Pediatrics International (2011) 53, 677682

Original Article

ped_3325

doi: 10.1111/j.1442-200X.2011.03325.x

677..682

Probiotic, zinc and lactose-free formula in children with rotavirus

diarrhea: Are they effective?
Nazan Dalgic,1 Mesut Sancar,3 Banu Bayraktar,2 Mine Pullu1 and Ozlem Hasim1
Divisions of 1Pediatric Infectious Diseases and 2Clinical Microbiology, Sisli Etfal Training and Research Hospital, Sisli and
3
Division of Clinical Pharmacy, Faculty of Pharmacy, Marmara University, Istanbul, Turkey
Abstract

Background: The aim of the present study was to evaluate the effectiveness of zinc, probiotic bacteria, and lactose-free
formula and their different combinations in the treatment of rotavirus diarrhea in young children.
Methods: Eight different treatment groups were formed: group 1, 60 patients receiving Saccharomyces boulardii; group
2, 60 patients receiving zinc; group 3, 60 patients receiving lactose-free formula; group 4, 60 patients receiving S.
boulardii plus zinc; group 5, 60 patients receiving S. boulardii plus lactose-free formula; group 6, 60 patients receiving
zinc plus lactose-free formula; group 7, 60 patients receiving S. boulardii plus zinc plus lactose-free formula; group 8,
60 patients receiving only oral and/or parenteral rehydration solutions.
Results: No statistically significant differences were found in the time to resolution of fever after intervention between
the treatment groups and the control group. The time to resolution of vomiting was significantly lower in group 4
compared with groups 1 and 5. The duration of diarrhea was significantly reduced in groups 2 and 4 compared to control.
A statistically significant difference in the duration of hospitalization was observed for the groups 2 and 4 in comparison
to the control group.
Conclusions: A different combination of adjunct therapies did not seem to bring additional value to rehydration therapy
in children with rotavirus diarrhea except for in those receiving only zinc and zinc plus S. boulardii. Further studies are
required to determine the optimal protocol of adjunct therapy use in children with rotavirus diarrhea.

Key words

children, lactose-free formula, probiotic, rotavirus, zinc.

Since their discovery in the 1970s, the human rotaviruses have

been recognized as the most common infectious agents associated with diarrhea in the pediatric age group worldwide.1 Virtually all children throughout the world are infected with rotavirus
by the time they are 35 years old. Every year, rotavirus causes
between 352 000 and 592 000 deaths globally among children <5
years old, mostly in developing countries.2
The treatment of rotavirus diarrhea has remained relatively
unchanged over the last 35 years. Oral rehydration, breastfeeding, and early refeeding are still the most important tools
in the management of children and infants with acute gastroenteritis and rotavirus diarrhea.1 Oral rehydration is inexpensive, accessible, and it significantly reduces morbidity and
mortality.3,4 Oral rehydration, however, does not reduce the
volume or duration of diarrhea. Other preparations used for
treatment of diarrhea include probiotics, immunoglobulins
administered orally and anti-peristaltic and anti-secretory
agents.5

Correspondence: Nazan Dalgic, MD, Halkali Cad. 45/3, Yesilkoy,

34149, Istanbul, Turkey. Email: nazandalgic@ttmail.com
Received 6 September 2010; revised 8 January 2011; accepted 12
January 2011.

2011 The Authors

Pediatrics International 2011 Japan Pediatric Society

The potential for probiotic therapy in acute infectious diarrhea has recently been studied. Among the probiotics most
widely tested and, in general, found to be more effective are
Lactobacillus GG and Saccharomyces boulardii. Several randomized, controlled trials (RCT) have been performed with S.
boulardii in children with acute gastroenteritis and these have
systematically shown a significant benefit compared with
placebo. Possible explanations for the observed effects include
inhibition of adhesion of pathogens, enhanced mucosal integrity, beneficial effects on the dysregulated immune response,
production of antimicrobial substances, and intestinal receptor
modification.69
Studies linking diarrheal diseases with zinc deficiency were
first described in reports of low plasma zinc levels in children
with diarrhea.10 Several studies showed that zinc reduced stool
output and diarrheal duration when administered as an adjunct to
oral rehydration solution (ORS) in hospitalized children aged
336 months with acute diarrhea and dehydration.11 In a pooled
analysis of nine randomized trials, zinc supplementation was
reported to decrease the incidence of diarrhea by 18%.12 The
World Health Organization (WHO) recommends 14 days of zinc
supplementation for all children who have acute diarrhea: 10 mg
daily for infants younger than 6 months of age and 20 mg daily
for all older infants and children.13

678

N Dalgic et al.

