Focus on Bronchiectasis/COPD Overlap: An Under-Recognized But Critically Important Condition

Gary Hansen, PhD

Former “Orphan Disease” Grows in Recognition Recognizing • Chronic productive cough Non-cystic fibrosis bronchiectasis (NCFB)1 is an important Bronchiectasis2 disease that remains largely unknown. Once thought to be a rare • Chronic mucus hypersecretion “orphan” condition—merely the aftermath of infectious diseases • Chronic antibiotic use that are now readily treated—emerging evidence now shows that NCFB is far more common than originally believed and is closely • Frequent hospitalizations associated with another better known major respiratory health • Reduced quality of life threat—COPD.3 Defined as the thickening and enlargement of the airways resulting from chronic inflammation, bronchiectasis damages normal airway clearance mechanisms and results in the The process is irreversible and there is no known cure— accumulation of excess secretions. As a result, patients face fortunately, appropriate care can substantially improve the chronic cough, excess sputum production, and a recurring cycle lives of affected patients. of hospitalizations.2 Appropriate diagnosis and treatment are key to improving quality of life and reducing the need for expensive While bronchiectasis may be found at any age, it is most often medical care. Specifically, airway clearance therapy directly a disease of middle-age and older. The profile of a patient with addresses the problem of purulent sputum retained in the bronchiectasis is in many ways similar to that of chronic airways and by “emptying the Petri dish” can help to reduce the bronchitis.8 Affected patients often have a chronic productive risk of future exacerbations without risking exposure to the cough for more than three months of the year along with negative effects of long-term orWhile rotating bronchiectasis antibiotics. may4 be found at any age,copious it is most sputum often production a disease of that middle is difficult-age and toolder fully. The clear. They 8 profile of a patient with bronchiectasis is inmay many have ways multiple similar to unsuccessful that of chronic attempts bronchitis. with Affected airway Bronchiectasis has rightly beenpatients called oftenan “orphan have a chronicwith many productive coughclearance for more techniques. than three As months a result, of the their year quality along withof life is often parents”5 because it is the late copiousstage of sputum a number production of pulmonary that is difficult poor to fully due clear. to cough, They may shortness have multiple of breath, unsuccessful and fatigue. attempts9 Typically, diseases and a disease with a pulmonarywith airway component.clearance techniques. Among As a result,by the their time quality they of are life diagnosed,is often poor patients due to cough, will have shortness received these are infectious diseases suchof breath, as tuberculosis and fatigue. and9 Typically, by the timemultiple they are courses diagnosed, of antibiotics patients will punctuated have received with multiple frequent nontuberculous mycobacteria courses(NTM), of severe antibiotics lower punctuated respiratory with frequentexacerbations, exacerbations, often often requiring requiring hospitalizations. hospitalizations. The The gold tract infections, chronic aspirationgold standard of gastric for contents, bronchiectasis inhaled diagnosis standardis the high -forresolution bronchiectasis CT scan, which diagnosis can show is the varying high-resolution degree CT foreign objects, and genetic conditionsof bronchial such wall as thickening cystic fibrosis, and dilation ofscan, the airways. which2 can It is showimportant varying to note degrees that patients of bronchial may have wall alpha-1 antitrypsin deficiency, radiographicand primary evidence ciliary dyskinesia.of bronchiectasis butthickening show no symptoms; and dilation indeed, of the they airways. may be2 stable It is important in the to note Autoimmune disorders, such ascondition rheumatoid for years. arthritis, However, the airway damagethat patients may develop may have into radiographicsignificant symptoms evidence at any of time sarcoidosis, and granulomatosisgiven with the polyangiitis appropriate havetrigger. also bronchiectasis but show no symptoms; indeed, they may be been linked to NCFB. Additionally, diseases that affect the stable in the condition for years. However, the airway damage immune system, for