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Diagnosis, Management&
Beyond
Steven E. Lommatzsch, MD
Associate Professor of Medicine
Director of Non-Cystic Fibrosis Bronchiectasis
National Jewish Health, Denver http://chestatlas.com/gallery/main.php?g2_itemId=841
Bronchiectasis:
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• I have no conflicts of interest with this topic or presentation on Non-CFbronchiectasis management.
Disclosures
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Objectives
• Summarize the etiology and evaluation of non-CF bronchiectasis
• Discuss the management of bronchiectasis and infectionsincluding Pseudomonas and Nontuberculous Mycobacterium(NTM)
• Review current and emerging therapies for the treatment ofbronchiectasis
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Etiology&
Evaluation
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Bronchiectasis Basics
• Definition of bronchiectasis: bronchial widening leading to a dilated airway larger than its associated blood vessel, which causes tortuosity of the bronchi and a propensity for infection
• Estimated that 350,000 to 500,000 adults in the US have the condition
• The condition is twice as common in women than men, and the disease increases in prevalence with increasing age
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Bronchiectasis Symptoms
• Cough (98%)
• Chronic sputum production (78%)
• Chronic sinusitis (73%)
• Dyspnea (62%)
• Fatigue (43%)
• Hemoptysis (27%)
• Wheezing (20%)Prop
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Bronchiectasis Etiologies
• Congenital:PCD
A1AT
Cystic Fibrosis
Tracheobronchomegaly
Cartilage deficiency
Pulmonary sequestration
Marfan’s syndrome
Yellow Nail Syndrome
Young’s Syndrome
• Immunodeficiencies:
Hypogammaglobulinemia
CLL
Chemo
Immunosuppression
• Postinfectious:
Bacteria
Mycobacterium
Aspergillus
Viruses
• Rheumatologic:
RA
SLE
Sjögren’s syndrome
Relapsing polychondritis
IBD
• Aspiration/Inhalation:
Chlorine
Overdoses
Foreign bodies
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• CXR abnormal in most patientsFocal pneumonitis
Irregular opacities
Atelectasis
Ring-like shadows
Tram lines
https://medpix.nlm.nih.gov/case?id=47d4298e-51bf-4f68-9396-197debc5d5a3
Radiographic CXR Patterns
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• Common findings:Airway lumen dilation
Lack of tapering
Varicose constrictions
Ballooned cysts
• Nonspecific findings:Consolidation
Thickened bronchial walls
Mucous plugs
Enlarged LNs
Reduction in vascular markingshttps://err.ersjournals.com/content/27/149/180016
Radiographic CT Patterns
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• 2 different presentations:
Local/Focal
Diffuse
• 3 different types:
Cylindrical/Tubular
Varicose
Saccular/Cystic
https://www.researchgate.net/figure/Tram-track-sign-seen-in-cylindrical-bronchiectasis-on-the-chest-CT-scan-in-a-patient_fig13_313820333
https://slideplayer.com/slide/4636158/
https://pt.slideshare.net/hytham_nafady/bronchiectasis-14219103/9
Radiographic Patterns
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Radiographic Patterns
• Upper Lobe Predominant• Cystic Fibrosis
• Sarcoidosis
• Pneumoconiosis related
• Central or RML/Lingular Location• ABPA
• NTM
• Lower Lobe Predominant• PCD
• CVID
• A1AT
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History and Physical
HRCT
PFTs
CBC and diff, IgG, IgA, and IgM
Rheumatoid factor/CCP, SSA, SSB
IgE (initial per BTS)
Aspergillus precipitins (initial per BTS)
IgG subclasses
A1AT level/genotype
Sinus CT
Antibody titers to pneumococcal vaccination (initial work-up per BTS)
Sputum bacterial, mycobacterial, and fungal cultures
Bronchoscopy with mucosal biopsy or cultures
Testing for PCD or CF (CF is first line per BTS if under40yo)
Aspiration and GERD evaluation
Diagnostic Evaluation
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So what do I actually need to order?
