Brazilian consensus on non-cystic fibrosis bronchiectasis

Once considered an orphan disease, 1 permanent airway dilatation, known as bronchiectasis, is a condition that is more common than previously thought. The widespread use of chest HRCT is probably the major factor in the increased diagnosis of bronchiectasis, since it contributes greatly to the detection and better visualization of dilated bronchi and other bronchial and bronchiolar abnormalities. Other important factors in the increased diagnosis of bronchiectasis are the aging of the population, the increased rates of other pathological conditions that can be associated with the development of bronchiectasis, and more widespread diagnostic suspicion. Data from the Brazilian National Ministry of Health show that, in Brazil, the rate of hospitalization for chronic respiratory diseases decreased from 434.4/100,000 population in 2003 to 241.8/100,000 population in 2013. Of the latter total, 54.5% were due to obstructive diseases and only 0.37% (0.9/100,000 population) were due to bronchiectasis. As regards the mortality rate in 2013, although obstructive diseases accounted for 64% of all deaths from chronic respiratory diseases (33.6/100,000 population), bronchiectasis resulted in a mortality rate of 0.2/100,000 population. 2 It should be emphasized here that these national data may be underestimated because they are based exclusively on hospital inpatient information. Global epidemiological data shows that the diagnosis of bronchiectasis has increased, with disease prevalence increasing with age and varying geographically and ethnically. 3 In the USA, an annual increase of 8.7% has been reported for the 2000-2007 period, 4 as has a similar increase among women and the elderly between 2009 and 2013. 5 In the United Kingdom, the incidence and prevalence rates of bronchiectasis have increased annually since 2004 and are associated with significant mortality. 6 Recent estimates indicate a prevalence rate of 1 in every 206 men and 1 in every 176 women in the United Kingdom; 1 in every 276 people in Spain; and 1 in every 1,492 people in Germany. 6 - 8 These numbers may be underestimated if we consider the fact that COPD patients can present with bronchiectasis on HRCT at rates ranging from 29-50% in different publications. 9 - 11 The socioeconomic impact of bronchiectasis has been more fully studied in recent years. In the USA, a pharmacoeconomic study based on a large database showed that the average increase in overall health costs after the first year of diagnosis of bronchiectasis, compared with controls, was US$2,319.00. 12 Treatment costs increase with disease severity and with factors such as age, chronic Pseudomonas aeruginosa infection, exacerbations, and hospital admissions. 13 In a study conducted in Spain, the mean annual cost per patient with bronchiectasis was €4,671.00, and this value doubled with each increase in severity (as determined by the FACED score ). In patients with mild disease, the costs were mainly due to the use of bronchodilators and inhaled corticosteroids, and, in those with severe disease, they were mainly due to exacerbations and the use of inhaled antibiotics. 13 The therapeutic management of some subgroups of patients, such as individuals with COPD, also consumes more financial resources. These findings underscore the importance of diagnosis and appropriate management of bronchiectasis patients. In addition, preventing exacerbations should be a goal not only to improve quality of life and preserve lung function but also to reduce the economic costs associated with bronchiectasis. 14 , 15 In Brazil, a survey conducted by the Committee on Respiratory Infections and Pulmonary Mycoses of the Sociedade Brasileira de Pneumologia e Tisiologia (SBPT, Brazilian Thoracic Association) showed that, in 2012, most bronchiectasis patients were treated in general outpatient clinics (66%). Only 22% were treated in specialized bronchiectasis outpatient clinics, and the remaining 12% were treated in integrated outpatient clinics combining pulmonology and cystic fibrosis care ( Figure 1 ; unpublished data). Figure 1 Pathophysiology of bronchiectasis: a “vicious cycle” of the various factors involved. Given the complexity of the etiologic diagnosis of bronchiectasis and the multisystem nature of this condition, there is a need for multidisciplinary management, preferably performed in centers with experience in the care of bronchiectasis patients. The improvement in the survival of cystic fibrosis patients is one example of the benefits of this type of approach. In addition to early diagnosis and access to medications, multidisciplinary care at a referral center is a determinant of disease course in cystic fibrosis patients. 16 A referral center for non-cystic fibrosis bronchiectasis should have resources to carry out a careful etiologic investigation that will enable the establishment of the correct diagnosis, as well as expertise for the pharmacological and non-pharmacological management of various levels of severity. The multidisciplinary team should include physicians (pulmonologists and chest surgeons), nurses, physical therapy professionals, pharmacists, nutritionists, and social workers. In addition, it should be associated with qualified pulmonary function and microbiology laboratories and have access to pulmonary rehabilitation programs. 17 , 18

The SBPT Committee on Respiratory Infections summoned 10 pulmonologists with expertise in bronchiectasis in Brazil to conduct a critical assessment of the available scientific evidence and international guidelines, as well as to identify aspects that are relevant to the understanding of the heterogeneity of the clinical presentation of bronchiectasis and its diagnostic and therapeutic management. Five broad topics were established (pathophysiology, diagnosis, monitoring of stable patients, treatment of stable patients, and management of exacerbations). After this subdivision, the topics were distributed among the authors, who conducted a nonsystematic review of the literature, giving priority to major publications in the specific areas, including original articles, review articles, and systematic reviews. All authors had the opportunity to review and comment on all topics, producing a single final document that was approved by consensus.

