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Non-CF bronchiectasis: Orphan disease no longer

  • Jaafer Saadi Imam
    Affiliations
    Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, TX, USA
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  • Alexander G. Duarte
    Correspondence
    Corresponding author. Division of Pulmonary, Critical Care and Sleep Medicine Department of Internal Medicine, University of Texas Medical Branch, 301 University Blvd., Suite 5 140 John Sealy Annex, Galveston, TX, USA.
    Affiliations
    Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, TX, USA
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Open ArchivePublished:March 27, 2020DOI:https://doi.org/10.1016/j.rmed.2020.105940

      Abstract

      Bronchiectasis is a complex, chronic respiratory condition, characterized by frequent cough and exertional dyspnea due to a range of conditions that include inherited mucociliary defects, inhalational airway injury, immunodeficiency states and prior respiratory infections. For years, bronchiectasis was classified as either being caused by cystic fibrosis or non-cystic fibrosis. Non-cystic fibrosis bronchiectasis, once considered an orphan disease, is more prevalent worldwide in part due to greater availability of chest computed tomographic imaging. Identification of the cause of non-cystic fibrosis bronchiectasis with the use of chest imaging, laboratory testing, and microbiologic assessment of airway secretions can lead to initiation of specific therapies aimed at slowing disease progression. Nonpharmacologic therapies such as airway clearance techniques and pulmonary rehabilitation improve patient symptoms. Inhaled corticosteroids should not be routinely prescribed unless concomitant asthma or COPD is present. Inhaled antibiotics prescribed to individuals with >3 exacerbations per year are well tolerated, reduce airway bacteria load and may reduce the frequency of exacerbations. Likewise, chronic macrolide therapy reduces the frequency of exacerbations. Medical therapies for cystic fibrosis bronchiectasis may not be effective in treatment of non-cystic fibrosis bronchiectasis.

      Keywords

      The disease that was bound to claim me sooner or laterGeorge Orwell

      1. Introduction

      Bronchiectasis is a chronic disease state presenting with persistent cough and production of excess airway secretions with a reduction in health-related quality of life. Those afflicted with bronchiectasis report daily symptoms as noted by the renowned author Eric Blair known by his pen name George Orwell who described frequent cough and bronchial infections treated with periods of convalescence throughout his life that resulted in his death [
      • Ross J.J.
      Shakespeare's Tremor and Orwell's Cough: the Medical Lives of Great Writers by John J. Ross.
      ]. Early understanding of bronchiectasis can be traced to a clinicopathologic description by Rene Theophile Hyacinthe Laennec published in 1819 in which he described a 72 year old woman with chronic cough, daily sputum production and hemoptysis that at autopsy was found to have saccular bronchiectasis [
      • Reynolds H.Y.
      President's address: R.T.H. Laënnec, M.D.--clinicopathologic observations, using the stethoscope, made chest medicine more scientific.
      ]. Decades later, Dominic Corrigan and William Stokes provided clinicopathological narratives of patients with bronchiectasis in which they described airway inflammation along with mucopurulent airway secretions and pathologic airway enlargement following pneumonia and tuberculous lung infections [
      • Stokes W.
      A treatise on the diagnosis and treatment of diseases of the chest. Part. I. Diseases of the lung and windpipe.
      ]. At the same time, the pathologist, Robert Carswell, created detailed anatomical illustrations of dilated airways with inspissated secretions and cystic cavities characteristic of bronchiectasis related to tuberculosis that complimented earlier narratives [] (Fig. 1). While bronchiectasis and chronic lung disease were readily recognized in the 19th and early 20th century, there was little effective therapy and those offered were airway expectorants and postural drainage. Subsequently, changes in living conditions and hygiene contributed to a decline in tuberculosis and a bronchiectasis such that by the latter part of the 20th century bronchiectasis was designated as an orphan disease [
      • Barker A.F.
      • Bardana E.J.
      Bronchiectasis: update of an orphan disease.
      ]. Currently, bronchiectasis is considered a disease with many causes that for the sake of simplicity are classified as arising from cystic fibrosis or non-cystic fibrosis.
      Fig. 1
      Fig. 1Colored lithograph plate of a postmortem lung that revealed dilated airways with cystic airspace enlargement and bronchial secretions described as cauliflower arrangements that was a result of pulmonary tuberculosis. Illustrations by Robert Carswell, Professor of Pathological Anatomy in University College, London, 1838. (Courtesy of Moody Medical Library, Truman Blocker History of Medicine Collections).

      2. Pathogenesis

      Non-cystic fibrosis bronchiectasis refers to a broad set of conditions that give rise to airway injury that result in inflammation, increased mucus secretions and infections that produce permanent airway dilatation. This pathological process involves a cycle of airway injury and inflammation followed by airway infection that results in permanent bronchiolar dilatation and parenchymal lung involvement [
      • Cole P.J.
      Inflammation: a two-edged sword - the model of bronchiectasis.
      ]. Following initial and repeated airway injury as a result of infections produces impairment of the mucociliary layer and changes in airway microbial flora. These repeated or sustained insults to the bronchial epithelium predispose the airway to inflammation, alteration of the microbiome and failure to clear pathogenic organisms that promote the disease process [
      • Flume P.A.
      • Chalmers J.D.
      • Olivier K.N.
      Advances in bronchiectasis : endotyping , genetics , microbiome , and disease heterogeneity.
      ]. Airway inflammation may be precipitated by bacterial, viral, fungal or mycobacterial organisms that lead to neutrophil migration and release of neutrophil derived proteases with airway injury and production of airway secretions followed by remodeling. Subsequently, changes in airway microbiome are associated with emergence of pathogenic organisms that are linked with recurrent lower respiratory tract infections. Furthermore, this chronic airway infection can generate a systemic inflammatory state manifesting as fatigue, weight loss and anorexia. While the cause for the initial injury may not be readily recognized, individuals with bronchiectasis develop symptoms after a severe lower airway infection, tuberculous lung infection, rheumatologic disorder, immunodeficient states or significant inhalational exposure to smoke or combustion products.

      3. Epidemiology of non-CF bronchiectasis

      Recent estimates of the frequency of bronchiectasis are greater than previously suspected as earlier epidemiologic studies relied on symptoms and chest radiography that do not accurately capture disease prevalence. With the increased availability of chest computerized tomography (CT) imaging, a radiographic diagnosis of bronchiectasis can be established that correlates with an individual's clinical history. Furthermore, use of large data bases provides evidence of an increase in disease prevalence particularly in the elderly. In the United Kingdom, from 2004 to 2013, the incidence of bronchiectasis in adults increased from 301 per 100,000 to 485 per 100,000 for men and from 350 per 100,000 to 566 per 100,000 for women [
      • Quint J.K.
      • Millett E.R.C.
      • Joshi M.
      • Navaratnam V.
      • Thomas S.L.
      • Hurst J.R.
      • Smeeth L.
      • Brown J.S.
      Changes in the incidence, prevalence and mortality of bronchiectasis in the UK from 2004 to 2013: a population-based cohort study.
      ]. Likewise, in the United States, between 2000 and 2007, the annual prevalence of bronchiectasis in patients ≥65 year of age increased 8.7% per year and prevalence increased with age for both sexes but was greater for women [
      • Seitz A.E.
      • Olivier K.N.
      • Adjemian J.
      • Holland S.M.
      • Prevots D.R.
      Trends in bronchiectasis among medicare beneficiaries in the United States, 2000 to 2007.
      ]. Another study examined the prevalence of bronchiectasis in patients ≥65 years of age using a pulmonary specialist submitted claim and chest CT imaging and excluded patients with cystic fibrosis, HIV infection and organ transplantation [
      • Henkle E.
      • Chan B.
      • Curtis J.R.
      • Aksamit T.R.
      • Daley C.L.
      • Winthrop K.L.
      Characteristics and health-care utilization history of patients with bronchiectasis in US medicare enrollees with prescription drug plans, 2006 to 2014.
      ]. From 2012 to 2014, the investigators reported the prevalence of non-CF bronchiectasis to be 701 per 100,000 persons and more frequent in women. The mean age for newly diagnosed patients was 76.4 ± 7.44 years and COPD and asthma were observed in 51% and 28%, respectively [
      • Henkle E.
      • Chan B.
      • Curtis J.R.
      • Aksamit T.R.
      • Daley C.L.
      • Winthrop K.L.
      Characteristics and health-care utilization history of patients with bronchiectasis in US medicare enrollees with prescription drug plans, 2006 to 2014.
      ]. In 2017, the U.S. Bronchiectasis Research Registry reported the characteristics of 1,826 patients with non-CF bronchiectasis [
      • Aksamit T.R.
      • O'Donnell A.E.
      • Barker A.
      • Olivier K.N.
      • Winthrop K.L.
      • Daniels M.L.A.
      • Johnson M.
      • Eden E.
      • Griffith D.
      • Knowles M.
      • Metersky M.
      • Salathe M.
      • Thomashow B.
      • Tino G.
      • Turino G.
      • Carretta B.
      • Daley C.L.
      Adult patients with bronchiectasis: a first look at the US bronchiectasis Research registry.
      ]. The registry population mean age was 64 ± 14 years and consisted primarily of non-Hispanic white subjects (89%) with a predominance of women (79%) that never smoked (60%). Common comorbidities included GERD (47%), asthma (29%) and COPD (20%). Of note, pulmonary function test results demonstrated airflow limitation in 51% of the entire cohort while 26% had normal spirometry. Registry data also provided microbiologic culture results for 1,406 subjects with the following findings: normal respiratory flora (74%), Pseudomonas aeruginosa (33%), Staphylococcus aureus (12%), Hemophilus influenza (8%), Stenotrophomonas maltophilia (5%) and Streptococcus pneumoniae (3%). Interestingly, nontuberculous mycobacterial (NTM) disease or NTM isolation was reported in 63% highlighting the role of this group of organisms in non-cystic fibrosis bronchiectasis.

      4. Clinical features

      Bronchiectasis is characterized as chronic disease manifesting as cough with daily sputum production and frequent lower airway infections. In the US Bronchiectasis Registry, the most frequent symptoms were cough (73%), productive sputum production (53%), dyspnea (64%) and fatigue (50%). Airway secretions were described as abundant and frequent, mucopurulent and at times difficult to expectorate, resulting in wheezing, chest congestion and hemoptysis [
      • Aksamit T.R.
      • O'Donnell A.E.
      • Barker A.
      • Olivier K.N.
      • Winthrop K.L.
      • Daniels M.L.A.
      • Johnson M.
      • Eden E.
      • Griffith D.
      • Knowles M.
      • Metersky M.
      • Salathe M.
      • Thomashow B.
      • Tino G.
      • Turino G.
      • Carretta B.
      • Daley C.L.
      Adult patients with bronchiectasis: a first look at the US bronchiectasis Research registry.
      ]. Furthermore, the frequency of cough and quantity of airway secretions may wax and wane over weeks or months [
      • Kapur N.
      • Masters I.B.
      • Chang A.B.
      Exacerbations in noncystic fibrosis bronchiectasis: clinical features and investigations.
      ]. Importantly, recurrent lower respiratory tract infections often lead to a decline in physical activity, breathlessness, malaise, weight loss as well as fatigue. In a cross-sectional study of 103 patients with newly diagnosed bronchiectasis, 70% of patients reported purulent rhinosinusitis and 30% indicated prior ear, nose and throat surgery [
      • King P.T.
      • Holdsworth S.R.
      • Freezer N.J.
      • Villanueva E.
      • Holmes P.W.
      Characterisation of the onset and presenting clinical features of adult bronchiectasis.
      ]. The nonspecific nature of patient symptoms may lead to a diagnosis and treatment of chronic bronchitis, asthma or chronic cough. Therefore, chest imaging in the form of a chest radiograph is a useful initial step to characterize symptoms of chronic cough, poorly controlled asthma or recurrent lower respiratory tract infections and distinguish these from bronchiectasis. However, chest radiography has limitations with reported sensitivity that ranges from 37% to 87% [
      • Currie D.C.
      • Cooke J.C.
      • Morgan A.D.
      • Kerr I.H.
      • Delany D.
      • Strickland B.
      • Cole P.J.
      Interpretation of bronchograms and chest radiographs in patients with chronic sputum production.
      ,
      • Van Der Bruggen-Bogaarts B.A.H.A.
      • Van Der Bruggen H.M.J.G.
      • Van Waes P.F.G.M.
      • Lammers J.W.J.
      Screening for bronchiectasis: a comparative study between chest radiography and high-resolution CT.
      ] and may not identify early forms of bronchiectasis. On the other hand, computed tomography (HRCT) of the chest has reported sensitivity of 71–96% and specificity of 93–99% [
      • Dodd J.D.
      • Souza C.A.
      • Müller N.L.
      Conventional high-resolution CT versus helical high-resolution MDCT in the detection of bronchiectasis.
      ,
      • Phillips M.S.
      • Williams M.P.
      • Flower C.D.R.
      How useful is computed tomography in the diagnosis and assessment of bronchiectasis?.
      ]. The diagnostic chest CT criteria of bronchiectasis include bronchoarterial ratio > one, lack of bronchial tapering and visualization of bronchial airways to within 1–2 cm of the pleura (Fig. 2, Fig. 3, Fig. 4) [
      • Bonavita J.
      • Naidich D.P.
      Imaging of bronchiectasis.
      ]. Additional CT radiographic features of bronchiectasis include peribronchial thickening, mucus plugs, centrilobular nodules, tree -in-bud nodules, mosaic perfusion, intra and inter-lobular septal thickening and focal atelectasis/consolidation [
      • Bonavita J.
      • Naidich D.P.
      Imaging of bronchiectasis.
      ]. In the US Bronchiectasis Registry dilated airway involvement in more than two lung regions was observed in 89% of patients and 60% were found to have tree in bud infiltrates involving all lobes. In addition, airway dilation of the right middle lobe, lingula, left upper and right upper lobes was more common in patients with bronchiectasis and NTM pulmonary infections [
      • Aksamit T.R.
      • O'Donnell A.E.
      • Barker A.
      • Olivier K.N.
      • Winthrop K.L.
      • Daniels M.L.A.
      • Johnson M.
      • Eden E.
      • Griffith D.
      • Knowles M.
      • Metersky M.
      • Salathe M.
      • Thomashow B.
      • Tino G.
      • Turino G.
      • Carretta B.
      • Daley C.L.
      Adult patients with bronchiectasis: a first look at the US bronchiectasis Research registry.
      ].
      Fig. 2
      Fig. 2Thoracic CT axial image demonstrates characteristic changes seen in bronchiectasis including air trapping and mosaic perfusion (yellow bracket) as well as increased bronchoarterial ratio (>1.5) (yellow arrow). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
      Fig. 3
      Fig. 3Thoracic CT axial image demonstrates lack of tapering of distal airways with dilated bronchus visualized near the lung periphery (yellow arrow) and increased bronchoarterial ratio (>1.5) (white arrows). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
      Fig. 4
      Fig. 4Thoracic CT coronal image demonstrates diffuse cylindrical and varicose bronchiectasis affecting both lungs, most evident in the lingula (yellow bracket), with associated bronchial wall thickening and peripheral small nodules that represent airway secretions. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
      The ability to determine the etiology of bronchiectasis is challenging and requires distinguishing cystic fibrosis from non-cystic fibrosis bronchiectasis. Cystic fibrosis is considered a childhood illness and newborn screening methods implemented in the Australia, New Zealand, France, England, Scotland and United States allow diagnosis before the development of symptoms. Yet, a small proportion of adults are diagnosed with cystic fibrosis and a retrospective study of 1,000 patients residing in Canada with cystic fibrosis reported 7% were diagnosed at age ≥18 years. A diagnosis of cystic fibrosis was determined using sweat chloride testing, genomic analysis of blood lymphocytes and nasal potential difference measurements. Adults with cystic fibrosis were more likely to present with gastrointestinal symptoms, diabetes mellitus and infertility [
      • Gilljam M.
      • Ellis L.
      • Corey M.
      • Zielenski J.
      • Durie P.
      • Tullis D.E.
      Clinical manifestations of cystic fibrosis among patients with diagnosis in adulthood.
      ]. A comparison of the characteristics of patients with cystic fibrosis diagnosed in childhood and non-CF bronchiectasis reveals distinctions that include older age, predominance of women and greater lower lobe involvement (Table 1). Patients diagnosed with cystic fibrosis as adults are more likely to have unusual genetic mutations and normal pancreatic function [
      • Gilljam M.
      • Ellis L.
      • Corey M.
      • Zielenski J.
      • Durie P.
      • Tullis D.E.
      Clinical manifestations of cystic fibrosis among patients with diagnosis in adulthood.
      ,
      • Rodman D.M.
      • Polis J.M.
      • Heltshe S.L.
      • Sontag M.K.
      • Chacon C.
      • Rodman R.V.
      • Brayshaw S.J.
      • Huitt G.A.
      • Iseman M.D.
      • Saavedra M.T.
      • Taussig L.M.
      • Wagener J.S.
      • Accurso F.J.
      • Nick J.A.
      Late diagnosis defines a unique population of long-term survivors of cystic fibrosis.
      ]. As for radiographic features, patients with cystic fibrosis diagnosed in adulthood demonstrate predominant upper lobe involvement and chronic sinus opacification [
      • Averill S.
      • Lubner M.G.
      • Menias C.O.
      • Bhalla S.
      • Mellnick V.M.
      • Kennedy T.A.
      • Pickhardt P.J.
      Multisystem imaging findings of cystic fibrosis in adults: recognizing typical and atypical patterns of disease.
      ]. While no gender difference has been recognized in cystic fibrosis diagnosed in childhood, a female predominance is observed in adults diagnosed with cystic fibrosis [
      • Nick J.A.
      • Rodman D.M.
      Manifestations of cystic fibrosis diagnosed in adulthood.
      ]. Furthermore, patients diagnosed in adulthood are reported to have a higher prevalence of NTM lung infections [
      • Rodman D.M.
      • Polis J.M.
      • Heltshe S.L.
      • Sontag M.K.
      • Chacon C.
      • Rodman R.V.
      • Brayshaw S.J.
      • Huitt G.A.
      • Iseman M.D.
      • Saavedra M.T.
      • Taussig L.M.
      • Wagener J.S.
      • Accurso F.J.
      • Nick J.A.
      Late diagnosis defines a unique population of long-term survivors of cystic fibrosis.
      ].
      Table 1Clinical characteristics that distinguish CF bronchiectasis from adult onset CF bronchiectasis and non-CF bronchiectasis.
      CharacteristicsCystic Fibrosis (CF)Adult onset CFNon-CF Bronchiectasis
      AgeChildhoodAge>18Age>60
      GenderNo gender differenceWomenWomen
      Lung predominanceUpper lobe predominanceLower lobe predominance
      Severity of diseaseSevere lung and GI diseaseEqual or less severe lung and GI diseaseVariable severity of lung disease
      EtiologyGenetic: ΔF508 CFTR mutationGenetic: lower prevalence of ΔF508 CFTR mutation; milder classes of CFTR mutationPost-infectious most common
      Comorbid conditionsPancreatic insufficiency, sinusitis, nasal polypsPancreatic insufficiency, sinusitis, nasal polypsCardiovascular disease, COPD, asthma, sinusitis

