Bronchiectasis

A chronic inflammatory disease, defined as a permanent dilatation of the bronchi.

Mucociliary dysfunction, parenchymal injury, dysregulated inflammation and airway parenchymal injury, are mechanistic processes.

Transmural bronchial inflammation often due to infection causes bronchial, epithelial disruption, and weakening of surrounding musculature, leading to airway dilatation that allows harbor of microbes and contributes to impaired ciliary function, which interferes with clearance of mucus, microbes, and inflammatory debris.

In some cases bronchiectasis is the only radiographic finding associated with few or no symptoms or exacerbations.

Major symptom is chronic sputum production.

Patients characteristically have a daily cough and sputum production and suffer with frequent exacerbations.

Exacerbations are associated with a poor quality of life, decreased lung function, and increased mortality.

Airways have injury and subsequent loss of integrity of muscle, elastic tissue, and sometime bronchial cartilage.

Dilated bronchi increases susceptibility of bacterial infection with chronic irritation and inflammation.

Radiographically associated with pathologic dilatation and mucosal thickening of small and medium sized bronchial tubes.

Structural abnormalities in the bronchial wall causes impaired clearance of lower airways resulting in chronic bacterial infection and inflammation.

Inflammation  is dominated by neutrophils that when activated, released neutrophil serine proteases, including neutrophil elastase, believed to be essential to the pathophysiology of bronchiectasis.

It is postulated that elevated levels of neutrophil elastase, proteinase 3 and cathepsin G overwhelm natural Inhibitors, such as alpha-1 anti-trypsin and secretory leukocyte protease inhibitor, which alters the environment that increases the risk of infection.

Higher levels of neutrophil elastase in sputum is associated with a higher bronchiectasis score, along with worse dyspnea scores, increased lung function abnormalities and more extensive radiologic findings.

The neutrophil elastase level increases with exacerbations and is a biomarker for disease activity and targets for treatment.

Neutrophil serine proteases, such as neutrophil elastase are a key component of containing inflammation.

Because of the damaging effective neutrophil elastase and other proteases on bronchial epithelial cells and alveoli, chronic bronchitis and panacinar emphysema develops in these patients at a young age.

In healthy individuals, macrophages are the predominant cell of the airways, but in person with bronchiectasis, the neutrophil predominates, and the neutrophil number correlates with the severity of disease.

In bronchiectasis, functional impairment of neutrophils is reported in both blood and airways, resulting in their impaired phagocytosis and killing of pseudomonas aeruginosa.

More than 2/3 of persons with bronchiectasis are chronically infected with pathogens, most commonly with Hemophilus influenzae, and P aeruginosa.

Bacterial loads drive airway inflammation, promoting further damage to the airways.

In advanced bronchiectasis free neutrophil elastase, and other proteases are present which overwhelms the endigenous protein inhibitors.

Elevated levels of free neutrophil elastase in the sputum of patients with bronchiectasis are associated with more severe disease, increased risk of exacerbation, and rapid decline of lung function.

There are multiple inciting factors that lead to the development of bronchiectasis and it’s associated with a cycle of remodeling in dilatation of the airways.

The process above is referred to as a vicious circle and if progressive may lead to respiratory insufficiency and need for lung transplantation or ultimately death.

An initial insult leads to airway dysfunction, followed by an inflammatory response and structural disease and infection, which is a progressive process over time and it overcomes local and systemic coast protective factors.

Impaired mucociliary clearance causes mucus retention, airway distortion, and vulnerability to infection.

May be a primary disease, or can complicate all the pulmonary diseases including asthma and COPD.

May exist with congenital and hereditary diseases including cystic fibrosis, primary ciliary dyskinesia, and alpha one antitrypsin deficiency.

May be seen with autoimmune diseases including rheumatoid arthritis Sjogren syndrome and inflammatory bowel disease.

May develop in patients with immune deficiency syndromes including variable immuno deficiency and human immunovirus deficiency virus infection, seen in conjunction with chronic rhinosinusitis, gastrointestinal reflux, dysphagia, and aspiration syndromes.

