Abstract
Background
Probiotics may be effective in reducing the duration of acute infectious diarrhoea.
Objectives
To assess the effects of probiotics in proven or presumed acute infectious diarrhoea.
Search methods
We searched the trials register of the Cochrane Infectious Diseases Group, MEDLINE, and Embase from inception to 17 December 2019, as well as the Cochrane Controlled Trials Register (Issue 12, 2019), in the Cochrane Library, and reference lists from studies and reviews. We included additional studies identified during external review.
Selection criteria
Randomized controlled trials comparing a specified probiotic agent with a placebo or no probiotic in people with acute diarrhoea that is proven or presumed to be caused by an infectious agent.
Data collection and analysis
Two review authors independently applied inclusion criteria, assessed risk of bias, and extracted data. Primary outcomes were measures of diarrhoea duration (diarrhoea lasting ≥ 48 hours; duration of diarrhoea). Secondary outcomes were number of people hospitalized in community studies, duration of hospitalization in inpatient studies, diarrhoea lasting ≥ 14 days, and adverse events.
Main results
We included 82 studies with a total of 12,127 participants. These studies included 11,526 children (age < 18 years) and 412 adults (three studies recruited 189 adults and children but did not specify numbers in each age group). No cluster‐randomized trials were included. Studies varied in the definitions used for "acute diarrhoea" and "end of the diarrhoeal illness" and in the probiotic(s) tested. A total of 53 trials were undertaken in countries where both child and adult mortality was low or very low, and 26 where either child or adult mortality was high.
Risk of bias was high or unclear in many studies, and there was marked statistical heterogeneity when findings for the primary outcomes were pooled in meta‐analysis. Effect size was similar in the sensitivity analysis and marked heterogeneity persisted. Publication bias was demonstrated from funnel plots for the main outcomes.
In our main analysis of the primary outcomes in studies at low risk for all indices of risk of bias, no difference was detected between probiotic and control groups for the risk of diarrhoea lasting ≥ 48 hours (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.91 to 1.09; 2 trials, 1770 participants; moderate‐certainty evidence); or for duration of diarrhoea (mean difference (MD) 8.64 hours shorter, 95% CI 29.4 hours shorter to 12.1 hours longer; 6 trials, 3058 participants; very low‐certainty evidence).
Effect size was similar and marked heterogeneity persisted in pre‐specified subgroup analyses of the primary outcomes that included all studies. These included analyses limited to the probiotics Lactobacillus rhamnosus GG and Saccharomyces boulardii. In six trials (433 participants) of Lactobacillus reuteri, there was consistency amongst findings (I² = 0%), but risk of bias was present in all included studies. Heterogeneity also was not explained by types of participants (age, nutritional/socioeconomic status captured by mortality stratum, region of the world where studies were undertaken), diarrhoea in children caused by rotavirus, exposure to antibiotics, and the few studies of children who were also treated with zinc. In addition, there were no clear differences in effect size for the primary outcomes in post hoc analyses according to decade of publication of studies and whether or not trials had been registered.
For other outcomes, the duration of hospitalization in inpatient studies on average was shorter in probiotic groups than in control groups but there was marked heterogeneity between studies (I² = 96%; MD ‐18.03 hours, 95% CI ‐27.28 to ‐8.78, random‐effects model: 24 trials, 4056 participants). No differences were detected between probiotic and control groups in the number of people with diarrhoea lasting ≥ 14 days (RR 0.49, 95% CI 0.16 to 1.53; 9 studies, 2928 participants) or in risk of hospitalization in community studies (RR 1.26, 95% CI 0.84 to 1.89; 6 studies, 2283 participants).
No serious adverse events were attributed to probiotics.
Authors' conclusions
Probiotics probably make little or no difference to the number of people who have diarrhoea lasting 48 hours or longer, and we are uncertain whether probiotics reduce the duration of diarrhoea. This analysis is based on large trials with low risk of bias.
Plain language summary
Do probiotics help to treat acute infectious diarrhoea?
What is the aim of this review?
Acute infectious diarrhoea is a major global disease that particularly affects people in low‐ and middle‐income countries. We wanted to know if taking probiotics is helpful in shortening the time taken for symptoms to resolve. We searched for studies that looked at the use of probiotics in people with acute diarrhoea. We looked for studies in which the treatments people received were decided randomly; these usually give reliable evidence.
Key messages
Probiotics may not affect how long acute diarrhoea lasts. We do not know if they can shorten the time to recovery from diarrhoea. We need reliable evidence from further studies to determine whether probiotics help treat acute infectious diarrhoea.
What was studied in the review?
”Diarrhoea” is the name for frequent bowel movements or the passing of unusually soft or watery faeces. Infections of the gut by bacteria, viruses, or parasites cause acute diarrhoea and are most often spread through water contaminated with faeces. Acute diarrhoea usually improves within a few days. However, in severe acute diarrhoea, water, salts, and nutrients that may be lost from the body are substantial, causing dehydration and even death. Treatments for acute diarrhoea aim to prevent or reverse dehydration, speed up recovery time, and shorten the time that a person may pass the infection to others.
Probiotics are live bacteria and yeasts that are thought to restore the natural balance of bacteria in the gut (intestines) when this has been disrupted by illness or treatment. Probiotics are often described as "good" or "friendly" bacteria; they may be present in yoghurts or taken as food supplements. In acute infectious diarrhoea, probiotics may act against the harmful microbes that are causing diarrhoea, help the gut to fight them, or reduce inflammation and damage to the gut.
What are the main results of the review?
We found 82 studies in 12,127 people (mostly children) with acute diarrhoea. Only 26 studies took place in countries that had high numbers of deaths (of any cause) among adults and children.
These studies compared the effects of different types of probiotics with no additional treatment or with a placebo (dummy) treatment. We were interested in:
• how many people had diarrhoea longer than 48 hours; and • how long, on average, the symptoms of diarrhoea lasted.
There were many differences in the ways these studies were designed and carried out. Studies used different definitions of "acute diarrhoea" and "the end of diarrhoea symptoms," and they tested many different probiotics. Therefore, we could not include the results of all studies in our analysis.
We did not detect a difference between taking a probiotic and taking a placebo or no additional treatment in the number of children who had diarrhoea longer than 48 hours (two studies in high‐income countries; 1770 children). We are uncertain whether taking probiotics affects the length of time that the symptoms of diarrhoea last (six studies; 3058 people). These findings were not affected by age, nutritional and socioeconomic status, region, or rotavirus infection of participants, nor by whether they were taking antibiotic medicines or zinc supplements.
Taking probiotics may not have affected:
• how many people had diarrhoea longer than 14 days (nine studies; 2928 people); or • how many people were admitted to hospital with diarrhoea (six studies; 2283 people).
It was unclear whether taking probiotics shortened the time spent in hospital compared with taking a placebo or no additional treatment (24 studies; 4056 people). Few studies reported on any unwanted effects of probiotics; no serious unwanted effects were reported among people who took probiotics.
How reliable are these results?
Previous published editions of this review drew conclusions from the many small studies in this field and indicated an effect.
This new analysis shows that in this topic there is publication bias, with small studies demonstrating a positive effect more likely to be published, which skews the results. This fresh analysis takes this into account.
How up‐to‐date is this review?
We included evidence published up to 17 December 2019.
Summary of findings
Summary of findings 1. Summary of findings table 1.
| Probiotic compared to placebo for treating acute infectious diarrhoea (analysis limited to studies at low risk of bias) | ||||||
| Patient or population: children and adults with acute infectious diarrhoea Setting: trials undertaken in health facilities and/or in the community in any country Intervention: probiotic Comparison: placebo or no probiotic/standard care | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with placebo | Risk with probiotic | |||||
| Diarrhoea lasting ≥ 48 hours | 536 per 1000 | 536 per 1000 (488 to 584) | RR 1.00 (0.91 to 1.09) | 1770 (2 RCTs) | ⊕⊕⊕⊝
MODERATEa Due to indirectness |
Probiotics probably make little or no difference to the number of people who have diarrhoea lasting 48 hours or longer |
| Mean duration of diarrhoea (hours) | ‐ | MD 8.64 hours lower (29.38 lower to 12.1 higher) | ‐ | 3058 (6 RCTs) | ⊕⊝⊝⊝
VERY LOWb,c Due to imprecision and inconsistency |
We are uncertain whether or not probiotics reduce the duration of diarrhoea |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio. | ||||||
| GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
aDowngraded by 1 for indirectness. Both trials conducted in high‐income countries and evaluating two probiotics. bDowngraded by 1 for imprecision. 95% confidence interval for the pooled estimate of probiotic effect includes a significant beneficial effect as well as the possibility that the duration of diarrhoea may be longer in people receiving probiotics. cDowngraded by 2 for serious inconsistency. Probiotic effect varied markedly between trials, represented by an I² value of 97%.
Background
Probiotics are recommended by some authorities for treatment of acute infectious diarrhoea, but the evidence base is limited. We updated our previous review (Allen 2010), to re‐evaluate the evidence for their use.
Description of the condition
Diarrhoea is defined by the World Health Organization (WHO) as three or more loose or watery stools (taking the shape of the container) in a 24‐hour period. Diarrhoea is classified as acute if the illness started less than 14 days previously, and as persistent if the episode has lasted 14 days or longer (Anonymous 1988). Normal infants who are exclusively breast‐fed may pass loose, "pasty" stools frequently. For this group, the definition is usually based on what the mother considers to be diarrhoea (WHO 1990). Infectious diarrhoea is an episode of diarrhoea that is caused by an infectious agent.
Although mortality due to diarrhoea fell by more than 30% between 2000 and 2015, diarrhoea accounted for 526,000 under five deaths in 2015 and was the second leading cause of death in children aged one to 59 months (Liu 2016a). Mortality rates amongst children have decreased despite low global usage of oral rehydration solution (ORS) and zinc for acute diarrhoea, with 43% of children globally receiving ORS between 2011 and 2016, and only an additional 9% receiving ORS plus zinc within the same period (UNICEF 2018). In industrialized countries, the trend is quite different, with deaths from infectious diarrhoea occurring mainly among the elderly (Savarino 1993). The incidence of childhood diarrhoea has seen a less promising decline (Das 2014). For children under five in low‐ and middle‐income countries, diarrhoea incidence declined from 3.4 episodes per child per year to 2.9 episodes between 1990 and 2010 (Fischer‐Walker 2012), and diarrhoea still accounts for a large proportion of hospital admissions (Das 2014).
More than 20 viruses, bacteria, and parasites are associated with acute diarrhoea (Gadewar 2005). The 2013 Global Enteric Multicenter Study (GEMS) and its subsequent reanalysis in 2016 identified six pathogen groups responsible for 77.8% of moderate to severe diarrhoeal episodes in children under five in countries in Africa and Asia: the bacteria Shigella spp, Campylobacter spp, and heat‐stable enterotoxin‐producing Escherichia coli (ST‐ETEC); the viruses rotavirus and adenovirus 40/41; and the parasite Cryptosporidium spp (Kotloff 2013; Liu 2016b). Although Shigella spp was the dominant pathogen associated with dysentery, it also accounted for a large burden of watery diarrhoea (Liu 2016b). In an extension of the GEMS study, the spectrum of pathogens causing less severe diarrhoea in under five children was similar to that causing more severe episodes, with norovirus GII also identified as an important pathogen in children under one year (Kotloff 2019). Acute diarrhoea is frequent among travellers, in whom enterotoxigenic E coli is particularly common (Black 1986).
In practice, most episodes of acute diarrhoea that are assumed to be caused by an infectious agent are treated without identification of the causative agent. WHO guidelines base treatment on clinical presentation (level of dehydration, malnutrition) and recommend additional management only for dysentery or suspected cholera (WHO 2005). Similarly, the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) recommends that, although some clinical features vary with different infectious diarrhoeal aetiologies, children with acute gastroenteritis do not routinely need to undergo investigation for the causative pathogen (Guarino 2014). Current WHO guidelines for children in low‐ and middle‐income countries recommend that in addition to fluid therapy for children with acute non‐bloody diarrhoea without severe dehydration, zinc supplementation should be given (WHO 2005).
Description of the intervention
The aims of treatment are to prevent or reverse dehydration, shorten the duration of illness (important for preventing progression to persistent diarrhoea, which is associated with adverse outcomes such as malnutrition), and reduce the period that a person is infectious. Available treatment options include oral and parenteral rehydration, zinc supplementation in children, antibiotics, adsorbents such as smectite, and probiotics.
For treatment of acute diarrhoea, Cochrane Reviews have examined ORS versus IV fluid (Hartling 2006), zinc supplementation (Lazzerini 2016), smectite (Pérez‐Gaxiola 2018), rice‐based oral rehydration solution (Fontaine 1998), polymer‐based oral rehydration solution (Gregorio 2016), and antiemetics in children and adolescents (Fedorowicz 2011). This review examines probiotics.
A recent expert panel created by the International Scientific Association for Probiotics and Prebiotics (ISAPP) recommended retaining the Food and Agriculture Organization of the United Nations (FAO)/WHO definition for probiotics as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” (Hill 2014). Common probiotics include the Lactobacillus and Bifidobacterium species of bacteria and the Saccharomyces species of yeast (Williams 2010).
How the intervention might work
Probiotics may improve infectious diarrhoea through multiple mechanisms including overt anti‐pathogen effects (competition for nutrients and binding sites within the gut, producing substances such as bacteriocins and organic acids, and neutralizing bacterial toxins) and general effects such as stimulation of mucosal immune responses and reduction of intestinal inflammation and permeability (Guarner 2012; Halloran 2019; Surendran Nair 2017). Relevant to pooling results of different probiotic organisms, the ISAPP expert panel proposes that there may be "core" mechanisms, such as competitive exclusion of pathogens, that are common to many probiotics, whilst mechanisms such as immunological effects are likely to be species or strain specific. The panel concludes that a specific strain and dose must be defined before a health claim can be made for a probiotic (Hill 2014). Therefore, reliable identification of organisms at the strain level is necessary for clinical studies.
A 2011 systematic review on the safety of probiotics, based on their use in clinical trials, concluded that no increase in adverse outcomes was seen in probiotic groups (Hempel 2011). However, case studies suggest that particularly vulnerable patients may be at increased risk for adverse events, mostly gastrointestinal in nature, such as diarrhoea, vomiting, and constipation. An overview of specific populations studied in clinical trials identified one case of invasive disease in an immunocompromised patient and noted that better documentation on the safety of probiotics is needed (Doron 2015). Concerns regarding the safety of probiotics are especially pertinent for highly vulnerable patients such as children receiving intensive care (Yelin 2019), as well as adults with severe acute pancreatitis (Besselink 2008).
Why it is important to do this review
Findings from the previous version of this Cochrane Review show that when probiotics were used, the mean duration of diarrhoea was shorter, and fewer children had diarrhoea lasting four days or longer. However, due to substantive heterogeneity of effect size between studies, evidence was insufficient to show a specific probiotic regimen as more effective than another (Allen 2010). Since the 2010 review, probiotics for the treatment of acute infectious diarrhoea have been evaluated in many more randomized controlled trials. However, in spite of this increased evidence base, recent systematic reviews have not identified a specific probiotic preparation for use in clinical practice. In a meta‐analysis, probiotics reduced the duration of diarrhoea among children (weighted mean difference ‐0.67 days, 95% confidence interval (CI) ‐0.95 to ‐0.38; Salari 2012). In children from middle‐ and high‐income countries, probiotics reduced diarrhoea duration by 14% (95% CI 3.8% to 24.2%) and stool frequency on day two by 13.1% (95% CI 0.8% to 25.3%; Applegate 2013). In both meta‐analyses, evidence was insufficient to support a specific strain or regimen. Finally, two recent studies each recruited a large number of participants, potentially making a significant contribution to the evidence base (Freedman 2018a; Schnadower 2018).
The 4th Triennial Yale/Harvard Workshop on Probiotic Recommendations considered that there was a good level of evidence to recommend Lactobacillus GG, Saccharomyces boulardii, and Lactobacillus reuteri SD2112 for treatment of infectious childhood diarrhoea (Floch 2015). In contrast, the European Society of Paediatric Gastroenterology and Nutrition strongly recommended two strains ‐ Saccharomyces boulardii and Lactobacillus rhamnosus GG ‐ but with support of only low‐quality evidence (Guarino 2015). Consistent with findings of the meta‐analysis, a review of six guidelines on the use of probiotics in acute infectious diarrhoea in children highlighted marked variability in the recommendations for which probiotic strain and dose should be used in clinical practice (Guarino 2015). A recent clinical practice guideline based on a systematic review by the American Gastroenterological Association recommended that probiotics should not be used for treatment of acute infectious diarrhoea in children in the USA and Canada (conditional recommendation based on moderate‐quality evidence; Su 2020).
We intended to assess whether the addition of trials undertaken since our previous review would reduce the statistical heterogeneity between studies, and whether there was greater evidence for any specific probiotic preparation. We also aimed to identify evidence gaps to ensure that further research informs the development of clinical guidelines.
Objectives
To assess the effects of probiotics in proven or presumed acute infectious diarrhoea.
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials reporting the effects of probiotic(s) on acute infectious diarrhoea. To maximize the use of available data, we included participants of all ages and non‐blinded (open) studies; however, to keep results as robust as possible, we did not include quasi‐randomized and unpublished studies. We also did not include studies of probiotics in acute diarrhoea that did not report clinical outcomes (e.g. effect on rotavirus shedding in stools).
Types of participants
Adults and children with acute diarrhoea (duration < 14 days) that was proven or presumed to be caused by an infectious agent. To maximize the relevance of our findings for clinical practice, we included studies in which participants with acute diarrhoea had received antibiotics.
We excluded studies on diarrhoea known or thought to have other causes (e.g. studies on antibiotic‐associated diarrhoea, studies of persistent diarrhoea).
Types of interventions
Interventions
Specific probiotic preparations (single strains and combinations of organisms).
Excluded was yogurt or other fermented foods in which specific probiotic organisms were not identified and killed probiotics.
Control
Placebo or no probiotic.
Intervention and control arms to be otherwise treated identically in relation to other treatments and drugs including zinc.
Types of outcome measures
In view of recent expert recommendations for a core outcome measurement set for acute diarrhoea in children (Karas 2016), we revised our outcomes to include the number of people hospitalized in community studies and the duration of hospitalization in inpatient studies as secondary outcomes. The Expert Panel also recommended degree of dehydration as an outcome measure. However, we did not include this outcome as it was rarely reported in trials included in our previous review (Allen 2010). We included diarrhoea lasting 14 days or longer to examine the proportion of patients progressing to persistent diarrhoea (Walker‐Smith 1993). We included studies that reported one or more of the following primary or secondary outcomes.
Primary outcomes
Diarrhoea lasting ≥ 48 hours
Duration of diarrhoea
Secondary outcomes
Numbers of people hospitalized in community studies
Duration of hospitalization in inpatient studies
Diarrhoea lasting ≥ 14 days
Adverse events
Incidence of adverse events (serious and non‐serious)
Search methods for identification of studies
Electronic searches
We attempted to identify all relevant studies regardless of language.
We searched the Cochrane Infectious Diseases Group's trials register using the following search terms: diarrhoea/; diarr$(tw); diarrhoea(tw); probiotic(tw); Lactobacill$(tw); Lactococc$(tw); Bifidobacter$(tw); Enterococc$(tw); Streptococc$(tw); Saccharomyces(tw). Full details of the methods of the Cochrane Infectious Diseases Group and the journals handsearched are published in the Cochrane Library in the section on 'Collaborative Review Groups'.
We searched the Cochrane Controlled Trials Register, published on the Cochrane Library, using the following search terms: diarrhea/; diarr$(tw); diarhea(tw); probiotic(tw); Lactobacill$(tw); Lactococc$(tw); Bifidobacter$(tw); Enterococc$(tw); Streptococc$(tw); Saccharomyces(tw).
We searched MEDLINE and Embase using the search strategy defined by Cochrane (Clarke 2003), and we used the following search terms: diarrhea/; diarr$(tw); diarhea(tw); probiotic(tw); Lactobacill$(tw); Lactococc$(tw); Bifidobacter$(tw); Enterococc$(tw); Streptococc$(tw); Saccharomyces(tw).
The detailed search strategy is shown in Appendix 1.
Searching other resources
In preparation for the original review (Allen 2003), we contacted organizations and individuals working in the field, as well as the following pharmaceutical companies that manufacture probiotic agents, to help identify additional published trials: BioGaia Biologics, Lund, Sweden; Nestle Foundation, Lausanne, Switzerland; Probiotics International Ltd, Somerset, UK; Ross Products Division of Abbott Laboratories, Columbus, Ohio, USA; and Yakult, London, UK. We did not re‐contact individuals or companies for this update.
We also drew on existing reviews of this topic and checked the citations of all trials identified by the above methods.
Data collection and analysis
SC, AD, and SA independently extracted data using standard forms. The number of participants recruited and the number for whom outcome data were reported were extracted and included in the Characteristics of included studies table.
In keeping with the ISAPP understanding of potential beneficial effects that are common to all probiotics (Hill 2014), the primary analysis pooled the findings from all eligible studies of probiotics in acute diarrhoea. We pooled data from studies that used comparable outcome measures. We reported the proportion of participants for whom outcome data were available in a ’Risk of bias’ table for each study.
Selection of studies
Two review authors independently reviewed the titles of articles and, when available, abstracts generated by the search to identify potentially relevant studies. All articles that could meet the inclusion criteria as identified by either of the review authors were selected and the full article reviewed. Eligibility was assessed independently by these two people using a standard form and based on the information presented in the article. We planned to contact trial authors if eligibility was unclear. Discrepancies among reviewers' eligibility assessments were resolved by discussion. Trial reports were scrutinized to ensure that multiple publications from the same trial were included only once. We have listed excluded studies and the reasons for their exclusion in the Characteristics of excluded studies table.
Data extraction and management
Two review authors independently extracted data using standard forms and compared the results. Key data items were participants' characteristics (nutrition and hydration status), location (countries classified according to region and mortality stratum, reflecting the level of child and adult mortality; WHO 2001), aetiology and duration of diarrhoea, details of probiotic organism(s), management as inpatients versus outpatients; and the outcome measures listed above. The number of participants recruited and the number for whom outcome data were reported were extracted, and details of studies were entered into the Characteristics of included studies table.
For dichotomous outcomes, we extracted the number of participants experiencing the event and the total number of participants in each intervention group. For continuous outcomes, we extracted arithmetic means, standard deviations (SDs), and numbers of participants in each intervention group. We calculated mean and standard deviation from median and interquartile range for non‐skewed data.
We also reported in the Characteristics of included studies table findings of trials that presented data that could not be included in pooled analyses (e.g. median and interquartile range (IQR) from skewed data) and outcomes other than primary and secondary outcomes.
Assessment of risk of bias in included studies
Two review authors independently assessed the risk of bias for each trial using the Cochrane ’Risk of bias’ assessment tool (Higgins 2012). Risk of bias was based on primary outcomes and was categorized as low (adequate measures taken), high (inadequate measures taken), or unclear.
Risk of bias was assessed according to generation of allocation sequence, allocation concealment, blinding of participants, blinding of outcome assessment, loss to follow‐up, and outcome reporting, and was recorded on a standard form.
We considered the generation of allocation sequence to be adequate if the study authors stated that they used a method resulting in unpredictable sequences (such as a random numbers table or list or computer‐generated random numbers), unclear if a trial was stated to be randomized but no further information was provided, and inadequate when allocation could be related to prognosis and therefore was at risk of selection bias (e.g. based on date of birth or date of admission to hospital).
We considered allocation concealment to be adequate if assignment to arms of the study could not be predicted by the investigators or participants (e.g. central randomization or numbered, identical drug containers), unclear if the method used was not described, and inadequate if a method such as alternation was used by which the allocation of participants could be predicted.
We considered blinding of participants to be adequate when an identical placebo was used and recruitment to intervention or control arms was not known by the participant, unclear if methods of blinding were not described adequately, and inadequate when blinding was not used.
We considered blinding of outcome assessment to be adequate when recruitment to intervention or control arms was not known by the investigator, unclear if methods of blinding or assessors were not described adequately, and inadequate when blinding was not used or when study authors stated that unblinding had occurred.
We considered loss to follow‐up to be adequate when study endpoints were reported in both intervention and control groups for 90% or more of participants enrolled at the beginning, inadequate when follow‐up was less than 90% in either group, and unclear when the number of participants recruited at the beginning of the study and/or the number of participants who completed the study was not clear.
We considered outcome reporting to be adequate if all outcomes specified in the methods were reported fully in the results; inadequate if any intended outcomes were not reported or were not reported adequately, or if reported outcomes were not pre‐specified; and unclear if it was not possible to judge based on the information given.
An independent person resolved disagreements regarding the assessment of risk of bias.
Measures of treatment effect
For the number of participants with diarrhoea lasting ≥ 48 hours, the number of people hospitalized in community studies, and the number with diarrhoea lasting 14 days or longer, we calculated a pooled estimate of the risk ratio (RR) among probiotic and non‐probiotic groups. For duration of diarrhoea and duration of hospitalization in inpatient studies, we achieved a pooled estimate of treatment effect by calculating the weighted mean difference between groups.
Unit of analysis issues
For trials with multiple treatment groups but a single control arm (no additional treatment or placebo), we selected the treatment group that was most relevant to contributing to the evidence base for use of a specific probiotic preparation. All intervention groups are detailed in the Characteristics of included studies table.
Dealing with missing data
We performed intention‐to‐treat analysis of available case data with no imputation of missing values; we excluded data if reported only from a per‐protocol analysis. In studies reporting continuous outcomes, if required, we calculated SDs from 95% CIs and standard errors.
Assessment of heterogeneity
We inspected forest plots to detect non‐overlapping CIs, applied the Chi² test and implemented the I² statistic (with value ≥ 50%) to assess heterogeneity in findings.
Assessment of reporting biases
We inspected funnel plots and undertook statistical analysis for the primary outcomes to assess publication bias.
Data synthesis
For analysis according to the intention‐to‐treat principle using an available case analysis approach, we planned to use fixed‐effect analysis unless there was significant heterogeneity (P < 0.1) for outcomes across studies assessed by the Chi² test, or when weighting was high for a small number of studies, in which case a random‐effects model would be used.
Network meta‐analysis (NMA)
NMA can compare the relative efficacy of probiotics that have been tested against placebo in different trials but without head‐to‐head comparisons. We planned to undertake NMA if we found sufficient trials and homogeneity in findings for specific probiotic preparations.
Certainty of the evidence
We assessed the certainty of evidence using the GRADE approach (Guyatt 2011). We rated the certainty of evidence for primary and secondary outcomes as:
high: we are very confident that the true effect lies close to that of the estimate of the effect;
moderate: we are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect;
low: our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect; or
very low: we have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
We downgraded the certainty of evidence if we noted significant risk of bias, imprecision, inconsistency, indirectness, and publication bias. We reported our overall assessment of the certainty of evidence for primary and secondary outcomes according to GRADE criteria in Table 1.
