Bronchiectasis

Bronchiectasis is estimated to affect 680/100,000 individuals annually worldwide (1). Bronchiectasis is best considered the common end-point of various disorders that cause chronic airway inflammation. Bronchiectasis may be diffuse (affecting many areas of the lungs) or focal (appearing in only 1 or 2 lung areas).

Bronchiectasis develops most often in patients with genetic, immunologic, or anatomic defects that affect the airways. The cause of many cases appears initially to be idiopathic, probably partly because onset is so slow that the triggering problem is not readily evident at the time bronchiectasis is recognized. However, after thorough investigation using genetic and immunologic testing, an etiology is more often found in these idiopathic cases (2).

Cystic fibrosis (CF) is commonly associated with diffuse bronchiectasis that classically predominates in the upper lobes, and previously undiagnosed CF may account for up to 20% of idiopathic cases. Even patients who are heterozygous, who typically have no clinical manifestations of CF, may have an increased risk of bronchiectasis.

Bronchiectasis also often coexists with more common conditions like chronic obstructive pulmonary disease (COPD) and asthma. It is an increasingly recognized complication of chronic, recurrent aspiration and gastroesophageal reflux.

Immunodeficiencies such as common variable immunodeficiency (CVID) may also lead to diffuse disease.

In regions where tuberculosis is common, bronchiectasis is a common complication, particularly in patients with impaired immune function due to undernutrition or human immunodeficiency virus (HIV) infection.

Rare abnormalities in airway structure may lead to diffuse bronchiectasis.

Congenital defects in mucociliary clearance such as primary ciliary dyskinesia (PCD) syndromes may also be a cause, explaining almost 3% of cases that were previously thought to be idiopathic.

Bronchiectasis sometimes complicates autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus (SLE), Sjögren syndrome, and inflammatory bowel disease. It can also occur in patients with hematologic malignancy or organ transplant, or it may be due to the immunocompromise associated with treatment in these conditions.

Allergic bronchopulmonary aspergillosis (ABPA), a hypersensitivity reaction to Aspergillus species that occurs most commonly in people with asthma, but sometimes in patients with CF, can cause or contribute to bronchiectasis.

Focal or localized bronchiectasis can develop as a result of untreated pneumonia or obstruction in the larger airways (eg, due to foreign bodies, tumors, postsurgical changes, lymphadenopathy). Mycobacteria (tuberculous or nontuberculous) can cause focal bronchiectasis and colonize the lungs of patients with bronchiectasis due to other disorders (see table Factors Predisposing to Bronchiectasis).

Bronchiectasis represents a common end-point of several disorders predisposing to chronic airway inflammation. The most widely accepted model describes a "vicious cycle" that results in airway damage and dilation (1). An initial insult to the airways (eg, infectious, autoimmune, toxic inhalations, etc) leads to airway inflammation and epithelial damage. This initial damage and the resulting inflammatory response create structural changes in the airways that impair mucociliary clearance and promote bacterial colonization and infection. This process perpetuates, ultimately resulting in irreversible airway damage if the cycle continues untreated (2).

The role of neutrophilic inflammation in the development of bronchiectasis is increasingly recognized. Inflammation of small and medium-sized airways from a causative disorder releases inflammatory mediators such as proteases (specifically, elastase) from intraluminal neutrophils. The inflammatory mediators destroy elastin, cartilage, and muscle in larger airways, resulting in irreversible bronchodilation. Neutrophil extracellular traps (NETs), a web of DNA ejected from neutrophils that are studded with neutrophil granule enzymes and proteins, are a key mechanism underlying chronic and self-perpetuating airway inflammation. Simultaneously, in the inflamed small and medium-sized airways, macrophages and lymphocytes form chronic infiltrates that thicken mucosal layers. This thickening causes the airway obstruction frequently noted during pulmonary function testing.

With disease progression, inflammation spreads beyond the airways, causing fibrosis of the surrounding lung parenchyma. What inflames the small airways depends on the etiology of bronchiectasis. Common contributors include impaired airway clearance (due to the production of thick, viscous mucus in CF, lack of ciliary motility in primary ciliary dyskinesia [PCD], or damage to the cilia and/or airways secondary to infection or injury) and impaired host defenses; these factors predispose patients to chronic infection and inflammation. Atopic inflammation involving IgE can contribute to airway damage in patients with asthma and ABPA. In the case of immune deficiency (particularly CVID) and autoimmune causes, autoimmune inflammation may also contribute.

