Bronchiectasis

What every physician needs to know:

Bronchiectasis is a disorder characterized radiographically by irreversible bronchial dilatation and clinically by cough, sputum production, and recurrent respiratory tract infections. Impaired airway clearance resulting in chronic infection and neutrophilic inflammation is the pathogenic hallmark. The differential diagnosis of the underlying causes of bronchiectasis is broad and includes infections, genetic disorders, and immunodeficiency states, among others.

Classification:

A number of pathologic classifications have been proposed. The most widely cited is the Reid classification (1950), which notes 3 patterns of bronchiectasis: cylindrical, varicose, and saccular or cystic. However, these patterns are not reliably associated with or predictive of specific underlying causes of bronchiectasis.

Are you sure your patient has bronchiectasis? What should you expect to find?

The symptoms of bronchiectasis are both respiratory and systemic in origin. The clinical hallmark is persistent or recurrent cough and sputum production that is often purulent and large volume. Bronchiectasis should be suspected in individuals, especially non-smokers, who develop frequent respiratory tract infections requiring antibiotic therapy.

Symptoms of bronchiectasis

• Respiratory: cough, purulent sputum production, hemoptysis, dyspnea, and chest pain.

• Systemic: fatigue, fever, chills, night sweats, and anorexia.

The hallmark symptom of bronchiectasis is daily purulent sputum production. Physical exam findings are often subtle and non-specific: crackles, rhonchi, wheezing, or mid-inspiratory squeaks, clubbing, and—in severe, advanced disease—evidence of right heart failure.

Beware: there are other diseases that can mimic bronchiectasis.

Studies have reported a lag time of several years between the onset of symptoms and a formal diagnosis of bronchiectasis. Individuals are often initially thought to have:

• COPD (especially in smokers)

• Asthma

• TB

• Chronic sinus disease

Hemoptysis or isolation of Pseudomonas aeruginosa from sputum should raise concerns for bronchiectasis.

How and/or why did the patient develop bronchiectasis?

The epidemiology of bronchiectasis in the U.S. and elsewhere has not been well described and the prevalence is likely underestimated. In general, about 2/3 of patients are women. An estimated 110,000 patients in the U.S. have bronchiectasis, with an overall prevalence of ~52 cases/100,000 persons, though recent data suggests increasing rates of diagnosis. The prevalence increases with age and is associated with a significant economic cost of care.

The pathogenesis of bronchiectasis results from a vicious cycle of impaired airway clearance which results in persistent airway infection and an ensuing, largely neutrophilic, inflammatory response that induces airway damage and remodeling. This vicious cycle can be initiated by a variety of mechanisms, such as abnormal mucus clearance, an impaired host response, abnormal airway inflammation, or recurrent direct injury to the airway (e.g., aspiration).

Which individuals are at greatest risk of developing bronchiectasis?

The clinical factors that underlie development of bronchiectasis are broad. One approach to the evaluation is based on consideration of the radiographic distribution of disease:

• Focal disease arises predominantly from sequelae of prior infections or endobronchial obstruction.

• Diffuse disease is associated with a more expansive list of possible causes. A specific underlying cause of bronchiectasis can be established in up to 90% of patients and may alter management, underscoring the importance of a well-conceived diagnostic plan.

Predisposing factors for development of bronchiectasis include:

• Infections:
  bacterial (pneumonia), mycobacterial (including TB and non-tuberculous mycobacterial infections), fungal, and viral.

• Immunodeficiency states:
  common variable immunodeficiency, primary or secondary hypogammaglobulinemias, and HIV.

• Genetic conditions: cystic fibrosis (CF), primary ciliary dyskinesia (PCD), alpha-1-antitrypsin deficiency.

• Hypersensitivity:
  allergic bronchopulmonary aspergillosis (ABPA).

• Endobronchial obstruction and anatomic anomalies: foreign bodies, benign or malignant lesions, tracheobronchomalacia, tracheobronchomegaly (Mounier-Kuhn syndrome), cartilage deficiency (Williams-Campbell syndrome).

• Autoimmune diseases:
  rheumatoid arthritis, Sjogren’s syndrome, inflammatory bowel disease.

