Pavlinac et al. BMC Public Health (2018) 18:208 DOI 10.1186/s12889-018-5092-7

Patricia B. Pavlinac1*, Rebecca L. Brander2, Hannah E. Atlas1, Grace C. John-Stewart1,2,3,4, Donna M. Denno1,3,5 and Judd L. Walson1,2,3,4

Abstract

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 middleincome countries, published between 1980 and 2016 that included children under 15 years of age with diarrhea and followup 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. Keywords: Pediatric diarrhea management, Child growth, Diarrhea interventions, Child mortality, Long-term sequelae of diarrhea

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

* Correspondence: [email protected]

Department of Global Health, University of Washington, Seattle, WA, USA Full list of author information is available at the end of the article

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

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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: birth18 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.

Forty-six trials were included in this review, the majority (27 studies [58.7%]) of which were conducted in the WHO-classified Southeast Asia region [8–34], with 19 (70.4%) conducted in Bangladesh alone (Table 1). Seven studies (15.2%) were conducted in the Americas [35–41], 7 studies (15.2%) reported data from Africa [42–48], 2 from the Eastern Mediterranean (Pakistan) [49, 50] and 2 from Europe (Turkey) [51, 52]. One study was conducted in 3 countries (Ethiopia, Pakistan, and India) [53]. The majority of the trials were conducted in inpatient settings (35 studies, 76.1%). Five (10.9%) trials were communitybased, and the remaining 6 (13.0%) were conducted in outpatient settings. The most common interventions included therapeutic zinc (15 studies [32.6%], 2 of which was assessed in the same trial as vitamin A), and high

protein diets (9 studies [19.6%]). Probiotics were assessed in 5 studies (10.9%), and 5 trials evaluated lactose-free diets (10.9%). Four were trials of ORS formulations (8.7%), and 3 (6.5%) trials evaluated dietary supplements, including dietary fiber (2 studies), and glutamine (1 study). Three (6.5%) trials were of other dietary interventions, a semi-elemental diet and 2, 3-armed trials evaluated readyto-use therapeutic food (RUTF) or micronutrient powder. Only 2 (4.3%) of the trials that fit our inclusion criteria evaluated antimicrobial treatments (1 antibiotic and 1 antiprotozoal). We did not find any trials of intravenous (IV) rehydration, antisecretory agents, or antiemetic agents that met our inclusion criteria. The sample size of included studies ranged from 18 to 8070 and only 11 (23.9%) of the 46 trials included more than 200 participants (1 ORS, 2 probiotic, 2 RUTF/micronutrient, 1 vitamin A + zinc, and 5 zinc trials). Just over half of included trials (52.2%) reported power/sample size calculations, the majority of which (11 [48%] of the 23) were powered for the outcome of diarrhea duration/stool output, outcomes not included in this systematic review.

Of the 46 clinical trials evaluated using the modified GRADE system, 6 (13.0%) scored high, 8 (17.4%) scored moderate, 11 (23.9%) scored low, and 21 (45.7%) scored very low (Table 1). The most common deduction was for sparse data (35 [76.1%]), followed by deductions related to follow-up and withdrawals (24 [52.2%]), or blinding/allocation process (21 [45.7%]).

Fig. 1 Flow chart of included trials of diarrhea management interventions

calculations not reported) ΩΦΨVery low

clinical response) ΩModerate

and power Modified

GRADE

score

suspension, twice daily for 3 days Placebo968 daysMortality (powered for outcome of

up data Pre-specified follow up timeRelevant outcomes measured

(150 mg/kg/day) 56 children21 daysMortality (power/sample size

[Ref #] CountryPopulationInterventionComparatorNumber with

follow

Low-dose ampicillin (50 mg/kg/day)High-dose

ampicillin

5 mL of 20 g/L nitazoxanide oral

1980 [8] BangladeshInpatient adults and children with blood,

pus cells, and mucus in stool, 4 or more

take the shape of a container or can be

diarrhea (at least 3 stools per day that

poured) andoocystsCryptosporidium

stools/day, and culture-confirmed

2002 [42] ZambiaInpatient children 12–85 mo with

Table 1Characteristics of included studies

infectionShigella

Antimicrobial Intervention

Reference

Gilman

Amadi

ΩModerate

ΩModerate

ΩϑLow

Dietary Supplements

ORS 1507 daysWeight gain at day 7 from enrollment

(powered for the outcome of stool

output)

Benefiber®) Standard WHO-

non-dysenteric diarrhea WHO ORS with dietary fiber(20 g/L

[26] BangladeshInpatient males 4–18 mo with acute

Alam 2000

[formed stool] at days 7, 8, 9, and 10

end of diarrhea Proportions recovered from diarrhea

(powered for outcome of diarrhea

recovery duration)

62At least 7 days, or until

rice-based diet

control diet:

only, 7 days

equivalent

Calorically

kg to 8 g/kg of pectin supplement)

7 days; or rice-based diet with 1 g/

Rice-based diet with dietary fiber

(250 m/L cooked, green banana,

7 days

mo with persistent diarrhea (> 3 loose

standard), inpatient male infants 5–12

2001 [15] BangladeshSeverely malnourished (< 60% NCHS

stools/day for 14 days), treated with

ciprofloxacin

Rabbani

day, for 7 days Placebo1433 monthsWeight gain at day 30, 60, and 90 from

enrollment (powered for the outcome

of diarrhea duration)

diarrhea Glutamine supplement - 0.3 g/kg/

[51] TurkeyInpatient children 6–24 mo with acute

Yalcin 2004

sample size calculations not reported) ΩΦVery low

ϑΨ

hospital diet 9615 daysWeight and MUAC at day 15 (power/

addition to standard hospital diet Standard

Extra servings of milk (30% of total

daily caloric requirements), in

ΩΦVery low

ϑΨ

ΩΦVery low

ϑΨ

ΩΦΨLow

2221 daysChange in weight, height, WAZ, WHZ,

(power/sample size calculations not

thickness at day 21 from admission

HAZ, MUAC, and triceps skinfold

reported)

6921 daysChange in WHZ, WAZ, and HAZ at day

21 from admission (power/sample size

calculations not reported)

7540 daysPercent change in WAZ and WHZ at 10,

and 40 from admission (power/sample

size calculations not reported)

protein), 21 days

energy from protein), 21 days Standard diet

(7.5% of total

energy from

High protein diet (15% of total

protein), 21 days

energy from protein), 21 days Standard diet

(7.5% of total

energy from

High protein diet (15% of total

hospital diet,

2480 kJ/l for

4960 kJ/l for 10 days Standard

10 days

High calorie and high protein diet,

ΩVery low

ϑΨ

discharge; proportion with nutritional

4116 days minimumWeight at end of intervention and at

(powered for outcome of diarrhea

iiiat end of interventionrecovery

duration)

diet) Standard cultural

(elemental diet

treatment for

or“Vivonex”)

diarrhea

dietary

chicken-based diet, or soy-based

High protein diet (2 groups:

