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Using Cystic Fibrosis Therapies for Non–Cystic Fibrosis Bronchiectasis
U s i n g C y s t i c Fi b ro s i s Thera pies f or Non–Cys t ic F i b ro s i s B ro n c h i e c t a s i s Wael ElMaraachli, MDa, Douglas J. Conrad, MDa,*, Angela C.C. Wang, MDb KEYWORDS Bronchiectasis Cystic fibrosis Non–cystic fibrosis Chest medicine Treatment
KEY POINTS Non–cystic fibrosis bronchiectasis is a significant cause of morbidity and mortality and its prevalence is increasing. A work-up must be initiated to determine the cause of the bronchiectasis but the etiology remains unknown in a significant percentage of cases. Unlike CF, adult non-CF bronchiectasis is a heterogeneous disease in regards to its cause, disease progression, and response to therapy. Hence, despite similarities in signs and symptoms, management of adult non-CF bronchiectasis cannot be routinely extrapolated from studies performed in patients with CF.
Non–cystic fibrosis bronchiectasis (NCFB) is an increasingly prevalent disease in the United States and Europe. Its incidence increases with age, and peaks at ages 75 to 84.1,2 NCFB is associated with longer hospital stays, more frequent clinic visits, more antibiotic use, and more extensive medical therapy than matched control subjects.3 A review of 30 US health plans estimates that NCFB results in medical care expenditures of $630 million annually (2001 US dollars). Mortality is also increased, with an estimate of 10.6% in patients with NCFB over a 3.5-year observation period in a single study.4 Many therapies used to treat cystic fibrosis (CF) are also used for patients with NCFB, with varying success. Unlike CF, however, NCFB is a heterogeneous disease, with a variety of predisposing factors and disease mechanisms implicated in its pathogenesis. This article explores
the evidence for which therapeutic strategies used to treat CF have been translated into the care of NCFB. We conclude that therapies for adult NCFB cannot be simply extrapolated from CF clinical trials, and in some instances, doing so may actually result in harm.
PATHOPHYSIOLOGY The “vicious cycle” hypothesis proposed by Cole5 is the generally accepted explanation for the evolution of bronchiectasis. It is thought that airway damage resulting from a neutrophilic-dominant inflammatory response to infection, or tissue injury, leads to mucus stasis and predisposes to persistent infections thus perpetuating a “vicious cycle” of inflammation and damage.5,6 Alternatively, endogenous innate immune deficiencies including ciliary dysfunction or immunoglobulin deficiencies, among many others, may initiate mucus stasis or
Disclosure Statement: The authors have nothing to disclose. a Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, 200 West Arbor Drive, MC 8372, San Diego, CA 92013, USA; b Division of Chest and Critical Care Medicine, Scripps Clinic, 10666 North Torrey Pines Road, W203, San Diego, CA 92037, USA * Corresponding author. E-mail address: [email protected] Clin Chest Med - (2015) -–http://dx.doi.org/10.1016/j.ccm.2015.11.005 0272-5231/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
chestmed.theclinics.com
INTRODUCTION
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ElMaraachli et al changes in the airway microbiome. Airway bacterial colonization is facilitated by impaired neutrophil opsonophagocytic killing. Neutrophil elastase, released by activated neutrophils, can impair bacterial clearance by slowing ciliary beat frequency and promoting mucus hypersecretion.7,8
Box 2 Historical and diagnostic evaluation of NCFB
PATIENT EVALUATION
Previous pneumonia
Causes of NCFB range from postinfectious to immune dysregulation (Box 1). The British Thoracic Society published guidelines for the evaluation of NCFB9 (Box 2). However, the cause remains unknown in 10% to 53% of cases even after extensive evaluation.10–12
Historical Neonatal symptoms Infertility Gastric aspiration Asthma Connective tissue Autoimmune symptoms Diagnostic Sputum culture; bacteria/mycobacteria
PHARMACOLOGIC TREATMENT OPTIONS
Pulmonary function testing
Pharmacologic and nonpharmacologic therapies are used in CF and NCFB with varying success. The differences in efficacy likely result from
IgA, IgE, IgG, and IgM Pneumococcal vaccine titers Sweat chloride test CFTR genetic analysis
Box 1 Etiologies of NCFB
ANA, RF, aCCP, SSA, SSB antibodies
Autoimmune disease
Ciliary ultrastructure
a1-Antitrypsin
Rheumatoid arthritis Sjo¨gren syndrome
differences in pathophysiology and patient demographics. The major areas of therapy used in CF and their utility in NCFB are reviewed next.
