How should the diagnosis of bronchiectasis be determined?

In whom should the diagnosis of bronchiectasis be suspected?

Investigations for causes of bronchiectasis

Research recommendations

Consensus criteria for diagnosis of ABPA need to be validated in bronchiectasis cohorts.

Consensus criteria for definition of abnormal post pneumococcal test immunisation antibody responses need to be validated in bronchiectasis cohorts.

Severity scoring

Stable state treatment

Which airway clearance techniques should be taught?

Airway clearance techniques during an acute exacerbation

How often should patients carry out airway clearance techniques?

How soon should the patient be reviewed after the initial assessment?

Good practice points

• Individuals that have been assessed and taught an airway clearance technique should be reviewed by a respiratory physiotherapist within 3 months of their initial assessment.

• Individuals with bronchiectasis who are followed up in secondary care should be assessed by a respiratory physiotherapist as part of their annual clinical review to ensure their airway clearance regimen is optimised.

• All individuals with a deterioration in their condition (increased frequency of exacerbations and/or worsening of symptoms) should have their airway clearance technique reviewed by a respiratory physiotherapist (See figure 1 – management of the deteriorating patient).

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

Management of the deteriorating patient.

Mucoactives in bronchiectasis

Good practice points

• Consider a trial of mucoactive treatment in patients with bronchiectasis who have difficulty in sputum expectoration.

• Perform an airway reactivity challenge test when inhaled mucoactive treatment is first administered.

• Consider pre-treatment with a bronchodilator prior to inhaled or nebulised mucoactive treatments especially in individuals where bronchoconstriction is likely (patients with asthma or bronchial hyper-reactivity and those with severe airflow obstruction FEV₁<1 litre).

• If carbocysteine is prescribed, a 6 month trial should be given and continued if there is ongoing clinical benefit.

See Figures 3 and 4 and Appendix 2.

• Download figure
• Open in new tab
• Download powerpoint

Figure 3

Physiotherapy management-stepwise airway clearance.

• Download figure
• Open in new tab
• Download powerpoint

Figure 4

Airway clearance - exacerbations.

Appendix 2

[SP2.pdf]

What is the evidence for long term anti-inflammatory therapies in bronchiectasis?

What treatments improve outcomes for patients with stable bronchiectasis? (see Figure 2 and Appendix 2 and 3)

• Download figure
• Open in new tab
• Download powerpoint

Figure 2

Stepwise management.

Does long term bronchodilator treatment improve outcomes for patients with bronchiectasis?

Pulmonary rehabilitation

What is the role of surgery in managing bronchiectasis?

Lung transplantation for bronchiectasis

What is the role of influenza and pneumococcal vaccination in management of bronchiectasis

Treatment of respiratory failure

Bronchiectasis and other treatments

Do pathogens have an impact on prognosis in bronchiectasis?

What is the evidence for the role of viruses/fungal disease in patients with bronchiectasis?

Does eradication of potentially pathogenic microorganisms improve outcomes in patients with stable bronchiectasis?

Does antibiotic therapy improve outcomes in patients with an exacerbation of bronchiectasis?

What treatments improve outcomes in patients with bronchiectasis and allergic broncho-pulmonary aspergillosis?

Does immunoglobulin replacement treatment therapy improve outcomes in patients with bronchiectasis due to antibody deficiency?

Gastro-oesophageal reflux disease (GORD) and bronchiectasis

What is the prevalence of rhinosinusitis in patients with stable bronchiectasis and what are the outcomes of treatment?

Should treatment of bronchiectasis be altered in the presence of co-morbidities?

How should we monitor bronchiectasis?

Is there a role for microbiological sensitivity testing?

Is there any evidence of cross-infection with pathogenic organisms (conventional bacteria and environmental mycobacteria)?

Specialist vs non-specialist setting

What are the complications of bronchiectasis?

Introduction

The BTS Guideline for non-CF Bronchiectasis was published in 2010. At the time of publication it was agreed by the Guideline Group and the BTS Standards of Care Committee that work on an update to the guideline should begin soon after publication to ensure that the guideline recommendations remained current in the light of new evidence.

Since the Guideline was published, BTS has produced Quality Standards for bronchiectasis in adults, and has offered an annual national audit, and from 2012, both adult and paediatric audit tools have been available. The BTS Standards of Care Committee approved a proposal to revise and update the guideline in 2013.

For guidance on treatment for patients with non-tuberculous mycobacteria and bronchiectasis please refer to the BTS Guideline on the management of non-tuberculous mycobacterial pulmonary disease.¹

The guideline covers adult bronchiectasis. CF bronchiectasis is excluded from the scope of the guideline. Paediatric bronchiectasis was also excluded due to the difference in aetiology and approach in this group.

Methodology

This guideline is based on the best available evidence. The methodology used to write the guideline adheres strictly to the criteria as set by the AGREE collaboration, which is available online www.agreetrust.org/resource-centre/agree-ii/. The British Thoracic Society Standards of Care Committee guideline production manual is available at http://www.brit-thoracic.org.uk/guidelines-and-quality-standards/.

Considered judgement and grading of evidence

The Guideline Development Group used the evidence tables to judge the body of evidence and grade recommendations for this guideline. Evidence tables (web appendix 3) are available online. Where evidence was lacking to answer the formulated clinical questions, expert opinions were obtained through consensus. The following were considered in grading of the recommendations:

• The available volume of the body of evidence.

• How applicable the obtained evidence was in making recommendations for the defined target audience of this guideline.

• Whether the evidence was generalisable to the target population for the guideline.

• Whether there was a clear consistency in the evidence obtained to support recommendations.

• What the implications of recommendations would be on clinical practice in terms of resources and skilled expertise.

• Cost-effectiveness was not reviewed in detail as in-depth economic analysis of recommendations falls beyond the scope of this guideline.

Recommendations were graded from A to D as indicated by the strength of the evidence as shown in table 3. In line with SIGN guidance, ‘minus’ evidence was considered in context but in the absence of other ‘plus’ supporting evidence, it was discussed among the GDG regarding that point and any recommendation hence made was Grade D. Important practical points lacking any research evidence, nor likely to be research evidence in the future were highlighted as ‘Good Practice Points’ (GPP).

Research recommendations are also provided and the overall research questions are presented in PICO format in appendix 8.

Drafting the guideline

The Guideline Development Group corresponded regularly by email and meetings of the co-chairs sub group and full group were held in January, May and June 2014, January, May, September and December 2015, January, April, December 2016, January and November 2017. A number of teleconferences were also held. The BTS Standards of Care Committee (SOCC) reviewed the draft guideline in November 2017. The draft guideline was made available on-line March – April 2018 for public consultation and circulated to all the relevant stakeholders. The BTS SOCC re-reviewed the revised draft guideline in June 2018 and final SOCC approval granted in July 2018.

This BTS Guideline will be reviewed within 5 years from the publication date.

Guideline group members and declarations of interest

All members of the Guideline Group made declarations of interest in line with the BTS Policy and further details can be obtained on request from BTS. Guideline Development Group members are listed in appendix 1.

Stakeholders

The following organisations contributed to the consultation exercise:

ACPRC, ARNS, ARTP, BGS, BSTI, Edge Hill University, PCRS-UK, ProAxsis Ltd, RCN, RCP Edinburgh, Trudell Medical.

How common is bronchiectasis?

UK data in 2013 revealed the prevalence in women was 566/100 000 and in men 486/100 000⁴.

Data from 12 US states over the period 1993–2006 demonstrate an average annual age-adjusted hospitalisation rate of 16.5 hospitalisations per 1 00 000 population. Women and those aged over 60 years had the highest rate of hospitalisations.² New Zealand hospital admission rates are reported as 25.7 per 100 000³ highest in childhood and the elderly, and related to sex, socioeconomic deprivation and race.

Regarding co-morbidity coding that may provide information on aetiology, the UK data found no significant co-morbidity in 34% of patients, and the most common coded co-morbidities to be asthma (42%) and COPD (36%).⁴ HIV was coded in 7%, rheumatoid arthritis in 6%, other connective tissue disease in 5%, inflammatory bowel disease in 3% and antibody deficiency in 1%.

How should the diagnosis of bronchiectasis be determined?

Evidence statements

Chest radiography (CXR) has limited sensitivity and specificity in diagnosing bronchiectasis particularly in mild disease (2+).

Compared with bronchography thin section CT performed with 10 mm interspaces has a high accuracy in diagnosing bronchiectasis. (2+)

Volumetric CT has improved sensitivity and interobserver agreement compared with incremental/interspaced thin slice CT. (2+)

Using modifications of technique radiation dose of volumetric CT can be reduced to comparable levels to incremental imaging while providing higher accuracy. (2+)

While clearance of inhaled radiolabeled tracers from the lung is impaired in bronchiectasis this is non-specific and seen in other airways disease so cannot be considered diagnostic of bronchiectasis. (2-)

Recommendations - Imaging

• Perform baseline chest X-ray in patients with suspected bronchiectasis. (D)

• Perform a thin section CT to confirm a diagnosis of bronchiectasis when clinically suspected. (C)

• Perform baseline imaging during clinically stable disease as this is optimal for diagnostic and serial comparison purposes. (D)

Good practice points

In whom should the diagnosis of bronchiectasis be suspected?

The most common symptom in bronchiectasis is cough particularly with sputum production.^{14 15}

Appendices 5 and 6 show the causes identified from international studies. Often no cause is found despite aetiological testing. Past infection (such as measles, whooping cough, pneumonia or tuberculosis) and is a possible cause of bronchiectasis, particularly if persistent symptoms develop soon after the infection.

Specific disease groups with associated bronchiectasis

Alpha-1 antitrypsin deficiency (A1AT)

A retrospective cohort study between 1995 and 2002 of 74 patients with PiZZ deficiency (mean age 50.6, SD 9.2 years) found radiological evidence of bronchiectasis in 94.5%.¹⁸ Another retrospective cohort study of 26 Irish patients with A1AT deficiency found that 14 had bronchiectasis, all of whom had PiZZ phenotype.¹⁹

Asthma

A careful cross-sectional analysis of 85 patients in secondary care with bronchiectasis found asthma in 27% of the clinic population while prevalence of asthma in the general population was 7%.²⁰ A large study of patients with difficult asthma found bronchiectasis on CT scan in 40% of selected patients; the criteria for scanning were not stated but the scanned patients were older, with a longer duration of disease, on more corticosteroid treatment and with poorer lung function and more neutrophilic airway inflammation on sputum cytology than those who were not scanned.²¹ In a case-control study matching patients with steroid-dependent asthma to those managed without regular oral corticosteroids, it was noted that bronchiectasis was much more common in the former group and the overall prevalence of otherwise unexplained bronchiectasis was 12% across both groups, rising to 20% in the steroid-dependent group.²²

Rhinosinusitis

Rhinosinusitis is common in bronchiectasis patients,²³ but only one study appears to have assessed the prevalence of bronchiectasis in chronic sinusitis, finding it in 3 out of 60 patients (5%).²⁴

Chronic systemic infection

Chronic infection such as HIV or HTLV-1 appears to increase the risk of bronchiectasis.^{25 26 27 28}

Rheumatoid arthritis

Clinical studies of patients with rheumatoid arthritis (RA) have found varying rates of bronchiectasis on CT scan ranging from 4% to 58%.^29–38

The diagnosis of bronchiectasis may occur in early or established RA, and presentation and diagnosis with bronchiectasis may pre-date the diagnosis of even seropositive RA. Significantly more erosive changes were observed on hand and foot radiology in 53 patients with bronchiectasis and RA versus 50 patients with RA alone, and both rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies were higher in those with bronchiectasis.³⁹ In that study, bronchiectasis preceded the onset of RA in 58%.³⁹

A large study on patients hospitalised with RA established the frequency of appropriate symptoms first and then investigated with CT scan. Out of 453 patients questioned, 13 had symptoms suspicious for bronchiectasis and 9 of the 10 patients scanned had confirmed bronchiectasis, giving a prevalence of 2.9% of symptomatic bronchiectasis in this population.⁴⁰

Other connective tissue diseases

Bronchiectasis has been noted in other connective tissue diseases including primary Sjogren’s syndrome, Marfan’s syndrome, systemic sclerosis, systemic lupus erythematosus, and ankylosing spondylitis.

A study of a 507 patient cohort with primary Sjogren’s syndrome (PSS) identified 120 patients with suspected pulmonary disease, and found bronchiectasis on CT scan in 50 patients.⁴¹ Retrospective studies confirm the association.^42–44

A retrospective review of 79 patients with Marfan’s who underwent HRCT imaging found evidence of bronchiectasis in 28%.⁴⁵ Airway dilatation was described as not severe, often confined to one lobe and was said to localise with anatomical abnormalities such as pectus excavatum, although fibrosis due to previous tuberculosis was noted in some patients.⁴⁵ Studies in ankylosing spondylitis have found incidence of bronchiectasis to range from 7.2% to 51.2%.^46–51 In 7 of 34 patients with systemic lupus erythematosus (SLE) who prospectively underwent HRCT imaging, bronchiectasis was observed.⁵² A small study of systemic sclerosis found a high rate of bronchiectasis on CT in 13 (59.1%) of 22 patients.⁵³ In a study of scleroderma and pulmonary hypertension, bronchiectasis independent of interstitial lung disease (ILD) was found on CT scan in 6 of 44 patients with restrictive lung function or crackles.⁵⁴

Inflammatory Bowel Disease

There is a recognised association between bronchiectasis and inflammatory bowel disease (IBD). A prospective study of 95 patients with IBD (83 ulcerative colitis (UC) and 12 Crohn’s disease (CD)) who underwent HRCT scans found evidence of bronchiectasis in 9, all of whom had UC and no reported respiratory symptoms.⁵⁵ A cohort study of 30 UC and 9 CD patients undergoing CT scans found bronchiectasis in two patients.⁵⁶ In 36 consecutive IBD patients (23 UC, 13 CD) studied for pulmonary disease, bronchiectasis was found on CT in three patients. 44% of the total study population had respiratory symptoms, but sputum production was described in only two patients- the relationship between symptoms and CT findings was not described.⁵⁷ A literature review found bronchiectasis in 44 out of 155 patients with inflammatory bowel disease.⁵⁸

A retrospective case note review of 10 patients with IBD (5 UC, 5 CD) and bronchiectasis found that eight had developed respiratory symptoms only following surgery for their IBD.⁵⁹ These patients had had IBD for a median of 15 (9-35) years and for those developing pulmonary symptoms following surgery, the time from surgery to symptoms ranged from 2 weeks to 30 years.⁵⁹ In a study of 17 IBD patients with respiratory symptoms, the diagnosis of IBD preceded the onset of their pulmonary symptoms in 16. 13 of these patients were found to have bronchiectasis.⁶⁰

Evidence statement

Studies in healthy populations do not provide a strong body of evidence but suggest that persistent mucopurulent or purulent sputum production in the stable state is suspicious for underlying bronchiectasis, particularly if there is a past history of major respiratory infection (eg, measles, whooping cough, pneumonia, tuberculosis) or ongoing rhinosinusitis (2-).

There is a high frequency of bronchiectasis in patients with COPD (2++), particularly with more severe airflow obstruction (2++).

The presence of bronchiectasis in patients with COPD is typically associated with chronic productive cough, isolation of PPMs from sputum, particularly P. aeruginosa, increased airway inflammation, frequent or severe exacerbations or admissions to hospital for exacerbations (2+).

Bronchiectasis is associated with alpha one antitrypsin deficiency, particularly with the phenotype PiZZ (2+)

Asthma is found in higher prevalence in patients with bronchiectasis than in the general population, (2+), and bronchiectasis appears more common in asthma, particularly in difficult to treat disease (2-).

