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Table 1 Characteristics of included studies

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

Reference [Ref #] Country Population Intervention Comparator Number with follow up data Pre-specified follow up time Relevant outcomes measured and poweri Modified GRADE score
Antimicrobial Intervention
 Gilman 1980 [8] Bangladesh Inpatient adults and children with blood, pus cells, and mucus in stool, 4 or more stools/day, and culture-confirmed Shigella infection Low-dose ampicillin (50 mg/kg/day) High-dose ampicillin (150 mg/kg/day) 56 children 21 days Mortality (power/sample size calculations not reported) Very lowΩ,ΦΨ
 Amadi 2002 [42] Zambia Inpatient children 12–85 mo with diarrhea (at least 3 stools per day that take the shape of a container or can be poured) and Cryptosporidium oocysts 5 mL of 20 g/L nitazoxanide oral suspension, twice daily for 3 days Placebo 96 8 days Mortality (powered for outcome of clinical response) ModerateΩ
Dietary Supplements
 Alam 2000 [26] Bangladesh Inpatient males 4–18 mo with acute non-dysenteric diarrhea WHO ORS with dietary fiber(20 g/L Benefiber®) Standard WHO-ORS 150 7 days Weight gain at day 7 from enrollment (powered for the outcome of stool output) ModerateΩ
 Rabbani 2001 [15] Bangladesh Severely malnourished (<  60% NCHS standard), inpatient male infants 5–12 mo with persistent diarrhea (> 3 loose stools/day for 14 days), treated with ciprofloxacin Rice-based diet with dietary fiber (250 m/L cooked, green banana, 7 days; or rice-based diet with 1 g/kg to 8 g/kg of pectin supplement) 7 days Calorically equivalent control diet: rice-based diet only, 7 days 62 At least 7 days, or until end of diarrhea Proportions recovered from diarrhea [formed stool] at days 7, 8, 9, and 10 (powered for outcome of diarrhea recovery duration) ModerateΩ
 Yalcin 2004 [51] Turkey Inpatient children 6–24 mo with acute diarrhea Glutamine supplement - 0.3 g/kg/day, for 7 days Placebo 143 3 months Weight gain at day 30, 60, and 90 from enrollment (powered for the outcome of diarrhea duration) LowΩ, ϑ
High Protein Diets
 Datta 1990 [9] India Inpatient children under 5 y/o with acute dysentery (visible blood and mucus in stools), treated with nalidixic acid Extra servings of milk (30% of total daily caloric requirements), in addition to standard hospital diet Standard hospital diet 96 15 days Weight and MUAC at day 15 (power/sample size calculations not reported) Very lowΩ, Φ, ϑΨ
 Kabir 1992 [10] Bangladesh Inpatient children 2–4 y/o with culture-confirmed Shigella dysentery, treated with nalidixic acid or other microbial High protein diet (15% of total energy from protein), 21 days Standard diet (7.5% of total energy from protein), 21 days 22 21 days Change in weight, height, WAZ, WHZ, HAZ, MUAC, and triceps skinfold thickness at day 21 from admission (power/sample size calculations not reported) Very lowΩ, Φ, ϑΨ
 Kabir 1993 [11] Bangladesh Outpatient children 2–5 y/o with acute diarrhea and culture-confirmed Shigella spp., treated with nalidixic acid or pivmecillinam High protein diet (15% of total energy from protein), 21 days Standard diet (7.5% of total energy from protein), 21 days 69 21 days Change in WHZ, WAZ, and HAZ at day 21 from admission (power/sample size calculations not reported) Very lowΩ, Φ, ϑΨ
 Mazumder 1997 [12] Bangladesh Malnourished (< 80% NCHS median), inpatient children 12–48 mo with bloody or bloody mucoid diarrhea and culture-confirmed Shigella, treated with nalidixic acid High calorie and high protein diet, 4960 kJ/l for 10 days Standard hospital diet, 2480 kJ/l for 10 days 75 40 days Percent change in WAZ and WHZ at 10, and 40 from admission (power/sample size calculations not reported) LowΩ, Φ, Ψ
