Home Educatione-Learning Non Cystic Fibrosis Bronchiectasis
  • Specialties
  • Pulmonary, Critical Care
  • Learning Categories
  • Learning Category 2: Self-Directed Learning
  • CME Credit
  • Credit not available as of July 1, 2013

Non Cystic Fibrosis Bronchiectasis

PCCSU Volume 25, Lesson 18

PCCSU

The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.

Objectives

  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

Hardware/software requirements: Web browsing device with working Web browser.

PCCSU Volume 25 Editorial Board

Editor-in-Chief
Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By Guang-Shing Cheng, MD

Dr. Cheng is Clinical Instructor, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, Washington.

Dr. Cheng has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within this chapter.

Objectives

  1. Recognize clinical and epidemiologic features of non-cystic (non-CF) bronchiectasis.
  2. Understand pathophysiologic principles and etiologies leading to development of non-CF bronchiectasis.
  3. Understand principles of evaluation of patients with non-CF bronchiectasis.
  4. Understand factors contributing to morbidity and mortality in non-CF bronchiectasis.
  5. Understand principles of management of non-CF bronchiectasis.

Key words: bronchiectasis exacerbations; non-cystic fibrosis bronchiectasis; nontuberculous mycobacteria; pulmonary disease

Abbreviations: AAT = α1-antitrypsin; CFTR = cystic fibrosis transmembrane conductance regulator; CPT = chest physiotherapy; HRCT = high-resolution CT; ICS = inhaled corticosteroids; non-CF = non-cystic fibrosis; NTM = nontuberculous mycobacteria; PCD = primary ciliary dyskinesia

Bronchiectasis, once considered an orphan disease in the Western nations, is now increasingly recognized as a condition responsible for clinically significant loss of lung function and one that can result in considerable morbidity and even early mortality. Clinically manifested as chronic cough and sputum production, bronchiectasis is characterized by abnormal dilatation of the airways as a result of bronchial wall damage arising from a cycle of recurrent infections and inflammation.1,2 While there are a number of anatomic, infectious, and inherited factors associated with bronchiectasis, the practicing clinician most frequently associates it with cystic fibrosis. The current gap in clinical practice lies primarily with recognition of bronchiectasis in adult patients without known cystic fibrosis, and the subsequent institution of appropriate therapies directed at addressing an underlying etiology and preserving lung function. The purpose of this update is to describe the recent findings with regard to the epidemiology, etiology, clinical features, natural history, and management of non-cystic fibrosis (non-CF) bronchiectasis.

Epidemiology

Although studies have been limited, there is evidence of a trend of increasing bronchiectasis prevalence in developed nations. Previous studies have suggested that bronchiectasis declined in Western nations owing to the decreased prevalence of TB, the widespread use of childhood immunizations, and use of broad-spectrum antibiotics in treating pulmonary infections. However, recent evidence shows that bronchiectasis disproportionately affects women and older individuals, and may be contributing to an increasing health-care burden. A recent retrospective survey of 5.6 million patients in a US cohort estimated a prevalence of 52.3 cases per 100,000 adults, with a prevalence of 271.8 per 100,000 for those aged ≥75 years. This corresponds to more than 110,000 persons in the United States being treated for bronchiectasis, resulting in medical expenditures of $630 million annually.3 A survey of hospitalized patients in the United States from 1993 to 2006 showed that 63% of bronchiectasis-associated hospitalizations occurred in women, and 70% were among patients ≥65 years of age. There was also a significant increase in the age-adjusted rate of bronchiectasis-associated hospitalizations, with an average annual increase of 2.4% in men and 3.0% in women.4 In the United Kingdom, there are about 1,000 bronchiectasis-related deaths a year, but from 2001 to 2007, the rate of death increased 3% per year and was correlated with increased age, suggesting an increasing public health burden of bronchiectasis, particularly in older patients.5 These increased rates may reflect the increasingly common use of high-resolution CT (HRCT) scans to identify the condition, although there is a general perception that bronchiectasis is no longer a rare condition.

In response to the growing recognition and prevalence of non-CF bronchiectasis in the United States, in 2008 a group of investigators initiated the Bronchiectasis Research Registry,6 a multicenter consortium to facilitate research into this condition.

