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Pediatr Gastroenterol Hepatol Nutr 2017 September 20(3):139-146 PGHN
Review Article
PEDIATRIC GASTROENTEROLOGY, HEPATOLOGY & NUTRITION
Probiotics in Children: What Is the Evidence?
Iva Hojsak*,†,‡
*Children’s Hospital Zagreb,
†
University of Zagreb, School of Medicine, Zagreb,
‡
University Josip Juraj Strossmayer,
S
chool of Medicine Osijek, Osijek, Croatia
The number of papers discussing probiotics increases tremendously that limits the possibility for primary care physi-
cians and clinicians to stay updated. Therefore, the aim of this paper will be to summarize available evidence of
probiotic use in well-defined clinical indications of importance for pediatricians. Based on currently available evidence
certain probiotic strains (Lactobacillus rhamnosus GG [LGG] and Saccharomyces boulardii) have proven effect in
the treatment of acute gastroenteritis and prevention of antibiotic associated diarrhea. Furthermore, LGG was proven
to be effective in prevention of nosocomial diarrhea and respiratory tract infection in day care centers. In conclusion,
not all probiotic strains have same efficacy for all clinical indications, therefore, only strains with proven efficacy and
safety should be recommended.
Key Words: Lactobacillus, Saccharomyces, Bifidobacterium, Diarrhea, Infection
Received:July 4, 2017, Accepted:July 31, 2017
Corresponding author: Iva Hojsak, Referral Center for Pediatric Gastroenterology and Nutrition, Children’s Hospital Zagreb, Klaićeva 16, 10000
Zagreb, Croatia. Tel: +385-1-4600130 , Fax: +385-1-4600160, E-mail: ivahojsak@gmail.com
Copyright ⓒ 2017 by The Korean Society of Pediatric Gastroenterology, Hepatology and Nutrition
T
his is an openaccess article distributed under the terms of the Creative Commons Attribution NonCommercial License (http://creativecommons.org/licenses/by-nc/4 .0/) which permits
unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
INTRODUCTION
Most widely used definition of probiotics was giv-
en by the Food and Agriculture Organization of the
United Nations and the World Health Organization
in 2002 [1]. That definition was accepted with mini-
mal change by expert panel (International Scientific
Association for Probiotics and Prebiotics) in 2014
stating that probiotics are live microorganisms that,
when administered in adequate amounts, confer a
health benefit on the host [2].
On the same document panel tried to emphasize
the probiotic action, emphasizing that some of pro-
biotics’ effect can be attributed only to specific pro-
biotic strain, but some effects can be ascribed to pro-
biotics in general or certain species of probiotics [2].
Same recognition of clinical effectiveness was also
approved and highlighted by European Society for
Pediatric Gastroenterology, Hepatology, and Nutrition
Working Group (ESPGHAN WG) on pre- and pro-
biotics. Stating that recommendations for probiotic
use should always be strain specific and aim is to rec-
ommend only the strains which have proven efficacy
by well-designed randomized controlled trials (RCTs).
There are many papers about probiotics produced
on daily basis which makes clinical up-date on their
effectiveness extremely difficult.
Therefore, the aim of this paper will be to summa-
140 Vol. 20, No. 3, September 2017
Pediatr Gastroenterol Hepatol Nutr
rize available evidence of probiotic use in well-de-
fined clinical indication including the treatment of
acute gastroenteritis, prevention of antibiotic asso-
ciated diarrhea and prevention of infections in
children.
TREATMENT OF ACUTE
GASTROENTERITIS
Acute gastroenteritis is usually defined as decrease
in the stool consistency (loose or liquid) and/or an in-
crease in the frequency (typically >3 stools/day),
with or without vomiting or fever [3]. Diarrhea typi-
cally lasts less than 7 days and not longer than 14
days [3]. The incidence of acute gastroenteritis is still
high, even in Europe, and it is estimated that the in-
cidence in small children ranges from 0.5 to 1.9 epi-
sodes/child/year [3]. Major causes are still rotavirus,
which decreases in countries with high rate of rotavi-
rus vaccination, followed by norovirus [4]. The treat-
ment strategy aims to treat and prevent dehydration,
shorten duration of diarrhea and to prevent pro-
longed diarrhea. Therefore, the mainstay of treat-
ment is rehydration which in majority of children
can be provided orally by using oral rehydration sol-
utions [3]. Yet, there is still no causal treatment. One
treatment option is racecadotril, enkephalinase in-
hibitor which was proven to be effective in short-
ening the diarrhea [5]. Other well-defined treatment
modalities include probiotics.