Rotavirus causes patchy damage to the small intestinal

epithelium, resulting in blunting of the villi. This is associated
with some reduction in the activity of lactase and other disaccharidases, leading to reduced absorption of carbohydrates.
This intestinal morphology and absorptive capacity returns to
normal within 23 weeks.14 Post-gastroenteritis lactose intolerance has been reported in 4.318.4% of children in general and
in 3050% after rotavirus infection.1518 There is some evidence
that a lactose-free diet may reduce the duration of diarrhea in
children with acute gastroenteritis. In a systematic review of
studies comparing lactose-free and lactose-containing diets
for children with diarrhea and mildmoderate dehydration,
lactose-free diets appeared to decrease the duration of diarrhea
in some subgroups of children.19 Lactose-free diet in the
treatment of rotavirus diarrhea in children, however, has not
been tested.
Intervention trials have demonstrated that the addition of oral
zinc to probiotics can also reduce the duration and severity
of acute diarrhea in children.7,20,21 The question as to whether
the combined administration will result in additional benefit,
in synergy with an antagonistic effect, has not been evaluated
because there is only one study that has evaluated the combined
effect of probiotic, prebiotic, and zinc.22 Data are needed on the
effect of the combination of zinc and probiotics. Moreover, no
clinical studies have been conducted using different combinations of zinc, probiotics and lactose-free formula to treat rotavirus
diarrhea.
Given the current uncertainty as to whether lactose avoidance,
and the administration of zinc and probiotic improves outcomes
for young children with acute diarrhea, the aim of the present
study was to evaluate the effectiveness of zinc, probiotic, and
lactose-free formula and their different combinations in the treatment of rotavirus diarrhea in young children.

Methods
Patients

In this prospective, randomized, single-blind, controlled trial,

480 children were enrolled, ranging in age from 1 to 28 months
and diagnosed with rotavirus diarrhea, and they were hospitalized between September 2008 and June 2010 at Sisli Etfal
Training and Research Hospital. The inclusion criteria were:
time interval between the onset of diarrhea and hospitalization
<96 h; presenting with an episode of 33 watery or looserthan-normal stools within a 24 h period and/or forceful
vomiting (excluding post-tussive vomiting); the presence of
mildmoderate dehydration; and, on admission, stool positive
for rotavirus antigen. The exclusion criteria were: malnutrition
as judged by the ratio of weight to height, duration of diarrhea
>96 h; severe dehydration; exclusively breast-feeding; toxic
clinical appearance; immunosuppression; and any known allergies to any drugs or foods.
The nutrition status of the patient was classified according to
z score and the WHO tables for developing countries. Patients
with a z score of 2-3 were considered to have severe malnutrition
and were excluded from the study.
2011 The Authors
Pediatrics International 2011 Japan Pediatric Society

Written informed consent was obtained from parents or guardians. The study was approved by the Ethics Committee of Sisli
Etfal Training and Research Hospital, Istanbul, Turkey (Number:
2008-66).
Study design

The patients were examined clinically, and the presence of mild

moderate dehydration was established as previously defined.23
The first stool obtained from each patient hospitalized was
analyzed with Immunocard Rotavirus (Meridian Diagnostics,
Cincinnati, OH, USA) for rotavirus antigen. All the children
underwent routine laboratory testing throughout the trial, including complete blood count, serum electrolytes, blood urea nitrogen, creatinine, glucose, aspartate aminotransferase, and alanine
aminotransferase.
For rehydration, the patients were offered ORS with a composition as recommended by the European Society for Pediatric
Gastroenterology, Hepatology and Nutrition.24 If necessary,
because of excessive vomiting and clinical signs of dehydration,
parenteral rehydration was established. The study preparation
was given right after randomization, and rehydration was not
awaited.
The patients were randomly assigned from a computerized
admissions list to one of the eight different treatment groups
described: group 1, 60 patients receiving S. boulardii; group 2, 60
patients receiving zinc; group 3, 60 patients receiving lactosefree formula (Bebelac Lactose Free Formula, 400 g; Nutricia,
Istanbul, Turkey); group 4, 60 patients receiving S. boulardii plus
zinc; group 5, 60 patients receiving S. boulardii plus lactose-free
formula; group 6, 60 patients receiving zinc plus lactose-free
formula; group 7, 60 patients receiving S. boulardii plus zinc
plus lactose-free formula; group 8, 60 patients receiving only oral
and/or parenteral rehydration solutions. Group 8 was regarded as
the control group.
Zinc acetate suspension was given 10 mg twice daily for the
infants younger than 6 months of age, and 20 mg daily for all the
older infants and children. Saccharomyces boulardii was given
250 mg once daily for a minimum of 5 days.
Clinical observations

