Interventions to reduce post-acute consequences of diarrheal disease in children: a systematic review

Background Although acute diarrhea often leads to acute dehydration and electrolyte imbalance, children with diarrhea also suffer long term morbidity, including recurrent or prolonged diarrhea, loss of weight, and linear growth faltering. They are also at increased risk of post-acute mortality. The objective of this systematic review was to identify interventions that address these longer term consequences of diarrhea. Methods We searched Medline for randomized controlled trials (RCTs) of interventions conducted in low- and middle-income countries, published between 1980 and 2016 that included children under 15 years of age with diarrhea and follow-up of at least 7 days. Effect measures were summarized by intervention. PRISMA guidelines were followed. Results Among 314 otherwise eligible RCTs, 65% were excluded because follow-up did not extend beyond 7 days. Forty-six trials were included, the majority of which (59%) were conducted in Southeast Asia (41% in Bangladesh alone). Most studies were small, 76% included less than 200 participants. Interventions included: therapeutic zinc alone (28.3%) or in combination with vitamin A (4.3%), high protein diets (19.6%), probiotics (10.9%), lactose free diets (10.9%), oral rehydration solution (ORS) formulations (8.7%), dietary supplements (6.5%), other dietary interventions (6.5%), and antimicrobials (4.3%). Prolonged or recurrent diarrhea was the most commonly reported outcome, and was assessed in ORS, probiotic, vitamin A, and zinc trials with no consistent benefit observed. Seven trials evaluated mortality, with follow-up times ranging from 8 days to 2 years. Only a single trial found a mortality benefit (therapeutic zinc). There were mixed results for dietary interventions affecting growth and diarrhea outcomes in the post-acute period. Conclusion Despite the significant post-acute mortality and morbidity associated with diarrheal episodes, there is sparse evidence evaluating the effects of interventions to decrease these sequelae. Adequately powered trials with extended follow-up are needed to identify effective interventions to prevent post-acute diarrhea outcomes. Electronic supplementary material The online version of this article (10.1186/s12889-018-5092-7) contains supplementary material, which is available to authorized users.


Background
Close to 600,000 children die each year from diarrheal disease, the majority in low-and middle-income countries (LMICs) [1]. Children with a single episode of moderateto-severe diarrhea (MSD) experience an 8.5-fold higher risk of dying in the 60-days following the episode compared to age-matched healthy children, despite standard diarrhea case management including rehydration and zinc [2]. A verbal autopsy study conducted in 7 LMICs found that 55.6% of pediatric diarrhea deaths occurred in children who had been rehydrated [3]. Although rehydration and zinc have resulted in millions of lives saved from diarrhea, they may be insufficient to prevent all diarrheaassociated mortality.
The consequences of diarrhea extend beyond acute dehydration and electrolyte imbalance. Over two-thirds of deaths associated with diarrhea occur more than 7 days after presentation [2]. An episode of MSD is also associated with subsequent loss of length/height-for-age z-score (LAZ/HAZ), a measure of chronic malnutrition [2,4]. Undernutrition is linked to half of all diarrheaassociated mortality and is associated with other longterm outcomes including reduced school attendance and future earning potential [2,5,6].
While mortality from diarrheal diseases has declined since the 1990's, incidence rates have remained stable and there is increasing recognition of the morbidity, disability, and long-term consequences associated with diarrhea. We conducted a systematic review to identify and summarize randomized controlled trials (RCTs) of diarrhea management interventions to determine effects on death, anthropometric status, and prevalence and incidence of diarrhea in the post-acute period.

