zinc for common cold 2

A randomized controlled trial of chelated zincfor prevention of the common cold in Thaischool children

Sanguansak Rerksuppaphol1, Lakkana Rerksuppaphol2

Departments of 1Paediatrics and 2Preventive Medicine, Faculty of Medicine, Srinakharinwirot University,Bangkok, Thailand

Background: The common cold is responsible for the largest proportion of school and work absenteeismand is a huge economic burden. None of the currently available interventions is clearly effective forprevention or treatment.Objective: To assess the efficacy of 15-mg chelated zinc (zinc bis-glycinate) given once a day for 3 monthsduring the winter season to healthy school children aged 8–13 years to prevent symptoms of the commoncold.Methods: In a double-blind randomized controlled trial, zinc bis-glycinate 15 mg or matching placebo oncea day for 3 months was administered to healthy school children aged 8–13 years. Primary outcomes wereany symptom of cold (fever, cough, rhinorrhoea) during the study period, and secondary outcomes werevomiting, diarrhoea, use of antibiotics, school absence for any reason, school absence because of a coldand duration of all symptoms.Results: Of 50 children in each group, 42 (84%) in the zinc group and 41 (82%) in the placebo group(P51.00) developed at least one symptom of a cold. There was no difference in the incidence of fever,cough, rhinorrhoea, school absence and school absence related to the common cold compared withchildren in the placebo group. However, duration of cough [median (IQR) 1.0 (0.0–6.0) vs 6.0 (0.0–13.3)days], rhinorrhoea [median (IQR) 2.0 (0.0–7.0) vs 5.5 (1.0–15.3) days] and the frequency of having two ormore symptoms of the common cold [median (IQR) 0.0 (0.0–1.0) vs 1.0 (0.0–5.3) days] were reducedsignificantly in the intervention group (P,0.01).Conclusions: Zinc bis-glycinate given in a dose of 15 mg once a day for 3 months failed to reduce theincidence of the common cold in 8 to 13-year-old school children, but decreased the number of days onwhich children suffered from cough, rhinorrhoea and the likelihood of having two or more symptoms of thecommon cold.

Keywords: Chelated zinc, Common cold, Cough, Fever, School children, Zinc bis-glycinate

IntroductionThe common cold is the most frequently occurring

acute illness in children. More than 80% of colds

requiring medical attention occur in children.1 It is

responsible for a large proportion of school absentee-

ism, absenteeism of care-givers from work and doctor

visits.1,2 It also leads to reduced efficiency and

productivity. Apart from this economic loss, billions

of dollars are spent every year worldwide on

‘potential’ but unproven remedies. Various methods

of preventing and treating the common cold have

been tried in all systems of medicine.3,4 However, to

date, none has proved to be of great benefit.

Zinc plays an important role in maintaining

healthy immune function and a mild deficiency has

been associated with defective natural killer-cell

function and defective interleukin-2 production.5,6

Zinc deficiency also increases the response to airway

inflammation and cell damage in respiratory infec-

tions and can increase the incidence of serious

infections.7,8 Zinc has been shown to inhibit rhino-

virus replication.9 Because of its impact on childhood

mortality, zinc has been studied extensively as an

adjunct to the prevention and treatment of pneumo-

nia, and shows considerable promise.10–12

Although pneumonia is responsible for many child

deaths, colds are much more common and substan-

tially affect absence from school and work and

economic productivity. Previous controlled trials

have shown that zinc given in various forms can

reduce the severity and duration of symptoms of the

common cold and decrease its incidence.13–17

However, this has not been seen consistently in all

Correspondence to: S Rerksuppaphol, Department of Paediatrics, Facultyof Medicine, Srinakharinwirot University, Bangkok, Thailand. Email:[email protected]

� W. S. Maney & Son Ltd 2013DOI 10.1179/2046905513Y.0000000064 Paediatrics and International Child Health 2013 VOL. 33 NO. 3 145

trials and a meta-analysis and a Cochrane systematic

review concluded that there is not enough evidence of

benefit.18,19 Only a limited number of studies in

developing countries have reported on the role of zinc

in preventing and managing the common cold. None

of the studies used chelated zinc which is more

digestible and has better absorption than zinc in ionic

form, and therefore may have fewer adverse effects.20

There are no studies of chelated zinc in preventing

the common cold in children. This study was

conducted to investigate the efficacy of zinc amino

acid chelate in preventing symptoms of the common

cold in school-age children aged 8–13 years.