      5. Etiology

      Bronchiectasis may present as either a focal process involving a pulmonary lobe or segment or a diffuse process with multi-lobar, bilateral involvement. The radiographic features may range from subtle airway dilation to parenchymal cavities with focal airway enlargement to cystic bronchi [
      • Milliron B.
      • Henry T.S.
      • Veeraraghavan S.
      • Little B.P.
      ]. Patients may experience no symptoms despite radiographic findings while others have daily cough and phlegm production punctuated by periodic exacerbations. There exists an array of conditions that can lead to bronchiectasis with a broad range of clinical presentations. An approach towards identification of the etiology involves a clinical history, physical examination, radiographic imaging, sputum cultures and laboratory and pulmonary function testing. Several investigators have reported the different causes of bronchiectasis and identified a post-infectious process in 20–32% of patients [
      • Pasteur M.C.
      • Helliwell S.M.
      • Houghton S.J.
      • Webb S.C.
      • Foweraker J.E.
      • Coulden R.A.
      • Flower C.D.
      • Bilton D.
      • Keogan M.T.
      An investigation into causative factors in patients with bronchiectasis.
      ,
      • Shoemark A.
      • Ozerovitch L.
      • Wilson R.
      Aetiology in adult patients with bronchiectasis.
      ,
      • Lonni S.
      • Chalmers J.D.
      • Goeminne P.C.
      • McDonnell M.J.
      • Dimakou K.
      • De Soyza A.
      • Polverino E.
      • Van de Kerkhove C.
      • Rutherford R.
      • Davison J.
      • Rosales E.
      • Pesci A.
      • Restrepo M.I.
      • Torres A.
      • Aliberti S.
      Etiology of non-cystic fibrosis bronchiectasis in adults and its correlation to disease severity.
      ,
      • Olveira C.
      • Padilla A.
      • Martínez-García M.-Á.
      • de la Rosa D.
      • Girón R.-M.
      • Vendrell M.
      • Máiz L.
      • Borderías L.
      • Polverino E.
      • Martínez-Moragón E.
      • Rajas O.
      • Casas F.
      • Cordovilla R.
      • de Gracia J.
      Etiology of bronchiectasis in a cohort of 2047 patients. An analysis of the Spanish historical bronchiectasis registry.
      ,
      • Visser S.K.
      • Bye P.T.P.
      • Fox G.J.
      • Burr L.D.
      • Chang A.B.
      • Holmes-Liew C.-L.
      • King P.
      • Middleton P.G.
      • Maguire G.P.
      • Smith D.
      • Thomson R.M.
      • Stroil-Salama E.
      • Britton W.J.
      • Morgan L.C.
      Australian adults with bronchiectasis: the first report from the Australian Bronchiectasis Registry.
      ] (Table 2). However, despite extensive laboratory and genetic testing a specific cause may not be identified in 26%–53% of patients. Additional causes include primary immunodeficient conditions, allergic bronchopulmonary aspergillosis (ABPA), chronic obstructive pulmonary disease (COPD), asthma, gastroesophageal reflux, pulmonary ciliary dyskinesia (PCD) and nontuberculous lung infections. While post-infectious causes for bronchiectasis were more common decades ago and classified as such, primarily from self-reported accounts, this etiology is subject to recall bias and thereby may be overrepresented. Moreover, recent investigations have identified fewer number of idiopathic cases while a greater frequency of cystic fibrosis is likely related to use of genetic testing [
      • Olveira C.
      • Padilla A.
      • Martínez-García M.-Á.
      • de la Rosa D.
      • Girón R.-M.
      • Vendrell M.
      • Máiz L.
      • Borderías L.
      • Polverino E.
      • Martínez-Moragón E.
      • Rajas O.
      • Casas F.
      • Cordovilla R.
      • de Gracia J.
      Etiology of bronchiectasis in a cohort of 2047 patients. An analysis of the Spanish historical bronchiectasis registry.
      ].
      Table 2Etiology of non-CF Bronchiectasis.
      CharacteristicsPasteur [
      • Pasteur M.C.
      • Helliwell S.M.
      • Houghton S.J.
      • Webb S.C.
      • Foweraker J.E.
      • Coulden R.A.
      • Flower C.D.
      • Bilton D.
      • Keogan M.T.
      An investigation into causative factors in patients with bronchiectasis.
      ] (2000)
      Shoemark [
      • Shoemark A.
      • Ozerovitch L.
      • Wilson R.
      Aetiology in adult patients with bronchiectasis.
      ] (2007)
      Lonni [
      • Lonni S.
      • Chalmers J.D.
      • Goeminne P.C.
      • McDonnell M.J.
      • Dimakou K.
      • De Soyza A.
      • Polverino E.
      • Van de Kerkhove C.
      • Rutherford R.
      • Davison J.
      • Rosales E.
      • Pesci A.
      • Restrepo M.I.
      • Torres A.
      • Aliberti S.
      Etiology of non-cystic fibrosis bronchiectasis in adults and its correlation to disease severity.
      ] (2015)
      Olveira [
      • Olveira C.
      • Padilla A.
      • Martínez-García M.-Á.
      • de la Rosa D.
      • Girón R.-M.
      • Vendrell M.
      • Máiz L.
      • Borderías L.
      • Polverino E.
      • Martínez-Moragón E.
      • Rajas O.
      • Casas F.
      • Cordovilla R.
      • de Gracia J.
      Etiology of bronchiectasis in a cohort of 2047 patients. An analysis of the Spanish historical bronchiectasis registry.
      ] (2017)
      Visser [
      • Visser S.K.
      • Bye P.T.P.
      • Fox G.J.
      • Burr L.D.
      • Chang A.B.
      • Holmes-Liew C.-L.
      • King P.
      • Middleton P.G.
      • Maguire G.P.
      • Smith D.
      • Thomson R.M.
      • Stroil-Salama E.
      • Britton W.J.
      • Morgan L.C.
      Australian adults with bronchiectasis: the first report from the Australian Bronchiectasis Registry.
      ] (2019)
      n15016512582047566
      Age52.7 ± 15.249 ± 166764.9 ± 18.471
      Female (%)62.742605571
      Idiopathic80 (53%)43 (26%)502 (40%)496 (24%)184 (32.5%)
      Post-infectious44 (29%)52 (32%)257 (20%)613 (30%)159 (28%)
      Immunodeficiency12 (8%)11 (7%)73 (5.8)192 (9.4)21 (3.7%)
      ABPA11 (7%)13 (8%)56 (4.5%)18 (0.9%)22 (3.9%)
      PCD (genetic)3 (1.5%)17 (10%)21 (1.7%)60 (2.9%)22 (3.9%)
      CTD/Rheumatoid arthritis4 (3%)3 (2%)128 (10%)29 (1.4%)8 (1.4%)
      Young syndrome5 (3%)5 (3%)5 (0.2%)
      Aspiration/GERD6 (4%)2 (1%)8 (0.6%)33 (1.5%)14 (2.5%)
      Yellow Nail syndrome1 (0.1%)4 (0.2%)
      NTM infection2 (1%)233 (11.4%)48 (8.5%)
      Cystic Fibrosis (genetic)4 (3%)2 (1%)255 (12.5%)
      IBD/Ulcerative colitis2 (<1%)5 (3%)24 (1.9%)5 (0.2%)
      Pan bronchiolitis1 (<1%)4 (2%)2 (0.1%)
      Congenital malformation1 (<1%)7 (0.6%)14 (0.7%)
      COPD129 (15%)160 (7.8%)19 (3.4%)
      Asthma41 (3.3%)110 (5.4%)21 (3.7%)
      Alpha-1-antitrypsin deficiency8 (0.6%)10 (0.5%)

      5.1 Infections

      A childhood severe lower respiratory tract infection is associated with development of bronchiectasis, yet the factors and mechanisms leading to this have not been thoroughly examined. Tuberculosis, pertussis, mycoplasma, viruses including adenovirus and measles have been implicated as causative infectious agents leading to permanent lung damage and bronchiectasis [
      • Jones E.M.
      • Peck W.M.
      Relationships between tuberculosis and bronchiectasis; a study of clinical and of post-mortem material.
      ,
      • Warner W.P.
      Some factors causing bronchial dilatation in bronchiectasis.
      ,
      • Kim C.K.
      • Chung C.Y.
      • Kim J.S.
      • Kim W.S.
      • Park Y.
      • Koh Y.Y.
      Late abnormal findings on high-resolution computed tomography after Mycoplasma pneumonia.
      ,
      • Herbert F.A.
      • Wilkinson D.
      • Burchak E.
      • Morgante O.
      Adenovirus type 3 pneumonia causing lung damage in childhood.
      ,
      • Kaschula R.O.C.
      • Druker J.
      • Kipps A.
      Late morphologic consequences of measles: a lethal and debilitating lung disease among the poor.
      ]. In the past, pulmonary tuberculosis was more common in industrialized nations that resulted in segmental or lobar bronchiectasis [
      • Rosenzweig D.Y.
      • Stead W.W.
      The role of tuberculosis and other forms of bronchopulmonary necrosis in the pathogenesis of bronchiectasis.
      ]. Interestingly, in industrialized countries the incidence of tuberculosis has declined over the years while the frequency of NTM lung infections associated with bronchiectasis has risen. The U.S. Bronchiectasis Registry reported 63% of patients to have NTM lung infection while in Europe 1–12% of patients with bronchiectasis had NTM sputum isolation [
      • Faverio P.
      • Stainer A.
      • Bonaiti G.
      • Zucchetti S.C.
      • Simonetta E.
      • Lapadula G.
      • Marruchella A.
      • Gori A.
      • Blasi F.
      • Codecasa L.
      • Pesci A.
      • Chalmers J.D.
      • Loebinger M.R.
      • Aliberti S.
      Characterizing non-tuberculous mycobacteria infection in bronchiectasis.
      ,
      • Máiz L.
      • Girón R.
      • Olveira C.
      • Vendrell M.
      • Nieto R.
      • Martínez-García M.A.
      Prevalence and factors associated with nontuberculous mycobacteria in non-cystic fibrosis bronchiectasis: a multicenter observational study.
      ]. The large disparity between these findings likely reflects a referral bias in the U.S. Bronchiectasis registry as many of the centers are also NTM centers of expertise. Over 140 NTM species have been identified, with Mycobacterium avium complex (MAC), M. kansasii and M. abscessus being the most common pulmonary pathogens associated with bronchiectasis. NTM pulmonary infections associated with bronchiectasis have been described to occur in immunocompetent, elderly women and nonsmokers with pectus excavatum, scoliosis and mitral valve prolapse without a recognized immune defect [
      • Kim R.D.
      • Greenberg D.E.
      • Ehrmantraut M.E.
      • Guide S.V.
      • Ding L.
      • Shea Y.
      • Brown M.R.
      • Chernick M.
      • Steagall W.K.
      • Glasgow C.G.
      • Lin J.
      • Jolley C.
      • Sorbara L.
      • Raffeld M.
      • Hill S.
      • Avila N.
      • Sachdev V.
      • Barnhart L.A.
      • Anderson V.L.
      • Claypool R.
      • Hilligoss D.M.
      • Garofalo M.
      • Fitzgerald A.
      • Anaya-O’Brien S.
      • Darnell D.
      • DeCastro R.
      • Menning H.M.
      • Ricklefs S.M.
      • Porcella S.F.
      • Olivier K.N.
      • Moss J.
      • Holland S.M.
      Pulmonary nontuberculous mycobacterial disease: prospective study of a distinct preexisting syndrome.
      ,
      • Kartalija M.
      • Ovrutsky A.R.
      • Bryan C.L.
      • Pott G.B.
      • Fantuzzi G.
      • Thomas J.
      • Strand M.J.
      • Bai X.
      • Ramamoorthy P.
      • Rothman M.S.
      • Nagabhushanam V.
      • McDermott M.
      • Levin A.R.
      • Frazer-Abel A.
      • Giclas P.C.
      • Korner J.
      • Iseman M.D.
      • Shapiro L.
      • Chan E.D.
      Patients with nontuberculous mycobacterial lung disease exhibit unique body and immune phenotypes.
      ]. Of note, 36% of these patients were found to have mutations in the cystic fibrosis transmembrane conductance (CFTR) regulator gene that suggests various factors are involved in development of NTM associated bronchiectasis including a defect in mucociliary clearance [
      • Kim R.D.
      • Greenberg D.E.
      • Ehrmantraut M.E.
      • Guide S.V.
      • Ding L.
      • Shea Y.
      • Brown M.R.
      • Chernick M.
      • Steagall W.K.
      • Glasgow C.G.
      • Lin J.
      • Jolley C.
      • Sorbara L.
      • Raffeld M.
      • Hill S.
      • Avila N.
      • Sachdev V.
      • Barnhart L.A.
      • Anderson V.L.
      • Claypool R.
      • Hilligoss D.M.
      • Garofalo M.
      • Fitzgerald A.
      • Anaya-O’Brien S.
      • Darnell D.
      • DeCastro R.
      • Menning H.M.
      • Ricklefs S.M.
      • Porcella S.F.
      • Olivier K.N.
      • Moss J.
      • Holland S.M.
      Pulmonary nontuberculous mycobacterial disease: prospective study of a distinct preexisting syndrome.
      ].
      Whole exome sequence analysis in 69 white patients with NTM pulmonary infection identified variants in immune, CFTR, cilia and connective tissue genes that suggests susceptibility to pulmonary NTM infection is related to combinations of genetic variants, in the above categories, plus environmental exposure [
      • Szymanski E.P.
      • Leung J.M.
      • Fowler C.J.
      • Haney C.
      • Hsu A.P.
      • Chen F.
      • Duggal P.
      • Oler A.J.
      • McCormack R.
      • Podack E.
      • Drummond R.A.
      • Lionakis M.S.
      • Browne S.K.
      • Prevots D.R.
      • Knowles M.
      • Cutting G.
      • Liu X.
      • Devine S.E.
      • Fraser C.M.
      • Tettelin H.
      • Olivier K.N.
      • Holland S.M.
      Pulmonary nontuberculous mycobacterial infection a multisystem, multigenic disease.
      ]. Additional genetic linkage analysis in humans identified the TTK protein kinase gene on chromosome 6q14.1 that is important for DNA repair and may contribute to the increased susceptibility to NTM infection [
      • Chen F.
      • Szymanski E.P.
      • Olivier K.N.
      • Liu X.
      • Tettelin H.
      • Holland S.M.
      • Duggal P.
      Whole-exome sequencing identifies the 6q12-q16 linkage region and a candidate gene, TTK, for pulmonary nontuberculous mycobacterial disease.
      ]. Still, the natural history of bronchiectasis needs further investigation as to the cause and effect. It is less clear that NTM disease may precede bronchiectasis formation as there are no animal models or series of patients that specifically demonstrate this.
      Aspergillus is recognized to lead to bronchiectasis in patients with asthma and cystic fibrosis. Under normal circumstances, inhaled fungal conidia do not pose a health hazard and are readily cleared from the airways [
      • Agarwal R.
      Allergic bronchopulmonary aspergillosis.
      ]. However, in patients with asthma and cystic fibrosis, impaired airway clearance can lead to organism deposition that produces an inflammatory airway response responsible for the development of central bronchiectasis. Allergic bronchopulmonary aspergillosis (ABPA) is associated with development of bronchiectasis with the following diagnostic criteria; peripheral eosinophilia, total serum IgE > 1000 IU/mL, Apergillus-specific IgE and a positive skin Aspergillus skin test [
      • Agarwal R.
      • Chakrabarti A.
      • Shah A.
      • Gupta D.
      • Meis J.F.
      • Guleria R.
      • Moss R.
      • Denning D.W.
      Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria.
      ]. Inquiry into the pathogenesis resulted in a study comparing healthy individuals, patients with atopic asthma and patients with ABPA and the latter group were identified with single nucleotide polymorphisms in IL13, IL4 and TLR3 implicating these pathways in the susceptibility to ABPA [
      • Overton N.L.D.
      • Denning D.W.
      • Bowyer P.
      • Simpson A.
      Genetic susceptibility to allergic bronchopulmonary aspergillosis in asthma: a genetic association study, Allergy, Asthma.
      ].

      5.2 Disorders of immunity

      Genetic immune deficiency such as X linked agammaglobulinemia, common variable immune deficiency and hyper IgE syndrome are associated with frequent lower respiratory tract infections and bronchiectasis. X-linked agammaglobulinemia results from an X-linked recessive gene mutation in the Bruton's tyrosine kinase gene characterized by the absence of all immunoglobulin isotypes and circulating B lymphocytes. This results in otitis, conjunctivitis, frequent sinopulmonary infections and bronchiectasis [
      • Tarzi M.D.
      • Grigoriadou S.
      • Carr S.B.
      • Kuitert L.M.
      • Longhurst H.J.
      Clinical immunology review series: an approach to the management of pulmonary disease in primary antibody deficiency.
      ]. Common variable immune deficiency, an underdiagnosed cause of non-CF bronchiectasis, is characterized by defective B lymphocyte differentiation, impaired antibody production and hypogammaglobulinemia [
      • Gupta S.
      • Pattanaik D.
      • Krishnaswamy G.
      Common variable immune deficiency and associated complications.
      ]. This condition manifests as recurrent bacterial sinopulmonary infections and bronchiectasis. The reported incidence of common variable immune deficiency is 1:20,000 to 1:50,000 in Caucasians and frequently diagnosed in adults between the ages of 20–40 years. Hyper IgE syndrome, also referred as Job's syndrome, is a rare condition found in males and females characterized by eczema, recurrent pyogenic Streptococcus, Staphylococcus and Haemophilus infections that manifest as skin abscesses and recurrent bacterial pneumonia complicated by bronchiectasis [
      • Chandesris M.-O.O.
      • Melki I.
      • Natividad A.
      • Puel A.
      • Fieschi C.
      • Yun L.
      • Thumerelle C.
      • Oksenhendler E.
      • Boutboul D.
      • Thomas C.
      • Hoarau C.
      • Lebranchu Y.
      • Stephan J.-L.L.
      • Cazorla C.
      • Aladjidi N.
      • Micheau M.
      • Tron F.
      • Baruchel A.
      • Barlogis V.
      • Palenzuela G.
      • Mathey C.
      • Dominique S.
      • Body G.
      • Munzer M.
      • Fouyssac F.
      • Jaussaud R.
      • Bader-Meunier B.
      • Mahlaoui N.
      • Blanche S.
      • Debré M.
      • Le Bourgeois M.
      • Gandemer V.
      • Lambert N.
      • Grandin V.
      • Ndaga S.
      • Jacques C.
      • Harre C.
      • Forveille M.
      • Alyanakian M.-A.A.
      • Durandy A.
      • Bodemer C.
      • Suarez F.
      • Hermine O.
      • Lortholary O.
      • Casanova J.-L.L.
      • Fischer A.
      • Picard C.
      Autosomal Dominant STAT3 Deficiency and Hyper-IgE Syndrome: Molecular, Cellular, and Clinical Features from a French National Survey.
      ]. Elevated serum IgE levels >1,000 IU/mL and peripheral eosinophilia are common laboratory findings [
      • Holland S.M.
      • DeLeo F.R.
      • Elloumi H.Z.
      • Hsu A.P.
      • Uzel G.
      • Brodsky N.
      • Freeman A.F.
      • Demidowich A.
      • Davis J.
      • Turner M.L.
      • Anderson V.L.
      • Darnell D.N.
      • Welch P.A.
      • Kuhns D.B.
      • Frucht D.M.
      • Malech H.L.
      • Gallin J.I.
      • Kobayashi S.D.
      • Whitney A.R.
      • Voyich J.M.
      • Musser J.M.
      • Woellner C.
      • Schäffer A.A.
      • Puck J.M.
      • Grimbacher B.
      STAT3 mutations in the hyper-IgE syndrome.
      ,
      • Alsum Z.
      • Hawwari A.
      • Alsmadi O.
      • Al-Hissi S.
      • Borrero E.
      • Abu-Staiteh A.
      • Khalak H.G.
      • Wakil S.
      • Eldali A.M.
      • Arnaout R.
      • Al-Ghonaium A.
      • Al-Muhsen S.
      • Al-Dhekri H.
      • Al-Saud B.
      • Al-Mousa H.
      Clinical, immunological and molecular characterization of DOCK8 and DOCK8-like deficient patients: single center experience of twenty-five patients.
      ]. Individuals with this condition commonly have defects in signal transducer and activator of transcription 3 (STAT3) and this signaling pathway abnormality impairs T helper 17 differentiation and function [
      • Woellner C.
      • Gertz E.M.
      • Schäffer A.A.
      • Lagos M.
      • Perro M.
      • Glocker E.-O.
      • Pietrogrande M.C.
      • Cossu F.
      • Franco J.L.
      • Matamoros N.
      • Pietrucha B.
      • Heropolitańska-Pliszka E.
      • Yeganeh M.
      • Moin M.
      • Español T.
      • Ehl S.
      • Gennery A.R.
      • Abinun M.
      • Breborowicz A.
      • Niehues T.
      • Kilic S.S.
      • Junker A.
      • Turvey S.E.
      • Plebani A.
      • Sánchez B.
      • Garty B.-Z.
      • Pignata C.
      • Cancrini C.
      • Litzman J.
      • Sanal O.
      • Baumann U.
      • Bacchetta R.
      • Hsu A.P.
      • Davis J.N.
      • Hammarström L.
      • Davies E.G.
      • Eren E.
      • Arkwright P.D.
      • Moilanen J.S.
      • Viemann D.
      • Khan S.
      • Maródi L.
      • Cant A.J.
      • Freeman A.F.
      • Puck J.M.
      • Holland S.M.
      • Grimbacher B.
      Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome.
      ].

