Non-CF bronchiectasis: Orphan disease no longer

Respiratory Medicine 166 (2020) 105940

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Review article

Non-CF bronchiectasis: Orphan disease no longer Jaafer Saadi Imam, Alexander G. Duarte * Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Texas Medical Branch (UTMB), Galveston, TX, USA

A R T I C L E I N F O

A B S T R A C T

Keywords: Bronchiectasis Cystic fibrosis Non-cystic fibrosis bronchiectasis Non-CF bronchiectasis Chronic pulmonary infection

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 rehabil­ itation 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 mac­ rolide therapy reduces the frequency of exacerbations. Medical therapies for cystic fibrosis bronchiectasis may not be effective in treatment of non-cystic fibrosis bronchiectasis.

The disease that was bound to claim me sooner or later George 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 [1]. 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 [2]. 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 [3]. 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 [4] (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. Subse­ quently, 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 [5]. 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. 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 dila­ tation. This pathological process involves a cycle of airway injury and

* 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. E-mail addresses: [email protected] (J.S. Imam), [email protected] (A.G. Duarte). https://doi.org/10.1016/j.rmed.2020.105940 Received 9 November 2019; Received in revised form 13 March 2020; Accepted 18 March 2020 Available online 27 March 2020 0954-6111/Published by Elsevier Ltd.

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Respiratory Medicine 166 (2020) 105940

reported the prevalence of non-CF bronchiectasis to be 701 per 100,000 persons and more frequent in women. The mean age for newly diag­ nosed patients was 76.4 � 7.44 years and COPD and asthma were observed in 51% and 28%, respectively [10]. In 2017, the U.S. Bron­ chiectasis Research Registry reported the characteristics of 1,826 pa­ tients with non-CF bronchiectasis [11]. 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 cul­ ture results for 1,406 subjects with the following findings: normal res­ piratory 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.

inflammation followed by airway infection that results in permanent bronchiolar dilatation and parenchymal lung involvement [6]. 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 [7]. Airway inflammation may be precipitated by bac­ terial, 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. Subse­ quently, 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, rheumato­ logic disorder, immunodeficient states or significant inhalational expo­ sure to smoke or combustion products.

4. Clinical features

3. Epidemiology of non-CF bronchiectasis

Bronchiectasis is characterized as chronic disease manifesting as cough with daily sputum production and frequent lower airway in­ fections. 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 [11]. Further­ more, the frequency of cough and quantity of airway secretions may wax and wane over weeks or months [12]. 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 bronchiec­ tasis, 70% of patients reported purulent rhinosinusitis and 30% indi­ cated prior ear, nose and throat surgery [13]. 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 symp­ toms of chronic cough, poorly controlled asthma or recurrent lower respiratory tract infections and distinguish these from bronchiectasis.

Recent estimates of the frequency of bronchiectasis are greater than previously suspected as earlier epidemiologic studies relied on symp­ toms and chest radiography that do not accurately capture disease prevalence. With the increased availability of chest computerized to­ mography (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 [8]. 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 [9]. 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 [10]. From 2012 to 2014, the investigators

Fig. 1. Colored 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

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However, chest radiography has limitations with reported sensitivity that ranges from 37% to 87% [14,15] 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% [16,17]. 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 (Figs. 2–4) [18]. Additional CT radiographic features of bronchiectasis include peri­ bronchial thickening, mucus plugs, centrilobular nodules, tree -in-bud nodules, mosaic perfusion, intra and inter-lobular septal thickening and focal atelectasis/consolidation [18]. 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 [11]. 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 Zea­ land, 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 diag­ nosed 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 [19]. A comparison of the characteristics of pa­ tients with cystic fibrosis diagnosed in childhood and non-CF bronchi­ ectasis reveals distinctions that include older age, predominance of women and greater lower lobe involvement (Table 1). Patients diag­ nosed with cystic fibrosis as adults are more likely to have unusual ge­ netic mutations and normal pancreatic function [19,20]. As for radiographic features, patients with cystic fibrosis diagnosed in adult­ hood demonstrate predominant upper lobe involvement and chronic sinus opacification [21]. While no gender difference has been recog­ nized in cystic fibrosis diagnosed in childhood, a female predominance is observed in adults diagnosed with cystic fibrosis [22]. Furthermore, patients diagnosed in adulthood are reported to have a higher preva­ lence of NTM lung infections [20].