Pathophysiology

The definition of bronchiectasis remains an essentially anatomic one: the permanent dilatation of bronchi. The development of bronchiectasis is caused by inflammation, which is thought to require an environmental insult against a background of impaired host defense, resulting in microbial colonization and infection. The inflammation induced by infection results in airway tissue damage, leading to impairment in mucociliary clearance, setting up a vicious cycle of further infection and inflammation and ultimately leading to anatomic distortion of the larger airways and parenchymal destruction.7 Increased concentrations of proinflammatory mediators, such as elastase, interleukin-8, and tumor necrosis factor-α, have been found in the sputum of bronchiectatic patients.1,2 Neutrophilic and lymphocytic infiltration of the bronchial mucosa is observed in biopsy specimens.7

Etiology

Bronchiectasis may be idiopathic or be associated with postinfectious status, anatomy, or an underlying systemic or genetic disease. Because definitive causation can be difficult to prove, it may be more appropriate to consider some conditions to be associated with the development of bronchiectasis or to be risk factors for the disease. In clinical practice, establishing an underlying etiology for bronchiectasis can be difficult, reflecting our limited understanding of this heterogeneous syndrome. Studies of cohorts in the United States, United Kingdom, Australia, and Spain have shown that up to 80% of cases of bronchiectasis have no specific identifiable etiology despite extensive genetic and clinical testing.1,8-10,13 These cases of idiopathic bronchiectasis occur predominantly in Caucasian nonsmoking women under 60 years of age and may represent a phenotype of an as yet unrecognized local or systemic defect in host defense. In a recent survey of 240 patients in a subspecialty referral clinic in the UK, however, clinicians did uncover an etiology in 74% of patients, resulting in a change in management in one third of patients.8 In spite of high numbers of idiopathic bronchiectasis cases in some clinic populations, recognition of a specific condition such as cystic fibrosis or immunodeficiency that leads to or predisposes to bronchiectasis may influence management.

A hodgepodge of inherited diseases, immune disorders and deficiencies, congenital conditions, and inhalational insults can cause diffuse bronchiectasis (Table 1). Focal bronchiectasis generally represents a localized obstructive process, whereas diffuse bronchiectasis suggests a systemic condition accompanied by other sinopulmonary diseases. The common thread in these conditions is an impairment in mucociliary clearance, often in the setting of a known or unknown defect in host defense. Historically, the most common cause of bronchiectasis was thought to be an antecedent respiratory infection, often during childhood, in which airways damage is sustained and structural abnormalities in the developing lung impair clearance of bacterial infection, ultimately leading to bronchiectasis in adulthood.7 Aspiration is commonly present in patients with bronchiectasis, particularly in the older population, and likely represents an understudied risk factor.

 


Table 1Conditions Associated With Bronchiectasis in Adults

Category Condition
Infectious Postinfectious: Severe pneumonia, pertussis, TB
Chronic NTM infection
Viral
Bacterial
Fungal
Anatomic (focal bronchiectasis) Foreign body
Right middle lobe syndrome (extrinsic compression from postinfectious adenopathy)
Postsurgical displacement
Postinflammatory pneumonitis Chronic aspiration/gastroesophageal reflux disorder
Chronic sinusitis
Inhalational injury
Genetic Cystic fibrosis
Primary ciliary dyskinesia
α1-Antitrypsin deficiency
Connective tissue disease Rheumatoid arthritis
Sjögren syndrome
Pulmonary disease COPD
Bronchomalacia
Diffuse panbronchiolitis
Asthma
Idiopathic pulmonary fibrosis (traction bronchiectasis)
Altered immune response Allergic bronchopulmonary aspergillosis
Hypersensitivity pneumonitis
Immunodeficiency Hypogammaglobulinemia
Chronic granulomatous disease
Congenital Mounier-Kuhn syndrome
Other Inflammatory bowel disease
Idiopathic  

 


Diseases with a genetic basis must be considered in the differential diagnosis in bronchiectasis cases without a clear etiology.12,13 Cystic fibrosis, although usually diagnosed in early childhood, is increasingly manifesting in adulthood as pulmonary disease. In a recent prospective study, 20% of adult patients with bronchiectasis without a clear etiology with or without concurrent pulmonary nontuberculous mycobacteria (NTM) infection were shown to meet sweat chloride and genetic mutation criteria for the de novo diagnosis of cystic fibrosis.14 Interestingly, 24 of the 50 patients studied had a cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation, suggesting that CFTR dysfunction is common and important in the susceptibility to and pathogenesis of adult bronchiectasis.