      5.3 Genetic causes

      Several genetic causes of bronchiectasis have been identified and categorized as congenital airway defects and mutations that impair mucociliary clearance.

      5.4 Congenital defects of the airways

      Among the congenital defects of the airways, familial congenital bronchiectasis (Williams-Campbell Syndrome) and tracheobronchomegaly (Mounier-Kuhn syndrome) are associated with bronchiectasis. Williams-Campbell Syndrome is a rare condition characterized by diffuse tracheobronchomalacia due to partial or complete absence of bronchial cartilage [
      • Jones V.F.
      • Eid N.S.
      • Franco S.M.
      • Badgett J.T.
      • Buchino J.J.
      Familial congenital bronchiectasis: williams-Campbell syndrome.
      ]. Mounier- Kuhn syndrome is a rare condition caused by atrophy or complete absence of elastic fibers with thinning of muscular components of the trachea and main bronchi [
      • Krustins E.
      • Kravale Z.
      • Buls A.
      Mounier-Kuhn syndrome or congenital tracheobronchomegaly: a literature review.
      ]. The condition predominantly affects males and manifests in the third decade of life as recurrent respiratory infections with a chronic cough. Tracheomalacia may be identified with chest CT imaging and expiratory images allows identification of airway narrowing that is the impediment to adequate clearance of airway secretions [
      • Schwartz M.
      • Rossoff L.
      ].

      5.5 Defects leading to impaired mucociliary clearance

      Cystic Fibrosis is the most common autosomal recessive disorder in Europe and North America and the most common known cause of bronchiectasis in the developed world. Disease incidence is approximately 1 in 3,000 to 4,000 live births, with a carrier frequency in non-Hispanic Whites of ~1 in 25 [
      • Sanders D.B.
      • Fink A.K.
      Background and epidemiology.
      ]. Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes an adenosine triphosphate-binding protein that functions as a chloride ion channel and regulator of salt and water transport across the apical membrane of exocrine epithelial cells. The typical form develops multisystemic disease involvement of one or more organ systems and has an elevated sweat chloride test (>60 mmol/L). Children and adolescents manifest upper and lower respiratory tract infections, steatorrhea, distal intestinal obstruction, rectal prolapse, liver disease, delayed puberty and infertility [
      • Sullivan B.P.O.
      • Freedman S.D.
      Seminar cystic fibrosis.
      ]. In contrast, patients may lack the previously mentioned typical features or exhibit mild symptoms with normal or intermediate sweat chloride results. Patients with milder symptoms can be diagnosed with cystic fibrosis with use of genetic testing if two copies of CFTR mutations are identified or a with abnormal nasal potential difference [
      • Keating C.L.
      • Liu X.
      • DiMango E.A.
      Classic respiratory disease but atypical diagnostic testing distinguishes adult presentation of cystic fibrosis.
      ]. Adults diagnosed with cystic fibrosis (≥18 years) are more likely to have atypical symptoms and unusual CFTR mutations. Previously, this group of individuals was referred to as “atypical” or “non-classic” cystic fibrosis but this terminology is discouraged as it may refer to various phenotypes [
      • Farrell P.M.
      • White T.B.
      • Ren C.L.
      • Hempstead S.E.
      • Accurso F.
      • Derichs N.
      • Howenstine M.
      • Mccolley S.A.
      • Rock M.
      • Rosenfeld M.
      • Sermet-Gaudelus I.
      • Southern K.W.
      • Marshall B.C.
      • Sosnay P.R.
      Diagnosis of cystic fibrosis: consensus guidelines from the cystic fibrosis foundation.
      ]. Patients with clinical involvement of one organ with evidence of CFTR dysfunction not fulfilling genetic or functional testing are classified as CFTR-related disease. Up to 7% of patients with cystic fibrosis are diagnosed at age 18 or older and manifest bronchiectasis, chronic sinusitis, chronic pancreatitis or isolated obstructive azoospermia [
      • Bienvenu T.
      • Sermet-Gaudelus I.
      • Burgel P.R.
      • Hubert D.
      • Crestani B.
      • Bassinet L.
      • Dusser D.
      • Fajac I.
      Cystic fibrosis transmembrane conductance regulator channel dysfunction in non-cystic fibrosis bronchiectasis.
      ].
      Another inherited condition affecting mucociliary clearance is primary ciliary dyskinesia (PCD) that involves the respiratory and genitourinary tract. PCD is an autosomal recessive condition caused by ciliary dysfunction or immotility. The defect of the ciliary axoneme or sperm flagella results in chronic upper and lower airway infections and infertility. Most patients are diagnosed in childhood but presentation in adults is recognized [
      • Knowles M.R.
      • Daniels L.A.
      • Davis S.D.
      • Zariwala M.A.
      • Leigh M.W.
      Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease.
      ,
      • Yiallouros P.K.
      • Kouis P.
      • Middleton N.
      • Nearchou M.
      • Adamidi T.
      • Georgiou A.
      • Eleftheriou A.
      • Ioannou P.
      • Hadjisavvas A.
      • Kyriacou K.
      Clinical features of primary ciliary dyskinesia in Cyprus with emphasis on lobectomized patients.
      ]. The estimated incidence is approximately 1 per 15,000 live births but the prevalence is difficult to determine due to limitations in diagnostic testing. The challenges associated with establishment of a diagnosis of pulmonary ciliary dyskinesia are related to the variation in clinical phenotype, limited commercial genetic testing and a spectrum of ciliary ultrastructural deficits [
      • Lucas J.S.
      • Barbato A.
      • Collins S.A.
      • Goutaki M.
      • Behan L.
      • Caudri D.
      • Dell S.
      • Eber E.
      • Escudier E.
      • Hirst R.A.
      • Hogg C.
      • Jorissen M.
      • Latzin P.
      • Legendre M.
      • Leigh M.W.
      • Midulla F.
      • Nielsen K.G.
      • Omran H.
      • Papon J.-F.
      • Pohunek P.
      • Redfern B.
      • Rigau D.
      • Rindlisbacher B.
      • Santamaria F.
      • Shoemark A.
      • Snijders D.
      • Tonia T.
      • Titieni A.
      • Walker W.T.
      • Werner C.
      • Bush A.
      • Kuehni C.E.
      European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia.
      ,
      • Shapiro A.J.
      • Davis S.D.
      • Polineni D.
      • Manion M.
      • Rosenfeld M.
      • Dell S.D.
      • Chilvers M.A.
      • Ferkol T.W.
      • Zariwala M.A.
      • Sagel S.D.
      • Josephson M.
      • Morgan L.
      • Yilmaz O.
      • Olivier K.N.
      • Milla C.
      • Pittman J.E.
      • Leigh Anne Daniels M.
      • Jones M.H.
      • Janahi I.A.
      • Ware S.M.
      • Daniel S.J.
      • Cooper M.L.
      • Nogee L.M.
      • Anton B.
      • Eastvold T.
      • Ehrne L.
      • Guadagno E.
      • Knowles M.R.
      • Leigh M.W.
      • Lavergne V.
      • Daniels M.L.A.
      • Jones M.H.
      • Janahi I.A.
      • Ware S.M.
      • Daniel S.J.
      • Cooper M.L.
      • Nogee L.M.
      • Anton B.
      • Eastvold T.
      • Ehrne L.
      • Guadagno E.
      • Knowles M.R.
      • Leigh M.W.
      • Lavergne V.
      American Thoracic Society Assembly on Pediatrics, Diagnosis of primary ciliary dyskinesia: an official American thoracic society clinical practice guideline.
      ]. Recent recommendations for diagnosis of patients with clinical features of primary ciliary dyskinesia include nasal nitric oxide, extended genetic panel (>12 genes) and electron microscopy of ciliary structures and referral to a PCD specialty center [
      • Shapiro A.J.
      • Davis S.D.
      • Polineni D.
      • Manion M.
      • Rosenfeld M.
      • Dell S.D.
      • Chilvers M.A.
      • Ferkol T.W.
      • Zariwala M.A.
      • Sagel S.D.
      • Josephson M.
      • Morgan L.
      • Yilmaz O.
      • Olivier K.N.
      • Milla C.
      • Pittman J.E.
      • Leigh Anne Daniels M.
      • Jones M.H.
      • Janahi I.A.
      • Ware S.M.
      • Daniel S.J.
      • Cooper M.L.
      • Nogee L.M.
      • Anton B.
      • Eastvold T.
      • Ehrne L.
      • Guadagno E.
      • Knowles M.R.
      • Leigh M.W.
      • Lavergne V.
      • Daniels M.L.A.
      • Jones M.H.
      • Janahi I.A.
      • Ware S.M.
      • Daniel S.J.
      • Cooper M.L.
      • Nogee L.M.
      • Anton B.
      • Eastvold T.
      • Ehrne L.
      • Guadagno E.
      • Knowles M.R.
      • Leigh M.W.
      • Lavergne V.
      American Thoracic Society Assembly on Pediatrics, Diagnosis of primary ciliary dyskinesia: an official American thoracic society clinical practice guideline.
      ].

      5.6 Chronic airflow obstruction

      A causal relationship between cigarette smoke exposure and chronic airflow limitation is well established, but not with bronchiectasis. While COPD and bronchiectasis are distinct conditions that share symptoms of chronic cough and episodes of acute worsening there are patients with cigarette exposure resulting in fixed airflow limitation with chronic cough and chest CT findings that may be designated as COPD-bronchiectasis overlap syndrome [
      • Hurst J.R.
      • Elborn J.S.
      • De Soyza A.
      • Bronch-Uk Consortium
      COPD–bronchiectasis overlap syndrome.
      ]. The prevalence of COPD and bronchiectasis ranges from 19.8% to 69% and this variation may be related to inconsistent definitions of bronchiectasis, inclusion of patients with COPD during an acute exacerbation and retrospective study design [
      • Polverino E.
      • Dimakou K.
      • Hurst J.
      • Martinez-Garcia M.-A.
      • Miravitlles M.
      • Paggiaro P.
      • Shteinberg M.
      • Aliberti S.
      • Chalmers J.D.
      The overlap between bronchiectasis and chronic airway diseases: state of the art and future directions.
      ]. Factors associated with bronchiectasis and COPD are severity of airflow limitation, isolation of a pathogen on airway cultures and prior hospital admission [
      • Martínez-García M.Á.
      • Soler-Cataluña J.J.
      • Donat-Sanz Y.
      • Catalán-Serra P.
      • Agramunt-Lerma M.
      • Ballestín-Vicente J.
      • Perpiñá-Tordera M.
      Factors associated with bronchiectasis in chronic obstructive pulmonary disease patients.
      ]. Furthermore, the presence of COPD and bronchiectasis is associated with increased mortality in patients with moderate to severe COPD [
      • Martínez-García M.-A.
      • De La D.
      • Carrillo R.
      • Soler-Cataluña J.-J.
      • Donat-Sanz Y.
      • Serra P.C.
      • Lerma M.A.
      • Ballestín J.
      • Valero Sánchez I.
      • Jose M.
      • Ferrer S.
      • Dalfo A.R.
      • Valdecillos M.B.
      • de la Rosa Carrillo D.
      • Soler-Cataluña J.-J.
      • Donat-Sanz Y.
      • Serra P.C.
      • Lerma M.A.
      • Ballestín J.
      • Sánchez I.V.
      • Selma Ferrer M.J.
      • Dalfo A.R.
      • Valdecillos M.B.
      Prognostic value of bronchiectasis in patients with moderate-to-severe chronic obstructive pulmonary disease.
      ,
      • Goeminne P.C.C.
      • Nawrot T.S.S.
      • Ruttens D.
      • Seys S.
      • Dupont L.J.J.
      ]. However, the reported poor outcomes may be more indicative of increased age, frailty and severity of airflow obstruction. Whether COPD is causative of bronchiectasis or just associated remains unclear as long-term longitudinal imaging studies and assessments of airway inflammation have not been performed. It should be pointed out that to consider a causal relationship between COPD and bronchiectasis requires exposure to cigarette smoke or a causative agent, otherwise the presence of airflow limitation may be attributed to bronchiectasis. The European Bronchiectasis Audit and Research collaboration (EMBARC) has been established to perform large scale epidemiological studies to further elucidate the relationship between COPD and bronchiectasis.

      5.7 Alpha antitrypsin deficiency

      Past case reports have reported associations with alpha antitrypsin deficiency and bronchiectasis [
      • Scott J.H.
      • Anderson C.L.
      • Shankar P.S.
      • Stavrides A.
      Alpha1-antitrypsin deficiency with diffuse bronchiectasis and cirrhosis of the liver.
      ,
      • Shin M.S.
      • Ho K.J.
      Bronchiectasis in patients with alpha 1-antitrypsin deficiency. A rare occurrence?.
      ,
      • Rodriguez-Cintron W.
      • Guntupalli K.
      • Fraire A.E.
      Bronchiectasis and homozygous (P1ZZ) α1-antitrypsin deficiency in a young man.
      ]. A case series from a large referral center described 74 patients with severe alpha antitrypsin deficiency (PiZ phenotype) and severe airflow limitation [
      • Parr D.G.
      • Guest P.G.
      • Reynolds J.H.
      • Dowson L.J.
      • Stockley R.A.
      Prevalence and impact of bronchiectasis in alpha1-antitrypsin deficiency.
      ]. The group mean age was 50.6 years with 77% found to have radiographic bronchiectasis involvement of four or more lobes and 27% with chronic sputum production. A descriptive report from the U.S. Bronchiectasis Registry identified 58 patients with alpha antitrypsin deficiency; 37 (63.8%) PiSZ and 21 (36.2%) PiZZ [
      • Eden E.
      • Choate R.
      • Barker A.
      • Addrizzo-Harris D.
      • Aksamit T.R.
      • Daley C.L.
      • Daniels M.L.A.
      • DiMango A.
      • Fennelly K.
      • Griffith D.E.
      • Johnson M.M.
      • Knowles M.R.
      • Metersky M.L.
      • Noone P.G.
      • O'Donnell A.E.
      • Olivier K.N.
      • Salathe M.A.
      • Schmid A.
      • Thomashow B.
      • Tino G.
      • Turino G.M.
      • Winthrop K.L.
      The clinical features of bronchiectasis associated with alpha-1 antitrypsin deficiency, common variable immunodeficiency and primary ciliary dyskinesia--results from the U.S. Bronchiectasis Research registry.
      ]. The group had severe airflow obstruction with a greater proportion of NTM airway culture isolates compared with other patients with bronchiectasis.

      5.8 Connective tissue disorders & inflammatory bowel disease

      Bronchiectasis resulting from complications of connective tissue disorders notably rheumatoid arthritis has been reported [
      • Perry E.
      • Stenton C.
      • Kelly C.
      • Eggleton P.
      • Hutchinson D.
      • De Soyza A.
      RA autoantibodies as predictors of rheumatoid arthritis in non-cystic fibrosis bronchiectasis patients.
      ,
      • Demoruelle M.K.
      • Weisman M.H.
      • Simonian P.L.
      • Lynch D.A.
      • Sachs P.B.
      • Pedraza I.F.
      • Harrington A.R.
      • Kolfenbach J.R.
      • Striebich C.C.
      • Pham Q.N.
      • Strickland C.D.
      • Petersen B.D.
      • Parish M.C.
      • Derber L.A.
      • Norris J.M.
      • Holers V.M.
      • Deane K.D.
      Brief report: airways abnormalities and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating site of autoimmunity?.
      ]. In a small study of 12 patients with rheumatoid arthritis associated with bronchiectasis, the authors reported women comprised 52% of the group with 38% being ever smokers and 76% had radiographic findings of bronchiectasis [
      • Demoruelle M.K.
      • Weisman M.H.
      • Simonian P.L.
      • Lynch D.A.
      • Sachs P.B.
      • Pedraza I.F.
      • Harrington A.R.
      • Kolfenbach J.R.
      • Striebich C.C.
      • Pham Q.N.
      • Strickland C.D.
      • Petersen B.D.
      • Parish M.C.
      • Derber L.A.
      • Norris J.M.
      • Holers V.M.
      • Deane K.D.
      Brief report: airways abnormalities and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating site of autoimmunity?.
      ]. The authors proposed that the airways of susceptible patients with rheumatoid arthritis may be an early site of autoimmune related injury. Finally, inflammatory bowel disease has been associated with bronchiectasis [
      • Black H.
      • Mendoza M.
      • Murin S.
      Thoracic manifestations of inflammatory bowel disease.
      ]. In a review of the thoracic manifestations of inflammatory bowel disease, the authors reported bronchiectasis was reported in 66% of the group and more frequently in patients with ulcerative colitis than Crohn's disease.