• Everyone:HRCT
Spirometry - PFTs
Sputum cultures
CBC with diff
IgG/IgM/IgA/IgE
A1AT level/genotype
Often:
Esophagram
Tailored swallow
• In selected patients:CF/PCD testingSinus CT IgG subclasses and titers to
vaccinesABPA panel or STRF, CCP, ANA, ANCA, SSA/BMethacholine and eNOO2 assessmentpH probeBronchoscopy
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Targeted Management&
Treatment Strategies
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Treatment Section
• Discuss methods of airway clearance
• Review indications for chronic macrolide therapy
• Examine the utility of inhaled antibiotics
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Bronchiectasis Treatment
• Start with detailed history and evaluation to try and identify cause• Treat underlying disease
• Infection: TB, NTM, etc.
• Immunodeficiency states: CVID
• Aspiration: oropharyngeal, GERD
• Allergic Bronchopulmonary Aspergillosis (ABPA)
• Rheumatologic/Inflammatory disease: RA, Sjogren’s, Sarcoidosis, IBD
• Alpha-1 Antitrypsin deficiency
• Tracheobronchomegaly Propert
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Bronchiectasis Treatment
• Goals of Chronic Maintenance Regimen
• Reduce symptoms and improve quality of patient life
• Prevent exacerbations
• Slow or stop disease progression and lung function decline
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Cornerstones of Management
1. Airway clearance
2. Airway clearance
3. Airway clearance
Amazingly this cornerstone is often forgotten and overlooked!Propert
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Maintenance Therapy
• Improving bronchial hygiene• Airway clearance
• Reducing airway inflammation• Anti-inflammatory treatment
• Treat conditions like asthma or COPD
• Smoking cessation
• Controlling airway microbiota• Identify organisms present by surveillance sputum cultures
• Vaccination
• Suppressive antibiotic therapy
Treat comorbidities such as GERD, aspiration, chronic rhinosinusitis, etc. as they can worsen airway disease control
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Improving Bronchial Hygiene
• Recommended• Use one to two times per day
• Short acting Beta-agonist prior to treatments
• Mechanical Airway Clearance
• Hypertonic Saline Nebulization
• Aerobic Exercise is a great form of airway clearance
• Not Recommended• Dornase alpha nebulization (1, 2)
• Routine use of anticholinergics – unless there is another indication
(1) O’Donnell AE, et al. Treatment of Idiopathic Bronchiectasis with Aerosolized Recombinant Human DNase. CHEST. 1998;113(5): 1329-1334.
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Improving Bronchial Hygiene
• Mechanical Airway Clearance• Postural drainage
• Manuel percussion
• Flutter valve devices (3)
• Vest-type mobilization devices (4)
• Hypertonic saline• Normal saline (5)
• 3%, 7%, and 10% (6)
(6) Nicolson, CHH, et al. The Long Term Effect of Inhaled Hypertonic Saline 6% in Non-Cystic Fibrosis Bronchiectasis. Respiratory Medicine. 2012;106: 661-667.
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• Recommended• Chronic macrolide therapy in those with frequent exacerbations (7)
• Not Recommended• Routine daily use of systemic steroids; unless there is another indication (8)
• Routine use of inhaled steroids; unless there is another indication (9)
• Ibuprofen; no established role in non-CF bronchiectasis
• Chronic daily statins (10)
Reducing Airway Inflammation
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Reducing Airway Inflammation
• Chronic Macrolide Benefits
• Reduction of biofilms
• Decreasing neutrophil activation/migration
• Promotion of gastric emptying
https://www.123rf.com/photo_13070392_human-stomach-and-medical-healthcare-symbol-of-the-digestive-system-featuring-the-abdominal-internal.html
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Reducing Airway Inflammation
• Chronic Macrolide Therapy
• Which and what dose?• Azithromycin proven more affective than erythromycin (11)
• Typically Azithromycin 250mg daily or 500mg on Mon/Wed/Fri
(11) Li W, et al. Azithromycin or Erythromycin? Macrolides for Non-Cystic Fibrosis Bronchiectasis in Adults: A Systematic Review and Adjusted Indirect Treatment Comparison. Chronic Respiratory Disease. 2018:16: 1-9.
