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Exercise versus airway clearance for people with cystic fibrosis.

Review question

Can exercise replace other methods of airway clearance for people with cystic fibrosis (CF)?

CF affects many systems in the body, mainly the respiratory system. It causes a build-up of thick, sticky mucus in the lungs which causes irritation and damage to the lining of the airways. CF treatment involves chest physiotherapy, also called airway clearance, which uses a range of devices or techniques to get rid of this mucus. It has been suggested that exercise may have a similar effect. Exercising results in a person taking different volumes and depths of breaths. This leads to pressure changes and forces within the airways that move secretions out of the lungs. We compared the effect on lung function of exercise versus other techniques, to see if exercise is a suitable alternative for people with CF. We wanted to answer our review question to potentially reduce their treatment burden.

Search date

The evidence is current to 15 February 2022.

Study characteristics

We searched the literature for studies where people received at least two treatment sessions of exercise or another airway clearance technique, and report on four studies including 86 people with CF in the review. The people in the studies were aged between 7 and 41 years and had varying degrees of disease severity. Three studies included people who were clinically well and one study included people admitted to hospital for a chest infection. The studies lasted between four days and six months and compared exercise (alone or in combination with another airway clearance technique) to other techniques. Two studies compared exercise with postural drainage and percussion (PD&P), one study compared exercise with the active cycle of breathing technique (ACBT) and one study compared exercise with underwater positive expiratory pressure (uPEP), also known as bubble PEP. Three studies received financial support from funding bodies such as the Cystic Fibrosis Trust, the Buffalo Foundation and the Romanian National Council for Scientific Research in Higher Education.

Key results

We did not find enough evidence to conclude whether or not exercise can replace other methods of airway clearance. We did not find any evidence to suggest that exercise was either better or worse than other methods to improve lung function or clear mucus from the airways, although exercising did improve people's exercise ability, and it was the preferred choice of treatment in one study. None of the studies reported any negative effects of exercise therapy. None of the studies evaluated quality of life or the need for extra antibiotic treatment. One study did suggest that exercise alone was less effective at clearing sputum than ACBT.

Exercise versus ACBT

One study (18 participants) found that a measure of lung function temporarily (up to 30 minutes) increased in the exercise group only, otherwise there was no difference between the ACBT or the exercise group. No adverse events were reported, and it is not certain if ACBT was thought to be more effective or was preferred. The exercise group produced less sputum than the ACBT group. The study did not report on exercise capacity, quality of life, adherence, hospitalisations and need for additional antibiotics.

Exercise plus PD&P versus PD&P alone

Two studies (55 participants) compared exercise plus PD&P to PD&P alone. At two weeks, one trial described a greater increase in lung function with PD&P alone, while at six months the second study reported a greater increase with exercise plus PD&P (but did not provide data for the PD&P group). One study reported no side effects at all, and also reported no difference between groups in exercise capacity (maximal work rate), sputum volume or the average length of time spent in hospital. Conversely, the second study reported fewer hospitalisations due to exacerbations in the exercise and PD&P group. Neither study reported on quality of life, preference and the need for antibiotics.

Exercise versus uPEP

One study (13 participants) compared exercise to uPEP (also known as bubble PEP). No adverse events were recorded in either group and investigators reported that those taking part thought that, while exercise was more tiring, it was also more enjoyable than bubble PEP. We found no differences in the total weight of sputum collected during treatment sessions. The study did not report on lung function, quality of life, exercise capacity, adherence, need for antibiotics or hospitalisations.

Certainty of the evidence

Overall, we had very little confidence in the evidence because all four studies had few participants and two studies only presented results as a shortened report given at a conference. 

We do not think the fact that participants and people measuring the outcomes knew which treatment the participants were receiving influenced the results of outcomes such as lung function and sputum weight. We do not think the fact that these studies were financed should influence the interpretation of the results in this review. 

As one of the top 10 research questions identified by clinicians and people with CF, it is important to systematically review the literature regarding whether or not exercise is an acceptable and effective ACT, and whether it can replace traditional methods. We identified an insufficient number of trials to conclude whether or not exercise is a suitable alternative ACT, and the diverse design of included trials did not allow for meta-analysis of results. The evidence is very low-certainty, so we are uncertain about the effectiveness of exercise as an ACT. Longer studies examining outcomes that are important to people with CF are required to answer this question.

There are many accepted airway clearance techniques (ACTs) for managing the respiratory health of people with cystic fibrosis (CF); none of which demonstrate superiority. Other Cochrane Reviews have reported short-term effects related to mucus transport, but no evidence supporting long-term benefits. Exercise is an alternative ACT thought to produce shearing forces within the lung parenchyma, which enhances mucociliary clearance and the removal of viscous secretions.

Recent evidence suggests that some people with CF are using exercise as a substitute for traditional ACTs, yet there is no agreed recommendation for this. Additionally, one of the top 10 research questions identified by people with CF is whether exercise can replace other ACTs.

Systematically reviewing the evidence for exercise as a safe and effective ACT will help people with CF decide whether to incorporate this strategy into their treatment plans and potentially reduce their treatment burden. The timing of this review is especially pertinent given the shifting landscape of CF management with the advent of highly-effective small molecule therapies, which are changing the way people with CF are cared for.

To compare the effect of exercise to other ACTs for improving respiratory function and other clinical outcomes in people with CF and to assess the potential adverse effects associated with this ACT.

On 28 February 2022, we searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews.

We searched online clinical trial registries on 15 February 2022.

We emailed authors of studies awaiting classification or potentially eligible abstracts for additional information on 1 February 2021.

We selected randomised controlled studies (RCTs) and quasi-RCTs comparing exercise to another ACT in people with CF for at least two treatment sessions.

Two review authors independently extracted data and assessed risk of bias for the included studies. They assessed the certainty of the evidence using GRADE. Review authors contacted investigators for further relevant information regarding their publications.

We included four RCTs. The 86 participants had a wide range of disease severity (forced expiratory volume in one second (FEV 1 ) ranged from 54% to 95%) and were 7 to 41 years old. Two RCTs were cross-over and two were parallel in design. Participants in one RCT were hospitalised with an acute respiratory exacerbation, whilst the participants in three RCTs were clinically stable. All four RCTs compared exercise either alone or in combination with another ACT, but these were too diverse to allow us to combine results. The certainty of the evidence was very low; we downgraded it due to low participant numbers and high or unclear risks of bias across all domains.

Exercise versus active cycle of breathing technique (ACBT)

One cross-over trial (18 participants) compared exercise alone to ACBT. There was no change from baseline in our primary outcome FEV 1 , although it increased in the exercise group before returning to baseline after 30 minutes; we are unsure if exercise affected FEV 1 as the evidence is very low-certainty. Similar results were seen for other measures of lung function. No adverse events occurred during the exercise sessions (very low-certainty evidence). We are unsure if ACBT was perceived to be more effective or was the preferred ACT (very low-certainty evidence). 24-hour sputum volume was less in the exercise group than with ACBT (secondary outcome). Exercise capacity, quality of life, adherence, hospitalisations and need for additional antibiotics were not reported.

Exercise plus postural drainage and percussion (PD&P) versus PD&P only

Two trials (55 participants) compared exercise and PD&P to PD&P alone. At two weeks, one trial narratively reported a greater increase in FEV 1 % predicted with PD&P alone. At six months, the other trial reported a greater increase with exercise combined with PD&P, but did not provide data for the PD&P group. We are uncertain whether exercise with PD&P improves FEV 1 as the certainty of evidence is very low. Other measures of lung function did not show clear evidence of effect. One trial reported no difference in exercise capacity (maximal work rate) after two weeks. No adverse events were reported (1 trial, 17 participants; very low-certainty evidence). Adherence was high, with all PD&P sessions and 96% of exercise sessions completed (1 trial, 17 participants; very low-certainty evidence). There was no difference between groups in 24-hour sputum volume or in the mean duration of hospitalisation, although the six-month trial reported fewer hospitalisations due to exacerbations in the exercise and PD&P group. Quality of life, ACT preference and need for antibiotics were not reported.

Exercise versus underwater positive expiratory pressure (uPEP)

One trial (13 participants) compared exercise to uPEP (also known as bubble PEP). No adverse events were recorded in either group (very low-certainty evidence). Trial investigators reported that participants perceived exercise as more fatiguing but also more enjoyable than bubble PEP (very low-certainty evidence). There were no differences found in the total weight of sputum collected during treatment sessions. The trial did not report the primary outcomes (FEV 1 , quality of life, exercise capacity) or the secondary outcomes (other measures of lung function, adherence, need for antibiotics or hospitalisations).

Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis

Affiliations.

Background: Respiratory tract infections with Pseudomonas aeruginosa occur in most people with cystic fibrosis (CF). Established chronic P aeruginosa infection is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate. This is an updated review.

Objectives: Does giving antibiotics for P aeruginosa infection in people with CF at the time of new isolation improve clinical outcomes (e.g. mortality, quality of life and morbidity), eradicate P aeruginosa infection, and delay the onset of chronic infection, but without adverse effects, compared to usual treatment or an alternative antibiotic regimen? We also assessed cost-effectiveness.

Search methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and conference proceedings. Latest search: 24 March 2022. We searched ongoing trials registries. Latest search: 6 April 2022.

Selection criteria: We included randomised controlled trials (RCTs) of people with CF, in whom P aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous (IV) antibiotics with placebo, usual treatment or other antibiotic combinations. We excluded non-randomised trials and cross-over trials.

Data collection and analysis: Two authors independently selected trials, assessed risk of bias and extracted data. We assessed the certainty of the evidence using GRADE.

Main results: We included 11 trials (1449 participants) lasting between 28 days and 27 months; some had few participants and most had relatively short follow-up periods. Antibiotics in this review are: oral - ciprofloxacin and azithromycin; inhaled - tobramycin nebuliser solution for inhalation (TNS), aztreonam lysine (AZLI) and colistin; IV - ceftazidime and tobramycin. There was generally a low risk of bias from missing data. In most trials it was difficult to blind participants and clinicians to treatment. Two trials were supported by the manufacturers of the antibiotic used. TNS versus placebo TNS may improve eradication; fewer participants were still positive for P aeruginosa at one month (odds ratio (OR) 0.06, 95% confidence interval (CI) 0.02 to 0.18; 3 trials, 89 participants; low-certainty evidence) and two months (OR 0.15, 95% CI 0.03 to 0.65; 2 trials, 38 participants). We are uncertain whether the odds of a positive culture decrease at 12 months (OR 0.02, 95% CI 0.00 to 0.67; 1 trial, 12 participants). TNS (28 days) versus TNS (56 days) One trial (88 participants) comparing 28 days to 56 days TNS treatment found duration of treatment may make little or no difference in time to next isolation (hazard ratio (HR) 0.81, 95% CI 0.37 to 1.76; low-certainty evidence). Cycled TNS versus culture-based TNS One trial (304 children, one to 12 years old) compared cycled TNS to culture-based therapy and also ciprofloxacin to placebo. We found moderate-certainty evidence of an effect favouring cycled TNS therapy (OR 0.51, 95% CI 0.31 to 0.82), although the trial publication reported age-adjusted OR and no difference between groups. Ciprofloxacin versus placebo added to cycled and culture-based TNS therapy One trial (296 participants) examined the effect of adding ciprofloxacin versus placebo to cycled and culture-based TNS therapy. There is probably no difference between ciprofloxacin and placebo in eradicating P aeruginosa (OR 0.89, 95% CI 0.55 to 1.44; moderate-certainty evidence). Ciprofloxacin and colistin versus TNS We are uncertain whether there is any difference between groups in eradication of P aeruginosa at up to six months (OR 0.43, 95% CI 0.15 to 1.23; 1 trial, 58 participants) or up to 24 months (OR 0.76, 95% CI 0.24 to 2.42; 1 trial, 47 participants); there was a low rate of short-term eradication in both groups. Ciprofloxacin plus colistin versus ciprofloxacin plus TNS One trial (223 participants) found there may be no difference in positive respiratory cultures at 16 months between ciprofloxacin with colistin versus TNS with ciprofloxacin (OR 1.28, 95% CI 0.72 to 2.29; low-certainty evidence). TNS plus azithromycin compared to TNS plus oral placebo Adding azithromycin may make no difference to the number of participants eradicating P aeruginosa after a three-month treatment phase (risk ratio (RR) 1.01, 95% CI 0.75 to 1.35; 1 trial, 91 participants; low-certainty evidence); there was also no evidence of any difference in the time to recurrence. Ciprofloxacin and colistin versus no treatment A single trial only reported one of our planned outcomes; there were no adverse effects in either group. AZLI for 14 days plus placebo for 14 days compared to AZLI for 28 days We are uncertain whether giving 14 or 28 days of AZLI makes any difference to the proportion of participants having a negative respiratory culture at 28 days (mean difference (MD) -7.50, 95% CI -24.80 to 9.80; 1 trial, 139 participants; very low-certainty evidence). Ceftazidime with IV tobramycin compared with ciprofloxacin (both regimens in conjunction with three months colistin) IV ceftazidime with tobramycin compared with ciprofloxacin may make little or no difference to eradication of P aeruginosa at three months, sustained to 15 months, provided that inhaled antibiotics are also used (RR 0.84, 95 % CI 0.65 to 1.09; P = 0.18; 1 trial, 255 participants; high-certainty evidence). The results do not support using IV antibiotics over oral therapy to eradicate P aeruginosa, based on both eradication rate and financial cost.

Authors' conclusions: We found that nebulised antibiotics, alone or with oral antibiotics, were better than no treatment for early infection with P aeruginosa. Eradication may be sustained in the short term. There is insufficient evidence to determine whether these antibiotic strategies decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials comparing two active treatments have failed to show differences in rates of eradication of P aeruginosa. One large trial showed that intravenous ceftazidime with tobramycin is not superior to oral ciprofloxacin when inhaled antibiotics are also used. There is still insufficient evidence to state which antibiotic strategy should be used for the eradication of early P aeruginosa infection in CF, but there is now evidence that intravenous therapy is not superior to oral antibiotics.

Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Scientific Reports volume  9 , Article number:  7234 ( 2019 ) Cite this article

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Several placebo-controlled trials have been recently published evaluating novel therapies targeting the defective CFTR protein. This systematic review examines the clinical efficacy and safety of CFTR modulators in individuals with cystic fibrosis (CF) with specific genetic mutations. Online sources were searched for placebo-controlled, parallel-design clinical trials investigating CFTR modulators from January 1, 2005 to March 31, 2018. The primary outcome of interest was FEV 1 % predicted (ppFEV 1 ). Fourteen RCTs met our eligibility criteria. The largest improvement in ppFEV 1 favouring treatment was observed for ivacaftor (IVA) in G551D individuals (≥6 years old). Both tezacaftor-ivacaftor (TEZ-IVA) and lumacaftor-ivacaftor (LUM-IVA) also improved ppFEV 1 in F508del homozygous individuals but there was increased reporting of respiratory adverse events with LUM-IVA compared to placebo. IVA also significantly improved ppFEV 1 in a sub-group of individuals ≥18 years old with an R117H mutation. No significant improvements in ppFEV 1 were observed for IVA, LUM, or TEZ in F508del homozygous individuals, LUM or LUM-IVA in F508del heterozygous individuals, or ataluren in individuals with a nonsense mutation. Significant improvements in ppFEV 1 and other clinical outcomes were observed for IVA in G551D individuals, TEV-IVA and LUM-IVA in F508del homozygous individuals, and IVA in adults with a R117H mutation.

Introduction

Cystic fibrosis (CF) is a genetic condition caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is located at the apical surface of epithelial cells and the absence of CFTR activity leads to loss of chloride secretion and deficient fluid transport 1 . This results in thick and sticky secretions involving a range of epithelial tissues such as the airways and pancreatic ducts, eventually culminating in end-organ damage and failure. Since the discovery of the CFTR gene in 1989 2 , significant progress has been made in the understanding of how CFTR gene mutations alter protein structure and function leading to reduced CFTR activity 3 .

Although over 2000 variants in the CFTR gene have been identified to date, F508del accounts for most CFTR alleles in patients with CF. This particular mutation leads to abnormal CFTR folding and trafficking causing reduced delivery of CFTR to the cell surface 4 . Another class of CFTR mutations, referred to as “nonsense” mutations, leads to a premature termination codon and reduced synthesis and hence delivery of CFTR to the cell surface 5 . In contrast, “gating” mutations are missense mutations that lead to CFTR proteins that are sufficiently synthesized, processed and trafficked to the cell surface but once they arrive they have defective channel opening leading to diminished chloride secretion 6 .

