Mucolytics for bronchiectasis (Review) rP re vie w On ly Wilkinson M, Sugumar K, Milan SJ, Hart A, Crockett A, Crossingham I Fo This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2014, Issue 5 http://www.thecochranelibrary.com Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. TABLE OF CONTENTS Fo rP re vie w On ly HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Bromhexine versus placebo, Outcome 1 Adverse events. . . . . . . . . . . . Analysis 1.2. Comparison 1 Bromhexine versus placebo, Outcome 2 FEV1 (mL). . . . . . . . . . . . . Analysis 2.1. Comparison 2 5 mg RhDNase versus placebo, Outcome 1 Hospitalisations for infective exacerbations. . Analysis 2.2. Comparison 2 5 mg RhDNase versus placebo, Outcome 2 % change FEV1 at day 15. . . . . . . Analysis 2.3. Comparison 2 5 mg RhDNase versus placebo, Outcome 3 % change FVC at day 15. . . . . . . . Analysis 2.4. Comparison 2 5 mg RhDNase versus placebo, Outcome 4 Quality of Life. . . . . . . . . . . Analysis 2.5. Comparison 2 5 mg RhDNase versus placebo, Outcome 5 Sputum colour. . . . . . . . . . . Analysis 2.6. Comparison 2 5 mg RhDNase versus placebo, Outcome 6 Deaths. . . . . . . . . . . . . . Analysis 3.1. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 1 Hospitalisations for infective exacerbations. Analysis 3.2. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 2 % change FEV1 at day 15. . . . . . . Analysis 3.3. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 3 % change FVC at day 15. . . . . . . Analysis 3.4. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 4 Quality of life. . . . . . . . . . . Analysis 3.5. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 5 Sputum colour. . . . . . . . . . . Analysis 3.6. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 6 Deaths. . . . . . . . . . . . . Analysis 3.7. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 7 Antibodies to RhDNase. . . . . . . Analysis 4.1. Comparison 4 Erdosteine versus no treatment, Outcome 1 Mucus density. . . . . . . . . . . Analysis 4.2. Comparison 4 Erdosteine versus no treatment, Outcome 2 Mucus purulence. . . . . . . . . . Analysis 4.3. Comparison 4 Erdosteine versus no treatment, Outcome 3 Mucus volume production. . . . . . . Analysis 4.4. Comparison 4 Erdosteine versus no treatment, Outcome 4 Change in FEV1 (mL) at day 15. . . . . Analysis 4.5. Comparison 4 Erdosteine versus no treatment, Outcome 5 Change in FEV1 %Pred at day 15. . . . Analysis 4.6. Comparison 4 Erdosteine versus no treatment, Outcome 6 Change in FVC (mL) at day 15. . . . . Analysis 4.7. Comparison 4 Erdosteine versus no treatment, Outcome 7 Change in FVC %Pred at day 15. . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1 1 2 4 6 6 6 8 9 10 12 14 19 20 20 20 23 32 34 34 35 35 36 36 37 38 38 39 39 40 41 41 42 42 43 43 44 44 45 45 45 48 48 48 48 49 49 i [Intervention Review] Mucolytics for bronchiectasis ly Mark Wilkinson1 , Karnam Sugumar2 , Stephen J Milan3 , Anna Hart4 , Alan Crockett5 , Iain Crossingham6 Hospitals of Morecambe Bay NHS Foundation Trust, Lancaster, UK. 2 Department of Paediatrics, Royal Preston Hospital, Lancashire Teaching Hospitals NHS Trust, Preston, UK. 3 Population Health Sciences and Education, St George’s, University of London, London, UK. 4 Lancaster Medical School, Clinical Research Hub, Lancaster University, Lancaster, UK. 5 School of Health Sciences, University of South Australia, Adelaide, Australia. 6 Royal Blackburn Hospital, Blackburn, UK On 1 University Contact address: Stephen J Milan, Population Health Sciences and Education, St George’s, University of London, London, UK. s.milan@lancaster.ac.uk. w Editorial group: Cochrane Airways Group. Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 5, 2014. Review content assessed as up-to-date: 19 June 2013. Citation: Wilkinson M, Sugumar K, Milan SJ, Hart A, Crockett A, Crossingham I. Mucolytics for bronchiectasis. Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No.: CD001289. DOI: 10.1002/14651858.CD001289.pub2. vie Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. ABSTRACT re Background rP Bronchiectasis is predominantly an acquired disease process that represents the end stage of a variety of unrelated pulmonary insults. It is defined as persistent irreversible dilatation and distortion of medium-sized bronchi. It has been suggested that with widespread use of high-resolution computed tomography, more bronchiectasis diagnoses are being made. Patients diagnosed with bronchiectasis frequently have difficulty expectorating sputum. Sputum therefore is retained in the lungs and may become infected, leading to further lung damage. Mucolytic agents target hypersecretion or changed physiochemical properties of sputum to make it easier to clear. One drug, recombinant human DNase, breaks down the DNA that is released at the site of infection by neutrophils. Mucus clearance along with antimicrobial therapy remains an integral part of bronchiectasis management. Chest physiotherapy along with mucolytic agents is commonly used in practice without clear supportive evidence. Fo Objectives To determine whether ingested or inhaled mucolytics are effective in the treatment of patients with bronchiectasis. Search methods We searched the Cochrane Airways Group Specialised Register and reference lists of relevant articles. We contacted experts in the field and drug companies. Searches were current as of June 2013. Selection criteria Randomised trials of mucolytic treatment in people with bronchiectasis but not cystic fibrosis. Data collection and analysis Data extraction was performed independently by two review authors. Study authors were contacted for confirmation. Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1 Main results Four trials (with a combined total of 528 adult participants) were included, but almost none of the data from these studies could be aggregated in a meta-analysis. ly One trial (with 88 participants) compared bromhexine versus placebo. Compared with placebo, high doses of bromhexine with antibiotics eased difficulty in expectoration (mean difference (MD) -0.53, 95% confidence interval (CI) -0.81 to -0.25 at 16 days); the quality of the evidence was rated as low. A reduction in sputum production was noted with bromhexine (MD -21.5%, 95% CI -38.9 to -4.1 at day 16); again the quality of the evidence was rated as low. No significant differences between bromhexine and placebo were observed with respect to reported adverse events (odds ratio (OR) 2.93; 95% CI 0.12 to 73.97), and again the quality of the evidence was rated as low. On In a single small, blinded but not placebo-controlled trial of older (> 55 years) participants with stable bronchiectasis and mucus hypersecretion, erdosteine combined with physiotherapy over a 15-day period improved spirometry and sputum purulence more effectively compared with physiotherapy alone. The spirometric improvement was small (MD 200 mL in forced expiratory volume in one second (FEV1 ) and 300 mL in forced vital capacity (FVC)) and was apparent only at day 15, not at earlier time points. vie Authors’ conclusions w The remaining two studies (with a combined total of 410 participants) compared recombinant human DNase (RhDNase) versus placebo. These two studies were very different (one was a two-week study of 61 participants, and the other ran for 24 weeks and included 349 participants), and the opportunity for combining data from the two studies was very limited. Compared with placebo, recombinant human DNase showed no difference in FEV1 or FVC in the smaller study but showed a significant negative effect on FEV1 in the larger and longer study. For reported adverse events, no significant differences between recombinant human DNase and placebo were noted. In all of the above comparisons of recombinant human DNase versus placebo, the quality of the evidence was judged to be low. Given the harmful effects of recombinant human DNase in one trial and no evidence of benefit, this drug should be avoided in noncystic fibrosis bronchiectasis, except in the context of clinical trials. Evidence is insufficient to permit evaluation of the routine use of other mucolytics for bronchiectasis. High doses of bromhexine coupled with antibiotics may help with sputum production and clearance, but long-term data and robust clinical outcomes are lacking. Similarly, erdosteine may be a useful adjunct to physiotherapy in stable patients with mucus hypersecretion, but robust longer-term trials are required. re Generally, clinical trials in children on the use of various mucolytic agents are lacking. As the number of agents available on the market, such as RhDNase, acetylcysteine and bromhexine, is increasing, improvement of the evidence base is needed. rP PLAIN LANGUAGE SUMMARY Mucolytic drugs (to help make phlegm easier to cough up) for people with bronchiectasis Review question: This review considered the question of whether mucolytics may be helpful for people with bronchiectasis who do not also have cystic fibrosis. Studies of participants with cystic fibrosis were not included in this review, and we are unable to draw any conclusions on this treatment’s relevance to people with cystic fibrosis. Fo Background: Bronchiectasis is a lung condition that usually develops after a series of lung problems (such as childhood infections, problems in lung structure, tuberculosis and cystic fibrosis). A lot of mucus (phlegm) collects in the lungs, causing discomfort and the need to cough it up. The phlegm also collects bacteria, which can add to breathing difficulties. Mucolytic drugs break down phlegm, which can make it easier to cough up. Study characteristics: Four studies (with a total of 528 participants) were identified that met the inclusion criterion of comparing mucolytic treatment versus no mucolytic treatment. All studies were conducted in adults. One study considered bromhexine versus placebo, two compared RhDNase versus placebo (one for a period of two weeks and the other over a period of 24 weeks) and the fourth compared erdosteine with physiotherapy versus physiotherapy alone in elderly patients. The small number of studies available for review and their different designs meant that only descriptions of the individual studies were possible with very limited opportunities for combining the studies in single analyses. Key results: No strong evidence is available to support the use of these drugs in people with bronchiectasis (from causes other than cystic fibrosis); however it is not possible to draw any clear conclusions, as so few studies have been reported. Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 2 Fo rP re vie w On ly Quality of the evidence: Details of the way patients were allocated to receive or not receive mucolytics were not clearly described in any of the four studies. This was considered carefully in the review in relation to our level of uncertainty in interpreting the results. When this is taken into account, together with the imprecision of the results, estimates of the usefulness of mucolytics as treatment were generally judged to be of low quality in relation to (non-cystic fibrosis) bronchiectasis. Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 3 On w Bromhexine compared with placebo for bronchiectasis Illustrative comparative risks* (95% CI) re Outcomes vie Patient or population: patients with bronchiectasis Settings: community Intervention: bromhexine Comparison: placebo Corresponding risk Placebo Bromhexine rP Assumed risk Relative effect (95% CI) No. of participants (studies) Quality of the evidence (GRADE) Comments Frequency and duration See comment of exacerbations See comment See comment See comment N/A Outcome not reported Hospitalisations See comment See comment See comment See comment N/A Outcome not reported Adverse events 0 per 100 3 2.2 per 100 (0.05 to 11.7) OR 2.93 (0.12 to 73.97) 88 (1 study) ⊕⊕ low1,2 See comment See comment See comment See comment Symptoms difficulty in Absolute values not re- Absolute values not re- MD -0.53 expectoration ported ported (-0.81 to -0.25) Follow-up: 16 days 88 (1 study) ⊕⊕ low1,2 Deaths See comment See comment See comment Lung function FEV1 Follow-up: 13 days Mean FEV1 in the control Mean FEV1 in the inter- MD 184.00 group was 1614 mL vention groups was 184 (-149.75 to 517.75) mL higher (149.75 lower to 517.75 higher) 88 (1 study) ⊕⊕ low1,2 Fo Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation] Health-related quality of See comment life See comment See comment Outcome not reported Outcome not reported 4 On w vie GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 One re point deducted to reflect risk of bias assessment of randomisation (judged as unclear risk of bias). point deducted to reflect imprecision in the estimate, with data coming from only one trial, leading to low event rate and wide confidence intervals. 