Primary ciliary dyskinesia Connective tissue disease Tracheobronchomegaly syndrome)
(Mounier-Kuhn
Marfan syndrome Cartilage deficiency syndrome)
(Williams-Campbell
Allergic bronchopulmonary aspergillosis Immune deficiency Human immunodeficiency virus Immunoglobulin deficiency Hyper-IgE syndrome Inflammatory bowel disease Previous infections Aspiration Smoke inhalation Malignancy Chronic lymphocytic leukemia Stem cell transplantation, graft-versus-host disease Obstruction (tumor, foreign body) a1-Antitrypsin syndrome
Bronchodilators There is no definitive evidence that b-adrenergic or anticholinergic agents significantly improve outcomes in CF or NCFB.13 Although bronchodilator therapies can potentially improve lung physiology and patient symptoms by improving mucociliary clearance, relieving bronchospasm, and reducing air-trapping, there is insufficient evidence to recommend regularly prescribing short-acting b2-adrenergic agonists or anticholinergics for patients with CF or NCFB. These medications may be used safely if there is evidence of bronchospasm or air-trapping on pulmonary function testing, and continued if there is evidence for clinical improvement.14,15
Anti-inflammatory Therapy The goal of anti-inflammatory therapy is to mitigate the airway remodeling, gas exchange abnormalities, and symptoms driven by inflammation without exacerbating airway infection or causing serious toxicity. Corticosteroids Theoretically, inhaled corticosteroids (ICS) may decrease airway inflammation without the increased
Using CF Therapies for Non-CF Bronchiectasis side effects of systemic steroids. Currently, however, ICS is not recommended for routine use in CF.16 In one study of NCFB, high-dose ICS reduced sputum volume and inflammatory markers but did not affect lung function or frequency of exacerbations.17 Martı´nez-Garcı´a and colleagues15 compared mediumdose budesonide (640 mg) plus formoterol with high-dose budesonide (1600 mg) in patients with NCFB in a 12-month randomized, double-blind, parallel-group trial. Patients receiving medium-dose budesonide plus formoterol experienced less dyspnea, required fewer rescue b-agonist inhalations, had an increase in cough-free days, and improved healthrelated quality of life scores compared with the high-dose budesonide group. However, lung function, exacerbation frequency, and chronic bacterial colonization were not different between the two study groups. In addition, the long-term use of high-dose ICS is associated with cataracts and osteoporosis. Therefore, the routine use of ICS in NCFB is not recommended except when there is airflow reversibility or allergic bronchopulmonary aspergillosis. Systemic corticosteroids can benefit patients with CF and NCFB through incompletely understood anti-inflammatory effects. However, the chronic use of corticosteroids in NCFB and CF is associated with substantial side effects that are believed to outweigh potential benefits.18,19 Therefore, except in cases of allergic bronchopulmonary aspergillosis or concomitant asthma, in which short courses are reasonable, long-term administration of systemic corticosteroids is not recommended in either CF or NCFB. Nonsteroidal anti-inflammatory therapy The use of nonsteroidal anti-inflammatory drugs in CF has been found to decrease the rate of lung function decline, particularly in the pediatric population.20,21 In contrast, the use of inhaled or systemic nonsteroidal anti-inflammatory drugs is not established in NCFB and routine use is not recommended without further evidence.22 Macrolides Macrolides possess several properties of potential benefit to patients with NCFB and CF. These include anti-infective effects on susceptible bacterial populations, anti-inflammatory properties, and their ability to alter bacterial virulence.23,24 Longterm azithromycin is widely used in patients with CF and is recommended for use in patients with and without Pseudomonas aeruginosa (PA) infection.25 Three multicenter, randomized trials (EMBRACE, BAT, and BLESS trials) using different doses of azithromycin (500 mg three times weekly
in EMBRACE26; 250 mg daily in BAT27) or erythromycin (400 mg twice daily in BLESS28) have shown reduced rates of exacerbations with use of a macrolide as compared with placebo in patients with NCFB. The trials are small but consistently show a reduction in exacerbations.26–28 Therefore, maintenance macrolide use may be considered to reduce exacerbation frequency in NCFB. The benefits of macrolide therapy in CF and NCFB must be balanced against its potential cardiovascular toxicity and ototoxicity, both of which require regular monitoring. In addition, the development of resistant strains of mycobacteria remains a major concern. In CF and NCFB, infection with nontuberculous mycobacteria must be ruled out before initiating chronic macrolide therapy.