There is an association between rheumatoid arthritis and bronchiectasis (2+). The diagnosis of bronchiectasis may precede the onset of rheumatoid arthritis (2-).

There is an association between bronchiectasis and other connective tissue diseases (2-).

There is an association between inflammatory bowel disease and bronchiectasis (2+).

Bronchiectasis has been reported in patients with HIV infection at a frequency higher than in the general population (2-).

Bronchiectasis has been reported in patients with HTLV-1 infection with inflammatory complications at a frequency higher than in the general population. (3)

Recommendations

• Consider investigation for bronchiectasis in patients with persistent production of mucopurulent or purulent sputum particularly with relevant associated risk factors. (D)

• Consider investigation for bronchiectasis in patients with rheumatoid arthritis if they have symptoms of chronic productive cough or recurrent chest infections. (C)

• Consider investigation for bronchiectasis in patients with COPD with frequent exacerbations (two or more annually) and a previous positive sputum culture for P. aeruginosa while stable. (B)

• Consider investigation for bronchiectasis in patients with inflammatory bowel disease and chronic productive cough. (C)

Good practice points

• In at risk groups, if bronchiectasis is suspected, bronchiectasis needs confirmation.

• In patients with COPD, investigation for bronchiectasis may be appropriate especially in the presence of chronic productive cough with positive sputum cultures for PPM while stable or two or more exacerbations in the preceding 12 months.

• In patients with asthma, investigation for bronchiectasis may be appropriate with severe or poorly-controlled disease.

• In patients with a history of HIV-1 infection, solid organ and bone marrow transplant, and history of immunosuppressive therapy for lymphoma and vasculitis, investigation for bronchiectasis may be appropriate with symptoms of chronic productive cough or recurrent chest infections.

• In patients with chronic rhinosinusitis, investigation for bronchiectasis may be appropriate with symptoms of chronic productive cough or recurrent chest infections.

• In patients with other connective tissue disease or inflammatory bowel disease, investigation for bronchiectasis may be appropriate if they have symptoms such as chronic productive cough or recurrent chest infections.

• Investigation for bronchiectasis may be appropriate in otherwise healthy individuals with a cough that persists for longer than 8 weeks, especially with sputum production or a history of an appropriate trigger (see BTS Recommendations for the management of cough in adults⁶¹).

Investigations for causes of bronchiectasis

Standard laboratory tests

The evidence for the role of aetiological investigations is derived from studies of low to moderate quality; other significant limitations include a lack of standardised diagnostic testing panels for bronchiectasis, resulting in marked variation in the performance of some diagnostic assays (CF mutation analysis, test immunisation of vaccine responses), use of different technological platforms for some diagnostic assays which may give rise to discrepancy in test results (measurement of pneumococcal and aspergillus IgG antibodies) and variation in the use of reference intervals to define presence or absence of disease even when using same or very similar diagnostic tests (Aspergillus blood IgE levels).

Although most individual studies are of low/moderate quality, the overall findings indicate that antibody deficiency syndromes and ABPA should be investigated in all newly presenting patients with bronchiectasis (see appendix 5).

Tests for specific disease groups with associated bronchiectasis

Research recommendations

Consensus criteria for diagnosis of ABPA need to be validated in bronchiectasis cohorts.

Consensus criteria for definition of abnormal post pneumococcal test immunisation antibody responses need to be validated in bronchiectasis cohorts.

Prognosis: what is the outlook for these patients?

A UK epidemiology study examined mortality and noted the age adjusted mortality rate for women with bronchiectasis to be 1438 per 1 00 000 against 636 for the general population (comparative mortality of 2.26) and, in men, the age adjusted mortality rate for bronchiectasis population was 1915 per 1 00 000 compared with 895 for the general population (comparative mortality of 2.14).⁴

A comprehensive assessment by Martinez-Garcia et al¹¹⁹ 2014 in Spanish patients comparable to the UK population introduced the mortality prediction score (FACED), based on a study showing that of 154 deaths during follow-up, 42.9% were attributed to respiratory disease with 9.1% due to neoplasia and 9.1% to cardiovascular disease.¹¹⁹ Similarly the Bronchiectasis Severity Index (BSI) tool was based on studies of outcome in patients with bronchiectasis across several different centres, and the study reported a mortality rate of 62 (10.2%), directly relevant to bronchiectasis in 32 cases (listed as exacerbation of bronchiectasis, end-stage bronchiectasis, pneumonia, LRTI, chronic respiratory failure or pneumothorax).¹²⁰ Otherwise, myocardial infarction was the cause of death in 12 cases, malignancy in eight cases, and other causes included heart failure, stroke, other sepsis, pulmonary embolism, trauma, alcoholic liver disease and post-operative complications.

Severity scoring

The availability of the two clinical scoring systems, the Bronchiectasis Severity Index (BSI) (table 4)¹²⁰ and FACED¹¹⁹ (see tables 4 and 5), has increased our ability to predict future mortality in patients with bronchiectasis. The BSI additionally provides information on morbidity, hospital admissions and exacerbations. As bronchiectasis is not a rapidly fatal condition, these latter outcomes are regarded as more important for clinical decision making. Reassuringly, being derived in different cohorts, the two scores include similar variables. The major limitation of the FACED score is the absence of exacerbations which are regarded by many clinicians as the most important modifiable marker of severity. Prior exacerbations are also the strongest predictor of future exacerbations which explains why a number of studies have found FACED to be poorly predictive of future morbidity.^121–123 For this reason the BSI is the preferred scoring system. At the time of writing, modifications of the FACED score to include exacerbations are undergoing evaluation. There may be some relevant omissions from both scores, notably the presence of co-morbidities which are important in the prognosis of other chronic respiratory diseases.

FACED includes FEV₁, Age, P. aeruginosa colonisation, Extent of bronchiectasis (counting lobar involvement on CT) and Dyspnoea (using the modified MRC scale). All the variables are dichotomised and scored 0 vs 1 or 2. The 5 year mortality in mild, moderate and severe disease (defined as a score of 0–2, 3–4 and 5–7 points respectively) is 4%, 25% and 56% respectively. It has been shown to predict 5 year mortality, although the study used the score calculated at the time of initial diagnosis (and is not, therefore, designed for follow-up of existing patients, an important limitation) and it is not known whether a change in score reflects a change in prognosis.

The BSI combines age, body mass index, FEV₁, previous hospitalisation, exacerbation frequency, colonisation status and radiological appearances. The score was designed to predict future exacerbations and hospitalisations, health-status, and death over 4 years. Patients with NTM were excluded. Data were provided which examine how the score performed in annual prediction of events, a more relevant clinical scenario than provided for FACED, and the team have developed a useful online calculator (available at www.bronchiectasisseverity.com). A score of 0–4 (mild) is associated with 0%–2.8% mortality and 0%–3.4% hospitalisation rate over 1 year, and 0%–5.3% mortality and 0%–9.2% hospitalisation rate over 4 years.

Outcomes in moderate bronchiectasis (score 5–8) were 0.8%–4.8% mortality and 1.0%–7.2% hospitalisation rate at 1 year and 4%–11.3% mortality and 9.9%–19.4% hospitalisation rate at 4 years. A score over 9 (severe bronchiectasis) was associated with 1 year 7.6%–10.5% mortality, and 16.7%–52.6% hospitalisation rate and a 4 year 9.9%–29.2% mortality and 41.2%–80.4% hospitalisation rates. Understanding the factors associated with future morbidity and mortality in bronchiectasis provides a rationale, discussed further elsewhere, for which variables should be assessed and monitored in bronchiectasis.

Stable state treatment

Which patients should be taught airway clearance techniques?

A single randomised crossover trial has been published which assesses the efficacy of regular respiratory physiotherapy versus no respiratory physiotherapy in participants with bronchiectasis and chronic sputum expectoration.¹²⁴ Twenty stable outpatients who did not practice regular respiratory physiotherapy were included. The intervention comprised of twice daily 20–30 min sessions of respiratory physiotherapy using an oscillating positive expiratory pressure device (Acapella Choice) over a 3 month period. There was a significant improvement in all domains and the total Leicester Cough Questionnaire (LCQ) score with regular respiratory physiotherapy (median (IQR) (1.3 (−0.17–3.25) units; P=0.002). It should be noted that the MCID for LCQ is 1.3 units.¹²⁷ Sputum volume measured over 24 hours increased significantly with regular respiratory physiotherapy (2 (0–6) mL; P=0.02) as did exercise capacity as measured by the incremental shuttle walk test (ISWT) (40 (15-80) m; P=0.001). There was also a significant improvement in quality of life (QoL) with a significant improvement in the St George’s Respiratory Questionnaire (SGRQ) total score (7.77 (−0.99–14.5) unit improvement; P=0.004). No sham treatment was provided in the no respiratory physiotherapy arm and so there is some potential for a placebo effect. However, this study does provide low-quality evidence that regular twice daily respiratory physiotherapy is effective in stable patients.

A consecutive before-after case series assessed the effect of bronchopulmonary hygiene physical therapy (BHPT) on health-related QOL in 53 stable outpatients with bronchiectasis¹²⁸). BHPT comprised two sessions at least 2 weeks apart and included education and instruction on an appropriate airway clearance technique to be used at home. The LCQ and cough symptom severity visual analogue score (VAS) were administered at initial assessment and more than 4 weeks later. At the follow-up visit, all patients reported administering their BHPT regime at least once per day. After BHPT, there were significant improvements in cough symptoms (mean cough VAS before 43.3 (3.6) vs. after 27.5 (3.1); mean difference 15.8; 95% CI of difference 9.6 to 22; P<0.0001) and cough-related health status (mean LCQ total score before 14.2 vs. after 17.3; mean difference 3.1; 95% CI of difference 2.4 to 3.9; P<0.001). Limitations to the study including the lack of a control group and the use of only subjective outcome measures. In addition, such a variety of components were included as part of BHPT that the efficacy of individual components has not been determined.

Adherence

In an observational, non-comparative study, 75 patients with bronchiectasis and P. aeruginosa were reviewed over a year to determine if baseline beliefs about treatment, clinical factors and QoL predicted adherence.¹²⁹ 41% of patients were adherent to airway clearance. Younger participants and those with a decreased understanding of the necessity of airway clearance were more likely to have reduced adherence.

Evidence statement

Regular twice daily respiratory physiotherapy increases sputum expectoration, improves cough-related health status, quality of life and exercise capacity in individuals with stable bronchiectasis and chronic sputum expectoration (1-)

Bronchopulmonary hygiene therapy (including education and instruction of an appropriate airway clearance technique) at least once per day does lead to an improvement in cough symptoms and cough-related health status in stable outpatients with bronchiectasis (3)

Younger patients (usually considered to be age 50 and under but not limited to this age group) and those with decreased understanding of the necessity of airway clearance may have reduced adherence levels (3)

Recommendation

• Teach individuals with bronchiectasis to perform airway clearance. (D)

Good practice points

• Airway clearance techniques should be taught by a respiratory physiotherapist.

• At initial assessment, a respiratory physiotherapist should educate the patient about their condition and if appropriate give advice on adjuncts (inhaled/oral therapy or exercise) that may enhance effectiveness of their chosen airway clearance technique.

• Patients admitted with an exacerbation of bronchiectasis should be seen daily by a respiratory physiotherapist until their airway clearance is optimised.

Which airway clearance techniques should be taught?

There are a number of airway clearance techniques that can be used in the management of bronchiectasis. However, it is beyond the scope of this guideline to describe each airway clearance technique and the reader is referred to detailed descriptions of the techniques for further information.¹³⁰

In 2002, a survey of the current physiotherapy management of patients with bronchiectasis in the UK found that 91% of senior physiotherapists taught the active cycle of breathing techniques (ACBT) routinely.¹³¹ Other techniques such as positive expiratory pressure (PEP), oscillating positive expiratory pressure (OPEP), autogenic drainage (AD) and intermittent positive pressure breathing (IPPB) were used much less frequently.¹³¹ Most respondents also used ambulation, exercise and education on the use of inhaled therapy.¹³¹

Exercise

A study investigated the impact of an 8 week pulmonary rehabilitation programme.¹⁵⁰ The authors suggested a small but significant impact on exacerbation frequency over 12 months in the intervention group (PR) (median 1 (IQR 1–3)) compared with physiotherapy alone (median 2 (IQR 1–3)) (P=0.012).

Evidence statements for airway clearance techniques

The active cycle of breathing techniques is as effective as oscillating positive expiratory pressure (Flutter and Acapella) at clearing sputum. (1-)

The active cycle of breathing techniques plus postural drainage enhances the quantity of sputum expectorated compared with the active cycle of breathing techniques in the sitting position or oscillating positive expiratory pressure (Flutter) in the sitting position. (1-)

The active cycle of breathing techniques (plus postural drainage and vibration) is more effective at clearing sputum than the test of incremental respiratory endurance. (1-)

Oscillating positive expiratory pressure (Acapella) is more effective at clearing sputum than a threshold inspiratory muscle trainer. (1-)

Oscillating positive expiratory pressure (Acapella) improves QoL, sputum volume expectorated and exercise capacity compared with no airway clearance technique over a 3 month period. (1-)

High frequency chest wall oscillation improves breathlessness, quality of life, sputum volume and lung function. (1-)

Recommendations

• Offer active cycle of breathing techniques or oscillating positive expiratory pressure to individuals with bronchiectasis. (D)

• Consider gravity assisted positioning (where not contraindicated) to enhance the effectiveness of an airway clearance technique. (D)

Good practice points

• CT imaging should be reviewed to complement the physiotherapy assessment. Where indicated, this information could be used in order to teach the patient the appropriate postural drainage position(s) for their affected bronchopulmonary segment(s).

• Patients should be made aware of the range of available airway clearance techniques.

• Consider patient preference and adherence when recommending an airway clearance technique.

• Consider the inclusion of the forced expiration technique (huff) should be considered for all airway clearance techniques.

• Consider modified postural drainage (no head down tilt) in patients for whom postural drainage is contraindicated or not tolerated.

• If symptoms of gastro-oesophageal reflux increase with modified postural drainage (no head down tilt), an airway clearance technique in the sitting position should be taught.

• Consider autogenic drainage, positive expiratory pressure, high frequency chest wall oscillation and intrapulmonary percussive ventilation as an alternative airway clearance technique if other techniques are not effective or acceptable to the patient.

• Patients should be encouraged to perform regular physical exercise (plus the forced expiration technique/huff) to promote airway clearance.

• If there is ongoing haemoptysis, refer back to the respiratory physiotherapist to determine the optimum airways clearance technique.

Evidence statement

Oscillating positive expiratory pressure (Acapella) (plus postural drainage) is effective and safe to use during an acute exacerbation. (1-)

Good practice points

• Manual techniques may be offered to enhance sputum clearance when the patient is fatigued or undergoing an exacerbation.

• Consider intermittent positive pressure breathing or non-invasive ventilation during an acute exacerbation to offload the work of breathing so fatigued and/or breathless patients can tolerate a longer treatment session and can adopt postural drainage positions.

Research recommendations

Randomised controlled trials using clinically important outcome measures are required to assess the effectiveness of airway clearance techniques in varying severities of bronchiectasis.

Randomised controlled trials are required to evaluate the effects of airway clearance techniques in patients who are undergoing an exacerbation.

How often should patients carry out airway clearance techniques? How long should an airway clearance session last?

Good practice points

• The frequency and duration of the airway clearance technique should be tailored to the individual and may alter during periods of exacerbation.

• Advise individuals to perform their airway clearance technique for a minimum of 10 minutes (up to a maximum of 30 minutes). After this time they should continue until two clear huffs or coughs are completed, or until the patient is starting to become fatigued.

How soon should the patient be reviewed after the initial assessment?

