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Division of Pulmonary, Critical Care and Sleep Medicine, New York University Grossman School of Medicine, 462 First Avenue, Administration Building OBV, A601, New York, NY, 10016, USA
Division of Pulmonary, Critical Care and Sleep Medicine, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT, 06030-1321, USA
Bronchiectasis (BE) is increasing in prevalence but clinical guidelines are limited.
•
Few established standards of care exist for BE based on high-quality evidence.
•
Guidance for airway clearance and appropriate antimicrobial use is lacking.
•
Clinical trials with more accurate inclusion criteria and relevant endpoints are needed for improved BE management.
•
New assessment frameworks/evidence-based treatment recommendations are required.
Abstract
Bronchiectasis (BE) is a chronic condition characterized by airway dilation as a consequence of a variety of pathogenic processes. It is often associated with persistent airway infection and an inflammatory response resulting in cough productive of purulent sputum, which has an adverse impact on quality of life. The prevalence of BE is increasing worldwide. Treatment guidelines exist for managing BE, but they are generally informed by a paucity of high-quality evidence. This review presents the findings of a scientific advisory board of experts held in the United States in November 2020. The main focus of the meeting was to identify unmet needs in BE and propose ways to identify research priorities for the management of BE, with a view to developing evidence-based treatment recommendations. Key issues identified include diagnosis, patient evaluation, promoting airway clearance and appropriate use of antimicrobials. Unmet needs include effective pharmacological agents to promote airway clearance and reduce inflammation, control of chronic infection, clinical endpoints to be used in the design of BE clinical trials, and more accurate classification of patients using phenotypes and endotypes to better guide treatment decisions and improve outcomes.
Bronchiectasis (BE) is a chronic condition characterized by irreversible airway dilation resulting from injury to the bronchial walls. BE incidence and prevalence are increasing globally [
Characteristics and health-care utilization history of patients with bronchiectasis in US Medicare enrollees with prescription drug plans, 2006 to 2014.
]. The actual prevalence of BE is likely to be greater, as there is a lack of universal screening and uncertainty about which is the predominant condition in patients with comorbid chronic obstructive pulmonary disease (COPD) [
The hallmark symptoms described by patients include cough and sputum production; however, there is considerable individual heterogeneity in the symptomatology and disease severity. Some patients are asymptomatic, while others experience daily symptoms and frequent pulmonary exacerbations (PEx, defined later in the text) [
]. For those patients, the impact of BE can be considerable. BE is estimated to have a health-related quality of life (HRQoL) and economic burden similar to that of COPD, and mortality rates are as high as 30% following severe PEx [
]. CF is the approved indication for several therapies and CF transmembrane conductance regulator (CFTR) modulators are now available for the treatment of patients with CF whose specific genetic mutations are responsive [
]. Despite – or possibly because of – the lack of approved therapies, there are no US-specific guidelines for managing BE. The exception is BE related to CF where there are numerous US guidelines [
US cystic fibrosis foundation, European cystic fibrosis society, US cystic fibrosis foundation and European cystic fibrosis society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis.
], but these may not be applicable for patients with BE due to other etiologies. There are guidelines for the management of BE in other countries and regions, including in the UK [
To help address these issues, an advisory board of experts was convened in the US in November 2020 with the goal of identifying the unmet needs in BE. A systematic review was not performed as part of this exercise as there were existing published reviews. Literature was made available to the panel as requested and consensus was derived regarding diagnostic and therapeutic questions. This manuscript is intended to relate the findings of the advisory panel and to propose research priorities to improve the evidence base for management of BE that best reflects the complexity of this condition.
2. Pathophysiology of bronchiectasis
The complex nature of BE has been the subject of much research in recent years, with attempts to classify it according to underlying etiology (endotype), clinical features (phenotype) or multidimensional approaches, such as the treatable traits concept [
], this may merely indicate that a specific etiology has yet to be identified. The pathogenesis of BE is thought to be multifactorial, and a useful model of pathogenesis addresses the key consequences of airways disease (i.e. inflammation, infection, and abnormal airway mucociliary clearance) [
], but as these factors influence and exacerbate each other, the pathogenic process is perhaps better described as a ‘vortex’ contributing to disease progression and airway injury [
]. BE is a common manifestation of many immune disorders, and has been associated with autoimmune diseases, in particular rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) [
]. BE can also be associated with inflammatory airways diseases, including advanced asthma, COPD and allergic bronchopulmonary aspergillosis (ABPA). Recent research has also examined various inflammatory markers and their association with BE disease heterogeneity, describing three main categories of inflammation in BE: eosinophilic and epithelial inflammation; systemic inflammation; and airway neutrophilic inflammation. It is likely these categories of inflammation represent different treatable traits that could be targeted with individualized treatment [
Another common feature in BE is the persistence of opportunistic pathogens in the airways. Bacteria (e.g. Pseudomonas aeruginosa, Haemophilus influenzae), fungi (e.g. Candida, Aspergillus) and mycobacteria (e.g. Mycobacterium avium complex) are commonly found in cultures of respiratory specimens. The role that these pathogens play in the cause of BE is unclear [
]. What is evident, however, is that the persistence of pathogens in the airways is associated with symptomatic consequences and is thought to contribute to progression of disease.
