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Jornal de Pediatria

Print version ISSN 0021-7557On-line version ISSN 1678-4782

J. Pediatr. (Rio J.) vol.91 no.4 Porto Alegre July/Aug. 2015

http://dx.doi.org/10.1016/j.jped.2014.10.009 

Original Articles

Lactobacillus reuteri DSM 17938 shortens acute infectious diarrhea in a pediatric outpatient setting

Ener Cagri Dinleyici a   * 

Nazan Dalgic b  

Sirin Guven c  

Ozge Metin d  

Olcay Yasa e  

Zafer Kurugol f  

Ozden Turel g  

Gonul Tanir d  

Ahmet Sami Yazar c  

Vefik Arica h  

Mesut Sancar i  

Adem Karbuz h  

Makbule Eren j  

Metehan Ozen h  

Ates Kara i  

Yvan Vandenplas k  

aFaculty of Medicine, Department of Pediatrics, Pediatric Intensive Care and Infectious Disease Unit, Eskisehir Osmangazi University, Eskisehir, Turkey

bDivision of Pediatric Infectious Diseases, Sisli Etfal Training and Research Hospital, Istanbul, Turkey

cDepartment of Pediatrics, Umraniye Education & Research Hospital, Istanbul, Turkey

dPediatric Infectious Disease Unit, Dr. Sami Ulus Research and Training Hospital of Women's and Children's Health and Diseases, Ankara, Turkey

eDepartment of Pediatrics, Goztepe Training and Research Hospital, SB Istanbul Medeniyet University, Istanbul, Turkey

fDepartment of Pediatrics, Faculty of Medicine, Ege University, Izmir, Turkey

gDepartment of Pediatric Infectious Disease Unit, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey

hDepartment of Pediatrics, Okmeydani Education and Research Hospital, Istanbul, Turkey

iFaculty of Pharmacy, Clinical Pharmacy Department, Marmara University, Istanbul, Turkey

jFaculty of Medicine, Pediatric Infectious Disease Unit, Hacettepe University, Ankara, Turkey

kDepartment of Pediatrics, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium

ABSTRACT

OBJECTIVE:

Two randomized controlled clinical trials have shown thatLactobacillus (L) reuteri DSM 17938 reduces the duration of diarrhea in children hospitalized due to acute infectious diarrhea. This was the first trial evaluating the efficacy of L. reuteri DSM 17938 in outpatient children with acute infectious diarrhea.

METHODS:

This was a multicenter, randomized, single-blinded, case control clinical trial in children with acute watery diarrhea. A total of 64 children who presented at outpatient clinics were enrolled. The probiotic group received 1 × 108 CFU L. reuteri DSM 17938 for five days in addition to oral rehydration solution (ORS) and the second group was treated with ORS only. The primary endpoint was the duration of diarrhea (in hours). The secondary endpoint was the number of children with diarrhea at each day of the five days of intervention. Adverse events were also recorded.

RESULTS:

The mean duration of diarrhea was significantly reduced in the L. reuteri group compared to the control group (approximately 15 h, 60.4 ± 24.5 h [95% CI: 51.0-69.7 h] vs. 74.3 ± 15.3 h [95% CI: 68.7-79.9 h], p < 0.05). The percentage of children with diarrhea was lower in the L. reuteri group (13/29; 44.8%) after 48 h than the control group (27/31; 87%; RR: 0.51; 95% CI: 0.34-0.79,p < 0.01). From the 72nd hour of intervention onwards, there was no difference between the two groups in the percentage of children with diarrhea. No adverse effects related to L. reuteri were noted.

CONCLUSION:

L. reuteri DSM 17938 is effective, safe, and well-tolerated in outpatient children with acute infectious diarrhea.

Key words: Lactobacillus reuteri DSM 17938; Diarrhea; Children; Probiotic; Ambulatory care