Subgroup analysis and investigation of heterogeneity
We undertook pre‐planned subgroup analysis to explore the effects of clinical diversity on heterogeneity in results between studies and to re‐assess the evidence base for specific probiotic preparations to better inform clinical practice. We also undertook subgroup analysis according to specific cause of diarrhoea when identified, age of participants, WHO region, mortality stratum to attempt to capture differences in major causes of diarrhoea, host characteristics such as nutritional/immune status, and exposure to infections according to availability of clean water and sanitation. Exposure to antibiotics may prolong diarrhoea duration or modify the effect of the probiotic; therefore, subgroup analysis also considered antibiotic exposure. Finally, to date, no reviews have assessed the effects of probiotics for treatment of acute infectious diarrhoea when zinc is also provided; therefore, we performed a subgroup analysis of studies that also provided zinc.
We conducted pre‐planned subgroup analyses for the primary outcomes according to the following variables when there were five or more studies in each subgroup.
Strain(s) of probiotic organism.
Major causes of diarrhoea as identified in children in the GEMS multi‐country study in Africa and Asia: Shigella spp, Campylobacter spp, heat‐stable enterotoxin‐producing E coli (ST‐ETEC), rotavirus, adenovirus 40/41, and Cryptosporidium spp (Liu 2016b), as well as any additional pathogens that were reported such as norovirus.
Age (0 to 5 years, 6 to 17 years, 18 to 64 years, 65 years plus).
Severity of diarrhoeal illness according to whether participants were managed as inpatients versus outpatients.
Countries where studies were conducted classified according to WHO region (Africa (Afr), Americas (Amr), Eastern Mediterranean (Emr), Europe (Eur), South‐East Asia (Sear), and Western Pacific (Wpr)) and country mortality stratum (A ‐ very low child mortality, low adult mortality; B ‐ low child mortality, low adult mortality; C ‐ low child mortality, high adult mortality; D ‐ high child mortality, high adult mortality; or E ‐ high child mortality, very high adult mortality; WHO 2001).
Exposure to antibiotics.
Treatment of children with zinc.
We also conducted post hoc subgroup analysis according to publication decade, trial registration, and study setting to further investigate heterogeneity.
Sensitivity analysis
To investigate the robustness of findings, we conducted sensitivity analyses according to each of the six criteria of trial methodological quality (as part of the GRADE approach; GRADEpro GDT 2014) for the two primary outcomes. Sensitivity analysis was conducted in the subset of studies that were scored at low risk of bias for each of these criteria in turn and also in studies for which risk of bias was rated as low for all six parameters.
Results
Description of studies
Results of the search
Our search identified 192 potentially relevant studies published since the 2010 review, 30 of which met the inclusion criteria. Of the 63 studies included in the 2010 review, 46 met the updated inclusion criteria. Six additional studies were identified through peer review (Figure 1). In total, 82 studies met the inclusion criteria (Characteristics of included studies). Eligibility regarding inclusion in this review was clear for all studies, and clarification from trial authors was not required. No studies were cluster‐randomized.
1.
Study flow diagram.
Eight studies were ongoing (search undertaken 17 December 2019; Characteristics of ongoing studies).
Included studies
Publication status
Of the 82 included studies, 17 were published in the 1980s and 1990s, 28 between 2000 and 2009, and 37 between 2010 and 2019.
Study locations
According to country mortality strata for children/adults (WHO 2001), 53 trials were undertaken in countries where both child and adult mortality was classified as low or very low, and 26 where either child or adult mortality was high. Two international studies recruited participants from countries crossing the mortality strata (Guandalini 2000; Jasinski 2002), and Ritchie 2010 was undertaken in Australia (very low child and low adult mortality) but recruited Aboriginal children who commonly had comorbidities such as pneumonia and malnutrition related to poverty and social disadvantage in the top end of the Northern Territory. Therefore, data from these three studies were not included in analysis according to country mortality strata. A total of 58 studies were conducted at a single centre; 22 recruited participants from 2 to 19 centres. The number of recruitment centres was unclear in two studies (D'Apuzzo 1982; Dinleyici 2015a).
Participants
The 82 selected studies recruited a total of 12,127 participants, including 11,526 children (age < 18 years) and 412 adults. In three studies (189 participants), the exact ages of participants were not clear or outcomes were not reported for children and adults separately (Bruno 1983; Simadibrata 2013; Wunderlich 1989). A total of 53 studies recruited inpatients, 11 recruited outpatients, and 14 recruited both inpatients and outpatients. It is unclear in four studies whether participants were inpatients or outpatients (Billoo 2006; Cetina‐Sauri 1994; D'Apuzzo 1982; Kowalska‐Duplaga 1999). Hydration status of participants was reported in 54 studies; 25 studies included participants with severe dehydration, 27 included participants with mild or moderate dehydration, 1 excluded participants with dehydration, and 1 presented median hydration scores but did not make clear whether any participants with severe dehydration were included.
Although all studies recruited participants with acute diarrhoea, the criteria for acute diarrhoea varied markedly among studies (see Characteristics of included studies). Criteria used for stool consistency included watery, loose(r), or liquid stools; semi‐liquid or semi‐watery; increased fluidity; mucus‐y; and non‐formed, taking the shape of the container or a combination of these terms. The minimum number of stools per day was specified in 58 studies; this ranged from one or more to five or more stools, with the most commonly used criteria being three or more (35 studies) and four or more (13 studies) stools in 24 hours. One study specified stool frequency as at least twice normal frequency (Kurugol 2005), and in another study, stool consistency was taken into account (Mao 2008). The maximum duration of diarrhoea at recruitment was specified in 43 studies and varied between 1 and 14 days. One study excluded children with chronic diarrhoea but did not specify the duration (Hochter 1990).
Criteria used for the end of the diarrhoeal episode were reported in 58 studies and varied markedly. The most common were last liquid, watery, or fluid stool and first normal stool. Many studies used various criteria based on stool frequency and consistency in a specified period (e.g. first formed stool if followed by two consecutive non‐watery stools, 12 hours without evacuation; Mao 2008). Four studies also included the resolution of associated symptoms (e.g. fewer than two stools/d; formed, yellow/brown stools without mucus; no abdominal pain, vomiting, or fever for the whole day; D'Apuzzo 1982).
Twenty‐seven studies were restricted to children with rotavirus diarrhoea or reported relevant outcomes for a subgroup of children with rotavirus diarrhoea (two study authors kindly provided this information on request: Freedman 2018a and Szymanski 2019). Twelve studies did not exclude participants with bloody diarrhoea, whereas 39 studies did exclude these participants. It is unclear whether participants with bloody diarrhoea were included in 31 studies. Thirty‐seven studies excluded participants who had received antibiotic treatment before recruitment, 12 included participants who had received antibiotic treatment before recruitment, and this information was unclear in 33 studies.
No study specifically recruited or excluded travellers, and none identified any participants as suffering from travellers' diarrhoea. No study specifically recruited participants known to have HIV infection, and no study stated HIV positivity as an exclusion criterion, but many studies excluded participants with chronic illness or immunosuppression, or both. Seven studies recruited malnourished children only or included malnourished children. Forty studies excluded children with severe malnutrition; 10 of these also excluded children with moderate malnutrition.
Interventions
Many different probiotics were tested. Most studies tested preparations of lactic acid bacteria and bifidobacteria. Several studies identified probiotic organisms only by species name without specific identification details such as culture collection number. Few studies undertook analyses to confirm the identity or viability of the organism(s).
Fifty‐seven studies tested a single organism, and 25 tested combinations of two to eight organisms. The organisms most commonly evaluated were S boulardii (21 studies), L casei strain GG (15 studies), and L reuteri spp (7 studies, 4 of which tested L reuteri DSM17938). Canani 2007 allocated children to one of five different probiotic regimens and compared outcomes with those of a single control group. For the purposes of this review, we selected the L casei GG group because several other studies tested this probiotic and we wanted to maximize the data available for meta‐analysis. Similarly, Bhat 2018, Erdogan 2012, and Vidjeadevan 2018 allocated children to one of two different probiotic regimens and compared outcomes with those of a single control group. For the purposes of this review, we selected S boulardii as the most commonly studied organism across the other included studies.
Three studies compared different dosages (number of organisms) of the same probiotic with a single control (Basu 2009; Mao 2008; Shornikova 1997b). We selected the higher probiotic dose group for inclusion in meta‐analysis but included results from the lower dose group in the Characteristics of included studies table. Freedman 2015 compared administration of a probiotic once daily and twice daily to use of a single control, presenting results separately and as a combined figure; the combined outcome was selected for inclusion in the review. Overall, 15 studies used a higher dose of organisms (> 1010 colony‐forming units (CFUs)/d), 39 used a lower dose (≤ 1010 CFUs/d), and the dose was unclear in 27 studies.
As well as differences in doses or organisms, clinical variation between studies was marked with wide variation in treatment regimens according to timing of intervention, means of administration, and duration of treatment. Probiotics were administered directly to participants or were mixed with a variety of fluids and foods. Although expressed breast milk was used to administer probiotics in some studies, other studies excluded exclusively breast‐fed infants.
Fifty‐four studies used a placebo in the no probiotic control group; the remaining studies treated participants according to usual clinical practice.
Risk of bias in included studies
Risk of bias varied considerably (see Characteristics of included studies; Figure 2). Forty‐one (50.0%) studies were considered low risk for generation of the allocation sequence, 12 (14.6%) for concealment of allocation, 36 (43.9%) for blinding of participants and personnel, 30 (36.6%) for blinding of outcome assessment, 65 (79.3%) for loss to follow‐up, and 71 (86.6%) for selective reporting (Figure 3). Seven studies (8.5%) were at low risk for all of the six methodological quality assessment parameters.
2.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3.
Risk of bias graph: review authors' assessments about each risk of bias item presented as percentages across all included studies.
Effects of interventions
See: Table 1
Primary outcomes
We used random‐effects analysis because of marked statistical heterogeneity in findings. The risk of diarrhoea lasting ≥ 48 hours was reduced in people receiving a probiotic compared with controls (36 trials/6053 participants; risk ratio (RR) 0.64, 95% confidence interval (CI) 0.52 to 0.79; Analysis 1.1). Mean duration of diarrhoea was also reduced in the probiotic group (56 trials/9138 participants; mean difference (MD) 21.3 hours, 95% CI 15.7 to 26.9; Analysis 1.2). However, heterogeneity between studies was very high for both primary outcomes and this undermined confidence in estimates of probiotic effect.
1.1. Analysis.
Comparison 1: Primary diarrhoea outcomes, Outcome 1: Diarrhoea lasting ≥ 48 hours
1.2. Analysis.
Comparison 1: Primary diarrhoea outcomes, Outcome 2: Mean duration of diarrhoea
A notable finding was that two recently conducted large trials undertaken in children did not show a probiotic effect for the number of children with diarrhoea lasting ≥ 48 hours (Analysis 1.1) or for mean duration of diarrhoea (Analysis 1.2; Freedman 2018a; Schnadower 2018).
The funnel plots are suggestive of publication bias for diarrhoea lasting ≥ 48 hours (Figure 4; Habord test; t = ‐4.57, P < 0.001) and possibly also mean duration of diarrhoea (Figure 5; Egger’s test; t = ‐3.33, P = 0.002).
4.
Funnel plot of comparison: 1 Primary diarrhoea outcomes, outcome: 1.1 Diarrhoea lasting ≥ 48 hours.
5.
Funnel plot of comparison: 1 Primary diarrhoea outcomes, outcome: 1.2 Mean duration of diarrhoea.
Below we explore the heterogeneity in relation to potential subgroup effects and in relation to risk of bias in the studies, taking into account the likelihood of publication bias.
Secondary outcomes
Secondary outcomes were reported in fewer studies. As for primary outcomes, random‐effects analysis was used for all analyses because of marked statistical heterogeneity in findings or high weighting attributed to a small number of studies.
In seven trials (2333 participants) of acute diarrhoea in the community, probiotics did not reduce the risk of hospitalization (RR 1.21, 95% CI 0.86 to 1.69) with consistency in findings between studies (I² = 0%; Analysis 2.1). In 24 inpatient trials (4056 participants), duration of hospitalization was reduced in the probiotic arm (MD 18.0 hours, 95% CI 8.8 to 27.3) but with marked statistical heterogeneity (I² = 95%; Analysis 2.2). In nine trials (2928 participants), probiotics did not reduce the risk of diarrhoea lasting ≥ 14 days (RR 0.49, 95% CI 0.16 to 1.53) with heterogeneity in findings between studies (I² = 60%; Analysis 2.3).
2.1. Analysis.
Comparison 2: Secondary diarrhoea outcomes, Outcome 1: Number of people hospitalized in community studies
2.2. Analysis.
Comparison 2: Secondary diarrhoea outcomes, Outcome 2: Duration of hospitalization in inpatient studies
2.3. Analysis.
Comparison 2: Secondary diarrhoea outcomes, Outcome 3: Diarrhoea lasting ≥ 14 days
Exploration of heterogeneity
Strain(s) of probiotic organisms
Either or both of the two primary outcomes were reported in five or more studies for three probiotic preparations.
The Lactobacillus casei group comprises the closely related species L casei, L paracasei, and L rhamnosus, including L rhamnosus GG, and it is difficult to differentiate between these species (Hill 2018). Terminology varied between studies. Amongst studies that specified strain GG, six studies (1557 participants) reported the number of participants with diarrhoea lasting ≥ 48 hours (Analysis 3.1: subgroup 1) and 14 studies (3344 participants) reported mean duration of diarrhoea (Analysis 3.2: subgroup 1). The effects in these analyses were similar to the main analysis of all probiotics, and marked statistical heterogeneity persisted in both analyses.
3.1. Analysis.
Comparison 3: Strain of probiotic organisms, Outcome 1: Diarrhoea lasting ≥ 48 hours
3.2. Analysis.
Comparison 3: Strain of probiotic organisms, Outcome 2: Mean duration of diarrhoea
The effect estimate for diarrhoea lasting ≥ 48 hours among participants taking S boulardii was similar to the main analysis but was not statistically significant and findings show marked heterogeneity (RR 0.70, 95% CI 0.37 to 1.33; 9 studies, 1823 participants; I² = 99%; Analysis 3.1: subgroup 2). The reduction in duration of diarrhoea was similar to that in the main analysis, and marked statistical heterogeneity persisted (MD 24.6 hours, 95% CI 14.0 to 35.3; 11 studies, 1617 participants; I² = 89%; Analysis 3.2: subgroup 2).
In fewer studies, the effect estimate for L reuteri in reducing the duration of diarrhoea was similar to that in the main analysis but with less heterogeneity across studies (6 studies/433 participants; MD 22.8 hours, 95% CI 13.7 to 32.0; I² = 48%; Analysis 3.2: subgroup 3). However, risk of bias was present in all of the included studies.
Given the high degree of quantitative heterogeneity in studies that evaluated the same probiotic organism, we did not proceed to NMA.
The identity and viability of probiotic organisms were evaluated by bacteriology and molecular methods in seven studies (Freedman 2015; Freedman 2018a; Hong Chau 2018; Mao 2008; Rosenfeldt 2002a; Rosenfeldt 2002b; Schnadower 2018), and were evaluated independently of the study team in two of these studies (Freedman 2015; Schnadower 2018). Hegar 2015 reported that stability of the probiotic organisms at different storage temperatures had been confirmed. Stools were tested for probiotic organisms in eight studies (Chen 2010; Isolauri 1994; Lee 2001; Rosenfeldt 2002a; Rosenfeldt 2002b; Shornikova 1997b; Shornikova 1997c; Szymanski 2006). The identity and viability of the probiotic organisms were not evaluated in 74 studies.
Diarrhoea pathogen
Rotavirus was the only infectious cause of diarrhoea for which sufficient studies reported outcomes to consider meta‐analysis. In 20 studies (1414 participants, all of whom were children), the reduction in duration of diarrhoea was similar to that in the main analysis, and marked statistical heterogeneity between studies persisted (MD 22.1 hours, 95% CI 14.2 to 29.9; I² = 84%; Analysis 4.1).
4.1. Analysis.
Comparison 4: Diarrhoea pathogen: rotavirus, Outcome 1: Mean duration of diarrhoea
Age of participants
For children younger than five years, the effect estimate for diarrhoea lasting ≥ 48 hours was lower than in the main analysis (26 studies, 5033 children; RR 0.72, 95% CI 0.59 to 0.88) and marked statistical heterogeneity persisted (I² = 97%; Analysis 5.1: subgroup 1). The reduction in diarrhoea duration was similar to the main analysis, and marked statistical heterogeneity persisted (45 studies, 6697 children; Analysis 5.2).
5.1. Analysis.
Comparison 5: Age of participants, Outcome 1: Diarrhoea lasting ≥ 48 hours
5.2. Analysis.
Comparison 5: Age of participants, Outcome 2: Mean duration of diarrhoea
We were unable to extract data according to the other pre‐specified age groups; however, in fewer studies of adults (≥ 18 years; 5 studies, 393 participants), probiotics reduced the RR of diarrhoea lasting ≥ 48 hours to a lesser degree than in the main analysis but with consistency between studies (RR 0.62, 95% CI 0.54 to 0.71; I² = 0%; Analysis 5.1: subgroup 2).
Severity of diarrhoea
Diarrhoea lasting ≥ 48 hours was reported in 21 studies (2354 participants) of participants who required admission and therefore were likely to have more severe illness. The effect estimate in these trials (RR 0.62, 95% CI 0.52 to 0.74) was similar to all studies, and marked heterogeneity in findings persisted (I² = 75%; Analysis 6.1).
6.1. Analysis.
Comparison 6: Severity of diarrhoea (inpatient vs outpatient), Outcome 1: Diarrhoea lasting ≥ 48 hours
Mean duration of diarrhoea was reported in 36 inpatient studies (5071 participants) and in 8 outpatient studies (828 participants). The effect estimate was similar in these two groups, and marked heterogeneity was present in both analyses (I² = 97% and 94%, respectively; Analysis 6.2).
6.2. Analysis.
Comparison 6: Severity of diarrhoea (inpatient vs outpatient), Outcome 2: Mean duration of diarrhoea
Country mortality stratum
For both diarrhoea lasting ≥ 48 hours and mean duration of diarrhoea, effect estimates were similar when studies were grouped according to mortality stratum (Analysis 7.1; Analysis 7.2).
7.1. Analysis.
Comparison 7: Country mortality stratum, Outcome 1: Diarrhoea lasting ≥ 48 hours
7.2. Analysis.
Comparison 7: Country mortality stratum, Outcome 2: Mean duration of diarrhoea
Geographical region
Effect estimates were also similar when studies were grouped according to geographical region. Statistical heterogeneity persisted in these analyses with the exception of studies done in the Eur‐A region (Analysis 8.1: subgroup 3; I² = 27%).
8.1. Analysis.
Comparison 8: Geographical region, Outcome 1: Diarrhoea lasting ≥ 48 hours
Exposure to antibiotics
For both diarrhoea lasting ≥ 48 hours and mean duration of diarrhoea, effect estimates were similar in studies where participants may have been exposed to antibiotics before recruitment and marked statistical heterogeneity between studies persisted (Analysis 9.1; Analysis 9.2).
9.1. Analysis.
Comparison 9: Exposure to antibiotics, Outcome 1: Diarrhoea lasting ≥ 48 hours
9.2. Analysis.
Comparison 9: Exposure to antibiotics, Outcome 2: Duration of diarrhoea
Treatment of children with zinc
The effect estimate for probiotics on the duration of diarrhoea in children treated with zinc was similar to that in the main analysis, and marked statistical heterogeneity persisted (Analysis 10.1).
10.1. Analysis.
Comparison 10: Use of zinc, Outcome 1: Duration of diarrhoea
Sensitivity analysis for primary outcomes
For both primary outcomes, we conducted sensitivity analysis against each individual risk of bias, examining the effect estimates for low risk against each parameter. This did not explain the heterogeneity (Analysis 11.1; Analysis 11.2).
11.1. Analysis.
Comparison 11: Risk of bias, Outcome 1: Diarrhoea lasting ≥ 48 hours
11.2. Analysis.
Comparison 11: Risk of bias, Outcome 2: Mean duration of diarrhoea
When analysis was restricted to studies where all indicators of risk of bias were low, there was no heterogeneity with consistent estimates of null effect in the two large studies meeting these criteria for number of participants with diarrhoea lasting ≥ 48 hours between study arms (RR 1.00, 95% CI 0.91 to 1.09; I² = 0%; two trials, 1770 participants; Analysis 11.1: subgroup 7). Similarly, for trials reporting mean duration of diarrhoea that were at low risk of bias for all six indices of study quality, no difference was demonstrated between intervention and control (MD 8.6 hours less, 95% CI 29.4 less to 12.1 hours more; 6 trials, 3058 participants). Heterogeneity persisted (I² = 97%; Analysis 11.2: subgroup 7).
Given the marked statistical heterogeneity in nearly all analyses that was not explained by sensitivity analysis, we assessed in post hoc analyses whether effect estimates varied according to decade of publication. The effect estimate for diarrhoea lasting ≥ 48 hours was similar according to decade of publication (Analysis 12.1), and the difference between groups was of borderline statistical significance in the most recent studies (from 2010; 15 trials/3972 participants; RR 0.78, 95% CI 0.63 to 0.98; Analysis 12.1; subgroup 4). For mean duration of diarrhoea, effect estimates according to decade of publication were also similar to the main analysis (Analysis 12.2).
12.1. Analysis.
Comparison 12: Publication decade, Outcome 1: Diarrhoea lasting ≥ 48 hours
12.2. Analysis.
Comparison 12: Publication decade, Outcome 2: Mean duration of diarrhoea
Fifteen studies were registered in a trial database. For both primary outcomes, effect estimates were similar to the main analysis in these studies, and marked statistical heterogeneity persisted (Analysis 13.1; Analysis 13.2).
13.1. Analysis.
Comparison 13: Prospective trial registration, Outcome 1: Diarrhoea lasting ≥ 48 hours
13.2. Analysis.
Comparison 13: Prospective trial registration, Outcome 2: Mean duration of diarrhoea
In the light of the marked quantitative and qualitative heterogeneity unexplained by subgroup analysis; the clear evidence of publication bias; and the large, recent, well conducted trials showing null effect, we concluded that the most robust and reliable analysis is for trials with low risk of bias in all parameters, and this analysis we used in our summary of findings table.
Adverse events
Fifty studies reported that no adverse events (AEs) were attributed to the probiotic(s), and two studies stated that no serious AEs (SAEs) were attributed to the probiotic (Phavichitr 2013; Simadibrata 2013). Javeed 2018 reported no deaths in either group. Khan 2017 commented that the probiotic was safe but did not present adverse event data. Henker 2008 reported one participant with a mild hypersensitivity reaction that was possibly related to E coli strain Nissle 1917. Schnadower 2018 reported similar rates of adverse events in the two groups, except that wheezing was more common in children receiving L rhamnosus GG than in controls (5/472 versus 0/479 children; P = 0.03; borderline statistical significance in view of multiple comparisons); SAEs occurred in a similar number of children in each group. Freedman 2015 reported that AEs including abdominal cramps and rash occurred in both groups but frequency was higher in the control group; no SAEs occurred. Freedman 2018a reported that the frequency of AEs was similar in the two groups; no SAEs occurred in the probiotic group. Szymanski 2019 reported a similar frequency of AEs in both groups; no SAEs occurred. The remaining 17 studies did not report on adverse events.
Discussion
Summary of main results
This review included 82 studies with a total of 12,127 participants. Because of marked heterogeneity in the pooled analyses and high or unclear risk of bias in many studies, we report the main comparisons in studies at low risk of bias in the 'Summary of findings' table. In these studies at low risk of bias, we consider that there was moderate certainty evidence that probiotics probably make little or no difference to the risk of diarrhoea lasting 48 hours or more. We cannot make a reliable estimate of the efficacy of probiotics in reducing the duration of diarrhoea because certainty of evidence was very low.
We do not know whether or not probiotics reduce the duration of hospitalization or diarrhoea lasting 14 or more days due to marked statistical heterogeneity between studies. Probiotics did not prevent hospitalization with acute diarrhoea, with consistency in study findings.
Probiotics were not associated with adverse events, but reporting was limited.
Overall completeness and applicability of evidence
The included trials were undertaken in many different countries from different world regions and, therefore, were adequate to address the main research question. However, most study participants were children, and available data for adults are sparse.
Despite the addition of 36 studies undertaken since our previous review (Allen 2010), there was marked heterogeneity between studies. Effect sizes were similar and heterogeneity persisted in our pre‐planned subgroup analyses according to probiotic strain, diarrhoea caused by rotavirus, age, severity of illness, country mortality stratum or region, exposure to antibiotics, treatment with zinc in children, and risk of bias. Between‐study heterogeneity may be due to other differences between trials such as the definitions used for "acute diarrhoea" and "the end of the diarrhoeal episode." Also great variability in reported outcomes is evident, which limited data available for meta‐analysis for the primary outcomes. Further development of core outcome sets for clinical trials in acute diarrhoea (e.g. to include patient/public perspectives and adult patients), which also include criteria for diagnosis of gastroenteritis (Karas 2016), should help to ensure greater consistency in trial methods and reporting outcomes that will strengthen the evidence base for the treatment of diarrhoea.
The recent 2013 Global Enteric Multicenter Study (GEMS) in children in sub‐Saharan Africa and south Asia has highlighted the multiple infectious agents responsible for acute diarrhoea and the importance of bacteria as common diarrhoeal pathogens (Kotloff 2013; Kotloff 2019; Liu 2016b). Although many studies included participants with bacterial diarrhoea or bloody stools, too few studies reported outcomes for these participants for meta‐analysis to be performed. Differences in causes of diarrhoea likely account for some of the statistical heterogeneity between studies and have likely changed over time, for example, as a result of immunization programmes such as those for rotavirus. Future studies should determine main infectious causes of diarrhoea and should archive samples for analysis as enteric diagnostic technology evolves.
Confirmation of probiotic identity, viability, and number of organisms by quantitative culture and molecular methods was done in only eight trials but should be standard in research studies (Rijkers 2010; Wolvers 2010).
Although post hoc analysis limited to registered trials did not significantly modify the effect estimate, the absence of published trial protocols for most trials limited our assessment of bias due to selective outcome reporting. In addition, we found that publication bias may have limited the research studies included in this review; a recent systematic review of probiotics in the management of constipation also reported evidence of publication bias (Harris 2019). However, a recent review found no evidence that the source of funding for trials of probiotics in diarrhoea had affected trial results (Saa 2019).
Although most studies reported absence of adverse events due to probiotics, few studies provided a description of the methods used for detecting and classifying adverse events and few reported specific data on adverse events. This is consistent with poor adverse event reporting in probiotic trials in general and highlights the need for improved practice in reporting of harms in probiotic studies especially in vulnerable people (Bafeta 2018; Besselink 2008; Yelin 2019).