Mucociliary clearance can be impaired in patients with BE [
]. The inability to effectively clear mucus leads to bacterial infection and further inflammation. The effectiveness of mucociliary clearance depends on ciliary beating and also on the quantity and characteristics of respiratory secretions. Such secretions in patients with BE have been shown to have properties (increased adhesiveness and purulence) that cause impaired mucociliary transport [
Describing phenotypes has become important in identifying patients who may be more responsive to specific treatments. To qualify as a phenotype, a characteristic or group of characteristics should be measurable, consistent over time and linked to clinically relevant outcomes [
]. Patients with P. aeruginosa infection have a three times greater rate of mortality, a marked increase in the risk of hospital admissions and reduced lung function compared to those without P. aeruginosa infection [
]. The presence of nontuberculous mycobacteria (NTM) may also define an important phenotype since it is such a frequent finding; one US study reported a confirmed NTM infection in 37% of patients with non-CF BE who were being investigated because of clinical suspicion of mycobacterial disease [
]. The frequent exacerbator phenotype (i.e. those with at least three PEx per year) is the strongest predictor of patients likely to have future exacerbations. It is also associated with a lower HRQoL, more hospital admissions, and greater mortality rates [
]. Another identified phenotype is dry BE (defined as those with cough but without sputum production), which is associated with lower symptom scores, higher forced expiratory volume (FEV), and less long-term antibiotic treatment but similar mortality rates when compared with patients with BE associated with chronic infection or high sputum production [
]. In addition, advances in interpretation of radiographic images through machine learning have identified objective means of quantifying the extent of disease and increased airway phlegm, which may correlate with disease activity [
]. Further identification of distinct phenotypes should allow greater insight into the characteristics, prognosis and management of BE.
It has been argued that phenotype should not be considered independently from endotype, and thus the concept of treatable traits has also been applied to BE [
]. In this approach, BE is classified into four broad categories (pulmonary, extrapulmonary, behavior/lifestyle and etiological treatable traits), based on the originally proposed airways disease treatable traits concept [
]. These treatable traits may include, but are not limited to, underlying infections, immunodeficiencies, autoimmune conditions (e.g. IBD or connective tissue disease), rhinosinusitis and gastro-esophageal reflux disease (GERD) [
]. However, the treatable traits hypothesis needs to be formally tested in clinical trials in order to prove its feasibility, efficacy and safety in clinical practice [
]. The definition of BE is generally described as an enlargement of the airway, greater than the adjacent artery (e.g. airway to artery ration >1.1), or a lack of tapering of the airway towards the periphery. There is a widely recognized delay to diagnosis for patients with BE [
]. Over 90% of patients with BE present with cough and 75% with sputum, but these symptoms commonly occur in a range of conditions, and it can be difficult for physicians to identify patients who may need a work-up for BE. Defining the characteristics of patients who should undergo low dose chest CT is key to making an earlier diagnosis. Diagnostic clues that a patient may have BE include persistent unexplained cough especially if productive of purulent sputum, recurring bronchitis or infection, hemoptysis, or relentless fatigue of unknown cause [
Following radiographic diagnosis, current guidelines suggest a thorough medical history and a panel of further investigations to identify potential causes or comorbidities, especially if there are disease-specific therapies, as well as to establish other treatable aspects of the individual's condition (e.g. infection) [
]. Guidelines classify investigations as either necessary or discretionary testing in patients with a new diagnosis of BE but there is considerable variance in these recommendations (Table 1) [
Adults aged <50 years or in those with episodes of pancreatitis, bowel obstruction, heat prostration, and in patients with coexisting liver disease or male infertility.
There are >2000 mutations known to occur in CFTR. The guidelines did not recommend specific analyses, but discussion with a local genetic counselor would be advised.