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Reducing Airway Inflammation
• Chronic Macrolide Therapy• Benefits (12, 13, 14):
• Proven to decrease exacerbations
• Proven to reduce sputum production
• Proven to improve FEV1 and attenuate its decline
• Risks:• Associated with increased risk of bacterial resistance - NTM
• Prolonged QTc
• Hearing decrements
PIVOTAL TRIALS
-- EMBRACE (12)
-- BAT (13)
-- BLESS (14)
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Controlling Airway Microbiota
• Inhaled antibiotic therapy: Meta-analysis (16)
• Proven to eradicate bacteria from sputum
• Proven to reduce sputum bacterial load
• Proven to help reduce risk of acute exacerbations
(16) Brodt AM, Stovold E, Zhang L. Inhaled Antibiotics for Stable Non-cystic Fibrosis Bronchiectasis: A Systematic Review. European Respiratory Journal. 2014;44(2): 382-393
https://www.medicalnewstoday.com/articles/323215.php https://www.smithsonianmag.com/innovation/instead-killing-bacteria-can-we-just-turn-off-its-ability-to-cause-infections-180967533/
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Controlling Airway Microbiota
• Inhaled antibiotic therapy for Pseudomonas eradication
• Pseudomonas is associated with patients having more daily symptoms, exacerbations and FEV1 decline (17, 18)
• The ERS guidelines suggest eradication attempt of a new Pseudomonas isolation (8)
• There are different regimens• Inhaled antibiotic after IV antibiotic course
• Inhaled antibiotic with oral antibiotic
(18) Finch S, et al. A Comprehensive Analysis of the Impact of Pseudomonas aeruginosa Colonization on Prognosis in Adult Bronchiectasis. Ann Am Thorac Soc.
2015; 12(11): 1602-1611.
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Controlling Airway Microbiota
• Inhaled antibiotic therapy agents
• Tobramycin: decrease sputum Pseudomonas (19), decreased exacerbations (20), improved symptoms (21)
• Gentamycin: reduced sputum bacteria, reduced exacerbations (22)
• Colistin: reduced sputum bacteria, improved symptoms, and longer time to median time to exacerbation (23)
• Aztreonam: one study with small change in symptom score (24)
• Amikacin: now FDA approved for nontuberculous mycobacterial infections (25, 26)
• Ciprofloxacin: not available in the US
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Controlling Airway Microbiota
• Antibiotics: Inhaled vs Oral
• If Pseudomonas is present, the ERS recommends antibiotic therapy for patients experiencing > 3 exacerbations per year (8)
• If Pseudomonas aeruginosa (PSA) is present, then start chronic INHALED antibiotic.
• If Pseudomonas is present and patient is intolerant or can not take inhaled antibiotic, then chronic ORAL macrolide recommended.
• If Pseudomonas is present and patient is on inhaled antibiotic but still having exacerbations, then ADD a chronic ORAL macrolide.Prop
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Controlling Airway Microbiota
• Antibiotics: Inhaled vs Oral
• If no Pseudomonas is present, the ERS recommends antibiotic therapy for patients experiencing > 3 exacerbations per year (8)
• If no Pseudomonas, then consider starting ORAL macrolide antibiotic.
• If no Pseudomonas and macrolide contraindicated (allergy, QTc prolonged, intolerance) or not effective, then consider ORAL antibiotic of choice.
• If no Pseudomonas and oral antibiotic contraindicated, not tolerated or ineffective, then a trail of INHALED antibiotic treatment is recommended.Prop
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Controlling Airway Microbiota
• Do patients without exacerbations get inhaled antibiotics and/or macrolide therapy?
• ANSWER is MAYBE• Patients with severe disease and exacerbation could be life threatening
• Patients with severe symptoms despite good compliance with airway clearance
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Controlling Airway Microbiota
• Nontuberculous Mycobacterium (NTM)
• Broad group of bacteria that can either lead to bronchiectasis or can develop as a result of bronchiectasis.
• Generally found throughout the environment.
• Roughly 200 NTM species.
