09 - 301 Bronchiectasis

301 Bronchiectasis

Rebecca M. Baron, Beverly W. Baron,

Miriam Baron Barshak

Bronchiectasis Bronchiectasis refers to an irreversible airway dilation that involves the lung in either a focal or a diffuse manner and that classically has been categorized as cylindrical or tubular (the most common form), vari­ cose, or cystic. This chapter will focus largely on non–cystic fibrosis (CF) bronchiectasis. The reader is referred to Chapter 302 for a more focused discussion on CF bronchiectasis. PART 7 Disorders of the Respiratory System ■ ■ETIOLOGY Bronchiectasis can arise from infectious or noninfectious causes (Table 301-1). Clues to the underlying etiology often are provided by the pattern of lung involvement. Focal bronchiectasis refers to bronchi­ ectatic changes in a localized area of the lung and can be a consequence of obstruction of the airway—either extrinsic (e.g., due to compression by adjacent lymphadenopathy or parenchymal tumor mass) or intrin­ sic (e.g., due to an airway tumor or aspirated foreign body, a scarred/

stenotic airway, or bronchial atresia from congenital underdevelopment TABLE 301-1  Major Etiologies of Bronchiectasis and Proposed Workup PATTERN OF LUNG INVOLVEMENT ETIOLOGY BY CATEGORY (EXAMPLES) WORKUP Focal Obstruction (e.g., aspirated foreign body, tumor mass) Chest imaging (chest x-ray and/or chest CT) a; bronchoscopy Diffuse Infection (e.g., bacterial, nontuberculous mycobacterial) Sputum Gram’s stain/ culture; stains/cultures for acid-fast bacilli and fungi. If no pathogen is identified, consider bronchoscopy with bronchoalveolar lavage.   Immunodeficiency (e.g., hypogammaglobulinemia, HIV infection, bronchiolitis obliterans after lung transplantation) Complete blood count with differential; immunoglobulin measurement; HIV testing   Genetic causes (e.g., cystic fibrosis, Kartagener’s syndrome, α1 antitrypsin deficiency) Measurement of chloride levels in sweat (for cystic fibrosis), α1 antitrypsin levels; nasal or respiratory tract brush/biopsy (for dyskinetic/immotile cilia syndrome); genetic testing   Autoimmune or rheumatologic causes (e.g., rheumatoid arthritis, Sjögren’s syndrome, inflammatory bowel disease); immune-mediated disease (e.g., allergic bronchopulmonary aspergillosis) Clinical examination with careful joint exam, serologic testing (e.g., for rheumatoid factor). Consider workup for allergic bronchopulmonary aspergillosis, especially in patients with refractory asthma.b   Recurrent aspiration Test of swallowing function and general neuromuscular strength   Miscellaneous (e.g., yellow nail syndrome, traction bronchiectasis from postradiation fibrosis or idiopathic pulmonary fibrosis) Guided by clinical condition   Idiopathic Exclusion of other causes aChest imaging is included in the general workup for all etiologies of bronchiectasis as described in the text. bSkin testing for Aspergillus reactivity; measurement of serum precipitins for Aspergillus, serum IgE levels, serum eosinophils, etc.

