Abstract
Introduction
Bronchiectasis is usually a complication of previous lower respiratory infection and/or inflammation. It causes chronic cough, copious production of sputum (often purulent), and recurrent infections, and may cause airway obstruction bearing some similarities with that seen in COPD. It may complicate respiratory conditions such as asthma or COPD. It can be associated with primary ciliary dyskinesia, primary immunodeficiencies, certain systemic diseases such as inflammatory bowel disease and rheumatoid arthritis, and foreign body inhalation. Bronchiectasis can be due to cystic fibrosis but this is excluded from this review.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments in people with non-cystic fibrosis (non-CF) bronchiectasis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We performed a GRADE evaluation of the quality of evidence for interventions.
Results
We found 23 studies that met our inclusion criteria.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: airway clearance techniques, corticosteroids (inhaled), exercise or physical training, hyperosmolar agents (inhaled), mucolytics, prolonged-use antibiotics, and surgery.
Key Points
Bronchiectasis is characterised by irreversible widening of medium to small-sized airways, with inflammation, chronic bacterial infection, and destruction of bronchial walls.
Bronchiectasis is usually a complication of previous lower respiratory infection and/or inflammation, and causes chronic cough, production of copious sputum (often purulent), and recurrent infections. It may cause airway obstruction bearing some similarities with that seen in COPD.
Bronchiectasis may complicate respiratory conditions such as asthma or COPD. It can be associated with primary ciliary dyskinesia, primary immunodeficiencies, certain systemic diseases such as inflammatory bowel disease and rheumatoid arthritis, and foreign body inhalation. Bronchiectasis can be due to cystic fibrosis but this is excluded from this review.
Exercise or inspiratory muscle training may improve quality of life and exercise endurance in people with non-CF bronchiectasis.
Prolonged-use antibiotics may reduce exacerbation rates and severity of symptoms (physician assessment of diary cards or of overall medical condition, sputum weight or volume).
Prolonged-use antibiotics may also reduce some measures for infection (such as sputum bacterial density) compared with placebo, although this seems to vary depending on the antibiotic regimen used.
We don’t know whether prolonged-use antibiotics decrease mortality, hospital admission for exacerbations, and number of days off work compared with placebo. Inconsistent results have led to uncertainty on the effect of prolonged-use antibiotics on quality of life scores.
Interpretation of studies concerning prolonged-use antibiotics and translation of results to individual patient care needs to be considered carefully. There may be a different pathogenesis for the condition and unknown co-existent use of other treatments, such as airway clearance techniques.
We don't know whether airway clearance techniques, mucolytics, or inhaled hyperosmolar agents are beneficial, as we found few studies.
We don't know whether inhaled corticosteroids are more effective than placebo at improving symptom scores at 6 months or at reducing exacerbations.
Surgery is often considered for people with extreme damage to one or two lobes of the lung who are at risk of recurrent infection or bleeding, but we found no good-quality trials.
Clinical context
About this condition
Definition
Bronchiectasis is defined as irreversible widening of medium to small-sized airways (bronchi) in the lung. It is characterised by inflammation, destruction of bronchial walls, and frequent colonisation with bacteria. The condition may be limited to a single lobe or lung segment, or it may affect one or both lungs more diffusely. Clinically, the condition manifests as chronic cough and chronic over-production of sputum, which is often purulent. People with severe bronchiectasis may have life-threatening haemoptysis, and may develop features of chronic obstructive airway disease, such as wheezing, chronic respiratory failure, pulmonary hypertension, and right-sided heart failure.
Incidence/ Prevalence
We found few reliable data. Overall, over the past 50 years, incidence has declined. However, one study, using data from 640 GP practices in the UK, found that the incidence of people given a diagnosis of bronchiectasis increased over time (18 per 100,000 person-years at risk in 2004; 32 per 100,000 person-years at risk in 2011). Over an 8-year period, 0.7% of patients (27,258 people) had been given a diagnostic code for bronchiectasis, and prevalence increased over time. Prevalence is generally low in higher-income countries, but much higher in lower-income countries, where bronchiectasis is a major cause of morbidity and mortality.