With advances in our understanding of CFTR biology, a new class of small molecule therapies, referred to as CFTR modulators, have been identified using high-throughput small molecule screening; these drugs are unique as they directly target molecular defects in the CFTR protein to increase CFTR activity 7 , 8 , 9 , 10 , 11 . For example, CFTR “potentiators” are small molecules capable of increasing the amount of time the CFTR channel is spent in the open position and thus targets CFTR mutations with defective “gating” 10 . CFTR “correctors” are small molecules that can target mutations such as F508del as they can improve CFTR trafficking or transport to the cell surface by stabilizing the 3D conformation of the protein, even if misfolded 11 . Other CFTR modulators, including CFTR “amplifiers” and “translational read-through” agents increase the amount of CFTR protein produced, the latter being specific to mutations leading to a premature termination codon 12 , 13 .

In recent years, several placebo-controlled clinical trials have been conducted investigating the efficacy and safety of CFTR modulators but the results have varied depending on the specific CF genotype and therapy under investigation 8 . The primary objective of this systematic review was to evaluate the impact of CFTR modulators on lung function and other clinically important outcomes including pulmonary exacerbations, hospitalizations, respiratory symptoms, nutritional status, and adverse events in individuals with CF.

Search strategy

Our search strategy was developed in accordance with PRISMA guidelines 14 . A systematic search of online databases using key phrases was conducted to identify randomized, placebo-controlled trials published from January 1, 2005 to March 31, 2018. Online databases searched included: MEDLINE, EMBASE, ACP Journal Club, Cochrane Central Register for Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), Cochrane Methodology Register (CMR), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), and NHS Economic Evaluation Database (NHSEED). For comprehensiveness, clinical trial registries such as the European Medicines Agency, U.S. National Institute of Health, and the World Health Organization records were accessed and screened. We used the following key phrases which were designed to maximize sensitivity for detecting therapeutic trials in CF: (“cystic fibrosis” OR “CFTR”) AND (“drug therapy” OR “clinical trial”).

Selection criteria

The literature search and abstracts were reviewed for eligibility independently by two investigators (A.R.H and M.K.). Randomized controlled trials (RCTs) with a parallel design comparing CFTR modulators (e.g. potentiators, correctors, translational read-through agents) to placebo in patients with CF were included. Study inclusion/exclusion were summarized in a PRISMA flow diagram 14 . The level of agreement in the articles selected for full text review and then for inclusion in the review by the two investigators were reported and discrepancies were resolved by the principal investigator (B.S.Q).

Data extraction

The review protocol used in this study is available in the Appendix and was developed in accordance with the PRISMA statement 14 . Two reviewers (A.R.H. and M.K.) independently extracted data. The level of agreement in the data extracted broken down by study characteristics, risk of bias, and effects of the intervention by the two investigators were reported and discrepancies were resolved by the principal investigator (B.S.Q).

Risk of bias assessment

Risk of bias was assessed using the Cochrane Risk of Bias tool 15 . A detailed review of the randomization process, blinding, and allocation sequence concealment was performed.

Change in percent-predicted forced expiratory volume in one second (ppFEV 1 ) was our primary outcome. Secondary efficacy outcomes included protocol-defined pulmonary exacerbations (PEx), hospitalization due to PEx, respiratory symptoms ( i . e ., Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory domain), and nutritional status ( i . e ., body mass index and weight). Adverse events with a prevalence of >10% (and involving >2 subjects) from either experimental or control groups, serious adverse events (including deaths) leading to treatment discontinuation, and the prevalence of elevated liver function tests (LFTs) were evaluated.

Statistical analysis

The statistical analysis was performed using ReviewManager (RevMan 5.3, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) in accordance with the Cochrane Handbook 16 . For each clinical outcome, the results were stratified by genotype and type/dose of CFTR modulator. If two or more studies evaluated the same drug at the same dose in the same genotype, the data was pooled using a fixed-effect meta-analysis (Appendix). For the primary outcome, ppFEV 1 , sub-group analyses were planned based on age and baseline ppFEV 1 .

Study selection

The search yielded a total of 789 potentially relevant articles and abstracts. Following full-text review, thirteen articles (14 placebo-controlled, parallel-group studies) met the inclusion and exclusion criteria (Fig.  1 ).

figure 1

PRISMA Study Flow Diagram 42 . ^Subgroup analysis of a pooled study from TRAFFIC and TRANSPORT 43 . *One study by Wainwright et al . 17 pooled data from two phase 3 RCTs (TRAFFIC and TRANSPORT) with identical study designs and methods of data analysis resulting in a total of 14 RCTs.

Characteristics of included studies

A total of eight phase 3 and six phase 2 studies from thirteen original articles were identified. The article by Wainwright et al . included two phase 3 studies accounting for the discordance between the number of articles and studies 17 . The proposed class/mechanism of action for each CFTR modulator along with the number of studies evaluating the therapy is described in Table  1 . Characteristics of the included studies and its participants are detailed in Table  2 and Appendix Table  1 . The a priori outcomes of interest for the included studies are summarized in Appendix Table  2 .

Risk of bias of included studies

Risk of bias for each included article is summarized in Appendix Fig.  1 . Most studies were considered ‘low risk’ for selection, performance, and attrition bias (Fig.  2 ) 17 , 18 , 19 , 20 .

figure 2

Risk of Bias Summary for Included Studies. Selective outcome reporting was noted for Kerem et al . 18 as the study authors did not report in their full text publication all outcomes listed in their study protocol including antibiotic use and hospitalization due to CF-related symptoms, disruption to school or work due to CF-related symptoms, and pharmacokinetics. Similarly, Ramsey et al . 20 did not report on all CFQ-R domain items or tertiary outcomes pre-defined in their clinical trial protocol including EQ-5D, oxygen saturation, and outpatient sick visits to the clinic or hospital for CF-related complications. Ratjen et al . 19 did not report data on exacerbations (time to first, number) and the Treatment Satisfaction Questionnaire despite these being listed as secondary endpoints in the publication. Wainwright et al . 17 did not report data on the EQ-5D or Treatment Satisfaction Questionnaire despite it being listed in their trial protocol.

Effects of the intervention

Primary outcome.

ppFEV 1 : Of all the CFTR modulators examined to date, individuals with a G551D mutation treated with IVA experienced the largest improvement in ppFEV 1 compared to placebo (n = 2 studies; n = 213; weighted absolute mean difference 10.8, 95% CI: 9.0–12.7) (Fig.  3A ) with no heterogeneity (I 2  = 0%) in results between studies (Fig.  3B ) 20 , 21 .

figure 3

Absolute Difference in ppFEV 1 for Patients Randomized to CFTR Modulators vs. Placebo. ( A ) Data from individual studies; ( B ) Meta-analysis combining data if identical CFTR modulator and dose. Footnote: (1) Individuals received IVA at baseline as part of routine clinical care and therefore the control group received IVA + Placebo. Abbreviations: D1–14 = day 1 to day 14; D1–21 = day 1 to day 21; D1–28 = day 1 to day 28; D1–56 = day 1 to day 56; IVA = ivacaftor; LUM = lumacaftor; TEZ = tezacaftor; ^2 = twice a day.

For F508del homozygous individuals 12 years and older, ppFEV 1 significantly improved with LUM-IVA and TEZ-IVA compared to placebo (Fig.  3A ). The effect size was similar for TEZ-IVA (n = 2 studies; n = 535; weighted absolute mean difference 4.0, 95% CI: 3.2–4.8) 22 , 23 and higher dose LUM-IVA (n = 3 studies; n = 755; weighted absolute mean difference 3.4, 95% CI: 2.4–4.4) (Fig.  3B ) 17 , 24 . For individuals 6–11 years, there was a mild increase in ppFEV 1 for LUM-IVA compared to placebo (n = 1 study; n = 204; absolute mean difference 2.4, 95% CI: 0.4–4.4) 19 . No significant treatment effect was observed with IVA or TEZ alone, and there was a trend toward worsening in ppFEV 1 for F508del homozygous individuals treated with higher doses of LUM (Fig.  3A ) 22 , 24 , 25 .

For F508del heterozygous individuals, there was no significant improvement in ppFEV 1 on LUM or LUM-IVA (Fig.  3A ) 24 , 26 . In a small study involving individuals with F508del/G551D, TEZ-IVA did not lead to a significant improvement in ppFEV 1 compared to IVA alone 22 .

For individuals with the R117H mutation on at least one allele, IVA did not lead to an overall improvement in ppFEV 1 compared to placebo, but there was a significant improvement in a pre-defined subgroup analysis restricted to adults (n = 50; absolute mean difference 5.0, 95% CI 1.2–8.8) 27 . For individuals with a nonsense mutation on at least one allele, ataluren did not result in a significant relative improvement in ppFEV 1 compared to placebo 18 .

Secondary outcomes

Pulmonary exacerbations (PEx): Eight studies examined protocol-defined PEx as described in Appendix Table  3 . Of all the CFTR modulators examined, individuals (≥12 years old) with a G551D mutation receiving IVA derived the greatest reduction in PEx risk compared to placebo (n = 1 study; n = 161; OR 0.39, 95% CI: 0.21–0.74) (Appendix Fig.  2A ) 20 . LUM-IVA and TEZ-IVA also significantly reduced the risk of PEx compared to placebo in F508del homozygous individuals (≥12 years old) but the risk reduction was less than that observed with IVA in G551D (Appendix Fig.  2A,B ) 17 , 23 . In comparison to placebo, no significant reduction in PEx risk was observed for F508del homozygous individuals or individuals with the R117H mutation on at least one allele receiving IVA, nor for individuals with a nonsense mutation receiving ataluren (Appendix Fig.  2A ) 18 , 25 , 27 .

Pulmonary exacerbations (PEx) requiring hospitalization: LUM-IVA reduced the risk of PEx requiring hospitalization in F508del homozygous individuals (Appendix Fig.  3A,B ) 17 . TEZ-IVA also significantly reduced the rate of PEx leading to hospitalization compared to placebo (n = 1 study; n = 504; rate ratio 0.53, 95% CI 0.34–0.82) but a risk ratio could not be calculated 23 . Individuals with the G551D mutation on at least one allele treated with IVA also experienced a reduction in the risk of PEx requiring hospitalization but this was not statistically significant (Appendix Fig.  3A ) 20 .

CFQ-R respiratory domain: Compared to placebo, CFQ-R Respiratory domain scores improved to a similar extent for IVA treated individuals (≥6 years old) with the G551D mutation on at least one allele (n = 3 studies; n = 236; weighted absolute mean difference: 7.2, 95% CI: 3.3–11.1) 20 , 21 , 28 , IVA treated individuals ≥18 years old with at least one R117H mutation (n = 1 study; n = 69; absolute mean difference: 8.4, 95% CI: 2.2–14.6) 27 , and for LUM-IVA treated F508del heterozygous individuals ≥18 years old (n = 1 study; n = 125; absolute mean difference: 6.5, 95% CI 1.4–11.6) (Appendix Fig.  4A,B ). CFQ-R Respiratory domain scores also significantly improved with TEZ-IVA and LUM-IVA in F508del homozygous individuals (≥12 years old) but the mean difference did not exceed the minimal clinically important difference (MCID) for LUM-IVA 17 , 23 , 24 . Furthermore, there was no significant improvement in CFQ-R Respiratory domain scores for patients 6–11 years old on LUM-IVA compared to placebo 19 .

There was worsening of the CFQ-R Respiratory domain score for F508del homozygous and heterozygous individuals (≥18 years old) on LUM alone (Appendix Fig.  4A ) 24 . In a small phase 2 study involving individuals with F508del/G551D, TEZ-IVA did not lead to significant improvement in the CFQ-R Respiratory domain compared to IVA alone 22 . For individuals with a nonsense mutation on at least one allele, ataluren did not modify CFQ-R Respiratory domain score compared to placebo 18 .

Nutritional outcomes (BMI and weight): For individuals with at least one G551D mutation (≥6 years old), significant improvements in weight were observed on IVA compared to placebo (n = 2 studies; n = 213; weighted absolute mean difference: 2.8 kg, 95% CI: 1.8–3.8) (Appendix Fig.  5A,B ) 20 , 21 . For F508del homozygous individuals (≥12 years old), a clinically modest but statistically significant increase in BMI was observed for both doses of LUM-IVA compared to placebo (Appendix Fig.  6A,B ) 17 ; however, no significant treatment effect was seen in individuals 6–11 years on LUM-IVA (Appendix Fig.  6A ) 19 . TEZ-IVA did not lead to improvement in BMI compared to placebo in individuals 12 years and older (Appendix Fig.  6A ) 23 . For F508del heterozygous individuals (≥18 years old), LUM-IVA did not result in significant improvement in weight or BMI compared to placebo 26 . There were no significant improvements in BMI compared to placebo among IVA treated individuals with an R117H mutation (Appendix Fig.  6A ) or ataluren treated individuals with a nonsense mutation (data not shown) 18 , 27 .

Adverse event reporting: CFTR modulators were generally well tolerated compared to placebo (Appendix Figs  7 – 30 ) . For studies involving F508del homozygous and heterozygous individuals, those assigned to LUM had increased dyspnea and “abnormal respiration” compared to placebo (Appendix Figs  11 and 13 ). F508del homozygous and heterozygous subjects assigned to LUM and LUM-IVA also had more respiratory-related adverse events leading treatment discontinuation compared to placebo (Appendix Table  4 ) 17 , 24 . For the one study involving individuals with a nonsense mutation, subjects receiving ataluren had increased incidence of acute kidney injury compared to placebo (15% vs. <1%) resulting in higher rates of treatment discontinuation 18 .

The prevalence of LFT abnormalities was generally similar between treatment and placebo, however there were a few exceptions. A greater proportion of G551D patients had severe ALT elevations (>8x ULN) on IVA compared to placebo (3.6% vs 0%) (Appendix Table  5 ) 20 . Milder elevations in AST (2–3X ULN) were observed for G551D patients on IVA and ALT or AST (>3X ULN) in F508del homozygous children aged 6–11 on LUM-IVA compared to placebo (Appendix Table  5 ) 19 , 20 .

Level of agreement for study selection and data extraction: There was a strong level of agreement (95%) for the articles selected between the two reviewers for full text review and 100% agreement between the two reviewers for the articles meeting eligibility criteria for inclusion in this review. The level of agreement for data extraction were as follows: study characteristics (n = 88 data points, 95% agreement), risk of bias (n = 92 data points, 84% agreement), and effects of the intervention (n = 480 data points, 81% agreement).

This study represents the most comprehensive systematic review of the efficacy and safety of CFTR modulators performed to date. While evidence-based recommendations for the use of CFTR modulators were recently published and provides a valuable resource for practicing clinicians, this review provides a more concise and up-to-date synthesis of all the placebo-controlled clinical trial data 29 . No prior systematic review has compared all investigational CFTR modulators from phase 2 and 3 RCTs in specific CF genotypes 30 , 31 , 32 .

As this review highlights, patients with gating mutations such as G551D benefit the most from current CFTR modulators and those that are F508 homozygous have moderate benefit in comparison. Based on published parallel design trials, CFTR modulators have not been effective in F508 heterozygotes or those with nonsense mutations. However, in a recent phase 3 cross-over study evaluating IVA and TEZ-IVA in individuals ≥12 years old with F508del and a residual CFTR function mutation, improvements in ppFEV1 of 4.7% and 6.8%, respectively, were observed compared to placebo 33 . Furthermore, unpublished phase 2 data evaluating TEZ-IVA in combination with “next-generation” corrector molecules have demonstrated significant improvements in ppFEV1 in subjects with F508del and a minimal CFTR function mutation, some of whom have nonsense mutations.

When comparing the efficacy of CFTR modulators across all genotypes for ppFEV 1 , CF individuals (≥6 years old) with the G551D mutation on at least one allele receiving IVA experienced the largest benefit 20 , 21 . F508del homozygous subjects receiving TEZ-IVA (≥12 years old) and LUM-IVA (≥6 years old) also had improvements in ppFEV 1 compared to placebo but the effect sizes were modest compared to IVA in G551D 17 , 19 , 24 . Individuals (≥18 years old) with the R117H mutation on at least one allele treated with IVA experienced similar improvement in ppFEV 1 to F508del homozygous subjects treated with TEZ-IVA and LUM-IVA.

