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INTRODUCTION

Bronchiectasis is a suppurative lung disease with heterogeneous phenotypic characteristics (1). In structural terms, it is defined as a permanent and abnormal dilation of the bronchi due to chronic bronchial inflammation, the result of a vicious circle of recurrent infection, inflammation and damage to the bronchial wall. Dilation is determined by the ratio between the size of the airway with the pulmonary artery that accompanies it, broncho-arterial ratio convention >1-1.5 is abnormal (2). The broncho-arterial ratio increases with age. In preschool children, the normal upper limit is up to 0.7. The diameter of the airway also increases when lung volume increases due to air trapping, so it is important to keep this in mind when evaluating the presence of bronchiectasis in HRCT (3). In the 1950s, Reid described (4) the histological analysis of surgical specimens, demonstrating that the disease involved a progressive destruction of the architecture of the bronchial wall. He categorized bronchiectasis in different patterns, which are still used: cylindrical bronchiectasis (mild

dilatation with increased cross-sectional diameter of the bronchi), varicosities (tortuous and irregular bronchial dilatations) and cystic or saccular (bronchial dilatations).

EPIDEMIOLOGY

There is a shortage of epidemiological data on non–cystic fibrosis bronchiectasis (NCFB), due to sub-registration and underdiagnosis of the disease. In global terms, bronchiectasis is more frequent in males before puberty and in women after puberty and in adulthood (5). In developed countries, incidence has declined due to vaccination programs, tuberculosis programs, and the availability of antibiotics and earlier medical care. The prevalence fluctuates between 0.42 / 100,000 at 18-34 years and 27 / 100,000 at 75 years of age. In the United Kingdom, an increasing incidence and prevalence was observed for older groups between 2004 and 2013 (6). In Chile, information is scarce. In 2005, 18 cases were published with a diagnosis of bronchiectasis, average age 44 ± 13.9, predominance in males (55%) and smoking in >50% of patients (7). Highlighting a younger population than what is described in literature. The average time of evolution of the disease was 22 ± 9 years. NCFB implies a significant economic burden. It requires prolonged hospital stays, often in highly complex units, frequent outpatient visits and prolonged treatment. In spite of

REVIEW ARTICLES

Correspondence:Dr. Ramiro González rgonzalezv@clinicalascondes.clClínica Las CondesEstoril 450, Las Condes, Región MetropolitanaSantiago, ChilePhone: (562) 26108000

NON-CYSTIC FIBROSIS BRONCHIECTASIS. FROM CHILDHOOD TO ADULT. DIAGNOSTIC AND THERAPEUTIC APPROACH

ABSTRACT Bronchiectasis is a suppurative lung disease with heterogeneous phenotypic characteristics. It is defined as abnormal dilation of the bronchi, losing the existing relationship between bronchial sizes and accompanying artery. According to their form, they can be cylindrical, varicose, saccular or cystic. According to its location, they could be diffuse or localized. The diagnosis of bronchiectasis is usually suspected in patients with chronic cough, mucopurulent bronchorrea, and recurrent respiratory infections. The etiology can be varied, being able to classify in cystic fibrosis bronchiectasis, when there is cystic fibrosis transmembrane regulator (CFTR) gene mutation and not cystic fibrosis, being post infectious the most frequent. Its relationship with childhood is unknown. Severe respiratory infections can predispose in a susceptible subject the so-called theory of the "vicious circle" and the development of these. Persistent bacterial bronchitis in children has been described as a probable cause of not cystic fibrosis bronchiectasis in adults. The treatment is based on the management of symptoms and the prevention of exacerbations. The evidence is poor and many treatments are extrapolated from cystic fibrosis bronchiectasis. We are going to describe the diagnostic and therapeutic approach of non-cystic fibrosis bronchiectasis in adults. Key words: Bronchiectasis, Cystic fibrosis, and exacerbations.

Dr. Felipe Reyes C.Adult Pulmonologist, Hospital Clínico Universidad de Chile.Dr. Gilda Müller S.Pediatrician, Hospital Felix Bulnes.