There are guidelines for the diagnosis of PCD [40].
X
X
Pulmonary function
Spirometry
X
X
Lung volumes
X
X
Microbiology
Culture airway secretions, including mycobacteria
X
X
Rheumatologic disease
Rheumatoid factor
X
Antinuclear antibodies
X
Alpha 1 antitrypsin deficiency (in patients with coexisting basal panacinar emphysema)
X
ABPA: allergic bronchopulmonary aspergillosis; BTS: British Thoracic Society; CF: cystic fibrosis; ERS: European Respiratory Society; Ig: immunoglobulin; NTM: nontuberculous mycobacteria; PCD: primary ciliary dyskinesia; TSANZ: Thoracic Society of Australia and New Zealand.
a Minimum recommended investigations.
b Adults aged <50 years or in those with episodes of pancreatitis, bowel obstruction, heat prostration, and in patients with coexisting liver disease or male infertility.
c There are >2000 mutations known to occur in CFTR. The guidelines did not recommend specific analyses, but discussion with a local genetic counselor would be advised.
American thoracic society assembly on pediatrics, diagnosis of primary ciliary dyskinesia, an official American thoracic society clinical practice guideline.
We note that not all radiographically-defined bronchiectasis is clinically relevant, such that not all need therapy. For those who do, current management of BE has three main components: clearance of airway secretions, identifying (when possible) and treating the underlying condition and comorbidities, and (when indicated) treatment of airway pathogens. Because of the heterogeneity of presenting symptoms of BE, the goals of treatment will differ between patients, but often include reducing symptoms, improving HRQoL, preventing PEx and hospital admissions, preserving lung function, and, ultimately, prolonging life [
]. As noted earlier we lack therapies approved specifically for BE, so symptomatic treatment options developed and approved for CF are often implemented in the management of BE complications.
3.2.1 Airway clearance
Although studies that offer evidence of benefit from airway clearance therapies suffer from small sample sizes and limitations of study design, airway clearance therapies are generally accepted as being beneficial [
]. Airway clearance refers specifically to techniques that mobilize and remove abnormal airway material composed of bacteria and inflammatory cells. It is thought that these techniques, in conjunction with aerosol medications, alter the viscoelastic properties of airway phlegm [
]. Training is conducted by respiratory or physical therapists, nurses, or when these are not available, by clinicians themselves. Educational resources (e.g. websites) that were developed by qualified healthcare professionals are available, including videos with instructions on airway clearance techniques for better patient engagement (see the Individual Management of Patient Airway Clearance Therapy [https://impact-be.com/] and the Bronchiectasis Toolbox [https://bronchiectasis.com.au/] websites).
Medications that may help with airway clearance include mucoactive agents and bronchodilators. The European Respiratory Society (ERS) and British Thoracic Society (BTS) guidelines suggest long-term mucoactive treatment (e.g. nebulized hypertonic saline) in adult patients with BE if standard airway clearance techniques alone fail to control symptoms [
]. Dornase alfa is often used to treat bronchiectasis in patients with CF but should be used with caution in those without CF; a previous study demonstrated no clinical benefit and perhaps some harm [
]. Bronchodilators may be beneficial in patients with significant breathlessness, but are not routinely recommended for other patients and may not benefit patients without bronchial reversibility. If bronchodilators are included as one of multiple inhalation therapies, guidelines generally recommend that bronchodilators should be administered first (i.e. prior to other inhaled agents), although this is based on expert opinion and not specific evidence [
3.2.2 Treatment of underlying conditions causing BE and comorbidities
If an underlying cause is identified and treatable, then specific therapy is warranted (Fig. 2). Examples include intravenous immunoglobulin (Ig) replacement in IgG-deficient patients, corticosteroids and/or anti-fungal therapy for ABPA; alpha 1 antitrypsin replacement (if available), optimized anti-inflammatory therapy for patients with autoimmune inflammatory conditions, such as RA or IBD; allergy medications or intranasal steroids for rhinosinusitis; and conservative measures and possible proton pump inhibitors for GERD [
National Institute for Health and Care Excellence Clinical Guideline [CG184]. Gastro-Oesophageal Reflux Disease and Dyspepsia in Adults: Investigation and Management.