      6. Approach to diagnosis

      The initial evaluation of a patient with bronchiectasis includes a detailed history regarding onset of symptoms, frequency and severity of respiratory ailments and comorbidities. The symptoms that warrant further evaluation include chronic cough (>3 months duration), daily sputum production, exertional dyspnea, > 1 lower respiratory tract infection per year requiring antibiotic therapy, rhinosinusitis and a diagnosis of asthma or COPD. Notably, a clinical phenotype associated with bronchiectasis is the tall, thin, post-menopausal woman with chronic cough. A family history regarding pulmonary disease may offer clues concerning a genetic etiology and provide a pattern of inheritance. Initial chest imaging is important as this provides information regarding the extent (focal vs widespread), distribution (upper vs lower lobe) and severity of parenchymal involvement [
      • Milliron B.
      • Henry T.S.
      • Veeraraghavan S.
      • Little B.P.
      ]. Compared to chest CT imaging, an initial chest radiograph is less costly, easier to obtain and provides lower amount of radiation exposure thus may be useful to monitor disease. However, chest radiography lacks sensitivity for the detection of mild or moderate bronchiectasis and underestimates the extent of structural lung involvement, thus is rarely adequate for diagnostic purposes. In contrast, high resolution chest CT imaging offers greater detail concerning the distribution and extent of disease and is considered the gold standard. Importantly, a sputum sample for bacterial, mycobacterial and fungal culture is essential and may require sputum induction with inhaled saline that may be used for future antibiotic prescriptions [
      • Polverino E.
      • Goeminne P.C.
      • McDonnell M.J.
      • Aliberti S.
      • Marshall S.E.
      • Loebinger M.R.
      • Murris M.
      • Cantón R.
      • Torres A.
      • Dimakou K.
      • De Soyza A.
      • Hill A.T.
      • Haworth C.S.
      • Vendrell M.
      • Ringshausen F.C.
      • Subotic D.
      • Wilson R.
      • Vilaró J.
      • Stallberg B.
      • Welte T.
      • Rohde G.
      • Blasi F.
      • Elborn S.
      • Almagro M.
      • Timothy A.
      • Ruddy T.
      • Tonia T.
      • Rigau D.
      • Chalmers J.D.
      European Respiratory Society guidelines for the management of adult bronchiectasis.
      ]. Initial laboratory studies should include complete blood count with differential to assess for leukopenia and eosinophilia. Several professional societies recommend obtaining quantitative serum immunoglobulins (IgG, IgA, IgM) to assess for immunoglobulin deficiencies and quantitative IgE to assess for allergic bronchopulmonary aspergillosis [
      • Polverino E.
      • Goeminne P.C.
      • McDonnell M.J.
      • Aliberti S.
      • Marshall S.E.
      • Loebinger M.R.
      • Murris M.
      • Cantón R.
      • Torres A.
      • Dimakou K.
      • De Soyza A.
      • Hill A.T.
      • Haworth C.S.
      • Vendrell M.
      • Ringshausen F.C.
      • Subotic D.
      • Wilson R.
      • Vilaró J.
      • Stallberg B.
      • Welte T.
      • Rohde G.
      • Blasi F.
      • Elborn S.
      • Almagro M.
      • Timothy A.
      • Ruddy T.
      • Tonia T.
      • Rigau D.
      • Chalmers J.D.
      European Respiratory Society guidelines for the management of adult bronchiectasis.
      ,
      • Pasteur M.C.
      • Bilton D.
      • Hill A.T.
      British thoracic society guideline for non-CF bronchiectasis.
      ,
      • Chang A.B.
      • Bell S.C.
      • Torzillo P.J.
      • King P.T.
      • Maguire G.P.
      • Byrnes C.A.
      • Holland A.E.
      • O'Mara P.
      • Grimwood K.
      • Alison J.
      • Cull C.
      • Currie B.
      • Gardner I.
      • Holmes P.
      • Hunter C.
      • Kolbe J.
      • Maclennan C.
      • McDonald M.
      • Morris P.
      • Nicolson C.
      • Petsky H.
      • Pillarisetti N.
      • Reynolds E.
      • Serisier D.
      • Thein F.
      • van Asperen P.
      • Voss L.
      • Wong C.
      Chronic suppurative lung disease and bronchiectasis in children and adults in Australia and New Zealand.
      ]. Additional testing should include sweat chloride testing and/or genetic testing for cystic fibrosis especially in patients with a family history of cystic fibrosis, chronic sinus or lower respiratory infections, pancreatic insufficiency or recurrent pancreatitis, failure to thrive, male infertility, upper lobe predominant bronchiectasis on imaging with reduced lung function, or airway culture isolates with Pseudomonas, Stenotrophomonas or Burkholderia species [
      • Pasteur M.C.
      • Bilton D.
      • Hill A.T.
      British thoracic society guideline for non-CF bronchiectasis.
      ,
      • Sosnay P.R.
      • White T.B.
      • Farrell P.M.
      • Ren C.L.
      • Derichs N.
      • Howenstine M.S.
      • Nick J.A.
      • De Boeck K.
      Diagnosis of cystic fibrosis in nonscreened populations.
      ]. While sweat chloride testing may lack sensitivity particularly in those with intermediate sweat chloride results (30–59 mmoL/L), current consensus guidelines recommend for repeat sweat chloride testing and if diagnostic uncertainty remains then CFTR gene sequencing and/or CFTR functional analysis to identify CF-causing variants should be performed [
      • Farrell P.M.
      • White T.B.
      • Ren C.L.
      • Hempstead S.E.
      • Accurso F.
      • Derichs N.
      • Howenstine M.
      • Mccolley S.A.
      • Rock M.
      • Rosenfeld M.
      • Sermet-Gaudelus I.
      • Southern K.W.
      • Marshall B.C.
      • Sosnay P.R.
      Diagnosis of cystic fibrosis: consensus guidelines from the cystic fibrosis foundation.
      ]. Alpha-1-antitrypsin deficiency should be considered in individuals with a diagnosis of COPD or lower lobe emphysema with or without liver disease. In patients with a history of unclear neonatal respiratory distress, daily productive cough, rhinosinusitis or laterality defects (situs inversus) nasal nitric oxide (nNO) testing should be performed to assess for primary ciliary dyskinesia. If access to this testing is not available, then extended genetic testing and/or electron microscopy of ciliary ultrastructure can be performed [
      • Shapiro A.J.
      • Davis S.D.
      • Polineni D.
      • Manion M.
      • Rosenfeld M.
      • Dell S.D.
      • Chilvers M.A.
      • Ferkol T.W.
      • Zariwala M.A.
      • Sagel S.D.
      • Josephson M.
      • Morgan L.
      • Yilmaz O.
      • Olivier K.N.
      • Milla C.
      • Pittman J.E.
      • Leigh Anne Daniels M.
      • Jones M.H.
      • Janahi I.A.
      • Ware S.M.
      • Daniel S.J.
      • Cooper M.L.
      • Nogee L.M.
      • Anton B.
      • Eastvold T.
      • Ehrne L.
      • Guadagno E.
      • Knowles M.R.
      • Leigh M.W.
      • Lavergne V.
      • Daniels M.L.A.
      • Jones M.H.
      • Janahi I.A.
      • Ware S.M.
      • Daniel S.J.
      • Cooper M.L.
      • Nogee L.M.
      • Anton B.
      • Eastvold T.
      • Ehrne L.
      • Guadagno E.
      • Knowles M.R.
      • Leigh M.W.
      • Lavergne V.
      American Thoracic Society Assembly on Pediatrics, Diagnosis of primary ciliary dyskinesia: an official American thoracic society clinical practice guideline.
      ]. Lastly, patients with symptoms of gastroesophageal reflux disease or a history of aspiration/dysphagia should undergo barium swallow testing. Establishing a specific cause of bronchiectasis is important as several investigators have reported identification of a specific etiology led to changes in management in 7–37% of patients [
      • Shoemark A.
      • Ozerovitch L.
      • Wilson R.
      Aetiology in adult patients with bronchiectasis.
      ,
      • Lonni S.
      • Chalmers J.D.
      • Goeminne P.C.
      • McDonnell M.J.
      • Dimakou K.
      • De Soyza A.
      • Polverino E.
      • Van de Kerkhove C.
      • Rutherford R.
      • Davison J.
      • Rosales E.
      • Pesci A.
      • Restrepo M.I.
      • Torres A.
      • Aliberti S.
      Etiology of non-cystic fibrosis bronchiectasis in adults and its correlation to disease severity.
      ,
      • Coulden R.A.
      • Bilton D.
      • Helliwell S.M.
      • Keogan M.T.
      • Houghton S.J.
      • Foweraker J.E.
      • Webb S.C.
      • Pasteur M.C.
      • Flower C.D.
      An investigation into causative factors in patients with bronchiectasis.
      ,
      • Anwar G.A.
      • McDonnell M.J.
      • Worthy S.A.
      • Bourke S.C.
      • Afolabi G.
      • Lordan J.
      • Corris P.A.
      • Desoyza A.
      • Middleton P.
      • Ward C.
      • Rutherford R.M.
      Phenotyping adults with non-cystic fibrosis bronchiectasis: a prospective observational cohort study.
      ].

      7. Management

      Bronchiectasis management aims to promote airway clearance, prevent exacerbations and improve patient quality of life [
      • Wilson C.B.
      • Jones P.W.
      • O'Leary C.J.
      • Cole P.J.
      • Wilson R.
      Validation of the st. George's respiratory questionnaire in bronchiectasis.
      ,
      • Quittner A.L.
      • O'Donnell A.E.
      • Salathe M.A.
      • Lewis S.A.
      • Li X.
      • Montgomery A.B.
      • O'Riordan T.G.
      • Barker A.F.
      Quality of Life Questionnaire-Bronchiectasis: final psychometric analyses and determination of minimal important difference scores.
      ,
      • Chalmers J.D.
      • Aliberti S.
      • Blasi F.
      Management of bronchiectasis in adults.
      ]. Initial preventive strategy involves providing annual influenza and pneumococcal vaccinations. Although, there is limited data regarding immunization of individuals with bronchiectasis pneumococcal and influenza vaccines given together have reduced the frequency of acute exacerbations [
      • Chang C.C.
      • Singleton R.J.
      • Morris P.S.
      • Chang A.B.
      Pneumococcal vaccines for children and adults with bronchiectasis.
      ]. In patients that use inhalational tobacco products, cessation counseling should be provided to reduce the frequency of exacerbations and minimize further decline in lung function. Moreover, coronary artery and cerebrovascular disease are reported to be more prevalent in patients with bronchiectasis compared to those without bronchiectasis after adjustment for age, sex, smoking and risk factors for cardiovascular disease [
      • Navaratnam V.
      • Millett E.R.C.
      • Hurst J.R.
      • Thomas S.L.
      • Smeeth L.
      • Hubbard R.B.
      • Brown J.
      • Quint J.K.
      Bronchiectasis and the risk of cardiovascular disease: a population-based study.
      ,
      • Chen Y.F.
      • Lin H.H.
      • Lin C.S.
      • Turbat B.
      • Wang K.A.
      • Chung W.S.
      Bronchiectasis and increased risk of ischemic stroke: a nationwide population-based cohort study.
      ]. Thus, tobacco cessation in patients with non-cystic fibrosis bronchiectasis may decrease the morbidity associated with vascular disease as well as airway inflammation.

      7.1 Inhaled bronchodilators and corticosteroids

      In the management of bronchiectasis, inhaled drug delivery is preferred to systemic therapy as drug is administered directly to the involved airways and minimizes systemic side effects. Thus, inhalational administration of bronchodilators, corticosteroids and antibiotics are essential in management. There is variability in the prescribing pattern of inhaled therapies to patients with non-CF bronchiectasis that may be related the presence of concomitant diagnoses of asthma or COPD. Inhaled bronchodilators are frequently prescribed to patients with non-CF bronchiectasis and in the US Bronchiectasis Research Registry 61% of patients were prescribed a bronchodilator [
      • Aksamit T.R.
      • O'Donnell A.E.
      • Barker A.
      • Olivier K.N.
      • Winthrop K.L.
      • Daniels M.L.A.
      • Johnson M.
      • Eden E.
      • Griffith D.
      • Knowles M.
      • Metersky M.
      • Salathe M.
      • Thomashow B.
      • Tino G.
      • Turino G.
      • Carretta B.
      • Daley C.L.
      Adult patients with bronchiectasis: a first look at the US bronchiectasis Research registry.
      ]. While inhaled short acting and long acting bronchodilators are prescribed to patients with bronchiectasis to improve mucociliary clearance and for symptomatic relief, the benefit of this therapy has not been clearly demonstrated [
      • Restrepo R.D.
      Inhaled adrenergics and anticholinergics in obstructive lung disease: do they enhance mucociliary clearance?.
      ,
      • Goyal V.
      • Chang A.B.
      Combination inhaled corticosteroids and long-acting beta2-agonists for children and adults with bronchiectasis.
      ]. For management of the individual patient, spirometry before and after albuterol administration should be obtained in order to assess for bronchodilator responsiveness that can guide the clinician to prescribe a short acting bronchodilator.
      While non-CF bronchiectasis is associated with neutrophilic airway inflammation, clinicians feel obliged to prescribe inhaled corticosteroids for symptom relief and improve patient outcomes even though this therapy is primarily effective in eosinophilic driven airway disease. In the US Bronchiectasis Research Registry, inhaled corticosteroids were prescribed to 39% of the registry cohort while asthma and COPD were diagnosed in 29% and 20% of the registry patients, respectively [
      • Aksamit T.R.
      • O'Donnell A.E.
      • Barker A.
      • Olivier K.N.
      • Winthrop K.L.
      • Daniels M.L.A.
      • Johnson M.
      • Eden E.
      • Griffith D.
      • Knowles M.
      • Metersky M.
      • Salathe M.
      • Thomashow B.
      • Tino G.
      • Turino G.
      • Carretta B.
      • Daley C.L.
      Adult patients with bronchiectasis: a first look at the US bronchiectasis Research registry.
      ]. A systematic review of the short term (<6 months) and long term effects (>6 months) of inhaled corticosteroid administration in patients with bronchiectasis reported no improvement in pulmonary function tests, rate of exacerbations or health related outcomes [
      • Kapur N.
      • Petsky H.L.
      • Bell S.
      • Kolbe J.
      • Chang A.B.
      Inhaled corticosteroids for bronchiectasis.
      ]. The authors of the meta-analysis concluded that that there is insufficient evidence to recommend the routine use of inhaled corticosteroids in adults with clinically stable bronchiectasis. A consensus document from the European Respiratory Society also acknowledged that while the quality of evidence is low, clinicians should not prescribe inhaled corticosteroids to patients with non-CF bronchiectasis unless asthma or COPD are concomitantly identified [
      • Polverino E.
      • Goeminne P.C.
      • McDonnell M.J.
      • Aliberti S.
      • Marshall S.E.
      • Loebinger M.R.
      • Murris M.
      • Cantón R.
      • Torres A.
      • Dimakou K.
      • De Soyza A.
      • Hill A.T.
      • Haworth C.S.
      • Vendrell M.
      • Ringshausen F.C.
      • Subotic D.
      • Wilson R.
      • Vilaró J.
      • Stallberg B.
      • Welte T.
      • Rohde G.
      • Blasi F.
      • Elborn S.
      • Almagro M.
      • Timothy A.
      • Ruddy T.
      • Tonia T.
      • Rigau D.
      • Chalmers J.D.
      European Respiratory Society guidelines for the management of adult bronchiectasis.
      ]. Furthermore, concerns about harm associated with inhaled steroids were observed in a randomized clinical trial of fluticasone (500 mcg) administered twice daily to patients with non-CF bronchiectasis that revealed a decrease in airway leucocytes but an increase in airway bacterial density in the fluticasone treated group [
      • Tsang K.W.T.
      • Ho P.-L.
      • Lam W.-K.
      • Ip M.S.M.
      • Chan K.-N.
      • Ho C.-S.
      • Ooi C.C.G.
      • Yuen K.Y.
      Inhaled fluticasone reduces sputum inflammatory indices in severe bronchiectasis.
      ]. Moreover, inhaled corticosteroids use is associated with an increased risk for pneumonia and NTM lung infections and raises questions about the safety of this therapy in patients with bronchiectasis [
      • Calverley P.M.A.
      • Anderson J.A.
      • Celli B.
      • Ferguson G.T.
      • Jenkins C.
      • Jones P.W.
      • Yates J.C.
      • Vestbo J.
      Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.
      ,
      • Liu V.X.
      • Winthrop K.L.
      • Lu Y.
      • Sharifi H.
      • Nasiri H.U.
      • Ruoss S.J.
      Association between inhaled corticosteroid use and pulmonary nontuberculous mycobacterial infection.
      ]. Additional investigations are needed to address the role of inhaled corticosteroids in the management of non-CF bronchiectasis.

      7.2 Mucolytic agents

      In patients with bronchiectasis, impairment in mucociliary clearance is a result of abnormal epithelial fluid reabsorption that depletes the airway surface of fluid and increases mucus concentration [
      • Boucher R.C.
      Muco-obstructive lung diseases.
      ]. In patients with cystic fibrosis and non-CF bronchiectasis, mucus hyper concentration and airway mucus stasis can lead ciliary dysfunction that can contribute to airway inflammation and infections [
      • Henderson A.G.
      • Ehre C.
      • Button B.
      • Abdullah L.H.
      • Cai L.H.
      • Leigh M.W.
      • DeMaria G.C.
      • Matsui H.
      • Donaldson S.H.
      • Davis C.W.
      • Sheehan J.K.
      • Boucher R.C.
      • Kesimer M.
      Cystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressure.
      ]. Mucus may be eliminated through coughing; however, mucus that is not expelled accumulates, obstructs the airway lumen and creates a source of infection. Pharmacologic agents have been examined to decrease mucus concentration through hydration or decrease mucus viscosity to thereby facilitate clearance of airway secretions. Administration of nebulized hypertonic saline (7%) to patients with non-CF bronchiectasis improved lung function, health related quality of life, decreased antibiotic use as well as emergency room use compared to nebulized isotonic saline [
      • Kellett F.
      • Robert N.M.
      Nebulised 7% hypertonic saline improves lung function and quality of life in bronchiectasis.
      ]. Subsequently, another group of investigators compared the long term effects of nebulized hypertonic (6%) and isotonic (0.9%) saline administered daily for 12 months to 40 patients with non-CF bronchiectasis and reported both groups had similar improvements in quality of life, lung function and exacerbation rate [
      • Nicolson C.H.H.
      • Stirling R.G.
      • Borg B.M.
      • Button B.M.
      • Wilson J.W.
      • Holland A.E.
      The long term effect of inhaled hypertonic saline 6% in non-cystic fibrosis bronchiectasis.
      ]. These findings indicate that nebulized saline solutions are safe and effective mucolytic agents, but the tonicity of the solution remains unclear. Inhaled mannitol has also been evaluated as a pharmacologic aid to hydrate the airways and evaluated in a randomized trial of 461 patients that reported no reduction in the rate of exacerbations over a 12 month period [
      • Bilton D.
      • Tino G.
      • Barker A.F.
      • Chambers D.C.
      • De Soyza A.
      • Dupont L.J.A.
      • O'Dochartaigh C.
      • van Haren E.H.J.
      • Vidal L.O.
      • Welte T.
      • Fox H.G.
      • Wu J.
      • Charlton B.
      B-305 Study Investigators, Inhaled mannitol for non-cystic fibrosis bronchiectasis: a randomised, controlled trial.
      ]. Other mucolytic agents such as N-acetylcysteine are used in clinical practice, however there are no trials that demonstrate clinical benefit [
      • Tarrant B.J.
      • Le Maitre C.
      • Romero L.
      • Steward R.
      • Button B.M.
      • Thompson B.R.
      • Holland A.E.
      Mucoactive agents for chronic, non-cystic fibrosis lung disease: a systematic review and meta-analysis.
      ]. Lastly, recombinant human DNase (rhDNase, Pulmozyme, Genentech, San Francisco, CA) is a commercially available mucolytic agent that in clinical trials involving cystic fibrosis patients demonstrated improvements in lung function and decreased frequency of exacerbations [
      • Fuchs H.J.
      • Christiansen D.H.
      • Borowitz D.S.
      • Nash M.L.
      • Ramsey B.W.
      • Smith A.L.
      • Morris E.M.
      • Rosenstein B.J.
      • Wohl M.E.
      Effect of aerosolized recombinant human dnase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis.
      ,
      • Laube B.L.
      • Auci R.M.
      • Shields D.E.
      • Christiansen D.H.
      • Lucas M.K.
      • Fuchs H.J.
      • Rosenstein B.J.
      Effect of rhDNase on airflow obstruction and mucociliary clearance in cystic fibrosis.
      ]. In contrast, patients with non-CF bronchiectasis randomized to receive inhaled rhDNase for 6 months were found to have more frequent exacerbations, hospitalizations, as well as antibiotic and corticosteroid prescriptions compared to the control group [
      • O'Donnell A.E.
      • Barker A.F.
      • Ilowite J.S.
      • Fick R.B.
      Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase I.
      ]. This has led to professional societies recommendations against the use of rhDNase in management of non-CF bronchiectasis [
      • Polverino E.
      • Goeminne P.C.
      • McDonnell M.J.
      • Aliberti S.
      • Marshall S.E.
      • Loebinger M.R.
      • Murris M.
      • Cantón R.
      • Torres A.
      • Dimakou K.
      • De Soyza A.
      • Hill A.T.
      • Haworth C.S.
      • Vendrell M.
      • Ringshausen F.C.
      • Subotic D.
      • Wilson R.
      • Vilaró J.
      • Stallberg B.
      • Welte T.
      • Rohde G.
      • Blasi F.
      • Elborn S.
      • Almagro M.
      • Timothy A.
      • Ruddy T.
      • Tonia T.
      • Rigau D.
      • Chalmers J.D.
      European Respiratory Society guidelines for the management of adult bronchiectasis.
      ,
      • Pasteur M.C.
      • Bilton D.
      • Hill A.T.
      British thoracic society guideline for non-CF bronchiectasis.
      ,
      • Chang A.B.
      • Bell S.C.
      • Torzillo P.J.
      • King P.T.
      • Maguire G.P.
      • Byrnes C.A.
      • Holland A.E.
      • O'Mara P.
      • Grimwood K.
      • Alison J.
      • Cull C.
      • Currie B.
      • Gardner I.
      • Holmes P.
      • Hunter C.
      • Kolbe J.
      • Maclennan C.
      • McDonald M.
      • Morris P.
      • Nicolson C.
      • Petsky H.
      • Pillarisetti N.
      • Reynolds E.
      • Serisier D.
      • Thein F.
      • van Asperen P.
      • Voss L.
      • Wong C.
      Chronic suppurative lung disease and bronchiectasis in children and adults in Australia and New Zealand.
      ]. Furthermore, the lack of clinical benefit of rhDNase highlights the observation that therapies for cystic fibrosis bronchiectasis may not be beneficial for patients with non-CF bronchiectasis. Moreover, before adoption of treatments in the management of patients with cystic fibrosis bronchiectasis there is a need for well-designed clinical trials to adequately assess the efficacy of medical therapies for use in non-CF bronchiectasis.