High Protein Diets

mucus in stools), treated with nalidixic

[9] IndiaInpatient children under 5 y/o with

acute dysentery (visible blood and

acid

Datta 1990

culture-confirmeddysentery,Shigella

treated with nalidixic acid or other

[10] BangladeshInpatient children 2–4 y/o with

microbial

Kabir 1992

acute diarrhea and culture-confirmed

spp., treated with nalidixicShigella

[11] BangladeshOutpatient children 2–5 y/o with

acid or pivmecillinam

Kabir 1993

and culture-confirmed, treatedShigella

1997 [12] BangladeshMalnourished (< 80% NCHS median),

bloody or bloody mucoid diarrhea

inpatient children 12–48 mo with

with nalidixic acid

Mazumder

third-degree malnutrition (< 60% NCHS

stools/day for 14 days or longer) and

persistent diarrhea (3 or more loose

median), treated with TMP-SMX or

1997 [36] MexicoInpatient children 3–36 mo with

metronidazole

Nurko

ΩΦVery low

ΩΦVery low

ΩϑVery low

ΩVery low

and power Modified

GRADE

ΦϑΨ

score

ϑΨ

Ψ

Ψ

10426 weeksMortality, median change in weight-SDs

and weight at end of intervention and

measurements (powered for outcome

intervention Change in weight, height, WHZ, WAZ,

1019 monthsDifference in knee-heel length, height

sample size calculations not reported)

compared to admission WAZ (power/

−stunted (LAZ <2 SDs) at 26 weeks

ivand WAZ at 26 weeks; proportions

(power/sample size calculations not

and HAZ at 6 months compared to

7510 daysPercent change in WAZ at day 10,

−underweight (WAZ <2 SDs) and

(powered for outcome of weight

post-intervention measurements

day 90, compared to admission

up data Pre-specified follow up timeRelevant outcomes measured

of diarrhea duration)

reported)

change)

596 months post-

[Ref #] CountryPopulationInterventionComparatorNumber with

follow

energy from protein), 21 days Standard protein

of breastfeeding

porridge + milk

the importance

support: maize

Counseling on

cereal formula

nutritious diet

from protein),

formula, until

formula (4960 kJ/l), 10 days Control milk-

diet (7.5% of

total energy

(2480 kJ/l),

nutritional

Standard

and of a

resolved

diarrhea

10 days

21 days

with a multivitamin tablet (including

diet, and a high protein millet gruel

standard nutritional support + extra

protein to provide 150 kcal/kg/day

depending on age), until diarrhea

mothers report Counseling on the importance of

High calorie & protein milk-cereal

breastfeeding and of a nutritious

and 4.0–5.5 g protein/kg/day (as

nalidixic acid or pivmecillinam High protein diet (15% of total

watery stools/day, for 5 days or more) Enhanced nutritional support:

zinc), until the end of a 7 day

milk or powdered protein,

period without diarrhea

resolved

Table 1Characteristics of included studies(Continued)

persistent diarrhea (4 or more loose or

with acute bloody or mucoid diarrhea,

[13] BangladeshInpatient children 2–60 mo with acute

Bissau Community-based children under 3 y/

Africa Inpatient HIV+ children 6–36 mo with

bloody mucoid diarrhea, treated with

median) inpatient children 12–48 mo

2000 [14] BangladeshMalnourished (< 80% of NCHS

o with persistent diarrhea per

treated with nalidixic acid of

pivmecillinim

2001 [43] Guinnea-

2007 [44] South

Valentiner-

Mazumder

Kabir 1998

Reference

Branth

Rollins

ΩΦVery low

ΩΦVery low

for outcomes of diarrhea duration) ΩΦVery low

ΩΦVery low

ΩΦVery low

ϑΨ

ϑΨ

ϑΨ

ϑΨ

Ψ

to admission weight (power/sample size

1164–6 weeks after dischargeProportion of patients whose weight on

compared to admission weight (power/

21 days 526 weeks post-dischargeWeight increment at 6 weeks (powered

14 days 7314 daysWeight gain at day 7 and 14 compared

each day to day 12 (power/sample size

admission measurements (powered for

outcomes of stool output and diarrhea

diet 1547 days post-dischargeDifference in weight gain and change

sample size calculations not reported)

until end of diarrhea Weight gain at day 7 and at recovery

day 7 was lower than at rehydration;

probability of continuing diarrhea at

in WHZ at discharge compared to

calculations not reported)

calculations not reported)

duration)

57At least 7 days, or

21 days Feeding formula

until recovery or

cereal, sugar, oil,

protein (lactose-

equivalent milk-

and egg white

based formula,

a minimum or

vdiet Yogurt-based

with lactose,

7 days Khitchri and

free), 120 h

milk protein, 120 h Puffed rice

yogurt for

minimum of 7 days Calorically

7 days

stools per day for 14 days) Amino-acid based diet or soy-based

followed by khitchri and yogurt for

[16] IndiaOutpatient children 3–24 moLegume and cereal-based formula

diet, or hydrolyzed protein-based

Soy milk (lactose-free) for 7 days,

Puffed rice cereal, sugar, oil, and

(lactose-free), until recovery or a

24 h period) and dehydration Lactose-free feeding formula,

persistant diarrhea (increased frequeny

children 324 mo, with persistent

diarrhea (4 or more watery stools in a

diarrhea (3 or more liquid stools/

2009 [37] BrazilInpatient male infants 1–30 mo with

persistent diarrhea (3 or more liquid

1991 [50] PakistanOutpatient males 6 mo - 3 yo with

1994 [38] ColombiaInpatient children 1–24 mo with

and reduced consistency lasting

day for 14 days)

2 weeks or more)

1996 [17] IndiaInpatient \

Lactose Free Diet

Bhan 1988

Bhatnagar

de Mattos

Lozano

Bhutta

and power Modified

GRADE

score

up data Pre-specified follow up timeRelevant outcomes measured

[Ref #] CountryPopulationInterventionComparatorNumber with

follow

Table 1Characteristics of included studies(Continued)

Other Dietary Interventions

Reference

Standard hospital diet3821 days

lactalbumin

hydrolyzed

content of

osmolarity

elemental

and high

diet with

Semi-

low

ϑΨLow

ϑΨLow

MUAC < 115 mm, or nutritional oedema

−WHZ <3, MUAC < 115 mm, nutritional

follow up (powered for combined

oedema. Or > 10% weight loss during

outcome of negative nutritional

−: Incidence of WHZ <2,enrollment

during follow up.For malnourished

: Incidence ofchildren at enrollment

follow up. Powered for combined

diarrhea only −6 monthsIncidence of WHZ <2, MUAC <

or nutritional oedema during

diarrhea only 6 monthsFor non-malnourished children at

outcome of negative nutritional

vioutcome)

viioutcome

115 mm,

1171 with

941 with

Eichenberger 1984 [35]BrazilInpatient infants

1–11 mo with

gastroenteritis

with diarrhea

subacute

acute to

An instruction to

an extra meal/

feed the child

day for 14 d

(RUTF), plus instructions to feed the

child an extra meal/day for 14 d; or

Ready-to-use Therapeutic Foods

instructions to feed the child an

micronutrient powder plus

extra meal/day for 14 d

ΩVery low

ΦϑΨ

not reported)

compared to

beginning of

calculations

sample size

Weight at

weight at

(power/

therapy

day 21

children 6–59 mo with diarrhea (3 or

report), malaria, or lower respiratory

nonbloody] per 24 h by mothers’

