Introduction

Worldwide, lower respiratory tract infections remain the leading cause of illness and death among young children accounting for 120 million cases and 1.3 million deaths every year (1, 2). An estimated 17% of the world’s population lack sufficient dietary zinc to maintain a healthy immune system and reduce risk for acquiring infections, including pneumonia (3–5). In addition to impairment of immune function, zinc deficiency also likely contributes to growth failure (6). A continuous dietary supply of this micronutrient is required since humans have limited capacity to store it (4). Zinc supplementation has been shown to improve outcomes in children with diarrhoea (7), with a growing interest in any role it may play in improving outcomes from respiratory infections. This commentary focuses on the current evidence related to effects of zinc supplementation in the prevention and treatment of childhood pneumonia.

Methodology summary

Respiratory tract infections can be broadly divided into ‘upper’ and ‘lower’ respiratory infections. Upper respiratory tract infections (URTI) refer to infections of airway structures above the bifurcation of the trachea (windpipe) and include the common cold, sinus infections, pharyngitis (sore throat), epiglottitis (infection of the tissue that protects the windpipe) and laryngotracheitis (infection of the voicebox and windpipe). Lower respiratory tract infections (LRTI) include infection of medium (bronchitis) and small airways (bronchiolitis) and air sacs (alveoli). Pneumonia refers to infection of the alveolar sacs and is often used interchangeably with LRTI (8). Even though URTIs are an important cause of illness in children, the focus of this commentary is on the more serious group of LRTIs (2, 8).

Three systematic reviews published under the guidance of the Cochrane collaboration (9–11) were identified. Two of the reviews addressed the prevention of childhood pneumonia with zinc supplementation (10, 11) and one assessed zinc supplementation as an adjunct to antibiotic treatment for pneumonia (9). All three reviews included randomized trials and followed the standardized methods of the Cochrane Collaboration. Authors defined the questions a priori, set inclusion/exclusion criteria, searched multiple electronic databases, performed double data extraction and reported the results with the risk of bias assessment. Two reviews (10, 11) reported the quality of the overall evidence based on The Grades of Recommendation, Assessment, Development and Evaluation (GRADE) criteria (12) that considers methodological flaws within studies, consistency in reporting of results across studies, extent to which results apply to other settings, and effectiveness of treatments and categorize the overall quality of evidence as 'high', ‘moderate', 'low' or 'very low'.

Evidence summary

Zinc supplementation for prevention of lower respiratory tract infections

Mayo-Wilson et al. reviewed broad objectives including assessing the role of zinc supplementation in preventing death, infection (diarrhoea, pneumonia, malaria, and others.) and growth failure in children 6 months to 12 years (11). With regard to respiratory infections, only LRTI were included. The authors reported that compared to placebo, zinc supplementation did not affect incidence (new cases per year), deaths or total hospitalizations from LRTI (Table). These results were similar when the different studies were sub-grouped based on the age of participants, dose, duration, and formulation of the zinc supplement (11). Data on LRTI prevalence (snapshot of cases at one point in time) showed the unexpected finding that zinc supplementation increased the risk of LRTI by 20 % (95 % CI: 10%-30%) (Table); however, significant heterogeneity was seen among the studies included in this analysis (11). The review also assessed side effects of zinc supplementation and reported that participants who received zinc had a higher risk of at least one episode of vomiting compared to control. In addition, serum copper levels were lower in the zinc supplemented group compared to placebo (11).

The review by Lassi et al. considered preventive zinc supplementation among children 2-59 months of age (10). Data from six randomized trials showed that zinc supplementation reduces the incidence of pneumonia (Table). The authors further considered two definitions of pneumonia. The first definition was based on rapid ‘breathing with and without intercostal indrawing’. Pooled data from four studies did not show a significant effect of zinc supplementation for prevention of pneumonia when using this definition. The second definition was also based on rapid breathing but included a requirement for a physical examination and/or the presence of radiologic evidence supporting the diagnosis of pneumonia. The four randomized trials contributing data for that pooled analysis showed that zinc supplementation decreased the incidence of pneumonia by 31 % (95 % CI: 22%-39%) (Table).