Similar to ppFEV 1 , the effect of CFTR modulators on PEx risk and respiratory symptoms were most pronounced with IVA in G551D adolescents and adults (≥12 years old), with a 60% reduction in PEx risk and a 7-point improvement in the CFQ-R Resp domain 20 , 21 . F508del homozygous adolescents and adults also had a 40–45% reduction in PEx risk on TEZ-IVA and LUM-IVA. While F508del homozygous subjects experienced improvements in the CFQ-R Resp domain on both TEZ-IVA and LUM-IVA, this was not clinically significant for LUM-IVA. Individuals with a R117H mutation also experienced improvements in the CFQ-R Resp domain on IVA, with a magnitude of change in the adults comparable to that observed with IVA in G551D. The effect of CFTR modulators on weight were most significant with IVA in G551D individuals (≥6 years old). While F508del homozygous individuals (≥12 years old) had improvement in BMI with LUM-IVA, the effect size was modest.

Most of the CFTR modulator therapies examined in this review were well tolerated with the exception of increased reporting of respiratory adverse events (e.g. dyspnea) leading to higher rates of treatment discontinuation in patients randomized to LUM and LUM-IVA. The molecular mechanism responsible for the adverse respiratory effects (e.g. dyspnea, abnormal respiration) for patients on LUM remain unclear but appears to be an off-target effect specific to LUM, as opposed to being related to F508del CFTR correction per se, as similar adverse effects have not been observed with F508del CFTR correction with TEZ-IVA 22 , 23 , 34 . There was also increased reporting of acute kidney injury for nonsense mutation patients assigned to ataluren compared to placebo. The long-term safety of CFTR modulator therapies beyond one year could not be assessed in this review and therefore the detection of infrequent or long-term side effects will require ongoing post-marketing surveillance 35 , 36 .

There are several potential limitations of this review. We excluded cross-over, open-label, and observational studies to avoid carryover effects and to ensure we incorporated the highest level of evidence. We also limited our inclusion to full-text studies which could have resulted in publication bias. We focused on pre-defined clinically important outcomes but did not include multiple-breath washout measurement (e.g. LCI 2.5 ) given the lack of clinical trials utilizing this outcome measure 19 .

There remain several gaps in the placebo-controlled evidence base for CFTR modulators. RCTs to date have excluded young children (<6 years old) and therefore the earliest age of safe use of CFTR modulators remains uncertain. However, small open-label 24-week studies have demonstrated a similar safety profile of IVA in children 1–5 years old with CFTR gating mutations compared to older age groups studied 37 , 38 . Most RCTs have also excluded CF individuals with severe lung disease (ppFEV 1  < 40%), individuals colonized/infected with bacteria associated with rapid lung function decline (e.g. Burkholderia cenocepacia , Mycobacterium abscessus ), and individuals with very frequent pulmonary exacerbations requiring continuous or near continuous systemic antibiotics by virtue of requiring clinical stability and no systemic antibiotics 4 weeks prior to randomization and therefore the efficacy and safety of CFTR modulators in these sub-groups remain unclear. For example, based on observational data, F508del homozygous individuals with advanced lung disease started on LUM-IVA have increased respiratory-related adverse events leading to treatment discontinuation; therefore, closer monitoring following treatment initiation is recommended 39 , 40 .

Most placebo-controlled RCTs to date have been limited to a maximum duration of 48 weeks and therefore the long-term placebo-controlled effects of these therapies remain unclear. However, an open-label extension trial evaluating the long-term effects of ivacaftor up to 144 weeks has demonstrated sustained clinical benefits of ivacaftor on lung function, weight, patient-reported respiratory symptoms and PEx risk reduction with no new safety concerns 35 . Furthermore, based on combined data from an open-label extension trial and U.S. CF patient registry data, the rate of lung function decline over 3 years was lower in G551D patients treated with ivacaftor compared to propensity-matched controls from the CF registry, suggestive of a disease-modifying effect over the longer term.

In conclusion, based on randomized placebo-controlled parallel design trials, CFTR potentiation with IVA in individuals with a G551D mutation is safe, and results in robust clinical benefits compared to placebo and to date is superior to the effects observed with CFTR modulators in other CF genotypes. The effects of TEZ-IVA and LUM-IVA in F508del homozygous individuals are comparable with respect to the magnitude of change in ppFEV 1 and PEx risk reduction but TEZ-IVA is safer and leads to greater improvement in respiratory symptoms.

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Acknowledgements

B.S.Q. receives salary support from a Michael Smith Foundation for Health Research Scholar Award and CF Canada Clinician-Scientist Award. No grants or third-party funding was provided for this study.

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Al-Rahim R. Habib and Majid Kajbafzadeh contributed equally.

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School of Medicine, The University of Sydney, Sydney, Australia

Al-Rahim R. Habib & Majid Kajbafzadeh

School of Population and Public Health, University of British Columbia, Vancouver, Canada

Sameer Desai

Division of Respiratory Medicine, Department of Pediatrics, University of British Columbia, Vancouver, Canada

Connie L. Yang

Division of Respirology, Department of Medicine, University of Calgary, Alberta, Canada

Kate Skolnik

Centre for Heart Lung Innovation, St. Paul’s Hospital, Department of Medicine, University of British Columbia, Vancouver, Canada

Bradley S. Quon

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A.H., M.K., B.S.Q. contributed to all aspects of this study including study concept and design, conducting the literature search, study design, data collection, data analysis, data interpretation and writing of the manuscript. S.D., C.L.Y., K.S. contributed to data analysis, data interpretation, and writing of the manuscript.

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Habib, AR.R., Kajbafzadeh, M., Desai, S. et al. A Systematic Review of the Clinical Efficacy and Safety of CFTR Modulators in Cystic Fibrosis. Sci Rep 9 , 7234 (2019). https://doi.org/10.1038/s41598-019-43652-2

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Airway clearance techniques for cystic fibrosis: an overview of Cochrane systematic reviews

Cystic fibrosis is a life‐limiting genetic condition in which thick mucus builds up in the lungs, leading to infections, inflammation, and eventually, deterioration in lung function. To clear their lungs of mucus, people with cystic fibrosis perform airway clearance techniques daily. There are various airway clearance techniques, which differ in terms of the need for assistance or equipment, and cost.

To summarise the evidence from Cochrane Reviews on the effectiveness and safety of various airway clearance techniques in people with cystic fibrosis.

For this overview, we included Cochrane Reviews of randomised or quasi‐randomised controlled trials (including cross‐over trials) that evaluated an airway clearance technique (conventional chest physiotherapy, positive expiratory pressure (PEP) therapy, high‐pressure PEP therapy, active cycle of breathing techniques, autogenic drainage, airway oscillating devices, external high frequency chest compression devices and exercise) in people with cystic fibrosis.

We searched the Cochrane Database of Systematic Reviews on 29 November 2018.

Two review authors independently evaluated reviews for eligibility. One review author extracted data from included reviews and a second author checked the data for accuracy. Two review authors independently graded the quality of reviews using the ROBIS tool. We used the GRADE approach for assessing the overall strength of the evidence for each primary outcome (forced expiratory volume in one second (FEV 1 ), individual preference and quality of life).

Main results

We included six Cochrane Reviews, one of which compared any type of chest physiotherapy with no chest physiotherapy or coughing alone and the remaining five reviews included head‐to‐head comparisons of different airway clearance techniques. All the reviews were considered to have a low risk of bias. However, the individual trials included in the reviews often did not report sufficient information to adequately assess risk of bias. Many trials did not sufficiently report on outcome measures and had a high risk of reporting bias.

We are unable to draw definitive conclusions for comparisons of airway clearance techniques in terms of FEV 1 , except for reporting no difference between PEP therapy and oscillating devices after six months of treatment, mean difference ‐1.43% predicted (95% confidence interval ‐5.72 to 2.87); the quality of the body of evidence was graded as moderate. The quality of the body of evidence comparing different airway clearance techniques for other outcomes was either low or very low.

Authors' conclusions

There is little evidence to support the use of one airway clearance technique over another. People with cystic fibrosis should choose the airway clearance technique that best meets their needs, after considering comfort, convenience, flexibility, practicality, cost, or some other factor. More long‐term, high‐quality randomised controlled trials comparing airway clearance techniques among people with cystic fibrosis are needed.

Plain language summary

Airway clearance techniques for cystic fibrosis: an overview of Cochrane Reviews

We reviewed the evidence from Cochrane Reviews about the effect of airway clearance techniques in people with cystic fibrosis.

Cystic fibrosis is a life‐limiting genetic condition that affects the respiratory and digestive systems. People with cystic fibrosis produce thick mucus that builds up in the lungs leading to infections and inflammation and eventually to a deterioration in lung function. People with cystic fibrosis perform airway clearance techniques at least daily to help keep their lungs clear of mucus. There are various airway clearance techniques, which differ in terms of the need for assistance or equipment, and cost. The airway clearance techniques included in this overview are conventional chest physiotherapy, various breathing techniques (active cycle of breathing technique, autogenic drainage), devices that create a positive pressure (positive expiratory pressure therapy (PEP) or high‐pressure PEP therapy) or a vibration (oscillating devices) to move mucus, and exercise.

The condition is progressive and as lung function worsens, airway clearance techniques may not be sufficient. It may be useful to consider other therapies, such as hypertonic saline or dornase alfa, in addition to airway clearance techniques. These additional therapies are not covered in this overview.

Search date

The evidence is current to: 29 November 2018.

Study characteristics

This overview included six Cochrane Reviews. One review compared any type of chest physiotherapy (conventional chest physiotherapy, PEP therapy, high‐pressure PEP therapy, active cycle of breathing technique, autogenic drainage, exercise, vibrating (oscillating) devices) with no chest physiotherapy or coughing alone. The remaining five reviews included head‐to‐head comparisons of different airway clearance techniques, thus these five reviews often overlapped with each other.

Key results

In this overview, we found moderate evidence that PEP therapy and vibrating (oscillating) devices have a similar effect on lung function (forced expiratory volume in one second (FEV 1 ) after six months of treatment. We are unable to draw definitive conclusions for all other comparisons in terms of FEV 1 because the quality of evidence is currently lacking. Likewise, we are unable to draw any definitive conclusions for other outcome measures such as individual preference and quality of life. Harms, such as acid reflux, collapsed lungs, coughing up blood, or decreased oxygen, were rarely mentioned in the original trials. There is a lack of evidence to determine if any particular airway clearance therapy is riskier than the other therapies.

Quality of the evidence

All of the reviews were considered to be well‐conducted. However, the individual trials included in the reviews often did not report enough detailed information to allow us to properly determine trial quality. Many trials did not report enough information on outcome measures; it is unclear how this missing information would influence the results. We graded the evidence for lung function when PEP was compared to vibrating (oscillating) devices as moderate, but the evidence comparing different airway clearance techniques for other outcomes, such as individual preference and quality of life was of low or very low quality. More long‐term, high‐quality trials (where participants are put into groups at random) which compare different airway clearance techniques among people with CF are needed.

Description of the condition

Cystic fibrosis (CF) is a life‐limiting genetic condition that affects the respiratory and digestive systems. People with CF have a genetic mutation encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which regulates ion transport ( Rowe 2005 ). People with abnormal CFTR activity produce thick mucus secretions that build up in the lungs, digestive system, and other organs, causing a wide range of challenging symptoms affecting the entire body. This build up of mucus in the lungs leads to infections and inflammation and eventually to deterioration in lung function ( Cantin 1995 ; Konstan 1997 ).

While CF can affect people of any racial or ethnic background, it is most common among people of northern European descent ( Farrell 2018 ). There were approximately 30,000 people living with CF in the USA in 2016 ( CF Foundation 2016 ). In the European Union, the prevalence of CF is estimated to be 0.737 per 10,000 births ( Farrell 2008 ).

Description of the interventions

The use of airway clearance therapies is recommended for all people with CF as this facilitates the movement of, and expectoration of, mucus to keep the lungs clear ( ACPCF 2017 ; Flume 2009 ; IPG/CF 2009 ). People with CF usually start airway clearance therapies soon after diagnosis, and perform them at least daily for the rest of their lives.

There are a variety of airway clearance techniques, including conventional chest physiotherapy, positive expiratory pressure (PEP) therapy, high‐pressure PEP therapy, active cycle of breathing techniques, autogenic drainage, airway oscillating devices (e.g., Flutter®, Cornet®, Acapella®, Quake®, Aerobika®, and intrapulmonary percussive ventilation), external high frequency chest compression devices (e.g., The Vest™, ThAIRapy Vest®, SmartVest®, and Hayek Oscillator), and exercise. While these airway clearance techniques may differ in terms of the need for assistance or equipment, they all have the same goal of removing mucus secretions from the lungs. Selecting the most appropriate airway clearance technique is influenced by age, individual preference, adverse events, an individual's airway pathophysiology, and cost. Descriptions of each airway clearance therapy included in this review are provided in the 'Types of Interventions' section below ( Criteria for considering reviews for inclusion ).

CF is a progressive disease and as respiratory function deteriorates, airway clearance techniques may not be sufficient. It may be useful to consider an adjunctive therapy, such as hypertonic saline or dornase alfa, or a combination of adjunctive therapies in conjunction with airway clearance techniques ( Dentice 2016 ; Elkins 2016 ). However, it is beyond the scope of this overview to evaluate the efficacy and safety of adjunctive therapies.

How the intervention might work

The goal of airway clearance techniques is to clear the airways of mucus, thus helping to prevent infection and improve lung function. Conventional chest physiotherapy uses manual techniques of percussion and vibration (and on occasion modified gravity‐assisted positioning) to loosen and move mucus through the airways. Active cycle of breathing techniques and autogenic drainage use a series of breathing manoeuvres to move mucus secretions. Techniques such as PEP therapy, high‐pressure PEP therapy, airway oscillation devices, and external high frequency chest compression can be used independently of an assistant or carer, thus affording the individual with CF independence and a more flexible approach to airway clearance management. In PEP and high‐pressure PEP therapy, the devices clear mucus by causing pressure to build up in the airways. High‐pressure PEP therapy is a modification of PEP which involves the full forced expiration against a fixed mechanical resistance usually between 40 cm H 2 O to 140 cm H 2 O ( Prasad 1993 ). Airway oscillating devices and external high frequency chest compression devices use intra‐ or extra‐thoracic oscillation to help loosen mucus. Exercise improves physical health and strength, and exercise is proposed to improve mucus clearance by changes to airflow and mucus. Exercise increases ventilatory demand, which is met by increases in tidal volume and respiratory flow. In CF, the increase in ventilation and peak expiratory flow (PEF) with exercise could increase the propulsion or mechanical clearance of mucus ( Dwyer 2011 ).

Why it is important to do this overview

In a 2006 publication, Bradley summarised five Cochrane Reviews of physical therapies, including airway clearance and physical training, for people with CF ( Bradley 2006 ). They concluded that there was a lack of evidence of the long‐term efficacy of physical therapies and that no physical therapy was more or less efficacious than another. Since then, at least three more Cochrane Reviews on airway clearance therapies have been published ( McKoy 2016 ; Morrison 2017 ; McCormack 2017 ) and other reviews have been updated. Some of the Cochrane Reviews overlap with each other in terms of the interventions and comparisons included and the results are organised in various ways.

An overview of reviews is needed to summarise the current evidence of the effectiveness of various airway clearance techniques and to identify research gaps. Furthermore, this overview can serve as a 'friendly front end' for policy makers, healthcare providers, and people with CF by reducing duplication of information and presenting the results of the Cochrane Reviews in a standard format.

To summarise the evidence from Cochrane Reviews on the effectiveness and safety of airway clearance techniques in people with CF.

Criteria for considering reviews for inclusion

Types of reviews.

For this overview, we included Cochrane Reviews of randomised controlled trials (RCTs) or quasi‐RCTs (including cross‐over trials) that evaluated an airway clearance technique in people with CF.

Types of participants

We included Cochrane Reviews of people with CF diagnosed on the basis of clinical criteria and sweat testing or genotype analysis. We did not have any restrictions based on age, disease severity, or exacerbation status.

Types of interventions

We included Cochrane Reviews that compared an airway clearance technique, either as a single technique or as a combination of techniques, with no intervention, with coughing, or with another airway clearance technique. The airway clearance techniques we included are:

Conventional chest physiotherapy

Conventional chest physiotherapy (or postural drainage with percussion and vibration) combines postural or modified postural drainage, percussion, or vibration or a combination of these. This technique requires assistance.

PEP therapy

In PEP mask, mouthpiece or 'bottle' therapy, the individual exhales against a positive pressure of 10 cm H 2 O to 25 cm H 2 O . Devices can be used to open up and recruit obstructed lung, allowing air to move behind secretions and assist in mobilising them. Breathing out against a slight resistance prevents the smaller bronchial tubes from collapsing down and thus permits the continuing upward movement of any secretions ( McIlwaine 2015 ).

Following a series of exhalations through the device, the individual would be instructed to perform a forced expiration manoeuvre and follow up with a cough to expectorate any mucus cleared.