Aetiology/ Risk factors
Bronchiectasis is most commonly a long-term complication of previous lower respiratory infections, such as pneumonia (especially with measles, Bordetella pertussis, and Mycobacterium tuberculosis complex). Foreign-body inhalation and allergic, autoimmune (for instance, associated with rheumatoid arthritis or ulcerative colitis), and chemical lung damage also predispose to the condition. Underlying congenital disorders such as cystic fibrosis, cilial dysmotility syndromes, alpha1 antitrypsin deficiency, and congenital immunodeficiencies may also predispose to bronchiectasis, and may be of greater aetiological importance in higher-income countries than respiratory infection. Cystic fibrosis is the most common congenital cause (excluded from this review).
Prognosis
Bronchiectasis is a chronic condition, with frequent relapses of varying severity. Long-term prognosis is variable. Data on morbidity and mortality are still sparse. One study reported retrospective data exploring the factors influencing survival. It found lung function characteristics and chronic Pseudomonas infection may be associated with mortality. The more recently published FACED score and BSI index (published later than our search for this update) confirm these findings and provide a more detailed scoring system for morbidity and mortality. Bronchiectasis frequently co-exists with other respiratory disease, making it difficult to distinguish prognosis for bronchiectasis alone.
Aims of intervention
To alleviate symptoms; to reduce morbidity and mortality, with minimal adverse effects of treatment.
Outcomes
Mortality, infection rates, exacerbation rates, symptom severity (including sputum volume, cough, expectoration rates, haemoptysis), functional improvement (including lung function and exercise tolerance), hospital admission, days off work, quality of life, adverse effects.
Methods
Clinical Evidence search and appraisal January 2014. The following databases were used to identify studies for this systematic review: Medline 1966 to January 2014, Embase 1980 to January 2014, and The Cochrane Database of Systematic Reviews 2013, issue 12 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were: published RCTs and systematic reviews of RCTs in the English language, containing 20 or more individuals (10 in each arm), of whom more than 80% were followed up. There was no minimum length of follow-up. Open studies were included. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Bronchiectasis.
| Important outcomes | Days off work, Exacerbation rates, Functional improvement, Hospital admission, Infection rates, Mortality, Quality of life, Symptom severity | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of treatments in people with non-cystic fibrosis (non-CF) bronchiectasis? | |||||||||
| 1 (20) | Symptom severity | Airway clearance techniques versus no airway clearance techniques | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and weak methods |
| 1 (20) | Functional improvement | Airway clearance techniques versus no airway clearance techniques | 4 | –2 | –1 | 0 | 0 | Very low | Quality points deducted for sparse data and weak methods; consistency point deducted for conflicting results with different measures of lung function |
| 1 (20) | Quality of life | Airway clearance techniques versus no airway clearance techniques | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and weak methods |
| 3 (220) | Exacerbation rates | Inhaled corticosteroids versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results and weak methods |
| 3 (224) | Symptom severity | Inhaled corticosteroids versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results and weak methods |
| at least 4 (at least 178) | Functional improvement | Inhaled corticosteroids versus placebo | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for incomplete reporting of results, sparse data, and weak methods |
| 1 (70) | Hospital admission | Inhaled corticosteroids versus placebo | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for incomplete reporting of results, sparse data, and weak methods |
| 1 (70) | Quality of life | Inhaled corticosteroids versus placebo | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for incomplete reporting of results, sparse data, and weak methods |
| 3 (70) | Functional improvement | Exercise versus no intervention/sham intervention | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, weak methods, and not stating method of assessment for endurance in 1 RCT; directness point deducted for co-intervention in active control groups |
| 3 (70) | Quality of life | Exercise versus no intervention/sham intervention | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and weak methods; directness point deducted for co-intervention in active control groups |
| 1 (27) | Symptom severity | Exercise versus no intervention/sham intervention | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and weak methods; directness point deducted for co-intervention in active control group |
