In canine acute diarrhoea with no identifiable cause, does daily oral probiotic improve the clinical outcomes?

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They were recruited from the Clinic of Small Animal Medicine at University of Munich, from Oct 2013 to Mar 2015.
Dogs were excluded if they had: -drug treatment that might cause mucosal irritation -antibiotic treatment before diarrhoea or during hospitalisation -parasite or parvovirus infection -pancreatitis Sample size: 84 dogs were recruited. 59 dogs were excluded due to the above mentioned reasons or the refusal to participate. 25 dogs completed the study. Signalment (age, breed, weight and sex) was comparable between probiotic and placebo group. Experimental setup: -probiotic treatment was mixed with food for appetent dogs -probiotic was diluted in water and administered with 5 mL syringe for anorexic dogs -probiotic was fed every 24 hours for 21 days -gastrointestinal diet (Royal Canin) was fed to all dogs -canine haemorrhagic diarrhoea severity index (CHDSI) was measured from day 0 to day 8 -dogs were discharged if CHDSI was < 2 -faecal samples were collected on day 0, 7  Outcome studied: 1. CHDSI -It was assessed by the owners at home or clinicians during hospitalisation -Six parameters: • activity • appetite • vomiting • faecal consistency • defaecation frequency • blood admixture in stool -A score from 0 (normal) to 3 (severe) was given to each parameter -Cumulative score: • < 3: clinically insignificant • 4-5: mild presentation • 6-8: moderate presentation • ≥ 9: severe presentation • the maximum possible score was 18 -The score on each day was compared to the baseline (day 0) -The study measured the number of days taken for a statistically significant improvement (compared to its own baseline) in both groups 2. Faecal microbiota -The data was measured on day 0, 7 and 21 -Dysbiosis index -the abundance of seven bacteria: 2. Faecal microbiota -There was no significant difference in the dysbiosis index between the two groups. -The abundance of C. perfringens: • It was significantly lower (P=0.011) on day 7 in the probiotic group (mean: 5.80 logDNA/g faeces, SD: 1.15), compared to its own baseline (day 0) (mean: 6.98 logDNA/g faeces, SD: 1.17). • It was significantly lower (p < 0.05) on day 21 (mean: 4.79 logDNA/g faeces, SD: 1.41) in the probiotic group, compared to its own baseline (day 0). • Compared to its own baseline (day 0), there was no significant finding on day 7 and 21 in the placebo group.
-Enterotoxin expressing C. perfringens • On day 7, the percentage of dogs positive for enterotoxin expressing C. perfringens was not significantly different between the two groups • On day 7, both probiotic group (P=0.016) and placebo (P=0.016) had a lower abundance of enterotoxin gene in comparison to their own baseline † • On day 21, the abundance of enterotoxin gene was significantly lower in the probiotic group than placebo group (P=0.028) † • On day 21, the percentage of dogs positive for enterotoxin expressing C. perfringens was significantly lower (P=0.019) in the probiotic group (1/10, 10%) than the placebo group (5/8, 62.5%) -There was no significant difference between the two groups in the abundance of netF gene or the percentage of dogs positive for netF toxin expressing C. perfringens on day 7 and 21 † The data was not described here as the abundance of gene (log DNA) was presented graphically in the paper. The measure of variation was presented as error bars. Please refer to figure 4 of this paper for further detail.
Limitations: -CHDSI was evaluated by two groups of people with different knowledge backgrounds (i.e. clinicians and owners). It may have resulted in a different assessment -Risk of bias -one author received a travel fund from the probiotic provider (MENDES S.A.) to go to an international conference. Another author received a consultation fee from the probiotic manufacturer (ExeGi Pharma) -The authors did not explain the inconsistent number of faecal samples for microbiota analysis on days 0, 7 and 21. For instance, the number of faecal samples analysed on day 0, 7, and 21 in the placebo group was 10, 12 and 8 respectively -The dependent variable described in the abstract was different from the results of this paper. In the abstract, it was mentioned that a clinical recovery was observed on day 3 and day 4 in the probiotic and placebo group respectively. Yet, the study actually measured the number of days taken for a statistically significant improvement in CHDSI. A statistically significant improvement in CHDSI does not necessarily imply a clinical recovery (i.e. the mean score of the probiotic group on day 3 was 5.0, while score < 3 was classified as clinically irrelevant)
They were recruited from clinics in southern Finland.