• Aspiration pneumonitis:
  gastroesophageal reflux disease (GERD), dysphagia.

• Idiopathic

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

In the evaluation of a patient with suspected bronchiectasis, two goals are present: establishing the diagnosis and identifying an underlying cause. Taking a thorough history and obtaining a high resolution chest CT (HRCT) are imperative in achieving both these goals. For example, a patient with a history of prior severe bacterial pneumonia may not require extensive laboratory testing in order to identify the underlying cause. Determination of the etiology of bronchiectasis has been shown to change management in the majority of patients.

Basic laboratory studies may be helpful in the evaluation:

• Sputum gram stain and culture for bacteria and mycobacteria: if sputum is not able to be produced, sputum induction can be performed by nebulization of hypertonic saline

• CBC with differential

• Serum quantitative immunoglobulin levels: IgG, IgA, IgM

• Sweat chloride (2 measurements) and CF transmembrane conductance regulator (CFTR) genetic mutation analysis to exclude cystic CF: details of CF diagnosis and management are discussed elsewhere (Cystic Fibrosis)

In selected cases, one should also consider:

• IgG subclasses if immunodeficiency is suspected, despite normal total IgG

• Alpha-1-antitrypsin level, especially in setting of concurrent basilar or early-onset emphysema in a non-smoker

• Serum IgE level and Aspergillus specific IgE and IgG or Aspergillus precipitins

• Autoimmune serologies, including CRP, RF, anti-CCP, ANA, SSA/B, ANCA

• HIV test

• Exhaled nasal nitric oxide level to exclude primary ciliary dyskinesia (PCD)

What imaging studies will be helpful in making or excluding the diagnosis of bronchiectasis?

HRCT is the most important study to identify the presence and distribution of bronchiectasis. Bronchial dilatation, bronchial wall thickening, and the lack of normal airway tapering characterize the disorder (Figure 1) (Figure 2).

Recognizing the radiographic distribution and pattern of bronchiectasis may be helpful in suggesting a specific diagnosis. For example, the presence of central bronchiectasis with mucus impaction is highly suggestive of ABPA. Bronchiectasis involving the right middle lobe and lingula, particularly if associated with nodular densities, is suggestive of nontuberculous mycobacterial infection. Lower lobe disease should raise the concern of chronic aspiration.

The severity of bronchiectasis seen on HRCT correlates with lung function. However, repeated imaging to document progression of disease is not recommended due to the radiation exposure.

The role of CXR is limited, as it is often normal or shows nonspecific findings. It is difficult to visualize the subtle changes in mild to moderate cases of bronchiectasis without HRCT.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of bronchiectasis?

Pulmonary diagnostic studies are an important part of the work-up of bronchiectasis:

• Pulmonary function testing, including spirometry before and after bronchodilators, lung volumes, and diffusing capacity, is important in establishing the degree of physiologic impairment. Airflow obstruction, often accompanied by hyperinflation, is a classic finding. The diffusing capacity may be reduced in advanced disease. Spirometry should be repeated in patients at least annually to assess for disease progression and may be considered before and after initiation of long-term oral or nebulized antibiotics.

• Six-minute walk testing can be useful to identify the presence of exertional hypoxemia.

What diagnostic procedures will be helpful in making or excluding the diagnosis of bronchiectasis?

In selected patients, clinicians should consider:

• Evaluation for GERD

• Speech pathology consultation to evaluate possible risk of aspiration

• Sweat chloride testing (3 measurements) and CF transmembrane conductance regulator (CFTR) genetic mutation analysis

• Evaluation of ciliary disorders/ primary ciliary dyskinesia (PCD) which can include electron microscopy, high speed direct microscopy, and genetic mutation analysis.

• Flexible bronchoscopy is not routinely indicated for the diagnosis of bronchiectasis but may be useful in obtaining material for culture. Bronchoscopy is typically reserved for patients with suspected mycobacterial infection who are unable to produce sputum spontaneously and by induction, or in cases of high clinical suspicion despite negative sputum cultures. Bronchoscopy is also indicated in persistent focal bronchial obstruction.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of bronchiectasis?

The role of pathology and cytology studies in the initial diagnosis of bronchiectasis is limited.