      7.3 Airway clearance

      Effective airway clearance is an essential component in the management of non-CF bronchiectasis and strongly recommended by numerous professional respiratory societies [
      • Polverino E.
      • Goeminne P.C.
      • McDonnell M.J.
      • Aliberti S.
      • Marshall S.E.
      • Loebinger M.R.
      • Murris M.
      • Cantón R.
      • Torres A.
      • Dimakou K.
      • De Soyza A.
      • Hill A.T.
      • Haworth C.S.
      • Vendrell M.
      • Ringshausen F.C.
      • Subotic D.
      • Wilson R.
      • Vilaró J.
      • Stallberg B.
      • Welte T.
      • Rohde G.
      • Blasi F.
      • Elborn S.
      • Almagro M.
      • Timothy A.
      • Ruddy T.
      • Tonia T.
      • Rigau D.
      • Chalmers J.D.
      European Respiratory Society guidelines for the management of adult bronchiectasis.
      ,
      • Pasteur M.C.
      • Bilton D.
      • Hill A.T.
      British thoracic society guideline for non-CF bronchiectasis.
      ,
      • Chang A.B.
      • Bell S.C.
      • Torzillo P.J.
      • King P.T.
      • Maguire G.P.
      • Byrnes C.A.
      • Holland A.E.
      • O'Mara P.
      • Grimwood K.
      • Alison J.
      • Cull C.
      • Currie B.
      • Gardner I.
      • Holmes P.
      • Hunter C.
      • Kolbe J.
      • Maclennan C.
      • McDonald M.
      • Morris P.
      • Nicolson C.
      • Petsky H.
      • Pillarisetti N.
      • Reynolds E.
      • Serisier D.
      • Thein F.
      • van Asperen P.
      • Voss L.
      • Wong C.
      Chronic suppurative lung disease and bronchiectasis in children and adults in Australia and New Zealand.
      ]. A range of airway clearance strategies have been developed including exercise, forced expiration (Huff cough), chest physical therapy (postural drainage, hand or mechanical chest clapping), positive expiratory pressure (PEP), oscillatory PEP (flutter valve) and high frequency chest wall oscillation (HFCWO). Much of the evidence concerning airway clearance techniques has been gathered in the care of patients with cystic fibrosis and in this population there is no airway clearance technique that is superior over another [
      • Flume P.A.
      • Robinson K.A.
      • O'Sullivan B.P.
      • Finder J.D.
      • Vender R.L.
      • Willey-Courand D.-B.
      • White T.B.
      • Marshall B.C.
      Clinical practice guidelines for pulmonary therapies committee, cystic fibrosis pulmonary guidelines: airway clearance therapies.
      ,
      • Wilson L.M.
      • Morrison L.
      • Robinson K.A.
      Airway clearance techniques for cystic fibrosis: an overview of Cochrane systematic reviews.
      ]. Consensus groups have concluded that airway clearance methods should be individualized based on patient comfort, convenience, practical application and cost [
      • Wilson L.M.
      • Morrison L.
      • Robinson K.A.
      Airway clearance techniques for cystic fibrosis: an overview of Cochrane systematic reviews.
      ]. Though the mechanisms that impair clearance of airway secretions are similar in cystic fibrosis and non-CF bronchiectasis, there are fewer published reports regarding the latter. A Cochrane review of airway clearance techniques in non-CF bronchiectasis examined seven studies concerning 105 subjects with the primary endpoints that varied from sputum production, lung function, gas exchange, duration and frequency of hospitalizations, cough severity, dyspnea and quality of life. The authors concluded that airway clearance strategies are safe in stable bronchiectasis and may lead to improvements in symptoms, quality of life and reduce hyperinflation [
      • Lee A.L.
      • Burge A.
      • Holland A.E.
      ]. More recently, a review of nine studies involving 213 subjects examined oscillatory PEP therapy in adults with bronchiectasis and concluded that daily PEP therapy for 4 weeks provided improvements in quality of life [
      • Lee A.L.
      • Burge A.T.
      • Holland A.E.
      Positive expiratory pressure therapy versus other airway clearance techniques for bronchiectasis.
      ]. While, no specific airway clearance technique is more effective than another patient, an individualized approach that accounts for disease severity as well as patient preference, motivation and insight can be combined with availability to provide an optimally effective treatment [
      • McIlwaine M.
      • Bradley J.
      • Elborn J.S.
      • Moran F.
      Personalising airway clearance in chronic lung disease.
      ].

      7.4 Pulmonary rehabilitation

      Clinical trials have reported benefits of pulmonary rehabilitation on exercise tolerance and quality of life in patients with non-CF bronchiectasis. An earlier retrospective study in 95 patients with bronchiectasis that completed twice a week sessions for 6–8 weeks of pulmonary rehabilitation reported a 53 m improvement compared to baseline [
      • Ong H.K.
      • Lee A.L.
      • Hill C.J.
      • Holland A.E.
      • Denehy L.
      Effects of pulmonary rehabilitation in bronchiectasis: a retrospective study.
      ]. Subsequently, a systematic review of pulmonary rehabilitation or exercise training in patients with bronchiectasis identified four small clinical trials that included 164 patients [
      • Lee A.L.
      • Hill C.J.
      • McDonald C.F.
      • Holland A.E.
      Pulmonary rehabilitation in individuals with non–cystic fibrosis bronchiectasis: a systematic review.
      ]. This meta-analysis confirmed the short-term improvements in exercise tolerance and quality of life assessment with supervised pulmonary rehabilitation and exercise. Investigators enrolled 213 patients with bronchiectasis participating in 8 weeks of supervised pulmonary rehabilitation and used propensity matching to select a group of 213 patients with COPD that underwent a similar outpatient pulmonary rehabilitation program and compared outcomes and completion rates between the groups. The authors reported similar improvements in exercise capacity and quality of life outcomes for both groups as well as similar completion rates. These reports provide support for the consensus recommendation from several respiratory societies that support use of pulmonary rehabilitation. Important in the implementation of this therapy also involves airway clearance and self-management.

      7.5 Antibiotic therapy

      Management of bronchiectasis with antibiotics is directed at treatment of acute exacerbations as well as prevention of future events. Frequent exacerbations are predictive of future exacerbations that are associated with reductions in quality of life, increases in hospitalization and greater mortality [
      • Chalmers J.D.
      • Aliberti S.
      • Filonenko A.
      • Shteinberg M.
      • Goeminne P.C.
      • Hill A.T.
      • Fardon T.C.
      • Obradovic D.
      • Gerlinger C.
      • Sotgiu G.
      • Operschall E.
      • Rutherford R.M.
      • Dimakou K.
      • Polverino E.
      • De Soyza A.
      • McDonnell M.J.
      Characterization of the “frequent exacerbator phenotype” in bronchiectasis.
      ]. Acute exacerbations present as an increase in sputum volume or change in color coupled with fatigue, increased dyspnea, pleuritic chest pain and hemoptysis. In the patient with an exacerbation, antibacterial therapy can be guided by prior sputum bacterial cultures, success or failure with previous regimens and allergic reactions to antibiotics. Initiation of antibiotics involves a 10-14-day course of antibiotics using an oral or parenteral route of administration and the inhaled route of administration is not recommended for acute exacerbation.
      Prevention of exacerbations is an essential management strategy and involves counseling on tobacco cessation and updating pneumococcal and influenza vaccines. In addition, patients with a history of exacerbations should be educated about the daily use of airway clearance techniques and provide bacterial and mycobacterial sputum samples as part of their visit. In the past, rotating oral antibiotics were considered a preventative strategy and are not recommended [
      • Polverino E.
      • Goeminne P.C.
      • McDonnell M.J.
      • Aliberti S.
      • Marshall S.E.
      • Loebinger M.R.
      • Murris M.
      • Cantón R.
      • Torres A.
      • Dimakou K.
      • De Soyza A.
      • Hill A.T.
      • Haworth C.S.
      • Vendrell M.
      • Ringshausen F.C.
      • Subotic D.
      • Wilson R.
      • Vilaró J.
      • Stallberg B.
      • Welte T.
      • Rohde G.
      • Blasi F.
      • Elborn S.
      • Almagro M.
      • Timothy A.
      • Ruddy T.
      • Tonia T.
      • Rigau D.
      • Chalmers J.D.
      European Respiratory Society guidelines for the management of adult bronchiectasis.
      ].

      7.6 Inhaled antibiotic therapy

      The inhaled route of administration has long been recognized as an effective method of drug delivery [
      • Segal M.S.
      • Ryder C.M.
      Penicillin inhalation therapy.
      ]. The appeal of inhaled antimicrobial therapy is that it allows for direct airway delivery to the site of infection with high airway concentrations of antibiotic and avoidance of systemic toxicity. Consequently, cyclic administration of inhaled antibiotics has been developed as a preventative strategy to reduce the airway bacterial load and target pathogenic organisms in individuals with frequent exacerbations [
      • Dhand R.
      The rationale and evidence for use of inhaled antibiotics to control Pseudomonas aeruginosa infection in non-cystic fibrosis bronchiectasis.
      ]. An early clinical trial reported the use of nebulized tobramycin administered twice a day in patients with non-CF bronchiectasis that resulted in a decrease in the burden of Pseudomonas without improvements in lung function [
      • Barker A.F.
      • Couch L.
      • Fiel S.B.
      • Gotfried M.H.
      • Ilowite J.
      • Meyer K.C.
      • O'Donnell A.
      • Sahn S.A.
      • Smith L.J.
      • Stewart J.O.
      • Abuan T.
      • Tully H.
      • Van Dalfsen J.
      • Wells C.D.
      • Quan J.
      Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis.
      ]. Another trial examined inhaled gentamicin in 65 patients with non-CF bronchiectasis and similarly found a reduction in bacterial density and fewer exacerbations but no change in lung function compared to the control group [
      • Murray M.P.
      • Govan J.R.W.
      • Doherty C.J.
      • Simpson A.J.
      • Wilkinson T.S.
      • Chalmers J.D.
      • Greening A.P.
      • Haslett C.
      • Hill A.T.
      A randomized controlled trial of nebulized gentamicin in non–cystic fibrosis bronchiectasis.
      ]. A multicenter trial of inhaled aztreonam resulted in decreases in bacterial load and those individuals with the greatest reduction in bacterial load experienced improvements in quality of life [
      • Barker A.F.
      • O'Donnell A.E.
      • Flume P.
      • Thompson P.J.
      • Ruzi J.D.
      • De Gracia J.
      • Boersma W.G.
      • De Soyza A.
      • Shao L.
      • Zhang J.
      • Haas L.
      • Lewis S.A.
      • Leitzinger S.
      • Montgomery A.B.
      • McKevitt M.T.
      • Gossage D.
      • Quittner A.L.
      • O'Riordan T.G.
      Aztreonam for inhalation solution in patients with non-cystic fibrosis bronchiectasis (AIR-BX1 and AIR-BX2): two randomised double-blind, placebo-controlled phase 3 trials.
      ]. Recently, investigators performed two prospective studies and reanalysis of an earlier inhaled clinical trial and reported improvements in quality of life for non-CF bronchiectasis patients with a high bacterial load treated with inhaled aztreonam compared to placebo [
      • Sibila O.
      • Laserna E.
      • Shoemark A.
      • Keir H.R.
      • Finch S.
      • Rodrigo-Troyano A.
      • Perea L.
      • Lonergan M.
      • Goeminne P.C.
      • Chalmers J.D.
      Airway bacterial load and inhaled antibiotic response in bronchiectasis.
      ]. Moreover, a meta-analysis reported inhaled antibiotics were more effective than placebo in the reduction of airway bacterial load, eradication of pathogenic bacteria from sputum and a reduction in acute exacerbations [
      • Brodt A.M.
      • Stovold E.
      • Zhang L.
      Inhaled antibiotics for stable non-cystic fibrosis bronchiectasis: a systematic review.
      ]. Subsequently, a multicenter clinical trial (RESPIRE 1) examined the time to first exacerbation and frequency of exacerbations in patients with non-CF bronchiectasis randomized to receive a dry powder formulation of ciprofloxacin in a cycled regimen of 14 and 28 days over 48 weeks. The investigators reported a statistically significant delay to time of first exacerbation in the 14 day group but no difference in the 28 day group compared to the control group [
      • De Soyza A.
      • Aksamit T.
      • Bandel T.-J.
      • Criollo M.
      • Elborn J.S.
      • Operschall E.
      • Polverino E.
      • Roth K.
      • Winthrop K.L.
      • Wilson R.
      Respire 1: a phase III placebo-controlled randomised trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis.
      ]. The RESPIRE 2 trial used the same study design and end points to assess dry powder ciprofloxacin in patients with non-CF bronchiectasis but compared to RESPIRE 1 enrolled more subjects from Asia and Eastern Europe and altered the statistical analysis. The RESPIRE 2 findings were such that neither the 14 day or 28 day regimens of ciprofloxacin met the primary end-points of increasing time to first exacerbation or reducing frequency of exacerbations [
      • Aksamit T.
      • De Soyza A.
      • Bandel T.-J.
      • Criollo M.
      • Elborn J.S.
      • Operschall E.
      • Polverino E.
      • Roth K.
      • Winthrop K.L.
      • Wilson R.
      Respire 2: a phase III placebo-controlled randomised trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis.
      ]. More recently, two phase III trials (ORBIT-3, ORBIT-4) conducted over 48 weeks examined the effect of liposomal ciprofloxacin on the time to first exacerbation in patients with non-CF bronchiectasis, however the pooled analysis found no significant difference in the primary end point between the liposomal ciprofloxacin and control groups [
      • Haworth C.S.
      • Bilton D.
      • Chalmers J.D.
      • Davis A.M.
      • Froehlich J.
      • Gonda I.
      • Thompson B.
      • Wanner A.
      • O'Donnell A.E.
      Inhaled liposomal ciprofloxacin in patients with non-cystic fibrosis bronchiectasis and chronic lung infection with Pseudomonas aeruginosa (ORBIT-3 and ORBIT-4): two phase 3, randomised controlled trials.
      ]. In summary, these clinical trial results indicate that inhaled antibiotics are well tolerated and reduce airway bacterial load. A comprehensive meta-analysis of inhaled antibiotic trials reported reduction in bacterial loads and small but statistically significant decrease in exacerbation rate without significant improvements in quality of life compared to placebo [
      • Laska I.F.
      • Crichton M.L.
      • Shoemark A.
      • Chalmers J.D.
      The efficacy and safety of inhaled antibiotics for the treatment of bronchiectasis in adults: a systematic review and meta-analysis.
      ]. In addition, antibiotic resistance increased in the treatment arm but was not associated with treatment failure. Limitations of this meta-analysis include the diversity of underlying causes of non-CF bronchiectasis and a substantial amount of study heterogeneity. These findings support professional society recommendations that suggest long term inhaled antibiotic treatment (>3 months) may be initiated in patients with >3 exacerbations/year with chronic P. aeruginosa infection [
      • Polverino E.
      • Goeminne P.C.
      • McDonnell M.J.
      • Aliberti S.
      • Marshall S.E.
      • Loebinger M.R.
      • Murris M.
      • Cantón R.
      • Torres A.
      • Dimakou K.
      • De Soyza A.
      • Hill A.T.
      • Haworth C.S.
      • Vendrell M.
      • Ringshausen F.C.
      • Subotic D.
      • Wilson R.
      • Vilaró J.
      • Stallberg B.
      • Welte T.
      • Rohde G.
      • Blasi F.
      • Elborn S.
      • Almagro M.
      • Timothy A.
      • Ruddy T.
      • Tonia T.
      • Rigau D.
      • Chalmers J.D.
      European Respiratory Society guidelines for the management of adult bronchiectasis.
      ].