Methods
The systematic review followed PRISMA guidelines. We searched Medline for English-language RCTs published between January 1, 1980 and October 31, 2016 conducted among children under 15 years of age presenting with diarrhea (all diarrhea definitions accepted) at the time of treatment. Specifically, we searched for trials evaluating 1 of the following interventions: antiemetics, antibiotics, antiprotozoals, antisecretories, dietary supplements, intravenous hydration therapy, oral rehydration therapy, probiotics, prebiotics, lactose replacement, and therapeutic zinc. These interventions were chosen based on consultation with experts in the field. The search terms used were as follows: ((((((((((((antibiotic OR antiinfective OR anti-infective OR antimicrobial OR antiparasitic OR anti-parasitic OR antiprotozoa* OR anti-protozoa* OR ciprofloxacin OR erythromycin OR metronidazole OR antiemetic* OR anti-emetic OR anti-vomit* OR antidiarrheal OR secretoinhibit* OR antipropulsive OR antisecret* OR antisecret OR breast* OR formula* OR milk OR wean* OR treatment OR management OR "amylose maize starch" OR hams OR lams OR prebiotics OR "resistant starch" OR bifidobacter* OR lactobacill* OR lactococc* OR microbi* OR probiotic* OR fluid OR intravenous OR IV OR ORS OR "oral rehydration salt" OR ORT OR "oral rehydration therapy" OR polymer OR rehydration OR minerals OR zinc)))) AND ("1980/01/01"[Date -Publication]: "2016/10/31"[Date -Publication])) AND ((("bloody stool" OR diarrh* OR dysentery OR gastroenterit*))))) AND ((((clinical trial) OR placebo-controlled trial) OR randomized controlled trial))))) NOT cancer) NOT antibiotic associated diarrhea) Filters: Clinical Trial; Humans; English; Child: birth-18 years We excluded studies in 2 steps. The first step aimed to exclude trials that did not address the populations or interventions of interest. Specifically, studies conducted in high-income countries (as defined by the World Bank as of June 2015) [7], those that did not include children with diarrhea at enrollment, utilized a design other than an RCT, or did not present individual-level outcome data were excluded in the first round. The second round excluded trials with insufficient follow up (less than 7 days) and those that lacked outcome data on mortality, length/height, LAZ/HAZ, weight, weight-for-age z-score (WAZ), weight-for-height z-score (WHZ), mid upper arm circumference (MUAC), or diarrhea presence at a pre-specified follow-up point ≥7 days after enrollment. Although weight may be misclassified during diarrhea illness due to fluid loss, in the context of an RCT, groups were assumed to be balanced with regard to hydration status. Therefore, weight, WAZ, and WHZ were considered valid outcomes. Diarrhea duration (other than presence of diarrhea at a pre-specified time point beyond 7-days) and stool output were not included as outcomes because they were considered intermediate to the outcomes of interest in this review.
All titles and abstracts were screened by 2 reviewers (PBP and HEA) and abstracts of agreed-upon titles were examined for inclusion. Full texts of agreedupon abstracts were reviewed for inclusion by RLB and HEA with final input from PBP. The following study-specific information was abstracted from included trials: intervention, control group, population, dates of enrollment, sample size, duration of follow up, reported outcomes, and data on effect sizes of relevant outcomes, and associated confidence intervals (CIs). Details on data abstraction and calculations are provided in the supplementary material for this manuscript (Additional file 1).
A modified Grading of Recommendations Assessment Development and Evaluation (GRADE) approach was developed to assess study design elements including sample size, number of participants lost to follow up or withdrawn from the study, and blinding and allocation concealment methods to evaluate the quality of studies. We did not assess the GRADE elements of directness or consistency, as these elements are specific to results reported within a given intervention and outcome category and this review assessed multiple interventions and outcomes. All trials started with 4 points because all were randomized controlled trials and 1 point was deducted for each of the following elements: sparse data (< 200 trial participants), > 5% loss-to-follow-up or withdraws, or lack of double-blinding. Reviewers (HA and RB) applied the modified GRADE system included in this review and categorized each study as high quality (4 points), moderate (3 points), low (2 points), or very low (1 point) based on their final score. In addition to the elements required for GRADE, from included trials we abstracted whether or not a primary endpoint was declared (and whether the primary endpoint was 1 of the endpoints included in this review) and any mention of power calculations for included outcomes.

Results
The Medline search returned 2815 titles, of which 693 abstracts and 432 full texts were reviewed, and 385 excluded based on full-text review (Fig. 1). Among the 314 studies that were eligible based on study location, design, and population (included based on first exclusion step), most (205 [65.2%]) were excluded for failure to meet our criteria for length of follow up (7 days or more) and 51 (16.2%) were excluded because no outcomes of interest were reported in the second exclusion phase.
Of the 46 clinical trials evaluated using the modified GRADE system, 6 (13.0%) scored high, 8

Mortality
Seven studies (15.2%) presented data on post-acute mortality, with follow-up ranging from 8-days to 2 years. Four were trials of therapeutic zinc interventions, [24,27,28,53], 2 antimicrobial treatments [8,42], and 1 of a high protein diet [44]. Two of the zinc trials were large studies (8070 and 1042 subjects, respectively) [27,53] but the remaining 5 included less than 150 participants (Fig. 2, Table 2). None of the 7 trials were adequately powered for a mortality endpoint. Only 1 trial, a cluster randomized trial of zinc, found a lower non-injury mortality rate in children living in communities randomized to ORS and zinc compared to those using ORS alone (relative risk [RR] = 0.49 [95% confidence interval {95% CI}: 0.25, 0.94]) [27]. The remaining 6 studies reported non-significant risk differences ranging in magnitude from 70 more to 105 less deaths per 1000 children [8,44] and relative risks ranging from 0.18 to 1.34 [24,44].