Dogs were excluded if they had: -systemic illnesses -diarrhoea lasting ≥ 2 weeks -hypoproteinaemia -antibiotic or corticosteroid treatment 30 days prior to the trial -recurrent vomiting -Giardia infection -probiotic administration or new medication, other than the experimental probiotic product, during the study -veterinary visit for diarrhoea medications other than the experimental probiotic product during the study Sample size: 66 dogs were recruited. 44 dogs completed the study.
Intervention details: Probiotic group (n=25): -2 dL sour-milk probiotic product daily -2 x 10 9 cfu of each of the following strains: • Lactobacillus fermentum VET 9A • Lactobacillus rhamnosus VET 16A • Lactobacillus plantarum VET 14A -Owners might opt to split the daily probiotic treatment over two feeding times, or administer it in one feeding time Placebo group (n=19): -Sterilised water with 10% titanium (I.V) oxide (Sigma-Aldrich, Finland) Experiment set-up: -The participants visited one of the five study clinics in southern Finland to receive the test product -The treatment period was 7 days, with a 6-month follow-up period -Treatment period: • The diet consisted of a low-fat protein source (e.g. chicken, fish) and rice • The participants visited the same vets on day 0 and day 7 • The vets filled in a questionnaire on the physical exam for each visit • Faecal samples were collected on day 0 and day 7 • The owners filled in a validated questionnaire (Roine, Uusitalo and Hielm-Björkman., 2016) on stool consistency each day -6-month follow-up period: • The dogs gradually returned to their normal diet • The owners filled in a questionnaire on recurrence of diarrhoea and other gastrointestinal signs, on day 14, 21, 28 and at 6 months Study design: Randomised, blinded, controlled trial 1. Stool consistency # -Compared to day 0, the mean score was reduced by 1.712 in the probiotic group and 1.279 in the placebo group on day 7. The difference was statistically significant (P=0.043) -During the first month post-treatment, the average reduction in the mean stool consistency score in the probiotic group was greater than the placebo group, with a difference of 0.271 (P=0.033) 2. Faecal microbiota # -The decrease in the number of C. perfringens alphatoxin producing strain (P=0.05) and E. faecium (P=0.032) was greater in the probiotic group than the placebo group, with statistical significance -The mean changes in the other bacteria from day 0 to day 7 were not statistically significant  The measure of variation was reported graphically as error bars in the paper. Please refer to figure 1 (stool consistency) and figure 2 (faecal microbiotia) for further detail. Limitations: -The paper did not evaluate the baseline variations in age, sex, breed and weight between the two groups -The administration frequency (once daily or split into two feedings) were not tightly controlled in this study -The author intended to collect data on day 14, 21, 28 and at 6 months to evaluate the diarrhoea recurrence and other gastrointestinal signs. However, no data at 6 months was presented -It was not explicitly clear on how the authors executed two of the exclusion criteria -i.e. how they kept track of whether the participants had veterinary visits for other diarrhoea medication, or received medications and probiotics other than the experimental product during the study
They were recruited from the small animal clinic at the Norwegian School of Veterinary Science.
Dogs were excluded if they: -had clinical signs for ≥ 2 weeks -received a probiotic 1 month before the trial -required supportive therapy during hospitalisation 2. There was no statistically significant difference between the probiotic (mean: 2.9 days, 95% CI: 2.1-3.7 days) and the placebo (mean: 3.4 days, 95% CI: 2.6-4.2 days) from day 0 to first normal stool 3. The number of stools was reduced in both groups during the first three days (P0.01). No descriptive data (e.g. the mean number of reduction and measure of variation) was provided. The difference between groups was not statistically significant Limitations: -The paper did not evaluate the baseline variation in age, sex, breed and weight between the two groups -In the evaluation of clinical signs before the trial, the number of respondents did not add up to 36 (sample size) in the categories of fever (n=29), appetite (n=34), change in diet (n=34), antiparasitic treatment (n=35), vaccination (n=35) and consumption of spoiled food (n=35). The author did not explain the inconsistent number of respondents -Single-centre study -Faecal analyses on parasite and Salmonella infection before the trial were not performed in 19 dogs and three dogs respectively -Nine dogs in the probiotic group and four dogs in the placebo group consumed spoiled food before the trial. This may complicate the aetiologies of the diarrhoea of the participating dogs -The paper did not state explicitly who were blinded in the trial. They received no prior treatment and were referred to vet clinics.