Introduction

Diarrhea remains an important cause of morbidity and mortality in children worldwide.1 The European Society of Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) and the European Society of Paediatric Infectious Diseases (ESPID) together published evidence-based guidelines on the management of acute gastroenteritis, and confirmed that rehydration is the key treatment. The guidelines also stated that selected probiotics may reduce the duration and intensity of symptoms and can be used as an adjuvant to oral rehydration solution (ORS).2Current evidence also indicates that probiotic effects are strain-specific.3 Various strains of Lactobacillus reuteri species have been studied in acute diarrhea and have been found to be beneficial. L. reuteri DSM 17938 is a new probiotic strain with removed transferable resistance traits for tetracycline and lincomycin from the original L. reuteri ATCC 55730 strain. 4 It has been previously reported that L. reuteri DSM 17938 reduced the duration of diarrhea and the length of hospital stay in children requiring hospitalization due to acute infectious diarrhea. 5 A recent meta-analysis of L. reuteri DSM 17938 in children with acute infectious diarrhea showed reduced duration of diarrhea and concluded that outpatient data and country-specific cost-effectiveness analyses are needed. 6This study is the first report of the effects of L. reuteri DSM 17938 on acute infectious diarrhea in an outpatient pediatric setting.

Patient and methods

This was a multicenter, randomized, single-blinded, case control clinical trial in children of both genders, aged between 3 and 60 months, with acute infectious diarrhea (defined as the passage of three or more loose or watery stools per day) lasting 12-72 h before presentation at the outpatient clinic. The main investigator (ECD) did not enroll children and was blinded to the treatment of the patients. Approval for the study was granted by the Local Ethics Committee and an informed consent was obtained from the parents of the children. This study was registered at www.clinicaltrials.gov (NCT01927094).

Children who presented at the outpatient clinic with acute infectious diarrhea, and who were followed up with ambulatory care were enrolled in the study. Exclusion criteria were need for hospitalization, use of antibiotics or probiotics for one month prior to a new episode of diarrhea, severe malnutrition, or severe chronic underlying disease, including immunocompromising conditions.

All children were randomly assigned to the probiotic or control group using a computer-generated randomization list. Block randomization was applied with a computer-generated random number list by the main investigator (ECD), who did not enroll any patients. The first group received the five drops containing 1 × 108 CFU L. reuteri DSM 17938 (BioGaia(r), Stockholm, Sweden) for five days, in addition to ORS. The second group received ORS only (control group). The probiotics preparations were provided by the distribution company (Eczacibasi) in Turkey. Hypo-osmolar ORS (glucose 20 g; sodium 60 mmol/L; potassium 20 mmol/L; bicarbonate 30 mmol/L) was used. The primary endpoint was the duration of diarrhea (in hours). The secondary endpoint was the number of children with diarrhea at each day of the five days of the intervention. Adverse events were also recorded. The duration of diarrhea was defined as the time in hours from admission until cessation of diarrhea, which in turn was defined as the first normal stool according to the Bristol score (a score of <5 was considered as normalization of the stools).

The sample size needed was calculated based on the mean duration of diarrhea and standard deviation (SD) from previous similar studies. With the assumption of mean difference on duration of diarrhea of one day (24 h) between the treatment and control group, the authors calculated that a sample of 64 children would be required for the study to have 80% power with a significance level = 0.05 and sigma = 2 (two tailed test). Statistical analysis was performed using SPSS software, version 16.0 (SPSS Inc., IL, USA). Variables were tested for normal distribution and compared using the Mann-Whitney U-test and t-test (for mean difference) and χ 2 or Fisher's exact tests, as appropriate. MedCalc(r) program (Microsoft Partner Network, USA) was performed to calculate relative risk (RR). Statistical significance was set at p< 0.05.

Results

The study included 64 children. After exclusion of three children from the L. reuteri group and one child from the control group due to antibiotic prescription post-randomization ( Fig. 1), a total of 60 remained for evaluation; 29 (20 male, 9 female) in the L. reuteri group and 31 (22 male, nine female) in the control group. The demographic findings, mean duration of diarrhea before intervention and mean number of stools at 24 h prior to inclusion are summarized in Table 1.

Figure 1  Flow diagram of the study group. 

Table 1  Demographic and clinical findings of the study groups. 

Lactobacillus reuteri DSM 17938 (n = 29) Control group (n = 31)
Age (months) 27.9 ± 18.2 22.6 ± 14.4
Gender 20 boys, 9 girls 22 boys, 9 girls
Mean number of stools during the 24 h prior to inclusion 7.13 ± 3.8 6.1 ± 0.9
Mean duration of diarrhea before intervention (hours) 18.1 ± 6.5 20.1 ± 8.7

The mean duration of diarrhea was significantly reduced in the L. reuteri group when compared to the control group (approximately 15 h; 60.4 ± 24.5 h [95% CI: 51.0-69.7 h] vs. 74.3 ± 15.3 h [95% CI: 68.7-79.9 h];p < 0.05; Table 2).