Growth
Studies reported impact on growth in several different ways: Height/Length, HAZ//LAZ Ten studies presented data related to length or height, with follow-up time ranging from 21 days to 9 months and none reported sample size calculations/being powered for these outcomes (Table 1). Five trials evaluated a high protein diet, 4 therapeutic zinc and 1 probiotic. Of 4 studies that reported difference in change in (Δ) HAZ/LAZ between intervention groups, 1 high protein diet trial reported a 0.9 z-score greater gain in HAZ/LAZ in the intervention group after 3 weeks of follow-up (95% CI: 0.05, 0.13), [11] but 2 high protein diet trials (with 3 and 29 weeks of follow-up) and a large zinc with 12 weeks of follow-up trial found no significant benefit (Fig. 3a) [10,13,32]. Four studies presented data on Δ absolute height at follow-up, 2 of which were trials of high protein diets with follow-up times of 3 and 29 weeks. Of the 2 high protein diet trials, the trial with 29 weeks of follow-up found a benefit in height change (Fig. 3b) a 1.10 cm greater change in height compared to the control groups (95% CI: 0.56, 1.64) [10,13]. Of the other 2 studies evaluating height attainment, a trial of a high protein diet with micronutrients with 36 weeks of follow-up, and another of therapeutic zinc with 8 weeks of follow-up, only the former showed benefit (a greater gain in height of 0.65 cm in the intervention group [95% CI: 0.11, 1.19]) [43,53]. Percent Δlength was evaluated in 2 therapeutic zinc studies, both of which found a significantly greater length gain among children treated with zinc, but this result was only among underweight children in 1 of the trials [25,28]. Among 2 studies evaluating prevalence of stunting during follow-up, 1 found that the group treated with probiotics (L. rhamnosus GG) had higher stunting prevalence at 4 weeks of follow-up [54] and a high protein diet trial reported no significant difference at 26 weeks [44].

MUAC
Four studies reported MUAC data during follow-up periods ranging from 15 to 28 days, 2 were high protein studies, 1 was a trial of therapeutic zinc, and 2 trials of RUTF/micronutrient (which assessed MUAC as 1 of the indicators of acute malnutrition). One of the high protein diet studies reported that children in the intervention group gained 0.44 cm more in MUAC on average compared to children given a standard protein diet (95% CI: 0.08, 0.80) [10]. However, neither the remaining high protein diet study nor the zinc trial reported a significant difference in MUAC during follow-up [9,50]. None of the studies provided sample size estimates making it Fig. 2 Effect of diarrhea management interventions on mortality (relative risk, risk difference, and associated 95% confidence interval)    Table 2 Intervention effects on post-acute (≥7 days after enrollment) mortality, length, weight, and/or diarrhea presence (Continued) Data presented were assumed to be mean ± SD iv Duration of diets was variable. Diets were started at low concentrations and were advanced every 48 hours if no sign of intolerance. If there were signs of intolerance, diets were maintained or decreased as necessary. When full concentrations were reached, the diet was given for an additional 7 days.

Reference
v Appropriate data for calculation of weight gain or difference in weight gain not presented vi Defined as when diarrhea had ceased and patient had consistent weight gain for at least 48 hours vii All outcome measurements were compared against measurements at entry, when the child had had diarrhea for 14 days viii Units were assumed to be cm/y due to description of results in the manuscript (rather than (cm/y)2 as presented in the study's Four) ix Defined as age-and sex-specific weight standard deviation scores, from the National Center for Health Statistics median value unclear whether they were adequately powered to detect differences in MUAC. Both trials of RUTF and micronutrient powder reported the incidence of acute malnutrition (WHZ < 2, MUAC < 115 mm, or oedema) to be similar across all combinations of groups (RUTF vs controls; micronutrients vs. controls, and RUTF vs. micronutrients) in the subgroup of children from both trials who had diarrhea at enrollment [45,46].

