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Three Part Question

In a [child admitted with acute gastroenteritis], does [the use of Probiotics] reduce the [duration of hospital stay, frequency and severity of diarrhoea]?

Clinical Scenario

You are a Paediatric Registrar on duty. The S.H.O asks you to review a child recently returning from Spain, presenting with acute gastroenteritis. The mother shows you a prescription indicating treatment with a Probiotic preparation started by the doctor abroad and wonders about whether you would continue with the same. The S.H.O also quotes some studies supportive of this intervention. You have some time and go off to search for evidence in this regard.

Search Strategy

Secondary Sources- Cochrane Database: Topic registered but no reports.
Primary Sources- MEDLINE [1966-Sept'2003];
Search Terms-
"Acute Gastroenteritis"/ "Infectious Diarrhoea" AND/OR "Probiotics"/ "Lactobacillus"; Limits: English; Human; Child<18 years.

Search Outcome

There were 28 reported RCT's of Lactobacillus treatment of Infectious diarrhoea/Acute gastroenteritis in this period of which 11 were included in the systematic review carried out earlier in 2002. There have been two further RCT's carried out since then, that also meet the criteria laid down for the earlier review. See Table 1 below.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Szajewska et al 2001 Poland	Systematic review of 13 double-blinded RCT's including 3 prevention trials comparing the use of probiotics versus placebo in the treatment and prevention of acute infectious diarrhoea in infants and children	Systematic review(Level 1a)	(1) Risk of diarrhoea lasting for greater than 3 days (2) Number of watery stools per day and duration of hospitalisation (3) Prevention trials: Incidence rates of diarrhoea	(1) Pooled estimate relative risk of diarrhoea lasting >3 days was 0.43(95% CI 0.34-0.53; p< 0.0001; significant) (2) Reduction in the duration of diarrhoea with probiotics(versus placebo)- Pooled weighted mean difference was -20.1 hours (95% CI WERE -26.1 to -14.2 hours)	Diverse range of probiotics employed which makes exact comparison of outcomes difficult. Stool output(Volume) not measured Significant methodological and statistical heterogeneity across studies
Van Niel CW et al 2002 U.S.A	Nine RCT's over a 27 year period comparing the use of Lactobacillus versus placebo for the treatment of infectious diarrhoea in children. Only adequately blinded studies were included.	Systematic review(Level 1a)	(1) Duration(in days) of diarrhoea (2) Frequency(number of stools per day)	(1) Significant reduction in diarrhoea duration of 0.7 days(95% CI 0.3 to 1.2 days) in subjects given Lactobacillus compared to placebo (2) Summary point estimate for frequency of stools(only in 3 studies) was 1.6/day fewer in the intervention group(95% CI 0.7-2.6 fewer stools)	Not all studies reported variance in measurement of diarrhoea duration and frequency Heterogeneity of treatment effects across studies (Most were children with mild-to-moderately severe dehydration) seen.
Rosenfeldt et al 2002 Denmark	69 children hospitalised for acute diarrhoea randomised to receive probiotic Lactobacillus strains or placebo	RCT(Level 1b)	(1) Duration(in hours) of diarrhoea (2) Length of hospital stay( in hours) (3)Absence of Rotaviral antigen in stools at the end of the 5-day intervention period	(1) Lactobacillus intervention reduced diarrhoea duration(82 versus 101 hours;p=0.07;not significant) (2) Length of hospitalisation reduced by 48% in intervention group(3.5 versus 1.7 days; p=0.03; significant) (3) Rotaviral antigen found in 12% 9vs 46% in placebo group;p=0.02; not significant)	Frequency and stool volume were not measured
Costa-Ribeiro et al 2003 U.S.A	124 male children under 2 years of age admitted with moderate dehydration randomised to recieve either Lactobacillus or placebo	RCT(Level 1b)	(1) 24 hour estimation of stool output(Volume) (2) Duration(in hours) of diarrhoea (3) Proportion of children requiring Intravenous rehydration	(1) No significant reduction in duration of diarrhoea(38.27±3.78 versus 39.09± 4.60 hours; p=0.59) (2) No significant reduction in stool output/kilogram body weight(139.74 ± 171.16 versus 184.63 ± 274.13 ml/kg; p=0.81)	Greater proportion of moderate to severely dehydrated as well as very young children. Children with severe malnutrition and bloody diarrhoea were excluded.

Comment(s)

Acute diarrhoeal illnesses are a leading cause of childhood morbidity and mortality in young children, especially in the developing world. Oral Probiotic therapy supplementing oral rehydration treatment has in the recent years been suggested to have a substantial therapeutic potential for reducing the severity and duration of diarrhoea. Numerous bacteria have been identified of possible benefit of which Lactobacillus GG has been most extensively studied. The systematic review by Van Niel et al found that treatment with Lactobacillus brought about a significant reduction in the duration of diarrhoea as well as stool frequency. Szajewska et al however, in their review, studied trials employing a diverse range of Probiotics in relation to not only their therapeutic value in established diarrhoeal illness but also their potential value as a preventive in reducing the incidence of diarrhoea. Though these two reviews favour Probiotics as a valuable intervention, the trials included in both show a great degree of diversity in terms of the subjects involved, nature of the illness and its severity. More importantly, these reviews have not addressed the effect of Probiotics on Stool output [Volume]. The World Health Organization (WHO) recommends that the main criterion to assess the potential benefit of any planned intervention in acute gastroenteritis should be quantifiable in terms of its effect on reducing stool volume. Costa-Ribeiro et al in their recent study found that Lactobacillus GG therapy did not bring about a statistically significant reduction in either the stool output or duration of diarrhoea. It should however be noted that many subjects in their study had moderate to severe dehydration often requiring intravenous fluids and all were under two years of age. They concluded that any potential benefits accruing from Probiotics might be limited to children with prolonged diarrhoea and possibly in high-risk populations. No significant adverse effects were reported. Further large-scale controlled trials particularly focussing on an ambulatory child population are essential to identify the exact benefits of these agents.

Clinical Bottom Line

Probiotics are a useful adjuvant along with rehydration therapy in Acute Gastroenteritis. Their role in prevention of diarrhoeal illness and children treated as outpatients is still not established. Cost-effectiveness particularly in developing nations is an important and unresolved issue

References

1. Szajewska H and Mrukowicz JZ. Probiotics in the treatment and prevention of Acute Infectious Diarrhea in Infants and Children: A Systematic Review of Published Randomized, Double-Blind, Placebo-Controlled Trials. Journal of Pediatric Gastroenterology and Nutrition Vol.33, Suppl 2, S17-S25, 2001.
2. Van Niel CW. Feudtner C. Garrison MM. Christakis DA. Lactobacillus Therapy for Acute Infectious Diarrhea in Children: A Meta-analysis. Pediatrics Vol.109 (4):April 2002;678-684.
3. Rosenfeldt V. Michaelsen KF. Jakobsen M et al. Effect of probiotic Lactobacillus strains in young children hospitalized with acute diarrhoea. Pediatric Infectious Diseases Journal 2002 May;21(5):411-16.
4. Costa-Ribeiro H. Ribeiro TC. Mattos AP et al. Limitations of Probiotic Therapy in Acute, Severe Dehydrating Diarrhea. Journal of Pediatric Gastroenterology and Nutrition Vol 36 (1), January 2003:112-115.