[45] UgandaNon-malnourished, outpatient

more loose stools [bloody or

tract infections

Kam 2016

van der

An instruction to

an extra meal/

feed the child

day for 14 d

(RUTF), plus instructions to feed the

child an extra meal/day for 14 d; or

Ready-to-use Therapeutic Foods

instructions to feed the child an

micronutrient powder plus

extra meal/day for 14 d

stools [bloody or nonbloody] per 24 h

59 mo with diarrhea (3 or more loose

by mothersreport), malaria, or lower

malnourished outpatient children 6–

[46] NigeriaNon-malnourished or moderately

respiratory tract infections

Kam 2016

van der

ΩΦVery low

size calculations not reported) ΩModerate

ΦΨLow

Ψ

9314 daysWeight at day 14, weight gain at day 14

ORS 187 daysWeight gain at day 7 (power/sample

(power/sample size calculations not

weight gain at day 16 (powered for

based ORS 47116 daysProportion with diarrhea at day 14,

outcomes of stool output, diarrhea

duration and weight gain [70 g])

as percent of enrollment weight

reported)

or standard WHO-ORS Standard diet for

bananas, cereals,

alanine Standard WHO-

management

non-dysenteric diarrhea Glucose based ORSRice-powder

beverages,

and apple

(aerated

diarrhea

sauce)

dehydration Standard WHO-ORS with 30 mmol/L

than 3 watery stools per day) High potassium and chloride ORS,

1997 [21] BangladeshInpatient children 3–35 mo with acute

1983 [39] PanamaInpatient 3 mo - 2 y/o who were well

nourished, with acute diarrhea (more

1991 [40] BrazilInpatient male infants less than 12

mo, with acute diarrhea and

Oral Rehydration Solution Formulations

Santosham

Faruque

Ribeiro

and power Modified

ΩΨLow

GRADE

score

sample size calculations not reported)

starch Rice-based ORS1376 weeksTime to attain 80% of median WLZ

diarrhea at or after day 7 (power/

from enrollment; proportion with

up data Pre-specified follow up timeRelevant outcomes measured

[Ref #] CountryPopulationInterventionComparatorNumber with

follow

based ORS plus amylase resistant

Glucose-based ORS, or Glucose-

Table 1Characteristics of included studies(Continued)

[55] BangladeshSeverely malnourished (< 70% NCHS

standard), inpatient infants 6–60 mo

with acute diarrhea and culture-

confirmedV. cholerae

Alam 2009

Reference

size calculations not reported) ΩΦVery low

ΩϑLow

ϑΨ

placebo 721 monthProportion of patients with diarrhea at

based formula 977 daysWeight gain at day 7 (power/sample

or after day 7 (power/sample size

calculations not reported)

per day (patients 1 yo and older) WHO-ORS and

(lactose and calorically equivalent) Standard milk-

per day (patients < 1 yo) or 500 mg

the previous 24 h) Standard formula fermented withL.

loose stools in the preceding 24 h) WHO-ORS and S. boulardii, 250 mg

andbulgaricusS. thermophilus

2001 [47] AlgeriaInpatient children 3–24 mo with acute

2007 [41] ArgentinaOutpatient children 3 mo - 2 yo, with

watery diarrhea (> 3 loose stools in

acute diarrhea (3 or more liquid or

Boudraa

Villaruel

Probiotics

ΩModerate

ΩModerate

ΩVery low

duration) High

duration) High

ΦΨ

diarrhea at day 7 (powered for outcome

live bacteria) Placebo2076 weeksChange in WHZ at 6 weeks(powered for

diarrhea during follow-up (powered for

outcomes of stool output and diarrhea

syrup only 937 daysWeight at day 7, weight gain at day 7

ixZinc acetate, 15 days, or both Placebo65617 daysProportion with diarrhea at day 7 and

16 (powered for outcome of diarrhea

compared to day 1, proportions with

−wasted (WHZ <2 SD) at 4 weeks,

(10^10 organisms) −Placebo1234 weeksProportions stunted (HAZ <2 SD),

17,938 (10^8 CFU) for 5 days WHO-ORS only12712 daysProportion with diarrhea at day 12

proportion with diarrhea or severe

−underweight (WAZ <2 SD), and

(powered for outcome of diarrhea

outcome of L:M ratio)

of clinical recovery)

duration)

Multivitamin (D,

C, B1 B2 B6)

200,000 for children > 1 yo), or both

acetate, 5 ml twice daily for 7 days),

in the previous 24 h) μ4500g vitamin A, 15 day, 14.2 mg

14 days duration) Multivitamin (D, C, B1 B2 B6) syrup

that take the shape of their container) Lactobacillus rhamnosus GG (10^9

and 20 mg elemental zinc (as zinc

watery diarrhea WHO-ORS +lactobacillus reuteri

(100,000 IU for children < 1 yo,

Cryptosporidium infection Lactobacillus rhamnuosus GG

multivitamin syrup with Vit A

2014 [52] TurkeyInpatient children 3–60 mo with acute

acute diarrhea (3 or more liquid stools

2014 [20] IndiaChildren 6 m to 5 years with diarrhea

testing positive for either rotavirus or

diarrhea (more than 3 stools per day

1999 [34] BangladeshInpatient children 6 mo - 2 yo with

2001 [22] BangladeshInpatient children 6 mo - 4 yo with

persistent diarrhea (diarrhea for >

[19] IndiaInpatient infants < 36 mo with

viiiTherapeutic Micronutrients (Vitamin A and Zinc)

Misra 2009

Dinleyici

Faruque

Khatun

Sindhu

Therapeutic Micronutrients (Zinc Alone)

High

ΩΦVery low

ϑ

ΩϑLow

D3, E) only 937At least 120 daysProportion of diarrhea episodes that last

diarrhea episodes taken to a physician

during follow up (power/sample size

longer than 7 days, proportion of

calculations not reported)

syrup (A, B2, B6,

elemental zinc) Multivitamin

stools in the preceding 24 h) Multivitamin syrup (A, B2, B6, D3, E)

plus zinc gluconate (20 mg of

acute diarrhea (at least 4 unformed

1995 [23] IndiaInpatient children 6–35 mo, with

Sazawal

proportion with diarrhea after day 15

14115 daysMortality, weight gain at discharge

(powered for outcome of diarrhea

compared to admission weight,

duration)

(powered for outcome of day 14 weight

day 7 and 14; overall MUAC increment

weightincrement at day 14; MUAC at

7728 daysWeight gain at day 7 and 14; overall

gain)

B2, B3, B6, D, Ca)

only for 14 days

syrup (Vit A, B1,

zinc per day for 14 days Multivitamin

diarrhea Multivitamin syrup (Vit A, B1, B2, B3,

B6, D, Ca) with 20 mg elemental

[24] BangladeshInpatient 3–24 mo with persistent

Roy 1998

1. B2, B3, B6, B12,
2. C, D, Ca) only for

syrup (Vit A, B1,

Multivitamin

28 days

persistent diarrhea Multivitamin syrup (Vit A, B1, B2, B3,

elemental zinc per kg per day for

B6, B12, C, D, Ca) with 3 mg

28 days

1999 [49] PakistanInpatient children 6–36 mo with

Bhutta

and power Modified

ΦΨLow

ΩϑLow

GRADE

score

8 weeks (power/sample size calculations

(powered for the outcomes of diarrhea

8 weeks, length gain at each week for

acute lower respiratory infections, and

lower respiratory infections incidence,

admission to hospital for diarrhoea or

duration, diarrhea incidence, acute

2910 weeksWeight gain at each week of for

14 days xORS only80702 yearsIncidence of diarrhea, mortality

up data Pre-specified follow up timeRelevant outcomes measured

child mortality)

not reported)

[Ref #] CountryPopulationInterventionComparatorNumber with

follow

syrup (vit A, B1,

B2, B6, D, and

zinc per day for 14 days Multivitamin

Ca) only for

14 days

24 months with acute diarrhea Multivitamin syrup (vit A, B1, B2, B6,

D, and Ca) with 20 mg elemental

with diarrhea of any duration ORS with 20 mg zinc per day,

Table 1Characteristics of included studies(Continued)

