The role of probiotics in the prevention and treatment of childhood infectious diarrhea
VLoga probiotikov pri preprečevanju in zdravljenju infekcijske diareje pri otrocih
Maria Maragkoudaki, Alexandra Papadopoulou
First Department of Pediatrics, University of Athens
Athens Children's Hospital »AGIA SOFIA«
Korespondenca/ Correspondence:
Alexandra Papadopoulou, Division of Gastroenterology & Nutrition, First Department of Pediatrics, University of Athens, Athens Children's Hospital »AGIA SOFIA«, Thivon &
PapadiamadopouLou, 115 27 Athens, Greece email: papadop5@otenet. gr
Ključne besede:
Probiotics, infectious diarrhea, Clostridium difficile diarrhea, community acquired diarrhea,traveler's diarrhea, children
Key words:
probiotiki, infekcijska driska, driska povzročena s Clostridium difficile, driska v domačem okolju, driska na potovanjih
Citirajte kot/Cite as:
Zdrav Vestn 2013; 82 supl 1: I-94-102
Prispelo: 21. jun. 2013, Sprejeto: 24. juL. 2013
Abstract
Probiotics are beneficial bacteria that colonize and replicate in the human intestinal tract providing a positive benefit to the host. Several clinical trials support the efficacy of certain probiotics in the prevention and treatment of various diarrheal illnesses. This paper reviews published clinical trials assessing the efficacy of various probiotic species and strains in preventing and treating acute diarrhea in children. The available evidence shows that few probiotic species (mostly Lactobacillus GG and Saccharomyces boular-dii) are efficacious in decreasing the duration and the severity of acute gastroenteritis, with the most prominent of the reported benefits, the reduction of the duration of diarrhea by approximately 1 day. With regard to the prevention of acute diarrhea in the community and the hospital, there is modest evidence that some probiotic species may be efficacious in preventing community acquired diarrhea (Bifidobacterium lactis, Lactobacillus reuteri, Lactobacillus GG), nosocomial acquired diarrhea (Lactobacillus GG) and Clostridium difficile diarrhea (Lactobacillus GG and Saccharomyces boulardii). In conclusion, the available evidence suggests that probiotics are safe when used in healthy children and effective in reducing the duration of acute infectious diarrhea. Further studies are required to assess the efficacy of selected probiotic species and strains at different dosages for different clinical indications and patient groups.
Izvleček
Probiotiki so koristne bakterije, ki se naseljujejo in razmnožujejo v človeškem prebavnem traktu in ugodno delujejo na gostitelja. Mnogi klinični preskusi potrjujejo učinkovitost nekaterih probiotikov pri preprečevanju in zdravljenju različnih vrst driske. Ta pregledni članek obravnava objavljena klinična preskušanja, ki ocenjujejo učinkovitost različnih vrst in sevov probiotikov pri preprečevanju in zdravljenju akutne diareje pri otrocih. Iz razpoložljivih dokazov je razvidno, da nekaj vrst probiotikov (predvsem Lactobacillus GG in Saccharomyces boulardii) učinkovito zmanjšuje trajanje in resnost akutnega gastroen-teritisa, pri čemer je med navedenimi koristmi najočitnejše skrajšanje trajanja driske za približno 1 dan. V zvezi s preprečevanjem akutne di-areje v skupnosti in bolnišnicah obstajajo skromni dokazi, da lahko nekatere vrste probiotikov učkovito preprečujejo pojav okužb z drisko v skupnosti (Bifidobacterium lactis, Lactobacillus reuteri, Lactobacillus GG), bolnišničnih okužb z drisko (Lactobacillus GG) in drisk, ki jih povzroča bakterija Clostridium difficile (Lactobacillus GG in Saccharomyces boulardii). Skratka, razpoložljivi podatki kažejo, da je uporaba probiotikov, kadar se uporabljajo pri zdravih otrocih, varna in učinkovito skrajša trajanje akutne infekcijske driske. Za oceno učinkovitosti izbranih vrst in sevov probiotikov v različnih odmerkih pri različnih kliničnih indikacijah in skupinah bolnikov so potrebne nadaljnje raziskave.