of the airway). Diffuse bronchiectasis is characterized by widespread bronchiectatic changes throughout the lung and often arises from an underlying systemic or infectious disease process. More pronounced involvement of the upper lung fields is most common in CF and also is observed in postradiation fibrosis, cor­ responding to the lung region encompassed by the radiation port. Bronchiectasis with predominant involvement of the lower lung fields usually has its source in chronic recurrent aspiration (e.g., due to esophageal motility disorders like those in scleroderma), end-stage fibrotic lung disease (e.g., traction bronchiectasis from idiopathic pulmonary fibrosis), or recurrent immunodeficiency-associated infec­ tions (e.g., hypogammaglobulinemia). Bronchiectasis resulting from infection by nontuberculous mycobacteria (NTM), most commonly the Mycobacterium avium-intracellulare complex (MAC), often prefer­ entially affects the midlung fields. Congenital causes of bronchiectasis with predominant midlung field involvement include the dyskinetic/ immotile cilia syndrome. Finally, predominant involvement of the central airways is reported in association with allergic bronchopulmo­ nary aspergillosis (ABPA), in which an immune-mediated reaction to Aspergillus damages the bronchial wall. Congenital causes of central airway–predominant bronchiectasis resulting from cartilage defi­ ciency include tracheobronchomegaly (Mounier-Kuhn syndrome) and Williams-Campbell syndrome. In many cases, the etiology of bronchiectasis is not determined. In case series, as many as 25–50% of patients referred for bronchiectasis have idiopathic disease. There is increasing appreciation for the need to define disease subphenotypes in this heterogeneous group of under­ lying causes of bronchiectasis, which might permit better targeting of clinical trials and treatment strategies. ■ ■EPIDEMIOLOGY The overall reported prevalence of bronchiectasis in the United States has recently increased, but the epidemiology of bronchiectasis varies greatly with the underlying etiology. For example, patients with CF often develop significant clinical bronchiectasis in late adolescence or early adulthood, although atypical presentations of CF in adults in their thirties and forties also are possible. In contrast, bronchiectasis resulting from MAC infection classically affects nonsmoking women

50 years of age. In general, the incidence of bronchiectasis increases with age. Bronchiectasis is more common among women than among men. Bronchiectasis may also frequently be co-diagnosed with chronic obstructive pulmonary disease (COPD) or asthma. In areas where tuberculosis is prevalent, bronchiectasis more fre­ quently occurs as a sequela of granulomatous infection. Focal bronchi­ ectasis can arise from extrinsic compression of the airway by enlarged granulomatous lymph nodes and/or from development of intrinsic obstruction as a result of erosion of a calcified lymph node through the airway wall (e.g., broncholithiasis). Especially in reactivated tuber­ culosis, parenchymal destruction from infection can result in areas of more diffuse bronchiectasis. Apart from cases associated with tubercu­ losis, an increased incidence of non-CF bronchiectasis with an unclear underlying mechanism has been reported as a significant problem in developing nations. It has been suggested that the high incidence of malnutrition in certain areas may predispose to immune dysfunction and development of bronchiectasis. ■ ■PATHOGENESIS AND PATHOLOGY The most widely cited mechanism of infectious bronchiectasis is the “vicious cycle hypothesis,” in which susceptibility to infection and poor mucociliary clearance result in microbial colonization of the bronchial tree. Some organisms, such as Pseudomonas aeruginosa, exhibit a particular propensity for colonizing damaged airways and evading host defense mechanisms. Impaired mucociliary clearance can result from inherited conditions such as CF or dyskinetic cilia syndrome, and it has been proposed that a single severe infection (e.g., pneumonia caused by Bordetella pertussis or Mycoplasma pneu­ moniae) can result in significant airway damage and poor secretion clearance. The presence of the microbes incites continued chronic