When the initial insult is localized, for example when a large airway becomes obstructed, the damage may be more focal within the lungs. The resulting inability to clear secretions leads to a similar cycle of infection, inflammation, and airway wall damage as described above. The right middle lobe is involved most often because its bronchus is small, angulated, and has lymph nodes in close proximity. Lymphadenopathy due to mycobacterial infection sometimes causes bronchial obstruction and focal bronchiectasis.

As ongoing inflammation changes airway anatomy, pathogenic bacteria (sometimes including mycobacteria), colonize the airways (3). Common organisms include:

• Pseudomonas aeruginosa

• Staphylococcus aureus

• Haemophilus influenzae

• Nontuberculous mycobacteria

• Moraxella catarrhalis

• Streptococcus pneumoniae

S. aureus colonization is strongly associated with CF; a culture finding of S. aureus should raise concern for undiagnosed CF.

Colonization with P. aeruginosa tends to indicate severe disease and predicts worse outcomes, including increased risk of exacerbations, hospitalization, poor quality of life, rapid decline in lung function, and death.

Colonization by multiple organisms is common, and antibiotic resistance is a concern in patients who require frequent courses of antibiotics for treatment of exacerbations.

Symptoms characteristically begin insidiously, gradually worsen over years, and may be accompanied by episodes of acute exacerbation. A small proportion of patients may have no symptoms.

The most common presenting symptom is chronic cough that produces thick, tenacious, and often purulent sputum. Dyspnea and wheezing are common, and pleuritic chest pain can develop. In advanced cases, hypoxemia and right-sided heart failure due to pulmonary hypertension may increase dyspnea. Hemoptysis can occur in some patients due to airway neovascularization and can be massive and life-threatening.

Acute exacerbations can be common and frequently result from new or worsened infection. Exacerbations are marked by a worsening cough and increases in dyspnea and the volume and purulence of sputum. Low-grade fever and constitutional symptoms (eg, fatigue, malaise) may also be present.

Halitosis and abnormal breath sounds, including crackles, rhonchi, and wheezing, are typical physical examination findings. Dullness over parenchymal or airway areas obstructed by mucus may be present on percussion. Digital clubbing is uncommon but may be present, particularly in patients with CF. Chronic rhinosinusitis and nasal polyps may be present, also in patients with CF or PCD. Lean body mass commonly decreases in patients with CF or malabsorption.

• Chest -radiograph

• High-resolution chest computed tomography (CT)

• Pulmonary function tests for baseline evaluation and monitoring disease progression

• Sputum culture for bacteria and mycobacteria to determine colonizing organisms

• Specific tests for suspected predisposing diseases

Diagnosis is based on history, physical examination, and radiologic testing, beginning with a chest radiograph. Chronic bronchitis may mimic bronchiectasis clinically, but bronchiectasis is distinguished by increased purulence and volume of daily sputum and by dilated airways shown on imaging studies.

Imaging

Chest radiograph alone may sometimes be diagnostic. Radiography findings suggestive of bronchiectasis involve thickening of the airway walls and/or airway dilation; typical findings include ill-defined linear perihilar densities with indistinctness of the central pulmonary arteries, indistinct rings due to thickened airways seen in cross section (parallel to the x-ray beam), and “tram lines” (or tram-track sign) caused by thickened, dilated airways perpendicular to the x-ray beam. Dilated airways filled with mucous plugs can also cause scattered elongated, tubular opacities.

Radiographic patterns may differ depending on the underlying disease; bronchiectasis due to CF develops predominantly in the upper lobes, whereas bronchiectasis due to an endobronchial obstruction causes more focal radiographic abnormalities.

High-resolution CT is the imaging modality of choice to definitively diagnose as well as define the extent of bronchiectasis. Typical CT findings include airway dilation (in which the inner lumen of 2 or more airways exceeds the diameter of the adjacent artery) and the signet ring sign, in which a thickened, dilated airway appears adjacent to a smaller artery in transaxial view. Lack of normal bronchial tapering can result in visible medium-sized bronchi extending almost to the pleura. "Tram lines" may be easily visible on CT and are indicative of dilated, thickened airway walls (parallel lines) filled with mucus.

As airway damage increases over time, bronchiectasis changes progress from cylindrical to varicose and then cystic findings on imaging. Atelectasis, consolidation, mucous plugs, and decreased vascularity are nonspecific findings.

Traction bronchiectasis occurs due to tension and opening of the airways by adjacent fibrotic lung parenchyma, which is a secondary finding and hallmark of various fibrotic lung diseases including idiopathic pulmonary fibrosis (IPF) or other forms of interstitial lung disease. Traction bronchiectasis is not considered a primary bronchiectasis.