Antibiotics The use of antibiotics in patients with NCFB is driven mostly by studies in patients with CF, which are limited by their reliance on traditional sampling methods and culture techniques. Studies of the airway microbiome in CF and NCFB using culture-independent assessments are beginning to provide critical insights into taxonomy, dynamics, and metabolism of the airway microbial community that have the potential to provide new pathophysiologic insights and identify novel therapies targeting the ecologic dependencies of the bacterial, viral, and fungal populations. For instance, microbial community diversity in NCFB correlates positively with clinical health measurements.29–32 These early microbiome studies in NCFB suggest that anaerobic bacterial populations may serve as an important therapeutic target. Systemic antibiotics In patients with CF, Pseudomonas spp, Staphylococcus aureus, Stenotrophomonas maltophilia, Achromobacter spp, and mycobacteria are frequently isolated from airway secretions. In NCFB, the most common pathogen is also PA, followed by S aureus, Moraxella catarrhalis, and Haemophilus influenza.33 In CF and NCFB, exacerbation frequency, lung function, and disease extent are worse in patients infected with PA.34 Aggressive treatment of initial colonization by PA can result in eradication of the organism and prevent, or delay, colonization. In addition, PA eradication therapy has been demonstrated to reduce exacerbation frequency in NCFB.35 Therefore, as in CF, eradication of PA in NFCB should be attempted, especially following initial colonization. Oral fluoroquinolones, such as ciprofloxacin, or intravenous aminoglycosides in combination with inhaled antibiotics are frequently used.
3
4
ElMaraachli et al The treatment of acute exacerbations of NCFB should be guided by a patient’s prior sputum cultures. Although no strong evidence is available to dictate duration of therapy, a 2-week course is currently recommended.9 The use of higher doses of ciprofloxacin may be required to treat PA infection in NFCB.36 This has been directly extrapolated from the CF literature. However, this higher dose must be used with caution in older patients given the higher incidence of side effects, such as Clostridium difficile colitis and tendinopathy. The use of inhaled tobramycin in combination with high-dose ciprofloxacin has also been studied.37 Although the combination was found to be more effective than placebo at eradicating PA, no additional clinical benefit was demonstrated, possibly because of the increased wheezing caused by inhaled tobramycin.37 Inhaled antibiotics Inhaled antibiotics offer significant advantages compared with oral therapies by delivering higher concentrations of drug to the airway with less systemic absorption and fewer side effects. Inhaled antibiotics reduce airway bacterial load and associated airway inflammation in NCFB.38 In the CF population, inhaled antibiotics have been shown to reduce exacerbations and hospital admissions.39 Older studies demonstrated no differences in exacerbation frequency.40–42 A single-blind randomized controlled trial of nebulized gentamicin for 12 months in NFCB reported significant benefits.43 The study enrolled patients with chronic bacterial colonization (three positive sputum cultures in the past 12 months), two exacerbations in the previous year, and a forced expiratory volume in 1 second (FEV1) greater than 30%, and excluded smokers and patients receiving other long-term antibiotics. A total of 27 patients were randomized to gentamicin, 80 mg twice daily, and 30 patients to 0.9% saline twice daily. After 12 months, in the gentamicin group, there was a significant reduction in bacterial density and improvement in the quality of life and exacerbation frequency. There was still a significant rate of bronchospasm at 21.9%, but only two patients were withdrawn from the study for this reason. No nephrotoxicity or ototoxicity was reported. A recent, large phase III trial of inhaled colistin has been completed.44 This trial recruited 144 patients with chronic PA colonization in the United Kingdom, Russia, and Ukraine. The study failed to meet the primary outcome of a difference in time to first exacerbation (colistin group 165 days vs placebo 111 days; P 5 .11). However, in the secondary end points, a significant improvement
in quality of life using the St. George’s Respiratory Questionnaire was noted (mean difference, 10.5 points; P 5 .006). Inhaled aztreonam therapy is used frequently in CF. Two recent randomized trials in patients with NCFB compared aztreonam with placebo for two 28-day cycles separated by 28 days off.45 The primary outcome of improvement in quality of life was not reached, and there was a high rate of intolerance with up to 20% of patients discontinuing aztreonam therapy compared with 3% with placebo treatment. A dry powder inhaled formulation of ciprofloxacin has the potential to significantly reduce treatment burden in patients with NCFB. In a phase II study (N 5 60 patients for ciprofloxacin and N 5 64 patients for placebo) ciprofloxacin was associated with a significant reduction in bacterial load during a 28-day treatment period, without any significant differences in exacerbations.46 The dual-release liposomal ciprofloxacin preparation seeks to improve drug tolerance by decreasing the amount of free drug in contact with the pulmonary epithelium. Slow release of the drug from liposomes allows for once-daily dosing, which may also aid compliance.47 The phase II study demonstrated a significant reduction in PA CFU$mL 1 in the treatment arm over 24 weeks. There was also a reduction in time to next exacerbation (median, 134 days vs 58 days; P 5 .046 in the per protocol population). In contrast to previous experience with aminoglycosides and aztreonam, the dry powder and liposomal ciprofloxacin preparations were well tolerated. There are currently phase III trials for each of these preparations actively recruiting patients. The primary outcome for both of these trials is time to first exacerbation.48,49