inflammation, with consequent damage to the airway wall, contin­ ued impairment of secretions and microbial clearance, and ongoing propagation of the infectious/inflammatory cycle. Moreover, it has been proposed that mediators released directly from bacteria can interfere with mucociliary clearance. A recent study suggested that there exist molecular endotypes of bronchiectasis with differential inflammatory markers and microbiome signatures that correlate with risk of exacerbations. Classic studies of the pathology of bron­ chiectasis from the 1950s demonstrated significant small-airway wall inflammation and larger-airway wall destruction as well as dilation, with loss of elastin, smooth muscle, and cartilage. It has been proposed that inflammatory cells in the small airways release proteases and other mediators, such as reactive oxygen species and proinflammatory cytokines, that damage the larger airway walls. Furthermore, the ongoing inflammatory process in the smaller air­ ways results in airflow obstruction. It is thought that antiproteases, such as α1 antitrypsin, play an important role in neutralizing the damaging effects of neutrophil elastase and in enhancing bacte­ rial killing. Bronchiectasis and emphysema have been observed in patients with α1 antitrypsin deficiency. Interestingly, a recent phase 2 study demonstrated improved bronchiectasis outcomes with an oral inhibitor of neutrophil serine protease activity. Proposed mechanisms for noninfectious bronchiectasis include immune-mediated reactions that damage the bronchial wall (e.g., those associated with systemic autoimmune conditions such as Sjögren’s syndrome and rheumatoid arthritis). Recent studies suggest that there might exist a new bronchiectasis endophenotype of patients with sen­ sitization to multiple environmental allergens. Traction bronchiectasis refers to dilated airways arising from parenchymal distortion as a result of lung fibrosis (e.g., postradiation fibrosis or idiopathic pulmonary fibrosis). ■ ■CLINICAL MANIFESTATIONS The most common clinical presentation is a persistent productive cough with ongoing production of thick, tenacious sputum. Physical findings frequently include crackles and wheezing on lung ausculta­ tion, and some patients with bronchiectasis exhibit clubbing of the digits. Mild to moderate airflow obstruction often is detected on pul­ monary function tests, overlapping with that seen at presentation with other conditions, such as COPD. Acute exacerbations of bronchiectasis usually are characterized by changes in the nature of sputum produc­ tion, with increased volume and purulence. However, typical signs and symptoms of lung infection, such as fever and new infiltrates, may not be present. ■ ■DIAGNOSIS The diagnosis usually is based on presentation with a persistent chronic cough and sputum production accompanied by consistent radiographic features. Although chest radiographs lack sensitivity, the presence of “tram tracks” indicating dilated airways is consistent with bronchiectasis. Chest CT is more specific for bronchiectasis and is the imaging modality of choice for confirming the diagnosis. CT findings include airway dilation (detected as parallel “tram tracks” or as the “signet-ring sign”—a cross-sectional area of the airway with a diameter at least 1.5 times that of the adjacent vessel), lack of bron­ chial tapering (including the presence of tubular structures within 1 cm from the pleural surface), bronchial wall thickening in dilated airways, inspissated secretions (e.g., the “tree-in-bud” pattern), or cysts emanating from the bronchial wall (especially pronounced in cystic bronchiectasis) (Fig. 301-1). Recently, a group of international experts put forth consensus guidelines for clinical and radiologic diagnosis of bronchiectasis, proposing that a diagnosis of bronchiectasis should require radiologic criteria (at least one of the following on chest CT: [1] inner- or [2] outer-airway-artery diameter ratio ≥1.5; [3] lack of airway tapering; and, [4] visibility of airways in the periphery) along with the clinical syndrome (at least two of the following: [1] cough most days of the week; [2] sputum production most days of the week; and [3] history of exacerbations).

Bronchiectasis CHAPTER 301 FIGURE 301-1  Representative chest CT image of severe bronchiectasis. This patient’s CT demonstrates many severely dilated airways, seen both longitudinally (arrowhead) and in cross-section (arrow). APPROACH TO THE PATIENT Bronchiectasis The evaluation of a patient with bronchiectasis entails elicitation of a clinical history, chest imaging, and a workup to determine the underlying etiology. Evaluation of focal bronchiectasis almost always requires bronchoscopy to exclude airway obstruction by an underlying mass or foreign body. A workup for diffuse bronchiec­ tasis includes analysis for the major etiologies (Table 301-1), with an initial focus on excluding CF. Pulmonary function testing is an important component of a functional assessment of the patient. TREATMENT Bronchiectasis Treatment of infectious bronchiectasis is directed at the control of active infection and improvements in secretion clearance and bron­ chial hygiene so as to decrease the microbial load within the airways and minimize the risk of repeated infections. ANTIBIOTIC TREATMENT Antibiotics targeting the causative or presumptive pathogen (with Haemophilus influenzae and P. aeruginosa isolated com­ monly) should be administered in acute exacerbations, usually for a minimum of 7–10 days and perhaps for as long as 14 days. Decisions about treatment of NTM infection can be difficult, given that these organisms can be colonizers as well as pathogens, and the prolonged treatment course often is not well tolerated. Consensus guidelines have advised that diagnostic criteria for true clinical infection with NTM should be considered in patients with symptoms and radiographic findings of lung disease who have at least two sputum samples positive on culture; at least one bronchoalveolar lavage (BAL) fluid sample positive on culture; a biopsy sample displaying histopathologic features of NTM infec­ tion (e.g., granuloma or a positive stain for acid-fast bacilli) along with one positive sputum culture; or a pleural fluid sample (or a sample from another sterile extrapulmonary site) positive on culture. MAC strains are the most common NTM pathogens, and the recommended regimen for HIV-negative patients infected with macrolide-sensitive MAC includes a macrolide combined with rifampin and ethambutol. Consensus guidelines recom­ mend macrolide susceptibility testing for clinically significant MAC isolates.

