Indian J Pediatr DOI 10.1007/s12098-015-1719-1
EDITORIAL COMMENTARY
Probiotics in Pediatrics Meenakshi Bothra & Shinjini Bhatnagar
Received: 29 January 2015 / Accepted: 29 January 2015 # Dr. K C Chaudhuri Foundation 2015
Probiotics refer to the live microorganisms which, when ingested in an adequate amount, provide health benefit to the host. Most of the probiotics are bacteria, while Saccharomyces boulardii is a yeast [1]. The postulated mechanisms by which probiotics exert their beneficial effects include improvement in host barrier function, competitive inhibition of pathogenic bacteria, strengthening of tight junctions between enterocytes, promoting maturation of the intestinal brush border membrane and stimulation of production of secretory IgA. There has been substantial evidence in the recent past to suggest some beneficial effects of probiotics in the treatment of acute diarrhea in children. The recent Cochrane review on the use of probiotics for treating acute infectious diarrhea, which included 63 trials (56 in infants and children), reported shortened duration of diarrhea by 25 h (95 % CI 15.9 to 33.6 h), decrease in the risk of diarrhea lasting four or more days by 59 % and one fewer loose stool on day 2 after the initiation of probiotic [2]. In another more recent systematic review in children, which included 8 randomized controlled trials (RCTs), probiotics were found to reduce the duration of community-acquired acute diarrhea by 14.0 % (95 % CI: 3.8– 24.2 %) and stool frequency on the second day of treatment by
M. Bothra (*) Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India e-mail: [email protected] S. Bhatnagar Pediatric Biology Centre, Translational Health Science and Technology Institute, Gurgaon, India
13.1 % (95 % CI: 0.8–25.3 %) [3]. These data need to be interpreted with caution as most of the studies were not from LMIC (low middle income countries) and there was marked variability across the studies, such as use of different strains, variable doses, and different breast feeding and dietary practices. Additionally, these studies did not evaluate the effects of probiotics with the concurrent use of zinc, which is currently the accepted adjunct to ORS in the treatment of diarrhea. Most of the earlier studies that evaluated the effect of probiotics in the prevention of acute diarrhea were once again from developed countries and the effects were dependent on the host and the particular strain used [4]. The only large RCT evaluating the effect of probiotics on prevention of diarrhea in India was in an urban slum that found a protective efficacy of 14 % (95 % CI 4–23%) in 3758 children, followed for a period of 24 wk. However, one must note that the 95 % CI was very wide [5]. The RCT by Hegar et al., published in this edition of the journal, tested the efficacy of a combination of Lactobacillus rhamnosus R0011 1.9 × 109 & Lactobacillus acidophilus R0052 0.1×109 colony forming units/day in 112 children aged 6–36 mo with acute infectious diarrhea and moderate dehydration in Jakarta, Indonesia [6]. This study is important as it has evaluated therapeutic efficacy of probiotics in childhood diarrhea in the setting of a developing country and also where the study subjects were given zinc in addition to ORS as standard therapy. In earlier studies, zinc was not a part of standard treatment regime in the study subjects. The study reported a reduction in the median duration of diarrhea [61.5 h (range 21–166) vs. 68.5 h (range 13–165)] and the median daily frequency of defecation (5.0 vs. 5.5) in the probiotic supplemented group as compared to the control group, but these differences were not statistically significant. The
Indian J Pediatr
lack of significant difference may be because of the small sample size of the study. The authors have argued that the negative results in their study could also have been due to the interaction between zinc and probiotics. However, it is important to evaluate the effects of probiotics along with zinc, as the latter is standard of care in the treatment of diarrhea, both globally and within our country. Some of the limitations of this study, as acknowledged by the investigators themselves, include possibility of recall bias, non-compliance to therapy, and inability to perform an independent quality analysis of the tested probiotic product. It may also be difficult to compare the result of this study with the earlier studies because the definitions of diarrhea (based on the Bristol criteria) and severe dehydration (capillary refill time >4 s) used are different from the conventionally used WHO definitions by other groups. While most of the preventive and therapeutic effects of probiotics have been evaluated in diseases involving the gastrointestinal tract, their use has also been evaluated in other infections and allergic disorders. Therapeutic benefits have been reported in severe necrotizing enterocolitis (Bells stage II or more) (RR 0.35, 95 % CI 0.24 to 0.52), but not with nosocomial sepsis (RR 0.90, 95 % CI 0.76 to 1.07) [7, 8]. A Cochrane review found insufficient evidence for the use of probiotics in the prevention or treatment of atopic dermatitis, but another Cochrane meta-analysis of 10 clinical trials found that probiotics were more beneficial than placebo in reducing the rate of acute upper respiratory tract infection and frequency of antibiotic use, but did not decrease the duration of each episode [9, 10]. Due to the heterogeneous and lack of convincing evidence on the use of probiotics in childhood diseases particularly diarrhea, larger, well planned, multicentric studies are required with different probiotic preparations, in varying dose ranges in developing countries. Data from studies done in the west cannot be extrapolated to children in our settings where the infection rates, the gut microbiome, breast feeding practices and the dietary patterns are very different. The standard of care for the treatment of acute diarrhea in children remains oral rehydration solution (ORS), zinc and continued oral feeding, as recommended by WHO as well as the IAP [11].
