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KEY WORDS
acute diarrhea, calcium, children, developing country, probiotics,
Indonesia, Lactobacillus casei CRL431, Lactobacillus reuteri
DSM17938
ABBREVIATIONS
ARTIacute respiratory tract infection
CFUcolony-forming unit
CIcondence interval
DSMBdata safety monitoring board
IQRinterquartile range
LClow calcium
RCregular calcium
RRrelative risk
WHOWorld Health Organization
abstract
OBJECTIVE: To investigate the effects of calcium and probiotics on the
incidence and duration of acute diarrhea and acute respiratory tract
infections (ARTIs) in low-socioeconomic communities of Jakarta, Indonesia.
e1155
Study Design
METHODS
A randomized, double-blind, placebocontrolled trial was conducted between August 2007 and September 2008
in low socioeconomic urban communities representing nonooding and
ooding areas of East Jakarta, Indonesia. The protocol was approved by the
medical ethics committees of the Faculty of Medicine, University of Indonesia,
and of WageningenUniversity. All parents
provided written informed consent before inclusion.
Subjects
Children aged 1 to 6 years were selected
from a community registry for the rst
screening phase to assess eligibility on
the basis of the following inclusion
criteria: apparently healthy, not being
breastfed, and if consuming milk, calcium intake was ,75% of the agespecic recommended daily allowances. In the second phase, registered
physicians interviewed mothers and
examined the children to check the exclusion criteria: symptoms of chronic/
congenital diseases and disabilities,
pulmonary tuberculosis, history of allergy, diarrhea on admission, antibiotic
use within 2 weeks before study start,
severe wasting (less than 23 SD of
weight-for-height z score), calcium
intake .375 mg/day according to
AGUSTINA et al
ARTICLE
LC
RC
Casei
Reuteri
93.8
3.5
3.9
11.7
0.07
32
15
32
6
0.30
0.14
98.0
3.9
3.8
12.0
0.09
30
129
77
6
0.30
0.14
98.0
3.9
3.8
12.0
0.09
30
129
77
6
0.30
0.14
98.0
3.9
3.8
12.0
0.09
30
129
77
6
0.30
0.14
5 3 108
5 3 108
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Intention-to-treat analysis was performed for all outcomes and for all eligible children who were randomly
allocated to treatment and had consumed the intervention products at
least once. Analyses were conducted
according to a predened data analysis protocol.
RESULTS
AGUSTINA et al
ARTICLE
DISCUSSION
FIGURE 1
Flow diagram of study subjects. ITT, intention-to-treat; TB, tuberculosis.
children with below-median weight-forage z score (RR for WHO-dened diarrhea compared with RC group: 0.44
[95% CI: 0.210.92]; RR for all reported
diarrhea: 0.54 [95% CI: 0.310.94]) and
in children with below-median heightfor-age z score (RR for WHO-dened
diarrhea: 0.44 [95% CI: 0.210.90]; RR
for all reported diarrhea: 0.53 [95% CI:
0.300.92]). In children above the median z scores, the results for the reuteri group were not signicantly
different from the RC group. The prevalence of underweight and stunting
was not signicantly changed by the
interventions (data not shown).
e1159
LC
(n = 124)
81 (65)
67 (54)
59.3 6 14.3
5.1 6 1.7
189 6 97
43 (35)
20 (16)
48 (39)
0.79 (0.231.82)
0.79 (0.690.93)
24 (19)
RC
(n = 126)
82 (65)
68 (54)
58.9 6 14.2
5.4 6 1.7
194 6 139
43 (34)
13 (10)
51 (40)
0.75 (0.282.90)
0.82 (0.700.95)
33 (26)
Casei
(n = 120)
78 (65)
66 (55)
60.3 6 13.7
5.2 6 1.8
159 6 69
52 (43)
24 (20)
52 (43)
0.75 (0.302.50)
0.83 (0.700.97)
24 (20)
Reuteri
(n = 124)
82 (66)
68 (55)
58.9 6 15.1
5.0 6 1.8
203 6 181
50 (40)
15 (12)
56 (45)
0.66 (0.253.03)
0.81 (0.710.94)
24 (19)
21.27 6 1.1
21.53 6 1.0
20.51 6 1.0
7.6 (4.711.1)
21.40 6 0.9
21.65 6 0.9
20.59 6 1.2
7.5 (4.810.4)
21.15 6 1.1
21.39 6 1.0
20.58 6 1.0
6.6 (4.89.3)
21.26 6 1.2
21.47 6 1.1
20.65 6 0.9
7.8 (5.111.4)
1033 6 368
34.3 6 13.5
155 6 58
32.2 6 13.2
4.5 6 3.1
235 6 95
6.1 6 2.7
4.4 6 2.0
1066 6 329
36.3 6 12.9
157 6 48
34.5 6 13.9
5.1 6 3.5
241 6 97
6.6 6 2.6
4.8 6 1.9
1024 6 369
33.5 6 13.6
156 6 58
31.8 6 13.7
4.9 6 3.7
228 6 105
6.2 6 2.7
4.4 6 2.0
976 6 310
32.9 6 11.0
146 6 49
30.9 6 11.4
4.6 6 2.8
228 6 94
6.1 6 2.4
4.4 6 1.6
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AGUSTINA et al
ARTICLE
FIGURE 2
Adjusted Cox survival curve of the WHO-dened diarrhea ($3 loose/liquid stools in 24 hours) episodes.
