Lies, Damned Lies, and Bronchiectasis

Compared to other chronic airway disorders like asthma and chronic obstructive pulmonary disease (COPD), bronchiectasis is generally among the least understood. This may be due, in part, to the sheer volume of diagnoses. An estimated 350,000 to 500,000 adults in the United States live with bronchiectasis compared to 25 million people with asthma and 12 million adults with COPD.^1,2 And although the availability of chest computed tomography (CT) has increased identification, bronchiectasis remains underdiagnosed and undertreated in the United States.

The local and systemic consequences of bronchiectasis (Table 1) underscore the impact on the patient’s quality of life and the potential dangers from this progressive disease. In this review, we will share our current approach to diagnosing bronchiectasis, describe the “vicious cycle of bronchiectasis,” detail the treatment and management of patients living with bronchiectasis, and offer pearls from past pitfalls in clinical practice. But first, what is bronchiectasis?

Table 1. Consequences of bronchiectasis

Bronchiectasis: A Confusing Term
Bronchiectasis can be a confusing term that is used interchangeably for both a radiographic finding and a clinical disease diagnosis. Definitions of bronchiectasis (both clinically and radiographically) can vary even among pulmonologists. The diagnosis of bronchiectasis cannot be confirmed without chest CT. Most radiologists could identify bronchiectasis if a patient’s airway diameters were exceeding those of associated arteries. However, up to 20% of patients who have these airway dilations are without the typical clinical characteristics we associate with bronchiectasis.³ Such characteristics should prompt clinicians to ask key questions, most notably, “why not bronchiectasis?” (Table 2)

For example, patients with bronchiectasis present initially with chronic cough (≥ 8 weeks) productive of purulent sputum with frequent exacerbations of symptoms that require prompt treatment, and frequent use of health care resources. Patients with poorly controlled asthma or COPD who fail treatment plans with chronic cough productive of purulent sputum may be concealing bronchiectasis without the clinician’s knowledge. Purulent sputum in bronchiectasis is a thick and sticky yellowish or greenish opaque material consisting of white blood cells and bacteria with tissue debris, and on occasion streaked with blood. Purulent color to sputum (yellowish or greenish) is caused by neutrophil myeloperoxidase,⁴ which catalyzes the conversion of hydrogen peroxide to hypochlorous acid (bleach), and aids in the killing of microorganisms.

Table 2. Key questions to ask in the workup of bronchiectasis

The prevalence of bronchiectasis is more common in women than in men, and the incidence increases with age, particularly among people 60 years and older.⁵ There is no cure for bronchiectasis, and because of this, one of the challenges for clinicians is suspecting bronchiectasis early and reducing the risk of exacerbation after diagnosis, and even death. The Bronchiectasis Severity Index (BSI) is an important predictive tool clinicians can use if they suspect bronchiectasis. (Table 3) Validated internationally, the BSI identifies patients at risk of future mortality, hospitalization, and exacerbations across healthcare settings and fosters shared decision-making between clinician and patient.⁶

Table 3. BSI Score Calculation (Mild: 0 to 4 points; Moderate: 5 to 8 points; Severe: 9+ points)

Bronchiectasis is associated with many disparate etiologies and underlying conditions. In the United States, cystic fibrosis (CF) is the most well-known etiologic cause of cystic fibrosis bronchiectasis (or what we will term simply as “bronchiectasis” throughout the paper) in children and adults. Approximately 50% to 70% of the approximately 40,000 patients with CF develop bronchiectasis that can be confirmed by chest CT at 3 to 5 years of age.^7,8

Despite these numbers, CF is not the most common cause of bronchiectasis. Instead, post-infectious phenotype from prior and/or repeated lower respiratory tract infection, primarily tuberculosis in developing countries, is the most common cause of bronchiectasis worldwide. There are non-post-infectious phenotypes as well. The myriad causes of bronchiectasis outlined in this review requires both an alert clinician and a detailed clinical care approach. (Table 4) This is important because an inexperienced clinician may examine the patient’s clinical presentation and conclude incorrectly that asthma or COPD is the most likely diagnosis instead of asking the key question: “Why not bronchiectasis?”