All patients should be assessed for current coexisting illness and history of predisposing disorders including: COPD, asthma, gastroesophageal reflux or aspiration, rheumatologic diseases and inflammatory bowel diseases.

A complete CBC with differential and immunoglobulin levels are required.

If immunoglobulin levels are reduced antibody response to vaccinations can be assessed.

Patients should have morning sputum samples for bacterial, micro, bacterial, and fungal cultures.

Patients should undergo spirometry to assess lung function and to evaluate associated conditions, such as COPD or asthma.

Testing for cystic fibrosis especially in early onset bronchiectasis and those with associated disorders such as male infertility, malabsorption or pancreatitis

The course of the process is variable and may be associated with infectious exacerbations with increased cough, hemoptysis, and dyspnea.

Ciiliary disorders and alpha one antitrypsin deficiency are considerations for diagnosis.

Exacerbations are associated with impaired quality of life.

Of patients with bronchiectasis 68% had a history of pneumonia, 20% had COPD, 29% had a diagnosis of asthma, 47% had gastroesophageal reflux disease, 8% of history of rheumatologic disease, 3% inflammatory bowel disease, 5% an immuno deficiency disease, and 3% had primary ciliary dyskinesia.

Early recognition of the disease may improve quality of life and overall prognosis.

Improvements in pullmonary function may eventually affect survival, as impaired lung function is an independent risk factor for mortality in patients with bronchiectasis.

Differential diagnosis includes multiple other primary pulmonary disorders, but it is distinguished by its productive cough and pattern of exacerbations.

Diagnosis often made with considerations of chronic bronchitis, chronic rhinosinusitis and other causes of chronic cough with the patient receiving multiple courses of  antibiotics  and inhaled steroids and bronchodilators before correct diagnosis.

The patient must have a cough that produces sputum on most days of the week, a history of exacerbations, and at least one of the following findings on high resolution CT: a ratio of the inner or outer airway diameter to the artery diameter of 1.0 or more, lack of tapering of the airways, and the presence of radio graphically visible airways in the perimeter.

Other CT findings include mucus plugging, treein bud nodularity, and waxing and waning pattern to the nodules.

Chest imaging, specifically CT chest scans are required to make the diagnosis.

Chest CT diagnostic criteria include a bronchi airway diameter greater than the diameter of an adjacent blood vessel, lack of airway tapering, which allows small airways to be visible at the periphery of a lung in contrast to normal bronchioles, additional findings may include tree-in-bud opacities caused by mucus impaction in small airways and cysts in ends of airways.

Bronchiectasis distinct features is this tendency towards exacerbations with deterioration in cough and sputum volume for at least 48 hours, with increase in sputum purulence, breathlessness or exercise intolerance, fatigue or malaise, or hemoptysis.

Frequent exacerbators have a higher five-year mortality rate.

All patients with bronchiectasis should have respiratory secretion cultures at the time of diagnosis and at regular intervals for surveillance, and ideally at the time of exacerbations.

The presence of Pseudomonas aeruginosa is a marker for severity of disease: it is consistently associated with increase mortality, hospitalizations, number of exacerbations, worst quality of life, deterioration in pulmonary function, and radiographic findings.

The presence of staphylococcus infection has less effect on the severity of disease than pseudomonas.

Approximately 1/3 of patients with sputum cultures and bronchiectasis are positive for P. aeruginosa and Staph aureus was detected in 12% of patients and Haemophilus influenza in 8%, in a bronchiectasis research registry.

Other organism seen at less of frequency include: Streptococcus pneumoniae, Stenotrophomonas malthilia, Klebsiella pneumonia, Moraxella catarrhalis, E. coli, and achromobacter species.

Norcardis species but sometimes isolated from respiratory cultures from patients with bronchiectasis,but its clinical significance is uncertain.

Fungal cultures most commonly aspergillus and can do the species or not always pathogenic findings in patients with bronchiectasis.

Nontuberculous mycobacterial infections are common with bronchiectasis, and speculation exists that it may be a cause of agent in the development of bronchiectasis.

