstracts for inclusion. If the relevance cannot be ascertained by screening the title and abstract, the full text of the article will be retrieved and reviewed. Two review authors (BAH, QH) will retrieve full texts of all potentially relevant articles and assess the eligibility independently by filling out eligibility forms designed in accordance with the specified inclusion criteria. We will resolve any disagreements by discussion or, if required, a third review author (ZAB) will be consulted. We will display studies excluded from the review in the 'Characteristics of excluded studies' table along with the reason for exclusion.
Data extraction and management
Two review authors (BAH, QH) will pilot, test and subsequently use a data extraction form to collect data. Both review authors will then compare the extracted data to enable them to correct errors and resolve any disagreements through discussion. We will use the Review Manager (RevMan) software (RevMan 2008) to double enter all the data or a sub‐sample.
When information regarding any of the above is unclear, we will attempt to contact the trial authors to provide further details.
Assessment of risk of bias in included studies
Two review authors (BAH, QH) will independently assess the methodological quality of the selected trials by using methodological quality assessment forms. We will undertake quality assessment of the trials using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Any disagreements between the two review authors will be resolved by discussion.
Selection bias (randomization and allocation concealment)
We will assign a quality score for each trial using the following criteria:
A. adequate concealment of allocation: for example, telephone randomization, consecutively numbered, sealed opaque envelopes;
B. unclear whether adequate concealment of allocation: e.g. list or table used, sealed envelopes, or study does not report any concealment approach;
C. inadequate concealment of allocation: e.g. open list of random number tables, use of case record numbers, dates of birth or days of the week.
Attrition bias (loss of participants, for example, withdrawals, drop‐outs, protocol deviations)
We will assess completeness of follow up using the following criteria:
A. less than 5% loss of participants;
B. 5% to 9.9% loss of participants;
C. 10% to 19.9% loss of participants;
D. more than 20% loss of participants.
We will exclude trials with more than 20% loss of participants from the review because of the risk of bias.
Performance bias (blinding of participants, researchers and outcome assessment)
We will assess blinding using the following criteria:
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blinding of participants (yes/no/unclear);
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blinding of caregiver (yes/no/unclear);
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blinding of outcome assessment (yes/no/unclear).
Assessment of heterogeneity
We will apply tests of heterogeneity between trials, if appropriate, using the I‐squared (I2) statistic. If we identify high levels of heterogeneity among the trials (exceeding 50%) we will explore this by subgroup analysis, as specified below, and perform sensitivity analysis. A random‐effects meta‐analysis model will be used as an overall summary if this is considered appropriate.
Data synthesis
We will carry out statistical analysis using the Review Manager (RevMan 2008) software. In the absence of significant heterogeneity, where trials are sufficiently similar, we will use a fixed‐effect meta‐analysis model for combining data. If heterogeneity is found this will be explored by the use of a sensitivity analysis followed by the use of a random‐effects model, if required.
For dichotomous data, we will present results as summary of relative risks (RR) with 95% confidence intervals (CI). For continuous data, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardized mean difference (SMD) to combine trials that measure the same outcome, but use different methods.
Subgroup analysis and investigation of heterogeneity
We plan to carry out the following subgroup analyses:
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different doses of zinc used;
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different durations of zinc supplementation;
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baseline zinc deficiency in the population;
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severity of disease (defined by the presence of either chest in‐drawing or at least one other critical sign, such as central cyanosis, excessive sleepiness, inability to drink, convulsions);
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hemoglobin level of participants;
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wheezing at the time of enrolment;
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co‐interventions.
Sensitivity analysis
We will carry out a sensitivity analysis to explore the effect of trial quality (assessed by concealment of allocation), by excluding studies with clearly inadequate allocation of concealment (rated C).