 Nurko 1997 [36] Mexico Inpatient children 3–36 mo with persistent diarrhea (3 or more loose stools/day for 14 days or longer) and third-degree malnutrition (< 60% NCHS median), treated with TMP-SMX or metronidazole High protein diet (2 groups: chicken-based diet, or soy-based diet)ii Standard cultural dietary treatment for diarrhea (elemental diet or “Vivonex”) 41 16 days minimum Weight at end of intervention and at discharge; proportion with nutritional recoveryiii at end of intervention (powered for outcome of diarrhea duration) Very low Ω, ϑ, Ψ
 Kabir 1998 [13] Bangladesh Inpatient children 2–60 mo with acute bloody mucoid diarrhea, treated with nalidixic acid or pivmecillinam High protein diet (15% of total energy from protein), 21 days Standard protein diet (7.5% of total energy from protein), 21 days 59 6 months post- intervention Change in weight, height, WHZ, WAZ, and HAZ at 6 months compared to post-intervention measurements (power/sample size calculations not reported) Very low Ω, Φ, ϑ, Ψ
 Mazumder 2000 [14] Bangladesh Malnourished (<  80% of NCHS median) inpatient children 12–48 mo with acute bloody or mucoid diarrhea, treated with nalidixic acid of pivmecillinim High calorie & protein milk-cereal formula (4960 kJ/l), 10 days Control milk-cereal formula (2480 kJ/l), 10 days 75 10 days Percent change in WAZ at day 10, compared to admission WAZ (power/sample size calculations not reported) Very lowΩ, ϑ, Ψ
 Valentiner-Branth 2001 [43] Guinnea-Bissau Community-based children under 3 y/o with persistent diarrhea per mother’s report Counseling on the importance of breastfeeding and of a nutritious diet, and a high protein millet gruel with a multivitamin tablet (including zinc), until the end of a 7 day period without diarrhea Counseling on the importance of breastfeeding and of a nutritious diet 101 9 months Difference in knee-heel length, height and weight at end of intervention and day 90, compared to admission measurements (powered for outcome of diarrhea duration) Very lowΩ, Φ, Ψ
 Rollins 2007 [44] South Africa Inpatient HIV+ children 6–36 mo with persistent diarrhea (4 or more loose or watery stools/day, for 5 days or more) Enhanced nutritional support: standard nutritional support + extra protein to provide 150 kcal/kg/day and 4.0–5.5 g protein/kg/day (as milk or powdered protein, depending on age), until diarrhea resolved Standard nutritional support: maize porridge + milk formula, until diarrhea resolved 104 26 weeks Mortality, median change in weight-SDs ivand WAZ at 26 weeks; proportions underweight (WAZ < − 2 SDs) and stunted (LAZ < −  2 SDs) at 26 weeks (powered for outcome of weight change) Very lowΩ, Φ, ϑ, Ψ
Lactose Free Diet
 Bhan 1988 [16] India Outpatient children 3–24 mo Legume and cereal-based formula (lactose-free), until recovery or a minimum of 7 days Calorically equivalent milk-based formula, until recovery or a minimum or 7 days 57 At least 7 days, or until end of diarrhea Weight gain at day 7 and at recovery compared to admission weight (power/sample size calculations not reported) Very lowΩ, Φ, ϑ, Ψ
 Bhutta 1991 [50] Pakistan Outpatient males 6 mo - 3 yo with persistant diarrhea (increased frequeny and reduced consistency lasting 2 weeks or more) Soy milk (lactose-free) for 7 days, followed by khitchri and yogurt for 7 days Khitchri and yogurt for 14 days 73 14 days Weight gain at day 7 and 14 compared to admission weight (power/sample size calculations not reported) Very lowΩ, Φ, ϑ, Ψ
