Zinc supplementation for the treatment of measles in children

  • Protocol
  • Intervention

Authors

  • Ajibola A Awotiwon,

    Corresponding author
    1. Faculty of Health Sciences, Stellenbosch University, Department of Community Health, Cape Town, Western Cape, South Africa
    • Ajibola A Awotiwon, Department of Community Health, Faculty of Health Sciences, Stellenbosch University, Cape Town, Western Cape, South Africa. docjibbs@yahoo.com.

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  • Olabisi Oduwole,

    1. University of Calabar Teaching Hospital (ITDR/P), Institute of Tropical Diseases Research and Prevention, Calabar, Cross River State, Nigeria
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  • Anju Sinha,

    1. Indian Council of Medical Research, Reproductive and Child Health, Ansari Nagar, New Delhi, India
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  • Charles I Okwundu

    1. Stellenbosch University, Centre for Evidence-based Health Care, Faculty of Medicine and Health Sciences, Cape Town, South Africa
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Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of zinc supplementation in reducing morbidity and mortality in children with measles.

Background

Description of the condition

Measles is an important cause of childhood morbidity and mortality in high-income and low-income countries. It is an acute viral infection characterised by high fever and maculopapular rash (Maldonado 2003). According to the World Health Organization (WHO), 53,5000 children died of measles in 2000, accounting for 5% of all under-five mortalities (UNICEF 2011). Between 2000 and 2010, there was a 74% reduction in measles deaths globally as a result of improved vaccine coverage efforts (Simons 2012). However, recently large outbreaks have occurred in some countries such as Bulgaria in 2009 to 2010 and France in 2011, as a result of sub-optimal immunisation levels (Carrillo-Santisteve 2012). In low-income countries, such as Sierra Leone (between 2009 and 2010) and South Africa (between 2003 and 2005; 2009 and 2011), there were outbreaks of measles probably as a result of HIV infection and poor vaccine coverage (Sartorius 2013). Amongst young children in low-income countries, case-fatality rates for measles still hover at around 5% to 6% (Wolfson 2009). Acute lower respiratory infection is a common complication of measles, associated with mortality. Other important complications of measles include otitis media, laryngotracheobronchitis (croup), diarrhoea, encephalitis and cortical damage leading to blindness (Perry 2004).

Worldwide, the prevalence of zinc deficiency is estimated to be more than 20% (Wuehler 2005), and in many low-income countries it is extremely prevalent amongst children (World Bank 2012). The majority of zinc excretion takes place through the gastrointestinal tract, therefore children exposed to gastrointestinal pathogens on a regular basis and who have a poor diet, low in animal products and high in phytate, are most at risk of zinc deficiency (Lazzerini 2012). Zinc deficiency results in dysfunction of both humoral and cell-mediated immunity and increases the susceptibility to infectious diseases such as diarrhoea and respiratory infection (Tuerk 2009). Respiratory tract infections such as acute lower respiratory tract infections (ALRIs) are a common complication of measles infection (Aggarwal 2007; Roth 2008; Shakur 2009).

Description of the intervention

Zinc is one of the most important trace elements in the human body. It is a component of over 1000 transcription factors and is required in more than 300 zinc-containing enzymes (Haase 2009; Stefanidou 2006). Zinc supplementation may reduce the duration of acute and persistent diarrhoea in children over six months of age (Lazzerini 2012), as well as the frequency of diarrhoeal and respiratory illnesses in children (Aggarwal 2007). Zinc supplements can be given in the form of either zinc sulphate, zinc gluconate, zinc acetate or zinc chloride. The recommended daily dose is 10 mg to 20 mg of zinc for children with diarrhoea (WHO/UNICEF 2004).