BRONCHIAL HYGIENE The numerous approaches used to enhance secretion clearance in bronchiectasis include hydration and mucolytic administration, aerosolization of bronchodilators and hyperosmolar agents (e.g., hypertonic saline), and chest physiotherapy (e.g., postural drainage, traditional mechanical chest percussion via hand clapping to the chest, or use of devices such as an oscillatory positive expiratory pressure flutter valve or a high-frequency chest wall oscillation vest). Pulmonary rehabilitation and a regular exercise program may assist with secretion clearance as well as with other aspects of bronchiectasis, including improved exercise capacity and quality of life. The mucolytic dornase (DNase) is recommended routinely in CF-related bronchiectasis but not in non-CF bronchiectasis, given concerns about lack of efficacy and potential harm in the non-CF population. ANTI-INFLAMMATORY THERAPY It has been proposed that control of the inflammatory response may be of benefit in bronchiectasis, and relatively small-scale tri­ als have yielded evidence of alleviated dyspnea, decreased need for inhaled β-agonists, and reduced sputum production with inhaled glucocorticoids. However, no significant differences in lung func­ tion or bronchiectasis exacerbation rates have been observed. Risks of immunosuppression and adrenal suppression must be carefully considered with use of anti-inflammatory therapy in infectious bronchiectasis. Nevertheless, administration of oral/systemic gluco­ corticoids may be important in treatment of bronchiectasis due to certain etiologies, such as ABPA, or of noninfectious bronchiectasis due to underlying conditions, especially that in which an autoim­ mune condition is believed to be active (e.g., rheumatoid arthritis or Sjögren’s syndrome). Patients with ABPA also may benefit from a prolonged course of treatment with an oral antifungal agent such as itraconazole. REFRACTORY CASES In select cases, surgery can be considered, with resection of a focal area of suppuration. In advanced cases, lung transplantation can be considered.

PART 7 Disorders of the Respiratory System ■ ■COMPLICATIONS In more severe cases of infectious bronchiectasis, recurrent infections and repeated courses of antibiotics can lead to microbial resistance to antibiotics. In certain cases, combinations of antibiotics that have inde­ pendent toxicity profiles may be necessary to treat resistant organisms. Recurrent infections can result in injury to superficial mucosal ves­ sels, with bleeding and, in severe cases, life-threatening hemoptysis. Management of massive hemoptysis usually requires intubation to stabilize the patient, identification of the source of bleeding, and pro­ tection of the nonbleeding lung. Control of bleeding often necessitates bronchial artery embolization and, in severe cases, surgery. ■ ■PROGNOSIS Outcomes of bronchiectasis can vary widely with the underlying etiology and comorbid conditions and may also be influenced by the frequency of exacerbations and (in infectious cases) the specific pathogens involved (with worse outcomes associated with P. aeruginosa colonization). Increasing attention is being given to defining clinical subphenotypes of bronchiectasis in light of heterogeneous clinical, radiographic, and microbial features and to developing screening tools for the assessment of quality of life and disease severity. In one study, the decline of lung function in patients with non-CF bronchiectasis was similar to that in patients with COPD, with the forced expiratory volume in 1 s (FEV1) declining by 50–55 mL per year as opposed to 20–30 mL per year for healthy controls. ■ ■PREVENTION Reversal of an underlying immunodeficient state (e.g., by administra­ tion of gamma globulin for immunoglobulin-deficient patients) and

