Abstract: We identified 17 trials and included 12 RCTs (11 completed and one trial protocol - this trial was terminated early) (464 participants). Eight trials included only children, whilst four trials included both children and adults. Trial duration ranged from one to 12 months. Nine trials compared a probiotic (seven single strain and three multistrain preparations) with a placebo preparation, two trials compared a synbiotic (multistrain) with a placebo preparation and one trial compared two probiotic preparations. Overall we judged the risk of bias in the 12 trials to be low. Three trials had a high risk of performance bias, two trials a high risk of attrition bias and six trials a high risk of reporting bias. Only two trials were judged to have low or unclear risk of bias for all domains. Four trials were sponsored by grants only, two trials by industry only, two trials by both grants and industry and three trials had an unknown funding source. Combined data from four trials (225 participants) suggested probiotics may reduce the number of pulmonary exacerbations during a four to 12 month time-frame, mean difference (MD) -0.32 episodes per participant (95% confidence interval (CI) -0.68 to 0.03; P = 0.07) (low-certainty evidence); however, the 95% CI includes the possibility of both an increased and a reduced number of exacerbations. Additionally, two trials (127 participants) found no evidence of an effect on the duration of antibiotic therapy during the same time period. Combined data from four trials (177 participants) demonstrated probiotics may reduce faecal calprotectin, MD -47.4 µg/g (95% CI -93.28 to -1.54; P = 0.04) (low-certainty evidence), but the results for other biomarkers mainly did not show any difference between probiotics and placebo. Two trials (91 participants) found no evidence of effect on height, weight or body mass index (low-certainty evidence). Combined data from five trials (284 participants) suggested there was no difference in lung function (forced expiratory volume at one second (FEV1) % predicted) during a three- to 12-month time frame, MD 1.36% (95% CI -1.20 to 3.91; P = 0.30) (low-certainty evidence). Combined data from two trials (115 participants) suggested there was no difference in hospitalisation rates during a three- to 12-month time frame, MD -0.44 admissions per participant (95% CI -1.41 to 0.54; P = 0.38) (low-certainty evidence). One trial (37 participants) reported health-related quality of life and while the parent report favoured probiotics, SMD 0.87 (95% CI 0.19 to 1.55) the child self-report did not identify any effect, SMD 0.59 (95% CI -0.07 to 1.26) (low-certainty evidence). There were limited results for gastrointestinal symptoms and intestinal microbial profile which were not analysable. Only four trials and one trial protocol (298 participants) reported adverse events as a priori hypotheses. No trials reported any deaths. One terminated trial (12 participants and available as a protocol only) reported a severe allergic reaction (severe urticaria) for one participant in the probiotic group. Two trials reported a single adverse event each (vomiting in one child and diarrhoea in one child). The estimated number needed to harm for any adverse reaction (serious or not) is 52 people (low-certainty evidence). Probiotics significantly reduce faecal calprotectin (a marker of intestinal inflammation) in children and adults with CF, however the clinical implications of this require further investigation. Probiotics may make little or no difference to pulmonary exacerbation rates, however, further evidence is required before firm conclusions can be made. Probiotics are associated with a small number of adverse events including vomiting, diarrhoea and allergic reactions. In children and adults with CF, probiotics may be considered by patients and their healthcare providers. Given the variability of probiotic composition and dosage, further adequately-powered multicentre RCTs of at least 12 months duration are required to best assess the efficacy and safety of probiotics for children and adults with CF.

Plain-language summary: The review included 12 randomised controlled trials (11 completed and one trial protocol (plan) - this trial was terminated early but reported some results on side effects) with 464 people with cystic fibrosis. Eight trials included only children, whilst four trials included both children and adults. The trials lasted between one and 12 months. Eight trials used a probiotic with a single type of bacteria and four trials used a probiotic with two or more types of bacteria. Only one trial compared different bacteria and the others compared probiotics to a placebo (dummy treatment with no active medication). Probiotics may reduce the rate of pulmonary exacerbations, however, this is not definite; pulmonary exacerbations are events where breathing symptoms are worsened (e.g. increased cough, sputum or shortness of breath) and lung function declines. Probiotics may reduce a marker of gut inflammation called calprotectin, however, the benefit of this to an individual is unknown. There were no differences between probiotics and placebo for height, weight or body mass index (BMI). Results did not show that probiotics affect lung function, need for admission to hospital or abdominal symptoms. One small trial measured quality of life and the parents questionnaire favoured probiotics, but the children's self report did not show a difference between probiotics and placebo. Probiotics may cause vomiting, diarrhoea and allergic reactions. We estimate 52 people need to take probiotics for one person to have an adverse event. We could not analyse the results of the trial comparing different probiotics because of its design. Future trials should look into the use of probiotics for at least 12 months and assess measures of lung and gut health, growth, abdominal symptoms, quality of life and adverse events. Given the wide range or probiotics (single and multi-strain combinations), doses used and degree of effectiveness, determining the best regimen(s) to investigate further will be challenging. There were several issues with the overall certainty of the evidence which affects our confidence in the results from these trials. We think the fact that some participants did not complete their treatment or were not included in the reports may affect the results on weight. We think the fact that not all planned outcomes were reported in four trials may affect the results of intestinal inflammation, growth and abdominal symptoms. We think the fact that the pharmaceutical industry sponsored at least four of the trials should be considered when looking at the results of this review. As most trials only included children we are not certain that the results would also apply to adults and there were also some issues related to whether people taking part in the trial knew which treatment they were receiving. We judged the certainty of evidence for changes in pulmonary exacerbations, intestinal inflammation, lung function, hospital admissions, weight and health-related quality of life to be low. Adverse events were only recorded by four trials and the protocol for the terminated trial and the certainty of the evidence was also judged to be low.