Sei sulla pagina 1di 7

A randomized controlled trial of chelated zinc

for prevention of the common cold in Thai


school 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 absenteeism
and is a huge economic burden. None of the currently available interventions is clearly effective for
prevention or treatment.
Objective: To assess the efficacy of 15-mg chelated zinc (zinc bis-glycinate) given once a day for 3 months
during the winter season to healthy school children aged 813 years to prevent symptoms of the common
cold.
Methods: In a double-blind randomized controlled trial, zinc bis-glycinate 15 mg or matching placebo once
a day for 3 months was administered to healthy school children aged 813 years. Primary outcomes were
any symptom of cold (fever, cough, rhinorrhoea) during the study period, and secondary outcomes were
vomiting, diarrhoea, use of antibiotics, school absence for any reason, school absence because of a cold
and 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 with
children in the placebo group. However, duration of cough [median (IQR) 1.0 (0.06.0) vs 6.0 (0.013.3)
days], rhinorrhoea [median (IQR) 2.0 (0.07.0) vs 5.5 (1.015.3) days] and the frequency of having two or
more symptoms of the common cold [median (IQR) 0.0 (0.01.0) vs 1.0 (0.05.3) days] were reduced
significantly 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 the
incidence of the common cold in 8 to 13-year-old school children, but decreased the number of days on
which children suffered from cough, rhinorrhoea and the likelihood of having two or more symptoms of the
common cold.
Keywords: Chelated zinc, Common cold, Cough, Fever, School children, Zinc bis-glycinate

Introduction
The 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 absenteeism, 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
Correspondence to: S Rerksuppaphol, Department of Paediatrics, Faculty
of Medicine, Srinakharinwirot University, Bangkok, Thailand. Email:
sanguansak_r@hotmail.com

W. S. Maney & Son Ltd 2013


DOI 10.1179/2046905513Y.0000000064

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 infections and can increase the incidence of serious
infections.7,8 Zinc has been shown to inhibit rhinovirus replication.9 Because of its impact on childhood
mortality, zinc has been studied extensively as an
adjunct to the prevention and treatment of pneumonia, and shows considerable promise.1012
Although pneumonia is responsible for many child
deaths, colds are much more common and substantially 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.1317
However, this has not been seen consistently in all

Paediatrics and International Child Health

2013

VOL .

33

NO .

145

Rerksuppaphol and Rerksuppaphol

Zinc & the common cold

any vitamin, zinc or mineral supplements during the


study period.

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 813 years.

Data collection and monitoring


After 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, diarrhoea), 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 sideeffects 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.

Subjects and Methods


Study design and subjects
This 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 813 years who were in grades 36 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 conditions, immune deficiency, diabetes mellitus, malignancy, 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.

Outcome measures
The 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 size
A 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.

Intervention
Using 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 sequence 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

146

Paediatrics and International Child Health

2013

VOL .

33

NO .

Statistical analysis
Pearsons x2 or Fisher Exact test were used to
compare proportions between the groups. The
normality of distributions of continuous variables
was assessed by the KolmogorovSminov test. The
MannWhitney U test was used to compare the

Rerksuppaphol and Rerksuppaphol

continuous data as most distributions were nonnormal. 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 indentified 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).

Results
Of 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 rhinorrhoea 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
0.161.66), cough (OR 0.74, 95% CI 0.212.57),
rhinorrhoea (OR 0.45, 95% CI 0.111.94), school
absence (OR 2.44, 95% CI 0.728.30) or cold-related
absence from school (OR 1.92, 95% CI 0.536.92).
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

Zinc & the common cold

the study. The rash subsided uneventfully after a


couple of days.

Discussion
Zinc 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 bioavailability 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 prophylactically 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 .

147

Rerksuppaphol and Rerksuppaphol

Zinc & the common cold

Figure 1 Flow chart of children in the trial

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

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
Table 1 Demographic prole of the study population

Age, yr, mean (SD)


Boys, n (%)
Weight, kg, median (IQR)
Height, cm, median (IQR)
Body mass index, kg/m2, mean (SD)
* Students t-test;

148

Zinc (n550)

Placebo (n550)

P-value

10.0 (0.5)
30 (60.0)
29.0 (25.033.3)
135.5 (129.8141.0)
16.9(3.8)

11.4
26.0
33.5
141.0
17.8

,0.0001*
0.54
0.01{
,0.0001{
0.23*

Mann Whitney U test.