3 Assumed risk is based on the control group (N = 43) of the one trial reporting adverse events. rP 2 One Fo Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio. 5 How the intervention might work Bronchiectasis is a disease characterised by excessive mucus production and retention. By reducing the viscosity of mucus, mucolytics may aid clearance of sputum from the airways. Removal of mucus plugs from small and medium-sized airways allows recruitment of the associated lung and hence improvement in spirometric measures of lung function. Retained sputum could potentially act as a culture medium for bacteria (Stockley 1995), leading to recurrent or persistent chest infection. By enhancing mucus removal, this risk is reduced. rP re vie w Bronchiectasis is predominantly an acquired disease process that represents the end stage of a variety of unrelated pulmonary insults and antecedent events. It is defined in anatomical terms as persistent and irreversible dilatation and distortion of mediumsized bronchi. Focal or diffuse forms of bronchial disease also predispose to the development of bronchiectasis. Bronchial obstruction due to varied and unrelated causes (e.g. aspiration of foreign bodies, carcinoma, extrinsic compression by surrounding enlarged lymph nodes, inspissated viscid secretions) can cause obstructive or localised forms of bronchiectasis. Diffuse bronchiectasis is usually associated with previous widespread pneumonic damage (e.g. pertussis and measles pneumonia, severe influenza and varicella pneumonia, necrotising bacterial pneumonias due to Klebsiella, Staphylococcus aureus, Pseudomonas and anaerobic infections), chronic granulomatous disease (e.g. tuberculosis, sarcoidosis, histoplasmosis, coccidioidomycosis), hypersensitivity and immunodeficiency disorders (e.g. congenital or acquired ahypogammaglobulinaemia) or genetic syndromes (e.g. cystic fibrosis, tracheobronchomegaly, bronchial cartilage deficiency, Kartagener’s syndrome, Young’s syndrome, immotile cilia disease). Many of these conditions predispose to recurrent lower respiratory infection as a result of poor tracheobronchial clearance. It has been suggested that with widespread use of high-resolution computed tomography, more bronchiectasis diagnoses are being made (Goeminne 2010), and mucus clearance along with antimicrobial therapy remains an integral part of management of the condition (Stafler 2010). ly Description of the condition that are a constituent of the pus that can form a considerable part of the mucus in infected lungs (Henke 2007). Mucolytics may be given orally or parenterally. Alternatively, some, such as recombinant human DNase (RhDNase), are delivered directly to the lungs by nebulisation and inhalation. National guidelines (BTS 2010; TSANZ 2010) consider RhDNase to be contraindicated in non-cystic fibrosis (CF) bronchiectasis following a trial that reported deleterious effects on both lung function and exacerbation rate in adults (O’Donnell 1998). By extrapolation from this study, the same recommendation has been given for children with non-CF bronchiectasis. Based primarily on an earlier version of this Cochrane review (Crockett 2001), guidelines in the Southern hemisphere (TSANZ 2010) recommend against the use of mucoactive drugs including mucolytics in bronchiectasis. On BACKGROUND Why it is important to do this review It is important to gain further clarity on the clinical benefits and adverse events associated with ingested or inhaled mucolytics in the treatment of bronchiectasis. Description of the intervention Fo Several agents are known to alter the physical or chemical characteristics of sputum such that removal of sputum from the airway becomes easier. These drugs are collectively known as mucolytics. The precise mechanism of action of many of these drugs is not known (Cotgreave 1987; Rogers 2007) but may include breaking down large molecules within the mucus to reduce viscosity and reducing the biological activity of various proteins (Zafarullah 2003). Attempts have been made to classify mucoactive drugs (Balsamo 2010) as true mucolytics (thin mucus), expectorants (work by inducing cough) and mucokinetics (increase mucus transport within the lungs), but in practice these drugs probably work through several of these mechanisms simultaneously (Tomkiewicz 1995). The mechanism of action of recombinant human DNase (RhDNase or dornase alfa) is known. This is a mucolytic that enzymatically degrades the long chains of DNA derived from neutrophils OBJECTIVES To determine whether ingested or inhaled mucolytics are effective in the treatment of patients with bronchiectasis. METHODS Criteria for considering studies for this review Types of studies We included randomised trials comparing treated and untreated groups of participants with bronchiectasis. Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 6 Types of interventions Intervention group: any mucolytic given by nebuliser or orally in single or repeated doses alone or in combination with glucocorticosteroids, beta2 -agonists (long- or short-acting or both) or xanthine bronchodilators. Control group: single or repeated doses of nebulised or oral placebo combined with glucocorticosteroids, beta2 -agonists or xanthine bronchodilators. Important co-interventions: physical interventions (physiotherapy) and drugs that increase mucociliary clearance (beta2 -agonists) or change viscoelastic characteristics of sputum (corticosteroids). Primary outcomes Full publications of all references identified as randomised controlled trials (RCTs) or unclear were obtained and reviewed independently by two review authors (SJM, MW). Reference lists of all identified RCTs were checked to identify potentially relevant citations. The international headquarters of Boehringer Ingelheim, the pharmaceutical company that produces bromhexine, was contacted. Enquiries regarding other published or unpublished studies known and/or supported by this company or its subsidiaries were made so that these results could be included in our review. Finally, personal contact was made with colleagues and trialists working in the field of bronchiectasis to ask them to identify potentially relevant trials. In addition, all identified papers and reviews were handsearched for further references, and study authors were contacted to ask whether they could identify any unpublished or missed trials. vie • Frequency and duration of exacerbations. • Hospitalisations. • Adverse events. Searching other resources w Types of outcome measures searched all databases from their inception to June 2013, with no restriction on language of publication. ly Adults with a diagnosis of bronchiectasis, but not cystic fibrosis. On Types of participants Data collection and analysis Secondary outcomes • Mortality. • Symptoms: cough, sputum volume and ease of expectoration, wheeze, dyspnoea. • Lung function. • In vitro characteristics of sputum. • Measurement of tracheobronchial clearance. • Health-related quality of life (e.g. Short Form (SF)-36, St George’s Respiratory Questionnaire (SGRQ)). Selection of studies Electronic searches Data extraction and management We identified trials from the Cochrane Airways Group Specialised Register (CAGR), which is maintained by the Trials Search Co-ordinator for the Group. The Register contains trial reports identified through systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO, and handsearching of respiratory journals and meeting abstracts (please see Appendix 1 for further details). We searched all records in the CAGR using the search strategy in Appendix 2. We also conducted a search of ClinicalTrials.gov (www.ClinicalTrials.gov) and the World Health Organization (WHO) trials portal (www.who.int/ictrp/en/). We Data for included trials were extracted independently by two review authors (SJM and MW) and were entered into the software programme of The Cochrane Collaboration (Review Manager (RevMan)) by SJM. Data entry was checked by AH. Fo rP re Search methods for identification of studies MW and IC independently screened the identified references using the abstract, title and medical subject heading (MeSH) terms, and independently assessed studies for potential relevance. At the next stage, using the full text of the potentially relevant studies, the same review authors (MW and IC) independently selected trials for inclusion in the review. Had disagreements arisen, we planned to involve an independent third party adjudicator (SJM); however, this was not necessary. Assessment of risk of bias in included studies Two review authors (SJM and MW) assessed the trials with respect to selection bias, performance and detection bias, attrition bias, reporting bias and other potential sources of bias using the ’Risk of bias’ tool of The Cochrane Collaboration (Higgins 2011). Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 7 Measures of treatment effect • Hospitalisations. • Adverse events. Secondary • Health-related quality of life. • Symptoms: cough, sputum volume and ease of expectoration, wheeze, dyspnoea. • Mortality. • Lung function. ly For dichotomous variables, we expressed data as odds ratios (ORs) with 95% confidence intervals (CIs). Data for continuous variables were reported as mean differences (MDs) with 95% CIs or as standardised mean differences (SMDs) with 95% CIs in analyses for which it was necessary to pool data from different measures. The unit of analysis was the participant. Dealing with missing data We planned to contact study authors if outcome data or information on trial design was missing; however, this issue did not arise. Assessment of heterogeneity w We tested heterogeneity among pooled estimates using the DerSimonian and Laird method; we considered a P value < 0.05 as the threshold for statistical significance. Heterogeneity was assessed at first by visual inspection of forest plots. The Chi2 test was similarly considered (P value < 0.10) but was interpreted with caution owing to the low power associated with this test. I2 was also considered and was interpreted in relation to the following guidance (Higgins 2011). • 0% to 40%: might not be important. • 30% to 60%: may represent moderate heterogeneity. • 50% to 90%: may represent substantial heterogeneity. • 75% to 100%: shows considerable heterogeneity. We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence as it relates to the studies that contributed data to the meta-analyses for prespecified outcomes. We applied methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) by using GRADEpro software. We justified all decisions to downgrade or upgrade the quality of studies by using footnotes and included comments to aid readers’ understanding of the review when necessary. On Unit of analysis issues Subgroup analysis and investigation of heterogeneity re vie Subgroup and sensitivity analyses were performed by pooling absolute and relative data to include sufficient studies at each time point. In these cases, we calculated individual and pooled statistics as SMDs and 95% CIs using a random-effects model. Subgroup analysis was performed using the following subgroups. rP When we encountered heterogeneity according to the above mentioned criteria, we applied fixed-effect and random-effects models and commented on differences, reporting the random-effects model in the review. Sensitivity analysis We planned to conduct sensitivity analyses by comparing randomeffects versus fixed-effect modelling if issues of significant heterogeneity arose. However this was not necessary. RESULTS We planned to examine publication bias by using funnel plots if we had included an adequate number of trials (10 or more) aggregated in a single meta-analysis. We recognise that an asymmetrical funnel plot can reflect heterogeneity, outcome reporting bias and small-study effects and therefore is not necessarily a reflection of publication bias. Description of studies Fo Assessment of reporting biases Data synthesis Summary of findings table We created a ’Summary of findings’ table using the following outcomes. Primary • Frequency and duration of exacerbations. Results of the search Thirty-six reports were identified in the June 2013 searches; they included the three studies already identified in the previous version of this review (Crockett 2001). Identified studies were independently evaluated against the inclusion criteria by MW and IC, and four studies were judged as appropriate for inclusion (details are provided in Characteristics of included studies). Thirtytwo reports were excluded (details provided in Characteristics of excluded studies). See Figure 1 for a study flow diagram. Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 8 Fo rP re vie w On ly Figure 1. Study flow diagram. Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 9 ly Excluded studies Thirty-two reports were excluded (details in Characteristics of excluded studies). Twelve (38%) reports described participants with a variety of respiratory conditions, and data were not reported separately for those with bronchiectasis; a further 12 (38%) reports were excluded, as the intervention was not a mucolytic agent. An additional five (16%) reports were excluded, as the participants had a diagnosis other than bronchiectasis, and two (6%) reports were excluded on the basis of having a non-randomised design. The remaining trial (3%) was excluded, as the mucolytic agent was not compared with placebo/no treatment. w Four RCTs were identified, with a total of 528 participants who were randomly assigned (504 completed the study). Details are provided in Characteristics of included studies. Only one study (Olivieri 1991) compared oral bromhexine versus placebo in the treatment of acute exacerbations of bronchiectasis (88 participants were randomly assigned, with 21 participants withdrawing from the study; participants in both treatment arms received an antibiotic (ceftazidine 1 g, intramuscular (IM), twice daily) for the first week of the 15-day trial, and the choice of antibiotic was not based on microbiological assessment). All participants in this trial were suffering from an acute infective exacerbation of bronchiectasis, with morning cough and purulent sputum. Another study (Crisafulli 2007) (30 participants randomly assigned, with no participants withdrawing from the study) compared oral erdosteine and physiotherapy versus physiotherapy alone over a 15-day period. Participants were over 55 years of age and were non-smokers or ex-smokers with moderate airflow obstruction and stable disease. The remaining two studies compared RhDNase versus placebo. Wills 1996, a 14-day trial with 61 participants (all completed the study, but three had treatment interrupted), included participants who were in a stable state, with moderate airflow obstruction, and compared two doses of RhDNase (2.5 mg and 5 mg) versus placebo. The largest study (O’Donnell 1998), with 349 participants (of whom 346 completed the study), also included partici- pants who were in a stable state and compared 2.5 mg aerosolised RhDNase twice daily versus placebo for 24 weeks. Participants had a mean age of 60 years, with daily sputum production and airflow limitation. Attempts to obtain more detailed information from the included studies were unsuccessful. On Included studies re vie Risk of bias in included studies Allocation All four included studies were assessed as unclear in terms of allocation concealment bias (Figure 2). In terms of random sequence generation, one trial (Crisafulli 2007) was assessed as having low risk of bias, and the remaining three studies were judged to be unclear in this respect. Fo rP Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies. Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 10 Blinding Fo rP re vie w On ly The risk of performance and detection bias in three included studies (O’Donnell 1998; Olivieri 1991; Wills 1996) was judged to be low (Figure 3). Crisafulli 2007 was an unblinded study in which erdosteine and physiotherapy versus physiotherapy alone were compared. The risk of performance bias was evaluated as high; however outcomes were assessed by personnel blinded and not directly associated with the study administration, and detection bias was therefore rated as low. Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 11 Fo rP re vie w On ly Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study. Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 12 Selective reporting All four included studies were assessed as unclear in terms of reporting bias. Other potential sources of bias Effects of interventions rP re One study of 15 days’ duration compared bromhexine versus placebo (Olivieri 1991). Primary outcomes, exacerbations and hospitalisations were not reported. No significant difference was noted between bromhexine and placebo in terms of adverse events (OR 2.93, 95% CI 0.12 to 73.97; Analysis 1.1). As for secondary outcomes, no deaths were reported. Symptoms were reported in terms of “difficulty in expectoration,” sputum production, cough score and sputum quality. Difficulty in expectoration was significantly improved in the bromhexine-treated participants at day 10 (MD -0.45, 95% CI -0.89 to -0.03) and day 16 (MD -0.53, 95% CI -0.81 to -0.25). Our GRADE assessments of the quality of evidence in this trial produced a rating of low (Summary of findings for the main comparison). The percentage change in sputum production was greater in the bromhexine group at days seven, 10 and 16 (MD -21.5, 95% CI 38.9 to -4.1 at day 16). The cough score was significantly reduced at day 13 (MD -0.48, 95% CI -0.89 to -0.06). The quality of sputum was improved at both day 13 and day 16 (MD -0.45, 95% CI -0.87 to -0.034 at day 13). The analyses reported above were conducted by the authors of the previous version of this review (Crockett 2001), and additional data were supplied by the trial author (Olivieri 1991). Fo One trial of two weeks’ duration compared 5 mg RhDNase versus placebo (Wills 1996). Our GRADE assessments of the quality of evidence in this trial produced a rating of low (Summary of findings 2). No significant differences were reported between RhDNase (5 mg) and placebo with respect to the numbers of participants requiring hospitalisation for infective exacerbation (OR 5.54, 95% CI 0.25 to 123.08; Analysis 2.1). The table of adverse events in the trial report provides numbers of incidents of adverse events, rather than numbers of participants experiencing adverse events; for this reason we have not entered the data using RevMan software. The authors of the trial report described no significant differences between RhDNase (5 mg) and placebo in terms of most of the 19 reported adverse events, with the only exception being the incidence of influenza syndrome as diagnosed by participants, with more occurrences reported in the RhDNase arm. In terms of secondary outcomes, no deaths occurred and no symptoms were reported. No significant difference in FEV1 (MD 2.10 L, 95% CI -2.90 to 7.10; Analysis 2.2) or percentage change in forced vital capacity (FVC) (MD -2.00, 95% CI -6.16 to 2.16; Analysis 2.3) was observed at day 15 of this trial. A significant difference favouring placebo over RhDNase (5 mg) was observed (MD -3.20, 95% CI -6.30 to -0.10; Analysis 2.4) in relation to the change between baseline and day 15 on the immediate activities component of the functional status questionnaire quality of life assessment. No other significant differences were observed in the other quality of life measures (Analysis 2.4) nor in sputum colour (Analysis 2.5). vie See: Summary of findings for the main comparison Bromhexine compared with placebo for bronchiectasis; Summary of findings 2 5 mg RhDNase compared with placebo for bronchiectasis; Summary of findings 3 Erdosteine versus no treatment for bronchiectasis Bromhexine versus placebo RhDNase (5 mg) versus placebo w All four included studies were assessed as unclear in terms of other potential sources of bias. ly Only two of the four included studies were assessed as having low risk of bias in terms of attrition bias (O’Donnell 1998; Wills 1996), whereas the risk of attrition bias in Olivieri 1991 was regarded as high, and in Crisafulli 2007, the risk of attrition bias was judged as unclear. No significant difference between bromhexine and placebo in forced expiratory volume in one second (FEV1 ) was noted at seven days (MD 108.60 mL, 95% CI -242.38 to 459.58; Analysis 1.2) or at 13 days (MD 184.00 mL, 95% CI -149.75 to 517.75; Analysis 1.2). The analysis of auscultatory findings provided in the trial report indicated an advantage for bromhexine; however insufficient details of the analysis are provided to clarify whether the advantage was evident at day 16 (the final day) or, on average, throughout the trial. On Incomplete outcome data RhDNase (2.5 mg) versus placebo One study of two weeks’ duration compared 2.5 mg RhDNase versus placebo (Wills 1996). Our GRADE assessments of the quality of evidence in this trial produced a rating of low. No participants in the RhDNase (2.5 mg) or placebo arms were hospitalised for infective exacerbation. Again, we did not perform an analysis of the adverse events, as they were reported as numbers of events rather than as numbers of people experiencing one or more events. Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 13 reported between control and study groups. However, the study authors report higher levels of antibodies to RhDNase in the treatment group (OR 28.19, 95% CI 3.77 to 210.85; Analysis 3.7). Erdosteine versus no treatment On ly One study of 15 days’ duration compared erdosteine versus no treatment (Crisafulli 2007). Our primary outcomes of exacerbations, hospital admissions and adverse events were not reported. In terms of secondary outcomes, no deaths were reported. The impact on mucus density was evaluated in Analysis 4.1. No significant differences between erdosteine and control were seen at five days (MD -0.07, 95% CI -0.41 to 0.27), 10 days (MD -0.27, 95% CI -0.68 to 0.14) or 15 days (MD -0.27, 95% CI -0.63 to 0.09). Similarly, for mucus purulence (Analysis 4.2), no significant differences between erdosteine and control were noted at five days (MD -0.03, 95% CI -0.36 to 0.30) and 10 days (MD -0.20, 95% CI -0.58 to 0.18); however, the significant difference at 15 days indicated benefit for erdosteine versus control (MD -0.47, 95% CI -0.79 to -0.15). No significant differences were described between erdosteine and control at five days (MD -0.13, 95% CI -0.62 to 0.36), 10 days (MD 0.20, 95% CI -0.28 to 0.68) or 15 days (MD 0.40, 95% CI -0.03 to 0.83) in terms of mucus volume production (Analysis 4.3). By applying GRADE criteria, review authors evaluated the quality of evidence on these outcomes as low (Summary of findings 3). A significant difference was indicated between erdosteine and control in change from baseline to day 15 for FEV1 (mL) (MD 200.00, 95% CI 39.97 to 360.03; Analysis 4.4), but no significant difference was noted for FEV1 %predicted (MD 4.50, 95% CI 3.11 to 12.11; Analysis 4.5). Similarly, a significant difference was observed between erdosteine and control in change from baseline to day 15 for FVC (mL) (MD 300.00, 95% CI 27.48 to 572.52; Analysis 4.6) but not for FVC %predicted (MD 8.90, 95% CI 2.55 to 20.35; Analysis 4.7). Again, by applying GRADE criteria, review authors evaluated the quality of evidence on these outcomes as low. Fo rP re vie w Neither percentage change in FEV1 (MD 2.10 L, 95% CI -2.95 to 7.15; Analysis 3.2) nor percentage change in FVC (MD -2.40, 95% CI -6.42 to 1.62; Analysis 3.3) was significantly different between groups. Only one significant difference between RhDNase (2.5 mg) and placebo was reported in changes from baseline on components of the functional status questionnaire quality of life assessment (Analysis 3.4), and this involved the dyspnoea component, favouring RhDNase (2.5 mg) (MD 1.70, 95% CI 0.17 to 3.23; Analysis 3.4). No significant difference in sputum colour was reported (Analysis 3.5). An additional, considerably longer, study of 24 weeks’ duration compared 2.5 mg RhDNase versus placebo (O’Donnell 1998). Results were generally reported in a format that could not be included in the meta-analyses. The study authors reported that the RhDNase group had a higher but non-significant protocol-defined exacerbation rate of 0.66 exacerbations per participant per 168 days compared with 0.56 exacerbations per participant in the placebo group (risk ratio (RR) 1.17, 95% CI 0.85 to 1.65). The RhDNase group also had a higher non-protocol-defined exacerbation rate than the placebo group (RR 2.01, 95% CI 1.15 to 3.50), and when both of these types of exacerbations were combined, a significant increase in occurrence was noted in the RhDNase group (RR 1.35, 95% CI 1.01 to 1.79). RhDNase had a statistically significant negative effect (P value ≤ 0.05) on FEV1 , (mean percentage decline -1.7% in the placebo group and -3.6% in the RhDNase group; confidence intervals were not included in the trial report). Hospitalisation rates were increased in the RhDNase group (0.21 in the placebo group vs 0.39 in the treated group; RR 1.85, confidence intervals were not included in the trial report). Placebo-treated participants used antibiotics less (44.1 vs 56.9 days; P value ≤ 0.05; confidence intervals were not included in the trial report) and steroids less (23.4 vs 29.4 days; P value ≤ 0.05; confidence intervals were not included in the trial report) when compared with participants given RhDNase. No significant difference in the incidence of adverse events was Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 