vaccination of patients with chronic respiratory conditions (e.g., influ­ enza, pneumococcal, COVID, and RSV vaccines) can decrease the risk of recurrent infections. Patients who smoke should be counseled about smoking cessation. After resolution of an acute infection in patients with recurrences (e.g., ≥3 episodes per year), the use of suppressive antibiotics to minimize the microbial load and reduce the frequency of exacerba­ tions has been proposed. Although there is less consensus about this approach in non-CF-associated bronchiectasis than in CF-related bronchiectasis, small studies have supported benefits of selected therapies, though with concerns for development of antibiotic resis­ tance over time. Possible suppressive treatments include (1) admin­ istration of an oral antibiotic (e.g., ciprofloxacin) daily for 1–2 weeks per month; (2) use of a rotating schedule of oral antibiotics (to mini­ mize the risk of development of drug resistance); (3) administration of a macrolide antibiotic (see below) daily or three times per week (with mechanisms of possible benefit related to non-antimicrobial properties, such as anti-inflammatory effects and reduction of gramnegative bacillary biofilms); (4) inhalation of aerosolized antibiotics (e.g., tobramycin inhalation solution) for select patients on a rotating schedule (e.g., 30 days on, 30 days off), with the goal of decreasing the microbial load without eliciting the side effects of systemic drug administration; other studies examining inhaled aztreonam and inhaled ciprofloxacin formulations have shown conflicting results, suggesting there might be subpopulations of patients with bronchiec­ tasis who might benefit from specific therapies; and (5) intermittent administration of IV antibiotics (e.g., “clean-outs”) for patients with more severe bronchiectasis and/or resistant pathogens. In relation to macrolide therapy (point 3 above), a number of double-blind, placebo-controlled, randomized trials have been published in nonCF bronchiectasis and support a benefit of long-term macrolides (6–12 months of azithromycin or erythromycin) in decreasing rates of bronchiectasis exacerbation, mucus production, and decline in lung function. However, two of these studies and a meta-analysis also reported increased macrolide resistance in commensal pathogens, dampening enthusiasm for universal use of macrolides in this setting and raising the question of whether there might be select non-CF bronchiectasis patients with higher morbidity for whom benefits of long-term macrolides might outweigh the risks of emergence of anti­ biotic resistance. In particular, development of macrolide-resistant NTM is a potential concern, making treatment of those pathogens much more difficult. Furthermore, patients with different patterns of microbial colonization may not all experience similar benefits with macrolide therapy. Therefore, before chronic macrolide therapy is considered, it is advisable to rule out NTM infection and carefully consider each patient’s scenario closely, obtaining an electrocardio­ gram to rule out a prolonged QT interval that might place the patient at increased risk of arrhythmias. In addition, ongoing consistent attention to bronchial hygiene can promote secretion clearance and decrease the microbial load in the airways. ■ ■FURTHER READING Aliberti S et al: Criteria and definitions for the radiological and clinical diagnosis of bronchiectasis in adults for use in clinical tri­ als: International consensus recommendations. Lancet Respir Med 10:298, 2022. Chalmers JD, Chotirmall SH: Bronchiectasis: New therapies and new perspectives. Lancet Respir Med 6:715, 2018. Choi H et al: Inflammatory molecular endotypes in bronchiectasis: A European multicenter cohort study. Am J Respir Crit Care Med 208:1166, 2023. Guan W-J et al: A double-blind randomized placebo-controlled phase 3 trial of tobramycin inhalation solution in adults with bronchiectasis with Pseudomonas aeruginosa infection. Chest 163:64, 2023. Herrero-Cortina B et al: European Respiratory Society statement on airway clearance techniques in adults with bronchiectasis. Eur Respir J 62:2202053, 2023.