How the intervention might work

The importance of zinc in the maintenance of normal immune functions has been demonstrated by several studies (Bach 1989; Prasad 1998; Prasad 2000; Prasad 2009; Stefanidou 2006; Tapiero 2003). Zinc is said to be crucial for effective innate and acquired immunity and insufficient zinc status could be the most common cause of secondary immunodeficiency in humans (Tapiero 2003). Zinc deficiency impairs phagocytosis of macrophages and neutrophils, oxidative burst activity and complement natural killer (NK) cell activity (Prasad 2000). Zinc is also involved in T-cell differentiation and enhancement of T-cell and NK cell actions through its role in thymulin activity (Bach 1989). In the absence of zinc, lymphocyte proliferation is depressed, as well as delayed-type hypersensitivity skin responses and T-cell dependent antigen-antibody responses (Prasad 1998). Zinc has also been shown to have anti-inflammatory as well as antioxidant properties (Prasad 2009; Stefanidou 2006). Supplements will increase the availability of zinc for these immunologic processes and may improve measles morbidity and mortality. In children, zinc supplementation is reported to reduce morbidity, mortality and recovery time from acute infectious diseases (Cuevas 2005). Sazawal 2007 showed that zinc supplements given to children aged between 1 and 48 months resulted in reduced mortality from acute infections including measles. Zinc supplementation has also been shown to reduce respiratory morbidity significantly in preschool children (Sazawal 1998), and may reduce the incidence of ALRIs by improving measles morbidity.

Why it is important to do this review

Several published reviews have shown that zinc supplementation is associated with reduced incidence and prevalence of pneumonia in children (Aggarwal 2007; Bhutta 1999; Lassi 2010). Other Cochrane Reviews evaluating zinc supplementation in children have looked at otitis media, diarrhoea and common cold (Gulani 2012; Lazzerini 2012; Singh 2013). This review aims to identify, critically appraise and synthesise data from studies evaluating the effects of zinc supplementation in children with measles.

Objectives

To assess the effects of zinc supplementation in reducing morbidity and mortality in children with measles.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and quasi-RCTs evaluating the effects of zinc in reducing morbidity and mortality in children with measles.

Types of participants

Children up to the age of 18 years diagnosed with measles.

Types of interventions

Zinc supplementation (irrespective of dosage, duration and route of administration) combined with standard treatment compared with standard treatment alone or standard treatment with placebo. (Standard treatment is defined as relief of common symptoms such as fever, cough, blocked nose, conjunctivitis and sore mouth, provision of nutritional support and vitamin A) (WHO 2004).

Types of outcome measures

Primary outcomes
  1. All-cause mortality.

Secondary outcomes
  1. Duration of fever, coryza, cough and exanthema (rash).

  2. Duration of hospitalisation.

  3. Incidence of complications such as pneumonia, otitis media, diarrhoea and croup.

  4. Effect on disability-adjusted life years (DALYs).

  5. Adverse events.

Search methods for identification of studies

Electronic searches

We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (latest issue), which contains the Cochrane Acute Respiratory Infections Group (CRG) Specialised Register, MEDLINE (1966 to present date), EMBASE (1974 to present date), CINAHL (1981 to present date), LILACS (1982 to present date), Web of Science (1985 to present date) and BIOSIS Previews (1985 to present date).

We will use the following search strategy to search CENTRAL and MEDLINE. We will combine the MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE (Lefebvre 2011). We will adapt the search strategy to search the other databases. We will not use any language or publication restrictions.

MEDLINE (Ovid)

1 exp Measles/
2 exp Measles virus/
3 Morbillivirus Infections/
4 Morbillivirus/
5 (measles* or rubeola*).tw.
6 or/1-5
7 exp Zinc/
8 exp Zinc Acetate/
9 Zinc Sulfate/
10 exp Zinc Compounds/
11 (zinc or zn).tw,nm.
12 Trace Elements/
13 Dietary Supplements/
14 or/7-13
15 6 and 14

Searching other resources

We will search, using the relevant search terms, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) to identify unpublished and ongoing studies. We will scrutinise the reference lists of the included studies and relevant review articles for additional references.

We will handsearch the conference proceedings of relevant professional organisations. We will contact trial authors and topic specialists to seek further published studies, if required.

Data collection and analysis

Selection of studies

Two review authors will independently screen the titles and abstracts of articles identified by the searches for eligibility. We will classify these studies as included, unclear or excluded. We will retrieve full articles of studies that do not have an abstract or have a limited abstract and assess them for inclusion. Two review authors will independently assess full articles classified as 'include' or 'unclear' for inclusion using a standardised form with explicit inclusion and exclusion criteria. The two review authors will resolve any disagreements by discussion and, if required, by consultation with a third review author.