Initial assessment may take up to an hour, with education and instruction of an appropriate airway clearance technique included. A review of the individual’s ability to effectively carry out this technique should be undertaken within 3 months of this initial appointment.¹²⁶

Good practice points

• Individuals that have been assessed and taught an airway clearance technique should be reviewed by a respiratory physiotherapist within 3 months of their initial assessment.

• Individuals with bronchiectasis who are followed up in secondary care should be assessed by a respiratory physiotherapist as part of their annual clinical review to ensure their airway clearance regimen is optimised.

• All individuals with a deterioration in their condition (increased frequency of exacerbations and/or worsening of symptoms) should have their airway clearance technique reviewed by a respiratory physiotherapist (See figure 1 – management of the deteriorating patient).

Mucoactives in bronchiectasis

Mucoactive medications describe medications which may have a direct impact on the clearance of mucus from airways. These can be defined by their different methods of action including expectorants (aid and/or induce cough), mucolytics (thin mucus), mucokinetics (facilitate cough transportability), and mucoregulators (suppress mechanisms underlying chronic mucus hyper secretion, such as glucocorticosteroids). Bronchiectasis research has mainly focused on mucolytics (DNase),^{151 152} mucokinetics/expectorants (humidification, normal/isotonic saline (0.9% saline) (IS), hypertonic saline (3% saline and above) (HS)^153–158 and mannitol^{159 160} and there is a small amount of evidence in mucoregulators (erdosteine)¹⁶¹ and bromhexine.¹⁶²

Evidence statements

Recombinant human DNase increases exacerbation frequency in bronchiectasis. (1+)

Isotonic and hypertonic saline can improve cough related quality of life QoL and health related quality of life (HQoL) in patients with bronchiectasis in addition to airway clearance. (1-)

Mannitol did not improve exacerbation frequency but was shown to increase the time to first exacerbation, demonstrated a small improvement in QoL and may reduce sputum plugging. (1+)

The use of humidification prior to airway clearance improves sputum yield and radiolabeled clearance, when used in short term interventions (>1 month). (3)

Oral mucolytics can improve sputum expectoration. (1-)

Recommendations

• Do not routinely use recombinant human DNase in adults with bronchiectasis. (A)

• Consider the use of humidification with sterile water or normal saline to facilitate airway clearance. (D)

Good practice points

• Consider a trial of mucoactive treatment in patients with bronchiectasis who have difficulty in sputum expectoration.

• Perform an airway reactivity challenge test when inhaled mucoactive treatment is first administered.

• Consider pre-treatment with a bronchodilator prior to inhaled or nebulised mucoactive treatments especially in individuals where bronchoconstriction is likely (patients with asthma or bronchial hyper-reactivity and those with severe airflow obstruction FEV₁ <1 litre).

• If carbocysteine is prescribed, a 6 month trial should be given and continued if there is ongoing clinical benefit.

See figures 3 and 4.

See appendix 2: Challenge test details

Research recommendation

Randomised controlled trials are needed to assess the long term impact of muco-active therapies.

What is the evidence for long term anti-inflammatory therapies in bronchiectasis?

Airway inflammation is dominated by neutrophils although there is evidence to implicate multiple other inflammatory cells and pathways in the pathophysiology of bronchiectasis.^{167 168}

Evidence statements

Inhaled corticosteroids may reduce sputum volume in bronchiectasis but are associated with adverse events including local and systemic effects. (1+)

There was insufficient evidence to evaluate the role of oral corticosteroids, PDE4 inhibitors, methylxanthines or leukotriene receptor antagonists in bronchiectasis. (4)

A small trial of inhaled indomethacin which included some patients with bronchiectasis showed reduced sputum volume and improved dyspnoea. (1-)

A small randomised trial of oral neutrophil elastase inhibitors in bronchiectasis showed improved FEV₁ but no other benefits. (1-)

A small trial of CXCR2 antagonists showed reduced sputum neutrophil counts but no clinical benefits. (1-)

A small randomised trial of statins in bronchiectasis showed improved cough, but an increase in adverse events. (1-)

A small randomised trial of statins in bronchiectasis chronically infected with P. aeruginosa showed improved health related quality of life. (1-)

Recommendations

• Do not routinely offer inhaled corticosteroids to patients with bronchiectasis without other indications (such as ABPA, chronic asthma, COPD and inflammatory bowel disease). (B)

• Do not offer long-term oral corticosteroids for patients with bronchiectasis without other indications (such as ABPA, chronic asthma, COPD, inflammatory bowel disease). (D)

• Do not routinely offer PDE4 inhibitors, methylxanthines or leukotriene receptor antagonists for bronchiectasis treatment. (D)

• Do not routinely offer CXCR2 antagonists, neutrophil elastase inhibitors or statins for bronchiectasis treatment. (B)

Good practice point

• Inhaled corticosteroids have an established role in the management of asthma and a proportion of patients with COPD which are common co-morbid conditions in bronchiectasis.

Research recommendation

Randomised controlled trials are needed to assess the long term impact of anti-inflammatory therapies.

What treatments improve outcomes for patients with stable bronchiectasis?

Macrolides

Wong et al studied 500 mg three times weekly azithromycin for 6 months in 141 patients,¹⁹⁰ Altenburg et al azithromycin 250 mg od for 1 year in 83 patients,¹⁹¹ and Serisier et al 250 mg bd erythromycin for 48 weeks in 117 patients.¹⁹² Each study used different entry criteria: 71/141 in the Wong study did not culture pathogens at baseline, and 17 cultured P. aeruginosa¹⁹⁰ ; Altenburg required at least one pathogen cultured from sputum in the previous year and 12/83 had P. aeruginosa¹⁹¹ ; Serisier stratified for P. aeruginosa at baseline and had a relatively high (41/117) number of patients with this pathogen that is associated with more severe disease.¹⁹² Wong et al required at least one exacerbation, Serisier et al at least 2, and Altenburg et al at least 3.^190–192

In fact patients had a wide variation in the number of exacerbations in the previous year, but on average more than these entry criteria: Wong et al 3–4¹⁹⁰ and Altenburg et al 4-5.¹⁹¹ All three studies showed a significant reduction in exacerbation frequency: Wong et al 0.59 exacerbations per patient with azithromycin cf 1.57 with placebo P<0.0001¹⁹⁰; Altenburg et al median number of exacerbations 0 with azithromycin cf two with placebo P<0001, which is 0.84 per patient with azithromycin cf 2.05 with placebo¹⁹¹; Serisier et al 1.29 per patient with erythromycin cf 1.97 with placebo P=0.003.¹⁹²There have been four meta-analyses which have all included these three studies together with shorter studies and/or paediatric studies.^193–196 The following consistent findings have been: a reduction in the number of patients who had at least one exacerbation (RR 0.55–0.7); small improvements in FEV₁ occurred in 2 of the three trials and was confirmed in the meta analyses; the benefit was not dependent on microbiology; quality of life results were more variable Wu et al¹⁹⁶ 2014 in the five trials included in the meta analysis that used SGRQ a 5.4 fall in total score P=0.02,¹⁹⁶ but in the Guang-Ying¹⁹⁵ 2014 meta analysis that included three studies which used SGRQ the changes were not significant¹⁹⁵); there were no significant increase in adverse events with macrolide, but GI side effects increase on macrolide (low dose erythromycin better tolerated than azithromycin), but in most cases not sufficient to lead to withdrawal; increased macrolide resistance occurs which was best studied by Serisier et al 2013 which showed a 27.7% increase on oropharyngeal streptococci resistance with erythromycin compared with 0.04% with placebo P<0.001.¹⁹²

The results were variable at follow-up after treatment stopped, Wong suggests benefit maintained in 6 months after cessation,¹⁹⁰ Altenburg that it is lost (in terms of exacerbations).¹⁹¹ Wong found treatment effects significantly greater in patients with higher SGRQ scores.¹⁹⁰ There is some evidence favouring azithromycin. The Guang Ying et al meta analysis showed that on subgroup analysis azithromycin demonstrated lower exacerbation frequency whereas erythromycin did not.¹⁹⁵ In addition, the benefit of erythromycin compared with placebo was more delayed in the erythromycin study compared with the other two azithromycin studies. The latter observation may however be accounted for by the higher proportion of P. aeruginosa patients in this study.

A further analysis by 16S RNA gene sequencing of paired sputum samples, baseline and end of treatment, from the BLESS trial showed a reduced abundance of H. influenzae, and an increased relative abundance of P. aeruginosa, in patients treated with erythromycin without P. aeruginosa at the start of the trial.¹⁹² This was not shown by routine bacteriology, but raises a concern which requires further investigation.¹⁹⁷

Inhaled/nebulised antibiotics

In addition to the use of long term oral antibiotics, there have been several studies assessing the efficacy of long term inhaled antibiotics in bronchiectasis. Several of these have provided proof of concept data demonstrating a reduction in bacterial counts, usually at the 28 day time point.^{198 199} Haworth et al studied 144 bronchiectasis patients with chronic pseudomonas infection treated with Promixin (colistin) or 0.45% saline who were followed up until the first exacerbation or 6 months.²⁰⁰ Although the study did not reach significance in its primary endpoint of time to next exacerbation (165 days vs 111 days P=0.11), this was significant in a predetermined ‘compliant’ population (those that took the medication for>=80% of the time (168 vs 103 days P=0.028)). This could be accurately defined because of an electronic chip on the nebuliser. In the whole group analysis they also demonstrated a significant reduction in P. aeruginosa colony forming unit (CFU) count at 12 weeks and a significant improvement in the SGRQ total score at 26 weeks. There was no difference in FEV₁, sputum weight or adverse events. The incidence of adverse effects leading to discontinuation was low and similar in both groups.

A similar increase in time to next exacerbation was also seen in the per protocol population of a small phase 2 study of 42 bronchiectasis patients with P. aeruginosa with three on/off cycles of dual release inhaled ciprofloxacin. In this study, the median time to exacerbation was 134 vs 58 days (P=0.057 modified intention to treat, 0.046 per protocol).¹⁹⁹

Time to next exacerbation was also extended with the use of inhaled gentamicin (80 mg bd) compared with normal saline control in a 65 patient RCT with patients who had potentially pathogenic micro-organisms, who were treated for 1 year with a 3 month follow-up (61.5 vs 120 days P=0.02) and the exacerbation number was also reduced in the active group (0 (0–1) vs 1.5 (1–2) p<0.0001).²⁰¹ Quality of life measures improved, sputum became less purulent and exercise capacity increased. Emergence of resistance did not occur, however benefits were lost quickly on stopping treatment during the 3 month follow-up. In this study patients were not masked to intervention. Although 7/32 patients in the gentamicin arm reported bronchoconstriction, this only led to withdrawal in two patients (the same as the saline arm). Further analysis of this study also documented reductions in sputum inflammatory markers (including myeloperoxidase activity, neutrophil elastase, interleukin-8 and tumour necrosis factor-alpha).¹⁶⁸

Barker and colleagues conducted two large double blinded multi-centre trials (AIR-BX1 (n=266) and AIR-BX2 (n=274)) administering inhaled aztreonam 75 mg (aztreonam for inhalation solution or AZLI) or placebo for two 4 week periods followed by a 4 week washout period after each.²⁰² The primary end point which was change in QOL-B respiratory symptom scores (RSS) from baseline to 4 weeks was not attained in either of the studies. The secondary end points were change in QOL-B-RSS from baseline to week 12 and time to first protocol defined exacerbation to week 16. Although the QOL-B-RSS numerically increased in all groups in both studies at week 4 and week 12, the mean change from baseline was only statistically significant in week four in the AIR-BX2 study alone. However, this change of 4.6 points although statistically significant was not clinically significant as the minimal important difference for the QOL-B-RSS is 8.0 points. The median time to first protocol defined exacerbation was reached in only the placebo group in AIR-BX1. In the AZLI treated group there were more treatment related adverse events necessitating patients to drop out. In summary, although this is a large multi centred RCT with aztreonam, there were perhaps some inherent faults with the design of the study, notably the heterogeneity of the cohorts in the study. AZLI treatment was not associated with significant clinical benefit in bronchiectasis as measured by the QOL-B-RSS and time to next exacerbation.

Most recently, Ciprofloxacin (32.5 mg) dry powder for inhalation (DPI) twice-daily was studied in two large (RESPIRE 1 n=416 and RESPIRE 2 n=521) randomised, double-blind, placebo-controlled (two active:1 placebo) trials.^{203 204} A novel aspect of the studies was that 14- or 28 day on/off cycles were compared for 48 weeks. Patients had a documented history of two or more exacerbations in the previous year and had positive sputum cultures for a pathogenic species at screening. The primary end points were time to first exacerbation and frequency of exacerbations. Patients had to meet a strict definition of an exacerbation during the trial, and the number occurring were low (42.8% in RESPIRE 1% and 58% in RESPIRE 2 of placebo patients did not have an exacerbation). In RESPIRE one ciprofloxacin DPI 14 day on/off significantly delayed time to first exacerbation versus pooled placebo (median time >336 days versus 186 days, HR 0.53, 97.5% CI 0.36 to 0.80, P=0.0005) and reduced frequency of exacerbations versus matched placebo by 39% over 48 weeks (mean number of exacerbations 0.6 vs 1.0, incidence rate ratio 0.61, 97.5% CI 0.40 to 0.91 P=0.0061). The 28 day on/off cycle results were not significant, and in RESPIRE 2, neither on/off cycle met the primary end points, although there were positive trends. A liposomal ciprofloxacin preparation for inhalation has also been studied with the complete results not published at the time of writing. The pooled results of the RESPIRE studies suggest a positive signal for response to inhaled ciprofloxacin, but the drug has not been granted marketing authorisation. Future trials must include patients more likely to exacerbate.

Evidence statements

Long term antibiotics reduce exacerbations in bronchiectasis. (1++)

Inhaled colistin 1 MU twice daily delivered through the I-neb improves quality of life in bronchiectasis patients with chronic P. aeruginosa infection and one or more exacerbations per year. (1+)

Inhaled colistin 1 MU twice daily delivered through the I-neb extends the time to exacerbation in treatment compliant bronchiectasis patients with chronic P. aeruginosa infection and one or more exacerbations per year. (1+)

Inhaled gentamicin increases the time to exacerbation, reduces exacerbation rate and improves quality of life in patients with bronchiectasis with chronic infection with a potentially pathogenic micro-organism and two or more exacerbations per year. (1+)

Azithromycin and erythromycin reduce exacerbation number, and the number of patients that had at least one exacerbation, in patients with bronchiectasis. (1++)

Tetracyclines may reduce exacerbation number in patients with bronchiectasis. (2+)

Patients recruited into the long term antibiotic RCTs had more (≥3) exacerbations in the preceding year than defined by the inclusion criteria. (1+)

Inhaled aztreonam twice daily for 4 weeks is not associated with clinically significant benefit as measured by changes in the QOL-B-RSS and time to first exacerbation. Additionally, aztreonam has a higher incidence of treatment related adverse events and discontinuation secondary to adverse events. (1+)

Cyclical intravenous antibiotics may reduce exacerbation number and hospital bed days in patients with ≥5 exacerbations and subjective ill health between exacerbations. (3)

Recommendations

• Consider long term antibiotics in patients with bronchiectasis who experience three or more exacerbations per year. (A)

• In these patients, the following are recommended (see figure 2 and appendix 2 and 3)

Good practice points

• Antimicrobial stewardship is important

• Prior to starting long term macrolides, for safety reasons: 1) ensure no active NTM infection with at least one negative respiratory NTM culture; 2) use with caution if the patient has significant hearing loss needing hearing aids or significant balance issues.