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 sub­ tle airway dilation to parenchymal cavities with focal airway enlarge­ ment to cystic bronchi [23]. 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 etiol­ ogy involves a clinical history, physical examination, radiographic im­ aging, sputum cultures and laboratory and pulmonary function testing. Several investigators have reported the different causes of bronchiec­ tasis and identified a post-infectious process in 20–32% of patients [24–28] (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 idio­ pathic cases while a greater frequency of cystic fibrosis is likely related to use of genetic testing [27]. 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 [29–33]. In the past, pulmonary tuberculosis was more common in industrialized nations that resulted in segmental or lobar bronchiectasis [34]. 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 bronchi­ ectasis had NTM sputum isolation [35,36]. 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 [37,38]. 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 [37]. 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 [39]. Additional genetic link­ age 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 [40]. Still, the natural history of bronchiectasis needs further investigation as to the cause and effect. It is less clear that NTM disease may precede

Fig. 2. Thoracic 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 interpreta­ tion of the references to color in this figure legend, the reader is referred to the Web version of this article.) 3

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Fig. 3. Thoracic 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.)

airways [42]. However, in patients with asthma and cystic fibrosis, impaired airway clearance can lead to organism deposition that pro­ duces 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 [43]. 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 poly­ morphisms in IL13, IL4 and TLR3 implicating these pathways in the susceptibility to ABPA [44]. 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 bron­ chiectasis. X-linked agammaglobulinemia results from an X-linked recessive gene mutation in the Bruton’s tyrosine kinase gene charac­ terized by the absence of all immunoglobulin isotypes and circulating B lymphocytes. This results in otitis, conjunctivitis, frequent sinopulmo­ nary infections and bronchiectasis [45]. Common variable immune deficiency, an underdiagnosed cause of non-CF bronchiectasis, is char­ acterized by defective B lymphocyte differentiation, impaired antibody production and hypogammaglobulinemia [46]. 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

Fig. 4. Thoracic CT coronal image demonstrates diffuse cylindrical and vari­ cose bronchiectasis affecting both lungs, most evident in the lingula (yellow bracket), with associated bronchial wall thickening and peripheral small nod­ ules 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.)

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

Table 1 Clinical characteristics that distinguish CF bronchiectasis from adult onset CF bronchiectasis and non-CF bronchiectasis. Characteristics

Cystic Fibrosis (CF)

Adult onset CF

Non-CF Bronchiectasis

Age Gender Lung predominance Severity of disease Etiology

Childhood No gender difference Upper lobe predominance

Age>18 Women

Age>60 Women Lower lobe predominance

Severe lung and GI disease Genetic: ΔF508 CFTR mutation

Variable severity of lung disease Post-infectious most common

Comorbid conditions

Pancreatic insufficiency, sinusitis, nasal polyps

Equal or less severe lung and GI disease Genetic: lower prevalence of ΔF508 CFTR mutation; milder classes of CFTR mutation Pancreatic insufficiency, sinusitis, nasal polyps

4

Cardiovascular disease, COPD, asthma, sinusitis

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impediment to adequate clearance of airway secretions [53].

Table 2 Etiology of non-CF Bronchiectasis. Characteristics

Pasteur [24] (2000)

Shoemark [25] (2007)

Lonni [26] (2015)

Olveira [27] (2017)

Visser [28] (2019)

n Age

165 49 � 16

1258 67

42 43 (26%)

ABPA

11 (7%)

13 (8%)

PCD (genetic)

3 (1.5%)

17 (10%)

CTD/Rheumatoid arthritis Young syndrome Aspiration/GERD

4 (3%)

3 (2%)

5 (3%) 6 (4%)

5 (3%) 2 (1%)

60 502 (40%) 257 (20%) 73 (5.8) 56 (4.5%) 21 (1.7%) 128 (10%)

2047 64.9 � 18.4 55 496 (24%) 613 (30%) 192 (9.4) 18 (0.9%) 60 (2.9%) 29 (1.4%) 5 (0.2%) 33 (1.5%) 4 (0.2%)

566 71

Immunodeficiency

150 52.7 � 15.2 62.7 80 (53%) 44 (29%) 12 (8%)

233 (11.4%) 255 (12.5%) 5 (0.2%)

48 (8.5%)

Female (%) Idiopathic Post-infectious

Yellow Nail syndrome NTM infection Cystic Fibrosis (genetic) IBD/Ulcerative colitis Pan bronchiolitis Congenital malformation COPD

52 (32%) 11 (7%)

2 (1%) 4 (3%)

2 (1%)

2 (<1%)

5 (3%)

1 (<1%) 1 (<1%)

4 (2%)

Asthma Alpha-1antitrypsin deficiency

8 (0.6%) 1 (0.1%)

24 (1.9%) 7 (0.6%) 129 (15%) 41 (3.3%) 8 (0.6%)

2 (0.1%) 14 (0.7%) 160 (7.8%) 110 (5.4%) 10 (0.5%)

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 approxi­ mately 1 in 3,000 to 4,000 live births, with a carrier frequency in nonHispanic Whites of ~1 in 25 [54]. Cystic fibrosis is caused by muta­ tions 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 [55]. 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 [56]. 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 termi­ nology is discouraged as it may refer to various phenotypes [57]. Pa­ tients 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 [58]. Another inherited condition affecting mucociliary clearance is pri­ mary ciliary dyskinesia (PCD) that involves the respiratory and genito­ urinary 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 infer­ tility. Most patients are diagnosed in childhood but presentation in adults is recognized [59,60]. 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 estab­ lishment 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 [61,62]. Recent recommen­ dations 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 [62].

