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Probiotics: do they have a role in children?
Probiotics have been extensively studied for a variety of potential uses in children including acute infectious diarrhea, antibiotic-associated diarrhea and inflammatory bowel disease.
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Probiotics are microorganisms that, when taken orally, can be beneficial to humans in the treatment or prevention of infections. This concept is not a new one — Pasteur recognized the potential benefit of administering nonpathogenic microorganisms over 125 years ago.
| Pasteur recognized the potential benefit of nonpathogenic microorganisms over 125 years ago. |
Virtually hundreds of microorganisms comprise the natural flora of the human gastrointestinal tract. When this natural microbial environment is altered, by disease, infection with exogenous microbial pathogens, or by antibiotic administration, the beneficial effects of the natural flora may be decreased. Adverse outcomes, such as diarrhea, may result. Administration of probiotics may assist in restoring GI flora and may counter such adverse effects. Numerous microorganisms have been touted as behaving as probiotics.
However, these various organisms vary greatly in their actions and potential benefits upon the GI tract. Lactobacilli have been most extensively studied. Indeed, several lactobacillus species are natural inhabitants of the GI tract (eg, Lactobacillus acidophilus). Probiotics have been extensively studied for potential use in children, including acute infectious diarrhea, antibiotic-associated diarrhea, inflammatory bowel disease and intestinal allergic conditions. This month’s column will review the use of probiotics in the treatment of perhaps the most common of these disorders – acute, infectious diarrhea.
The mechanisms of probiotics’ beneficial effects have not been well delineated. Their proposed mechanisms include production of antimicrobial compounds that affect pathogen function and survival, immunostimulatory effects, competitive binding of pathogen adhesion in the GI tract, or competition for nutrients. Numerous microorganisms have been evaluated as potential probiotics, including several lactobacilli species (L. acidophilus, L. reuteri, L. rhamnosus GG), Saccharomyces boulardii (yeast), and Streptococcus thermophilus, among others. There are large differences, even among lactobacilli, in these organisms’ probiotic effects. The organism that is an effective probiotic must have the ability to traverse and survive the acidic gastric environment, adhere to intestinal binding sites, and temporarily colonize the GI site.
Studies
Numerous studies have evaluated the potential benefits of probiotics in children and adults. These studies, however, have varied greatly in the probiotic organisms tested, dosing, indications and methodology. Several good reviews have also been published. Recently, several meta-analyses have also been published.
Haung evaluated studies of probiotic efficacy in the treatment of acute diarrhea of otherwise healthy children. Studies evaluated were randomized with control groups. Eighteen studies (26 treatment arms) met the inclusion criteria and were included in the analysis. One-half of the studies were double blinded and placebo controlled. Children included in these studies were 1 to 60 months of age, with most having viral or idiopathic acute diarrhea; four trials included patients with bacterial diarrhea. A variety of probiotic organisms were included, with lactobacilli the most common. Probiotic doses varied by up to 1,000-fold among the studies. Overall, there was considerable heterogeneity among the studies. Results of this meta-analysis revealed a reduction in duration of diarrhea among children treated with probiotics of approximately one day (0.6 to 1.2 day). Various subanalyses were completed, with an analysis that lactobacilli were most effective. Lactobacillus rhamnosus GG (LGG) was the most commonly used lactobacillus species.
| Commercially Available Probiotic Products
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| Source: Edward Bell, PharmD, BCPS |
Szajewska evaluated probiotics in the treatment and prevention of acute diarrhea in children in another meta-analysis. Some studies were also evaluated in Haung’s meta-analysis. Published randomized, double-blind, placebo-controlled studies were included in this evaluation, and 10 trials were included for analysis. All trials included children from outside the United States, although all were from developed countries. Probiotic use revealed a reduced risk of nearly 60% of diarrhea lasting greater than three days. The composite data also revealed a reduction in the duration of diarrhea by 20 to 24 hours. Lactobacilli were most commonly used in these studies, with the LGG species used extensively. This species showed the most consistent beneficial effect. Four trials documented diarrhea induced by rotavirus, and the beneficial effect of probiotic administration appeared greatest when diarrhea was caused by this viral pathogen.
Van Niel included randomized, blinded, placebo-controlled studies of children with infectious diarrhea in a meta-analysis of only lactobacilli probiotics. Nine studies met these inclusion criteria, with some overlap in studies evaluated as compared with the above analyses. All studies enrolled patients from outside of the United States (mostly developed countries). Four studies evaluated LGG. Because of considerable study heterogeneity, however, no differing effects among various lactobacilli strains could be assessed. Overall, use of lactobacilli resulted in a reduction of duration of diarrhea of 0.7 days and a reduction of 1.6 stools on the second day of treatment. Analysis of data from these studies revealed a positive dose-response effect, with a dose of at least 10 billion colony-forming units (CFU) given in the initial 48 hours as most effective.