Table 2  Duration of diarrhea in study groups. 

Lactobacillus reuteri DSM 17938 (n = 29) Control group (n = 31)
Duration of diarrhea (hours) 60.4 ± 24.5a 74.3 ± 15.3

Values are expressed as mean ± SD (95% CI). a p = 0.01; L. reuteri vs. control group.

At the 48th hour of the study, 45% of the children receiving L. reuteri DSM 17938 had watery diarrhea, while this was still the case in 87% of the children in the control group (13/29; 44.8% vs. 27/31; 87%; RR: 0.51; 95% CI: 0.34-0.79; p < 0.01). From the 72nd hour of the intervention, the percentage of children without diarrhea was similar between the groups ( Table 3). No adverse effects related to L. reuteri DSM 17938 were observed.

Table 3  Percentage of children with diarrhea in study groups. 

Lactobacillus reuteri DSM 17938 (n = 29) Control group (n = 31) Relative risk (95% CI) p
24th hour 25/29 (86.2%) 31/31 (100%) 0.86 (0.74–1.01) p > 0.05
48th hour 13/29 (44.8%) 27/31 (87.0%) 0.51 (0.34–0.79) p < 0.01
72nd hour 5/29 (17.2%) 4/31 (12.9%) 1.34 (0.4–4.5) p > 0.05
96th hour 1/29 (3.4%) 1/31 (3.2%) 1.07 (0.07–16.3) p > 0.05
120th hour 0/29 (0%) 0/31 (0%) NA p > 0.05

Discussion

The results of the present study showed that ORS in combination with five days ofL. reuteri DSM 17938 reduced the duration of acute infectious diarrhea to approximately 15 h in children aged between 3 and 60 months. The effect was mainly observed after 48 h of intervention, when 55% of the children in the intervention group were diarrhea-free, while this was the case in only 13% in the control group. In a previous study, performed by the same study team and with the same design, except for the fact that the study was applied to hospitalized children, 127 children aged 3-60 months were enrolled. In hospitalized children, the administration of L. reuteri DSM 17938 reduced the duration of diarrhea significantly to approximately 33 h. 5 The effect (percentage of children without diarrhea) of L. reuteri DSM 17938 started to be observed after 24 h of intervention and was greatest after 48 and 72 h. It was observed also that the mean length of hospital stay was shortened by more than 24 h in the L. reuteri DSM 17938 group. 5 Francavilla et al. 7 performed a randomized double-blinded, placebo-controlled clinical trial on 74 children aged 6-36 months with acute diarrhea, randomized to receive L. reuteri DSM 17938 or placebo for seven days, in three hospitals in Southern Italy. Compared with the placebo group, the L. reuteri DSM 17938 group presented a significant reduction in the duration of diarrhea, in the risk of watery diarrhea on day 2 and day 3, and in the risk of relapse of diarrhea, although no reduction of the duration of hospitalization was observed. 7 Szajewska et al. 6 pooled the data from these two RCTs of hospitalized children, confirming that L. reuteri DSM 17938 significantly reduced the duration of diarrhea to approximately 32 h and increased the chance of cure on day 3. 6 Two independent studies, one in Indonesia and one in Mexico, demonstrated that the prophylactic use of L. reuteri DSM 17938 reduces the frequency and duration of diarrheal episodes, 8 and 9 although their clinical relevance can be questioned. 10 L. reuteri DSM 17938 was well tolerated, and no associated adverse events have been reported in any trial. 6

The current study had some limitations, as it was not a double-blinded, placebo-controlled clinical trial. To access stool consistency, the Bristol Stool Form Scale was used, which has a limited validation for the youngest children, although it offers a more objective form of assessing stool consistency rather than just relying on the perceptions of caregivers.11 The duration of diarrhea was used as the primary endpoint, which is not considered optimal. However, there is a major reluctance of caregivers and healthcare providers to conduct the cumbersome stool collection. The question of generalization of findings in clinical trials, specifically on infectious gastroenteritis and probiotics, is challenging. However, these findings can be considered as generalized, since worldwide viral gastroenteritis is the most common cause. Moreover, as a multi-center study, the participants came from urban and rural regions, including economically developed and poor areas. Therefore, these findings are likely to allow for generalization.