 Lozano 1994 [38] Colombia Inpatient children 1–24 mo with diarrhea (4 or more watery stools in a 24 h period) and dehydration Lactose-free feeding formula, 21 days Feeding formula with lactose, 21 days 52 6 weeks post-discharge Weight increment at 6 weeks (powered for outcomes of diarrhea duration) Very lowΩ, Φ, ϑ, Ψ
 Bhatnagar 1996 [17] India Inpatient \children 3–24 mo, with persistent diarrhea (3 or more liquid stools/day for 14 days) Puffed rice cereal, sugar, oil, and milk protein, 120 h Puffed rice cereal, sugar, oil, and egg white protein (lactose-free), 120 h 116 4–6 weeks after discharge Proportion of patients whose weight on day 7 was lower than at rehydration; probability of continuing diarrhea at each day to day 12 (power/sample size calculations not reported) Very lowΩ, Φ, Ψ
 de Mattos 2009 [37] Brazil Inpatient male infants 1–30 mo with persistent diarrhea (3 or more liquid stools per day for 14 days) Amino-acid based diet or soy-based diet, or hydrolyzed protein-based dietv Yogurt-based diet 154 7 days post-discharge Difference in weight gain and change in WHZ at discharge compared to admission measurements (powered for outcomes of stool output and diarrhea duration) Very lowΩ, Φ, ϑ, Ψ
Other Dietary Interventions
 Eichenberger 1984 [35] Brazil Inpatient infants 1–11 mo with acute to subacute gastroenteritis with diarrhea Semi-elemental diet with low osmolarity and high content of hydrolyzed lactalbumin Standard hospital diet 38 21 days Weight at day 21 compared to weight at beginning of therapy (power/sample size calculations not reported) Very low Ω, Φ, ϑ, Ψ
 van der Kam 2016 [45] Uganda Non-malnourished, outpatient children 6–59 mo with diarrhea (3 or more loose stools [bloody or nonbloody] per 24 h by mothers’ report), malaria, or lower respiratory tract infections Ready-to-use Therapeutic Foods (RUTF), plus instructions to feed the child an extra meal/day for 14 d; or micronutrient powder plus instructions to feed the child an extra meal/day for 14 d An instruction to feed the child an extra meal/day for 14 d 941 with diarrhea only 6 months Incidence of WHZ < − 2, MUAC < 115 mm, or nutritional oedema during follow up (powered for combined outcome of negative nutritional outcome)vi Low ϑ, Ψ
 van der Kam 2016 [46] Nigeria Non-malnourished or moderately malnourished outpatient children 6–59 mo with diarrhea (3 or more loose stools [bloody or nonbloody] per 24 h by mothers’ report), malaria, or lower respiratory tract infections Ready-to-use Therapeutic Foods (RUTF), plus instructions to feed the child an extra meal/day for 14 d; or micronutrient powder plus instructions to feed the child an extra meal/day for 14 d An instruction to feed the child an extra meal/day for 14 d 1171 with diarrhea only 6 months For non-malnourished children at enrollment: Incidence of WHZ < − 2, MUAC < 115 mm, or nutritional oedema during follow up. For malnourished children at enrollment: Incidence of WHZ < − 3, MUAC < 115 mm, nutritional oedema. Or > 10% weight loss during follow up. Powered for combined outcome of negative nutritional outcomevii Low ϑ, Ψ
Oral Rehydration Solution Formulations
 Santosham 1983 [39] Panama Inpatient 3 mo - 2 y/o who were well nourished, with acute diarrhea (more than 3 watery stools per day) High potassium and chloride ORS, or standard WHO-ORS Standard diet for diarrhea management (aerated beverages, bananas, cereals, and apple sauce) 93 14 days Weight at day 14, weight gain at day 14 as percent of enrollment weight (power/sample size calculations not reported) Very lowΩ, Φ, Ψ
 Ribeiro 1991 [40] Brazil Inpatient male infants less than 12 mo, with acute diarrhea and dehydration Standard WHO-ORS with 30 mmol/L alanine Standard WHO-ORS 18 7 days Weight gain at day 7 (power/sample size calculations not reported) ModerateΩ
