Exercise versus airway clearance techniques for people with cystic fibrosis.

BACKGROUND: 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. OBJECTIVES: 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. SEARCH METHODS: 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. SELECTION CRITERIA: We selected randomised controlled studies (RCTs) and quasi-RCTs comparing exercise to another ACT in people with CF for at least two treatment sessions. DATA COLLECTION AND ANALYSIS: 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. MAIN RESULTS: We included four RCTs. The 86 participants had a wide range of disease severity (forced expiratory volume in one second (FEV1) 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 FEV1, although it increased in the exercise group before returning to baseline after 30 minutes; we are unsure if exercise affected FEV1 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 FEV1 % 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 FEV1 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 (FEV1, quality of life, exercise capacity) or the secondary outcomes (other measures of lung function, adherence, need for antibiotics or hospitalisations). AUTHORS' CONCLUSIONS: 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.

Eradication therapy for Burkholderia cepacia complex in people with cystic fibrosis.

BACKGROUND: Chronic infection with Burkholderia cepacia complex species remains a significant problem for clinicians treating people with cystic fibrosis. Colonisation with Burkholderia cepacia complex species is linked to a more rapid decline in lung function and increases morbidity and mortality. There remain no objective guidelines for strategies to eradicate Burkholderia cepacia complex in cystic fibrosis lung disease, as these are inherently resistant to the majority of antibiotics and there has been very little research in this area. This review aims to examine the current treatment options for people with cystic fibrosis with acute infection with Burkholderia cepacia complex and to identify an evidence-based strategy that is both safe and effective. This is an updated version of the review. OBJECTIVES: To identify whether treatment of Burkholderia cepacia complex infections can achieve eradication, or if treatment can prevent or delay the onset of chronic infection. To establish whether following eradication, clinical outcomes are improved and if there are any adverse effects. SEARCH METHODS: 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.Last search: 12 March 2019.We also searched electronic clinical trials registers for the USA and Europe.Date of last search: 12 March 2019. SELECTION CRITERIA: Randomised or quasi-randomised studies in people with cystic fibrosis of antibiotics or alternative therapeutic agents used alone or in combination, using any method of delivery and any treatment duration, to eradicate Burkholderia cepacia complex infections compared to another antibiotic, placebo or no treatment. DATA COLLECTION AND ANALYSIS: Two authors independently assessed for inclusion in the review the eligibility of 52 studies (79 references) identified by the search of the Group's Trial Register and the other electronic searches. MAIN RESULTS: No studies looking at the eradication of Burkholderia cepacia complex species were identified. AUTHORS' CONCLUSIONS: The authors have concluded that there was an extreme lack of evidence in this area of treatment management for people with cystic fibrosis. Without further comprehensive studies, it is difficult to draw conclusions about a safe and effective management strategy for Burkholderia cepacia complex eradication in cystic fibrosis. Thus, while the review could not offer clinicians evidence of an effective eradication protocol for Burkholderia cepacia complex, it has highlighted an urgent need for exploration and research in this area, specifically the need for well-designed multi-centre randomised controlled studies of a variety of (novel) antibiotic agents.

