1. Objectives

To evaluate zinc supplementation for the prevention of pneumonia in children aged two to 59 months

2. How studies were identified

The following databases were searched in October 2016:

• Cochrane Acute Respiratory Infections Group’s Register
• CENTRAL (The Cochrane Library 2016)
• MEDLINE
• EMBASE
• LILACS
• CINAHL
• Web of Science
• WHO ICTRP
• ClinicalTrials.gov

Reference lists and relevant conference proceedings were also hand-searched

3. Criteria for including studies in the review

3.1 Study type

Randomized controlled trials

(Studies were eligible for inclusion provided they defined pneumonia in the following ways: i) reported cough or difficulty breathing with a respiratory rate above the WHO-defined age-specific values of 50 breaths/minute for infants aged two to 11 months and 40 breaths/minute for children 12 to 59 months of age, plus documented fever >38°C or chest in-drawing; ii) a diagnosis of pneumonia based on chest examination by a physician; or iii) a diagnosis of pneumonia based on chest X-ray)

3.2 Study participants

Children aged two months to 59 months

3.3 Interventions

Oral supplement containing the recommended daily allowance of zinc or more (≥5 mg for infants two to 11 months and ≥10 mg for children 12 to 59 months), with or without other micronutrients, compared to a placebo or the same micronutrients without added zinc

(Trials were considered eligible if supplements were administered for at least three months and outcome surveillance was conducted for at least four weeks)

3.4 Primary outcomes

• Numbers of new episodes of pneumonia in children aged two months to 59 months

The single secondary outcome was the prevalence (number of cases of pneumonia at a given time per total days of observation) of pneumonia in children two to 59 months of age

4. Main results

4.1 Included studies

Six randomized controlled trials, enrolling 5193 children, were included in this review

• One trial was conducted in 238 children with diarrhoea lasting two weeks or more; children were randomized to zinc alone, zinc plus vitamins or placebo
• In one trial 2482 children aged six to 30 months were randomized to elemental zinc (10 mg/day for infants, 20 mg/day for children) or placebo for four months
• In one trial 226 infants aged four to six months born to HIV-positive and HIV-negative mothers were randomized to receive vitamin A, vitamin A plus zinc, or vitamin A plus zinc and multiple micronutrients for 18 to 20 months. Thirty-two children were born with HIV infection, and 154 HIV-exposed infants were born without HIV infection
• One trial was conducted in children aged six to 60 months with HIV 1 infection; children were randomized to receive either placebo or 10 mg elemental zinc sulphate/day for six months
• In one trial 609 children aged six to 36 months were assigned to a 5 mL of an oral liquid zinc supplement supplying 10 mg elemental zinc/day (raised to 10 mL for children with diarrhoea) or a similar placebo liquid
• In one trial 1665 infants aged from two to 12 months were randomized to 70 mg oral zinc/day or placebo
• In most studies, exclusion criteria included co-morbidities such as tuberculosis, congenital heart disease, <60% median weight-for-age Z-score, and nutritional oedema

4.2 Study settings

• Bangladesh, India (2 trials), Peru, and South Africa (2 trials)
• One trial was conducted in an outpatient setting in children with HIV infection, and three trials were conducted in disadvantaged urban areas in South Asia. In one community-based trial in children with diarrhoea, children were assessed in their homes

4.3 Study settings

How the data were analysed
One comparison was made: zinc versus placebo for the prevention of pneumonia. Fixed effects meta-analysis was used to generate risk ratios (RR) and corresponding 95% confidence intervals (CI). If substantial statistical heterogeneity (I²>50%) had been detected in any analyses, meta-analysis using random effects models was planned. If detected, heterogeneity was to be investigated using subgroup analyses by zinc dosage, participants’ age, recent health of the child, and baseline zinc levels. Subgroup analysis by case definition of pneumonia was conducted. Sensitivity analyses excluding trials with inadequate methods of allocation concealment were planned but not conducted due to a lack of data.

Results
Zinc supplementation versus placebo
Incidence of pneumonia
Overall, pooled analysis of six trials including 5193 children revealed a statistically significant 13% reduction in the incidence of pneumonia with zinc supplementation in comparison to placebo (RR 0.87, 95% CI [0.81 to 0.94], p=0.00025). In subgroup analysis of cases in which the clinical definition of pneumonia was used for diagnosis (age-specific fast-breathing, with or without lower chest in-drawing), no significant effect of zinc supplementation was found (RR 0.95. 95% CI [0.86 to 1.06], 4 trials/1932 children). Conversely, in pooled analysis of cases in which pneumonia was diagnosed on the basis of chest examination or chest X-ray, a statistically significant 21% reduction in the incidence of pneumonia was found (RR 0.79, 95% CI [0.71 to 0.88], p=0.000018; 4 trials/3261 children; p=0.02 for subgroup differences).

Prevalence of pneumonia
In one trial conducted in India in 609 children, the prevalence of pneumonia was statistically significantly reduced by 41% with zinc supplementation in comparison to placebo (RR 0.59, 95% CI [0.35 to 0.99], p=0.047).

5. Additional author observations*

The overall methodological quality of the included trials was fair, with adequate methods of allocation concealment described in three of the six studies, and a low risk of attrition bias in four trials. GRADE quality of evidence assessment rated both outcomes as being low quality due to unclear risk of bias, differing diagnosis criteria for pneumonia between trials, and a small number of pneumonia cases. As most trials were conducted in low-socioeconomic urban areas in low- and middle-income countries, the findings of this review are most applicable to these settings.

Both the incidence and prevalence of pneumonia in children aged two to 59 months were reduced with zinc supplementation in comparison to placebo. These findings suggest that children in low-income countries with inadequate zinc intakes might benefit from zinc supplementation.

Further high-quality trials are needed to evaluate zinc supplementation for preventing pneumonia in children aged two to 59 months. In addition, other interventions to improve children’s zinc status, such as plant breeding, genetic engineering of crops to increase the bioavailability of zinc, and intermittent supplementation, should be investigated.