Introduction
Acute gastroenteritis is one of the most common infectious diseases in childhood. Viruses (rotaviruses, noroviruses), bacterial pathogens (Escherichia coli, toxigenic Clostridium difficile, Campylobacter jejuni and
Vibrio cholerae) and parasites can all cause acute gastroenteritis. However, the most common cause of gastroenteritis in children, especially in young children aged 3-24 months, is rotavirus infection. Around 1.4
million of the 9 million child deaths reported in 2008 were due to acute diarrhea, with 49 % of the deaths occurring in the following five countries: India, Nigeria, Democratic Republic of the Congo, Pakistan and China.1'2 In the countries with low and middle socioeconomic status, the incidence of acute diarrhea was estimated in 2010 to be around 2.9 episodes per child annually, mostly affecting infants aged 6-11 months (4.5 episodes per child annually).3 In Europe, the incidence of diarrhea in children up to 3 years of age ranges from 0.5 to 1.9 episodes per child per year.4 Furthermore, infectious agents, such as enteropathogenic E. coli (EPEC), may cause protracted diarrhea in children, increasing the risk of long-term morbidities/ Furthermore, some studies have shown that an early onset of episodes of diarrhea predisposes children to lasting disabilities, stunted growth and impaired cognition and school performance.5 In 2008, the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society of Pediatric Infectious Diseases (ESPID) developed management guidelines in acute gastroenteritis for pediatricians practicing in Europe.6 The above Societies in collaboration with the National Institute for Health and Clinical Excellence (NICE) agree that the primary management of acute gastroenteritis is the rehydration using an oral rehydration solution (ORS). It should be noted however, that ORS neither reduces the frequency of fluid loss, nor shortens the duration of diarrhea. Due to a need for alternatives to routine treatment, the use of probiotics has gained favor in the past decade, although the concept of using them for prevention and treatment of some human illnesses has been around for more than a century.7 Up to now, numerous studies assessing the efficacy and safety of various probiotic species and strains in preventing and treating childhood infectious diarrhea are available as well as several meta-analyses. The ESPGHAN/ESPID evidence-based guidelines for the management of acute gastroenteritis in children in Europe summarized data from several meta-analyses consistently showing a significant effect and moderate clinical benefit of selected probiotic strains
in the treatment of acute watery diarrhea (primarily rotaviral), mainly in infants and young children.6 In 2011, the consensus opinion of 10 experts participating at the third Yale Workshop updated recommendations on probiotic use of the previous two meetings that were published in 2005 and 2008.8 The concept of probiotic use in acute diar-rheal diseases is based on the assumption that they act against enteric pathogens with various mechanisms. They may be involved in immune signaling pathways, stimulate immunity, produce factors against enteric pathogens, and/or induce the host to secrete antipathogenic factors.9 The "defense and protection" function of the microflora is mediated by a number of mechanisms, including competition with pathogenic bacteria for binding sites and nutrients, increased production of secretory IgA and mucin, increased gut barier function and production of antimicrobial substances.10-12 While various bacteria in various daily doses have been studied, specific species of bifidobacteria (B. breve, B. lactis) and lactobacilli (LGG, L. casei, L. reuteri) are better documented than others in terms of beneficial effects in infants and children.
The aim of this paper is to review studies addressing the efficacy of probiotics in the treatment and prevention of infectious diarrhea occurring in the community, of the hospital-acquired acute diarrhoea, and the traveler's diarrhea, as well as their efficacy in the prevention or treatment of Clostridium difficile-associated diarrhea.