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Non-cystic fibrosis bronchiectasis. From childhood to adult. Diagnostic and therapeutic approach

which, in Chile it is not included in the country’s Explicit Health Guarantees (GES). A cohort study in Germany described a mortality rate between 10 and 16% during an observation period of approximately 4 years (9). Patients with idiopathic bronchiectasis had lower mortality rates (3.4% at 3.3 years) compared to bronchiectasis from another cause (9). The observed cause of death was mainly due to respiratory failure. The decrease in FEV1 and dyspnea are correlated with the increase in mortality. Other independent mortality risk factors described are: colonization of the airway by Pseudomonas sp, low BMI, male, advanced age and COPD (9).

PHYSIOLOGY

Vicious cycle theory It is the most accepted theory to explain the evolution of bronchiectasis (10). In this model, a predisposed individual develops an inflammatory response to a lung infection or tissue injury. The resulting inflammation is partially responsible for the structural damage to the respiratory tract. Structural anomalies allow the stasis of the mucus, which favors a continuous chronic infection and the vicious cycle persists. Neutrophils play an important role in tissue damage in bronchiectasis, they are recruited in the respiratory tract in response to infection, by the bacterial chemokines IL-8, IL-17, LTB4, and TNF-α. Once in the airways, activated neutrophils release cathepsin G and elastase, causing epithelial damage, reduced ciliary movement, hyperplasia of the mucous glands, and increased mucus secretion. This damage and subsequent mucociliary stagnation allows colonization of bacteria and recruitment of new neutrophils, perpetuating the mechanism (Figure 1). Lymphocytes also have a role in the progression of bronchiectasis. Whitwell and Col (11), were the first to describe "follicular bronchiectasis", characterized by lymphoid follicles within the bronchial wall that, with the progression of the disease, enlarge and obstruct the small airways. These lymphoid follicles are similar to those described in COPD and represent ectopic germ centers with T and B lymphocytes, which are activated by the Th17 cells.

From childhood to adult Predisposition to respiratory infections during childhood can contribute to the continuous from discrete inflammatory changes in the small airway of children, to the development of bronchiectasis in adults. On the one hand, there are serious acute infections that can leave sequelae in the airway and subsequent development of bronchiectasis, such as Tuberculosis, Adenovirus, Respiratory Syncytial Virus etc. However, the subacute or chronic form is the most difficult to identify. Chronic productive cough in children (daily, for more than 4 weeks) has been called protracted bacterial bronchitis (PBB) (12). Although it is more common in preschool children, PBB is also diagnosed in older children. It is defined as a lower respiratory tract infection insecretion with colony-forming units and neutrophilia in BAL or induced sputum. Typical pathogens are H. influenzae, M. catarrhalis and S. pneumoniae. Many patients remit completely with a single antibiotic treatment, but others need repeated or prolonged

Figure 1. Diagram of the role of neutrophils in the tissue damage produced in bronchiectasis. They are recruited in the respiratory tract in response to infection, by the bacterial chemokines IL-8, IL-17, LTB4, and TNF-α. Once in the airways, activated neutrophils release cathepsin G and elastase, causing epithelial damage, reduced ciliary movement, hyperplasia of the mucous glands, and increased mucus secretion.

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courses. The pathophysiology is not clear; it is possible that an initial viral infection may cause transient local immune paralysis in some cases. In others, there may be an iatrogenic cause, such as an inappropriate prescription of inhaled corticosteroids (ICS) that are local immunosuppressants (12). It is important to make sure that PBB is resolved, to avoid development of bronchiectasis (13, 14). There are many microbiological and physiopathology elements in common between PBB and bronchiectasis, which may be extremes of the same spectrum of a chronic suppurative pulmonary disease (14).

CLINICAL PICTURE

Diagnosis of bronchiectasis is usually suspected in patients with chronic cough, mucus hypersecretion (bronchorrhea), mucopurulent secretion and recurrent respiratory infections. Cough is present in 90-96% of patients and expectoration in 75%, with an average daily volume of 30-40 ml in the adult at the time of diagnosis (15). Other common symptoms include dyspnea, hemoptysis, chest pain and wheezing. Hemoptysis is an alarm symptom and is present in 25-30% of cases, usually in the context of infectious exacerbations (15). The physical examination may be normal or present abundant rhonchi and / or wheezing, depending on the amount of secretions within the bronchus and the underlying pathology. If the airways are clear and there is no lobar collapse, there may be no physical signs. When bronchiectasis are in the upper lobes, drainage of secretions is favored decreasing bronchorrhea and pulmonary signology.