Hyperosmolar and Mucolytic Therapy Nebulized hypertonic saline, inhaled mannitol, and N-acetylcysteine seek to improve airway clearance by increasing hydration, decreasing viscosity, and improving mucus rheology by disrupting disulfide bond formation.50,51 Inhaled DNase, however, was found to be potentially harmful in NCFB. Nebulized hypertonic saline Hypertonic saline benefits patients with CF older than 6 years of age by improving quality of life and reducing pulmonary exacerbations. In adults, hypertonic saline has been found to improve lung function.52,53 The evidence for the use of hypertonic saline in NCFB is mixed. The studies are small and provide conflicting results. In one study of patients with NCFB, the use of 7% nebulized
Using CF Therapies for Non-CF Bronchiectasis hypertonic saline improved lung function, quality of life, and health care use through changes in mucus rheology, increased ciliary motility, and enhanced cough clearance.54 However, another study, which compared daily hypertonic saline (6%) with daily isotonic saline for 12 months, found no difference in exacerbation rates, quality of life, FEV1, or sputum colonization.55 Although there are no strong recommendations for routine use of hypertonic saline in NCFB, some patients seem to clearly benefit from this therapy. Inhaled mannitol In a recent international, multicenter, randomized, controlled trial, patients were treated with either inhaled mannitol, 400 mg, or low-dose mannitol control twice daily.56 Although exacerbation rates were not affected, there were significant improvements in time to first exacerbation and quality of life as measured by the St. George’s Respiratory Questionnaire.56 Inhaled mannitol is not currently approved for use in the United States. Inhaled DNase Aerosolized dornase alpha reduces mucus viscosity, improves lung function, and reduces hospitalizations in patients with CF.57 Dornase alpha was initially viewed as a potentially beneficial therapy in NCFB but eventually was found to cause greater reductions in FEV1.58 Its use is therefore not recommended in patients with bronchiectasis without CF.
NONPHARMACOLOGIC TREATMENT OPTIONS Exercise Exercise in patients with CF and NCFB improves cardiac conditioning and mobilization of airway secretions. Patients with NCFB who participate in regular exercise programs demonstrate significant improvement in exertional tolerance and healthrelated quality of life scores, and experience fewer respiratory exacerbations.59–61
Airway Clearance Therapy Airway clearance therapy (ACT) is an integral component of CF care. It is recommended for all patients with CF with a grade B recommendation using the United States Preventive Services Task Force grading scheme.62 There is insufficient evidence to recommend one particular method of ACT over another. The prescription of ACT in CF should be individualized based on such factors as age, patient preference, and adverse events, among others.63 ACTs include active cycle of breathing techniques, postural
drainage, oscillatory positive expiratory pressure, autogenic drainage, and high-frequency chest wall oscillation. Studies examining the benefits of ACT in NCFB are small, uncontrolled, and use different comparators. Many of these studies do not have patientimportant end points and use different outcome efficacy measures to assess the specific therapy.64–71 Despite these shortcomings, it is still recommended that ACT be taught to all patients with bronchiectasis.9 As in CF, the particular ACT to be used should be individualized.
SURGICAL TREATMENT OPTIONS Although surgical options for CF, other than transplantation, are rare given the diffuse nature of lung disease, surgical evaluation for a lobectomy or segmentectomy in NFCB can be considered for patients with localized disease, or massive hemoptysis, who have failed medical management.72–75
EXPERIMENTAL THERAPIES Experimental therapies currently under investigation for patients with CF include antiproteases (eg, a1-antitrypsin supplementation, and neutrophil elastase inhibition) and mucolytics, such as N-acetylcysteine. Specific studies of these therapies in NCFB remain lacking.76–78
SUMMARY/DISCUSSION Many aspects of the management of bronchiectasis in patients with no CF have been based on the experience gained from and the more extensive research studies performed in CF. However, therapies for NCFB cannot simply be extrapolated from CF, and some treatments, such as the use of inhaled DNase, may even be harmful. Clinical studies that specifically target patients with NCFB are sorely needed.