The duration of diarrhea, that is, the time from start of treatment
until the first normal stool, was chosen as the main outcome
criterion. Body mass (without clothing) was recorded by electronic scales within 50 g on admission and at discharge. Daily
routine clinical examination and extent of dehydration during
hospital stay were closely monitored. For each child, the number
of vomiting episodes, the number of bowel movements, and the
rectal temperature were recorded. Diarrhea resolution was established when stools consistency ceased to be watery, or when the
number of bowel movements was fewer than three times in 24
hours. Due to the ambulatory setting of the study, after diarrhea
resolution, the parents were instructed to return to the clinic if
diarrhea resumed, and daily telephone calls were made to ensure
that there were no relapses. We also investigated safety and
tolerability. In addition, the number of hospitalization days for
each patient was recorded.

41 (8.5)
19 (4)
21.23 1 17.88
39 (8.1)
21 (4.4)
23.16 1 19.11

679

Group 1, 60 patients receiving Saccharomyces boulardii; group 2, 60 patients receiving zinc; group 3, 60 patients receiving lactose-free formula; group 4, 60 patients receiving S. boulardii
plus zinc; group 5, 60 patients receiving S. boulardii plus lactose-free formula; group 6, 60 patients receiving zinc plus lactose-free formula; group 7, 60 patients receiving S. boulardii plus
zinc plus lactose-free formula; control group, 60 patients receiving only oral and/or parenteral rehydration solutions.

0.78

41 (8.5)
19 (4)
19.85 1 16.71
44 (9.2)
16 (3.3)
22.38 1 17.92
39 (8.1)
21 (4.4)
19.61 1 13.48
43 (9)
17 (3.5)
23.13 1 19.93

Group 5
2.63 1 1.99
19 (4)
52 (10.8)
Group 4
2.20 1 1.39
19 (4)
48 (10)
Group 3
2.78 1 1.98
21 (4.4)
50 (10.4)
Group 2
3.13 1 1.91
23 (4.8)
52 (10.8)
Group 1
2.41 1 1.15
26 (5.4)
53 (11)

Diarrhea prior to enrollment (days)

Fever on admission (>38 C)
Vomiting
Degree of dehydration
Mild
Moderate
Time to resolution of fever (h)

Table 1 Study group clinical characteristics (mean 1 SD or n, %)