Viral infections may play a role in bronchiectasis exacerbations.

In a study comparing Azithromycin 250 mg daily or placebo for 12 months in patients with bronchiectasis resulted in a better quality of life, and lower rate of infectious exacerbations (BAT. Randomized Controlled Trial, Altenburg J et al).

In the EMBRACE trial the reduction in exacerbations with six months of macrolide treatment was also significant.

Brensocatib an oral, selective. competitive and reversible inhibitor of DPP-1 inhibits neutrophils serine protease activity, and and in a randomized controlled trial resulted in improvement in bronchiectasis clinical symptoms and a lower annualized rate of pulmonary exacerbations, and decline in FEV than placebo.

Goals of treatment include: symptom reduction and improvement in quality of life, preservation of lung function, and reduction in morbidity and mortality.

Treatment of the underlying disorders to prevent disease progression and potentially reverse bronchiectasis is required for diseases such as cystic fibrosis, immunoglobulin deficiencies, allergic bronchopulmonary aspergillosis, gastroesophageal reflux disease, alpha-one plasma concentrates with anttrypsin deficiency.

If sputum cultures are not available or results do not demonstrate a pathogen during an exacerbation, treatment with doxycycline or amoxicillin is reasonable.

If P aeruginosa has previously been cultured, Ciprofloxacin is first load treatment.

Preventing exacerbation relies mainly on improving airway clearance and managing infections with antibiotics.

Patients with severe bronchiectasis exacerbations with hypoxemia, hypertension, tachycardia, and tachypnea should be hospitalized and treated with parental antibiotics, which may include anti-pseudomonal penicillin, ceftazadime, aztreonam, or carbapenem.

Management includes airway clearance therapies including nonpharmacologic strategies, mucoactive treatments, pulmonary rehabilitation and exercise aimed to mobilize secretions to reduce cough and dyspnea and prevent further the airway damage.

Airway clearance usually includes a combination of three interventions: inhalation or ingestion of a mucoactive agent, application of positive expiratory pressure, or pulsatile agitation to the airways, and deliberate coughing, huffing, and slow exhalations to clear the central airways.

Surgery may be considered for patients with bronchiectasis confined to a single lobe of lung, resistant microbes, uncontrolled hemptysis, or patients who do not improve or who worsen with medical therapy.

Non-pharmacological airway clearance options include, breathing techniques, photogenic drainage involving controlling the speed and depth of exhalation to mobilize secretions, slow exhalation with the glottis open in the lateral decubitus position, the use of positive expiratory pressure isolating devices, and high frequency chest wall oscillation.

Nebulized hypertonic saline is a mucoactive treatment that is shown benefits in bronchiectasis.

Routine use of inhaled oral glucocorticoids may promote airway infections.

Inhaled short, acting bronchodilators, such as albuterol may reduce cough and dyspnea in patients with bronchiectasis who have a history of asthma, COPD.

Routine vaccinations and nutritional counseling are recommended for all patients.

Guidelines recommend treatment with long-term oral macrolides for patients with bronchiectasis and three or more exacerbations per year.

Macrolides are highly efficient at reducing the frequency of exacerbations, because of their dual antimicrobial and anti-inflammatory properties.

The preferred macrolide is azithromycin whose antimicrobial effects down regulate pro inflammatory cytokines, and reduce inflammatory mediators, and biofilms.

Guidelines recommend the use of inhaled antibiotics for patients who have three or more bronchiectasis exacerbations per year and who are infected with known bacteria.

The use of mucolytic agents benefits are inconsistent.

In a randomized trial, neither hypertonic saline nor carbocysteine significantly reduced the mean incidence of pulmonary exacerbation over a period of 52 weeks (CLEAR Investigator Team).

Neutrophils are the core airway inflammatory cell in bronchiectasis and Brensocatib reduces neutrophil serine protease activity during neutrophil development in the bone marrow.

Brensocatib sold under the brand name Brinsupri, is a medication used for the treatment of bronchiectasis.