Certainty of the evidence
Details of downgrading for GRADE for the few trials at low risk of bias are contained in Table 1. For diarrhoea lasting 48 hours or longer, certainty of evidence was moderate due to indirectness resulting from the inclusion of only two trials, both of which were conducted in high‐income countries, and evaluation of only two probiotics. For mean duration of diarrhoea, certainty of evidence was very low due to marked variability in findings between studies and imprecision in the effect estimate.
Among all trials included in this review, there was evidence of publication bias in trials reporting numbers of participants with diarrhoea lasting 48 hours or longer, with a greater number of smaller studies reporting a positive effect of probiotics (Figure 4). Although less clear, this may have also been the case for studies reporting mean duration of diarrhoea (Figure 5).
There was great variability in the methodological quality of trials, but this did not appear to have contributed to heterogeneity. Heterogeneity was not resolved in sensitivity analysis according to individual parameters of risk of bias nor in subgroup analysis of trials where risk of bias for all six parameters was low. The importance of careful assessment of risk of bias in studies included in meta‐analyses has been highlighted recently (Harris 2019; Schnadower 2019a). Because of the persistence of marked statistical heterogeneity in the subgroup analyses, we also analysed primary outcomes according to decade of publication (Analysis 12.1; Analysis 12.2) and whether or not trials had been registered in a trial database (Analysis 13.1; Analysis 13.2; Kaplan 2015). However, there were no clear differences in effect sizes in these analyses, and heterogeneity persisted.
Based on our criterion of five or more trials reporting the primary outcomes, we pooled data for Lactobacillus rhamnosus GG, Saccharomyces boulardii, and Lactobacillus reuteri. Pooled estimates of probiotic effect for these strains were similar to our overall findings, and statistical heterogeneity persisted for the first two strains. Of note, a recent large, well‐conducted trial of L rhamnosus GG in children in the USA did not observe a probiotic effect (Schnadower 2018). Trials that evaluated L reuteri had less heterogeneity but risk of bias was present in all included studies.
In keeping with clinical management, diarrhoea aetiology was determined in only a minority of studies and meta‐analysis was possible only for rotavirus diarrhoea. All of these studies were done in children. For this diarrhoeal pathogen, the effects of probiotics were similar to those in the main analyses, but again with marked statistical heterogeneity and risk of bias in many studies.
Although there was greater consistency among trials of adults (I² = 0%), only a few of these trials were included in this analysis and risk of bias was present in many.
We categorized trials according to World Heath Organization (WHO) world region and country mortality stratum (WHO 2001) in an attempt to capture regional differences in diarrhoea aetiology, exposure to infection, and host characteristics. Heterogeneity persisted in these analyses with the exception of studies done in the Eur‐A region, where consistency was greater when diarrhoea lasting 48 hours or longer was reported (I² = 27%) but marked heterogeneity persisted for the mean duration of diarrhoea (I² = 78%), and risk of bias was present in many of the included studies for both outcomes.
Marked statistical heterogeneity and presence of risk of bias were also evident in studies that included people exposed to antibiotics and in the few studies of children treated with zinc.
Agreements and disagreements with other studies or reviews
Our previous review concluded that probiotics appeared to shorten the duration of acute infectious diarrhoea although there was insufficient evidence to recommend a specific probiotic regimen (Allen 2010). In this update, the use of GRADE has highlighted limitations in the evidence and we also found clear evidence of publication bias. As a result, we limited our evaluation to trials at low risk of bias. Analysis of these trials has changed our conclusion as they do not provide evidence of probiotic efficacy.
Other reviews on this topic have also reported marked statistical heterogeneity and low certainty of evidence. A recent systematic review and network meta‐analysis of interventions for acute diarrhoea in children reported high statistical heterogeneity for duration of diarrhoea for L rhamnosus GG, S boulardii, and other probiotics grouped together versus standard treatment and certainty of evidence was graded as low or very low (Florez 2018). A recent update of a meta‐analysis of L rhamnosus GG in acute diarrhoea in children reported high statistical heterogeneity between studies (Szajewska 2019a). Correspondence following this review highlighted that the effect of the probiotic was not statistically significant when analysis was limited to studies at low risk of bias (Schnadower 2019b), and that marked heterogeneity persisted in these analyses (Szajewska 2019b). Similarly, marked statistical heterogeneity in the duration of diarrhoea was reported in another recent review of L rhamnosus GG in paediatric diarrhoea (Li 2019).
A systematic review of L reuteri DSM 17938 for treating acute gastroenteritis in children reported marked statistical heterogeneity and very low certainty of evidence for both duration of diarrhoea and duration of hospitalization (Patro‐Gołab 2019).
Our findings regarding rotavirus diarrhoea in children are consistent with a review that reported marked heterogeneity between studies (Ahmadi 2015). A recent systematic review that summarised trials of S boulardii in children with rotavirus diarrhoea (n = 548 children; five RCTs) reported a modest reduction in diarrhoea duration (MD –0.57 days; 95% CI –0.83 to –0.30) with consistency in findings (I2 = 0%) and moderate certainty evidence (Padayachee 2019). However, small sample sizes, unclear and inconsistent quality of methodology, and possible reporting bias prevented the authors from making a definitive conclusion regarding the efficacy of S boulardii and they emphasised the need for further research.
Authors' conclusions
Implications for practice.
Our findings do not support the use of probiotics for the treatment of acute infectious diarrhoea. In analysis limited to trials evaluating the same probiotic strain, there was marked heterogeneity in findings and risk of bias in many of the included trials. Our findings do not support recommendations for the use of specific probiotics for acute infectious diarrhoea in children (Floch 2015; Guarino 2018; Sniffen 2018). The challenge of selecting specific probiotics for particular patient groups is highlighted by two well‐conducted recent studies that reported negative results (Freedman 2018a; Schnadower 2018).
Implications for research.
Given the large number of studies already reported, the ways further research will contribute significantly to the evidence base that informs clinical practice needs careful consideration. The very marked heterogeneity between studies in this and other reviews argues against "core" properties shared by different probiotics that are effective against diarrhoea due to many different infectious agents and its occurrence in different populations and regions (Hill 2014). This finding is consistent with the importance of considering strain‐specific effects of probiotics. With the exception of a recent trial in children in the USA that did not find Lactobacillus rhamnosus GG to be effective (Schnadower 2018), large‐scale, high‐quality studies that follow up on previously encouraging findings of specific probiotics in specific populations have not been done. Future studies should focus on probiotics that have evidence of possessing properties that address specific underlying pathogenic mechanisms, which may be limited to specific infectious agents and populations (Brüssow 2019; Florez 2018; Glanville 2015).
Marked variability in study design likely contributed to the high level of statistical heterogeneity. Future studies should use standardized definitions for acute diarrhoea and resolution of the illness, determine diarrhoea aetiology, and confirm the identity of the probiotic being tested and the number of viable organisms at the point of use.
Finally, we identified evidence of publication bias. Effect estimates may vary according to whether or not trials are registered (Kaplan 2015). To improve the reliability of findings, future systematic reviews of probiotics should consider including only trials that have been registered in a clinical trials database.
What's new
| Date | Event | Description |
|---|---|---|
| 1 December 2020 | New search has been performed | We updated the search to 17 December 2019, and have included 36 new studies in this review update. In this review, only published, randomized controlled trials of live probiotics were included. Seventeen trials that were unpublished, were quasi‐randomized, assessed killed probiotics, or had no usable outcome data that were included in Allen 2010 were excluded. We revised the outcomes according to a consensus statement regarding a core outcome measurement set for clinical trials in acute diarrhoea (Karas 2016). To better assess the quality of research methods and publication bias, we have included analyses according to the decade of trial publication and trial registration. |
| 1 December 2020 | New citation required and conclusions have changed | In our conclusions, under Implications for practice, we now consider that our findings do not support the use of probiotics for treatment of acute diarrhoea. Under Implications for research, we have highlighted that limiting inclusion of trials to those registered in a clinical trials database may improve the reliability of study findings. |
History
Protocol first published: Issue 2, 2001 Review first published: Issue 2, 2004
| Date | Event | Description |
|---|---|---|
| 9 November 2010 | Amended | Detailed search strategy added to appendices |
| 11 August 2010 | New citation required but conclusions have not changed | Title changed ("acute" added) to emphasize that persistent diarrhoea is not considered. The authorship of the update has changed due to the untimely death of Dr Okoko |
| 11 August 2010 | New search has been performed | The table showing clinical variability among studies has been removed and this information added to the Characteristics of included studies table. A table has been added to show the marked statistical heterogeneity in primary outcomes and subgroup analyses (Table 1) The following secondary outcomes have been removed as they were uncommon or were not reported: need for unscheduled intravenous (IV) rehydration after randomization; death; adverse events, such as vomiting; withdrawal from the study. Details regarding adverse events and reasons for withdrawal are included in the "Details of included studies" table |
| 22 July 2008 | Amended | Converted to new review format |
| 8 December 2007 | New citation required and conclusions have changed | Substantive amendments made |
Acknowledgements
The Academic Editor is Professor Paul Garner and Sign‐off Editor is Dr Hellen Gelband.
The editorial base of the Cochrane Infectious Diseases Group (CIDG) is funded by UK aid from the UK government for the benefit of low‐ and middle‐income countries (project number 300342‐104). The views expressed do not necessarily reflect the UK government’s official policies.
We thank Deirdre Walshe, CIDG Managing Editor, for assistance with undertaking this review; Vittoria Lutje, CIDG Information Specialist for performing the literature searches; and Artemis Koukounari, Statistical Epidemiologist, LSHTM, for advice regarding NMA. We also thank Paul Garner, Marty Chaplin, and Melissa Taylor (CIDG); and external peer reviewers Stephen Freedman, David Schnadower, Phillip I Tarr, Hania Szajewska, and Bartłomiej M Zalewski for their very valuable feedback on a draft of the review.
Appendices
Appendix 1. Detailed search strategy
| Search set | CIDG SRa | CENTRAL | MEDLINEb | Embaseb | LILACSb |
| 1 | Diarrhea* | DIARRHEA | DIARRHEA | INFECTIOUS DIARRHEA | Diarrhea$ |
| 2 | Diarrhoea* | Diarrhoea* | Diarrhoea* | Diarrhoea* | Diarrhoea$ |
| 3 | 1 or 2 | 1 or 2 | 1 or 2 | 1 or 2 | 1 or 2 |
| 4 | Probiotic* | Probiotic* | PROBIOTICS | PROBIOTIC AGENT | Probiotic$ |
| 5 | Lactobacill* | Lactobacill* | Lactobacill* | Lactobacill$ | Lactobacill$ |
| 6 | Lactococc* | Lactococc* | Lactococc* | Lactococc$ | Lactococc$ |
| 7 | Bifidobacter* | Bifidobacter* | Bifidobacter* | Bifidobacter$ | Bifidobacter$ |
| 8 | Enterococc* | Enterococc* | Enterococc* | Enterococc$ | Enterococc$ |
| 9 | Streptococc* | Streptococc* | Streptococc* | Streptococc$ | Streptococc$ |
| 10 | saccharomyces | saccharomyces | saccharomyces | saccharomyces | saccharomyces |
| 11 | 4 or 5 or 6 or 7 or 8 or 9 or 10 | 4 or 5 or 6 or 7 or 8 or 9 or 10 | 4 or 5 or 6 or 7 or 8 or 9 or 10 | 4 or 5 or 6 or 7 or 8 or 9 or 10 | 4 or 5 or 6 or 7 or 8 or 9 or 10 |
| 12 | 3 and 11 | 3 and 11 | 3 and 11 | 3 and 11 | 3 and 11 |
| 13 | Limit 12 to Humans | Limit 12 to Human |
Footnotes
aCochrane Infectious Diseases Group Specialized Register. bSearch terms used in combination with the search strategy for retrieving trials developed by Cochrane (Higgins 2008); upper case: MeSH or EMTREE heading; lower case: free text term.
Data and analyses
Comparison 1. Primary diarrhoea outcomes.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1.1 Diarrhoea lasting ≥ 48 hours | 36 | 6053 | Risk Ratio (M‐H, Random, 95% CI) | 0.64 [0.52, 0.79] |
| 1.2 Mean duration of diarrhoea | 56 | 9138 | Mean Difference (IV, Random, 95% CI) | ‐21.29 [‐26.88, ‐15.71] |
Comparison 2. Secondary diarrhoea outcomes.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 2.1 Number of people hospitalized in community studies | 7 | 2333 | Risk Ratio (M‐H, Random, 95% CI) | 1.21 [0.86, 1.69] |
| 2.2 Duration of hospitalization in inpatient studies | 24 | 4056 | Mean Difference (IV, Random, 95% CI) | ‐18.03 [‐27.28, ‐8.78] |
| 2.3 Diarrhoea lasting ≥ 14 days | 9 | 2928 | Risk Ratio (M‐H, Random, 95% CI) | 0.49 [0.16, 1.53] |
Comparison 3. Strain of probiotic organisms.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 3.1 Diarrhoea lasting ≥ 48 hours | 15 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 3.1.1 Lactobacillus rhamnosus GG | 6 | 1557 | Risk Ratio (M‐H, Random, 95% CI) | 0.79 [0.65, 0.97] |
| 3.1.2 Saccharomyces boulardii | 9 | 1823 | Risk Ratio (M‐H, Random, 95% CI) | 0.70 [0.37, 1.33] |
| 3.2 Mean duration of diarrhoea | 31 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 3.2.1 Lactobacillus rhamnosus GG | 14 | 3344 | Mean Difference (IV, Random, 95% CI) | ‐22.50 [‐32.73, ‐12.26] |
| 3.2.2 Saccharomyces boulardii | 11 | 1617 | Mean Difference (IV, Random, 95% CI) | ‐24.64 [‐35.30, ‐13.98] |
| 3.2.3 Lactobacillus reuteri | 6 | 433 | Mean Difference (IV, Random, 95% CI) | ‐22.83 [‐31.95, ‐13.72] |
Comparison 4. Diarrhoea pathogen: rotavirus.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 4.1 Mean duration of diarrhoea | 20 | 1414 | Mean Difference (IV, Random, 95% CI) | ‐22.06 [‐29.93, ‐14.18] |
Comparison 5. Age of participants.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 5.1 Diarrhoea lasting ≥ 48 hours | 31 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 5.1.1 Participants aged < 5 years | 26 | 5033 | Risk Ratio (M‐H, Random, 95% CI) | 0.72 [0.59, 0.88] |
| 5.1.2 Participants aged ≥ 18 years | 5 | 393 | Risk Ratio (M‐H, Random, 95% CI) | 0.62 [0.54, 0.71] |
| 5.2 Mean duration of diarrhoea | 45 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 5.2.1 Participants aged < 5 years | 45 | 6697 | Mean Difference (IV, Random, 95% CI) | ‐21.63 [‐27.83, ‐15.42] |
Comparison 6. Severity of diarrhoea (inpatient vs outpatient).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 6.1 Diarrhoea lasting ≥ 48 hours | 21 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 6.1.1 Inpatient | 21 | 2354 | Risk Ratio (M‐H, Random, 95% CI) | 0.62 [0.52, 0.74] |
| 6.2 Mean duration of diarrhoea | 44 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 6.2.1 Inpatient | 36 | 5071 | Mean Difference (IV, Random, 95% CI) | ‐21.71 [‐29.72, ‐13.70] |
| 6.2.2 Outpatient | 8 | 828 | Mean Difference (IV, Random, 95% CI) | ‐28.55 [‐43.09, ‐14.01] |
Comparison 7. Country mortality stratum.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 7.1 Diarrhoea lasting ≥ 48 hours | 33 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 7.1.1 Child and adult mortality low or very low | 23 | 4100 | Risk Ratio (M‐H, Random, 95% CI) | 0.62 [0.54, 0.71] |
| 7.1.2 Child or adult mortality high | 10 | 1505 | Risk Ratio (M‐H, Random, 95% CI) | 0.79 [0.59, 1.06] |
| 7.2 Mean duration of diarrhoea | 53 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 7.2.1 Child and adult mortality low or very low | 34 | 5225 | Mean Difference (IV, Random, 95% CI) | ‐19.18 [‐24.98, ‐13.39] |
| 7.2.2 Child or adult mortality high | 19 | 3465 | Mean Difference (IV, Random, 95% CI) | ‐24.05 [‐35.28, ‐12.83] |
Comparison 8. Geographical region.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 8.1 Diarrhoea lasting ≥ 48 hours | 8 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 8.1.1 Eur‐A | 8 | 500 | Risk Ratio (M‐H, Random, 95% CI) | 0.54 [0.43, 0.70] |
| 8.2 Mean duration of diarrhoea | 35 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 8.2.1 Eur‐A | 8 | 601 | Mean Difference (IV, Random, 95% CI) | ‐32.95 [‐45.40, ‐20.50] |
| 8.2.2 Eur‐B | 9 | 1271 | Mean Difference (IV, Random, 95% CI) | ‐16.33 [‐23.63, ‐9.03] |
| 8.2.3 Sear‐D | 12 | 2402 | Mean Difference (IV, Random, 95% CI) | ‐17.42 [‐27.09, ‐7.75] |
| 8.2.4 Wpr‐B | 6 | 850 | Mean Difference (IV, Random, 95% CI) | ‐17.14 [‐26.05, ‐8.23] |
8.2. Analysis.
Comparison 8: Geographical region, Outcome 2: Mean duration of diarrhoea
Comparison 9. Exposure to antibiotics.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 9.1 Diarrhoea lasting ≥ 48 hours | 8 | 1717 | Risk Ratio (M‐H, Random, 95% CI) | 0.80 [0.67, 0.95] |
| 9.2 Duration of diarrhoea | 6 | 1674 | Mean Difference (IV, Random, 95% CI) | ‐18.94 [‐37.35, ‐0.52] |
Comparison 10. Use of zinc.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 10.1 Duration of diarrhoea | 7 | 934 | Mean Difference (IV, Random, 95% CI) | ‐14.68 [‐22.94, ‐6.42] |
Comparison 11. Risk of bias.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 11.1 Diarrhoea lasting ≥ 48 hours | 36 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 11.1.1 Adequate random sequence generation | 19 | 4183 | Risk Ratio (M‐H, Random, 95% CI) | 0.76 [0.66, 0.86] |
| 11.1.2 Adequate allocation concealment | 4 | 2203 | Risk Ratio (M‐H, Random, 95% CI) | 1.00 [0.99, 1.01] |
| 11.1.3 Adequate blinding of participants and personnel | 16 | 3677 | Risk Ratio (M‐H, Random, 95% CI) | 0.69 [0.60, 0.81] |
| 11.1.4 Adequate blinding of outcome assessment | 16 | 3941 | Risk Ratio (M‐H, Random, 95% CI) | 0.73 [0.65, 0.83] |
| 11.1.5 Adequate participant follow‐up | 25 | 4622 | Risk Ratio (M‐H, Random, 95% CI) | 0.63 [0.50, 0.80] |
| 11.1.6 Adequate outcome reporting | 33 | 5803 | Risk Ratio (M‐H, Random, 95% CI) | 0.65 [0.53, 0.81] |
| 11.1.7 Low risk of bias for all parameters | 2 | 1770 | Risk Ratio (M‐H, Random, 95% CI) | 1.00 [0.91, 1.09] |
| 11.2 Mean duration of diarrhoea | 56 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 11.2.1 Adequate random sequence generation | 28 | 5949 | Mean Difference (IV, Random, 95% CI) | ‐22.20 [‐30.88, ‐13.51] |
| 11.2.2 Adequate allocation concealment | 10 | 3599 | Mean Difference (IV, Random, 95% CI) | ‐11.77 [‐24.11, 0.57] |
| 11.2.3 Adequate blinding of participants and personnel | 22 | 4956 | Mean Difference (IV, Random, 95% CI) | ‐18.78 [‐30.37, ‐7.18] |
| 11.2.4 Adequate blinding of outcome assessment | 24 | 5630 | Mean Difference (IV, Random, 95% CI) | ‐21.43 [‐31.85, ‐11.02] |
| 11.2.5 Adequate participant follow‐up | 43 | 7785 | Mean Difference (IV, Random, 95% CI) | ‐20.93 [‐27.24, ‐14.62] |
| 11.2.6 Adequate outcome reporting | 53 | 8861 | Mean Difference (IV, Random, 95% CI) | ‐21.60 [‐27.39, ‐15.81] |
| 11.2.7 Low risk of bias for all parameters | 6 | 3058 | Mean Difference (IV, Random, 95% CI) | ‐8.64 [‐29.38, 12.10] |
Comparison 12. Publication decade.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 12.1 Diarrhoea lasting ≥ 48 hours | 36 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 12.1.1 1980s | 4 | 187 | Risk Ratio (M‐H, Random, 95% CI) | 0.50 [0.34, 0.74] |
| 12.1.2 1990s | 7 | 589 | Risk Ratio (M‐H, Random, 95% CI) | 0.68 [0.54, 0.86] |
| 12.1.3 2000s | 10 | 1305 | Risk Ratio (M‐H, Random, 95% CI) | 0.62 [0.52, 0.74] |
| 12.1.4 2010s | 15 | 3972 | Risk Ratio (M‐H, Random, 95% CI) | 0.78 [0.63, 0.98] |
| 12.2 Mean duration of diarrhoea | 56 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 12.2.1 1990s | 6 | 377 | Mean Difference (IV, Random, 95% CI) | ‐33.18 [‐51.33, ‐15.03] |
| 12.2.2 2000s | 22 | 3471 | Mean Difference (IV, Random, 95% CI) | ‐24.08 [‐36.09, ‐12.07] |
| 12.2.3 2010s | 28 | 5290 | Mean Difference (IV, Random, 95% CI) | ‐17.15 [‐22.27, ‐12.03] |
Comparison 13. Prospective trial registration.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 13.1 Diarrhoea lasting ≥ 48 hours | 8 | 2756 | Risk Ratio (M‐H, Random, 95% CI) | 0.81 [0.70, 0.93] |
| 13.2 Mean duration of diarrhoea | 12 | 3437 | Mean Difference (IV, Random, 95% CI) | ‐16.43 [‐22.43, ‐10.43] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Aggarwal 2014.
| Study characteristics | ||
| Methods | Open‐label randomized controlled trial; 1 centre Duration: 18 months (October 2010 to March 2012) |
|
| Participants | Inclusion criteria: aged 6 months to 5 years; presented with acute diarrhoea (less than 7 days' duration) to the outpatient department (OPD) or to paediatric emergency services Exclusion criteria: severe malnutrition (weight for height < 3 SD of WHO charts); dysentery (presence of visible blood in stools); clinical evidence of coexisting acute systemic illness (e.g. meningitis, sepsis, pneumonia); clinical evidence of chronic disease (e.g. chronic gastrointestinal disease, chronic liver disease, chronic renal disease, nephrotic syndrome); use of probiotics in the preceding 3 weeks; use of antibiotics for current episode of diarrhoea Number completing the study: 87/100* (87%) in the probiotic group (6 non‐contactable, 6 discontinued intervention); 88/100* (88%) in the control group (10 non‐contactable; 3 discontinued intervention). All randomized patients analysed for primary outcomes. *Numbers lost to follow‐up do not add up in the paper |
|
| Interventions |
Timing of start of administration not stated. All participants were given reduced osmolarity ORS and zinc sulphate dispersible tablets 20 mg/d for 14 days and continued feeding. Severe dehydration was managed with IV Ringer's lactate as per WHO guidelines |
|
| Outcomes |
No adverse events were attributed to the probiotic |
|
| Notes | Study location: India (high child and adult mortality) Cause of diarrhoea: rotavirus identified in 21/85 (24.7%) probiotic and 20/85 (23.5%) control. Bloody diarrhoea excluded Nutritional status: weight for height 86.07% (± 8.44) probiotic and 84.25% (± 10.80) control. Severe malnutrition excluded (weight for height < 3 SD of WHO charts) Hydration status: no dehydration 70 (70%) probiotic, 64 (64%) control; some dehydration 28 (28%) probiotic, 31 (31%) control; severe dehydration 2 (2%) probiotic, 5 (5%) control Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Block randomization |
| Allocation concealment (selection bias) | Unclear risk | Unclear method of allocation concealment. Open study – fixed block size may allow prediction of allocation |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label study |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | Open‐label study |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Primary outcomes reported for > 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All pre‐stated primary outcomes reported |
Azim 2014.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 7 months (April to October 2010) |
|
| Participants | Inclusion criteria: children aged 1 to 5 years; acute diarrhoea with dehydration Exclusion criteria: severe dehydration with danger signs as defined by WHO classification for dehydration assessment; grade 3 and 4 malnutrition as defined by modified Gomez classification; dysentery; more than 2 episodes of diarrhoea in the past 2 months; any other coexisting acute systemic illness Number completing the study: 45/45 in the probiotic group (100%); 45/45 in the control group (100%) |
|
| Interventions |
Saccharomyces boulardii, 250 mg twice daily for 5 days Timing of start of intervention not stated All participants were given oral/parenteral rehydration therapy and electrolyte replacement when needed |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Pakistan (high child and adult mortality) Causes of diarrhoea: dysentery excluded Nutritional status: grade 3 and 4 malnutrition excluded (modified Gomez classification) Hydration status: all participants had moderate dehydration Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Patients were divided into 2 groups by lottery method |
| Allocation concealment (selection bias) | Unclear risk | Unclear |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No placebo used |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not stated |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All outcomes reported |
Basu 2007.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 1 year (January to December 2003) |
|
| Participants | Inclusion criteria: inpatients; infants and children with ≥ 3 watery stools/d without visible blood or mucus (duration not stated); < 10 white blood cells/high power field and no red cells, mucus flakes, or bacteria on stool microscopy; negative hanging drop preparation; negative bacterial stool culture Exclusion criteria: systemic illness other than diarrhoea on admission; systemic complication of diarrhoea during hospital stay; failure to give informed consent Number completing the study: 323/330 (97.9%) in the probiotic group (3 participants had electrolyte imbalance, 2 had septicaemia, 2 withdrew consent); 323/332 (97.3%) in the control group (3 participants had electrolyte imbalance, 2 had septicaemia, 2 withdrew consent, 1 was discharged, 1 died) |
|
| Interventions |
Dehydration was corrected using oral rehydration fluid (ORF) according to WHO guidelines |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: India (high child and adult mortality) Cause of diarrhoea: bacterial diarrhoea excluded. Rotavirus identified in 241 (74.6%) probiotic and 249 (77.1%) control Nutritional status: most participants malnourished ‐ probiotic: 198/323 moderately malnourished, 31/323 severely malnourished; control: 185/323 moderately malnourished, 33/323 severely malnourished Hydration status: all participants dehydrated ‐ probiotic: 48 mild, 173 moderate, 102 severe dehydration; control: 51 mild, 168 moderate, 104 severe dehydration Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer randomization |
| Allocation concealment (selection bias) | Low risk | Opaque and sealed envelopes |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo; intervention in numbered packets |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Investigators blinded to intervention |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All pre‐stated outcomes reported |
Basu 2009.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 1 year (period not stated) |
|
| Participants | Inclusion criteria: inpatients; infants and children with ≥ 3 watery stools/d without macroscopic blood or mucus; < 10 white cells per high power field and absent red blood cells; mucus flakes and bacteria on stool microscopy; negative hanging drop preparation; negative bacterial stool culture Exclusion criteria: symptoms of illness other than diarrhoea; development of any systemic complication of diarrhoea during hospitalization; failure to give informed consent Numbers completing the study: probiotic group: 186/196 (94.9%; withdrawals: 5 electrolyte imbalance, 3 septicaemia, 2 withdrawal of consent); placebo group: 185/196 (94.4%; withdrawals: 4 electrolyte imbalance, 3 septicaemia, 2 withdrawal of consent, 1 discharge on request, 1 death) |
|
| Interventions |
Interventions started after initial rehydration and stabilization |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: India (high child and adult mortality) Cause of diarrhoea: bacterial diarrhoea excluded. Rotavirus identified in 106 (57.0%) probiotic and 102 (55.1%) control Nutritional status: severe malnutrition in 17 (9.1%) probiotic and 12 (6.5%) control; mild/moderate malnutrition in 102 (54.8%) probiotic and 100 (54.1%) control Hydration status: severe dehydration in 35 (18.8%) probiotic and 39 (21.1%) control; mild/moderate dehydration in 121 (65.1%) probiotic and 122 (66.0%) control Source of funding not stated, but no study authors had a financial arrangement regarding this study |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated random numbers |
| Allocation concealment (selection bias) | Low risk | Opaque, sealed envelopes |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo; intervention in numbered packets |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Investigators blinded to intervention |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All pre‐stated outcomes reported |
Bhat 2018.