14 On w 5 mg RhDNase compared with placebo for bronchiectasis Illustrative comparative risks* (95% CI) re Outcomes vie Patient or population: patients with bronchiectasis Settings: community Intervention: 5 mg RhDNase* Comparison: placebo Corresponding risk Placebo 5 mg RhDNase rP Assumed risk Relative effect (95% CI) No. of participants (studies) Quality of the evidence (GRADE) Comments Hospitalisations for infective exacerbations reported, see below Frequency and duration See comment of exacerbations See comment See comment See comment See comment Hospitalisations for in- 0 per 100 3 fective exacerbations Follow-up: 15 days 10 per 100 (1.2 to 31.7) OR 5.54 (0.25 to 123.08) 40 (1 study) ⊕⊕ low1,2 Adverse events See comment See comment See comment See comment Fo Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation] See comment The authors of the trial report there were no significant differences between RhDNase (5 mg) versus placebo on most of the 19 reported adverse events with the only exception being the incidence of influenza syndrome as diagnosed by the participants, with more occurrences in the RhDNase arm 15 On w See comment See comment Mean change on placebo Mean % change FEV1 at MD 2.10 (-2.90 to 7.10) was -0.5% day 15 in the intervention groups was 2.1% higher (2.95 lower to 7.15 higher) See comment See comment Outcome not reported 40 (1 study) ⊕⊕ low1,2 We cannot interpret this finding since the difference is not statistically significant and we do not know what scale sputum colour was measured on See comment See comment Outcome not reported 40 (1 study) ⊕⊕ low1,2 rP Lung function % change FEV1 Follow-up: 15 days See comment re Deaths Follow-up: 15 days colour Mean sputum colour in MD 0.28 (-0.04 to 0.60) the intervention groups was 0.28 higher (0.04 lower to 0.6 higher) vie Symptoms sputum Mean sputum colour score was 3.2 Scale used not reported See comment See comment *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio. Fo Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Health-related quality of See comment life GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. ∗ The review also reports data for 2.5 mg RhDNase; no hospital admissions and no differences in FEV1 , quality of life, sputum colour or deaths were reported. 1 One point deducted to reflect risk of bias assessment of randomisation (judged as unclear risk of bias). 2 One point deducted to reflect imprecision in the estimate, with data coming from only one trial, leading to wide confidence intervals. 3 Assumed risk is based on the control group (N = 20) of the one trial reporting adverse events. 16 On w Outcomes vie Patient or population: patients with bronchiectasis Settings: community Intervention: erdosteine versus no treatment Illustrative comparative risks* (95% CI) Relative effect (95% CI) No. of participants (studies) Quality of the evidence (GRADE) Comments See comment See comment See comment See comment Outcome not reported Hospitalisations for in- See comment fective exacerbations See comment See comment See comment See comment Outcome not reported Adverse events See comment See comment See comment See comment See comment Outcome not reported Health-related quality of See comment life See comment See comment See comment See comment Outcome not reported Symptoms Mean mucus production Mean mucus volume pro- MD 0.40 mucus volume produc- 0.93 mL duction day 15 in the in- (-0.03 to 0.83) tion tervention groups was Follow-up: 15 days 0.4 mL higher (0.03 lower to 0.83 higher) 30 (1 study) ⊕⊕ low1,2 Deaths See comment See comment 30 (1 study) ⊕⊕ low1,2 re Assumed risk No treatment rP Frequency and duration See comment of exacerbations Fo Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Erdosteine versus no treatment for bronchiectasis See comment Corresponding risk Erdosteine See comment See comment Lung function change in Mean change on placebo Mean change in FEV1 at MD 0.40 (-0.03 to 0.83) FEV1 (L) at day 15 was 0 mL day 15 in the intervention groups was 200 mL higher Outcome not reported 17 On w vie *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval. 1 re GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. One point deducted to reflect risk of bias assessment (unblinded study). point deducted to reflect imprecision (data contributed by one small study). rP 2 One Fo Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. (40 to 360 mL higher) 18 Overall completeness and applicability of evidence Only three trials (with a total of 498 participants) provided data to this review, and opportunities for aggregation of the data were very limited. Several studies included a small number of participants with bronchiectasis in samples including participants with a range of respiratory conditions, and it was not possible to isolate the bronchiectasis data in those trials (details provided in Characteristics of excluded studies). The overall completeness and applicability of data eligible for inclusion in this review are therefore limited to three very different studies, with only one considering the comparison of bromhexine versus placebo (Olivieri 1991; N = 88), one comparing RhDNase versus placebo over a period of two weeks (Wills 1996; N = 61) and another comparing RhDNase versus placebo over a period of 24 weeks (O’Donnell 1998; N = 349), Fo rP re vie w Only four trials could be included in this review, and the results of one of the trials could not be entered into the meta-analysis, as no standard deviations were available. It was not possible to combine the other three trials in an overall analysis because they used different drugs in different clinical settings. Scant data were reported on the primary outcomes of interest to this review and on outcomes important to the patient, such as quality of life. The study by Olivieri 1991 tested the efficacy of adding bromhexine hydrochloride to an antibiotic during an acute infective exacerbation. The test dose chosen, 30 mg orally three times per day, is higher than the dose currently used in conventional medical practice. The drug was effective in improving sputum expectoration after ten days’ treatment in participants with an acute exacerbation of bronchiectasis. It further reduced sputum production at seven, 10 and 16 days. It reduced cough significantly at only one time point and improved quality of sputum on days 13 and 16. The FEV1 remained unchanged throughout the trials. The clinical conclusions derived from these data are that oral bromhexine at a dose above the usual recommended level can be effective in changing sputum production and clearance during an acute infective exacerbation. This effect was seen after only seven days of treatment. It is impossible to judge whether concurrent use of bromhexine with the antibiotic ceftazidine introduced a synergistic interaction. A recommendation for widespread use of bromhexine in bronchiectasis cannot be made on the basis of one trial alone, and it is clear that further well-designed randomised controlled studies are required to evaluate the role of this agent. Two trials (O’Donnell 1998; Wills 1996) compared nebulised RhDNase versus placebo in participants with chronic bronchiectasis. Wills 1996 was a two-week study, whereas O’Donnell 1998 ran for 24 weeks. Only one of the two trials (Wills 1996) considered RhDNase at 5 mg, and no important significant differences favouring RhDNase versus placebo were observed. Both trials evaluated nebulised RhDNase at a lower dose (2.5 mg), and the only significant difference between RhDNase (2.5 mg) and placebo reported in Wills 1996 was change from baseline in the dyspnoea component of the functional status questionnaire quality of life assessment, favouring the RhDNase (2.5 mg) arm. In the 24-week trial (O’Donnell 1998), the study authors reported a higher incidence of exacerbations and hospital admissions in the RhDNase arm and higher levels of antibodies to RhDNase in the treatment group; stronger evidence would be required to justify its use outside of a clinical trial. Erdosteine combined with physiotherapy slightly improved sputum purulence and small but clinically useful changes in spirometry over a 15-day period compared with physiotherapy alone (Crisafulli 2007). No significant improvements were seen at earlier ly Summary of main results time points. This trial included 30 participants, all older than 55 years, with stable disease and at least moderate airflow limitation. This single, small trial provides insufficient evidence on its own to advocate the use of erdosteine, and further studies are required. Randomised controlled trials are needed to examine the role of the other available mucolytics in stable bronchiectasis and in the subset of patients experiencing exacerbations. On DISCUSSION Quality of the evidence In terms of random sequence generation, three trials (O’Donnell 1998; Olivieri 1991; Wills 1996) were evaluated as unclear, and one (Crisafulli 2007) was judged as low risk. All four were judged to have unclear risk with respect to allocation concealment. On performance bias, three trials (O’Donnell 1998; Olivieri 1991; Wills 1996) were assessed as low risk, and one (Crisafulli 2007) was assessed as high risk. In terms of blinding of personnel, all four trials were judged to be at low risk of bias (detection bias). Potential biases in the review process The support provided by the Cochrane Airways Review Group in identification of potentially relevant trials is of a very high order; nevertheless, uncertainties regarding study selection bias or publication bias are inevitably a concern in all reviews. Failure to identify unpublished trials may lead to an incomplete estimation of mucolytic agents. Whilst a comprehensive search of the published literature for potentially relevant clinical trials was conducted without language restrictions using a systematic search strategy to minimise the likelihood of bias, we recognise the possibility that additional unpublished trials may have been missed. Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 19 The availability of data in this update is similar to that in the previous version of this review (Crockett 2001), and we have added only one small trial (Crisafulli 2007) (N = 30) comparing erdosteine and physiotherapy versus physiotherapy alone; however it has been possible to include several additional analyses in the update. children with non-CF bronchiectasis are clearly needed. These should examine short-term use of mucolytics with or instead of antibiotics to reduce exacerbation duration and long-term effects of mucolytics on exacerbation frequency and lung function. ly Agreements and disagreements with other studies or reviews ACKNOWLEDGEMENTS Implications for practice w Little evidence is available to recommend the routine use of mucolytics in bronchiectasis. However, bromhexine treatment for longer than seven days at a high dose has been reported to produce some beneficial changes in sputum production and clearance during an acute exacerbation. This finding is based on one rather old trial (Olivieri 1991) that included only 88 participants. Lung function was not altered with this drug, and quality of life and other outcome measures were not examined. No trial evidence exists at all for its use for longer than about two weeks. The authors of the original version of this review acknowledged the support of the Cochrane Airways Review Group staff (Steve Milan, Anna Bara and Jane Dennis) in identifying trials from the register and in obtaining copies of the papers, as well as editorial support from Dr Peter Gibson, Australian Co-ordinator of the Cochrane Airways Review Group. Anna Bara provided extra support in teaching us the correct way to use RevMan. They also thanked Professors Tom Petty and Dario Olivieri for responding to correspondence and supplying additional data to allow assessment of whether some studies should be included. On AUTHORS’ CONCLUSIONS vie In the 2013 update, we would particularly like to acknowledge the contributions of Josephine M Cranston, John H Alpers, Karen M Latimer, authors of the original version of this review (Crockett 2001), and the excellent support and assistance received from Emma Welsh, Liz Stovold and Emma Jackson of the Cochrane Airways Review Group, together with greatly appreciated guidance from Chris Cates (Cochrane Airways Review Group Co-ordinating Editor). We would also like to thank Diogo Bugano, Federica Davolio, Zhirajr Mokini Poturljan and Uwe Wollina for help with translation of non-English language studies. We are grateful to Yoshinori Hasegawa for providing helpful clarification of nonavailability of bronchiectasis participants’ data from Itoh 1984. The support provided by librarians Judith Scammel, Jane Appleton and Hilary Garrett at St Georges University London is also very much