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of incremental respiratory endurance. Chron Respir Dis 2004;1:127–30. Patterson JE, Bradley JM, Hewitt O, et al. Airway clearance in bronchiectasis: a randomized crossover trial of active cycle of breathing techniques versus Acapella. Respiration 2005;72:239–42. Thompson CS, Harrison S, Ashley J, et al. Randomised crossover study of the Flutter device and the active cycle of breathing technique in noncystic fibrosis bronchiectasis. Thorax 2002;57: 446–8. Tsang SMH, Jones AYM. Postural drainage or flutter device in conjunction with breathing and coughing compared to breathing and coughing alone in improving secretion removal and lung function in patients with acute exacerbation of bronchiectasis: a pilot study. Hong Kong Physiother J 2003;21:29–36. Mitchell JD, Yu JA, Bishop A, et al. Thoracoscopic lobectomy and segmentectomy for infectious lung disease. Ann Thorac Surg 2012;93:1033–9 [discussion: 1039–40]. Vallilo CC, Terra RM, de Albuquerque ALP, et al. Lung resection improves the quality of life of patients with symptomatic bronchiectasis. Ann Thorac Surg 2014;98:1034–41. Weber A, Stammberger U, Inci I, et al. Thoracoscopic lobectomy for benign disease: a single centre study on 64 cases. Eur J Cardiothorac Surg 2001;20:443–8. Zhang P, Zhang F, Jiang S, et al. Video-assisted thoracic surgery for bronchiectasis. Ann Thorac Surg 2011;91:239–43. Quinn DJ, Weldon S, Taggart CC. Antiproteases as therapeutics to target inflammation in cystic fibrosis. Open Respir Med J 2010;4:20–31. Stockley R, De Soyza A, Gunawardena K, et al. Phase II study of a neutrophil elastase inhibitor (AZD9668) in patients with bronchiectasis. Respir Med 2013;107:524–33. Tirouvanziam R, Conrad CK, Bottiglieri T, et al. Highdose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis. Proc Natl Acad Sci U S A 2006;103:4628–33.
KEY POINTS Non–cystic fibrosis bronchiectasis is a significant cause of morbidity and mortality and its prevalence is increasing. A work-up must be initiated to determine the cause of the bronchiectasis but the etiology remains unknown in a significant percentage of cases. Unlike CF, adult non-CF bronchiectasis is a heterogeneous disease in regards to its cause, disease progression, and response to therapy. Hence, despite similarities in signs and symptoms, management of adult non-CF bronchiectasis cannot be routinely extrapolated from studies performed in patients with CF.
Non–cystic fibrosis bronchiectasis (NCFB) is an increasingly prevalent disease in the United States and Europe. Its incidence increases with age, and peaks at ages 75 to 84.1,2 NCFB is associated with longer hospital stays, more frequent clinic visits, more antibiotic use, and more extensive medical therapy than matched control subjects.3 A review of 30 US health plans estimates that NCFB results in medical care expenditures of $630 million annually (2001 US dollars). Mortality is also increased, with an estimate of 10.6% in patients with NCFB over a 3.5-year observation period in a single study.4 Many therapies used to treat cystic fibrosis (CF) are also used for patients with NCFB, with varying success. Unlike CF, however, NCFB is a heterogeneous disease, with a variety of predisposing factors and disease mechanisms implicated in its pathogenesis. This article explores
the evidence for which therapeutic strategies used to treat CF have been translated into the care of NCFB. We conclude that therapies for adult NCFB cannot be simply extrapolated from CF clinical trials, and in some instances, doing so may actually result in harm.
PATHOPHYSIOLOGY The “vicious cycle” hypothesis proposed by Cole5 is the generally accepted explanation for the evolution of bronchiectasis. It is thought that airway damage resulting from a neutrophilic-dominant inflammatory response to infection, or tissue injury, leads to mucus stasis and predisposes to persistent infections thus perpetuating a “vicious cycle” of inflammation and damage.5,6 Alternatively, endogenous innate immune deficiencies including ciliary dysfunction or immunoglobulin deficiencies, among many others, may initiate mucus stasis or
Disclosure Statement: The authors have nothing to disclose. a Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, 200 West Arbor Drive, MC 8372, San Diego, CA 92013, USA; b Division of Chest and Critical Care Medicine, Scripps Clinic, 10666 North Torrey Pines Road, W203, San Diego, CA 92037, USA * Corresponding author. E-mail address: [email protected] Clin Chest Med - (2015) -–http://dx.doi.org/10.1016/j.ccm.2015.11.005 0272-5231/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
chestmed.theclinics.com
INTRODUCTION
2
ElMaraachli et al changes in the airway microbiome. Airway bacterial colonization is facilitated by impaired neutrophil opsonophagocytic killing. Neutrophil elastase, released by activated neutrophils, can impair bacterial clearance by slowing ciliary beat frequency and promoting mucus hypersecretion.7,8
Box 2 Historical and diagnostic evaluation of NCFB
PATIENT EVALUATION
Previous pneumonia
Causes of NCFB range from postinfectious to immune dysregulation (Box 1). The British Thoracic Society published guidelines for the evaluation of NCFB9 (Box 2). However, the cause remains unknown in 10% to 53% of cases even after extensive evaluation.10–12
Historical Neonatal symptoms Infertility Gastric aspiration Asthma Connective tissue Autoimmune symptoms Diagnostic Sputum culture; bacteria/mycobacteria
PHARMACOLOGIC TREATMENT OPTIONS
Pulmonary function testing
Pharmacologic and nonpharmacologic therapies are used in CF and NCFB with varying success. The differences in efficacy likely result from
IgA, IgE, IgG, and IgM Pneumococcal vaccine titers Sweat chloride test CFTR genetic analysis
Box 1 Etiologies of NCFB
ANA, RF, aCCP, SSA, SSB antibodies
Autoimmune disease
Ciliary ultrastructure
a1-Antitrypsin
Rheumatoid arthritis Sjo¨gren syndrome
differences in pathophysiology and patient demographics. The major areas of therapy used in CF and their utility in NCFB are reviewed next.