Diagnosis of bronchiectasis is defined by the presence of (non-reversible) bronchial dilatations on HRCT, which means that this is the imaging modality required and sufficient to confirm or rule out the diagnosis. The causes and associated conditions should then be investigated ( Chart 1 ). Since its introduction in the 1980s, HRCT has become the gold standard for the diagnosis and evaluation of the extent of airway structural changes. HRCT allows the identification of changes in large diameter airways, such as luminal dilatation and wall thickening. In general, changes in the small airways are also detected and can be described as direct and indirect signs; in some cases, these signs can be eventually seen with no dilatation in central bronchi. Direct signs are the visualization of bronchioles that may be dilated (bronchiolectasis), with their lumen filled with secretion (small, low-density nodules; tree-in-bud pattern) or with thick walls. The tree-in-bud pattern is the visualization of millimetric airway branching, invisible in normal situations, and made possible to be seen by the accumulation of secretion, inflammatory changes, and airway dilatation. 34 The presence of mosaic attenuation, more easily identifiable on TC scan slices obtained during exhalation, is the so-called “indirect sign”, which is due to trapping of air in the lobules as a result of subocclusion of the bronchiolar lumen due to bronchiolar wall inflammation/fibrosis. 35 Signs of collapse of lung regions because of recurrent infections may also be seen in some cases. Some of the changes described above can be observed in Figures 2 , 3, and 4. Figure 2 Chest HRCT scan. In A, tree-in-bud pattern (arrows). In B, mucoid impaction (mucus plug) in small airways (circles) and bronchial wall thickening (arrows). Figure 3 Chest HRCT scan. Mosaic perfusion (or attenuation). Although present in A (inhalation), it is more visible in B (exhalation). The darker areas indicate air trapping due to small airways impairment, associated with oligemia. Figure 4 Chest HRCT scan. In A, cystic bronchiectasis in fibroatelectatic areas. In B, varicose bronchiectasis (arrows) and cystic bronchiectasis (circle). Note the loss of bronchial generations (loss of millimetric branching) and impaired visualization of bronchovascular markings, suggestive of air trapping (even during inhalation). Additional HRCT findings can suggest a specific cause. For example, presence of concomitant emphysema is suggestive of COPD, evidence of situs inversus or profusion of nodules suggestive of bronchiolar mucoid impaction in the lower lung fields should lead to ciliary dyskinesia, and evidence of tracheomegaly or pseudodiverticula in the tracheobronchial walls should bring to mind the Mounier-Kuhn syndrome. The regional distribution of bronchiectasis can provide useful information for the etiologic diagnosis, 36 especially if the bronchiectasis is upper-lobe predominant, a common finding in cystic fibrosis. Predominant involvement of anterior regions (middle lobe and lingula) should lead to nontuberculous mycobacteria 37 or diffuse panbronchiolitis, the latter being classically described in Asians 38 and being rare in Brazil. Predominant involvement of lower lung fields is common to several conditions, such as ciliary dyskinesia 29 ; conditions associated with chronic aspiration (a cause that should be remembered in patients with an altered mental status); swallowing impairment or gastroesophageal reflux disease 39 ; bronchiectasis secondary to hypogammaglobulinemia; immunosuppression; and chronic rejection in (lung, bone marrow) transplant recipients. Central predominance with large mucoid impactions (finger-in-glove sign) is suggestive of allergic bronchopulmonary aspergillosis. In cases of bronchiectasis after pulmonary tuberculosis, the distribution of bronchiectasis is often asymmetric, with preferential involvement of upper lobes or apical segments of lower lobes; in addition, pleural thickening and adjacent parenchymal distortion are common. Localized bronchiectasis can be caused by bronchial obstruction, and, in such cases, bronchoscopic investigation is indicated. Evidence of bronchiectasis on HRCT is usually obtained during the evaluation of patients with a productive cough and/or recurrent respiratory infections of the upper and lower airways, and may be accompanied or not by chest X-ray abnormalities. For such patients, etiologic investigation after confirmation of the diagnosis by HRCT scan is recommended ( Figure 5 ). Figure 5 Algorithm for the diagnosis and etiologic investigation of bronchiectasis. BMT: bone marrow transplantation; and Tx: transplantation. Bronchiectasis may also be detected in patients with respiratory symptoms and with diseases/conditions that occasionally present with airway involvement (COPD, asthma, collagen diseases, inflammatory bowel diseases, cystic fibrosis, and gastroesophageal reflux disease). Even when the cause is known, the possibility of concomitant conditions should be remembered; for example, asthma associated with gastroesophageal reflux disease or allergic bronchopulmonary aspergillosis, and collagen disease associated with infections, such as mycobacterial infection. The major causes of and major conditions associated with bronchiectasis are listed in Chart 1 . In published series, the frequency of each of them may vary according to the region studied (higher prevalence of infections) and the availability of ancillary tests that are necessary for the diagnostic investigation. In most series, post-infectious etiologies are some of the most common, accounting for 20% to 32% of cases. 40 - 42 Bronchiectasis should be considered to be of “unknown cause” (24-40% of cases) 40 , 41 only in patients in whom a diagnosis cannot be established even after all recommended tests are performed. In a study 41 that analyzed 1,258 patients from seven databases (Italy, the United Kingdom, Belgium, Spain, Greece, and Ireland), the cause of bronchiectasis was not established in 40%, was post-infective in 20%, was COPD-related in 15%, was connective tissue disease-related in 15%, was immunodeficiency-related in 5.8%, and was asthma-related in 3.3%. In the study validating the FACED score, conducted in six centers in Latin America (four of which in Brazil), among the 651 patients enrolled, the cause of bronchiectasis was classified as post-infective in 40.3%; idiopathic in 31.1%; ciliary dyskinesia-related in 9.0%; airway disease-related (COPD, asthma, or bronchiolitis) in 5.1%; and rheumatic disease-related in 4.3%. 43 The relevance of etiologic investigation lies in the fact that some conditions may benefit from specific therapeutic measures (allergic bronchopulmonary aspergillosis, collagen diseases, immunodeficiencies, aspiration, ciliary dyskinesia, cystic fibrosis, bronchial obstruction, COPD, and asthma), and this may occur in 13% 41 to 37% 42 of cases.