All the 480 children completed the study. The patients consisted
of 288 boys (60%) and 192 girls (40%) with a mean 1 SD age of
13.71 1 6.21 months (range, 128 months). Four hundred and
seventy infants (95.8%) were partially breast-fed and 10 (2.1%)
were receiving cows milk-based formula only. The mean z
score was 0.66 1 0.26 (z score > -3SD) in all the study groups.
Vomiting, dehydration, and fever were common at presentation.
Two hundred and eleven (87.9%) suffered from vomiting, and
ninety-four (39.2%) had fever on admission. No significant differences regarding duration of illness, fever, vomiting and degree
of dehydration were found among the groups at the time of
hospitalization (Table 1). Four hundred and forty patients
(91.6%) received parenteral rehydration (no statistically significant difference between the treatment groups and control group,
P > 0.05).
During the hospitalization period, no significant difference
was found in the time until resolution of fever after intervention
between the treatment groups and the control group (P > 0.05).
There was a statistically significant difference in patient age
among the treatment groups (P < 0.05; Table 2). No statistically
significant difference was found when the treatment groups
(groups 17) and the controls (group 8) were compared for
patient age (P > 0.05). We also compared weight between the
eight groups, and found a difference among the treatment groups
and between group 1 and controls, and group 4 and controls (P <
0.05; Table 2).
Time to resolution of vomiting in the treatment groups was
compared with the controls: no statistically significant difference was found (P > 0.05). When comparison was made within
the treatment groups, time to resolution of vomiting was significantly lower in group 4 (10.40 1 8.73 days) compared with
group 1 (20.31 1 12.94 days) and 5 (17.58 1 13.13 days),
respectively.
The duration of diarrhea was significantly reduced in groups 2
and 4 compared to the control group (P < 0.05). The median
duration of diarrhea for group 4 (3.11 1 1.81 days) was shorter
than that for the group 2 (3.41 1 1.38 days) but without statistical
significance (P > 0.05). We also compared duration of diarrhea
between the groups, and found a significant difference between
groups 1 and 2; groups 1 and 4; groups 2 and 3; groups 2 and 5;
groups 2 and 7; groups 3 and 4; groups 4 and 5; and groups 4 and
7 (P < 0.05). The diarrheal phase was the shortest in groups 4 and
2 within the total study group. In group 4, the diarrheal phase was
shorter than in group 2 but the difference did not reach significance (the duration of diarrhea was 3.11 1 1.81 days in group 4
vs 3.41 1 1.38 days in group 2).

Group 6
2.50 1 1.51
18 (3.8)
54 (11.2)

Results

37 (7.7)
23 (4.8)
24.75 1 21.24

Group 7
2.71 1 1.69
25 (5.2)
51 (10.6)

Control group
2.31 1 1.21
24 (5)
48 (10)

The c2 test was used to evaluate categorical variables, and analysis of variance (ANOVA) of Tukey-Kramer multiple comparison test for continuous variables, when analyzing differences
between group 8 and groups 17. All the analyses were conducted using SPSS version 16.0.0 for Windows (SPSS, Chicago,
IL, USA). P 2 0.05 was considered statistically significant.

42 (18.8)
18 (3.8)
22.86 1 19.15

P
0.059
0.70
0.72

Statistical analysis

0.89

Adjunct therapies for rotavirus diarrhea

2011 The Authors

Pediatrics International 2011 Japan Pediatric Society

680

N Dalgic et al.

Table 2 Comparative analysis (mean 1 SD)

Group 1
Group 2
Group 3
Group 4
Group 5
Group 6
Group 7
Control

Age (months)

Weight (kg)

16.95 1 4.87a,b
15.83 1 5.34b,c
11.31 1 4.79d
15.39 1 6.38a
11.20 1 5.63d
11.35 1 5.03d
13.15 1 6.87c,d
13.80 1 6.28a,b,c,d

11.37 1 1.78a,b
10.33 1 2.32b,c
9.43 1 1.94c,d
10.61 1 2.48b
9.11 1 1.76d
8.91 1 1.33d
9.39 1 1.70c,d
9.47 1 1.69c,d

Time to resolution of
vomiting (h)
20.31 1 12.94a
13.63 1 10.33a,b
13.91 1 10.63a,b
10.40 1 8.73 b
17.58 1 13.13a,c
15.46 1 13.97a,b
16.96 1 14.30a,b
16.35 1 11.34a,b

Time to resolution of
diarrhea (days)
4.78 1 1.46a
3.41 1 1.38b
4.46 1 1.22a,c
3.11 1 1.81b,d
4.55 1 1.32a,c
4.75 1 1.35a,b
4.36 1 1.85a,c
5.35 1 1.80a,c

Duration of hospitalization
(days)
5.30 1 1.73a,b,c
4.33 1 1.38b,c
5.23 1 1.54a,b
4.11 1 1.64c,d
5.15 1 1.77a,b
4.85 1 1.99a,b,c,d
5.66 1 2.05a
5.81 1 2.08a