WHZ, WAZ, or absolute weight
Thirty-two trials (74.4%) with follow-up periods ranging from 7 days to 29 weeks, reported data on weight, WAZ, or WHZ. Of these, 9 assessed a high protein diet, 7 assessed therapeutic zinc (including 1 which also assessed vitamin A), and 5 tested lactose-free diets. Four were trials of ORS formulations, 3 of probiotics, and 1 each of semi-elemental diet, glutamine, and dietary fiber. Of the 4 trials evaluating differences in ΔWAZ between study groups, 3 high protein and 1 therapeutic zinc trials, 2 (both high protein) reported a statistically significant improvement (ranging from 0.23 [11] to 0.3 z-scores [10]) compared to a standard diet (Fig. 4a) although none were explicitly powered for this outcome. The same 2 diet trials also reported a significant benefit in WHZ, with high protein groups gaining 0.25 [31] to 0.4 units [11] more in WHZ than the standard diet group (Fig. 4b) whereas the 2 zinc trials assessing ΔWHZ, 1 of which was explicitly powered to address WHZ, found no difference [32,53]. Two additional trials assessed WHZ although did not present quantitative results for calculation of effect size and 95% confidence intervals; A probiotics trial concluded there was no difference in ΔWHZ at 6 weeks between the treated and untreated groups, [19] while a high protein diet trial reported a greater median ΔWAZ in children given high protein diets at 26 weeks of follow-up [44].
Twenty-two studies presented data on absolute weight gain (Fig. 4c) or weight at follow-up: 6 high protein diet trials, 6 zinc (1 of which also assessed vitamin A), 4 lactose free diets, 2 ORS, and 1 each of a probiotic, semielemental diet, dietary fiber, and glutamine. Three of the 6 high protein trials found a statistically significant improvement in weight associated with the intervention group, [10,43,44] as did 3 of the 6 zinc trials, [22,25,48] 1 of which also assessed vitamin A which did not appear to have a weight benefit [22]. Two of the 4 lactose-free diets [16,50] and 1 of 2 ORS trials demonstrated a significant benefit in weight [39]. This trial found a greater percent improvement in weight 14 days after presentation in the groups of children treated with ORS (90 mmol/l or 50 mmol/l of sodium) vs. no ORS but did not find a statistically significant difference when measured as absolute difference in weight. Weight gain was significantly improved in the trial of a semi-elemental diet [35] and the single trial of glutamine found intervention children to have 130 g more weight gain than the placebo group at follow-up day 30, but not at days 60 or 90 of follow-up a b Fig. 3 a Effect of diarrhea management interventions on change in HAZ/LAZ (difference in change in HAZ/LAZ and 95% confidence interval). b Effect of diarrhea management interventions on change in height (difference in change in height (cm) and 95% confidence interval) a b c d Fig. 4 (See legend on next page.) [51]. The single dietary fiber and probiotic trials evaluating weight gain did not find a significant effect [26,47].

Recurrent or prolonged diarrhea at follow-up
Twenty studies (45.7% of total) reported on diarrhea frequencies during follow-up periods ranging from 7 days to 3 months. The majority were trials of therapeutic zinc (13), including 2 that also assessed vitamin A, followed by probiotic trials (3), ORS formulation (3 comparisons in 2 trials) and 1 diet fiber and 1 lactose-free diet. Only 4 of the trials explicitly described being powered to address diarrhea prevalence or incidence during follow-up [22,27,31,53]. Figure 5 shows the 12 trials (providing 15 estimates due to 3 trials including 3 arms) that reported data on prevalence of diarrhea 7 days or more after presentation (8 zinc [2 of which also assessed vitamin A], 2 ORS (1 of which compared 3 formulations), and 2 probiotic). Only 2 zinc studies [22,31] and 1 probiotic (Saccharomyces boulardii) trial found a reduction in diarrhea prevalence associated with the intervention [41]. The other 6 zinc trials [23,24,[32][33][34]53] and probiotic trial of Lactobacillus rhamnosus GG [54] did not find a significant effect on diarrhea prevalence during follow-up. The lactose-free diet reported no effect on the presence of diarrhea at day 12 (p = 0.76) but did not report specific prevalences [17]. The 2 trials assessing ORS formulations (providing 3 estimates) did not demonstrate a benefit [34,55] nor did the 2 vitamin A trials [22,34].
Of studies reporting on diarrhea frequency indicators other than prevalence of diarrhea at follow-up, findings were heterogeneous. One study found that children given a rice-based diet with green banana or pectin (dietary fiber) were more likely to have recovered from diarrhea by day 5 of follow-up, while most children given the rice-based diet alone continued to have diarrhea until day 10 of follow-up [15]. Another found no children treated with Lactobacillus reuteri 17938 to have diarrhea beyond 7-days whereas 17.4% of children without probiotic treatment did have prolonged diarrhea [52]. A trial of 8070 community-based children found that those given zinc with ORS had 2.9 fewer episodes of diarrhea per 100 child-years (95%CI: 0.8, 5.1) than those given ORS alone [27]. A study contrasting 10 day therapeutic zinc (20 mg/day) with 3 months of supplemental zinc (10 mg/day) to the therapeutic zinc course alone found that the long term zinc reduced diarrhea incidence over a 9 month period by 21% (2.05 vs.2.59 episodes / child years) [30]. Compared to children given the multivitamin alone, children given a multivitamin with zinc had an average of 0.33 fewer subsequent diarrhea episodes (95% (See figure on previous page.) Fig. 4 a Effect of diarrhea management interventions on change in WAZ (difference in change in WAZ and 95% confidence interval). b Effect of diarrhea management interventions on change in WHZ/WLZ (difference in change in WHZ/WLZ and 95% confidence interval). c Effect of diarrhea management interventions on weight gain (difference in weight gain [g] and 95% confidence interval). d Effect of diarrhea management interventions on weight at follow up (difference in weight [kg] and 95% confidence interval) CI: -0.39, − 0.27) and diarrhea incidence was similarly reduced in the 6 month follow-up period [28,29]. Conversely, a placebo-controlled trial of therapeutic zinc among 1042 children reported no difference in the mean number of subsequent diarrhea episodes during a 3 month follow-up period nor did 2 smaller zinc trials [29,32,48].