Adjusted for area of living, gender, age, diarrhea and ARTIs 2 weeks before the study, household expenditure. and weight-for-height z score. No signicant differences between interventions were observed. Probability of survival without diarrhea in relation to duration of diarrheal episodes (days) for
4 groups. No signicant differences between interventions were observed.
TABLE 3 Effects of Probiotics and Calcium on Incidence of Diarrhea and ARTIs Among Indonesian Children
Outcome Measures
WHO-dened diarrhea episodes ($3 loose/liquid stools in 24 h)
Mean incidence/child per year
No. of episodes, mean 6 SD
Adjusted RR (95% CI)a
Duration of episodes, mean 6 SD, d
All diarrhea episodes (2 and $3 loose/liquid stools in 24 h)
Mean incidence/child/y
Number of episodes, mean 6 SD
Adjusted RR (95% CI)a
Duration of episodes, mean 6 SD, d
ARTIs episodes
Mean incidence/child/y
No. of episodes, mean 6 SD
Adjusted RR (95% CI)b
Duration of episodes, mean 6 SD, d
LC
(n = 124)
RC
(n = 126)
Casei
(n = 120)
Reuteri
(n = 124)
0.91
0.40 6 0.81
1.00 (ref)
3.06 6 4.43
0.86
0.38 6 0.78
0.99 (0.621.58)
1.00 (ref)
2.94 6 3.25
1.05
0.47 6 0.87
1.21 (0.761.92)
2.37 6 2.68
0.67
0.30 6 0.56
0.76 (0.461.25)
2.68 6 3.05
1.73
0.73 6 1.14
1.00 (ref)
2.57 6 4.09
1.86
0.77 6 1.38
1.10 (0.771.59)
1.00 (ref)
2.03 6 2.84
2.04
0.87 6 1.32
1.06 (0.741.53)
2.08 6 2.40
1.28
0.56 6 0.77
0.68 (0.460.99)
1.91 6 2.52
7.22
2.41 6 1.59
1.00 (ref)
4.87 6 4.05
7.52
2.43 6 1.61
1.00 (0.861.18)
1.00 (ref)
4.90 6 3.70
7.07
2.36 6 1.62
0.97 (0.821.14)
4.96 6 3.71
7.45
2.48 6 1.56
0.99 (0.841.16)
4.58 6 3.43
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FIGURE 3
Adjusted Cox survival curve of all reported diarrhea ($2 loose/liquid stools in 24 hours) episodes.
Adjusted for area of living, gender, age, diarrhea and ARTIs 2 weeks before the study, household expenditure, and weight-for-height z score. Probability of survival without diarrhea in relation to duration
of diarrheal episodes (days) for 4 groups. Signicant differences occurred between the RC and reuteri
groups (P = .036).
CONCLUSIONS
Supplementation of L reuteri, at least on
a diet including regular calcium milk, is 1
of the potential interventions to reduce
the burden of acute infectious diarrhea in
children. These results need to be conrmed by at least 1 other independent
study in a comparable community.
FIGURE 4
Adjusted Cox survival curve of ARTI episodes. Adjusted for area of living, gender, age, diarrhea and ARTIs 2
weeks before the study, household expenditure, and weight-for-height z score. Probability of survival
without acute respiratory infections in relation to duration of episodes (days) for 4 groups. No signicant differences between interventions were observed.
ACKNOWLEDGMENTS
We thank Dr Christien van Beusekom, Mr
Peter Spiekstra, Mr Jan van der Leij, and
Ms Vicky Valentina (FrieslandCampina
Research) for their contribution to
study milk production, and Martin Jkel,
MD (Unilever Research and Development) for his advice on adverse-event
analysis. We thank the highly dedicated
and motivated children, parents, physicians, and research team members, especially Ms Ratna Wulanti, Ms Imas
Maliha, Ms Siti Mulyani, Santi Sinarwati,
MD, and Ms Devy Davelyna. We acknowledge the support of the head, elders,
women leaders, and volunteers in
Kampung Melayu and Rawabunga.
We also thank Prof Purwantyastuti,
Prof Arini Setiati, Sri Lestari, MD, Dr
Moesijanti Soekarti, Ms Yulianti Wibowo,
Mr Jeroen Sterken, Iwan Setiawan, MD,
Dr Miren Iturriza-Gmara, and Mr Ahmad
Sadariskar.
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ARTICLE
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