ETIOLOGY

Bronchiectasis may reflect not only local lung damage, but also systemic diseases that affect the lung. The causes can be divided into two large groups; cystic fibrosis bronchiectasis, although its manifestation is more frequent starting at childhood, we must not forget that

the presentation in adults may be different, with a more subtle picture and focused only on the lung (example in figure 2). The other etiologies have been denominated in general BNCF, the causes are varied and depend on the patient's environment and age of presentation. Table 1 shows the most frequent etiologies.

Post infectious bronchiectasis In adults with post-infectious bronchiectasis the mechanism seems to be a significant infection during childhood, causing structural damage to the lung, allowing subsequent bacterial infiltration that inhibits its proper elimination. This persistent infection can lead to bronchiectasis.

Lung immunodeficiency Bronchiectasis can be the presentation of an immunodeficiency that can solely affect the defenses of the lung or be systemic (for example, severe combined immunodeficiency). Human immunodeficiency viral (HIV) infection is a non-iatrogenic acquired immunodeficiency. Congenital immunodeficiency can be more difficult to diagnose and delay in diagnosis is frequent. More than 350 different genetic mutations have been described that cause immunodeficiency.

Allergy disease of the respiratory tract Allergic bronchopulmonary aspergillosis (ABPA) is a complication of CF that affects in all age groups and as asthma in adults, rarely in children. ABPA is one of the clinical forms of Aspergillus lung disease that includes respiratory sensitization, wheezing, Aspergillus bronchitis, and airway obstruction. ABPA is associated with an important allergic response to aspergillus and the release of proteolytic enzymes that can lead to severe proximal bronchiectasis (17). Figure 3 shows an example of this disease.

Autoinmune disease Ulcerative colitis, Crohn's disease and rheumatoid arthritis may be associated with bronchiectasis. The mechanism is not known with certainty, but in this group of pathologies, the

Figure 2. A HRCT cut of a 40-year-old man with central cylindrical bronchiectasis is observed. As part of the testing a positive sweat test stands out, without pancreatic or malabsorptive compromise.

Figure 3. HRCT of an asthmatic patient with poor control, highlighting cylindrical bronchiectasis, elevated IgEt and specific aspergillus IgE elevated, with excellent response to corticosteroid therapy.

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role of T and B lymphocytes becomes more important in their genesis.

DIAGNOSIS

Chest x-ray: may be useful initially but does not allow adequate characterization. High resolution computed tomography to the chest (HRCT): has replaced the x-ray diagnosis. The presence of dilated bronchi; with the internal diameter of the bronchus, greater than that of its adjacent vessel; absence of bronchial narrowing towards the periphery and thickening of the wall of the airways, are elements that suggest bronchiectasis. We can find mucous plugs, tree-in-bud-images and a mosaic attenuation pattern, which leads to inflammation of the smaller airway. Pulmonary function:: pre and post bronchodilator spirometry should be performed in all patients at diagnosis and follow-up. The most frequent finding is obstructive limitation, but a reduced FVC can also be observed in advanced disease (7). Sputum culture and tuberculosis and non-tuberculosis mycobacteria sample: at diagnosis and every six months, since colonization of the airway is associated with worse clinical prognosis and recurrent exacerbations, making management difficult. CF study: CF diagnosis is mainly made during childhood, however there are presentations that are characterized solely by lung involvement. In adults with CF some mutations of CFTR manifest late and behave as in patients with BNFQ. In a series of 122 patients with idiopathic bronchiectasis, 18% of the CFTR mutations were heterozygous and 12% homozygous (14).

