We conducted a systematic review of RCTs to estimate the effect of probiotic microorganisms for the treatment of community-acquired acute diarrhea in children. Results of this systematic review indicate that probiotics reduced stool frequency on the second day of treatment by 13.1%. When we combined all the study arms we found a 14.0% reduction in diarrhea duration among those who received probiotics compared to those who received placebo. Of the 10 study arms included in the analysis, only 1 LGG arm [13] and 3 probiotic mixtures [12, 13, 15] found a significant reduction in diarrhea duration with effect sizes of 32%, 28.5%, 39.4% and 13.9% respectively (Table 4).
Probiotics did not have an effect on the relative risk of hospitalization between children in the treatment and control groups. None of the included studies reported diarrhea deaths, thus we were limited to outcomes that reflected diarrhea morbidity. Based on the available data, relative risk of hospitalization was the best measure of severe morbidity, but this outcome had a limited number of events across the two included studies [13, 17] (Table 3). None of the individual study arms reported a significant difference in hospital admissions between treatment and control groups, but studies were not powered for this outcome measure.
Despite a number of systematic reviews on the efficacy of probiotic treatment in infectious diarrhea, this is the first to apply the CHERG guidelines to estimate the effect of probiotic treatment on community-acquired acute diarrhea among children for inclusion in the LiST software. This review follows the CHERG systematic review methods required of all LiST interventions to estimate the effect of the intervention on cause-specific mortality [9]. The LiST tool is designed to provide international agencies and policymakers with evidence-based estimations of lives that could be saved with the scale-up of key interventions [20]. Thus, the implications of this review are important for programmatic and policy decisions in the management of childhood diarrheal disease in low- and middle-income countries (LMIC).
Our review indicates a reduction in diarrhea duration and stool frequency, which may be indicative of attenuated intensity of the intestinal infection [21]. These results are consistent with findings in previous systematic reviews [3, 8]. Previous studies have shown that benefits of probiotics on diarrhea may be strain and/or etiology specific [6, 13, 22], meaning only certain strains may be efficacious in the treatment of a particular etiology of diarrhea. Prior systematic reviews have found larger effect sizes for probiotic treatment on diarrhea duration than what we report here [3, 6], but they included studies among specialized populations such as young children with confirmed rotavirus diarrhea or populations of infants who were completely weaned. Given that the etiologies of most childhood diarrhea episodes in developing countries are not confirmed, we designed this review to include only studies that did not exclude based on etiology. To be programmatically relevant at the community/household level the intervention must demonstrate efficacy for episodes of non-specific origin.
As a secondary aim of this review, we evaluated the efficacy of individual probiotic strains for acute diarrhea treatment. We evaluated strain-specific differences in therapeutic properties for probiotics with 3 or more study arms. Based on the limited number of included studies and wide variation in probiotic organisms, we were only able to examine the specific pooled effect of LGG on diarrhea duration. These results were not found to be significant. Also, we were not able to separate the various mixtures of probiotics to evaluate the efficacy by individual strain or dose.
There are limitations associated with the studies we included and analysis as it pertains to the CHERG guidelines. Ideally, we would have included only community-based studies conducted in LMIC. Because we only found 5 studies from LMIC and of these 3 reported diarrhea duration [12, 14, 16], 2 reported stool frequency on day 2 [18, 19], and none reported diarrhea hospitalizations, we chose to include studies from high-income countries [13, 15, 17]. No studies were conducted in the community, all were in outpatient or hospital settings, and thus results may not be generalizable to home-based treatment of diarrhea episodes. All included RCTs had a control group that received a blinded placebo and/or standard of care, but the placebo substances were not standardized across studies. We controlled for potential confounding effects of varying placebos by excluding studies that used placebos with potential therapeutic properties in treating diarrhea (e.g., prebiotics or calcium supplements).
In addition, WHO has recommended low osmolarity ORS, continued feeding, and zinc for the treatment of diarrhea since 2004 [2]. None of the included studies provided zinc as part of the recommended treatment. To best estimate the effect probiotics could have on current home management of diarrhea, additional RCTs should be conducted to compare the currently recommended treatment, ORS, continued feeding, and zinc supplementation, with and without the addition of probiotics.
Interventions included in the LiST software are those that have been shown to reduce cause-specific mortality, or provide strong evidence of a reduction of severe morbidity among children less than five years of age [9]. We used the adapted GRADE technique [9] to assess the quality of evidence associated with the included studies by outcome. Despite being RCTs the combined quality score of included studies was low/moderate, primarily due to small sample size, inadequate blinding, and reduced generalizability (Tables 2 &3). Based on the lack of mortality data, no effect on severe morbidity (i.e., hospitalizations), and the low-moderate quality evidence for mild outcomes (i.e., diarrhea duration and stool frequency), there is insufficient evidence to conclude probiotics for the treatment of diarrhea will reduce diarrhea mortality, and thus at this time this intervention should not be included in LiST (Figure 3).