Delayed neutrophil apoptosis enhances NET formation in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) lung disease is defined by large numbers of neutrophils and associated damaging products in the airway. Delayed neutrophil apoptosis is described in CF although it is unclear whether this is a primary neutrophil defect or a response to chronic inflammation. Increased levels of neutrophil extracellular traps (NETs) have been measured in CF and we aimed to investigate the causal relationship between these phenomena and their potential to serve as a driver of inflammation. We hypothesised that the delay in apoptosis in CF is a primary defect and preferentially allows CF neutrophils to form NETs, contributing to inflammation. METHODS: Blood neutrophils were isolated from patients with CF, CF pigs and appropriate controls. Neutrophils were also obtained from patients with CF before and after commencing ivacaftor. Apoptosis was assessed by morphology and flow cytometry. NET formation was determined by fluorescent microscopy and DNA release assays. NET interaction with macrophages was examined by measuring cytokine generation with ELISA and qRT-PCR. RESULTS: CF neutrophils live longer due to decreased apoptosis. This was observed in both cystic fibrosis transmembrane conductance regulator (CFTR) null piglets and patients with CF, and furthermore was reversed by ivacaftor (CFTR potentiator) in patients with gating (G551D) mutations. CF neutrophils formed more NETs and this was reversed by cyclin-dependent kinase inhibitor exposure. NETs provided a proinflammatory stimulus to macrophages, which was enhanced in CF. CONCLUSIONS: CF neutrophils have a prosurvival phenotype that is associated with an absence of CFTR function and allows increased NET production, which can in turn induce inflammation. Augmenting neutrophil apoptosis in CF may allow more appropriate neutrophil disposal, decreasing NET formation and thus inflammation.

Emerging therapies in adult and paediatric bronchiectasis.

Bronchiectasis is a chronic respiratory disorder characterized by persistent productive cough and recurrent chest infections secondary to permanent structural airway damage. The current treatment strategies for this debilitating disorder are limited to prompt antibiotic treatment of infective exacerbations and regular airway clearance techniques. Despite its high morbidity and associated mortality across all age groups, it has been a neglected area of research in respiratory medicine and there remain no licensed disease-modifying therapies. In this review, we have explored the numerous potential therapeutic targets to break the vicious cycle of infection and inflammation seen in these patients and the novel therapeutic agents that have been developed to target them. We have reviewed the role of novel anti-inflammatory agents designed to target the persistent neutrophilic inflammatory infiltrate seen in bronchiectatic airways, including neutrophil elastase inhibitors, CXCR2 (CXC chemokine receptor 2) antagonists, DPP-1 (dipeptidyl peptidase 1) inhibitors, PDE4 (phosphodiesterase 4) inhibitors and statins. Furthermore, we have explored novel targets to improve mucociliary clearance, namely ENaC (epithelial sodium channel) inhibitors, and discussed the potential of alternative antimicrobial strategies such as inhaled phages. Our review highlights the importance of a multi-faceted approach to bronchiectasis management, which aims not only to eradicate or suppress bronchial infection but also to break the cycle of persistent airway inflammation that results in progressive lung damage in these patients.

Inhaled anti-pseudomonal antibiotics for long-term therapy in cystic fibrosis.