ad
Different superscript letters between groups show significant differences at P < 0.05. Significant differences found between groups: for age,
13, 15, 6, 17, 23, 24, 25, 26, 34, 45, 46; for weight, 13, 15, 6, 17, 1control, 25, 26, 34, 45, 46, 47, 4control; for time to
resolution of vomiting, 14, 45; for time to resolution of diarrhea, 12, 14, 23, 25, 26, 2control, 34, 45, 47, 4control; for duration of
hospitalization, 27, 2control, 34, 45, 47, 4control.
Group 1, 60 patients receiving Saccharomyces boulardii; group 2, 60 patients receiving zinc; group 3, 60 patients receiving lactose-free formula;
group 4, 60 patients receiving S. boulardii plus zinc; group 5, 60 patients receiving S. boulardii plus lactose-free formula; group 6, 60 patients
receiving zinc plus lactose-free formula; group 7, 60 patients receiving S. boulardii plus zinc plus lactose-free formula; control group, 60 patients
receiving only oral and/or parenteral rehydration solutions.

A statistically significant difference in the duration of hospitalization was observed for groups 2 and 4 in comparison to the
control group. In group 4, the duration of hospitalization was
shorter than in group 2 but the difference did not reach significance (the duration of hospitalization was 4.11 1 1.64 days
in group 4 vs 4.33 1 1.38 days in group 2). We also compared
duration of hospitalization between the groups and found a significant difference between groups 1 and 4; groups 2 and 7;
groups 3 and 4; groups 4 and 5, and groups 4 and 7 (P < 0.05).
No adverse effects were observed in the treatment groups by
the investigators or nursing staff. All the patients who concluded
the study were followed up until after 5 days from discharge
without signs of recurrence of the diarrhea.

Discussion
Diarrheal diseases are a leading cause of childhood mortality and
morbidity in developing countries and an important cause of
malnutrition.25 The majority of diarrheal deaths are caused by
dehydration that can be treated with ORS or parenteral rehydration. ORS or parenteral rehydration, however, cannot reduce the
volume, frequency, and duration of diarrhea.26 Available antiperistaltic or anti-secretory drugs to reduce the severity of
diarrhea can cause serious side-effects in children.5 Various auxiliary treatments aimed at shortening the diarrheal episodes are
optional.
Probiotics are live microorganisms and, when administered in
adequate amounts, confer a beneficial effect on the health of the
host.9 Several studies have shown that probiotic bacteria can
shorten the clinical course of acute rotavirus gastroenteritis
(RVGE).2729 Five RCT testing S. boulardii in a total of 619
patients were included in a recent meta-analysis, and the authors
concluded that S. boulardii exerts a moderate clinical benefit by
significantly reducing the duration of diarrhea.30 There is not
sufficient evidence to generally recommend continued use of
probiotics for the prevention of acute diarrhea or RVGE in infants
and young children.31 In the present study we found no significant
2011 The Authors
Pediatrics International 2011 Japan Pediatric Society

differences in the time to resolution of diarrhea, time to resolution of vomiting and duration of hospitalization in those receiving
only S. boulardii compared to the control group. We confirmed
the beneficial effect of probiotic in combination with zinc in the
current study. The combination of probiotic and zinc decreased
the duration of diarrhea and hospitalization in comparison to the
control group in the present study. Also, the combined administration significantly reduced the duration of vomiting compared
to those receiving only S. boulardii and those receiving the combination of S. boulardii and lactose-free formula. Intervention
trials have demonstrated that the addition of oral zinc to probiotics can reduce the duration and severity of acute diarrhea in
children, similar to the present results.7,20,21 The question as to
whether the combined administration will result in additional
benefit, in synergy with an antagonistic effect, has not been
evaluated because there only one study has been conducted that
evaluated the combined effect of probiotic, prebiotic, and zinc
treatment.22 That study demonstrated that the addition of 6
109 c.f.u. of Streptococcus thermophilus, Bifidobacterium lactis,
Lactobacillus acidophilus (2 109 c.f.u. of each strain) and
10 mg/day of zinc significantly reduced the duration of acute
gastroenteritis in children aged 612 months by nearly 15 h, and
induced quicker resumption of normal stool consistency. In
contrast, the addition of probiotics to infant formula in rhesus
monkeys decreased the severity of experimentally induced diarrhea, but no additional benefit was obtained by adding zinc to the
probiotics.32 Data are needed on the effect of the combination of
zinc and probiotics in children with RVGE to confirm the present
results.
Zinc supplementation during diarrhea is recommended in
developing countries by the WHO and the United Nations Childrens Fund (UNICEF) based on several trials demonstrating a
significant effect of zinc in reducing the duration, severity, and
recurrence of diarrhea in immunocompetent and in severely
malnourished or immune-deficient children.11,3335 We found a
positive effect of zinc on duration of diarrhea and duration of
hospitalization days in the present study when we compared