The apparent differences observed across the two reviews could be a result of the differences in the inclusion and exclusion criteria, or in the total number of studies included in each effort (Table). Specifically, Lassi et al. included children aged 2–59 months, required supplementation for at least a 3 month duration and included children infected with human immune deficiency virus (HIV), while Mayo-Wilson et al. included children aged 6 months to 12 years of age, had no restriction on duration of zinc supplementation, and excluded studies that included children with HIV infection.

Zinc supplementation as an adjunct to the treatment of pneumonia

The single review to evaluate the potential role for zinc supplementation as an adjunct to antibiotic treatment for pneumonia was reported by Haider et al. in 2011 (9). The pooled results did not support a protective effect of zinc supplementation for time to recovery from pneumonia, fast breathing, chest indrawing or time to hospital discharge (Table). Researchers further assessed these outcomes in patients with severe and non-severe pneumonia and the results were similar for all the outcomes. None of the included studies reported deaths or readmission rates associated with pneumonia. Side effects were not evaluated in the review.

Two trials have been published since the publication of the Cochrane review discussed above (13, 14). A randomized trial by Sempertegui et al. studied 450 Ecuadorean children aged 2–59 months with pneumonia. Half of the children received supplemental zinc and half received placebo. There were no differences in the primary outcome of time to resolution of respiratory symptoms or the secondary outcome of treatment failure between the two groups (13). Another study of paediatric pneumonia that was conducted in Uganda included 352 children aged 6-59 months randomized to receive either zinc supplementation or placebo in addition to routine antibiotics (14). The addition of zinc supplementation did not result in more rapid resolution of respiratory symptoms; however, deaths due to pneumonia (termed case fatality rate) were lower in children who were randomized to receive zinc supplementation (RR= 0.33, 95% CI: 0.15 to 0.76).

Discussion

Applicability of the results

Evidence for a protective effect of zinc supplementation for prevention of paediatric lower respiratory tract infection is inconsistent. One of the two reviews showed no differences in new cases, hospitalizations or death related to pneumonia (11). This review also highlighted the concern of vomiting after a dose of zinc was administered, even though this might be related to taste of the zinc solution. The observation that serum copper levels were lower among those receiving a relatively long duration of zinc supplementation is worth noting. The second review reported ‘low’ quality evidence that zinc supplementation may reduce the risk of paediatric pneumonia when a specific definition of pneumonia included either physical examination findings or radiographic evidence to support the diagnosis.

Evidence suggests that zinc supplementation is not effective in the treatment of pneumonia. The review by Haider et al. did not show any beneficial effect of zinc supplementation during the antibiotic treatment for pneumonia. Moreover, two additional studies that were published since that review supported the earlier findings of Haider et al. One of the two new studies suggested that zinc supplementation might reduce pneumonia-associated deaths, however, the effect was seen only among children infected with HIV and should not be generalized to other populations (14).

Implementation in settings with limited resources

Pneumonia is the leading cause of death among children under five years of age and together with diarrhoea, are the most frequent childhood illnesses in low-income and middle-income countries (2). The majority of the studies that were included in the systematic reviews were conducted in low and middle-income countries making the conclusions most applicable to those settings. Current evidence suggests that zinc supplementation is not effective in the prevention or treatment of pneumonia. Therefore, a discussion of implementation is not relevant at this time.