• Prior to starting long term inhaled aminoglycosides, for safety reasons: 1) avoid using if creatinine clearance <30 mL/min; 2) use with caution if the patient has significant hearing loss needing hearing aids or significant balance issues; 3) avoid concomitant nephrotoxic medications.

• Counsel patients about potential major side effects with long term antibiotics, and to seek urgent attention if these develop.

  1. Review the patient’s culture and mycobacterial status, optimise airway clearance and treat other associated conditions before starting long term antibiotics.

  2. Prophylactic antibiotics should be only started by respiratory specialists.

  3. Review patients on long term antibiotics 6 monthly with assessment of efficacy, toxicity and continuing need. Monitor sputum culture and sensitivity regularly, although in vitro resistance may not affect clinical efficacy.

• As adverse event frequency of azithromycin is likely to be dose related, 250 mg 3 x/week is a pragmatic starting dose which can then be increased according to clinical response and adverse events.

• Thresholds for long term treatment may reduce if the patient is symptomatic between exacerbations and/or the exacerbations respond poorly to treatment and/or the patient is at high risk of severe exacerbation for example, immunosuppressed.

• Long term antibiotic choice is complex and has to take into account factors such as tolerance, allergies and sensitivity, therefore in some circumstances, other long term antibiotic regimens may be appropriate (see appendix 3).

• Perform a suitable challenge test when stable before starting inhaled antibiotics (see appendix 2)

• Consider cyclical IV antibiotics in patients with repeated infections (≥5/year) despite other treatments.

• Alternative inhaled/nebulised agents may become licensed as international studies are completed.

• For patients receiving long term prophylactic oral antibiotics, the preferred option is to remain on the same antibiotic as opposed to monthly rotation of antibiotics. If there is a subsequent lack of efficacy, the antibiotic can be changed guided by sensitivity results.

Research recommendation

Long term randomised controlled trials of oral and inhaled antibiotics are needed to assess their efficacy and safety in patients with bronchiectasis who have frequent respiratory tract infections with recurrent P. aeruginosa infection or other potential pathogenic micro-organisms.

Does long term bronchodilator treatment improve outcomes for patients with bronchiectasis?

Patients with bronchiectasis frequently have airflow obstruction and more than 60% of bronchiectasis patients have daily symptoms of breathlessness.¹²⁰ There is limited supporting evidence for the use of bronchodilators, although both beta-2-agonists and anticholinergic bronchodilators are commonly used in clinical practice.¹⁶⁶

Long acting Beta-2-agonists

A systematic review published in 2014 identified only one eligible randomised controlled trial of long acting beta-2-agonists.²⁰⁸ This included 40 patients with a primary outcome of health related quality of life. It indicated improved quality of life with the use of budesonide/formoterol versus budesonide alone. The Cochrane review identified significant methodological issues with this trial including inadequate and incorrectly reported blinding and inadequate reporting of the data.²⁰⁸

Long acting anticholinergic agents

There are no randomised controlled trials of long acting muscarinic antagonists in bronchiectasis.²⁰⁹ Although studies suggest that some patients with bronchiectasis will have significant reversibility to anti-cholinergic bronchodilators, there is no evidence to establish that reversibility is a requirement for benefit.²¹⁰

Short acting bronchodilators

There are no randomised controlled trials to demonstrate if short acting bronchodilators are beneficial in bronchiectasis.²¹¹

As there are no large randomised controlled trials of bronchodilators in bronchiectasis there are limited data on the safety of these agents. Data from COPD and asthma, however, suggests that they have an acceptable safety profile.

Evidence statement

Long acting beta-2-agonists may be beneficial in patients with symptoms of breathlessness. (4)

Long acting anti-cholinergics in bronchiectasis may be beneficial in patients with symptoms of breathlessness. (4)

No evidence was identified to support the use of short acting beta-2-agonists. (4)

Bronchodilator treatment may include short or long acting beta-agonists, short or long acting anti-cholinergic bronchodilators, or combined bronchodilators. There is no evidence to guide which of these is the optimal strategy in bronchiectasis (4)

Recommendations

• Use of bronchodilators in patients with bronchiectasis and co-existing COPD or asthma should follow the guideline recommendations for COPD or asthma. (D)

• Offer a trial of long acting bronchodilator therapy in patients with symptoms of significant breathlessness. (D)

• Reversibility testing to beta-2-agonists or anticholinergic bronchodilators may help to identify patients with co-existing asthma but there is no evidence to suggest that a response is required in order to benefit from bronchodilators. (D)

Pulmonary rehabilitation

Inspiratory muscle training

Two studies investigate the effects of inspiratory muscle training (IMT).^{214 219} The study by Liaw et al²¹⁹ found that an 8 week home-based IMT training programme resulted in a significant difference in inspiratory and expiratory muscle strength in the intervention group when compared with the control. However, there were no significant between group differences in any other measure including pulmonary function, quality of life or walking capacity. This study was at high risk of bias due to significant differences between groups at baseline in some measures of pulmonary function and also age. There were a relatively high number of drop outs and intention to treat analysis was not employed. There were 19 participants in each group but six participants dropped out in each group and therefore only 13 participants in each group were included for final analysis. A final consideration is that the participants were not blinded as the control group did not receive any form of sham IMT.

The study by Newall et al²¹⁴ was well-conducted but had a small number of participants (n=32).²¹⁴ This study had three groups: PR plus IMT, PR plus sham IMT and a control group which received no intervention. Exercise capacity increased significantly in both the PR-SHAM and PR-IMT groups. HRQOL was significantly better in the PR-IMT group than the PR-SHAM. After 3 months, exercise capacity had declined significantly in the PR-SHAM group but had been maintained in the PR-IMT group. The findings of this study suggest that there is no additional advantage of simultaneous IMT with PR to increase exercise capacity. However, IMT may be important in prolonging the benefit of the training effects.

Field walking tests

Research has now been conducted to support the use of the 6MWT and ISWT as reliable and responsive measures of exercise capacity in the bronchiectasis population (Lee et al).²²⁰ This study also found that there was a small learning effect in both measures at baseline and it is therefore recommended that two of each test are performed to accurately assess exercise capacity. In addition, a minimal important difference has been estimated for the 6MWT (25 m) and ISWT (35 m) in bronchiectasis (Lee et al).²²¹ Therefore, these are suitable outcome measures to assess exercise capacity before and after PR in the bronchiectasis population.

Evidence statements

Pulmonary rehabilitation increases exercise capacity and can improve quality of life in individuals with bronchiectasis. (1+)

Pulmonary rehabilitation can reduce frequency of exacerbations over a 12 month period and can increase the time to first exacerbation. (1-)

IMT, when used in conjunction with pulmonary rehabilitation, can enhance the longevity of the training effects. (1+)

IMT in isolation does not increase exercise capacity or quality of life in individuals with bronchiectasis. (1-)

6MWT and ISWT are reliable and responsive outcome measures for use in bronchiectasis to evaluate exercise capacity pre and post pulmonary rehabilitation. (3)

There is currently no evidence assessing the incidence of cross infection of respiratory pathogens between individuals with bronchiectasis in the group exercise setting.

Recommendations

• Offer pulmonary rehabilitation to individuals who are functionally limited by shortness of breath (Modified Medical Research Council (MMRC) Dyspnoea Scale≥1). (B)

• Consider the use of inspiratory muscle training in conjunction with conventional pulmonary rehabilitation to enhance the maintenance of the training effect. (B)

Good practice points

• Educate all individuals with bronchiectasis on the importance of an exercise training programme.

• Consider the 6MWT and/or the ISWT when evaluating exercise capacity pre/post pulmonary rehabilitation in bronchiectasis. Prior to this, practice tests should be carried out to eliminate any learning effect.

• Pulmonary rehabilitation providers should offer education sessions tailored to the needs of individuals with bronchiectasis (eg, airway clearance techniques, the pathophysiology of bronchiectasis and relevant inhaled therapy).

• Pulmonary rehabilitation exercise and education sessions should be provided by appropriately qualified healthcare practitioners.

Further information on Pulmonary rehabilitation is provided in the BTS Quality Standards for Pulmonary rehabilitation (https://www.brit-thoracic.org.uk/standards-of-care/quality-standards/bts-pulmonary-rehabilitation-quality-standards/)

Research recommendation

The role of education, self management plans and who delivers the pulmonary rehabilitation needs to be explored.

The role of pulmonary rehabilitation after exacerbations requiring hospital admission needs to be explored.

The incidence of cross-infection of respiratory pathogens in the group exercise setting should be investigated in the bronchiectasis population.

What is the role of surgery in managing bronchiectasis?

Multiple case series of surgical resection for bronchiectasis are available.^222–237 A Cochrane review concluded there are no high quality randomised control studies and the benefits of surgery over conservative management were unclear. It is also likely there is a reporting bias for the available case series.²³⁸

Generally surgery should not be considered until there is optimisation of medical management. With this caveat the consistency of available evidence supports a role for surgery in bronchiectasis in selected patients.

The indications for surgical resection in bronchiectasis include

• persistent symptoms despite up to a year of comprehensive medical treatment,

• exacerbations that are either severe or frequent and interfere with social/professional life,

• recurrent refractory or massive haemoptysis,

• post obstruction bronchiectasis distal to tumours

• localised severely damaged lobe/segment that may be a source of sepsis that left in situ may lead to extension of lung damage.

Surgery is generally applied when there is focal disease in the presence of the above clinical scenarios. Therefore the population both requiring and suitable for surgery is likely to be small. Notably many series reported to date included patients with a lower mean age than seen in many clinics, ranging from 30 to 48 years of age.^{222 225 239} The median duration of symptoms prior to surgery in the reported series was usually prolonged e.g. 6 years.²²⁵

A variety of operative techniques have been described. In experienced hands video assisted thoracoscopic (VAT) performs as well as open surgery^{231 233 239} and may be associated with lower rates of complications such as blood loss and shorter hospitalisations.²³³ There is however an intraoperative conversion rate from VATS to open surgery of up to 12%.²³³ The resection limits range from segmentectomy to pneumonectomy but the available literature does not provide robust decision making tools to aid decision making on the optimal resection limits in day to day practice.^{222 225 231 233 239}

With this in mind pre-surgical safety assessment should be undertaken to define the expected amount of residual lung, underlying cardiopulmonary reserve and anticipated overall risks. Pulmonary rehabilitation and optimisation of nutrition are important aspects with which respiratory physicians can support their patients.

In the available series the 60 day mortality outcomes ranged from 0%–11%.^{224 232 237 239} Common post-operative complications included wound infection, empyema, systemic sepsis, post thoracotomy pain, prolonged air leak and recurrence of bronchiectasis.^{224–226 234 235} Early morbidity rates ranged from 13% to 24%^{222 225 232 235 239} with wound infection reported as the most common complication (6%) in one large series of 277 patients.²⁴⁰

For long term complications the recurrence rate is likely to depend on the completeness of resection and underlying aetiology of bronchiectasis. Perceived complete resection is associated with significantly better long term outcomes than cases where incomplete resection has occurred.^{223 225 232 239 240} In one small case series of 31 patients, the mean time to recurrence of symptoms was 34 months.²³² An immunocompromised status, persistent infection with P. aeruginosa and the extent of residual bronchiectasis after surgery have been associated with a significantly shorter recurrence-free interval.²³² The primary cause of bronchiectasis may influence post-surgical outcomes with likely better outcomes after post obstructive bronchiectasis and poorer outcomes in immunodeficiency.²³² There are however limited data to guide clinicians in defining risk benefit ratios.^{229 238} Even when the primary cause of bronchiectasis persists, successful outcomes are reported. Surgery can be successful in primary ciliary dyskinesia.²²⁶

Freedom from symptoms of bronchiectasis have reported as high as 61%–84% when followed up from between 1 to 5 years or more post-operatively.^{224 225 234}

Evidence statement

Surgery may be successful in bronchiectasis in reducing exacerbations or treating haemoptysis. (3)

The ideal candidate(s), timing for surgery and operative approach remain ill-defined. (3)

Video assisted thoracoscopic technique can provide outcomes at least as successful as open surgery. (3)

Improvements in bronchiectasis symptoms can be seen after surgery for bilateral disease. (3)

Recommendations

• Consider lung resection in patients with localised disease whose symptoms are not controlled by medical treatment optimised by a bronchiectasis specialist. (D)

• Offer multidisciplinary assessment, including a bronchiectasis physician, a thoracic surgeon and an experienced anaesthetist, of suitability for surgery and pre-operative assessment of cardiopulmonary reserve post resection. (D)

Good practice point

• Consider nutritional support and pre-operative pulmonary rehabilitation before surgical referral.

Lung transplantation for bronchiectasis

Lung transplantation is an effective therapy for bronchiectasis when maximal medical therapy is failing. Lung transplantation is generally reserved for those with diffuse bilateral disease and bilateral transplantation is then performed. There are however reports of single lung transplantation with contralateral pneumonectomy. Generally lung transplantation is felt indicated where survival is anticipated at 50% at 2 years without lung transplantation.²⁴¹ International guidelines note the risks of transplantation in general appear to increase with age and generally patients above the age of 65 are felt to have an unfavourable risk: benefit mortality ratio.²⁴¹

Internationally bronchiectasis is reported as a rare indication for lung transplantation representing less than 5% of all bilateral lung transplantations recorded in the international registry. Overall less than 1200 transplant procedures for bronchiectasis were recorded in the international registry as compared with 1280 for pulmonary hypertension, 6862 for cystic fibrosis and 13 672 for COPD (https://www.ishlt.org/registries/slides.asp?slides=heartLungRegistry accessed Aug 2015).

The available case series focus on lung transplantation for adults with bronchiectasis with no significant data reported for paediatric transplantation. While collectively less than 200 patients, these case series report good outcomes following transplantation. In a case series of 22 patients transplanted in the UK between 1988 and 2001 undergoing bilateral lung transplantation either as bilateral sequential single-lung transplants (BSSLTX), heart-lung transplants (HLTX) or single-lung transplants (SLTX) the reported outcomes included lung function and mortality data.²⁴² Overall the 1 year Kaplan-Meier survival for all patients was 68% (95% CI, 54% to 91%), with the 5 year survival reaching 62% (95% CI, 41% to 83%). In those undergoing SLTX for bronchiectasis the 1 year survival was lower at 57% (95% CI, 20% to 94%) compared with those receiving 2 lungs 73% (95% CI, 51% to 96%). At 6 months, mean forced expiratory volume in 1 s was 73% predicted (range, 58%–97%), and mean forced vital capacity was 68% predicted (range, 53%–94%) after receiving two lungs (n=10).

A small single centre case series of 37 patients from Cambridge, UK reported transplantation outcomes in those with bronchiectasis due to immunodeficiency syndromes (n=5, predominantly antibody deficiency patients on replacement therapy) compared with other causes of bronchiectasis (n=32).²⁴³ The actuarial survival was comparable between the two groups. The 1 year survival was 81% in the bronchiectasis group and 80% in bronchiectasis-antibody deficiency recipients. Functional outcomes following transplant were good with the FEV₁ (mean +/-SD) at 1 year post transplant being 83.7%+/-24.2% in the bronchiectasis group and 83.0%+/-30.4% in the bronchiectasis-antibody deficiency recipients.