Bronchiectasis is a cardinal feature of primary ciliary dyskinesia (PCD), in which ciliary dysfunction leads to retained airway secretions and recurrent infections. PCD should be suspected when there is a history of chronic rhinitis and sinusitis, or the presence of situs inversus. Recent molecular studies have characterized mutations in two genes that encode for components of the outer dynein arm.8

α1-Antitrypsin (AAT) deficiency usually manifests as emphysema, but a recent study showed that bronchiectasis is an important component of the disorder.15 HRCT scans of AAT-deficient patients showed that bronchiectatic change was common and that a quarter of patients have clinically significant bronchiectasis. The severity of bronchiectasis was also correlated with increased impairment in health status. Interestingly, a subgroup of patients had severe bronchiectasis with less severe emphysema, suggesting a distinct phenotype of AAT deficiency manifesting primarily as bronchiectasis.

Bronchiectasis in association with COPD has been documented in recent cohort studies. In one large cohort of COPD patients, the overall prevalence of bronchiectasis was about 4%, with an increased prevalence correlating with the GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage of COPD severity.16 In a prospective study of 92 patients with moderate-severe COPD, more than half had bronchiectasis based on CT scan, which was associated with severe airflow obstruction.17

Nontuberculous Mycobacteria

Pulmonary NTM disease is encountered with increasing frequency in clinical practice, most notably in older nonsmoking women who present with chronic cough or sputum production. The most common isolate is Mycobacterium avium complex, which can cause nodular bronchiectasis, frequently in the right middle lobe and lingula. NTM was cultured in the sputum of 10% of the patients in a tertiary-referral bronchiectasis clinic in the United Kingdom, 3% of whom met American Thoracic Society criteria for pulmonary disease caused by NTM.18 On HRCT, more of the NTM-positive patients had mucus plugging than did matched NTM-negative patients, and further investigation showed that the patients with NTM in the sputum had a higher frequency of an occult diagnosis of CF than patients without NTM in the sputum.

Clinical Features

The clinical syndrome of bronchiectasis is characterized by chronic cough productive of purulent sputum. Patients can also present with progressive dyspnea, intermittent wheezing, and hemoptysis, which results from airways damage during an acute infection. The hemoptysis can be chronic and occasionally life-threatening. Nonspecific constitutional symptoms, such as fatigue and weight loss, may be present, especially in the presence of NTM infection. Patients may report a history of frequent respiratory infections and concurrent sinus symptoms. Auscultation of the chest can reveal crackles, which represent the opening of mucus-plugged airways. Wheezing and rhonchi may also be present. Patients tend to be older and female. Often patients are diagnosed after many years of symptoms, when the chronic cough or hemoptysis becomes debilitating.1,2,12,13

Patients with non-CF bronchiectasis experience recurrent acute exacerbations that are generally precipitated by bacterial infection and can be severe enough to require hospitalization. While there is no standard definition of an acute exacerbation, it generally involves increased cough and a change in sputum quality (ie, volume and purulence), as well as increased dyspnea, wheezing, or onset of hemoptysis accompanied by constitutional symptoms. Lung function by spirometry can be impaired and hypoxemia may be present. Imaging may reveal new infiltrates or pneumonitis.2,19

Diagnostic Evaluation

Radiology
Plain chest radiographs can show parallel-line opacities, ring opacities, and tubular structures. However, mild to moderate disease is often missed on plain radiography. Therefore, the diagnosis is usually confirmed by HRCT scanning, which has become the diagnostic modality of choice.20 The finding that defines bronchiectasis on CT scan is an airway that is more than 1.5 times as wide as an adjacent blood vessel, also known as the “signet ring” sign from the appearance when the dilated airway is seen on end. Other specific findings include parallel tram track lines of a thickened airway and lack of tapering toward the periphery of the airway. Mucoid impaction of distal airways and air trapping can also be seen. Classic varieties of bronchiectasis include cylindric, varicose, or cystic, the latter typically reflecting more severe disease. Nonspecific findings often associated with airways dilatation include focal pneumonitis, scattered ground-glass opacities, and linear atelectasis. The appearance and pattern of bronchiectasis on HRCT can be helpful in suggesting an underlying etiology21 (Fig 1, Table 2). It should be noted, however, that airway dilatation can also be found in association with other pulmonary diseases, such as asthma and idiopathic pulmonary fibrosis, in which so-called traction bronchiectasis is a common feature, which may add to the confusion regarding the diagnosis.2

 


L18Fig1A

L18Fig1B

L18Fig1C

Figure 1. Examples of bronchiectasis seen via HRCT of the chest. A, Bronchiectasis appearing as tram-track lines in the right upper lobe in a woman with allergic bronchopulmonary aspergillosis. B, Upper-lobe cystic bronchiectasis in a patient with cystic fibrosis. C, Lower-lobe centrally distributed bronchiectasis in a patient with Kartagener syndrome. Notice the dextrocardia. Mucus plugging is also present.


