Probiotics for people with cystic fibrosis
Information
- DOI:
- https://doi.org/10.1002/14651858.CD012949.pub2Copy DOI
- Database:
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- Cochrane Database of Systematic Reviews
- Version published:
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- 22 January 2020see what's new
- Type:
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- Intervention
- Stage:
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- Review
- Cochrane Editorial Group:
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Cochrane Cystic Fibrosis and Genetic Disorders Group
- Copyright:
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- Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Authors
Contributions of authors
Protocol 2017
Dr Michael J. Coffey (MC) designed the review and drafted the protocol. Millie Garg (MG), Dr Nusrat Homaira (NH) and Professor Adam Jaffe (AJ) all revised the protocol. Dr Chee Y. Ooi (CO) conceived the study and revised the protocol.
| Roles and Responsibilities | |
| Task | Author(s) responsible |
| Protocol stage: draft the protocol | MC, NH, AJ and CO |
| Review stage: select which trials to include (2 + 1 arbiter) | MC and MG with CO as arbiter |
| Review stage: extract data from trials (2 people) | MC and MG |
| Review stage: enter data into RevMan | MC |
| Review stage: carry out the analysis | MC and NH |
| Review stage: interpret the analysis | MC, NH, AJ and CO |
| Review stage: draft the final review | MC and CO |
| Review stage: review the final review | MC, MG, NH, AJ and CO |
| Update stage: update the review | MC and CO |
Sources of support
Internal sources
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No sources of support supplied
External sources
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National Institute for Health Research, UK.
This systematic review was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Cystic Fibrosis and Genetic Disorders Group.
Declarations of interest
Drs Chee Y. Ooi, Michael J. Coffey and Adam Jaffe are conducting an international, multicentre, double‐blind, randomised, placebo‐controlled trial on probiotics for infants and children with cystic fibrosis (Australian and New Zealand Clinical Trials Registry Number: ACTRN12616000797471).
Dr Chee Y. Ooi is a consultant for Vertex Pharmaceuticals Incorporated and a member of the advisory board for Evolution Health. Dr Adam Jaffe has received funding from Vertex Pharmaceuticals for membership to a medical advisory committee and an honorarium to host an educational event.
Millie Garg and Dr Nusrat Homaira have no known conflicts.
Acknowledgements
This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Cystic Fibrosis and Genetic Disorders Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.
We would like to acknowledge the support of Professor Katrina Williams and Cochrane Australia. We also acknowledge the support of the Sydney Children's Hospital Foundation, the Australian Government Department of Education and Training, and the staff at the School of Women's and Children's Health, Faculty of Medicine, University of New South Wales.
We would also like to thank the investigators on two trials for providing additional and unpublished information to improve the quality of this review (del Campo 2014; Van Biervliet 2018).
We would like to thank Nikki Jahnke and the Cochrane Cystic Fibrosis and Genetic Disorders Group for their help and support of this review.
Version history
| Published | Title | Stage | Authors | Version |
| 2020 Jan 22 | Probiotics for people with cystic fibrosis | Review | Michael J Coffey, Millie Garg, Nusrat Homaira, Adam Jaffe, Chee Y Ooi | |
| 2018 Feb 12 | Probiotics for people with cystic fibrosis | Protocol | Michael J Coffey, Millie Garg, Nusrat Homaira, Adam Jaffe, Chee Y Ooi | |
Differences between protocol and review
The only difference between the protocol and review was the handling of missing standard deviations (SDs). Missing SDs for mean change from baseline results were imputed using a correlation coefficient calculated from another trial that presented means and SDs for change as well as for baseline and final measurements; these calculations were performed according to the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011c). If only the means and P value were available for a trial, the SDs were estimated using the RevMan Calculator (Finding standard deviations by using numbers calculated from between groups (Higgins 2011c).