 Faruque 1997 [21] Bangladesh Inpatient children 3–35 mo with acute non-dysenteric diarrhea Glucose based ORS Rice-powder based ORS 471 16 days Proportion with diarrhea at day 14, weight gain at day 16 (powered for outcomes of stool output, diarrhea duration and weight gain [70 g]) Low Φ, Ψ
 Alam 2009 [55] Bangladesh Severely malnourished (<  70% NCHS standard), inpatient infants 6–60 mo with acute diarrhea and culture-confirmed V. cholerae Glucose-based ORS, or Glucose-based ORS plus amylase resistant starch Rice-based ORS 137 6 weeks Time to attain 80% of median WLZ from enrollment; proportion with diarrhea at or after day 7 (power/sample size calculations not reported) LowΩ, Ψ
Probiotics
 Boudraa 2001 [47] Algeria Inpatient children 3–24 mo with acute watery diarrhea (>  3 loose stools in the previous 24 h) Standard formula fermented with L. bulgaricus and S. thermophilus (lactose and calorically equivalent) Standard milk-based formula 97 7 days Weight gain at day 7 (power/sample size calculations not reported) Very lowΩ, Φ, ϑ, Ψ
 Villaruel 2007 [41] Argentina Outpatient children 3 mo - 2 yo, with acute diarrhea (3 or more liquid or loose stools in the preceding 24 h) WHO-ORS and S. boulardii, 250 mg per day (patients < 1 yo) or 500 mg per day (patients 1 yo and older) WHO-ORS and placebo 72 1 month Proportion of patients with diarrhea at or after day 7 (power/sample size calculations not reported) LowΩ, ϑ
 Misra 2009 [19] India Inpatient infants < 36 mo with diarrhea (more than 3 stools per day that take the shape of their container) Lactobacillus rhamnosus GG (10^9 live bacteria) Placebo 207 6 weeks Change in WHZ at 6 weeks(powered for outcomes of stool output and diarrhea duration) High
 Sindhu 2014 [20] India Children 6 m to 5 years with diarrhea testing positive for either rotavirus or Cryptosporidium infection Lactobacillus rhamnuosus GG (10^10 organisms) Placebo 123 4 weeks Proportions stunted (HAZ < − 2 SD), underweight (WAZ < −  2 SD), and wasted (WHZ < −  2 SD) at 4 weeks, proportion with diarrhea or severe diarrhea during follow-up (powered for outcome of L:M ratio) ModerateΩ
 Dinleyici 2014 [52] Turkey Inpatient children 3–60 mo with acute watery diarrhea WHO-ORS + lactobacillus reuteri 17,938 (10^8 CFU) for 5 days WHO-ORS only 127 12 days Proportion with diarrhea at day 12 (powered for outcome of diarrhea duration) Very lowΩ, Φ,Ψ
Therapeutic Micronutrients (Vitamin A and Zinc)viii
 Faruque 1999 [34] Bangladesh Inpatient children 6 mo - 2 yo with acute diarrhea (3 or more liquid stools in the previous 24 h) 4500 μg vitamin A, 15 day, 14.2 mg Zinc acetate, 15 days, or bothix Placebo 656 17 days Proportion with diarrhea at day 7 and 16 (powered for outcome of diarrhea duration) High
 Khatun 2001 [22] Bangladesh Inpatient children 6 mo - 4 yo with persistent diarrhea (diarrhea for > 14 days duration) Multivitamin (D, C, B1 B2 B6) syrup and 20 mg elemental zinc (as zinc acetate, 5 ml twice daily for 7 days), multivitamin syrup with Vit A (100,000 IU for children < 1 yo, 200,000 for children > 1 yo), or both Multivitamin (D, C, B1 B2 B6) syrup only 93 7 days Weight at day 7, weight gain at day 7 compared to day 1, proportions with diarrhea at day 7 (powered for outcome of clinical recovery) ModerateΩ
Therapeutic Micronutrients (Zinc Alone)
 Sazawal 1995 [23] India Inpatient children 6–35 mo, with acute diarrhea (at least 4 unformed stools in the preceding 24 h) Multivitamin syrup (A, B2, B6, D3, E) plus zinc gluconate (20 mg of elemental zinc) Multivitamin syrup (A, B2, B6, D3, E) only 937 At least 120 days Proportion of diarrhea episodes that last longer than 7 days, proportion of diarrhea episodes taken to a physician during follow up (power/sample size calculations not reported) High