The Working Group on Probiotics of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) concluded that the use ofL. reuteri DSM 17938 should be considered in the management of acute gastroenteritis as an adjunct intervention to ORS. 3 Probiotics may be of help for the management of acute diarrhea. However, the effect is strain-specific, and efficacy needs to be proven in different settings, such as hospital or outpatients settings. The results of the present study have shown that L. reuteri DSM 17938 as an adjunct to ORS therapy is efficacious in the treatment of acute diarrhea, reducing the duration of the disease in an outpatient setting.

References

Walker CL, Rudan I, Liu L, Nair H, Theodoratou E, Bhutta ZA, et al. Global burden of childhood pneumonia and diarrhoea. Lancet. 2013;381:1405-16. [ Links ]

Guarino A, Albano F, Ashkenazi S, Gendrel D, Hoekstra JH, Shamir R, et al. European Society for Paediatric Gastro- enterology, Hepatology, and Nutrition/European Society for Paediatric Infectious Diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe: executive summary. J Pediatr Gastroenterol Nutr. 2008;46:619-21. [ Links ]

Szajewska H, Guarino A, Hojsak I, Indrio F, Kolacek S, Shamir R, et al. Use of probiotics for management of acute gastro- enteritis: a position paper by the ESPGHAN Working Group for Probiotics and Prebiotics. J Pediatr Gastroenterol Nutr. 2014;58:531-9. [ Links ]

Urban´ska M, Szajewska H. The efficacy of Lactobacillus reu- teri DSM 17938 in infants and children: a review of the current evidence. Eur J Pediatr. 2014;173:1327-37. [ Links ]

Dinleyici EC, Vandenplas Y. PR0BAGE Study Group Lactoba- cillus reuteri DSM 17938 effectively reduces the duration of acute diarrhoea in hospitalised children. Acta Paediatr. 2014;103:e300-e305. [ Links ]

Szajewska H, Urban´ska M, Chmielewska A, Weizman Z, Shamir R. Meta-analysis. Lactobacillus reuteri strain DSM 17938 (and the original strain ATCC 55730) for treating acute gastroenteritis in children. Benef Microbes. 2014;5:285-93. [ Links ]

Francavilla R, Polimeno L, Demichina A, Maurogiovanni G, Principi B, Scaccianoce G, et al. Lactobacillus reuteri strain combination in Helicobacter pylori infection: a randomized, double-blind, placebo-controlled study. J Clin Gastroenterol. 2014;48:407-13. [ Links ]

Agustina R, Kok FJ, van de Rest 0, Fahmida U, Firmansyah A, Lukito W, et al. Randomized trial of probiotics and calcium on diarrhea and respiratory tract infections in Indonesian children. Pediatrics. 2012;129:e1155-64. [ Links ]

Gutierrez-Castrellon P, Lopez-Velazquez G, Diaz-Garcia L, Jimenez-Gutierrez C, Mancilla-Ramirez J, Estevez-Jimenez J, et al. Diarrhea in preschool children and Lactobacillus reu- teri: a randomized controlled trial. Pediatrics. 2014;133: e904-9. [ Links ]

Vandenplas Y. Lactobacillus reuteri is an effective option for the prevention of diarrhoea in preschool children but may not be cost-effective in all settings. Evid Based Med. 2014;19:212. [ Links ]

Ghanma A, Puttemans K, Deneyer M, Benninga MA, Vandenplas Y. Amsterdam infant stool scale is more useful for assessing chil- dren who have not been toilet trained than Bristol stool scale. Acta Paediatr. 2014;103:e91-2. [ Links ]

Please cite this article as: Dinleyici EC, Dalgic N, Guven S, Metin O, Yasa O, Kurugol Z, et al. Lactobacillus reuteri DSM 17938 shortens acute infectious diarrhea in a pediatric outpatient setting. J Pediatr (Rio J). 2015;91:392-6.

Received: August 01, 2014; Accepted: October 23, 2014

* Corresponding author. E-mail: timboothtr@yahoo.com (E.C. Dinleyici).

Conflicts of interestE.C. Dinleyici is speaker bureau and advisory board member of Biocodex. M. Ozen is speaker bureau of Pfizer Consumer Health. Y. Vandenplas is a consultant for Biocodex, United Pharmaceuticals. Other authors declare no conflicts of interest.

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