Keywords
MeSH
Medical Subject Headings (MeSH) Keywords
Medical Subject Headings Check Words
Humans;
PICOs
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Comparison 1 Probiotic versus placebo, Outcome 1 Pulmonary exacerbation (mean number per participant).
Comparison 1 Probiotic versus placebo, Outcome 2 Pulmonary exacerbation (duration of antibiotic therapy ‐ any route).
Comparison 1 Probiotic versus placebo, Outcome 3 Faecal calprotectin (µg/g).
Comparison 1 Probiotic versus placebo, Outcome 4 Faecal calprotectin (µg/g) ‐ change from baseline ‐ sensitivity analysis.
Comparison 1 Probiotic versus placebo, Outcome 5 Faecal calprotectin (µg/g) ‐ post treatment ‐ sensitivity analysis.
Comparison 1 Probiotic versus placebo, Outcome 6 Serum cytokines.
Comparison 1 Probiotic versus placebo, Outcome 7 Sputum cytokines ‐ change from baseline.
Comparison 1 Probiotic versus placebo, Outcome 8 Adverse events.
Comparison 1 Probiotic versus placebo, Outcome 9 Height (z score) ‐ post treatment.
Comparison 1 Probiotic versus placebo, Outcome 10 Weight (z score) ‐ post treatment.
Comparison 1 Probiotic versus placebo, Outcome 11 Weight (kg) ‐ change from baseline.
Comparison 1 Probiotic versus placebo, Outcome 12 BMI (z score).
Comparison 1 Probiotic versus placebo, Outcome 13 Lung function (FEV1 % predicted).
Comparison 1 Probiotic versus placebo, Outcome 14 Lung function (FEV1 % predicted) ‐ change from baseline ‐ sensitivity analysis.
Comparison 1 Probiotic versus placebo, Outcome 15 Lung function (FEV1 % predicted) ‐ post treatment ‐ sensitivity analysis.
Comparison 1 Probiotic versus placebo, Outcome 16 Hospitalisations (number ‐ all causes).
Comparison 1 Probiotic versus placebo, Outcome 17 HRQoL (validated questionnaire).
| Probiotics compared to placebo for children and adults with CF | ||||||
| Patient or population: children and adults with CF | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | No. of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with probiotics | |||||
| Number of pulmonary exacerbations | The mean (range) number of pulmonary exacerbations in the placebo group was 1.42 (0.37 to 2.2) episodes per participant. | The mean number of pulmonary exacerbations in the probiotics group was 0.32 episodes per participant lower (0.68 lower to 0.03 higher). | NA | 225 | ⊕⊕⊝⊝ | Probiotics probably reduce pulmonary exacerbations (mean number per participant) slightly. |
| Faecal calprotectin | The mean (range) faecal calprotectin in the placebo group was 132.9 µg/g (67 µg/g to 182.1 µg/g). | The mean faecal calprotectin in the probiotics group was 47.4 µg/g lower (93.28 lower to 1.54 lower). | NA | 177 | ⊕⊕⊝⊝ | Probiotics result in a reduction in faecal calprotectin. |
| Adverse events (serious adverse reaction and adverse reaction) | There were 0 adverse events in the placebo group. | There were 4 adverse events in the probiotics group. | RR 3.00 | 310 | ⊕⊕⊝⊝ | Probiotics result in a small number of adverse events. The terminated RCT reported a serious adverse event (severe urticaria) in 1 participant on probiotics. No mortalities were reported in any included RCTs. |