A single centre experience of 17 bronchiectasis patients from Madrid, Spain reported that in a series of 171 patients, 44 (26%) were transplanted for suppurative lung diseases.²⁴⁴ Of these 27 had cystic fibrosis (61%) and 17 (39%) were classified as bronchiectasis. The reported survival of cystic fibrosis patients was 85% at 1 year and 45% at 5 years while that of bronchiectasis patients demonstrated an initially higher mortality rate (survival 70% at 1 year) but similar long term survival (54% at 5 years). P. aeruginosa infection in pre-transplant recipients was common but not invariable. No clear association was seen between pre transplant P. aeruginosa and poorer post transplant outcomes, though the study was unlikely to be powered. Persistence of the pre-transplant infecting organism was common at 1 year following transplantation.²⁴⁴

One study of over 1000 patients in the UK waiting for lung transplantation included adults with cystic fibrosis (n=430), bronchiectasis (n=123), pulmonary hypertension (n=74), diffuse parenchymal lung disease (n=564), chronic obstructive pulmonary disease (COPD n=647) and miscellaneous indications (n=159). The proportion of patients in each group who died while on an active transplant list listed varied significantly (respectively 37%, 48%, 41%, 49%, 19%, 38%). Hence these data demonstrate that bronchiectasis has one of the highest ‘on-list’ mortality rates with up to 60% mortality on list at 2 years.²⁴⁵

Furthermore in the 54 of 123 bronchiectasis patients on the waiting list that survived to transplantation, median survival was 3001 days which was better post-transplant survival rates than more common indications for transplantation such as COPD (n=483 transplanted, median survival 1795 days) and cystic fibrosis (n=234, 2436 days).²⁴⁵

Consistent with international guidelines, those transplanted had severe disease (mean FEV₁ 26% predicted) and were younger than the median age of patients reported in the UK national audit of outpatient bronchiectasis with average age at transplantation 49.7 years.²⁴⁵

Evidence statement

As stated in international Lung transplantation guidelines, post-transplant morbidity and mortality increase with age and hence transplantation is in general reserved for those aged 65 years or less. (3)

In selected patients with bronchiectasis, lung transplantation improves quality of life and is associated with post-transplant survival of over 60% at 5 years. (3)

Bronchiectasis patients have poor outcomes on lung transplant waiting lists with mortality rates of up to 60% at 2 years. (3)

The majority of transplantation procedures performed for bronchiectasis are bilateral lung transplants in patients with severely impaired quality of life or rapid deterioration. (3)

Recommendation

• Consider transplant referral in bronchiectasis patients aged 65 years or less if the FEV₁ is <30% with significant clinical instability or if there is a rapid progressive respiratory deterioration despite optimal medical management. (D)

• Consider earlier transplant referral in bronchiectasis patients with poor lung function and the following additional factors: massive haemoptysis, severe secondary pulmonary hypertension, ICU admissions or respiratory failure (particularly if requiring NIV). (D)

Good practice points

• Discuss appropriate patients with a transplant centre prior to formal referral.

• Optimise management of comorbidities such as osteoporosis and maintaining physical condition through pulmonary rehabilitation prior to transplant.

What is the role of influenza and pneumococcal vaccination in management of bronchiectasis

Pneumococcal vaccination

There is limited evidence supporting the use of 23 valent pneumococcal vaccine to prevent exacerbations of bronchiectasis.²⁴⁸ One randomised controlled trial comparing pneumococcal and influenza vaccination versus influenza vaccination alone in patients with chronic lung disease including COPD and bronchiectasis showed that patients given the 23 valent pneumococcal vaccine had fewer exacerbations.²⁴⁹ The NNV was 6 (95% CI 4 to 32) over 2 years. No difference between groups was observed for pneumonia incidence, and pulmonary function test data were not reported. The limitations of this study include open label design, small number of patients with bronchiectasis enrolled (n=20), lack of microbiological evidence for pneumococcal infection and failure to document severity of chronic lung disease.

Randomised controlled trials show that 23 valent pneumococcal vaccination can prevent all cause pneumonia (OR 0.72 95% CI 0.56 to 0.93).²⁵⁰ There is however marked statistical heterogeneity between studies, according to study site (high income v low income countries), population (healthy adults v those with chronic medical illnesses) and the pneumococcal vaccine used (14 valent v 23 valent). The 23 valent pneumococcal vaccine was effective against all cause pneumonia in low income countries (OR 0.54 (5% CI 0.43 to 0.67) but in high income countries, studies in healthy adults and in those with chronic medical illnesses were negative.²⁵⁰ The 23 valent pneumococcal vaccine is still offered in the UK, based on the evidence that, for adults between the ages of 65–74 with chronic lung disease, the 23 valent polysaccharide pneumococcal vaccine continues to provide short term protection against invasive pneumococcal disease and remains cost effective.^{251 252}

The role of protein conjugate pneumococcal vaccination is contentious. There is no evidence as to the efficacy of protein conjugate pneumococcal vaccination in patients with bronchiectasis.

Evidence statements

The potential benefit of influenza vaccination in reducing exacerbations and influenza infection is derived from studies of individuals with COPD, some of whom will also have bronchiectasis. In the absence of direct evidence, influenza vaccination can be justified based on individual patient needs (presence of COPD, immune deficiency, nursing home residence, patient preference and expert opinion) and adherence to national guidelines. (4)

The 23 valent polysaccharide pneumococcal vaccination with influenza immunisation may reduce exacerbations of bronchiectasis. (1-)

Meta-analysis of RCTs supported the use of 23 valent pneumococcal vaccine in reducing the rate of all cause pneumonia in healthy adults and those with chronic illnesses although there was marked statistical heterogeneity. (1+)

Recommendations

• Offer annual influenza immunisation to all patients with bronchiectasis. (D)

• Offer polysaccharide pneumococcal vaccination to all patients with bronchiectasis. (D)

Good practice point

• Consider influenza vaccination in household contacts of patients with immune deficiency and bronchiectasis to reduce the risks of secondary transmission.

• Consider use of 13 valent protein conjugate pneumococcal vaccine in patients with bronchiectasis who do not have an appropriate serological response to standard polysaccharide vaccine (23 valent carbohydrate Pneumococcal vaccine).

Treatment of respiratory failure

A study of survival of 48 patients in the intensive care unit (ICU) where one of the interventions was NIV (n=13, 27%) found cumulative mortality of 19% (n=9) for a first admission to ICU for respiratory failure in patients with bilateral non-CF bronchiectasis and 40% (n=19) at 1 year.²⁵³ The actuarial survival rate at 1 year was 60%. Intubation requirement was associated with reduced survival in univariate analysis, suggesting that NIV may be advantageous. Multivariate analysis found that age >65 years and long-term oxygen therapy were independent factors predicting reduced survival. Survival was not increased for those treated with long-term non-invasive positive pressure ventilation. A retrospective analysis of patients treated with non-invasive (n=31) versus invasive (n=26) ventilation for respiratory failure reported a 32% failure rate with NIV for progression to IV or death.²⁵⁴ The overall in hospital mortality was around 25%, not different between NIV and IV, and predicted by APACHE score. Bronchiectasis in the context of COPD may increase the duration of ICU stay (median 14 vs 9 days) but did not influence mortality in a study of 93 patients with COPD on invasive ventilation, 31% of whom had radiological bronchiectasis.²⁵⁵

A study of the outcome of domiciliary NIV noted that the response to NIV in this group of patients (n=13) was disappointing.²⁵⁶ The patient group had more severe hypoxaemia and hypercapnia at the start, suggesting that NIV was introduced later in the natural history of the disease than in previous studies. The probability of continuing NIV after 2 years in the bronchiectasis group was <20% and most patients became increasingly more ventilator dependent with time. However, all reported improvement in quality of sleep and in levels of daytime activity. Eight considered that the improvement in their respiratory status outweighed the discomfort due to NIV.

A retrospective study of 16 patients with severe diffuse bronchiectasis investigating NIV as rescue therapy for nocturnal home use with daytime oxygen found a significant increase in FEV₁ 12 months after initiation of NIV. In patients alive after 24 months there was a significant decrease in the length of hospital admissions.²⁵⁷ This could be a reflection of the three deaths being the high intensity users.

In a study which compared patients with bronchiectasis treated with NIV with those treated with long-term oxygen therapy only, differences were found between the two groups. In the year before NIV was commenced, mean/SD length of time in hospital for the NIV and long-term oxygen therapy groups was 48+/-55 and 5+/-8 days, respectively; the year following home NIV the length of time in hospital for the two groups was 10+/-31 and 9+/-16 days, respectively.²⁵⁸ In contrast, a further study did not find a reduction in hospital days with the instigation of non-invasive positive pressure ventilation in patients with bronchiectasis.²⁵⁹

Evidence statements

There are no specific studies of LTOT for respiratory failure in bronchiectasis, but expert opinion based on data in COPD is that this is likely to be a beneficial intervention. (4)

NIV may lead to a reduction in hospitalisation days in patients with bronchiectasis and hypercapnic respiratory failure however the proportion of patients remaining on NIV at 2 years is low. (3)

Recommendations

• Consider long term oxygen therapy for patients with bronchiectasis and respiratory failure, using the same eligibility criteria as for COPD. (D)

• Consider domiciliary non-invasive ventilation with humidification for patients with bronchiectasis and respiratory failure associated with hypercapnia, especially where this is associated with symptoms or recurrent hospitalisation. (D)

Bronchiectasis and other treatments: cough suppression, nutritional supplements, complementary therapy/homeopathy, supplemental treatments

The majority of studies of alternative therapies and bronchiectasis are mainly observational with small patient numbers. There is a lack of randomised controlled trials.

A small (n=35) randomised, partially blinded study (over 8 weeks) involving three groups, on the role of self-administered acupressure to reduce the symptoms of bronchiectasis and improve QOL.²⁶⁰ The three groups were standard care +self administered acupressure (n=11), standard care +sham acupressure (n=11) (not applied to real acu-points) and standard care alone (n=13). All aged 40–70 years (sex not identified). Originally 49 enrolled, 12 dropped out by week 4, 2 by week 8.

The findings showed that after 8 weeks of self-administered acupressure seemed to be useful in reducing the effects of bronchiectasis on patients’ daily activities, however, the authors conceded that sham acupressure administered for the same amount of time was capable of improving some of the symptoms of bronchiectasis. A Cochrane review, Singing for children and adults with bronchiectasis, found no eligible trials, therefore, no data were available for analysis.²⁶¹ A review²⁶² and a controlled study²⁶³ around vitamin D both concluded that vitamin D deficiency was common in bronchiectasis, however, there were no RCTs assessing vitamin D. A case control study on a small number of patients (n=34 with bronchiectasis, n=29 without) found that the patients with bronchiectasis had significantly lower serum zinc level than the control group, however, there were no trials to evaluate the prophylactic or therapeutic use of zinc supplements.²⁶⁴

Evidence statement

Alternative treatments such as complementary therapy/homeopathy and supplemental treatments have limited evidence to support their use.

Recommendation

• Do not routinely recommend alternative treatments (for example cough suppression, nutritional supplementation, complementary therapy/homeopathy, supplemental treatments) as part of the management of patients with bronchiectasis. (D)

Good practice point

• Record patient’s weight and BMI at each clinic appointment.

Research recommendations

Further interventional/randomised controlled trials needed to establish the role of any alternative therapies in the management of bronchiectasis.

Studies assessing the benefits of nutritional supplementation in patients with bronchiectasis should be undertaken.

Do pathogens have an impact on prognosis in bronchiectasis?

In UK studies, the most frequent pathogen isolated from traditional culture in bronchiectasis is Haemophilus influenzae (20%–40%), followed typically by P. aeruginosa (10%–30%), Moraxella catarrhalis, Streptococcus pneumoniae, Staphylococcus aureus and enterobacteriaceae.^{68 120 265 266} Patients with NTM account for 1%–10% of cases.^{267 268}

There is a clear and consistent association between the presence of P. aeruginosa and poor outcome. All studies that have examined this outcome conclude that P. aeruginosa is associated with a three-fold or greater increased risk of mortality, even after adjustment for potential confounders.^{120 266 269 270}

Patients with P. aeruginosa are also more likely to require hospital admission due to a greater disease severity and a more frequent requirement for intravenous antibiotic treatment, either due to outpatient antibiotic failure or antibiotic resistance.¹²⁰ Patients with P. aeruginosa colonisation also have worse health related quality of life using the St. Georges Respiratory Questionnaire, more frequent exacerbations, and worse lung function in cross-sectional studies.^{120 265 271–273}

The relationship between P. aeruginosa and lung function decline has been evaluated in relatively few patients and shows inconsistent results. Two studies show no relationship between P. aeruginosa and FEV₁ decline,^{15 274} while two show a significant relationship.^{271 275} Therefore no firm conclusion on this relationship can be made without further studies.

There is less evidence for a prognostic impact of organisms other than P. aeruginosa. One large study shows that colonisation with any organism other than P. aeruginosa is associated with a poorer outcome compared with patients not colonised with pathogens.¹²⁰

There is limited data on prognosis with specific pathogens such as NTM and A. fumigatus.^{267 268 276} There is a consistent relationship between airway bacterial load and airway inflammation across several studies using both sputum and bronchial wash.^{168 277 278}

An increasing number of studies using molecular techniques to characterise the airway microbiome are being published.^{279 280} Microbiome studies demonstrate that loss of bacterial diversity is associated with worse disease defined by FEV₁ or exacerbation frequency.²⁷⁹ While this has been a valuable research tool, at present this is not available for daily practice and the extent to which it provides clinically relevant information beyond that available from culture has not been established.

Evidence statements

Chronic colonisation with P. aeruginosa is independently associated with

 Higher mortality during follow-up (2++)

 Higher risk of admissions to hospital (2++)

 Increased exacerbations (2++)

 Poorer quality of life (2++)

 Worse radiological severity of disease (2+)

 Lower FEV₁ and FVC cross-sectionally (2++)

Chronic colonisation with pathogens other than P. aeruginosa are associated with

 Hospital admissions (2++)

 Greater airway inflammation (2++)

Sputum bacterial load is associated with

 Greater airway inflammation (2++)

 More frequent exacerbations and hospital admissions (2+)

Recommendations

• Consider patients with chronic P. aeruginosa colonisation at higher risk of bronchiectasis-related complications. (B)

• Perform regular sputum microbiology screening for patients with clinically significant bronchiectasis to monitor for pathogens and detect new isolation of P. aeruginosa. (C)

What is the evidence for the role of viruses/fungal disease in patients with bronchiectasis?

A single prospective study has reported on the prevalence of respiratory viruses in adult patients with bronchiectasis. Nasopharyngeal swabs and sputum samples, collected from 119 patients at baseline, when clinically stable and at exacerbation, were assayed for 16 respiratory viruses. Viruses were found more frequently in nasopharyngeal swabs and sputum during exacerbations (49/100, 49.0%) than during steady state (11/58, 19%). Virus-positive exacerbations were associated with a greater increase in markers of systemic and airway inflammation but no differences in lung function, quality of life, and bacterial density were apparent.²⁸¹

Similarly, data regarding the potential role of fungi in bronchiectasis is lacking. A retrospective cohort study was performed using 252 patients from 4 Centres in Spain.²⁸² All patients had at least one sputum sample cultured for fungi, with a mean ±SD of 7±6 cultures per patient. Persistent Aspergillus spp. and C. albicans were defined as the presence of 2 or more positive sputum cultures for Aspergillus spp. and C. albicans, respectively, taken at least 6 months apart; eighteen (8.7%) and 71 (34.5%) patients had persistent positive cultures for Aspergillus spp. and C. albicans, respectively. Logistic regression, to determine the most significant predictors of fungal persistence, revealed that the presence of mucopurulent or purulent sputum was associated with persistence of Aspergillus spp. with long-term antibiotic therapy associated with persistence of C. albicans.

Evidence statement

There is insufficient evidence to evaluate the role of fungi and viruses in patients with bronchiectasis. (2-)

Good practice points

• Testing to detect viral infection should be considered in patients with an exacerbation of bronchiectasis.

• Do not routinely use anti-fungal therapy without evidence of fungal disease. Fungal cultures can be positive on those receiving long-term antibiotic therapy.

Does eradication of potentially pathogenic microorganisms improve outcomes in patients with stable bronchiectasis?