 Roy 1998 [24] Bangladesh Inpatient 3–24 mo with persistent diarrhea Multivitamin syrup (Vit A, B1, B2, B3, B6, D, Ca) with 20 mg elemental zinc per day for 14 days Multivitamin syrup (Vit A, B1, B2, B3, B6, D, Ca) only for 14 days 141 15 days Mortality, weight gain at discharge compared to admission weight, proportion with diarrhea after day 15 (powered for outcome of diarrhea duration) Very lowΩ, Φ, ϑ
 Bhutta 1999 [49] Pakistan Inpatient children 6–36 mo with persistent diarrhea Multivitamin syrup (Vit A, B1, B2, B3, B6, B12, C, D, Ca) with 3 mg elemental zinc per kg per day for 28 days Multivitamin syrup (Vit A, B1, B2, B3, B6, B12, C, D, Ca) only for 28 days 77 28 days Weight gain at day 7 and 14; overall weightincrement at day 14; MUAC at day 7 and 14; overall MUAC increment (powered for outcome of day 14 weight gain) LowΩ, ϑ
 Roy 1999 [25] Bangladesh Malnourished (< 76% of NCHS median), inpatient children 3–24 months with acute diarrhea Multivitamin syrup (vit A, B1, B2, B6, D, and Ca) with 20 mg elemental zinc per day for 14 days Multivitamin syrup (vit A, B1, B2, B6, D, and Ca) only for 14 days 29 10 weeks Weight gain at each week of for 8 weeks, length gain at each week for 8 weeks (power/sample size calculations not reported) LowΩ, ϑ
 Baqui 2002 [27] Bangladesh Community-based children 3–59 mo with diarrhea of any duration ORS with 20 mg zinc per day, 14 days ORS only 8070 2 yearsx Incidence of diarrhea, mortality (powered for the outcomes of diarrhea duration, diarrhea incidence, acute lower respiratory infections incidence, admission to hospital for diarrhoea or acute lower respiratory infections, and child mortality) Low Φ, Ψ
 Walker 2007 [53] Ethiopia, Pakistan, and India Infants 1–5 mo with acute diarrhea, identified through home visits by health workers and community based study clinics ORS with 10 mg zinc sulfate, daily for 14 days ORS with placebo 1042 8 weeks Weight at week 4 and 8, length at week 4 and 8, proportion of infants with ≥1 episode of any diarrhea, ≥ 2 episode of any diarrhea, or ≥1 episode of dysentery (any day with blood in the stool); incidence and prevalence of diarrhea; mortality (powered for anthropometry and morbidity outcomes) High
 Roy 2007 [28] Bangladesh Convalescent children 3–24 mo, after recovery from persistent diarrhea Multivitamin syrup (Unspecified) with 20 mg elemental zinc, 14 days Multivitamin syrup (unspecified) only, 14 days 147 12 weeks Mortality, gain in length and weight at 12 weeks, incidence of subsequent diarrhea episodes (power/sample size calculations not reported) LowΩ, Φ, ϑ
 Roy 2008 [29] Bangladesh Moderately malnourished (weight/age 61–75% of NCHS median), inpatient children age 12–59 m with acute bloody-mucoid diarrhea or febrile diarrhea, and lab-confirmed Shigella spp Multivitamin syrup (A, D, B complex, Ca) with zinc acete (10 mg elemental Zn/5 mL), for 14 days Multivitamin syrup (Vit A, D, B complex, Ca) only 30xi 6 months Diarrhea incidence and duration of episodes during 6 mo follow up (power/sample size calculations not reported) LowΩ, ϑ
 Fajolu 2008 [48] Nigeria Outpatient children 6–24 mo with acute diarrhea (3 or more loose, liquid or watery stools in a 24 h period) 20 mg of elemental zinc (zinc sulphate monohydrate) for patients > 1 y/o, 10 mg of elemental zinc, 14 days, for patients < 1 y/o Placebo 60 3 months Weight gain at 3 months, number and duration of subsequent diarrhea episodes during follow up (power/sample size calculations not reported) ModerateΩ