All bronchiectasis patients should undergo periodic functional assessment to detect any sign of decreased pulmonary function as early as possible. To that end, spirometry with bronchodilator use is satisfactory in the vast majority of cases. Obstructive lung disease is the most common finding, but significant reductions in FVC can be found in more advanced disease, with increased lung parenchymal destruction. End-expiratory flows are reduced, the RV/TLC ratio is increased (suggesting air trapping), and FVC and TLC are normal or low. 44 , 45 Decreased FEV 1 correlates with the presence of dyspnea-as assessed by the modified Medical Research Council (mMRC) scale-and with the extent of disease on HRCT. 46 Approximately 33% of bronchiectasis patients have positive methacholine or histamine challenge test results. DLCO test results are usually normal; DLCO may be reduced in advanced disease and in the presence of associated emphysema. 47 The six-minute walk test and the incremental shuttle walk test can provide additional functional information to spirometry. 48 , 49 The first has the advantage of having been extensively validated in respiratory diseases, and basically requires space and trained personnel in order to be performed. 50 In this context, the six-minute walk distance correlates better with quality of life than with functional tests. 51 The shuttle test can be useful especially in patients with preserved pulmonary function, because of the potential “ceiling effect” of the six-minute walk test, and has been validated for bronchiectasis patients. 49 , 52 Our recommendation: Perform spirometry with bronchodilator use every 6 months, lung volume assessment (if available) annually, and the six-minute walk test (at the physician’s discretion). The identification of potentially pathogenic microorganisms (PPMs) in the airways of bronchiectasis patients is a common finding related to increased bronchial inflammation and, consequently, progressive clinical deterioration. 53 Colonization is understood as the presence, growth, and multiplication of a microorganism in a host without there being any clinical expression or detection of immune response. 54 In this context, the term “bronchial colonization” should be avoided, because the presence of PPMs in the lower airways is not innocuous, and it would therefore be more appropriate to use the term “chronic bronchial infection”. There is strong evidence that PPMs are associated with an accelerated decline in pulmonary function, a higher number of exacerbations, worsening of quality of life, and higher mortality. 17 , 53 , 55 , 56 PPMs are understood as various species of gram-negative and gram-positive bacteria, mycobacteria, and fungi that have the ability to directly cause lung injury. Recent studies assessing the microbiome have revealed the existence of a great abundance and variety of bacteria in the lower respiratory tract, a finding that is one of the determinants of proper lung functioning and protection against recurrent infections. In bronchiectasis patients, this variety of bacteria is reduced as the proportion of a potentially pathogenic species increases with the severity of the disease. Given the loss of bronchial architecture and the impairment of local defense mechanisms in such patients, there is a greater risk that a PPM will chronically infect their respiratory tract. Chronic bronchial infection may produce changes in the balance of the lung microbiota, and this has a negative impact on the clinical course of the disease. 57 , 58 The association of a PPM with the sharp decline caused by the disease is well documented in patients with chronic bronchial infection with P. aeruginosa . 59 The presence of other bacteria may also cause an accelerated clinical deterioration; however, the real impact of such infections has yet to be fully determined. 60 For example, a recent study using a large American database showed that the identification of methicillin-sensitive Staphylococcus aureus does not appear to be an independent risk factor for severe disease in bronchiectasis patients. 61 Some definitions should be highlighted in this context: Primary infection: when a first positive culture for a PPM that was not isolated in previous periodic tests is obtained Intermittent bronchial infection: when culture results for a specific PPM are sometimes positive and sometimes negative in samples collected at intervals of at least 1 month after a primary infection Chronic bronchial infection: when two or more cultures are positive for the same PPM over a 12-month period in samples collected at intervals of at least 3 months Eradication: when a specific PPM is no longer detected in at least two consecutive samples collected at an interval of at least 1 month over a 6-month period Primary infection: when a first positive culture for a PPM that was not isolated in previous periodic tests is obtained Intermittent bronchial infection: when culture results for a specific PPM are sometimes positive and sometimes negative in samples collected at intervals of at least 1 month after a primary infection Chronic bronchial infection: when two or more cultures are positive for the same PPM over a 12-month period in samples collected at intervals of at least 3 months Eradication: when a specific PPM is no longer detected in at least two consecutive samples collected at an interval of at least 1 month over a 6-month period Sputum is the specimen of choice for culture in order to identify PPMs in bronchiectasis patients. Sputum samples should be immediately delivered to the laboratory or kept under refrigeration for as long as 3 h after collection. 