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Acute gastroenteritis is generally defined as a decrease in the consistency of stools (loose or liquid) and/or an increase in the frequency of evacuations (typically more than 3 in 24 h), with or without fever or vomiting. Diarrhoea typically lasts less than 7 days and not longer than 14 days.
The incidence of acute diarrhoea ranges from 0.5 to 1.9 episodes per child per year in children younger than 3 years old in Europe, with Rotavirus being the most frequent agent.
Oral rehydration therapies (ORT) are the mainstay of management of acute diarrhoea.[1, 2] Although its composition continues to improve, the oral glucose-electrolyte rehydration solution (ORS) recommended by the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and United Nations Children's Fund neither shortens the duration of the illness nor reduces the stool loss and may in fact increase the stool volume at least during the first hours in children with acute diarrhoea.
Probiotics may be an effective adjunct to the management of acute diarrhoea and a recent meta-analysis has shown that used alongside rehydration therapy, probiotics appear to be safe and have clear beneficial effects in shortening the duration and reducing stool frequency in acute infectious diarrhoea. However, more research is needed to guide the use of particular probiotic regimens and strain[1, 2, 4] and as there is still no evidence of efficacy for many preparations, the ESPGHAN and the National Institute for Health and Clinical Excellence have suggested the use of probiotic strains with proven efficacy and in appropriate doses for the management of children with acute gastroenteritis as an adjunct to rehydration therapy.[1, 2]
Previously, in two separate prospective randomised trials Lactobacillus reuteri (L. reuteri) ATCC 55730 was shown to effectively colonise the gastrointestinal tract and to significantly shorten the duration of watery diarrhoea associated with rotavirus infection.[5, 6] Recently, this strain was found to carry specific, unusual, potentially transferable resistance traits for tetracycline and lincomycin, which led to the development of a new daughter strain, L. reuteri DSM 17938 derived from L. reuteri ATCC 55730 by the natural removal of these unwanted plasmid-borne resistances. The daughter strain retained the probiotic properties and its safety and tolerance in adults.
The aim of the present study was to assess the efficacy of this new strain of L. reuteri DSM 17938 as an adjunct to rehydration therapy in the treatment of children hospitalised with acute diarrhoea.
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Of 96 patients enrolled, nine (11%) had started a probiotic/antibiotic treatment before admission, seven (8%) received exclusively or mainly intravenous fluids for rehydration, in three (2%) a bacterial origin was identified (two patients Campylobacter, and in 1 Salmonella spp.) and three (2%) refused to participate therefore, a total of 74 patients were enrolled into the study, 37 in the L. reuteri group and 37 in the control group. Five patients, two from the L. reuteri group and three from the control group, were withdrawn from the study (Figure 1) because of either one of the following reasons: parental noncompliance (three patients); protocol deviations (two patients). Sixty-nine children, mean age 23.5 months, completed the study (Figure 1).
Data are available in 64 children; in 10 children with prompt recovery, additional test would have not been justified on the basis of routine clinical care. Rotavirus antigen was identified in 43 patients (62%) and adenovirus in 10 (14%) while in 11 (24%) no aetiology was found. No significant differences regarding age, gender or duration of diarrhoea before intervention were found between the study groups. The clinical characteristics and severity of gastroenteritis did not differ between treatment group and control group.
The clinical characteristics of the treatment groups are presented in the Table 1. Both groups were similar in age, nutritional status, duration of diarrhoea before admission, stool output (first 4 h of the rehydration phase), percentage of dehydration and ethology. On admission most patients had mild dehydration. The serum sodium was between 130 and 144 mmol/L, with a mean of 138 mmol/L. The degree of dehydration in rotavirus-positive children was not significantly more severe than in negative patients.