Particular care should be made to confirm a diagnosis of asthma or COPD before prescribing inhaled corticosteroids (ICS), as these agents have not shown benefits for patients with BE and some have suggested there is increased risk of harm, perhaps in part by increasing the risk of NTM infection, as well as higher rates of Pseudomonas infection and acute PEx [
Exacerbating conditions, such as viral infections and pneumonia, should be prevented (where possible) through vaccination. Comorbidities that are known to adversely affect outcomes in patients with BE, such as cardiovascular disorders, GERD, psychological illnesses, pulmonary hypertension, cognitive impairment and COPD, should be evaluated and (where possible) treated [
]. Pulmonary rehabilitation, involving appropriate exercise and education, has been shown to improve exercise parameters and respiratory symptoms in patients with BE [
], or more specifically, deterioration in three or more of the following key signs or symptoms for ≥48 h: cough; sputum volume and/or consistency; sputum purulence; breathlessness and/or exercise intolerance; fatigue and/or malaise; and hemoptysis; AND a clinician determines that a change in BE treatment is required [
]. In patients with CF, PEx are associated with a marked reduction in HRQoL, with full recovery of physical functioning and vitality taking several weeks [
]; a substantial portion of patients do not recover pulmonary function after an exacerbation. A prospective observational study of subjects with BE (but not CF) assessing lung function, symptoms and inflammation revealed a similar long recovery time for patient-reported symptoms after PEx [
]. This is consistent with clinical experience and is explained by the fact that PEx are systemic events that require time to resolve.
The severity of PEx is difficult to quantify; hospitalization has often been used as a marker of severity; however, there may be many reasons for hospitalization and not all may imply a more severe event. Both frequency of PEx and hospitalizations are reflected in the Bronchiectasis Severity Index (BSI), which has been validated to predict long-term prognosis [
Persistent infection is a common feature in BE, so it is important to perform surveillance cultures for bacteria, fungi and mycobacteria. The presence of pathogens does not always mandate treatment, but knowledge of their presence can inform current or future treatment decisions. Antimicrobial treatment can be used for short periods (e.g. treatment of PEx) and, in some cases, chronic long-term suppressive therapy to reduce the risk of PEx [
Short-term antimicrobial treatment is generally reserved for patients with acute PEx and antibiotics should target pathogens known to be present in respiratory cultures [
]. If not known, then coverage of pathogens commonly found in BE, such as P. aeruginosa or H. influenzae, is recommended. Other pathogens that are increasingly reported in BE include Moraxella catarrhalis, Streptococcus pneumoniae, Burkholderia and Stenotrophomonas spp [
]. Susceptibility testing may be useful for guiding treatment decisions, but these results are sometimes viewed with a degree of skepticism; susceptibility testing has not demonstrated to be predictive of clinical outcomes in patients with CF [
Antimicrobial Resistance in Cystic Fibrosis International Working Group, Antimicrobial susceptibility testing (AST) and associated clinical outcomes in individuals with cystic fibrosis: a systematic review.
], but it is unknown if this would be the same for BE unrelated to CF. The ERS guidelines recommend 14 days of antimicrobials for the treatment of acute PEx [
Efficacy of oral amoxicillin-clavulanate or azithromycin for non-severe respiratory exacerbations in children with bronchiectasis (BEST-1): a multicentre, three-arm, double-blind, randomised placebo-controlled trial.
]. Although these studies do not provide sufficient evidence for a specific duration, a study designed to test treatment durations conducted in CF exacerbations appears to support the recommendation for 14 days of antibiotic treatment [
Patients who have frequent PEx may benefit from chronic antimicrobial treatment. The ERS guidelines define frequent PEx as at least three events per year [
]. There is debate as to whether these benefits are the result of an anti-inflammatory effect, as similar benefits have been seen in reducing exacerbations in other conditions (e.g. COPD) [
], or an antimicrobial effect. Macrolide monotherapy should not be prescribed for patients known to have NTM present in respiratory cultures to avoid selection of macrolide-resistant pathogens [
]; efforts should be made to rule out the presence of NTM prior to beginning macrolides and periodically during their chronic use to minimize macrolide resistance. Baseline electrocardiogram should be considered to assess for prolonged QT interval, which may be a contraindication to treatment. Although other oral antimicrobials (e.g. quinolones, sulphonamides or amoxycillin/clavulanic acid), either chronically or in rotation, have been used in patients with frequent PEx, they appear to be less effective than macrolides and there are limited data to support this approach [
Inhaled antibiotics have been approved for the treatment of persistent Pseudomonas infection in patients with CF, with the benefit of increased lung function and a reduction in PEx [
Aztreonam for inhalation solution in patients with non-cystic fibrosis bronchiectasis (AIR-BX1 and AIR-BX2): two randomised double-blind, placebo-controlled phase 3 trials.