Table 2Radiographic Distribution of Bronchiectasis

Distribution Etiologies
Focal Endobronchial tumor
  Extrinsic compression from lymphadenopathy
Diffuse Idiopathic
Central Allergic bronchopulmonary aspergillosis
Upper lobe Cystic fibrosis
Right middle lobe/lingula NTM
  Primary ciliary dyskinesia
Lower lobe Primary ciliary dyskinesia
  Idiopathic
  Chronic aspiration

 


Laboratory Studies
In addition to a HRCT scan, diagnostic testing to look for an underlying etiology of the non-CF bronchiectasis or pulmonary NTM infection should be performed if the cause is not clinically apparent. Relevant laboratory tests are summarized in Table 3.

 


Table 3Diagnostic Evaluation of Bronchiectasis

Modality Specific Test
Radiology HRCT of chest
Laboratory Sputum culture with antibiotic sensitivity testing
CBC
Antineutrophil cytoplasmic antibodies, rheumatoid factor
Immunoglobulins (IgA, IgM, IgG)
CFTR gene mutation analysis
α1-Antitrypsin phenotyping
Pulmonary function testing Spirometry, lung volumes, Dlco
Bronchodilator response
Other Tailored barium swallow (evaluate aspiration)
Exhaled nitric oxide (evaluate primary ciliary dyskinesia)

 


Pulmonary Function
Spirometry will reveal airflow limitation, with reduced FEV1 and FEV1/FVC ratio. The obstructive physiology likely reflects distal air trapping from thickening of small and medium airway walls, rather than airflow in the dilated larger airways.7 The vital capacity may be reduced, which likely reflects mucus plugging of distal airways or a concurrent pneumonitis. Obstructive physiology can be worsened by cigarette smoking. In a good proportion of patients, a bronchodilator challenge also demonstrates a reversible component of the airflow obstruction.

Microbiology
Understanding patterns of microbial infection in bronchiectatic patients can aid in management and prognosis. The most recent survey of sputum bacteriology in patients with non-CF bronchiectasis by King and coworkers22 confirms prior reports that Haemophilus influenzae as the most common isolate (47%), followed by Pseudomonas aeruginosa (12%). No identifiable organism was isolated in >20% of patients. Moraxella catarrhalis, Streptococcus pneumoniae, and Staphylococcus aureus, and M avium complex are also encountered. Over a follow-up period of about 5 years, the bacteriology of the patients’ sputum remained similar; 56% of the patients grew the same organism, and they also had more exacerbations per year than noncolonized patients. Additionally, those patients with P aeruginosa had the most severe disease, whereas those without an identifiable organism had mild disease.

The quality of the sputum is predictive of the bacterial colonization in patients with stable bronchiectasis, and correlates with severity of disease. In a recent UK study of 141 stable adults with non-CF bronchiectasis in a bronchiectasis referral clinic, sputum samples were graded by color: mucoid (clear), mucopurulent (pale yellow/green), and purulent (dark yellow/green). Patients with purulent sputum were colonized at a much higher rate than those with mucopurulent or mucoid sputum (86.4% vs 43.5% and 5%, respectively), with H influenzae and P aeruginosa being the most common isolates.23 These patients were also diagnosed at a younger age, had more severe disease radiographically, worse FEV1, and poorer quality of life.

Natural History

Recent studies have focused on factors influencing the clinical course of non-CF bronchiectasis, which can be variable. Martínez-Garcia and colleagues24 conducted a prospective study of 76 stable patients with non-CF bronchiectasis and found that the mean annual decline in FEV1 was 52.7 mL, which is consistent with prior reports. When the cohort was stratified into rapid decliners (mean FEV1 decline, 91.1 mL/yr) vs nonrapid decliners (mean FEV1 decline, 11.1 mL/yr), factors strongly associated with accelerated lung function decline included colonization with P aeruginosa, increased frequency of severe exacerbations, and elevated markers of systemic inflammation. The association between frequency of exacerbations and lung function decline parallels the association found in COPD patients. Additionally, the finding of elevation in systemic markers of inflammation suggests that ongoing inflammation is responsible for the development of more severe disease; this finding may prompt more aggressive therapies while the patient is clinically stable.

