Mucolytics for bronchiectasis

Abstract

Background

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.

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.

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.

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.

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.

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.

Authors' conclusions

Given the harmful effects of recombinant human DNase in one trial and no evidence of benefit, this drug should be avoided in non–cystic 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.

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.

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.

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.

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.

Summary of findings

Summary of findings for the main comparison. Bromhexine compared with placebo for bronchiectasis.

Bromhexine compared with placebo for bronchiectasis
Patient or population: patients with bronchiectasis Settings: community Intervention: bromhexine Comparison: placebo
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Bromhexine
Frequency and duration of exacerbations	See comment	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 1003	2.2 per 100 (0.05 to 11.7)	OR 2.93 (0.12 to 73.97)	88 (1 study)	⊕⊕⊝⊝ low1,2
Health‐related quality of life	See comment	See comment	See comment	See comment	See comment	Outcome not reported
Symptoms difficulty in expectoration Follow‐up: 16 days	Absolute values not reported	Absolute values not reported	MD ‐0.53 (‐0.81 to ‐0.25)	88 (1 study)	⊕⊕⊝⊝ low1,2
Deaths	See comment	See comment	See comment	See comment	See comment	Outcome not reported
Lung function FEV1 Follow‐up: 13 days	Mean FEV1 in the control group was 1614 mL	Mean FEV1 in the intervention groups was 184 mL higher (149.75 lower to 517.75 higher)	MD 184.00 (‐149.75 to 517.75)	88 (1 study)	⊕⊕⊝⊝ low1,2
*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.
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.

¹One point deducted to reflect risk of bias assessment of randomisation (judged as unclear risk of bias).
 ²One point deducted to reflect imprecision in the estimate, with data coming from only one trial, leading to low event rate and wide confidence intervals.

³Assumed risk is based on the control group (N = 43) of the one trial reporting adverse events.

Summary of findings 2. RhDNase compared with placebo for bronchiectasis.

2.5 mg twice daily RhDNase compared with placebo for bronchiectasis
Patient or population: patients with bronchiectasis Settings: community Intervention: 2.5 mg twice daily RhDNase** Comparison: placebo
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	5 mg RhDNase
Frequency and duration of exacerbations	See comment	See comment	See comment	See comment	See comment	Hospitalisations for infective exacerbations reported, see below
Hospitalisations for infective exacerbations Follow‐up: 15 days	0 per 1003	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	See comment	Wills 1996 (N = 40) reports no significant differences between RhDNase (2.5 mg twice daily) versus placebo on most of the 19 reported adverse events. The only exception to this being the incidence of influenza syndrome as diagnosed by the participants, with more occurrences in the RhDNase arm. In ODonnell 1998 (N = 349) no significant difference in the incidence of adverse events was 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
Health‐related quality of life	See comment	See comment	See comment	See comment	See comment	Outcome not reported
Symptoms sputum colour Scale used not reported	Mean sputum colour score was 3.2	Mean sputum colour in the intervention groups was 0.28 higher (0.04 lower to 0.6 higher)	MD 0.28 (‐0.04 to 0.60)	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.
Deaths Follow‐up: 24 weeks	0.6 per 100	1.83 per 100 (0.19 to 15.32)	OR 3.09 (0.32 to 29.98)	349 (1 study)	⊕⊕⊝⊝ low1,2	Events were very infrequent
Lung function % change FEV1 Follow‐up: 15 days	Mean change on placebo was ‐0.5%	Mean % change FEV1 at day 15 in the intervention groups was 2.1% higher (2.95 lower to 7.15 higher)	MD 2.10 (‐2.90 to 7.10)	40 (1 study)	⊕⊕⊝⊝ low1,2
*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.
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 once daily RhDNase; no hospital admissions and no differences in FEV₁, quality of life or sputum colour were reported.

¹One point deducted to reflect risk of bias assessment of randomisation (judged as unclear risk of bias).
 ²One point deducted to reflect imprecision in the estimate, with data coming from only one trial, leading to wide confidence intervals.