| Study characteristics | ||
| Methods | Open‐label randomized controlled trial; 1 centre Duration: 2 years (2010 to 2012) |
|
| Participants | Inclusion criteria: children aged 6 months to 5 years; admitted to hospital with acute watery diarrhoea of less than or equal to 48 hours' duration Exclusion criteria: history of blood or pus in stools; severely dehydrated (WHO criteria); severely malnourished (grade III and IV according to IAP classification); treatment with antibiotics, probiotics, or prebiotics within 2 weeks before enrolment; history of conditions known to produce immunodeficiency (AIDS, other congenital immunodeficiency syndrome, drug therapy with steroids, anticancer drugs etc.); presence of acute systemic illness (meningitis, pneumonia, sepsis); chronic diarrhoea; known hypersensitivity to Bacillus clausii and Saccharomyces boulardii or other probiotics Number completing study: 40/40 in both probiotic groups (100%); 40/40 in control group (100%) |
|
| Interventions |
Timing of start of intervention not stated. All participants received oral rehydration therapy and zinc |
|
| Outcomes |
No comment regarding adverse events |
|
| Notes | Study location: India (high child and adult mortality) Cause of diarrhoea: bloody diarrhoea excluded Nutritional status: no malnutrition: 19 (47.5%), grade 1 malnutrition: 18 (45%), grade 2 malnutrition: 3 (7.5%) in S boulardii group; no malnutrition: 21 (52.5%), grade 1 malnutrition: 17 (42.5%), grade 2 malnutrition: 2 (5%) in B clausii group; no malnutrition: 24 (60.0%), grade 1 malnutrition: 14 (35.0%), grade 2 malnutrition: 2 (5%) in control group Hydration status: some dehydration in 24 (60%) in the S boulardii group, 29 (72.5%) in the B clausii group, and 22 (55.0%) in the control group. Severe dehydration excluded Source of funding: no funding sources identified |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Method of randomization not stated |
| Allocation concealment (selection bias) | Unclear risk | Not stated |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Open‐label trial; no placebo |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | Open‐label trial; no placebo |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All outcomes reported |
Bhatnagar 1998.
| Study characteristics | ||
| Methods | Randomized controlled trial; 2 centres Duration: 16 months |
|
| Participants | Inclusion criteria: inpatients; malnourished boys aged 4 to 48 months (weight for height < 80% NCHS median) with diarrhoea (≥ 5 liquid stools in preceding 24 hours) for ≤ 96 hours. Nearly all children were dehydrated (48/49 milk group and 43/47 yogurt group) Exclusion criteria: female; severe non‐gastrointestinal illness; gross blood in the stools; exclusive breast‐feeding Numbers completing study: 47/49 (95.9%) in probiotic group (2 were withdrawn because of cholera in stool cultures); 49/53 (92.5%) in control group (2 were withdrawn because of cholera in stool cultures, 2 left against medical advice) |
|
| Interventions |
Given after 8 hours' initial observation. All participants received rehydration fluids (IV if stool > 4 g/kg/h), IV cephalosporin, and gentamicin, and were fed with rice lentil oil gruel |
|
| Outcomes |
No comment regarding adverse events |
|
| Notes | Study location: India (high child and adult mortality) Cause of diarrhoea: excluded if gross bloody stools Nutritional status: all malnourished boys (weight for height < 80% NCHS median); mean weight for length and length for age (% NHCS median) similar in both groups Hydration status: nearly all children were dehydrated: 43/47 (91.5%) probiotic and 48/49 (98.0%) control Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Block randomization list |
| Allocation concealment (selection bias) | Unclear risk | Not stated |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Interventions not identical |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear who assessed outcomes |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All pre‐stated outcomes reported |
Billoo 2006.
| Study characteristics | ||
| Methods | Randomized trial; probably open study; 1 centre Duration: not stated |
|
| Participants | Inclusion criteria: inpatients; infants and children with acute watery diarrhoea of mild to moderate severity Exclusion criteria: severe intercurrent illness; severe diarrhoea and dehydration requiring admission and IV rehydration; temperature > 38.5° C; anti‐diarrhoeals or antibiotics in last 24 hours; severe malnutrition Numbers completing study: 50/50 (100%) in probiotic group; 50/50 (100%) in control group |
|
| Interventions |
Timing of interventions not stated |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Pakistan (high child and adult mortality) Cause of diarrhoea: rotavirus identified in 8 (16.0%) probiotic and 10 (20.0%) control. Bacterial diarrhoea identified in 13 (26.0%) probiotic and 6 (12.0%) control Nutritional status: severe malnutrition excluded; no further data presented Hydration status: severe dehydration excluded; no further data presented Source of funding: supported by Laboratoires Biocedex (France); Hilton Pharma (Pvt) Ltd (Pakistan) |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Randomized controlled trial but methods not described |
| Allocation concealment (selection bias) | Unclear risk | Methods not described |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear who assessed outcomes |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All pre‐stated outcomes reported |
Boudraa 2001.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: not stated |
|
| Participants | Inclusion criteria: inpatients; well‐nourished children aged 3 to 24 months with watery diarrhoea < 5 days' duration and > 3 watery stools in previous 24 hours. All children were dehydrated, including some with severe dehydration Exclusion criteria: exclusive breast‐feeding; history of allergy to cow's milk; severe malnutrition (weight or height < 70% or oedema) Numbers completing study: 49/56 (87.5%) in probiotic group (3 with urinary tract infection and 1 with bronchopneumonia were withdrawn, others were withdrawn by parents); 48/56 (85.7%) in non‐probiotic group (2 with urinary tract infection and 1 with amebiasis were withdrawn, 1 failed to attend for follow‐up, others were withdrawn by parents). Reasons for withdrawal by parents not stated. Diarrhoea outcomes reported for all randomized children |
|
| Interventions |
180 mL/kg/d of fermented or non‐fermented infant formula given after initial oral rehydration. All infants also received other foods |
|
| Outcomes |
Frequency of vomiting similar in both groups. No other comment regarding adverse events |
|
| Notes | Study location: Algeria (high child and adult mortality) Cause of diarrhoea: rotavirus identified in 25/56 (44.6%) probiotic and 26/56 (46.4%) control. No bacterial pathogens isolated Nutritional status: all well nourished Hydration status: all dehydrated; severe dehydration 5 (8.9%) probiotic and 4 (7.1%) control Reduced duration of diarrhoea in probiotic compared with non‐probiotic group observed only in children with reducing substances in stools Source of funding: not stated Secondary outcome reporting: outcome data presented for < 90% in both groups |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Interventions not identical |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear who assessed outcomes |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Outcomes reported for > 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All pre‐stated outcomes reported |
Bruno 1981.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: not stated |
|
| Participants | Inclusion criteria: inpatients; adults with acute enteritis (diarrhoea, fever, vomiting, nausea, abdominal pain with or without toxicity; duration not stated) Exclusion criteria: typhoid cases Number completing study: stool cultures available after randomization; participants with Salmonella typhi were withdrawn (number not stated); for non‐typhoid participants, results were presented for 25/25 (100%) probiotic and 24/24 (100%) control |
|
| Interventions |
Timing of start of administration not stated |
|
| Outcomes |
Resolution of diarrhoea defined as 2 or fewer formed stools/d and no abdominal pain or fever No adverse events attributed to probiotic |
|
| Notes | Study location: Italy (very low child and adult mortality) Cause of diarrhoea: non‐typhoid. Bacterial stool culture (probiotic group/placebo group): Salmonella 4/3; enteropathogenic E coli 18/20; other enteropathogen 1/3 Nutritional status: no data presented Hydration status: no data presented Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding not adequately described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear who assessed outcomes |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All pre‐stated outcomes reported |
Bruno 1983.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: not stated |
|
| Participants | Inclusion criteria: inpatients; adults (although ages not specified) with acute febrile enteritis (duration of diarrhoea not stated) Exclusion criteria: typhoid cases Numbers completing study: 10/10 (100%) probiotic, 11/11 (100%) control |
|
| Interventions |
Intervention started after initial treatment with chloramphenicol (all participants) and after stool culture results available |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Italy (very low child and adult mortality) Cause of diarrhoea: non‐typhoid Nutritional status: no data presented Hydration status: no data presented Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Method of randomization unclear |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Placebo not described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All pre‐stated outcomes reported |
Burande 2013.
| Study characteristics | ||
| Methods | Prospective, parallel, single‐blind, randomized controlled trial; 1 centre Duration: 2 years (July 2009 to July 2011) |
|
| Participants | Inclusion criteria: children diagnosed with acute diarrhoea (≥ 3 unformed stools in last 24 hours with duration < 48 hours); no dehydration or some dehydration as per WHO criteria Exclusion criteria: concurrent chronic illness; severe and very severe undernutrition (weight for age < 60% of 50th percentile ‐ CDC 2000 Standards); severe dehydration (as per WHO criteria); allergy or history of use of probiotic, antibiotic, or anti‐diarrhoeal in last 24 hours Numbers completing study: 35/36 (97%) probiotic (1 lost to follow‐up); 35/36 (97%) control (1 lost to follow‐up). Reasons for loss to follow‐up not given |
|
| Interventions |
Timing of start of administration not stated. All participant children received ORS ad libitum (as much as required after passing of each stool or vomiting, or both, and whenever child demand for it) until resolution of diarrhoea, and zinc (10 mg/d if aged < 6 months and 20 mg/d if aged ≥ 6 months) for 14 days. Paracetamol was given as required for fever |
|
| Outcomes |
No specific comment regarding adverse events |
|
| Notes | Study location: India (high child and adult mortality) Cause of diarrhoea: Vibrio cholerae, Entamoeba histolytica, and Giardia lamblia excluded Nutritional status: severe undernutrition excluded (weight for age < 60% of 50th percentile ‐ CDC 2000 Standards) Hydration status: no dehydration 32 (91.4%) probiotic, 31 (88.6%) control; some dehydration 3 (8.6%) probiotic, 4 (11.4%) control. Severe dehydration excluded Source of funding: DY Patil University, Kolhapur, and management to provide financial support |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated random numbers |
| Allocation concealment (selection bias) | Unclear risk | Not adequately described |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No placebo |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | Open‐label study |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All pre‐stated outcomes reported |
Burki 2017.
| Study characteristics | ||
| Methods | Prospective randomized study; 1 centre Duration: 4 months (May to October 2016) |
|
| Participants | Inclusion criteria: children aged 6 months to 5 years, irrespective of hydration status; present or past status of use of antibiotics; ability to tolerate Saccharomyces boulardii Exclusion criteria: recurrent or chronic diarrhoea; acute dysentery; thalassaemia; congenital heart disease Numbers completing study: 200/234 (85.5%) both probiotic and control (21 patients prematurely discharged and 13 left against medical advice). Unclear number originally allocated to each group and from which group withdrawals came; 100 ultimately allocated to both probiotic and control groups |
|
| Interventions |
Timing of start of administration not stated. All participants received 'routine management' of acute diarrhoea (not described) |
|
| Outcomes |
No specific comment regarding adverse events |
|
| Notes | Study location: Pakistan (high child and adult mortality) Cause of diarrhoea: acute dysentery excluded Nutritional status: not stated Hydration status: mild dehydration 17 (17%) probiotic, 14 (14%) control; moderate dehydration 57 (57%) probiotic, 66 (66%) control; severe dehydration 26 (26%) probiotic, 20 (20%) control Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not adequately described |
| Allocation concealment (selection bias) | High risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Follow‐up < 90% |
| Selective reporting (reporting bias) | Low risk | All pre‐stated outcomes reported |
Buydens 1996.
| Study characteristics | ||
| Methods | Randomized controlled trial; 2 centres Duration: not stated |
|
| Participants | Inclusion criteria: inpatients and outpatients; adults with acute diarrhoea (≥ 3 watery or loose stools in last 24 hours) Exclusion criteria: diarrhoea > 3 days; blood in faeces; faecal leukocytes; temperature > 39° C; friable and haemorrhagic mucosa in rectosigmoid; history of chronic diarrhoea; polyps; colon cancer; Crohn's disease; ulcerative colitis; malabsorption; use of anti‐diarrhoeals or antibiotics in past 7 days; severe diarrhoea (dehydration with weight loss > 10%); associated major disease Numbers completing study: 93/105 (88.6%) probiotic (4 violated protocol, 5 did not comply with study medications, 3 were lost to follow‐up); 92/106 (86.8%) control (5 violated protocol, 7 did not comply with study medications, 2 were lost to follow‐up) |
|
| Interventions |
Started on day of presentation |
|
| Outcomes |
Diarrhoea resolved when stool frequency < 3/d and semi‐solid or solid and no associated symptoms No adverse events attributed to probiotic |
|
| Notes | Study location: Belgium (very low child and adult mortality) Cause of diarrhoea: bloody diarrhoea excluded. Bacterial diarrhoea identified in 12 (11.4%) probiotic and 16 (15.1%) control Nutritional status: no data presented Hydration status: > 10% dehydration excluded; no further data presented Highly significant reduction in duration of diarrhoea in probiotic group confirmed by intention‐to‐treat analysis, which included excluded participants as non‐recovered on day 7 (but no data shown) Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomization by central computer |
| Allocation concealment (selection bias) | Unclear risk | No specific details of allocation concealment |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Identical placebo; outcomes assessed by blinded patients |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Follow‐up < 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All pre‐stated outcomes reported |
Canani 2007.
| Study characteristics | ||
| Methods | Randomized controlled trial; 6 centres Duration: 12 months (October 1999 to September 2000) |
|
| Participants | Inclusion criteria: outpatients; infants and children aged 3 to 36 months with > 2 loose or liquid stools/d for < 48 hours Exclusion criteria: malnutrition; severe dehydration; coexisting acute systemic illness (meningitis, sepsis, pneumonia); immunodeficiency; underlying severe chronic disease; cystic fibrosis; food allergy or other chronic GI disease; use of probiotics in the previous 3 weeks; antibiotic or any other anti‐diarrhoeal medication in the previous 3 weeks; poor compliance (< 4 doses of study medication administered) Numbers completing study: 95/100 probiotic (2 did not receive allocated intervention, 1 faster remission, 1 worsening symptoms, 1 poor compliance); 88/92 control (1 did not receive allocated intervention, 1 worsening symptoms, 1 contracted pneumonia, 1 coeliac disease) |
|
| Interventions |
Intervention started within 48 hours of admission. ORF given for 3 to 6 hours after admission, lactose‐containing formula milk or cow's milk according to age |
|
| Outcomes |
1 participant with poor compliance in the probiotic group; 31 and 34 participants with vomiting in probiotic and placebo groups, respectively. No adverse events attributed to probiotic |
|
| Notes | Study location: Italy (very low child and adult mortality) Cause of diarrhoea: stool culture in only a few participants; no data presented Nutritional status: malnutrition excluded Hydration status: severe dehydration excluded; no other data presented Source of funding: none Single‐blind trial: parents instructed to buy probiotic preparation This study also allocated children to 4 other probiotic groups: (1) S boulardii 5 × 10⁹ live organisms daily (Codex) for 5 days; (2) B clausii O/C84, N/R84, T84, SIN84 (Enterogermina) 10⁹ CFUs bd for 5 days; (3) combination of L delbrueckii var bulgaricus LMG‐P17550 10⁹ CFUs daily, L acidophilus LMG‐P 17549 109 CFUs daily, S thermophilus LMG‐P 17503 10⁹ CFUs daily, and B bifidum LMG‐P 17500 5 × 10⁸ CFUs daily (Lactogermina) for 5 days; (4) Enterococcus faecium SF 68 (Bioflorin) 7.5 × 10⁷ CFUs daily for 5 days; and compared each of the probiotic groups with the single control group. Mean duration of diarrhoea and mean stool frequency on days 2 and 3 were significantly shorter for intervention groups 1 and 3 than for the control group. These outcomes were similar to the control group for the other probiotic groups To avoid a unit of analysis error as a result of multiple comparisons between intervention groups and the single control group, we elected to include data for the Lrhamnosus GG group only in this review. We selected L rhamnosus GG because this was the probiotic most frequently evaluated in acute infectious diarrhoea, and we wished to maximize the body of evidence. We rejected the alternative approach of pooling data from all of the different probiotic intervention groups into a single group because this would not be helpful in selecting a specific probiotic intervention for use in clinical practice |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomization list; allocation in blocks of 6 |
| Allocation concealment (selection bias) | Unclear risk | No specific details of allocation concealment |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Parents of participants told which treatment to purchase |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessors blinded to intervention |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All pre‐stated outcomes reported |
Cetina‐Sauri 1994.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 11 months (1 April 1988 to 15 March 1989) |
|
| Participants | Inclusion criteria: unclear whether inpatients or outpatients, or both; children aged 3 months to 3 years with acute (duration not stated) non‐bloody diarrhoea; no dehydration; no concomitant illness; no antibiotics or drugs affecting gut motility. Numbers completing study: unclear how many participants randomized; participants who deteriorated, developed concomitant illness, and needed other drugs, or who wished to withdraw, were excluded from the analysis (details not given) |
|
| Interventions |
No details of when interventions started |
|
| Outcomes |
Cure defined as < 4 stools in 24 hours and absence of liquid stools No adverse events attributed to probiotic |
|
| Notes | Study location: Mexico (low child and adult mortality) Cause of diarrhoea: bloody diarrhoea excluded Nutritional status: all well nourished Hydration status: dehydration excluded Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Random numbers table |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Unclear whether placebo and probiotic identical |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear who assessed outcomes |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Unclear how many participants were randomized at start of study |
| Selective reporting (reporting bias) | Unclear risk | N/A ‐ neither primary outcome reported |
Chen 2010.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 22 months (February 2006 to November 2007) |
|
| Participants | Inclusion criteria: inpatients; children aged 3 months to 6 years with acute diarrhoea defined as 3 or more loose or liquid stools per day of less than 72 hours' duration Exclusion criteria: immunodeficiency; severe abdominal distension with risk of bowel perforation; severe infection or sepsis; history with gastrointestinal tract surgery; use of probiotics in the preceding week Numbers completing study: 304 children enrolled and 293 were included in the analysis (150 probiotic and 143 control). Overall, 7 children discontinued medication and 4 were lost to follow‐up; group allocation unclear |
|
| Interventions |
When interventions were started is not stated |
|
| Outcomes |
Duration of diarrhoea also reported for children with rotavirus diarrhoea and those with bacterial diarrhoea No adverse events attributed to probiotic |
|
| Notes | Study location: Taiwan (low child and adult mortality) Cause of diarrhoea: 47 (31.3%) children in probiotic group and 44 (30.8%) in control group had rotavirus in stools. Norovirus and adenovirus were also identified. 27 (18.0%) children in probiotic group and 30 (20.0%) in control group had bacteria in stools (either Salmonella enterica or Campylobacter jejuni) Nutritional status: no data presented Hydration status: no data presented Source of funding: this study was supported in part by a grant from Chang Gung Memorial Hospital research project grant XMRPG440021, Northern Taiwan First author was contacted and was asked to clarify
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomization |
| Allocation concealment (selection bias) | Unclear risk | Unclear method of allocation concealment |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessors blinded to intervention |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcomes reported |
Correa 2011.
| Study characteristics | ||
| Methods | Double‐blind randomized placebo‐controlled parallel‐group trial; 2 centres Duration: 18 months (April 2007 to September 2008) |
|
| Participants | Inclusion criteria: children of both sexes aged 6 to 48 months; no other diarrhoea episode or use of antibiotics 2 weeks before the trial; acute diarrhoea within 72 hours before hospitalization Exclusion criteria: exclusive breast‐feeding; macroscopic blood in the faeces; severe malnutrition (weight/height < 70% National Center for Health Statistics); impossibility of oral nutrition; existence of underlying pathology (e.g. sepsis, cystic fibrosis, renal insufficiency, liver disease); children needing specific treatment Numbers completing study: 90/95 (94.7%) probiotic group (3 lost to follow‐up (needed antibiotics); 2 did not complete treatment (no reason)); 86/91 (94.5%) control (2 lost to follow‐up (needed antibiotics); 3 did not complete treatment (no reason given)). All randomized patients were analysed under intention‐to‐treat analysis |
|
| Interventions |
Timing of start of administration not stated |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Brazil (low child and adult mortality) Cause of diarrhoea: rotavirus detected in 58.5% in probiotic group and in 56.3% in control group. Bloody diarrhoea excluded Nutritional status: severe malnutrition excluded Hydration status: 88/90 (97.8%) probiotic had moderate to grave dehydration, as did 85/86 (98.8%) control Source of funding: supported by Conselho Nacional de Desenvolvimento Cient́ıfico e Tecnológico (CNPq) and Coordenac ¸ão de Aperfeic ¸oamento do Pessoal de Ensino Superior (CAPES) |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated numbers |
| Allocation concealment (selection bias) | Unclear risk | Unclear method of allocation concealment |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessors blinded to intervention |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Costa‐Ribeiro 2003.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: not stated |
|
| Participants | Inclusion criteria: inpatients; boys age 1 to 24 months with acute diarrhoea (3 or more watery or loose stools per 24 hours during at least one 24‐hour period in the 72 hours before admission) with moderate dehydration or severe dehydration after correction by rapid IV fluids Exclusion criteria: systemic infection requiring antibiotic; severe malnutrition (weight for age < 65% of NCHS standards); bloody diarrhoea Numbers completing study: 61/61 (100%) probiotic and 63/63 (100%) control |
|
| Interventions |
Interventions started after correction of severe dehydration if required |
|
| Outcomes |
No comment regarding adverse events |
|
| Notes | Study location: Brazil (low child and adult mortality) Cause of diarrhoea: bloody diarrhoea excluded; 52% of children probiotic and 48% control had rotavirus in stools; no data shown for outcomes in rotavirus diarrhoea, although stated as "no significant difference" between groups Nutritional status: severe malnutrition excluded; median WHZ score ‐1.13 (IQR ‐1.63 to ‐0.43) in control group and ‐1.22 (‐1.87 to ‐0.62) in probiotic group Hydration status: all dehydrated; moderate or severe dehydration in 92% probiotic and 94% control Source of funding: this study was supported in part by a grant from Pronex/CNPq (661086/1998‐4), Brazil |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not adequately described |
| Allocation concealment (selection bias) | Unclear risk | Not adequately described |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear who assessed outcomes |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcomes reported |
D'Apuzzo 1982.
| Study characteristics | ||
| Methods | Randomized controlled trial; unclear whether single centre or multi‐centre Duration: not stated |
|
| Participants | Inclusion criteria: unclear whether inpatients or outpatients, or both; children with acute enteritis (duration and definition not given) Exclusion criteria: none stated Numbers completing study: 21/21 (100%) probiotic and 18/18 (100%) control |
|
| Interventions |
When interventions started is not stated |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Switzerland (very low child and adult mortality) Cause of diarrhoea: 7 participants in each group had positive stool culture for bacteria Nutritional status: no data presented Hydration status: no data presented S faecium 68 also appeared to promote recovery from abdominal pain, fever, and vomiting Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not adequately described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not adequately described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Dalgic 2011.
| Study characteristics | ||
| Methods | Prospective randomized single‐blind controlled trial; 1 centre Duration: 22 months (September 2008 to June 2010) |
|
| Participants | Inclusion criteria: time between onset of diarrhoea and hospitalization < 96 hours; presenting with an episode of 3 or more watery or looser‐than‐normal stools within a 24‐hour period and/or forceful vomiting (excluding post‐tussive vomiting); mild to moderate dehydration; on admission, stool positive for rotavirus antigen Exclusion criteria: malnutrition as judged by the ratio of weight to height; duration of diarrhoea > 96 hours; severe dehydration; exclusively breast‐feeding; toxic clinical appearance; immunosuppression; any known allergies to any drugs or foods Numbers completing study: 60/60 (100%) probiotic plus zinc; 60/60 (100%) zinc only |
|
| Interventions |
Saccharomyces boulardii: 250 mg once daily, for a minimum of 5 days (not stated whether probiotic alive or killed) Zinc: zinc acetate suspension, 10 mg twice daily for infants < 6 months of age; 20 mg daily for all other participants Lactose‐free formula: Bebelac Lactose Free Formula, 400 g; Nutricia, Istanbul, Turkey Intervention started directly after randomization. All participants offered ORS for rehydration, with IV rehydration given if excessive vomiting or clinical signs of dehydration |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Turkey (low child and adult mortality) Cause of diarrhoea: all patients had rotavirus diarrhoea Nutritional status: severe malnutrition excluded (Z score ≤ ‐3) Hydration status: mild dehydration in 7.7% probiotic plus zinc and in 8.5% zinc only; moderate dehydration in 4.8% probiotic plus zinc and in 4% zinc only. Severe dehydration excluded Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not adequately described |
| Allocation concealment (selection bias) | Unclear risk | Not stated |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Different treatments given in each arm |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not adequately described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Das 2016.