Bronchiectasis (Computed Tomography)

Image

Photo courtesy of Başak Çoruh, MD.

Bronchiectasis (Radiograph)

Image

Photo courtesy of Başak Çoruh, MD.

• Prevention of exacerbations with regular vaccinations and sometimes suppressive antibiotics

• Measures to help clear airway secretions

• Bronchodilators in patients with airflow obstruction and/or significant dyspnea

• Inhaled corticosteroids if complicating asthma or ABPA

• Antibiotics and bronchodilators for acute exacerbations

• Early treatment with antivirals of any viral infections, particularly influenza and COVID-19

• Sometimes surgical resection for localized disease with intractable symptoms or bleeding

• Lung transplantation in carefully selected patients who have advanced disease despite maximal therapy

The key treatment goals are to control symptoms and improve quality of life, reduce the frequency of exacerbations, and preserve lung function (1).

As for all patients with chronic pulmonary disease, recommendations include the following:

• Smoking cessation

• Referral to pulmonary rehabilitation

• Annual influenza vaccination

• Pneumococcal vaccination

• COVID-19 vaccination

• Respiratory syncytial virus vaccination as clinically indicated

Pulmonary rehabilitation is recommended for patients with bronchiectasis to improve exercise capacity and health-related quality of life, and to reduce symptoms such as dyspnea and fatigue (2). Patients can also be instructed and coached on performing airway clearance during rehabilitation sessions.

Airway clearance techniques are key components of treatment that aim to reduce chronic cough in patients with significant sputum production and mucous plugging and to reduce symptoms during exacerbations. Such techniques include regular exercise, chest physiotherapy with postural drainage and chest percussion, positive expiratory pressure devices, intrapulmonary percussive ventilators, pneumatic vests, and autogenic drainage or active cycle of breathing (breathing techniques thought to help move secretions from peripheral to central airways, thus facilitating expectoration). Patients should be taught these techniques by a respiratory therapist and should use whichever one is most effective and sustainable for them; no evidence favors one particular technique. Patients should be advised to continue their airway clearance techniques for at least 10 minutes and may stop when they produce 2 clear coughs or huffs (3) or 30 minutes has passed.

Airway clearance sessions for bronchiectasis should be done in the following order, depending on which agents are prescribed:

1. Inhaled short-acting bronchodilators

2. Mucolytic therapy (if prescribed)

3. Airway clearance technique

4. Any prescribed inhaled or nebulized antibiotics, long-acting bronchodilators, or corticosteroids

For patients with airway obstruction, bronchodilator therapy (eg, with some combination of a long-acting beta-adrenergic agonist [LABA] and/or a long-acting muscarinic antagonist [LAMA]) may be used as indicated by symptoms and severity of lung obstruction, similar to the use in patients with COPD. Limited evidence suggests bronchodilator therapy can help improve lung function (4). Inhaled corticosteroids (ICS) may be used in some patients, specifically in those with coexisting asthma, but may increase risk of infection in other patients without clear indications (1). Short-acting beta-adrenergic agonists (SABA) such as albuterol are used to relieve acute airway obstruction causing wheezing or dyspnea. In some patients with eosinophilic airway inflammation, such as those with asthma, biologic therapies targeting Th2 T-helper cell induced IgE-mediated responses and eosinophil activity (eg, omalizumab, mepolizumab, dupilumab) may be required for long-term maintenance therapy. Maintaining adequate hydration is also important.). Short-acting beta-adrenergic agonists (SABA) such as albuterol are used to relieve acute airway obstruction causing wheezing or dyspnea. In some patients with eosinophilic airway inflammation, such as those with asthma, biologic therapies targeting Th2 T-helper cell induced IgE-mediated responses and eosinophil activity (eg, omalizumab, mepolizumab, dupilumab) may be required for long-term maintenance therapy. Maintaining adequate hydration is also important.

Patients with cystic fibrosis may receive nebulized treatments, including a mucolytic (rhDNase, also called dornase alfa) and hypertonic (7%) saline, to help reduce sputum viscosity and enhance airway clearance. In patients without CF, evidence of benefit with these measures is inconclusive, so only humidification and saline are recommended as inhaled treatments. Inhaled rhDNase may be harmful in patients with bronchiectasis not caused by CF. Patients with cystic fibrosis may receive nebulized treatments, including a mucolytic (rhDNase, also called dornase alfa) and hypertonic (7%) saline, to help reduce sputum viscosity and enhance airway clearance. In patients without CF, evidence of benefit with these measures is inconclusive, so only humidification and saline are recommended as inhaled treatments. Inhaled rhDNase may be harmful in patients with bronchiectasis not caused by CF.