TREATMENT (Figure 4)

Studies emphasize non-pharmacological treatment, which includes modifications in lifestyle and physical therapy. At the same time, after identifying the underlying cause, pharmacological therapy is aimed at reducing microbial invasion with antibiotics, as well as at symptomatic relief with anti-inflammatory drugs and mucolytic agents. Quitting to smoking and vaccines are effective preventive measures that reduce the number of exacerbations. Early detection is the most important

factor that affects prognosis (14).Airway hygiene The goal of airway clearance is to mobilize secretions and interrupt the vicious cycle of inflammation and infection. An inhaled agent (eg, 7% hypertonic saline solution) is used for this, along with chest physiotherapy or some device, such as a valve or flutter valve, which create turbulent airway flow to drain secretions. Nebulized hypertonic saline solution and inhaled mannitol as a dry powder improve mucus clearance, however no benefits were achieved in reducing exacerbations or lung function improvement (18).

Anti-inflammatory therapy Systemic corticosteroids do not alter the FEV1 decrease

Table 1. Causes of non-cystic fibrosis bronchiectasis in the adult. TB tuberculosis. GER: gastroesophageal reflux. ABPA: allergic bronchopulmonary aspergillosis. HIV: human immunodeficiency virus.

Figure 4. Bronchiectasis treatment.BD: bronchodilators, ICs: inhaled corticosteroids, ATB: antibiotics.

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rate in non-CF bronchiectasis. Adverse effects increase, without clinical benefit. Inhaled corticosteroids (ICS) have poor evidence on NCFB (19). The combination of LABA (long-acting bronchodilators) -ICS may marginally improve symptom control, but with an increased risk of hemoptysis (20). ICS must be used with caution and select the appropriate population. If the pathophysiology of inflammation is more similar to COPD, perhaps LABA + LAMA could be more useful.

Macrolides Macrolides exert immunomodulatory effects on host inflammatory responses without deletion of the immune system. The immunomodulatory effects of macrolides are numerous and include the modification of mucus production, the inhibition of biofilm production, the suppression of inflammatory mediators and the moderation of leukocyte recruitment and function (21, 22). Clinical benefits of azithromycin have been observed in both CF patients and patients with NCFB; in the reduction in the frequency of respiratory exacerbations, the decrease in sputum volume during 24 hours and improvement in quality of life (21). Macrolides can prolong the QT interval and cause cardiac arrhythmias, ventricular tachycardia, and ventricular fibrillation through their effect on the potassium channel, although these effects have not been found in the patients studied (22).

Antibiotics Antibiotics are used in the following scenarios:

a) Attempt to eradicate Pseudomonas and / or MRSA (Meticillin-resistant Staphylococcus aureus).b) Suppress the burden of chronic bacterial colonization.c) Treat exacerbations.

BTS guidelines advocate an attempt to eradicate Pseudomonas and MRSA at first identification, with an antibiotic treatment aimed at interrupting the vicious circle of infection, inflammation and damage to the respiratory tract. There is growing evidence that long-term inhaled antibiotics may play an important role in NCFB therapy. They reduce the bacterial load or eradication of the sputum bacteria and reduce the risk of acute exacerbations. The most commonly used are: amikacin, aztreonam, ciprofloxacin, gentamicin, colistin and tobramycin, for 1-12 months. Tolerable bronchospasm is observed in 10% of cases (23).

Surgical Treatment It is reserved for selected patients, with the aim of removing damaged areas of lung parenchyma that act as an inflammatory focus and reservoir for microorganisms, with little penetration of entibiotics and infection and persistent inflammation (20). It is indicated in localized disease, anatomical resection, failure of medical treatment, severe symptoms, recurrent infections and recurrent hemoptysis.

Immunizations Annual anti-influenza and anti-pneumococcal vaccination is recommended.

CONCLUSIONS

Bronchiectasis is a suppurative lung disease with heterogeneous phenotypic characteristics. Cystic fibrosis and non-cystic fibrosis can be classified into bronchiectasis of diverse etiologies, with the vast majority being post-infectious. They can originate at pediatric ages or in the adult. Persistent bacterial bronchitis in children has been described as a probable cause in the development of non-cystic fibrosis bronchiectasis in adults. The treatment is based on the management of symptoms and the prevention of exacerbations. Evidence is scarce and most therapies have been investigated in cystic fibrosis-type bronchiectasis.

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