Conflict of Interest None. Source of Funding None.
References 1. Vandenplas Y, Brunser O, Szajewska H. Saccharomyces boulardii in childhood. Eur J Pediatr. 2009;168:253–65. 2. Allen SJ, Martinez EG, Gregorio GV, Dans LF. Probiotics for treating acute infectious diarrhea. Cochrane Database Syst Rev. 2010;11: CD003048. 3. Applegate JA, Walker CLF, Ambikapathi R, Black RE. Systematic review of probiotics for the treatment of community-acquired acute diarrhea in children. BMC Public Health. 2013;13:S16. 4. Sazawal S, Hiremath G, Dhingra U, Malik P, Deb S, Black RE. Efficacy of probiotics in prevention of acute diarrhoea: a metaanalysis of masked, randomised, placebo-controlled trials. Lancet Infect Dis. 2006;6:374–82. 5. Sur D, Manna B, Niyogi SK, Ramamurthy T, Palit A, Nomoto K, et al. Role of probiotic in preventing acute diarrhoea in children: a community-based, randomized, double-blind placebo-controlled field trial in an urban slum. Epidemiol Infect. 2011;139:919–26. 6. Hegar B, Waspada MI, Gunardi H, Vandenplas Y. A double blind randomized trial showing probiotics to be ineffective in acute diarrhea in Indonesian children. Indian J Pediatr. 2014. doi:10.1007/ s12098-014-1408-5. 7. Alfaleh K, Anabrees J, Bassler D, Al-Kharfi T. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2011;3:CD005496. 8. Szajewska H, Chmielewska A. Growth of infants fed formula supplemented with Bifidobacterium lactis Bb12 or Lactobacillus GG: a systematic review of randomized controlled trials. BMC Pediatr. 2013;13:185. 9. Osborn DA, Sinn JK. Probiotics in infants for prevention of allergic disease and food hypersensitivity. Cochrane Database Syst Rev. 2007;4:CD006475. doi:10.1002/14651858.CD006475.pub2. 10. Hao Q, Lu Z, Dong BR, Huang CQ, Wu T. Probiotics for preventing acute upper respiratory tract infections. Cochrane Database Syst Rev. 2011;9: CD006895. 11. WHO/UNICEF: Joint statement: clinical management of acute diarrhea (WHO/FCH/CAH/04.07). Geneva & New York: World Health Organization, Department of Child and Adolescent Health and Development, and the United Nations Children’s Fund, Programme Division; 2004.
EDITORIAL COMMENTARY
Probiotics in Pediatrics Meenakshi Bothra & Shinjini Bhatnagar
Received: 29 January 2015 / Accepted: 29 January 2015 # Dr. K C Chaudhuri Foundation 2015
Probiotics refer to the live microorganisms which, when ingested in an adequate amount, provide health benefit to the host. Most of the probiotics are bacteria, while Saccharomyces boulardii is a yeast [1]. The postulated mechanisms by which probiotics exert their beneficial effects include improvement in host barrier function, competitive inhibition of pathogenic bacteria, strengthening of tight junctions between enterocytes, promoting maturation of the intestinal brush border membrane and stimulation of production of secretory IgA. There has been substantial evidence in the recent past to suggest some beneficial effects of probiotics in the treatment of acute diarrhea in children. The recent Cochrane review on the use of probiotics for treating acute infectious diarrhea, which included 63 trials (56 in infants and children), reported shortened duration of diarrhea by 25 h (95 % CI 15.9 to 33.6 h), decrease in the risk of diarrhea lasting four or more days by 59 % and one fewer loose stool on day 2 after the initiation of probiotic [2]. In another more recent systematic review in children, which included 8 randomized controlled trials (RCTs), probiotics were found to reduce the duration of community-acquired acute diarrhea by 14.0 % (95 % CI: 3.8– 24.2 %) and stool frequency on the second day of treatment by
M. Bothra (*) Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India e-mail: [email protected] S. Bhatnagar Pediatric Biology Centre, Translational Health Science and Technology Institute, Gurgaon, India
13.1 % (95 % CI: 0.8–25.3 %) [3]. These data need to be interpreted with caution as most of the studies were not from LMIC (low middle income countries) and there was marked variability across the studies, such as use of different strains, variable doses, and different breast feeding and dietary practices. Additionally, these studies did not evaluate the effects of probiotics with the concurrent use of zinc, which is currently the accepted adjunct to ORS in the treatment of diarrhea. Most of the earlier studies that evaluated the effect of probiotics in the prevention of acute diarrhea were once again from developed countries and the effects were dependent on the host and the particular strain used [4]. The only large RCT evaluating the effect of probiotics on prevention of diarrhea in India was in an urban slum that found a protective efficacy of 14 % (95 % CI 4–23%) in 3758 children, followed for a period of 24 wk. However, one must note that the 95 % CI was very wide [5]. The RCT by Hegar et al., published in this edition of the journal, tested the efficacy of a combination of Lactobacillus rhamnosus R0011 1.9 × 109 & Lactobacillus acidophilus R0052 0.1×109 colony forming units/day in 112 children aged 6–36 mo with acute infectious diarrhea and moderate dehydration in Jakarta, Indonesia [6]. This study is important as it has evaluated therapeutic efficacy of probiotics in childhood diarrhea in the setting of a developing country and also where the study subjects were given zinc in addition to ORS as standard therapy. In earlier studies, zinc was not a part of standard treatment regime in the study subjects. The study reported a reduction in the median duration of diarrhea [61.5 h (range 21–166) vs. 68.5 h (range 13–165)] and the median daily frequency of defecation (5.0 vs. 5.5) in the probiotic supplemented group as compared to the control group, but these differences were not statistically significant. The
