Paediatrics and International Child Health

ISSN: 2046-9047 (Print) 2046-9055 (Online) Journal homepage: https://www.tandfonline.com/loi/ypch20

Efficacy of zinc supplementation in the

management of acute diarrhoea: a randomised
controlled trial

Lakkana Rerksuppaphol & Sanguansak Rerksuppaphol

To cite this article: Lakkana Rerksuppaphol & Sanguansak Rerksuppaphol (2019): Efficacy of zinc
supplementation in the management of acute diarrhoea: a randomised controlled trial, Paediatrics
and International Child Health, DOI: 10.1080/20469047.2019.1673548

To link to this article: https://doi.org/10.1080/20469047.2019.1673548

Published online: 03 Oct 2019.

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PAEDIATRICS AND INTERNATIONAL CHILD HEALTH
https://doi.org/10.1080/20469047.2019.1673548

Efficacy of zinc supplementation in the management of acute diarrhoea: a

randomised controlled trial
Lakkana Rerksuppaphola and Sanguansak Rerksuppapholb
a
Department of Preventive Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand; bDepartment of Paediatrics,
Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand

ABSTRACT ARTICLE HISTORY

Background: Zinc has been recommended for the treatment of acute diarrhoea; however, Received 7 June 2019
there are heterogeneous reports regarding its efficacy. Accepted 24 September 2019
Aim: This study investigated the efficacy of zinc supplementation on the treatment outcomes KEYWORDS
of children admitted to hospital with acute diarrhoea. Child; diarrhoea; dietary
Methods: A double-blind, randomised, placebo-controlled trial was conducted in the supplements; randomised
Srinakharinwirot University Hospital’s Paediatric Department, Thailand. Eligible children were controlled trial; zinc;
randomly allocated to receive either zinc bisglycinate (15 mg elemental zinc) or a placebo. The antidiarrhoeals;
study protocol was registered in the Thai Clinical Trials Registry (TCTR20190423004). gastroenteritis; therapy
Results: Of 86 patients, 50 (58.1%) were male and the mean age (range) was 2.5 years
(6 months to 9.3 years). The median (IQR) number of hours to recovery from diarrhoea was
significantly less in the zinc group than in the controls [44 (24–48) vs 52 (36–80) hours,
respectively, p < 0.01]. The median (IQR) number of stools was significantly lower in the zinc
group [5 (3–12)] than in the controls [7 (4–17), p = 0.02]. The median (IQR) duration of
intravenous fluid therapy was 40 (24–56) hours in the zinc group and 56 (40–73) in the
control group (p < 0.01). The duration of hospitalisation was 60 (44–72) hours in the zinc
group and 84 (56–136) hours in the controls (p < 0.01). There was good compliance by all
participants in both groups.
Conclusion: Zinc supplementation can reduce the time to resolution of acute diarrhoea, the
length of hospital stay and the frequency of stools. Zinc supplementation is recommended as
a routine strategy for Thai children with acute diarrhoea.

Introduction enhancing water and electrolyte transportation [6]. In

addition, pooled analyses of randomised controlled
Diarrhoea is a major cause of morbidity and mortality,
trials (RCTs) have estimated that zinc can lessen the
especially in children <5 years old. The highest incidence
duration and severity of diarrhoeal episodes and the
of childhood diarrhoea has been reported in Asia and
duration of hospitalisation [7]. A 2-week administra-
Africa [1,2]. However, diarrhoea related-mortality is an
tion of zinc for a diarrhoeal episode reduced the
intrinsic global burden on communities and a challenge
incidence of recurrent episodes in the subsequent
for public health practitioners [1,2]. A systematic analysis
3 months [8].
estimated that, globally, diarrhoea caused >1.3 million
There is a wide degree of heterogeneity between
deaths at all ages and was the fourth leading cause of
the results of published trials of the efficacy of zinc for
death in children <5 years with an estimated 499,000
acute diarrhoea. This might be because zinc is not
child deaths annually [3].
effective against all organisms, and the causes of
Diarrhoeal episodes lead to loss of micronutrients
diarrhoea in LMIC are not similar [9]. In general, zinc
stores such as zinc and copper. Therefore, malnour-
is not prescribed routinely for the management of
ished children living in low- and middle-income coun-
acute diarrhoea in Thai children. It has been estimated
tries (LMIC) have the greatest risk of zinc depletion [4].
that approximately 40% of Thailand’s population is
Based on the outcomes of several randomised trials,
potentially at risk of zinc deficiency [10]. No clinical
the United Nations Children’s Fund (UNICEF) and the
reports from Thailand have examined the effect of
World Health Organization (WHO) in 2004 established
zinc supplementation on the outcome of treatment
a strategy for the management of acute diarrhoea. It
of acute diarrhoea in children.
was based on administering oral rehydration solutions
Given the above, the aim of the study was to
together with zinc supplementation for 2 weeks [5].
undertake a randomised clinical trial to assess the
Zinc plays a substantial role in the growth and integ-
efficacy of zinc supplementation on the outcome of
rity of the immune system growth and integrity. It
treatment in Thai children admitted to hospital with
works directly on the intestinal villi and brush border,