Primary ciliary dyskinesia Connective tissue disease Tracheobronchomegaly syndrome)
(Mounier-Kuhn
Marfan syndrome Cartilage deficiency syndrome)
(Williams-Campbell
Allergic bronchopulmonary aspergillosis Immune deficiency Human immunodeficiency virus Immunoglobulin deficiency Hyper-IgE syndrome Inflammatory bowel disease Previous infections Aspiration Smoke inhalation Malignancy Chronic lymphocytic leukemia Stem cell transplantation, graft-versus-host disease Obstruction (tumor, foreign body) a1-Antitrypsin syndrome
Bronchodilators There is no definitive evidence that b-adrenergic or anticholinergic agents significantly improve outcomes in CF or NCFB.13 Although bronchodilator therapies can potentially improve lung physiology and patient symptoms by improving mucociliary clearance, relieving bronchospasm, and reducing air-trapping, there is insufficient evidence to recommend regularly prescribing short-acting b2-adrenergic agonists or anticholinergics for patients with CF or NCFB. These medications may be used safely if there is evidence of bronchospasm or air-trapping on pulmonary function testing, and continued if there is evidence for clinical improvement.14,15
Anti-inflammatory Therapy The goal of anti-inflammatory therapy is to mitigate the airway remodeling, gas exchange abnormalities, and symptoms driven by inflammation without exacerbating airway infection or causing serious toxicity. Corticosteroids Theoretically, inhaled corticosteroids (ICS) may decrease airway inflammation without the increased
Using CF Therapies for Non-CF Bronchiectasis side effects of systemic steroids. Currently, however, ICS is not recommended for routine use in CF.16 In one study of NCFB, high-dose ICS reduced sputum volume and inflammatory markers but did not affect lung function or frequency of exacerbations.17 Martı´nez-Garcı´a and colleagues15 compared mediumdose budesonide (640 mg) plus formoterol with high-dose budesonide (1600 mg) in patients with NCFB in a 12-month randomized, double-blind, parallel-group trial. Patients receiving medium-dose budesonide plus formoterol experienced less dyspnea, required fewer rescue b-agonist inhalations, had an increase in cough-free days, and improved healthrelated quality of life scores compared with the high-dose budesonide group. However, lung function, exacerbation frequency, and chronic bacterial colonization were not different between the two study groups. In addition, the long-term use of high-dose ICS is associated with cataracts and osteoporosis. Therefore, the routine use of ICS in NCFB is not recommended except when there is airflow reversibility or allergic bronchopulmonary aspergillosis. Systemic corticosteroids can benefit patients with CF and NCFB through incompletely understood anti-inflammatory effects. However, the chronic use of corticosteroids in NCFB and CF is associated with substantial side effects that are believed to outweigh potential benefits.18,19 Therefore, except in cases of allergic bronchopulmonary aspergillosis or concomitant asthma, in which short courses are reasonable, long-term administration of systemic corticosteroids is not recommended in either CF or NCFB. Nonsteroidal anti-inflammatory therapy The use of nonsteroidal anti-inflammatory drugs in CF has been found to decrease the rate of lung function decline, particularly in the pediatric population.20,21 In contrast, the use of inhaled or systemic nonsteroidal anti-inflammatory drugs is not established in NCFB and routine use is not recommended without further evidence.22 Macrolides Macrolides possess several properties of potential benefit to patients with NCFB and CF. These include anti-infective effects on susceptible bacterial populations, anti-inflammatory properties, and their ability to alter bacterial virulence.23,24 Longterm azithromycin is widely used in patients with CF and is recommended for use in patients with and without Pseudomonas aeruginosa (PA) infection.25 Three multicenter, randomized trials (EMBRACE, BAT, and BLESS trials) using different doses of azithromycin (500 mg three times weekly
in EMBRACE26; 250 mg daily in BAT27) or erythromycin (400 mg twice daily in BLESS28) have shown reduced rates of exacerbations with use of a macrolide as compared with placebo in patients with NCFB. The trials are small but consistently show a reduction in exacerbations.26–28 Therefore, maintenance macrolide use may be considered to reduce exacerbation frequency in NCFB. The benefits of macrolide therapy in CF and NCFB must be balanced against its potential cardiovascular toxicity and ototoxicity, both of which require regular monitoring. In addition, the development of resistant strains of mycobacteria remains a major concern. In CF and NCFB, infection with nontuberculous mycobacteria must be ruled out before initiating chronic macrolide therapy.