Colonization with P aeruginosa is recognized as a major factor in increased morbidity and mortality in CF patients; this was the strongest factor associated with accelerated lung function decline in the Martínez-Garcia study.24 However, a causal link, while plausible and also suggested in prior studies, is not definitive. Davies and coworkers25 studied followed 163 adults with non-CF bronchiectasis in the outpatient setting and showed that P aeruginosa infected patients with greater airflow obstruction but that it did not correlate with an increased rate of decline in lung function. Thus, P aeruginosa colonization was a marker for more severe disease rather than a factor in disease progression. However, it is recognized that this group of patients with more severe disease and more frequent hospitalizations also receive more antibiotic therapy, which may slow their decline in lung function. A longitudinal study of mortality from the same UK group recently showed that P aeruginosa has an independent effect on mortality, suggesting that it has a causal relationship rather than just being marker of severe disease.26 The influence of P aeruginosa colonization and infection has implications for more aggressive detection and targeted therapies against the pathogen. Larger clinical studies are needed to elucidate its influence on long-term morbidity and mortality.

Bronchiectasis can also contribute to early mortality, although how significantly is less clear in the era of modern antibiotic therapy. In the aforementioned study out of the United Kingdom, out of a long-term cohort of 91 patients with non-CF bronchiectasis, about 30% died during a 13-year follow-up period, an excess age-adjusted death rate of 15% for males and 21% for females; the majority of deaths were related to the underlying bronchiectasis.26 The median age of those who died was 60 years; early mortality was associated with male sex, P aeruginosa colonization, and decreased functional activity in addition to increased air trapping, restrictive physiology, and diffusing capacity impairment.

Per a recent US study by Finklea and colleagues,27 hospitalization with an acute exacerbation of bronchiectasis is also associated with significant in-hospital mortality (9%) and 1-year mortality rate of 30%, likely reflecting the advanced age of those with the condition and baseline severity of disease. Interestingly, there has been no study to date that has shown a difference among groups of etiologies of non-CF bronchiectasis with regard to morbidity and mortality.

Management

The primary goals of treatment are to reduce the number of exacerbations and improve quality of life. Specific management recommendations can be found in the British Thoracic Society guidelines, published in 2010.13 In addition to addressing the underlying etiology, the mainstays of treatment include appropriate antimicrobial therapy, aggressive airways clearance, reduction in airways inflammation, and (in some instances) surgical resection. Many clinical practices have been extrapolated from the CF literature because of the dearth of clinical trials focusing specifically on non-CF bronchiectasis; however, given the difference in morbidity and long-term prognosis, the costs and benefits of certain treatments must be carefully evaluated in the context of the individual patient’s quality of life.

Antimicrobial Therapy
During an acute exacerbation, antibiotic treatment should be directed towards a specific organism grown in sputum culture; antibiotics are frequently started empirically based on the patient’s previous sputum cultures. Although there is a paucity of data to suggest an optimal combination of agents or duration of therapy, in clinical practice, some patients with severe exacerbations are treated with 2 to 3 weeks of IV antibiotics tailored to microbial culture.

The efficacy of inhaled antibiotics in the cystic fibrosis population has led to a similar interest in their use for non-CF bronchiectasis. In a placebo-controlled trial of 53 patients with non-CF bronchiectasis known to be colonized with P aeruginosa, the addition of twice-daily inhaled tobramycin to oral ciprofloxacin resulted in a significant reduction in organism burden during an acute exacerbation, without microbiologic cure or significant differences in clinical efficacy.28 However, subjects receiving inhaled tobramycin reported increased frequency of wheezing compared with those taking a placebo.

Maintenance therapy with intermittent antibiotics is not used routinely in patients with non-CF bronchiectasis and the decision to use long-term antibiotics should be individualized. Continuous use of oral quinolones is discouraged because of the high likelihood of resistance in patients colonized with P aeruginosa.13 A recent randomized trial involving 65 patients showed that nebulized gentamicin taken twice daily for a year resulted in significant eradication of pathogens as well as fewer exacerbations and subjective clinical improvement without significant changes in pulmonary function. No gentamicin-resistant isolates of P aeruginosa were found at the end of the trial period.29 Thus, inhaled aminoglycosides can be of benefit in chronic non-CF bronchiectasis; however, the treatment needs to be of a sustained duration.

The use of macrolide antibiotics as prophylaxis in non-CF bronchiectasis has been largely extrapolated from their efficacy in the cystic fibrosis population and other airway diseases (eg, bronchiolitis obliterans). Macrolides’ activity owes more to antiinflammatory rather than antimicrobial effects. Several small studies have shown macrolide therapy to be of benefit of in reducing the number of exacerbations and sputum volume.30 The most recent published study to date examined the use of low-dose azithromycin (250 mg three times weekly) for >3 months in a cohort of 56 patients with non-CF bronchiectasis who experienced three or more exacerbations within 6 months despite optimization of care; there was a significant reduction in the frequency of exacerbations and the number of positive sputum cultures, as well as a significant improvement in FEV1 in those patients with pulmonary function data.31 While these results are encouraging, a significant number of patients (11%) discontinued the medication because of abdominal side effects and skin rash. The benefits of macrolide therapy in non-CF bronchiectasis await confirmation in larger prospective trials.