³Assumed risk is based on the control group (N = 20) of the one trial reporting adverse events.

Summary of findings 3. Erdosteine versus no treatment for bronchiectasis.

Erdosteine versus no treatment for bronchiectasis
Patient or population: patients with bronchiectasis Settings: community Intervention: erdosteine versus no treatment
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	No treatment	Erdosteine
Frequency and duration of exacerbations	See comment	See comment	See comment	See comment	See comment	Outcome not reported
Hospitalisations for infective exacerbations	See comment	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 life	See comment	See comment	See comment	See comment	See comment	Outcome not reported
Symptoms mucus volume production Follow‐up: 15 days	Mean mucus production 0.93 mL	Mean mucus volume production day 15 in the intervention groups was 0.4 mL higher (0.03 lower to 0.83 higher)	MD 0.40 (‐0.03 to 0.83)	30 (1 study)	⊕⊕⊝⊝ low1,2
Deaths	See comment	See comment	See comment	See comment	See comment	Outcome not reported
Lung function change in FEV1 (L) at day 15	Mean change on placebo was 0 mL	Mean change in FEV1 at day 15 in the intervention groups was 200 mL higher (40 to 360 mL higher)	MD 200 mL (40 to 360)	30 (1 study)	⊕⊕⊝⊝ low1,2
*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.
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.

¹One point deducted to reflect risk of bias assessment (unblinded study).
 ²One point deducted to reflect imprecision (data contributed by one small study).

Background

Description of the condition

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 medium‐sized 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).

Description of the intervention

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 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.

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.

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.

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.

Types of participants

Adults with a diagnosis of bronchiectasis, but not cystic fibrosis.

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).

Types of outcome measures

Primary outcomes

• Frequency and duration of exacerbations.

• Hospitalisations.

• Adverse events.

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)).

Search methods for identification of studies

Electronic searches

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 searched all databases from their inception to June 2013, with no restriction on language of publication.

Searching other resources

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.

Data collection and analysis

Selection 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.

Data extraction and management

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.

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).

Measures of treatment effect

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.

Unit of analysis issues

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

We tested heterogeneity among pooled estimates using the Der‐Simonian 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.

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.

Assessment of reporting biases

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.

Data synthesis

Summary of findings table

We created a 'Summary of findings' table using the following outcomes.

Primary

• Frequency and duration of exacerbations.

• Hospitalisations.

• Adverse events.

Secondary

• Health‐related quality of life.

• Symptoms: cough, sputum volume and ease of expectoration, wheeze, dyspnoea.

• Mortality.

• Lung function.

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.

Subgroup analysis and investigation of heterogeneity

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.

Sensitivity analysis

We planned to conduct sensitivity analyses by comparing random‐effects versus fixed‐effect modelling if issues of significant heterogeneity arose. However this was not necessary.

Results

Description of studies

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). Thirty‐two reports were excluded (details provided in Characteristics of excluded studies).

See Figure 1 for a study flow diagram.

1.

Study flow diagram.

Included studies

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 RhDNase regimens (2.5 mg daily and 2.5 mg twice daily) with placebo. The largest study (O'Donnell 1998), with 349 participants (of whom 346 completed the study), also included participants 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.

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.

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.

2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Blinding

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.

3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Incomplete outcome data

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.

Selective reporting

All four included studies were assessed as unclear in terms of reporting bias.

Other potential sources of bias

All four included studies were assessed as unclear in terms of other potential sources of bias.

Effects of interventions

See: Table 1; Table 2; Table 3

Bromhexine versus placebo

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).

1.1. Analysis.

Comparison 1 Bromhexine versus placebo, Outcome 1 Adverse events.

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 (Table 1).

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).

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.

1.2. Analysis.

Comparison 1 Bromhexine versus placebo, Outcome 2 FEV₁ (mL).