Subjects and MethodsStudy design and subjectsThis was a double-blind randomized controlled trial,

conducted in a public school in Ongkharuck district,

Nakorn Nayok, Thailand in the winter season from

November 2010 to January 2011. Healthy children

aged 8–13 years who were in grades 3–6 were eligible

for inclusion. The trial was concurrent with another

trial of probiotics for the prevention of upper

respiratory infections in the same population.

Parents and children were informed about the two

trials and had the choice of enter one or the other.

Children with a history of chronic illness such as

chronic cough or chronic respiratory disease, asthma,

chronic gastro-intestinal conditions, behavioural or

psychiatric problems or other neurological condi-

tions, immune deficiency, diabetes mellitus, malig-

nancy, chronic renal diseases, congenital heart

diseases or chronic liver disease were excluded.

Children who were taking vitamin or mineral

supplements or had a history of any drug allergy

were also excluded.

InterventionUsing a computerized programme (GraphPad

QuickCals), the enrolled children were randomized

to the zinc or placebo group using blocks of two by a

statistical consultant who was not involved in the

implementation phase of the study. The investigators,

teachers, children and parents were masked to the

intervention. The code to the randomization se-

quence was opened only after the study was complete.

Children in the treatment group were given

chelated zinc in the form of a zinc bis-glycinate

(QualimedH, Thailand) tablet, 15 mg once a day for

3 months. Placebo tablets were prepared by the same

company and were of identical colour, size and taste.

Trained staff distributed the medication to teachers

and parents for administration to the children. The

teachers and parents were trained to give the assigned

tablet on week days and during weekends, holidays

and absence days. Parents were instructed not to give

any vitamin, zinc or mineral supplements during the

study period.

Data collection and monitoringAfter enrolment, demographic characteristics and

clinical data were recorded by nursing staff. Weight

was measured to the nearest 100 g using an electronic

scale (Tanita Body Composition Analyzer, model no.

BF-680W, Tokyo, Japan). Height was measured to

the nearest 0.1 cm. Body mass index was calculated

as the ratio of weight/(height)2 [kg/m2]. During the

course of the study, symptoms of a cold (fever, cough

and rhinorrhoea), other symptoms (vomiting, diar-

rhoea), antibiotics used during sickness, school

absence and school absence related to cold symptoms

were recorded every day by trained teachers. During

weekends, holidays and school absence, symptoms

were recorded by parents and reported on the next

working day. Open-ended questions assessed side-

effects in both groups. Before the study commenced,

teachers and parents were trained in data-collection

methods. Tablets were provided for 1 month at a

time and, to measure compliance, the remaining

tablets were counted every month.

Outcome measuresThe primary outcome was the occurrence of any

symptom of cold (fever, cough, rhinorrhoea) at any

time during the 3-month study period. Fever was

defined as oral temperature .37.7uC as measured

by digital thermometer (model CT-513W, Citizen

Systems Japan Co. Ltd, Tokyo, Japan). Secondary

outcomes were the occurrence of vomiting, diarrhoea,

use of antibiotics, school absence for any reason,

school absence owing to a cold and duration of all

symptoms during the 3-month study period.

Sample sizeA previous trial of zinc in children reported an 86%

incidence of the common cold in winter.13 To detect a

30% relative decrease in the incidence (absolute

decrease of 60%) with 80% power and two-tailed

alpha error of 0.05, a sample size of 45 per group was

required. To account for attrition, we planned to

enrol 100 children (50 in each group).