instance, HIVThe andCOPD common Connection variable may develop into significant symptoms at any time given the immunodeficiency, may lead to chronic or recurrent infections appropriate trigger. resulting in bronchiectasis in theToday susceptible a large and host. growing Despite number of patients with COPD also have been diagnosed with bronchiectasis. considerable effort, no identifiableMore causethan 20 is million found peoplein 30-50 in the U.S. 10 percent of cases.6 Once the airwayslive with are COPD distended; of these and more ciliary than 7.7 Million four million patients may be affected by 20 Million Diagnosable COPD Moderate-Very transport damaged, a “vicious cycle” will often begin: mucus is 10 Diagnosable COPD Severe10 retained in the airways becomingbronchiectasis, a site for bacterial yet only about 500,000 colonization; this in turn provokeshave anbeen inflammatory diagnosed with response the condition ,

a number rising at an annual7 rate of 8.7 4.2 Million that, if it becomes chronic, causes additional damage. The 12 percent, most likely due to increased Diagnosable Bronchiectasis progression may be slow or swift depending on a number of awareness and surveillance of the factors, but once begun, the patient faces an ongoing cycle of disease.11 A recent meta-analysis of 500 Thousand+ recurring infections, resulting in reduction in lung function Diagnosed Bronchiectasis19 available data found that over 50 and quality of life, and the likelihood of ongoing medical care. percent of patients with moderate-to- severe COPD also have evidence of Gary Hansen is the Senior Managerbronchiectasis. of Scientific Affairs,12 The RespirTech, causes, a FigureFigure 1. 1 EstimateEstimatess of of the the prevalence prevalence of of diagnosable diagnosable COPD, COPD, diagnosable Philips Company. treatments, and relationships diagnosablebronchiectasis, bronchiectasi and diagnoseds, and diagnosedbronchiectasis. bronchiectasis. between comorbid conditions within COPD are controversial and a subject of intensive research. The evidence has led some researchers to Respiratory Therapy Vol. 13 No. 4 n Fall 2018 55 propose a “COPD-bronchiectasis overlap syndrome,”13 while this concept is still debatable.14 Nonetheless, COPD may be considered a possible cause of bronchiectasis15, and bronchiectasis is certainly an exacerbating factor in COPD.16

It has long been known that COPD patients often experience a cycle of exacerbation followed by temporary recovery. More recently, a study by Suissa et al. has shown that exacerbations follow a distinct pattern: after the first event, each subsequent exacerbation follows within a shorter time and tends to be more severe than the last.17 In this study, risk of a severe exacerbation increased three times after the first exacerbation, and 24 times after the tenth. This finding emphasizes the importance of early intervention in recognizing and treating the disease, particularly when combined with bronchiectasis. A recent meta-analysis by Du et al., of 5,329 COPD patients found a greatly increased exacerbation risk due to comorbid COPD with bronchiectasis compared to COPD alone.18 The risk of exacerbations rose almost two times higher, colonization of the lungs four times higher, severe airway obstruction 30 percent higher, and mortality two times higher. It is not surprising that these elevated risks are also associated with higher healthcare costs. A recent study found that compared to COPD alone, COPD + bronchiectasis resulted in 32 percent more hospitalizations and 27 percent higher hospitalization costs.19 With these issues at stake, there is a clear need to focus on these at-risk The COPD Connectionpatients. New treatment guidelines for bronchiectasis have recently been Today a large and growing number of patients with COPD also released by the European Respiratory Society (ERS).4 This have been diagnosedNew Guidelines with bronchiectasis. for Treatment More than 20 million important report contains a broad survey of available evidence, people in the US live with COPD10; of these more than four including drug treatments and a discussion of airway clearance. million patients may be affected by bronchiectasis, yet only The ERS guidelines state that “before considering the about 500,000Given have been that diagnoseda sizable withfraction the condition, of COPD apatients whoprescription are troubled of long-term with excess antibiotics, sputum general production