RhDNase (2.5 mg twice daily) versus placebo

One trial of two weeks' duration compared 2.5 mg RhDNase twice daily versus placebo (Wills 1996). Our GRADE assessments of the quality of evidence in this trial's outcomes, and our assessment of those from O'Donnell 1998,where estimable, produced a rating of low (Table 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.

2.1. Analysis.

Comparison 2 5 mg RhDNase versus placebo, Outcome 1 Hospitalisations for infective exacerbations.

In terms of secondary outcomes, 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) or mortality Analysis 2.6.

2.2. Analysis.

Comparison 2 5 mg RhDNase versus placebo, Outcome 2 % change FEV₁ at day 15.

2.3. Analysis.

Comparison 2 5 mg RhDNase versus placebo, Outcome 3 % change FVC at day 15.

2.4. Analysis.

Comparison 2 5 mg RhDNase versus placebo, Outcome 4 Quality of Life.

2.5. Analysis.

Comparison 2 5 mg RhDNase versus placebo, Outcome 5 Sputum colour.

2.6. Analysis.

Comparison 2 5 mg RhDNase versus placebo, Outcome 6 Deaths.

An additional, considerably longer, study of 24 weeks' duration compared 2.5 mg RhDNase twice daily 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 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 2.7).

2.7. Analysis.

Comparison 2 5 mg RhDNase versus placebo, Outcome 7 Antibodies to RhDNase.

RhDNase (2.5 mg daily) versus placebo

One study of two weeks' duration compared 2.5 mg RhDNase daily 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.

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).

3.2. Analysis.

Comparison 3 2.5 mg RhDNase versus placebo, Outcome 2 % change FEV₁ at day 15.

3.3. Analysis.

Comparison 3 2.5 mg RhDNase versus placebo, Outcome 3 % change FVC at day 15.

3.4. Analysis.

Comparison 3 2.5 mg RhDNase versus placebo, Outcome 4 Quality of life.

3.5. Analysis.

Comparison 3 2.5 mg RhDNase versus placebo, Outcome 5 Sputum colour.

Erdosteine versus no treatment

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 (Table 3).

4.1. Analysis.

Comparison 4 Erdosteine versus no treatment, Outcome 1 Mucus density.

4.2. Analysis.

Comparison 4 Erdosteine versus no treatment, Outcome 2 Mucus purulence.

4.3. Analysis.

Comparison 4 Erdosteine versus no treatment, Outcome 3 Mucus volume production.

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.

4.4. Analysis.

Comparison 4 Erdosteine versus no treatment, Outcome 4 Change in FEV₁ (mL) at day 15.

4.5. Analysis.

Comparison 4 Erdosteine versus no treatment, Outcome 5 Change in FEV₁ %Pred at day 15.

4.6. Analysis.

Comparison 4 Erdosteine versus no treatment, Outcome 6 Change in FVC (mL) at day 15.

4.7. Analysis.

Comparison 4 Erdosteine versus no treatment, Outcome 7 Change in FVC %Pred at day 15.

Discussion

Summary of main results

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. Both trials (Wills 1996,O'Donnell 1998) considered RhDNase at 5 mg total daily dose, and no important significant differences favouring RhDNase versus placebo were observed. 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. Wills 1996 also evaluated nebulised RhDNase at a lower dose (2.5 mg daily), and the only significant difference between RhDNase (2.5 mg daily) 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 daily) arm.

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 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.

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),

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.

Agreements and disagreements with other studies or reviews

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.

Authors' conclusions

Implications for practice.

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.

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).

Evidence is insufficient to allow a firm recommendation for either agent.

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.

Further randomised controlled trials of mucolytics in adults and 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.

Feedback

Error in analysis, 10 April 2018

Summary

On page 43, the study by O'Donnell has been included in the 2.5 mg RhDNase versus placebo analysis but this study is 2.5 mg twice a day and should be in the 5 mg analysis.