Table 1. Demographic characteristics of children who completed the study
| ||L. reuteri (n: 37)||Placebo (n: 37)||P|
|Age (months)||26.1 ± 4.1||25.4 ± 2.1||N.S.|
|Duration diarrhoea before admission (days)||1.5 (1–4)||1.5 (1–5)||N.S.|
|No. of stool motions 24 h before admission||5.6 ± 4.5||6.4 ± 5.1||N.S.|
|Rotavirus/Adenovirus/no aetiology found||22/6/9||22/5/10||N.S.|
|Vomiting||24 (65%)||24 (65%)||N.S.|
|Fever (>38.5 °C)||19 (51%)||18 (49%)||N.S.|
|Watery diarrhoea on admission||37 (100%)||37 (100%)||N.S.|
No patient was lost in follow-up before stool consistency had normalised; no patient was excluded from the analysis.
The clinical outcome of the two treatment arms was similar for weight gain (190 ± 152 g), consumption of ORS solution (310.5 ± 215.3 mL/kg) correction of acidosis (base deficit -0.9 ± 1.5 mmol/L) and serum Na (138 ± 2 mmol/L).
Days 0–7 were calculated as 24-h periods after the initiation of treatment. L. reuteri significantly reduced the duration of watery diarrhoea as compared with placebo (2.1 ± 1.7 vs. 3.3 ± 2.1 days; P < 0.03) and the effect of L. reuteri was mostly seen in the second/third day of treatment (Figure 2). The intention-to-treat analysis shows that on the first day of treatment, watery diarrhoea persisted in 100% of those receiving placebo and in 87% of those receiving L. reuteri; on the second day of treatment watery diarrhoea persisted in 81% of the placebo and 55% of the L. reuteri recipients (P < 0.02). The frequency of watery diarrhoea per 24-h period was still significantly reduced on the third day of treatment in the L. reuteri recipients as compared with placebo recipients (73% vs. 46%; P < 0.03). Therefore, the number of children with a normalised stool consistency was significantly higher on day 2 and day 3 in the L. reuteri group. The per protocol analysis is reported in Table 2.
Figure 2. Percentage of patients with persisting watery diarrhoea in the groups receiving placebo (grey) and Lactobacillus reuteri (white).
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Table 2. Number and percent (%) of patients with watery diarrhoea at days of treatment (per protocol analysis)
|Day||L. reuteri (n: 35)||Placebo (n: 34)||P|
|0||35 (100)||34 (100)||N.S.|
|1||31 (91)||34 (100)||N.S.|
|2||19 (54)||28 (82)||<0.01|
|3||16 (46)||25 (74)||<0.03|
|4||14 (40)||17 (50)||N.S.|
|5||9 (26)||11 (32)||N.S.|
|6||2 (6)||3 (9)||N.S.|
The mean (±s.d.) frequencies of watery diarrhoea in placebo and L. reuteri groups at day 1, 2, 3 and 4 were 7.2 (2.4) vs. 6.9 (3.2), 6.3 (2.1) vs. 4.3 (1.7), 4.3 (2.3) vs. 2.1 (1.8) and 1.8 (1.3) vs. 1.5 (0.9) (P = N.S.; P < 0.02; P < 0.03; P = N.S. respectively).
Fewer patients receiving L. reuteri, compared with those receiving placebo, had vomiting, starting from the second day of treatment (35% vs. 55%; P = 0.16).
Side effects were not reported by the parents or physicians and none was excluded for low compliance. There was not a significant difference in hospital stay between the groups.
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Our study shows that L. reuteri DSM 17938 as an adjunct to rehydration therapy is effective in the treatment of acute diarrhoea reducing the frequency and duration, of the disease.
