Evidence-Based Medicine Online First, published on July 11, 2014 as 10.1136/ebmed-2014-110039 Therapeutics/Prevention Randomised controlled trial
Lactobacillus reuteri is an effective option for the prevention of diarrhoea in preschool children but may not be cost-effective in all settings 10.1136/ebmed-2014-110039
Yvan Vandenplas Department of Pediatrics, Universitair Ziekenhuis Brussel, Brussels, Belgium Correspondence to: Dr Yvan Vandenplas, Department of Pediatrics, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium; [email protected]
Commentary on: Gutierrez-Castrellon P, Lopez-Velazquez G, Diaz-Garcia L, et al. Diarrhea in preschool children and Lactobacillus reuteri: a randomized controlled trial. Pediatrics 2014;133:e904–9.
Context Diarrhoea remains a serious health burden for young children worldwide, with a high incidence of morbidity and mortality in the developing world. Oral rehydration solution dramatically improves outcomes, but does not influence the duration of diarrhoea. Selected probiotic strains have been shown to reduce the duration of acute gastroenteritis by around 24 h.1 Gutierrez-Castrellon and colleagues set out to evaluate whether probiotics administered in prevention could reduce the incidence of infectious gastroenteritis.
Methods Much attention has been paid to the study design by the authors. The probiotics and placebo arms were identical, except for the presence of the probiotic Lactobacillus reuteri, given daily over 12 weeks to 336 children attending four different day-care centres in the South-Eastern area of Mexico city over a 14-month inclusion period. The primary endpoint was the number of days’ diarrhoea per child. Diarrhoea was defined using the WHO definition of three or more loose or watery stools passed within a 24 h period. Relevant secondary outcomes were also considered. A costeffectiveness analysis of the intervention was planned.
absenteeism, and number of medical visits. The cost-effectiveness analysis demonstrated that prophylactic use of L. reuteri was associated with a reduction of US$36 per case of diarrhoea and of US$37per case of upper respiratory tract infection.
Commentary This is a well-designed trial demonstrating that L. reuteri reduces frequent gastrointestinal and respiratory tract infectious diseases in young children attending day-care centres. L. reuteri was recommended by the Working Group on Probiotics of the European Society of paediatric gastroenterology, hepatology and nutrition, and since then new data has confirmed the efficacy of this strain in the treatment of acute gastroenteritis.2 As reported in the discussion, two previous studies evaluate L. reuteri in prevention. In one study, the strain was added to infant formula, while in another L. reuteri was also given as oral drops, significantly reducing diarrhoea incidence in children with lower nutritional status, but having no effect on respiratory tract infections.3 4 This paper confirms that administration of probiotics has a healthpromoting benefit and is safe—the statistical analysis confirms the benefit beyond doubt. However, a question remains regarding whether these findings are clinically relevant. These kinds of studies are setup in environments (eg, Mexico or Indonesia) in which the incidence of infectious diarrhoea is high. The reasons to do so are obvious, since even in this high-risk environment the number of participants needs to be several hundred in order to obtain enough power to show a statistical benefit. Even then, the clinical relevance of these findings can be questioned; although the ‘number of days with diarrhoea per child’ was significantly reduced ( p 0.03), the difference is only half a day over a period of 6 months (0.32 vs 0.96 days). Interestingly the study design was such that the probiotic was given for 3 months, while the children were followed for 6 months. Unfortunately, there is no separate analysis comparing the results after 3 and 6 months. Although the analysis showed benefit after 6 months, it would have been interesting to have data for the period between 3 and 6 months. Although a cost–benefit was shown, one should realise that the data were collected in a high-risk population, a developed country where costs were reduced. Also, a high-risk population may not be able to justify the cost of a treatment that only offers a half-day reduction in diarrhoea incidence over a 6-month period. Competing interests YV is a consultant for Biocodex and United Pharmaceuticals. Provenance and peer review Not commissioned; internally peer reviewed. References
Findings In healthy children attending day-care centres, daily administration of L. reuteri resulted in a significant reduction in the number of episodes (99 episodes in the intervention group vs 152 episodes in the placebo group, p=0.01) and the duration of diarrhoea (1.6 days in the intervention group vs 2.7 days in the placebo group, p=0.02). Incidence of respiratory tract infections were also reduced during the study period (93 vs 204 episodes, p=0.02) and during the follow-up period (129 vs 197 episodes, p=0.04). Subjects in the intervention group had a significant decrease of other secondary outcomes such as fever, days of day care and work
1. Szajewska H, Guarino A, Hojsak I, et al. Use of probiotics for management of acute gastroenteritis: a position paper by the ESPGHAN Working Group for probiotics and prebiotics. J Pediatr Gastroenterol Nutr 2014;58:531–9. 2. Dinleyici EC, Vandenplas Y; PROBAGE Study Group. Lactobacillus reuteri DSM 17938 effectively reduces the duration of acute diarrhoea in hospitalised children. Acta Paediatr 2014;103:e300–5. 3. Weizman Z, Asli G, Alsheikh A. Effect of a probiotic infant formula on infections in child care centers: comparison of two probiotic agents. Pediatrics 2005;115:5–9. 4. Agustina R, Kok FJ, van de Rest O, et al. Randomized trial of probiotics and calcium on diarrhea and respiratory tract infections in Indonesian children. Pediatrics 2012;129:e1155–64.
Evid Based Med Month 2014 | volume 0 | number 0 |
Copyright Article author (or their employer) 2014. Produced by BMJ Publishing Group Ltd under licence.