Sarah Wood

I do not have any affiliation with or involvement in any organisation with a financial interest in the subject matter of my comment

Reply

We are most grateful to Sarah Wood for kindly drawing our attention to an error in the above review. We accept that the proposed revision is necessary and, on reflection, we agree that the data in O'Donnell 1998 should be grouped in the 5 mg (2.5 mg twice per day) category rather than the 2.5 mg (2.5 mg once per day) category. By and large, it was not possible to aggregate data from O'Donnell 1998 with the data from the other RhDnase study in the review and the data from O'Donnell 1998 was originally reported narratively. In the results section of the review we have now moved the narrative report of O'Donnell 1998 to the 5 mg section (from the 2.5 mg section). The difficulties we experienced originally, in 2014, in handling the O'Donnell 1998 data in anything other than a narrative report apply equally to the revision of the review, where we have moved the study to the RhDnase 5 mg section of Effects of Interventions. However, there was an opportunity to aggregate mortality data with the same outcome from Wills 1996 in a meta‐analysis and we have included this revision; it does not change the original conclusions of the review. For further clarity here it should be noted that Wills 1996 compared nebulised RhDNase twice 2.5 mg per day and at once 2.5 mg per day versus placebo in participants with chronic bronchiectasis, whereas O'Donnell 1998 compared nebulised RhDNase twice 2.5mg per day versus placebo in participants with chronic bronchiectasis.

Accordingly we have adjusted text elsewhere (in the Discussion), where necessary, in the review to reflect this revision. The revision does not change in any important way the original conclusions of the review. Essentially the 2014 version of the review noted the paucity of evidence in this area and that issue still applies. Having completed this revision of the review we are still of the view that there is too little data available from randomised controlled trials in this area to draw robust conclusions on the efficacy of mucolytics for bronchiectasis

Alan Crockett , Iain Crossingham, Steve Milan

Contributors

Feedback contributor: Sarah Wood.

Affiliation: Medicines and Technologies Programme, National Institute for Health and Care Excellence, Manchester, UK

What's new

Date	Event	Description
3 July 2018	Feedback has been incorporated	Feedback added. Changes made to the review ‐ see Feedback 1.

History

Protocol first published: Issue 1, 1997
 Review first published: Issue 2, 2000

Date	Event	Description
23 October 2014	Amended	Typo in summary of findings table edited
30 September 2013	New citation required and conclusions have changed	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
19 June 2013	New search has been performed	New literature search run
19 January 2010	New search has been performed	Literature search re‐run; no new studies identified.
8 August 2008	Amended	Converted to new review format.
10 October 2000	New citation required and conclusions have changed	Substantive amendment

Appendices

Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR)

Electronic searches: core databases

Database	Frequency of search
CENTRAL (The Cochrane Library)	Monthly
MEDLINE (Ovid)	Weekly
EMBASE (Ovid)	Weekly
PsycINFO (Ovid)	Monthly
CINAHL (EBSCO)	Monthly
AMED (EBSCO)	Monthly

 

Handsearches: core respiratory conference abstracts

Conference	Years searched
American Academy of Allergy, Asthma and Immunology (AAAAI)	2001 onwards
American Thoracic Society (ATS)	2001 onwards
Asia Pacific Society of Respirology (APSR)	2004 onwards
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

 

Bronchiectasis search

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

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

Appendix 2. Search strategy for the Cochrane Airways Group Register

2013 update

#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]

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]

Data and analyses

Comparison 1. Bromhexine versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Adverse events	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 FEV1 (mL)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.1 At 7 days	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 At 13 days	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 2. 5 mg RhDNase versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Hospitalisations for infective exacerbations	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 % change FEV1 at day 15	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3 % change FVC at day 15	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4 Quality of Life	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.1 Cough and congestion	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Dyspnoea	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Basic activity limitations	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 Intermediate activity limitations	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.5 Emotional well‐being	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.6 Fatigue	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.7 Not able to carry out usual activities	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.8 Days stayed in bed	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.9 Perception of overall health	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Sputum colour	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
6 Deaths	2		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
7 Antibodies to RhDNase	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 3. 2.5 mg RhDNase versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Hospitalisations for infective exacerbations	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 % change FEV1 at day 15	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3 % change FVC at day 15	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4 Quality of life	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4.1 Cough and congestion	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Dyspnoea	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Basic activity limitations	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 Intermediate activity limitations	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.5 Emotional well‐being	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.6 Fatigue	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.7 Not able to carry out usual activities	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.8 Days stayed in bed	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.9 Perception of overall health	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Sputum colour	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
6 Deaths	2	390	Odds Ratio (M‐H, Fixed, 95% CI)	3.09 [0.32, 29.98]