62 In addition, sputum should be microscopically evaluated to ensure the quality of the sample obtained and its representativeness in terms of the lower respiratory tract, it being necessary that more than 25 leukocytes and less than 10 epithelial cells should be identified per field at a magnification of ×100. In patients who have difficulty expectorating, samples obtained by BAL may be necessary. In such cases, the samples must be quantitatively cultured. 63 When a PPM is identified, antibiotic susceptibility testing is recommended for guiding the choice of systemic antibiotic therapy. However, there is increasing evidence of poor correlation between in vitro susceptibility and in vivo clinical response, especially in the case of biofilm-producing bacteria. 64 Therefore, clinical judgment should guide therapeutic decisions. It is important to emphasize that susceptibility testing is not appropriate for the choice of an inhaled antibiotic. When the inhalation route is used, the drugs reach high concentrations in the lower respiratory tract and their clinical efficacy may remain even in situations of bacterial resistance demonstrated in vitro. 65 Our recommendation: Collect samples from the lower respiratory tract (sputum, for example) at regular intervals of 3-4 months and during pulmonary exacerbations for aerobic culture, as well as annually for culture for fungi and mycobacteria. If the patient is being treated with chronic macrolide therapy, culture for mycobacteria should be performed every 6 months. Some studies have revealed that bronchiectasis patients have reduced quality of life, fatigue symptoms, and asthenia, as well as high scores on depression and anxiety measures. 66 , 67 Higher levels of depression are associated with greater severity of dyspnea. 68 Patients with chronic bronchial infection with P. aeruginosa have poorer quality of life than those with chronic infections with other bacteria. 66 In addition, chronic cough has a negative impact on the quality of life of such patients and their families. 69 However, one group of authors demonstrated that disease severity as measured by CT does not correlate with psychological well-being. 67 Inflammatory markers, such as C-reactive protein (CRP) and total leukocyte counts, are related to the extent of disease and to poorer pulmonary function. 70 One study demonstrated that, in stable patients, increased bronchiectasis severity, as assessed by the Bronchiectasis Severity Index (BSI) and the FACED score, correlated with higher CRP levels but not with total leukocyte counts or with the neutrophil/lymphocyte ratio. 71 Airway inflammation has a predominance of neutrophils, which means that some inflammatory cytokines, such as IL-1, IL-6, and TNF-α, are increased, but IL-10 is decreased. 72 However, these cytokines are not markers used in clinical practice. Our recommendation: Although CRP appears to be an inflammation-related marker and is available for use in clinical practice, there is insufficient evidence to recommend its routine use to assess disease severity. Although there is a clear relationship of increased disease severity and mortality in bronchiectasis patients to chronic P. aeruginosa infection, 73 other factors contribute to the clinical and functional course of such patients. Since this is a difficult-to-manage condition, associated with various causes and great clinical heterogeneity, multidimensional scores have been developed in order to better estimate severity and prognosis. The most commonly used are the FACED score 74 and the BSI. 59 The FACED score uses the following variables: FEV 1 (% predicted); age; chronic colonization with P. aeruginosa ; extent of findings on chest HRCT (number of affected lobes; the lingula is counted as a separate lobe); and dyspnea, as assessed by the mMRC scale. 74 The E-FACED score added severe exacerbation in the previous year to the other variables of the FACED score and was found to be able to predict not only mortality but also the risk of exacerbation. 75 The FACED and the E-FACED scores are user-friendly and have been validated in patients in Brazil ( Chart 2 ). 43 In addition to being useful to predict all-cause mortality and exacerbations, they showed excellent ability to discriminate between different levels of disease severity (from mild to severe). These scores can also be used in order to aid in the assessment of therapeutic response to the adopted interventions. 76 Chart 2 E-FACED score: acronym for E xacerbation, F EV 1 , A ge, C hronic colonization with Pseudomonas aeruginosa , E xtent (of CT findings), and D yspnea. Variables Result Score Exacerbation No Zero Yes 2 FEV 1 ,% predicted ≥ 50% Zero < 50% 2 Age 2 lobes 1 Dyspnea, mMRC scale 0-II Zero III-IV 1 TOTAL: 0-9 points Severity: 0-3 points: mild; 4-6 points: moderate; and 7-9 points: severe. mMRC: modified Medical Research Council . mMRC: modified Medical Research Council . The BSI includes, in addition to the variables of the FACED score, body mass index, chronic infection with microorganisms other than P. aeruginosa , hospitalizations, and exacerbations in the previous year. Although completing the BSI is a little more laborious, there is a homepage to that end on the Internet ( http://www.bronchiectasisseverity.com/15-2/ ). The BSI also has good ability to estimate future mortality and exacerbations. 59 Our recommendation: A severity score and a prognostic estimate should be calculated at the time patients are diagnosed with bronchiectasis. Periodic calculation of the score (annually, for example) aids in therapeutic management. To date, the FACED and the E-FACED scores are the ones that have been validated for use in Brazil.

