Jennifer Joyce Antionette Kruger Gretchen Storman

Evidence Question: Does the probiotic Lactobacillus help to treat diarrhea among children?

Szajewska, H., et al. Meta-analysis: lactobacillus gg for treating acute diarrhoea in children. Aliment Pharmacol Ther. 2007; 25.8: 871-881.

Dutta, P, et al. Randomised controlled clinical trial of lactobacillus sporogenes (bacillus coagulans), used as probiotic in clinical practice, on acute watery diarrhoea in children. Trop Med Parasitol. 2011; 16.5: 555-561.

P. B. Heczko, et al. Treatment of acute infectious diarrhoea in infants and children with a mixture of three lactobacillus rhamnosus strains a randomized, double-blind, placebocontrolled trial. Aliment Pharmacol Ther. 2006; 23.2: 247-253.

Plesclk-Lech M., Urbanska M., Szajewska H. Lactobacillus gg (lgg) and smectite versus lgg alone for acute gastroenteritis: a double-blind, randomized controlled trial. Eur Arch Paediatr Dent. 2013; 172: 247253.

Rerksuppaphol, S., L. Rerksuppaphol. Lactobacillus acidophilus and bifidobacterium bifidum stored at ambient temperature are effective in the treatment of acute diarrhoea. Ann Trop Paediatr. 2010; 30.4: 299-304.

Szajewska, H., M. Wanke, B. Patro. Meta-analysis: the effects of lactobacillus rhamnosus gg supplementation for the prevention of healthcare-associated diarrhoea in children. Aliment Pharmacol Ther. 2011; 34.9: 1079-1087.

Does the probiotic Lactobacillus help to treat diarrhea among children?

Randomized Control Trials (RCT) comprising of children with diarrhea

In a randomized, double-blind, placebo-controlled study, Plesclk et al (2013) examined 81 children aged 4 to 60 months with diarrhea lasting >1 day or < 5 days and found that the control group, LGG plus smectite at a dose of 3 g (n=44) appeared to be equally effective to the placebo group, LGG alone at a dose of 3 g (n=37) for treating children with diarrhea. The outcomes measured were the duration of diarrhea, no stool for 12 hours, stool frequency, antibiotic therapy, vomiting, diarrhea recurrence, tolerance of study products, hospitalization, and unscheduled intravenous rehydration therapy. The duration of diarrhea was shown to be similar in both groups (p=0.43). However, there was a significant difference in stool frequency between groups on day 4, in which LGG/placebo group had a shorter stool frequency as compared to LGG/smectite group (p=0.03). According to the Bristol Stool Form Scale, the stools were harder in the LGG/placebo as compared to the LGG/smectite group. There was a significantly shorter duration of intravenous therapy after randomization in LGG/smectite group compared to LGG/placebo (p=0.02) The baseline characteristics of gender, age, weight, initial symptoms, and pathogens in the stool were not different among both groups. Eligible children received a daily dosage of 6 x 102 forming units (CFU) in a dose for 7 days plus randomly either placebo (glucose) or smectite that was administered in an oral dose of 3 g. The children also used a diary to record their stool frequency and consistency of bowel movements that were assessed and analyzed by the study physician on day 7. One of the limitations in the study was the lack of perfect blinding. Thus, both LGG/smectite and LGG/placebo came in white powder form and when dissolved in water, they turned into different colors that could have been a problem if either the parent or caregiver had previous experience with smectite. The Bristol Stool Form Scale was a limitation because it did not validate the youngest child.

In a double-blind, randomized, placebo-controlled, hospital-based clinical trial, Dutta et al (2011) determined the clinical efficacy of L. sporogenes (B. coagulans) or placebo as a probiotic preparation against dehydrating diarrhea in boys aged 6 months to 24 months old (n=148). Recruitment for the study took place at the Diarrhea Treatment and Training Unit of Dr. B.C. Roy Memorial Hospital for Children, Kolkata, India between September 2003 and July 2005. The study found that L. sporogenes (B. coagulans) when administered at 240 million spores daily until recovery or up to five days in combination with oral rehydration salt solution (n=78) had no therapeutic impact on management of acute dehydrating diarrhea of diverse etiology including rotavirus associated diarrhea in children compared to the control group (n=70). There was no significant difference between control and treatment group baseline information (age, body weight, height, MAC, frequency of stools/ day, or pathogens present in stool at enrollment). The differences of measured values were not found to be significant between the treatment and control groups: recovery rate (P = 0.2); mean values of duration of diarrhea (P = 0.5); frequency of stool (P = 0.05); stool output (P = 0.1); oral rehydration salt solution intake (P = 0.2); and intake of other fluids (P = 0.1). Rotavirus was the sole pathogen in 25 children of the study group and 26 children of the control group. There was no significant difference in rotavirus subgroup analysis. A major limit to the study is it excluded female children and the hospitalbased trial did not allow for a broad demographic to be studied. Another limit to the study was that the participants diet was not standardized. More importantly, the major limit to the study is that gut colonization of L. sporogenes (B. coagulans) was not confirmed and it cannot be said if the probiotic tablets were in fact viable.