High‐pressure PEP therapy

In high‐pressure PEP therapy, the technique has been modified so the individual is exhaling against a pressure of 40 cm H 2 O to 140 cm H 2 O. Both PEP and high‐pressure PEP therapies can be self‐administered, but require the use of a device.

Active cycle of breathing techniques

Active cycle of breathing techniques include breathing control, thoracic expansion exercises, and the forced expiration technique. This technique can be self‐administered and does not require an assistant or device.

Autogenic drainage

Autogenic drainage involves a series of breathing techniques at different lung volumes to mobilise mucus secretions. There are three phases ‐ the Unstick, Collect, and Evacuate when breathing at low, mid, and high lung volumes to mobilise, collect, and expectorate secretions respectively. This technique can be self‐administered and does not require an assistant or device.

Airway oscillating devices

Exhalation through these devices generate both oscillation of positive pressure and repeated accelerations of expiratory airflow that have been shown to result in improved sputum clearance ( Rogers 2005 ). Airway oscillating devices include Flutter®, Cornet®, Acapella®, Quake®, Aerobika®, and intrapulmonary percussive ventilation. These techniques are self‐administered, but require the use of a device.

Mechanical percussive devices and external high frequency chest compression devices

Mechanical percussive devices and external high frequency chest compression devices provide external chest wall compressions through the use of a device, such as a vest (e.g., The Vest™ and Hayek Oscillator). These devices or techniques can be self‐administered.

Exercise includes both aerobic and strength training.

Other techniques

We may consider other techniques for inclusion as new Cochrane Reviews on airway clearance techniques are published.

Types of outcomes

Primary outcomes.

Secondary outcomes

Search methods for identification of reviews

We searched the Cochrane Database of Systematic Reviews using the phrase "airway clearance" in the title, abstract, or keywords. We searched for any updates to the included reviews and for any full publications of any protocols.

Date of latest search: 29 November 2018.

Data collection and analysis

Selection of reviews.

Two review authors independently evaluated all reviews retrieved through the search for eligibility using the criteria listed above ( Criteria for considering reviews for inclusion ). We resolved all conflicts through discussion to arrive at a consensus.

Data extraction and management

We extracted the data from each included review into a Microsoft Excel spreadsheet. One review author extracted the data, and a second review author checked the abstracted data for accuracy and completeness.

From each of the included reviews, we extracted data on the review characteristics (inclusion criteria (i.e., population, intervention, comparison, outcomes, trials), date of last search, number of included trials, and number of included participants) and statistical outcome data. We extracted the narrative text of the results, if statistical results were not available. We anticipated that most of these data would have already been entered into Review Manager ( RevMan 2014 ). For the primary outcomes, we only included studies that followed participants for longer than one day. This is to allow time for the outcome to develop and for the participant to learn the airway clearance technique.

We noted the types of trials included in each of the reviews. Since data from cross‐over trials can be synthesised in a variety of ways in a systematic review ( Elbourne 2002 ), we extracted information on how each review handled cross‐over trials. We also used data extracted by another review team who had previously evaluated how these reviews analysed data from cross‐over trials ( Nolan 2016 ). Since participants in cross‐over trials receive each intervention, there should be a sufficient washout period between participants receiving the different interventions to reduce any carry‐over effect. To provide some consistency in analysing cross‐over trials, we required a washout period of at least one day for the outcomes of FEV 1 , FVC, FEF 25‐75 , and sputum. For the other outcomes, we did not have any limitations for the washout period and we presented results based on the most appropriate analysis (i.e., first‐ and second‐arm results if there is an adequate washout period; and only first‐arm results if there is an inadequate washout period).

Given that this is an overview of reviews, we had planned on relying on the data presented in the reviews and not repeating a review of the original trials for additional data. When needed for clarification, we confirmed data by reviewing the original trials.

We also extracted the quality and risk of bias assessments of the included trials within the included reviews; we did not re‐assess individual trial quality.

Assessment of methodological quality of included reviews

Quality of included reviews.

Two review authors independently assessed the methodological quality of the included reviews and resolved differences through discussion. We had planned to use the Assessment of Multiple Systematic Reviews (AMSTAR) measurement tool ( Shea 2007 ). However, we decided to use the risk of bias in systematic review (ROBIS) tool ( Whiting 2016 ) because ROBIS assesses the risk of bias in systematic reviews whereas AMSTAR also includes assessment of reporting quality. The ROBIS tool assesses the risk of bias of systematic reviews in three phases: assessment of the relevance, identification of concerns with the review process, and judgements on the risk of bias. There are five domains: trial eligibility criteria; identification and selection of trials; data collection and trial appraisal; synthesis and findings; and interpretation of review findings. After answering signalling questions in each domain ( Appendix 1 ), review authors assessed their level of concern (low, high, or no information) about bias.

Quality of evidence in included reviews

We used the GRADE approach for assessing the overall strength of the evidence for each primary outcome ( Guyatt 2008 ). We had planned to extract the grading from each eligible Cochrane Review. Since only two of the reviews had conducted grading, we graded the body of evidence for each comparison in terms of short‐term trials (follow‐up duration of one week or shorter), medium‐term trials (follow‐up duration longer than one week and up to six months), and long‐term trials (follow‐up duration longer than six months). We based our assessments on the information provided in the review, but when needed, we confirmed the data by checking the original trial reports. Two review authors evaluated the quality of the body of evidence and resolved their differences through discussion. The quality of the body of evidence was based on trial design, directness of the evidence, consistency of results, precision of results, and probability of publication bias. We classified the strength of the evidence as:

Data synthesis

We had intended that our unit of analysis would be the included systematic reviews. We provided a narrative description of the summary statistics from the included reviews. We summarised the results that were reported in the included reviews in an 'Overview of Reviews' table. For the primary outcomes, we also generated a gap map, which shows the number of trials, a summary of the results, and the evidence grade for each comparison. We organised results by outcome and then by comparison. We anticipated that there would be some overlap in the trials included among the Cochrane Reviews. When this occurred, we abstracted the results from both reviews and compared and contrasted the findings. Because of the heterogeneity in how the reviews reported and analysed their results, we often had to present the results of the individual trials.

Since this is a Cochrane overview, we did not conduct any additional indirect comparisons or network meta‐analyses.

We discussed and presented the limitations in both the evidence base and in the systematic reviews. We used this information to identify research gaps and to make recommendations for future research.

Our search of the Cochrane Database of Systematic Reviews retrieved 43 citations. We included six Cochrane Reviews ( Main 2005 ; McCormack 2017 ; McIlwaine 2015 ; Morrison 2017 ; McKoy 2016 ; Warnock 2015 ). We excluded 37 reviews because they did not include people with CF, they did not evaluate an airway clearance therapy, or they were in the protocol stage ( Appendix 2 ). This process is illustrated in a PRISMA diagram ( Figure 1 ).

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Flow diagram.

Description of included reviews

We present the characteristics of the included reviews ‐ including the date the review was last assessed as up‐to‐date, the number of included trials and participants, the population, interventions, comparisons, and outcomes of interest, and the review limitations in the additional tables ( Table 1 ). All of the reviews included people with CF, diagnosed on the basis of clinical criteria, sweat testing, or genotype analysis. None of the reviews excluded trials based on the participants' age or exacerbation status. One review excluded trials of people post lung transplant ( McIlwaine 2015 ). One review compared any type of chest physiotherapy (conventional chest physiotherapy, PEP therapy, high‐pressure PEP therapy, active cycle of breathing technique, autogenic drainage, exercise, oscillating devices) with no chest physiotherapy or coughing alone ( Warnock 2015 ). The other five reviews included head‐to‐head comparisons of different airway clearance techniques ( Main 2005 ; McIlwaine 2015 ; McKoy 2016 ; McCormack 2017 ; Morrison 2017 ). Thus, the syntheses in these five reviews often overlapped with each other.

CF: cystic fibrosis FEF 25‐75 : forced expiratory flow between 25% and 75% FEV 1 : forced expiratory volume in one second FVC: forced vital capacity PEP: positive expiratory pressure

Three reviews included trials of any duration ( McIlwaine 2015 ; McKoy 2016 ; Warnock 2015 ). Two reviews excluded trials that evaluated airway clearance therapies after a single treatment ( McCormack 2017 ; Morrison 2017 ) and one review excluded trials with less than seven days of follow‐up ( Main 2005 ).

All reviews included RCTs and quasi‐RCTs, including those with a cross‐over design. However, the reviews differed in terms of how they handled cross‐over data. Some provided a narrative description of the cross‐over study ( McIlwaine 2015 ; McKoy 2016 ; Morrison 2017 ; Warnock 2015 ), some analysed first‐period data only ( McIlwaine 2015 ; McKoy 2016; McCormack 2017 ), or performed paired analyses ( Main 2005 ; McKoy 2016 ; McCormack 2017 ).

Because we did not conduct a network meta‐analysis, we did not formally assess assumptions such as transitivity (i.e., the assumption that any participant in these trials could receive any of the included airway clearance techniques). Because many of the trials had similar eligibility criteria, we feel that the transitivity assumption would hold for older children and adults with CF. Certain techniques, such as autogenic drainage, cannot be performed by infants or younger children. For these individuals, we can assume transitivity for the interventions that are age appropriate.

Methodological quality of included reviews

All of the reviews were considered to have a low risk of bias in terms of trial eligibility criteria, the identification and selection of trials, data collection and trial appraisal, synthesis and findings, and interpretation ( Table 2 ). All of the reviews adhered to their pre‐defined eligibility criteria, which were appropriate and unambiguous. All of the reviews used a variety of sources to identify relevant trials and used methods to minimise error in trial selection. All of the reviews used methods to minimise errors in data collection, reported sufficient trial characteristics and all trial results, and used appropriate criteria for assessing risk of bias. All of the reviews reported on their pre‐defined analyses and used appropriate methods. None of the reviews conducted any sensitivity analyses, but this is likely because the data was sparse and heterogeneous. All of the reviews used appropriate methods for interpreting the results.

Five reviews used the Cochrane tool for assessing the risk of bias ( McIlwaine 2015 ; McKoy 2016 ; McCormack 2017 ; Morrison 2017 ; Warnock 2015 ) and one used the Jadad scale ( Main 2005 ). All of the reviews expressed a frustration with the limited reporting in the included trials. In the reviews that used the Cochrane risk of bias tool, this frustration is reflected in the majority of the included trials being judged as having an unclear risk of bias for random sequence generation, allocation concealment, and blinding of outcome assessors. In the review that used the Jadad scale, most of the included trials were rated as having a quality score of two out of five or as insufficient information to generate a quality score. All of the reviews acknowledged that the quality of the included trials was limited because it is not possible to blind participants or trial personnel. Two reviews mentioned that many of the included cross‐over trials had issues with either the reporting of or the duration of the washout periods ( McIlwaine 2015 ; McKoy 2016 ).

Effect of interventions

1. lung function (fev 1 ).

The comparative effects of airway clearance techniques on FEV 1 in terms of the change from baseline in L or % predicted are summarised in the additional tables ( Table 3 ) and we present a gap map summarizing the results and the quality of the evidence (GRADE) for FEV 1 as a figure ( Figure 2 ).

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Gap map summarizing the results and quality of the evidence (GRADE) for FEV 1 .

Abbreviations : CI : confidence interval; MD : mean difference; PEP : positive expiratory pressure; RCT : randomised controlled study.

a. Results are based on a single RCT. A second RCT reported no significant difference in the % change from baseline in FEV 1 for conventional chest physiotherapy (14% change) and oscillating devices (21% change).

b. Range of results from 5 trials ‐ 2 trials were not included in the range; one reported no significant difference in the % change from baseline in FEV 1 for conventional chest physiotherapy (24% change) and oscillating devices (31% change) and the second did not report sufficient information to include in the analysis.

c. Results from 1 trial; the second trial did not provide sufficient information to provide an estimate of effect.

d. Range of results from 2 trials; the other trials did not provide sufficient quantitative data, but reported no significant difference between PEP mask therapy and oscillating devices in FEV 1 .

e. Range of results from 4 trials. An additional trial reported FEV 1 L; there were no statistically significant differences between PEP mask therapy and Cornet (MD ‐0.12 L (95% CI ‐1.47 L to 1.23 L)) and Flutter® (MD ‐0.12 L (95% CI ‐1.55 L to 1.31 L)).

Conventional chest physiotherapy versus PEP therapy

This comparison was addressed in two reviews which included a total of seven trials with 181 participants; both reviews evaluated FEV 1 ( Main 2005 ; McIlwaine 2015 ). Four of the trials were included in both reviews ( Darbee 1990 ; Gaskin 1998 ; McIlwaine 1997 ; van Asperen 1987 ). The Main review excluded one trial ( Braggion 1995 ) because the follow‐up duration was less than one week ( Main 2005 ). The two reviews classified one trial into different comparisons ( McIlwaine 1991 ); a second trial reported FEV 0.75 instead of FEV 1 ( Tyrrell 1986 ) and the FEV 0.75 results were included in the one review ( McIlwaine 2015 ), but not the second review ( Main 2005 ).

Short‐term trials with a follow‐up of one week or less

One cross‐over trial (16 participants) followed participants for two days and reported on FEV 1 but did not have a sufficient washout period, and is therefore excluded from our analysis ( Braggion 1995 ).

Medium‐term trials with a follow‐up longer than one week and up to six months

Four cross‐over trials (63 participants) with follow‐up ranging from four weeks to three months compared conventional chest physiotherapy with PEP therapy ( Darbee 1990 ; McIlwaine 1991 ; Tyrrell 1986 ; van Asperen 1987 ). We excluded three trials from the overview due to an insufficient washout period ( Darbee 1990 ; Tyrrell 1986 ; van Asperen 1987 ). The only cross‐over trial with a sufficient washout period found no significant difference in FEV 1 % predicted between the two groups, mean difference (MD) ‐0.65% (95% CI ‐5.66 to 4.36), but the strength of evidence was graded as very low and we are unable to draw conclusions ( McIlwaine 1991 ). We considered this trial to have an unclear risk of bias because it did not report on random sequence generation, allocation concealment, or blinding of the outcome assessors. The results were imprecise and may be subject to reporting bias.

Long‐term trials with a follow‐up longer than six months

Two trials (102 participants) with follow‐up ranging from one to two years compared conventional chest physiotherapy to PEP therapy and reported on FEV 1 ( Gaskin 1998 ; McIlwaine 1997 ). One of the trials was conducted in children and showed a significant difference favouring PEP therapy, MD ‐8.26% predicted (95% CI ‐15.76 to ‐0.76% predicted) ( McIlwaine 1997 ). The second trial was conducted in adults and showed no significant difference between treatment groups, MD 0.65% predicted (95% CI ‐1.95 to 3.35% predicted) ( Gaskin 1998 ).

Both trials had unclear to low risk of bias. One of the trials blinded the outcome assessors, had a low rate of withdrawals, and specified the randomisation sequence generation ( McIlwaine 1997 ). The second trial was published only as an abstract and did not provide sufficient details about the methodology to adequately assess trial quality ( Gaskin 1998 ). Due to the inconsistency and imprecision of the results, we are unable to draw a conclusion about the long‐term effects of conventional chest physiotherapy compared with PEP therapy on FEV 1 (very low strength of evidence).

Conventional chest physiotherapy versus active cycle of breathing technique

This comparison was addressed in two reviews which included a total of four trials (102 participants) which evaluated FEV 1 ( Main 2005 ; McKoy 2016 ). One trial was included in both reviews ( Reismann 1988 ). A further trial ( Osman 2008 ) was included in one review ( McKoy 2016 ) and is being considered for inclusion in the second review ( Main 2005 ). Main excluded two trials because the duration of follow‐up was less than one week ( Pryor 1979 ; Webber 1985 ).

Three cross‐over trials (39 participants) with two to four days of follow‐up compared conventional chest physiotherapy with active cycle of breathing technique ( Osman 2008 ; Pryor 1979 ; Webber 1985 ). Two trials were excluded due to an insufficient washout period ( Pryor 1979 ; Webber 1985 ). The third trial also had an insufficient washout period, but was considered because first‐arm data were obtained. However, there was only one participant who received the active cycle of breathing technique during that period ( Osman 2008 ). No conclusions can be drawn about the short‐term effects of conventional chest physiotherapy versus active cycle of breathing technique on FEV 1 due to the lack of data.

Neither review included any medium‐term trial for this comparison.

Long‐term trials with a follow up longer than six months

One trial (63 participants) with 2.4 years of follow‐up compared conventional chest physiotherapy with active cycle of breathing technique and reported on FEV 1 ( Reismann 1988 ). The change in FEV 1 % predicted between interventions was not statistically significant, MD 2.8% predicted (95% CI ‐0.39 to 5.99). This trial had an unclear risk of bias because it did not report on several methodological details, such as sequence generation, allocation concealment or blinding of outcome assessors. We graded the strength of evidence as low due to the unclear risk of bias and the imprecise results. Both airway clearance techniques had a similar effect on FEV 1 .

