Bronchiectasis is a general term of a group of heterogeneous diseases, in which bronchial suppurative inflammation relapses after acute and chronic respiratory tract infections and bronchial obstruction, resulting in the destruction of the bronchial wall structure, thickened wall, and abnormal and persistent dilation of bronchi. It can be primary or secondary, and is caused by cystic fibrosis and non-cystic fibrosis. In recent years, with proper treatment of acute and chronic respiratory infections, its incidence is decreasing. However, with the popularization of CT, especially the application of high-resolution CT, a certain proportion of bronchiectasis has also been found in some patients with advanced COPD.
Etiology and pathogenesis
Bronchiectasis can be divided into congenital bronchiectasis and acquired bronchiectasis. Congenital bronchiectasis is rare, and obvious etiology is absent in some patients, but diffuse bronchiectasis often occurs in patients with genetic, immunological, or anatomical defects, such as cystic fibrosis, ciliary dyskinesia, and severe α1-antitrypsin deficiency. Focal bronchiectasis can result from untreated pneumonia or airway obstruction, caused by foreign bodies, tumors, exogenous compression, or anatomical displacement after lobectomy.
Bronchiectasis is in vicious cycle. Chronic bronchial infection caused by various precipitating factors can cause inflammatory responses in the respiratory tract, resulting in hypersecretion of airway mucus, mucus clearance dysfunction, and bacterial colonization and reproduction, which cause structural damage to the airways and lungs and deterioration of lung function, thereby promoting the further occurrence of lung infections. In fact, there are interactions in these factors. For example, structural damage to the airway leads to poor drainage, promoting bacterial colonization and proliferation. In the lungs of patients with bronchiectasis, there are interactions in the vicious cycle, and the treatment of bronchiectasis requires interdiction or reversion of the vicious cycle, including promotion of drainage and excretion of sputum, reduction of bacterial colonization and infection, enhancement of the defense ability of the respiratory tract, improvement of airway inflammation, reduction and prevention of acute exacerbations, and improvement of lung function and airway remodeling.
Hosts are susceptible to infections and inflammation. Secondary bronchiectasis occurs mostly after bacterial, tuberculous, nontuberculous mycobacterial, viral, or fungal infections. Recurrent bacterial infections can cause the airways filled with viscous purulent fluids containing inflammatory mediators and pathogens to gradually dilate, forming scars and distortions. The bronchial walls thicken due to edema, inflammation, and neovascularization.
The destruction of the peripheral interstitial tissue and alveoli leads to fibrosis, emphysema, or both. Patients with bronchiectasis in combination with emphysema have a poor prognosis and a significantly lower 5-year survival; patients with concurrent Pseudomonas aeruginosa colonization have a more significant decline in lung function.
High-risk population includes patients with chronic cough and expectoration, particularly with purulent sputum or hemoptysis; patients with frequent acute exacerbations (≥ 2 times/year) of chronic obstructive pulmonary disease, severe or poorly controlled asthma, and positive Pseudomonas aeruginosa in sputum culture; patients with chronic sinusitis, rheumatic diseases, or other connective tissue diseases, and with chronic cough and expectoration or recurrent pulmonary infections; patients with HIV infection, solid organ transplantation, or immunosuppressant therapy, and with chronic cough and expectoration. These patients need screening for bronchiectasis
Pathology and pathophysiology
Bronchiectasis is often the destruction and inflammatory changes of the segmental or subsegmental bronchial walls. The affected walls, including cartilage, muscle, and elastic tissue, are destroyed and replaced by fibrous tissue, forming cylindrical or tubular bronchiectasis, cystic bronchiectasis, and varicose bronchiectasis.
In cylindrical or tubular bronchiectasis, the bronchi are uniformly tubular and suddenly thin in one place, and distal small airways are often obstructed by secretions.
In cystic bronchiectasis, the dilated bronchial lumen is cystic, and the blind end of the terminal bronchioles also presents an unrecognizable cystic structure.
In varicose bronchiectasis, the bronchial lumen presents varicose changes or beaded changes.
Bronchial inflammation and fibrosis, bronchial wall ulcers, squamous epithelial metaplasia, and mucous gland hyperplasia can be seen in microscopy. The adjacent lung parenchyma of the diseased bronchi may also have fibrosis, emphysema, bronchopneumonia, and atelectasis. Inflammation can cause hypervascularity in the bronchial walls, accompanied by bronchial artery dilatation and anastomosis of bronchial arteries and pulmonary arteries. Various pathogenic factors lead to chronic airway inflammation, increased airway secretions, airway clearance disorders, sputum accumulation, and airway obstruction. Subsequently, colonization and proliferation of pathogenic microorganisms increase the risk of infection, and repeated bacterial infections aggravate the airway inflammation response and cause destruction and thickening of the airway wall, thereby reducing the ability of sputum clearance. 50% of patients with bronchiectasis may have obstructive ventilatory dysfunction, and restrictive ventilatory dysfunction is more common.