The term bronchiectasis refers to evidence of irreversible bronchial dilatation, usually found on chest CT scans. There are many congenital and acquired conditions related to the onset of bronchiectasis ( Chart 1 ). 19 The most widely accepted hypothesis to explain the onset of bronchiectasis is the one that proposes an interaction, at different levels of intensity, between an environmental insult and an individual with congenitally susceptible lungs. Increased susceptibility is an impairment of pulmonary defense mechanisms, such as mucociliary transport and availability of IgG and antiproteases in the distal air spaces. 20 Chart 1 Causes and conditions associated with bronchiectasis. Congenital conditions Cystic fibrosis a Alpha-1 antitrypsin deficiency a Primary ciliary dyskinesia a Young’s syndrome Primary ((humoral, cellular, or combined) immunodeficiencies a Anatomical defects in the tracheobronchial tree (tracheobronchomalacia [Williams-Campbell syndrome], tracheobronchomegaly [Mounier-Kuhn syndrome]) Pulmonary sequestration Acquired conditions Post-infectious Tuberculosis, nontuberculous mycobacterial infections Fungal infections (e.g., Paracoccidioides brasiliensis ) Viral infections (adenovirus, measles virus) Swyer-James-MacLeod’s syndrome Bacterial diseases ( Staphylococcus aureus , other bacteria) Chronic obstructive respiratory diseases COPD, bronchial asthma Secondary immunodeficiencies HIV, neoplasms, treatment with immunosuppressants or biological agents Systemic diseases (autoimmune mechanisms) Rheumatoid arthritis, Sjögren’s syndrome, systemic lupus erythematosus Inflammatory bowel disease (Chron’s disease, ulcerative colitis) Hypersensitivity-mediated Allergic bronchopulmonary aspergillosis Secondary to inflammatory pneumonitis Gastroesophageal reflux disease, chronic microaspiration, radiotherapy, inhalation of gases or other toxic agents Localized (obstructive) processes Intrabronchial (benign tumors, foreign body aspiration) Extrabronchial (lymph node enlargement, tumors) Post-transplant (immune-mediated) Host-versus-graft reaction (bone marrow transplantation, lung transplantation) Other (rare) conditions Yellow nail syndrome, sarcoidosis, endometriosis, amyloidosis, diffuse panbronchiolitis Idiopathic conditions (unknown cause) a Conditions known to be hereditary. Conditions known to be hereditary. Impaired defense mechanisms make the elimination of inhaled biological and non-biological particles and toxic gases less efficient. These agents remain in both the proximal and distal airways. Retained bacteria and viruses proliferate within the airways, change the composition of the normal lung microbiome, and trigger inflammation. Prolonged inflammation causes pulmonary structural damage and further impairs the mechanisms of airway clearance. Thus, the well-known vicious cycle implicated in the pathophysiology of bronchiectasis is initiated ( Figure 1 ). 20 A characteristic common to several conditions associated with the onset of bronchiectasis is the concomitant lesion of the small and large airways. This has been demonstrated in chronic bronchitis of COPD and in cystic fibrosis. 21 , 22 Nonspecific inflammatory processes of the small airways (bronchiolitis and bronchiolectasis) may even precede disease onset. The condition that triggers the vicious cycle described above cannot always be identified. In such cases, patients have a presumptive diagnosis of idiopathic bronchiectasis. Although pulmonary involvement in bronchiectasis is usually diffuse and bilateral, in rare cases, bronchial obstruction may lead to localized bronchial dilatation because it prevents the proper functioning of mucociliary transport. Chief among the conditions that affect the lungs diffusely are some viral infections (adenovirus; measles) 23 - 25 and bacterial infections (pertussis; bacterial pneumonias), 26 all of which can act as triggers for the development of bronchiectasis. In Brazil, pulmonary tuberculosis is also of note because it is a disease that has high incidence and prevalence 27 and leaves lung sequelae in the form of different size areas of chronic bronchial dilatation. 28 Conditions that directly affect airway clearance, such as ciliary dyskinesia and cystic fibrosis, can also be triggers of events leading to diffuse bronchiectasis. Ciliary dyskinesia impairs the functioning of the ciliary apparatus and leads to accumulation of secretions, especially in the small airways. 29 Cystic fibrosis, whose genetic defect results in thicker, harder to clear secretions, shows a trend toward accumulation of these secretions in the small airways and an increased risk of bacterial contamination. 16 , 22 The design of the airways, similar to a tree, in which new branches grow dichotomously, allows the identification of bronchial generations. From the trachea to approximately bronchial generation 6, air is transported by convection (pressure gradient) and there is airflow. As the cross-sectional area progressively increases with every new airway generation, the airflow progressively decreases until, at around bronchial generation 15, there is no airflow and the gas molecules move by diffusion. 30 From this airway structure, we can conclude that cough, which is dependent on flow generation, replaces mucociliary transport completely only up to bronchial generation 6. From generation 7 onward, cough progressively loses its effectiveness, and cough cannot compensate for impaired mucociliary transport from generation 15 onward. 