BACKGROUND: Inhaled antibiotics are commonly used to treat persistent airway infection with Pseudomonas aeruginosa that contributes to lung damage in people with cystic fibrosis. Current guidelines recommend inhaled tobramycin for individuals with cystic fibrosis and persistent Pseudomonas aeruginosa infection who are aged six years or older. The aim is to reduce bacterial load in the lungs so as to reduce inflammation and deterioration of lung function. This is an update of a previously published review. OBJECTIVES: To evaluate the effects long-term inhaled antibiotic therapy in people with cystic fibrosis on clinical outcomes (lung function, frequency of exacerbations and nutrition), quality of life and adverse events (including drug sensitivity reactions and survival). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched ongoing trials registries.Date of last search: 13 February 2018. SELECTION CRITERIA: We selected trials if inhaled anti-pseudomonal antibiotic treatment was used for at least three months in people with cystic fibrosis, treatment allocation was randomised or quasi-randomised, and there was a control group (either placebo, no placebo or another inhaled antibiotic). DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, judged the risk of bias, extracted data from these trials and judged the quality of the evidence using the GRADE system. MAIN RESULTS: The searches identified 333 citations to 98 trials; 18 trials (3042 participants aged between five and 56 years) met the inclusion criteria. Limited data were available for meta-analyses due to the variability of trial design and reporting of results. A total of 11 trials (1130 participants) compared an inhaled antibiotic to placebo or usual treatment for a duration between three and 33 months. Five trials (1255 participants) compared different antibiotics, two trials (585 participants) compared different regimens of tobramycin and one trial (90 participants) compared intermittent tobramycin with continuous tobramycin alternating with aztreonam. One of the trials (18 participants) compared to placebo and a different antibiotic and so fell into both groups. The most commonly studied antibiotic was tobramycin which was studied in 12 trials.We found limited evidence that inhaled antibiotics improved lung function (four of the 11 placebo-controlled trials, n = 814). Compared to placebo, inhaled antibiotics also reduced the frequency of exacerbations (three trials, n = 946), risk ratio 0.66 (95% confidence interval (CI) 0.47 to 0.93). There were insufficient data for us to be able to report an effect on nutritional outcomes or survival and there were insufficient data for us to ascertain the effect on quality of life. There was no significant effect on antibiotic resistance seen in the two trials that were included in meta-analyses. Tinnitus and voice alteration were the only adverse events significantly more common in the inhaled antibiotics group. The overall quality of evidence was deemed to be low for most outcomes due to risk of bias within the trials and imprecision due to low event rates.Of the eight trials that compared different inhaled antibiotics or different antibiotic regimens, there was only one trial in each comparison. Forced expiratory volume at one second (FEV1) % predicted was only found to be significantly improved with aztreonam lysine for inhalation compared to tobramycin (n = 273), mean difference -3.40% (95% CI -6.63 to -0.17). However, the method of defining the endpoint was different to the remaining trials and the participants were exposed to tobramycin for a long period making interpretation of the results problematic. No significant differences were found in the remaining comparisons with regard to lung function. Pulmonary exacerbations were measured in different ways, but one trial (n = 273) found that the number of people treated with antibiotics was lower in those receiving aztreonam than tobramycin, risk ratio 0.66 (95% CI 0.51 to 0.86). We found the quality of evidence for these comparisons to be directly related to the risk of bias within the individual trials and varied from low to high. AUTHORS' CONCLUSIONS: Inhaled anti-pseudomonal antibiotic treatment probably improves lung function and reduces exacerbation rate, but pooled estimates of the level of benefit were very limited. The best evidence is for inhaled tobramycin. More evidence from trials measuring similar outcomes in the same way is needed to determine a better measure of benefit. Longer-term trials are needed to look at the effect of inhaled antibiotics on quality of life, survival and nutritional outcomes.

Eradication therapy for Burkholderia cepacia complex in people with cystic fibrosis.

BACKGROUND: Chronic infection with Burkholderia cepacia complex species remains a significant problem for clinicians treating people with cystic fibrosis. Colonisation with Burkholderia cepacia complex species is linked to a more rapid decline in lung function and increases morbidity and mortality. There remain no objective guidelines for strategies to eradicate Burkholderia cepacia complex in cystic fibrosis lung disease, as these are inherently resistant to the majority of antibiotics and there has been very little research in this area. This review aims to examine the current treatment options for people with cystic fibrosis with acute of Burkholderia cepacia complex and to identify an evidence-based strategy that is both safe and effective. This is an updated version of the review. OBJECTIVES: To identify whether treatment of Burkholderia cepacia complex infections can achieve eradication, or if treatment can prevent or delay the onset of chronic infection. To establish whether following eradication, clinical outcomes are improved and if there are any adverse effects. SEARCH METHODS: 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.Last search: 14 July 2016.We also searched electronic clinical trials registers for the USA and Europe.Date of last search: 14 July 2016. SELECTION CRITERIA: Randomised or quasi-randomised studies in people with cystic fibrosis of antibiotics or alternative therapeutic agents used alone or in combination, using any method of delivery and any treatment duration, to eradicate Burkholderia cepacia complex infections compared to another antibiotic, placebo or no treatment. DATA COLLECTION AND ANALYSIS: Two authors independently assessed for inclusion in the review the eligibility of 50 studies (70 references) identified by the search of the Group's Trial Register and the other electronic searches. MAIN RESULTS: No studies looking at the eradication of Burkholderia cepacia complex species were identified. AUTHORS' CONCLUSIONS: The authors have concluded that there was an extreme lack of evidence in this area of treatment management for people with cystic fibrosis. Without further comprehensive studies, it is difficult to draw conclusions about a safe and effective management strategy for Burkholderia cepacia complex eradication in cystic fibrosis. Thus, while the review could not offer clinicians evidence of an effective eradication protocol for Burkholderia cepacia complex, it has highlighted an urgent need for exploration and research in this area, specifically the need for well-designed multi-centre randomised controlled studies of a variety of (novel) antibiotic agents.