Antibiotics The use of antibiotics in patients with NCFB is driven mostly by studies in patients with CF, which are limited by their reliance on traditional sampling methods and culture techniques. Studies of the airway microbiome in CF and NCFB using culture-independent assessments are beginning to provide critical insights into taxonomy, dynamics, and metabolism of the airway microbial community that have the potential to provide new pathophysiologic insights and identify novel therapies targeting the ecologic dependencies of the bacterial, viral, and fungal populations. For instance, microbial community diversity in NCFB correlates positively with clinical health measurements.29–32 These early microbiome studies in NCFB suggest that anaerobic bacterial populations may serve as an important therapeutic target. Systemic antibiotics In patients with CF, Pseudomonas spp, Staphylococcus aureus, Stenotrophomonas maltophilia, Achromobacter spp, and mycobacteria are frequently isolated from airway secretions. In NCFB, the most common pathogen is also PA, followed by S aureus, Moraxella catarrhalis, and Haemophilus influenza.33 In CF and NCFB, exacerbation frequency, lung function, and disease extent are worse in patients infected with PA.34 Aggressive treatment of initial colonization by PA can result in eradication of the organism and prevent, or delay, colonization. In addition, PA eradication therapy has been demonstrated to reduce exacerbation frequency in NCFB.35 Therefore, as in CF, eradication of PA in NFCB should be attempted, especially following initial colonization. Oral fluoroquinolones, such as ciprofloxacin, or intravenous aminoglycosides in combination with inhaled antibiotics are frequently used.
3
4
ElMaraachli et al The treatment of acute exacerbations of NCFB should be guided by a patient’s prior sputum cultures. Although no strong evidence is available to dictate duration of therapy, a 2-week course is currently recommended.9 The use of higher doses of ciprofloxacin may be required to treat PA infection in NFCB.36 This has been directly extrapolated from the CF literature. However, this higher dose must be used with caution in older patients given the higher incidence of side effects, such as Clostridium difficile colitis and tendinopathy. The use of inhaled tobramycin in combination with high-dose ciprofloxacin has also been studied.37 Although the combination was found to be more effective than placebo at eradicating PA, no additional clinical benefit was demonstrated, possibly because of the increased wheezing caused by inhaled tobramycin.37 Inhaled antibiotics Inhaled antibiotics offer significant advantages compared with oral therapies by delivering higher concentrations of drug to the airway with less systemic absorption and fewer side effects. Inhaled antibiotics reduce airway bacterial load and associated airway inflammation in NCFB.38 In the CF population, inhaled antibiotics have been shown to reduce exacerbations and hospital admissions.39 Older studies demonstrated no differences in exacerbation frequency.40–42 A single-blind randomized controlled trial of nebulized gentamicin for 12 months in NFCB reported significant benefits.43 The study enrolled patients with chronic bacterial colonization (three positive sputum cultures in the past 12 months), two exacerbations in the previous year, and a forced expiratory volume in 1 second (FEV1) greater than 30%, and excluded smokers and patients receiving other long-term antibiotics. A total of 27 patients were randomized to gentamicin, 80 mg twice daily, and 30 patients to 0.9% saline twice daily. After 12 months, in the gentamicin group, there was a significant reduction in bacterial density and improvement in the quality of life and exacerbation frequency. There was still a significant rate of bronchospasm at 21.9%, but only two patients were withdrawn from the study for this reason. No nephrotoxicity or ototoxicity was reported. A recent, large phase III trial of inhaled colistin has been completed.44 This trial recruited 144 patients with chronic PA colonization in the United Kingdom, Russia, and Ukraine. The study failed to meet the primary outcome of a difference in time to first exacerbation (colistin group 165 days vs placebo 111 days; P 5 .11). However, in the secondary end points, a significant improvement
in quality of life using the St. George’s Respiratory Questionnaire was noted (mean difference, 10.5 points; P 5 .006). Inhaled aztreonam therapy is used frequently in CF. Two recent randomized trials in patients with NCFB compared aztreonam with placebo for two 28-day cycles separated by 28 days off.45 The primary outcome of improvement in quality of life was not reached, and there was a high rate of intolerance with up to 20% of patients discontinuing aztreonam therapy compared with 3% with placebo treatment. A dry powder inhaled formulation of ciprofloxacin has the potential to significantly reduce treatment burden in patients with NCFB. In a phase II study (N 5 60 patients for ciprofloxacin and N 5 64 patients for placebo) ciprofloxacin was associated with a significant reduction in bacterial load during a 28-day treatment period, without any significant differences in exacerbations.46 The dual-release liposomal ciprofloxacin preparation seeks to improve drug tolerance by decreasing the amount of free drug in contact with the pulmonary epithelium. Slow release of the drug from liposomes allows for once-daily dosing, which may also aid compliance.47 The phase II study demonstrated a significant reduction in PA CFU$mL 1 in the treatment arm over 24 weeks. There was also a reduction in time to next exacerbation (median, 134 days vs 58 days; P 5 .046 in the per protocol population). In contrast to previous experience with aminoglycosides and aztreonam, the dry powder and liposomal ciprofloxacin preparations were well tolerated. There are currently phase III trials for each of these preparations actively recruiting patients. The primary outcome for both of these trials is time to first exacerbation.48,49