[27] BangladeshCommunity-based children 3–59 mo

[25] BangladeshMalnourished (< 76% of NCHS

median), inpatient children 3–

Baqui 2002

Roy 1999

Reference

High

ΩΦϑLow

ΩϑLow

ΩModerate

ϑModerate

placebo 10428 weeksWeight at week 4 and 8, length at week

≥episode of any diarrhea,2 episode of

≥4 and 8, proportion of infants with1

dysentery (any day with blood in the

stool); incidence and prevalence of

diarrhea; mortality (powered for

≥any diarrhea, or1 episode of

anthropometry and morbidity

outcomes)

for 14 days ORS with

ORS with 10 mg zinc sulfate, daily

health workers and community based

and India Infants 1–5 mo with acute diarrhea,

identified through home visits by

study clinics

2007 [53] Ethiopia,

Pakistan,

Walker

14712 weeksMortality, gain in length and weight at

diarrhea episodes (power/sample size

(power/sample size calculations not

xi6 monthsDiarrhea incidence and duration of30

12 weeks, incidence of subsequent

episodes during 6 mo follow up

calculations not reported)

reported)

only, 14 days

(unspecified)

with 20 mg elemental zinc, 14 days Multivitamin

syrup

recovery from persistent diarrhea Multivitamin syrup (Unspecified)

[28] BangladeshConvalescent children 3–24 mo, after

Roy 2007

syrup (Vit A, D, B

complex, Ca)

elemental Zn/5 mL), for 14 days Multivitamin

only

Multivitamin syrup (A, D, B complex,

Ca) with zinc acete (10 mg

[29] BangladeshModerately malnourished (weight/age

61–75% of NCHS median), inpatient

diarrhea, and lab-confirmedShigella

bloody-mucoid diarrhea or febrile

children age 12–59 m with acute

spp

Roy 2008

Placebo603 monthsWeight gain at 3 months, number and

sample size calculations not reported)

episodes during follow up (power/

duration of subsequent diarrhea

sulphate monohydrate) for patients

> 1 y/o, 10 mg of elemental zinc,

or watery stools in a 24 h period) 20 mg of elemental zinc (zinc

14 days, for patients < 1 y/o

acute diarrhea (3 or more loose, liquid

2008 [48] NigeriaOutpatient children 6–24 mo with

Fajolu

follow up (powered for the incidence of

(10 mg/d) only 3339 monthsIncidence rate of diarrhea illness during

acute upper respiratory tract infections)

supplementation (10 mg/d) 10 days of zinc

confirmed ETEC 10 days of zinc (10 mg/d) +

additional 3 months of zinc

2010 [30] BangladeshCommunity-based children 6–23 mo

with acute diarrhea and culture-

Larson

High

of diarrhea during follow up; proportion

162290 daysNumber of diarrheal episodes and days

(powered for the outcome of diarrhea

with at least 1 subsequent episode of

persistent diarrhea during follow up;

diarrhea episode during follow up

day of onset of first subsequent

diarrhea, prolonged diarrhea, or

incidence)

zinc, 5 days Standard course

elemental zinc,

zinc - 20 mg

10 days

liquid stools in the previous 24 h) Short course zinc - 20 mg elemental

[31] BangladeshCommunity-based children 4–59 mo

with diarrhea (3 or more loose or

Alam 2011

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)

xDiarrhea morbidity data were collected fromsamples of time periodsthroughout the 2 year follow up period. Mortality rates were calculated using 11,881 child-years of person-time, and incidence rates were calcu-“”

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)

and power Modified

ΩϑLow

GRADE

score

High

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 signsof intolerance, diets were maintained or decreased as

sample size calculations not reported)

number and duration of subsequent

dysentery episode during follow up;

Zinc (20 mg/day) for 14 daysPlacebo1343 monthsRisk of having at least 1 episode of

diarrhea episodes; change in WAZ,

0.2 mg/kg/day), 14 days Placebo72412 weeksProportion with at least 1 diarrhea

diarrhea during follow up (power/

ixInvestigators included 2 strata of study subjects: Astandard dose stratumwith the dosages given, and aHigh dose stratumwith 40 mg zinc acetate daily, 15 days (Vit A dosage was unchanged)“”“”

episode, 2 diarrhea episodes, or 1

measurements every 2 weeks for

WHZ, and HAZ from enrollment

up data Pre-specified follow up timeRelevant outcomes measured

12 weeks (power/sample size

calculations not reported)

[Ref #] CountryPopulationInterventionComparatorNumber with

viiiStudies in this intervention category are randomized controlled trials with a factorial design, evaluating both Vitamin A and Zinc

follow

ivDefined as age- and sex-specific weight standard deviation scores, from the National Center for Health Statistics median value

iiiDefined as when diarrhea had ceased and patient had consistent weight gain for at least 48 hours

copper (Zn 2 mg/kg/day + Cu

the previous 24 h per mothers report) Zinc (2 mg/kg/day) or zinc +

necessary. When full concentrations were reached, the diet was given for an additional 7 days.

iOutcome listed are only the outcomes of interest for the present systematic review

xiThirty completed 6 month follow up; 50 completed 7-day clinical study

Table 1Characteristics of included studies(Continued)

acute diarrhea (> 3 unformed stools in

pediatric emergency units with acute

watery diarrhea (3 or more episodes

of loose stools over 24 h of < 72 h

[32] IndiaOutpatient children 659 mo with

vAll diets were equivalent in calorie and protein composition

dehydration, and having had no

[33] IndiaChildren 512 yrs. presenting to

duration), with some or severe

ΩSparse data (sample size is <200 participants total)

ΦBlinding and allocation process (not double-blind)

ϑFollow up and withdrawals (>5% of sample size)

lated using 41,788 child-weeks of person-time

treatment

ΨLack of placebo

Patel 2013

Negi 2015

Reference

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

1. 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
2. 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)

(95% CI) −−0.11 (0.24, 0.03)

1980 [8] Low dose ampicillin (50 mg/kg/day)Standard dose ampicillin (150 mg/kg/day)MortalityRisk Difference

≥Table 2Intervention effects on post-acute (7 days after enrollment) mortality, length, weight, and/or diarrhea presence

ReferenceInterventionComparatorRelevant Outcomes and Results

Antimicrobial Interventions

Gilman

(95% CI) −−0.07 (0.21, 0.06)

(95% CI) Undefined

for 3 days PlaceboMortalityRisk Difference

Relative Risk

2002 [42] 5 mL of 20 g/L nitazoxanide, twice daily

Amadi

(95% CI) 0.58 (0.21, 1.63)

Relative Risk

[26] −ORS with dietary fiber (Benefiber®)WHO- ORS onlyDifference in weight gain at day 7, g (95% CI)52 (18.73, 122.73)

Dietary Supplements

Alam 2000

banana or pectin supplement), 7 days Rice-based diet onlyProportions recovered from diarrhea (formed stool) at each day to day 10Higher in banana and pectin groups

iithan in control group

−Difference in weight gain at day 90, g (95% CI)107 (57.30, 271.30)

−Difference in weight gain at day 60, g (95% CI)45 (80.80, 170.80)

7 days iiiPlaceboDifference in weight gain at day 30, g (95% CI)130 (12.67, 247.33)

[51] Glutamine supplement, 0.3 g/kg/day, for

2001 [15] Rice-based diet with dietary fiber (green

Yalcin 2004

Rabbani

[9] −High protein diet, length unspecifiedStandard hospital dietDifference in weight at day 15, kg (95% CI)0.30 (0.18, 0.78)

−Difference in MUAC at day 15, cm (95% CI)0.00 (0.37, 0.37)

High Protein Diets

Datta 1990

−Difference in change in height at day 21, from admission, cm (95% CI)0.09 (0.57, 0.75)

protein), 21 days Difference in change in weight at day 21 from admission, kg (95% CI)0.47 (0.12, 0.82)

from protein), 21 days Standard diet (7.5% of total energy from

[10] High protein diet (15% of total energy

Kabir 1992

Difference in change in WAZ at day 21 from admission (95% CI)0.30 (0.03, 0.57)