Inhaled liposomal ciprofloxacin in patients with non-cystic fibrosis bronchiectasis and chronic lung infection with Pseudomonas aeruginosa (ORBIT-3 and ORBIT-4): two phase 3, randomised controlled trials.
], and therefore, no products are approved for this indication. However, not all data are negative. In a Phase 2, randomized, placebo-controlled trial, an inhaled formulation of colistin significantly prolonged the time to PEx in patients with BE and P. aeruginosa infection who were adherent to therapy, although the difference versus placebo did not reach statistical significance in the intent-to-treat population [
]. In addition, an open-label randomized trial with nebulized gentamicin showed a significant reduction in PEx and improvements in exercise capacity and symptoms (including cough) compared with placebo in patients with non-CF BE [
]. Symptomatic improvements may be mediated by a reduction in the P. aeruginosa density in sputum, which has been noted in several trials with inhaled antibiotics [
Microbiological changes observed over 48 weeks of treatment with inhaled liposomal ciprofloxacin in individuals with non-cystic fibrosis bronchiectasis and chronic Pseudomonas aeruginosa lung infection.
]. Retrospective clinical data have also suggested that inhaled antibiotics are beneficial in some patients, especially those with more frequent PEx, poorer lung function and higher BSI scores [
]. Taken together, these data suggest that despite there being no antibiotics currently approved for treatment, chronic suppressive inhaled antibiotic therapy may represent a novel treatment method in some patients with BE unrelated to CF. Phase 3 studies in patients with BE and chronic P. aeruginosa infection are currently underway (NCT03093974, NCT03460704). Inhaled antibiotics that have been used-off label or are currently under investigation for BE within the United States are shown in Table 2.
Table 2Agents under investigation for bronchiectasis or currently used-off label in the United States.
There are many opportunities to understand the optimal use of antimicrobials in BE including proper selection and dosing, treatment duration, empirical treatment, and over-reliance on antimicrobials instead of airway clearance. In addition, there should be increased knowledge regarding the safety of antimicrobials used with great frequency or long durations (e.g. chronic macrolides, aminoglycosides) [
]. Extrapolation from trials in CF should be avoided since individuals with non-CF BE tend to be older and differ in many other ways. Further research is also needed to compare the efficacy of inhaled versus systemic delivery of antimicrobial therapies [
Although we have described therapies commonly used for the treatment of BE, there is a great need for therapies specific for BE and to define which patients will benefit the most from each therapy. Unanswered questions in relation to the diagnosis, evaluation and treatment of BE, and in clinical trial design are presented in Table 3.
Table 3Unanswered questions in bronchiectasis diagnosis and management.
Area
General questions
Examples of specific questions
Diagnosis
•
Who should undergo HRCT chest?
•What is the prevalence of BE on CT chest imaging performed on patients with persistent cough
•What diagnostic tests should be performed to establish etiology?
•What is the prevalence of airways obstruction on spirometry in patients with BE but without emphysema?
Evaluation
•What are the factors that predict a PEx?
•Does the history of PEx in the previous year predict the number of events in subsequent years?
•What is the value of surveillance microbiology testing?
•What is the incidence and prevalence of bacteria, mycobacteria and fungi in quarterly respiratory cultures in a BE population?
•How often should it be performed?
•What is the value of surveillance imaging?
•What is the progression of disease seen on annual CT chest imaging in a BE population?
•Are there biomarkers that can predict clinical outcomes?
•Does CRP predict PEx in patients with BE?
Treatment
•Who benefits from airway clearance therapies?
•Do symptoms and PEx improve with airway clearance in patients with BE with and without mucus plugging seen on CT chest imaging?
•Who would benefit from other approved therapies?
•Does dornase alfa or hypertonic saline improve symptoms in BE patients with specific findings on CT chest imaging?
•What symptomatic therapies are effective to improve health and prevent PEx?
•Do inhaled antibiotics reduce the occurrence of PEx in BE patients who meet the frequent exacerbator phenotype?
•Do anti-inflammation medications have a role?
•Do inhaled steroids improve clinical outcomes in BE patients who have eosinophilia?
•Which patients would benefit?
•What safety monitoring is appropriate?
•What is the prevalence of hearing loss identified on audiology in BE patients on chronic inhaled aminoglycosides and/or oral macrolides?
Clinical trials
•What are the appropriate clinical endpoints for a trial?