Recently, ESPGHAN WG on pre- and probiotic
performed systematic review and provided guide-
lines on the use of different probiotic strains for the
treatment of acute gastroenteritis [6]. Based on
available, well designed RCTs, ESPGHAN WG rec-
ommended only two probiotic strains proved to be
effective in at least two RCTs; these are Lactobacillus
rhamnosus GG (LGG) and Saccharomyces boulardii.
Based on the Cochrane review from 2010 [7], LGG
was investigated in 11 RCTs (n=2,072) and this
meta-analysis found that use of LGG reduced the du-
ration of diarrhea for mean of 27 hours (95% con-
fidence interval [CI], −41 to −13). Subsequent sys-
tematic review performed by Szajewska et al. [8] in
2013 identified 15 RCTs (n=2,963). This review con-
firmed superiority of LGG in significantly decreasing
duration of diarrhea comparing to placebo (mean
difference [MD], −1.05 days; 95% CI, −1.7 to −0.4;
based on 11 RCTs). However, there was no influence
on stool volume (MD, 8.97 mL/g; 95% CI, −86.26 to
104.2; based on 2 RCTs). Regarding the dose, ≥1010
colony-forming units (CFU) was more effective than
<1010 CFU [8].
Other strain with well-proven effect is S. boulardii.
The above-mentioned Cochrane review found 6
RCTs (n=606) and reported reduced risk of diarrhea
lasting ≥4 days (risk ratio [RR], 0.37; 95% CI, 0.2 to
0.65) if S. boulardii was used [7]. More recent system-
atic review analyzing 11 RCTs (n=1,306) showed
that S. boulardii significantly reduced diarrhea dura-
tion (MD, −0.99 days; 95% CI, −1.4 to −0.6) [9].
None of the studies evaluated the influence on stool
volume.
Finally, strain Lactobacillus reuteri ATCC 55730 had
proven moderate clinical effect in treating acute gas-
troenteritis in children; however, this strain was
found to carry transferable resistance trait for anti-
biotic resistance and was replaced by a new strain, L.
reuteri DSM 17938 [10]. This, new strain L. reuteri
DSM 17938 was investigated by 3 RCTs; two RCTs
(n=196) were analyzed in systematic review from
2014 and showed significantly reduced diarrhea du-
ration (MD, −32 hours; 95% CI, −41 to −24) [11].
Subsequently, one more RCT was published includ-
ing 64 infants and children, showing similar results
in the reduction of diarrhea duration [12].
Generally, after reviewing these results ESPGHAN
WG on pre- and probiotics recommended the use of
the following probiotic strains as an adjunct to rehy-
dration therapy: LGG (quality of evidence: low; rec-
ommendation: strong), S. boulardii (quality of evi-
dence: low; recommendation: strong) and L. reuteri
DSM 17938 (quality of evidence: very low; recom-
mendation: weak) [6].
It should be emphasized once again that system-
atic review of the literature did not found enough
evidence (or evidence was negative) to recommend
other probiotic strains.
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141
Iva Hojsak:Probiotics in Children: What Is the Evidence?
For clinicians, it is of importance to know that pro-
biotics have been proven mostly in watery (mainly
viral) diarrhea and that their efficacy is more pro-
nounced on the duration of diarrhea (study showed
ability to shorten diarrhea for 1 day) than in stool
volume [3,6]. Furthermore, when recommended
they should be recommended only as an adjunct to
rehydration and it is better to use them in the early
course of disease [6].
PREVENTION OF ANTIBIOTIC
ASSOCIATED DIARRHEA
Antibiotic-associated diarrhea (AAD) is a com-
mon complication of antibiotic therapy, defined as
diarrhea that occurs in relation to antibiotic treat-
ment with the exclusion of other etiologies [13]. It is
more commonly caused by antibiotics that target
anaerobic bacteria (e.g. clindamycin, penicillin, amoxi-
cillin and clavulanic acid etc.) which cause significant
disruption of the enteric microbiome [14,15]. Clini-
cally, AAD may present as mild diarrhea, but it can
also present as fulminant pseudomembranous colitis
caused by Clostridium difficile [13]. Measures which
can prevent AAD are limited mainly to reduction in
antibiotic use, type of antibiotic prescribed and the
use of probiotics.