Conventional chest physiotherapy versus autogenic drainage

This comparison was addressed in two reviews ( Main 2005 ; McCormack 2017 ) which included two trials (54 participants) evaluating FEV 1 ( Davidson 1992 ; McIlwaine 1991 ). The McCormack review considered the evidence from both of these trials and graded the evidence comparing conventional chest physiotherapy and autogenic drainage for FEV 1 % predicted as very low ( McCormack 2017 ).

The review did not include any short‐term trials comparing conventional chest physiotherapy with autogenic drainage.

One cross‐over trial (18 participants) with a two‐month follow‐up and a sufficient washout period compared conventional chest physiotherapy with autogenic drainage ( McIlwaine 1991 ). The trial reported that the difference between treatments in FEV 1 % predicted was not statistically significant, MD 1.29% predicted (95% CI ‐4.07 to 6.65). This trial was only published as an abstract and did not provide sufficient information to assess trial quality. The strength of evidence was graded as very low because of the unclear risk of bias, the imprecise results, and the strong suspicion of reporting bias. No conclusions can be drawn based on this evidence.

One trial lasting one year (36 participants) compared conventional chest physiotherapy with autogenic drainage and reported on FEV 1 % predicted ( Davidson 1992 ). Results showed no difference between treatments, MD 2.79% predicted (95% CI ‐4.54 to 10.12). This trial was only published as an abstract and did not provide sufficient information to assess trial quality. The strength of evidence was graded as very low because of the unclear risk of bias, the imprecise results, and the strong suspicion of publication bias.

Conventional chest physiotherapy versus oscillating devices

This comparison was addressed by two reviews including a total of 11 trials (389 participants) ( Main 2005 ; Morrison 2017 ). Three trials were included in both reviews ( Arens 1994 ; Homnick 1995 ; Homnick 1998 ). There were differences between the reviews; Morrison excluded one trial because the authors did not consider acoustic percussion as an oscillating device ( Kirkpatrick 1995 ) and did not mention a further trial ( Bauer 1994 ); while Main excluded one trial because the duration of follow‐up was less than one week ( Braggion 1995 ) and listed five trials for consideration for inclusion in a future update ( Giles 1996 ; Gondor 1999 ; Hare 2002 ; Modi 2006 ; Padman 1999 ). The Morrison review graded the evidence comparing conventional chest physiotherapy and oscillating devices for FEV 1 % predicted as very low ( Morrison 2017 ).

Three trials (86 participants), one of which was of cross‐over design, compared conventional chest physiotherapy with an oscillating device and evaluated FEV 1 between two days to one week ( Arens 1994 ; Braggion 1995 ; Gondor 1999 ). The cross‐over trial was not included in the analysis due to an insufficient washout period ( Braggion 1995 ). One trial reported no significant differences in the % change from baseline in FEV 1 % predicted between groups ( Arens 1994 ). The third trial showed no significant differences between groups in the change in FEV 1 % predicted, MD ‐13.00% predicted (95% CI ‐34.91 to 8.91% predicted) ( Gondor 1999 ). Based on these two trials, we conclude that the two airway clearance techniques had a similarly positive effect on FEV 1 % predicted.

Both trials were considered to have an unclear risk of bias since, with a few exceptions, they did not report sufficient details about methodology to assess trial quality. One of the trials blinded the outcome assessors, but it also had a high loss to follow‐up ( Gondor 1999 ). We graded the strength of evidence as low because of the unclear risk of bias and the imprecise results.

There were 10 trials (373 participants) with a follow‐up ranging from two weeks to six months which compared conventional chest physiotherapy with an oscillating device and reported on FEV 1 ( Arens 1994 ; Bauer 1994 ; Giles 1996 ; Gondor 1999 ; Hare 2002 ; Homnick 1995 ; Homnick 1998 ; Kirkpatrick 1995 ; Modi 2006 ; Padman 1999 ). Three trials were of cross‐over design ( Giles 1996 ; Kirkpatrick 1995 ; Padman 1999 ), two of which were excluded because they did not have a sufficient washout period between treatment groups ( Kirkpatrick 1995 ; Padman 1999 ). The mean between‐group difference from five trials for FEV 1 % predicted ranged from ‐18% to 0.70% predicted ( Bauer 1994 , Giles 1996 , Gondor 1999 , Homnick 1995 , Homnick 1998 ). Two further trials reported no between‐group differences in FEV 1 % predicted, but reported the results as % change ( Arens 1994 ) and longitudinal change ( Modi 2006 ). A final trial did not provide sufficient data to include in the analysis ( Hare 2002 ).

The trials were considered to have an unclear to high risk of bias since, with a few exceptions, they did not report sufficient details about methodology to assess trial quality. One of the trials blinded the outcome assessors ( Gondor 1999 ). Three trials had a high loss to follow‐up ( Gondor 1999 ; Homnick 1995 ; Modi 2006 ). Four trials had a high risk of reporting bias ( Giles 1996 ; Hare 2002 ; Homnick 1998 ; Modi 2006 ), and two trials were published only as conference abstracts ( Giles 1996 ; Hare 2002 ). We graded the evidence as very low because of the high risk of bias and the strong suspicion of publication bias.

Neither review included any trials that evaluated this comparison after six months of follow‐up.

Conventional chest physiotherapy versus exercise

This comparison was addressed in one review ( Main 2005 ), which included one medium‐term trial (17 participants) which reported on FEV 1 ( Cerny 1989 ).

The review did not include any short‐term trials comparing conventional chest physiotherapy to exercise.

One trial (17 participants) with a two‐week follow‐up compared conventional chest physiotherapy with exercise among people with CF who had been hospitalised for an acute exacerbation ( Cerny 1989 ). Participants in the conventional chest physiotherapy group improved significantly more than those in the exercise group (low strength of evidence). The difference in the change in FEV 1 % predicted was significant, MD 7.05% predicted (95% CI 3.15% to 10.95% predicted). However, these results should be interpreted with caution because the conventional chest physiotherapy group had a worse respiratory function at baseline. This trial was considered to have an unclear risk of bias and imprecise results.

The review did not include any long‐term trials that compared conventional chest physiotherapy with exercise.

PEP therapy versus active cycle of breathing technique

This comparison was addressed by two reviews ( McIlwaine 2015 ; McKoy 2016 ). The two reviews included two trials which followed a total of 46 participants for longer than one day and reported on FEV 1 ( Kofler 1994 ; Pryor 2010 ). One trial was included in both reviews ( Pryor 2010 ); but one review did not include the comparison for PEP therapy and active cycle of breathing technique and lists the Kofler trial as awaiting classification ( McIlwaine 2015 ).

Neither review included any short‐term trials that evaluated this comparison.

One trial (20 participants) with a four‐month follow‐up compared PEP therapy with active cycle of breathing technique and reported on FEV 1 ( Kofler 1994 ). This trial did not report on the duration of the washout period and could therefore be subject to a carry‐over effect. This trial was excluded from the analysis.

One trial recruited 75 participants and randomised them to one of five treatment groups (two of which were active cycle of breathing technique and PEP therapy with 26 participants randomised to these treatment groups) and reported on FEV 1 L at 12 months ( Pryor 2010 ). There was no significant difference in FEV 1 L between the two treatments at the end of the 12 months, MD ‐0.08 L (95% CI ‐0.85 to 0.69 L) (low strength of evidence). This trial had an adequate randomisation scheme and it blinded the outcome assessors, but it lost a high proportion of participants during follow‐up. The results were imprecise.

PEP therapy versus autogenic drainage

This comparison was addressed in two reviews ( McCormack 2017 ; McIlwaine 2015 ), which included two trials (48 participants) which reported on FEV 1 ( McIlwaine 1991 ; Pryor 2010 ). One trial ( McIlwaine 1991 ) was included in both reviews, but the second trial ( Pryor 2010 ) was included only in the McCormack review. The McCormack review graded the evidence comparing PEP therapy with autogenic drainage as low for FEV 1 L ( McCormack 2017 ).

The review did not include any short‐term trials comparing PEP therapy with autogenic drainage.

One trial (18 participants) with a cross‐over design and with an adequate washout period compared PEP therapy with autogenic drainage and reported on FEV 1 ( McIlwaine 1991 ). There was no significant difference in FEV 1 after two months of treatment (very low strength of evidence). We considered this trial to have an unclear risk of bias because it did not provide adequate details on the trial methodology. We were unable to assess precision because no quantitative results were presented. We suspected publication bias because the trial was only published as an abstract.

One RCT recruited 75 participants and randomised them to one of five treatment groups (two of which were PEP therapy and autogenic drainage with 30 participants randomised to these groups) and reported on FEV 1 L at 12 months ( Pryor 2010 ). There was no significant difference in FEV 1 L between the two treatments at the end of the 12 months, MD ‐0.62 L (95% CI ‐1.54 to 0.30 L) (low strength of evidence). This trial had an adequate randomisation scheme and it blinded the outcome assessors, but it lost a high proportion of participants during follow‐up. The results were imprecise.

PEP therapy versus oscillating devices

This comparison was addressed by two reviews which between them included 13 trials (421 participants) with a duration of follow‐up longer than one day and which reported on FEV 1 ( McIlwaine 2015 ; Morrison 2017 ). Seven trials were included in both reviews ( Braggion 1995 ; McIlwaine 2001 ; McIlwaine 2013 ; Newbold 2005 ; Prasad 2005 ; Pryor 2010 ; van Winden 1998 ). The earlier review lists five trials to be considered in a future update of the review ( Davies 2012 ; Gotz 1995 ; Grzincich 2008 ; Khan 2014 ; West 2010 ) and excludes one trial ( Padman 1999 ) which is included in the Morrison review since the intervention did not meet their criteria for PEP therapy ( McIlwaine 2015 ). Morrison graded the evidence comparing PEP therapy with oscillating devices as very low for FEV 1 ( Morrison 2017 ).

Three trials (69 participants) with two to seven days of follow‐up compared PEP therapy with oscillating devices and reported on FEV 1 ( Braggion 1995 , Grzincich 2008 , Khan 2014 ). We excluded one of these trials from our analysis of FEV 1 because it was a cross‐over trial with an insufficient washout period ( Braggion 1995 ). The remaining two trials reported no significant differences between PEP therapy and oscillating devices in FEV 1 % predicted (very low strength of evidence) ( Grzincich 2008 ; Khan 2014 ). In one trial, the final between‐group difference was MD 0% predicted (95% CI ‐10.98 to 10.98% predicted) ( Grzincich 2008 ). Both trials were judged to have an unclear risk of bias because neither reported sufficient detail about the methodology to assess trial quality. The results were imprecise and could be subject to publication bias.

Five trials (103 participants), three of which were cross‐over trials, with two to four weeks of follow‐up compared PEP therapy with oscillating devices ( Davies 2012 ; Gotz 1995 ; Padman 1999 ; van Winden 1998 ; West 2010 ). We excluded one trial from the analysis because it was a cross‐over trial and did not specify the duration of the washout period ( Padman 1999 ). The remaining two cross‐over trials had washout periods of one to two weeks ( Gotz 1995 , van Winden 1998 ). The four trials reported no significant differences between treatments for FEV 1 % predicted (very low strength of evidence). The mean between‐group differences from the two trials that reported sufficient quantitative data ranged from 0.49% to 9.37% predicted ( van Winden 1998 ; West 2010 ). The four trials had a low to unclear risk of bias; the results were imprecise, and there were concerns about publication bias ( Davies 2012 ; Gotz 1995 ; van Winden 1998 ; West 2010 ).

Five trials (249 participants) with 12 to 13 months of follow‐up compared PEP therapy with oscillating devices and reported on FEV 1 ( McIlwaine 2001 ; McIlwaine 2013 ; Newbold 2005 ; Prasad 2005 ; Pryor 2010 ). All of the trials reported there were no statistically significant between‐group differences. The between‐group difference in FEV 1 % predicted from four of these trials ranged from ‐9.71% to 3.59% predicted ( McIlwaine 2001 ; McIlwaine 2013 ; Newbold 2005 ; Prasad 2005 ). The fifth trial, which reported results in FEV 1 L, randomised participants to one of five treatment groups, three of which were PEP therapy (13 participants), Cornet® oscillating device (14 participants), and Flutter® oscillating device (12 participants). There were no statistically significant differences in the between‐group difference in FEV 1 L between PEP therapy and Cornet, MD ‐0.12 L (95% CI ‐1.47 to 1.23 L) and between PEP and Flutter, MD ‐0.12 L (95% CI ‐1.55 to 1.31 L) ( Pryor 2010 ).

We graded the strength of the evidence as moderate. These five trials had a low to unclear risk of bias because many of the included trials had an adequate randomisation scheme, blinded the outcome assessors, and had a low loss to follow‐up ratio, but the results were imprecise ( Davies 2012 ; Gotz 1995 ; Padman 1999 ; van Winden 1998 ; West 2010 ).

PEP therapy versus exercise

This comparison was eligible for inclusion in one review, but it did not include any trials ( McIlwaine 2015 ).

Active cycle of breathing technique versus autogenic drainage

This comparison was addressed in two reviews ( McCormack 2017 ; McKoy 2016 ). Both reviews included two trials (48 participants) which had a duration of follow‐up longer than one day ( Miller 1995 ; Pryor 2010 ). The later review graded the evidence comparing active cycle of breathing technique with autogenic drainage as low ( McCormack 2017 ).

One cross‐over trial (18 participants) with a sufficient washout period compared active cycle of breathing technique with autogenic drainage and followed participants for two days ( Miller 1995 ). The trial reported no significant differences in pulmonary function tests between the two airway clearance techniques, but did not provide any data to support this statement. This trial did not provide sufficient information to assess trial quality or to determine the precision of the results. We graded the strength of evidence as very low because of the unclear risk of bias, the imprecise results, and the strong suspicion of reporting bias ( Miller 1995 ).

The review did not include any medium‐term trials that compared active cycle of breathing technique with autogenic drainage.

One trial recruited 75 participants and randomised them to one of five treatment groups, two of which were the active cycle of breathing technique (15 participants) and autogenic drainage (15 participants) ( Pryor 2010 ). The between‐group difference in final values for FEV 1 L was not statistically significant, MD ‐0.7 L (95% CI ‐1.49 L to 0.09 L) (low strength of evidence). This trial had an adequate randomisation scheme and it blinded the outcome assessors; however, it also lost a high percentage of participants to follow‐up and the results were imprecise ( Pryor 2010 ).

Active cycle of breathing technique versus oscillating devices

This comparison was addressed by two reviews ( McKoy 2016 ; Morrison 2017 ), which included one long‐term trial with 45 participants ( Pryor 2010 ). The Morrison review graded the evidence comparing breathing techniques, including active cycle of breathing technique, with oscillating devices as low ( Morrison 2017 ).

The review did not include any short‐term trials that compared active cycle of breathing technique with an oscillating device.

The review did not include any medium‐term trials that compared active cycle of breathing technique with an oscillating device.

One trial recruited 75 participants and randomised them to one of five treatment groups (three of which were active cycle of breathing technique, and the Cornet® and Flutter® oscillating devices with 45 participants randomised to these groups); it reported FEV 1 L at 12 months ( Pryor 2010 ). There was no significant difference in FEV 1 L between the active cycle of breathing technique and Cornet®, MD 0.04 L (95% CI ‐0.60 L to 0.68 L) and Flutter®, MD ‐0.49 L (95% CI ‐1.18 L to 0.20 L) at the end of the 12 months (low strength of evidence). This trial had an adequate randomisation scheme and it blinded the outcome assessors; however, it also lost a high percentage of participants to follow‐up and the results for both comparisons were imprecise ( Pryor 2010 ).

Active cycle of breathing technique versus exercise

One review addressed this comparison, but did not include any eligible trials ( McKoy 2016 ).

Autogenic drainage versus oscillating devices

Two reviews addressed this comparison ( McCormack 2017 ; Morrison 2017 ). Both reviews included two trials that followed 59 participants for longer than one day and reported on FEV 1 ( App 1998 ; Pryor 2010 ). One review graded the evidence comparing autogenic drainage with Cornet® as moderate and the evidence comparing autogenic drainage with Flutter® as low ( McCormack 2017 ). The second review graded the evidence comparing breathing techniques, including autogenic drainage, with oscillating devices as low ( Morrison 2017 ).

This review did not include any short‐term trials that compared autogenic drainage with oscillating devices.