Three genetic diseases can lead to bronchiectasis: cystic fibrosis (CF), primary ciliary dysfunction (PCD), and alpha-1 antitrypsin (ATT) deficiency. CF is discussed elsewhere (Cystic Fibrosis). Current guidelines for the care of non-CF bronchiectasis recommend testing to rule out CF as a cause of newly diagnosed bronchiectasis, especially in patients 40 and younger. This can be done first with 2 measurements of sweat chloride, followed by confirmatory genetic mutation analysis of the CFTR gene. In PCD, initial screening involves measurement of exhaled nasal nitric oxide followed by analysis of ciliary function or cilia ultrastructure. Genetic testing for PCD mutations is reserved for patients with a strongly suggestive clinical history but negative ciliary function testing. AAT deficiency should be suspected in patients with early onset or basilar emphysema unrelated to smoking and in cases of chronic liver disease. AAT levels +/- genotyping of the protease inhibitor (Pi) gene can be obtained.

If you decide the patient has bronchiectasis, how should the patient be managed?

Management of bronchiectasis is multifaceted and includes both supportive and specific measures. Core therapeutic interventions include airway clearance techniques, antimicrobial therapy, surgery, and treatments for specific underlying conditions. Unfortunately, evidence-based data to guide the clinician in the use of many of these options is lacking.

Airway Clearance Techniques

One of the hallmarks of bronchiectasis is the presence of thick, tenacious mucus that is difficult to mobilize and expectorate. Airway clearance techniques are designed to enhance mucociliary clearance and improve ventilatory function. It is recommended that all bronchiectasis patients receive regular airway clearance therapy with at least one of the following:

• Regular exercise

• Manual chest percussion therapy

• Positive expiratory pressure (PEP) device

• Oscillatory PEP device

• Vibration vest

Pharmacologic approaches to enhancing airway clearance include:

• Bronchodilators: Drugs like albuterol are most useful in patients with reversible airflow obstruction. No quality studies have shown efficacy of the routine use of bronchodilators in bronchiectasis.

• Hyperosmolar agents: Nebulized hypertonic saline used twice daily is efficacious in CF, but data for benefit is limited in non-CF bronchiectasis. Nebulized hypertonic saline, used twice daily, may be considered in patients with thick tenacious sputum as an adjunct therapy. Inhaled mannitol has been studied and not found to be efficacious.

• Mucolytics: Aerosolized rhDNA-ase, which is efficacious in CF, should be avoided in non-CF bronchiectasis as it has been shown to be potentially deleterious. Inhaled acetylcysteine has not been shown to be beneficial and is not recommended.

Antibiotic Therapy

Antibiotic therapy is the mainstay of management of acute exacerbations of bronchiectasis and can be used as chronic therapy for exacerbation prevention in select cases.

Acute infectious exacerbations of bronchiectasis are characterized by worsening cough or dyspnea, increased sputum volume or purulence, fever, malaise, and/or declining lung function. Acute exacerbations may be difficult to distinguish from baseline symptoms of bronchiectasis and require clinical judgement. The differential for an acute exacerbation of bronchiectasis may include an asthma exacerbation, viral respiratory infection, or pneumonia. Once an acute exacerbation is diagnosed, a sputum sample should be sent for bacterial and acid-fast analysis. Antibiotic choice is best guided by sputum gram stain and culture and antibiotic susceptibility testing. Common pathogens include Haemophilus influenza, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Staphylococcus aureus.

• Empiric antibiotics should be initiated while awaiting sputum cultures. In the absence of available prior culture data, an antibiotic with anti-pseudomonal activity should be considered. Ciprofloxacin is a respiratory fluoroquinolone with anti-pseudomonal coverage; a dose of 750 mg orally twice daily is recommended.

• Patients with prior or current cultures demonstrating sensitive organisms without the presence of Pseudomonas aeruginosa may be treated with amoxicillin 500 mg three times a day or a macrolide, either azithromycin 500 mg on day one followed by 250 mg once daily on days 2-5 or clarithromycin 250 mg every 12 hours. The selection of antibiotic depends on the organisms growing from sputum culture.