Difference in change in WHZ at day 21 from admission (95% CI)0.40 (0.05, 0.75)

from admission, cm (95% CI) −0.32 (0.29, 0.93)

Difference in change in MUAC at day 21 from admission, cm (95% CI)0.44 (0.08, 0.80)

Difference in change in triceps skinfold thickness at day 21

[11] High protein diet, 21 daysStandard protein diet, 21 daysDifference in change in WAZ at day 21, from admission (95% CI)0.23 (0.07, 0.39)

Difference in change in WHZ at day 21, from admission (95% CI)0.25 (0.05, 0.45)

Kabir 1993

Difference in change in HAZ at day 21, from admission (95% CI)0.90 (0.05, 0.13)

diet, 4960 kJ/l (10 days) Standard diet, 2480 kJ/l (10 days)Difference in percent change in WAZ at day 10 and 40, fromadmission (95% CI)Day 10: 3.50 (1.86, 5.14)

Day 40: 3.11 (0.92, 5.30)

1997 [12] High calorie & high protein milk-cereal

Mazumder

Difference in percent change in WHZ at day 10 and 40, from admission (95% CI)Day 10: 3.76 (1.92, 3.60)

Day 40: 3.34 (0.76, 5.90)

(1178.40, 770.40)

to control −445 (1522.70,

control −92 (1189.60,

1005.60)

632.70)

control 204

Difference in weight at discharge from enrollment, g (95% CI)Comparing soy

diet”(Vivonex) vDifference in weight at end of protocol, g(95% CI)Comparing soy

chicken group

Comparing

group to

group to

≥Table 2Intervention effects on post-acute (7 days after enrollment) mortality, length, weight, and/or diarrhea presence(Continued)

ReferenceInterventionComparatorRelevant Outcomes and Results

ivprotein soy-based diet (Nursoy formula) Calorically equivalent standard“elemental

1997 [36] High protein chicken-based diet or high

Nurko

to control 428 (1539.80,

control 1.13 (0.79, 1.61)

683.80)

vi(RR [95%])Comparing soyProportion with nutritional recovery

chicken group

Comparing

group to

to control 1.20 (0.86, 1.7)

−Difference in change in WHZ at 6 mo, from post-intervention WHZ (95% CI)0.09 (0.35, 0.17)

energy from protein), 21 days −Difference in change in weight at 6 mo, from post-intervention weight, kg (95% CI)0.10 (0.24, 0.44)

−Difference in change in WAZ at 6 mo, from post-intervention WAZ (95% CI)0.07 (0.17, 0.31)

Difference in change in height at 6 mo, from post-intervention height, cm (95% CI)1.10 (0.56, 1.64)

chicken group

Comparing

from protein), 21 days Standard protein diet (7.5% of total

[13] High protein diet (15% of total energy

Kabir 1998

Difference in change in HAZ at 6 mo, from post-intervention HAZ (95% CI)0.28 (0.12, 0.44)

breastfeeding and of a nutritious diet vii(95% CI)Day 9061.50 (49.20, 73.80)Difference in weight gain at end of intervention and day 90, g/wk.

mm/y (95% CI) −Day 902.70 (4.60, 10.00)

intervention 12.50 (7.70, 17.30)

intervention 7.50 (4.80, 10.20)

10 days Difference in percent change in WAZ at day 10, from admission WAZ (95% CI)3.50 (2.08, 4.91)

2viii(95% CI)0.65 (0.11, 1.19)Difference in change in height between groups at day 90, (cm/y)

End of

End of

Difference in change in knee heel length at end of intervention and day 90,

(4960 kJ/l), 10 days Control milk-cereal formula (2480 kJ/l),

Counseling on the importance of

breastfeeding and of a nutritious diet, and

2000 [14] High calorie & protein milk-cereal formula

multivitamin tablet (including zinc), until

the end of a 7 day period without

2001 [43] Counseling on the importance of

a high protein millet gruel with a

diarrhea

Valentiner-

Mazumder

Branth

−Risk difference7.4% (4.7%,20.5%)

porridge + milk formula Mortality at 26 weeksRelative risk1.34 (95% CI: 0.79,

ixat 26 weeksGreater gain in interventionMedian change in weight- SDs

2.27)

group (< 0.001)p

4.05.5 g protein/kg/day Standard nutritional support: maize

protein to provide 150 kcal/kg/day and

2007 [44] Standard nutritional support + extra

Rollins

Median change in WAZ at 26 weeksGreater gain in intervention

group (< 0.05)p

−Proportion underweight (WAZ <2 SDs) at 26 weeks (Prevalence Ratio [95% CI])0.48 (0.30, 0.77)

Proportion stunted (LAZ <2 SDs) at 26 weeks (Prevalence Ratio[95% CI])0.87 (0.67, 1.13)

by khitchri and yogurt for 7 days −−−Khitchri and yogurt for 14 daysDifference in weight gain at day 7 and 14, g/wk. (95% CI)Day 7:400 (559.40,240.60)

Day 14: 385.7 (209.60, 561.80)

−−−Difference in weight gain at recovery, g/kg admission weight/24 h (95% CI)3.80 (7.15,0.44)

1994 [38] −−Corn-based (lactose-free) formula, 21 daysMilk-based formula, 21 daysDifference in weight increment at 6 weeks, kg (95% CI)0.02 (0.30, 0.26)

until recovery or 7 days min −−Difference in weight gain at day 7, g/kg admission weight/24 h (95% CI)3.20 (6.86, 0.46)

≥Table 2Intervention effects on post-acute (7 days after enrollment) mortality, length, weight, and/or diarrhea presence(Continued)

ReferenceInterventionComparatorRelevant Outcomes and Results

(lactose-free), until recovery or 7 days min Calorically equivalent milk-based formula,

1991 [50] Soy milk (lactose-free) for 7 days, followed

[16] Legume and cereal-based formula

Lactose Free Diets

Bhan 1988

Lozano

Bhutta

xiiiChange in WHZ at dischargeSimilar improvement in all groups

xProbability of continuing diarrhea at each day to day 12No significant difference (p = 0.76)

xixiiYogurt-based dietuntil dischargeDifference in weight gain at discharge among groups at dischargeNo difference among groups

rehydration (Prevalence Ratio [95% CI]) 0.97 (0.06, 15.19)

until discharge Proportion of patients whose weight on day 7 was lower than at

protein (lactose-free), until discharge Rice-based formula with milk protein,

2009 [37] Amino-acid based diet, isolated soy-based,

or hyrolyzed casein-based diet; until

1996 [17] Rice-based formula with egg white

discharge

Bhatnagar

de Mattos

xivStandard hospital dietWeight at day 21 compared to weight at beginning of therapyBetter in intervention group

group 0.68 (0.37, 1.22)

micronutrient

meal/day for 14 d Relative Risk of first event of malnutrition (95% CI)RUTF vs

An instruction to feed the child an extra

group 0.62 (0.35, 1.10)

RUTF vs control

Other Dietary Interventions

and high hydrolyzed lactalbumin, at least

1984 [35] Semi-elemental diet with low osmolarity

21 days

Eichenberger

micronutrient powder plus instructions to

feed the child an extra meal/day for 14 d

RUTF, plus instructions to feed the child

an extra meal/day for 14 d; or

Kam 2016

(Uganda)

van der

[45]

control 0.92 (0.54, 1.54)

Micronutrient

group vs

group 1.12 (0.84, 1.50)

micronutrient

meal/day for 14 d Relative Risk of first event of malnutrition (95% CI)RUTF vs

An instruction to feed the child an extra

xv)0.81 (0.61,1.09

group 0.91 (0.69, 1.20)