| Weight (z score) | The mean (range) weight (z score) in the placebo group was ‐1.2 (‐1.79 to ‐0.81). | The mean weight (z score) in the probiotics group was0.24 SD lower (0.52 lower to 0.05 higher). | NA | 91 | ⊕⊕⊝⊝ | Insufficient evidence to determine if probiotics result in little to no difference in weight. A third RCT (n = 38) reported weight in kg and also reported no significant difference in weight. |
| Lung function (FEV1 % predicted) | The mean (range) FEV1 (% predicted) in the placebo group was 84.8% (52.7% to 104%) | The mean FEV1 (% predicted) in the probiotics group was 1.36% higher (1.20 lower to 3.91 higher). | NA | 284 | ⊕⊕⊝⊝ | Insufficient evidence to determine if probiotics result in little to no difference in lung function (FEV1 % predicted). |
| Hospitalisations (all causes) | The mean number of hospitalisations (all causes) in the placebo group was 0.53 admissions per participant. | The mean number of hospitalisations in the probiotics group was 0.44 admissions per participant lower (1.41 lower to 0.54 higher). | NA | 115 | ⊕⊕⊝⊝ | Insufficient evidence to determine if probiotics result in little to no difference in hospitalisation rates. |
| HRQoL (PedsQLTM 4.0 SF 15 (Scale from: 0 to 100)) | The mean HRQoL score from the PedsQLTM 4.0 SF 15 ‐ Parent Report in the placebo group was 81.4. | The standardised mean HRQoL score from the PedsQLTM 4.0 SF 15 ‐ Parent Report in the probiotics group was 0.87 SD higher (0.19 higher to 1.55 higher). | NA | 37 | ⊕⊕⊝⊝ | Insufficient evidence to determine if probiotics result in a small effect in HRQoL. |
| The mean HRQoL score from the PedsQLTM 4.0 SF 15 ‐ Child Report in the placebo group was 85.9. | The standardised mean HRQoL score from the PedsQLTM 4.0 SF 15 ‐ Child Report in the probiotics group was 0.59 SD higher (0.07 lower to 1.26 higher). | NA | 37 | ⊕⊕⊝⊝ | Insufficient evidence to determine if probiotics result in a small effect in HRQoL. | |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| a Downgraded once due to high risk of bias due to selective reporting. b Downgraded due to high risk of bias due to incomplete outcome data. c Downgraded due to lack of generalisability as majority of the studies only include children. d Downgraded due to high risk of bias due to blinding. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Pulmonary exacerbation (mean number per participant) Show forest plot | 4 | 225 | Mean Difference (IV, Random, 95% CI) | ‐0.32 [‐0.68, 0.03] |
| 1.1 Over 3 months and up to 6 months | 3 | 148 | Mean Difference (IV, Random, 95% CI) | ‐0.39 [‐0.80, 0.02] |
| 1.2 Over 9 months and up to 12 months | 1 | 77 | Mean Difference (IV, Random, 95% CI) | 0.10 [‐0.75, 0.95] |
| 2 Pulmonary exacerbation (duration of antibiotic therapy ‐ any route) Show forest plot | 2 | 127 | Mean Difference (IV, Random, 95% CI) | ‐0.45 [‐9.04, 8.14] |