Viewed from a global perspective, gastroenteritis in children is of enormous public health importance. In the 1970s, there were almost 5 million childhood deaths worldwide from gastroenteritis each year. The use of ORT, contributed to a marked reduction in this death rate. Nevertheless, gastroenteritis still causes between 1.6 and 2.6 million deaths in children younger than 5 years each year and even in developed countries, at least 30% of hospital admissions for acute gastroenteritis in young children are the result of Rotavirus infection.[9, 10]
The research of new therapeutic strategies for the treatment of acute diarrhoea suggested the hypothesis that probiotics may play a role.[1, 2, 4, 5] According to the currently adopted definition by FAO/WHO, probiotics are ‘Live microorganisms which when administered in adequate amounts confer a health benefit on the host’. Microorganisms most commonly used in clinical practice are lactic acid-producing bacteria such as Lactobacillus spp., and Bifidobacteria.
Much research has been directed towards examining the potential benefit of a variety of probiotics in the treatment of infectious gastroenteritis. A recent Cochrane review including 56 trials in children concluded that specific probiotics are able to reduce the duration of diarrhoea of about 24 h and the frequency of stools was decreased on the second day 2. There is evidence suggesting that lactobacilli [Lactobacillus rhamnosus GG, L. reuteri (ATCC 55730), Lactobacillus acidophilus LB], Saccharomyces boulardii and a mixture of Streptococcus thermophilus, Lactobacillus acidophilus and Lactobacillus bulgaricus have the best therapeutic effect for this particular indication.[12-15]
Shornikova evaluated L. reuteri in two separate trials and showed a significantly shortened duration of watery diarrhoea associated with its use with higher efficacy for higher doses (1010−1011 CFU/day).[5, 6] In our study we decided to use the new strain of L. reuteri DSM 17938 to assess if it still retains the same therapeutic activity of the parental strain ATCC 55730. The present study demonstrates that children receiving L. reuteri DSM 17938 on days 2 and 3 were statistically significantly more likely to be diarrhoea-free and passed significantly fewer stools compared with those receiving placebo.
The possible mechanisms by which L. reuteri DSM 17938 may exert its beneficial effect include (i) the production of a broad-spectrum antimicrobial substance, called reuterin, (which may be responsible for the inhibition of pathogenic microorganisms in the gastrointestinal tract); (ii) competition with pathogens for binding sites and substrates; (iii) stabilisation of the mucosal barrier with a decrease in intestinal permeability and (iv) stimulation of intestinal immune responses.[12, 16-18]
We are aware of some limits of the present study such as the small sample size, that, however, was appropriate for the statistical power and the fact that children were admitted in hospital and L. reuteri therapy was started at a relatively late stage of diarrhoea. Indeed it has been suggested that probiotics might be more effective when given early when patients might be less ill, however, if this is the case, the efficacy of L. reuteri might have been even more pronounced if administered as early as possible.
Strengths of our study are the demonstration that L. reuteri DSM 17938 derived from ATCC 55730 is efficacious and safe for the sake of all physicians and parents who will prescribe and use this probiotic and the fact that children included in this study (6 months to 3 years) probably represent the most severe type of patients with diarrheal disease presenting with acute watery diarrhoea and signs of mild to moderate dehydration, thus, we can argue that the results of this study can be applied to patients with less severe diarrhoea.
Lactobacillus reuteri has been extensively studied and is widely used as a food additive to improve human gastrointestinal health. Oral administration delivers L. reuteri to the gastrointestinal tract, leading to shedding of live bacteria in the faeces.[19, 20] Clinical trials have shown that L. reuteri administration is safe both in adults and children[5, 6, 21-24] and we recently demonstrated its efficacy on the prevention of antibiotic-associated diarrhoea during anti-Helicobacter pylori treatment. The bioequivalence of L. reuteri DSM 17938 with parent strain L. reuteri ATCC 55730 has been demonstrated in recent clinical trials on faecal recovery of live bacteria, infantile colic and gastrointestinal function in infants. The present study provides an evidence of equivalence in acute diarrhoea in comparison with earlier studies.
In conclusion, the present study confirms that L. reuteri DSM 17938, as the parental strain ATCC 55730, is efficacious and safe alongside with rehydration therapy, shortening the duration and reducing stool frequency in acute infectious diarrhoea in young children.