Data extraction and management

Two review authors will independently extract data from each included study using a pre-designed data extraction form. We will try to contact trial authors for incompletely reported data. We will extract the following information:

  • general information (study ID, date of extraction, title, authors and source of study if not published);

  • study characteristics (study design, participants and inclusion/exclusion criteria used in the study);

  • details of the interventions (including zinc dosage, treatment duration, comparison details, duration of follow-up);

  • outcomes as described in Types of outcome measures above;

  • details necessary for 'Risk of bias' assessment.

We will resolve disagreements between the review authors by discussion or by consultation with a third review author.

Assessment of risk of bias in included studies

We will use the 'Risk of bias' assessment tool and criteria set out in the Cochrane Handbook for Systematic Reviews of Interventions to assess the risk of bias in the included studies (Higgins 2011). Two review authors will independently assess the risk of bias in the included studies by assessing randomisation sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, incomplete outcome data, selective outcome reporting and other sources of bias. We will resolve any disagreements through discussion or by consultation with a third review author. We will report the results in the 'Risk of bias' tables.

Measures of treatment effect

We will perform statistical analysis according to the statistical guidelines referenced in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011). For dichotomous outcomes (e.g. mortality), we will express the measure of effect as risk ratio (RR) and absolute risk (AR) with 95% confidence intervals (CI). For continuous outcomes (e.g. duration of hospital stay), we will express the measure of effect as a mean difference (MD) with 95% CI. In the event that continuous data are reported on different continuous scales, we will standardise outcomes, where possible, to calculate the standardised MD.

Dealing with missing data

We will contact trial authors to verify or obtain missing data when necessary. If we receive no reply, we will employ intention-to-treat (ITT) analysis (which considers all missing data as treatment failure) only as a sensitivity analysis, when pooling the data. We will clearly label analyses including imputed data.

Assessment of heterogeneity

We will assess statistical heterogeneity via visual inspection of forest plots of the included trials, using the Chi2 test and the I2 statistic, where data from included trials can be pooled. We will examine the trial characteristics (participants, design, interventions, outcomes and risk of bias) to identify the source of any heterogeneity observed.

Assessment of reporting biases

We will assess reporting biases by trying to identify whether the study was included in a trial registry, whether a protocol is available and whether the methods section provides a list of outcomes. We will compare the list of outcomes from those sources to the outcomes reported in the published paper. We will also create an inverted funnel plot in order to check for possible publication bias if a sufficient number of studies are available for specific outcomes.

Data synthesis

We will combine data for outcomes from studies that meet the inclusion criteria in the meta-analysis using RevMan 2012 software, provided the studies are sufficiently similar. We will perform statistical analyses according to the statistical guidelines of the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011) and the Cochrane Acute Respiratory Infections Group. We will conduct a random-effects meta-analysis if appropriate. We will not conduct meta-analysis where a high level of heterogeneity is evident. In instances where data cannot be combined in a meta-analysis, we will provide a narrative summary of the trial findings.

We will use the GRADEpro 2008 software to create GRADE evidence profiles and 'Summary of findings' tables. We will assess the quality of evidence across each outcome measure using the GRADE methodology (Schünemann 2011). The quality rating has four levels: high, moderate, low or very low. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence. Evidence from RCTs is initially graded as high quality but can be downgraded. We will justify all decisions to downgrade the quality of studies using footnotes and by making comments.

Subgroup analysis and investigation of heterogeneity

We plan to explore any significant heterogeneity observed by conducting subgroup analyses based on the characteristics of participants (inpatient/outpatient, age group), type of comparison (placebo/standard treatment), type of supplement, dose and duration of supplement and immunisation status. We will conduct post hoc subgroup analyses, as necessary, for interventions/outcomes with significant heterogeneity.

Sensitivity analysis

We will conduct sensitivity analyses to assess the impact of high risk of bias on the outcome of meta-analyses by gradually adding studies with a high risk of bias to pooled studies with low risk of bias.

Acknowledgements

We want to thank Sarah Thorning for helping with the search strategy.

Contributions of authors

Ajibola Awotiwon wrote the protocol with insightful comments from Olabisi Oduwole, Anju Sinha and Charles Okwundu.

Declarations of interest

Ajibola Awotiwon: none known.
Olabisi Oduwole: none known.
Anju Sinha: none known.
Charles Okwundu: none known.

Sources of support

Internal sources

  • Center for Evidence-based Health Care, Stellenbosch University, South Africa.

External sources

  • No sources of support supplied

Ancillary