Approval was obtained from the Ethics Committee

of the Faculty of Medicine, Srinakharinwirot

University, Thailand. Written informed consent and

assent were obtained from parents or legal guardians

and children, respectively, before enrolment. Children

were allowed to withdraw from the study at any time

and the reason for withdrawal was recorded.

Statistical analysisPearson’s x2 or Fisher Exact test were used to

compare proportions between the groups. The

normality of distributions of continuous variables

was assessed by the Kolmogorov–Sminov test. The

Mann–Whitney U test was used to compare the

Rerksuppaphol and Rerksuppaphol Zinc & the common cold

146 Paediatrics and International Child Health 2013 VOL. 33 NO. 3

continuous data as most distributions were non-

normal. Data were analyzed as per intention-to-treat

until the day of withdrawal. After adjusting for age,

gender and body mass index (BMI), binary logistic

regression analysis was used to estimate the adjusted

odds ratios (95% CI) for having common cold-like

symptoms in the zinc supplement group compared

with the placebo group. Multicollinearity was inden-

tified in the anthropometric data (weight, height

and BMI), and so BMI was used to represent the

anthropometric data in the logistic model. Statistical

analysis was performed with SPSS (version 11.0,

SPSS, Chicago, IL, USA).

ResultsOf the 100 children, 47 in the zinc group and 48 in the

placebo group completed the study (Fig. 1). The

parents of three children in the zinc group withdrew

their consent in the first week of the study owing to

concern about potential adverse effects of the

medication. Two children in the placebo group were

withdrawn, one on day 31 owing to moving to a

different school and another on day 2 because of

having a rash. Up to the withdrawal date, none of the

withdrawn children had any cold symptoms.

Compliance was good and similar in both groups –

87% of medication was taken by the zinc group and

88% by the placebo group (P50.12).

Table 1 shows the baseline demographic data.

Children in the zinc group were younger, lighter

and shorter than those in the placebo group, but the

gender distribution and body mass index were

similar. The incidences of fever, cough, rhinorrhoea,

vomiting, diarrhoea, antibiotic usage and school

absence were comparable between the two groups

(Table 2). The proportion of children who developed

at least one cold symptom was also similar between

the two groups (Table 2). Zinc group children tended

to have fewer symptoms, but the differences were not

significant. Although the proportion of children

developing various symptoms did not differ between

the two groups, the duration of cough and rhinor-

rhoea and the frequency of having two or more

symptoms was significantly reduced in children who

received zinc (Table 3). Logistic regression analysis

adjusting for gender, age and BMI showed no

significant differences between the two groups with

regard to the occurrence of fever (OR 0.5, 95% CI

0.16–1.66), cough (OR 0.74, 95% CI 0.21–2.57),

rhinorrhoea (OR 0.45, 95% CI 0.11–1.94), school

absence (OR 2.44, 95% CI 0.72–8.30) or cold-related

absence from school (OR 1.92, 95% CI 0.53–6.92).

No adverse event or bad taste was reported except

one episode of rash in the placebo group on day 2 of

the study, resulting in withdrawal of the child from

the study. The rash subsided uneventfully after a

couple of days.

DiscussionZinc bis-glycinate, a form of chelated zinc, 15 mg

once a day administered to school children aged 8–

13 years for 3 months period during the winter

season, did not result in significant reduction in the

incidence of symptoms of the common cold or

absenteeism from school. However, it significantly

decreased the duration of cough and rhinorrhoea,

and the frequency of having two or more symptoms.