• In patients with cultures demonstrating beta-lactamase producing Haemophilus influenzae, antibiotics may be selected based on sensitivities. Options may include amoxicillin-clavulanate 875 mg every 12 hours or 500 mg every 8 hours, a macrolide, a fluoroquinolone, doxycycline 100 mg twice daily, trimethoprim-sulfamethoxazole 800/160 mg every 12 hours, or a second or third generation cephalosporin.

• Patients colonized with Pseudomonas aeruginosa should receive therapy with anti-pseudomonal coverage. Resistant Pseudomonas aeruginosa often requires IV therapy based on culture sensitivities. IV antibiotics should be used to treat resistant pathogens when dictated by sputum analysis, for severe exacerbations, and in patients who fail to respond to oral antibiotics. Data are lacking for routine administration of combination antibiotics for Pseudomonas aeruginosa resistant to one or more antipseudomonal antibiotics, but can be considered in severe life-threatening exacerbations.

• IV anti-pseudomonal antibiotics include ceftazidime 2 g every 8 hours, cefepime 2 g every 8 hours, meropenem 2 g every 8 hours, piperacillin-tazobactam 4.5 g every 6 hours or 3.375 g every 4 hours, and aztreonam 2 g every 8 hours. A second antibiotic for combination therapy may be added with gentamicin, tobramycin, amikacin, or colistin. Initial dosing for aminoglycosides is guided by the patient’s weight and renal function. Analysis of serum levels can refine the dosing regimen.

• Methicillin resistant Staphylococcus aureus (MRSA) should be treated based on culture sensitivities. Oral options include trimethoprim-sulfamethoxazole 800/160 mg every 12 hours, doxycycline 100 mg twice daily, or linezolid 600 mg every 12 hours if the organism is resistant to the first 2 antibiotics. IV therapy may be required in severe cases.

• Combination antibiotics should be used when culture data reveals multiple pathogens that cannot be covered sufficiently with a single antibiotic.

• Indications for hospitalization include the need for IV antibiotics, large volume hemoptysis, and toxic or life threatening exacerbations.

• Duration for antibiotic treatment is generally recommended to be 14 days, although a range of 10-21 days can be considered for patients who historically respond quickly or who are slow to improve on therapy.

Antibiotics are also the cornerstone of chronic suppressive therapy in bronchiectasis patients who have recurrent exacerbations, defined as two or more in a 12 month period.

• Several studies demonstrate that macrolides reduce the frequency of exacerbations for patients with frequent flares (i.e. two or more/year). The mechanism is likely at least in part due to the immunomodulatory or anti-inflammatory properties. There have been three clinical trials in bronchiectasis patients that support the use of chronic suppressive azithromycin prescribed at a dose of 250 mg daily or three times weekly.

  Bronchiectasis and Long Term Azithromycin Treatment (BAT) trial: Azithromycin 250 mg once daily in patients with three or more exacerbations in one year and positive sputum cultures resulted in a reduced number of exacerbations and improved FEV1.

  Bronchiectasis and Low Dose Erythromycin Study (BLESS) trial: Erythromycin 400 mg twice daily in patients with two or more exacerbations in one year resulted in a reduced number of exacerbations and a decreased rate of FEV1 decline.

  Azithromycin for Prevention of Exacerbation in non-CF Bronchiectasis (EMBRACE) trial: Azithromycin 500 mg three times a week in patients with at least one exacerbation in one year resulted in a reduced number of exacerbations but had no significant effect on FEV1.

• Sputum cultures for AFB and an EKG to evaluate for QTc prolongation should be obtained prior to starting chronic macrolide therapy. Patients should be cautioned about risk of hearing loss and audiology testing should be considered for high-risk patients.

  Macrolide therapy should be avoided in cases with non-tuberculous mycobacteria due to development of macrolide resistance with single drug exposure.

  Macrolide therapy should be used judiciously in patients with prolonged QTc, bradyarrhythmias, liver disease, and hearing loss. The risks must be balanced with the benefits of therapy.