CONTACT Sanguansak Rerksuppaphol sanguansak_r@hotmail.com

© 2019 Informa UK Limited, trading as Taylor & Francis Group
2 L. RERKSUPPAPHOL AND S. RERKSUPPAPHOL
acute diarrhoea. The hypothesis was that zinc supple-
mentation can hasten recovery.
Subjects and methods
Study setting
From June 2018 to April 2019, a double-blind, rando-
mised, placebo-controlled trial was conducted in the
Paediatric Department of Srinakharinwirot University
Hospital, Nakorn Nayok. The study aimed to measure
the efficacy of zinc supplementation in children
admitted with acute diarrhoea.
Sample size and eligibility criteria
The sample size was calculated on the basis of
a previous report which demonstrated that the mean
(SD) time to resolution of acute diarrhoea was 114.3
(30.9) hours [11]. A sample size of 43 patients for each
group was determined to detect a 20% reduction in the
duration of diarrhoea with a sample power of 90% and
95% confidence.
Children aged ≥6 months admitted with acute diar-
rhoea were eligible to participate in the trial. Acute
diarrhoea was defined according to the following cri-
teria: (i) patients who passed abnormal watery and/or
mucous stool, (ii) more than three times within the
previous 24 hours, and (iii) for less than 2 weeks. The
exclusion criteria were (i) patients with severe dehydra-
tion, (ii) evidence of systemic infection, (iii) chronic med-
ical conditions such as chronic liver or renal diseases,
immune deficiency or chronic gastrointestinal condi-
tions, and (iv) who had received zinc or vitamin supple-
mentation within the last 3 months. Eligible children
were randomly allocated to receive either zinc or pla-
cebo. All randomisation procedures were performed
using a computer programme (GraphPad QuickCalcs,
San Diego, CA, USA). Patients’ personal information
were entirely encrypted to randomisation sequence
codes. Patients’ families, research investigators, the sta-
tistician and the attending healthcare workers were
blinded to these codes.
Intervention and procedures
Enrolled children were randomised to receive either zinc
bisglycinate (15 mg elemental zinc) or a placebo twice
a day until discharge from hospital. The zinc bisglycinate
and placebo were prepared in powder form in a single-
dose sachet (Qualimed, Bangkok, Thailand) and dis-
solved in water for administration. The manufacturing
company which produced both the zinc and the pla-
cebo had no role in the study design, data analysis,
interpretation of results or the publication process. The
powder form of zinc bisglycinate and the placebo were
indistinguishable in colour, taste and appearance. Each
arm of the trial received the treatment according to the
registered protocol and the trial contributors were not
able to recognise the treatment or the placebo.
Attending physicians were responsible for the manage-
ment of diarrhoea, the close observation of patients and
decisions to discharge, as per the study protocol.
Data collection and outcome definition
At enrolment, a detailed clinical assessment including the
history and clinical examination was undertaken by the
attending physicians. Baseline demographic data includ-
ing age, gender, bodyweight and height were collected
and analysed. Weight was measured using an electronic
scale to the nearest 0.1 kg. For children <2 years old,
length was measured in the recumbent position using
an infantometer, and in a standing position for children
aged ≥2 to the nearest millimetre using a stadiometer.
Body mass index (BMI) was calculated as weight (kg)/
height (m2). Children with a weight for height <-2 SD
(≤5 years) or BMI <-2 SD (>5 years) were defined as
wasted and children with a length (height) for age <-2
SD were defined as stunted [12]. Clinical dehydration was
determined according to WHO guidelines [13]. Fever was
defined as a body temperature of ≥37.8°C and the resolu-
tion of fever was defined as the first decrease of body
temperature to a normal level on two consecutive mea-
surements with a 4-hour interval.
Laboratory procedures
A venous blood sample was collected using trace
element-free vacutainers for estimation of zinc levels.
Serum zinc was measured by flame atomic absorption
spectrometry and levels <9.9 μmol/L were considered
to indicate zinc deficiency [14]. Haemoglobin, haema-
tocrit, total and differential leucocyte counts and fae-
cal examination were performed on admission by the
central laboratory. In addition, faecal examination for
rotavirus was undertaken by an immunochromatogra-
phy assay (Rota-strip, Coris Bioconcept, Belgium).
Stool culture was performed by a central laboratory
unit. At the end of the study, adverse events were
estimated by interviewing children and/or parents
with non-leading questions. Compliance was evalu-
ated by total drug intake.
The primary outcome of the study was the time to
recovery from diarrhoea; it was defined as the period
between hospital enrolment until the passage of two
consecutive semi-formed stools or not passing stool
for 12 hours since the last defaecation. Secondary
outcomes were the number of abnormal watery or
mucous stools, time of intravenous fluid administra-
tion and length of hospital admission.
 PAEDIATRICS AND INTERNATIONAL CHILD HEALTH 3