| Study characteristics | ||
| Methods | Double‐blind randomized controlled trial; 1 centre Duration: 17 months (November 2007 to March 2009) |
|
| Participants | Inclusion criteria: children with acute rotavirus diarrhoea of < 48 hours' duration; moderate to severe dehydration; aged between 3 months and 5 years Exclusion criteria: severe malnutrition (weight for height < 3 SD of WHO growth chart); coexisting systemic illness and chronic disease; taking probiotics including during preceding week; taking antibiotics for current episode of diarrhoea; history of receiving rotavirus vaccine Numbers completing study: 30/30 (100%) probiotic; 28/30 (93.3%) control (2 non‐contactable). All randomized participants analysed under intention‐to‐treat analysis |
|
| Interventions |
Intervention started after participant was clinically stabilized and maintained hydration and randomization. All cases managed as per WHO guidelines for management of acute diarrhoea (details not given). Carers advised to avoid any warm/hot food within 2 hours of giving probiotics |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: India (high child and adult mortality) Cause of diarrhoea: rotavirus detected in 100% of participants in probiotic and control groups Nutritional status: severe malnutrition excluded Hydration status: no dehydration in 14 (46.7%) probiotic and in 15 (50%) control; some dehydration in 8 (26.7%) probiotic and in 7 (23.3%) control Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not adequately described |
| Allocation concealment (selection bias) | Low risk | Serially numbered opaque envelopes |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Unclear whether different advice given for both arms |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not adequately described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcomes reported |
Dinleyici 2014.
| Study characteristics | ||
| Methods | Randomized single‐blind parallel‐group controlled trial; 11 centres Duration: not stated |
|
| Participants | Inclusion criteria: children aged 3 to 60 months; acute watery diarrhoea lasting 12 to 72 hours; hospitalized in 1 of 11 Turkish centres; clinical signs of mild to moderate dehydration (prolonged capillary refill time, abnormal skin turgor, and 3% to 9% loss of body weight) Exclusion criteria: clinical features of hypovolaemic shock and/or necessitating admission to intensive care unit; use of antibiotics or probiotics up to 1 month before admission; malnutrition (weight < P3); chronic underlying disease, including immunocompromised condition Numbers completing study: 64/70 (91.4%) probiotic (3 antibiotic prescriptions (post randomization); 1 parental refusal to continue; 2 lack of data after hospital discharge (lack of parental compliance)); 63/70 (90%) control (3 antibiotic prescriptions (post randomization); 1 parental refusal to continue; 1 detection of underlying disease during hospitalization; 1 lack of data after hospital discharge (lack of parental compliance); 1 unaccounted for) |
|
| Interventions |
Intervention administered after randomization. All participants received hypo‐osmolar ORS and/or IV therapy |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Turkey (low child and adult mortality) Cause of diarrhoea: bloody diarrhoea excluded Nutritional status: malnutrition excluded Hydration status: hypovolaemic shock excluded Source of funding: no funding; free medication provided (unclear from whom) |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomization |
| Allocation concealment (selection bias) | Unclear risk | No specific details of allocation concealment |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessor blinded to intervention |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Dinleyici 2015a.
| Study characteristics | ||
| Methods | Randomized single‐blind case‐control trial; number of centres not stated Duration: not stated |
|
| Participants | Inclusion criteria: age 3 to 60 months; acute infectious diarrhoea (passage of 3 or more loose or watery stools per day) lasting 12 to 72 hours before presentation at the outpatient clinic; followed up with ambulatory care Exclusion criteria: need for hospitalization; use of antibiotics or probiotics for 1 month before a new episode of diarrhoea; severe malnutrition; severe chronic underlying disease, including immunocompromising conditions Numbers completing study: 29/32 (90.6%) probiotic (3 discontinued intervention (antibiotic prescription)); 31/32 (96.9%) control (1 discontinued intervention (antibiotic prescription)) |
|
| Interventions |
Timing of start of administration not stated. All participants received hypo‐osmolar ORS |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Turkey (low child and adult mortality) Cause of diarrhoea: acute watery diarrhoea. No comment regarding specific cause of diarrhoea Nutritional status: severe malnutrition excluded Hydration status: not stated Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomization |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Dinleyici 2015b.
| Study characteristics | ||
| Methods | Prospective single‐blind randomized controlled trial; 8 centres Duration: not stated |
|
| Participants | Inclusion criteria: hospitalized and ambulatory children aged 3 to 60 months (ECU and outpatients); acute watery diarrhoea lasting 12 to 72 hours; clinical signs of mild to moderate dehydration (prolonged capillary refill time, abnormal skin turgor, and percentage loss of body weight) Exclusion criteria: use of antibiotics or probiotics up to 1 month before admission; malnutrition (weight under the third percentile); chronic underlying disease including immunocompromised condition. For hospitalized children, also clinical features of hypovolaemic shock, and/or need for ICU admission Numbers completing study: 220/240 (91.7%) (148/160 hospitalized; 72/80 ambulatory) probiotic (hospitalized: 2 had had antibiotics, 2 discontinued intervention as needed antibiotics, 8 were lost to follow‐up; ambulatory: 3 had had antibiotics, 5 were lost to follow‐up); 143/160 (89.4%) (72/80 hospitalized; 71/80 ambulatory) control (hospitalized: 3 had had antibiotics, 5 were lost to follow‐up; ambulatory: 4 had had antibiotics, 3 discontinued intervention due to antibiotics, 2 were lost to follow‐up). NB combined results of all participants in probiotic groups used in analyses |
|
| Interventions |
Timing of start of administration not stated. All participants received ORS and/or IV therapy |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Turkey (low child and adult mortality) Cause of diarrhoea: acute watery diarrhoea. No comment regarding specific cause of diarrhoea Nutritional status: malnutrition excluded Hydration status: hypovolaemic shock excluded Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomization |
| Allocation concealment (selection bias) | Unclear risk | No specific details of allocation concealment |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessor blinded to intervention |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Overall follow‐up ≥ 90%; no marked differences between arms |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Dubey 2008.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: February 2005 to February 2007 |
|
| Participants | Inclusion criteria: inpatients; infants and children with watery diarrhoea (defined as watery stools) < 72 hours' duration due to rotavirus infection; parental consent Exclusion criteria: systemic infection; chronic disease; body weight < 60% NCHS standard; vomiting; need for antibiotics Numbers completing study: 113/113 (100%) probiotic and 111/111 (100%) control. Six children did not complete the study; no group allocation reported or reasons given |
|
| Interventions |
When interventions were started is not stated |
|
| Outcomes | Significantly lower mean stool frequency seen in probiotic group from days 2 to 4; otherwise results between groups comparable. Significantly improved stool consistency in probiotic group on day 2. Probiotic group received significantly smaller volume of ORS on days 2 and 3 Overall recovery rate was better in the probiotic group (89.4% vs 39.6%; P < 0.001) No adverse effects were attributed to probiotic |
|
| Notes | Study location: India (high child and high adult mortality) Cause of diarrhoea: all rotavirus Nutritional status: severe malnutrition excluded; statement: "malnutrition status similar in two groups" Hydration status: dehydration status similar in 2 groups at baseline but no data presented Source of funding: supported by grant from VSL Secondary outcome reporting: all pre‐stated outcomes reported |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical interventions; participants and personnel unaware of assignment to arms |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not adequately described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | High risk | Primary outcome not reported in results |
Dutta 2011.
| Study characteristics | ||
| Methods | Double‐blind randomized placebo‐controlled trial; 1 centre Duration: 23 months (September 2003 to July 2005) |
|
| Participants | Inclusion criteria: boys (for ease of collection of stool and urine separately); aged 6 to 24 months; suffering from dehydrating acute watery diarrhoea of less than 3 days’ duration; clinical signs and symptoms of ‘some’ dehydration (thirst or eagerness to drink, sunken eyes, dry mouth and tongue, loss of skin elasticity) Exclusion criteria: history of an episode of diarrhoea within 1 month of the present illness to exclude recurrent and persistent diarrhoea; exclusively breast‐fed; severe dehydration; diarrhoea associated with another systemic illness (e.g. septicaemia, pneumonia, urinary tract infection, otitis media) or chronic underlying disease (e.g. tuberculosis, liver disease); severe malnutrition; needing extensive care (e.g. life support system, blood transfusion, total parental nutrition); received an antibiotic before enrolment Numbers completing study: 78/80 (97.5%) probiotic (2 discontinued intervention due to unwillingness of parents); 70/80 (87.5%) control (10 discontinued intervention due to unwillingness of parents) |
|
| Interventions |
Timing of start of administration not stated. All participants received reduced osmolar ORS solution to correct initial dehydration and continued as maintenance; more fluid and/or plain water if wanted/clinical indication; IV Ringer’s lactate for severe dehydration/intractable vomiting. Participants allowed to continue breast‐feeding, formula feeding, animal milk, or normal diet |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: India (high child and adult mortality) Cause of diarrhoea: rotavirus detected in 25 (32%) probiotic and in 26 (37.1%) control. A range of other pathogens were detected less commonly, including V cholerae, Shigella spp, E coli, astrovirus and Cryptosporidium. No pathogens were identified in 18 (23.1%) probiotic and in 17 (24.3%) control Nutritional status: severe malnutrition excluded Hydration status: severe dehydration excluded Source of funding: supported by the Indian Council of Medical Research (ICMR) as intramural project of National Institute of Cholera and Enteric Diseases, Kolkata, India |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated random numbers |
| Allocation concealment (selection bias) | Low risk | Interventions kept in coded blister foil, externally prepared |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessors blinded to intervention |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Overall follow‐up ≥ 90%; no marked differences between arms |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcomes reported |
El‐Soud 2015.
| Study characteristics | ||
| Methods | Prospective double‐blind randomized study; 1 centre Duration: 3 months (July to September 2014) |
|
| Participants | Inclusion criteria: aged 1 to 23 months; acute diarrhoea due to gastroenteritis Exclusion criteria: severe malnutrition (weight for height < 3 SD of WHO charts); dysentery; clinical evidence of coexisting acute systemic illness (e.g. meningitis, sepsis, pneumonia); clinical evidence of chronic disease (e.g. chronic gastrointestinal disease, chronic liver disease, chronic renal disease); probiotics used in the preceding 4 weeks; antibiotics used for current episode of diarrhoea; severe dehydration Numbers completing study: 25/25 (100%) probiotic; 25/25 (100%) control |
|
| Interventions |
Timing of start of administration is not stated. All participants received usual treatment according to WHO guidelines and milk formula |
|
| Outcomes |
No adverse events are attributed to probiotic |
|
| Notes | Study location: Egypt (low child and adult mortality) Cause of diarrhoea: dysentery excluded. Rotavirus detected in 66% of participants. No samples were positive for routine bacterial culture Nutritional status: severe malnutrition excluded Hydration status: severe dehydration excluded Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not adequately described |
| Allocation concealment (selection bias) | Low risk | Serially numbered, sealed opaque envelopes |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear who assessed outcomes |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Erdogan 2012.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 8 months (October 2009 to May 2010) |
|
| Participants | Inclusion criteria: children aged 5 months to 5 years; admitted to Bezmialem Hospital Pediatric Emergency Department with 3 or more episodes of watery diarrhoea per day in the last 48 hours; diagnosed as rotavirus gastroenteritis Exclusion criteria: severe dehydration; stool tests and microscopic examination positive for bacterial pathogens Numbers completing study: 25/25 (100%) in both probiotic groups; 25/25 (100%) in control group |
|
| Interventions |
Treatment start following detection of rotavirus antigen All participants received oral rehydration therapy and rapid refeeding with a normal diet |
|
| Outcomes |
No comment regarding adverse events |
|
| Notes | Study location: Turkey (low child and adult mortality) Cause of diarrhoea: all participants positive for rotavirus antigen Nutritional status: not stated Hydration status: dehydration < 5%: 12 (48%), 5% to 10%: 13 (52%) in S boulardii group; < 5%: 14 (44%), 5% to 10%: 11 (56%) in B lactis group; < 5%: 13 (52%), 5% to 10%: 12 (48%) in control group Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Method of randomization not stated |
| Allocation concealment (selection bias) | Unclear risk | Not stated |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No mention of who assessed outcomes |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All outcomes reported |
Francavilla 2012.
| Study characteristics | ||
| Methods | Randomized double‐blind placebo‐controlled trial; 3 centres Duration: 7 months (January to July 2009) |
|
| Participants | Inclusion criteria: aged 6 to 36 months; hospitalized with acute diarrhoea (no longer than 7 days); clinical signs of mild to moderate dehydration (prolonged capillary refill time, abnormal skin turgor, percentage loss of body weight); no features of hypovolaemic shock Exclusion criteria: underlying chronic disease; bloody stools at the moment of first examination; current use of antibiotic/probiotic/anti‐diarrhoeal medication; demonstration of a bacterial cause for diarrhoea; need for parenteral rehydration Numbers completing study: 35/37 (94.6%) probiotic (2 parental non‐compliance); 34/37 (91.9%) control (2 protocol deviation; 1 parental non‐compliance) |
|
| Interventions |
Intervention started immediately after informed consent given. All participants received ORS to correct dehydration |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Italy (very low child and adult mortality) Cause of diarrhoea: rotavirus detected in 22/37 (59.5%) in both probiotic and control groups; adenovirus detected in 6 (16.2%) in the probiotic group and in 5 (13.5%) in the control group; no pathogens identified in 9 (24.3%) in the probiotic group and in 10 (27%) in the control group. Bloody diarrhoea excluded. Bacterial cause of diarrhoea excluded Nutritional status: not stated Hydration status: mild dehydration 25/37 (67.6%) probiotic and 26/37 (70.3%) control; moderate dehydration in 12/37 (32.4%) in the probiotic group and in 11/37 (29.7%) in the control group. No participants in either group had severe dehydration Source of funding: no funding interests to declare Discrepancy between data in text and tables for proportion of participants with ongoing diarrhoea at 48 hours; data not used. There was no statistically significant difference in duration of hospital stay between groups, but no data were presented |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomization |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessor blinded to intervention; code revealed after study |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcomes reported |
Freedman 2015.
| Study characteristics | ||
| Methods | Prospective double‐blind randomized placebo‐controlled trial; 3 centres Duration: 4 years, 5 months (April 2009 to September 2013) |
|
| Participants | Inclusion criteria: aged 4 to 48 months; attended day care (≥ 2 half‐days (2.5 hours/d per week attendance) at a day care centre or at home or in someone else’s home, where there are, on average, ≥ 3 children including the index child); diagnosed by supervising physician as having gastroenteritis; alternative diagnostic terminologies (e.g. viral illness, diarrhoea, vomiting, viral infection) that reflect a similar diagnosis were acceptable; duration of vomiting or diarrhoea < 96 hours Exclusion criteria: if they (or a family member living in the house) had an indwelling vascular access line or congenital heart disease, were taking immunosuppressive therapy, or had a known immunodeficiency disorder; oral or gastrointestinal surgery within the preceding 7 days; pancreatic dysfunction; bloody diarrhoea; chronic gastrointestinal disease (not including constipation, irritable bowel syndrome, gastroesophageal reflux); short bowel syndrome; undergoing radiation therapy; bilious or bloody vomitus; previous enrolment in the trial; inability to speak or read English or French; supplemental probiotics in the form of powder or pill; exclusively breast‐fed Numbers completing study: high dose: 30/32 (93.8%), low dose: 31/34 (91.2%) in the probiotics group (5 lost to follow‐up); 62/66 (93.9%) in the control group (4 lost to follow‐up) |
|
| Interventions |
Intervention was started immediately in the emergency department. All participant caregivers were instructed to give ORS and to continue normal meals. All interventions were manufactured by Institut Rosell Inc (Montreal, Quebec, Canada) NB combined results of both probiotics groups used in analyses |
|
| Outcomes |
Side effects including abdominal cramps and rash recorded for both groups; frequency of side effects higher in control group. No serious adverse events attributed to probiotic |
|
| Notes | Study location: Canada (very low child and adult mortality) Cause of diarrhoea: 39 (30%) had stools tested for viruses; rotavirus detected in 9/18 (50%) probiotic and in 12 (57%) control; adenovirus detected in 2 (11%) probiotic and in 1 (5%)control; no common bacterial pathogens detected in either group. Bloody diarrhoea excluded Nutritional status: not stated Hydration status: baseline clinical dehydration scale score (mean ± SD) 1.6 ± 1.7 probiotic and 1.3 ± 1.7 control Source of funding: funding to conduct the study provided to Stephen Freedman by Institut Rosell Lallemand Inc, which also provided study drug and placebo. Philip Sherman is the recipient of a Canada Research Chair in Gastrointestinal Disease |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomization |
| Allocation concealment (selection bias) | Low risk | Externally generated allocation sequence |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessors blinded to intervention |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Freedman 2018a.
| Study characteristics | ||
| Methods | Double‐blind randomized placebo‐controlled trial; 6 centres Duration: 4 years, 5 months (November 2013 to April 2017) |
|
| Participants | Inclusion criteria: aged 3 to 48 months; 3 or more episodes of watery stools in a 24‐hour period; vomiting or diarrhoea for less than 72 hours; clinical diagnosis of acute intestinal infection Exclusion criteria: they or person living in their household having an indwelling vascular access catheter; structural heart disease; immunocompromised or receiving immunosuppressive therapy; hematochezia; bilious vomiting; chronic gastrointestinal disorder; pancreatic dysfunction or insufficiency; use of probiotics during the preceding 14 days; allergy to soy; inability to complete follow‐up; undergone oral or gastrointestinal surgery within preceding 7 days; previously participated in the trial Numbers completing the study: 414/444 (93%) probiotics (18 lost to follow‐up, 12 withdrew) and 413/442 (93%) control (10 lost to follow‐up, 19 withdrew) |
|
| Interventions |
Participants given IV fluids as needed |
|
| Outcomes |
Adverse events were reported in 144 (34.8%) probiotics and in 160 (38.7%) placebo; 2 (0.5%) in the placebo group had serious adverse events |
|
| Notes | Study location: Canada (very low child and adult mortality) Cause of diarrhoea: of those who had a stool sample tested (432 probiotic and 428 placebo), 124 (28.7%) and 85 (19.9%) had rotavirus A detected, 102 (23.6%) and 124 (29.0%) had norovirus GI/GII detected, 50 (11.6%) and 45 (10.5%) had adenovirus 40/41 detected, 51 (11.8%) and 61 (14.3%) had Clostridium difficile toxon A/B detected, and 11 (2.6%) and 9 (2.1%) had Salmonella detected in probiotic and placebo groups, respectively Nutritional status: not stated Hydration status: median clinical dehydration scale score (IQR): 1 (0 to 2) probiotic and 0 (0 to 2) placebo Source of funding: Canadian Institutes of Health Research (grants 286384 and 325412), Alberta Children’s Hospital Foundation Professorship in Child Health and Wellness (to Dr Freedman), grant from the Alberta Children’s Hospital Foundation to the Pediatric Emergency Medicine Research Associates’ Program, Calgary Laboratory Services (in kind), Provincial Laboratory for Public Health–Alberta Public Laboratories, Luminex, and Copan Italia. Dr Sherman reports receiving fees for continuing medical education from Abbott Nutrition, advisory board fees from Mead Johnson Nutritionals, fees for attending a workshop from Nestlé Nutrition Institute, and grant support from Lallemand Health Solutions and Bio‐K Plus International |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Random number‐generating software used |
| Allocation concealment (selection bias) | Low risk | Assignment sequence restricted to research pharmacy at the co‐ordinating centre and www.randomize.net until databases were locked |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double‐blind trial: participants and all staff unaware of allocations |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Double‐blind trial: participants and all staff unaware of allocations |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcomes reported |
Guandalini 2000.
| Study characteristics | ||
| Methods | Randomized controlled trial; multi‐centre Duration: 1 year (1996) |
|
| Participants | Inclusion criteria: inpatients and outpatients; infants and children with > 4 liquid or semi‐liquid stools/d for 1 to 5 days Exclusion criteria: previous probiotic usage; underlying chronic untreated small bowel disease; inflammatory bowel disease; any underlying chronic disease or immunosuppressive disease or treatment Numbers completing study: 287 forms (269 participants) of total of 323 forms (88.9%) received at the co‐ordinating centre were analysed (36 incomplete data or not compliant with protocol); unclear whether withdrawals occurred at participating centres |
|
| Interventions |
Interventions added to ORF and started at recruitment |
|
| Outcomes |
Some outcomes also reported for rotavirus, bacterial infection, and no organism‐isolated subgroups No comment regarding adverse events |
|
| Notes | Study locations: Poland (low child and adult mortality), Egypt (high child and high adult mortality), Croatia, Italy, Slovenia, The Netherlands, Greece, Israel, United Kingdom, Portugal (all very low child and very low adult mortality) Cause of diarrhoea: rotavirus (56 probiotic/45 placebo); bacterial infection (35/34); parasites (7/6); no pathogen (45/54). 10 (6.8) probiotic and 15 (10.7) control had bloody diarrhoea Nutritional status: no data presented Hydration status: severe dehydration in 1 (0.7) probiotic and 1 (0.7) control; mild/moderate dehydration in 107 (72.7%) probiotic and 96 (68.2%) control Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not adequately described |
| Allocation concealment (selection bias) | Unclear risk | Not adequately described |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Allocation code broken after study completion |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Unclear whether withdrawals occurred at participating centres; 36/323 (11.2%) participant data forms received at the co‐ordinating centre were not analysed as incomplete and/or not compliant with protocol |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Guarino 1997.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 3 months (November 1995 to January 1996) |
|
| Participants | Inclusion criteria: consecutive outpatients attending 3 family physicians; infants and children with ≥ 3 watery stools/d of < 48 hours' duration Exclusion criteria: antibiotic treatment in preceding 3 weeks, breast‐feeding, weight:height ratio < 5th percentile Numbers completing study: 52/52 (100%) probiotic and 48/48 (100%) control |
|
| Interventions |
Interventions started after 6 hours of ORF |
|
| Outcomes |
Results for rotavirus subgroup also presented No comment regarding adverse events |
|
| Notes | Study location: Italy (very low child and adult mortality) Cause of diarrhoea: rotavirus identified in 30 (57.7%) probiotic and 31 (64.6%) control Nutritional status: weight:height ratio < 5th percentile excluded Hydration status: all had mild to moderate dehydration Study author clarified that Figure 5 in the published article reports mean and standard error for duration of diarrhoea; SDs derived from graph. We also extracted data from Canani 1997 (abstract), which reports standard errors Probiotic also reduced prevalence of rotavirus in stools on day 6 Source of funding: Ministero della Sanità, AIDS Project (9205.30) |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Random numbers table |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No placebo |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | Outcome assessed by participant's parent, who was aware of intervention |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Hamid 2019.
| Study characteristics | ||
| Methods | Single‐blind randomized controlled trial; 1 centre Duration: 1 year (March 2017 to February 2018) |
|
| Participants | Inclusion criteria: previously healthy children aged 6 months to 6 years; acute watery diarrhoea Exclusion criteria: shock; dysentery; chronic diarrhoea; other acute systemic illness; severe malnutrition and/or immunosuppressive state; use of probiotic or antibiotic in previous 3 weeks Numbers completing study: 160/160 (100%) probiotic; 150/150 (100%) control |
|
| Interventions |
Timing of start of intervention not stated All participants received oral rehydration solution, intravenous fluid as indicated, and zinc supplementation |
|
| Outcomes |
No comment regarding adverse events |
|
| Notes | Study location: Bangladesh (high child and adult mortality) Cause of diarrhoea: dysentery excluded Nutritional status: grade 1 malnutrition 48 (30%), grade 2 malnutrition 22 (14%) in probiotic group; grade 1 malnutrition 42 (28%), grade 2 malnutrition 30 (20%) in control group Hydration status: some dehydration 108 (72%), severe dehydration 29 (19%) in probiotic group; some dehydration 114 (71%), severe dehydration 33 (21%) in control group Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Method of randomization not stated |
| Allocation concealment (selection bias) | Unclear risk | Not stated |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No placebo |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | Single‐blind study |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All outcomes reported |
Hegar 2015.
| Study characteristics | ||
| Methods | Randomized double‐blind placebo‐controlled prospective trial; 1 centre Duration: 5 months (January to May 2012) |
|
| Participants | Inclusion criteria: acute diarrhoea (defined as (semi‐) watery stools according to Bristol criteria > type 4 lasting 48 hours or less; mild to moderate dehydration; minimum level of parental education was junior high school Exclusion criteria: malnutrition (weight < P3); administration of zinc; chronic condition (such as known chronic intestinal disease, cystic fibrosis, food allergy, immune deficiency, inflammatory bowel disease, GI malformation, abnormal GI motility); acute condition (antibiotic treatment during previous 7 days, macroscopic blood in the faeces, use of probiotics except for the probiotics present in infant formula) Numbers completing the study: 56/56 (100%) probiotic; 56/56 (100%) control |
|
| Interventions |
Timing of start of administration not stated. All participants given ORS (Indoralite®) ad libitum, 20 mg zinc sulphate/d for 10 days and normal food intake after initial rehydration |
|
| Outcomes |
*Outcomes not stated in methods, but given in results No adverse events attributed to probiotic |
|
| Notes | Study location: Indonesia (low child and adult mortality) Cause of diarrhoea: bloody diarrhoea excluded. Nutritional status: malnutrition excluded Hydration status: no participants were severely dehydrated Source of funding: Dexa Medica (Jakarta, Indonesia) provided the probiotics, and Indofarma (Jakarta, Indonesia) zinc and ORS, for free Median (range) duration of diarrhoea (hours) 68.5 (13 to 165) probiotic and 61.5 (21 to 166) control (P = 0.596). We did not convert these data to mean (SD) because IQR was not reported |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomization |
| Allocation concealment (selection bias) | Low risk | Sequential, identical envelopes |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Henker 2007a.
| Study characteristics | ||
| Methods | Randomized controlled trial; 11 centres Duration: 3 months (February to April 2005) |
|
| Participants | Inclusion criteria: outpatients; infants and toddlers < 4 years with > 3 watery or loose and non‐bloody stools/d for ≤ 3 days Exclusion criteria: > 5% dehydration; intake of E coli Nissle 1917 in last 3 months; intake of food supplements or drugs that contain living micro‐organisms or their metabolic products or components within 7 days before enrolment or during the trial; other anti‐diarrhoeal drugs; breast‐feeding, premature birth; severe or chronic disease of the bowel or severe concomitant disease. Antibiotics stated as exclusion criteria but some children included Numbers completing the study: 54/55 (98.2%) probiotic and 45/58 (77.6%) control. Reasons for withdrawal in both groups stated as intervention no longer suitable or required other treatment. All randomized participants included in analyses |
|
| Interventions |
|
|
| Outcomes |
Diarrhoea resolution: reduction in stool frequency to < 3 watery or loose stools in 24 hours over a period of at least 2 consecutive days Adverse effects: in the probiotic group, 1 had rhinitis and 1 had abdominal cramps. In the placebo group, 2 had acute otitis media and 1 showed poor compliance. No adverse events attributed to probiotic |
|
| Notes | Study location: Ukraine, Russia (low child, high adult mortality) Cause of diarrhoea: bloody diarrhoea excluded; 16/55 (29.1%) probiotic and 19/58 (32.8%) control had viral diarrhoea. Bacterial pathogens isolated from 9/55 (16.4%) probiotic and 4/58 (6.8%) control Nutritional status: most children well nourished Hydration status: > 5% dehydration excluded; 0/55 probiotic and 1/58 control children had mild dehydration Better outcomes with probiotic than placebo for abdominal pain (28/30 vs 24/33) and abdominal cramps (17/18 vs 21/26) Parents reported slightly better tolerance of probiotic than placebo, although investigators noted no difference Study authors supplied data regarding SDs for diarrhoea duration Source of funding: ARDEYPHARM provided verum and placebo medications and reimbursed study‐related expenses |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomly permuted blocks of 4 |
| Allocation concealment (selection bias) | Unclear risk | Unclear method of allocation concealment |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Study personnel blinded to intervention |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Outcomes reported for > 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Henker 2008.