Inhaled Corticosteroids
Although inhaled corticosteroids (ICS) have an important role in the treatment of asthma and COPD in some instances, their usefulness in bronchiectasis has not been established. In the most recent trial of ICS in non-CF bronchiectasis in which 93 patients were randomly assigned to receive no ICS, fluticasone 250 mg bid, or fluticasone 500 mg bid, there was a significant decrease in sputum production and cough at 1 month, with improvement in quality of life after 3 months.32 However there was no substantive change in pulmonary function, number or severity of exacerbations, or microbiologic profile. A meta-analysis of existing randomized, placebo-controlled trials found that ICS had no effect of on any outcomes, and therefore the routine use of ICS in patients with stable non-CF bronchiectasis cannot be recommended.33 There have been no studies of ICS in acute exacerbations.

Airway Clearance
Because bronchiectasis is characterized by an impairment in mucociliary clearance, airway clearance techniques are widely advocated in clinical care as the mainstay of daily maintenance therapy even though there few studies have prospectively validated its routine use in the non-CF bronchiectasis population.

The only randomized, controlled trial of chest physiotherapy (CPT) in non-CF bronchiectasis to date studied the effect of twice-daily CPT with an oscillatory positive expiratory pressure device vs no CPT for 3 months in 20 patients with clinically significant bronchiectasis.34 Cough, exercise tolerance, and subjective dyspnea and activity levels were improved with CPT, while there was no difference in pulmonary function or sputum bacterial load. Sputum volume increased significantly with CPT, which is consistent with the stated goal of loosening secretions to aid expectoration. While the differences in the clinical end points were small, they were clinically significant in terms of patient functionality and quality of life, confirming the importance of CPT in the long-term management of bronchiectasis.

Various methods of CPT can be employed, including manual chest percussion and drainage, mechanical percussion vests, oscillatory positive expiratory pressure devices, and high-frequency assisted airway clearance, although none has been shown to have superiority over another. Efficacy with CPT appears to depend more on patient preference. Manually held oscillatory positive expiratory pressure devices, such as Flutter valves (Axcan Scandipharm Inc; Birmingham, Alabama) and acapella (Smiths Medical; St. Paul, Minnesota), have become popular in clinical practices, given the ease of use and patient independence. The optimal duration of daily CPT has not established; a common recommendation is 20 to 30 min per session.13 Treatment should be tailored to the individual and have the aim of clearing away excess secretions during each treatment session. More than one modality way be used.

With regard to inhaled adjunctive therapies for airway clearance, the data have been mixed. Although the inhaled mucolytic recombinant human DNase I is effective for cystic fibrosis, in non-CF bronchiectasis it was shown to increase the number of exacerbations and worsen FEV1 in an oft-cited randomized, controlled trial.35 β-Adrenergic and anticholinergic bronchodilator agents are commonly prescribed, although there are no trials that support routine use. Inhaled mannitol increases mucus clearance and reduces sputum viscosity,36,37 but the clinical significance of this finding has not been established. Nebulized normal or hypertonic saline has been shown to improve secretion clearance and can be used prior to CPT techniques to improve sputum production.13

Surgery
Surgical resection should be considered in patients with symptomatic focal bronchiectasis refractory to conventional therapy. For those with persistent hemoptysis or a life-threatening episode, surgery can be definitive therapy. There has been significant experience with the video-assisted thorascopic approach at certain centers, particularly in the setting of NTM infection. In the largest surgical series38 of patients with NTM-related bronchiectasis to date, 134 patients underwent 172 operations. In the majority of patients, postoperative cultures were negative for NTM; 29% of that group converted to negative cultures and smears only after the resection of culture-positive parenchymal disease. The most common procedure is lobectomy with generally low morbidity and mortality in other large series of surgery for non-CF bronchiectasis, which come from areas that have high numbers of post-infectious bronchiectasis.39 Lung transplantation has been performed successfully in patients with non-CF bronchiectasis, but experience with this group of patients is limited and data are frequently extrapolated from the CF literature.40

Summary

In summary, the following points may be made:

  • Bronchiectasis is becoming more prevalent in Western nations and is a source of considerable morbidity, especially in older populations.
  • The underlying pathophysiology of bronchiectasis involves chronic inflammation in the setting of infection, leading to damaged and dilated airways, impaired mucociliary clearance, and a cycle of persistent infection and further airways damage.
  • A variety of conditions can cause or be associated with bronchiectasis, although in many cases a specific condition cannot be identified. An underlying etiology or associated condition should be sought for non-CF bronchiectasis and may influence management.
  • Bronchiectasis presents as chronic cough with sputum production. Other symptoms may include wheezing, dyspnea, and hemoptysis. The clinical course is punctuated by recurrent respiratory infections that lead to acute exacerbations requiring antibiotic treatment, as well as a progressive decline in lung function.
  • Definitive diagnosis is made by HRCT scan findings that reveal dilated airways.
  • Principles of management include the following:
    • Evaluate and treat the underlying etiology and any associated conditions.
    • Reduce exacerbations and improve quality of life:
      • Treat acute exacerbations promptly with antibiotics directed at the patient’s specific sputum microbiology.
      • Use active airway clearance techniques, such as postural drainage and oscillatory positive expiratory pressure devices.
      • Consider adjunctive inhaled medications for airway clearance.
      • Consider long-term, low-dose macrolide therapy for maintenance therapy.
      • Consider surgical management for severe cases with focal disease.

 