Hyperosmolar and Mucolytic Therapy Nebulized hypertonic saline, inhaled mannitol, and N-acetylcysteine seek to improve airway clearance by increasing hydration, decreasing viscosity, and improving mucus rheology by disrupting disulfide bond formation.50,51 Inhaled DNase, however, was found to be potentially harmful in NCFB. Nebulized hypertonic saline Hypertonic saline benefits patients with CF older than 6 years of age by improving quality of life and reducing pulmonary exacerbations. In adults, hypertonic saline has been found to improve lung function.52,53 The evidence for the use of hypertonic saline in NCFB is mixed. The studies are small and provide conflicting results. In one study of patients with NCFB, the use of 7% nebulized
Using CF Therapies for Non-CF Bronchiectasis hypertonic saline improved lung function, quality of life, and health care use through changes in mucus rheology, increased ciliary motility, and enhanced cough clearance.54 However, another study, which compared daily hypertonic saline (6%) with daily isotonic saline for 12 months, found no difference in exacerbation rates, quality of life, FEV1, or sputum colonization.55 Although there are no strong recommendations for routine use of hypertonic saline in NCFB, some patients seem to clearly benefit from this therapy. Inhaled mannitol In a recent international, multicenter, randomized, controlled trial, patients were treated with either inhaled mannitol, 400 mg, or low-dose mannitol control twice daily.56 Although exacerbation rates were not affected, there were significant improvements in time to first exacerbation and quality of life as measured by the St. George’s Respiratory Questionnaire.56 Inhaled mannitol is not currently approved for use in the United States. Inhaled DNase Aerosolized dornase alpha reduces mucus viscosity, improves lung function, and reduces hospitalizations in patients with CF.57 Dornase alpha was initially viewed as a potentially beneficial therapy in NCFB but eventually was found to cause greater reductions in FEV1.58 Its use is therefore not recommended in patients with bronchiectasis without CF.
NONPHARMACOLOGIC TREATMENT OPTIONS Exercise Exercise in patients with CF and NCFB improves cardiac conditioning and mobilization of airway secretions. Patients with NCFB who participate in regular exercise programs demonstrate significant improvement in exertional tolerance and healthrelated quality of life scores, and experience fewer respiratory exacerbations.59–61
Airway Clearance Therapy Airway clearance therapy (ACT) is an integral component of CF care. It is recommended for all patients with CF with a grade B recommendation using the United States Preventive Services Task Force grading scheme.62 There is insufficient evidence to recommend one particular method of ACT over another. The prescription of ACT in CF should be individualized based on such factors as age, patient preference, and adverse events, among others.63 ACTs include active cycle of breathing techniques, postural
drainage, oscillatory positive expiratory pressure, autogenic drainage, and high-frequency chest wall oscillation. Studies examining the benefits of ACT in NCFB are small, uncontrolled, and use different comparators. Many of these studies do not have patientimportant end points and use different outcome efficacy measures to assess the specific therapy.64–71 Despite these shortcomings, it is still recommended that ACT be taught to all patients with bronchiectasis.9 As in CF, the particular ACT to be used should be individualized.
SURGICAL TREATMENT OPTIONS Although surgical options for CF, other than transplantation, are rare given the diffuse nature of lung disease, surgical evaluation for a lobectomy or segmentectomy in NFCB can be considered for patients with localized disease, or massive hemoptysis, who have failed medical management.72–75
EXPERIMENTAL THERAPIES Experimental therapies currently under investigation for patients with CF include antiproteases (eg, a1-antitrypsin supplementation, and neutrophil elastase inhibition) and mucolytics, such as N-acetylcysteine. Specific studies of these therapies in NCFB remain lacking.76–78
SUMMARY/DISCUSSION Many aspects of the management of bronchiectasis in patients with no CF have been based on the experience gained from and the more extensive research studies performed in CF. However, therapies for NCFB cannot simply be extrapolated from CF, and some treatments, such as the use of inhaled DNase, may even be harmful. Clinical studies that specifically target patients with NCFB are sorely needed.
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