In a similar trial, Vakili et al. reported significant

reduction in the incidence of the common cold in

Iranian children.17 However, they used zinc sulfate

and gave it for 5 months during the winter. Variation

between different zinc preparations in the bio-

availability of free zinc may cause differences in its

effects. The duration of prophylactic treatment might

also affect the results. Vakili et al. used a different

definition of the common cold. In their study, if a

participant experienced two of the following 10

symptoms, he/she was considered to have a cold:

cough, headache, hoarseness, muscle ache, nasal

drainage, nasal congestion, scratchy throat, sore

throat, sneezing and fever. Kurugol et al. also

reported positive results of a trial of zinc sulfate

(15 mg daily) vs placebo when administered prophy-

lactically to children in Turkey over a 7-month

period.13 In another trial, however, zinc gluconate

glycine lozenges failed to demonstrate a positive

impact in the treatment of American children with

the common cold.21

Zinc deficiency is an important cause of childhood

morbidity in developing countries and 95% of the

population in south-east Asian countries are at risk

of zinc deficiency.22,23 Zinc deficiency in these

populations is attributed to poor intake, high dietary

phytate/zinc ratio and increased faecal loss owing

diarrhoea.24 Most earlier studies were in adults or

very young children and used ionic zinc, usually as

zinc sulfate. The studies with positive results may also

have had an element of bias because of the ability of

subjects to recognize adverse effects and the taste of

zinc.18,25 The conflicting results in different trials

might be attributable to different methods, doses,

formulations, subjective outcomes and inadequate

blinding. A meta-analysis of zinc lozenges showed

that the large variation in results might be because of

variation in the total daily dose of zinc obtained from

lozenges.26 The composition of lozenges might affect

the availability of free zinc ions and hence their

effectiveness.26 Zinc lozenges also tend to leave a bad

taste in the mouth.

The design of our study was robust. It was

conducted in a vulnerable group of children and


Paediatrics and International Child Health 2013 VOL. 33 NO. 3 147

was able to ensure effective double-blinding. A

chelated form of zinc was used, ensuring virtually

no adverse effects, very good compliance and

effective blinding. This form of zinc is also absorbed

better and thus may have better systemic effects.20

We did not assess zinc status which would have

involved invasive blood-sampling. However, the

prevalence of zinc deficiency is estimated to be

.40% in our region and Thailand is classified as a

medium risk country.22 The International Zinc

Nutrition Consultative Group recommends that if

.20% of the population or a sub-group has serum

zinc below the cut-off level, the whole population

should be considered to be at risk.22 Apart from

Figure 1 Flow chart of children in the trial

Table 1 Demographic profile of the study population

Zinc (n550) Placebo (n550) P-value

Age, yr, mean (SD) 10.0 (0.5) 11.4 (0.8) ,0.0001*Boys, n (%) 30 (60.0) 26.0 (52.0) 0.54Weight, kg, median (IQR) 29.0 (25.0–33.3) 33.5 (27.0–41.4) 0.01{

Height, cm, median (IQR) 135.5 (129.8–141.0) 141.0 (137.0–141.0) ,0.0001{

Body mass index, kg/m2, mean (SD) 16.9(3.8) 17.8 (4.4) 0.23*

* Student’s t-test; { Mann Whitney U test.



fever, which was objectively measured, other symp-

toms of the common cold in our study were based on

report. It may not be possible to firmly differentiate

between infection and other causes of respiratory

symptoms such as allergies, but a combination of

symptoms along with fever is more likely to point

towards an infective aetiology. Similar definitions

have been used in earlier studies. Despite strict

randomization and a double blind design, there was

an imbalance in the study between the demographic

profiles of the two groups. This was most likely

because of statistical probability and was addressed

by using logistic regression analysis. Two other

limitations of the study are failure to assess the

severity of symptoms and that the symptoms were

reported through a third party. The study did not see

a significant reduction in the incidence of the

common cold even though the duration of cough

and rhinorrhoea was decreased. Moreover, the

chelated zinc form was well tolerated and was

virtually free of any adverse effects. This makes it

more acceptable, with high achievable compliance

rates, than previously studied zinc preparations. A

major limitation of the study was the small sample

size, which might not have been sufficiently large to

detect modest benefits. In the case of the common

cold with its high prevalence, even a modest effect

size could have tremendous economic benefits. To

detect an absolute reduction of 10% in the incidence

found in this study, more than 1000 children would

have had to be enrolled to achieve 90% power. Hence,

there is a need to conduct larger multi-centre trials on

the prevention of the common cold by chelated zinc.