Statistical analysis different between the two groups. Enteric pathogens

were detected in 14 patients, non-typhoidal Salmonella
Statistical analysis was performed using IBM SPSS
in six, one in the intervention group had shigella infection
Statistics 23.0 (IBM Corp., Armonk, NY, USA). A one-
and seven had rotavirus. Mean (SD) serum zinc concen-
sample Kolmogorov–Smirnov test was employed to
trations at baseline were 10.6 (2.6) µmol/L in the zinc
assess the normal distribution of variables. Normally dis-
group and 10.3 (2.6) μmol/L in the controls, with no
tributed variables were presented as means and standard
significant difference. Baseline characteristics including
deviations (SD) and non-normally distributed variables as
demographic data, stool frequency and characteristics,
median and interquartile ranges (IQR). Student’s t-test
the severity of clinical status and laboratory findings for
and the Mann–Whitney U-test were used to examine
both trial arms are compared and detailed in Table 1.
the differences between normally and non-normally dis-
tributed variables, respectively. Pearson’s χ2 or Fisher’s
Exact test were introduced to compare proportions
Clinical outcomes
between groups, as appropriate. Cox-proportional
regression models were employed to investigate the The median (IQR) hourly time to recovery from diarrhoea
effects of zinc supplementation and baseline zinc status was significantly less in the zinc group than in the control
on time to recovery from diarrhoea by calculating the group [44 (24–48) vs 52 (36–80), respectively, p < 0.01]
hazard ratio (HR); p < 0.05 was considered to be statisti- (Table 2). In addition, the Cox proportional hazards
cally significant. regression model showed a significant effect of zinc
supplementation in reducing the time to recovery from
diarrhoea [HR 0.412, 95% CI 0.256–0.663)] (Figure 1).
Ethics clearance
Baseline zinc status did not affect the time to remission
The study protocol was approved by the Ethics of diarrhoea in either group [HR 1.003, 95% CI
Committee of Srinakharinwirot University and registered 0.651–1.544]. Forty-two (97.7%) patients in the zinc
in the Thai Clinical Trials Registry (TCTR20190423004). group recovered from diarrhoea 3 days after receiving
Written informed consent was obtained from parents or the treatment and 30 (69.8%) controls recovered 3 days
legal guardians of eligible children before participation, after receiving the placebo, a difference which is statisti-
and all participants were free to withdraw from the study cally significant (p < 0.01). By the 5th day of therapy, no
at any time.