RUTF vs control

Micronutrient

group vs

control

micronutrient powder plus instructions to

feed the child an extra meal/day for 14 d

RUTF, plus instructions to feed the child

an extra meal/day for 14 d; or

Kam 2016

(Nigeria)

van der

[46]

control −−0.50 (1.86, 0.76)

−−0.3 (1.45, 0.85)

standard WHO-ORS, with regular diet Standard diet for diarrhea managementDifference in weight at day 14, kg (95% CI)Comparing high

standard ORS to

Comparing

potassium/

chloride to

control

1983 [39] High potassium/ high chloride ORS, or

ORS Formulations

Santosham

potassium/ 2.00 (1.57, 2.42)

Difference in percent weight gain at day 14 (95% CI)Comparing high

chloride to

control

≥Table 2Intervention effects on post-acute (7 days after enrollment) mortality, length, weight, and/or diarrhea presence(Continued)

ReferenceInterventionComparatorRelevant Outcomes and Results

control 2.30 (1.82, 2.77)

1991 [40] −Alanine-based ORSStandard WHO-ORSDifference in weight gain at day 7, g (95% CI)18 (94.37, 130.38)

standard ORS to

Comparing

Ribeiro

−−0.06 (1.19,

−−0.08 (1.20,

xviDifference in weight gain at day 16, gSimilar between groups

1.07)

1.04)

glucose and rice

electrolyte content Proportion with diarrhea at day 14 (RR [95% CI])0.80 (0.21, 2.95)

resistant starch

and rice ORS

glucose with

with amylase-resistant starch (ARS) Rice-based ORSDifference in time to attain 80% of median WLZ, days (95% CI)Difference

Difference

between

between

amylase

ORS

1997 [21] Glucose-based ORSRice powder-based ORS, equivalent in

[55] Glucose-based ORS, or glucose-based ORS

Alam 2009

Faruque

1.00 (0.15, 6.86)

rice ORS group

Proportion with diarrhea at or after day 7 (RR [95% CI])Risk in glucose

(RR, [95% CI])

compared to

ORS group

0.49 (0.05, 5.27)

rice ORS groups

with ARS group

Risk in glucose

(RR, [95% CI])

compared to

sbulgaricuS. andthermophilus −Milk-based formula onlyDifference in weight gain at day 7, g (95% CI)43 (109.18, 195.18)

−Difference in weight gain at day 7, g/kg (95% CI)4.4 (5.50, 14.30)

2001 [47] Milk-based formula fermented withL.

Boudraa

Probiotics

[19] 9CFUPlaceboDifference in change in WHZ at 6 weeksNo difference betweenGG 10L. rhamnosus

groups (= 0.06)p

2014 [20] 10CFUPlaceboProportion with diarrhea at 4 weeks follow up (Prevalence Ratio [95% CI])0.65 (0.40, 1.07)GG 10L. rhamnosus

Proportion with severe diarrhea during follow-up (Prevalence Ratio [95% CI])1.15 (0.65, 2.05)

2007 [41] capsulesPlaceboProportion with diarrhea on day 7 (Prevalence Ratio [95% CI])0.39 (0.20, 0.74)S. boulardii

Proportion with diarrhea after day 7 (Prevalence Ratio [95% CI])0.25 (0.07, 0.82)

Misra 2009

Villarruel

Sindhu

−Proportion underweight (WAZ <2 SD) at week 4 (Prevalence Ratio [95% CI])1.66 (0.83, 3.30)

−Proportion stunted (HAZ <2 SD) at week 4 (Prevalence Ratio [95% CI])1.77 (1.00, 3.13)

−Proportion wasted (WHZ <2 SD) at week 4 (Prevalence Ratio [95% CI])0.53 (0.16, 1.71)

(Prevalence Ratio [95% CI]) 1.03 (0.54, 1.98)

2014 [52] 8xviiCFUORS onlyProportion with diarrhea at day 12 (Prevalence Difference [95% CI])0.17 (0.08, 0.26)ORS with17,938 10L. reuteri

Proportion with diarrhea requiring hospitalization during follow-up

Dinleyici

0.64 (0.43, 0.96)

supplemented

supplemented

vs. non-

xviiixixor bothdaily for 15 days), PlaceboProportion with diarrhea on day 7 (Prevalence Ratio [95% CI])Zinc-

≥Table 2Intervention effects on post-acute (7 days after enrollment) mortality, length, weight, and/or diarrhea presence(Continued)

ReferenceInterventionComparatorRelevant Outcomes and Results

daily for 15 days), zinc acetate (14.2 mg

1999 [34] μVitamin A (4500g retinol equivalent

Therapeutic Micronutrients (Vitamin A and Zinc)

Faruque

0.78 (0.52, 1.49)

supplemented

supplemented

Vitamin A–

vs. non-

0.67 (0.24, 1.85)

supplemented

supplemented

vs. non-

Proportion with diarrhea on day 16 (Prevalence Ratio [95% CI])Zinc-

control 0.11 kg (= 0.045)p

0.67 (0.24, 1.85)

group vs. non-

supplemented

supplemented

xxiZinc group vsMultivitamin syrup onlyDifference in change in weight at day 7 compared to day 1, g

Vitamin A–

vs control 0.07 kg (= 0.21)p

Vitamin A group

2001 [22] Multivitamin syrup with 20 mg elemental

xxormultivitamin syrup with Vitamin A

zinc (twice daily for 7 days), or

both

Khatun

vs. control 0.06 kg (= 0.074)p

Zinc+Vitamin A

control 0.23 (0.08, 0.71)

Proportion with diarrhea at day 7, (Prevalence Ratio [95% CI])Zinc group vs.

vs. control 0.92 (0.54, 1.59)

Vitamin A group

vs. control 0.62 (0.31, 1.21)

Zinc+Vitamin A

Therapeutic Micronutrients (Zinc alone)

xxiizinc Multivitamin syrup onlyProportion of episodes lasting longer than 7 days (Prevalence Ratio [95% CI])0.87 (0.65, 1.16)

(Prevalence Ratio [95% CI]) 0.78 (0.57, 1.07)

Proportion of diarrhea episodes taken to a physician during follow up

1995 [23] Multivitamin syrup with 20 mg elemental

Sazawal

(95% CI) −−0.05 (0.11, 0.01)

weight decreased in control group

group was maintained while body

xxiiiMean body weight in interventionChange in weight at discharge, g

(95% CI) 0.18 (0.02, 1.49)

per kg of body weight, 28 days xxv−−−(95% CI)Day 7:0.57 (1.14,0.002)Multivitamin onlyDifference in weight at day 7 and 14, kg

−−Day 14:0.46 (1.06, 0.14)

−Difference in overall weight increment at day 14, g/kg/day1.60 (1.48, 4.68)

xxiv0.99 (0.53, 1.88)Proportion with diarrhea after day 15 (RR [95% CI])

Risk Difference

zinc, 14 days Multivitamin syrup onlyMortalityRelative Risk

1999 [49] Multivitamin with 3 mg of elemental zinc

[24] Multivitamin syrup with 20 mg elemental

Roy 1998

Bhutta

1. −−Week 2:4 (202.60, 194.60)
2. −−Week 3:45 (303.70, 213.70)
3. −−Week 4:60 (347.70, 227.70)
4. −−Week 5:79 (361.40, 203.40)
5. −−Week 6:57 (354.38, 240.40)
6. −−Week 7:53 (352.70, 246.70)
7. −−Week 8:19.00 (394.15, 356.15)

zinc, 14 days −Multivitamin onlyDifference in weight gain at each week of 8 week follow up, g (95% CI)Week 1: 30 (204.70, 264.73)