| Study characteristics | ||
| Methods | Randomized controlled trial; 11 centres Duration: 3 months (February to April 2005) |
|
| Participants | Inclusion criteria: inpatients; > 3 loose or watery stools without blood/24 hours for > 4 days and < 14 days; moderate dehydration (5% to 10% loss of body weight) Exclusion criteria: other severe organic or infectious disease; participation in another trial; intake of trial preparation in the past 3 months; intake of probiotic preparation within the past 7 days; antibiotic or anti‐diarrhoeal; severe dehydration (> 10% weight loss); weight < 5th percentile; growth faltering; breast‐feeding; preterm birth Numbers completing study: 72/75 (96.0%) probiotic (trial intervention no longer suitable/different treatment needed 2; personal reasons 1); 59/76 (77.6%) control (trial intervention no longer suitable/different treatment needed 11; personal reasons 5; intolerable adverse event 1). All randomized participants included in analyses |
|
| Interventions |
|
|
| Outcomes |
1 participant in probiotic group had a mild hypersensitivity reaction, which was assessed as possibly related to the intervention. In the control group, 1 participant had vomiting, 1 abdominal pain, and 1 dermatitis, and 1 withdrew because of influenza. Study authors commented that the probiotic was safe and well tolerated |
|
| Notes | Study location: Ukraine, Russia (low child, high adult mortality) Cause of diarrhoea: bloody diarrhoea excluded; 12 (16.0) probiotic and 15 (21.1) control had viral diarrhoea. Bacterial pathogens isolated from 15 (20.0) probiotic and 19 (25.0) control Nutritional status: weight < 5th percentile and growth faltering excluded; 2 (2.7) probiotic and 3 (3.9) control had mild/moderate malnutrition Hydration status: all had moderate dehydration (5% to 10% loss of body weight) Fewer children with dehydration at the end of the study in the probiotic group than in the placebo group. General state of health improved to a greater extent in the probiotic group than in the placebo group Significantly fewer children with diarrhoea > 21 days in the probiotic group than in the placebo group At the end of the study, the rates of mucus in stool, abdominal cramps, and abdominal pain were all lower in the probiotic group Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomly permuted blocks of 4 |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessed by parents; blinded to intervention |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Outcomes reported for > 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Hernandez 1998.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: not stated |
|
| Participants | Inclusion criteria: inpatients; uncomplicated acute diarrhoea (not defined); mild dehydration Exclusion criteria: fever; malnutrition; bloody stools Numbers completing study: 25/25 (100%) probiotic; 25/25 (100%) control |
|
| Interventions |
|
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Mexico (low child and adult mortality) Cause of diarrhoea: bloody diarrhoea excluded Nutritional status: malnutrition (not defined) excluded. Hydration status: all had mild dehydration. Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not adequately described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not adequately described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | High risk | No outcomes pre‐stated |
Hochter 1990.
| Study characteristics | ||
| Methods | Randomized controlled trial; multi‐centre Duration: not stated |
|
| Participants | Inclusion criteria: outpatients, attending general practitioners, gastroenterologists, and internal physicians; adults with acute diarrhoea (> 3 liquid stools in last 24 hours; in great majority, duration 2 days or less; 1 participant in the placebo group had diarrhoea for > 10 days) Exclusion criteria: chronic diarrhoea; blood in stools; drug‐induced diarrhoea; antimicrobial treatment; inflammatory bowel disease Numbers completing the study: 92/107 (86.0%) randomized participants completed the study (15 ineligible: 1 took additional drugs, 14 < 3 liquid stools at presentation). 3/92 participants dropped out (2 probiotic, 1 placebo) because intervention was not effective; results included in analysis |
|
| Interventions |
Interventions started at presentation |
|
| Outcomes |
Mean (SD) stool frequency on day 1: 7.6 (4.2) probiotic, 6.9 (3.3) placebo; day 3: 2.4 (2.1) probiotic, 3.0 (2.8) placebo (P = 0.019); day 8: 1.3 (1.1) probiotic, 1.6 (1.1) placebo No adverse events attributed to probiotic |
|
| Notes | Study location: Germany (very low child and adult mortality) Cause of diarrhoea: stool analyses in first 50 participants only: 2 had rotavirus and 3 Salmonella Nutritional status: all well nourished Hydration status: no data presented Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Outcomes reported for > 90% in both groups |
| Selective reporting (reporting bias) | Unclear risk | Unclear if all outcomes reported |
Hong Chau 2018.
| Study characteristics | ||
| Methods | Randomized double‐blind placebo‐controlled trial; 1 centre Duration: 1 year (October 2014 to September 2015) |
|
| Participants | Inclusion criteria: children aged 9 to 60 months; hospitalized with acute watery diarrhoea; 3 watery stools/d without visible blood or mucus (duration not stated) Exclusion criteria: at least 1 episode of diarrhoea in the month before admission; known to have short bowel syndrome or chronic (inflammatory) gastrointestinal disease; immunocompromised or immunosuppressed; on prolonged steroid therapy; diagnosed as severely dehydrated Numbers completing study: 143/150 (95.3%) probiotics (3 withdrew; 1 was lost to follow‐up; 3 were self‐prescribed); 147/150 (98%) control (2 withdrew; 1 took only 6 doses of study medication) |
|
| Interventions |
All participants received standard of care according to national guidelines, including ORS and zinc; typically participants were not given antimicrobials but were not excluded if they were |
|
| Outcomes |
Additional exploratory outcomes
No adverse events attributed to probiotic |
|
| Notes | Study location: Vietnam (low child and adult mortality) Cause of diarrhoea: bloody diarrhoea excluded. Rotavirus detected in 64/150 (43%) probiotic and in 56/150 (37%) control; norovirus detected in 30/150 (20%) probiotic and in 38/150 (25%) control. Bacterial pathogens: Campylobacter in 11/150 (7%), Shigella in 17/150 (11%), and Salmonella in 14/150 (9%) in the probiotic group; Campylobacter in18/150 (12%), Shigella in 20/150 (13%), and Salmonella in 21/150 (14%) in the control group Nutritional status: not stated Hydration status: severe dehydration excluded Source of funding: this work was supported by The Wellcome Trust and the OAK Foundation. SB is funded by a Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society (100087/Z/12/Z) Median (IQR) duration of diarrhoea (hours) 35 (20 to 68) probiotic and 43 (15 to 66) control (P = 1.62). Median (IQR) duration of diarrhoea (hours) in children with rotavirus diarrhoea 45 (21 to 76) probiotic (n = 64) and 48 (18 to 66) control (n = 56). We did not convert these data to mean (SD) because of non‐normal distribution |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomization list using block randomization |
| Allocation concealment (selection bias) | Low risk | Sequentially numbered treatment packs prepared according to randomization list |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessors blinded to intervention |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All pre‐stated outcomes reported; no additional outcomes reported |
Huang 2014.
| Study characteristics | ||
| Methods | Open‐label randomized controlled trial; 1 centre Duration: 21 months (February 2009 to October 2010) |
|
| Participants | Inclusion criteria: aged 3 months to 14 years; hospitalized due to mild to moderate dehydration; acute diarrhoea for < 72 hours Exclusion criteria: immunodeficiency; severe abdominal distension with risk of bowel perforation; severe infection or sepsis; history of gastrointestinal tract surgery; multiple pathogens identified on culture; probiotic or antibiotic used in the preceding week; Campylobacter‐positive, adenovirus‐positive, or multiple pathogen‐positive patients Numbers completing the study: 82/82 (100%) probiotics; 77/77 (100%) control |
|
| Interventions |
Intervention was started after randomization. All participants received supportive treatment (IV fluid, ORS, rice, and half‐strength milk formula) |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Taiwan (low child and adult mortality) Cause of diarrhoea: rotavirus detected in 22/82 (26.8%) probiotic and in 20/77 (26%) control; Salmonella detected in 23/82 (28%) probiotic and in 25/77 (32.5%) control; unknown origin in 37/82 (45.1%) probiotic and in 32/77 (41.6%) control. Adenovirus, Campylobacter, and multiple‐pathogen‐positive patients excluded Nutritional status: not stated Hydration status: no participants had severe dehydration Source of funding: supported by a Kaohsiung Veterans General Hospital research project grant (No. VGHKS98‐081) Secondary outcome reporting: adverse events not pre‐specified in the methods but reported in the results |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated 2‐block randomization list |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No placebo |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | Open‐label study |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Isolauri 1994.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: not stated |
|
| Participants | Inclusion criteria: inpatients; infants and children with > 3 watery stools/d for < 7 days and stools positive for rotavirus. Average dehydration about 5% in both groups Exclusion criteria: not stated Number completing study: 21/21 (100%) probiotic and 21/21 (100%) control |
|
| Interventions |
Interventions started after 6 hours ORF |
|
| Outcomes |
No comment regarding adverse events |
|
| Notes | Study location: Finland (very low child and adult mortality) Cause of diarrhoea: all rotavirus diarrhoea Nutritional status: all well nourished Hydration status: mean dehydration about 5% in both groups Source of funding: Academy of Finland and the Foundation for Nutrition Research (Finland) |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear who assessed outcomes |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | High risk | Outcomes not pre‐stated in methods |
Jasinski 2002.
| Study characteristics | ||
| Methods | Randomized controlled trial; 12 centres Duration: not stated |
|
| Participants | Inclusion criteria: inpatients and outpatients; age 1 month to 3 years; acute diarrhoea (3 or more liquid stools in 12 hours or single liquid or semi‐solid stool with mucus or blood, or both, for 5 days or less) Exclusion criteria: antibiotics or probiotics in last 5 days; chronic disease of small or large intestine (e.g. coeliac, cow milk protein allergy, inflammatory bowel disease), immunosuppression, phenylketonuria Numbers completing study: 45/45 (100%) probiotic and 52/52 (100%) placebo |
|
| Interventions |
Start time for administration unclear |
|
| Outcomes |
No comment regarding adverse events |
|
| Notes | Study locations: Europe, Egypt, Africa, and single site (Montevideo) in South America (variable child and adult mortality) Cause of diarrhoea: bacterial pathogens: probiotic group 29 (64.4%) and placebo group 37 (71.2%); rotavirus: probiotic group 18 (40.0%) and placebo group 21 (40.4%); parasites: probiotic group 2 (4.4%) and placebo group 4 (7.7%); no pathogens identified: probiotic group 11 (24.4%) and placebo group 14 (26.9%) Nutritional status: 15 (33.3%) in the probiotic group and 20 (38.5%) in the control group had at least some malnutrition Hydration status: mild/moderate dehydration in 15 (33.3%) probiotic and 17 (32.7%) control. More severe dehydration in 0 in the probiotic group and in 2 (3.8%) in the control group Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | Alternate allocation |
| Allocation concealment (selection bias) | Unclear risk | Alternative allocation but unclear if concealed |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not adequately described |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessors blinded to intervention |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcomes reported |
Javeed 2018.
| Study characteristics | ||
| Methods | Randomized controlled open trial; 1 centre Duration: 6 months (January to June 2017) |
|
| Participants | Inclusion criteria: aged 6 months to 5 years; acute watery diarrhoea; hospitalized Exclusion criteria: not stated Number completing study: 157/157 (100%) in both probiotic and control groups |
|
| Interventions |
Participants given ORS on admission; IV fluids as needed; ciprofloxacin if bacterial diarrhoea |
|
| Outcomes |
Adverse events not stated |
|
| Notes | Study location: Pakistan (high child and adult mortality) Cause of diarrhoea: acute watery diarrhoea, cause not specified Nutritional status: not stated Hydration status: not stated Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not adequately described |
| Allocation concealment (selection bias) | Low risk | Opaque envelopes used |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcomes reported |
Khan 2017.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 6 months (April to October 2015) |
|
| Participants | Inclusion criteria: both genders; aged 6 months to 5 years; duration of illness less than 7 days; watery diarrhoea Exclusion criteria: chronic diarrhoea; blood in stool; using antibiotics or probiotics; in coma; shock; persistent vomiting Whether children with dehydration were included/excluded is unclear Numbers completing study: 48/48 (100%) in both probiotic and control groups |
|
| Interventions |
Interventions started on admission. Participants given standard management protocol for diarrhoea including ORT |
|
| Outcomes |
Adverse events not stated |
|
| Notes | Study location: Pakistan (high child and adult mortality) Cause of diarrhoea: not stated Nutritional status: not stated Hydration status: not clear Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Placebo not described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐specified outcomes reported |
Kianifar 2009.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 18 months (April 2006 to September 2007) |
|
| Participants | Inclusion criteria: inpatients; infants and children aged 6 to 36 months with acute non‐bloody, non‐bacterial diarrhoea (not defined) of less than 2 days' duration; moderate dehydration Exclusion criteria: severe dehydration, antibiotic consumption, severe vomiting, convulsion, inflammatory cells in stool samples Numbers completing study: 32/34 (94.1%) probiotic and 30/34 (88.2%) placebo; participants excluded because of poor compliance |
|
| Interventions |
Start time for administration not stated All children received IV fluid therapy, oral rehydration solution, and mother’s milk (breast‐feeding infants), or complementary food according to the patient's age |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Iran (low child and adult mortality) Cause of diarrhoea: non‐bloody, non‐bacterial diarrhoea (not defined) Nutritional status: not stated Hydration status: all had moderate dehydration; severe dehydration excluded Source of funding: grant from the Vice Chancellery for Research, Mashad University of Medical Sciences |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Random numbers table |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessors blinded to intervention |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Overall follow‐up ≥ 90%; no marked differences between arms |
| Selective reporting (reporting bias) | High risk | Outcomes not pre‐stated |
Kowalska‐Duplaga 1999.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: not stated |
|
| Participants | Inclusion criteria: unclear whether inpatients or outpatients, or both; aged < 24 months with acute rotavirus diarrhoea (> 3 loose or watery stools/24 hours lasting < 48 hours before inclusion) Exclusion criteria: not stated Numbers completing study: 33/33 (100%) probiotic and 30/30 (100%) control |
|
| Interventions |
Timing of administration not stated |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Poland (low child and adult mortality) Cause of diarrhoea: all rotavirus diarrhoea Nutritional status: no data presented Hydration status: dehydration status similar in both groups; no other data presented Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not adequately described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Kowalska‐Duplaga 2004.
| Study characteristics | ||
| Methods | Randomized controlled trial; 3 centres Duration: not stated |
|
| Participants | Inclusion criteria: inpatients; infants and children with 3 or more loose stools within 24‐hour period of < 72 hours' duration Exclusion criteria: history of acute diarrhoea within 14 days preceding inclusion in the study; antibiotic treatment; received probiotic up to 7 days before participation in the study; exclusively breast‐fed; chronic alimentary disease; diagnosis of malabsorption; lack of parental consent; lack of diarrhoea Numbers completing study: 86/87 (98.9%) probiotic and 87/89 (97.8%) placebo |
|
| Interventions |
Interventions administered from recruitment |
|
| Outcomes |
Mean duration of diarrhoea reported for children with rotavirus diarrhoea No adverse effects attributed to probiotic |
|
| Notes | Study location: Poland (low child and adult mortality) Cause of diarrhoea: rotavirus identified in 31 (37.3%) probiotic and 22 (26.8%) placebo. Bacterial pathogens identified in 6 (7.2%) probiotic and 14 (17%) placebo Nutritional status: no data presented Hydration status: no data presented Source of funding: interventions provided by Allergon, Sweden |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | Allocated according to order of presentation |
| Allocation concealment (selection bias) | High risk | Allocated according to order of presentation |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not adequately described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Unclear risk | Unclear |
Kurugol 2005.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: not stated |
|
| Participants | Inclusion criteria: inpatients; aged 3 months to 7 years with acute diarrhoea (liquid, mucous, or bloody stools passed at least twice as frequently as usual for ≥ 24 hours and < 7 days) Exclusion criteria: chronic disease; malnutrition; use of antibiotic, anti‐diarrhoeal, or other drug influencing gut motility Numbers completing study: probiotic 100/115 (87.0%; 10 required antibiotics, 5 non‐compliant); control 100/117 (85.5%; 13 required antibiotics, 4 non‐compliant) |
|
| Interventions |
Interventions administered from admission. All children received ORF, normal food for age, and IV fluids as required |
|
| Outcomes |
1 child had meteorism (group allocation unclear). No adverse events attributed to probiotic |
|
| Notes | Study location: Turkey (low child and adult mortality) Cause of diarrhoea: 39 (39.0%) children in probiotic group and 44 (44.0%) in control group had rotavirus diarrhoea. Overall, bacterial pathogens were isolated in 9 and parasites in 11 children Nutritional status: malnutrition excluded; no other data presented Hydration status: severe or moderate dehydration in 3 (3.0%) probiotic and 5 (5.0%) control; mild/moderate dehydration in 17 (17.0%) probiotic and 24 (24.0%) control Source of funding: not stated Secondary outcome reporting: length of hospital stay not pre‐specified in the methods but reported in the results |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Follow‐up < 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Lee 2001.
| Study characteristics | ||
| Methods | Randomized controlled trial, non‐blinded; 1 centre Duration: 6 months (October 1999 to March 2000) |
|
| Participants | Inclusion criteria: inpatients; consecutive admissions; aged 6 to 60 months; diarrhoea < 5 days and > 3 watery stools in last 24 hours (average dehydration about 5% in both groups) Exclusion criteria: bloody stools; anti‐diarrhoeal or anti‐peristaltic drugs; children receiving lactose‐free protein hydrolysated formula for malabsorptive disorder; compromised immune system Numbers completing study: 50/50 (100%) probiotic and 50/50 (100%) control |
|
| Interventions |
All children had IV fluids because of vomiting. Interventions were administered after initial fluid therapy |
|
| Outcomes |
No comment regarding adverse effects |
|
| Notes | Study location: Taiwan (low child and adult mortality) Cause of diarrhoea: bloody diarrhoea excluded Nutritional status: no data presented Hydration status: % average dehydration 4.3 (SD 1.5) probiotic and 4.0 (1.4) control Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Maity 2019.
| Study characteristics | ||
| Methods | Randomized, double‐blind, placebo‐controlled clinical trial; 1 centre Duration: 3 months (January to March 2018) |
|
| Participants | Inclusion criteria: male and female; 18 to 65 years of age; symptoms of acute diarrhoea manifesting within 48 hours before entering the trial; ≥ 3 incidences of unformed stool and last stool passed of unformed consistency (type 7 Bristol stool form scale) within 24 hours before entering the trial; complaints of abdominal discomfort within the last hour; written informed consent by study participants Exclusion criteria: severe form of diarrhoea or symptoms of more severe disease complexity; purulent or bloody stools; presence of erythrocytes or leukocytes in stools; required antibiotic treatment; presence of ulcers Numbers completing study: 30/30 (100%) in both probiotic and control groups |
|
| Interventions |
Participants given supportive treatment as needed |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: India (high child and adult mortality) Cause of diarrhoea: not specified Nutritional status: not stated Hydration status: not stated Source of funding: Advanced Enzyme Technologies Ltd provided technical inputs, study drugs, and laboratory facilities to carry out the study |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated random numbers |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Identical placebo |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐specified outcomes reported |
Mao 2008.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: not stated |
|
| Participants | Inclusion criteria: inpatients; infants and children with severe acute diarrhoea (defined as 1 watery or mucous stool or 3 or more loose stools daily for > 24 hours) Exclusion criteria: moderate or severe malnutrition; total or partial breast‐feeding; diarrhoea > 48 hours; need for antibiotic treatment; allergy to cow's milk; gastrointestinal or other chronic pathology 12/212 (5.7%; 3 study groups) withdrawn after recruitment as they did not match the age criteria. Numbers completing study: 70/70 (100%) probiotic and 71/71 (100%) control |
|
| Interventions |
Interventions administered after oral or parenteral rehydration |
|
| Outcomes |
No specific comment regarding adverse effects |
|
| Notes | Study location: China; low child and adult mortality Cause of diarrhoea: rotavirus diarrhoea occurred in 87% and bacterial diarrhoea in 13% in both groups Nutritional status: moderate or severe malnutrition excluded Hydration status: no data presented Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Narayanappa 2008.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: not stated |
|
| Participants | Inclusion criteria: inpatients; infants and children with acute rotavirus diarrhoea (stool frequency and consistency not stated) of duration ≤ 3 days Exclusion criteria: infectious diarrhoea other than rotaviral diarrhoea; serum sodium > 155 mmol/L or < 130 mmol/L; history of malabsorption, respiratory or systemic infection Numbers completing study: 40/40 (100%) probiotic and 40/40 (100%) control |
|
| Interventions |
When interventions started is not stated |
|
| Outcomes |
No adverse effects attributed to the probiotic |
|
| Notes | Study location: India; high child and adult mortality Cause of diarrhoea: all rotavirus diarrhoea Nutritional status: no data presented Hydration status: no data presented Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcomes reported |
Nixon 2012.
| Study characteristics | ||
| Methods | Double‐blind randomized placebo‐controlled trial; 1 centre Duration: 9 months (November 2008 to July 2009) |
|
| Participants | Inclusion criteria: aged 6 months to 6 years; presenting with a complaint of acute diarrhoea; English or Spanish speaking; had access to a telephone and was available to receive calls daily for 5 days Exclusion criteria: admitted to inpatient service; had risk factors for non‐viral diarrhoea (prolonged diarrhoea longer than 7 days, gross blood, antibiotic exposure, or inflammatory bowel disease); immune compromised; risk factors for probiotic‐associated systemic illness (indwelling central line, short gut syndrome); allergy to milk products Numbers completing study: 67/77 (87%) probiotics (10 lost to follow‐up); 71/78 (91%) control (7 lost to follow‐up) |
|
| Interventions |
Intervention started in paediatric emergency department. Participants advised to avoid yogurt |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: USA (very low child and adult mortality) Cause of diarrhoea: bloody diarrhoea excluded Nutritional status: not stated Hydration status: not stated Source of funding: this study was sponsored by Amerifit Brands (Cromwell, CT, USA), which provided LGG and placebo powder, as well as a small monetary compensation for participants’ telephone airtime; supported in part by CTSA Grants UL1 RR025750, KL2 RR025749, and TL1 RR025748 from the National Center for Research Resources (NCRR), a component of the NIH, and an NIH roadmap for Medical Research Median (IQR) duration of diarrhoea (hours) 60 (37, 111) probiotic and 74 (43, 120) control (P = 0.37). We did not convert these data to mean (SD) because of non‐normal distribution. However, study authors provided the following further information regarding the duration of diarrhoea, which we have included in this review
|
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Random numbers table |
| Allocation concealment (selection bias) | Unclear risk | Staff doing allocation may have known identity of A and B |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessors blinded to intervention until analyses completed |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Overall follow‐up <90% |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcomes reported |
Ozkan 2007.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 6 months (October 2004 to March 2005) |
|
| Participants | Inclusion criteria: inpatients and outpatients; previously healthy children; aged 6 months to 10 years; acute diarrhoea (not defined) Exclusion criteria: severe systemic infection or sepsis; chronic disease; previous antibiotics; anti‐diarrhoeal drugs; primary/secondary immune deficiency Numbers completing study: 16/16 (100%) probiotic and 11/11 (100%) control |
|
| Interventions |
Start of intervention unclear |
|
| Outcomes |
Mean (SD) number of stools on day 3: 1.68 (0.23) probiotic, 3.36 (0.38) placebo (P < 0.05); day 4: 0.43 (0.22) probiotic, 1.81 (0.42) placebo (P < 0.05); no significant differences between groups for stool frequency on days 1 and 2 No adverse events attributed to probiotic |
|
| Notes | Study location: Turkey (low child, low adult mortality) Cause of diarrhoea: 1 (6.3%) child in probiotic group and 0 in control group had bacterial diarrhoea Nutritional status: mild/moderate malnutrition in 2 (12.5%) probiotic and in 1 (9.1%) control Hydration status: severe dehydration in 1 (6.3%) in probiotic group and in 0 in control group; mild/moderate dehydration in 3 (18.8%) probiotic and 2 (18.2%) control Source of funding: Sanofi‐Aventis (Paris, France) provided laboratory reagents and a commercial preparation of S boulardii |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear who assessed outcomes |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All outcomes reported |
Pant 1996.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 6 weeks (July to mid‐August 1993) |
|
| Participants | Inclusion criteria: inpatients; infants and children with > 3 watery stools in last 24 hours and diarrhoea for < 14 days Mean (SD) weight‐for‐age z score ‐1.15 (0.95) probiotic and ‐1.8 (1.4) placebo Exclusion criteria: exclusive breast‐feeding; septicaemia Numbers completing study: 20/20 (100%) probiotic and 19/19 (100%) placebo. However, data extractable for subset with watery diarrhoea only: 14/20 (70%) probiotic and 12/19 (63.2%) placebo. No data for children with bloody stools presented |
|
| Interventions |
Interventions started after 6 hours ORF |
|
| Outcomes |
Vomiting occurred in 1 child in the placebo group. No adverse events were attributed to probiotic |
|
| Notes | Study location: Thailand (low child and adult mortality) Cause of diarrhoea: bloody stools in 6 children in probiotic group and in 7 in placebo group. All negative for parasites and cryptosporidium; 2 rotavirus and 1 astrovirus patients in the probiotic group and 5 rotavirus patients in the control group Nutritional status: no data presented Hydration status: severe dehydration in 2 (10%) probiotic and 4 (21%) control; mild/moderate dehydration in all remaining children Source of funding: Scientific Hospital Supplies, UK, provided the probiotic |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessors blinded to intervention; code broken after analysis completion |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Follow‐up < 90% |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Park 2017.
| Study characteristics | ||
| Methods | Double‐blind randomized placebo‐controlled trial; 1 centre Duration: not stated |
|
| Participants | Inclusion criteria: aged 9 to 16 months; diagnosed as infected with rotavirus via a latex agglutination test Exclusion criteria: not stated Numbers completing study: 28/28 (100%) probiotics; 29/29 (100%) control |
|
| Interventions |
Timing of start of administration not stated |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: South Korea (low child and adult mortality) Cause of diarrhoea: all rotavirus diarrhoea Nutritional status: not stated Hydration status: not stated Source of funding: support of the “Cooperative Research Program for Agriculture Science & Technology Development (Project No. PJ01123001)”, the Rural Development Administration, and “the Promoting Regional specialized Industry (Project No. R0004140)”; the Ministry of Trade, Industry and Energy (MOTIE); and the Korea Institute for Advancement of Technology (KIAT), Republic of Korea |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | "...double‐blind, randomized, and placebo‐controlled clinical study..."; no further description |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not adequately described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All pre‐specified outcomes reported; no additional outcomes reported |
Phavichitr 2013.