Discussion
While significant progress has been made over the past 25 years in reducing deaths attributed to diarrhea, there is increasing recognition that diarrhea is associated with mortality, subsequent morbidities, and malnutrition in the period after a diarrheal episode [56,57]. These postacute sequelae highlight the need, and opportunity, to identify interventions to reduce morbidity and mortality among children presenting with diarrhea. This systematic review appraised diarrhea intervention trials for evidence of effects on post-acute sequelae of diarrhea, including mortality, nutritional status, and diarrhea presence during an extended follow-up period.
We found very few trials that evaluated post-acute diarrheal mortality, and only 1 (of zinc) was explicitly powered to address mortality and found mortality benefit [27]. The other zinc trials did not report a mortality benefit. As summarized in a recent Cochrane review, zinc appears to reduce diarrhea duration, particularly in malnourished children, although the degree to which this effect translates to mortality benefit remains unknown [58]. Therapeutic zinc also appears to have limited to no efficacy on morbidity or growth in children under 6 months of age [53,59].
Post-acute mortality was assessed in 2 trials of antibiotics that found no mortality benefit, yet were underpowered to do so. Both trials included less than 100 children and only 1 was placebo-controlled. The role of antibiotics in diarrhea management remains controversial. In the absence of diagnostics, diarrhea management guidelines recommend antibiotics only for dysentery or suspected cholera [60,61]. Limiting antibiotics to these 2 indications may miss other serious enteric infections amenable to antibiotics [62,63]. In practice however, many children without these indications are treated with an antibiotic, the benefits of which are not well understood [64]. Large placebo-controlled clinical trials are needed to determine the potential harm and/or benefit of antibiotics to reduce post-acute diarrhea morbidity and mortality.
Over 30 trials reported on growth outcomes. Dietary supplementation with macro-or micro-nutrients, high protein and lactose-free diets, and probiotics were assessed for effects on growth with mixed results. We found substantial variability in how growth outcomes were evaluated, making comparisons between studies challenging. Two of the 5 trials of dietary interventions found beneficial impacts on WAZ/WHZ with a high protein isocaloric diet. In a single study, glutamine demonstrated a signal of benefit at 1 time point which was not sustained. Most trials that assessed weight reported no intervention effect; perhaps because weight gain restored through hydration during the acute phase of diarrhea overshadowed weight gain from trialed interventions. High protein diets, either alone or in combination with micronutrients such as zinc, had a modest impact on short to medium term linear growth (3 weeks to 9 months). However, this effect was inconsistently demonstrated. High protein diets may restore the protein loss that can occur during and immediately after infection [65,66]. Replacing protein may modify growth consequences of diarrhea by increasing protein availability or by influencing hormonal regulation [67][68][69]. The combination of high protein and zinc may restore integrity of damaged mucosal surfaces and improve nutrient absorption [70][71][72]. However evidence around the effect of zinc on markers of intestinal permeability, as measured by the lactulose to mannitol ratio, are inconsistent [49,73,74]. Specific amino acids may also be important; glutamine has been shown to protect against bacterial translocation through maintenance of the gut barrier in animal models [75][76][77].
Diarrhea during follow-up was the most commonly reported outcome assessed in this review. Numerous systematic reviews of therapeutic zinc on diarrheal outcomes have been conducted, all of which suggest some benefit [58,[78][79][80]. The effects of zinc on diarrhea at a specified day of follow-up were recently summarized in a Cochrane review and pooled relative risks of diarrhea at day 3, day 5, and day 7 associated with zinc all showed a statistically significant benefit [58]. Our review included diarrhea assessed at 7 days and beyond (7 days to 4 months) and found inconsistent results, perhaps demonstrating a waning in effect or sub-optimal statistical power at longer follow-up time points. Given therapeutic zinc is recommended for 14 days in current WHO management guidelines yet the data on benefit seems most pronounced within the first 7 days, days 7-14 of the currently recommended zinc course may need further evaluation.