One cross‐over trial (14 participants) with four weeks of follow‐up and an adequate washout period compared autogenic drainage with an oscillating device and reported on FEV 1 ( App 1998 ). The between‐group difference for the change in FEV 1 L was not significant, MD ‐0.1 L (95% CI ‐1.96 L to 1.76 L) (very low strength of evidence). We considered the trial to have an unclear risk of bias because it did not report sufficient details about its methodology to assess trial quality and the results were imprecise ( App 1998 ).

One trial recruited 75 participants and randomised them to one of five treatment groups (three of which were autogenic drainage, and the Cornet® and Flutter® oscillating devices with 45 participants randomised to these groups) and reported on FEV 1 L at 12 months ( Pryor 2010 ). At the end of the 12 months, there was no significant difference in FEV 1 L between the autogenic drainage and Cornet® groups, MD ‐0.01 L (95% CI ‐1.44 L to 1.42 L) or the autogenic drainage and Flutter® groups, MD ‐0.01 L (95% CI ‐1.51 L to 1.49 L) (low strength of evidence). The trial had an adequate randomisation scheme and it blinded the outcome assessors; but it also lost a high percentage of participants to follow‐up and the results for both comparisons were imprecise ( Pryor 2010 ).

Autogenic drainage versus exercise

One review addressed this comparison, but did not include any eligible trials ( McCormack 2017 ).

Oscillating devices versus exercise

One review addressed this comparison, but it did not include any eligible trials ( Morrison 2017 ).

Airway oscillating devices versus external high frequency chest compression devices

One review addressed this comparison ( Morrison 2017 ); it included two medium‐term trials with 190 participants and reported on FEV 1 ( Modi 2006 ; Oermann 2001 ). The review graded the evidence comparing an oscillating device with any other oscillating device as very low.

This review did not include any short‐term trials comparing an airway oscillating device with an external high frequency chest compression device.

Two trials (190 participants) compared an airway oscillating device with an external high frequency chest compression device and reported on FEV 1 ( Modi 2006 ; Oermann 2001 ). One of these trials was a three‐arm trial of parallel design lasting two months ( Modi 2006 ) and the second was a cross‐over trial with a two‐week washout period and a four‐week follow‐up period ( Oermann 2001 ). In the cross‐over trial, the between‐group difference in the change in FEV 1 % predicted was not significant, MD ‐2.3% predicted (95% CI ‐5.44% to 0.84% predicted) ( Oermann 2001 ). The three‐arm trial reported no significant differences between the treatment groups ( Modi 2006 ). Both trials had an unclear risk of bias because neither reported sufficient detail about trial methodology and the results were imprecise and subject to reporting bias.

This review did not include any long‐term trials for this comparison.

Airway oscillating devices (Flutter®) versus airway oscillating devices (Cornet®)

One review addressed this comparison ( Morrison 2017 ); it included one long‐term trial with 30 participants reporting on FEV 1 ( Pryor 2010 ). The review graded the evidence comparing an oscillating device with any other oscillating device as very low ( Morrison 2017 ).

This review did not include any short‐term trials that compared Flutter® with Cornet®.

This review did not include any medium‐term trials comparing Flutter® with Cornet®.

One trial recruited 75 participants and randomised them to one of five treatment groups (two of which were the Cornet® and Flutter® oscillating devices with 30 participants randomised to these groups) and reported on FEV 1 L at 12 months ( Pryor 2010 ). There was no significant difference in FEV 1 L between the Flutter® and Cornet® at the end of the 12 months, MD 0 L (95% CI ‐1.22 L to 1.22 L) (low strength of evidence). This trial had an adequate randomisation scheme and it blinded the outcome assessors, but it also lost a high percentage of participants to follow‐up and the results for were imprecise ( Pryor 2010 ).

Airway oscillating devices versus intrapulmonary percussive ventilation

One review addressed this comparison ( Morrison 2017 ); it included one medium‐term trial with 16 participants ( Marks 2001 ). The review graded the evidence comparing an oscillating device with any other oscillating device as very low.

This review did not include any short‐term trials that compared an airway oscillating device with intrapulmonary percussive ventilation.

One trial (16 participants) with a six‐month follow‐up compared an airway oscillating device with intrapulmonary percussive ventilation ( Marks 2001 ). The between‐group differences in FEV 1 were not significant (P = 0.217). We are unable to draw a conclusion (very low strength of evidence). The trial had an unclear risk of bias because it did not report sufficient detail about its methodology. We were unable to assess precision because the trial did not report sufficient data on their results ( Marks 2001 ).

This review did not include any long‐term trials that compared an airway oscillating device with intrapulmonary percussive ventilation.

Chest physiotherapy versus no chest physiotherapy

One review addressed this comparison ( Warnock 2015 ); it included two short‐term trials with 35 participants ( Braggion 1995 ; Jarad 2010 ).

Two cross‐over trials (35 participants) followed participants for two days and reported on FEV 1 ( Braggion 1995 ; Jarad 2010 ). One trial did not have a sufficient washout period and is therefore excluded from our analysis ( Braggion 1995 ). We included the second cross‐over trial which had a one‐week washout period between therapies ( Jarad 2010 ). The between‐group difference in the change in FEV 1 L was not significant, MD ‐0.02 L (95% CI ‐0.77 L to 0.73 L) (low strength of evidence). The trial had an unclear risk of bias because it did not report sufficient detail about its methodology and the results were imprecise.

This review did not include any medium‐term trials that compared chest physiotherapy with no chest physiotherapy.

This review did not include any long‐term trials that compared chest physiotherapy with no chest physiotherapy.

2. Participant preference

The results for participant preference for airway clearance techniques are summarised in the additional tables ( Table 4 ) and we present a gap map summarizing the results and the quality of the evidence (GRADE) for participant preference as a figure ( Figure 3 ).

An external file that holds a picture, illustration, etc. Object name is nCD011231-AFig-FIG03.jpg

Gap map summarizing the results and quality of the evidence (GRADE) for participant preference.

Abbreviations : CI : confidence interval; PEP : positive expiratory pressure; RCT : randomised controlled trial.

This comparison was addressed in two reviews ( Main 2005 ; McIlwaine 2015 ) including a total of five trials (87 participants) that evaluated participant preference. Three trials were included in both reviews ( Costantini 2001 ; Darbee 1990 ; McIlwaine 1997 ). Main excluded one trial because the follow‐up duration was shorter than one week ( Braggion 1995 ). One trial reported the airway clearance technique used by participants six months after the trial ( Tyrrell 1986 ); one review captured this as preference ( Main 2005 ), but the second review did not ( McIlwaine 2015 ).

Participant preference was assessed by one cross‐over trial that followed seven participants for two days ( Braggion 1995 ). Preference was measured indirectly using a three‐point rating scale of tolerance. The trial reported no significant differences between conventional chest physiotherapy and PEP therapy, but did not provide sufficient details about their methodology to assess trial quality, nor did it provide sufficient information about the results to assess precision. Due to the unclear risk of bias, the indirect measurement of precision, and the unclear precision of results, we cannot draw a conclusion about the short‐term preference for conventional chest physiotherapy compared with PEP therapy (very low strength of evidence).

Two cross‐over trials (32 participants) with two to three months of follow‐up evaluated participant preference for conventional chest physiotherapy compared with PEP therapy ( Darbee 1990 ; Tyrrell 1986 ). Both trials reported that participants preferred PEP therapy over conventional chest physiotherapy (very low strength of evidence). However, we are unable to draw a conclusion based on this evidence. Firstly, both trials had an unclear risk of bias as neither provided sufficient detail to assess quality. Secondly, there were serious limitations to how participant preference was assessed; one of the trials did not directly assess preference, but rather reported the number of participants using each therapy six months after the trial ( Tyrrell 1986 ), and the second trial did not describe how preference was measured ( Darbee 1990 ). Furthermore, neither trial provided sufficient detail to assess precision; and finally, the results are subject to reporting bias. One trial was published only as an abstract ( Darbee 1990 ) and both trials failed to report sufficient outcome data ( Darbee 1990 ; Tyrrell 1986 ).

Two trials (48 participants) with one year of follow‐up compared participant preference for conventional chest physiotherapy and PEP therapy ( Costantini 2001 ; McIlwaine 1997 ). Both trials were conducted in children, so participant preference was answered by the caregivers. Both trials reported that caregivers preferred PEP therapy over conventional chest physiotherapy (very low strength of evidence); the trials had an unclear to low risk of bias. One of the trials blinded the outcome assessors, had a low rate of withdrawals, and specified the randomisation sequence generation ( McIlwaine 1997 ). The second trial was published only as an abstract and did not provide sufficient details about their methodology to adequately assess trial quality ( Costantini 2001 ). There are some serious limitations to the body of evidence that prevents us from drawing a conclusion. Firstly, it is unclear if either trial directly measured participant preference; one trial assessed preference only in participants who received PEP therapy and the second trial did not specify how preference was assessed. Secondly, neither trial reported sufficient information for the results to assess their precision. Lastly, publication bias is strongly suspected because one of the trials is published only as an abstract.

This comparison was addressed in two reviews, but neither included any trials that reported on participant preference ( Main 2005 ; McKoy 2016 ).

This comparison was addressed in two reviews ( Main 2005 ; McCormack 2017 ); both reviews included one long‐term trial (36 participants) that evaluated participant preference ( Davidson 1992 ). The McCormack review considered the evidence from this trial and graded the evidence comparing conventional chest physiotherapy and autogenic drainage for participant preference as very low ( McCormack 2017 ).

The reviews did not include any short‐term trials that compared conventional chest physiotherapy with autogenic drainage.

The reviews did not include any medium‐term trials that compared conventional chest physiotherapy with autogenic drainage.

Participant preference was assessed in one trial that followed 36 participants for one year ( Davidson 1992 ). Participants preferred autogenic drainage over conventional chest physiotherapy, but there are several limitations that prevent us from drawing a conclusion (very low strength of evidence). The trial did not provide sufficient information about methodology to assess quality, so it was considered to have an unclear risk of bias. Participant preference was not formally assessed; rather, it was observed that participants who received autogenic drainage first refused to switch treatments during the second period. Since preference was not assessed in both groups, there is insufficient information to assess precision. Publication bias is strongly suspected because results were reported only as conference abstracts.

This comparison was addressed in two reviews ( Main 2005 ; Morrison 2017 ), which included a total of nine trials (366 participants) which evaluated participant preference ( Arens 1994 ; Bauer 1994 ; Braggion 1995 ; Giles 1996 ; Hare 2002 ; Homnick 1995 ; Modi 2006 ; Padman 1999 ; Varekojis 2003 ). Two trials were included in both reviews ( Arens 1994 ; Homnick 1995 ), but the Morrison review did not mention one trial ( Bauer 1994 ). One trial had a follow‐up duration of less than one week and was therefore excluded from the Main review ( Braggion 1995 ); the same review listed five trials ( Giles 1996 ; Hare 2002 ; Modi 2006 ; Padman 1999 ; Varekojis 2003 ) as being considered for inclusion in future updates ( Main 2005 ). The Morrison review graded the evidence comparing conventional chest physiotherapy and oscillating devices for participant preference as very low ( Morrison 2017 ).

Two cross‐over trials (40 participants) with a two‐day follow‐up evaluated participant preference for conventional chest physiotherapy compared to oscillating devices ( Braggion 1995 ; Varekojis 2003 ). Both trials had a high risk of bias; one had a high loss to follow‐up and was subject to reporting bias, and the second had recruitment issues where participants may have been double‐counted. We are unable to draw a conclusion about participant preference (very low strength of evidence).

Seven trials (two of cross‐over design) (326 participants), with between two weeks and six months of follow‐up, evaluated participant preference for conventional chest physiotherapy or an oscillating device ( Arens 1994 ; Bauer 1994 ; Giles 1996 ; Hare 2002 ; Homnick 1995 ; Modi 2006 ; Padman 1999 ). These trials had an unclear to high risk of bias; none of them were blinded or described their randomisation scheme. One trial had a high risk of selection bias ( Hare 2002 ), three trials had a high risk of attrition bias ( Homnick 1995 ; Modi 2006 ; Padman 1999 ) and four trials had a high risk of reporting bias ( Giles 1996 ; Hare 2002 ; Modi 2006 ; Padman 1999 ). Most of the seven trials reported a preference for or a satisfaction with oscillating devices, but two trials only assessed preference among the participants assigned to the oscillating device group ( Arens 1994 ; Bauer 1994 ; Giles 1996 ; Hare 2002 ; Homnick 1995 ; Modi 2006 ). The strength of evidence was graded as very low, and we are unable to draw a conclusion.

Neither review included any long‐term trials that evaluated this comparison.

The review which addressed this comparison did not include any eligible trials ( Main 2005 ).

This comparison was addressed by two reviews ( McIlwaine 2015 ; McKoy 2016 ). There was a single relevant medium‐term trial (20 participants) ( Kofler 1994 ); this trial is included in one review ( McKoy 2016 ) and listed as awaiting classification in the second review ( McIlwaine 2015 ).

Medium‐term trials with a follow up longer than one week and up to six months

One cross‐over trial (20 participants) with a four‐month follow‐up compared PEP therapy with active cycle of breathing technique and reported on participant preference ( Kofler 1994 ). This trial, with an unclear risk of bias and imprecise results, suggested that individuals may prefer PEP therapy over active cycle of breathing technique (very low strength of evidence). However, we are unable to draw a conclusion.

Neither review included any long‐term trials evaluating this comparison.

This comparison was addressed in two reviews ( McIlwaine 2015 ; McCormack 2017 ), which included a total of two trials (48 participants) ( McIlwaine 1991 ; Pryor 2010 ). Each review evaluated a different trial for participant preference; we suspect the discrepancy in inclusion is due to different interpretations of preference, such as participant satisfaction. The McCormack review graded the evidence for participant preference for PEP therapy versus autogenic drainage as low ( McCormack 2017 ).

The review did not include any short‐term trials that compared PEP therapy with autogenic drainage.

One two‐month cross‐over trial (18 participants) compared PEP therapy with autogenic drainage and reported on participant preference ( McIlwaine 1991 ). Preference was indirectly assessed by rating five measures that may influence preference. Participants considered PEP therapy to have a shorter treatment time than autogenic drainage, but the two treatments were rated similarly on comfort, flexibility of treatment times, control in performing their own treatment, and interruptions to daily living. However, we are unable to draw a conclusion because of the very low strength of evidence. We considered this trial to have an unclear risk of bias because it did not provide adequate details on the methodology. We were unable to assess precision because there were no standard deviations reported and we suspect publication bias because the trial was only published as an abstract and the outcomes were not fully reported ( McIlwaine 1991 ).

One trial recruited 75 participants and randomised them to one of five treatment groups (two of which were PEP therapy and autogenic drainage with 30 participants randomised to these groups) ( Pryor 2010 ). This trial reported on the total number of participants who withdrew from the trial because they did not like their assigned treatment, but did not report this by treatment group. We graded the strength of evidence as very low because of the risk of bias, the indirect measure of participant preference, the lack of data to determine precision, and the suspicion of publication bias ( Pryor 2010 ).

This comparison was addressed by two reviews ( McIlwaine 2015 ; Morrison 2017 ); however, one review included only participant satisfaction as an outcome ( Morrison 2017 ) while the second considered either participant preference or satisfaction ( McIlwaine 2015 ). The two reviews included a total of seven trials (253 participants) of sufficient duration and reporting on participant preference ( Braggion 1995 ; McIlwaine 2001 ; McIlwaine 2013 ; Padman 1999 ; Prasad 2005 ; van Winden 1998 ; West 2010 ). Although five of the trials were included in both reviews, not all five were included in the analysis for participant preference ( Braggion 1995 ; McIlwaine 2001 ; McIlwaine 2013 ; Prasad 2005 ; van Winden 1998 ); we suspect that the differences between reviews are related to the differences in outcome definition. Morrison reported that there were no consistent differences across seven trials in terms of participant satisfaction and graded the evidence as very low ( Morrison 2017 ).

One cross‐over RCT (16 participants) with two days of follow‐up compared PEP therapy with oscillating devices and reported on participant preference using a three‐point scale of effectiveness and tolerance ( Braggion 1995 ). No significant differences between treatments were reported (data not provided). We graded the strength of evidence as very low. The trial had an unclear risk of bias because it did not provide sufficient detail about its methodology. We could not assess the directness and precision of the results because the trial did not provide sufficient information. We suspect publication bias because the trial was only published as an abstract and the outcomes were not fully reported ( Braggion 1995 ).