      7.7 Macrolides

      Macrolides exert immunomodulatory effects on innate and adaptive immune responses without suppression of the immune system that are employed as a preventive strategy in patients with chronic lung disease such as bronchiectasis. These immunomodulatory effects include modification of mucus production, inhibition of biofilm production, suppression of inflammatory mediators and modulation of leukocyte recruitment [
      • Altenburg J.
      • de Graaff C.S.
      • van der Werf T.S.
      • Boersma W.G.
      Immunomodulatory effects of macrolide antibiotics - part 1: biological mechanisms.
      ,
      • Altenburg J.
      • de Graaff C.S.
      • van der Werf T.S.
      • Boersma W.G.
      Immunomodulatory effects of macrolide antibiotics - part 2: advantages and disadvantages of long-term, low-dose macrolide therapy.
      ,
      • Levert H.
      • Gressier B.
      • Moutard I.
      • Brunet C.
      • Dine T.
      • Luyckx M.
      • Cazin M.
      • Cazin J.
      Azithromycin impact on neutrophil oxidative metabolism depends on exposure time. - PubMed - NCBI.
      ,
      • Elborn J.S.
      • Tunney M.M.
      Macrolides and bronchiectasis.
      ,
      • Albert R.K.
      • Connett J.
      • Bailey W.C.
      • Casaburi R.
      • Cooper J.A.D.
      • Criner G.J.
      • Curtis J.L.
      • Dransfield M.T.
      • Han M.K.
      • Lazarus S.C.
      • Make B.
      • Marchetti N.
      • Martinez F.J.
      • Madinger N.E.
      • McEvoy C.
      • Niewoehner D.E.
      • Porsasz J.
      • Price C.S.
      • Reilly J.
      • Scanlon P.D.
      • Sciurba F.C.
      • Scharf S.M.
      • Washko G.R.
      • Woodruff P.G.
      • Anthonisen N.R.
      • Copd Clinical Research Network
      • Crooks M.G.
      • Hart S.P.
      • Morice A.H.
      Azithromycin for prevention of exacerbations of COPD.
      ]. Three well designed clinical investigations provide strong evidence to support use of macrolides in patients with non-CF bronchiectasis (Table 3) [
      • Wong C.
      • Jayaram L.
      • Karalus N.
      • Eaton T.
      • Tong C.
      • Hockey H.
      • Milne D.
      • Fergusson W.
      • Tuffery C.
      • Sexton P.
      • Storey L.
      • Ashton T.
      • Tuffery C.
      • Fergusson W.
      • Hockey H.
      • Milne D.
      • Storey L.
      • Wong C.
      • Jayaram L.
      • Tong C.
      • Karalus N.
      • Ashton T.
      • Eaton T.
      • Tong C.
      • Hockey H.
      • Milne D.
      • Fergusson W.
      • Tuffery C.
      • Sexton P.
      • Storey L.
      • Ashton T.
      Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial.
      ,
      • Altenburg J.
      • De Graaff C.S.
      • Stienstra Y.
      • Sloos J.H.
      • van Haren E.H.J.J.
      • Koppers R.J.H.H.
      • van der Werf T.S.
      • Boersma W.G.
      Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non–cystic fibrosis bronchiectasis: the BAT randomized controlled trial.
      ,
      • Serisier D.J.
      • Martin M.L.
      • McGuckin M.A.
      • Lourie R.
      • Chen A.C.
      • Brain B.
      • Biga S.
      • Schlebusch S.
      • Dash P.
      • Bowler S.D.
      • Chen A.C.
      • McGuckin M.A.
      • Brain B.
      • Bowler S.D.
      • Martin M.L.
      • Lourie R.
      • Schlebusch S.
      • Serisier D.J.
      Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non–cystic fibrosis bronchiectasis.
      ]. Two trials examined azithromycin; 250 mg daily administered over 12 months and 500 mg twice per week administered over 6 months compared to placebo. Both regimens resulted in a reduction in the rate of infectious exacerbations [
      • Wong C.
      • Jayaram L.
      • Karalus N.
      • Eaton T.
      • Tong C.
      • Hockey H.
      • Milne D.
      • Fergusson W.
      • Tuffery C.
      • Sexton P.
      • Storey L.
      • Ashton T.
      • Tuffery C.
      • Fergusson W.
      • Hockey H.
      • Milne D.
      • Storey L.
      • Wong C.
      • Jayaram L.
      • Tong C.
      • Karalus N.
      • Ashton T.
      • Eaton T.
      • Tong C.
      • Hockey H.
      • Milne D.
      • Fergusson W.
      • Tuffery C.
      • Sexton P.
      • Storey L.
      • Ashton T.
      Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial.
      ,
      • Altenburg J.
      • De Graaff C.S.
      • Stienstra Y.
      • Sloos J.H.
      • van Haren E.H.J.J.
      • Koppers R.J.H.H.
      • van der Werf T.S.
      • Boersma W.G.
      Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non–cystic fibrosis bronchiectasis: the BAT randomized controlled trial.
      ]. A third randomized, placebo control trial examined the effect of daily erythromycin 250 mg administered over 12 months to 117 adults with non-CF bronchiectasis and demonstrated a modest decrease in pulmonary exacerbations with an increase in the proportion of macrolide-resistant oropharyngeal streptococci [
      • Serisier D.J.
      • Martin M.L.
      • McGuckin M.A.
      • Lourie R.
      • Chen A.C.
      • Brain B.
      • Biga S.
      • Schlebusch S.
      • Dash P.
      • Bowler S.D.
      Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS randomized controlled trial.
      ]. A meta-analysis of long term macrolide therapy reported significant decreases in rate of exacerbations with similar results in patients with and without Pseudomonas airway infection [
      • Chalmers J.D.
      • Boersma W.
      • Lonergan M.
      • Jayaram L.
      • Crichton M.L.
      • Karalus N.
      • Taylor S.L.
      • Martin M.L.
      • Burr L.D.
      Long-term macrolide antibiotics for the treatment of bronchiectasis in adults : an individual participant data meta-analysis.
      ]. Of note, an increase in macrolide resistance oropharyngeal organism was reported the 12 month azithromycin study raising concerns that chronic macrolide can lead to development of resistant bacterial strains [
      • Altenburg J.
      • De Graaff C.S.
      • Stienstra Y.
      • Sloos J.H.
      • van Haren E.H.J.J.
      • Koppers R.J.H.H.
      • van der Werf T.S.
      • Boersma W.G.
      Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non–cystic fibrosis bronchiectasis: the BAT randomized controlled trial.
      ]. Furthermore, chronic macrolide use may foster macrolide-resistant strains of nontuberculous mycobacteria and assessment for these organisms with mycobacterial sputum cultures is suggested before initiation of therapy [
      • Chang A.B.
      • Bell S.C.
      • Torzillo P.J.
      • King P.T.
      • Maguire G.P.
      • Byrnes C.A.
      • Holland A.E.
      • O'Mara P.
      • Grimwood K.
      • Alison J.
      • Cull C.
      • Currie B.
      • Gardner I.
      • Holmes P.
      • Hunter C.
      • Kolbe J.
      • Maclennan C.
      • McDonald M.
      • Morris P.
      • Nicolson C.
      • Petsky H.
      • Pillarisetti N.
      • Reynolds E.
      • Serisier D.
      • Thein F.
      • van Asperen P.
      • Voss L.
      • Wong C.
      Chronic suppurative lung disease and bronchiectasis in children and adults in Australia and New Zealand.
      ]. Macrolide antibiotics are associated with prolongation of QT intervals and assessment of this risk in an individual patient with cardiovascular risk factors is warranted and includes a baseline electrocardiogram [
      • Ray W.A.
      • Murray K.T.
      • Hall K.
      • Arbogast P.G.
      • Stein C.M.
      Azithromycin and the risk of cardiovascular death.
      ]. Current consensus guidelines recommend macrolide (azithromycin or erythromycin) therapy for patients with >3 exacerbations per year with bronchiectasis without Pseudomonas aeruginosa [
      • Polverino E.
      • Goeminne P.C.
      • McDonnell M.J.
      • Aliberti S.
      • Marshall S.E.
      • Loebinger M.R.
      • Murris M.
      • Cantón R.
      • Torres A.
      • Dimakou K.
      • De Soyza A.
      • Hill A.T.
      • Haworth C.S.
      • Vendrell M.
      • Ringshausen F.C.
      • Subotic D.
      • Wilson R.
      • Vilaró J.
      • Stallberg B.
      • Welte T.
      • Rohde G.
      • Blasi F.
      • Elborn S.
      • Almagro M.
      • Timothy A.
      • Ruddy T.
      • Tonia T.
      • Rigau D.
      • Chalmers J.D.
      European Respiratory Society guidelines for the management of adult bronchiectasis.
      ]. The recent meta-analysis indicates that chronic macrolide therapy may be considered in individuals with Pseudomonas infection but this should be balanced by the consequences of therapy [
      • Chalmers J.D.
      • Boersma W.
      • Lonergan M.
      • Jayaram L.
      • Crichton M.L.
      • Karalus N.
      • Taylor S.L.
      • Martin M.L.
      • Burr L.D.
      Long-term macrolide antibiotics for the treatment of bronchiectasis in adults : an individual participant data meta-analysis.
      ].
      Table 3Randomized Controlled Trials that have demonstrated macrolide antibiotics significantly reduced bronchiectasis exacerbations.
      Study (Dates)Number of participants (Intervention vs Placebo)Macrolide treatmentStudy durationPrimary endpointOutcome (Intervention vs Placebo)
      EMBRACE Trial [
      • Wong C.
      • Jayaram L.
      • Karalus N.
      • Eaton T.
      • Tong C.
      • Hockey H.
      • Milne D.
      • Fergusson W.
      • Tuffery C.
      • Sexton P.
      • Storey L.
      • Ashton T.
      • Tuffery C.
      • Fergusson W.
      • Hockey H.
      • Milne D.
      • Storey L.
      • Wong C.
      • Jayaram L.
      • Tong C.
      • Karalus N.
      • Ashton T.
      • Eaton T.
      • Tong C.
      • Hockey H.
      • Milne D.
      • Fergusson W.
      • Tuffery C.
      • Sexton P.
      • Storey L.
      • Ashton T.
      Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial.
      ] (Wong, 2012)
      141 (71 vs 70)Azithromycin (500 mg three times per week)6 monthsPulmonary exacerbations, change in FEV1 and change in SGRQAzithromycin reduced the frequency of exacerbations; no change in FEV1; no change in SGRQ
      BAT Trial [
      • Altenburg J.
      • De Graaff C.S.
      • Stienstra Y.
      • Sloos J.H.
      • van Haren E.H.J.J.
      • Koppers R.J.H.H.
      • van der Werf T.S.
      • Boersma W.G.
      Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non–cystic fibrosis bronchiectasis: the BAT randomized controlled trial.
      ] (Altenburg, 2013)
      83 (43 vs 40)Azithromycin (250 mg daily)12 monthsPulmonary exacerbationsLower rate of infectious exacerbations with daily use of azithromycin
      BLESS Trial [
      • Serisier D.J.
      • Martin M.L.
      • McGuckin M.A.
      • Lourie R.
      • Chen A.C.
      • Brain B.
      • Biga S.
      • Schlebusch S.
      • Dash P.
      • Bowler S.D.
      Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS randomized controlled trial.
      ] (Serisier, 2013)
      117 (59 vs 58)Erythromycin (400 mg twice daily)48 weeksPulmonary exacerbationsErythromycin significantly reduced exacerbations

      8. Conclusion

      Non-CF bronchiectasis is more common than previously suspected in part due to improvements in chest imaging and diagnostic testing. A diverse set of conditions are associated with bronchiectasis and a structured approach allows determination of the underlying cause that can be treated in a disease focused fashion. Initial assessment should include a detailed history and physical examination further complimented by chest imaging, laboratory tests and microbiologic samples of airway secretions. Effective non-pharmacologic therapies include use of airway clearance techniques and referral for pulmonary rehabilitation. Therapies directed at reducing frequency of exacerbations and improvement in quality is paramount. Notably, therapies directed at treatment of cystic fibrosis may not be effective for individuals with non-CF bronchiectasis. In patients with frequent exacerbations, chronic macrolide and inhaled antibiotic therapy can provide symptomatic relief and reduce the number of episodes of acute worsening. Continued investigation is needed to identify groups of patients with non-CF bronchiectasis that will benefit from specific therapies directed at clearance of secretions, airway inflammatory cells and the respiratory microbiome.

      9. Authorship

      Jaafer Saadi Imam, MD, PhD: Study conception and design; drafting of manuscript; analysis and interpretation of scientific literature; critical revision; review.
      Alexander G. Duarte, MD: Study conception and design; drafting of manuscript; analysis and interpretation of scientific literature; critical revision; review.

      Declaration of competing interest

      The authors of this article titled “Non-CF bronchiectasis: Orphan disease no longer” declare no real or apparent conflicts of interest and no funding was received for this project.