 Larson 2010 [30] Bangladesh Community-based children 6–23 mo with acute diarrhea and culture-confirmed ETEC 10 days of zinc (10 mg/d) + additional 3 months of zinc supplementation (10 mg/d) 10 days of zinc (10 mg/d) only 333 9 months Incidence rate of diarrhea illness during follow up (powered for the incidence of acute upper respiratory tract infections) Moderateϑ
 Alam 2011 [31] Bangladesh Community-based children 4–59 mo with diarrhea (3 or more loose or liquid stools in the previous 24 h) Short course zinc - 20 mg elemental zinc, 5 days Standard course zinc - 20 mg elemental zinc, 10 days 1622 90 days Number of diarrheal episodes and days of diarrhea during follow up; proportion with at least 1 subsequent episode of diarrhea, prolonged diarrhea, or persistent diarrhea during follow up; day of onset of first subsequent diarrhea episode during follow up (powered for the outcome of diarrhea incidence) High
 Patel 2013 [32] India Outpatient children 6–59 mo with acute diarrhea (> 3 unformed stools in the previous 24 h per mother’s report) Zinc (2 mg/kg/day) or zinc + copper (Zn 2 mg/kg/day + Cu 0.2 mg/kg/day), 14 days Placebo 724 12 weeks Proportion with at least 1 diarrhea episode, 2 diarrhea episodes, or 1 dysentery episode during follow up; number and duration of subsequent diarrhea episodes; change in WAZ, WHZ, and HAZ from enrollment measurements every 2 weeks for 12 weeks (power/sample size calculations not reported) High
 Negi 2015 [33] India Children 5–12 yrs. presenting to pediatric emergency units with acute watery diarrhea (3 or more episodes of loose stools over 24 h of < 72 h duration), with some or severe dehydration, and having had no treatment Zinc (20 mg/day) for 14 days Placebo 134 3 months Risk of having at least 1 episode of diarrhea during follow up (power/sample size calculations not reported) LowΩ, ϑ
  1. iOutcome listed are only the outcomes of interest for the present systematic review
  2. iiDuration 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.
  3. iiiDefined as when diarrhea had ceased and patient had consistent weight gain for at least 48 hours
  4. ivDefined as age- and sex-specific weight standard deviation scores, from the National Center for Health Statistics median value
  5. vAll diets were equivalent in calorie and protein composition
  6. viStudy included children with multiple admission (not just diarrhea) therefore only included data for children who had diarrhea at time of treatment. Power was determined for all children (not stratified by diagnosis)
  7. viiStudy included children with multiple admission (not just diarrhea) therefore only included data for children who had diarrhea at time of treatment. Power was determined for all children (not stratified by diagnosis)
  8. viiiStudies in this intervention category are randomized controlled trials with a factorial design, evaluating both Vitamin A and Zinc
  9. ixInvestigators included 2 strata of study subjects: A “standard dose stratum” with the dosages given, and a “High dose stratum” with 40 mg zinc acetate daily, 15 days (Vit A dosage was unchanged)
  10. xDiarrhea morbidity data were collected from “samples of time periods” throughout the 2 year follow up period. Mortality rates were calculated using 11,881 child-years of person-time, and incidence rates were calculated using 41,788 child-weeks of person-time
  11. xiThirty completed 6 month follow up; 50 completed 7-day clinical study
  12. ΩSparse data (sample size is <200 participants total)
  13. ΦBlinding and allocation process (not double-blind)
  14. ϑFollow up and withdrawals (>5% of sample size)
  15. ΨLack of placebo