• Inhaled antibiotics are routinely used in CF-related bronchiectasis, and their efficacy has been studied in non-CF bronchiectasis in recent years. Currently, no inhaled antibiotics are approved for use in non-CF bronchiectasis based on a lack of strong evidence for benefit. However an off-label trial of a nebulized anti-pseudomonal antibiotic may be considered in patients with three or more exacerbations per year who are chronically colonized with Pseudomonas aeruginosa if they are not candidates or intolerant of macrolide suppressive therapy. Importantly, bronchospasm can occur with any nebulized antibiotic and initial administration should be in an observed setting with frequent reassessments of the risk/benefit ratio of therapy. A selection of relevant clinical trials of inhaled antibiotics in non-CF bronchiectasis is highlighted below.

  Nebulized tobramycin 300 mg twice daily given to 37 bronchiectasis patients with Pseudomonas aeruginosa positive sputum for four weeks decreased Pseudomonas bacterial load but had no improvement in FEV1.

  Nebulized tobramycin 300 mg twice daily given to 15 patients colonized with Pseudomonas aeruginosa for six months decreased number of hospitalizations without a difference in number of exacerbations.

  Nebulized gentamicin 80 mg twice daily given to 27 patients with sputum positive for any organism reduced exacerbations, increased exercise capacity, and lowered sputum bacterial density with a 30.8% eradication of Pseudomonas aeruginosa in those patients with Pseudomonas colonization at the time of enrollment.

  Nebulized colistin 1 million IU twice daily given to 73 patients with Pseudomonas aeruginosa positive sputum following two weeks of anti-pseudomonal IV therapy for an exacerbation reduced time to next exacerbation.

  AIR-BX1 and AIR-BX2: Inhaled aztreonam 75 mg three times daily for four weeks was given to bronchiectasis patients with a gram negative organism in AIR-BX1 (n =134) and AIR-BX2 (n =136). The only clinical outcome that met statistical significance was Quality of Life-Bronchiectasis Respiratory Symptoms scores in the AIR-BX2 cohort.

  RESPIRE I: Ciprofloxacin dry power for inhalation (DPI) 32.5 mg was studied in 416 patients randomized to 28 days on and 28 days off as well as 14 days on and 14 days off. Primary endpoints in treatment groups were significant for reduced frequency of exacerbations and prolonged time to first exacerbation.

  ORBIT II: Dual release ciprofloxacin for inhalation (DRCFI) 28 days on and 28 days off given to 20 Pseudomonas aeruginosa-colonized patients with two or more exacerbations within the last year reduced Pseudomonas load and time to first exacerbation.

  RESPIRE II and ORBITS III and IV have completed enrollment, with results forthcoming.

• A strategy of rotating antibiotics has been used for years to prevent acute exacerbations of bronchiectasis; however, no evidence-based data are available to support its benefit.

A third approach of antibiotic administration is the eradication of certain bacterial species upon first infection. Additional sputum samples should be obtained prior to and after attempted eradication to document success or failure.

• Because of worse outcomes and increased rates of exacerbations in patients colonized with Pseudomonas aeruginosa, guidelines recommend attempted eradication for patients with Pseudomonas isolated from sputum for the first time. There is a relative paucity of data guiding recommendations for the specific antibiotic regimen. However, based on the available literature, the following regimens are reasonable:

  Oral ciprofloxacin 750 mg twice daily for 14 days. If there is clinical failure for eradication, the initial therapy can be followed with either IV anti-pseudomonal antibiotic for two weeks, combination oral ciprofloxacin 750 mg twice daily and nebulized colistin 2 million IU twice daily for 3 months, or nebulized colistin alone 2 million IU twice daily for 3 months.

  Oral ciprofloxacin 500 mg twice daily for 3 months, followed by nebulized colistin 2 million IU twice daily for 3 months.

  IV two anti-pseudomonal drug combination for 14 days such as ceftazidime and an aminoglycoside, followed by nebulized colistin 2 million IU twice daily for 3 months.

  IV two anti-pseudomonal drug combination for 14 days such as ceftazidime and tobramycin, followed by nebulized tobramycin 300 mg twice daily for 3 months.

  IV anti-pseudomonal antibiotics include ceftazidime 2 g every 8 hours, cefepime 2 g every 8 hours, meropenem 2 g every 8 hours, piperacillin-tazobactam 4.5 g every 6 hours or 3.375 g every 4 hours, and aztreonam 2 g every 8 hours. A second antibiotic for combination therapy may be added with gentamicin, tobramycin, amikacin, or colistin.