There is one randomised controlled study that directly addresses whether antibiotic treatment following first isolation of P. aeruginosa improves outcomes in patients with bronchiectasis. Six RCTs report the frequency of negative cultures following antibiotic treatment and one retrospective study reports the outcomes of antibiotic regimens prescribed specifically for P. aeruginosa eradication.

In a randomised, but unregistered, study evaluating the effect of 2 weeks of ceftazidime and tobramycin followed by either nebulised tobramycin 300 mg (Tobi) or placebo twice daily for 3 months in 35 patients with bronchiectasis and a first growth of P. aeruginosa, the median time to recurrence of P. aeruginosa was higher (P=0.048) in the nebulised tobramycin group (n=11) compared with placebo group (n=17), with the proportion free of P. aeruginosa after 12 months follow-up being 55% and 29%, respectively.²⁸³ The number of exacerbations (1.27±1.62 vs 2.5±1.63, P=0.04), the number of hospital admissions (0.06±0.25 vs 0.47±0.51, P=0.04) and the number of days in hospital (0.90±3.01 vs 13.56±22.64, P=0.03) were also significantly lower in the nebulised tobramycin group. Five patients in the nebulised tobramycin group discontinued treatment due to bronchospasm and two patients in the placebo group withdrew from the study.

In a randomised single blind trial evaluating the effect of nebulised gentamicin in patients with bronchiectasis, negative sputum cultures after 12 months treatment were more common in the gentamicin group (18/27, 67%) compared with the control group (1/30, 3%).²⁰¹ However, a lesser treatment effect was seen in patients with P. aeruginosa at baseline, with 7/13 (54%) gentamicin treated patients and 9/12 (75%) control patients reculturing the organism after 12 months treatment. In the whole group, gentamicin treatment was also associated with less sputum purulence (9% vs 39%; P<0.0001); greater exercise capacity (510 (350–690) m vs. 415 (268–530) m; P=0.03); and fewer exacerbations (0 (0–1) vs. 1.5 (1-2); P<0.0001) with increased time to first exacerbation (120 [87–162] days vs. 62 [21–123] days; P=0.02). The gentamicin group had greater improvements in Leicester Cough Questionnaire (81% vs 20%; P<0.01) and St. George's Respiratory Questionnaire (88% vs 19%; P<0.004) score. However, 3 months after treatment cessation, all outcome measures were similar to baseline.

In a randomised double blind placebo controlled trial evaluating the effect of dual release liposomal ciprofloxacin in patients with bronchiectasis and ciprofloxacin sensitive P. aeruginosa, failure to culture P. aeruginosa after 28 days treatment was more common in the ciprofloxacin group compared with the control group (12 (60%) vs 3 (14%), OR 9.5, 95% CI 1.8 to 63.0, P=0.003).¹⁹⁹ In the per protocol analysis, time to first exacerbation was delayed in the ciprofloxacin group compared with the placebo group (134 vs 58 days, P=0.046).

In a randomised double blind placebo controlled trial evaluating the effect of dry powder ciprofloxacin in patients with bronchiectasis and predefined potential respiratory pathogens including P. aeruginosa and H. influenzae, negative bacterial cultures after 28 days treatment was more common in the ciprofloxacin group compared with the placebo group (14 (35%) vs 4 (8%), P=0.001).¹⁹⁸

In a 12 month randomised double blind placebo controlled trial evaluating the effect of erythromycin in patients with bronchiectasis, eradication of pathogens (defined as a negative end of treatment sputum culture in participants with pathogenic bacteria identified in baseline samples) occurred more commonly in the erythromycin group compared with the placebo group (17 (30%) vs 6 (11%), OR 3.6, 95% CI 1.3 to 10.6, P=0.01).¹⁹² Overall, erythromycin treated patients also had fewer protocol defined pulmonary exacerbations, a lower 24 hours sputum volume and a smaller lung function decline over 12 months compared with controls. However, two contemporary RCTs evaluating the effect of azithromycin in patients with bronchiectasis found no difference between azithromycin and placebo treated patients regarding the eradication of respiratory pathogens (despite there being significant clinical benefits associated with azithromycin treatment)^{190 191} and two subsequent meta-analyses of macrolide trials in this patient population found no overall benefit in this respect.^{193 196}

A retrospective study assessed the clinical and microbiological outcomes of eradication therapy following initial P. aeruginosa isolation.²⁸⁴ Eradication therapy involved intravenous antibiotics (n=12), intravenous antibiotics followed by oral ciprofloxacin (n=13), or ciprofloxacin alone (n=5), combined with 3 months of nebulised colistin. P. aeruginosa was eradicated from sputum in 24 patients (80.0%). While 11/24 (46%) subsequently recultured P. aeruginosa (median time 6.2 months), isolates were not genotyped to assess whether this represented relapse or reinfection. Exacerbation frequency was significantly reduced from 3.9 per year pre-eradication to 2.1 post-eradication (P=0.002). Admission rates were unchanged. 20/30 patients reported initial clinical improvement, while at 1 year follow-up, 19/21 had further improved or remained stable. Lung function was unchanged.

Patients with bronchiectasis may also culture a number of other drug resistant pathogens such as MRSA, Stenotrophomonas maltophilia and Achromobacter species.²⁸⁰ While it is not known if antibiotics prescribed following first isolation reliably result in eradication or improved patient outcomes, in clinical practice antibiotics are often prescribed in an attempt to prevent chronic infection.

A recent meta-analysis of eight randomised controlled trials recruiting 539 patients showed that long-term inhaled antibiotics reduced sputum bacterial density and augmented eradication of sputum P. aeruginosa. No evidence showed higher risk of P. aeruginosa resistance after inhaled therapy. In addition, nebulized therapy reduced the number of patients with exacerbation. However, patients with inhaled antibiotics were more likely to suffer wheeze and bronchospasm.²⁰⁷

In summary, the available RCT data suggest that inhaled antibiotics improve outcomes in patients with bronchiectasis and that a proportion of patients’ cultures convert as a result of treatment. However, only one RCT evaluated outcomes of treatment prescribed to eradicate the first growth of a microorganism. The most clinically relevant definition of eradication has not been established (single negative culture vs sequential negative cultures vs negative PCRs); and it is not known if true bacterial eradication is an achievable endpoint in patients with bronchiectasis, nor whether it is superior to reducing bacterial density at improving patient outcomes. Apparent clearance of P. aeruginosa is achieved in some studies. However, the most cost effective antibiotic regimen has not been established, nor whether relapse occurs due to re-emergence of the original strain or de novo infection. Furthermore, it appears that spontaneous P. aeruginosa clearance can occur, as some patients only culture P. aeruginosa intermittently.^{266 274}

Recommendations

• Offer patients with bronchiectasis associated with clinical deterioration and a new growth of P. aeruginosa (1st isolation or regrowth in the context of intermittently positive cultures) eradication antibiotic treatment: (first line treatment: ciprofloxacin 500–750 mg bd for 2 weeks; second line treatment: iv anti-pseudomonal beta-lactam ±an iv aminoglycoside for 2 weeks, followed by a 3 month course of nebulised colistin, gentamicin or tobramycin). (D)

• Discuss with patients the potential risks and benefits of starting eradication antibiotic treatment versus clinical observation following a new growth of P. aeruginosa in the context of stable bronchiectasis. This will include consideration of the likelihood of achieving sustained eradication, the risk of developing chronic infection, and the risk of adverse events with each management approach. (D)

• Offer patients with bronchiectasis associated with clinical deterioration and a new growth of methicillin-resistant S. aureus (MRSA) (1st isolation or regrowth in the context of intermittently positive cultures) eradication. This should be attempted especially in view of infection control issues. (D)

Good practice point

• Send sputum for culture and sensitivity immediately before and at each clinical attendance following antibiotics prescribed for bacterial eradication to determine the outcome of treatment.

Research recommendation

A randomised control trial of P. aeruginosa eradication therapy is needed to determine the microbiological and clinical outcomes of eradication therapy.

Exacerbations

Evidence statement

There is insufficient evidence to evaluate the efficacy of antibiotics in exacerbations in adults with bronchiectasis. (2-)

Good practice points

• A patient self management plan should be considered, an example is provided here https://www.brit-thoracic.org.uk/standards-of-care/quality-standards/bts-bronchiectasis-quality-standards/)

• There should be prompt treatment of exacerbations and suitable patients should have antibiotics to keep at home.

• Previous sputum bacteriology results can be useful in deciding which antibiotic to use. Table 6 highlights the first-line and alternative treatments for the common bacterial pathogens implicated in exacerbations of bronchiectasis.

• Where possible, sputum (spontaneous or induced) should be obtained for culture and sensitivity testing prior to commencing antibiotics.

• Empirical antibiotics can then be started while awaiting sputum microbiology.

• Once a pathogen is isolated, antibiotics can be modified if there is no clinical improvement, with treatment guided by antibiotic sensitivity results.

• In general, antibiotic courses for 14 days are standard and should always be used in patients infected with P. aeruginosa. Shorter courses may suffice in patients with mild bronchiectasis.

• Intravenous antibiotics should be considered when patients are particularly unwell, have resistant organisms or have failed to respond to oral therapy (this is most likely to apply to patients with P. aeruginosa).

Specific treatments

What treatments improve outcomes in patients with bronchiectasis and Allergic Broncho-Pulmonary Aspergillosis (ABPA)?

Limited evidence suggests that if clinical and immunological features of ABPA are identified before radiological features are present, without evidence of proximal bronchiectasis, progressive lung damage occurs rarely once treatment is started.²⁸⁸

There are no studies to identify how many patients with bronchiectasis are sensitised to A. fumigatus or have seropositive ABPA.

The aims of treatment of ABPA are to control symptoms, prevent and treat exacerbations, reduce inflammation and prevent further progression and damage to the lung.²⁸⁹

The mainstay of treatment is immunosuppression with corticosteroids, with or without the addition of antifungal agents.

Oral corticosteroids

There are no randomised controlled trials of corticosteroid use in patients with ABPA and bronchiectasis.

Corticosteroids are the mainstay of therapy. Starting and maintenance doses vary in the literature.

A tapering dose of corticosteroid is usually used with monitoring of total serum IgE every 6–8 weeks as a marker of disease activity. Regimes vary from Prednisolone, 0.5 mg/kg/d, for 1–2 weeks, then on alternate days for 6–8 weeks before tapering by 5–10 mg every 2 weeks and discontinue²⁹⁰ to more prolonged courses of Prednisolone, 0.75 mg/kg, for 6 weeks, 0.5 mg/kg for 6 weeks, then tapered by 5 mg every 6 weeks to continue for a total duration of at least 6 to 12 months.^{81 291}

Patients are considered in remission when they remain without pulmonary infiltrates and/or eosinophilia for 6 months after oral steroid withdrawal.²⁹⁰

Inhaled corticosteroids

Inhaled corticosteroids (ICS) provide a theoretical advantage to oral corticosteroids (OCS) by minimising systemic effects.

The role of high dose ICS was evaluated in a retrospective study of patients with seropositive ABPA and asthma. The conclusion was that there was no role for ICS in isolation as a treatment although they could provide a useful adjunct alongside oral steroids to better control asthma symptoms.²⁹²

Other small case studies had suggested a role for ICS in weaning patients from high doses of OCS who were otherwise difficult to wean with reported relapses in disease activity when doses of OCS were reduced.²⁹³

There is no data to support or refute the use of ICS in patients with ABPA and bronchiectasis.

Intravenous corticosteroids

There are very few studies evaluating the role of pulsed IV steroid therapy in ABPA and none in bronchiectasis with ABPA.

A study of pulsed therapy with monthly intravenous methylprednisolone, in conjunction with itraconazole, in nine patients with CF and ABPA was shown to be effective with all patients showing clinical and laboratory improvement - FEV₁ increase, serum IgE levels and total eosinophil counts.²⁹⁴ There is no evidence to support the use of IV steroid in patients with ABPA and bronchiectasis.

Azoles

Itraconazole has been shown in a randomised controlled trial to reduce the need for corticosteroids with fewer exacerbations requiring oral corticosteroids in those treated with itraconazole than in the placebo group.²⁹⁵

Other studies of patients with asthma and ABPA have suggested a reduction or elimination of glucocorticoid use while on itraconazole.²⁹⁶

A Cochrane review of the role of azoles in ABPA associated with asthma concluded that itraconazole modifies the immunologic activation associated with ABPA and improves clinical outcome, at least over a period of 16 weeks, but noted that adrenal suppression with inhaled corticosteroids and itraconazole is a potential concern.²⁹⁷

In current UK practice, itraconazole is used for patients who are steroid dependent and for those who have relapsed after a course of steroids. On occasion it has been utilised from the outset in conjunction with commencement of steroid therapy. The recommended adult dose for itraconazole is 100–200 mg twice daily.²⁸⁹

A systematic review of the efficacy and safety of antifungal treatments in patients with ABPA and either asthma or cystic fibrosis, including itraconazole, voriconazole, posaconazole, ketoconazole, natamycin, nystatin and amphotericin B, concluded that there was an improvement in symptoms, frequency of exacerbations and lung function in most of the studies and this was seen more commonly with the azoles.²⁹⁸

There is however a lack of controlled studies evaluating the use of antifungal agents.

Voriconazole and posaconazole are reported to be an effective adjunct therapy in the management of ABPA, with clinical improvement in 70% of patients with ABPA treated with voriconazole and 78% of patients with ABPA treated with posaconazole in studies concerning patients with severe asthma.²⁹⁹

There are no studies concerning the use of these antifungals in patients with bronchiectasis.

Amphotericin B and anti-IgE therapies

The potential role of agents such as amphotericin B and monoclonal antibody therapy with agents such as omalizumab, are of interest but require further evaluation in ABPA.

Evidence statements

Itraconazole use in corticosteroid dependent patients is associated with a reduction in corticosteroid dose, improved pulmonary function and improved exercise capacity. (1+)

Total IgE is the most sensitive marker for monitoring treatment response. (2+)

Recommendations

• Offer oral corticosteroid to patients with active ABPA. An initial dose of 0.5 mg/kg/d for 2 weeks is recommended. Wean steroids according clinical response and serum IgE levels. (D)

• Consider itraconazole as a steroid sparing agent for patients dependent on oral corticosteroids where difficulty in weaning is experienced. (B)

• Monitor patients with active ABPA with total IgE level to assess treatment response. (C)

Does immunoglobulin replacement treatment therapy improve outcomes in patients with bronchiectasis due to antibody deficiency?