• Can lead to several complications in humans:
• Pulmonary Disease
• Superficial Lymphadenitis
• Disseminated Disease in Immunocompromised
• Skin and Soft Tissue Disease
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Controlling Airway Microbiota
• Nontuberculous Mycobacterium (NTM)• Clinical and microbiologic criteria for diagnosing lung disease:
Clinical (both required)
1. Pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a high-resolution computed tomography scan that shows multifocal bronchiectasis with multiple small nodules.
and
2. Appropriate exclusion of other diagnoses.
Microbiologic
1. Positive culture results from at least two separate expectorated sputum samples. If the results from the initial sputum samples are nondiagnostic, consider repeat sputum acid-fast bacilli (AFB) smears and cultures.
or
2. Positive culture result from at least one bronchial wash or lavage.
or
3. Transbronchial or other lung biopsy with mycobacterial histopathologic features (granulomatous inflammation or AFB) and positive culture for NTM or biopsy showing mycobacterial histopathologic features (granulomatous inflammation or AFB) and one or more sputum or bronchial washings that are culture-positive for NTM.
Griffith DE, Aksamit T, Brown-Elliott BA, et al. An Official ATS/IDSA Statement: Diagnosis, treatment and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007; 175:367. Copyright © 2007 American Thoracic Society
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Controlling Airway Microbiota
• Nontuberculous Mycobacterium (NTM)
• Treatment is complicated and long, so the first step is deciding who should be treated. Those that meet diagnostic criteria who should be treated are:
• Patients with fibrocavitary disease.
• Patients with nodular bronchiectatic disease who are symptomatic or declining.
• Initial treatment is a minimum of three drug therapy based on susceptibility and the type of organism species:
• Typically: oral Azithromycin, Rifampin, Ethambutol (three times weekly vs daily is based on severity of disease)
• For more advanced disease: IV streptomycin or amikacin, and/or inhaled amikacin
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Each is interrelated in a “vicious cycle”
European Respiratory Society guidelines 2017
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Take Home Points
• Airway clearance is a must!
• Get sputum cultures at regular intervals.
• Chronic macrolide therapy for those experiencing recurrent exacerbations with or without chronic Pseudomonas aeruginosa(PSA).
• Inhaled antibiotics for:• Patients with PSA and recurrent exacerbations
• Monitor for AFB, and remember that one must meet criteria for diagnosis of NTM based on both microbiolic and clinical findings.
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Future Therapy&
Beyond
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Currently Planning for the Future
• Developing ways to increase compliance with current therapies.
• Statin therapy.
• Neutrophil elastase (NE) inhibitor therapy continues to be considered and studied.
• CXCR2 antagonism therapy to decrease neutrophils.
• New inhaled antibiotic therapy.
• Novel antimicrobials based on the peptide protegrin.
• Plasmapheresis followed by IVIG for five days has been studied in decreasing bronchiectasis exacerbations of those who are chronically infected with Pseudomonas aeruginosa.
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References(1) O’Donnell AE, et al. Treatment of Idiopathic Bronchiectasis with Aerosolized Recombinant Human DNase. CHEST. 1998;113(5): 1329-1334.
(2) Wilkinson M, et al. Mucolytics for bronchiectasis. Cochrane Database Syst Rev. 2014; 5: CD001289.
(3) Lee AL, Burge A, Holland AE. Airway clearance techniques for bronchiectasis. Cochrane Database Syst Rev. 2013; 5: CD008351
(4) Nicolini, A, et al. Effectiveness of treatment with high-frequency chest wall oscillation in patients with bronchiectasis. BMC Pulmonary Medicine. 2013. 1471-2466. https://doi.org/10.1186/1471-2466-13-21
(5) Kellett, J, et al. Evaluation of nebulized hypertonic saline (7%) as an adjunct to physiotherapy in patients with stablebronchiectasis. Respiratory Medicine. 2005; 99(1): 27-31.
(6) Nicolson, CHH, et al. The Long Term Effect of Inhaled Hypertonic Saline 6% in Non-Cystic Fibrosis Bronchiectasis. Respiratory Medicine. 2012;106: 661-667.
(7) Lasserson, T, et al. Oral steroids for bronchiectasis (stable and acute exacerbations). Cochrane Database Syst Rev. 2001; 4: CD002162
(8) Polverino E, et al. European Respiratory Society Guidelines for the Management of Adult Bronchiectasis. European Respiratory Journal. 2017;50: 1700629.