−−Day 14:0.40 (1.08, 0.28)

−−Difference in MUAC at day 7 and 14, cm (95% CI)Day 7:0.30 (0.98, 0.38)

−Difference in overall MUAC increment, cm (95% CI)0.00 (0.13, 0.13)

≥Table 2Intervention effects on post-acute (7 days after enrollment) mortality, length, weight, and/or diarrhea presence(Continued)

ReferenceInterventionComparatorRelevant Outcomes and Results

[25] Multivitamin with 20 mg of elemental

Roy 1999

Difference in gain in length at week 8, mm4.40 mm, 30% greater gain (<p

xxvi0.03)

xxviixxviiiRD (95% CI)2.9 (0.80, 5.10)

[27] ORS with 20 mg zinc per day, 14 daysORS onlyIncidence of diarrhea during 2 year follow upRR (95% CI)0.85 (0.76, 0.96)

Baqui 2002

xxixRD (95% CI)2.2 (0.60, 3.70)

Mortality during 2 year follow upRR (95% CI)0.49 (0.25, 0.94)

−−Difference in length at week 4 and 8, cm (95% CI)Week 4:0.09 (0.61, 0.43)

−−Week 8:0.12 (0.63, 0.39)

−Week 8: 0.06 (0.08, 0.20)

2007 [53] −ORS with 10 mg zinc, 14 daysORS with placeboDifference in weight at week 4 and 8, kg (95% CI)Week 4: 0.06 (0.08, 0.20)

1. xxx≥1.01 (0.92, 1.12)Proportion of infants with1 episode of any diarrhea (RR [95% CI])
2. xxxi≥Proportion of infants with2 episode of any diarrhea (RR [95% CI])0.79 (0.67, 0.95)

stool) (RR [95% CI]) 2.10 (0.96, 4.61)

≥Proportion of infants with1 episode of dysentery (any day with blood in the

Walker

SD) 0.62 ± 0.68

group (mean ±

Incidence of diarrhea (episodes/month)Intervention

(mean ± SD) 0.61 ± 0.70

Control group

SD) 2.68 ± 4.11

group (mean ±

Prevalence of diarrhea (days/mo)Intervention

(mean ± SD) 2.20 ± 3.19

Control group

MortalityRR (95% CI)0.99 (0.01, 77.9)

xxxii−−0.18 (66.42,RD (95% CI)

66.06)

xxxivPercent gain in length at 12 weeks, mmComparable between groups when

all patient were compared (= 0.6)p

14 days Difference in mean number of diarrhea episodes during 6 mo follow up (95%

≥Table 2Intervention effects on post-acute (7 days after enrollment) mortality, length, weight, and/or diarrhea presence(Continued)

ReferenceInterventionComparatorRelevant Outcomes and Results

xxxiiiCI)

[28] Multivitamin with 10 mg zinc per 5 ml,

Roy 2007

≤(WAZ70% NCHS median) (p < 0.03)

24% greater among underweight

−−RD (95% CI)0.01 (0.10, 0.07)

MortalityRR (95% CI)0.84 (0.29,2.37)

[29] Multivitamin with 20 mg zinc, 14 daysMultivitamin onlyGeometric mean diarrhea incidenceStatistically significantly higher in

control group (= 0.03)p

Roy 2008

for patients < 1 y PlaceboNumber of subsequent diarrhea episodes during 2 month follow upDifference not significant (= 0.53)p

Weight gain at 2 months, gHigher in intervention group (<p

−−Diarrhea episodes during follow up, months 4–6 (Risk Difference, [95% CI])0.37 (0.35, 1.07)

−−Diarrhea episodes during follow up, months 7–9 (Risk Difference, [95% CI])0.18 (0.41, 0.75)

follow up (95% CI) −0.06 (0.07, 0.19)

xxxv−months 1–3 Risk Difference, [95% CI])1.02 (0.26, 1.79)Diarrhea episodes during follow up,

−Diarrhea episodes during entire 9 month follow up (Risk Difference, [95% CI])0.54 (0.07, 1.01)

−Difference in mean number of days of diarrhea during 3 month follow up (95% CI)0.2 (0.35, 0.75)

0.001)

10 days Difference in mean number of diarrhea episodes during 3 month

followed by 3 mo supplementary zinc

[31] Short course zinc–20 mg zinc, 5 daysStandard course zinc–20 mg zinc,

by 3 mo supplementary zinc (10 mg) 10 days therapeutic zinc (20 mg)

placebo

2010 [30] 10 days therapeutic zinc (20 mg) followed

2008 [48] 20 mg zinc for patients > 1 y; 10 mg zinc

Alam 2011

Larson

Fajolu

xxxviiDay of onset of first subsequent diarrhea episode during follow upNo difference between groups

xxxviCI]) 0.63 (0.50, 0.79)

CI]) 0.63 (0.48, 0.81)

up (RR [95% CI]) 1.03 (0.95, 1.14)

≥Proportion of children with persistent diarrhea (14 days) (Prevalence Ratio [95%

≥Proportion of children with prolonged diarrhea (7 days) (Prevalence Ratio [95%

Proportion of children with at least 1 episode of diarrhea during 3 month follow

placebo 1.01 (0.76, 1.33)

placebo 0.96 (0.72, 1.27)

placebo 2.25 (1.10, 4.63)

Zinc + Copper

Ratio [95% CI]) Zinc group vs

(Prevalence Ratio [95% CI]) Zinc group vs

group vs

14 days PlaceboProportion with at least 1 diarrhea episode during 3 month follow up (Prevalence

xxxviiiProportion with at least 2 episodes of diarrhea during 3 month follow up

[32] Zinc (2 mg/kg/day) or zinc + copper (Zn

2 mg/kg/day + Cu 0.2 mg/kg/day),

Patel 2013

group 1.12 (0.64, 1.97)

Zinc + Copper

Zinc group vs

placebo 1.31 (0.30, 5.77)

follow up (Prevalence Ratio[95% CI]) Zinc group vs

Proportion with at least 1 dysentery episode during 3 month

group 1.37 (0.31, 6.04)

Zinc + Copper

Zinc group vs

placebo −−0.01 (0.18, 0.16)

placebo −−0.1 (0.12, 0.10)

placebo −0.08 (0.05, 0.21)

placebo −0.05 (0.07, 0.17)

placebo −0.06 (0.04, 0.16)

placebo −0.09 (0.07, 0.25)

placebo −0.03 (0.08, 0.14)

placebo −0.02 (0.09, 0.13)

Zinc + copper

Zinc + copper

Zinc + copper

Zinc + copper

Difference in change in WAZ at month 3 (95% CI)Zinc group vs

Difference in change in WHZ at month 3 (95% CI)Zinc group vs

Difference in change in HAZ at month 3 (95% CI)Zinc group vs

3 month follow up (95% CI) Zinc group vs

group vs

group vs

group vs

group vs

Difference in mean number of subsequent diarrhea episodes per child during

≥Table 2Intervention effects on post-acute (7 days after enrollment) mortality, length, weight, and/or diarrhea presence(Continued)

ReferenceInterventionComparatorRelevant Outcomes and Results

subjects 0.65 (0.37, 1.23)

[95%]) Among all

[33] Zinc (20 mg/day) for 14 daysPlaceboRisk of having at least 1 episode of diarrhea during 3 mo follow up (Relative risk

