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25th May 2022
A probiotic mixture given to preschool children suffering from wheeze resulted in a significant reduction in the number of episodes over a 16 week period, according to the findings of a subgroup analysis of data by Italian researchers.
Wheezing is a musical sound, high-pitched and continuous, emitting from the chest during breath exhalation. It is not a specific disorder, but rather a symptom with the two most common causes in young children being bronchiolitis and asthma. Wheeze is a relatively common with one study of over a million preschool children, finding a prevalence of 7.7%. Almost 50% of children experiences wheeze in the first 6 years of life but only 40% of these will continue to experience the condition after childhood.
Increasingly, research suggests an important link between viral infections and the microbiome, which is increasingly recognised as a significant player in the host immune system, influencing immunity and host defence mechanisms. Moreover, there appears to be a link between the respiratory microbiota in early life and an increased risk and frequency of subsequent respiratory infections, and occurrence of wheeze in later childhood. Furthermore, there is mounting evidence to suggest that probiotics containing Lactobacillus rhamnosus GG modestly reduces the duration of respiratory tract infections in children.
As a result, the Italian team wondered if probiotics could reduce the level of wheeze experienced by young children. In trying to answer this, they turned to a subgroup of patients included in the PRObiotics in Pediatric Management (PROPAM) trial. This randomised, double-blind, placebo-controlled trial, was designed to explore the potential role of probiotics in reducing wheeze episodes and asthma exacerbations in children. For the present analysis, the team focused on children between the ages of 3 and 6 years and who had with a history of persistent wheeze (> 3 episodes in their lifetime) but who were not diagnosed with asthma. The children were randomised 1:1, to either a probiotic mixture or placebo and which was taken twice daily for a total of 8 weeks and then once daily for a further 8 weeks. The mixture contained live cells of B. breve B632 and L. salivarius LS01 and the primary outcome of interest was a reduction in the number of wheezing episodes.
Probiotic mixture and wheeze episodes
A total of 160 children with a mean age of 4.3 years (42.5% female) were included, of whom, 64.4% had a family history of atopy. At the end of the study, children taking the probiotic mixture were significantly less likely to experience one wheezing episode compared to those assigned to placebo (odds ratio, OR = 0.42, 95% CI 0.18 – 0.95, p = 0.037). In addition, a higher proportion of those using the probiotic mixture experienced no wheezing episodes (87.6% vs 74.6%, probiotic vs placebo). However, the mean duration of wheezing episodes was not significantly different (3.7 vs 4.1 days, p = 0.58, probiotic vs placebo). Interestingly, children taking the probiotic mixture used inhaled corticosteroids less frequently (40% vs 56.5%, p < 0.05).
The authors concluded that the probiotic mixture may prevent wheezing episodes in preschool children and that it was safe and well tolerated.
Ciprandi G et al. The PRObiotics in Pediatric Asthma Management (PROPAM) study: A post hoc analysis in preschoolers Pediatr Pulmonol 2022
10th February 2022
Addition of probiotics to oral peanut immunotherapy does not lead to a meaningful increase in the proportion of children achieving clinical remission but may reduce the gastrointestinal symptom burden. This was the conclusion of a randomised trial by researchers from the Murdoch Children’s Research Institute, Victoria, Australia.
In a study of 2848 infants, the prevalence of any sensitisation to peanut was 8.9% and there is accumulating evidence that peanut oral immunotherapy (OIT) is effective at inducing desensitisation through down-regulation of effector pathways in the allergic reaction cascade. With some evidence that ingestion of probiotic bacteria strains have anti-inflammatory properties in children with atopic eczema, the Australian team wanted to examine the additional benefit of probiotics with OIT as a means of improving clinical remission of peanut allergy. The same team had already showed that the combination of probiotics with peanut OIT was effective in inducing sustained unresponsiveness in children with a peanut allergy but their study did not employ a peanut OIT only arm and therefore it was not possible to determine the incremental benefit of probiotics compared to OIT alone.
For the present study, the Australian team included an OIT arm in addition of the probiotics and OIT group and sought to determine if adding a probiotic induced a higher level of sustained unresponsiveness (i.e., clinical remission) compared to peanut OIT alone. They undertook a multi-centre, randomised trial, the PPOIT-003 study, in children aged 1 to 10 years of age with a confirmed peanut allergy. The participants were randomised 2:2:1 to receive probiotics and peanut OIT (PP0IT group), OIT alone or placebo for a period of 18 months and were then followed-up after completion of treatment. Oral immunotherapy was gradually increased until a 2000 mg daily maintenance dose was reached and tolerated. They set the primary outcome as the proportion of participants with an 8-week sustained unresponsiveness, which was defined as passing both food challenges (i.e., no reaction) to a cumulative dose of 4950 mg of peanut protein, at both completion of treatment (i.e., 18 months) and 8 weeks after cessation of treatment.