      References

        • Ross J.J.
        Shakespeare's Tremor and Orwell's Cough: the Medical Lives of Great Writers by John J. Ross.
        St Martin’s Press, 2012
        • Reynolds H.Y.
        President's address: R.T.H. Laënnec, M.D.--clinicopathologic observations, using the stethoscope, made chest medicine more scientific.
        Trans. Am. Clin. Climatol. Assoc. 2004; 115 (accessed May 7, 2019): 1-29
        • Stokes W.
        A treatise on the diagnosis and treatment of diseases of the chest. Part. I. Diseases of the lung and windpipe.
        Br. Foreign Med. Rev. 1838; 5 (accessed May 7, 2019): 423
        • Carswell R.
        Pathological Anatomy. Illustrations of the Elementary Forms of Disease.
        1838 (accessed May 7, 2019)
        • Barker A.F.
        • Bardana E.J.
        Bronchiectasis: update of an orphan disease.
        Am. Rev. Respir. Dis. 1988; 137: 969-978https://doi.org/10.1164/ajrccm/137.4.969
        • Cole P.J.
        Inflammation: a two-edged sword - the model of bronchiectasis.
        Eur. J. Respir. Dis. 1986; 147: 6-15
        • Flume P.A.
        • Chalmers J.D.
        • Olivier K.N.
        Advances in bronchiectasis : endotyping , genetics , microbiome , and disease heterogeneity.
        Lancet. 2018; 392: 880-890https://doi.org/10.1016/S0140-6736(18)31767-7
        • Quint J.K.
        • Millett E.R.C.
        • Joshi M.
        • Navaratnam V.
        • Thomas S.L.
        • Hurst J.R.
        • Smeeth L.
        • Brown J.S.
        Changes in the incidence, prevalence and mortality of bronchiectasis in the UK from 2004 to 2013: a population-based cohort study.
        Eur. Respir. J. 2016; 47: 186-193https://doi.org/10.1183/13993003.01033-2015
        • Seitz A.E.
        • Olivier K.N.
        • Adjemian J.
        • Holland S.M.
        • Prevots D.R.
        Trends in bronchiectasis among medicare beneficiaries in the United States, 2000 to 2007.
        Chest. 2012; 142: 432-439https://doi.org/10.1378/chest.11-2209
        • Henkle E.
        • Chan B.
        • Curtis J.R.
        • Aksamit T.R.
        • Daley C.L.
        • Winthrop K.L.
        Characteristics and health-care utilization history of patients with bronchiectasis in US medicare enrollees with prescription drug plans, 2006 to 2014.
        Chest. 2018; 154: 1311-1320https://doi.org/10.1016/j.chest.2018.07.014
        • Aksamit T.R.
        • O'Donnell A.E.
        • Barker A.
        • Olivier K.N.
        • Winthrop K.L.
        • Daniels M.L.A.
        • Johnson M.
        • Eden E.
        • Griffith D.
        • Knowles M.
        • Metersky M.
        • Salathe M.
        • Thomashow B.
        • Tino G.
        • Turino G.
        • Carretta B.
        • Daley C.L.
        Adult patients with bronchiectasis: a first look at the US bronchiectasis Research registry.
        Chest. 2017; 151: 982-992https://doi.org/10.1016/j.chest.2016.10.055
        • Kapur N.
        • Masters I.B.
        • Chang A.B.
        Exacerbations in noncystic fibrosis bronchiectasis: clinical features and investigations.
        Respir. Med. 2009; 103: 1681-1687https://doi.org/10.1016/j.rmed.2009.05.007
        • King P.T.
        • Holdsworth S.R.
        • Freezer N.J.
        • Villanueva E.
        • Holmes P.W.
        Characterisation of the onset and presenting clinical features of adult bronchiectasis.
        Respir. Med. 2006; 100: 2183-2189https://doi.org/10.1016/j.rmed.2006.03.012
        • Currie D.C.
        • Cooke J.C.
        • Morgan A.D.
        • Kerr I.H.
        • Delany D.
        • Strickland B.
        • Cole P.J.
        Interpretation of bronchograms and chest radiographs in patients with chronic sputum production.
        Thorax. 1987; 42: 278-284https://doi.org/10.1136/thx.42.4.278
        • Van Der Bruggen-Bogaarts B.A.H.A.
        • Van Der Bruggen H.M.J.G.
        • Van Waes P.F.G.M.
        • Lammers J.W.J.
        Screening for bronchiectasis: a comparative study between chest radiography and high-resolution CT.
        Chest. 1996; 109: 608-611https://doi.org/10.1378/chest.109.3.608
        • Dodd J.D.
        • Souza C.A.
        • Müller N.L.
        Conventional high-resolution CT versus helical high-resolution MDCT in the detection of bronchiectasis.
        AJR Am. J. Roentgenol. 2006; 187: 414-420https://doi.org/10.2214/AJR.05.0723
        • Phillips M.S.
        • Williams M.P.
        • Flower C.D.R.
        How useful is computed tomography in the diagnosis and assessment of bronchiectasis?.
        Clin. Radiol. 1986; 37: 321-325https://doi.org/10.1016/S0009-9260(86)80261-6
        • Bonavita J.
        • Naidich D.P.
        Imaging of bronchiectasis.
        Clin. Chest Med. 2012; 33: 233-248https://doi.org/10.1016/j.ccm.2012.02.007
        • Gilljam M.
        • Ellis L.
        • Corey M.
        • Zielenski J.
        • Durie P.
        • Tullis D.E.
        Clinical manifestations of cystic fibrosis among patients with diagnosis in adulthood.
        Chest. 2004; 126: 1215-1224https://doi.org/10.1378/chest.126.4.1215
        • Rodman D.M.
        • Polis J.M.
        • Heltshe S.L.
        • Sontag M.K.
        • Chacon C.
        • Rodman R.V.
        • Brayshaw S.J.
        • Huitt G.A.
        • Iseman M.D.
        • Saavedra M.T.
        • Taussig L.M.
        • Wagener J.S.
        • Accurso F.J.
        • Nick J.A.
        Late diagnosis defines a unique population of long-term survivors of cystic fibrosis.
        Am. J. Respir. Crit. Care Med. 2005; 171: 621-626https://doi.org/10.1164/rccm.200403-404OC
        • Averill S.
        • Lubner M.G.
        • Menias C.O.
        • Bhalla S.
        • Mellnick V.M.
        • Kennedy T.A.
        • Pickhardt P.J.
        Multisystem imaging findings of cystic fibrosis in adults: recognizing typical and atypical patterns of disease.
        Am. J. Roentgenol. 2017; 209: 3-18https://doi.org/10.2214/AJR.16.17462
        • Nick J.A.
        • Rodman D.M.
        Manifestations of cystic fibrosis diagnosed in adulthood.
        Curr. Opin. Intern. Med. 2005; 5: 68-73https://doi.org/10.1097/01.mcp.0000183052.56728.76
        • Milliron B.
        • Henry T.S.
        • Veeraraghavan S.
        • Little B.P.
        Bronchiectasis: Mechanisms and Imaging Clues of Associated Common and Uncommon Diseases. vol. 35. 2015https://doi.org/10.1148/rg.2015140214
        • Pasteur M.C.
        • Helliwell S.M.
        • Houghton S.J.
        • Webb S.C.
        • Foweraker J.E.
        • Coulden R.A.
        • Flower C.D.
        • Bilton D.
        • Keogan M.T.
        An investigation into causative factors in patients with bronchiectasis.
        Am. J. Respir. Crit. Care Med. 2000; 162: 1277-1284https://doi.org/10.1164/ajrccm.162.4.9906120
        • Shoemark A.
        • Ozerovitch L.
        • Wilson R.
        Aetiology in adult patients with bronchiectasis.
        Respir. Med. 2007; 101: 1163-1170https://doi.org/10.1016/j.rmed.2006.11.008
        • Lonni S.
        • Chalmers J.D.
        • Goeminne P.C.
        • McDonnell M.J.
        • Dimakou K.
        • De Soyza A.
        • Polverino E.
        • Van de Kerkhove C.
        • Rutherford R.
        • Davison J.
        • Rosales E.
        • Pesci A.
        • Restrepo M.I.
        • Torres A.
        • Aliberti S.
        Etiology of non-cystic fibrosis bronchiectasis in adults and its correlation to disease severity.
        Ann. Am. Thorac. Soc. 2015; 12: 1764-1770https://doi.org/10.1513/AnnalsATS.201507-472OC
        • Olveira C.
        • Padilla A.
        • Martínez-García M.-Á.
        • de la Rosa D.
        • Girón R.-M.
        • Vendrell M.
        • Máiz L.
        • Borderías L.
        • Polverino E.
        • Martínez-Moragón E.
        • Rajas O.
        • Casas F.
        • Cordovilla R.
        • de Gracia J.
        Etiology of bronchiectasis in a cohort of 2047 patients. An analysis of the Spanish historical bronchiectasis registry.
        Arch. Bronconeumol. 2017; 53: 366-374https://doi.org/10.1016/j.arbres.2016.12.003
        • Visser S.K.
        • Bye P.T.P.
        • Fox G.J.
        • Burr L.D.
        • Chang A.B.
        • Holmes-Liew C.-L.
        • King P.
        • Middleton P.G.
        • Maguire G.P.
        • Smith D.
        • Thomson R.M.
        • Stroil-Salama E.
        • Britton W.J.
        • Morgan L.C.
        Australian adults with bronchiectasis: the first report from the Australian Bronchiectasis Registry.
        Respir. Med. 2019; 155: 97-103https://doi.org/10.1016/j.rmed.2019.07.016
        • Jones E.M.
        • Peck W.M.
        Relationships between tuberculosis and bronchiectasis; a study of clinical and of post-mortem material.
        Am. Rev. Tubercul. 1950; 61 (accessed November 2, 2019): 387-398
        • Warner W.P.
        Some factors causing bronchial dilatation in bronchiectasis.
        Trans. Am. Clin. Climatol. Assoc. 1934; 50 (accessed November 2, 2019): 172-182
        • Kim C.K.
        • Chung C.Y.
        • Kim J.S.
        • Kim W.S.
        • Park Y.
        • Koh Y.Y.
        Late abnormal findings on high-resolution computed tomography after Mycoplasma pneumonia.
        Pediatrics. 2000; 105: 372-378https://doi.org/10.1542/peds.105.2.372
        • Herbert F.A.
        • Wilkinson D.
        • Burchak E.
        • Morgante O.
        Adenovirus type 3 pneumonia causing lung damage in childhood.
        Can. Med. Assoc. J. 1977; 116 (accessed November 2, 2019): 274-276
        • Kaschula R.O.C.
        • Druker J.
        • Kipps A.
        Late morphologic consequences of measles: a lethal and debilitating lung disease among the poor.
        Rev. Infect. Dis. 1983; 5: 395-404https://doi.org/10.1093/clinids/5.3.395
        • Rosenzweig D.Y.
        • Stead W.W.
        The role of tuberculosis and other forms of bronchopulmonary necrosis in the pathogenesis of bronchiectasis.
        Am. Rev. Respir. Dis. 1966; 93: 769-785https://doi.org/10.1164/arrd.1966.93.5.769
        • Faverio P.
        • Stainer A.
        • Bonaiti G.
        • Zucchetti S.C.
        • Simonetta E.
        • Lapadula G.
        • Marruchella A.
        • Gori A.
        • Blasi F.
        • Codecasa L.
        • Pesci A.
        • Chalmers J.D.
        • Loebinger M.R.
        • Aliberti S.
        Characterizing non-tuberculous mycobacteria infection in bronchiectasis.
        Int. J. Mol. Sci. 2016; 17https://doi.org/10.3390/ijms17111913
        • Máiz L.
        • Girón R.
        • Olveira C.
        • Vendrell M.
        • Nieto R.
        • Martínez-García M.A.
        Prevalence and factors associated with nontuberculous mycobacteria in non-cystic fibrosis bronchiectasis: a multicenter observational study.
        BMC Infect. Dis. 2016; 16: 437https://doi.org/10.1186/s12879-016-1774-x
        • Kim R.D.
        • Greenberg D.E.
        • Ehrmantraut M.E.
        • Guide S.V.
        • Ding L.
        • Shea Y.
        • Brown M.R.
        • Chernick M.
        • Steagall W.K.
        • Glasgow C.G.
        • Lin J.
        • Jolley C.
        • Sorbara L.
        • Raffeld M.
        • Hill S.
        • Avila N.
        • Sachdev V.
        • Barnhart L.A.
        • Anderson V.L.
        • Claypool R.
        • Hilligoss D.M.
        • Garofalo M.
        • Fitzgerald A.
        • Anaya-O’Brien S.
        • Darnell D.
        • DeCastro R.
        • Menning H.M.
        • Ricklefs S.M.
        • Porcella S.F.
        • Olivier K.N.
        • Moss J.
        • Holland S.M.
        Pulmonary nontuberculous mycobacterial disease: prospective study of a distinct preexisting syndrome.
        Am. J. Respir. Crit. Care Med. 2008; 178: 1066-1074https://doi.org/10.1164/rccm.200805-686OC
        • Kartalija M.
        • Ovrutsky A.R.
        • Bryan C.L.
        • Pott G.B.
        • Fantuzzi G.
        • Thomas J.
        • Strand M.J.
        • Bai X.
        • Ramamoorthy P.
        • Rothman M.S.
        • Nagabhushanam V.
        • McDermott M.
        • Levin A.R.
        • Frazer-Abel A.
        • Giclas P.C.
        • Korner J.
        • Iseman M.D.
        • Shapiro L.
        • Chan E.D.
        Patients with nontuberculous mycobacterial lung disease exhibit unique body and immune phenotypes.
        Am. J. Respir. Crit. Care Med. 2013; 187: 197-205https://doi.org/10.1164/rccm.201206-1035OC
        • Szymanski E.P.
        • Leung J.M.
        • Fowler C.J.
        • Haney C.
        • Hsu A.P.
        • Chen F.
        • Duggal P.
        • Oler A.J.
        • McCormack R.
        • Podack E.
        • Drummond R.A.
        • Lionakis M.S.
        • Browne S.K.
        • Prevots D.R.
        • Knowles M.
        • Cutting G.
        • Liu X.
        • Devine S.E.
        • Fraser C.M.
        • Tettelin H.
        • Olivier K.N.
        • Holland S.M.
        Pulmonary nontuberculous mycobacterial infection a multisystem, multigenic disease.
        Am. J. Respir. Crit. Care Med. 2015; 192: 618-628https://doi.org/10.1164/rccm.201502-0387OC
        • Chen F.
        • Szymanski E.P.
        • Olivier K.N.
        • Liu X.
        • Tettelin H.
        • Holland S.M.
        • Duggal P.
        Whole-exome sequencing identifies the 6q12-q16 linkage region and a candidate gene, TTK, for pulmonary nontuberculous mycobacterial disease.
        Am. J. Respir. Crit. Care Med. 2017; 196: 1599-1604https://doi.org/10.1164/rccm.201612-2479OC
        • Agarwal R.
        Allergic bronchopulmonary aspergillosis.
        Chest. 2009; 135: 805-826https://doi.org/10.1378/chest.08-2586
        • Agarwal R.
        • Chakrabarti A.
        • Shah A.
        • Gupta D.
        • Meis J.F.
        • Guleria R.
        • Moss R.
        • Denning D.W.
        Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria.
        Clin. Exp. Allergy. 2013; 43: 850-873https://doi.org/10.1111/cea.12141
        • Overton N.L.D.
        • Denning D.W.
        • Bowyer P.
        • Simpson A.
        Genetic susceptibility to allergic bronchopulmonary aspergillosis in asthma: a genetic association study, Allergy, Asthma.
        Clin. Immunol. 2016; 12https://doi.org/10.1186/s13223-016-0152-y
        • Tarzi M.D.
        • Grigoriadou S.
        • Carr S.B.
        • Kuitert L.M.
        • Longhurst H.J.
        Clinical immunology review series: an approach to the management of pulmonary disease in primary antibody deficiency.
        • Gupta S.
        • Pattanaik D.
        • Krishnaswamy G.
        Common variable immune deficiency and associated complications.
        Chest. 2019; 156: 579-593https://doi.org/10.1016/j.chest.2019.05.009
        • Chandesris M.-O.O.
        • Melki I.
        • Natividad A.
        • Puel A.
        • Fieschi C.
        • Yun L.
        • Thumerelle C.
        • Oksenhendler E.
        • Boutboul D.
        • Thomas C.
        • Hoarau C.
        • Lebranchu Y.
        • Stephan J.-L.L.
        • Cazorla C.
        • Aladjidi N.
        • Micheau M.
        • Tron F.
        • Baruchel A.
        • Barlogis V.
        • Palenzuela G.
        • Mathey C.
        • Dominique S.
        • Body G.
        • Munzer M.
        • Fouyssac F.
        • Jaussaud R.
        • Bader-Meunier B.
        • Mahlaoui N.
        • Blanche S.
        • Debré M.
        • Le Bourgeois M.
        • Gandemer V.
        • Lambert N.
        • Grandin V.
        • Ndaga S.
        • Jacques C.
        • Harre C.
        • Forveille M.
        • Alyanakian M.-A.A.
        • Durandy A.
        • Bodemer C.
        • Suarez F.
        • Hermine O.
        • Lortholary O.
        • Casanova J.-L.L.
        • Fischer A.
        • Picard C.
        Autosomal Dominant STAT3 Deficiency and Hyper-IgE Syndrome: Molecular, Cellular, and Clinical Features from a French National Survey.
        2012https://doi.org/10.1097/MD.0b013e31825f95b9
        • Holland S.M.
        • DeLeo F.R.
        • Elloumi H.Z.
        • Hsu A.P.
        • Uzel G.
        • Brodsky N.
        • Freeman A.F.
        • Demidowich A.
        • Davis J.
        • Turner M.L.
        • Anderson V.L.
        • Darnell D.N.
        • Welch P.A.
        • Kuhns D.B.
        • Frucht D.M.
        • Malech H.L.
        • Gallin J.I.
        • Kobayashi S.D.
        • Whitney A.R.
        • Voyich J.M.
        • Musser J.M.
        • Woellner C.
        • Schäffer A.A.
        • Puck J.M.
        • Grimbacher B.
        STAT3 mutations in the hyper-IgE syndrome.
        N. Engl. J. Med. 2007; 357: 1608-1619https://doi.org/10.1056/NEJMoa073687
        • Alsum Z.
        • Hawwari A.
        • Alsmadi O.
        • Al-Hissi S.
        • Borrero E.
        • Abu-Staiteh A.
        • Khalak H.G.
        • Wakil S.
        • Eldali A.M.
        • Arnaout R.
        • Al-Ghonaium A.
        • Al-Muhsen S.
        • Al-Dhekri H.
        • Al-Saud B.
        • Al-Mousa H.
        Clinical, immunological and molecular characterization of DOCK8 and DOCK8-like deficient patients: single center experience of twenty-five patients.
        J. Clin. Immunol. 2013; 33: 55-67https://doi.org/10.1007/s10875-012-9769-x
        • Woellner C.
        • Gertz E.M.
        • Schäffer A.A.
        • Lagos M.
        • Perro M.
        • Glocker E.-O.
        • Pietrogrande M.C.
        • Cossu F.
        • Franco J.L.
        • Matamoros N.
        • Pietrucha B.
        • Heropolitańska-Pliszka E.
        • Yeganeh M.
        • Moin M.
        • Español T.
        • Ehl S.
        • Gennery A.R.
        • Abinun M.
        • Breborowicz A.
        • Niehues T.
        • Kilic S.S.
        • Junker A.
        • Turvey S.E.
        • Plebani A.
        • Sánchez B.
        • Garty B.-Z.
        • Pignata C.
        • Cancrini C.
        • Litzman J.
        • Sanal O.
        • Baumann U.
        • Bacchetta R.
        • Hsu A.P.
        • Davis J.N.
        • Hammarström L.
        • Davies E.G.
        • Eren E.
        • Arkwright P.D.
        • Moilanen J.S.
        • Viemann D.
        • Khan S.
        • Maródi L.
        • Cant A.J.
        • Freeman A.F.
        • Puck J.M.
        • Holland S.M.
        • Grimbacher B.
        Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome.
        J. Allergy Clin. Immunol. 2010; 125 (e8): 424-432https://doi.org/10.1016/j.jaci.2009.10.059
        • Jones V.F.
        • Eid N.S.
        • Franco S.M.
        • Badgett J.T.
        • Buchino J.J.
        Familial congenital bronchiectasis: williams-Campbell syndrome.
        Pediatr. Pulmonol. 1993; 16: 263-267https://doi.org/10.1002/ppul.1950160410
        • Krustins E.
        • Kravale Z.
        • Buls A.
        Mounier-Kuhn syndrome or congenital tracheobronchomegaly: a literature review.
        Respir. Med. 2013; 107 (1822–8)https://doi.org/10.1016/j.rmed.2013.08.042
        • Schwartz M.
        • Rossoff L.
        Tracheobronchomegaly., Chest. 1994; 106: 1589-1590https://doi.org/10.1378/chest.106.5.1589
        • Sanders D.B.
        • Fink A.K.
        Background and epidemiology.
        Pediatr. Clin. 2016; 63: 567-584https://doi.org/10.1016/j.pcl.2016.04.001
        • Sullivan B.P.O.
        • Freedman S.D.
        Seminar cystic fibrosis.
        Lancet. 2009; 373: 1891-1904https://doi.org/10.1016/S0140-6736(09)60327-5
        • Keating C.L.
        • Liu X.
        • DiMango E.A.
        Classic respiratory disease but atypical diagnostic testing distinguishes adult presentation of cystic fibrosis.
        Chest. 2010; 137: 1157-1163https://doi.org/10.1378/chest.09-1352
        • Farrell P.M.
        • White T.B.
        • Ren C.L.
        • Hempstead S.E.
        • Accurso F.
        • Derichs N.
        • Howenstine M.
        • Mccolley S.A.
        • Rock M.
        • Rosenfeld M.
        • Sermet-Gaudelus I.
        • Southern K.W.
        • Marshall B.C.
        • Sosnay P.R.
        Diagnosis of cystic fibrosis: consensus guidelines from the cystic fibrosis foundation.
        J. Pediatr. 2017; 181: S4-S15.e1https://doi.org/10.1016/j.jpeds.2016.09.064
        • Bienvenu T.
        • Sermet-Gaudelus I.
        • Burgel P.R.
        • Hubert D.
        • Crestani B.
        • Bassinet L.
        • Dusser D.
        • Fajac I.
        Cystic fibrosis transmembrane conductance regulator channel dysfunction in non-cystic fibrosis bronchiectasis.
        Am. J. Respir. Crit. Care Med. 2010; 181: 1078-1084https://doi.org/10.1164/rccm.200909-1434OC
        • Knowles M.R.
        • Daniels L.A.
        • Davis S.D.
        • Zariwala M.A.
        • Leigh M.W.
        Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease.
        Am. J. Respir. Crit. Care Med. 2013; 188: 913-922https://doi.org/10.1164/rccm.201301-0059CI
        • Yiallouros P.K.
        • Kouis P.
        • Middleton N.
        • Nearchou M.
        • Adamidi T.
        • Georgiou A.
        • Eleftheriou A.
        • Ioannou P.
        • Hadjisavvas A.
        • Kyriacou K.
        Clinical features of primary ciliary dyskinesia in Cyprus with emphasis on lobectomized patients.
        Respir. Med. 2015; 109: 347-356https://doi.org/10.1016/j.rmed.2015.01.015
        • Lucas J.S.
        • Barbato A.
        • Collins S.A.
        • Goutaki M.
        • Behan L.
        • Caudri D.
        • Dell S.
        • Eber E.
        • Escudier E.
        • Hirst R.A.
        • Hogg C.
        • Jorissen M.
        • Latzin P.
        • Legendre M.
        • Leigh M.W.
        • Midulla F.
        • Nielsen K.G.
        • Omran H.
        • Papon J.-F.
        • Pohunek P.
        • Redfern B.
        • Rigau D.
        • Rindlisbacher B.
        • Santamaria F.
        • Shoemark A.
        • Snijders D.
        • Tonia T.
        • Titieni A.
        • Walker W.T.
        • Werner C.
        • Bush A.
        • Kuehni C.E.
        European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia.
        Eur. Respir. J. 2017; 49https://doi.org/10.1183/13993003.01090-2016
        • Shapiro A.J.
        • Davis S.D.
        • Polineni D.
        • Manion M.
        • Rosenfeld M.
        • Dell S.D.
        • Chilvers M.A.
        • Ferkol T.W.
        • Zariwala M.A.
        • Sagel S.D.
        • Josephson M.
        • Morgan L.
        • Yilmaz O.
        • Olivier K.N.
        • Milla C.
        • Pittman J.E.
        • Leigh Anne Daniels M.
        • Jones M.H.
        • Janahi I.A.
        • Ware S.M.
        • Daniel S.J.
        • Cooper M.L.
        • Nogee L.M.
        • Anton B.
        • Eastvold T.
        • Ehrne L.
        • Guadagno E.
        • Knowles M.R.
        • Leigh M.W.
        • Lavergne V.
        • Daniels M.L.A.
        • Jones M.H.
        • Janahi I.A.
        • Ware S.M.
        • Daniel S.J.
        • Cooper M.L.
        • Nogee L.M.
        • Anton B.
        • Eastvold T.
        • Ehrne L.
        • Guadagno E.
        • Knowles M.R.
        • Leigh M.W.
        • Lavergne V.
        American Thoracic Society Assembly on Pediatrics, Diagnosis of primary ciliary dyskinesia: an official American thoracic society clinical practice guideline.
        Am. J. Respir. Crit. Care Med. 2018; 197: e24-e39https://doi.org/10.1164/rccm.201805-0819ST
        • Hurst J.R.
        • Elborn J.S.
        • De Soyza A.
        • Bronch-Uk Consortium
        COPD–bronchiectasis overlap syndrome.
        Eur. Respir. J. 2015; 45: 310-313https://doi.org/10.1183/09031936.00170014
        • Polverino E.
        • Dimakou K.
        • Hurst J.
        • Martinez-Garcia M.-A.