aspects ofmay number risingharbor at an annual bronchiectasis, rate of 8.7 percent, it seem mosts prudent likely due to evaluatebronchiectasis for the condition management using need a high to be-resolution optimized suchCT scan as airway. to increased awarenessAlong with and bronchodilators surveillance of the and disease. mucolytics,11 A bronchiectasisclearance.” Thepatients list of are airway sometimes clearance treated methods with includes long - recent meta-analysisterm antibiotics of available, such data foundas macrolides that over .50 While usefulpulmonary in addressing physiotherapy, severe exacerbations, oscillating positive long expiratory-term use of percent of patients with moderate-to-severe COPD also have pressure (PEP) devices and high-frequency chest wall oscillation evidence of bronchiectasis.such drugs raises12 The thecauses, risk treatments,of antibiotic and resistance (HFCWOand side or effects “vest therapy”). such as cardiac As a non-pharmacological complications and method 4 relationships hearingbetween losscomorbid. A recent conditions study within found COPD that are bronchiectasis for clearing patients sputum, are airway frequently clearance colonized devices byare antibioticeffective, - controversialresistant and a subject pathogens. of intensive20 Amongresearch. NCFB The evidence patients whoreadily received accepted testing, by patients, 69 percent and support had a positiveantibiotic sputum has led some culture;researchers of these,to propose 20 percenta “COPD-bronchiectasis were multiply -drug-stewardship.resistant organisms22 Aside from (MDR) directly that addressing are also thedeemed needs of 13 14 overlap syndrome,”“urgent” while or “serious” this concept threats is still accordingdebatable. to the CDC.symptomatic21 MDR organisms patients, airway are not clearance only difficult has been to shown eradicate, to Nonetheless, COPD may be considered a possible cause of reduce the risk of exacerbations23 and enhance quality of life.24 A bronchiectasisbut15, andpose bronchiectasis a long-term is threat certainly to anantibiotic stewardship.database Therefore, housing the any self-reported measure outcomesthat that ofcan more reduce than 10,000the exacerbating bacterialfactor in COPD. load in16 patients’ lungs can be valuable inbronchiectasis breaking the patients vicious shows cycle that of infection after the initiation that such of vest patients face.15 therapy (inCourage® System, RespirTech, St Paul, Minn.), It has long been known that COPD patients often experience a antibiotic use was reduced by 15 percent and hospitalizations by cycle of exacerbation followed by temporary recovery. More 59 percent (Figure 2).25 recently, a studyNew by treatment Suissa et al guidelineshas shown thatfor bronchiectasisexacerbations follow a distincthave pattern: recently after been the first released event, eachby the subsequent Hospitalization Rate exacerbationEuropean follows within Respiratory a shorter timeSociety and (ERS)tends .to4 Thisbe After Initiating HFCWO Therapy 17 more severe thanimportant the last. report In this contain study, risks a broadof a severe survey of 1.20 exacerbation increased three times after the first exacerbation, available evidence, including drug 1.00 and 24 times after the tenth. This finding emphasizes the importance oftreatments early intervention and a indiscussion recognizing of and airway treating 0.80 the disease, particularlyclearance. when The combinedERS guidelines with bronchiectasis. state that 0.60 A recent meta-analysis“before considering by Du et al, of the 5,329 prescription COPD patients of long - 0.40 found a greatly increased exacerbation risk due to comorbid

term antibiotics, general aspects of Rate Hospitalization 0.20 COPD with bronchiectasis compared to COPD alone.18 Moreover, thebronchiectasis risk of exacerbations management rose almost need two totimes be 0.00 0 5 10 15 20 25 higher, colonizationoptimized of the such lungs as four airway times clearance higher, severe.” The list Months airway obstructionof airway 30 percent clearance higher, methods and mortality includes two times higher. It is not surprising that such elevated risks are also Figure 2 Reduction in hospitalization rate after initiating HFCWO therapy for pulmonary physiotherapy, oscillating over 10,000 patients with bronchiectasis.25 associated withpositive higher expiratoryhealthcare costs. pressure A recent (PEP study) devices found Figure 