| 2.1 Over 3 months and up to 6 months | 1 | 50 | Mean Difference (IV, Random, 95% CI) | ‐2.0 [‐12.89, 8.89] |
| 2.2 Over 9 months and up to 12 months | 1 | 77 | Mean Difference (IV, Random, 95% CI) | 2.10 [‐11.88, 16.08] |
| 3 Faecal calprotectin (µg/g) Show forest plot | 4 | 177 | Mean Difference (IV, Random, 95% CI) | ‐47.41 [‐93.28, ‐1.54] |
| 3.1 Up to 3 months | 2 | 69 | Mean Difference (IV, Random, 95% CI) | ‐105.02 [‐205.23, ‐4.81] |
| 3.2 Over 3 months and up to 6 months | 2 | 108 | Mean Difference (IV, Random, 95% CI) | ‐32.14 [‐83.73, 19.45] |
| 4 Faecal calprotectin (µg/g) ‐ change from baseline ‐ sensitivity analysis Show forest plot | 3 | 130 | Mean Difference (IV, Random, 95% CI) | ‐31.17 [‐81.56, 19.22] |
| 4.1 Up to 3 months | 1 | 22 | Mean Difference (IV, Random, 95% CI) | ‐11.0 [‐246.06, 224.06] |
| 4.2 Over 3 months and up to 6 months | 2 | 108 | Mean Difference (IV, Random, 95% CI) | ‐32.14 [‐83.73, 19.45] |
| 5 Faecal calprotectin (µg/g) ‐ post treatment ‐ sensitivity analysis Show forest plot | 3 | 119 | Mean Difference (IV, Random, 95% CI) | ‐45.46 [‐176.25, 85.32] |
| 5.1 Up to 3 months | 2 | 69 | Mean Difference (IV, Random, 95% CI) | ‐107.29 [‐171.20, ‐43.38] |
| 5.2 Over 3 months and up to 6 months | 1 | 50 | Mean Difference (IV, Random, 95% CI) | 77.0 [3.11, 150.89] |
| 6 Serum cytokines Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 6.1 TNF‐α (pg/ml) | 2 | 89 | Mean Difference (IV, Random, 95% CI) | 0.20 [‐0.72, 1.13] |
| 6.2 IL‐8 (pg/ml) | 2 | 95 | Mean Difference (IV, Random, 95% CI) | 26.93 [‐46.25, 100.11] |
| 6.3 IL‐1β (pg/ml) | 1 | 41 | Mean Difference (IV, Random, 95% CI) | 0.30 [‐0.28, 0.88] |
| 6.4 IL‐6 (pg/ml) | 1 | 41 | Mean Difference (IV, Random, 95% CI) | ‐0.29 [‐0.68, 0.10] |
| 6.5 IL‐10 (pg/ml) | 1 | 41 | Mean Difference (IV, Random, 95% CI) | ‐0.05 [‐0.43, 0.33] |
| 6.6 NOx (μmol/L) | 1 | 41 | Mean Difference (IV, Random, 95% CI) | 0.08 [‐0.26, 0.42] |
| 6.7 IL‐12 (pg/ml) | 1 | 41 | Mean Difference (IV, Random, 95% CI) | 0.53 [0.10, 0.96] |
| 6.8 MPO (mU/ml) | 1 | 41 | Mean Difference (IV, Random, 95% CI) | 0.05 [‐0.14, 0.24] |
| 7 Sputum cytokines ‐ change from baseline Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 7.1 TNF‐α (pg/ml) | 1 | 48 | Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐0.94, 0.54] |
| 7.2 IL‐8 (pg/ml) | 1 | 54 | Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐0.92, 0.52] |
| 8 Adverse events Show forest plot | 5 | Risk Ratio (IV, Random, 95% CI) | Subtotals only | |
| 8.1 Mortality (all causes) | 5 | 310 | Risk Ratio (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 8.2 Serious adverse reaction | 5 | 310 | Risk Ratio (IV, Random, 95% CI) | 3.0 [0.13, 67.06] |
| 8.3 Adverse reaction | 5 | 310 | Risk Ratio (IV, Random, 95% CI) | 3.0 [0.49, 18.46] |
| 9 Height (z score) ‐ post treatment Show forest plot | 2 | 91 | Mean Difference (IV, Random, 95% CI) | 0.10 [‐0.27, 0.47] |
| 9.1 Up to 3 months | 1 | 41 | Mean Difference (IV, Random, 95% CI) | 0.21 [‐0.62, 1.04] |