Paediatrics and International Child Health

2013

VOL .

33

NO .

(0.8)
(52.0)
(27.041.4)
(137.0141.0)
(4.4)

Rerksuppaphol and Rerksuppaphol

Zinc & the common cold

Table 2 Symptoms of the common cold during the study

Primary outcomes
Fever
Cough
Rhinorrhoea
Secondary outcomes
Vomiting
Diarrhoea
Antibiotic usage
School absence
Cold-related school absence
No. of symptoms
At least one symptom
At least two symptoms
All three symptoms

Zinc n550 (%)

Placebo n550 (%)

P-value*

RR (95% CI)

31 (62.0)
28 (56.0)
34 (68.0)

26 (52.0)
37 (74.0)
40 (80.0)

0.41
0.09
0.25

1.506 (0.6793.339)
0.447 (0.1921.039)
0.531 (0.2131.324)

8 (16.0)
10 (20.0)
2 (4.0)
16 (32.0)
13 (26.0)

12 (24.0)
16 (32.0)
5 (10.0)
20 (40.0)
14 (28.0)

0.45
0.25
0.43
0.53
1.00

0.603
0.531
0.375
0.706
0.903

42 (84.0)
19 (38.0)
6 (12.0)

41 (82.0)
27 (34.0)
13 (26.6)

1.00
0.16
0.12

1.152 (0.4053.277)
0.522 (0.2351.159)
0.388 (0.1341.122)

(0.2231.634)
(0.2131.324)
(0.0692.031)
(0.3111.603)
(0.3732.186)

* Pearsons x2 or Fischers Exact test.


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

Fever
Cough
Rhinorrhoea
Vomiting
Diarrhoea
Antibiotic usage
School absence
Cold-related school absence
At least two symptoms
At least three symptoms

Zinc (n550)

Placebo (n550)

P-value

1.0
1.0
2.0
0
0
0
0.0
0.0
0.0
0

1.0
6.0
5.5
0.0
0.0
0
0.0
0.0
1.0
0.0

0.68
,0.01
,0.01
0.32
0.15
0.23
0.50
0.81
,0.01
0.04

(0.04.0)
(0.06.0)
(0.07.0)

(0.01.0)
(0.01.0)
(0.01.0)

(0.04.0)
(0.013.3)
(1.015.3)
(0.00.3)
(0.01.0)
(0.01.3)
(0.01.0)
(0.05.3)
(0.01.0)

All values are median (IQR); * MannWhitney U test.

fever, which was objectively measured, other symptoms 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

Acknowledgments
The 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.

References
1 National Institute of Allergy and Infectious Diseases. The
Common Cold. NIAID fact sheet. National Institute of Allergy
and 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. The
economic burden of non-influenza-related viral respiratory
tract infection in the United States. Arch Intern Med.
2003;163:48794.
3 Nahas R, Balla A. Complementary and alternative medicine for
prevention and treatment of the common cold. Can Fam
Physician. 2011;57:316.
4 Simasek M, Blandino DA. Treatment of the common cold. Am
Fam Physician. 2007;75:51520.
5 Kaplan J, Hess JW, Prasad AS. Impairment of immune
function in the elderly: association with mild zinc deficiency.

Paediatrics and International Child Health

2013

VOL .

33

NO .