71 184 (32.5%) 159 (28%) 21 (3.7%) 22 (3.9%) 22 (3.9%) 8 (1.4%) 14 (2.5%)

19 (3.4%) 21 (3.7%)

Haemophilus infections that manifest as skin abscesses and recurrent bacterial pneumonia complicated by bronchiectasis [47]. Elevated serum IgE levels >1,000 IU/mL and peripheral eosinophilia are common laboratory findings [48,49]. 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 [50]. 5.3. Genetic causes Several genetic causes of bronchiectasis have been identified and categorized as congenital airway defects and mutations that impair mucociliary clearance.

5.6. 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 COPDbronchiectasis overlap syndrome [63]. 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 [64]. Factors associated with bronchiectasis and COPD are severity of airflow limitation, isolation of a pathogen on airway cultures and prior hospital admission [65]. Furthermore, the presence of COPD and bronchiectasis is associated with increased mortality in patients with moderate to severe COPD [66,67]. However, the reported poor

5.4. Congenital defects of the airways Among the congenital defects of the airways, familial congenital bronchiectasis (Williams-Campbell Syndrome) and tracheo­ bronchomegaly (Mounier-Kuhn syndrome) are associated with bron­ chiectasis. Williams-Campbell Syndrome is a rare condition characterized by diffuse tracheobronchomalacia due to partial or com­ plete absence of bronchial cartilage [51]. 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 [52]. 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 5

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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 per­ formed. 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 be­ tween COPD and bronchiectasis.

antibiotic prescriptions [76]. 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 [76–78]. 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 recur­ rent pancreatitis, failure to thrive, male infertility, upper lobe predom­ inant bronchiectasis on imaging with reduced lung function, or airway culture isolates with Pseudomonas, Stenotrophomonas or Burkholderia species [77,79]. 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 [57]. 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, rhino­ sinusitis 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 [62]. 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 [25,26,80,81].

5.7. Alpha antitrypsin deficiency Past case reports have reported associations with alpha antitrypsin deficiency and bronchiectasis [68–70]. A case series from a large referral center described 74 patients with severe alpha antitrypsin deficiency (PiZ phenotype) and severe airflow limitation [71]. 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 pro­ duction. 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 [72]. 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 [73,74]. 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 [74]. The authors proposed that the airways of sus­ ceptible patients with rheumatoid arthritis may be an early site of autoimmune related injury. Finally, inflammatory bowel disease has been associated with bronchiectasis [75]. 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.

7. Management Bronchiectasis management aims to promote airway clearance, prevent exacerbations and improve patient quality of life [82–84]. 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 [85]. 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 [86,87]. Thus, tobacco cessation in patients with non-cystic fibrosis bronchiectasis may decrease the morbidity associated with vascular disease as well as airway inflammation.

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 [23]. Compared to chest CT im­ aging, 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 diag­ nostic 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 bacte­ rial, mycobacterial and fungal culture is essential and may require sputum induction with inhaled saline that may be used for future

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 nonCF bronchiectasis and in the US Bronchiectasis Research Registry 61% of patients were prescribed a bronchodilator [11]. 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 [88, 89]. For management of the individual patient, spirometry before and after albuterol administration should be obtained in order to assess for 6

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Respiratory Medicine 166 (2020) 105940

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 [11]. 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 [90]. 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 Euro­ pean 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 [76]. 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 [91]. 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 [92,93]. Additional investigations are needed to address the role of inhaled corticosteroids in the management of non-CF bronchiectasis.

has led to professional societies recommendations against the use of rhDNase in management of non-CF bronchiectasis [76–78]. Further­ more, 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 bronchi­ ectasis 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 man­ agement of non-CF bronchiectasis and strongly recommended by numerous professional respiratory societies [76–78]. 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 tech­ niques 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 [103,104]. Consensus groups have concluded that airway clearance methods should be individualized based on patient comfort, convenience, practical application and cost [104]. Though the mecha­ nisms 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 sub­ jects 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 hyperin­ flation [105]. 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 improve­ ments in quality of life [106]. 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 [107].