31 , 32 In cases in which mucociliary transport is ineffective, all inhaled contaminants tend to settle out in the small diameter airways. The incoming bacteria find an environment that is highly conducive to proliferation in that region. The retained chemical and biological agents trigger an inflammatory response that causes more structural damage and further impairs mucociliary transport. A groundbreaking study by Reid 33 showed, by correlating bronchogram findings and pathology study of surgically resected lobes, that the involvement of large and small airways is often concomitant in bronchiectasis patients. In addition to the lesions in large airways, the author observed small airways whose lumens were partially or totally obstructed by inflammation and/or fibrosis. In many cases, the bronchioles disappeared from their normal position near the pulmonary arteriole and only remains of their structure were found. Depending on the severity of the bronchiolar obliteration, the bronchogram findings included cylindrical bronchiectasis (the least common bronchiolar obliteration), varicose bronchiectasis (the most common obliteration), or cystic/saccular bronchiectasis, in which all small diameter airways were obliterated. This loss of small airways resulted in a much smaller number of bronchial generations being identified. Bronchiectasis therefore appears to be a pattern of bronchial response to various types of injury, which as a rule involve (predominantly neutrophilic) inflammation and in most cases involve chronic airway infections.

Chart 6 summarizes the recommendations for the follow-up and treatment of non-cystic fibrosis bronchiectasis patients. Chart 6 Chart of recommendations for follow-up and treatment of non-cystic fibrosis bronchiectasis patients. Recommendations Follow-up Functional aspects Perform spirometry with bronchodilator use every 6 months, lung volume assessment (if available) annually, and the six-minute walk test (at the physician’s discretion). Microbiologic aspects Collect samples from the lower respiratory tract (sputum, for example) at regular intervals of 3-4 months and during pulmonary exacerbations for aerobic culture, as well as annually for culture for fungi and mycobacteria. If the patient is being treated with chronic macrolide therapy, culture for mycobacteria should be performed every 6 months. Systemic markers Although CRP appears to be an inflammation-related marker and is available for use in clinical practice, there is insufficient evidence to recommend its routine use to assess disease severity. Severity and prognostic scores A severity score and a prognostic estimate should be calculated at the time patients are diagnosed with bronchiectasis. Periodic calculation of the score (annually, for example) aids in therapeutic management. To date, the FACED and the E-FACED scores are the ones that have been validated for use in Brazil. Treatment of stable patients Chronic airway infection Primary infection Immediately following the first identification of P. aeruginosa in the sputum of a patient, the patient should be treated with a systemic antipseudomonal antibiotic combined with an inhaled antibiotic. Follow-up sputum culture is recommended 2-4 weeks after treatment completion. Chronic bronchial infection Bronchiectasis patients with chronic Pseudomonas aeruginosa infection and exacerbations may benefit from and should be treated with long-term inhaled antibiotics. The choice will depend on the availability of and access to medication . Chronic inflammation Macrolides Use macrolides as continuous therapy for at least 6-12 months for bronchiectasis patients with at least two exacerbations per year. Prefer azithromycin. The use of macrolides may be considered, although there is no evidence, for patients with fewer than two exacerbations per year but with a history of severe exacerbations or primary or secondary immunodeficiency, those whose exacerbations have a significant impact on their quality of life, and those with more severe bronchiectasis. Active nontuberculous mycobacterial infection should be ruled out. Inhaled corticosteroids There is insufficient evidence to support the routine use of inhaled corticosteroids in adults with bronchiectasis. Inhaled corticosteroid therapy may be justified in some subgroups of adults if there is associated asthma or COPD. Bronchodilators There is insufficient data to recommend the routine use of BDs in bronchiectasis patients without dyspnea. Long-acting BDs may be recommended if bronchiectasis is associated with asthma or COPD. Because of the potential risk of bronchospasm resulting from the use of inhaled mucoactive drugs and inhaled antibiotics, it is suggested that BDs be used prior to using these drugs. Airway clearance Respiratory therapy Respiratory therapy techniques for improving mucociliary clearance should be applied and taught to all bronchiectasis patients with chronic production of secretions and/or (CT scan) signs of mucus plugging. Physical exercise and pulmonary rehabilitation Refer bronchiectasis patients with exertional limitation for regular exercise and participation in pulmonary rehabilitation programs, if available. Osmotic agents The use of hypertonic saline (6-7%) should be considered in bronchiectasis patients with persistent secretions despite other measures. Hypertonic saline should be first administered under supervision to assess for adverse effects (bronchospasm), which can be prevented