1. Prevention of community-acquired diarrhea
Several studies have examined the efficacy of probiotics in preventing acute diarrhe-al episodes occurring in the community settings (Table 1). In 2000, Pedone CA et al/3 compared the incidence of diarrhea in 779 healthy children aged 6 to 24 months. The study consisted of 2 periods (supplementation period and observation period) and 2 groups (placebo and supplemented group). Subjects of the supplemented group consumed L. casei strain DN-114 001 in a standard yogurt, while the placebo group consumed
yogurt without probiotic. The study showed that at least one episode of diarrhea occurred in 22 % of placebo consuming children compared to 15.8 % of children receiving yogurt supplemented with probiotic.13 Since then, several studies have been published in Europe/4-!7 in Israel/8 in Australia/9 in Asia20 and in other countries assessing the efficacy of probiotics in this context. In some studies, the efficacy of a formula supplemented with a specific strain of probiotic2i was evaluated, while other studies compared two different concentrations of a formula containing a mixture of two probiotics.22 Weitzman et al.," studied 201 infants aged
4-10 months attending several care-centers in Israel, for a period of 12 weeks. Children were randomized to three groups: the 1st group received a formula enriched with Bifidobacterium lactis BB12, the 2nd group, a formula enriched with L. reuteri (American Type Culture Collection 55730) and the 3fd group, a formula with no probiotics. The results showed fewer febrile illnesses as well as diarrheal episodes in infants receiving probiotics compared to the control group, with L. reuteri showing greater efficacy." In 2007, a placebo controlled trial, conducted in 496 children in Australia, evaluated a milk product containing probiotics B. lactis
Table 1: Studies assessing the preventive effect of probiotics on the incidence of acute diarrhea in community and in hospitals
Reference	Patients	Age	Probiotics used	Source	Benefit in patients receiving probiotic
Pedone CA et aL.13	779 healthy children, attending day-care	age 6 to 24 months	L. casei DN114 001, 3.2 x 108 CFU, 5 days per week	Supplemented yogurt	b incidence of diarrhea
Thibault et aL.15	900 healthy infants	Age 4 to 6 months	Bifidobacterium brevis plus Streptococcus thermophilus 065	Reconstituted formula	No difference in incidence or duration of diarrheal episodes or hospital admissions Less severe the diarrheal episodes
Weitzman et aL.18	201 infants in 14 child care centers in Israel	Age 4 to 10 months	1st group Bifidobacterium lactis Bb-12 (1 x 107 CFUs/mL) 2nd group L.reuteri ATCC 55730 (1 x 107 CFUs/mL) 3rd group No probiotics	Supplemented formula	b diarrheal episodes b febrile illnesses Effects more prominent with L.reuteri
Chouraqui JP et aL.21	90 healthy children	Age < 4 months	Bifidobacterium lactis Bb-12 (1 x 106 CFU/g) Powder formula resulting in 1.5 x 108	Supplemented formula	b probability of diarrhea b number of days with diarrhea per child-year
OberheLman RA et aL.23	204 undernourished infants and children	6 to 24 months	LGG, 3.7 x 1010 CFU, 6 days/week	Added to liquid gelatin	b episodes of diarrhea
Szajewska H et aL. 24	81 children hospitalized for reasons other than diarrhea	age 1 to 36 months	LGG, 6 x 109 CFU; twice daily	Reconstituted sachet	b incidence of diarrhea b incidence of rotavirus gastroenteritis
CNCM and prebiotics (CUPDAY milk formula). The study showed no difference with regards to the frequency of diarrhea, but the duration of diarrhea in the study group was shorter compared to the control group. The children receiving the CUPDAY milk formula presented fewer diarrheal episodes compared to those receiving placebo.19 In a study conducted in Peru, 200 malnourished infants and children were randomized to receive either Lactobacillus GG (LGG) or placebo for 15 months. Children in the LGG group had significantly fewer diarrheal episodes (5.2 per child per year versus 6.0 in the placebo group, P < .03).23
In summary, there is modest evidence that some probiotics (Bifidobacterium lactis, L. reuteri, LGG) are efficacious in preventing community acquired diarrheal episodes in infants and children.
2. Prevention of nosocomial diarrhea
Development of acute diarrhea is common in hospitalized children, especially due to rotavirus infection. Two trials conducted in 2001 and 2002 assessed LGG in children hospitalized for reasons other than diarrhea and showed that children who were administered LGG had significantly fewer episodes of rotavirus diarrhea, but there was no difference with regards to the prevalence of the infection.24'25 Recently, Hojsak et al/6 in a randomized, double-blind, placebo controlled trial, examined 742 children admitted in the hospital, randomly allocated to receive either milk supplemented with LGG (at a dose of io9 CFU in loomL milk) or placebo. The study showed that the risk for developing gastroenteritis was reduced as well as the number of vomiting episodes and the duration of the infection^ No differences were reported with regard to the duration of hospital stay between the two groups.26
In summary, Lactobacillus GG may be useful as a measure for the prevention of no-socomial-acquired diarrhea.