Table 1. Baseline characteristics.
Results Placebo,
Characteristic Zinc, n = 43 n = 43 p-value
Flow and follow-up of participants Age, months 38.7 (25.1) 30.8 (23.1) 0.13
Age <5, n (%) 36 (83.7) 39 (90.7) 0.52
A total of 91 children with acute diarrhoea were consid- Age ≥5 y, n (%) 7 (16.3) 4 (9.3)
Male, n (%) 28 (65.1) 22 (51.2) 0.27
ered for participation. The parents of four children Weighta, kg 13.4 11.7 0.43b
refused. In addition, one child had signs of severe dehy- (10.8–15.3) (9.0–14.8)
Height, cm 93.1 (17.1) 88.2 (17.7) 0.19
dration and was excluded. Eventually, a total of 86 chil- Wasting, n (%) 6 (14.0) 6 (14.0) 1.00
dren were randomly assigned to receive either zinc or Stunting, n (%) 3 (7.0) 5 (11.6) 0.71
placebo. None of the participants discontinued the treat- Pre-enrolment diarrhoea 24 (12–48) 24 (12–48) 0.55b
durationa, hrs
ment or experienced any apparent complications. The Stool frequencya 5 (4–7) 5 (4–8) 0.90b
flowchart of the enrollment process and procedures is Stool characteristic, n (%) 0.55
Watery or loose stool 38 (88.4) 35 (81.4)
shown in the supplemental figure (available from Mucous 5 (11.6) 8 (18.6)
http://www.). Vomiting, n (%) 32 (74.4) 30 (69.8) 0.55
Fever, n (%) 35 (81.4) 34 (79.1) 1.00
Antimicrobial therapy before 7 (16.3) 8 (18.6) 1.00
admission, n (%)
Baseline characteristics of included patients Hydration status, n (%) 0.12
Minimal or no dehydration 21 (48.8) 13 (30.2)
Of 86 subjects, 50 (58.1%) were male and the mean age Moderate dehydration 22 (51.2) 30 (69.8)
(range) was 34.7 months (6 months to 9.25 years). There Laboratory findings
Haemoglobin, g/dL 12.2 (1.1) 11.9 (1.6 0.29
were no significant differences in age or gender distribu- Haematocrit, % 36.8 (2.9) 36.1 (4.8) 0.43
tion between the two groups. Median duration of diar- White blood cell 12.5 (5.0) 13.1 (6.9) 0.66
count ×109/L
rhoea in both arms before admission was 24 hours (IQR Neutrophil, % 65.0 (19.4) 67.6 (17.2) 0.39
12–48 hours) and the frequency of diarrhoeal episodes in Stool pathogens, n (%)
Bacteria 3 (7.0) 4 (9.3) 1.00
both groups was five times (IQR 3–8 times). Thirty-four Rotavirus 4 (9.3) 3 (7.0) 1.00
children (39.5%) had no or mild dehydration at the time Serum zinc concentration, 10.6 (2.6) 10.3 (2.6) 0.69
μmol/L
of enrolment and the remaining patients had moderate <9.9 μmol/L, n (%) 20 (46.5) 21 (48.8) 1.00
dehydration. Haemoglobin and haematocrit levels and Mean (SD) unless otherwise indicated; amedian (interquartile range);
b
leucocyte and neutrophils counts were not statistically Mann–Whitney U-test.
4 L. RERKSUPPAPHOL AND S. RERKSUPPAPHOL