Guandalini evaluated LGG administration in oral rehydration solution to children (1 month to 3 years of age) with acute onset diarrhea of all causes. This multicenter study was randomized, double blinded and placebo controlled. Two hundred sixty-nine children from several European countries were evaluated. Approximately two-thirds of children were infected with rotavirus or no identifiable pathogen (each one-third), with the remainder infected with bacterial or parasitic pathogens. Children given LGG received approximately 40 billion (4 x 1010) CFU. Overall, there was a decrease in diarrhea duration of about 14 hours in children receiving LGG as compared with placebo (P<0.05), and a 20 hour decrease in diarrhea duration in children with rotavirus (P<0.05). A beneficial effect of LGG was not noted in children with invasive enteritis (eg, Salmonella, Shigella, Campylobacter, Yersinia). In children with no identifiable cause of diarrhea, a beneficial effect of LGG was seen (P<0.05). Also important was the finding that diarrhea lasting longer than seven days occurred in 10.7% of children given placebo and in 2.7% given LGG (P<0.05). Hospital stays were also significantly less (by approximately 17 hours) in children given LGG.
Available products
Several probiotic products containing lactobacillus are available (Table). This listing of products is not a recommendation for use of all products, as published efficacy data for most are not available. They are listed for information purposes. Although they are available without a prescription, they are sold as nutritional supplements, not as therapeutic medications, and are not regulated by the FDA. The FDA does not consider lactobacillus products to be effective in the treatment of diarrhea. The available products differ in the specific organism and the number of organisms in each dosage unit.
Conclusions
Probiotics have been studied for various conditions in children, namely acute onset diarrhea. While numerous studies have been published, there exists many differences among them – specific probiotic organisms evaluated, doses, causes of diarrhea, and definitions and measurement of diarrhea, among others. Although not all of these studies have shown probiotics to be effective, many have. Authors of three meta-analyses have concluded that probiotics can be of benefit in the therapy of acute onset diarrhea of viral origin, especially rotavirus. Some studies have shown a benefit in reducing hospital stay as well. Although some evidence exists for a beneficial effect of probiotics on diarrhea in children, some important unknowns also exist, such as the most effective dose, the most beneficial probiotic species, the types (causes) of diarrhea most likely to respond to probiotics, or potential adverse effects of their use. Because of these unknowns, it is premature to recommend probiotics for all patients with acute onset diarrhea. More studies are needed before widespread use can be recommended. The American Academy of Pediatrics does not recommend probiotics to treat acute onset diarrhea (1996). It may reasonable, however, to employ their use for specific patients. Probiotics do not seem to be effective for diarrhea of bacterial origin. Numerous probiotic organisms have been evaluated, with lactobacillus the most common. Because of many potential differences in probiotic organisms, they cannot all be considered equal. LGG may have the best efficacy for use in children with acute onset diarrhea. The most effective dose, however, has not been determined. Doses of at least 10 billion CFU, and as high as 40 billion CFU, have been suggested in some published studies.
For Your Information:
- Huang JS. Efficacy of probiotic use in acute diarrhea in children, a meta-analysis. Digestive Diseases and Sciences. 2002;47:2625-34
- Szajewska H. Probiotics in the treatment and prevention of acute infectious diarrhea in infants and children: a systematic review of published randomized, double-blind, placebo-controlled trials. J Pediatr Gastroenterology Nutrition. 2001;33:S17-25
- Van Niel CW. Lactobacillus therapy for acute infectious diarrhea in children: a meta-analysis. Pediatrics. 2002;109:678-84
- Guandalini S. Lactobacillus GG administered in oral rehydration solution to children with acute diarrhea: a multicenter European trial. J Pediatr Gasterenterology Nutrition. 2000;30:54-60
- Provisional Committee on Quality Improvement, Subcommittee on Acute Gastroenteritis, American Academy of Pediatrics. Pediatrics. 1996;97:424-33.
- Markowitz JE. Probiotics in health and disease in the pediatric patient. Pediatric Clinics of North America. 2002;49:127-41
- Vanderhoof JA. Use of probiotics in childhood gastrointestinal disorders. J Pediatr Gastroenterology Nutrition. 1998;27:323-32.