•Can we identify a patient-reported PEx using wearable technology?
•What measures should a composite outcome include?
•How long does it take to have quality of life measures return to baseline after treatment of a PEx?
•Can decline in FEV1 be used to define PEx in BE?
•When is the right time to measure them?
•Does monthly measurement of symptoms identify PEx better than random assessment or relying on patient report only?
•Can a validated symptom score be useful to define exacerbation early?
•When do quality of life measures reach an asymptote during and after treatment of a PEx?
•How best to define inclusion and exclusion criteria for studies?
•Can increased airway wall thickness or other findings by CT chest imaging define patients likely to respond to a treatment in a study of BE?
BE, bronchiectasis; CRP, C-reactive protein; CT, computed tomography; FEV1, forced expiratory volume; HRCT, high resolution computed tomography; PEx, pulmonary exacerbation.
As stated earlier, many patients with BE are not diagnosed until well after symptom onset. It is believed that earlier diagnosis will lead to earlier intervention and could alleviate symptoms, as well as potentially prevent the progression of the disease. Identification of sensitive and specific clinical criteria to prompt radiological testing and education of the primary care community might achieve this goal. Evaluation of the patient to establish the etiology and comorbid factors could be improved with standardized testing recommendations. Moreover, improvements in describing clinical phenotypes would help in the development and use of specific therapies.
4.2 Treatment
Prescription of appropriate therapy should be based upon a careful assessment of the signs and symptoms exhibited by the patient. Most of the known causes of BE do not have specific therapies, underlining the opportunity for therapeutic development for those conditions. It is commonly accepted that airway clearance therapies are basic to the treatment of patients with BE, but the evidence to support use of medications to enhance clearance of sputum are less robust. Some medications, such as hypertonic saline, are proposed as beneficial, but some patients are not able to tolerate it, and other agents, such as dornase alfa, are not recommended based on a previous trial [
]. Research is needed to identify who might benefit (or not) from these medications and which endpoints are needed to accurately ascertain if a patient has benefited. In addition, there remain gaps in the development of therapies to relieve symptoms in BE patients.
4.2.1 Optimizing antimicrobial therapy
Although there is evidence that some patients with BE benefit from the use of intermittent or chronic antibiotic treatment, there are no approved drugs for this indication, indicating a clear gap in the management of patients with BE. Despite the evidence of benefit in some patients, there remains a concern about antibiotic resistance in bacteria present in these patients [
]. It is important to acknowledge that antimicrobial resistance can be driven by the inappropriate use of antibiotics, such as an incorrect selection of antibiotics, inadequate doses, prolonged durations, and treatment when an antibiotic is not indicated [
]. Clinical experience with CF patients suggests that some patients will benefit from suppressive antibiotic therapy, even in the presence of resistant pathogens [
Pseudomonas aeruginosa susceptibility patterns and associated clinical outcomes in people with cystic fibrosis following approval of aztreonam lysine for inhalation.
]; whether this is true in the non-CF BE population has yet to be demonstrated. As such, there may be a role for suppressive antibiotic therapy in some patients with BE, but such treatment should adhere to the principles of antimicrobial stewardship (i.e. using antibiotics appropriately). Again, this highlights the need for clinical trials to provide robust evidence for which patients will benefit the most from antimicrobial therapy.
The increasing frequency of antimicrobial resistance has warranted the development of novel antibiotic drug classes. However, in the absence of novel antibiotic drug classes, there remains potential to improve the efficacy, tolerability and pharmacokinetics of existing antimicrobials. For example, research into the structure-toxicity relationship of aminoglycosides can mitigate the ototoxicity and nephrotoxicity of these agents by reducing their uptake by and intracellular effects in eukaryotic cells [
]. Inhalational antibiotics may lessen the risk of systemic adverse effects, including selection of resistant pathogens; however, there remains some systemic absorption and exposure even through the inhalational route [
]. In addition, research into pharmaceutical matrices, coatings and mucoadhesive technology could optimize the pharmacokinetic–pharmacodynamic profiles of antibiotics to improve efficacy and limit the development of resistance and adverse events [
Inflammation is a critical feature of the BE airways. Higher measures of inflammation (e.g. elevated neutrophil counts and increased neutrophil elastase [NE]) have been associated with worse clinical outcomes, such as more frequent PEx [
]. Anti-inflammatory agents that target the airways, and strategies to optimize host immune response to infections, remain key unmet needs in the management of BE. The ERS guidelines highlight the importance of long-term management of inflammation, but do not recommend the long-term use of anti-inflammatory agents (i.e. ICS or statins) in adult BE patients because of a lack of data regarding adverse events and no clear evidence of benefit [
Pharmacotherapy for non-cystic fibrosis bronchiectasis. Results from an NTM info & research patient survey and the bronchiectasis and NTM research Registry.