References

  1. O’Donnell AE. Bronchiectasis. Chest. 2008;134(4):815-823.
  2. Barker AF. Bronchiectasis. N Engl J Med. 2002;346(18):1383-1393.
  3. Weycker D, Edelsberg J, Oster G, Tino G. Prevalence and economic burden of bronchiectasis. Clin Pulm Med. 2005;12(4): 205-209.
  4. Seitz AE, Olivier KN, Steiner CA, Montes de Oca R, Holland SM, Prevots R. Trends and burden of bronchiectasis-associated hospitalizations in the United States, 1993-2006. Chest. 2010;138(4):944-949.
  5. Roberts HJ, Hubbard R. Trends in bronchiectasis mortality in England and Wales. Respir Med. 2010;104(7):981-985.
  6. Bronchiectasis Research Registry. Sponsored by the Gillings School of Public Health, University of North Carolina at Chapel Hill, and the COPD Foundation. http://www.cscc.unc.edu/bron/whatistheregistrypub.php. Accessed June 12, 2011.
  7. King PT. The pathophysiology of bronchiectasis. Int J Chron Obstruct Pulmon Dis. 2009;4:411-419.
  8. Bilton D. Update on non-cystic fibrosis bronchiectasis. Curr Opin Pulm Med. 2008;14(6):595-599.
  9. King PT, Holdsworth SR, Farmer M, Freezer N, Villanueva E, Holmes PW. Phenotypes of adult bronchiectasis: onset of productive cough in childhood and adulthood. COPD. 2009;6(2):130-136.
  10. Shoemark A, Ozerovitch L, Wilson R. Aetiology in adult patients with bronchiectasis. Respir Med. 2007;101(6):1163-1170.
  11. Pasteur MC, Helliwell SM, Houghton SJ, et al. An investigation into causative factors in patients with bronchiectasis. Am J Respir Crit Care Med. 2000;162(4):1277-1284.
  12. Rosen MJ. Chronic cough due to bronchiectasis: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(1 Suppl):122S-131S.
  13. Pasteur MD, Bilton D, Hill AT, et al; British Thoracic Society Bronchiectasis non-CF Guideline Group. British Thoracic Society guideline for non-CF bronchiectasis. Thorax. 2010; 65 Suupl 1:i1-i58.
  14. Ziedalski TM, Kao PN, Henig NR, Jacobs SS, Ruoss SJ. Prospective analysis of cystic fibrosis transmembrane regulator mutations in adults with bronchiectasis or pulmonary nontuberculous mycobacterial infection. Chest. 2006;130(4):995-1002.
  15. Parr DG, Guest PG, Reynolds JH, Dowson LJ, Stockley RA. Prevalence and impact of bronchiectasis in αlpha1-antitrypsin deficiency. Am J Respir Crit Care Med. 2007;176(12):1215-1221.
  16. Agusti A, Calverley PM, Celli B, et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) investigators. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res. 2010;11(1):122.
  17. Martínez-Garcia MA, Soler-Cataluña JJ, Donat-Sanz Y, et al. Factors associated with bronchiectasis in chronic obstructive pulmonary disease patients [published online ahead of print May 5, 2011]. Chest. doi:10.1378/chest.10-1758.
  18. Fowler SJ, French J, Screaton NJ, et al., Nontuberculous mycobacteria in bronchiectasis: prevalence and patient characteristics. Eur Respir J. 2006;28(6):1204-1210.
  19. Chang AB, Bilton D. Exacerbations in cystic fibrosis: 4–non-cystic fibrosis bronchiectasis. Thorax. 2008;63(3):269-276.
  20. Cantin L, Bankier AA, Eisenberg RL. Bronchiectasis. AJR Am J Roentgenol. 2009;193(3):W158-W171.
  21. Javidan-Nejad C, Bhalla S. Bronchiectasis. Radiol Clin North Am. 2009;47(2):289-306.
  22. King PT, Holdsworth SR, Freezer NJ, Villanueva E, Holmes PW. Microbiologic follow-up study in adult bronchiectasis. Respir Med. 2007;101(8):1633-1638.
  23. Murry MP, Pentland JL, Turnbull K, MacQuarrie S, Hill AT. Sputum colour: a useful clinical tool in non-cystic fibrosis bronchiectasis. Eur Respir J. 2009;34(2):361-364.
  24. Martinez-García MA, Soler-Cataluña JJ, Perpiñá-Tordera M, Róman-Sánchez P, Soriano J. Factors associated with lung function decline in adult patients with stable non-cystic fibrosis bronchiectasis. Chest. 2007;132(5):1565-1572.
  25. Davies G, Wells AU, Doffman S, Watanabe S, Wilson R. The effect of Pseudomonas aeruginosa on pulmonary function in patients with bronchiectasis. Eur Respir J. 2006;28(5):974-979.
  26. Loebinger MR, Wells AU, Hansell DM, et al. Mortality in bronchiectasis: a long-term study assessing the factors influencing survival. Eur Respir J. 2009;34(4):843-849.
  27. Finklea JD, Khan G, Thomas S, Song J, Myers D, Arroliga AC. Predictors of mortality in hospitalized patients with acute exacerbation of bronchiectasis. Respir Med. 2010;104(6):816-821.
  28. Bilton D, Henig N, Morrissey B, Gotfried M. Addition of inhaled tobramycin to ciprofloxacin for acute exacerbations of Pseudomonas aeruginosa infection in adult bronchiectasis. Chest. 2006;130(5):1503-1510.
  29. Murray MP, Govan JR, Doherty CJ, et al. A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med. 2011;183(4):491-499.
  30. King P. Is there a role for inhaled corticosteroids and macrolide therapy in bronchiectasis? Drugs. 2007;67(7):965-974.
  31. Anwar GA, Bourke SC, Afolabi G, Middleton P, Ward C, Rutherford RM. Effects of long-term low-dose azithromycin in patients with non-CF bronchiectasis. Respir Med. 2008;102(10):1494-1496.
  32. Martínez-García MA, Perpiñá-Tordera M, Román-Sánchez P, Soler-Cataluña JJ. Inhaled steroids improve quality of life in patients with steady-state bronchiectasis. Respir Med. 2006;100(9):1623-1632.
  33. Kapur N, Bell S, Kolbe J, Chang AB. Inhaled steroids for bronchiectasis. Cochrane Database Syst Rev. 2009;(1):CD000996.
  34. Murray MP, Pentland JL, Hill AT. A randomised crossover trial of chest physiotherapy in non-cystic fibrosis bronchiectasis. Eur Respir J. 2009;34(5):1086-1092.
  35. O’Donnell AE, Barker AF, Ilowite JS, Fick RB. Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase I. rhDNase Study Group. Chest. 1998;113(5):1329-1334.
  36. Daviskas E, Anderson SD, Eberl S, Young IH. Effect of increasing doses of mannitol on mucus clearance in patients with bronchiectasis. Eur Respir J. 2008;31(4):765-772.
  37. Daviskas E, Anderson SD, Young IH. Effect of mannitol and repetitive coughing on the sputum properties in bronchiectasis. Respir Med. 2010;104(3):371-377.
  38. Yu JA, Pomerantz M, Bishop A, Weyant MJ, Mitchell JD. Lady Windermere revisited: treatment with thoracoscopic lobectomy/segmentectomy of right middle lobe and lingular bronchiectasis associated with non-tuberculous mycobacterial disease [published online ahead of print February 14, 2011]. Eur J Cardiothorac Surg. 2011;40(3):671-675. doi:10.1016/j.ejcts.2010.12.028
  39. Zhang, P, Jiang G, Ding J, Zhou X, Gao W. Surgical treatment of bronchiectasis: a retrospective analysis of 790 patients. Ann Thorac Surg. 2010;90(1):245-250.
  40. Hayes D Jr, Meyer KC. Lung transplantation for advanced bronchiectasis. Semin Respir Crit Care Med. 2010;31(2):123-138.