Clinical manifestations
Bronchiectasis can be divided into stable bronchiectasis and bronchiectasis acute exacerbation.
The main symptoms of stable bronchiectasis are persistent or repeated cough, expectoration, or purulent expectoration. Sputum is mucous, mucopurulent, or purulent, and may be yellowish green. After collection and layering, the uppermost layer is foam, the middle layer is turbid mucus, the lower layer is purulent components, and the bottom layer is necrotic tissue. Patients without obvious predisposing factors often have an insidious onset, with no or mild symptoms.
When bronchiectasis is accompanied by acute infection, patients may present with cough and purulent expectoration, with or without pneumonia. Hemoptysis may occur in 50% - 70% of patients, and massive hemorrhage is often caused by the invasion of small arteries or the destruction of proliferating blood vessels. Some patients have recurrent hemoptysis as the only symptom, which is termed dry bronchiectasis. Dyspnea and wheezing often suggest extensive bronchiectasis or underlying chronic obstructive pulmonary disease. Moist crackles and dry crackles can be heard on physical examination. Severe patients, especially patients with chronic hypoxia, cor pulmonale, and right heart failure, may present with clubbed fingers and right heart failure.
Acute exacerbation is at least 3 of 6 symptoms, composed of severe cough, excessive expectoration, purulent expectoration, dyspnea or decreased activity tolerance, fatigue or discomfort, and hemoptysis, occur, and requires urgent treatment.
Laboratory and auxiliary examinations
Main imaging examinations include chest x-ray and high-resolution chest CT, while laboratory examinations include routine blood test, inflammatory markers such as C-reactive protein, immunoglobulins (IgG, IgA, IgM), microbiological examinations, blood gas analysis, and pulmonary function test. Other examinations include nasal sinus CT, serum IgE, specific IgE, aspergillus fumigatus skin test, rheumatoid factor, antinuclear antibodies, cellular immune function test, and cystic fibrosis and primary ciliary dyskinesia test. If necessary, fiberoptic bronchoscopy can be conducted.
Chest x-ray
Severe bronchiectasis shows coarse reticular opacities. The airways of cystic bronchiectasis show significant cystic airspaces, with or without air-fluid level. When there is no air-fluid level in the cystic cavity, it is difficult to distinguish the disease from bullous emphysema and honeycomb lung of severe interstitial lung disease.
Figure 1 Bronchiectasis on chest x-ray
High-resolution CT (HRCT)
HRCT can clearly show dilated bronchi in the transverse section, and is non-invasive, repeatable, and acceptable. It has been the main diagnostic method for bronchiectasis. In normal individuals, the ratio of the inner diameters of the left and right bronchi to the diameters of the parallel pulmonary arteries is 0.75 and 0.72, respectively; while in patients with bronchiectasis, the ratio is often > 1. The main manifestations of bronchiectasis on HRCT are cylindrical or tubular and cystic changes in the bronchi, thickened airway wall (bronchial inner diameter < 80% of the outer diameter), mucus obstruction, tree-in-bud sign, and mosaic sign and air trapping in the expiratory phase. When the CT scanning plane is parallel to the bronchi, the dilated bronchi show tram track sign or beaded changes; when the scanning plane is perpendicular to the bronchi, the dilated bronchi and the accompanying pulmonary artery form signet ring sign; when multiple cystically dilated bronchi are adjacent to each other, they show honeycomb changes and coarse reticular changes. Some patients with aspergillus infection have aspergilloma.
Figure 2 Bronchiectasis on HRCT
Blood routine test and inflammatory marker test
When bacterial infection causes acute exacerbation of bronchiectasis, the white blood cell count, neutrophil percentage, and C-reactive protein in the blood may be increased.
Serum immunoglobulin
Serum immunoglobulin (IgG, IgA, IgM) deficiency can occur in patients with immunodeficiency.
Blood gas analysis
Hypoxemia and hypercapnia can be detected.
Microbiological examination
Sputum specimens should be collected for smear staining and sputum bacterial culture. The results of sputum culture and antibiotic sensitivity test can guide the selection of antimicrobials. When acid-fast bacilli are found in sputum, further typing is required to determine whether they are tuberculosis bacilli or non-tuberculous mycobacteria.