P. B. Heczko et al conducted a randomized, double-blind controlled trial (2006) to study whether a combination of three probiotics, Lactobacillius rhamnosus strains (573L/1, 573L/2, 573L/3), administered orally in a dose of 1.2 1010 CFU twice daily for five consecutive days would shorten acute diarrhea in infants and children aged 2 months-6 years of age (n=87). Recruited participants were being treated for acute diarrhea at the pediatric ward or outpatient department at the Department of Pediatrics, St Hedwig of Silesia Hospital, Trzebnica, Poland between September 2003 and June 2004. Baseline controlled measures were sex, age, duration of diarrhea before admission, duration of breast feeding, dehydration at admittance, and the etiology of diarrhea. P. B. Heczko et al measured duration of diarrhea, number of stools passed, weight gain after rehydration, and presence of the L. rhamnosus strains in the gut at day 5 and 14 in the treatment group. No significance was found in the duration of diarrhea between the treated group (n=46) and the placebo group (n=41). Yet significance was found when comparing duration of diarrhea in patients with rotavirus diarrhea in the treatment group (n=22) and the placebo group (n=17): 78 35 h vs. 115 67 hours (P = 0.03), respectively. Further subgroup analysis of rotavirus etiology found that the probiotics were the most effective in decreasing duration of diarrhea in infants younger than 12 months when comparing the treatment rotavirus infants (n=8) and placebo rotavirus infants (n=4) (P=0.001). There was a significant difference in duration of parenteral rehydration in the treatment vs placebo groups: (15 14 h vs. 38 33 h; P = 0.006). Gut colonization by administered strains was 80% and 41% at 5 and 14 days, respectively. The major limits of the study are small sample size in subgroup analysis and no analysis of differences among outpatient and inpatient results were run; there could be a discrepancy in patient diaries vs clinical measures by a physician.

In a randomized, double-blind study, Rerksuppaphol et al (2013) found Lactobacillus acidophilus to be effective with reducing both the duration of diarrhea and the number of abnormal watery stools compared to a placebo when refrigerated or not refrigerated. Recruitment took place at the pediatric ward of Srinakharinwirot University Hospital in Thailand from January to October 2008 of children between the ages of 2 months and 7 years with acute diarrhea (n=64). Regardless of the storage, children who received Lactobacillus acidophilus in a dosage of 109 CFUs per capsule as treatment for diarrhea showed a statistically significant decrease in duration of diarrhea compared to the placebo group. Of the children who received probiotics, half (21/45) had their diarrhea cease within 24 hours, only one-fifth (9/45) had diarrhea that lasted for more than 48 hours. The baseline characteristics consisted of the mean age, gender, weight, height, baseline hematological and biochemical parameters . The study also showed a significant reduction in the duration of diarrhea by 34.1-34.8 hours in children when using a Lactobacillus acidophilus supplement compared to the placebo group (58 hours) regardless of whether the supplement was refrigerated or stored at room temperature.The limitations of study consisted of having a small sample size because participant population was mainly focused on the young infants and children in Thailand.

Meta-Analyses of using LGG to treat diarrhea in children Using the Cochrane Collaborations tool for assessing risk of bias, Szajewska, et al (2011) conducted a meta analysis to systematically review three random controlled trials (RCTs) about the use Lactobacillus rhamnosus GG (LGG) to prevent health-care associated diarrhea (HAD). The participants (n=1000) between the ages 1 month to 18 years were included in the studies. Heterogeneity was not significant in the studies (p=0.26). The primary outcome measured was the incidence of diarrhea. The pooled results of the three studies revealed a significant reduction in the outcome of HAD in the LGG group compared to the placebo group (RR=0.49). There was no significant difference between the LGG and the placebo groups in the incidence of asymptomatic rotavirus infection (RR= 1.39). The researchers were unable to assess for bias because of the very small number of studies included.

In a meta-analysis study, Szajewska et al (2007) reviewed 14 RCTs to determine the effectiveness of LGG in treating diarrhea in children aged one month to thirty-six months. Two of the RCTs (n=303) that provided data on stool output showed no significant difference between LGG and the control group with total stool volume (p=0.85), stool volume on day 1 (p=0.32) and stool volume on day 2 (p=.20). However, total stool volume was found to be significant when taking into account the heterogeneity (p=0.04). A meta-analysis of seven RCTs (n=876) showed a reduction in the duration of diarrhea in participants that were treated with LGG as compared with the placebo by -1.1 days (p=0.008). LGG also significantly reduced the duration of rotavirus diarrhea by -2 days (p=0.06). European studies showed a significance in the duration of diarrhea by -1.27 days with treatment of LGG as compared to studies that were conducted in non-European countries by -0.76 days. In a small RCT study, LGG was found to reduce the risk of diarrhea on day 2 ( p=0.02) and the RR (fixed) at 0.37. Treatment of LGG with diarrhea >7 days was the most significant (p=0.01) and the RR (fixed) at 0.25. The limitations of study included small sample size, and no blinding and intention to treat analysis. Other limitations were the use of different definitions of diarrhea and reported outcomes in different trials and agreement and disagreements with other studies or reviews. There was also a risk of bias because there was unclear allocation concealment.

Conclusion: All of the studies had a strong experimental design and were either double blind randomized control trials or rigorous meta-analyses. These studies conclusively show that probiotic Lactobacillus is effective at preventing the occurrence and shortening the duration of rotavirus diarrhea among children. There are mixed results with treatment of any etiology. Lactobacillus probiotic treatment has been found to be just as effective without the additional use of smectite in the treatment plan. Furthermore, Lactobacillus probiotic treatment can effectively shorten the duration of of intravenous rehydration therapy needed in children with diarrhea. All of the studies varied in dosage and the strain of Lactobacillus used for treatment. Thus, further research should be done to standardize a dose and find the most effective strain to treat diarrhea in children, so that this can be used in practice. Grade II