Sample size: 45 dogs were recruited and 31 dogs completed the study. Signalment (age, breed and weight) of the probiotic and placebo group was comparable.
Intervention details: Probiotic group (n=13): -Bifidobacterium animalis AHC7, 1 x 10 10 cfu/dose Placebo group (n=18): -Same vehicle as the probiotic without the bacterium Experiment setup -All dogs were screened for Giardia and intestinal parasite infection -All dogs routinely received ivermectin or pyrantel to control internal parasites -Treatment was administrated as a cocoa butter treat, twice daily -Treatment was administrated for a maximum of 2 weeks or until the resolution of diarrhoea -Both groups received Eukanuba or Iams maintenance diet -Trained kennel staff monitored the behaviour and recorded the stool score daily -The administration of metronidazole was based on the following considerations: -number of abnormal stools -degree of diarrhoea -overall health -risk of outbreak to the neighbouring dogs 1. A significantly shorter time (P<0.01) to diarrhoea resolution was observed in the probiotic group (mean ± SE: 3.9 ± 2.3 days) than the placebo group (6.6 ± 2.7 days) 2. A lower percentage of dogs in the probiotic group (5/13, 38.5%) received metronidazole than the placebo group (9/18, 50%

Limitations:
-Dogs were recruited from one organisation only -Only one probiotic bacterium was included in the study -No statistical analysis was performed on the different percentage of dogs receiving metronidazole between the two groups -No statistical analysis was performed on the different percentage of dogs (without metronidazole treatment) recovered on day 4 between the probiotic and placebo group -An error in data presentation was suspected in the main findings (see point 3). The number of dogs in the probiotic group should be eight instead of nine, after the exclusion of the five dogs receiving metronidazole -Three dogs were identified as Giardiasis positive during the study. They continued the study and their data was included -The stool scoring system was not validated as it had no reference -The definition of acute diarrhoea (i.e. the duration of diarrhoea) was not specified in this study -The use of cocoa butter is not recommended due to the risk of theobromine toxicity

Nixon et. al (2019)
Population: Dogs who had a faecal score of 5 or 6 (watery stool) for  one occasion within 24 hours before the veterinary visit. They were recruited from 11 units in the UK and three units in Ireland. Dogs were excluded if they: -had diarrhoea for  7 days -received antibiotic or probiotic treatment < 4 weeks before the start of the study -required additional treatments other than the feed supplement -had diarrhoea known to be secondary to other diseases (e.g. endocrine disease) or a surgical condition -Diarrhoea was resolved when the dogs had normal defaecation three times consecutively -Faeces with a consistency score  3 was defined as normal.
-The faecal consistency score was based on the Nestle-Purina scoring system -It ranged from 1 (firm) to 6 (watery) -Dogs withdrawn for additional medical treatments were censored from the analysis for the duration of diarrhoea 2. Rate of diarrhoea resolution -It measured the proportion of dogs with diarrhoea against time (hours) 3. Additional medical intervention -It measured the percentage of dogs withdrawn for the additional treatment Main findings: (relevant to PICO question): 1. The probiotic group (median: 32 hours, range: 2-118 hours, n=51) had a significantly shorter duration of diarrhoea (P=0.008) than the placebo group (median: 47 hours, range: 4-167 hours, n=58). The inter-quartile range was reported in the box plot (figure 3B of the paper) 2. Probiotic group had a 1.6 times faster rate of resolution than placebo group (P=0.02) 3. A significantly (P=0.04) lower percentage of dogs in the probiotic group (3.5%, 2/57) required additional medical treatments than the placebo group (14.8%, 9/61) Limitations: -Although dogs with diarrhoea secondary to other diseases or surgical conditions were excluded, the other causes of diarrhoea, such as viral and parasitic infection, were not investigated before the trial -Risk of bias -one author is employed by the probiotic manufacturing company (Protexin) -The number of dogs completed the study did not match with the number of dogs included in the analysis for the duration of diarrhoea. For instance, 52 dogs in the placebo group completed the study, and 58 dogs were involved in the analysis for the duration of diarrhoea