Three trials, two of which were cross‐over in design, (60 participants) with two to four weeks of follow‐up compared PEP therapy with oscillating devices and reported on participant preference ( Padman 1999 ; van Winden 1998 ; West 2010 ). One trial rated preference on a five‐point scale ( West 2010 ), another trial asked participants their device preference ( van Winden 1998 ), but the third trial did not adequately describe how preference was measured and did not provide quantitative results ( Padman 1999 ). One trial had a low risk of bias, but the other two trials had an unclear to high risk of bias because they did not report sufficient details about their methodology and one trial had a high loss to follow‐up. In the three trials, there were no significant differences in participant preference for either device, but we are unable to draw a conclusion. We graded the evidence as very low because of the serious limitations to the risk of bias, directness, and precision of the results.

Three trials (177 participants) with one year of follow‐up compared PEP therapy to oscillating devices and reported on participant preference, but each measured this outcome differently ( McIlwaine 2001 ; McIlwaine 2013 ; Prasad 2005 ). One reported the number of participants who withdrew from the trial due to perceived ineffectiveness of the treatment ( McIlwaine 2001 ) and a second trial reported the number who decided to continue with their assigned treatment after the trial ( Prasad 2005 ). In the third trial, participants rated the comfort, independence, and flexibility of the device using a visual analogue scale ( McIlwaine 2013 ). All three trials report no statistically significant differences between PEP therapy and oscillating devices; although participants in one trial rated PEP therapy as more flexible ( McIlwaine 2013 ). The trials had a low to unclear risk of bias. However, none of the trials directly measures preference and the results were imprecise. We, therefore, graded the strength of evidence as low.

The only review presenting this comparison did not include any trials reporting on participant preference ( McIlwaine 2015 ).

One review assessed this comparison ( McKoy 2016 ), which included one short‐term cross‐over trial (18 participants) which reported on participant preference ( Miller 1995 ).

The included trial compared active cycle of breathing technique with autogenic drainage with a two‐day follow‐up and reported that participant preference was split similarly between the two airway clearance techniques. There was not sufficient information to assess trial quality and we graded the strength of evidence as low because of the unclear risk of bias and the imprecise results ( Miller 1995 ).

The review did not include any medium‐term trials comparing the active cycle of breathing technique with autogenic drainage.

The review did not include any long‐term trials comparing the active cycle of breathing technique with autogenic drainage.

This comparison was reported by two reviews, neither of which included any eligible trials ( McKoy 2016 ; Morrison 2017 ).

The only review which compared the active cycle of breathing technique to exercise did not include any eligible trials ( McKoy 2016 ).

This comparison was addressed by two reviews ( McCormack 2017 ; Morrison 2017 ), but only one of these reviews ( McCormack 2017 ) included any eligible trials for patient preference. The McCormack review ( McCormack 2017 ) graded the evidence comparing autogenic drainage with oscillating devices (Flutter® or Cornet®) as low.

Neither review included any short‐term trials comparing autogenic drainage with oscillating devices.

Neither review included any medium‐term trials comparing autogenic drainage with oscillating devices.

One trial recruited 75 participants and randomised them to one of five treatment groups (three of which were autogenic drainage, Flutter®, and Cornet® with 45 participants randomised to these groups) ( Pryor 2010 ). This trial reported on the total number of participants who withdrew from the trial because they did not like their assigned treatment, but not by treatment group. We graded the strength of evidence as very low because of the risk of bias, the indirect measure of participant preference, the lack of data to determine precision, and the suspicion of publication bias ( Pryor 2010 ).

Only one review compared oscillating devices to exercise, but it did not include any eligible trials ( Morrison 2017 ).

One review compared airway oscillating devices to external high frequency chest compression devices ( Morrison 2017 ). It included two medium‐term trials which followed 190 participants and reported on participant preference ( Modi 2006 ; Oermann 2001 ). The review graded the evidence comparing an oscillating device with any other oscillating device as very low.

No short‐term trials reporting this comparison were included in the review ( Morrison 2017 ).

Two trials (190) with one to three months of follow‐up compared an airway oscillating device with an external high frequency chest compression device and reported on participant preference ( Modi 2006 ; Oermann 2001 ); one of these had a cross‐over design ( Oermann 2001 ). In this trial, participants rated the airway oscillating device as significantly more convenient and the external high frequency chest compression device as significantly more efficacious, but neither was favoured for comfort ( Oermann 2001 ). In the second trial, there were no significant differences in participant satisfaction measured in terms of overall preference, comfort, convenience, and efficacy ( Modi 2006 ). We are unable to draw any conclusion about participant preference for airway oscillating devices or external high frequency chest compression devices. Both trials had an unclear risk of bias because neither reported sufficient detail about methodology and the results were imprecise and subject to reporting bias ( Modi 2006 ; Oermann 2001 ).

The review did not include any long‐term trials comparing an airway oscillating device with an external high frequency chest compression device.

The only review that addressed this comparison did not include any eligible trials ( Morrison 2017 ).

One review addressed this comparison ( Morrison 2017 ) and included one medium‐term trial with 16 participants and reported on their preference ( Marks 2001 ). The review graded the evidence comparing an oscillating device with any other oscillating device as very low.

This review did not include any short‐term trials with this comparison of devices ( Morrison 2017 ).

One trial (16 participants) compared an airway oscillating device with intrapulmonary percussive ventilation and followed participants for six months ( Marks 2001 ). Participant satisfaction was only assessed in the intrapulmonary percussive ventilation group and most (67%) of those participants stated they were willing to continue with that device. We are unable to draw a conclusion about participant preference for the two devices because the trial had an unclear risk of bias, preference was only indirectly assessed, precision could not be assessed, and the results are subject to reporting bias ( Marks 2001 ).

This review did not include any eligible long‐term trials ( Morrison 2017 ).

The only review presenting this comparison included one short‐term trial ( Warnock 2015 ); the included trial followed 18 participants and reported on participant preference ( Jarad 2010 ).

Short‐term trials with a follow up of one week or less

One cross‐over trial (19 participants) reported on participant preference for hydro‐acoustic therapy (intervention not included in this review), an oscillating device (Flutter®), and placebo ( Jarad 2010 ). Interventions were given in a random sequence for two days with a one‐week washout period between treatments and participants were asked at the end of the trial which of the three treatment options they preferred. More participants preferred placebo over the oscillating device. However, we are unable to draw a conclusion about preference because the trial had an unclear risk of bias, preference was only indirectly assessed, and precision could not be assessed ( Jarad 2010 ).

The review did not include any medium‐term trials for this comparison ( Warnock 2015 ).

The review did not include any long‐term trials for this comparison ( Warnock 2015 ).

3. Quality of life

Results for quality of life (total scores or domain scores from validated instruments) are summarised in the additional tables ( Table 5 ) and we present a gap map summarising the results and the quality of the evidence (GRADE) for quality of life as a figure ( Figure 4 ).

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Gap map summarizing the results and quality of the evidence (GRADE) for quality of life.

Abbreviations : PEP : positive expiratory pressure; RCT : randomised controlled trial.

Two reviews compared conventional chest physiotherapy to PEP therapy ( Main 2005 ; McIlwaine 2015 ). They included the same two‐year trial (66 participants) which evaluated quality of life ( Gaskin 1998 ).

Neither review included a short‐term trial reporting on quality of life ( Main 2005 ; McIlwaine 2015 ).

Neither review included a medium‐term trial reporting on quality of life ( Main 2005 ; McIlwaine 2015 ).

One trial (66 participants) with two years of follow‐up evaluated quality of life using the Quality of Well‐Being scale and reported no significant differences between the treatments in their ability to affect quality of life (very low strength of evidence) ( Gaskin 1998 ). The trial had an unclear risk of bias because it was published only as an abstract and did not provide sufficient information to assess quality. There was also insufficient detail on the results to allow an assessment of precision and the results may be susceptible to reporting bias.

This comparison was addressed in two reviews, but neither included any trials that evaluated quality of life ( Main 2005 ; McKoy 2016 ).

Two reviews compared conventional chest physiotherapy with autogenic drainage ( Main 2005 ; McCormack 2017 ). One review ( McCormack 2017 ) included two cross‐over trials ( Davidson 1992 ; McIlwaine 1991 ) which evaluated quality of life, but the second review did not present any trials ( Main 2005 ). McCormack graded the evidence for this comparison on quality of life as very low ( McCormack 2017 ).

Neither review included a short‐term trial that reported on quality of life ( Main 2005 ; McCormack 2017 ).

One cross‐over trial (18 participants) with two months of follow‐up reported on quality of life ( McIlwaine 1991 ). However, they did not use a validated instrument to assess quality of life and therefore, this trial was excluded from our analysis.

One cross‐over trial (36 participants) with one year of follow‐up reported on quality of life ( Davidson 1992 ). However, they did not use a validated instrument to assess quality of life and therefore, this trial was excluded from our analysis.

Two reviews compared conventional chest physiotherapy with oscillating devices ( Main 2005 ; Morrison 2017 ). One review included one medium‐term trial (166 participants) ( Morrison 2017 ), but the second review did not present any trials ( Main 2005 ).

Neither review included a short‐term trial reporting on quality of life ( Main 2005 ; Morrison 2017 ).

One trial (166 participants) with two months of follow‐up evaluated quality of life using the CFQ ( Modi 2006 ). This trial reported no significant differences between treatments for all of the CFQ domains after adjusting for multiple comparisons. We graded the evidence as low because of the high risk of bias and the imprecise results.

Neither review included a short‐term trial that reported on quality of life ( Main 2005 ; Morrison 2017 ).

One review presented this comparison but did not include any trials that reported on quality of life ( Main 2005 ).

Two reviews compared PEP therapy to active cycle of breathing technique ( McIlwaine 2015 ; McKoy 2016 ). One multi‐arm trial with sufficient follow‐up was included in both reviews ( Pryor 2010 ), but one review did not include this trial in the comparison of PEP therapy and active cycle of breathing technique ( McIlwaine 2015 ).

Neither review included a short‐term trial comparing PEP therapy with active cycle of breathing technique ( McIlwaine 2015 ; McKoy 2016 ).

Neither review included a medium‐term trial comparing PEP therapy with active cycle of breathing technique ( McIlwaine 2015 ; McKoy 2016 ).

One 12‐month trial randomised 75 participants to one of five treatment groups, two of which were PEP therapy (13 participants) and active cycle of breathing technique (13 participants) ( Pryor 2010 ). The trial evaluated quality of life using two validated measures, the Short Form‐36 and the Chronic Respiratory Questionnaire, but found no significant differences between groups for the physical and mental domains of the Short Form‐36 and for the dyspnoea, fatigue, emotion and mastery domains of the Chronic Respiratory Questionnaire. This trial had an adequate randomisation scheme and it blinded the outcome assessors, but it also lost a high percentage of participants to follow‐up. We are unable to evaluate precision because the trial only reported P values for comparisons across the five treatment groups. We are unable to draw a conclusion and graded the strength of the evidence as very low because of the serious risk of bias, the lack of information to determine precision, and the suspected reporting bias.

Two reviews compared PEP therapy to active cycle of breathing technique ( McIlwaine 2015 ; McCormack 2017 ). One multi‐arm trial with sufficient follow‐up was included in both reviews ( Pryor 2010 ), but one review did not include this trial in the comparison of PEP therapy and autogenic drainage ( McIlwaine 2015 ). The McCormack review graded the strength of evidence as low ( McCormack 2017 ).

Neither review included a short‐term trial comparing PEP therapy with autogenic drainage ( McIlwaine 2015 ; McCormack 2017 ).

Neither review included a medium‐term trial comparing PEP therapy with autogenic drainage ( McIlwaine 2015 ; McCormack 2017 ).

One 12‐month trial randomised 75 participants to one of five treatment groups, two of which were PEP therapy (13 participants) and autogenic drainage (13 participants) ( Pryor 2010 ). The trial evaluated quality of life using two validated measures, the Short Form‐36 and the Chronic Respiratory Questionnaire, but found no significant differences between groups for the physical and mental domains of the Short Form‐36 and for the dyspnoea, fatigue, emotion and mastery domains of the Chronic Respiratory Questionnaire. This trial had an adequate randomisation scheme and it blinded the outcome assessors, but it also lost a high proportion of participants to follow‐up. We were unable to evaluate precision because the trial only reported P values for comparisons across the five treatment groups. We are unable to draw a conclusion and graded the strength of the evidence as very low because of the serious risk of bias, the lack of information to determine precision, and the suspected reporting bias ( Pryor 2010 ).

Two reviews compared PEP therapy to oscillating devices and included a total of four long‐term trials (209 participants) that reported on quality of life ( McIlwaine 2015 ; Morrison 2017 ). Two trials were included in both reviews ( Prasad 2005 ; Pryor 2010 ), but it is unclear why the McIlwaine review did not include the quality of life outcomes for the remaining two trials ( McIlwaine 2013 ; Newbold 2005 ).

Neither review included a short‐term trial for this comparison that reported on quality of life ( McIlwaine 2015 ; Morrison 2017 ).

Neither review included a medium‐term trial for this comparison that reported on quality of life ( McIlwaine 2015 ; Morrison 2017 ).

Four trials (209 participants) with a follow‐up of 12 to 13 months compared PEP therapy with an oscillating device and reported on quality of life using different scales ( McIlwaine 2013 ; Newbold 2005 ; Prasad 2005 ; Pryor 2010 ). One trial used the Cystic Fibrosis Questionnaire‐Revised ( McIlwaine 2013 ), two trials used the Chronic Respiratory Questionnaire ( Newbold 2005 ; Pryor 2010 ), two trials also used the Quality of Well‐Being Scale ( Newbold 2005 ; Prasad 2005 ) and one trial used the Short Form‐36 ( Pryor 2010 ). None of the trials reported any significant differences between PEP therapy and an oscillating device for any of the quality of life domains or total scores. We considered the trials to have a low to unclear risk of bias; three trials described their randomisation scheme ( McIlwaine 2013 ; Newbold 2005 ; Pryor 2010 ) and three had a low loss to follow‐up ( McIlwaine 2013 ; Newbold 2005 ; Prasad 2005 ). We graded the strength of evidence as low because of the imprecise results and suspicions of reporting bias.

The only review comparing PEP therapy to exercise did not include any trials that reported on quality of life ( McIlwaine 2015 ).

Two reviews compared active cycle of breathing technique to autogenic drainage ( McKoy 2016 ; McCormack 2017 ) and both included one trial (26 participants) with 12‐month follow‐up which reported on quality of life ( Pryor 2010 ). The McCormack review graded the strength of evidence as low ( McCormack 2017 ).

Neither review included any short‐term trials comparing active cycle of breathing technique with autogenic drainage and reporting on quality of life ( McKoy 2016 ; McCormack 2017 ).

The review did not include any medium‐term trials comparing active cycle of breathing technique with autogenic drainage and reporting on quality of life ( McKoy 2016 ).

As already described, one 12‐month trial recruited 75 participants and randomised them to one of five treatment groups, two of which were active cycle of breathing technique (13 participants) and autogenic drainage (13 participants) ( Pryor 2010 ). The trial evaluated quality of life using two validated measures, the Short Form‐36 and the Chronic Respiratory Questionnaire. There were no significant differences between groups for the physical and mental domains of the Short Form‐36 or for the dyspnoea, fatigue, emotion and mastery domains of the Chronic Respiratory Questionnaire. This trial had an adequate randomisation scheme and it blinded the outcome assessors, but it also lost a high proportion of participants to follow‐up. We are unable to evaluate precision because the trial only reported P values for comparisons across the five treatment groups. We suspected publication bias because of the poor outcome reporting. We are unable to draw a conclusion and graded the strength of the evidence as very low because of the serious risk of bias, the lack of information to determine precision, and the suspected reporting bias.

Two reviews compared the active cycle of breathing technique to oscillating devices ( McKoy 2016 ; Morrison 2017 ). Both reviews included only one long‐term trial (45 participants) which reported on quality of life ( Pryor 2010 ).

The reviews did not include any short‐term trials for this comparison ( McKoy 2016 ; Morrison 2017 ).

The reviews did not include any medium‐term trials for this comparison ( McKoy 2016 ; Morrison 2017 ).

As described previously, one 12‐month trial randomised 75 participants to one of five treatment groups, three of which were active cycle of breathing technique (13 participants) and the different oscillating devices Cornet® (14 participants) and Flutter® (12 participants) ( Pryor 2010 ). The trial evaluated quality of life using two validated measures, the Short Form‐36 and the Chronic Respiratory Questionnaire, and found no significant differences between groups for the physical and mental domains of the Short Form‐36 or for the dyspnoea, fatigue, emotion and mastery domains of the Chronic Respiratory Questionnaire. This trial had an adequate randomisation scheme and it blinded the outcome assessors, but it also lost a high percentage of participants to follow‐up. We are unable to evaluate precision because the trial only reported P values for comparisons across the five treatment groups. We suspected publication bias because of the poor outcomes reporting. We are unable to draw a conclusion and graded the strength of the evidence as very low because of the serious risk of bias, the lack of information to determine precision, and the suspected reporting bias.