Three of the 4 probiotic trials evaluating diarrhea outcomes demonstrated a benefit on diarrhea during followup (Saccharomyces boulardii, Lactobacillus reuteri 17938 and 1 of the 2 Lactobacillus rhamnosus GG trials). However the Lactobacillus rhamnosus GG trial that did not find a benefit in diarrhea during follow-up did report improvements in intestinal function (as measured by the lactulose to mannitol test) and higher immunoglobulin G (IgG) in the subgroup of children with rotavirus infection treated with the probiotic [54]. Most clinical trials of probiotics have been conducted in high-resource settings and have treated and followed children for less than 7 days [81,82]. Although not included in this review because it was published after the search was conducted, a recent pilot study (n=76) conducted in Botswana found a greater increase in HAZ and reduced diarrhea recurrence over 60days of follow-up among admitted children with diarrhea randomized to Lactobacillus reuteri 17938, [62]. The European Society for Pediatric Gastroenterology recently recommended probiotics, specifically Saccharomyces boulardii or Lactobacillus rhamnosus GG, to reduce the duration and intensity of gastroenteritis [83]. The mechanisms by which probiotics may decrease diarrheal symptoms are largely unknown, but may act by out-competing pathogenic enteric infections for nutrients, restoring gut barrier functions, and/or by restoring gut microbial balance.
This review had several limitations. Most trials, particularly trials used to evaluate mortality, were underpowered. A 2-armed clinical trial powered to detect a 50% reduction in a 3-month diarrheal case fatality rate of 2% would require over 4000 participants, a sample size far larger than most trials reporting mortality outcomes in this review and far smaller than sample sizes required to detect smaller intervention effects or lower case fatality rates. Many trials were excluded because of short length of follow-up and included trials had follow-up times ranging from 7-days to 9 months which could explain heterogeneity between studies, particularly studies of growth outcomes. Some interventions were more represented than others based on available clinical trial data. Markers of enteric function were not included in this review as prespecified outcomes, despite a growing body of evidence suggesting that enteric dysfunction is linked to poor outcomes following acute illness [84]. Because of the heterogeneity in interventions, outcome measurements, and follow-up time, we did not calculate pooled measures of effect. For the same reason, we did not report a GRADE score for every individual result but rather for overall study quality, and most trials were graded as low or very low. Standardized measures of the nutritional consequences of diarrhea and diarrhea morbidity will be important to enable future meta-analyses. This review includes data from a wide range of geographic, demographic and epidemiologic settings. However, most included trials were conducted in Asia, with less than 15% of all included trials conducted in sub-Saharan Africa (SSA). Diarrhea-mortality rates are higher in SSA than in South Asia and recent projections of childhood mortality into 2030 predict that SSA will contribute to 60% of all childhood deaths [5,57]. Host characteristics, such as nutritional status and HIV-infection/−exposure vary greatly between these regions making generalizability of intervention effect challenging [85][86][87].

Conclusions
In many resource-limited settings, diarrheal episodes in young children are frequent and are associated with increased risk of mortality as well as growth failure and risk of subsequent infections. The mechanisms by which diarrhea and underlying enteric infections lead to morbidity, malnutrition, and mortality are multifactorial, likely requiring multiple complementary interventions to reduce likelihood of recurrence or persistence, promote healing of the gut mucosa, and to replenish lost protein and nutrients. Well-designed, multi-factorial, clinical trials evaluating the extended impact of diarrhea management interventions are urgently needed to reduce the long-term risks associated with diarrhea.