| 9.2 Over 3 months and up to 6 months | 1 | 50 | Mean Difference (IV, Random, 95% CI) | 0.07 [‐0.34, 0.48] |
| 10 Weight (z score) ‐ post treatment Show forest plot | 2 | 91 | Mean Difference (IV, Random, 95% CI) | ‐0.23 [‐0.51, 0.05] |
| 10.1 Up to 3 months | 1 | 41 | Mean Difference (IV, Random, 95% CI) | ‐0.4 [‐0.70, ‐0.10] |
| 10.2 Over 3 months and up to 6 months | 1 | 50 | Mean Difference (IV, Random, 95% CI) | ‐0.11 [‐0.30, 0.08] |
| 11 Weight (kg) ‐ change from baseline Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 11.1 Over 3 months and up to 6 months | 1 | 38 | Mean Difference (IV, Random, 95% CI) | 1.2 [‐0.04, 2.44] |
| 12 BMI (z score) Show forest plot | 2 | 91 | Mean Difference (IV, Random, 95% CI) | ‐0.02 [‐0.25, 0.22] |
| 12.1 Up to 3 months | 1 | 41 | Mean Difference (IV, Random, 95% CI) | ‐0.11 [‐0.54, 0.32] |
| 12.2 Over 3 months and up to 6 months | 1 | 50 | Mean Difference (IV, Random, 95% CI) | 0.02 [‐0.26, 0.31] |
| 13 Lung function (FEV1 % predicted) Show forest plot | 5 | 284 | Mean Difference (IV, Random, 95% CI) | 1.36 [‐1.20, 3.91] |
| 13.1 Up to 3 months | 1 | 41 | Mean Difference (IV, Random, 95% CI) | ‐8.07 [‐19.87, 3.73] |
| 13.2 Over 3 months and up to 6 months | 3 | 166 | Mean Difference (IV, Random, 95% CI) | 2.22 [‐0.51, 4.94] |
| 13.3 Over 9 months and up to 12 months | 1 | 77 | Mean Difference (IV, Random, 95% CI) | ‐2.80 [‐12.13, 6.53] |
| 14 Lung function (FEV1 % predicted) ‐ change from baseline ‐ sensitivity analysis Show forest plot | 3 | 166 | Mean Difference (IV, Random, 95% CI) | 2.22 [‐0.51, 4.94] |
| 14.1 Over 3 months and up to 6 months | 3 | 166 | Mean Difference (IV, Random, 95% CI) | 2.22 [‐0.51, 4.94] |
| 15 Lung function (FEV1 % predicted) ‐ post treatment ‐ sensitivity analysis Show forest plot | 3 | 168 | Mean Difference (IV, Random, 95% CI) | ‐1.31 [‐7.10, 4.48] |
| 15.1 Up to 3 months | 1 | 41 | Mean Difference (IV, Random, 95% CI) | ‐1.40 [‐14.48, 11.68] |
| 15.2 Over 3 months and up to 6 months | 1 | 50 | Mean Difference (IV, Random, 95% CI) | 0.10 [‐8.85, 9.05] |
| 15.3 Over 9 months and up to 12 months | 1 | 77 | Mean Difference (IV, Random, 95% CI) | ‐2.80 [‐12.13, 6.53] |
| 16 Hospitalisations (number ‐ all causes) Show forest plot | 2 | 115 | Mean Difference (IV, Random, 95% CI) | ‐0.44 [‐1.41, 0.54] |
| 16.1 Over 3 months and up to 6 months | 1 | 38 | Mean Difference (IV, Random, 95% CI) | ‐1.0 [‐1.74, ‐0.26] |
| 16.2 Over 9 months and up to 12 months | 1 | 77 | Mean Difference (IV, Random, 95% CI) | 0.0 [‐0.25, 0.25] |
| 17 HRQoL (validated questionnaire) Show forest plot | 1 | Std. Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 17.1 PedsQLTM 4.0 SF 15 ‐ Parent Report (performed 3 months post 1 month intervention period) | 1 | 37 | Std. Mean Difference (IV, Random, 95% CI) | 0.87 [0.19, 1.55] |
| 17.2 PedsQLTM 4.0 SF 15 ‐ Child Report (performed 3 months post 1 month intervention period) | 1 | 37 | Std. Mean Difference (IV, Random, 95% CI) | 0.59 [‐0.07, 1.26] |