]. The BTS guidelines advise against oral corticosteroids, phosphodiesterase type 4 inhibitors, methylxanthines, leukotriene receptor antagonists, oral CXC chemokine receptor 2 antagonists or NE inhibitors for BE treatment because of the lack of controlled clinical trials [
]. Yet, the observation of the presence of eosinophils in the airways of approximately 20% of BE patients may lead to the identification of a subset of patients who might benefit from corticosteroids [
]. Macrolides have been shown to reduce PEx frequency in large trials, and it has been suggested this benefit may be due to an anti-inflammatory effect [
Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial.
The effect of long-term macrolide treatment on respiratory microbiota composition in non-cystic fibrosis bronchiectasis: an analysis from the randomised, double-blind, placebo-controlled BLESS trial.
Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS randomized controlled trial.
]. A comparison of chronic suppressive macrolide with ICS use for BE showed that ICS were associated with a greater risk of secondary infection/exacerbation compared with macrolides [
], yet macrolides are infrequently used as a chronic therapy. Perhaps this is because of fear of NTM infection, and so trials to assess the risk of acquiring NTM, and especially macrolide-resistant NTM, are of interest [
Since neutrophils are the predominant inflammatory cells present in the BE airways, it is appropriate to target them or their products, including neutrophil serine proteases (NSP). Approaches to treatment have included direct inhibitors of NE or depletion of NE by reversible inhibitors of dipeptidyl peptidase 1 (DPP1) that block activation of NSPs. Data from a recent Phase 2 study using a DPP1 inhibitor showed improvements in clinical outcomes [
], and such agents are currently being investigated in human trials (NCT00769119; NCT04594369; NCT04656275).
4.3 Improvements in trial design
There are lessons to be learned from failed clinical trials. In some cases, trials may have failed because the investigational drug lacked sufficient efficacy, but it would be unfortunate to give up on treatments that failed because of problems with study design [
Aztreonam for inhalation solution in patients with non-cystic fibrosis bronchiectasis (AIR-BX1 and AIR-BX2): two randomised double-blind, placebo-controlled phase 3 trials.
]. To demonstrate a reduction in PEx, studies should enroll subjects with a sufficiently high baseline PEx rate. Moreover, a significant reduction in PEx was seen among patients who were adherent to colistin, indicating that identifying patients more likely to be adherent could be critical to success of a trial [
]. Improving the inclusion and exclusion criteria of a trial to better define those patients most likely to respond to the therapy under study is critical to appropriately testing the efficacy of a therapy. However, being overly specific with these criteria may reduce the number of patients who are eligible for the trial.
Clinical endpoint selection is also critical. The Food & Drug Administration (FDA) has provided guidance for the inclusion of patient-related outcomes in clinical trials of BE (grants.nih.gov/grants/guide/rfa-files/rfa-fd-19-014.html” title="https://grants.nih.gov/grants/guide/rfa-files/rfa-fd-19-014.html">https://grants.nih.gov/grants/guide/rfa-files/rfa-fd-19-014.html). Clinical trials in BE have included a single primary outcome measure, which may not measure the full treatment response. Because of the heterogeneity of BE symptoms, composite clinical endpoints may provide higher accuracy in measuring clinical benefit in randomized controlled trials. This was demonstrated in a recent pooled analysis of three randomized controlled trials, which found a significant clinical improvement when three endpoints from the original trials were combined: 1) absence of PEx during follow-up; 2) improvement in HRQoL above the minimum clinically important difference; and 3) improvement of FEV1 of ≥100 mL [
While the awareness of BE has increased somewhat in recent years, there is still much work to do to establish evidence to inform standards of care for the management of this condition. We have summarized the findings from a panel of experts; although a systematic review of the literature was not conducted for this meeting, there are previously published reviews and guidelines that were used in the discussion. There are limitations to the approach used here primarily because it includes the opinions of these experts, but they may not be fully reflective of others with similar experience. We did not use a systematic method of measuring the degree of consensus. However, this was intended to stimulate further investigation in the field of bronchiectasis. Addressing the issues raised in this review can provide a framework for future initiatives to improve the management of BE, starting with correct identification and classification of the disease. This will inform all aspects of management, from diagnostic work-up to optimizing airway clearance, addressing underlying inflammation, the correct identification of pathogens and optimal use of antimicrobial therapy. A combination of new, well-designed clinical trials in BE – including new agents, mucolytics and anti-inflammatory drugs – and a new assessment framework that includes appropriate endpoints, phenotype and endotype assessment may prove effective at defining evidence to establish a standard of care for BE. We note that we are considering all endotypes of bronchiectasis, including those with CF. The ultimate goal is a multimodal treatment approach. In patients with CF, provision of multidisciplinary care is now standard, demonstrating what can be achieved using multidimensional assessment and targeted therapy [
Treatable traits down under international workshop participants, treatable traits: a new paradigm for 21st century management of chronic airway diseases: treatable traits down under international workshop report.