Table 4. Clinical care approach to bronchiectasis

Timing is Everything
Bronchiectasis is characterized by frequent exacerbations that require prompt medical attention. Without early treatment, patients may require hospitalization or more complex treatment courses, such as intravenous antibiotics. Although less recognized, bronchiectasis may be a risk factor for lung cancer and cardiovascular disease as well.^9-16

Adult patients are frequently referred to a pulmonologist for chronic disease management or to confirm the extent and severity of disease with spirometry and a high-resolution chest CT (HRCT) scan. Indeed, there is a notion that diagnosis and chronic disease management is reserved for pulmonologists alone. (Table 5) However, the average wait for consultations with a pulmonologist could be between 4 to 6 months. At least one pulmonologist can be located within 10 miles for 97.5% of US adults living in urbanized areas, but only 38.3% in urban clusters and 34.5% in rural areas.¹⁷ It is imperative for primary care clinicians to suspect bronchiectasis and order a chest CT whenever patients with chronic purulent cough fail to improve despite best medical treatments and management. Timing is everything, and the sooner bronchiectasis treatment and management is provided by the primary care clinician, the less likely the patient will suffer consequences.

In our experience, bronchiectasis is more often diagnosed after another chronic disease has been recognized for months, if not years. In patients with COPD, bronchiectasis can remain unrecognized until detected by low-dose chest CT (LDCT) screening for lung cancer or assessment of non-specific chest radiograph findings. One study showed that bronchiectasis can be found in populations of patients with diagnosed COPD or severe asthma.¹⁸ In addition to co-existing asthma and/or COPD cases, 26% to 75% of patients with GERD¹⁹ or 50% to 70% with chronic rhinosinusitis²⁰ can also have bronchiectasis.

With knowledge and experience, primary care physicians, nurse practitioners, and physician assistants can order chest CT scans in appropriate patients to confirm the clinical diagnosis of bronchiectasis and initiate a targeted treatment plan to advance home management of bronchiectasis to prevent debilitating exacerbations, further loss of lung function (FEV1), and future disability while awaiting consultation.

Table 5. De-mystifying bronchiectasis

Ordering the CT Scan
In addition to a determining a patient’s history of symptoms (either acute or chronic) and exacerbations, clinicians should also assess the patient’s airways via chest CT. The clinical recognition and description of sounds heard with lung auscultation is highly subjective and prone to errors. Patients with bronchiectasis may wheeze or produce rhonchi and/or crackles that clear with coughing, which can lead clinicians down a path to erroneously diagnosing asthma and/or COPD. In fact, classic signs of cachexia, cyanosis, and digital clubbing represent advanced bronchiectasis. 

Not all chest CT scans are equal in providing radiographic images of airways.  A standard chest CT (5 to 10 mm thick slices) or LDCT (used for lung cancer screening) do not provide the necessary anatomic detail provided by a high-resolution chest CT (HRCT), which is specifically recommended to confirm the diagnosis of bronchiectasis and uses thinner slices (1.0 to 1.5 mm thick). HRCT may disclose not only bronchiectasis but unforeseen interstitial lung disease, emphysema, and/or lung nodules.

Radiographic bronchiectasis is confirmed on chest CT if there is: (1) a lack of normal tapering of bronchi, (2) a broncho-arterial ratio (B/A ratio) > 1.5 or greater (normal range is < 0.80), or (3) visualization of the peripheral bronchi within 1 cm of the costal pleural surface or adjacent mediastinal pleural surface. These radiographic findings (cylindrical, varicose, or cystic bronchiectasis) must be correlated with the clinical presentation of the patient who should have chronic daily productive cough and a history of frequent exacerbations.

It is important to look for other radiographic signs of bronchiectasis in addition to the signet ring and correlate clinically with the patient’s medical history.^27,28 Radiographic bronchiectasis can occur with aging and is found in 19% of otherwise healthy normal adults 75 years and older.²⁷ Functional or reversible bronchiectasis found on chest CT describes a temporary and reversible dilation of bronchi, which can occur during acute pneumonia that typically resolves within 6 months.^29,30

Once the radiographic and clinical findings consistent with bronchiectasis are confirmed, clinicians should work to identify or rule out targetable etiologies. This routinely includes family history, environmental exposure history, serologic assessment for immune deficiencies, alpha 1 anti-trypsin deficiency, sweat chloride testing (and further genetic testing for cystic fibrosis if indicated), primary ciliary dyskinesia, and autoimmune etiologies.

The “Vicious Cycle” of Bronchiectasis
Understanding the “vicious circle”²³ (at UC Davis, we prefer the word "cycle") of bronchiectasis (Figure 1) can help educate the patient and their non-paid caregiver(s) on their diagnosis.

Fig. 1. Vicious cycle of bronchiectasis begins with damage to ciliated lower airway epithelial cells from toxicants/infection/impaired host anatomy or immunity leading to ineffective cough.