3.	Prevention of traveler's diarrhea
Acute diarrhea occurs in about half of travelers who visit high-risk areas. Several studies were performed using probiotics for prevention. McFarland et al.,27 analyzed numerous studies in a recent meta-analysis and concluded that L. acidophilus and B. bi-fidum as a mixture, and S. boulardii as a single strain, were both effective in preventing traveler's diarrhea in adults (RR = 0.85, 95 % CI 0.79, 0.91; P < .001). In children, however, the role of probiotics in preventing traveller's diarrhea needs further investigation.
4.	Prevention of Clostridium difficile infection
Clostridium difficile (C. difficile) is a relatively common finding in healthy infants, suggesting it may be an incidental finding and forms part of the normal intestinal flora in this age group. On the other hand, particularly in children with significant co-morbidities, C. difficile may cause severe disease. Moreover, 25-35 % of patients with C. difficile infection manifest recurrent C. difficile colitis within few days to 4 weeks and a smaller percentage of them may develop complications such as toxic megacolon or pseudomembranous colitis. For all these reasons, scientists have been driven to developing new therapeutic strategies for the prevention and treatment of C. difficile-associated diarrhea.
C. difficile--associated diarrhea (CDAD) occurs primarily in patients who have been treated with anti-microbial therapy and is considered as complication in 25 % of cases. The use of broad-spectrum antibiotics and a prolonged duration of antibiotic treatment result in an increasing incidence of C. difficile-associated diarrhea, as well as in developing strains resistant to metronidazole and/ or vancomycin^ Furthermore, the use of proton-pump inhibitors was associated with a two-fold increase in risk for CDI/9
Several randomized placebo-controlled studies support the efficacy of probiotics in the prevention of antibiotic-associated diarrhea and, secondary, of C. difficile infec-
tion. Hickson et al.30 included 135 hospitali- group and 66 in the placebo group). The zed patients in a randomized double-blind, authors assessed the efficacy of a yogurt placebo-controlled trial (69 in the probiotic milk supplemented with a mixture contain-
TABLE 2: Studies assessing the effect of probiotics on the treatment of acute diarrhoea in children
Reference	Patients	Age	Probiotics use/dosage	Source	Benefit in patients receiving probiotics
IsoLauri E et aL.36	71 hospitalized infants and children with acute diarrhea	4 to 45 months	LGG, 2 x 1010 to 2 x 1011 CFU, twice daily	Supplemented formula	b duration of diarrhea
GuandaLini S et aL.39	287 children with acute diarrhea	1 to 36 months	LGG, 4 x 1010 CFU, daily	Supplemented formula	b duration of diarrhea b duration of hospital stay
Boudraa G et aL. 44	112 hospitalized infants and children with acute diarrhea	3 to 24 months	L. bulgaricus, 1 x 108 CFU/ day; S. thermophilus, 1 x 108 CFU/day	Supplemented formula	b duration of diarrhea b stool frequency
Canani RB et aL.45	571 children with acute diarrhea	15 to 20 months	L. casei rhamnosus GG, 6 x 109 CFU, twice daily; or S. boulardii, 5 x 109 CFU, twice daily; or Bacillus clausii, 1 x 109 CFU, twice daily; or Mixture of L. delbrueckii bulgaricus (LMG-P17550), 1 x 109 CFU, twice daily; L. acidophilus (LMG-P 17549), 1 x 109 CFU, twice daily; S. thermophilus, (LMG-P 17503), 1 x 109 CFU, twice daily; B. bifidum (LMG-P 17500), 5 x 108 CFU, twice daily; or Enterococcus faecium (SF 68), 7.5 x 107 CFU, twice daily	Supplement, Added to water	b duration of diarrhea for LGG and probiotic mix groups