3.1. Analysis.

Comparison 3 2.5 mg RhDNase versus placebo, Outcome 1 Hospitalisations for infective exacerbations.

3.6. Analysis.

Comparison 3 2.5 mg RhDNase versus placebo, Outcome 6 Deaths.

Comparison 4. Erdosteine versus no treatment.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mucus density	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.1 Day five	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Day 10	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.3 Day 15	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Mucus purulence	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.1 Day five	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Day 10	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.3 Day 15	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Mucus volume production	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3.1 Day five	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Day 10	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 Day 15	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Change in FEV1 (mL) at day 15	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
5 Change in FEV1 %Pred at day 15	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
6 Change in FVC (mL) at day 15	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
7 Change in FVC %Pred at day 15	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Crisafulli 2007.

Methods	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
Interventions	PO erdosteine 225 mg twice daily and routine chest physiotherapy versus routine chest physiotherapy alone
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
Notes	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 bias)	Low risk	Randomisation sequence achieved by selecting from an eight‐block number table
Allocation concealment (selection bias)	Unclear risk	Not specified in trial report
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	All measurements assessed by personnel blinded and not directly associated with study administration
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No withdrawals reported
Selective reporting (reporting bias)	Unclear risk	No apparent indication of selective reporting
Other bias	Unclear risk	No other indication of bias

O'Donnell 1998.

Methods	Double‐blind, randomised, placebo‐controlled, multi‐centre study
Participants	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 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
Interventions	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
Notes	24‐Week trial RhDNase provided by Genentech, San Francisco
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double‐blind and CT scans analysed by radiologists outside the study
Incomplete outcome data (attrition bias) All outcomes	Low risk	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
Selective reporting (reporting bias)	Unclear risk	No apparent indication of selective reporting
Other bias	Unclear risk	No other indication of bias

Olivieri 1991.

Methods	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
Interventions	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)
Outcomes	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
Notes	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	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind with matching placebo
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double‐blind with matching placebo
Incomplete outcome data (attrition bias) All outcomes	High 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
Selective reporting (reporting bias)	Unclear risk	No apparent indication of selective reporting bias
Other bias	Unclear risk	No other indication of bias

Wills 1996.

Methods	Double‐blind, randomised, placebo‐controlled trial
Participants	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: People with asthma or > 10% sputum eosinophilia, CF, lung cancer or mycobacterial disease excluded
Interventions	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
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double‐blind
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 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: twice daily; CT: computed tomography; FEV_1: forced expiratory volume in one second; FVC: forced vital capacity; od: once daily; RhDNase: recombinant human DNase; SD: standard deviation; VAS: visual analogue scale.

Characteristics of excluded studies [ordered by study ID]

Study	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
Bradley 2011	Not a mucolytic agent (hypertonic saline is not defined as a mucolytic by our prespecified entry criteria)
Cobbin 1971	Only two of fifteen participants treated had a diagnosis of bronchiectasis
Currie 1988	Mucolytic agent not compared with placebo/no treatment
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
Hasani 1994A	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
Stafanger 1988	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
Tambascio 2011	Not a mucolytic agent
Taskar 1992	The study combined participants with bronchiectasis, COPD, lung abscess. Separate data from the bronchiectasis participants in this sample were not reported
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

Differences between protocol and review

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.

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.

Sources of support

Internal sources

• NHS Research and Development, UK.

• National Institute for Health Research, UK.

External sources

• No sources of support supplied

Declarations of interest

None known.

Edited (no change to conclusions), comment added to review