Negi 2015

xxiNo SDs or CIs given for differences. P-value for the difference between zinc group and control is 0.045; for the difference between vitamin A group and control is 0.207; and for the difference between zinc + vitamin

subjects (= 60)n 0.65 (0.31, 1.38)

xixResults from comparison of zinc+vitamin A vs. placebo not reported (reported on zinc effect by combing the zinc alone and zinc+vitamin A group and reported on vitamin A effect by combining vitamin A alone

xviiiThe authors changed the dose after 417 children were enrolled (dosages listed, analyzed as "standard strata" of subjects), and the remaining 273 children received a higher dose of zinc (analyzed as "high dose

ivDuration of diets was variable. Diets were started at low concentrations and were advanced every 48 hours if no sign of intolerance. If there were signsof intolerance, diets were maintained or decreased as

Among zinc-

deficient

xvConfidence interval states in manuscript is (0.605, 0.090) which does not contain the relative risk estimate of 0.812 therefore have assumed the 0.090 was a typo and replaced with 1.090.

viiiUnits were assumed to be cm/y due to description of results in the manuscript (rather than (cm/y)2 as presented in the studys Four)’

ixDefined as age- and sex-specific weight standard deviation scores, from the National Center for Health Statistics median value

iEstimate may be interpreted as 11 fewer deaths per 100 children in the intervention group compared to the control group

viiAll outcome measurements were compared against measurements at entry, when the child had had diarrhea for 14 days

strata"): Vitamin A (4500 ug retinol equivalent daily for 15 days) and/or zinc acetate (40 mg daily for 15 days)

viDefined as when diarrhea had ceased and patient had consistent weight gain for at least 48 hours

iiQuantitative estimates not presented and reported p-values not specific to time-points of interest

necessary. When full concentrations were reached, the diet was given for an additional 7 days.

vAppropriate data for calculation of weight gain or difference in weight gain not presented

xxVitamin A dosage was 100000 IU for children < 1 yo, and 200000 for children > 1 yo

xiAll diets were equivalent in caloric and protein content

iiiData presented were assumed to be mean ± SD

xivNo estimates or statistical significance is given

xviNo estimates or statistical significance given

xiiiNo estimate or statistical significance given

xiiNo estimate or statistical significance given

xviiRR was undefined due to a0cell“”

xxiiDuration of intervention is unclear

xNo quantitative estimates given

with the zinc+vitamin A group).

A group is 0.074.

xxxviThe authors reported "The proportion of prolonged (>=7 d) and persistent diarrhea episodes (>=14 d) did not vary between the 5-d (19 vs. 16%; P 0.08) and10-d (12 vs. 10%; P = 0.14) groups" which suggests the

p-values correspond to the comparison of persistent and prolonged among children treated with 5-days and among children treated with 10-days. We have instead assumed the appropriate comparisons are propor-

xxxAll data presented are unadjusted. The authorsresults are discrepant from this tables results, as authors adjust for original diarrhea episode lasting > 7 days, exclusive breastfeeding upon enrollment, and WLZ at’’

xxviiDifference in mean diarrhea incidence rates. Estimate may be interpreted as 2.9 more episodes per 100 child-years of observation were experienced inthe control group compared to the intervention group

xxixDifference in mean mortality rates. Estimate may be interpreted as 2.2 more deaths per 1000 child years of observation experienced by the control group compared to the intervention group

tion of prolonged (19% vs. 12%, p-value=0.0001) and persistent (16% vs. 10%, p-value=0.0004) which would result in statistically significant differences (unlike what was reported).

xxxiCalculated values of lower and upper limits of 95% CI use data presented on unadjusted proportions and differed from what was represented in original publication

xxvFor this and all outcomes, data were not labeled. Data presented were assumed to be mean and SD based on labeled data on another figure in the paper

xxivAssessed by proportion of patients with delayed recovery, with recovery defined as the passage of formed stool followed by 2 days without diarrhea

xxxiiEstimate may be interpreted as 0.18 deaths fewer in intervention group per 100,000 child-weeks of observation compared to control group

xxxvRisk differences may be interpreted as excess number of acute diarrhea episodes per child-year attributed to lack of zinc supplementation

xxxviiiEstimates calculated for relative risk of at least 1, 2, or dysenteric diarrhea episodes are discrepant from published results

xxviiiCalculated values of lower and upper limits of 95% CI differed from what was represented in original publication

xxiiiData were presented but were not interpretable due to an ambiguous or incorrect title

xxxiiiData presented was assumed to be mean ± SD

xxxviiNo estimates or statistical significance given

xxxivQuantitative estimates not presented

xxviNo SDs or CIs given. P< 0.05.

beginning of follow up

1. a
2. b

1. 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)

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,

1. 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,

1. 2 (both high protein) reported a statistically significant improvement (ranging from 0.23 [11] to 0.3 z-scores

1. [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
2. [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

1. a
2. b
3. c
4. d

1. Fig. 4 (See legend on next page.)

(See figure on previous page.)

1. 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)
2. Fig. 5 Effect of diarrhea management interventions on diarrhea morbidity during follow up (relative risk or prevalence ratio of diarrhea at specified time during follow up [95% CI])

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].

[51]. The single dietary fiber and probiotic trials evaluating weight gain did not find a significant effect [26, 47].

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%

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

1. 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, 32–34, 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

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 [67–69]. The combination of high protein and zinc may restore integrity of damaged mucosal surfaces and improve nutrient absorption [70–72]. 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 [75–77].

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, 78–80]. 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 [85–87].

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.

Additional file

Additional file 1: Supplement. (DOCX 129 kb)

Abbreviations CI: Confidence Interval; GRADE: Grading of Recommendations Assessment Development and Evaluation; HAZ: Height-for-age z-score; LAZ: Length-forage z-score; LMICs: Low- and middle-income countries; MSD: Moderate-tosevere diarrhea; MUAC: Mid upper arm circumference; PR: Prevalence Ratio; RCT: Randomized controlled trial; RR: Relative Risk; RUTF: Ready-to-use therapeutic foods; WAZ: Weight-for-age z-score; WHZ: Weight-for-height zscore; WLZ: Weight-for-length z-score

Acknowledgements We would like to thank the Global Center for Integrated Health of Women, Adolescents, and Children, the Kenya Research and Training Center, and the Center for AIDS Research Enterics Working group for their support during the preparation of this article.

Funding Funding was provided by the Bill and Melinda Gates Foundation (OPP1132140) and the UW Global Center for Integrated Health of Women, Adolescents and Children (Global WACh). JLW and DMD are supported by the Childhood Acute Illness and Nutrition Network (CHAIN, OPP1131320). GJS is supported by a National Institute of Health mentoring award (grant number K24- HD054314) and PBP and GJS are supported by the International Core of the University of Washington Center for AIDS Research (CFAR; Seattle, WA, USA), an NIH funded program (P30 AI027757). The funders had no role in the study design, data abstraction, data interpretation, or writing of the manuscript.

Availability of data and materials All data generated or analyzed during this study are included in this published article.

Authors’ contributions PBP, JLW, DMD, and GJS conceived of the idea and developed the protocol for this review. All titles and abstracts were screened by PBP and HEA, RLB and HEA reviewed all abstracts and full text articles with final input from PBP. RLB and HEA abstracted data from, and conducted GRADE assessments of, included studies. All authors contributed to the development, reading, and approving the final version for publication.

Ethics approval and consent to participate Not applicable

Consent for publication Not applicable

Competing interests The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author details Department of Global Health, University of Washington, Seattle, WA, USA.

1. 2Department of Epidemiology, University of Washington, Seattle, WA, USA.
2. 3Department of Pediatrics, University of Washington, Seattle, WA, USA.
3. 4Department of Medicine (Infectious Disease), University of Washington, Seattle, WA, USA. 5Department of Health Services, University of Washington, Seattle, WA, USA. Received: 7 August 2017 Accepted: 17 January 2018

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