appreciated. Erdosteine in combination with physiotherapy showed a small benefit in spirometric parameters and sputum purulence after 15 days compared with physiotherapy alone. This finding comes from one small trial in stable older participants with mucus hypersecretion, which did not use a placebo (Crisafulli 2007). re Evidence is insufficient to allow a firm recommendation for either agent. rP Evidence has suggested possible harm and no evidence of benefit from RhDNase in non-CF bronchiectasis. This drug should not be used routinely in this condition. Implications for research Fo Further randomised controlled trials of mucolytics in adults and Michael Greenstone was the Editor of this review and commented critically on the review. REFERENCES References to studies included in this review human DNase I. rhDNase Study Group. Chest 1998;113 (5):1329–34. [CRS–ID: 4900100000006002] Crisafulli 2007 {published data only} Crisafulli E, Coletti O, Costi S, Zanasi E, Lorenzi C, Lucic S, et al.Effectiveness of erdosteine in elderly patients with bronchiectasis and hypersecretion: a 15-day, prospective, parallel, open-label, pilot study. Clinical Therapeutics 2007; 29(9):2001–9. Olivieri 1991 {published data only} Olivieri D, Ciaccia A, Marangio E, Marsico S, Todisco T, Del Vita M. Role of bromhexine in exacerbations of bronchiectasis. Double-blind randomized multicenter study versus placebo. Respiration 1991;58(3-4):117–21. [CRS–ID: 4900100000003559; : 4900100000003559] O’Donnell 1998 {published data only} O’Donnell AE, Barker AF, Ilowite JS, Fick RB. Treatment of idiopathic bronchiectasis with aerosolized recombinant Wills 1996 {published data only} Wills PJ, Wodehouse T, Corkery K, Mallon K, Wilson R, Cole PJ. Short-term recombinant human DNase in Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 20 improves clearance of mucus in patients with bronchiectasis. American Journal of Respiratory and Critical Care Medicine 1999;159(6):1843–8. [CRS–ID: 4900100000008890; : 4900100000008890] bronchiectasis. Effect on clinical state and in vitro sputum transportability. American Journal of Respiratory and Critical Care Medicine 1996;154(2 Pt 1):413–7. [CRS–ID: 4900100000005313; : 4900100000005313] Balzano 1973 {published data only} Balzano E, De Gaetani G. [D1-sobrerol in the treatment of acute and chronic bronchopulmonary phlogoses]. [Italian] [Il dl sobrerolo nel trattamento delle flogosi broncopolmonari acute e croniche]. Minerva Medica 1973; 64(37):1995–2002. [CRS–ID: 4900100000055881] ly Ghiringhelli 1981 {published data only} Ghiringhelli G. Feprazone plus bromhexine in treatment of flare-ups of chronic bronchopathies. [Italian]. Archivio Di Medicina Interna 1981;33(2):157–68. [CRS–ID: 4900100000050043] Hasani 1994 {published data only} Hasani A, Pavia D, Spiteri MA, Yeo CT, Agnew JE, Clarke SW, et al.Regional mucus transport following unproductive cough and forced expiration technique in patients with airways obstruction. European Respiratory Journal 1994;105 (5):1420–5. [CRS–ID: 4900100000004379] vie Bateman 1971 {published data only} Bateman PP. A new mucolytic, bromhexine (’bisolvon’). A double-blind study. Medical Journal of Australia 1971;1 (18):963–5. [CRS–ID: 4900100000009066] Germouty 1988 {published data only} Germouty J, Jirou-Najou JL. Clinical trial of ambroxol in 2 different dosage programs in 120 patients with bronchiectasis. [Portuguese]. Revista Brasileira de Clinica E Terapeutica 1988;17(1-2):33–6. [CRS–ID: 4900100000050034] On Alberto 1968 {published data only} Alberto S, Colongo PG, Brusasco L, Frigerio G. [Studies of the clinical and respiratory functional effects of a mucolyticantibiotic preparation in chronic bronchopulmonary diseases. Controlled double-blind single code studies] [Studi sugli effetti clinici e sulla funzionalità respiratoria di un preparato mucolitico–antibiotico nelle affezioni croniche broncopolmonari. Ricerca controllata doppio–cieca a codifica singola]. Minerva Medica 1968;59(53):2995–3002. [CRS–ID: 4900100000000090] Fadda 2001 {published data only} Fadda G. Oral neltenexine in patients with obstructive airways diseases: an open, randomised, controlled comparison versus sobrerol. Minerva Medica 2001; 92(4):269–75. [CRS–ID: 4900100000011117; : 4900100000011117] w References to studies excluded from this review Benjamin 1971 {published data only} Benjamin C. The use and efficacy of mucolytic agents. South African Medical Journal 1971; Vol. 45, issue 34: 948–52. [CRS–ID: 4900100000000295] rP re Bergogne 1985 {published data only} Bergogne Berezin E, Berthelot G, Kafe HP, Dournovo P. Influence of a fluidifying agent (bromhexine) on the penetration of antibiotics into respiratory secretions. International Journal of Clinical Pharmacology Research 1985;5(5):341–4. [CRS–ID: 4900100000001832] Fo Bradley 2011 {published data only} Bradley JM, Treacy K, O’Neill B, McCourt F, Green L, Gardner E, et al.A randomised double blind 13 week crossover trial of hypertonic saline (HTS) (6%) vs isotonic saline (ITS) (0.9%) in patients with bronchiectasis [Abstract]. Thorax 2011;66(Suppl 4):A49 [S106]. [CRS–ID: 4900100000054250] Cobbin 1971 {published data only} Cobbin DM, Elliott FM, Rebuck AS. The mucolytic agent bromhexine (Bisolvon) in chronic lung disease: a doubleblind crossover trial. Australian and New Zealand Journal of Medicine 1971;2:137–40. Currie 1988 {published data only} Currie DC, Greenstone M, Pavia D, Agnew JE, Pellow P, Clarke SW, et al.Efficacy of ’mucoregulatory’ agents in Young’s syndrome. Thorax 1988;43(6):480–1. [CRS–ID: 4900100000007454] Daviskas 1999 {published data only} Daviskas E, Anderson SD, Eberl S, Chan HK, Bautovich G, Anderson S, et al.Inhalation of dry powder mannitol Hasani 1994A {published data only} Hasani A, Pavia D, Agnew JE, Clarke SW. Regional lung clearance during cough and forced expiration technique (FET): effects of flow and viscoelasticity. Thorax 1994;49 (6):557–61. [CRS–ID: 4900100000004427] Itoh 1984 {published data only} Itoh K, Kounou O, Morise M, Iwakura M, Misutani N, Katayama T, et al.Clinical effects of proteinase, sfericase (AI-794), on chronic bronchitis and similar diseases. International Journal of Clinical Pharmacology, Therapy, and Toxicology 1984;22(1):32–8. [CRS–ID: 4900100000001525] Kawashima 1989 {published data only} Kawashima K, Yamamoto H, Kadoya M, Kato M, Nata T, Iida E, et al.Clinical role of Branhamella catarrhalis infection in pulmonary disorders. [Japanese]. Saishin Igaku [Modern Medicine] 1989;44(6):1268–72. [CRS–ID: 4900100000050022] Kellett 2005 {published data only} Kellett F, Redfern J, Niven RM, Kellet F. Evaluation of nebulised hypertonic saline (7%) as an adjunct to physiotherapy in patients with stable bronchiectasis. Respiratory Medicine 2005;99(1):27–31. [CRS–ID: 4900100000017992] Kossmagk 1980 {published data only} Kossmagk R. Ultrasonic aerosol apparatus hire system - Therapy of chronic obstructive bronchitis and bronchiectasia. [German]. Zeitschrift Fur Erkrankungen Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 21 Marthin 2007 {published data only} Marthin JK, Mortensen J, Pressler T, Nielsen KG. Pulmonary radioaerosol mucociliary clearance in diagnosis of primary ciliary dyskinesia. Chest 2007;132(3):966–76. [CRS–ID: 4900100000021265; : 4900100000021265] Verstraeten 1979 {published data only} Verstraeten JM. Mucolytic treatment in chronic obstructive lung disease: double-blind comparative clinical trial with Nacetylcysteine, bromhexine and placebo. Acta Tuberculosea et Pneumologica Belgica 1979;70(1):71–80. Wong 2012 {published data only} Wong C, Jayaram L, Karalus N, Eaton T, Tong C, Hockey H, et al.Azithromycin for prevention of exacerbations in non-cystic. Lancet 2012;380(9842):660–7. [CRS–ID: 4900100000063431] vie Noone 1999 {published data only} Noone PG, Bennett WD, Regnis JA, Zeman KL, Carson JL, King M, et al.Effect of aerosolized uridine-5’-triphosphate on airway clearance with cough in patients with primary ciliary dyskinesia. American Journal of Respiratory and Critical Care Medicine 1999;160(1):144–9. [CRS–ID: 4900100000006450; : 4900100000006450] ly Mareels 1983 {published data only} Mareels J. A long term tolerance trial of bromhexine. Acta Therapeutica 1983;9(3):305–15. [CRS–ID: 4900100000055851] Tsang 2003 {published data only} Tsang SMH, Jones AYM, Tsang SM H, Jones AYM. Postural drainage or flutter device in conjunction with breathing and coughing compared to breathing and coughing alone in improving secretion removal and lung function in patients with acute exacerbation of bronchiectasis. A pilot study. Hong Kong Physiotherapy Journal 2003;21:29–36. [CRS–ID: 4900100000016230] On Loukides 1998 {published data only} Loukides S, Kharitonov S, Wodehouse T, Cole PJ, Barnes PJ. Effect of arginine on mucociliary function in primary ciliary dyskinesia. Lancet 1998;352(9125):371–2. [CRS–ID: 4900100000023280; : 4900100000023280] Taskar 1992 {published data only} Taskar VS, Sharma RR, Goswami R, John PJ, Mahashur AA. Effect of bromhexine on sputum amoxycillin levels in lower respiratory infections. Respiratory Medicine 1992;86(2):157–60. [CRS–ID: 4900100000003765; : 4900100000003765] w der Atmungsorgane 1980;155(1):125–7. [CRS–ID: 4900100000050047] Patterson 2007 {published data only} Patterson JE, Hewitt O, Kent L, Bradbury I, Elborn JS, Bradley JM. Acapella versus ’usual airway clearance’ during acute exacerbation in bronchiectasis: a randomized crossover trial. Chronic Respiratory Disease 2007;4(2): 67–74. [CRS–ID: 4900100000024010] rP re Sahay 1982 {published data only} Sahay JN, Chatterjee SS, Ingram DF. The effect of methyl cysteine (Visclair) in respiratory diseases. A pilot study. Clinical Trials Journal 1982;19(3):137–43. [CRS–ID: 4900100000006790] Fo Serisier 2013 {published data only} Serisier DJ, Martin ML, McGuckin MA, Lourie R, Chen AC, Brain B, et al.Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS randomized controlled trial. JAMA 2013; Vol. 309, issue 12:1260–7. Stafanger 1988 {published data only} Stafanger G, Garne S, Howitz P, Morkassel E, Koch C. The clinical effect and the effect on the ciliary motility of oral N-acetylcysteine in patients with cystic fibrosis and primary ciliary dyskinesia. The European Respiratory Journal 1988;1(2):161–7. [CRS–ID: 4900100000002512; : 4900100000002512] Tambascio 2011 {published data only} Tambascio J, de Souza LT, Lisboa RM, Passarelli RDCV, de Souza HCD, Gastaldi AC. The influence of Flutter VRP1 components of mucus transport of patients with bronchiectasis. Respiratory Medicine 2011;105(9):1316–21. [CRS–ID: 4900100000050220] Yalçin 2006 {published data only} Yalçin E, Kiper N, Ozçelik U, Do ru D, Firat P, Sahin A, et al.Effects of clarithromycin on inflammatory parameters and clinical conditions in children with bronchiectasis. Journal of Clinical Pharmacy and Therapeutics 2006;31(1): 49–55. [CRS–ID: 4900100000019496] Additional references Balsamo 2010 Balsamo R, Lanata L, Egan CG. Mucoactive drugs. European Respiratory Review 2010;19(116):127-33. BTS 2010 Pasteur MC, Bilton D, Hill AT. BTS guideline for non-CF bronchiectasis. www.brit-thoracic.org.uk/LinkClick.aspx? link=496&tabid=69 (accessed 15 November 2013). Cotgreave 1987 Cotgreave I, Eklund A, Larsson K, Moldéus P. No penetration of orally administered N-acetylcysteine into bronchoalveolar lavage fluid. European Journal of Respiratory Diseases 1987;70(2):73–7. Goeminne 2010 Goeminne P, Dupont L. Non-cystic fibrosis bronchiectasis: diagnosis and management in 21st century. Postgraduate Medical Journal 2010;86:493–501. Henke 2007 Henke MO, Ratjen F. Mucolytics in cystic fibrosis. Paediatric Respiratory Reviews 2007;8(1):24-9. Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1 [updated Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 22 March 2011]. The Cochrane Collaboration, 2011. www.cochrane-handbook.org. Stockley 1995 Stockley RA. Role of inflammation in respiratory tract infections. American Journal of Medicine 1995;99(6):8S13S. References to other published versions of this review Crockett 2001 Crockett A, Cranston JM, Alpers JH, Latimer KM. Mucolytics for bronchiectasis. Cochrane Database of Systematic Reviews 2001, Issue 1. [DOI: 10.1002/ 14651858.CD001289] ∗ Indicates the major publication for the study Fo rP re vie Tomkiewicz 1995 Tomkiewicz RP, App EM, De Sanctis GT, Coffiner M, Maes P, Rubin BK, et al.A comparison of a new mucolytic ly Stafler 2010 Stafler P, Carr S. Non cystic fibrosis bronchiectasis: its diagnosis and management. Archives of Diseases in Childhood. Education and Practice Edition 2010;95:73–82. Zafarullah 2003 Zafarullah M, Li WQ, Sylvester J, Ahmad M. Molecular mechanisms of N-acetylcysteine actions. Cellular and Molecular Life Sciences 2003;60(1):6–20. On Rogers 2007 Rogers DF. Mucoactive agents for airway mucus hypersecretory diseases. Respiratory Care 2007;52(9):117697. TSANZ 2010 TSANZ and the Lung Foundation. Chronic suppurative lung disease and bronchiectasis in children and adults 2010. http://www.lungfoundation.com.au/professional-resources/ guidelines/ (accessed 15 November 2013). w Review Manager (RevMan) Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012. N-acetylcysteine l-lysinate with N-acetylcysteine: airway epithelial function and mucus changes in dog. Pulmonary Pharmacology 1995;8(6):259-65. Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 23 CHARACTERISTICS OF STUDIES Characteristics of included studies [ordered by study ID] ly Crisafulli 2007 Prospective, randomised, parallel, open-label, pilot study Participants Participants over 55 years of age with focal or diffuse bronchiectasis (with or without chronic airflow limitation), with no current smoking status Thirty participants (15 in erdosteine group and 15 in control group) Males: erdosteine group 11 (73 %), control group 10 (67 %) Mean age: erdosteine group 70 (SD 13.6), control group 71 (SD 9.3) FEV1 %predicted, erdosteine group 50.8 (SD 20.7), control group 43.9 (SD 12.5) Diagnosis of bronchiectasis based on a confirmed computerised tomography scan and previously recorded diagnostic criteria findings. Participants consecutively enrolled and randomly assigned into two groups Included participants in stable condition, having daily sputum production > 30 mL but with no evidence of ongoing exacerbation, as confirmed by medical history report and physical examination Patients excluded if they used antibiotics, mucolytics, systemic steroids or antitussive drugs, or if they reported a change in long-term medications in the four weeks before commencement of the study. Patients with a medical history of hypersensitivity to erdosteine, diabetes, liver failure or cancer were also excluded from the study Participants were enrolled in the hospital’s rehabilitation programme based on joint criteria of the American Thoracic Society and the European Respiratory Society vie w On Methods PO erdosteine 225 mg twice daily and routine chest physiotherapy versus routine chest physiotherapy alone re Interventions Fo Notes rP Outcomes Primary end point of the study was to establish the effectiveness (in terms of subjective semi-quantitative score of sputum characteristics) of erdosteine used adjunctive to routine chest physiotherapy in the study population. Secondary end point was to assess physiological changes associated with the treatment regimen. Measurements were assessed in all enrolled participants at 5-day time points: 0 (baseline), 5, 10, and 15 days after randomisation 15-Day trial All study drugs provided by Laboratori Baldacci SpA, Pisa, Italy Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection Low risk bias) Randomisation sequence achieved by selecting from an eight-block number table Allocation concealment (selection bias) Not specified in trial report Unclear risk Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 24 Crisafulli 2007 (Continued) Open-label study ly Blinding of participants and personnel High risk (performance bias) All outcomes Unclear risk Selective reporting (reporting bias) Unclear risk Other bias Unclear risk No withdrawals reported No apparent indication of selective reporting No other indication of bias w Incomplete outcome data (attrition bias) All outcomes All measurements assessed by personnel blinded and not directly associated with study administration On Blinding of outcome assessment (detection Low risk bias) All outcomes O’Donnell 1998 Double-blind, randomised, placebo-controlled, multi-centre study vie Methods Adult outpatients in stable condition with idiopathic bronchiectasis from 23 centres in North America, Great Britain and Ireland RhDNase group of 173 participants randomly assigned (172 completed), control group 176 participants randomly assigned (174 completed) Mean age: RhDNase group 60 years, control group 60 years (standard deviations not provided in trial report) Men: RhDNase group 60 (35%), control group 72 (41%) Baseline lung function: mean FEV1 L RhDNase group 1.34, control group 1.43 (standard deviations not provided in trial report) Baseline lung function: mean % predicted FEV1 RhDNase group 50.76%, control group 52.05% (standard deviations not provided in trial report) Inclusion criteria: • Radiographic (one of the following four criteria): ◦ Standard chest radiograph compatible with bronchiectasis ◦ Chest CT showing ectasia of peripheral bronchi, fluid-filled airways or thickening of the mucosa ◦ Contrast bronchography compatible with bronchiectasis ◦ Bacterial pneumonia localised to same lobe or segment • Daily purulent sputum production > 15 mL for most days in the three months before enrolment • Sweat chloride level < 60 mEq/L • Reproducible spirometry demonstrating FEV1 > 30% and < 80% predicted for age, sex and height Exclusion criteria: • Any deterioration in pulmonary status that caused a change in antibiotic, corticosteroid or bronchodilator regimen or any hospitalisation within 14 days before randomisation • History of major hemoptysis requiring interventional therapy or transfusion Fo rP re Participants Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 25 O’Donnell 1998 (Continued) ly within 180 days of randomisation. Active allergic bronchopulmonary aspergillosis, active mycobacterium tuberculosis or atypical mycobacterial infection • Cystic fibrosis, tracheostomy and non-dermal malignancy within past two years. Pregnant and lactating women not enrolled. Participants having used any investigational drug within 28 days of randomisation Run-in: three times clinical evaluation before drug administration Aerosolised 1.0 mg/mL RhDNase in 2.5 mL of excipient (150 mM NaC1, 1.5 mM calcium chloride pH 6.0) (2.5 mg of aerosolised RhDNase twice daily) versus excipient alone (twice daily) for 24 weeks All participants continued to receive usual care Active drug or placebo solution delivered by Marquest Acorn II Nebuliser (Marquest, Inglewood, CO) powered by compressor (De Vilbiss Pulmo Aide; DeVilbiss, Somerset, PA) Outcomes Primary outcomes: incidence of pulmonary exacerbations and mean percentage change in FEV1 from baseline Secondary outcomes: % change in FVC, health-related quality of life, adverse events Total of 5 visits over the study period. FEV1 ; quality of life and dyspnoea recorded at each visit; treatment FEV1 recorded as mean of all FEV1 on treatment. Total of exacerbations recorded over the duration of the study vie w On Interventions Notes 24-Week trial RhDNase provided by Genentech, San Francisco re Risk of bias Bias Authors’ judgement Support for judgement Not reported Allocation concealment (selection bias) Not reported rP Random sequence generation (selection Unclear risk bias) Unclear risk Fo Blinding of participants and personnel Low risk (performance bias) All outcomes Double-blind Blinding of outcome assessment (detection Low risk bias) All outcomes Double-blind and CT scans analysed by radiologists outside the study Incomplete outcome data (attrition bias) All outcomes Two placebo-treated participants (one with self limited haemoptysis and one with sinus symptoms) and one RhDNase-treated participant with increased sputum production withdrew from the study Low risk Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 26 O’Donnell 1998 (Continued) Unclear risk No apparent indication of selective reporting Other bias Unclear risk No other indication of bias ly Selective reporting (reporting bias) On Olivieri 1991 Double-blind, randomised, multi-centre study (four-centre study) Participants Data collected from four Italian university departments of lung disease Adult participants with acute bronchiectasis with morning cough and > 20 mL of sputum. Bronchiectasis confirmed by bronchography and/or CT scan Bromhexine group, 45; placebo group, 43 (data on FEV1 outcomes and percentage change in mean sputum volume not available from 21 participants) Mean age: bromhexine group 49.5 (2.6), range 20 to 71, Placebo group 54.3 (2.3), range 20 to 70 Men: bromhexine group 29 (64%), placebo group 28 (65%) Baseline lung function: mean FEV1 L (SD), bromhexine group 1.67 (0.11), placebo group 1.65 (0.14) Inclusion criteria: • Adults, during an exacerbation of bronchiectasis with morning cough, expectorating > 20 mL purulent sputum Exclusion criteria: • Severe liver, kidney or heart disease. Pregnant or nursing women. Surgical patients vie w Methods Fo Notes rP Outcomes Randomisation after three-day washout period (no mucolytics, beta2 -agonists, corticoids and/or antibiotics) Bromhexine 30 mg three times daily Placebo three times daily (first week on ceftazidine 1 g intramuscular injection antibiotic) re Interventions Clinical evaluation of cough, auscultatory findings and difficulty of expectoration using an arbitrary four-point scale with semi-quantitative scores. FEV1 . Rating scale of drug tolerability . Clinical parameters recorded at days 4, 7, 10, 13 and 16. FEV1 at days 7 and 13 15-Day trial A co-author on the trial (M Del Vita) based in the Medical Department at Boehringer Ingelheim Italia Risk of bias Bias Authors’ judgement Random sequence generation (selection Unclear risk bias) Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Support for judgement Not reported 27 Allocation concealment (selection bias) Unclear risk Not reported Double-blind with matching placebo ly Blinding of participants and personnel Low risk (performance bias) All outcomes Selective reporting (reporting bias) Unclear risk Other bias Unclear risk Only 67 participants contributed data to the FEV1 and % change in mean sputum volume after 10 days of treatment outcomes. Trial report does not clarify why data on these outcomes are available for only 76% of participants w High risk No apparent indication of selective reporting bias No other indication of bias vie Incomplete outcome data (attrition bias) All outcomes Double-blind with matching placebo On Blinding of outcome assessment (detection Low risk bias) All outcomes Wills 1996 Methods Double-blind, randomised, placebo-controlled trial Single-centre study (Royal Brompton Hospital, London, UK) Adult participants with moderate or severe bronchiectasis of more than one lobe, confirmed by bronchography or CT scan 61 participants between 33 and 72 years of age Men: 28 (46%) Randomly assigned to three groups (details of ages and number of men in each group not reported): • Group 1 bd dosing 20, Group 2 od dosing 21, Group 3 placebo 20 Baseline lung function: mean % predicted FEV1 (SE): Group 1 bd dosing 56.1 (4.9), Group 2 od dosing 61.2 (4.9), Group 3 placebo 63.9 (5.4) Inclusion criteria: • Participants with stable moderate or severe bronchiectasis of more than one lobe confirmed by bronchography or CT scanning, who did not have cystic fibrosis, active tuberculosis or lung cancer • Participants had to be able to perform pulmonary function tests reproducibly and had to have FVC greater than 40% of predicted, with FEV1 /FVC less than 75% • Pulse oximetry required to show oxygen saturation greater than 90% • Disease state stable at enrolment with no hospitalisation or change in antibiotic, steroid or bronchodilator therapy in previous 14 days • Participants had to be producing > 5 mL of sputum daily • None receiving other investigational drugs or regular opiates • Women with reproductive potential had to be using adequate contraceptive measures Exclusion criteria: Fo rP re Participants Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 28 Wills 1996 (Continued) • People with asthma or > 10% sputum eosinophilia, CF, lung cancer or mycobacterial disease excluded Visited site three times in five days to ensure that entry criteria were met First dose administered in hospital and a 14-day treatment period followed at home At end of the trial period, each participant re-attended 28 days later (28 days after day 14) No treatment changes in 14 days before randomisation RhDNase 2.5 mg in 2.5 mL twice daily versus RhDNase once daily and excipient placebo once daily versus excipient placebo twice daily Acorn II nebuliser (Marquest Medical) driven by Pulmo-Aide compressor (DeVilbiss) Outcomes Primary outcome: effect on FEV1 Secondary outcomes: effect on FVC, quality of life (functional status questionnaire); safety evaluation; sputum transportability; VAS of breathlessness; sputum assessment and exacerbations (exacerbations data not reported) Data collected at days 15 and 28 Notes 14-Day trial Two study authors recipients of grants from Genentech vie w On ly Interventions Risk of bias Bias Authors’ judgement Support for judgement Not reported Allocation concealment (selection bias) Not reported re Random sequence generation (selection Unclear risk bias) Unclear risk Double-blind Blinding of outcome assessment (detection Low risk bias) All outcomes Double-blind Fo rP Blinding of participants and personnel Low risk (performance bias) All outcomes Incomplete outcome data (attrition bias) All outcomes Low risk All participants completed all scheduled visits Selective reporting (reporting bias) Unclear risk No apparent indication of selective reporting Other bias Unclear risk No other clear indication of bias Treatment interrupted in 3 participants: • Consent withdrawn after an infective exacerbation developed • Dyspnoea occurred Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 29 Wills 1996 (Continued) On ly • Hospitalisation occurred and study drug was inadvertently discontinued All 3 were in the RhDNase twice-daily group Three hospitalisations of two participants for infective exacerbations-both were in the RhDNase twice-daily group Abbreviations: bd: twices daily; CT: computed tomography; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; od: once daily; RhDNase: recombinant human DNase; SD: standard deviation; VAS: visual analogue scale. w Characteristics of excluded studies [ordered by study ID] Reason for exclusion Alberto 1968 The study combined participants with chronic bronchitis, emphysema, asthma, cor pulmonale and bronchiectasis. Separate data from the bronchiectasis participants in this sample were not reported Balzano 1973 Not a randomised controlled trial. 