Adjunct therapies for rotavirus diarrhea

the control group with the other treatment groups, except for
those receiving zinc plus S. boulardii and zinc plus lactose-free
formula.
Post-gastroenteritis lactose intolerance has been reported in
4.318.4% of children in general and in 3050% after rotavirus
infection.1518 Szajewska et al. designed a study to determine the
prevalence of carbohydrate intolerance in Polish children during
an acute episode of diarrhea. They found that the frequency of
carbohydrate intolerance was significantly higher in children
with rotavirus gastroenteritis (13/14, 92.9%) than in children
without (1/14, 7.1%).17 Currently available clinical guidelines
(based on detailed literature evaluation and expert consensus)
offer conflicting advice on whether lactose avoidance should be
advised for young children with acute diarrhea.3638 A systematic
review published in 1994 found some evidence that lactose
avoidance improved important clinical outcomes for young
children with acute diarrhea, especially for children who were
severely dehydrated because of the acute diarrheal illness.17 Of
the five subsequent RCT,3943 three found that lactose-free feeds
significantly reduced the duration of diarrhea compared with
feeds containing lactose.39,42,43 The other two RCT found no significant difference.40,41 In the present study, no significant differences in the time to resolution of fever, time to resolution of
vomiting, time to resolution of diarrhea, and duration of hospitalization were found between the treatments groups, including
those receiving only lactose-free formula and combination of
lactose-free formula with zinc and/or probiotic. This result may
be due to inclusion of patients with mild/moderate dehydration in
the present study and shorter diarrhea time in the patients prior to
enrollment (2.59 1 1.90 days).
No clinical studies have been conducted using different combinations of zinc, probiotics, and lactose-free formula to treat
acute diarrhea. The present study was the first to evaluate different combinations of zinc, probiotics and lactose-free formula
in children with RVGE. In the present study, seven groups of
patients receiving different combinations of zinc, probiotics and
lactose-free formula were compared with the control group and
with each other, and no significant differences were found for the
time to resolution of fever, time to resolution of vomiting, time to
resolution of diarrhea, and duration of hospitalization except for
the patients receiving zinc, and zinc plus S. boulardii. In patients
receiving the combination of zinc and S. boulardii, time to resolution of diarrhea and duration of hospitalization were shorter
than in patients receiving only zinc, but the difference did not
reach significance. A different combination of adjunct therapies
did not seem to add value to oral/parenteral rehydration therapy
in hospitalized children with RVGE except for in those receiving
only zinc and zinc plus S. boulardii. Further studies, a costeffect
analysis, and large trials are required to determine the optimal
protocol of adjunct therapies (e.g. probiotic, zinc and lactose-free
formula) in children with RVGE.
Conclusion

Prospective randomized studies with a combination of zinc and

probiotics, and that are homogeneous for treatment, dose, methodology, definition of diarrhea and outcomes, are still necessary

681

to better define the duration of supplementation to be recommended in each child with RVGE.