1
Lactobacillus reuteri is an effective option for the prevention of diarrhoea in preschool children but may not be cost-effective in all settings 10.1136/ebmed-2014-110039
Yvan Vandenplas Department of Pediatrics, Universitair Ziekenhuis Brussel, Brussels, Belgium Correspondence to: Dr Yvan Vandenplas, Department of Pediatrics, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium; [email protected]
Commentary on: Gutierrez-Castrellon P, Lopez-Velazquez G, Diaz-Garcia L, et al. Diarrhea in preschool children and Lactobacillus reuteri: a randomized controlled trial. Pediatrics 2014;133:e904–9.
Context Diarrhoea remains a serious health burden for young children worldwide, with a high incidence of morbidity and mortality in the developing world. Oral rehydration solution dramatically improves outcomes, but does not influence the duration of diarrhoea. Selected probiotic strains have been shown to reduce the duration of acute gastroenteritis by around 24 h.1 Gutierrez-Castrellon and colleagues set out to evaluate whether probiotics administered in prevention could reduce the incidence of infectious gastroenteritis.
Methods Much attention has been paid to the study design by the authors. The probiotics and placebo arms were identical, except for the presence of the probiotic Lactobacillus reuteri, given daily over 12 weeks to 336 children attending four different day-care centres in the South-Eastern area of Mexico city over a 14-month inclusion period. The primary endpoint was the number of days’ diarrhoea per child. Diarrhoea was defined using the WHO definition of three or more loose or watery stools passed within a 24 h period. Relevant secondary outcomes were also considered. A costeffectiveness analysis of the intervention was planned.
absenteeism, and number of medical visits. The cost-effectiveness analysis demonstrated that prophylactic use of L. reuteri was associated with a reduction of US$36 per case of diarrhoea and of US$37per case of upper respiratory tract infection.
Commentary This is a well-designed trial demonstrating that L. reuteri reduces frequent gastrointestinal and respiratory tract infectious diseases in young children attending day-care centres. L. reuteri was recommended by the Working Group on Probiotics of the European Society of paediatric gastroenterology, hepatology and nutrition, and since then new data has confirmed the efficacy of this strain in the treatment of acute gastroenteritis.2 As reported in the discussion, two previous studies evaluate L. reuteri in prevention. In one study, the strain was added to infant formula, while in another L. reuteri was also given as oral drops, significantly reducing diarrhoea incidence in children with lower nutritional status, but having no effect on respiratory tract infections.3 4 This paper confirms that administration of probiotics has a healthpromoting benefit and is safe—the statistical analysis confirms the benefit beyond doubt. However, a question remains regarding whether these findings are clinically relevant. These kinds of studies are setup in environments (eg, Mexico or Indonesia) in which the incidence of infectious diarrhoea is high. The reasons to do so are obvious, since even in this high-risk environment the number of participants needs to be several hundred in order to obtain enough power to show a statistical benefit. Even then, the clinical relevance of these findings can be questioned; although the ‘number of days with diarrhoea per child’ was significantly reduced ( p 0.03), the difference is only half a day over a period of 6 months (0.32 vs 0.96 days). Interestingly the study design was such that the probiotic was given for 3 months, while the children were followed for 6 months. Unfortunately, there is no separate analysis comparing the results after 3 and 6 months. Although the analysis showed benefit after 6 months, it would have been interesting to have data for the period between 3 and 6 months. Although a cost–benefit was shown, one should realise that the data were collected in a high-risk population, a developed country where costs were reduced. Also, a high-risk population may not be able to justify the cost of a treatment that only offers a half-day reduction in diarrhoea incidence over a 6-month period. Competing interests YV is a consultant for Biocodex and United Pharmaceuticals. Provenance and peer review Not commissioned; internally peer reviewed. References
Findings In healthy children attending day-care centres, daily administration of L. reuteri resulted in a significant reduction in the number of episodes (99 episodes in the intervention group vs 152 episodes in the placebo group, p=0.01) and the duration of diarrhoea (1.6 days in the intervention group vs 2.7 days in the placebo group, p=0.02). Incidence of respiratory tract infections were also reduced during the study period (93 vs 204 episodes, p=0.02) and during the follow-up period (129 vs 197 episodes, p=0.04). Subjects in the intervention group had a significant decrease of other secondary outcomes such as fever, days of day care and work
1. Szajewska H, Guarino A, Hojsak I, et al. Use of probiotics for management of acute gastroenteritis: a position paper by the ESPGHAN Working Group for probiotics and prebiotics. J Pediatr Gastroenterol Nutr 2014;58:531–9. 2. Dinleyici EC, Vandenplas Y; PROBAGE Study Group. Lactobacillus reuteri DSM 17938 effectively reduces the duration of acute diarrhoea in hospitalised children. Acta Paediatr 2014;103:e300–5. 3. Weizman Z, Asli G, Alsheikh A. Effect of a probiotic infant formula on infections in child care centers: comparison of two probiotic agents. Pediatrics 2005;115:5–9. 4. Agustina R, Kok FJ, van de Rest O, et al. Randomized trial of probiotics and calcium on diarrhea and respiratory tract infections in Indonesian children. Pediatrics 2012;129:e1155–64.
Evid Based Med Month 2014 | volume 0 | number 0 |
Copyright Article author (or their employer) 2014. Produced by BMJ Publishing Group Ltd under licence.
1