Probiotics and sustained unresponsiveness
A total of 201 children with a mean age of 5.9 years (64% male) were randomised to PPOIT (79), OIT (83) or placebo.
A sustained unresponsiveness (i.e., remission) was achieved by 46% of those in the PPOIT group, 51% of the OIT group and 5% of those given placebo. This gave a rise difference of 40.4% (95% CI 27.4 – 53.4, p < 0.0001) for PPOIT vs placebo and and -5.03% (95% CI -20.4 – 10.34, p = 0.52) for the PPOIT vs OIT groups. In other words, there was no significant difference between the PPOIT and the OIT groups.
The researchers then assessed the exposure-adjusted incidence rate of adverse effects, which is a better measure of the burden of adverse effects, since it takes account of differences in the follow-up duration between treatment groups. Using this measure, the incidence was significantly lower in the PPOIT group compared to the OIT group (p = 0.042). This was seen for the incidence of abdominal pain, vomiting and allergic cough, allergic respiratory and respiratory adverse events.
The authors concluded that while addition of probiotics to the OIT had no noticeable effect on the level of sustained unresponsiveness, it did appear to reduce the burden of gastrointestinal symptoms and systemic reactions. They called for future studies to confirm this preliminary findings.
Lake P et al. Probiotic peanut oral immunotherapy versus oral immunotherapy and placebo in children with peanut allergy in Australia (PPOIT-003): a multicentre, randomised, phase 2b trial Lancet Child Adolesc Health 2022
27th September 2021
The gut microbiota refers to the community of bacterial species within the intestines and plays an important role in the overall health of the host. With approximately 100 trillion micro-organisms, the gut microbiota can be thought of as a virtual organ of the body that impacts on immune, metabolic and neurobehavioral traits. This wide range of effects on the host’s health are thought to be mediated by short-chain fatty acids (SCFAs), the main metabolic products of gut micro-organisms from the fermentation of dietary fibres and resistant starches.
Alterations in the gut flora are thought to be the main reason for diarrhoea, which is a common side-effect of antibiotics. One way of minimising antibiotic-induced diarrhoea is through the use of probiotics and in a 2017 systemic review, the pooled incidence diarrhoea was reduced to 8% in those using probiotics compared to 17.7% in the control group. However, what is less clear, is the impact of a probiotic on faecal levels of SCFAs and whether the use of probiotics alongside antibiotics can mitigate the changes in gut microbiota following a course of antibiotic treatment.
This was the question posed by a team from the Department of Family Medicine, Georgetown University Medical Centre, Washington, US. They set out to determine whether a yogurt containing the probiotic, Bifidobacterium animalis subsp. Lactis BB-12 (BB-12), could protect against the antibiotic-induced disruptions in both faecal SCFAs levels and gut microbiota composition. The undertook a randomised, controlled trial, in all participants received a 7-day course of amoxicillin-clavulanate 875 mg twice daily. The intervention group received a 14-day supply of a probiotic yogurt with BB-12 and the other group a control yogurt although participants were blinded to which yogurt they received. Faecal samples were collected and analysed for SCFAs and gut microbiota composition at baseline and then after 7, 14, 21 and 30 days. The primary measure of interest was changes in the level of the SCFA, acetate.
A total of 56 individuals with a mean age of 29.4 years (gender was not reported) were randomised in a 2:1 fashion to either BB-12 yogurt (38) or control. There was a significant decrease in the primary measure following administration of the antibiotics of 20.3% on day 7 in the control group. In contrast, in the BB-12 group, the corresponding reduction was lower at 15.6%. However, by day 30, acetate levels in the control group were still 25.1% lower than baseline values but only 1.6% lower in the BB-12 group. Using a measure of gut microbiota diversity, the authors found that at days 21 and 30, there was a greater decrease in diversity in the control compared to the BB-12 group.
From the participant perspective, by day 7, 42% of the control group reported at least one day of loose stools compared to 26% in the BB-12 group.
The authors concluded that concurrent administration of BB-12 with antibiotics was associated with a significantly smaller decrease in faecal SCFA levels and a more stable gut microbiota over time compared to a control yogurt.
Merenstein D et al. Bifidobacterium animalis subsp. lactis BB-12 Protects against Antibiotic-Induced Functional and Compositional Changes in Human Fecal Microbiome. Nutrients 2021
31st August 2021
Atopic eczema (AE) affects between 15 and 20% of children. Although at the present time the cause remains uncertain, immune dysfunction characterised by over-production of interleukins, is clearly involved as evidenced by the effectiveness of dupilumab, which targets interleukin 4 and 13. One potential preventative therapy which has been explored in the use of probiotics, which are live micro-organisms that have been shown to reduce inflammation by suppression of various interleukins. Although there have been several reviews examining the effectiveness of probiotics in the prevention of atopic eczema, there has been heterogeneity in the findings.