Eradication therapy for Burkholderia cepacia complex in people with cystic fibrosis.

BACKGROUND: Chronic infection with Burkholderia cepacia complex species remains a significant problem for clinicians treating people with cystic fibrosis. Colonisation with Burkholderia cepacia complex species is linked to a more rapid decline in lung function and increases morbidity and mortality. There remain no objective guidelines for strategies to eradicate Burkholderia cepacia complex in cystic fibrosis lung disease, as these are inherently resistant to the majority of antibiotics and there has been very little research in this area. This review aims to examine the current treatment options for people with cystic fibrosis with acute of Burkholderia cepacia complex and to identify an evidence-based strategy that is both safe and effective. OBJECTIVES: To identify whether treatment of Burkholderia cepacia complex infections can achieve eradication, or if treatment can prevent or delay the onset of chronic infection. To establish whether following eradication, clinical outcomes are improved and if there are any adverse effects. SEARCH METHODS: 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.Last search: 13 January 2014.We also searched electronic clinical trials registers for the USA and Europe.Date of last search: 28 November 2013. SELECTION CRITERIA: Randomised or quasi-randomised studies in people with cystic fibrosis of antibiotics used alone or in combination, using any method of delivery and any treatment duration, to eradicate Burkholderia cepacia complex infections compared to another antibiotic, placebo or no treatment. DATA COLLECTION AND ANALYSIS: Two authors independently assessed for inclusion in the review the eligibility of 43 studies (61 references) identified by the search of the Group's Trial Register and the other electronic searches. MAIN RESULTS: No studies looking at the eradication of Burkholderia cepacia complex species were identified. AUTHORS' CONCLUSIONS: The authors have concluded that there was an extreme lack of evidence in this area of treatment management for people with cystic fibrosis. Without further comprehensive studies, it is difficult to draw conclusions about a safe and effective management strategy for Burkholderia cepacia complex eradication in cystic fibrosis. Thus, while the review could not offer clinicians evidence of an effective eradication protocol for Burkholderia cepacia complex, it has highlighted an urgent need for exploration and research in this area, specifically the need for well-designed multi-centre randomised controlled studies of a variety of (novel) antibiotic agents.

Risk of Development of Resistance in Patients with Non-Cystic Fibrosis Bronchiectasis Treated with Inhaled Antibiotics.

PURPOSE OF REVIEW: Bronchiectasis is a debilitating chronic lung disease characterised by recurrent bacterial infection and colonisation with significant associated morbidity and mortality. To date, there are few licenced treatments, and the mainstay of clinical management is prompt antibiotic therapy for exacerbations and regular airway clearance. Inhaled antibiotics are a potential long-term treatment for those with recurrent exacerbations, and represent an obvious advantage over other routes of administration as they achieve high concentrations at the site of infection whilst minimising systemic side effects. The main caveat to such treatment is the development of antimicrobial resistance due to altered selection pressures. RECENT FINDINGS: Numerous studies of various inhaled antimicrobials have demonstrated favourable safety and efficacy profiles for bronchiectasis patients with chronic infection, which are supportive of their use in clinical practice. SUMMARY: There is no convincing evidence of treatment-emergent pathogens or pathogens developing resistance to the inhaled antibiotic therapy.