55 participants with various respiratory diagnoses on single treatment Bateman 1971 Participants did not have a diagnosis of bronchiectasis Benjamin 1971 Participants did not have a diagnosis of bronchiectasis Bergogne 1985 The study combined participants with chronic bronchitis and bronchiectasis. Separate data from the bronchiectasis participants in this sample were not reported Cobbin 1971 re Not a mucolytic agent (hypertonic saline is not defined as a mucolytic by our prespecified entry criteria) Only two of fifteen participants treated had a diagnosis of bronchiectasis Mucolytic agent not compared with placebo/no treatment Fo Currie 1988 rP Bradley 2011 vie Study Daviskas 1999 Not a mucolytic agent Fadda 2001 Participants did not have a diagnosis of bronchiectasis Germouty 1988 Participants did not have a diagnosis of bronchiectasis Ghiringhelli 1981 The study combined participants with various respiratory diagnoses. Separate data from the one bronchiectasis participant in this sample were not reported Hasani 1994 Participants did not have a diagnosis of bronchiectasis Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 30 (Continued) Not a mucolytic agent Itoh 1984 The study combined participants with chronic bronchitis, bronchiectasis, pulmonary tuberculosis, bronchial asthma, pulmonary pyosis, pulmonary emphysema, pulmonary fibrosis, pulmonary cancer, pneumonia and pleurisy. Separate data from the bronchiectasis participants in this sample were not reported Kawashima 1989 Not a randomised controlled trial and not a mucolytic agent Kellett 2005 Not a mucolytic agent (hypertonic saline is not defined as a mucolytic by our prespecified entry criteria) Kossmagk 1980 The study combined participants with various respiratory diagnoses. Separate data from the bronchiectasis participants in this sample were not reported Loukides 1998 Focus of study is ciliary beat frequency, not a measure of mucolysis Mareels 1983 The study combined participants with acute bronchitis and chronic bronchitis. Only one participant had a diagnosis of bronchiectasis. Data from the three groups were not reported separately Marthin 2007 Not a mucolytic agent Noone 1999 Intervention not used as a mucolytic agent but to enhance cilia function, changing the consistency/secretion of mucin Patterson 2007 Not a mucolytic agent Sahay 1982 The study combined five bronchiectasis participants (four completed) in sample of 36 participants with various respiratory diseases. Separate data from the bronchiectasis participants in this sample were not reported Serisier 2013 Not a mucolytic agent Taskar 1992 rP re vie w On ly Hasani 1994A Tsang 2003 Not a mucolytic agent Verstraeten 1979 Only two of 60 participants included in the study had a diagnosis of bronchiectasis. One participant was treated with bromhexine, the other with N-acetyl-cysteine Wong 2012 Not a mucolytic agent Yalçin 2006 Not a mucolytic agent Stafanger 1988 Not a mucolytic agent The study combined participants with bronchiectasis, COPD, lung abscess. Separate data from the bronchiectasis participants in this sample were not reported Fo Tambascio 2011 The study combined participants with cystic fibrosis and primary ciliary dyskinesia. Unclear in the trial report whether the primary ciliary dyskinesia participants also had a diagnosis of bronchiectasis Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 31 DATA AND ANALYSES Comparison 1. Bromhexine versus placebo Odds Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) On 1 1 1 1 vie Comparison 2. 5 mg RhDNase versus placebo No. of studies Outcome or subgroup title 1 No. of participants Totals not selected Totals not selected 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] Statistical method Effect size Totals not selected Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Totals not selected Totals not selected Totals not selected 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 1 1 1 Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 1 1 Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 1 1 Mean Difference (IV, Fixed, 95% CI) Odds Ratio (M-H, Fixed, 95% CI) Totals not selected Totals not selected 1 1 1 1 1 1 1 rP Fo Effect size Odds Ratio (M-H, Fixed, 95% CI) re 1 Hospitalisations for infective exacerbations 2 % change FEV1 at day 15 3 % change FVC at day 15 4 Quality of Life 4.1 Cough and congestion 4.2 Dyspnoea 4.3 Basic activity limitations 4.4 Intermediate activity limitations 4.5 Emotional well-being 4.6 Fatigue 4.7 Not able to carry out usual activities 4.8 Days stayed in bed 4.9 Perception of overall health 5 Sputum colour 6 Deaths Statistical method w 1 Adverse events 2 FEV1 (mL) 2.1 At 7 days 2.2 At 13 days No. of participants ly No. of studies Outcome or subgroup title Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 32 Comparison 3. 2.5 mg RhDNase versus placebo No. of studies Statistical method Effect size Odds Ratio (M-H, Fixed, 95% CI) 1 1 1 1 1 1 1 Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Totals not selected Totals not selected Totals not selected 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 1 1 1 Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] On ly 1 w 1 Hospitalisations for infective exacerbations 2 % change FEV1 at day 15 3 % change FVC at day 15 4 Quality of life 4.1 Cough and congestion 4.2 Dyspnoea 4.3 Basic activity limitations 4.4 Intermediate activity limitations 4.5 Emotional well-being 4.6 Fatigue 4.7 Not able to carry out usual activities 4.8 Days stayed in bed 4.9 Perception of overall health 5 Sputum colour 6 Deaths 7 Antibodies to RhDNase No. of participants 1 1 1 2 1 Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) vie Outcome or subgroup title 390 Mean Difference (IV, Fixed, 95% CI) Odds Ratio (M-H, Fixed, 95% CI) Odds Ratio (M-H, Fixed, 95% CI) Totals not selected 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] Totals not selected 3.09 [0.32, 29.98] Totals not selected No. of studies rP Outcome or subgroup title re Comparison 4. Erdosteine versus no treatment Fo 1 Mucus density 1.1 Day five 1.2 Day 10 1.3 Day 15 2 Mucus purulence 2.1 Day five 2.2 Day 10 2.3 Day 15 3 Mucus volume production 3.1 Day five 3.2 Day 10 3.3 Day 15 4 Change in FEV1 (mL) at day 15 5 Change in FEV1 %Pred at day 15 6 Change in FVC (mL) at day 15 7 Change in FVC %Pred at day 15 No. of participants Statistical method Effect size 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Totals not selected 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] Totals not selected 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] Totals not selected 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 0.0 [0.0, 0.0] Totals not selected Totals not selected 1 1 Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Totals not selected Totals not selected Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 33 Analysis 1.1. Comparison 1 Bromhexine versus placebo, Outcome 1 Adverse events. Review: Mucolytics for bronchiectasis Comparison: 1 Bromhexine versus placebo Outcome: 1 Adverse events Bromhexine Placebo n/N n/N 1/45 0/43 Odds Ratio M-H,Fixed,95% CI 2.93 [ 0.12, 73.97 ] On Olivieri 1991 Odds Ratio M-H,Fixed,95% CI ly Study or subgroup 0.01 0.1 1 10 100 Favours Placebo w Favours Bromhexine Review: Mucolytics for bronchiectasis Comparison: 1 Bromhexine versus placebo re Outcome: 2 FEV1 (mL) Study or subgroup N Mean(SD) 34 1740.4 (712.5423) 33 1631.8 (751.9633) 108.60 [ -242.38, 459.58 ] 34 1797.8 (693.8833) 33 1613.8 (699.6877) 184.00 [ -149.75, 517.75 ] rP Fo Olivieri 1991 Mean Difference Mean(SD) 1 At 7 days 2 At 13 days Mean Difference Control N Olivieri 1991 vie Analysis 1.2. Comparison 1 Bromhexine versus placebo, Outcome 2 FEV1 (mL). IV,Fixed,95% CI -500 -250 Favours Bromhexine Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 0 250 IV,Fixed,95% CI 500 Favours Placebo 34 Analysis 2.1. Comparison 2 5 mg RhDNase versus placebo, Outcome 1 Hospitalisations for infective exacerbations. Review: Mucolytics for bronchiectasis Comparison: 2 5 mg RhDNase versus placebo Study or subgroup 5 mg rhDNase Placebo n/N n/N 2/20 0/20 Odds Ratio Odds Ratio M-H,Fixed,95% CI M-H,Fixed,95% CI On Wills 1996 ly Outcome: 1 Hospitalisations for infective exacerbations 0.01 0.1 1 10 100 Favours placebo vie w Favours rhDNase 5.54 [ 0.25, 123.08 ] Analysis 2.2. Comparison 2 5 mg RhDNase versus placebo, Outcome 2 % change FEV1 at day 15. Review: Mucolytics for bronchiectasis Comparison: 2 5 mg RhDNase versus placebo Mean Difference Placebo N Mean(SD) N Mean(SD) 20 1.6 (7.6026) 20 -0.5 (8.4971) Mean Difference IV,Fixed,95% CI IV,Fixed,95% CI 2.10 [ -2.90, 7.10 ] -10 -5 Favours Placebo 0 5 10 Favours rhDNase Fo Wills 1996 5 mg rhDNase rP Study or subgroup re Outcome: 2 % change FEV1 at day 15 Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 35 Analysis 2.3. Comparison 2 5 mg RhDNase versus placebo, Outcome 3 % change FVC at day 15. Review: Mucolytics for bronchiectasis Comparison: 2 5 mg RhDNase versus placebo Outcome: 3 % change FVC at day 15 5 mg rhDNase N Mean(SD) N Mean(SD) 20 1.1 (6.7082) 20 3.1 (6.7082) Mean Difference IV,Fixed,95% CI On Wills 1996 Mean Difference Placebo ly Study or subgroup -10 -5 0 5 -2.00 [ -6.16, 2.16 ] 10 Favours rhDNase vie w Favours Placebo IV,Fixed,95% CI Analysis 2.4. Comparison 2 5 mg RhDNase versus placebo, Outcome 4 Quality of Life. Review: Mucolytics for bronchiectasis Comparison: 2 5 mg RhDNase versus placebo Study or subgroup re Outcome: 4 Quality of Life 5 mg rhDNase N Wills 1996 2 Dyspnoea Wills 1996 rP 1 Cough and congestion Mean(SD) Mean Difference Placebo N Mean(SD) Mean Difference IV,Fixed,95% CI IV,Fixed,95% CI 20 1.5 (3.1305) 20 1 (3.5777) 0.50 [ -1.58, 2.58 ] 20 0 (4.0249) 20 0 (2.6833) 0.0 [ -2.12, 2.12 ] 20 0 (1.3416) 20 -0.3 (0.8944) 0.30 [ -0.41, 1.01 ] 20 -1.5 (5.8138) 20 1.7 (4.0249) -3.20 [ -6.30, -0.10 ] 20 0.1 (2.2361) 20 0.2 (1.3416) -0.10 [ -1.24, 1.04 ] 3 Basic activity limitations Fo Wills 1996 4 Intermediate activity limitations Wills 1996 5 Emotional well-being Wills 1996 6 Fatigue -1 -0.5 Favours placebo 0 0.5 1 Favours rhDNase (Continued . . . ) Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 36 (. . . Study or subgroup 5 mg rhDNase Wills 1996 Mean Difference Placebo Continued) Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI 20 -1 (2.6833) 20 0.9 (3.5777) -1.90 [ -3.86, 0.06 ] 20 0.3 (0.8944) 20 -0.1 (0.8944) 0.40 [ -0.15, 0.95 ] 20 0.1 (0.4472) 20 -0.1 (0.4472) 20 -0.4 (2.2361) 20 0.3 (1.3416) Wills 1996 Wills 1996 9 Perception of overall health Wills 1996 On 8 Days stayed in bed ly 7 Not able to carry out usual activities -1 -0.5 0 -0.70 [ -1.84, 0.44 ] 0.5 1 Favours rhDNase vie w Favours placebo 0.20 [ -0.08, 0.48 ] Analysis 2.5. Comparison 2 5 mg RhDNase versus placebo, Outcome 5 Sputum colour. Review: Mucolytics for bronchiectasis Outcome: 5 Sputum colour Mean Difference Placebo N Mean(SD) N Mean(SD) 20 3.48 (0.4919) 20 3.2 (0.5367) Mean Difference IV,Fixed,95% CI IV,Fixed,95% CI 0.28 [ -0.04, 0.60 ] -0.5 -0.25 Favours rhDNase 0 0.25 0.5 Favours Placebo Fo Wills 1996 5 mg rhDNase rP Study or subgroup re Comparison: 2 5 mg RhDNase versus placebo Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 37 Analysis 2.6. Comparison 2 5 mg RhDNase versus placebo, Outcome 6 Deaths. Review: Mucolytics for bronchiectasis Comparison: 2 5 mg RhDNase versus placebo Outcome: 6 Deaths 5 mg rhDNase Placebo n/N n/N 0/20 0/20 Odds Ratio M-H,Fixed,95% CI On Wills 1996 Odds Ratio M-H,Fixed,95% CI ly Study or subgroup 0.01 0.1 1 10 100 Favours placebo w Favours rhDNase 0.0 [ 0.0, 0.0 ] Review: Mucolytics for bronchiectasis Comparison: 3 2.5 mg RhDNase versus placebo vie Analysis 3.1. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 1 Hospitalisations for infective exacerbations. Study or subgroup re Outcome: 1 Hospitalisations for infective exacerbations 2.5 mg rhDNase Placebo Odds Ratio Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI 0/20 0/20 0.0 [ 0.0, 0.0 ] 0.01 0.1 Favours rhDNase 1 10 100 Favours placebo Fo rP Wills 1996 Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 38 Analysis 3.2. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 2 % change FEV1 at day 15. Review: Mucolytics for bronchiectasis Comparison: 3 2.5 mg RhDNase versus placebo Outcome: 2 % change FEV1 at day 15 2.5 mg rhDNase N Mean(SD) N Mean(SD) 21 1.6 (11.4564) 20 -0.5 (8.4971) Mean Difference IV,Fixed,95% CI On Wills 1996 Mean Difference Placebo ly Study or subgroup -10 -5 0 5 2.10 [ -4.05, 8.25 ] 10 Favours rhDNase vie w Favours Placebo IV,Fixed,95% CI Analysis 3.3. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 3 % change FVC at day 15. Review: Mucolytics for bronchiectasis Comparison: 3 2.5 mg RhDNase versus placebo Mean Difference Placebo N Mean(SD) N Mean(SD) 21 0.7 (6.4156) 20 3.1 (6.7082) Mean Difference IV,Fixed,95% CI IV,Fixed,95% CI -2.40 [ -6.42, 1.62 ] -10 -5 Favours placebo 0 5 10 Favours rhDNase Fo Wills 1996 2.5 mg rhDNase rP Study or subgroup re Outcome: 3 % change FVC at day 15 Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 39 Analysis 3.4. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 4 Quality of life. Review: Mucolytics for bronchiectasis Comparison: 3 2.5 mg RhDNase versus placebo Outcome: 4 Quality of life 2.5 mg rhDNase Mean Difference Placebo N Mean(SD) N 21 0.3 (3.6661) 20 21 1.7 (2.291) 20 21 0.2 (1.3748) 20 21 1 (3.2078) 20 21 -0.6 (2.2913) 21 -1.1 (3.6661) 21 21 Mean(SD) Wills 1996 2 Dyspnoea Wills 1996 3 Basic activity limitations Wills 1996 Wills 1996 5 Emotional well-being 6 Fatigue Wills 1996 7 Not able to carry out usual activities Wills 1996 Wills 1996 9 Perception of overall health 21 0 (2.683) 1.70 [ 0.17, 3.23 ] -0.3 (0.8944) 0.50 [ -0.21, 1.21 ] 1.7 (4.0249) -0.70 [ -2.93, 1.53 ] -0.80 [ -1.94, 0.34 ] 20 0.9 (3.5777) -2.00 [ -4.22, 0.22 ] 0.1 (0.4583) 20 -0.1 (0.8944) 0.20 [ -0.24, 0.64 ] 0.01 (0.4583) 20 -0.1 (0.4472) 0.11 [ -0.17, 0.39 ] 20 0.3 (1.3416) -0.60 [ -1.31, 0.11 ] 20 -0.3 (0.9165) -4 -2 Favours placebo 0 2 4 Favours rhDNase Fo rP Wills 1996 -0.70 [ -2.92, 1.52 ] 0.2 (1.3416) re 8 Days stayed in bed 1 (3.5777) vie Wills 1996 IV,Fixed,95% CI w 4 Intermediate activity limitations IV,Fixed,95% CI On 1 Cough and congestion Mean Difference ly Study or subgroup Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 40 Analysis 3.5. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 5 Sputum colour. Review: Mucolytics for bronchiectasis Comparison: 3 2.5 mg RhDNase versus placebo Outcome: 5 Sputum colour 2.5 mg rhDNase N Mean(SD) N Mean(SD) 21 3.4 (0.5041) 20 3.2 (0.5367) Mean Difference IV,Fixed,95% CI On Wills 1996 Mean Difference Placebo ly Study or subgroup -0.25 0 0.25 0.20 [ -0.12, 0.52 ] 0.5 w -0.5 IV,Fixed,95% CI Review: Mucolytics for bronchiectasis Comparison: 3 2.5 mg RhDNase versus placebo Outcome: 6 Deaths 2.5 mg rhDNase O’Donnell 1998 Odds Ratio Odds Ratio n/N M-H,Fixed,95% CI M-H,Fixed,95% CI 3/173 1/176 3.09 [ 0.32, 29.98 ] 0/21 0/20 0.0 [ 0.0, 0.0 ] 196 3.09 [ 0.32, 29.98 ] rP Wills 1996 Total (95% CI) Placebo n/N re Study or subgroup vie Analysis 3.6. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 6 Deaths. 194 Total events: 3 (2.5 mg rhDNase), 1 (Placebo) Heterogeneity: Chi2 = 0.0, df = 0 (P = 1.00); I2 =0.0% Test for overall effect: Z = 0.97 (P = 0.33) Fo Test for subgroup differences: Not applicable 0.01 0.1 Favours rhDNase Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1 10 100 Favours placebo 41 Analysis 3.7. Comparison 3 2.5 mg RhDNase versus placebo, Outcome 7 Antibodies to RhDNase. Review: Mucolytics for bronchiectasis Comparison: 3 2.5 mg RhDNase versus placebo Outcome: 7 Antibodies to RhDNase 2.5 mg rhDNase Placebo n/N n/N 24/173 1/176 Odds Ratio M-H,Fixed,95% CI On O’Donnell 1998 Odds Ratio M-H,Fixed,95% CI ly Study or subgroup 0.005 0.1 1 10 200 Favours placebo w Favours rhDNase 28.19 [ 3.77, 210.85 ] Review: Mucolytics for bronchiectasis Outcome: 1 Mucus density Study or subgroup Erdosteine N Crisafulli 2007 3 Day 15 Mean(SD) 1.6 (0.48) 15 1.67 (0.48) -0.07 [ -0.41, 0.27 ] 15 1.13 (0.51) 15 1.4 (0.63) -0.27 [ -0.68, 0.14 ] 15 0.8 (0.56) 15 1.07 (0.45) -0.27 [ -0.63, 0.09 ] 15 Fo Crisafulli 2007 Mean Difference N rP 2 Day 10 Mean Difference Control Mean(SD) 1 Day five Crisafulli 2007 re Comparison: 4 Erdosteine versus no treatment vie Analysis 4.1. Comparison 4 Erdosteine versus no treatment, Outcome 1 Mucus density. Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. IV,Fixed,95% CI -1 -0.5 Favours erdosteine 0 0.5 IV,Fixed,95% CI 1 Favours control 42 Analysis 4.2. Comparison 4 Erdosteine versus no treatment, Outcome 2 Mucus purulence. Review: Mucolytics for bronchiectasis Comparison: 4 Erdosteine versus no treatment Outcome: 2 Mucus purulence Erdosteine Mean Difference Control N Mean(SD) N Mean(SD) IV,Fixed,95% CI 15 1 (0.53) 15 1.03 (0.37) -0.03 [ -0.36, 0.30 ] 15 0.6 (0.63) 15 0.8 (0.41) -0.20 [ -0.58, 0.18 ] 15 0.33 (0.48) 15 0.8 (0.41) -0.47 [ -0.79, -0.15 ] 2 Day 10 Crisafulli 2007 3 Day 15 -1 -0.5 0 Favours erdosteine 0.5 1 Favours control re vie w Crisafulli 2007 IV,Fixed,95% CI On 1 Day five Crisafulli 2007 Mean Difference ly Study or subgroup Analysis 4.3. Comparison 4 Erdosteine versus no treatment, Outcome 3 Mucus volume production. Mucolytics for bronchiectasis rP Review: Comparison: 4 Erdosteine versus no treatment Outcome: 3 Mucus volume production Erdosteine Fo Study or subgroup Mean Difference Control Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI 15 0.47 (0.64) 15 0.6 (0.73) -0.13 [ -0.62, 0.36 ] 15 1.07 (0.59) 15 0.87 (0.74) 0.20 [ -0.28, 0.68 ] 15 1.33 (0.48) 15 0.93 (0.7) 0.40 [ -0.03, 0.83 ] 1 Day five Crisafulli 2007 2 Day 10 Crisafulli 2007 3 Day 15 Crisafulli 2007 -1 -0.5 Favours erdosteine Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 0 0.5 1 Favours control 43 ly Analysis 4.4. Comparison 4 Erdosteine versus no treatment, Outcome 4 Change in FEV1 (mL) at day 15. Review: Mucolytics for bronchiectasis On Comparison: 4 Erdosteine versus no treatment Outcome: 4 Change in FEV1 (mL) at day 15 Study or subgroup Mean Difference Control N Mean(SD) N Mean(SD) 15 200 (300) 15 0 (100) Mean Difference IV,Fixed,95% CI -500 -250 0 Favours control IV,Fixed,95% CI 200.00 [ 39.97, 360.03 ] 250 500 Favours erdosteine re vie w Crisafulli 2007 Erdosteine Analysis 4.5. Comparison 4 Erdosteine versus no treatment, Outcome 5 Change in FEV1 %Pred at day 15. Mucolytics for bronchiectasis rP Review: Comparison: 4 Erdosteine versus no treatment Outcome: 5 Change in FEV1 %Pred at day 15 Study or subgroup Erdosteine Fo N Crisafulli 2007 15 Mean Difference Control Mean(SD) N Mean(SD) 5.8 (13.3) 15 1.3 (7) Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Mean Difference IV,Fixed,95% CI IV,Fixed,95% CI 4.50 [ -3.11, 12.11 ] -100 -50 Favours control 0 50 100 Favours erdosteine 44 Analysis 4.6. Comparison 4 Erdosteine versus no treatment, Outcome 6 Change in FVC (mL) at day 15. Review: Mucolytics for bronchiectasis Comparison: 4 Erdosteine versus no treatment Outcome: 6 Change in FVC (mL) at day 15 Mean Difference Control N Mean(SD) N Mean(SD) 15 300 (500) 15 0 (200) Mean Difference IV,Fixed,95% CI On Crisafulli 2007 Erdosteine ly Study or subgroup -500 -250 0 250 300.00 [ 27.48, 572.52 ] 500 Favours erdosteine vie w Favours control IV,Fixed,95% CI Analysis 4.7. Comparison 4 Erdosteine versus no treatment, Outcome 7 Change in FVC %Pred at day 15. Review: Mucolytics for bronchiectasis Comparison: 4 Erdosteine versus no treatment Study or subgroup Erdosteine N Mean(SD) N Mean(SD) 9.5 (20.8) 15 0.6 (8.9) rP 15 Mean Difference Control Mean Difference IV,Fixed,95% CI IV,Fixed,95% CI 8.90 [ -2.55, 20.35 ] -100 -50 Favours control 0 50 100 Favours erdosteine Fo Crisafulli 2007 re Outcome: 7 Change in FVC %Pred at day 15 Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 45 APPENDICES Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR) Frequency of search CENTRAL (The Cochrane Library) Monthly MEDLINE (Ovid) Weekly EMBASE (Ovid) Weekly PsycINFO (Ovid) Monthly CINAHL (EBSCO) Monthly AMED (EBSCO) Monthly vie w Database On ly Electronic searches: core databases re Handsearches: core respiratory conference abstracts rP Conference Years searched American Academy of Allergy, Asthma and Immunology (AAAAI) 2001 onwards 2001 onwards Asia Pacific Society of Respirology (APSR) 2004 onwards Fo American Thoracic Society (ATS) British Thoracic Society Winter Meeting (BTS) 2000 onwards Chest Meeting 2003 onwards European Respiratory Society (ERS) 1992, 1994, 2000 onwards International Primary Care Respiratory Group Congress (IPCRG) 2002 onwards Thoracic Society of Australia and New Zealand (TSANZ) 1999 onwards Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 46 MEDLINE search strategy used to identify trials for the CAGR Bronchiectasis search On ly 1. exp Bronchiectasis/ 2. bronchiect$.mp. 3. bronchoect$.mp. 4. kartagener$.mp. 5. (ciliary adj3 dyskinesia).mp. 6. (bronchial$ adj3 dilat$).mp. 7. or/1-6 Filter to identify RCTs vie w 1. exp “clinical trial [publication type]”/ 2. (randomised or randomised).ab,ti. 3. placebo.ab,ti. 4. dt.fs. 5. randomly.ab,ti. 6. trial.ab,ti. 7. groups.ab,ti. 8. or/1-7 9. Animals/ 10. Humans/ 11. 9 not (9 and 10) 12. 8 not 11 The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases re Appendix 2. Search strategy for the Cochrane Airways Group Register 2013 update Fo rP #1 BRONCH:MISC1 #2 MeSH DESCRIPTOR Bronchiectasis Explode All #3 bronchiect* #4 #1 or #2 or #3 #5 MeSH DESCRIPTOR Expectorants #6 mucolytic* #7 “mucociliary clearance” #8 N-acetylcysteine #9 bromhexine #10 S-carboxymethylcysteine #11 ambroxol #12 sobrerol #13 “iodinated glycerol” #14 “human DNase” #15 RhDNase #16 Bromhexine #17 #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 #18 #4 and #17 [Note; in search line #1, MISC1 denotes the field where the reference has bene coded for condition, in this case, bronchiectasis] Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 47 Previous versions Mucolytic* or “mucociliary clearance” or N-acetylcysteine or bromhexine or S-carboxymethylcysteine or ambroxol or sobrerol or “iodinated glycerol” or “human DNase” or RhDNase or Bromhexine [Limited to bronchiectasis records] ly WHAT’S NEW On Last assessed as up-to-date: 19 June 2013. Event Description 30 September 2013 New citation required and conclusions have changed 19 June 2013 New search has been performed Protocol first published: Issue 1, 1997 re Review first published: Issue 2, 2000 Event 19 January 2010 New search has been performed rP Date 8 August 2008 Description Literature search re-run; no new studies identified. Amended Converted to new review format. New citation required and conclusions have changed Substantive amendment Fo 10 October 2000 New literature search run vie HISTORY One new study added to the previous version of this review (Crockett 2001). Methodology updated (including new full risk of bias assessment). GRADE and risk of bias assessments added to the review. Review redrafted w Date CONTRIBUTIONS OF AUTHORS In the original version of this review (Crockett 2001), AC initiated the study. AC and KL reviewed the trials. JC and Anna Bara were responsible for data entry and analysis. All review authors were involved in the discussion and in interpretation of the results. AC, KL and JC wrote the paper. AC is guarantor for the study. In the 2013 update, MW, IC, KS, AC and SJM updated the background. MW and IC independently selected studies for inclusion. SJM and MW independently extracted data and completed risk of bias assessments. SJM and AH updated the results section. The results, risk of bias and summary of findings sections were completed by SJM and AH. SJM provided summary of findings tables and figures. SJM updated the methods section. AH, MW, IC, KS, AC and SJM completed the Discussion and Conclusions. Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 48 DECLARATIONS OF INTEREST None known. SOURCES OF SUPPORT ly Internal sources On • NHS Research and Development, UK. • National Institute for Health Research, UK. External sources • No sources of support supplied DIFFERENCES BETWEEN PROTOCOL AND REVIEW Fo rP re vie w In the 2013 update of this review, we defined primary and secondary outcomes. We brought the review up to date using current methodological standards consistent with Higgins 2011. Mucolytics for bronchiectasis (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 49