149

Rerksuppaphol and Rerksuppaphol

6
7
8
9
10

11

12

13
14
15

150

Zinc & the common cold

Essential and toxic elements in human health and disease. New


York, NY: Liss, 1988; 30917.
Roxas M, Jurenka J. Colds and influenza: a review of diagnosis
and conventional, botanical, and nutritional considerations.
Altern Med Rev. 2007;12:2548.
Prasad AS. Zinc: role in immunity, oxidative stress and chronic
inflammation. Curr Opin Clin Nutr Metab Care. 2009;12:646
52.
Shankar AH, Prasad AS. Zinc and immune function: the
biological basis of altered resistance to infection. Am J Clin
Nutr. 1998;68:44763S.
Korant BD, Butterworth BE. Inhibition by zinc of rhinovirus
protein cleavage: interaction of zinc with capsid polypeptides. J
Virol. 1976;18:298306.
Sazawal S, Black RE, Jalla S, Mazumdar S, Sinha A, Bhan
MK. Zinc supplementation reduces the incidence of acute lower
respiratory infections in infants and preschool children: a
double-blind, controlled trial. Pediatrics. 1998;102:15.
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. Cochrane
Database Syst Rev. 2011:CD007368.
Roth DE, Richard SA, Black RE. Zinc supplementation for the
prevention of acute lower respiratory infection in children in
developing countries: meta-analysis and meta-regression of
randomized trials. Int J Epidemiol. 2010;39:795808.
Kurugol Z, Akilli M, Bayram N, Koturoglu G. The prophylactic and therapeutic effectiveness of zinc sulphate on common
cold in children. Acta Paediatr. 2006;95:117581.
Eby GA, Davis DR, Halcomb WW. Reduction in duration of
common colds by zinc gluconate lozenges in a double-blind
study. Antimicrob Agents Chemother. 1984;25:204.
Godfrey JC, Conant Sloane B, Smith DS, Turco JH, Mercer N,
Godfrey NJ. Zinc gluconate and the common cold: a controlled
clinical study. J Int Med Res. 1992;20:23446.

Paediatrics and International Child Health

2013

VOL .

33

NO .

16 Mossad SB, Macknin ML, Medendorp SV, Mason P. Zinc


gluconate lozenges for treating the common cold. A randomized, double-blind, placebo-controlled study. Ann Intern
Med. 1996;125:818.
17 Vakili R, Vahedian M, Khodaei G, Mahmoudi M. Effects of
zinc supplementation in occurrence and duration of common
cold in school aged children during cold season: a double-blind
placebo-controlled trial. Iran J Pediatr. 2009;19:37680.
18 Jackson JL, Lesho E, Peterson C. Zinc and the common cold: a
meta-analysis revisited. J Nutr. 2000;130:15125S.
19 Marshall I. Zinc for the common cold. Cochrane Database Syst
Rev. 2000:CD001364.
20 Cooper B. What is zinc chelate? [cited 2012 Dec 30]. Available
from: http://www.ehow.com/about_5348347_zinc-chelate.html.
21 Macknin ML, Piedmonte M, Calendine C, Janosky J, Wald E.
Zinc gluconate lozenges for treating the common cold in
children: a randomized controlled trial. JAMA. 1998;279:1962
7.
22 Brown KH, Rivera JA, Bhutta Z, Gibson RS, King JC,
Lonnerdal B, et al. International Zinc Nutrition Consultative
Group (IZiNCG) technical document #1. Assessment of the
risk of zinc deficiency in populations and options for its control.
Food Nutr Bull. 2004;25:S99203.
23 Gibson RS, Ferguson EL. Assessment of dietary zinc in a
population. Am J Clin Nutr. 1998;68:4304S.
24 Gibson RS, Ferguson EL, Lehrfeld J. Complementary foods
for infant feeding in developing countries: their nutrient
adequacy and improvement. Eur J Clin Nutr. 1998;52:76470.
25 Singh M, Das RR. Zinc for the common cold. Cochrane
Database Syst Rev. 2011:CD001364.
26 Hemila H. Zinc lozenges may shorten the duration of colds: a
systematic review. Open Respir Med J. 2011;5:518.
27 Singh M, Das RR. Clinical potential of zinc in prophylaxis of
the common cold. Expert Rev Respir Med. 2011;5:3013.

Copyright of Paediatrics & International Child Health is the property of Maney Publishing
and its content may not be copied or emailed to multiple sites or posted to a listserv without
the copyright holder's express written permission. However, users may print, download, or
email articles for individual use.