Further research

To date, studies that have evaluated zinc supplementation for the treatment of pneumonia focused specifically on recovery from respiratory symptoms, which is an important outcome; however, there was a relative lack of data regarding other important outcomes such as antibiotic treatment failure, need for hospitalization, escalation to intensive care, and LRTI related deaths. Future studies should include these outcomes to better assess the therapeutic potential of zinc supplementation. The study by Srinivasan et al. (14) demonstrated that zinc supplementation was associated with reduced pneumonia case fatality rate. In that report, 11% of the children who had bacteraemia complicating their pneumonia died. Children who were receiving zinc supplementation also developed bacteraemia as a complication of their LRTI, but none of them died (14). Finally, a 2012 report on a study performed in India showed that zinc supplementation in infants 7 days to 120 days with probable serious bacterial infection decreased their risk for treatment failure (15). Taken together, such observations are promising that zinc supplementation may play a role in decreasing mortality associated with LRTIs. Large scale randomized trials across multiple populations are needed before a robust conclusion can be made.

References

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2. Walker CL, Rudan I, Liu L, Nair H, Theodoratou E, Bhutta ZA, et al. Global burden of childhood pneumonia and diarrhoea. Lancet. 2013;381(9875):1405-16.

3. Fischer Walker C, Black RE. Zinc and the risk for infectious disease. Annu Rev Nutr. 2004;24:255-75.

4. Roohani N, Hurrell R, Kelishadi R, Schulin R. Zinc and its importance for human health: An integrative review. J Res Med Sci. 2013;18(2):144-57.

5. Devrajani BR, Shah SZ, Shaikh MA. Serum zinc level in patients with pneumonia: a six-month long cross-sectional descriptive study at Liaquat University Hospital Hyderabad, Sindh, Pakistan. J Pak Med Assoc. 2013;63(3):369-73.

6. Black RE, Victora CG, Walker SP, Bhutta ZA, Christian P, de Onis M, et al. Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet. 2013;382(9890):427-51.

7. Lazzerini M, Wanzira H. Oral zinc for treating diarrhoea in children. The Cochrane database of systematic reviews. 2016;12:Cd005436.

8. Dasaraju PV, Liu CI. Infections of the Respiratory System:n: Baron S, editor. Medical Microbiology. 4th edition. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. Chapter 93. Available from: https://www.ncbi.nlm.nih.gov/books/NBK8142/.

9. Haider BA, Lassi ZS, Ahmed A, Bhutta ZA. Zinc supplementation as an adjunct to antibiotics in the treatment of pneumonia in children 2 to 59 months of age. The Cochrane database of systematic reviews. 2011(10):Cd007368.

10. Lassi ZS, Moin A, Bhutta ZA. Zinc supplementation for the prevention of pneumonia in children aged 2 months to 59 months. The Cochrane database of systematic reviews. 2016;12:Cd005978.

11. Mayo-Wilson E, Junior JA, Imdad A, Dean S, Chan XH, Chan ES, et al. Zinc supplementation for preventing mortality, morbidity, and growth failure in children aged 6 months to 12 years of age. The Cochrane database of systematic reviews. 2014(5):Cd009384.

12. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383-94.

13. Sempertegui F, Estrella B, Rodriguez O, Gomez D, Cabezas M, Salgado G, et al. Zinc as an adjunct to the treatment of severe pneumonia in Ecuadorian children: a randomized controlled trial. Am J Clin Nutr. 2014;99(3):497-505.

14. Srinivasan MG, Ndeezi G, Mboijana CK, Kiguli S, Bimenya GS, Nankabirwa V, et al. Zinc adjunct therapy reduces case fatality in severe childhood pneumonia: a randomized double blind placebo-controlled trial. BMC Med. 2012;10:14.

15. Bhatnagar S, Wadhwa N, Aneja S, Lodha R, Kabra SK, Natchu UC, et al. Zinc as adjunct treatment in infants aged between 7 and 120 days with probable serious bacterial infection: a randomised, double-blind, placebo-controlled trial. Lancet. 2012;379(9831):2072-8.

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The named authors alone are responsible for the views expressed in this document.

Declarations of interests

Conflict of interest statements were collected from all named authors and no conflicts were identified.