Bronchiectasis may develop in a patient from:

• Ineffective cough
• Repeated damage to airway epithelial cilia and the muco-ciliary escalator, which leads to impaired/abnormal mucus clearance or drainage
• Bacterial colonization and infection occurring with Hemophilus influenzae (most common), Staphylococcus aureus (MSSA, MRSA), Pseudomonas aeruginosa or other pathogens, e.g., Aspergillus fumigatus
• Neutrophils and eosinophils to a lesser extent accumulate in the airway and cause inflammation with release of myeloperoxidase, proteases (elastase that injures airway epithelium and destroys elastin), and release of neutrophil extracellular traps into the airways
• Mucus stasis from abnormal mucus and airway clearance leads to infection and inflammation. Purulent sputum from smaller airways move to larger airways remain in the tracheobronchial tree.
• Transmural airway wall inflammation, destruction of elastic connective tissue, and distortion/dilation leads to bronchial wall abscesses

The above describes the “vicious vortex”²⁴, which, in our view, has replaced the original “vicious circle” of bronchiectasis. The vortex emphasizes the interconnecting impaired muco-ciliary clearance, chronic airway inflammation, infection, and microbiome to transmural bronchial wall ulcerations.^25,26  

Considering this, the term “bronchiectasis” could be reimagined as a “chronic ulcerative bronchitis” because the bronchial wall abscesses caused by infection and inflammation (particularly from airway neutrophils) destroy bronchial elastin, muscle, and cartilage. The term “bronchiectasis” recognizes only the anatomy or ectasis (the dilatation or distension) of the bronchi but neither describes the mucus plugging, inflammation, nor infection that is chronically present.

The term “chronic ulcerative bronchitis” can support any educational discussion of bronchiectasis with the patient and caregiver. For example, the clinician can explain that inflammation leads to bronchitis. Then, the bronchitis becomes so severe that bronchial wall abscesses develop, which is the reason why it is important to drain airway pus daily with an effective cough.

Treatment and Management
After clinical diagnosis and phenotype is confirmed, a long-term written treatment and self-management plan is designed for the individual patient through shared decision-making. Such discussions would include several of the therapeutic strategies targeting inflammation modulation, mucus optimization, mechanical clearance, and antimicrobials (if indicated). Treatment and management of bronchiectasis needs to be comprehensive, combining pharmacological and non-pharmacological treatments. The British Thoracic Society provided an overview of the management of patients with bronchiectasis. (Table 6) Our mnemonic checklist, DAMN HELLO, also outlines bronchiectasis treatment options. (Table 7)

Table 6. Quality statements modified from the British Thoracic Society 2022³¹

Table 7. Management of bronchiectasis

Drainage of purulent sputum is a first-line treatment of bronchiectasis and necessary in all patients to reduce inflammation and the risk of exacerbations and complications, including pneumonia, hemoptysis, and lung abscesses. Nebulized hypertonic 3% to 7% saline can acutely reduce mucus concentration by 5%, which helps expectoration.³² Huff coughing technique and Oscillatory Positive Expiratory Pressure devices temporarily increase FRC and TV to allow better cough by splinting the airways open to reduce premature airway closure this causing more homogeneous airflow

High frequency chest wall oscillation (HFCWO) vest therapies are proven long-term treatments for sputum drainage by producing vibrations at various frequencies and pulse intensities, thinning mucus, and loosening it from the smaller airways into the larger airways of the lungs to promote expectoration. There is a paucity of data on long-term clinical effects of HFCWO for patients with bronchiectasis. But in a recent observational comparative retrospective cohort study, 65 patients with bronchiectasis from any cause received the same HFCWO vest system (Smart Vest®) and were enrolled into the algorithm for treatment during the study period. The mean FEV1 remained stable at 1-year post enrollment and the number of exacerbations requiring hospitalization was significantly reduced (1.3 ± 1.0 pre vs. 0.46 ± 0.81 hospitalizations, post initiation, p < 0.0001). Antibiotic use overall was also significantly reduced (2.5 ± 0.86 courses/year pre vs 2.1 ± 0.92 courses per year post initiation, p < 0.0001).³³

Results from this study suggested that standardized care for bronchiectasis employing an algorithm for muco-ciliary clearance that centers on initiation of HFCWO daily to twice daily may reduce lung function decline, need for oral antibiotics, and reduced hospitalization rate. Currently, no pharmacological drug is FDA-approved for the treatment of bronchiectasis in the United States or other countries, although there are ongoing clinical trials.