| Study characteristics | ||
| Methods | Randomized double‐blind placebo‐controlled trial; 1 centre Duration: 18 months (April 2010 to September 2011) |
|
| Participants | Inclusion criteria: children aged 3 to 72 months; hospitalized due to acute diarrhoea; parents consented to participate Exclusion criteria: previously treated during this diarrhoeal episode with probiotics or another anti‐diarrhoeal drug (i.e. kaolin, pectin, smectite, activated charcoal, racecadotril, or cholestyramine); had other gastrointestinal disease, chronic disease, or severe dehydration Numbers completing study: 53/53 (100%) probiotics; 53/53 (100%) control |
|
| Interventions |
Intervention started after randomization. All participants given rehydration therapy (orally and intravenously) |
|
| Outcomes |
First day of hospitalization was counted as 1 day only if the patient was admitted before 4:00 PM; discharge day was counted as 1 day only if the patient left after 12:00 PM. Patients were discharged after recovery No serious adverse events attributed to probiotic; no comment regarding non‐serious events |
|
| Notes | Study location: Thailand (low child and adult mortality) Cause of diarrhoea: rotavirus detected in 39.6% in the probiotic group and in 29.4 in the control group; bacteria detected in 8.2% probiotic and in 22.4% control. Bloody diarrhoea or mucus in 9.4% probiotic and in 13.2% control Nutritional status: not stated Hydration status: severe dehydration excluded Source of funding: probiotics and placebo and partial financial support for this study were provided by Laboratorio Farmaceutico SIT Median (IQR) duration of diarrhoea (days): 4 (3 to 6) probiotic and 5 (4 to 6) control (P = 0.068). We did not convert these data to mean (SD) because of non‐normal distribution Median (IQR) duration of hospitalization (days): 2 (2 to 3) probiotic and 3 (2 to 4) control (P = 0.049); no decimal place reported; therefore calculation of standard deviation unreliable |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomization |
| Allocation concealment (selection bias) | Unclear risk | No specific details of allocation concealment; not stated that envelopes were opaque |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not adequately described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcomes reported |
Rafeey 2008a.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 12 months (May 2005 to May 2006) |
|
| Participants | Inclusion criteria: inpatients; infants and children with 3 or more watery stools/d for less than 48 hours and clinical dehydration Exclusion criteria: bloody stools; hypovolaemic shock; acute systemic illness; antibiotic or anti‐diarrhoeal medication 18/178 children were withdrawn mainly because of parent non‐compliance; likely to have been withdrawn before recruitment. Numbers completing study: 40/40 (100%) probiotic and 40/40 (100%) placebo |
|
| Interventions | Children randomized to 1 of 4 groups: A, yogurt fermented with L acidophilus; B, L acidophilus supplement; C, conventional yogurt; D, placebo. Groups B and D selected for review
Start of administration not stated |
|
| Outcomes |
Mean (SD) stool frequency on day 2: 4.0 (3.2) probiotic, 4.0 (3.6) placebo; on day 3: 1.4 (2.6) probiotic, 2.3 (2.6) placebo No adverse effects attributed to probiotic |
|
| Notes | Study location: Iran; low child and adult mortality Cause of diarrhoea: bloody diarrhoea excluded; no bacteria or parasites identified in stool samples Nutritional status: severe malnutrition excluded Hydration status: severe dehydration in 1/40 (2.5%) probiotic and 2/40 (5%) control; all the rest had mild/moderate dehydration Source of funding: supported by a grant from Tabriz Medical University |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Restricted randomization using random permuted blocks |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Different forms of treatment given |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear who assessed outcomes |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Unclear risk | Primary outcomes not reported |
Raza 1995.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 2 months (July and August 1993) |
|
| Participants | Inclusion criteria: inpatients; undernourished infants and children with > 3 watery stools in last 24 hours for < 14 days' duration and at least moderate dehydration Exclusion criteria: severe malnutrition; septicaemia Numbers completing study: 36/40 participants; 4 withdrawals (2 diagnosed with cholera, 1 developed pneumonia, 1 refused anything by mouth). Results presented for 19/21 (90.5%) in the probiotic group and for 17/19 (89.5%) in the placebo group |
|
| Interventions |
Interventions started after 4 to 6 hours ORF |
|
| Outcomes |
Outcomes for watery (non‐bloody) diarrhoea also presented: mean (SD) stool frequency day 2 for probiotic (n = 16) vs placebo (n = 16) was 4.4 (2.0) vs 6.6 (4.2) (P ≤ 0.05), and persistent diarrhoea at 48 hours was seen in 5 (31%) vs 12 (75%) participants (P ≤ 0.01). Definition of persistent diarrhoea not stated Less vomiting in the probiotic group; myoclonic jerks occurred in 1 child in each group. No adverse events were attributed to probiotic |
|
| Notes | Study location: Pakistan (high child and adult mortality) Cause of diarrhoea: bloody diarrhoea included Nutritional status: all had mild/moderate malnutrition; severe malnutrition excluded Hydration status: severe dehydration in 14 (66.7) probiotic and 7 (37) control; all the rest had moderate dehydration Duration of diarrhoea not measured (many children discharged before stool character had changed) Source of funding: Scientific Hospital Supplies, UK, provided the probiotic |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Allocation code broken after analysis completion |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Overall follow‐up ≥ 90%; no marked differences between arms |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Rerksuppaphol 2010.
| Study characteristics | ||
| Methods | Double‐blind randomized controlled trial; 1 centre Duration: 10 months (January to October 2008) |
|
| Participants | Inclusion criteria: children aged 2 months to 7 years; admitted to paediatric unit of Srinakharinwirot University Hospital with a diagnosis of diarrhoea (watery/mucous stool ≥ 3 times in 24 hours) of > 72 hours' duration Exclusion criteria: evidence of systemic infection; neurological disturbance; history of convulsions; conditions such as chronic immunodeficient gastrointestinal condition; severe dehydration; children who had received treatment with probiotics and medications that interfere with intestinal motility during the present illness Numbers completing study: 20/22 (91%) in the room temperature probiotic group (2 for parental concern), 23/23 (100%) in the refrigerated probiotic group; 21/22 (95.5%) in the control group (1 for parental concern). All randomized participants were analysed |
|
| Interventions |
Timing of onset of administration not stated. All capsules opened and powder dissolved in milk or some other fluid and given as 1 capsule 3 times daily until the end of diarrhoea and up to maximum of 5 days |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Thailand (low child and adult mortality) Cause of diarrhoea: rotavirus detected in 7 (30.4%) in the refrigerated probiotic group and 9 (40.9%) in the room temperature probiotic group and in 5 (22.7%) in the control group Nutritional status: not stated Hydration status: mild/no dehydration 15 (68.2%) in the room temperature probiotic group, 18 (78.3%) in the refrigerated probiotic group, and 17 (72.3%) in the control group; moderate dehydration 7 (31.8%) in the room temperature probiotic group, 5 (21.3%) in the refrigerated probiotic group, and 5 (22.7%) in the control group; severe dehydration excluded Source of funding: this study was supported by grants from the Faculty of Medicine, Srinakharinwirot University, Thailand Median (IQR) duration of diarrhoea (hours) 28 (32) in the probiotic arm and 51.5 (44) in the control arm. Median (IQR) duration of hospitalization (hours) 46 (42) in the probiotic arm and 64 (48) in the control arm (P > 0.05). We did not convert these data to mean (SD) because of non‐normal distribution |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomization |
| Allocation concealment (selection bias) | Unclear risk | Not adequately described |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessor blinded to intervention |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Riaz 2012.
| Study characteristics | ||
| Methods | Randomized double‐blind placebo‐controlled trial; 1 centre Duration: 17 months (May 2008 to September 2009) |
|
| Participants | Inclusion criteria: children aged 3 to 59 months; acute onset of diarrhoea (of < 48 hours); admitted to DTTU (diarrhoea treatment and training unit) Exclusion criteria: clinical evidence of severe malnutrition; systemic infection; encephalopathy and/or convulsion; electrolyte imbalance; invasive diarrhoea; previous use of any probiotics Numbers completing study: 43/54 (79.6%) in the probiotics group (6 left the study; 5 treatment failure); 47/54 (87%) in the control group (3 left study; 4 treatment failure). All 108 patients included in analysis |
|
| Interventions |
Intervention was started following receipt of informed consent. All participants were managed with ORS, zinc, and feeding as per guidelines of the IAP task force on diarrhoea |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: India (high child and adult mortality) Cause of diarrhoea: rotavirus detected in 14/93 (15.1%) samples tested; V cholerae detected in 4 (7.4%) in both probiotic and control groups. Invasive diarrhoea excluded Nutritional status: moderate malnutrition 19 in the probiotic group and 23 in the control group. Mean weight for age 75.84% (± 13.13) in the probiotic group and 72.87% (± 11.22) in the control group; mean weight for height 83.39% (± 10.72) in the probiotic group and 82.31% (± 10.82) in the control group. Severe malnutrition excluded (weight for age below 60% or weight for length/height below 70%) Hydration status: no dehydration 22 in the probiotic group and 23 in the control group; some dehydration 26 in the probiotic group and 24 in the control group; severe dehydration 6 in the probiotic group and 7 in the control group Source of funding: no role for funding source in this trial |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | External block randomization |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not adequately described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Outcomes reported for > 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Ritchie 2010.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 21 months (June 2002 to March 2004) |
|
| Participants | Inclusion criteria: inpatients; Aboriginal children aged 4 months to 2 years with acute diarrhoea defined as ≥ 3 loose stools during 24 hours before presentation and duration < 7 days; able to tolerate ORF Exclusion criteria: oxygen required during the study period; chronic cardiac, renal, or respiratory disease; previous gastrointestinal surgery; proven sucrose intolerance; suspected or known immunodeficiency; received probiotic before enrolment; younger than 4 months Numbers completing study: 201 assessed for eligibility; 103 refused participation and 28 failed to consent. Probiotic arm: 4 discharged before intervention, 1 parental withdrawal, 33/38 (86.8%) completed study. Control arm: 1 parental withdrawal, 31/32 (96.9%) completed study |
|
| Interventions |
Interventions administered within 24 hours of admission |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Australia (very low child and low adult mortality). However, this study recruited Aboriginal children who commonly had comorbidities such as pneumonia and malnutrition related to poverty and social disadvantage in the top end of the Northern Territory. Therefore, data not included in analysis according to country mortality strata Cause of diarrhoea: bacterial pathogens identified in 4 (12%) probiotic and 4 (13%) control; rotavirus identified in 11 (33%) probiotic and 6 (19%) control; parasites identified in 2 (6%) probiotic and 2 (6%) control Nutritional status: mild/moderate malnutrition common amongst participants; no other data presented Hydration status: severe dehydration in 0 probiotic and in 1 (3.2%) control; all the rest had mild/moderate dehydration Source of funding: project supported by Australian National Health and Medical Research Council |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated block randomization |
| Allocation concealment (selection bias) | Unclear risk | No specific details of allocation concealment |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessors blinded to intervention |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Overall follow‐up ≥ 90%, but marked differences (> 10%) between study arms |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcomes reported |
Rosenfeldt 2002a.
| Study characteristics | ||
| Methods | Randomized controlled trial; 2 centres Duration: 6 months (December 1998 to May 1999) |
|
| Participants | Inclusion: inpatients; children aged 6 to 36 months with 2 or more consecutive loose stools in 24 hours and duration no longer than 7 days Exclusion criteria: underlying chronic disease; antibiotics prescribed during the study period Numbers completing study: 86 children enrolled, of whom 69 (80.2%) completed the study; exclusions were made after randomization because antibiotics were prescribed (3 in the control group and 2 in the probiotic group); rapid recovery before intervention started (3 in the control group and one in the probiotic group); non‐compliance with the protocol (4 in the control group and 4 in the probiotic group) |
|
| Interventions |
Interventions started as soon as possible after randomization and no wait for rehydration |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Denmark (very low child and adult mortality) Cause of diarrhoea: overall, rotavirus was the only pathogen in 40 (58%) children; 6 children had rotavirus and a bacterial pathogen was identified; in addition, Campylobacter jejuni was isolated in 3 children, and Salmonella typhimurium in 1 child Nutritional status: no data presented Hydration status: no severe dehydration; mild/moderate dehydration in 5 (16.7%) probiotic and in 17 (43.6%) control Probiotics appeared to reduce significantly the duration of diarrhoea in children treated within 60 hours of the onset of diarrhoea Hospital stay was shorter in the probiotic group than in the control group (mean 1.6 (SD 1.0) vs 2.7 (SD 2.0), respectively; P = 0.02) Probiotics also appeared to reduce significantly the number of children excreting rotavirus in stools on day 5 Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Follow‐up < 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcomes reported |
Rosenfeldt 2002b.
| Study characteristics | ||
| Methods | Randomized controlled trial; 19 day care centres Duration: 6 months (December 1998 to May 1999) |
|
| Participants | Inclusion criteria: outpatients; children aged 6 to 36 months with 2 or more consecutive loose stools in 24 hours as assessed by parents and with duration no longer than 7 days Exclusion criteria: underlying chronic disease; antibiotics prescribed during study period Numbers completing study: 50 children enrolled, of whom 43 (86%) participants completed the study. Exclusions were made because of hospitalization with excessive vomiting and moderate dehydration (2 in the placebo group and 3 in the probiotic group), prescribed antibiotics (1 in placebo group), and non‐compliance with protocol (1 in placebo group) |
|
| Interventions |
Interventions started as soon as possible after randomization |
|
| Outcomes |
One participant in the probiotic group complained of constipation (no stools passed from day 3 for 10 days). No adverse events attributed to probiotic |
|
| Notes | Study location: Denmark (very low child and adult mortality) Cause of diarrhoea: overall, rotavirus was the only pathogen in 25 children, 2 had rotavirus and a bacterial pathogen identified, 2 had infection with C jejuni and Salmonella typhimurium Nutritional status: no data presented Hydration status: mild/moderate dehydration in 3 patients (12.5%) in the probiotic group and in 4 (13.8%) in the control group; no severe dehydration Probiotics appeared to reduce significantly the duration of diarrhoea in children treated within 60 hours of the onset of diarrhoea Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not adequately described |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Follow‐up < 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Sarkar 2005.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 23 months (February 2001 to December 2002) |
|
| Participants | Inclusion criteria: inpatients; boys aged 4 to 24 months; acute watery diarrhoea (> 4 liquid stools during 24 hours) of < 48 hours' duration Exclusion criteria: severe malnutrition (< 65% weight for age by the standard of the National Centre for Health Statistics (NCHS)); systemic infection requiring antimicrobial therapy; bloody diarrhoea; spot sample of stool revealed V cholerae by dark‐field microscopy; antibiotic treatment in the preceding 2 weeks Numbers completing study: 112/115 (97.4%) probiotic (3 withdrawn by parents) and 115/115 (100.0%) control |
|
| Interventions |
Interventions started after enrolment. All children received ORF and continued feeding, including breast milk if breast‐fed |
|
| Outcomes |
No comment regarding adverse outcomes |
|
| Notes | Study location: Bangladesh (high child and adult mortality) Cause of diarrhoea: bloody diarrhoea excluded. Rotavirus detected in 78 (69.6%) in the probiotic group and in 73 (63.5%) in the placebo group; V cholera detected in 14 (12.2%) probiotic and in 16 (13.9%) placebo Nutritional status: severe malnutrition (weight < 65% weight for age of NCHS standard) excluded; no further data presented Hydration status: mild/moderate dehydration in 54 (47.0%) probiotic and in 65 (56.5%) control Source of funding: Nestlé Research provided L paracasei. Research supported by the Swedish Agency for Research in Developing Countries, the Karolinska Institute (Stockholm, Sweden), and Nestlé Research Centre (Lausanne, Switzerland) Rotavirus outcomes: results presented for < 90% of patients |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomly permutated blocks |
| Allocation concealment (selection bias) | Unclear risk | Unclear method of allocation concealment |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessors blinded to allocation |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Overall follow‐up ≥ 90% for primary outcome |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Schnadower 2018.
| Study characteristics | ||
| Methods | Prospective double‐blind randomized placebo‐controlled trial; 10 centres Duration: 3 years (July 2014 to June 2017) |
|
| Participants | Inclusion criteria: age 3 months to 4 years; diagnosed with acute gastroenteritis by an ED provider Exclusion criteria: risk factors for bacteraemia; chronic gastrointestinal disorder; pancreatitis; bilious emesis; hematochaezia; allergy to L rhamnosus GG, microcrystalline cellulose, erythromycin, clindamycin, and beta‐lactam antibiotic agents; caregiver did not speak English or Spanish Numbers completing study: 468/483 (96.9%) probiotic (15 lost to follow‐up) and 475/488 (97.3%) control (13 lost to follow‐up) |
|
| Interventions |
Interventions started after randomization in the ED |
|
| Outcomes |
Adverse events reported in 63 (13.3%) and 62 (12.9%) in the probiotic and placebo groups, respectively; serious adverse events reported in 8 (1.7%) in the probiotic group and in 13 (2.7%) in the placebo group Study authors were contacted and provided data for the outcomes in this review, including for children with rotavirus diarrhoea |
|
| Notes | Study location: USA (very low child and adult mortality) Cause of diarrhoea: of those who had a stool sample tested (379 in the probiotic group and 382 in the placebo group), 75 (19.8%) and 60 (15.7%) had rotavirus A, 79 (20.8%) and 70 (18.3%) had norovirus GI/GII, 28 (7.4%) and 41 (10.7%) had adenovirus 40/41, 25 (6.6%) and 31 (8.1%) had Clostridium difficile toxin A/B, 23 (6.1%) and 15 (3.9%) had Shigella, and 153 (40.4%) and 173 (45.3%) had no pathogen detected in the probiotic and placebo groups, respectively Nutritional status: not stated Hydration status: 133/483 (27.5%) in the probiotic group and 133/488 (27.3%) in the placebo group had dehydration Source of funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development and others. Product and placebo were provided in kind by iHealth, the distributors of Culturelle in the United States |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Web‐based randomization (www.randomize.net) |
| Allocation concealment (selection bias) | Low risk | Web‐based system |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo; participants and personnel who assessed trial outcomes were unaware of trial group assignments |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Participants and personnel who assessed trial outcomes were unaware of trial group assignments |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐specified outcomes reported |
Shornikova 1997a.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 1 year (1 April 1994 to 31 May 1995) |
|
| Participants | Inclusion criteria: inpatients; infants and children with ≥ 1 watery stool in the last 24 hours and diarrhoea for < 5 days Exclusion criteria: not stated Numbers completing study: 123/214 (57%) eligible children admitted during the study period enrolled; no reasons given for those not recruited. A total of 59/59 (100%) children allocated to the probiotic group and 64/64 (100%) in the placebo group completed the trial |
|
| Interventions |
Interventions started with oral rehydration solution. All participants with positive stool cultures received antibiotics Effect of isotonic vs hypotonic oral rehydration solution also assessed |
|
| Outcomes |
No comment regarding adverse events |
|
| Notes | Study location: Russia (low child and high adult mortality) Cause of diarrhoea: rotavirus identified in 13 (22.0%) probiotic and in 21 (32.8%) control. Bacterial diarrhoea identified in 11 (18.7%) probiotic and in 15 (23.4%) control Nutritional status: no data presented Hydration status: mean dehydration ~ 4% in both groups Among children with rotavirus diarrhoea, the probiotic (n = 13) reduced the number of watery stools compared with placebo (n = 21; P = 0.02, but no data given). No beneficial effect of the probiotic was seen in those with bacterial diarrhoea (probiotic (n = 11) and placebo (n = 115); P = 0.42) Stool samples tested for rotavirus (Rotazyme, Dakopotts AS, Denmark) and cultured for Salmonella and Shigella Source of funding: Leiras, Turku, Finland, and Valio, Helsinki, Finland Secondary outcome reporting: duration of hospital stay not pre‐specified in the methods but reported in the results |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not adequately described |
| Allocation concealment (selection bias) | Unclear risk | No specific details of allocation concealment |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not adequately described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not adequately described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Shornikova 1997b.
| Study characteristics | ||
| Methods | Randomized controlled trial; 2 centres Duration: 6 months (22 January to 15 July 1996) |
|
| Participants | Inclusion criteria: inpatients; infants and children with ≥ 3 watery stools in last 24 hours; diarrhoea for < 7 days; stools positive for rotavirus antigen (IDEIA rotavirus, UK). Mean dehydration about 4% in both groups Exclusion criteria: 20 participants who received exclusively or mainly IV fluids were excluded 86/97 (89%) enrolled participants were positive for rotavirus Numbers completing study: 97 patients enrolled; 86 were positive for rotavirus; 21 in the probiotics group and 25 in the placebo group (and 20 allocated to a low‐dose probiotic group) did not require IV rehydration and were analysed |
|
| Interventions | Participants randomized to 1 of 3 groups: 20 in the probiotic small dose (10⁷ CFUs/d) group, 21 in the probiotic large dose group, 25 in the placebo group. Data from the large dose group were used in this review
Interventions started with ORF |
|
| Outcomes |
No comment regarding adverse events |
|
| Notes | Study location: Finland (very low child and adult mortality) Cause of diarrhoea: all rotavirus Nutritional status: no data presented Hydration status: mean dehydration about 4% in both groups Data from high‐dose probiotic group used for continuous outcomes Duration of diarrhoea before admission greater in probiotic group (4.2 (SD 1.4) days) than in placebo group (2.9 (SD 1.2) days). Number with persistent diarrhoea on day 3 derived from graph Source of funding: BioGaia Biologicals AB |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Different dosing schedules |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear who assessed outcomes |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Follow‐up < 90% |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcomes reported |
Shornikova 1997c.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 5 months (29 January to 3 July 1995) |
|
| Participants | Inclusion criteria: inpatients; infants and children with ≥ 3 watery stools in last 24 hours; diarrhoea for < 7 days; ingested bovine dairy products Exclusion criteria: immunosuppressive therapy or immune deficiency; allergy to bovine milk; serious underlying disorder; receiving an investigational product during the preceding month Numbers completing study: 41 participants initially enrolled: 19/19 (100%) probiotic and 21/22 (95.5%) placebo (1 participant in the placebo group was removed because the probiotic agent (L reuteri) was detected in stool; the probiotic was administered to his sibling) |
|
| Interventions |
Interventions started at recruitment |
|
| Outcomes |
Less vomiting in the probiotic group. No adverse events attributed to probiotic |
|
| Notes | Study location: Finland (very low child and adult mortality) Cause of diarrhoea: rotavirus identified in 18 (86%) probiotic and in 12 (63%) control Nutritional status: no data presented Hydration status: mean dehydration at baseline greater in the probiotic group (3.9% (SD 1.3)) than in the control group (3.0 (SD 1.2)) Source of funding: BioGaia Biologicals, Inc., Raleigh, NC, USA |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not adequately described |
| Allocation concealment (selection bias) | Unclear risk | Not adequately described |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Matching placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear who assessed outcomes |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Simadibrata 2013.
| Study characteristics | ||
| Methods | Prospective double‐blind randomized controlled trial; 3 centres Duration: 2007 to 2010 |
|
| Participants | Inclusion criteria: acute diarrhea; aged 13 to 60 years; no severe complications Exclusion criteria: serious complication (renal failure, metabolic acidosis, severe dehydration, hypovolaemic shock, heart failure, vomiting, anorexia); history of allergy to Lactobacillus spp; diarrhoea caused by amoeba, colorectal cancer, or tumour; exclusion criteria with proven cause of diarrhoea, amoeba, colorectal cancer, or tumour; taking antibiotic therapy Numbers completing study: 38/45 (84.4%) probiotics (reason for withdrawals not stated); 38/45 (84.4%) control (reason for withdrawals not stated). All randomized patients analysed |
|
| Interventions |
Intervention started as soon after informed consent received as possible. All participants received ORS (Oralit®) |
|
| Outcomes |
No serious adverse events attributed to probiotic; no comment regarding non‐serious events |
|
| Notes | Study location: Indonesia (low child and adult mortality) Cause of diarrhoea: pathogen (not defined) detected in 8/38 (21.1%) probiotic and in 7/38 (18.4%) control. Amoebic diarrhoea excluded Nutritional status: not stated Hydration status: severe dehydration excluded Source of funding: financially supported by Dexa Medica Ltd and Rossel Institute |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not adequately described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Follow‐up < 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcomes reported |
Sirsat 2017.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: not stated |
|
| Participants | Inclusion criteria: children aged 2 months to 5 years; presenting with acute watery diarrhoea Exclusion criteria: not stated Numbers completing study: 145/145 (100%) probiotic; 145/145 (100%) control |
|
| Interventions |
Timing of onset of intervention not stated All participants received oral rehydration solution |
|
| Outcomes |
No comment regarding adverse events |
|
| Notes | Study location: India (high child and adult mortality) Cause of diarrhoea: rotavirus detected in 88/145 (60.7%) probiotic and in 77/145 (53.1%) control Nutritional status: not stated Hydration status: not stated Source of funding: none declared The frequency of diarrhoea after the third day of intervention was reduced in 60 (64%) probiotic vs 30 (39%) control (P < 0.001) |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomization using random numbers table |
| Allocation concealment (selection bias) | Unclear risk | Not stated |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No mention of who assessed outcomes |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All outcomes reported |
Sudha 2019.
| Study characteristics | ||
| Methods | Double‐blind randomized placebo‐controlled parallel‐group study; 2 centres Duration: September to November 2017 |
|
| Participants | Inclusion criteria: patients of either sex; aged 6 months to 5 years; clinical diagnosis of acute diarrhoea; not had any major illnesses; parents willing to give written informed consent and to follow study procedures Exclusion criteria: severe malnutrition; requiring antibiotics during study period; severe diarrhoea (requiring treatment other than investigational product and ORS); visible blood in stool; use of probiotics, antibiotics, or any anti‐diarrhoeal medication in the last 3 weeks; participation in any clinical trial or usage of any investigational product in the past 90 days; hypersensitivity to any of the active substances or excipients; previous use (within 48 hours) of kaolin, pectin, bismuth subsalicylate, racecadotril, loperamide, atropine, and other anticholinergic agents Numbers completing study: 59/60 (98.3%) probiotic (withdrawal due to protocol violation); 60/60 (100%) control |
|
| Interventions |
Timing of start of administration not stated. All participants received ORS |
|
| Outcomes | • Decrease in frequency of diarrhoea • Decrease in duration of diarrhoea • Improvement in consistency of stool • Decrease in frequency and duration of vomiting episodes • Decrease in duration of fever |
|
| Notes | Study location: India (high child and adult mortality) Cause of diarrhoea: bloody diarrhoea excluded Nutritional status: severe malnutrition excluded Hydration status: not stated Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated block randomization |
| Allocation concealment (selection bias) | Low risk | Opaque, sealed envelopes used |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Unclear whether placebo identical |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Investigators blinded to treatment group |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All pre‐defined outcomes reported |
Szymanski 2006.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 10 months (September 2003 to June 2004) |
|
| Participants | Inclusion criteria: inpatients and outpatients; aged 2 months to 6 years with acute diarrhoea (3 or more stools/d looser than normal that may contain blood or mucus for > 1 and < 5 days) Exclusion criteria: organic gut disease; underlying chronic illness; immunosuppression; exclusive breast‐feeding Numbers completing study: 46/49 (93.9%) probiotic; 41/44 (93.2) control. Withdrawals stated to be due to non‐compliance or incomplete data |
|
| Interventions |
Start of intervention delayed > 72 hours for many participants |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Poland (low child and adult mortality) Cause of diarrhoea: bloody diarrhoea included. Overall, 39/87 (45%) had rotavirus (22 probiotic and 17 control), 5/87 (6%) had adenovirus, 9/87 (10%) had a bacterial pathogen, and many children had norovirus infection Nutritional status: no data presented Hydration status: no severe dehydration. Mild/moderate dehydration in 34 (73.9%) probiotic and in 31 (75.6%) control Source of funding: Wellcome Travel Award |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated block randomization |
| Allocation concealment (selection bias) | Unclear risk | Unclear method of allocation concealment |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Randomization code broken after study completion |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Szymanski 2019.