References
1 Teran CG, Teran-Escalera CN, Villarroel P. Nitazoxanide vs. probiotics for the treatment of acute rotavirus diarrhea in children: A
randomized, single-blind, controlled trial in Bolivian children. Int.
J. Infect. Dis. 2009; 13: 51823.
2 Jayashree S, Bhan MK, Kumar R et al. Serum and salivary antibodies as indicators of rotavirus infection in neonates. J. Infect.
Dis. 1988; 158: 111720.
3 Rhoads M. Management of acute diarrhea in infants. J. Parenter.
Enteral Nutr. 1999; 23: S1819.
4 Nappert G, Barrios JM, Zello GA et al. Oral rehydration solution
therapy in the management of children with rotavirus diarrhea.
Nutr. Rev. 2000; 58: 8087.
5 Subbotina MD, Timchenko VN, Vorobyov MM et al. Effect of oral
administration of tormentil root extract (Potentilla tormentilla) on
rotavirus diarrhea in children: A randomized, double blind, controlled trial. Pediatr. Infect. Dis. J. 2003; 22: 70611.
6 Van Niel CW, Feudtner C, Garrison MM et al. Lactobacillus
therapy for acute infectious diarrhea in children: A meta-analysis.
Pediatrics 2002; 109: 67884.
7 Szajewska H, Mrukowicz JZ. Probiotics in the treatment and prevention of acute infectious diarrhea in infants and children: A
systematic review of published randomized, double-blind, placebocontrolled trials. J. Pediatr. Gastroenterol. Nutr. 2001; 33: S1725.
8 Reid G, Jass J, Sebulsky MT et al. Potential uses of probiotics in
clinical practice. Clin. Microbiol. Rev. 2003; 16: 65872.
9 Guarino A, Lo Vecchio A, Canani RB. Probiotics as prevention and
treatment for diarrhea. Curr. Opin. Gastroenterol. 2009; 25: 1823.
10 Naveh Y, Lightman A, Zinder O. Effect of diarrhea on serum zinc
concentrations in infants and children. J. Pediatr. 1982; 101: 730
32.
11 Bhatnagar S, Bahl R, Sharma PK et al. Zinc with oral rehydration
therapy reduces stool output and duration of diarrhea in hospitalized children: A randomized controlled trial. J. Pediatr. Gastroenterol. Nutr. 2004; 38: 3440.
12 Bhutta ZA, Black RE, Brown KH et al. Prevention of diarrhea and
pneumonia by zinc supplementation in children in developing
countries: Pooled analysis of randomized controlled trials. Zinc
Investigators Collaborative Group. J. Pediatr. 1999; 135: 8997.
13 Bass ES, Pappano DA, Humiston SG. Rotavirus. Pediatr. Rev.
2007; 28: 18391.
14 Alam NH, Ashraf H. Treatment of infectious diarrhea in children.
Paediatr. Drugs 2003; 5: 15165.
15 Hyams JS, Krause PJ, Gleason PA. Lactose malabsorption following rotavirus infection in young children. J. Pediatr. 1981; 99:
91618.
16 Bhatnagar S, Singh KD, Sazawal S et al. Efficacy of milk versus
yogurt offered as part of a mixed diet in acute noncholera diarrhea
among malnourished children. J. Pediatr. 1998; 132: 9991003.
17 Szajewska H, Kantecki M, Albrecht P et al. Carbohydrate intolerance after acute gastroenteritis: A disappearing problem in Polish
children. Acta Paediatr. 1997; 86: 34750.
18 Davidson GP, Goodwin D, Robb TA. Incidence and duration of
lactose malabsorption in children hospitalized with acute enteritis:
Study in a well-nourished urban population. J. Pediatr. 1984; 105:
58790.
19 Brown KH, Peerson JM, Fontaine O. Use of nonhuman milks in the
dietary management of young children with acute diarrhea: A
meta-analysis of clinical trials. Pediatrics 1994; 93: 1727.
20 Sazawal S, Black RE, Bhan MK et al. Zinc supplementation in
young children with acute diarrhea in India. N. Engl. J. Med. 1995;
333: 83944.

2011 The Authors

Pediatrics International 2011 Japan Pediatric Society

682

N Dalgic et al.