Bronchodilators are typically prescribed for asthma and COPD, but inhaled corticosteroids (ICS) are not recommended by international guidelines for bronchiectasis, unless asthma or eosinophilic COPD (blood eosinophils ≥ 300 cells/microL) is present. The airway microbiome may be changed with the empiric use of ICS for patients with bronchiectasis, inhibiting neutrophil phagocytosis and promoting Hemophilus, Streptococcus, and Pseudomonas bacteria as well as non-tuberculous mycobacteria to colonize and infect.^34,35

Annual influenza vaccinations, pneumococcal vaccines pneumococcal 20-valent conjugate vaccine (one-time dose only) and pneumococcal polysaccharide vaccine (perhaps repeating five times yearly) and other vaccines for COVID-19 and respiratory syncytial virus reduce morbidity and mortality in COPD and adults 65 years and older; data for bronchiectasis is less well known.³⁶

Long-term antibiotic therapy may be indicated in patients experiencing three or more exacerbations a year.  Azithromycin 500 mg thrice weekly for 1 year (EMBRACE clinical trial; 62% reduction in exacerbations) is most prescribed but is not FDA-approved for bronchiectasis.³⁷ Home nebulized prophylactic antibiotics or home IV antibiotic therapy for appropriate patients can be prescribed, supervised by a pulmonologist, or experienced primary care specialist.

Novel antibiotics like the FDA-approved lefamulin may have a role in treating bronchiectasis.³⁸ Biologic monoclonal antibodies such as dupilumab, mepolizumab, and benralizumab targeting type 2 inflammation^39,40 and eosinophils and small molecule medications like brensocatib inhibiting neutrophilic proteases may have a future place in bronchiectasis treatment algorithms. Brensocatib is a novel reversible inhibitor of dipeptidyl peptidase 1 (DPP1) shown to reduce exacerbation rates and sputum neutrophil counts and improve lung function in patients with bronchiectasis. DDP-1 is itself a protease that is involved in the activation of neutrophil serine proteases (including elastase), which affects the release of neutrophil serine proteases and neutrophil extracellular traps (NETs) in target organs like the lung airways. Brensocatib does not inhibit neutrophil elastase directly. NETs contribute to chronic inflammation and tissue damage in the lungs of patients with bronchiectasis.^41,42

The FDA granted breakthrough therapy designation for brensocatib in 2020 following the results of the Phase 2 WILLOW trial. This oral dipeptidyl peptidase 1 inhibitor was studied in patients with bronchiectasis and is designed to reduce neutrophil serine protease activity thus modulating the inflammatory milieu and delaying time to exacerbation. Phase 3 trials are currently in process.

It is a pitfall to presume cystic fibrosis treatment strategies can be applied universally to bronchiectasis. For example, aerosolized recombinant human DNase (rhDNase) was found to be harmful by increasing (not decreasing) exacerbations, antibiotic use, hospitalizations, and decreasing FEV1 among patients with bronchiectasis.⁴³

Conclusion
Bronchiectasis is under-diagnosed and under-treated. Most patients with bronchiectasis experience uncontrolled symptoms and exacerbations. When clinicians ask, “Why not bronchiectasis?” a search for multiple risk factors that contribute to the risk of having bronchiectasis can result in confirmation of this diagnosis with clinical and CT scan findings. Given the clinical heterogeneity of bronchiectasis, the search for an underlying cause(s) can prove to be just as heterogeneous. Neutrophilic airway inflammation, chronic infection, and release of neutrophil elastases are the immunologic hallmarks of bronchiectasis and are associated with potential exacerbations. 

The Vicious Cycle provides educational framework to begin an individualized approach that addresses ineffective cough, infectious exacerbations, and abnormal mucus and mucus clearance that can result in a chronic ulcerative bronchitis.  The control of bronchiectasis symptoms and exacerbations is a marathon, not a sprint. Airway hygiene with an effective cough supported by HFCWO and appropriate antibiotic use based on microbiologic sputum culture results can reduce the risk of exacerbations and healthcare resource utilizations.  Vaccines against pneumococcus, influenza, and RSV are highly recommended in any patient 60 to 65 years and older for to those adults who are clinically at risk.

An interdisciplinary team of clinicians working together with early referrals for persistent cough, shortness of breath and sputum production from primary care specialists to pulmonologists, registered respiratory therapists, registered nurses, and specialty pharmacists has improved clinical outcomes in our experience at UC Davis.   

Remember in any patient, young or old with a chronic cough for 8 weeks or longer, ask “Why not bronchiectasis?” And DAMN HELLO!