The one review addressed this comparison but did not include any trials with our pre‐specified follow‐up period which reported on quality of life ( McKoy 2016 ).

Two reviews compared autogenic drainage to oscillating devices ( Morrison 2017 ; McCormack 2017 ) and included one long‐term trial which randomised 75 participants to one of five treatment groups (45 participants in this comparison) that reported on quality of life ( Pryor 2010 ). The McCormack review graded the evidence as low ( McCormack 2017 ).

Neither review included any short‐term trials for this comparison ( Morrison 2017 ; McCormack 2017 ).

Neither review included any medium‐term trials for this comparison ( Morrison 2017 ; McCormack 2017 ).

As described above one 12‐month trial randomised 75 participants to one of five treatment groups (three of which were autogenic drainage and the different oscillating devices Cornet® and Flutter®) ( Pryor 2010 ). The trial evaluated quality of life using two validated measures, the Short Form‐36 and the Chronic Respiratory Questionnaire, and found no significant differences between groups for the physical and mental domains of the Short Form‐36 and for the dyspnoea, fatigue, emotion and mastery domains of the Chronic Respiratory Questionnaire. This trial had an adequate randomisation scheme and it blinded the outcome assessors, but it also lost a high percentage of participants to follow‐up. We are unable to evaluate precision because the trial only reported P values for comparisons across the five treatment groups. We suspected publication bias because of the poor outcome reporting. We are unable to draw a conclusion and graded the strength of the evidence as very low because of the serious risk of bias, the lack of information to determine precision, and the suspected reporting bias ( Pryor 2010 ).

One review addressed this comparison but did not include any trials with our pre‐specified intervention period which reported on quality of life ( Morrison 2017 ).

This comparison was evaluated by one review ( Morrison 2017 ), which included one long‐term trial (n = 30) reporting on quality of life ( Pryor 2010 ).

The review did not include any short‐term trials for this comparison ( Morrison 2017 ).

The review did not include any medium‐term trials for this comparison ( Morrison 2017 ).

As already described, one 12‐month trial randomised 75 participants to one of five treatment groups (two of which were the oscillating devices Cornet® and Flutter®) ( Pryor 2010 ). The trial evaluated quality of life using two validated measures, the Short Form‐36 and the Chronic Respiratory Questionnaire and found no significant differences between groups for the physical and mental domains of the Short Form‐36 or for the dyspnoea, fatigue, emotion and mastery domains of the Chronic Respiratory Questionnaire. This trial had an adequate randomisation scheme and it blinded the outcome assessors, but it also lost a high percentage of participants to follow‐up. We are unable to evaluate precision because the trial only reported P values for comparisons across the five treatment groups. We suspected publication bias because of the poor outcome reporting. We are unable to draw a conclusion and graded the strength of the evidence as very low because of the serious risk of bias, the lack of information to determine precision, and the suspected reporting bias ( Pryor 2010 ).

One review addressed this comparison but did not include any trials with our pre‐specified intervention period which reported on quality of life ( Warnock 2015 ).

1. Adverse events

Four reviews evaluated adverse events ( Main 2005 ; McIlwaine 2015 ; McKoy 2016 ; McCormack 2017 ). Adverse events were rarely reported in the trials included in these reviews but the available information is summarised in the additional tables ( Table 6 ). We were unable to present the results by the severity of the event because we did not have sufficient information to do this. There is little evidence to suggest that any particular airway clearance therapy is more strongly associated with adverse events.

Abbreviations : NA : not applicable; PEP : positive expiratory pressure.

2. Other measures of lung function (change from baseline in L or % predicted values)

All of the included reviews reported on FVC. The comparative effects of airway clearance techniques on FVC are summarised in the additional tables ( Table 7 ). None of the airway clearance therapies demonstrated any superiority in terms of FVC.

* Positive numbers favour the intervention groups

Abbreviations : CI : confidence interval; FVC : forced vital capacity; MD : mean difference; NA : not applicable; NR : not reported; PEP : positive expiratory pressure; RCT : randomised controlled trial; SD : standard deviation.

b. FEF 25‐75

Five reviews evaluated FEF 25‐75 ( Main 2005 ; McCormack 2017 ; McIlwaine 2015 ; Morrison 2017 ; Warnock 2015 ). The comparative effects of airway clearance techniques on FEF 25‐75 are summarised in the additional tables ( Table 8 ). All of the airway clearance therapies had a similar effect on FEF 25‐75 .

Abbreviations : CI : confidence interval; FEF 25‐75 : mid‐expiratory flow; MD : mean difference; NA : not applicable; NR : not reported; PEP : positive expiratory pressure; RCT : randomised controlled trial; SD : standard deviation.

3. Number or frequency of exacerbations

All of the reviews sought to evaluate the number or frequency of respiratory exacerbations, but most trials did not report on respiratory exacerbations. The available results for respiratory exacerbations are summarised in the additional tables ( Table 9 ). There is little evidence to suggest that any particular airway clearance therapy is more effective at reducing the number or frequency of exacerbations.

Abbreviations : CI : confidence interval; MD : mean difference; NA : not applicable; PEP : positive expiratory pressure; RCT : randomised controlled trial; RR : relative risk; SD : standard deviation.

4. Sputum clearance

All of the reviews planned to evaluate sputum weight or volume. However, most included trials did not report on sputum clearance outcomes; those which did generally reported sputum weight (wet, dry, or both), while a few reported sputum volume. The results are summarised in the additional tables ( Table 10 ). There was generally not enough information to draw any conclusion about the effectiveness of airway clearance techniques on removing sputum. None of the airway clearance therapies demonstrated any consistent superiority in sputum production.

Abbreviations : CI : confidence interval; MD : mean difference; NA : not applicable; PEP : positive expiratory pressure; RCT : randomised controlled trial; SD : standard deviation.

Two reviews evaluated LCI as an outcome; however, most of the included trials did not report LCI. The results for LCI are summarised in the additional tables ( Table 11 ). There is little evidence to suggest that any particular airway clearance therapy affects the LCI more than any other therapy.

Abbreviations : CI : confidence interval; LCI : lung clearance index; MD : mean difference; NA : not applicable; PEP : positive expiratory pressure; RCT : randomised controlled trial; SD : standard deviation.

Summary of main results

Six Cochrane Reviews evaluated airway clearance techniques for people with CF. Five of these reviews compared conventional chest physiotherapy, PEP therapy, active cycle of breathing technique, and oscillating devices with other airway clearance techniques. A sixth review compared chest physiotherapy with no chest physiotherapy or with coughing alone. There was considerable overlap in terms of what the reviews covered, but there were some differences in how the reviews were conducted and carried out, particularly in terms of their inclusion criteria and in their methods for handling cross‐over trials.

In this overview, we concluded that there is no evidence of a difference of effect on FEV 1 between PEP therapy and oscillating devices after six months of treatment. The relative effects of these devices at earlier time‐points, however, are not as clear.

We are unable to draw any definitive conclusions for all other comparisons in terms of FEV 1 . Most of the evidence comparing different airway clearance techniques is of low or very low grade. Many trials did not report sufficient detail of their trial methodology to adequately assess their risk of bias. The results were often imprecise because of the few number of trials and the small sample sizes in those trials. Additionally, the results were sometimes subject to publication bias. We excluded several cross‐over trials from the analysis of FEV 1 because the cross‐over trials did not have a sufficient washout period or did not report first‐period results.

Likewise, the evidence grade comparing different airway clearance techniques in terms of participant preference and quality of life was either low or very low. Most of the trials evaluating these measures did not sufficiently describe their methodology. Preference was often not directly assessed, or the trials did not describe how preference was assessed. In many cases, there was not sufficient quantitative information to assess the precision of these outcomes.

Evidence for the secondary outcomes was limited. Not all of the systematic reviews included adverse events or LCI as outcomes and those reviews that did include these outcomes found few trials that reported on them. There were no clear differences between the different airway clearance techniques in terms of FVC, FEF 25‐75 , sputum clearance, or adverse events. There was considerable heterogeneity in how exacerbations were reported.

Overall completeness and applicability of evidence

As of January 2019, the Cochrane Reviews included in this overview were reasonably up‐to‐date, with most having been updated within the last two years. The one exception is the Main 2005 review, which was last assessed as up to date in 2009 ( Main 2005 ). All of the reviews included participants with CF, regardless of age, sex, or disease severity. The reviews were also reasonably comprehensive in their inclusion of outcomes. All of the reviews included all of our primary outcomes and most of the reviews included the secondary outcomes.

All of the comparisons that we sought were included in at least one Cochrane Review. One third of the comparisons were addressed in two Cochrane Reviews. An airway clearance technique that has not been covered in a Cochrane review is exercise in conjunction with another airway clearance technique. None of the reviews addressed the potential effects of co‐interventions.

The overall completeness and applicability of the evidence was limited by the individual trials included in the reviews. In particular, many trials had incomplete outcome reporting, which limited our ability to assess the relative effects of the airway clearance techniques.

The Cochrane Reviews included in this overview appeared to follow the Cochrane guidance and were considered to have a low risk of bias ( Table 2 ).

However, the individual trials included in the reviews often did not report sufficient information to adequately assess their risk of bias. Nearly two thirds of the trials were considered to have an unclear risk of bias. Additionally, many trials did not sufficiently report on outcome measures and had a high risk of reporting bias.

Over half of the trials were conducted as randomised cross‐over trials and just over half of the cross‐over trials did not have a sufficient washout period (i.e., at least one day) to reduce any potential carryover effect. Due to the possible bias, we excluded these cross‐over trials from the FEV 1 analyses. Carryover effects are less relevant for assessing participant preference and quality of life.

Potential biases in the overview process

Since only two of the included Cochrane Reviews had graded the strength of evidence, we retroactively graded the strength of the evidence for each comparison for the primary outcomes. The process of grading the strength of evidence was complicated by the overlapping comparisons in the reviews, and the heterogeneity in the trials. We relied on information reported in the individual Cochrane Reviews and, if necessary, checked the individual trials for clarification or additional information. To grade the strength of evidence, we often combined trials that were reported separately in the Cochrane Reviews. Many of the trials were included in more than one review. When there were discrepancies in the inclusion status of an individual trial, we noted this in the text and alerted the Cochrane Review Group Managing Editor. These discrepancies are likely to be resolved in future updates of the overview. For our FEV 1 analysis, we excluded cross‐over trials that did not have a sufficient washout period (i.e., at least one day). We excluded these trials to avoid any potential carryover effect. Additionally, another study had noted how some reviews have been inconsistent in their analysis and reporting of cross‐over trials ( Nolan 2016 ). Although it is unconventional for an overview to exclude individual trials, we provide consistency in how cross‐over trials are analysed by limiting our analysis to those trials with a sufficient washout period.

We did not evaluate how the efficacy and safety of the airway clearance devices may have differed by the type of device. For instance, the efficacy of the PEP mask therapy may be different than the PEP mouthpiece therapy.

We did not update the searches for the individual Cochrane Reviews. It is possible that our overview missed more recent trials. However, the majority of the Cochrane Reviews were reasonably up‐to‐date.

There may be other considerations for selecting one airway clearance technique over another that were not measured in this overview. For instance, we could have used a finer measure (e.g., time to complete airway clearance session, availability of help, comfort) for evaluating participant preference. There may be clearer differences between the airway clearance techniques on these finer measures. However, participant preference was often difficult to assess because of the heterogeneity in how it was measured, incomplete descriptions on how it was assessed, and incomplete outcome reporting.

Agreements and disagreements with other studies or reviews

Similar to the Bradley 2006 review ( Bradley 2006 ), we found little evidence to support one airway clearance technique over another. Our overview adds to this review by including three new reviews ( McCormack 2017 ; McKoy 2016 ; Morrison 2017 ), and updates of the other reviews.

Implications for practice

No single airway clearance technique appears to be superior. There is little evidence to support the use of one airway clearance technique over another in terms of respiratory function, participant preference, and quality of life. People with cystic fibrosis (CF) should choose the airway clearance technique that best meets their needs, in relation to comfort, convenience, flexibility, practicality, cost, or some other factor.

Implications for research

There are a few areas that future Cochrane Reviews on airway clearance techniques for people with CF should consider. Firstly, review authors should consider how best to analyse cross‐over trials. The analysis plan for cross‐over trials should consider the minimum duration for the washout period that is needed for each outcome.

Secondly, review authors should consider how best to report on their outcome measures. The reviews differed on how they reported the lung function outcomes, with some reporting final values, absolute change from baseline, or percentage change from baseline. Some of these differences are due to the heterogeneity of how outcomes are reported in the included trials, but some of these differences represent heterogeneity in the reviews. Review authors need to clearly label the specific metrics that are being used. Review authors should also consider how to best report on participant preference and satisfaction. Trials use a myriad of methods for evaluating these outcomes. Reviewers may want to consider finer measures of evaluating preference and satisfaction, such as time to complete airway clearance session, availability of help, comfort.

Additionally, review authors should consider how best to combine studies, such as by length of follow‐up. They may also want to consider the possible influence of adjunctive therapies on the effectiveness of airway clearance techniques. Lastly, review authors should consider grading the strength of evidence.

Review authors may consider including non‐randomised trials. These airway clearance techniques are commonly used and non‐randomised trials could potentially provide additional information regarding effectiveness and safety. However, review authors would need to consider potential bias when assessing these trials, such as selection bias, confounding by indication, use of co‐interventions, time‐varying exposure to therapies, and confounding.

More long‐term, high‐quality randomised controlled trials (RCTs) comparing airway clearance techniques among people with CF are needed. Investigators should be encouraged to publish their results within full manuscripts, and not just as conference abstracts. They should provide sufficient detail about their methodology and fully report on all outcomes. Trial authors should consider following a reporting standard, such as the Consolidated Standards of Reporting Trials (CONSORT), when publishing their trials ( Schulz 2010 ). Multi‐centered trials may be needed to provide sufficient power to detect any meaningful differences in airway clearance techniques. Cross‐over trials, designed with a sufficient washout period, can also be considered because of their increased power. Both parallel and cross‐over RCTs should try to minimise the number of drop‐outs. Trial authors may also want to consider how an individual's airway pathophysiology may impact the effectiveness of a particular airway clearance technique. Trial authors could consider either limiting their trials to individuals with a similar pathophysiology or conducting subgroup analyses based on pathophysiology. By targeting the patient population, we may be better able to understand who could benefit from specific airway clearance techniques.

Finally, both trial authors and review authors should consider evaluating and reporting on outcomes that are most important to people with CF.

Acknowledgements

We would like to thank Oluwaseun Akinyede and Jennifer Agnew for their help in developing the protocol.

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.

Appendix 1. ROBIS Signalling Questions

Appendix 2. characteristics of excluded reviews, contributions of authors, sources of support, internal sources.

External sources

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

Two of the authors of this overview (LMW, KAR) have contributed to the review on the active cycle of breathing technique. One author (LM) has contributed to the review on oscillating devices.

References to included reviews

McCormack 2017

McIlwaine 2015

Morrison 2017

Warnock 2015

References to excluded reviews

Burrows 2014

Corley 2017

Dentice 2016

Elkins 2016

Enriquez 2012

Gillies 2011

Kassab 2015

Leonardi‐Bee 2011

McCullough 2015

Moresco 2016a

Moresco 2016b

Morrow 2013

Nevitt 2018

Osadnik 2012

Roqué 2016

Savage 2014

Wilkinson 2014

Wilson 2014

Winfield 2014

Additional references

Balshem 2011

Bradley 2006

Braggion 1995

Cantin 1995

CF Foundation 2016

Costantini 2001

Darbee 1990

Davidson 1992

Davies 2012

Elbourne 2002

Farrell 2008

Farrell 2018

Gaskin 1998

Gondor 1999

Grzincich 2008

Guyatt 2008

Homnick 1995

Homnick 1998

IPG/CF 2009

Kaplan 1989

Kirkpatrick 1995

Kofler 1994

Konstan 1997

McIlwaine 1991

McIlwaine 1997

McIlwaine 2001

McIlwaine 2013

Miller 1995

Newbold 2005

Oermann 2001

Padman 1999

Prasad 1993

Prasad 2005

Quittner 2009

Reismann 1988

RevMan 2014 [Computer program]

Rogers 2005

Schulz 2010

Tyrrell 1986

van Asperen 1987

van Winden 1998

Varekojis 2003

Webber 1985

Whiting 2016

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