| Study characteristics | ||
| Methods | Randomized double‐blind placebo‐controlled trial; 1 centre Duration: January 2017 to November 2018 |
|
| Participants | Inclusion criteria: younger than 5 years of age; acute gastroenteritis (defined as a change in stool consistency to loose or liquid form and/or an increase in frequency of evacuations (typically ≥ 3 in 24 hours) lasting no longer than 5 days Exclusion criteria: use of antibiotics, gelatin tannate, diosmectite, probiotics, racecadotril, or zinc within a week before enrolment; exclusive breast‐feeding; chronic diarrhoeal gastrointestinal disease; immunodeficiency disease; malnutrition Numbers completing study: 44/50 (88%) probiotic (5 LTFU; 1 excluded as mistaken randomization) and 47/50 (94%) control (3 LTFU) |
|
| Interventions |
Intervention started immediately after recruitment. All participants given standard rehydration therapy |
|
| Outcomes | • Duration of diarrhoea (time until normalization of stool consistency or normalization of number of stools and presence of normal stools for 48 hours) • Need for and duration of intravenous rehydration • Duration of hospitalization • Need for hospitalization of outpatients • Numbers of watery stools • Vomiting • Recurrence of diarrhoea (48 hours after intervention) • Severity of diarrhoea according to modified Vesikari Scale • Use of concomitant medications • Adverse events (whether or not they were considered to be related to study products) |
|
| Notes | Study location: Poland (low child and adult mortality) Cause of diarrhoea: rotavirus detected in 35/91 (38.5%) (18 (40.9%) probiotic and 17 (36.2%) placebo). Adenovirus detected in 2/91 (2.2%); Salmonella enteritidis in 2/91 (2.2%); unknown aetiology in 52/91 (57.1%) Nutritional status: severe malnutrition excluded Hydration status: 44 children (100%) in the probiotic arm and 44 (93.6%) in the control arm required intravenous fluids Source of funding: no external funding |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomization scheme |
| Allocation concealment (selection bias) | Unclear risk | No specific details of allocation concealment (and seemed to use fixed block size n = 6) |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Researchers, caregivers, outcome assessors, and a person responsible for statistical analysis were blinded |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | As above |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Follow‐up < 90% in intervention group |
| Selective reporting (reporting bias) | Low risk | Pre‐defined primary outcome reported |
Teran 2009.
| Study characteristics | ||
| Methods | Randomized single‐blind controlled trial; 1 centre Duration: 7 months (August 2007 to February 2008) |
|
| Participants | Inclusion criteria: inpatients; infants and children with history of acute watery diarrhoea (defined as ≥ 3 stools of liquid consistency/d < 72 hours' duration); positive for rotavirus and with moderate to severe dehydration Exclusion criteria: severe malnutrition; systemic infection requiring antibiotic therapy; severe chronic disease; identification of a second pathogen in the stool; ingestion of antibiotics, probiotics, or nitazoxanide 3 weeks before admission; recurrence of diarrhoea after discharge Numbers completing study: 25/30 (83.3%) probiotic; 25/31 (80.6%) control; 25/29 (86.2%) nitazoxanide. Patients with cause of diarrhoea other than rotavirus were withdrawn (probiotic group: 3 adenovirus, 2 E histolytica; control group: 3 E histolytica, 2 Giardia, 1 S flexneri; nitazoxanide group: 2 adenovirus, 1 E histolytica, 1 Giardia) |
|
| Interventions | Participants were allocated to 1 of 3 groups: a nitazoxanide group, a probiotic group, and a control group that received rehydration solutions only. Data from the probiotic group and from the control were used for this review
Time when interventions started not described |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Bolivia (high child and high adult mortality) Cause of diarrhoea: all rotavirus diarrhoea Nutritional status: severe malnutrition excluded; mild/moderate malnutrition in 5 (20%) probiotic and in 15 (60%) control Hydration status: all had moderate to severe dehydration; no further data presented Source of funding: research was not sponsored by any pharmaceutical company |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computerized admissions list |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Different dosing schedules |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | Outcomes assessed by nursing staff; different interventions administered |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Follow‐up < 90% |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Urganci 2001.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 1 year (June 200 to May 2001) |
|
| Participants | Inclusion criteria: consecutive inpatients aged 2 to 29 months with acute, non‐bacterial diarrhoea (definition not stated) lasting > 48 hours able to receive oral medication Exclusion criteria: concomitant illness; antimicrobial, anti‐diarrhoeal, or other drug affecting gut motility; severe electrolyte disturbance or dehydration Numbers completing study: 50 cases reported in both arms; numbers withdrawn because of deterioration in diarrhoea and concomitant disease requiring other drugs unclear |
|
| Interventions |
Time of starting interventions and duration of administration not stated |
|
| Outcomes | Number of children cured at 48 hours Number of children cured at 96 hours: 42 (84%) probiotic vs 32 (64%) control; P < 0.05 Mean (SD) stool frequency on day 2 after treatment: 3.78 days (0.71) probiotic and 4.24 days (0.99) placebo (P < 0.01) Mean (SD) stool frequency on day 4 after treatment: 2.70 days (0.67) probiotic and 3.12 days (0.93) placebo (P < 0.05) No adverse events attributed to probiotic |
|
| Notes | Study location: Turkey (low child and adult mortality) Cause of diarrhoea: non‐bacterial diarrhoea Nutritional status: no data presented Hydration status: none dehydrated Lactose intolerance identified in 8% in the probiotic group and in 26% in the placebo group Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear who assessed outcomes |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Number of children withdrawn not stated |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Vidjeadevan 2018.
| Study characteristics | ||
| Methods | Single‐blind randomized controlled trial; 1 centre Duration: 8 months (February to September 2017) |
|
| Participants | Inclusion criteria: children aged 6 months to 36 months; admitted to paediatric department with acute diarrhoea Exclusion criteria: blood in stools; clinical signs of a coexisting acute systemic illness like meningitis, sepsis, pneumonia; severely malnourished and immunocompromised children; prior probiotic or antibiotic drug administration; known hypersensitivity to probiotics Numbers completing study: 34/35 (97.1%) in S boulardii group (1 used antibiotics); 33/35 (94.3%) in B clausii group (1 used antibiotics, 1 LTFU); 32/35 (91.4%) in control group (2 used antibiotics, 1 LTFU) |
|
| Interventions |
Timing of start of intervention not stated All participants received oral rehydration solution and zinc |
|
| Outcomes |
No comment regarding adverse events |
|
| Notes | Study location: India (high child and adult mortality) Cause of diarrhoea: bloody diarrhoea excluded Nutritional status: not stated Hydration status: not stated Source of funding: no funding sources Median duration of diarrhoea, hours (IQR): 72 (72 to 96) in S boulardii group, 96 (72 to 96) in B clausii group, and 108 (96‐120) in control group. Not appropriate to convert median/IQR to mean/SD for duration of diarrhoea: small sample size and IQR for Group B either not correct or indicate skewed data |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Randomization using permuted blocks |
| Allocation concealment (selection bias) | Unclear risk | Not stated |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Study participants blinded |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | Single‐blind study |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | All outcomes reported |
Villarruel 2007.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 1 year |
|
| Participants | Inclusion criteria: outpatients; infants and children aged 3 months to 2 years (urban population, middle social class); acute, mild to moderate diarrhoea Exclusion criteria: use of probiotic in the preceding 7 days; chronic intestinal disease; short bowel syndrome; malabsorption; ≥ grade 2 malnutrition; severe disease (including dehydration requiring hospitalization at the time of consultation); known immunodeficiency; immunosuppressant treatment (oral or IV corticoids in the preceding 7 days); oral nystatin; oral or parenteral imidazoles; other systemic antifungal agents; macrolides; drugs that alter intestinal motility (antispasmodics, cisapride, antiemetics, and anti‐diarrhoeal drugs) in the preceding 7 days Numbers completing study: 6/50 (12.0%) excluded from probiotic group and 6/50 (12.0%) from control group for lack of compliance with protocol medication |
|
| Interventions |
ORF and antibiotics given when indicated |
|
| Outcomes |
No comment regarding adverse events |
|
| Notes | Study location: Argentina (low child and adult mortality) Cause of diarrhoea: none had bloody diarrhoea; no other data presented Nutritional status: ≥ grade 2 malnutrition excluded Hydration status: dehydration requiring hospitalization excluded; all had dehydration < 7% Stool frequency significantly lower in probiotic than placebo group on days 4 and 7 Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Random computer‐generated into blocks of 20 |
| Allocation concealment (selection bias) | Unclear risk | No specific details of allocation concealment |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Outcome assessors blinded to intervention |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Follow‐up < 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Vivatvakin 2006.
| Study characteristics | ||
| Methods | Randomized open study; 1 centre Duration: 11 months (March 2003 to January 2004) |
|
| Participants | Inclusion criteria: inpatients and outpatients; infants and children with watery diarrhoea (not defined) for < 5 days Exclusion criteria: immunocompromised; suspected dysentery; diagnosed with persistent or chronic diarrhoea; chronic cardiac, pulmonary, or haematological illness; undergoing antibiotic treatment in the last 2 weeks; severe dehydration or shock 4/75 withdrawn (1 febrile seizure, 1 urinary tract infection, 2 with pneumonia); 2 participants were withdrawn from each group Numbers completing study: 36/38 (94.7%) probiotic; 35/37 (94.6%) control |
|
| Interventions |
Timing of administration not stated |
|
| Outcomes |
Duration of diarrhoea reported for rotavirus diarrhoea No adverse events attributed to probiotic |
|
| Notes | Location: Thailand; low child and adult mortality Cause of diarrhoea: suspected dysentery excluded; overall, 34% had rotavirus and 12.1% Salmonella in stools Nutritional status: no data presented Hydration status: severe dehydration excluded; mild/moderate dehydration in 25 (69.4%) probiotic and 23 (65.7%) control Source of funding: AIS donation fund, Thai Red Cross Society |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not adequately described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No placebo |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | Open‐label study |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
Wunderlich 1989.
| Study characteristics | ||
| Methods | Randomized controlled trial; 10 centres Duration: not stated |
|
| Participants | Inclusion criteria: patients with acute diarrhoea (characteristics and duration not stated) Exclusion criteria: not stated 3 participants from each group were withdrawn on day 4 or later (causes for dropouts stated to be unrelated to medication); 4 participants assigned to the probiotic group and 5 assigned to the placebo group did not complete the study (reasons not stated). Numbers completing the study (for persisting diarrhoea outcomes): 40/47 (85.1%) probiotic and 38/46 (82.6%) placebo |
|
| Interventions |
Not stated when interventions started |
|
| Outcomes |
No adverse events attributed to probiotic |
|
| Notes | Study location: Switzerland and Lichtenstein (very low child and adult mortality) Cause of diarrhoea: no data presented Nutritional status: no data presented Hydration status: no data presented Source of funding: not stated |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not adequately described |
| Allocation concealment (selection bias) | Unclear risk | Not described |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Identical placebo |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Unclear who assessed outcomes |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Follow‐up < 90% in both groups |
| Selective reporting (reporting bias) | High risk | Primary outcome not pre‐stated in methods |
Xie 2013.
| Study characteristics | ||
| Methods | Randomized controlled trial; 1 centre Duration: 11 days |
|
| Participants | Inclusion criteria: infants with diarrhoea during autumn and winter; artificial feeding; first day of diarrhoea onset; loose stools; no mucus, pus, or blood in stools; rapid stool test of ELISA (Shenzhen Purcell Biotechnology Co., Ltd.) to detect rotavirus antigen positive; without any micro‐agents and antibiotics before clinic Exclusion criteria: severe complications, such as severe dehydration, shock, pneumonia, etc.; patients’ stool within pyocyte and erythrocyte, but to include patients with intestinal bacterial infection; treated with micro‐ecological agents and antibiotics; breast‐feeding during diarrhoea; change to lactose‐free feeding during diarrhoea Numbers completing study: 50/50 (100%) probiotics; 50/50 (100%) control |
|
| Interventions |
Intervention started on recruitment. Participants given basic treatment including oral montmorillonite powder and fluid replacement therapy and fed with customary milk powder |
|
| Outcomes |
No specific comment regarding adverse events |
|
| Notes | Study location: China (low child and adult mortality) Cause of diarrhoea: all rotavirus diarrhoea; bloody diarrhoea excluded Nutritional status: not stated Hydration status: not stated Source of funding: Youth Science Fund of Sichuan University (No. 2008053) |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not adequately described |
| Allocation concealment (selection bias) | Unclear risk | Not adequately described |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not described |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Not described |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Follow‐up ≥ 90% in both groups |
| Selective reporting (reporting bias) | Low risk | Pre‐stated outcome reported |
CFU: colony‐forming units. ED: emergency department. ELISA: enzyme‐linked immunosorbent assay. IQR: interquartile ratio. IV: intravenous. NCHS: National Centre for Health Statistics. ORF: oral rehydration fluid. RCT: randomized controlled trial. SD: standard deviation. WHO: World Health Organization.
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Agarwal 2001 | No non‐probiotic group. Participants included in Agarwal 2002 study |
| Agarwal 2002 | No non‐probiotic group |
| Ahmadipour 2018 | Control group received zinc |
| Alexander 1971 | Not a randomized controlled trial; no non‐probiotic group |
| Alvisi 1982 | Intervention groups not treated equally; antibiotics given to the non‐probiotic group |
| Asmat 2018 | No non‐probiotic group |
| Barone 2000 | No non‐probiotic group |
| Beck 1961 | Not a randomized controlled trial |
| Bellomo 1979 | Cause of diarrhoea unclear. Additional treatment given to children with persisting diarrhoea |
| Bellomo 1980 | No non‐probiotic group. Study included children with diarrhoea secondary to antibiotic treatment or associated with respiratory infection |
| Bellomo 1982 | Cause of diarrhoea unclear |
| Bin Li Xie 1995 | Intervention groups not treated equally; antibacterials given to the non‐probiotic group |
| Boulloche 1994 | Killed probiotic |
| Brewster 2004 | Secondary publication to Ritchie 2010 |
| Camarri 1981 | Intervention groups not treated equally; antibiotics given to the non‐probiotic group |
| Cetina Sauri 1990 | Secondary publication to Cetina‐Sauri 1994 |
| Chandra 2002 | Prevention of rotavirus diarrhoea study |
| Chapoy 1985 | Quasi‐randomized: alternate allocation to study arms |
| Chicoine 1973 | Unclear if acute diarrhoea |
| Costa‐Ribeiro 2000a | Unclear whether a randomized controlled trial |
| Costa‐Ribeiro 2000b | Prevention of diarrhoea study |
| Cui 2004 | No non‐probiotic group |
| Czerwionka 2009 | No outcomes reported that can be included in this review |
| Dash 2016 | Quasi‐randomized |
| de dios Pozo‐O 1978 | Assessment of probiotic in prevention of traveller's diarrhoea |
| Eren 2010 | No non‐probiotic group |
| Escribano 2018 | Prevention study |
| Fang 2009 | Study of effect of probiotic on rotavirus shedding in stools; no diarrhoea outcomes reported |
| Fourrier 1968 | No non‐probiotic group |
| Freedman 2018b | Abstract preceding definitive trial report |
| Frigerio 1986 | No efficacy data |
| Girola 1995 | Children with gastroenteritis and antibiotic‐associated diarrhoea studied together |
| Gracheva 1996 | No non‐probiotic group |
| Grandi 2009 | No usable efficacy data |
| Grandy 2010 | No outcomes reported that could be included in this review |
| Hafeez 2002 | Quasi‐randomized: allocation according to odd and even participant numbers |
| Henker 2007b | Secondary reference to Henker 2007a |
| Heydarian 2010 | No non‐probiotic group |
| Htwe 2008 | Quasi‐randomized: participants alternately assigned to intervention and control groups |
| Isolauri 1991 | No non‐probiotic group |
| Jimenez‐Rodriguez 2018 | No usable data to extract |
| Kaila 1992 | No non‐probiotic group |
| Kaila 1995 | No non‐probiotic group |
| Khan 2012 | No outcomes reported that could be included in this review |
| Khanna 2005 | Killed probiotic |
| Khoshdel 2018 | Synbiotic evaluated |
| Korviakova 2000 | Not a randomized controlled trial; probiotic vs antibiotic |
| Lahiri 2015a | No extractable data |
| Lahiri 2015b | No extractable data |
| Lei 2006 | Probiotic used was not specified |
| Le Leyur 2010 | Intervention group received an adapted lactose‐free formula fortified with S boulardii, and control group received a standard formula; difference in diarrhoea outcomes between groups cannot be attributed to the probiotic |
| Lievin Le‐Maol 2007 | Killed probiotic |
| Lin 2009 | Prevention study |
| Magreiter 2006 | No non‐probiotic control group |
| Majamaa 1995 | No non‐probiotic group |
| Maragkoudaki 2018 | Intervention group received zinc in addition to probiotic |
| Maugo 2012 | Unpublished MSc thesis |
| Mazo 2006 | Prevention study |
| Michielutti 1995 | Not a randomized controlled trial |
| Misra 2009 | No outcomes reported that could be included in this review |
| Mitra 1990 | No non‐probiotic group |
| Moraes 2001 | No non‐probiotic group |
| Niv 1963 | Not a randomized controlled trial; some children with diarrhoea thought to be caused by antibiotic treatment included |
| Ortlieb 1974 | Participants with acute diarrhoea and antibiotic‐associated diarrhoea combined |
| Pashapour 2006 | Pasteurized yoghurt; likely killed probiotic |
| Pearce 1974 | Intervention groups not treated equally; calcium carbonate given as placebo and may have reduced diarrhoea in the non‐probiotic group |
| Pedone 1999 | Prevention of diarrhoea study |
| Pedone 2000 | Prevention of diarrhoea study |
| Pene 1966 | No non‐probiotic group; participants with diarrhoea of various causes (infectious, post‐antibiotic) grouped together |
| Perez 2019 | Included children with acute diarrhoea and children with antibiotic‐associated diarrhoea |
| Pernica 2017 | No usable efficacy data |
| Rafeey 2008b | Secondary publication to Rafeey 2008a |
| Rautanen 1998 | No data for placebo group presented |
| Saint‐Marc 1991 | Not a randomized controlled trial; no non‐probiotic group |
| Salazar‐Lindo 2004 | Mean duration of diarrhoea reported from responders only; children with ongoing diarrhoea excluded from analysis |
| Salazar‐Lindo 2007 | Active placebo |
| Satoh 1984 | Not a randomized controlled trial; no non‐probiotic group |
| Savas‐Erdeve 2009 | Study of amoebiasis‐associated diarrhoea, not acute infectious diarrhoea |
| Schrezenmeir 2004 | Antibiotic‐associated diarrhoea included in the study |
| Sepp 1995 | No usable efficacy data |
| Sharif 2017 | Synbiotic evaluated and controls did not receive prebiotic |
| Simakachorn 2000 | Killed probiotic |
| Sindhu 2014 | Included children with chronic diarrhoea and with a recent history of yoghurt consumption |
| Singh 1987 | No probiotic specified |
| Singh 2018 | No control group |
| Sudarmo 2003 | Other than the probiotic, unclear whether 2 intervention groups were treated the same. Probiotic group received high‐lactose formula containing B bifidum. Unclear whether control group received high‐lactose or normal formula |
| Sugita 1994 | Quasi‐ramdomized study |
| Szymanski 2005 | Preliminary publication of Szymanski 2006 |
| Táborská 1997 | No efficacy data |
| Tojo 1987 | Unclear whether diarrhoea acute and whether a randomized controlled trial |
| Urtula 2009 | Unclear inclusion criteria |
| Zareen 2018 | Intervention group received zinc in addition to probiotic |
Characteristics of ongoing studies [ordered by study ID]
CTRI/2017/08/009543.
| Study name | Effect of probiotic Bacillus clausii UBBC07 in children with acute diarrhoea |
| Methods | RCT |
| Participants | Inclusion criteria
Exclusion criteria
|
| Interventions |
|
| Outcomes | Primary outcomes
Secondary outcomes
|
| Starting date | Registered 29 August 2017 (completed, not yet published) |
| Contact information | Dr DC Pandey; mvhrclko@gmail.com (principal investigator) |
| Notes | Location: India |
CTRI/2018/04/013360.
| Study name | Efficacy of Lactobacillus sporogenes in treating acute diarrhoea in adults ‐ randomized control study |
| Methods | RCT |
| Participants | Inclusion criteria
Exclusion criteria
|
| Interventions |
|
| Outcomes | Primary outcome
Secondary outcome
|
| Starting date | Registered 19 April 2018 (open to recruitment in July 2019) |
| Contact information | Meera Baby John; meerababyjohn@gmail.com (principal investigator) |
| Notes | Location: India |
CTRI/2018/06/014480.
| Study name | A multicentric, randomized, placebo controlled double blind study to compare safety and tolerability of Saccharomyces boulardii in acute diarrhoea |
| Methods | RCT |
| Participants | Inclusion criteria
Exclusion criteria
|
| Interventions |
|
| Outcomes | Primary outcomes
Secondary outcomes
|
| Starting date | Registered 8 June 2018 (not yet recruiting in July 2019) |
| Contact information | Dr Monjori Mitra; monjorimr@gmail.com (principal investigator) |
| Notes | Location: India |
IRCT2017010312437N2.
| Study name | Evaluation of the effect of ORS with probiotics, zinc and vitamin A on diarrhea in children: a double blind clinical trial |
| Methods | RCT |
| Participants | Inclusion criteria
Exclusion criteria
|
| Interventions |
|
| Outcomes |
|
| Starting date | Registered 17 August 2017 (recruitment complete in July 2019) |
| Contact information | Mohsen Taghizadeh; taghizadeh‐m@kaums.ac.ir |
| Notes | Location: Kashan, Iran |
IRCT2017090812897N3.
| Study name | The effect of yeast probiotic (Saccharomyces boulardii) on acute diarrhoea in children |
| Methods | RCT |
| Participants | Inclusion criteria
Exclusion criteria
|
| Interventions |
|
| Outcomes | Primary outcome
Secondary outcome
|
| Starting date | Registered 7 October 2017 (recruitment complete in July 2019) |
| Contact information | Abolfazl Mahyar amahyar@qums.ac.ir |
| Notes | Location: Qazvin, Iran |
ISRCTN18444252.
| Study name | Probiotics for treatment of acute childhood diarrhoea |
| Methods | RCT |
| Participants | Inclusion criteria
Exclusion criteria
|
| Interventions |
|
| Outcomes | Primary outcome
Secondary outcome
|
| Starting date | 1 November 2016 (completed, not yet published in July 2019) |
| Contact information | Dr Ke Chen, No. 1617 Riyue Avenue, Qingyang District, Chengdu, 610031, China |
| Notes | Location: Chengdu Women & Children’s Central Hospital, China |
NCT03539913.
| Study name | Efficacy and safety of probiotics in the treatment of acute gastroenteritis in children (SABINA) |
| Methods | Randomized parallel assignment trial |
| Participants | Inclusion criteria
|
| Interventions |
|
| Outcomes | Primary outcome
Secondary outcomes
|
| Starting date | June 2017; completed June 2018 |
| Contact information | Carine Francois (study director); contact information not provided |
| Notes | Location: Argentina |
NCT03684538.
| Study name | Efficacy of probiotics vs zinc vs probiotics‐zinc combination on acute diarrhea in children |
| Methods | RCT |
| Participants | Inclusion criteria
Exclusion criteria
|
| Interventions |
|
| Outcomes | Primary outcome
Secondary outcomes
|
| Starting date | 1 October 2018 (recruiting in July 2019) |
| Contact information | Mariam AlAbdullah A Rajab; drmariam1@hotmail.com (principal investigator) |
| Notes | Location: Makassed General Hospital, Beirut, Lebanon |
CFU: colony‐forming unit. ORS: oral rehydration solution. RCT: randomized controlled trial. WHO: World Health Organization.
Differences between protocol and review
Differences between review update (2010) and review update (2020)
This review is a substantial update of the original version, Allen 2003, and its update (Allen 2010).
In this review, only published, randomized controlled trials of live probiotics were included. Seventeen trials that were unpublished, were quasi‐randomized, assessed killed probiotics, or had no usable outcome data that were included in Allen 2010 were excluded.
We revised the outcomes according to a consensus statement regarding a core outcome measurement set for clinical trials in acute diarrhoea (Karas 2016).
Contributions of authors
Shelui Collinson and Stephen Allen identified articles for inclusion in the review. Leonila Dans, Germana Gregorio, April Padua, and Shelui Collinson assessed study quality, and Stephen Allen settled any disagreements. Shelui Collinson, Andrew Deans, and Stephen Allen extracted data. Chao Li advised on statistical analysis, assessment of publication bias, and NMA. Shelui Collinson wrote the first draft of the review. Stephen Allen took the main responsibility for analysis and for writing the final version of the review. All reviewers contributed to the final version.
Sources of support
Internal sources
Liverpool School of Tropical Medicine, UK
External sources
-
Foreign, Commonwealth and Development Office (FCDO), UK
Project number 300342‐104
Declarations of interest
Shelui Collinson has no known conflicts of interest.
Andrew Deans has no known conflicts of interest.
April Padua has no known conflicts of interest.
Germana V Gregorio has no known conflicts of interest.
Chao Li has no known conflicts of interest.
Leonila F Dans has no known conflicts of interest.
Stephen J Allen: travel and accommodation expenses to attend the Nutricia Neocate Syneo Meeting (November 2016) at the Nutricia Utrecht Research Centre were paid.
New search for studies and content updated (conclusions changed)
References
References to studies included in this review
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