]; perhaps this could provide a framework for future management of patients with BE.
Funding
Support for convening the advisory board and funding of medical writing assistance was provided by Zambon S.p.A.
Role of the funding source
Zambon S.p.A funded the convening of the advisory board and medical writing assistance.
Authorship
All listed authors made substantial contributions to the conception and design of the review, or the acquisition of data, or the analysis and interpretation of the data; drafting the article or revising it critically for important intellectual content; and provided final approval of the version submitted.
Author contributions
Patrick A. Flume: Data curation, Writing-original draft, Writing-reviewing and editing; Ashwin Basavaraj, Bryan Garcia, Kevin Winthrop, Emily Di Mango, Charles L. Daley, Julie V. Philley, Emily Henkle, Anne E. O'Donnell, Mark Metersky: Data curation, Writing-reviewing and editing. All authors approved the final version of the manuscript for submission.
Data availability statement
Data sharing is not applicable, as no new data were generated during the course of this study.
Declaration of competing interest
Patrick A. Flume has received grant support from Abbvie, Armata, AstraZeneca, Corbus Pharmaceuticals, Cystic Fibrosis Foundation Therapeutics, Insmed, Janssen, Merck, National Institutes of Health, Novartis, Novoteris, Novovax, Proteostasis Therapeutics, Savara, Sound Pharmaceuticals, Inc. and Vertex Pharmaceuticals, Inc., and consultancy fees from Arrevus, Chiesi, Corbus Pharmaceuticals, Eloxx Pharmaceuticals, Hill-Rom, Insmed, Ionis Pharmaceuticals, Janssen Research and Development, McKesson, Merck, Novartis, Polyphor, Proteostasis Therapeutics, Santhera, Savara and Vertex Pharmaceuticals, Inc. Ashwin Basavaraj has acted as a consultant and advisory board participant for Insmed, Hill-Rom, Dymedso, Physioassist and Zambon, is a principal investigator in a clinical trial with Hill-Rom, and has received grant support from Insmed. Bryan Garcia has received grant support from the Cystic Fibrosis Foundation, CHEST Foundation, and consulting honoraria from Zambon, Insmed, Synspira and Resbiotic. Kevin Winthrop has received grant support from Pfizer, BMS, Insmed and the Cystic Fibrosis Foundation, and consulting honoraria from Novartis, Zambon, Insmed, Janssen, Redhills Biopharma, Paratek and Bayer. Emily Di Mango reports receiving advisory board fees from Zambon in 2019 and from Contrafect Pharmaceuticals in 2021. Charles L. Daley has received grant support from the Cystic Fibrosis Foundation, Insmed, Spero, Paratek and BugWorks, and consulted with AstraZeneca, Genentech, Pfizer, Insmed, Spero, Paratek, Beyond Air, AN2, Matinas and Zambon. Julie V. Philley has received grant support from Insmed, AN2, Paratek, Redhill, Electromed, Zambon and Hill Rom, and has been a consultant for Insmed, Paratek, AN2 and Electromed. Emily Henkle has been an advisory board participant for Zambon. Anne E. O'Donnell has received grant support from Insmed, Paratek, Redhill, Zambon, Janssen, and Astra Zeneca and has received consulting honoraria from Insmed, Paratek, Zambon, Boehringer Ingelheim, Astra Zeneca and Electromed. Mark Metersky has been a consultant for Savara, Insmed, International Biophysics, Zambon and Boehringer Ingelheim, and received clinical trial funding from Insmed.
Acknowledgments
Medical writing assistance was provided by Marion Barnett, on behalf of Springer Healthcare Communications. This assistance was funded by Zambon S.p.A.
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