This led a team from the Department of Clinical Epidemiology, University of the Philippines, Manila, Philippines, to perform a network meta-analysis to synthesize the available evidence and compare different probiotics products in the prevention of AE. The use of a network meta-analysis offer advantages over a standard meta-analysis in that the former allows for a pairwise comparison of probiotics that have not been directly compared in studies. The team included studies with patients deemed to be at high-risk of developing AE, in particular those in which a family member already had allergic disease. They considered the oral administration of any probiotic strain or mixture of strains and also included studies in which probiotics were given to mothers during pregnancy. The primary outcome of interest was the prevention of AE and the secondary outcome of interest was the presence or absence of adverse effects.
A total of 35 studies were included, 14 of which were follow-ups of completed randomised controlled trials, using 15 different probiotics mixtures and 5406 children diagnosed with AE. There were only three probiotic mixtures that appeared to reduce the risk of developing AE compared to placebo, based on the 95% confidence intervals not crossing the line of no-effect. These mixtures were Mix8, Mix3 and Mix6. Compared to placebo, Mix8 reduced the risk of developing AE by 54% (relative risk, RR = 0.46, 95% CI 0.25 – 0.85), Mix3 by 50% (RR = 0.50, 95% CI 0.27 – 0.94) and Mix6 by 42% (RR = 0.58, 95% CI 0.37 – 0.92). In subgroup analysis, 8 studies compared administration of probiotics prenatally to pregnant women and postnatally to infants. However, pairwise comparisons were not statistically significant, suggesting no real effect. There was no evidence of any adverse effects from the use of probiotics although the wide confidence intervals for the relative risks precluded any definitive conclusions.
Commenting on their findings, the authors indicated that the data did suggest a possible beneficial effect from the use of some probiotics in preventing the development of AE. They also noted that it was probiotic mixtures that seemed to be most effective and speculated that there was a likely synergistic effect between the individual probiotic species. However, they concluded that based on the available data, it was not possible to determine the optimum timing, dose or duration of probiotics for a maximal effect.
Tan-Lim CSC et al. Comparative effectiveness of probiotic strains on the prevention of pediatric atopic dermatitis: A systematic review and network meta-analysis. Pediatr Allergy Immunol 2021
6th July 2021
The British Society of Gastroenterology (BSG) has revised its 2007 guidelines on the management of irritable bowel syndrome (IBS). The latest guidance covers all aspects of the condition ranging from initial assessment and management through to secondary care referral and any subsequent investigations that should be undertaken within that setting. The guideline makes reference to the revised diagnostic Rome IV criteria produced in 2016 and notes that while the criteria are an improvement on the earlier Rome III, the revision is perhaps more restrictive and calls into question whether these latest changes can be used to diagnose irritable bowel syndrome. The BSG therefore suggests that a more pragmatic definition of the condition is provided by NICE which states that the diagnosis should be considered only if the person has abdominal pain or discomfort that is either relieved by defecation or associated with altered bowel frequency or stool form. Furthermore, the BSG guidance recommends that all patients with IBS symptoms should have a full blood count, C-reactive protein or erythrocyte sedimentation rate, coeliac serology and that clinicians should discuss the underlying diagnosis, its causes and natural history to the patients. The guidance, while accepting a limited evidence-base, advises that all patients should take regular exercise and that soluble fibre is an effective treatment for global symptoms and abdominal pain. In contrast, it recommends against the use of insoluble fibre (e.g., wheat bran) as this might exacerbate symptoms.
Medical treatments endorsed for irritable bowel syndrome include loperamide, especially where IBS is associated with diarrhoea, antispasmodics and peppermint oil and polyethylene glycol for associated constipation. Where there is uncertainty over the diagnosis or if symptoms are refractory, a referral should be made to secondary care. Several second-line therapies including tricyclic antidepressants, selective serotonin re-uptake inhibitors, linaclotide, lubiprostone and plecanatide. There is also a discussion of new and emerging treatments together with a recognition of the value of cognitive behavioural therapy, gut-directed hypnotherapy and general psychological therapies.
One area new to the guideline is the acknowledgement of a potential pathological role of an altered microbiome and which has led to interest in the use of probiotics as a potential treatment for IBS. For the guideline, the authors updated a 2018 meta-analysis on the efficacy of probiotics and found that compared to placebo, a combination of probiotics, had a significant effect on global symptoms or abdominal pain (relative risk, RR = 0.79, 95% CI 0.70–0.89). This effect was also significant for individual species including lactobacillus, Bifidobacterium and Escherichia. Based on these data, the guidance recommended that patients wishing to use probiotics should take them for up to 3 months to assess the potential benefit.
The guideline concludes that irritable bowel syndrome is a multifactorial disorder that requires a positive diagnosis and the implementation of both non- and pharmacological therapy to improve symptoms and quality of life.
Vasant DH et al. British Society of Gastroenterology guidelines on the management of irritable bowel syndrome. BMJ 2021