Table 2. Effect of zinc supplementation on clinical outcome Regardless of baseline serum zinc status, time to
in children with acute diarrhoea. remission of diarrhoea and to resolution of fever
Characteristic Zinc, n = 43 Placebo, n = 43 p-value exponentially declined in patients receiving zinc com-
Time to recovery from 44 (24–48) 52 (36–80) <0.01
diarrhoea, hrs
pared with children receiving a placebo. There was
Recovery by 3 days, n (%) 42 (97.7) 30 (69.8) <0.01 a significant reduction in the number of diarrhoeal
Recovery by 5 days, n (%) 43 (100) 40 (93.0) 0.24 episodes in the zinc group compared with the control
Recovery by 7 days, n (%) 43 (100) 42 (97.7) 1.00
No. of diarrhoeal stools per 5 (3–12) 7 (4–17) 0.02 group. In addition, the duration of hospitalisation and
admission of rehydration with intravenous fluids were markedly
Duration of intravenous fluid 40 (24–56) 56 (40–73) <0.01
therapy, hrs reduced in children receiving zinc compared with
Time to resolution of 12 (4–44) 20 (8–48) <0.01 those receiving a placebo. Zinc supplementation was
fever, hrs
Duration of hospital stay, hrs 60 (44–72) 84 (56–136) <0.01 safe and compliance was good.
Median (IQR) unless otherwise indicated; p-values in bold type are Recent research has demonstrated that zinc is an
statistically significant. essential factor in minimising the morbidity and mor-
tality associated with acute and chronic diarrhoeal
child in the zinc group had persistent signs of diarrhoea diseases [15]. Experimental research has found that
compared with three (7.0%) in the placebo group. The zinc can maintain the mucosal immune response to
median (IQR) number of stools during the trial was sig- enteric pathogens as well as the integrity of the
nificantly lower in the zinc group [5 (3–12)] than in the intestinal epithelium [16,17]. Additionally, animal stu-
placebo group [7 (4–17), p = 0.02]. The median duration dies have shown that zinc deficiency increases the
of intravenous fluid therapy and of hospitalisation was susceptibility to diarrhoea through several mechan-
considerably less in the zinc group than in the controls (p isms; it may induce alteration of the intestinal mor-
= 0.001 for both). Fever in the patients receiving zinc phology and mucosal integrity by decreasing the
resolved within a median of 12 hours and within a median villous height and crypt depth. In addition, zinc can
of 20 in the control group (p < 0.01). No patient experi- enhance lamina propria infiltration through stimula-
enced any serious adverse event during the trial. After tion of specific inflammatory cell reactions and loss of
24 hours of treatment, 38 (88.4%) patients in the zinc intestinal mucosal integrity [18].
group had no vomiting compared with 35 (81.4%) Results of trials on the efficacy of zinc for diarrhoea
patients in control group. The median duration of vomit- are contradictory [19–25]. In this study, zinc supple-
ing in the zinc and placebo groups was similar [0 (0–8) mentation significantly reduced stool frequency.
and 0 (0–24), respectively] and the median number of Consistent results were demonstrated in another trial
vomits [0 (0–2) and 0 (0–3), respectively]. There was good in which administration of zinc reduced the frequency
compliance with zinc and placebo in both groups. of diarrhoeal episodes (62% reduction with zinc vs
26% reduction with a placebo) and normalised the
stool consistency [19]. In another randomised trial in
Discussion Bangladeshi children aged 3–24 months, zinc supple-
This randomised trial demonstrated that zinc supple- mentation in a multivitamin syrup reduced diarrhoeal
mentation ameliorated acute diarrhoea in children. episodes by 38% (p < 0.05) and diarrhoea duration by

Figure 1. Cox regression plots for the survival function that predicts the probability of diarrhoeal recovery in the placebo and
the zinc groups.

