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Three Part Question

Does [zinc given as adjunct therapy] in [children with acute severe respiratory infections] [improve mortality and morbidity]?

Clinical Scenario

A 5 year old child attends the ED with an acute respiratory tract infection that requires admission. A colleague mentions zinc supplementation is used in many rural areas in Asia for the prevention of respiratory tract infections. But is there evidence that zinc as an adjunctive therapy has a therapeutic role in the management of acute respiratory tract infections?

Search Strategy

Embase 1996-2015/03
MEDLINE 1946-2015/03 using the OVID interface

{[exp zinc/ OR zinc. mp] AND [exp respiratory tract infections/ OR exp pneumonia/ ]} LIMIT to human AND English Language AND Child (0-18 years) AND to therapy (optimised)

Search Outcome

436 papers were found from the literature search. 6 papers were considered relevant to the three-part-question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Brooks et al. 2004 Bangladesh	Children aged 2-23 months	Double-blinded, Randomised Controlled Trail. 270 children included.	Primary : Duration of severe pneumonia Secondary: Length of hospital stay	Zinc treated group had reduced duration of pneumonia (Relative Hazard=0.70, 95% CI 0.51-0.98) and overall hospital stay (RH 0.75, CI 0.57-0.99). Zinc had no effect on wheezing children.	No follow-up period included in project. Removal of children with wheeze from study reduced sample size analysed.
Shah et al. 2013 India	Children aged 6-59 months	Double-blinded, Randomised Controlled Trial. 96 children included.	Primary: Number of acute respiratory tract infections (ALRI) and ALRI free days per child Secondary: Recovery time	Zinc groups had lower number of episodes of ALRIs (p=0.009) and severe ALRI (p<0.001). Additionally ALRI free days were higher (p<0.001) and median recovery time of morbidity was shorter in zinc groups (p<0.001).	Small sample size in zinc deficient area. Heavily reliant on secondary information provided by carers reporting morbidity. Severity of initial ARLI not recorded which can affect future recovery/relapses. Seasonal factors not assessed in ALRI incidence.
Mahalanabis et al 2004 India	Children aged 2-24 months	Randomised Controlled Trial with factorial design. 153 children included.	Primary : time for resolution of very ill status Secondary: resolution of fever, tachypnea, and feeding difficulty	Recovery rates in zinc-treated boys from very ill status were 2.6 times (95% CI 1.35- 5.10) those in non-zinc-treated children. This effect was not seen in girls: Recovery rate ratio (RRR) 0.80 (95% CI 0.44- 1.43) Secondary: Recovery rates from fever in zinc-treated boys were 3 times (95% CI 1.47- 6.60) those in non-zinc-treated children. This effect was not seen in girls RRR 0.67 (95% CI 0.38-1.2) Feeding difficulty and tachypnea were not significantly different for both boys and girls.	Outcome variable of ‘very ill status’ was subject to interpretation by clinicians thus produces inconsistency.
Bansal et al 2011 India	Children aged 2-24 months	Triple-blinded, Randomised Controlled Trial. 106 children included.	Primary: ‘time to be asymptomatic’ Secondary: Duration of hospital stay	Primary: 60hrs (24-78) zinc treated group vs. 54hrs (30-72) control group, (p=0.98) Secondary: Shorter duration of hospital stay in the zinc treated group by 9 hours (p=0.53).	Small study size and underpowered. 400 children were needed to observe a clinically significant result but only 106 included. In addition mean duration of illness prior to admission was 4 days.
Bose et al. 2006 India	Children aged 2-23 months	Double-blinded, Randomised Controlled Trial. 272 children included.	Primary: time to resolution of severe pneumonia and duration of hospitalisation. Secondary: Time of resolution of wheeze	No association with zinc supplementation and length of hospitalisation (p=0.550). No overall effect on resolution of clinical signs of severe infection (tachypnea p=0.819, inability to feed p=0.511, hypoxia p=0.575, wheeze p=0.439).	Recovery status based on clinical judgement of differing attending paediatricians.
Chang et al. 2006 Australia	Children aged under 11 years	Double-blinded, Randomised Controlled Trial. 187 children included.	Primary: Readmission for ALRI within 120 days Secondary: Time to clinical recovery from fever and tachypnoea, oxygen saturation and duration of hospitalisation.	Primary: Increased risk of readmission for ALRI in zinc treated group (RR 2.4; 95% CI, 1.003-6.1). Secondary: Non-significant decrease in hospital stay (median 5 days in zinc-treated group vs. 9 days in placebo group (p=0.06).	Most children already treated in community with antibiotics, oxygen and paracetamol prior to transfer to study hospital and enrolment. Secondary outcomes therefore affected as few children had fever or tachypnoea. Children with wheezing and coryza excluded.

Comment(s)

The studies included were mainly performed on zinc deficient populations. Therefore, the clinical significance of these findings when applied to a well-nourished population in the UK, remains unclear. In addition, the varying dose, duration and time of introduction of zinc therapy between studies limits a standard treatment regime being advised. The aetiology of pneumonia (i.e. viral verse bacterial) was not adequately reported across studies, thus the application of a targeted use is unknown. Furthermore, cost analysis of adjunctive zinc therapy in reducing morbidity in acute severe respiratory infections is needed.

Clinical Bottom Line

There is some emerging evidence in the literature to support the use of adjunctive zinc therapy in acute severe respiratory tract infections in selective zinc deficient populations. However, further large scale RCTs are required to address its clinical relevance. We also need RCTs conducted in the context of well-nourished populations to assess its clinical application for the UK population.

References

1. Brooks W, et al. Zinc for severe pneumonia in very young children: double blind place controlled trial. The Lancet 2004; 363:1683-8.
2. Shah U, et al. The efficacy of zinc supplementation in young children with acute lower respiratory infections: A randomised double-blind controlled trial. American Journal of Clinical Nutrition 2013; 32:193-199.
3. Mahalanabis D, et al. Randomized, double-blind, placebo-controlled clinical trial of the efficacy of treatment with zinc or vitamin A in infants and young children with severe acute lower respiratory infection. American Journal of Clinical Nutrition 2004; 79:430-6.
4. Bansal A, et al. Zinc supplementation in severe acute lower respiratory tract infection in children: A triple-blind randomized placebo controlled trial. Indian Journal of Pediatrics 2011; 78:33-37.
5. Bose A, et al. Efficacy of zinc in the treatment of severe pneumonia in hospitalised children< 2 years old. American Journal of Clinical Nutrition 2006; 79:430-6.
6. Chang A, et al. and vitamin A supplementation in indigenous Australian children hospitalized with lower respiratory tract infection: A randomised controlled trial. Medical Journal of Australia 2006; 184:107-112.