The recommendation for eradication of MRSA is less clear. It may be reasonable to consider a course of antibiotics, though there are no specific recommendations for antibiotic selection or duration.Anti-inflammatory Agents

Airway inflammation is an important feature in the pathogenesis of bronchiectasis, so considerable interest has arisen in the potential role of anti-inflammatory therapies.

• Systemic corticosteroids have no role in the management of bronchiectasis patients without asthma or ABPA. Inhaled corticosteroids should be considered as chronic therapy only in patients with clinical evidence of asthma.

• Macrolide antibiotics have potent anti-inflammatory effects and are used in the treatment and prevention of bronchiectasis exacerbations, as described above.

Surgery

Surgery in the management of bronchiectasis is generally reserved for refractory hemoptysis or those who fail medical management or are infected with resistant mycobacteria, especially with focal disease. No studies are available that compare surgical with medical therapy, but retrospective studies have demonstrated that surgery for bronchiectasis may be performed with acceptable morbidity/mortality. Bilateral lung transplant may be an option for advanced disease.

Treatment of Underlying Disease

When indicated, targeted therapy should be given for specific conditions underlying bronchiectasis. Examples include systemic corticosteroids and antifungals for ABPA, immunosuppression for autoimmune disease, prevention of recurrent aspiration or GERD, augmentation therapy for AAT deficiency, immunoglobulin replacement therapy for hypogammaglobulinemias and common variable immunodeficiency (CVID), and appropriate antibiotics for mycobacterial infections. The detailed management of these conditions are discussed elsewhere: ABPA, rheumatoid arthritis, GERD, alpha-1-antitrypsin deficiency, hypogammaglobulinemia, CVID, non-TB mycobacteria.

Other Therapies

Pulmonary rehabilitation has been shown to improve exercise capacity and quality of life in bronchiectasis patients and similar to COPD, should be offered to all bronchiectasis patients with exertional dyspnea or moderate to severe airflow obstruction.

Nutrition is an important factor in bronchiectasis patients as pulmonary cachexia can be present in advanced disease. Nutritional evaluation and supplementation should be provided in these cases. The evidence for nutritional supplementation in patients without malnutrition is less clear.

GERD should be considered in patients with bronchiectasis as it can be a cause and also a culprit for recurrent exacerbations. There should be a low threshold for treatment of GERD.

Sinus disease is common in bronchiectasis; evaluation and treatment of sinus disease where appropriate is beneficial in reducing symptoms and the frequency of exacerbations.

Preventive measures like influenza and pneumococcal vaccinations are also important. Though no direct evidence exists for pneumococcal vaccination specifically in bronchiectasis patients, recommendations can be extrapolated from other patients with chronic lung diseases.

What is the prognosis for patients managed in the recommended ways?

The natural history and prognosis of bronchiectasis unrelated to CF is not well established. Some studies have suggested a more rapid loss of lung function and overall worse prognosis compared to CF-related bronchiectasis. Respiratory causes appear to account for a majority of deaths. Factors associated with a poor prognosis include advanced age, recurrent exacerbations, and infection with Pseudomonas aeruginosa. Mortality risk depends on severity of disease.

Two prognostication scores have been developed for non-CF bronchiectasis. The Bronchiectasis Severity Index (BSI) was developed from a 608 patient cohort in the UK and includes the following factors: age, BMI, FEV1, hospitalizations, exacerbations, mMRC score, colonization status with Pseudomonas aeruginosa, and radiographic extent of disease. The score predicts both mortality and hospitalization rates based on severity. Another predictor of bronchiectasis severity is the FACED score (FEV1, Age, Colonization by Pseudomonas aeruginosa, Extent of radiographic involvement, Dyspnea by mMRC scale), developed from an 819 patient cohort in Spain. Both scoring systems have been independently validated in other patient cohorts.

What other considerations exist for patients with bronchiectasis?

Genetic counseling should be considered for patients with heritable conditions as the etiology of their bronchiectasis, as is the case in CF, PCD, and AAT deficiency. Patients with PCD and CF may be offered consultation with a fertility expert if requested. CF patients should be referred to a center with expertise in CF care.

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