Etiological examination
When necessary, rheumatoid factor, antinuclear antibodies, and anti-neutrophil cytoplasmic antibodies can be tested. In patients with suspected ABPA, serum IgE measurement, aspergillus fumigatus skin test, and aspergillus precipitin test can be selectively conducted. If patients with childhood-onset bronchiectasis, with chronic sinusitis or otitis media, or with dextrocardia, PCD may be suspected, and nasal exhaled nitric oxide measurement can be performed. In suspected patients, ciliated epithelium electron microscopy should be performed, and genetic testing can be considered if necessary.
Fiberoptic bronchoscopy
When bronchiectasis is focal and located above the segmental bronchus, crater-like changes can be found, and fiberoptic bronchoscopy can be used for etiological and pathological diagnosis. Fiberoptic bronchoscopy can also identify the site of hemorrhage, dilation, or obstruction. Local lavage can also be performed through fiberoptic bronchoscopy, and lavage fluid specimens can be taken for smear and bacteriological and cytological examinations to assist in diagnosis and guide treatment.
Pulmonary function test
Some patients have restrictive, obstructive, or mixed ventilatory dysfunction.
Diagnosis
Based on a history of recurrent purulent expectoration, hemoptysis, a history of respiratory infections inducing bronchiectasis, and HRCT showing abnormal changes of bronchiectasis, bronchiectasis can be clearly diagnosed.
Differential diagnosis
Chronic bronchitis
Chronic bronchitis occurs mostly in middle-aged and older patients, with evident cough and expectoration in winter and spring, predominantly white mucus sputum. Purulent sputum may occur in acute exacerbation, but there is no history of repeated hemoptysis. Scattered dry and moist crackles can be heard in both lungs on auscultation.
Lung abscess
Lung abscess presents with acute onset, high fever, cough, and excessive purulent and odor sputum. Chest x-ray shows local dense inflammatory opacity with air-fluid level.
Pulmonary tuberculosis
Pulmonary tuberculosis is characterized by low-grade fever, diaphoresis, fatigue, and emaciation. Dry and moist crackles are mostly limited to the upper lungs. Chest x-ray and sputum Mycobacterium tuberculosis examination can assist in diagnosis.
Congenital pulmonary cyst
In congenital pulmonary cyst, chest x-ray shows multiple, circular or oval opacities with thin borders and thin walls, without peripheral inflammatory infiltration. Chest CT and bronchography can assist in diagnosis.
Diffuse panbronchiolitis
Diffuse panbronchiolitis is manifested by chronic cough, expectoration, dyspnea on exertion, and chronic sinusitis. Chest x-ray and CT show diffusely distributed small nodular opacities. Macrolides are effective.
Bronchogenic carcinoma
Bronchogenic carcinoma presents with cough, expectoration, thoracodynia, and bloody sputum. Massive hemoptysis is rare. Imaging, sputum cytology, and bronchoscopy are helpful for diagnosis.
Treatment
Treatment of underlying disease
Proper anti-tuberculosis treatment should be given to patients with pulmonary tuberculosis and bronchiectasis. Immunoglobulin replacement therapy can be used for hypoimmunoglobulinemia.
Control of infection
Anti-infective drugs should be used when patients with bronchiectasis show signs of acute infection such as increased sputum volume and increased purulent components. Before starting antimicrobial treatment during acute exacerbation, sputum culture should be routinely performed. Antibiotic application should be guided by sputum culture and antibiotic sensitivity test, but empirical antimicrobial treatment should initiate while waiting for culture results. Patients without high-risk factors for Pseudomonas aeruginosa infection should immediately use empirical antimicrobials against Haemophilus influenzae, such as ampicillin/sulbactam, amoxicillin/clavulanate, second-generation cephalosporins, third-generation cephalosporins (cefotaxime sodium, cefotaxime), moxifloxacin, and levofloxacin. In patients with high-risk factors for Pseudomonas aeruginosa infection, such as recent hospitalization, antibiotic use more than 4 times a year or within the past 3 months, severe airflow obstruction (FEV1＜ 30% predicted value), and daily oral prednisone > 10 mg in the past 2 weeks; β-lactam antibiotics with anti-pseudomonal activity such as ceftazidime, cefepime, piperacillin/tazobactam, cefoperazone/sulbactam; carbapenems such as imipenem and meropenem; aminoglycosides; and quinolones such as ciprofloxacin and levofloxacin can be used alone or in combination. In patients with chronic cough and with purulent expectoration, oral amoxicillin or inhaled aminoglycosides, or intermittent and regular use of single antibiotic and rotation of antibiotics can also be considered to enhance the clearance of lower respiratory tract pathogens. When complicated by ABPA, in addition to glucocorticoids such as prednisone, antifungals such as itraconazole is also required for combination treatment.