Indian J Pediatr
lack of significant difference may be because of the small sample size of the study. The authors have argued that the negative results in their study could also have been due to the interaction between zinc and probiotics. However, it is important to evaluate the effects of probiotics along with zinc, as the latter is standard of care in the treatment of diarrhea, both globally and within our country. Some of the limitations of this study, as acknowledged by the investigators themselves, include possibility of recall bias, non-compliance to therapy, and inability to perform an independent quality analysis of the tested probiotic product. It may also be difficult to compare the result of this study with the earlier studies because the definitions of diarrhea (based on the Bristol criteria) and severe dehydration (capillary refill time >4 s) used are different from the conventionally used WHO definitions by other groups. While most of the preventive and therapeutic effects of probiotics have been evaluated in diseases involving the gastrointestinal tract, their use has also been evaluated in other infections and allergic disorders. Therapeutic benefits have been reported in severe necrotizing enterocolitis (Bells stage II or more) (RR 0.35, 95 % CI 0.24 to 0.52), but not with nosocomial sepsis (RR 0.90, 95 % CI 0.76 to 1.07) [7, 8]. A Cochrane review found insufficient evidence for the use of probiotics in the prevention or treatment of atopic dermatitis, but another Cochrane meta-analysis of 10 clinical trials found that probiotics were more beneficial than placebo in reducing the rate of acute upper respiratory tract infection and frequency of antibiotic use, but did not decrease the duration of each episode [9, 10]. Due to the heterogeneous and lack of convincing evidence on the use of probiotics in childhood diseases particularly diarrhea, larger, well planned, multicentric studies are required with different probiotic preparations, in varying dose ranges in developing countries. Data from studies done in the west cannot be extrapolated to children in our settings where the infection rates, the gut microbiome, breast feeding practices and the dietary patterns are very different. The standard of care for the treatment of acute diarrhea in children remains oral rehydration solution (ORS), zinc and continued oral feeding, as recommended by WHO as well as the IAP [11].
Conflict of Interest None. Source of Funding None.
References 1. Vandenplas Y, Brunser O, Szajewska H. Saccharomyces boulardii in childhood. Eur J Pediatr. 2009;168:253–65. 2. Allen SJ, Martinez EG, Gregorio GV, Dans LF. Probiotics for treating acute infectious diarrhea. Cochrane Database Syst Rev. 2010;11: CD003048. 3. Applegate JA, Walker CLF, Ambikapathi R, Black RE. Systematic review of probiotics for the treatment of community-acquired acute diarrhea in children. BMC Public Health. 2013;13:S16. 4. Sazawal S, Hiremath G, Dhingra U, Malik P, Deb S, Black RE. Efficacy of probiotics in prevention of acute diarrhoea: a metaanalysis of masked, randomised, placebo-controlled trials. Lancet Infect Dis. 2006;6:374–82. 5. Sur D, Manna B, Niyogi SK, Ramamurthy T, Palit A, Nomoto K, et al. Role of probiotic in preventing acute diarrhoea in children: a community-based, randomized, double-blind placebo-controlled field trial in an urban slum. Epidemiol Infect. 2011;139:919–26. 6. Hegar B, Waspada MI, Gunardi H, Vandenplas Y. A double blind randomized trial showing probiotics to be ineffective in acute diarrhea in Indonesian children. Indian J Pediatr. 2014. doi:10.1007/ s12098-014-1408-5. 7. Alfaleh K, Anabrees J, Bassler D, Al-Kharfi T. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2011;3:CD005496. 8. Szajewska H, Chmielewska A. Growth of infants fed formula supplemented with Bifidobacterium lactis Bb12 or Lactobacillus GG: a systematic review of randomized controlled trials. BMC Pediatr. 2013;13:185. 9. Osborn DA, Sinn JK. Probiotics in infants for prevention of allergic disease and food hypersensitivity. Cochrane Database Syst Rev. 2007;4:CD006475. doi:10.1002/14651858.CD006475.pub2. 10. Hao Q, Lu Z, Dong BR, Huang CQ, Wu T. Probiotics for preventing acute upper respiratory tract infections. Cochrane Database Syst Rev. 2011;9: CD006895. 11. WHO/UNICEF: Joint statement: clinical management of acute diarrhea (WHO/FCH/CAH/04.07). Geneva & New York: World Health Organization, Department of Child and Adolescent Health and Development, and the United Nations Children’s Fund, Programme Division; 2004.