2. Reduction in hospitalization rate after initiating that compared to COPD alone, COPD + bronchiectasis HFCWO therapy for over 10,000 patients with bronchiectasis.24 resulted in 32and percent high more-frequency hospitalizations chest wall and oscillation 27 percent In summary, bronchiectasis is a progressive disease of the lungs higher hospitalization(HFCWO costs. or “vest19 With therapy”). these issues As at a stake, non- there that facilitates a cycle of exacerbation for affected patients. is a clear needpharmacological to focus on these mat-riskethod patients. for clearing sputum, airwayUnder-recognized clearance devices until recently, are effective, it is far more readily common accepted than by patients, and support antibiotic stewardship.22 Asidepreviously from believed. directly Combinedaddressing with the COPD, needs bronchiectasis of symptomatic adds New Guidelines for Treatment substantial risk of hospitalization 23and early death. Once Given that a sizablepatients, fraction airway of COPD clear ancepatients has who been are shown troubled to reducebronchiectasis the risk ofis identified,exacerbations although and irreversible, enhance it quality can be of 24 with excess sputumlife. A production database may housing harbor the bronchiectasis, self-reported it outcomesmanaged of moreby treating than the 10,000 underlying bronchiectasis cause (if identified) patients with seems prudentshows to evaluate that aft forer the the condition initiation using of avest high- therapy (inCourageappropriate® System, drug therapy RespirTech, and airway St. clearance Paul, Minn.), devices. resolution CTantibiotic scan. use was reduced by 15 percent and hospitalizations by 59 percent (Figure 2).25 References Along with bronchodilators and mucolytics, bronchiectasis 1. Because its causes are so well defined, cystic fibrosis is patients are sometimesIn summary, treated bronchiectasis with long-term is antibioticsa progressive such diseaseas oftenof the considered lungs that in facilitatesa separate category,a cycle of and exace whatrbation remains is macrolides. Whilefor affected useful in patients.addressing Under severe- recognizedexacerbations, until recently,normally it is far called more “non-cystic common fibrosis than previously bronchiectasis” believed. (NCFB). long-term useCombined of such drugs with raises COPD, the riskbronchiectasis of antibiotic adds substantiInal thisrisk article, of hospitalization we’ll follow the and same early distinction. death. Once When the resistance andbronchiectasis side effects such is asidentified, cardiac complications although irreversible, and it termcan be “bronchiectasis” managed by istreating used, it isthe understood underlying to because NCFB. (if hearing loss.4 Additionally, a recent study found that 2. Goeminne P, Dupont L. Non-cystic fibrosis bronchiectasis: bronchiectasisidentified) patients are with frequently appropriate colonized drug by therapyantibiotic- and airwaydiagnosis clearance and devices. management in 21st century. Postgrad Med J. resistant pathogens. 20 Among NCFB patients who received 2010;86(1018):493-501. testing, 69 percent had a positive sputum culture; of these, 20 3. Blasi F, Chalmers JD, Aliberti S. COPD and bronchiectasis: percent were multiply-drug-resistant organisms (MDR) that are phenotype, endotype or co-morbidity? COPD. 2014;11(6):603- also deemed “urgent” or “serious” threats according to the 604. CDC.21 MDR organisms are not only difficult to eradicate, but 4. Polverino E, Goeminne PC, McDonnell MJ, et al. European pose a long-term threat to antibiotic stewardship. Therefore, any Respiratory Society guidelines for the management of adult measure that can reduce the bacterial load in patients’ lungs can bronchiectasis. Eur Respir J. 2017;50(3). be valuable in breaking the vicious cycle of infection that such 5. Goeminne PC, De Soyza A. Bronchiectasis: how to be an patients face.15 orphan with many parents? Eur Respir J. 2016;47(1):10-13.