(9) Kapur N, et al. Inhaled Corticosteroids for Bronchiectasis. Cochrane Database of Systematic Reviews. 2018, Issue 5. Art. No.: CD000996.
(10) Mandal P, et al. Atorvastatin as a Stable Treatment in Bronchiectasis: A Randomized Controlled Trial. The Lancet. 2014;2: 455-463.
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References(11) Li W, et al. Azithromycin or Erythromycin? Macrolides for Non-Cystic Fibrosis Bronchiectasis in Adults: A Systematic Review and Adjusted Indirect Treatment Comparison. Chronic Respiratory Disease. 2018:16: 1-9.
(12) Wong C, et al. Azithromycin for Prevention of Exacerbations in Non-cystic Fibrosis Bronchiectasis (EMBRACE): A Randomized, Double-blind, Placebo-controlled Trial. The Lancet. 2012;380: 660-67.
(13) Altenburg J, et al. Effect of Azithromycin Maintenance Treatment on Infectious Exacerbations Among Patients With Non–CysticFibrosis Bronchiectasis: The BAT Randomized Controlled Trial. JAMA. 2013;309(12): 1251-1259.
(14) Serisier DJ, et al. Effect of Long-term, Low-Dose Erythromycin on Pulmonary Exacerbations Among Patients with Non-Cystic Fibrosis Bronchiectasis. JAMA. 2013;309(12): 1260-1267.
(15) CDC Vaccine Information for Adults. Retrieved from: https://www.cdc.gov/vaccines/adults/rec-vac/health-conditions/lung-disease.html
(16) Brodt AM, Stovold E, Zhang L. Inhaled Antibiotics for Stable Non-cystic Fibrosis Bronchiectasis: A Systematic Review. European Respiratory Journal. 2014;44(2): 382-393.
(17) Evans SA, et al. Lung function in bronchiectasis: the influence of Pseudomonas aeruginosa. European Respiratory Journal. 1996(9): 1601-1604.
(18) Finch S, et al. A Comprehensive Analysis of the Impact of Pseudomonas aeruginosa Colonization on Prognosis in Adult Bronchiectasis. Ann Am Thorac Soc. 2015; 12(11): 1602-1611.
(19) Barker AF, et al. Tobramycin Solution for Inhalation Reduces Sputum Pseudomonas aeruginosa Density in Bronchiectasis. Am J Respir Crit Care Med. 2000;162: 481-485.
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References(20) Drobnic ME, et al. Inhaled Tobramycin in Non-Cystic Fibrosis Patients with Bronchiectasis and Chronic Bronchial Infection with Pseudomonas aeruginosa. The Annals of Pharmacotherapy. 2005;39: 39-44.
(21) Scheinberg P, et al. A Pilot Study of the Safety and Efficacy of Tobramycin Solution for Inhalation in Patients with Severe Bronchiectasis. CHEST. 2005;127(4): 1420-1426.
(22) Murray MP, et al. A Randomized Controlled Trial of Nebulized Gentamicin in Non-Cystic Fibrosis Bronchiectasis. Am J Respir CritCare Med. 2011;183: 491-499.
(23) Haworth CS, et al. Inhaled Colistin in Patients with Bronchiectasis and Chronic Pseudomonas aeruginosa Infection. Am J Respir CritCare Medicine. 2014;189(8): 975-982.
(24) Barker AF, et al. Aztreonam for Inhalation Solution in Patients with Non-Cystic Fibrosis Bronchiectasis (AIR-BX1 and AIR-BX2): Two Randomized Double-Blind, Placebo-Controlled Phase 3 Trials. The Lancet. 2014;2: 738-749.
(25) Olivier KN, et al. Randomized Trial of Liposomal Amikacin for Inhalation and Nontuberculous Mycobacterial Lung Disease. Am J Respir Crit Care Med. 2017;195(6): 814-823.
(26) Olivier KN, et al. Inhaled Amikacin for treatment of refractory pulmonary nontuberculous mycobacterial disease. Ann Am ThoracSoc. 2014;11(1):30
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THANK YOU
• Any questions will be answered with the question session at end
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