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 [94]. In pa­ tients 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 [95]. Mucus may be eliminated through coughing; however, mucus that is not expelled accumulates, obstructs the airway lumen and creates a source of infec­ tion. 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 [96]. Subsequently, another group of investigators compared the long term effects of nebulized hypertonic (6%) and isotonic (0.9%) saline admin­ istered 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 [97]. 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 [98]. Other mucolytic agents such as N-acetylcysteine are used in clinical practice, however there are no trials that demonstrate clinical benefit [99]. Lastly, recombinant human DNase (rhDNase, Pulmozyme, Gen­ entech, 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 exacerba­ tions [100,101]. In contrast, patients with non-CF bronchiectasis ran­ domized 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 [102]. This

7.4. Pulmonary rehabilitation Clinical trials have reported benefits of pulmonary rehabilitation on exercise tolerance and quality of life in patients with non-CF bronchi­ ectasis. 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 [108]. Subsequently, a systematic review of pulmonary rehabilitation or exercise training in patients with bronchiectasis identified four small clinical trials that included 164 patients [109]. 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 rehabilita­ tion. Important in the implementation of this therapy also involves airway clearance and self-management. 7

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7.5. Antibiotic therapy

difference in the primary end point between the liposomal ciprofloxacin and control groups [120]. In summary, these clinical trial results indi­ cate that inhaled antibiotics are well tolerated and reduce airway bac­ terial load. A comprehensive meta-analysis of inhaled antibiotic trials reported reduction in bacterial loads and small but statistically signifi­ cant decrease in exacerbation rate without significant improvements in quality of life compared to placebo [121]. In addition, antibiotic resis­ tance 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 [76].

Management of bronchiectasis with antibiotics is directed at treat­ ment 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 [110]. 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 administra­ tion 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 exacer­ bations 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 [76].

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 [122–126]. Three well designed clinical investigations provide strong evidence to support use of macrolides in patients with non-CF bronchiectasis (Table 3) [127–129]. Two trials examined azi­ thromycin; 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 [127,128]. 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 [130]. 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 [131]. Of note, an increase in macrolide resistance oropharyngeal organism was reported the 12 month azi­ thromycin study raising concerns that chronic macrolide can lead to development of resistant bacterial strains [128]. 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 [78]. 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 [132]. Current consensus guidelines recommend macrolide (azithromycin or erythromycin) therapy for patients with >3 exacerbations per year with bronchiectasis without Pseudomonas aeruginosa [76]. The recent meta-analysis indicates that chronic macrolide therapy may be consid­ ered in individuals with Pseudomonas infection but this should be balanced by the consequences of therapy [131].

7.6. Inhaled antibiotic therapy The inhaled route of administration has long been recognized as an effective method of drug delivery [111]. The appeal of inhaled antimi­ crobial 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 anti­ biotics has been developed as a preventative strategy to reduce the airway bacterial load and target pathogenic organisms in individuals with frequent exacerbations [112]. 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 [113]. Another trial examined inhaled gentamicin in 65 patients with non-CF bronchi­ ectasis and similarly found a reduction in bacterial density and fewer exacerbations but no change in lung function compared to the control group [114]. A multicenter trial of inhaled aztreonam resulted in de­ creases in bacterial load and those individuals with the greatest reduc­ tion in bacterial load experienced improvements in quality of life [115]. Recently, investigators performed two prospective studies and rean­ alysis 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 [116]. Moreover, a meta-analysis reported inhaled antibiotics were more effective than placebo in the reduction of airway bacterial load, eradi­ cation of pathogenic bacteria from sputum and a reduction in acute exacerbations [117]. Subsequently, a multicenter clinical trial (RESPIRE 1) examined the time to first exacerbation and frequency of exacerba­ tions 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 [118]. 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 [119]. 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

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 compli­ mented 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 8

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Respiratory Medicine 166 (2020) 105940

Table 3 Randomized Controlled Trials that have demonstrated macrolide antibiotics significantly reduced bronchiectasis exacerbations. Study (Dates)

Number of participants (Intervention vs Placebo)

Macrolide treatment

Study duration

Primary endpoint

Outcome (Intervention vs Placebo)

EMBRACE Trial [127] (Wong, 2012) BAT Trial [128] (Altenburg, 2013) BLESS Trial [130] (Serisier, 2013)

141 (71 vs 70)

Azithromycin (500 mg three times per week)

6 months

83 (43 vs 40)

Azithromycin (250 mg daily) Erythromycin (400 mg twice daily)

12 months

Pulmonary exacerbations, change in FEV1 and change in SGRQ Pulmonary exacerbations

48 weeks

Pulmonary exacerbations

Azithromycin reduced the frequency of exacerbations; no change in FEV1; no change in SGRQ Lower rate of infectious exacerbations with daily use of azithromycin Erythromycin significantly reduced exacerbations

117 (59 vs 58)

treatment of cystic fibrosis may not be effective for individuals with nonCF 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.

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