Gaon D et aL.46	89 hospitalized infants with acute diarrhea	Average age 1 year	L. casei and L. acidophilus (CERELA), 1 x 1010 to 1 x 1012 CFU/g, twice daily	Supplemented formula	b duration of diarrhea
Guarino A et aL.47	100 children with mild diarrhea	1 % years	L. casei strain GG, 3 x 109 CFU, twice daily	Supplemented milk	b duration of diarrhea b rotavirus shedding
Lee MC et aL.48	100 infants and children with acute diarrhea	6 to 60 months	L. acidophilus and B. infantis, 6 x 109 CFU, daily	Capsules	b duration of diarrhea in both rotavirus positive and negative diarrhea
Reference	Patients	Age	Probiotics use/dosage
Source	Benefit in patients
	receiving probiotics
Mao M et al. 142 children with	1 year
severe acute diarrhea,
B. Lactis (Bb-12), 1 x 109 CFU/g; and S. thermophiLus, 5 x 108 CFU/g
Supplemented formula
b rotavirus shedding
RosenfeLdt V et aL.50	69 hospitalized children with acute diarrhea	average age 1 % years	L. rhamnosus 19070-2,1.7 x 1010 CFU, twice daily; and L. reuteri DSM 12246, 0.5 x 1010 CFU, twice daily	Powder supplement, reconstituted	b duration of hospital stay In children treated within 60 hours of diarrheal onset: b duration of diarrhea b rotavirus excretion
RosenfeLdt V et aL.51	43 children attending daycare with acute diarrhea,	average age 2 years	L. rhamnosus 19070-2,1 x 1010 CFU, twice daily; and L. reuteri DSM 12246, 1 x 1010 CFU, twice daily	Powder supplement, reconstituted	b duration of diarrhea b number of children with resolution of diarrhea within 5 days of supplementaton
Shornikova AV et aL.52
40 children hospitalized with acute diarrhea (75 % rotavirus)
6-36 months
L. reuteri SD2112
1 x 1010-1011 CFU,
Powder
supplement,
reconstituted
b number of children having
watery diarrhoea on the 2nd day b number of children with vomiting b duration of diarrhea
ing, Lactobacillus casei DN-114 001 (L casei imunitass) (1.0 x 108 colony forming units/ ml), S thermophilus (1.0 x 108 cfu/ml), and L bulgaricus (1.0 x 107 cfu/ml), compared to a non-supplemented milkshake. The participants administered the drinks within 2 days from the introduction of antibiotics until 1 week after the end of the treatment. The final analysis after the follow-up included 57 patients in the probiotic and 56 in the placebo group. The results showed a significant reduction in the incidence of antibiotic-associated diarrhea (P = .007) and C. difficile-associated diarrhea (P = .001) in the probiotic
30
group.
A systematic review in adults, published in 2005, did not justify the use of probiotics for either the prevention or the treatment of C. difficile with probiotics31. Although there have been some promising studies in children with CD AD using the probiotic yeast Saccharomyces boulardii32'33, further clinical trials are needed to prove the efficacy of the use of probiotics in the prevention of CDAD. The 2011 updated recommendations for probiotic use of 10 experts participating
at the third Yale Workshop concluded that Lactobacillus-containing probiotic mixtures and S. boulardii may be effective in the prevention of C. difficile-associated diarrhea in high-risk antibiotic recipients, but this finding was based on small, individual studies8. Further larger, well-controlled studies are needed to confirm preliminary positive findings and to better delineate the efficacy of probiotics in CDI prevention.
In summary, there is some evidence that Lactobacillus GG and Saccharomyces boular-dii may be helpful in preventing Cl. difficile infection, but more studies are needed before their use can be recommended routinely.