In recent reviews, large community-based trials have

also been recommended.27

AcknowledgmentsThe study was supported by grants from the Faculty

of Medicine, Srinakharinwirot University, Thailand.

The authors thank Qualimed (Bangkok, Thailand)

for supplying the zinc bis-glycinate and placebo. The

manufacturer had no role in the planning, execution

or analysis of the study.

References1 National Institute of Allergy and Infectious Diseases. The

Common Cold. NIAID fact sheet. National Institute of Allergyand Infectious Diseases, National Institutes of Health.Available at: http://www.niaid.nih.gov/factsheets/cold.htm.Accessed October 2011.

2 Fendrick AM, Monto AS, Nightengale B, Sarnes M. Theeconomic burden of non-influenza-related viral respiratorytract infection in the United States. Arch Intern Med.2003;163:487–94.

3 Nahas R, Balla A. Complementary and alternative medicine forprevention and treatment of the common cold. Can FamPhysician. 2011;57:31–6.

4 Simasek M, Blandino DA. Treatment of the common cold. AmFam Physician. 2007;75:515–20.

5 Kaplan J, Hess JW, Prasad AS. Impairment of immunefunction in the elderly: association with mild zinc deficiency.

Table 2 Symptoms of the common cold during the study

Zinc n550 (%) Placebo n550 (%) P-value* RR (95% CI)

Primary outcomes

Fever 31 (62.0) 26 (52.0) 0.41 1.506 (0.679–3.339)Cough 28 (56.0) 37 (74.0) 0.09 0.447 (0.192–1.039)Rhinorrhoea 34 (68.0) 40 (80.0) 0.25 0.531 (0.213–1.324)Secondary outcomes

Vomiting 8 (16.0) 12 (24.0) 0.45 0.603 (0.223–1.634)Diarrhoea 10 (20.0) 16 (32.0) 0.25 0.531 (0.213–1.324)Antibiotic usage 2 (4.0) 5 (10.0) 0.43 0.375 (0.069–2.031)School absence 16 (32.0) 20 (40.0) 0.53 0.706 (0.311–1.603)Cold-related school absence 13 (26.0) 14 (28.0) 1.00 0.903 (0.373–2.186)No. of symptoms

At least one symptom 42 (84.0) 41 (82.0) 1.00 1.152 (0.405–3.277)At least two symptoms 19 (38.0) 27 (34.0) 0.16 0.522 (0.235–1.159)All three symptoms 6 (12.0) 13 (26.6) 0.12 0.388 (0.134–1.122)

* Pearson’s x2 or Fischer’s Exact test.

Table 3 Duration of symptoms, school absence and antibiotic usage (in days)

Zinc (n550) Placebo (n550) P-value

Fever 1.0 (0.0–4.0) 1.0 (0.0–4.0) 0.68Cough 1.0 (0.0–6.0) 6.0 (0.0–13.3) ,0.01Rhinorrhoea 2.0 (0.0–7.0) 5.5 (1.0–15.3) ,0.01Vomiting 0 0.0 (0.0–0.3) 0.32Diarrhoea 0 0.0 (0.0–1.0) 0.15Antibiotic usage 0 0 0.23School absence 0.0 (0.0–1.0) 0.0 (0.0–1.3) 0.50Cold-related school absence 0.0 (0.0–1.0) 0.0 (0.0–1.0) 0.81At least two symptoms 0.0 (0.0–1.0) 1.0 (0.0–5.3) ,0.01At least three symptoms 0 0.0 (0.0–1.0) 0.04

All values are median (IQR); * Mann–Whitney U test.


Paediatrics and International Child Health 2013 VOL. 33 NO. 3 149

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