There are no double-blind randomised placebo-controlled trials of immunoglobulin replacement in patients with either primary or secondary antibody deficiency. Cohort studies show that introduction of IgG replacement therapy is associated with a reduced incidence of pneumonia in patients with CVID and XLA.^300–303

Randomised controlled trials comparing high dose and low dose intravenous immunoglobulin replacement therapy show that higher doses are associated with reduced incidence of acute sino-pulmonary³⁰⁴ and upper respiratory tract infections.³⁰⁵ Meta-analysis and cohort studies show an inverse relationship between trough IgG levels and rate of serious infections/and or pneumonia in patients with CVID and XLA receiving intravenous IgG therapy.^{300 306–308}

Current guidelines suggest that patients with CVID and bronchiectasis should be treated with an IgG replacement dose of 0.6 g/Kg/month compared with standard treatment of 0.4 g/Kg/month.⁹⁶ There is however no consensus on the dose of IgG replacement to treat lung disease in patients with primary antibody deficiency or the optimal trough IgG levels to prevent pneumonia and chest infections. North American guidelines for the use of IgG therapy in primary immune deficiency recommend that the goal of therapy should be to improve clinical outcomes rather than aim for a specific trough concentration.^{309 310}

There is no conclusive data to suggest that IgG replacement therapy prevents the progression of bronchiectasis and other pulmonary complication of primary antibody deficiency syndrome. Two longitudinal studies of patients with CVID and XLA on standard IgG replacement doses over 7–8 years showed greater than anticipated annual declines in airflow obstruction and transfer factor.^{311 312} Two European studies showed that the prevalence of bronchiectasis on CT scan increased over time in patients with primary antibody syndrome on IgG replacement therapy.^{300 313} The prevalence of bronchiectasis increased from 47.3% to 54.7% in CVID patients and from 33% to 39% in XLA patients over 5 years.³⁰⁰

Evidence statements

Cohort studies and randomised trials of high versus low-dose immunoglobulin replacement therapy in patients with CVID and XLA show a significant reduction in the rate of serious infections including pneumonia. (2++)

IgG replacement therapy may be useful in patients with minor antibody deficiency syndromes (specific polysaccharide antibody deficiency and/or (IgA or IgG subclass) deficiencies with absent/impaired pneumococcal antibodies vaccine responses) who continue to have objective evidence of bacterial sino-pulmonary infection and progressive disease despite appropriate management of bronchiectasis by a respiratory physician and physiotherapist. (2+)

There is no definite data to suggest that IgG replacement therapy prevents onset of bronchiectasis, or delays progression in bronchiectasis. (2+)

Recommendations

• Offer IgG therapy to all patients with CVID and XLA. (B)

• Consider IgG therapy for patients with specific polysaccharide antibody deficiency and/or IgA deficiency or IgG subclass deficiencies with absent/impaired pneumococcal vaccine antibody responses who continue to have objective evidence of bacterial sino-pulmonary infection and progressive disease despite appropriate management of bronchiectasis. (C)

Good practice points

• All patients receiving IgG replacement therapy should be under the joint care of a clinical immunologist and respiratory specialist in bronchiectasis.

• Offer patients receiving replacement IgG the choice of hospital or home-based therapy.

Research recommendation

Randomised controlled trials are needed to assess which patients with bronchiectasis would benefit from long term Immunoglobulin G replacement therapy alone or as an adjunct to long term antibiotic therapy- assessing the optimal dose of IgG replacement and identification of ideal trough IgG level to prevent recurrent infections.

Gastro-oesophageal reflux disease (GORD) and Bronchiectasis

There is an association between gastro-oesophageal reflux disease (GORD) and bronchiectasis. An increased prevalence of proximal and distal GORD (40%) was demonstrated by oesophageal monitoring in a cohort of 27 patients with bronchiectasis compared with controls. This finding was not confined to those with severe lung disease, and the detection of pepsin within sputum in this study did not correlate with the finding of GORD.³¹⁴

Increased severity of bronchiectasis has been observed in patients with significant reflux symptoms. In a cohort study of 163 patients with bronchiectasis, those with reflux symptoms according to the Hull Airways Reflux Questionnaire had a significantly lower FEV₁ and a greater number of lobes affected by bronchiectasis on CT scan. There was higher inflammation in sputum and increased chronic colonisation with PPMs. Symptoms of reflux were independently associated with cough severity and exacerbation frequency.⁹⁸ In another study of 100 patients with bronchiectasis, those patients with upper gastrointestinal symptoms also had a greater number of lobes affected and significantly worse lung function.³¹⁵

A possible relationship between H. pylori and bronchiectasis symptoms has been described.³¹⁴ Some studies of H. pylori serology have shown higher levels in bronchiectasis patients compared with control populations. In one study of 100 patients with bronchiectasis measuring specific IgG to H. pylori, seroprevalence was 76% compared with 54.3% of controls. Further analysis showed that those bronchiectasis patients who were defined as sputum producers had significantly higher H. pylori seroprevalence (83.1%) than those defined as non-producers (58.6%). Multiple regression analysis showed an association between H. pylori IgG concentrations (continuous values) and sputum volume and age. Lung function however did not correlate with H. pylori serology in this regression model.³¹⁶ A further cohort study of 40 patients with bronchiectasis showed H.pylori seropositivity in 75% of patients with bronchiectasis in comparison to 51.5% of healthy control subjects, but there were no significant differences in gastrointestinal symptoms between patients and controls.³¹⁷ On the other hand Angrill et al failed to find differences in H. pylori seropositivity between bronchiectasis patients and the general population, and studies of bronchial mucosal specimens taken from patients with bronchiectasis did not demonstrate the presence of H. pylori.³¹⁸

Evidence statement

GORD is common in patients with bronchiectasis and is associated with increased severity of bronchiectasis suggesting a causal relationship (level 2-).

There is a possible association between H. pylori seropositivity and bronchiectasis (2-)

Recommendation

• Treat GORD symptoms in patients with bronchiectasis according to existing NICE guidance³¹⁹. (D)

Good practice points

• GORD should be considered in patients with hiatus hernia, persistent coliforms in sputum samples or recurrent exacerbations with no other cause identified.

• Investigate patients who may have gastro-oesophageal reflux according to local policies.

• Consider the addition of prokinetic agents if symptoms of GORD increase with an airway clearance technique in sitting position. Avoid eating in the hour immediately prior to physiotherapy.

What is the prevalence of rhinosinusitis in patients with stable bronchiectasis and what are the outcomes of treatment?

Chronic rhinosinusitis is defined as persistent upper airway symptoms lasting >12 weeks and can be subdivided by the presence or absence of nasal polyps. The diagnosis of rhinosinusitis is predominantly clinical and made on history and examination with only a limited role for radiology.

Symptoms of rhinosinusitis are very commonly reported in patients with bronchiectasis. In a UK study, 65% of bronchiectasis patients had symptoms of rhinosinusitis (n=95). This was most common in patients with idiopathic disease, affecting 84% of patients.²³ In a study of 101 patients with bronchiectasis in Australia, 72% reported symptoms of rhinosinusitis.¹⁵

Among patients with upper airway symptoms, Guillemany et al reported that 41.6% had nasal polyps.³²⁰ In an unselected bronchiectasis population from Spain (n=91), 80.2% of stable bronchiectasis patients had rhinosinusitis according to EP30S criteria, and 26.4% had nasal polyps.³²¹ Patients with rhinosinusitis may have worse quality of life and worse radiological bronchiectasis than those without rhinosinusitis.^{322 323}

Chronic rhinosinusitis (CRS) can be a feature of idiopathic bronchiectasis, but patients with bronchiectasis and rhinosinusitis should undergo a comprehensive assessment for underlying aetiology as for all patients. Chronic infective rhinosinusitis can be a feature of primary ciliary dyskinesia along with middle ear infections and infertility.

There are no specific randomised controlled trials to guide the management of rhinosinusitis in bronchiectasis. In addition, there is no evidence to demonstrate that treatment of rhinosinusitis will improve respiratory outcomes, such as exacerbation frequency, in bronchiectasis.

In a high proportion of cases, response to treatment for chronic rhinosinusitis is partial and treatments need to be continued over medium to long term. Typical symptoms of nasal polyps include nasal obstruction, hyposmia/anosmia and decreased taste and post-nasal catarrh.

In the absence of specific recommendations and outcome data in bronchiectasis it seems reasonable to follow existing algorithms for the treatment of chronic rhinosinusitis, such as that provided by the European position paper on rhinosinusitis and nasal polyps or the British Society of Allergy and Clinical immunology guidelines.^{324 325}

Nasal irrigation with 0.9% saline is safe, inexpensive and widely used and has been shown to reduce symptoms of CRS, including in patients with CRS and PCD.³²⁶ Topic intranasal steroids are the other first line treatment to suppress inflammation in CRS.³²⁶ Nasal drops are preferred. Fluticasone and mometasone have the lowest bioavailability and as such as used in preference.³²⁷ Macrolides have evidence in the management in chronic rhinosinusitis but are not regarded as first line therapy.³²⁸

A proposed algorithm for initial assessment and treatment is shown in figure 5.

• Download figure
• Open in new tab
• Download powerpoint

Figure 5

Algorithm for initial assessment and treatment - rhinosinusitis.

Sinus CT’s are rarely helpful and reserved for patients failing medical therapy or those with features suggesting alternative diagnoses such as blood stained discharge, displaced globe or severe pain.³²⁶

The box above identifies a series of symptoms that indicate an alternative diagnosis, such as orbital symptoms (periorbital oedema, displaced globe, diplopia, ophthalmopegia or reduced visual acuity) severe pain and neurological symptoms. Facial pain without nasal symptoms is rarely due to rhinosinusitis.³²⁶

Evidence statements

Chronic rhinosinusitis is common in bronchiectasis and may contribute to impaired quality of life. (2+)

Recommendations

• The evaluation of patients with bronchiectasis should include assessment of symptoms of chronic rhinosinusitis. (D)

• Patients with bronchiectasis and symptoms of rhinosinusitis should be evaluated and treated according to existing evidence-based treatment pathways. (D)

Should treatment of bronchiectasis be altered in the presence of co-morbidities?

There are no studies addressing treatment of bronchiectasis in the presence of asthma and atopy although an accumulation of clinical experience suggests that these factors need to be addressed for good control of bronchiectasis to be achieved.³²⁹ In the presence of this co-morbidity, there is a risk of poor clearance of sputum due to bronchospasm, greater mucus secretion and endobronchial inflammation, all of which is likely to lead to reduction in lung function and poor control of infections.

Several studies have shown a higher than expected prevalence of bronchiectasis in patients with COPD and these patients probably have a worse prognosis than bronchiectasis without COPD; however there is an acknowledged lack of evidence as to implications for treatment.^{255 269 330–332}

Patients with HIV-related disease appear to be at greater risk of bronchiectasis than the general population but management implications were not discussed in the studies reviewed.^{333 334}

Inflammatory bowel disease

The majority of studies are undermined by low numbers, which may reflect the relatively small population of patients with bronchiectasis whose condition is associated with inflammatory bowel disease (IBD) (see online appendix 6 <1%–3%)^{23 62} Kelly et al studied 10 patients (time period not stated)⁵⁹ and Mahadeva et al identified 17 patients over a 14 year period with coexistent IBD and pulmonary disease.⁶⁰ Bronchiectasis appeared to be the most common feature although other abnormalities were seen on CT scan. In some cases a biopsy revealed evidence of lymphocytic inflammation⁵⁹ and a useful clinical response to oral or inhaled corticosteroids was observed.⁶⁰ The nature of the steroid treatment and its outcome were not described in detail although alveolitis and bronchiolitis were reported to resolve fully.⁶⁰

The overlap of IBD and bronchiectasis was comprehensively reviewed in a European Respiratory Monograph in 2011, again with an emphasis on corticosteroid responsiveness although the lack of evidence was acknowledged.³³⁵

Rheumatoid arthritis

In a study of the effects of immunosuppression, 37 patients with rheumatic diseases (and nine with IBD) were identified in a database of 539 patients with bronchiectasis: 26 had rheumatoid arthritis (RA).³³⁶ The majority developed bronchiectasis after the onset of autoimmune disease. All had received either conventional disease modifying anti-rheumatic drugs (DMARDs) - mostly methotrexate - or biologics. Methotrexate in particular was associated with a range of adverse effects. Patients with RA or IBD were not found to suffer more exacerbations than patients with bronchiectasis alone, and the frequency of colonising organisms such as P. aeruginosa and H. influenzae was similar. Longitudinal data were available for a small cohort of patients with RA and bronchiectasis. In these patients, control of RA disease activity appeared to track with spirometry, in that spirometry declined when the DAS score rose, and vice versa. DMARDs did appear to be associated with increased pneumonia and other infections.

The risk of infection in patients using DMARDs or biologics was assessed in a cohort of >3000 patients, of whom 86 had both a rheumatological disease and bronchiectasis.³³⁷ Sufficient data was available on only 47 patients receiving DMARDs or biologics. Of 40 patients with RA and bronchiectasis, 35 were seropositive. 13 had bronchiectasis prior to RA, 27 were diagnosed with bronchiectasis after the onset of RA but it was attributed directly to RA only in 13 cases, otherwise the aetiology was thought to be childhood infection. An OR of 8.7 (95% CI 1.7 to 43.4) was found for respiratory infections in patients treated with biologics compared with traditional DMARDs. The OR for infections was 7.4 (2.0–26.8) in the presence of previous sputum colonisation by potentially pathogenic micro-organisms. The authors therefore recommended using non-biologics in preference to biologics if possible. Etanercept and rituximab were associated with a lower rate of infections than the other biologics, but the numbers were very small in this study.

Evidence statements

Patients with bronchiectasis and comorbid COPD have more severe disease and worse prognosis than those with bronchiectasis alone. (2+)

Patients with co-morbid rheumatoid arthritis and bronchiectasis may have worse outcome than those with either disease alone. (3)

Immunosuppressive treatment for connective tissue disorders is associated with a higher risk of infection in general; biologics may promote infections more than traditional DMARDs, and the risk may be higher in patients already colonised with potentially pathogenic micro-organisms. (3)

Inflammatory bowel disease-related bronchiectasis may be responsive to corticosteroids. (3)

Recommendations

• Consider a trial of inhaled and/or oral corticosteroids in patients with bronchiectasis and IBD. (D)

• Ensure optimal control of asthma and allergies in patients with both bronchiectasis and asthma (D).

• Monitor patients with co-morbid COPD and bronchiectasis as they are at higher risk of death. (D)

• Patients with bronchiectasis and autoimmune conditions should be carefully assessed for autoimmune related lung disease and often require long term follow-up in a secondary care setting. (D)

• Patients with bronchiectasis who require DMARDs or biologics for rheumatoid arthritis should be referred to a chest physician for further assessment before treatment is started. (D)

How should we monitor bronchiectasis?

There are no studies in bronchiectasis comparing different monitoring schedules, or relating particular monitoring strategies to clinical outcomes. Factors associated with increased risk of exacerbations, hospitalisations and mortality in bronchiectasis include age, body mass index, past history of exacerbations and or hospitalisations, persistent infection, especially with P. aeruginosa, dyspnoea as measured on the MRC scale, radiological extent of disease and airflow limitation (FEV₁) (see tables 6 and 7). These components have recently been operationalised into two multi-component scores BSI¹²⁰ and FACED.¹¹⁹ Recently a comparative analysis has suggested BSI has greater sensitivity in predicting those at risk of future risk of exacerbations.¹²¹ In addition, co-morbidities such as COPD and rheumatoid arthritis have also been shown to affect mortality and therefore should be recorded.^{269 338} The role of the bronchiectasis aetiology and comorbidity index (BACI) in routine practice is yet to be determined.³³⁸

It seems reasonable to propose that routine monitoring should include reassessment of the variables above that have been shown to be relevant in bronchiectasis. In addition patient monitoring should include assessment of symptoms and the impact that these have on health status. This may be best achieved using a validated tool, of which there are many,³³⁹ including tools specifically for bronchiectasis such as the QOL-B.³⁴⁰ Systematic review has demonstrated that these tools may assess components of health status in bronchiectasis not measured using other outcomes.³³⁹ Routine monitoring of quality of life may not be needed in all cases but should be considered when higher cost interventions are planned. The optimal tool for monitoring treatment effects has however yet to be determined in bronchiectasis. As in other respiratory disease, exercise capacity can be assessed using 6MWD or ISWT and even small changes in these measures may reflect important changes in health.²²¹

The BTS Quality Standards for clinically significant bronchiectasis in adults 2012,³⁴¹ based on the 2010 BTS guideline for non-CF bronchiectasis, suggested that patients fulfilling the following criteria should continue to receive specialist input in secondary or specialist care. The guideline development group advise using the following criteria:

1. patients with chronic P. aeruginosa, non-tuberculous mycobacteria or methicillin-resistant S. aureus colonisation (MRSA);

2. deteriorating bronchiectasis with declining lung function;

3. recurrent exacerbations (≥3 per year);

4. patients receiving long term antibiotic therapy (oral, inhaled or nebulised);

5. patients with bronchiectasis and associated rheumatoid arthritis, immune deficiency, inflammatory bowel disease and primary ciliary dyskinesia;

6. patients with allergic bronchopulmonary aspergillosis;

7. patients with advanced disease and those considering transplantation.