In patients with pulmonary cavities, especially with smooth inner walls, with or without tree-in-bud sign, the possibility of atypical mycobacterial infection should be considered. Sputum acid-fast staining, sputum culture, and sputum microbial molecular detection can be used for diagnosis. Patients are also susceptible to tuberculosis, and patients may present with pulmonary cavities or nodules, exudation in combination with proliferative changes, low-grade fever, and diaphoresis. Patients are prone to colonization and infection of aspergillus, manifested by aspergilloma in the lumen, chronic fibrous cavitary changes, or acute or subacute invasive infections. Voriconazole is generally used to treat invasive aspergillus infections.
14-membered and 15-membered lactone macrolides, including azithromycin, clarithromycin, and erythromycin, have the characteristics of immunomodulatory effects. If there are not liver and kidney dysfunction, prolonged QT interval on the electrocardiogram, and significant hearing impairment, long-term (up to one year) oral treatment is given, which can reduce the frequency of acute exacerbations in some patients with bronchiectasis. During treatment, liver and kidney function, electrocardiogram, and hearing need to be monitored. Nebulized inhalation of antibiotics such as tobramycin can effectively clear the colonized microorganisms and reduce acute exacerbations. They have already been used in clinical practice, but the treatment course still needs further exploration.
In patients with Pseudomonas aeruginosa isolated for the first time and progression of the disease, a two-week treatment of oral ciprofloxacin (500mg, twice a day) can be given, and inhaled tobramycin is given in the subsequent three months. In patients with nontuberculous mycobacteria (NTM), an assessment can be conducted based on the severity of NTM infection and presence or absence of hemoptysis and cavities; in case of simple colonization or localized or mild lesion, anti-NTM treatment is not necessary; if NTM promote the progression of lung diseases or have a high risk, anti-NTM treatment containing at least three drugs may be required, and the longest course of treatment can be up to two years. Some patients often cannot tolerate the two-year course of treatment due to the side effects of the drugs.
Improvement of airflow limitation
Long-acting bronchodilators (long-acting β2-receptor agonists, long-acting anticholinergics, inhaled glucocorticoids/long-acting β2-receptor agonists) can improve airflow limitation and help clear secretions, and often have a certain effect on airway hyperresponsiveness and reversible airflow limitation. However, due to the lack of evidence-based medicine, there is currently no routine recommended indications for the selection of bronchodilators.
Clearance of airway secretion
Physical expectoration and expectorants are included. Physical expectoration includes postural drainage, nebulized inhalation of normal saline in the airway, chest wall vibration, positive pressure ventilation, and active breathing training; while expectorants include mucolytics, mucoactive agents, and antioxidants. Acetylcysteine has strong expectorant and antioxidant effects.
Immunomodulator
Some medications that promote respiratory immunity, such as bacterial lysates, can reduce acute exacerbation. Long-term use of 14- or 15-membered lactone macrolides in some patients can reduce acute exacerbation and improve symptoms, but attention should be paid to other side effects of long-term oral antibiotics, including damage to cardiovascular system, hearing, and liver function and bacterial resistance.
Treatment of hemoptysis
In patients with recurrent hemoptysis, mild hemoptysis can be treated using symptomatic treatment or oral administration of carbazochrome and carbazochrome sodium sulfonate; moderate hemoptysis can be treated using intravenous pituitrin or phentolamine; and severe hemoptysis requires interventional embolization or surgical treatment. When using pituitrin, attention should be paid to the occurrence of hyponatremia.
Surgical treatment
If bronchiectasis is localized and still recurs after adequate medical treatment, surgical resection of the diseased lung tissue can be considered. If massive hemoptysis comes from the hyperplastic bronchial arteries, and conservative treatment such as rest and antibiotics cannot relieve the symptoms and still causes massive hemoptysis, surgical treatment may be considered in patients with localized lesions, otherwise bronchial artery embolization may be used. In disabled patients who had all treatments, lung transplantation may be considered.
Prevention
Pneumococcal vaccination and influenza virus vaccination can prevent or reduce acute exacerbation, and immunomodulators are helpful in alleviating symptoms and reducing attacks. Smoking cessation is required. Rehabilitation exercises have a certain effect on maintaining lung function.
Prognosis
The prognosis of bronchiectasis depends on the extent of bronchiectasis and the presence or absence of complications. In patients with localized bronchiectasis, proper treatment can improve the quality of life and prolong lifespan. In patients with extensive bronchiectasis, lung function may be damaged, and respiratory failure may occur, leading to death. Massive hemoptysis can also seriously affect the prognosis. Patients with concurrent bronchiectasis, Pseudomonas aeruginosa colonization, and lung parenchymal damage such as emphysema and bullae have a poor prognosis. The mortality in patients with concurrent COPD and bronchiectasis increases.