21 Strand TA, Chandyo RK, Bahl R et al. Effectiveness and efficacy

of zinc for the treatment of acute diarrhea in young children.
Pediatrics 2002; 109: 898903.
22 Shamir R, Makhoul IR, Etzioni A et al. Evaluation of a diet containing probiotics and zinc for the treatment of mild diarrheal
illness in children younger than one year of age. J. Am. Coll. Nutr.
2005; 24: 37075.
23 Sandhu BK; European Society of Pediatric Gastroenterology,
Hepatology and Nutrition Working Group on Acute Diarrhoea.
Practical guidelines for the management of gastroenteritis in children. J. Pediatr. Gastroenterol. Nutr. 2001; 33: S369.
24 Brooth I, Cunha Ferreira R, Desjeux JF et al. Recommendations
for composition of oral rehydration solutions for the children of
Europe. Report of an ESPGAN Working Group. J. Pediatr. Gastroenterol. Nutr. 1992; 14: 11315.
25 Kosek M, Bern C, Guerrant RL. The global burden of diarrhoeal
disease, as estimated from studies published between 1992 and
2000. Bull. World Health Organ. 2003; 81: 197204.
26 Gregorio GV, Dans LF, Cordero CP et al. Zinc supplementation
reduced cost and duration of acute diarrhea in children. J. Clin.
Epidemiol. 2007; 60: 56066.
27 Szajewska H, Kotowska M, Mrukowicz JZ et al. Efficacy of Lactobacillus GG in prevention of nosocomial diarrhea in infants.
J. Pediatr. 2001; 138: 3615.
28 Mastretta E, Longo P, Laccisaglia A et al. Effect of Lactobacillus
GG and breast-feeding in the prevention of rotavirus nosocomial
infection. J. Pediatr. Gastroenterol. Nutr. 2002; 35: 52731.
29 Saavedra JM, Bauman NA, Oung I et al. Feeding of Bifidobacterium bifidum and Streptococcus thermophilus to infants in hospital
for prevention of diarrhoea and shedding of rotavirus. Lancet 1994;
344: 10469.
30 Szajewska H, Skrka A, Dylag M. Meta-analysis: Saccharomyces
boulardii for treating acute diarrhoea in children. Aliment. Pharmacol. Ther. 2007; 25: 25764.
31 Mrukowicz J, Szajewska H, Vesikari T. Options for the prevention
of rotavirus disease other than vaccination. J. Pediatr. Gastroenterol. Nutr. 2008; 46: S327.
32 Kelleher SL, Casas I, Carbajal N et al. Supplementation of infant
formula with the probiotic lactobacillus reuteri and zinc: Impact on

2011 The Authors

Pediatrics International 2011 Japan Pediatric Society

33

34

35

36

37

38

39

40

41

42

43

enteric infection and nutrition in infant rhesus monkeys. J. Pediatr.

Gastroenterol. Nutr. 2002; 35: 1628.
Bhutta ZA, Bird SM, Black RE et al. Therapeutic effects of oral
zinc in acute and persistent diarrhea in children in developing
countries: Pooled analysis of randomized controlled trials. Am. J.
Clin. Nutr. 2000; 72: 151622.
Canani RB, Ruotolo S. The dawning of the zinc era in the
treatment of pediatric acute gastroenteritis worldwide? J. Pediatr.
Gastroenterol. Nutr. 2006; 42: 2535.
Bobat R, Coovadia H, Stephen C et al. Safety and efficacy of zinc
supplementation for children with HIV-1 infection in South Africa:
A randomised double-blind placebo-controlled trial. Lancet 2005;
366: 18627.
American Academy of Pediatrics, Provisional Committee on
Quality Improvement, Subcommittee on Acute Gastroenteritis.
Practice parameter: The management of acute gastroenteritis in
young children. Pediatrics 1996; 97: 42435.
Armon K, Stephenson T, MacFaul R et al. An evidence and consensus based guideline for acute diarrhoea management. Arch. Dis.
Child. 2001; 85: 13242.
Murphy MS. Guidelines for managing acute gastroenteritis based
on a systematic review of published research. Arch. Dis. Child.
1998; 79: 27984.
Allen UD, McLeod K, Wang EE. Cows milk versus soy-based
formula in mild and moderate diarrhea: A randomized, controlled
trial. Acta Paediatr. 1994; 83: 1837.
Clemente Yago F, Tapia Collados C, Comino Almenara L et al.
Lactose-free formula versus adapted formula in acute infantile
diarrhea. An. Esp. Pediatr. 1993; 39: 30912.
Lozano JM, Cspedes JA. Lactose vs. lactose free regimen in
children with acute diarrhoea: A randomized controlled trial. Arch.
Latinoam. Nutr. 1994; 44: 611.
Fayad IM, Hashem M, Hussein A et al. Comparison of soy-based
formulas with lactose and with sucrose in the treatment of acute
diarrhea in infants. Arch. Pediatr. Adolesc. Med. 1999; 153: 675
80.
Wall CR, Webster J, Quirk P et al. The nutritional management of
acute diarrhea in young infants: Effect of carbohydrate ingested.
J. Pediatr. Gastroenterol. Nutr. 1994; 19: 17074.

Copyright of Pediatrics International is the property of Wiley-Blackwell 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.