Evidence statement

Variables exist which affect outcome in bronchiectasis and such variables can be monitored over time.^{119 120} (1+)

No studies have however measured the impact of such monitoring, or demonstrated that action taken in response to changes in measured variables will affect outcome.

Recommendation

• All patients with bronchiectasis should undergo routine monitoring in order to identify disease progression, pathogen emergence and modify treatment where necessary. (D)

Good practice points

• Tailor the frequency of routine monitoring to the patient’s disease severity (see table 7).

• Assess patients annually, and more frequently in more severe disease.

• Perform pulse oximetry to screen for patients who may need blood gas analysis to detect respiratory failure.

• A baseline CXR may provide a useful comparator in the event of clinical deterioration.

Is there a role for microbiological sensitivity testing?

Evidence statements

There is no evidence to show that antibiotic treatment guided by sensitivity results improves clinical outcomes for patients.⁴

Acute antibiotic treatment only occasionally results in the development of resistance. (1-)

Long-term macrolide use results in the emergence of macrolide resistance. (1-)

Good practice points

• Antibiotic sensitivity testing can be used to determine if resistance develops to either acute or long-term antibiotic treatment.

• Where possible, treatment should be guided by antibiotic sensitivity results but is often empirical based on previous sputum bacteriology.

• Some patients with an infective exacerbation may respond to antibiotic treatment despite resistance to that drug in vitro. Antibiotics should only be changed if there is no clinical response.

• For those on long term antibiotic treatment, there should be repeat sensitivity testing where there is a clinical concern regarding loss of efficacy with therapy.

Is there any evidence of cross-infection with pathogenic organisms (conventional bacteria and environmental mycobacteria)?

While there are numerous studies confirming the transmissibility of certain epidemic strains of P. aeruginosa and more recently Mycobacterium abscessus (M. abscessus) in cystic fibrosis (CF) there are few studies assessing the potential for cross-infection in bronchiectasis.^{346 347} The available studies of cross infection in bronchiectasis are mostly single centre design, often focus on P. aeruginosa, and have relatively limited longitudinal sampling with often limited description of the clinical setting.^{348 349} This latter aspect may be particularly important if facilities are shared with patients who have CF and carry known CF epidemic strains.

De Soyza et al reported a case series of 40 patients from a single adult bronchiectasis clinic in Newcastle, UK, not practising strict segregation but with reported limited sharing of facilities with CF patients.³⁴⁸ The study focused on P. aeruginosa. It was a predominantly cross- sectional design although it reported longitudinal follow-up of 10 patients for up to 4 years. Their data suggested no single common ‘epidemic strain’ was found. They identified however that certain common strains that are found widely within the natural environment for example, Pseudomonas Clone C can be found in patients attending bronchiectasis clinics. This raises the potential for environmental acquisition in the bronchiectasis population.

Pujana et al similarly used a single centre, short-term study using bacterial fingerprinting using a PCR approach.³⁴⁹ In this study of 16 patients with bronchiectasis from Bilbao, Spain, 64 P.aeruginosa isolates were examined. Cross-infection or common source acquisition did not appear to have occurred. A study of 125 isolates taken from 31 patients attending two clinics in Spain using pulsed field gel electrophoresis suggested certain strains may be predominant within a clinic.³⁵⁰

Two papers which have used the higher resolution of whole genome sequencing (WGS) have raised the possibility of cross infection. A summary of studies to date would support the conclusion that significant cross infection with P. aeruginosa has not been identified, but longitudinal studies are needed.^{351 352}

One study has suggested potentially similar clones of Mycobacterium avium (M. avium) are present in patients with chronic lung disease.³⁵³ The study included some patients with bronchiectasis though confirming the exact number was not possible. The study aims were primarily to compare the benefits of VNTR fingerprinting over PFGE, the present ‘gold standard’ to allow a worldwide database. This aim was achieved. The authors noted different patients’ isolates had the same VNTR types and these were mostly clonal by PFGE suggesting that clonal groups do exist with M. intracellulare. Despite this evidence, the authors provided no evidence or discussion on the question of transmission of M. avium. There are therefore inadequate data to provide a definitive statement on the risk of M. avium transmission in bronchiectasis. There are no extensive data on M. abscessus infection in bronchiectasis but this is a rapidly changing field.

Evidence statements

There is no evidence of transmissibility of epidemic P. aeruginosa in the available cohort studies. (2-)

There is no evidence of transmissibility of M. avium in the available cohort studies. (2-)

Recommendation

• Individual or cohort segregation based on respiratory tract microbiology results is not routinely required for patients with bronchiectasis. (D)

Good practice points

• Good cross infection prevention principles should be applied: seek advice on local policies.

• The transmissibility of P. aeruginosa in cystic fibrosis appears more common. In the case of shared facilities with cystic fibrosis patients the cross infection guidelines for cystic fibrosis should prevail.

Research recommendation

Large scale robust data that confirm or refute the transmissibility of key pathogens such as P. aeruginosa and non-tuberculous mycobacteria are needed.

Specialist vs non-specialist setting

There are no studies available describing differences in outcome for patients with bronchiectasis in specialist compared with non-specialist care settings. The consensus team (expert opinion) suggest there may be benefits to patients by attending a specialist clinic for bronchiectasis as this will facilitate access to appropriate diagnostic and management expertise through a multidisciplinary team (for example Respiratory Nurse Specialists, Pharmacists, Consultants with a special interest in bronchiectasis, Immunology Consultants, Respiratory Radiologists, Dieticians and Psychologists). This may be most relevant to patients with severe or complex disease.

Good practice point

• Specialist clinics should be considered in patients requiring hospital follow-up.

What are the complications of bronchiectasis?

Complications of bronchiectasis may have changed over the years. Haemoptysis and thoracic infections have always been important, but finger clubbing and metastatic infection such as cerebral abscesses are now rare.^{15 354}

Chronic respiratory failure

Most patients with bronchiectasis have some degree of lung function impairment, but lung function decline over time was only slightly greater than normal in a follow-up study of patients in Edinburgh.³⁵⁵ Lung function was shown to be capable of improvement as well as decline in a UK study focusing on potential impact of P. aeruginosa colonisation in patients with bronchiectasis.²⁷⁴ An Australian study linked risk of decline with higher volume of daily sputum at baseline.¹⁵

A recent analysis of patients recorded on the EMBARC European bronchiectasis database revealed that 86 of 1145 (7.5%) patients were using long term oxygen therapy for chronic respiratory failure. ³⁵⁶

Haemoptysis

A series at the Mayo Clinic from 1976 to 1993 identified 3421 patients seen for bronchiectasis, of whom 134 patients underwent pulmonary resection.³⁵⁷ Haemoptysis was present in 63 of the lung resection group, and was the indication for surgery in 26 (19.4%). The frequency of haemoptysis in medically managed patients was not given.

One study from Korea has suggested that use of inhalers may increase the risk of haemoptysis³⁵⁸.

The degree of haemoptysis can vary widely. Streaks of haemoptysis can be seen with chest infections and sometimes in stable patients with severe bronchiectasis who are treated with anti-platelet therapy or anti-coagulant therapy for comorbid conditions.

The volume of blood defining major haemoptysis is not known, with no internationally agreed definition.

Good practice point

• If haemoptysis 10 mls or less over a 24 hour period, treat with an appropriate oral antibiotic. If clinical deterioration, arrange emergency admission to hospital.

• Management of major haemoptysis should be multidisciplinary with involvement of respiratory physicians, interventional radiology and thoracic surgeons. Empirically treat patients with intravenous antibiotic therapy, based on their known microbiology, and consider adjunct treatment with tranexamic acid. Bronchial artery embolisation is the recommended first line treatment if significant haemoptysis persists.

Chest pain

Chest pain is reported in studies of symptoms of bronchiectasis, but not often well described. King et al prospectively assessed chest pain experienced by 1787 patients with bronchiectasis over a 8 year follow-up period at the Monash Medical Centre.³⁵⁹ A careful assessment of the nature of the pain was made to test the hypothesis of visceral pain sensation related to bronchial inflammation. This bronchiectasis population was comparable to the UK population, except that a smaller proportion in Monash (43/178) were taking inhaled corticosteroids than is suggested by the results of previous UK BTS bronchiectasis audits.^{166 360} 44 of the patients reported chest pain, and for 39 of these, the pain was associated with exacerbations. Only four had clear pleuritic pain, and 37 had other types of pain, with two having both pleuritic and other pain. The pain did appear to co-localise with the position of bronchiectasis on CT scan. It did not appear musculoskeletal related to coughing and was not associated with chest wall tenderness. It tended to occur early in the course of an exacerbation, and subside only towards the end of the recovery period. In 18 out of 33 patients who had imaging at the time of an exacerbation associated with chest pain, there were abnormalities such as consolidation, collapse or atelectasis. Only 13 subjects reported retrosternal discomfort associated with visceral airway pain receptors.

Lung cancer

A case series of post mortem specimens of 20 smokers and ex-smokers with peripheral nodular carcinoma of the lung showed that in 16 out of 20 cases the neoplasia arose out of clusters of non-segmental bronchiectasis.³⁶¹ A database study of 57 576 patients hospitalised with bronchiectasis between 1998 and 2010 in Taiwan showed an increased risk of lung cancer compared with a cohort of 2 30 304 patients without bronchiectasis, adjusted for age, sex and comorbidities (adjusted HR=2.36, 95%CI=2.19 to 2.35).³⁶² Conversely a case-control study in South Korea of patients with moderate to severe COPD and lung cancer found that bronchiectasis was less prevalent in the patients with lung cancer than in matched controls without lung cancer (OR 0.25, 95% CI 0.12 to 0.52), suggesting that the disease process in bronchiectasis may not increase the risk of lung cancer.³⁶³

Vascular complications

In a primary care database study, the rate of first coronary heart disease (CHD) and stroke were higher in people with bronchiectasis (HR for CHD 1.44 (95% CI 1.27 to 1.63) and HR for stroke 1.71 (95% CI 1.54 to 1.90)).³⁶⁴

Bronchiectasis severity (moderate or worse) has been shown to be an independent risk factor for vascular disease,³⁶⁵ with recurrent exacerbations (three or more per year) showing increased aortic stiffness.³⁶⁶

A retrospective UK study examined the CT scans of 91 patients with bronchiectasis previously recruited for a quality of life study, and inferred the presence of pulmonary hypertension from measurement of the pulmonary arteriesand found there was an increased risk of death (HR, 1.24; 95% CI, 1.13 to 1.35; P<0.0001) in the presence of pulmonary hypertension in this study.³⁶⁷

Severe pulmonary hypertension was found in 12 patients from a prospective cross sectional study in Saudi Arabia of 94 patients with bronchiectasis but no known cardiac disease or cardiac risk factors, all with cystic bronchiectasis. Poorer ventilatory function was associated with increased risk of pulmonary hypertension.³⁶⁸

Other

In patients with bronchiectasis, depression and anxiety do occur at higher rates than in the healthy population.^369–371 In a British study, there was a link between depression and exercise limitation due to breathlessness.³⁶⁹ In a Spanish study, using the Beck Depression Inventory and the State-Trait Anxiety Inventory, 34% of patients had depression, 58.1% were above the 50^th percentile for state anxiety and 56.8% were above the 50% percentile for trait anxiety. 30% of patients had both anxiety and depression. Anxiety showed some correlation with sputum volume and bacterial colonisation, particularly P. aeruginosa, while depression appeared more common in women.³⁷² A Korean study did not identify a link between mood disorders and specific clinical features of bronchiectasis.³⁷¹

An important finding from an uncontrolled cross sectional study of 76 women attending a specialist bronchiectasis clinic in Newcastle-upon-Tyne was that 55% of women had symptoms of urinary incontinence.³⁷³

A study of systemic comorbidities included assessment of bone mineral density, which was not significantly different in patients with bronchiectasis and healthy controls matched for age, sex and smoking status.³⁷⁴

Corticosteroid responses in patients with bronchiectasis, of whom a high proportion were taking inhaled fluticasone, were found to be impaired in a cross-sectional analysis.¹⁷⁶ Inhaled fluticasone treatment appeared to double the risk. Adrenal insufficiency was associated with poorer quality of life. This issue was addressed more fully in a case-control study of subjects with bronchiectasis and age- and sex-matched healthy controls, who were all subjected to low dose short synacthen tests.³⁷⁵ One patient with post-tuberculous bronchiectasis had absolute adrenal insufficiency and was treated with steroid replacement. In 38 patients with a valid baseline result, 15 had an impaired response to one microgram cosyntropin. The response was significantly better in controls, and was not affected by maintenance treatment with budesonide.

Nutritional deficiency has been noted incidentally in various studies³⁷⁶ and was studied specifically by Olveira et al, but this study included both CF and non-CF bronchiectasis, which limits its applicability to this guideline.³⁷⁷

Fatigue and reduced exercise tolerance are commonly reported in bronchiectasis. In a UK study of 117 consecutive patients, routine clinical assessment included lung function, MRC dyspnoea score, sputum microbiology and an assessment of fatigue on the fatigue impact scale (FIS).³⁷⁸ Significant fatigue was found in 45% and was positively correlated with the MRC score (r=0.57, P<0.001) and negatively correlated with FEV₁ % predicted (r=−0.30, P=0.001). An Australian study identified fatigue in 74% of 103 patients with bronchiectasis.³⁷⁹

Summary of research recommendations

See appendix 8 for details of the research recommendations in PICO format.

Consensus criteria for diagnosis of ABPA need to be validated in bronchiectasis cohorts.

Consensus criteria for definition of abnormal post pneumococcal test immunisation antibody responses need to be validated in bronchiectasis cohorts.

Randomised controlled trials using clinically important outcome measures are required to assess the effectiveness of airway clearance techniques in varying severities of bronchiectasis.

Randomised controlled trials are required to evaluate the effects of airway clearance techniques in patients who are undergoing an exacerbation.

Randomised controlled trials are needed to assess the long term impact of muco-active therapies.

Randomised controlled trials are needed to assess the long term impact of anti-inflammatory therapies.

Long term randomised controlled trials of oral and inhaled antibiotics are needed to assess their efficacy and safety in patients with bronchiectasis who have frequent respiratory tract infections with recurrent P. aeruginosa infection or other potential pathogenic micro-organisms.

Further interventional/randomised controlled trials needed to establish the role of any alternative therapies in the management of bronchiectasis.

Studies assessing the benefits of nutritional supplementation in patients with bronchiectasis should be undertaken.

The role of education, self management plans and who delivers the pulmonary rehabilitation needs to be explored.

The role of pulmonary rehabilitation after exacerbations requiring hospital admission needs to be explored.

The incidence of cross-infection of respiratory pathogens in the group exercise setting should be investigated in the bronchiectasis population.

A randomised control trial of P. aeruginosa eradication therapy is needed to determine the microbiological and clinical outcomes of eradication therapy.

Randomised controlled trials are needed to assess which patients with bronchiectasis would benefit from long term Immunoglobulin G replacement therapy alone or as an adjunct to long term antibiotic therapy- assessing the optimal dose of IgG replacement and identification of ideal trough IgG level to prevent recurrent infections.

Large scale robust data that confirm or refute the transmissibility of key pathogens such as P. aeruginosa and non-tuberculous mycobacteria are needed.