56 Respiratory Therapy Vol. 13 No. 4 n Fall 2018 6. Pasteur MC, Bilton D, Hill AT. British Thoracic Society Forced Oscillation Technique…continued from page 49 guideline for non-CF bronchiectasis. Thorax. 2010;65 Suppl 39 Saadeh C, Cross B, Gaylor M, Griffith M. Advantage of 1:i1-58. impulse oscillometry over spirometry to diagnose chronic 7. Cole PJ. Inflammation: a two-edged sword--the model of obstructive pulmonary disease and monitor pulmonary bronchiectasis. Eur J Respir Dis Suppl. 1986;147:6-15. responses to bronchodilators: an observational study. SAGE 8. King P. Pathogenesis of bronchiectasis. Paediatr Respir Rev. Open Med. 2015;3:2050312115578957. 2011;12(2):104-110. 40 Hafez MR, Abu-Bakr SM, Mohamed AA. Forced oscillometry 9. Smith MP. Non-cystic fibrosis bronchiectasis. J R Coll track sites of airway obstruction in bronchial asthma. Ann Physician Edinb. 2011;41(2):132-139; quiz 139. Allergy Asthma Immunol. 2015;115:28-32. 10. Tilert T, Dillon C, Paulose-Ram R, Hnizdo E, Doney B. 41 Larsen GL, Morgan W, Heldt GP, et al. Impulse oscillometry Estimating the U.S. prevalence of chronic obstructive versus spirometry in a long-term study of controller therapy pulmonary disease using pre- and post-bronchodilator for pediatric asthma. J Allergy Clin Immunol. 2009;123:861- spirometry: the National Health and Nutrition Examination 867 e1. Survey (NHANES) 2007-2010. Respir Res. 2013;14:103. 42 Yamaguchi M, Niimi A, Ueda T, et al. Effect of inhaled 11. Weycker D, Hansen GL, Seifer FD. Prevalence and incidence corticosteroids on small airways in asthma: investigation of noncystic fibrosis bronchiectasis among US adults in 2013. using impulse oscillometry. Pulm Pharmacol Ther. Chron Respir Dis. 2017:1479972317709649. 2009;22:326-332. 12. Ni Y, Shi G, Yu Y, Hao J, Chen T, Song H. Clinical 43 Pisi R, Tzani P, Aiello M, et al. Small airway dysfunction characteristics of patients with chronic obstructive by impulse oscillometry in asthmatic patients with normal pulmonary disease with comorbid bronchiectasis: a systemic forced expiratory volume in the 1st second values. Allergy review and meta-analysis. Int J Chron Obstruct Pulmon Dis. Asthma Proc. 2013;34:e14-e20. 2015;10:1465-1475. 44 Manoharan A, Anderson WJ, Lipworth J, Ibrahim I, Lipworth 13. Hurst JR, Elborn JS, De Soyza A. COPD-bronchiectasis BJ. Small airway dysfunction is associated with poorer overlap syndrome. Eur Respir J. 2015;45(2):310-313. asthma control. Eur Respir J. 2014;44:1353-1355. 14. Chalmers JD. Bronchiectasis and COPD Overlap: A Case of 45 Gonem S, Natarajan S, Desai D, et al. Clinical significance of Mistaken Identity? Chest. 2017;151(6):1204-1206. small airway obstruction markers in patients with asthma. 15. Martinez-Garcia MA, Miravitlles M. Bronchiectasis in COPD Clin Exp Allergy. 2014;44:499-507. patients: more than a comorbidity? Int J Chron Obstruct 46 Anderson WJ, Zajda E, Lipworth BJ. Are we overlooking Pulmon Dis. 2017;12:1401-1411. persistent small airways dysfunction in community-managed 16. Minov J, Stoleski S, Mijakoski D, Vasilevska K, Atanasovska asthma? Ann Allergy Asthma Immunol. 2012;109:185-189 e2. A. Exacerbations in COPD Patients with Bronchiectasis. Med 47 Matsumoto H, Niimi A, Jinnai M, et al. Association of Sci (Basel). 2017;5(2):7. alveolar nitric oxide levels with pulmonary function and its 17. Suissa S, Dell’Aniello S, Ernst P. Long-term natural history of reversibility in stable asthma. Respiration. 2011;81:311-317. chronic obstructive pulmonary disease: severe exacerbations 48 Al-Shamkhi N, Alving K, Dahlen SE, et al. Important non- and mortality. Thorax. 2012;67(11):957-963. disease related determinants of exhaled NO levels in mild 18. Du Q, Jin J, Liu X, Sun Y. Bronchiectasis as a Comorbidity asthma—results from the Swedish GA LEN study. Clin Exp of Chronic Obstructive Pulmonary Disease: A Systematic Allergy. 2016;9:1185-1193. Review and Meta-Analysis. PloS one. 2016;11(3):e0150532. 19. Weycker D, Hansen GL, Seifer FD. Healthcare Utilization and Expenditures among Patients with Comorbid COPD and Non- CF Bronchiectasis in US Clinical Practice. American Thoracic Society Conference, May 23, 2017:P129. 20. Menéndez R, Méndez R, Polverino E, et al. Risk factors for multidrug-resistant pathogens in bronchiectasis exacerbations. BMC Infect Dis. 2017;17(1):659. 21. Ventola CL. The Antibiotic Resistance Crisis Part 1: Causes and Threats. Pharm Ther. 2015;40(4):277-283. 22. Chalmers JD, Aliberti S, Blasi F. Management of bronchiectasis in adults. Eur Respir J. 2015;45(5):1446-1462. 23. Munoz G, de Gracia J, Buxo M, Alvarez A, Vendrell M. Long-term benefits of airway clearance in bronchiectasis: a randomised placebo-controlled trial. Eur Respir J. 2018;51(1). 24. 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. 25. Data from RespirTech Outcomes Registry, extracted June 30, 2018, including 11,904 patients.

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