5. Treatment of acute diarrhea
One of the major benefits that probio-tics demonstrated was in the treatment of mild-to-moderate acute viral diarrhea.34'35 In a double-blind, placebo-controlled study, Isolauri showed the efficacy of L. casei rha-mnous GG (LGG) in the treatment of acute diarrhea in patients that needed hospitali-zation.36 In 2010, Allen et al/7 in a publis-
hed Cochrane review extracted data from 63 RCTs, with more than 8000 participants and evaluated the efficacy of probiotics in the treatment of acute infectious diarrhea in patients of all ages. Most of the studies (56) were conducted in infants and young children. Some of the trials (17) studied a mixture of 2 to 8 probiotics, while the other 46 trials tested a single probiotic. Among the probiotics, the most commonly tested were Lactobacillus GG (i3RCTs) and S. boulardii (10 RCTs). LGG was reported to be effective in the treatment of acute gastroenteri-tis37 as the data extracted from the updated Cochrane review showed a reduction in the duration of diarrhea in 11 RCTs (n = 2072; MD:-26.69; 95 % CL-40.5 to - 12.88), with an average difference of 24 hours, as well as a reduction in the number of stools on day 2, in 6 RCTs (n = 1335; MD:-0.76; 95 %o CI:-1.32 to - 0.2).37 Another meta-analysis reported that the use of LGG was associated with moderate clinical benefits in the treatment of acute diarrhea in children, particularly in those with rotavirus infection/8 Similarly, Guandalini et al. showed in a RCT conducted in 287 patients that LGG was not effective in diarrheas of bacterial origin/9 A meta-analysis conducted by Szajewska H et al.40 reported that S. boulardii reduced the duration of diarrhea for 1 day on average, and the risk of diarrhea lasting more than 4 days (RR: 0.37; 95 % CI: 0.21-0.65; NNT 3, 95 <% CI: 2-3).40 Furthermore, Szajewska H et al. published a meta-analysis of controlled trials showing that L. reuteri ATCC 55730 was effective in reducing diarrheal episodes in the first 3 days of illness/1 A different strain of L. reuteri, called L. reuteri DSM 17938, replaced ATCC 55730 which presented antibiotic resistance. A recent study performed in Italy included 74 children, aged 6-36 months, hospitalized because of acute diarrhea ; the study evaluated the efficacy of the probiotic L. reuteri DSM 17938 in the treatment of acute diarrhea infections/2 The results showed a reduction in the duration of diarrhea in the group that received probiotics compared to the group receiving placebo, as well as a reduction in the risk of diarrhea on days 2 and 3 and in the relapse rate of diarrhea (15 % vs. 42 %, respectively;
p < 0.03)/2 There have been several studies showing the efficacy of several species of probiotics in the treatment of acute diarrhea (Table 2). Finally, a study conducted in India showed that VSL#3, which is a mixture of 7 different strains of probiotics, was also effective compared to placebo in the treatment of acute rotavirus-diarrhea.43
The ESPGHAN/ESPID evidence-based guidelines for the management of acute gastroenteritis in children in Europe6 reported that the beneficial effects of probiotics in acute diarrhea in children were moderate, strain-dependent, dose-dependent (greater for doses > io10-io11 colony-forming units), significant for watery diarrhea and viral gastroenteritis but not significant for invasive bacterial diarrhea. Furthermore, the effect was more evident when treatment with pro-biotics was initiated early in the course of disease, and in children in developed coun-tries.6 LGG and S. boulardii were reported to be beneficial in meta-analyses devoted to single probiotics.6 The authors recommended LGG and S. boulardii as an adjunct to rehydration therapy in children with acute gastroenteritis.6 Safety issues with probioti-cs were related to bacterial translocation and sepsis and to the risk of antibiotic resistance.
The 2011 updated recommendations for probiotic use by 10 experts participating at the third Yale Workshop concluded that Saccharomyces boulardii, LGG and Lactobacillus reuteri SD2112 were efficacious in treating infectious diarrhea.8
In summary, there is significant evidence that LGG and S. boulardii and modest evidence that Lactobacillus reuteri SD2112 are beneficial as an adjunct to rehydration therapy in children with acute gastroenteritis.
Conclusion
The available evidence suggests that certain probiotic species and strains are safe when used in healthy children and effective in preventing and treating infectious diarrhea. Further studies are required to assess the efficacy of selected probiotics in preventing childhood Cl. difficile-associated diarrhea and traveller's diarrhea.
Competing interests
The authors declare the following potential conflict of interest:
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