or minimized by prior administration of a short-acting bronchodilator. Mucolytics There is insufficient evidence to recommend the routine use of mucolytics in bronchiectasis patients. The use of DNase is contraindicated for adult non-cystic fibrosis bronchiectasis patients. Vaccines Bronchiectasis patients should receive influenza vaccine annually and should receive PCV13 and PPSV23 in the sequence recommended by the SBIm and the SBPT. Chronic respiratory failure Home oxygen therapy and noninvasive ventilation In patients with chronic hypoxemia despite optimal clinical treatment, long-term home oxygen therapy is indicated. In clinically stable patients with chronic hypercapnic respiratory failure, noninvasive mechanical ventilation by BiPAP should be used as an adjuvant to cardiopulmonary rehabilitation and respiratory therapy. Lung transplantation Lung transplantation should be considered for patients with FEV 1 < 30% of predicted or for those with higher FEV 1 values but with rapid lung function decline. Some factors, if present, should alert to the possibility of early referral of the patient for lung transplantation evaluation. These factors include severe and frequent exacerbations, with ICU admissions; recurrent or treatment-refractory pneumothorax or hemoptysis; chronic respiratory failure; and hypercapnia or pulmonary hypertension. Surgical treatment Surgical treatment should be reserved for individuals with localized bronchiectasis refractory to clinical treatment, and video-assisted thoracoscopy is the procedure of choice. Treatment of exacerbations Once an exacerbation is diagnosed, the severity of the exacerbation should be determined in order to decide between home care and hospitalization. Before initiating antibiotic therapy (based on previous culture results), another sputum sample should be collected for microbiological analysis, the results of which will be used if there is no response to treatment. Adjuvant measures (use of corticosteroids, bronchodilators, respiratory therapy, and/or hypertonic agents) should be instituted based on clinical judgment. CRP: C-reactive protein; FACED: acronym for E xacerbation, F EV 1 , A ge, C hronic colonization with Pseudomonas aeruginosa , E xtent (of CT findings), and D yspnea; BD: bronchodilator; PCV13: 13-valent pneumococcal conjugate vaccine; PPSV23: 23-valent pneumococcal polysaccharide vaccine; SBIm: Sociedade Brasileira de Imunização (Brazilian Immunization Association); SBPT: Sociedade Brasileira de Pneumologia e Tisiologia (Brazilian Thoracic Association); and BiPAP: bilevel positive airway pressure. CRP: C-reactive protein; FACED: acronym for E xacerbation, F EV 1 , A ge, C hronic colonization with Pseudomonas aeruginosa , E xtent (of CT findings), and D yspnea; BD: bronchodilator; PCV13: 13-valent pneumococcal conjugate vaccine; PPSV23: 23-valent pneumococcal polysaccharide vaccine; SBIm: Sociedade Brasileira de Imunização (Brazilian Immunization Association); SBPT: Sociedade Brasileira de Pneumologia e Tisiologia (Brazilian Thoracic Association); and BiPAP: bilevel positive airway pressure.

An exacerbation is characterized by worsening of three or more of the following symptoms for at least 48 h: 1) cough; 2) sputum volume or viscosity; 3) sputum purulence; 4) dyspnea or exercise intolerance; 5) fatigue; and 6) hemoptysis. 153 Chest X-ray may show preexisting bronchiectasis filled with secretion, with no signs of consolidation. The diagnosis is clinical, and ancillary tests can be used for differential diagnoses, such as pneumonia, pneumothorax, pulmonary thromboembolism, and heart diseases. The causes of exacerbations are not fully understood, but a relationship is known to exist between chronic bronchial bacterial infection and inflammation. Viral infections or other bacteria can trigger an imbalance in this relationship. 10 , 154 In addition to having a major impact on patient quality of life, exacerbations increase health care costs. Another important consequence is higher mortality rates, since patients with more than three exacerbations or a hospitalization in the previous 12 months experience increased mortality. 155 , 156 Once an exacerbation is diagnosed, history taking and physical examination should be targeted at determining the severity of the attack. Severe exacerbations require intravenous antibiotic therapy and/or hospitalization. Signs indicating the severity of an exacerbation are as follows 47 , 85 , 157 : respiratory rate ≥ 25 breaths/min; respiratory distress with use of accessory muscles; deterioration of oxygen saturation; cyanosis; body temperature ≥ 38°C; or another criterion for sepsis and hemoptysis (> 25 mL in 24 h). Patients with hemodynamic instability, an altered level of consciousness, or mental confusion should be considered for ICU treatment. Unavailability of home intravenous therapy may lead to the need for hospitalization in patients who used oral antibiotics and showed no response to treatment. It is of note that chronic infection with P. aeruginosa is associated with more frequent hospital admissions, longer hospital stays, worse pulmonary function, and higher mortality. 73 , 158 Therefore, patients with chronic infection with P. aeruginosa should be carefully evaluated for exacerbation severity. Among inpatients, predictors of higher mortality include male gender, use of systemic corticosteroids, low FEV 1 , increased creatinine, history of smoking, and need for mechanical ventilation. 