44% (p < 0.05) compared with a multivitamin syrup
without zinc [20] and these findings are consistent
with our trial. Furthermore, a small trial (n = 60)
demonstrated that, compared with rehydration solu-
tion alone, zinc supplementation in conjunction with
a rehydration solution lessened the cost by 5% and
the duration of diarrhoea by 17 hours [21]. A recent
study in Pakistan also showed the benefits of zinc
supplementation in reducing the number and dura-
tion of diarrhoeal episodes and improving stool con-
sistency in children with acute diarrhoea treated in
the outpatient department [22].
On the other hand, other trials have shown no ben-
efits of zinc supplementation for diarrhoea [23–25]. In an
open-label trial in Turkish children with acute diarrhoea,
zinc had no effect on the duration and severity of diar-
rhoea and there was no significant effect on the inci-
dence and prevalence of diarrhoea [23]. In a controlled
trial in patients aged 28 days to 5 months randomly
assigned to receive 10 mg zinc or a placebo, the mean
duration of diarrhoeal episodes was slightly longer in
those receiving zinc compared with a placebo, but the
effect was not statistically significant, and there were no
reported differences between the zinc and placebo
groups with regard to stool frequency, the proportion
of diarrhoeal attacks and vomiting rates [24]. In another
large-scale trial comparing zinc, placebo and zinc com-
bined with copper, no significant difference was
observed in any group in the duration and severity of
diarrhoea [25].
In an effort to establish a rigorous effect size, various
systematic reviews and meta-analyses have examined
the impact of zinc in acute diarrhoea [9,26,27]. In a meta-
analysis of 18 randomised trials including 7314 children
under 5 years of age, zinc was effective in reducing the
duration of diarrhoea [26]. However, the incidence of
vomiting was significantly higher in the zinc group than
in the controls. Furthermore, reduction in the duration
of diarrhoeal episodes was marked in malnourished
children. However, this quantitative meta-analysis was
limited by the considerable heterogeneity. Based on
a sensitivity analysis, the authors attributed this hetero-
geneity to the nutritional status of the patients. The
authors acknowledged that the evidence from this sub-
group analysis cannot be generalised since it comprised
a small number of studies and most of the trials did not
separate the subjects according to nutritional status
[26]. A recent systematic review of 33 trials including
10,841 children aged 1 month to 5 years with acute or
persistent diarrhoea found that there is insufficient evi-
dence in well conducted randomised controlled trials to
confirm the efficacy of zinc supplementation for acute
diarrhoea in reducing mortality or hospitalisation.
However, zinc supplementation may be beneficial in
children aged ≥6 months living in areas endemic for
zinc deficiency or where there is a high prevalence of
malnutrition [27].
PAEDIATRICS AND INTERNATIONAL CHILD HEALTH 5
As far as we know, this is the first randomised trial in
Thailand examining the efficacy and tolerability of zinc in
children with acute diarrhoea but it has several limita-
tions. Firstly, the attending physicians were responsible
for interventions and discharge decisions; however, all
procedures were randomly and blindly performed and
the remission of acute diarrhoea was recognised as
a primary treatment endpoint. Secondly, the trial did not
evaluate treatment outcomes by long-term follow-up.
Thirdly, the sample size was small which prevented any
subgroup analysis or the proposal of any future standard
practices. For instance, the age range of the study subjects
was 6 months to 9.25 years which is different from most
published reports which have studied children <5 years.
Future studies should examine age-specific outcomes of
zinc supplementation for acute diarrhoea. Lastly,
although the trial outcome was not influenced by the
baseline zinc level, various factors might have affected
the results such as dietary minerals, phytates and zinc
dosage. Phytates are common in Thai food [28] and the
parents and guardians might have given the children
many of these food ingredients. In addition, the zinc
dosage was approximately two-to-three times the recom-
mended daily allowance prescribed for the treatment of
zinc-deficient conditions [29]. Therefore, future large-
scale, randomised studies with longer follow-up and
direct diet observation are recommended to thoroughly
re-investigate and assess the efficacy of zinc supplemen-
tation in children with acute diarrhoea. Furthermore, sub-
group analysis of different variables such as age, gender,
and zinc form and zinc dosage are required.
In conclusion, supplementation with 15 mg ele-
mental zinc bisglycinate can reduce the time to reso-
lution of acute diarrhoea and lessen the length of
hospital stay and the frequency of stools. Treatment
outcome was not affected by baseline zinc status.
Zinc supplementation was safe and compliance was
good. These results need to be confirmed by large-
scale trials with extended follow-up.
Acknowledgments
We gratefully acknowledge the children, parents and
healthcare workers for their various contributions to the
research.
Author contributions
Both authors defined and developed the initial research
idea. Both were involved in designing and implementing
the study, as well as analysis and interpretation of the
results and writing the manuscript. Both authors have read
and approved the final manuscript.
Disclosure statement
No potential conflict of interest was reported by the
authors.
6 L. RERKSUPPAPHOL AND S. RERKSUPPAPHOL
Funding
The study was supported by grants from Srinakharinwirot
University, Thailand [grant number SWU 012/2561]
Notes on contributors
Lakkana Rerksuppaphol, MD, is Assistant Professor of
Preventive Medicine at Department of Preventive
Medicine, Faculty of Medicine, Srinakharinwirot University,
Bangkok, Thailand. Her research interests primarily include
paediatrics and child health, nutrition and acupuncture.
Sanguansak Rerksuppaphol, MD, is Associate Professor of
Pediatrics Gastroenterology and Clinical Nutrition at
Department of Pediatrics, Faculty of Medicine,
Srinakharinwirot University, Bangkok, Thailand. His research
interests primarily include Gastroenterology and Nutritional
disorders, zinc and probiotics.
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