        • Miravitlles M.
        • Paggiaro P.
        • Shteinberg M.
        • Aliberti S.
        • Chalmers J.D.
        The overlap between bronchiectasis and chronic airway diseases: state of the art and future directions.
        Eur. Respir. J. 2018; 52https://doi.org/10.1183/13993003.00328-2018
        • Martínez-García M.Á.
        • Soler-Cataluña J.J.
        • Donat-Sanz Y.
        • Catalán-Serra P.
        • Agramunt-Lerma M.
        • Ballestín-Vicente J.
        • Perpiñá-Tordera M.
        Factors associated with bronchiectasis in chronic obstructive pulmonary disease patients.
        Chest. 2011; 140: 1130-1137https://doi.org/10.1378/chest.10-1758
        • Martínez-García M.-A.
        • De La D.
        • Carrillo R.
        • Soler-Cataluña J.-J.
        • Donat-Sanz Y.
        • Serra P.C.
        • Lerma M.A.
        • Ballestín J.
        • Valero Sánchez I.
        • Jose M.
        • Ferrer S.
        • Dalfo A.R.
        • Valdecillos M.B.
        • de la Rosa Carrillo D.
        • Soler-Cataluña J.-J.
        • Donat-Sanz Y.
        • Serra P.C.
        • Lerma M.A.
        • Ballestín J.
        • Sánchez I.V.
        • Selma Ferrer M.J.
        • Dalfo A.R.
        • Valdecillos M.B.
        Prognostic value of bronchiectasis in patients with moderate-to-severe chronic obstructive pulmonary disease.
        Am. J. Respir. Crit. Care Med. 2013; 187: 823-831https://doi.org/10.1164/rccm.201208-1518OC
        • Goeminne P.C.C.
        • Nawrot T.S.S.
        • Ruttens D.
        • Seys S.
        • Dupont L.J.J.
        Mortality in Non-cystic Fibrosis Bronchiectasis: A Prospective Cohort Analysis. vol. 108. 2014https://doi.org/10.1016/j.rmed.2013.12.015
        • Scott J.H.
        • Anderson C.L.
        • Shankar P.S.
        • Stavrides A.
        Alpha1-antitrypsin deficiency with diffuse bronchiectasis and cirrhosis of the liver.
        Chest. 1977; 71: 535-538https://doi.org/10.1378/chest.71.4.535
        • Shin M.S.
        • Ho K.J.
        Bronchiectasis in patients with alpha 1-antitrypsin deficiency. A rare occurrence?.
        Chest. 1993; 104: 1384-1386https://doi.org/10.1378/chest.104.5.1384
        • Rodriguez-Cintron W.
        • Guntupalli K.
        • Fraire A.E.
        Bronchiectasis and homozygous (P1ZZ) α1-antitrypsin deficiency in a young man.
        Thorax. 1995; 50: 424-425https://doi.org/10.1136/thx.50.4.424
        • Parr D.G.
        • Guest P.G.
        • Reynolds J.H.
        • Dowson L.J.
        • Stockley R.A.
        Prevalence and impact of bronchiectasis in alpha1-antitrypsin deficiency.
        Am. J. Respir. Crit. Care Med. 2007; 176: 1215-1221https://doi.org/10.1164/rccm.200703-489OC
        • Eden E.
        • Choate R.
        • Barker A.
        • Addrizzo-Harris D.
        • Aksamit T.R.
        • Daley C.L.
        • Daniels M.L.A.
        • DiMango A.
        • Fennelly K.
        • Griffith D.E.
        • Johnson M.M.
        • Knowles M.R.
        • Metersky M.L.
        • Noone P.G.
        • O'Donnell A.E.
        • Olivier K.N.
        • Salathe M.A.
        • Schmid A.
        • Thomashow B.
        • Tino G.
        • Turino G.M.
        • Winthrop K.L.
        The clinical features of bronchiectasis associated with alpha-1 antitrypsin deficiency, common variable immunodeficiency and primary ciliary dyskinesia--results from the U.S. Bronchiectasis Research registry.
        Chronic Obstr. Pulm. Dis. (Miami, Fla.). 2019; 6: 145-153https://doi.org/10.15326/jcopdf.6.2.2018.0156
        • Perry E.
        • Stenton C.
        • Kelly C.
        • Eggleton P.
        • Hutchinson D.
        • De Soyza A.
        RA autoantibodies as predictors of rheumatoid arthritis in non-cystic fibrosis bronchiectasis patients.
        Eur. Respir. J. 2014; 44: 1082-1085https://doi.org/10.1183/09031936.00064014
        • Demoruelle M.K.
        • Weisman M.H.
        • Simonian P.L.
        • Lynch D.A.
        • Sachs P.B.
        • Pedraza I.F.
        • Harrington A.R.
        • Kolfenbach J.R.
        • Striebich C.C.
        • Pham Q.N.
        • Strickland C.D.
        • Petersen B.D.
        • Parish M.C.
        • Derber L.A.
        • Norris J.M.
        • Holers V.M.
        • Deane K.D.
        Brief report: airways abnormalities and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating site of autoimmunity?.
        Arthritis Rheum. 2012; 64: 1756-1761https://doi.org/10.1002/art.34344
        • Black H.
        • Mendoza M.
        • Murin S.
        Thoracic manifestations of inflammatory bowel disease.
        Chest. 2007; 131: 524-532https://doi.org/10.1378/chest.06-1074
        • Polverino E.
        • Goeminne P.C.
        • McDonnell M.J.
        • Aliberti S.
        • Marshall S.E.
        • Loebinger M.R.
        • Murris M.
        • Cantón R.
        • Torres A.
        • Dimakou K.
        • De Soyza A.
        • Hill A.T.
        • Haworth C.S.
        • Vendrell M.
        • Ringshausen F.C.
        • Subotic D.
        • Wilson R.
        • Vilaró J.
        • Stallberg B.
        • Welte T.
        • Rohde G.
        • Blasi F.
        • Elborn S.
        • Almagro M.
        • Timothy A.
        • Ruddy T.
        • Tonia T.
        • Rigau D.
        • Chalmers J.D.
        European Respiratory Society guidelines for the management of adult bronchiectasis.
        Eur. Respir. J. 2017; 50https://doi.org/10.1183/13993003.00629-2017
        • Pasteur M.C.
        • Bilton D.
        • Hill A.T.
        British thoracic society guideline for non-CF bronchiectasis.
        Thorax. 2010; 65: 577https://doi.org/10.1136/thx.2010.142778
        • Chang A.B.
        • Bell S.C.
        • Torzillo P.J.
        • King P.T.
        • Maguire G.P.
        • Byrnes C.A.
        • Holland A.E.
        • O'Mara P.
        • Grimwood K.
        • Alison J.
        • Cull C.
        • Currie B.
        • Gardner I.
        • Holmes P.
        • Hunter C.
        • Kolbe J.
        • Maclennan C.
        • McDonald M.
        • Morris P.
        • Nicolson C.
        • Petsky H.
        • Pillarisetti N.
        • Reynolds E.
        • Serisier D.
        • Thein F.
        • van Asperen P.
        • Voss L.
        • Wong C.
        Chronic suppurative lung disease and bronchiectasis in children and adults in Australia and New Zealand.
        Med. J. Aust. 2015; 202: 21-24https://doi.org/10.5694/mja14.00287
        • Sosnay P.R.
        • White T.B.
        • Farrell P.M.
        • Ren C.L.
        • Derichs N.
        • Howenstine M.S.
        • Nick J.A.
        • De Boeck K.
        Diagnosis of cystic fibrosis in nonscreened populations.
        J. Pediatr. 2017; 181: S52-S57.e2https://doi.org/10.1016/j.jpeds.2016.09.068
        • Coulden R.A.
        • Bilton D.
        • Helliwell S.M.
        • Keogan M.T.
        • Houghton S.J.
        • Foweraker J.E.
        • Webb S.C.
        • Pasteur M.C.
        • Flower C.D.
        An investigation into causative factors in patients with bronchiectasis.
        Am. J. Respir. Crit. Care Med. 2013; 162: 1277-1284https://doi.org/10.1164/ajrccm.162.4.9906120
        • Anwar G.A.
        • McDonnell M.J.
        • Worthy S.A.
        • Bourke S.C.
        • Afolabi G.
        • Lordan J.
        • Corris P.A.
        • Desoyza A.
        • Middleton P.
        • Ward C.
        • Rutherford R.M.
        Phenotyping adults with non-cystic fibrosis bronchiectasis: a prospective observational cohort study.
        Respir. Med. 2013; 107: 1001-1007https://doi.org/10.1016/j.rmed.2013.04.013
        • Wilson C.B.
        • Jones P.W.
        • O'Leary C.J.
        • Cole P.J.
        • Wilson R.
        Validation of the st. George's respiratory questionnaire in bronchiectasis.
        Am. J. Respir. Crit. Care Med. 1997; 156: 536-541https://doi.org/10.1164/ajrccm.156.2.9607083
        • Quittner A.L.
        • O'Donnell A.E.
        • Salathe M.A.
        • Lewis S.A.
        • Li X.
        • Montgomery A.B.
        • O'Riordan T.G.
        • Barker A.F.
        Quality of Life Questionnaire-Bronchiectasis: final psychometric analyses and determination of minimal important difference scores.
        Thorax. 2015; 70: 12-20https://doi.org/10.1136/thoraxjnl-2014-205918
        • Chalmers J.D.
        • Aliberti S.
        • Blasi F.
        Management of bronchiectasis in adults.
        Eur. Respir. J. 2015; 45: 1446-1462https://doi.org/10.1183/09031936.00119114
        • Chang C.C.
        • Singleton R.J.
        • Morris P.S.
        • Chang A.B.
        Pneumococcal vaccines for children and adults with bronchiectasis.
        Cochrane Database Syst. Rev. 2009; 2https://doi.org/10.1002/14651858.CD006316.pub3
        • Navaratnam V.
        • Millett E.R.C.
        • Hurst J.R.
        • Thomas S.L.
        • Smeeth L.
        • Hubbard R.B.
        • Brown J.
        • Quint J.K.
        Bronchiectasis and the risk of cardiovascular disease: a population-based study.
        Thorax. 2017; 72: 161-166https://doi.org/10.1136/thoraxjnl-2015-208188
        • Chen Y.F.
        • Lin H.H.
        • Lin C.S.
        • Turbat B.
        • Wang K.A.
        • Chung W.S.
        Bronchiectasis and increased risk of ischemic stroke: a nationwide population-based cohort study.
        Int. J. COPD. 2017; 12: 1375-1383https://doi.org/10.2147/COPD.S126102
        • Restrepo R.D.
        Inhaled adrenergics and anticholinergics in obstructive lung disease: do they enhance mucociliary clearance?.
        Respir. Care. 2007; 52 (discussion 1173-5) (accessed November 2, 2019): 1159-1173
        • Goyal V.
        • Chang A.B.
        Combination inhaled corticosteroids and long-acting beta2-agonists for children and adults with bronchiectasis.
        Cochrane Database Syst. Rev. 2013; 2013https://doi.org/10.1002/14651858.CD010327
        • Kapur N.
        • Petsky H.L.
        • Bell S.
        • Kolbe J.
        • Chang A.B.
        Inhaled corticosteroids for bronchiectasis.
        Cochrane Database Syst. Rev. 2018; 2018https://doi.org/10.1002/14651858.CD000996.pub3
        • Tsang K.W.T.
        • Ho P.-L.
        • Lam W.-K.
        • Ip M.S.M.
        • Chan K.-N.
        • Ho C.-S.
        • Ooi C.C.G.
        • Yuen K.Y.
        Inhaled fluticasone reduces sputum inflammatory indices in severe bronchiectasis.
        Am. J. Respir. Crit. Care Med. 1998; 158: 723-727https://doi.org/10.1164/ajrccm.158.3.9710090
        • Calverley P.M.A.
        • Anderson J.A.
        • Celli B.
        • Ferguson G.T.
        • Jenkins C.
        • Jones P.W.
        • Yates J.C.
        • Vestbo J.
        Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.
        N. Engl. J. Med. 2007; 356: 775-789https://doi.org/10.1056/NEJMoa063070
        • Liu V.X.
        • Winthrop K.L.
        • Lu Y.
        • Sharifi H.
        • Nasiri H.U.
        • Ruoss S.J.
        Association between inhaled corticosteroid use and pulmonary nontuberculous mycobacterial infection.
        Ann. Am. Thorac. Soc. 2018; 15: 1169-1176https://doi.org/10.1513/AnnalsATS.201804-245OC
        • Boucher R.C.
        Muco-obstructive lung diseases.
        N. Engl. J. Med. 2019; 380: 1941-1953https://doi.org/10.1056/NEJMra1813799
        • Henderson A.G.
        • Ehre C.
        • Button B.
        • Abdullah L.H.
        • Cai L.H.
        • Leigh M.W.
        • DeMaria G.C.
        • Matsui H.
        • Donaldson S.H.
        • Davis C.W.
        • Sheehan J.K.
        • Boucher R.C.
        • Kesimer M.
        Cystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressure.
        J. Clin. Invest. 2014; 124: 3047-3060https://doi.org/10.1172/JCI73469
        • Kellett F.
        • Robert N.M.
        Nebulised 7% hypertonic saline improves lung function and quality of life in bronchiectasis.
        Respir. Med. 2011; 105: 1831-1835https://doi.org/10.1016/j.rmed.2011.07.019
        • Nicolson C.H.H.
        • Stirling R.G.
        • Borg B.M.
        • Button B.M.
        • Wilson J.W.
        • Holland A.E.
        The long term effect of inhaled hypertonic saline 6% in non-cystic fibrosis bronchiectasis.
        Respir. Med. 2012; 106: 661-667https://doi.org/10.1016/j.rmed.2011.12.021
        • Bilton D.
        • Tino G.
        • Barker A.F.
        • Chambers D.C.
        • De Soyza A.
        • Dupont L.J.A.
        • O'Dochartaigh C.
        • van Haren E.H.J.
        • Vidal L.O.
        • Welte T.
        • Fox H.G.
        • Wu J.
        • Charlton B.
        B-305 Study Investigators, Inhaled mannitol for non-cystic fibrosis bronchiectasis: a randomised, controlled trial.
        Thorax. 2014; 69: 1073-1079https://doi.org/10.1136/thoraxjnl-2014-205587
        • Tarrant B.J.
        • Le Maitre C.
        • Romero L.
        • Steward R.
        • Button B.M.
        • Thompson B.R.
        • Holland A.E.
        Mucoactive agents for chronic, non-cystic fibrosis lung disease: a systematic review and meta-analysis.
        Respirology. 2017; 22: 1084-1092https://doi.org/10.1111/resp.13047
        • Fuchs H.J.
        • Christiansen D.H.
        • Borowitz D.S.
        • Nash M.L.
        • Ramsey B.W.
        • Smith A.L.
        • Morris E.M.
        • Rosenstein B.J.
        • Wohl M.E.
        Effect of aerosolized recombinant human dnase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis.
        N. Engl. J. Med. 1994; 331: 637-642https://doi.org/10.1056/NEJM199409083311003
        • Laube B.L.
        • Auci R.M.
        • Shields D.E.
        • Christiansen D.H.
        • Lucas M.K.
        • Fuchs H.J.
        • Rosenstein B.J.
        Effect of rhDNase on airflow obstruction and mucociliary clearance in cystic fibrosis.
        Am. J. Respir. Crit. Care Med. 1996; 153: 752-760https://doi.org/10.1164/ajrccm.153.2.8564129
        • O'Donnell A.E.
        • Barker A.F.
        • Ilowite J.S.
        • Fick R.B.
        Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase I.
        Chest. 1998; 113: 1329-1334https://doi.org/10.1378/chest.113.5.1329
        • Flume P.A.
        • Robinson K.A.
        • O'Sullivan B.P.
        • Finder J.D.
        • Vender R.L.
        • Willey-Courand D.-B.
        • White T.B.
        • Marshall B.C.
        Clinical practice guidelines for pulmonary therapies committee, cystic fibrosis pulmonary guidelines: airway clearance therapies.
        Respir. Care. 2009; 54 (accessed May 8, 2019): 522-537
        • Wilson L.M.
        • Morrison L.
        • Robinson K.A.
        Airway clearance techniques for cystic fibrosis: an overview of Cochrane systematic reviews.
        Cochrane Database Syst. Rev. 2019; 1: CD011231https://doi.org/10.1002/14651858.CD011231.pub2
        • Lee A.L.
        • Burge A.
        • Holland A.E.
        Lee A.L. Airway Clearance Techniques for Bronchiectasis. John Wiley & Sons, Ltd, Chichester, UK2013: CD008351https://doi.org/10.1002/14651858.CD008351.pub2 (Cochrane Database Syst. Rev.)
        • Lee A.L.
        • Burge A.T.
        • Holland A.E.
        Positive expiratory pressure therapy versus other airway clearance techniques for bronchiectasis.
        Cochrane Database Syst. Rev. 2017; 9: CD011699https://doi.org/10.1002/14651858.CD011699.pub2
        • McIlwaine M.
        • Bradley J.
        • Elborn J.S.
        • Moran F.
        Personalising airway clearance in chronic lung disease.
        Eur. Respir. Rev. 2017; 26https://doi.org/10.1183/16000617.0086-2016
        • Ong H.K.
        • Lee A.L.
        • Hill C.J.
        • Holland A.E.
        • Denehy L.
        Effects of pulmonary rehabilitation in bronchiectasis: a retrospective study.
        Chron. Respir. Dis. 2011; 8: 21-30https://doi.org/10.1177/1479972310391282
        • Lee A.L.
        • Hill C.J.
        • McDonald C.F.
        • Holland A.E.
        Pulmonary rehabilitation in individuals with non–cystic fibrosis bronchiectasis: a systematic review.
        Arch. Phys. Med. Rehabil. 2017; 98 (774-782.e1)https://doi.org/10.1016/j.apmr.2016.05.017
        • Chalmers J.D.
        • Aliberti S.
        • Filonenko A.
        • Shteinberg M.
        • Goeminne P.C.
        • Hill A.T.
        • Fardon T.C.
        • Obradovic D.
        • Gerlinger C.
        • Sotgiu G.
        • Operschall E.
        • Rutherford R.M.
        • Dimakou K.
        • Polverino E.
        • De Soyza A.
        • McDonnell M.J.
        Characterization of the “frequent exacerbator phenotype” in bronchiectasis.
        Am. J. Respir. Crit. Care Med. 2018; 197: 1410-1420https://doi.org/10.1164/rccm.201711-2202OC
        • Segal M.S.
        • Ryder C.M.
        Penicillin inhalation therapy.
        N. Engl. J. Med. 1947; 236: 132-138https://doi.org/10.1056/NEJM194701232360403
        • Dhand R.
        The rationale and evidence for use of inhaled antibiotics to control Pseudomonas aeruginosa infection in non-cystic fibrosis bronchiectasis.
        J. Aerosol Med. Pulm. Drug Deliv. 2017; 31: 121-138https://doi.org/10.1089/jamp.2017.1415
        • Barker A.F.
        • Couch L.
        • Fiel S.B.
        • Gotfried M.H.
        • Ilowite J.
        • Meyer K.C.
        • O'Donnell A.
        • Sahn S.A.
        • Smith L.J.
        • Stewart J.O.
        • Abuan T.
        • Tully H.
        • Van Dalfsen J.
        • Wells C.D.
        • Quan J.
        Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis.
        Am. J. Respir. Crit. Care Med. 2000; 162: 481-485https://doi.org/10.1164/ajrccm.162.2.9910086
        • Murray M.P.
        • Govan J.R.W.
        • Doherty C.J.
        • Simpson A.J.
        • Wilkinson T.S.
        • Chalmers J.D.
        • Greening A.P.
        • Haslett C.
        • Hill A.T.
        A randomized controlled trial of nebulized gentamicin in non–cystic fibrosis bronchiectasis.
        Am. J. Respir. Crit. Care Med. 2011; 183: 491-499https://doi.org/10.1164/rccm.201005-0756OC
        • Barker A.F.
        • O'Donnell A.E.
        • Flume P.
        • Thompson P.J.
        • Ruzi J.D.
        • De Gracia J.
        • Boersma W.G.
        • De Soyza A.
        • Shao L.
        • Zhang J.
        • Haas L.
        • Lewis S.A.
        • Leitzinger S.
        • Montgomery A.B.
        • McKevitt M.T.
        • Gossage D.
        • Quittner A.L.
        • O'Riordan T.G.
        Aztreonam for inhalation solution in patients with non-cystic fibrosis bronchiectasis (AIR-BX1 and AIR-BX2): two randomised double-blind, placebo-controlled phase 3 trials.
        Lancet Respir. Med. 2014; 2: 738-749https://doi.org/10.1016/S2213-2600(14)70165-1
        • Sibila O.
        • Laserna E.
        • Shoemark A.
        • Keir H.R.
        • Finch S.
        • Rodrigo-Troyano A.
        • Perea L.
        • Lonergan M.
        • Goeminne P.C.
        • Chalmers J.D.
        Airway bacterial load and inhaled antibiotic response in bronchiectasis.
        Am. J. Respir. Crit. Care Med. 2019; 200: 33-41https://doi.org/10.1164/rccm.201809-1651OC
        • Brodt A.M.
        • Stovold E.
        • Zhang L.
        Inhaled antibiotics for stable non-cystic fibrosis bronchiectasis: a systematic review.
        Eur. Respir. J. 2014; 44: 382-393https://doi.org/10.1183/09031936.00018414
        • De Soyza A.
        • Aksamit T.
        • Bandel T.-J.
        • Criollo M.
        • Elborn J.S.
        • Operschall E.
        • Polverino E.
        • Roth K.
        • Winthrop K.L.
        • Wilson R.
        Respire 1: a phase III placebo-controlled randomised trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis.
        Eur. Respir. J. 2018; 51https://doi.org/10.1183/13993003.02052-2017
        • Aksamit T.
        • De Soyza A.
        • Bandel T.-J.
        • Criollo M.
        • Elborn J.S.
        • Operschall E.
        • Polverino E.
        • Roth K.
        • Winthrop K.L.
        • Wilson R.
        Respire 2: a phase III placebo-controlled randomised trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis.
        Eur. Respir. J. 2018; 51: 1702053https://doi.org/10.1183/13993003.02053-2017
        • Haworth C.S.
        • Bilton D.
        • Chalmers J.D.
        • Davis A.M.
        • Froehlich J.
        • Gonda I.
        • Thompson B.
        • Wanner A.
        • O'Donnell A.E.
        Inhaled liposomal ciprofloxacin in patients with non-cystic fibrosis bronchiectasis and chronic lung infection with Pseudomonas aeruginosa (ORBIT-3 and ORBIT-4): two phase 3, randomised controlled trials.
        Lancet. Respir. Med. 2019; 7: 213-226https://doi.org/10.1016/S2213-2600(18)30427-2
        • Laska I.F.
        • Crichton M.L.
        • Shoemark A.
        • Chalmers J.D.
        The efficacy and safety of inhaled antibiotics for the treatment of bronchiectasis in adults: a systematic review and meta-analysis.
        Lancet. Respir. Med. 2019; 7: 855-869https://doi.org/10.1016/S2213-2600(19)30185-7
        • Altenburg J.
        • de Graaff C.S.
        • van der Werf T.S.
        • Boersma W.G.
        Immunomodulatory effects of macrolide antibiotics - part 1: biological mechanisms.
        Respiration. 2011; 81: 67-74https://doi.org/10.1159/000320319
        • Altenburg J.
        • de Graaff C.S.
        • van der Werf T.S.
        • Boersma W.G.
        Immunomodulatory effects of macrolide antibiotics - part 2: advantages and disadvantages of long-term, low-dose macrolide therapy.
        Respiration. 2011; 81: 75-87https://doi.org/10.1159/000320320
        • Levert H.
        • Gressier B.
        • Moutard I.
        • Brunet C.
        • Dine T.
        • Luyckx M.
        • Cazin M.
        • Cazin J.
        Azithromycin impact on neutrophil oxidative metabolism depends on exposure time. - PubMed - NCBI.
        Inflammation. 1998; 22 (accessed May 8, 2019): 191-201
        • Elborn J.S.
        • Tunney M.M.
        Macrolides and bronchiectasis.
        J. Am. Med. Assoc. 2013; 309: 1295https://doi.org/10.1001/jama.2013.2780
        • Albert R.K.
        • Connett J.
        • Bailey W.C.
        • Casaburi R.
        • Cooper J.A.D.
        • Criner G.J.
        • Curtis J.L.
        • Dransfield M.T.
        • Han M.K.
        • Lazarus S.C.
        • Make B.
        • Marchetti N.
        • Martinez F.J.
        • Madinger N.E.
        • McEvoy C.
        • Niewoehner D.E.
        • Porsasz J.
        • Price C.S.
        • Reilly J.
        • Scanlon P.D.
        • Sciurba F.C.
        • Scharf S.M.
        • Washko G.R.
        • Woodruff P.G.
        • Anthonisen N.R.
        • Copd Clinical Research Network
        • Crooks M.G.
        • Hart S.P.
        • Morice A.H.
        Azithromycin for prevention of exacerbations of COPD.
        N. Engl. J. Med. 2011; 365 (accessed May 8, 2019)
        • Wong C.
        • Jayaram L.
        • Karalus N.
        • Eaton T.
        • Tong C.
        • Hockey H.
        • Milne D.
        • Fergusson W.
        • Tuffery C.
        • Sexton P.
        • Storey L.
        • Ashton T.
        • Tuffery C.
        • Fergusson W.
        • Hockey H.
        • Milne D.
        • Storey L.
        • Wong C.
        • Jayaram L.
        • Tong C.
        • Karalus N.
        • Ashton T.
        • Eaton T.
        • Tong C.
        • Hockey H.
        • Milne D.
        • Fergusson W.
        • Tuffery C.
        • Sexton P.
        • Storey L.
        • Ashton T.
        Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial.
        Lancet. 2012; 380: 660-667https://doi.org/10.1016/s0140-6736(12)60953-2