Due to large number of studies and different rec-
ommendations available ESPGHAN WG on pre- and
probiotics preformed systematic review with meta-ana-
lysis with aim to provide evidence based guidelines
for every specific probiotic strain in the prevention of
AAD [13]. This systematic review found only two
probiotic strains with enough evidence (efficacy pro-
ven in more than 2 well-designed RCTs); these
strains are LGG and S. boulardii [13].
LGG was investigated in 5 RCTs (n=445) and ad-
ministration in children reduced the risk of AAD
from 23% to 9.6% (RR, 0.48; 95% CI, 0.26 to 0.89), re-
gardless of the reason for which antibiotics and pro-
biotics were used [13]. However, only one trial [16]
evaluated the effect of LGG in the prevention of C. dif-
ficile-associated diarrhea in children and found no
effect.
Similarly, S. boulardii used in children reduced the
risk of AAD based on 6 RCTs (n=1,653) from 20.9%
to 8.8% (RR, 0.43; 95% CI, 0.30 to 0.60) [13]. Further-
more, the administration of S. boulardii reduced the
risk of C. difficile-associated diarrhea in children (2
RCTs, n=579; RR, 0.25; 95% CI, 0.08 to 0.73) [13].
However, there is a constant discussion whether
probiotics should be used every time antibiotic is
prescribed. The reasons for their routine use are the
proven effect and the fact that AAD can be serious ill-
ness [13,17]. On contrary, reasons not to use them is
usually related to their costs and fact that AAD is
usually self-limited mild disease. There are certain
groups of patients that would benefit the most from
probiotic use including children of younger age, hos-
pitalized children and children who experienced
AAD (especially C. difficile-associated diarrhea) be-
fore [17]. Once again, the recent review identified
only two strains to be effective in prevention of AAD;
these are LGG (quality of evidence: moderate, rec-
ommendation: strong) and S. boulardii (quality of
evidence: moderate, recommendation: strong) [13].
For prevention of C. difficile-associated diarrhea only
S. boulardii showed efficacy (quality of evidence:
moderate, recommendation: conditional) [13].
There is always a question when to administer
probiotic in order not to be killed by antibiotic; there
are no scientific evidence for that. However, some
probiotic strains (like S. boulardii) are resistant to an-
tibiotics used for bacterial infections. On the other
hand, other strains (like LGG) were effective in RCTs
when used for AAD, therefore their administration
should follow the same scheme like in RCTs.
PREVENTION OF INFECTIONS
Infectious diseases are the most important cause
of morbidity in children where respiratory and gas-
trointestinal (GI) infections encounter for majority
of them [18]. Recurrent respiratory tract infections
are common problem in preschool age, mainly due to
the presence of unfavorable environmental con-
ditions including early socialization in daycare cen-
ters and the physiologic immaturity of the immune
142 Vol. 20, No. 3, September 2017
Pediatr Gastroenterol Hepatol Nutr
system [19]. There are two major settings where
children acquire respiratory and GI infections and
those are hospital and day care centers.
Prevention of infections in day care centers
Children who attend daycare centers have 2-3
times more infections than children who stay at
home, they have more outpatient doctor and emer-
gency room visits and increased usage of prescribed
antibiotics [20]. Furthermore, they cause a sub-
stantial economic burden not only for child’s family,
but healthcare in general; their costs are estimated to
be $1.8 billion per year in the United States [21].
Taking all that into account, together with possible
complications, respiratory tract and GI infections are
important health care problem for pediatricians who
are facing a real task to discriminate the children
who are at higher risk and try to offer preventive
measures. These preventive measures usually in-
clude good hand hygiene, absenteeism of ill child
from daycare center in order to prevent spreading of
infection and vaccination for influenza and rotavirus
[22]. However, all those measures often are in-
effective leaving a place for possible new modalities,
like probiotics. In the last two decades, there have
been an increasing number of trials investigating the
role of probiotics on the prevention of common in-
fections in children.
As presented in Table 1, there are several trials
which evaluated probiotics in the prevention of res-
piratory tract infection in children attending daycare
centers [23-34]. Interestingly, majority of studies be-
yond infancy found positive effect on the lowering of
respiratory tract infections [23,24,26-29,31]. Recent
meta-analysis reviewed available literature and
found that probiotics (in general) reduce the risk of
respiratory tract infections (RR, 0.89; 95% CI, 0.82 to
0.96) [35]. Unfortunately, this meta-analysis in-
cluded all age groups, was not strain specific and was
not stratified based on the type of facility where pro-
biotics were used. However, it was reported that al-
though there was no effect on the duration of illness,
absenteeism from the kindergarten was decreased
[35].