159 The use of antibiotics is essential for treating exacerbations in bronchiectasis. Upon diagnosis of an exacerbation, sputum sample collection is indicated, but treatment initiation should not wait for results, which will be used only if the patient does not respond adequately to the initially chosen treatment. The choice of an antibiotic regimen should take into consideration results of previous aerobic sputum cultures and response to antibiotics in previous exacerbations, as illustrated in Figure 7 . Regardless of the antibiotic chosen, it is always suggested that the maximum recommended doses be used in order to ensure better penetration of the drug into dilated, structurally altered airways with accumulation of secretions. Figure 7 Flow chart for the therapeutic management of exacerbations. a If intravenous treatment is necessary in non-severe exacerbations, consider the possibility of intravenous administration at home. b The dose of ciprofloxacin, 750 mg, 12/12 h should be reserved for severe exacerbations in patients weighing more than 50 kg. Few studies have evaluated the duration of treatment for exacerbations. Currently, 14-day to 21-day treatment courses are recommended. In mild cases, in which the patient rapidly returns to baseline symptoms after treatment initiation, a treatment course of only 10 days can be considered. 15 There is no literature evidence on which outcomes are the best for use in determining the resolution of exacerbations. For patients with severe exacerbations, it is recommended that clinical improvement be associated with inflammatory markers and pulmonary function (spirometry or PEF). There is a significant increase in leukocytes, neutrophils, CRP, and fibrinogen in exacerbations; however, a small percentage of patients do not show inflammatory improvement by the end of treatment. Pulmonary function declines in exacerbations, and often recovers within 2 weeks of treatment completion. The greater the decline is, the greater is the risk of a long recovery period. 160 - 162 There is little evidence to support the use of other medications and adjuvant measures; however, some may be considered in specific situations: Systemic corticosteroids: Systemic corticosteroids should be used if there is associated asthma or COPD. They may be considered in patients with hypersecretion, at low doses (0.25 to 0.5 mg/kg of prednisone or equivalent), with attention being paid to the risks of side effects. Inhaled bronchodilators: Inhaled bronchodilators may be added to treat patients with significant dyspnea, especially during hospitalization, always taking into consideration the possible adverse events. Respiratory therapy: It is recommended that exercises for bronchial hygiene be increased during an exacerbation, regardless of the technique usually used by the patient. In cases of hospitalization, daily follow-up with a physical therapist, at least two sessions per day, is indicated. Hyperosmolar agents: Hyperosmolar agents may be considered in order to improve bronchial hygiene. The most commonly used option is hypertonic saline, starting at 3%, with the possibility of increasing up to a concentration of 7% if well tolerated. Because of the risk of hyperosmolar-induced bronchospasm, rapid-onset bronchodilators should be used 15-30 min prior to inhalation and the patient should be supervised when using a hyperosmolar agent for the first time. Systemic corticosteroids: Systemic corticosteroids should be used if there is associated asthma or COPD. They may be considered in patients with hypersecretion, at low doses (0.25 to 0.5 mg/kg of prednisone or equivalent), with attention being paid to the risks of side effects. Inhaled bronchodilators: Inhaled bronchodilators may be added to treat patients with significant dyspnea, especially during hospitalization, always taking into consideration the possible adverse events. Respiratory therapy: It is recommended that exercises for bronchial hygiene be increased during an exacerbation, regardless of the technique usually used by the patient. In cases of hospitalization, daily follow-up with a physical therapist, at least two sessions per day, is indicated. Hyperosmolar agents: Hyperosmolar agents may be considered in order to improve bronchial hygiene. The most commonly used option is hypertonic saline, starting at 3%, with the possibility of increasing up to a concentration of 7% if well tolerated. Because of the risk of hyperosmolar-induced bronchospasm, rapid-onset bronchodilators should be used 15-30 min prior to inhalation and the patient should be supervised when using a hyperosmolar agent for the first time. Inhaled antibiotics: Inhaled antibiotics are not routinely recommended for the treatment of exacerbations. If the patient is already using chronic inhaled antibiotics, he/she can continue the medication as long as the risks of side effects from concurrent use of inhaled and systemic antibiotic therapy are assessed. 163 , 164 Our recommendation: Once an exacerbation is diagnosed, the severity of the exacerbation should be determined in order to decide between home care and hospitalization. Before initiating antibiotic therapy (based on previous culture results), another sputum sample should be collected for microbiological analysis, the results of which will be used if there is no response to treatment. Adjuvant measures (use of corticosteroids, bronchodilators, respiratory therapy, and/or hypertonic agents) should be instituted based on clinical judgment.