Use of suppressive antibiotics regularly or on a rotating schedule reduces symptoms and exacerbations but may increase the risk that future infections will involve resistant organisms. Guidelines suggest using antibiotics in patients with ≥ 3 exacerbations per year and possibly also in those with fewer exacerbations who have culture-proven P. aeruginosa colonization. Some guidelines suggest attempting eradication of organisms such as P. aeruginosa or S. aureus when they are first detected in sputum cultures (3).

Chronic macrolide therapy (eg, oral azithromycin given once daily or 3 times a week) reduces acute exacerbations in patients with bronchiectasis, and can slow the decline in lung function in patients with CF (Chronic macrolide therapy (eg, oral azithromycin given once daily or 3 times a week) reduces acute exacerbations in patients with bronchiectasis, and can slow the decline in lung function in patients with CF (5). Macrolides are thought to be beneficial mainly due to their anti-inflammatory or immunomodulatory effects. Nebulized antibiotics (eg, amikacin, aztreonam, ciprofloxacin, gentamicin, tobramycin) can reduce sputum bacterial load, and may also reduce the frequency of exacerbations. The evidence supporting their use and benefit is strongest in patients with CF.). Macrolides are thought to be beneficial mainly due to their anti-inflammatory or immunomodulatory effects. Nebulized antibiotics (eg, amikacin, aztreonam, ciprofloxacin, gentamicin, tobramycin) can reduce sputum bacterial load, and may also reduce the frequency of exacerbations. The evidence supporting their use and benefit is strongest in patients with CF.

Most patients with bronchiectasis who develop influenza or SARS-CoV-2 infection should be treated with antiviral medications to prevent complications and development of severe disease. For influenza, treatment is typically with oseltamivir regardless of the duration of viral symptoms. SARS-CoV-2 infections should be treated as soon as possible in patients with bronchiectasis, especially in those with underlying immune suppression. The treatment approach is individualized, depending on the severity of infection and other patient risk factors. Oral corticosteroids are not recommended for outpatients with COVID-19 in the absence of a co-existing condition, such as asthma or COPD, that is known to benefit from corticosteroids. Patients with bronchiectasis should be monitored closely for bacterial co-infection, and any exacerbation triggered by viral infection should be treated.infection should be treated with antiviral medications to prevent complications and development of severe disease. For influenza, treatment is typically with oseltamivir regardless of the duration of viral symptoms. SARS-CoV-2 infections should be treated as soon as possible in patients with bronchiectasis, especially in those with underlying immune suppression. The treatment approach is individualized, depending on the severity of infection and other patient risk factors. Oral corticosteroids are not recommended for outpatients with COVID-19 in the absence of a co-existing condition, such as asthma or COPD, that is known to benefit from corticosteroids. Patients with bronchiectasis should be monitored closely for bacterial co-infection, and any exacerbation triggered by viral infection should be treated.

Underlying conditions should be treated to slow the progression of lung disease.

• For patients with underlying immunodeficiency states: Scheduled intravenous or subcutaneous immunoglobulin replacement therapies (which reduce the frequency of lower respiratory infections [6])

• For patients with cystic fibrosis: Antibiotics and inhaled bronchodilators as well as comprehensive support, and dietary supplementation. Most patients with cystic fibrosis benefit from CFTR modulator therapy, which can decrease exacerbations. Patients with CF should receive all or part of their care by teams with expertise in CF, generally at a designated CF care center.

• For patients with allergic bronchopulmonary aspergillosis: Corticosteroids and sometimes azole antifungals.

• Biologic agents may be used to target type 2 (Th2-high) asthma with eosinophilic airway inflammation.

• For patients with alpha-1 antitrypsin deficiency: Replacement therapy for those who qualify based on serum levels and FEV1.

Approaches that have shown promise are under investigation for treatment of bronchiectasis.

Prognosis varies widely. In the United States, the overall all-cause mortality rate at 5 years for patients with any kind of bronchiectasis was 12.1%, indicating a generally favorable prognosis (1). Mean yearly decrease in FEV1 is about 50 to 55 mL (normal decrease in healthy people is about 20 to 30 mL).

Patients with CF historically have had the poorest prognosis, with a median survival of 36 years. However, the advent of CFTR (cystic fibrosis transmembrane regulator) modulator therapy has resulted in meaningful improvements in outcomes, even in patients with advanced lung disease (2).