Based on the presented results in Table 1, it can be
concluded that probiotics could have a place in the
prevention of upper respiratory tract infections.
However, questions that remain are what strain to
use, in which dose and when. Based on well-de-
signed RCTs in children (Table 1), LGG was exam-
ined in 3 studies [24,26,27] involving all together
1,375 children and all studies reported positive effect
on the lowering the incidence of respiratory tract
infections. Other strain Bifidobacterium animalis
subsp. lactis was evaluated in 4 RCTs [25,30,32,34]
from which all found negative results.
The question is whether to recommend probiotic
use routinely in all children who are at increased risk
for respiratory infection. Based on currently avail-
able evidence, it seems prudent to use strains with
proven efficacy in more than 2 RCT (which is LGG).
However, there are no cost-effective analyses. Regres-
sion analysis determined that children who would
benefit the most from the LGG use were children of
younger age and with recurrent respiratory in-
fections during winter months [26].
Majority of studies which investigated probiotic
use in the prevention of respiratory tract infections
also investigated the risk of acquiring GI infection
(Table 1). Results from those studies are weak. There
is no meta-analysis which assessed overall effect,
however, based on literature search there are no 2
RCTs which investigated same probiotic strain and
yielding positive results. Of note is that both studies
investigating LGG found no effect [24,26], similarly
is for B. animalis subsp. lactis investigated by other
two studies [30,32].
All these results, however, should be interpreted
with caution because most of them were performed
in the winter period when the incidence of GI in-
fections is much lower, and therefore someone can
argue that the sample size was not powered enough
to assess GI risk.
Nosocomial infections
Nosocomial, hospital-acquired or healthcare-asso-
ciated infections, develop during a hospital stay and
they are not present or incubating at the admission;
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Iva Hojsak:Probiotics in Children: What Is the Evidence?
Table 1.
Probiotics in Prevention of Respiratory and Gastrointestinal Infections in Children Attending Day Care Centers
Author n (age) Probiotic (dose) Effect on respiratory infection
Effect on
gastrointestinal
infection
Hatakka et al.
[24] (2001)
571 (1-6 y) LGG (1-2×108 CFU/day) Lower number of upper respiratory
tract infections
Lower number of prescribed
antibiotics
NS
Saavedra et al.
[33] (2004)
118 (3-24 mo) Bifidobacterium animalis
subsp. lactis (Bb12)
(107 CFU)+Streptococcus
thermophilus (106 CFU)
Not significant difference in the
incidence of upper respiratory
tract infection
Lower number of prescribed
antibiotics
NS
Weizman et al.
[34] (2005)
210 (4-10 mo) Bifidobacterium animalis subsp.
lactis (Bb12) or Lactobacillus
reuteri 55730 (minimum 107
CFU)
Not significant difference in the
incidence of upper respiratory
tract infection
L. reuteri group-lower number of
prescribed antibiotics
Not assessed
Lin et al.
[29] (2009)
1,062
(preschool
children)
Lactobacillus casei rhamnosus
(108 CFU), Lactobacillus
rhamnosus T cell-1 (1010 CFU),
multiple probiotic strains
Reduction in respiratory infection
in the L. casei rhamnosus group
Not significant for other strains
Multiple strain
group showed
reduction in
gastrointestinal
illness
Leyer et al.
[28] (2009)
326 (3-5 y) Lactobacillus acidophilus NCFM
(1010 CFU) vs. Lactobacillus
acidophilus NCFM+Bifidobacterium
animalis subsp. lactis Bi-07
(1010 CFU)
Lower fiver and coughing episodes,
lower antibiotic use in single and
combination group
Not assessed
Hojsak et al.
[26] (2010)
281 (1-7 y) LGG (109 CFU) Lower number of upper respiratory
tract infections
No difference in prescribed antibiotics
NS
Merenstein et al.
[31] (2010)
638 (3-6 y) Lactobacillus casei DN-114
001/CNCM I-1518 (108 CFU)
(in yoghurt with Streptococcus
thermophilus and Lactobacillus
bulgaricus)
Lower number of upper respiratory
tract infections
Lower number of prescribed
antibiotics
NS
Merenstein et al.
[32] (2010)
182 (13 y) Bifidobacterium animalis subsp.
lactis (Bb12) (1010 CFU)
(yoghurt containing also
Streptococcus thermophilus
and Lactobacillus bulgaricus)
NS NS
Merenstein et al.