| 1 (243) | Mortality | Hyperosmolar agents (inhaled) versus placebo | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for weak methods and incomplete reporting of results; directness point deducted for short follow-up |
| 1 (243) | Exacerbation rates | Hyperosmolar agents (inhaled) versus placebo | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for weak methods and incomplete reporting of results; directness point deducted for short follow-up |
| 1 (243) | Symptom severity | Hyperosmolar agents (inhaled) versus placebo | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for weak methods and incomplete reporting of results; directness point deducted for short follow-up |
| 1 (243) | Functional improvement | Hyperosmolar agents (inhaled) versus placebo | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for weak methods and incomplete reporting of results; directness point deducted for short follow-up |
| 1 (243) | Quality of life | Hyperosmolar agents (inhaled) versus placebo | 4 | –2 | 0 | –1 | 0 | Very low | Quality point deducted for weak methods and incomplete reporting of results; directness point deducted for short follow-up |
| 1 (45) | Symptom severity | Bromhexine versus placebo | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results; directness point deducted for uncertainty about clinical importance |
| 1 (42) | Infection rates | Recombinant human deoxyribonuclease (rhDNase) versus placebo | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and uncertainty about length of follow-up |
| 1 (349) | Exacerbation rates | Recombinant human deoxyribonuclease (rhDNase) versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (42) | Functional improvement | Recombinant human deoxyribonuclease (rhDNase) versus placebo | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, incomplete reporting of results, and uncertainty about length of follow-up |
| 3 (193) | Mortality | Prolonged-use antibiotics versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 5 (454) | Infection rates | Prolonged-use antibiotics versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results and early discontinuation in 1 RCT |
| 10 (693) | Exacerbation rates | Prolonged-use antibiotics versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for weak methods and incomplete reporting of results |
| 6 (402) | Symptom severity | Prolonged-use antibiotics versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results and weak methods |
| 9 (598) | Functional improvement | Prolonged-use antibiotics versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results and weak methods |
| 6 (478) | Quality of life | Prolonged-use antibiotics versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for weak methods and incomplete reporting of results |
| 1 (89) | Hospital admission | Prolonged-use antibiotics versus placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data; directness point deducted for small number of comparators |
| 1 (89) | Days off work | Prolonged-use antibiotics versus placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data; directness point deducted for small number of comparators |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Inspiratory muscle training (IMT)
People are required to breathe through inspiratory devices of progressively decreasing diameter, with the goal of increasing the load on the respiratory muscles. Another technique involves the use of a threshold loading device that lets inspiration commence only after a certain threshold mouth pressure is reached. The threshold pressure can be set by means of a weighted plunger. In most programmes, subjects have to train for 30 minutes a day, 5 days a week.
- Jadad scale
This measures factors that have an impact on trial quality. Poor description of the factors, rated by low figures, is associated with greater estimates of effect. The scale includes three items: was the study described as randomised? (0–2); was the study described as double blind? (0–2); was there a description of withdrawals? (0–1).
- Low-quality evidence
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.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Very low-quality evidence
Any estimate of effect is very uncertain.
- Visual Analogue Scale (VAS)
A commonly used scale in pain assessment. It is a 10-cm horizontal or vertical line with word anchors at each end, such as 'no pain' and 'pain as bad as it could be'. The person is asked to make a mark on the line to represent pain intensity. This mark is converted to distance in either centimetres or millimetres from the 'no pain' anchor to give a pain score that can range from 0–10 cm or 0–100 mm.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Cecile Magis-Escurra, Radboud University Medical Centre, Radboud University, Nijmegen, The Netherlands.
Monique HE Reijers, Radboud University Medical Centre, Radboud University, Nijmegen, The Netherlands.
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