[30] (2011)
172 (2-4 y) Bifidobacterium animalis subsp.
lactis (Bb12) (1010 CFU)
(yoghurt containing also
Streptococcus thermophilus
and Lactobacillus bulgaricus)
NS NS
Kumpu et al.
[27] (2012)
523 (2-6 y) LGG (6.7×105 to 1.9×106
CFU/mL)
Lower risk of respiratory infection
in completed cases subgroup
(recovery of LGG in fecal samples)
Not assessed
Gutierrez-Castrellon
et al. [23] (2014)
336 (0.5-3 y) Lactobacillus reuteri DSM 17938
(108 CFU)
Lower risk of respiratory tract
infections
Lower risk of
diarrhea
Hojsak et al.
[25] (2016)
210 (1-7 y) Bifidobacterium animalis subsp.
lactis (Bb12) (109 CFU)
NS NS
LGG: Lactobacillus rhamnosus GG, CFU: colony-forming units, NS: not significant.
144 Vol. 20, No. 3, September 2017
Pediatr Gastroenterol Hepatol Nutr
infections that occur more than 48 hours after the
admission are usually considered as nosocomial
[36]. The incidence of nosocomial infections on pe-
diatric wards even in developed countries is still
high, ranging from 5% to 10% and GI and respiratory
tract infections account for the majority of them
[37]. Nosocomial infections have several negative
impacts; they worsen the treatment outcome, could
prolong the hospitalization, and significantly increase
hospital costs [38]. Standard preventive measures,
mainly hand hygiene, isolation of sick children and
reduction in the number of hospitalized patients de-
creases infection spreading, but cannot successfully
prevent them [39,40]. Therefore, there is a place for
new strategies, one of which is the use of probiotics.
Recently, ESPGHAN WG on pre- and probiotics
performed systematic review on the role of different
probiotic strains in the prevention of nosocomial di-
arrhea [41]. This meta-analysis identified 8 RCTs out
of which 3 investigated LGG. The administration of
LGG reduced the risk of nosocomial diarrhea from
13.9% to 5.2% (2 RCTs, n=1823; RR, 0.35; 95% CI,
0.19 to 0.65) [41]. On contrary, L. reuteri DSM 17938
was investigated by two studies (same probiotic
strain but different doses: 108 CFU/day [42] and 109
CFU/day [43]) and had negative results (RR, 1.11;
95% CI, 0.68 to 1.81) [41]. Based on the evidence
ESPGHAN WG concludes that if probiotics for pre-
venting nosocomial diarrhea in children are consid-
ered, LGG (at least 109 CFU/day, for the duration of
hospital stay) should be used (quality of evidence:
moderate, recommendation: strong) [41].
Due to lack of cost effectiveness, currently there is
a need for identifying children in risk for acquiring
nosocomial diarrhea. Based on regression analysis
published in one of the RCTs [38] children who stay
longer in hospital are especially prone to nosocomial
infection, therefore this group of children would
benefit the most.
On contrary to role of probiotics in the prevention
of nosocomial diarrhea, we have only limited evi-
dence of the role of probiotics in the prevention of
nosocomial respiratory tract infection outside of in-
tensive care unit. There are only two (although big)
RCTs. One RCT investigated LGG (n=742) at the
dose of 109 CFU and found reduction in risk of upper
respiratory tract infection [41]. Other study, per-
formed at the same center used different probiotic
strain, B. animalis subsp. lactis (Chr Hansen,
Denmark) at the same dose, was not able to prove
positive effect [44]. Authors also identified that chil-
dren who stayed longer in the hospital and who were
younger had higher chance of acquiring upper respi-
ratory tract infections [41]. Although there is an evi-
dence that some probiotic strain could have effect in
the prevention of infection, still there is no enough
evidence to recommend probiotics for the prevention
of nosocomial respiratory tract infections.
CONCLUSION
Above mentioned evidence further demonstrates
that not all probiotics have the same efficacy for ev-
ery specific clinical indication. Based on currently
available evidence certain probiotic strains (LGG and
S. boulardii) have proven effect in the treatment of
acute gastroenteritis and prevention of AAD. Fur-
thermore, LGG was proven to be effective in pre-
vention of nosocomial diarrhea and respiratory tract
infection in day care centers.
Field of probiotics increases tremendously, thus it
is hard for clinicians to follow the literature. Therefore,
it is of utmost importance to recognize scientific au-
thorities and to follow up their guidelines.
ACKNOWLEDGEMENTS
Iva Hojsak has participated as a clinical inves-
tigator for Biogaia and Chr Hansen and speaker for
Biogaia and Medis Adria.
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