Pathogenesis of bronchiectasis

Ciliary function is impaired by cigarette smoke, bacterial toxins, and viral antigens that cause the shedding of ciliated respiratory cells and disruption to the MCE. Damage to the epithelial cells can take several weeks to repair, even after the common cold. Impaired ciliary function results in a build‐up of mucus within the dilated bronchi. Bacteria and viruses get trapped in the mucus, multiply rapidly and colonise the lung, causing persistent infection and chronic mucus production. Bacteria prevent the healing of the damaged respiratory epithelium by binding to, and disrupting, the functioning of certain epithelial receptors: fibronectin, which is important in cell migration, and integrin, which is necessary for the adhesion of cells.

Bronchiectasis results in inflammation of the airways and airflow obstruction. Bacterial infection results in the outpouring of inflammatory cytokines, including interleukin 8 and interleukin 6, which recruit neutrophils through interaction with the chemokine receptor CXCR1. Proteases from bacterial pathogens, for example, Pseudomonas aeruginosa, cleave and disable CXCR1, resulting in a reduction in neutrophil recruitment, ineffective neutrophil function, and failure of bacterial killing. Neutrophils release proteases and reactive oxygen intermediates, such as hydrogen peroxide, as well as several inflammatory cytokines. High levels of human neutrophil peptides, called alpha defensins, are found in the sputum of patients with bronchiectasis. These impair neutrophil phagocytosis and reduce antimicrobial activity. Anti‐proteases, such as alpha ‐1 antitrypsin, restore CXCR1 and enhance bacterial killing. Increased neutrophil elastase activity results in mucus which is more viscous and harder to clear. Collagen deposition in the bronchial wall causes permanent distortion and dilatation of major bronchi.

Aetiology of bronchiectasis

Bronchiectasis that results from infection and inflammation is referred to as non‐cystic fibrosis bronchiectasis, thus differentiating it from the severe bronchiectasis that occurs in cystic fibrosis. The prevalence of bronchiectasis is unknown as it can arise from several different causes. The prevalence of bronchiectasis has declined in the developed world but is a common cause of morbidity and mortality in developing countries. Bronchiectasis is commoner in females compared to males, perhaps because of the higher prevalence of rheumatoid arthritis and related conditions in the female population. Bronchiectasis can occur after damage to the bronchial mucosa, due to immunodeficiency states which predispose to recurrent infections, abnormal ciliary function or abnormal viscosity of the respiratory secretions. Table 12.1 lists these conditions.

Bronchiectasis may be localised to a small area of the lung or be more diffuse due to generalised infection and inflammation. Localised bronchiectasis can occur after inhalation of a foreign body, such as a peanut, which traps purulent material within that segment, causing bronchial wall damage. An enlarged lymph node can compress a bronchus, resulting in bronchiectasis more distally.

Several international studies which looked at how often a specific aetiology for the bronchiectasis could be identified found a specific cause in 60–93% of patients after comprehensive tests. Severe and recurrent respiratory tract infections are the commonest cause of ciliary and bronchial wall damage, accounting for 20% of bronchiectasis. Bronchiectasis secondary to childhood infections, particularly measles and pertussis (whooping cough), was common prior to immunisation in the UK and still is a common cause of bronchiectasis in developing countries. In adults, bronchiectasis can develop after community acquired pneumonia, especially after infections with Staphylococcus aureus and Klebsiella pneumonia, although severe bronchiectasis is much less common now with prompt antibiotic treatment. Tuberculosis is still a common cause of bronchiectasis, especially in developing countries.

A heterozygous mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene may contribute to the development of diffuse bronchiectasis through dysfunction of the airway sodium and chloride channels.

Vitamin D deficiency may predispose to increased colonisation with bacteria, including Pseudomonas, and increase the frequency of exacerbations. Increased markers of neutrophilic inflammation were found in the sputum of those with bronchiectasis and vitamin D deficiency.

Recurrent aspiration pneumonia is a common cause of bronchiectasis in the elderly. The risk of aspiration pneumonia is increased in patients with reduced consciousness, for example, after a stroke, after a seizure, or when intoxicated with alcohol or other drugs. Neurological and neuromuscular conditions, such as Parkinson’s disease, multiple sclerosis, and motor neurone disease, result in impaired swallowing and aspiration, as do oesophageal diseases, such as reflux and achalasia.

Foreign body aspiration is more likely to occur in small children and the elderly. Common items aspirated include small toys, nut and seeds in children, and bones and a bolus of food in the elderly. There is usually a history of choking and coughing preceding the development of chronic symptoms, often weeks earlier. The foreign body is more likely to enter the right lung and lodge in the middle lobe. Clinical examination may reveal a monophonic wheeze. The CXR and CT thorax will be abnormal, showing signs of collapse or atelectasis. Flexible bronchoscopy may be required to remove the foreign body. In some cases, if the foreign body is lodged very far down the bronchial tree, rigid bronchoscopy under general anaesthetic, or surgery may be indicated. Post‐obstructive pneumonia can progress to bronchiectasis or to a lung abscess.

While non‐tuberculous mycobacteria (NTM) infection can result in bronchiectasis with the characteristic tree in bud appearance, bronchiectasis from a different aetiology can predispose to NTM infection, particularly with Mycobacterium avium complex (MAC). These patients are more likely to develop ABPA and aspergilloma.

Tracheobronchomalacia (Williams‐Campbell syndrome) and tracheobronchomegaly (Mounier‐Kuhn syndrome) are diffuse or segmental weaknesses of the trachea or main stem bronchi due to anatomic defects of the airways arising from a deficiency of cartilage in the fourth to sixth order bronchi. Deficient cartilage support results in airway collapse during forced exhalation. This results in inefficient clearance of respiratory secretions and predisposes to the development of bronchiectasis. The CXR will show dilated trachea and bronchi. The diameter of the trachea (measured 2 cm above the main carina) will be greater than 3 cm, the right main bronchus greater than 2.5 cm and the left main bronchus greater than 2 cm. CT thorax with expiratory views will demonstrate airway collapse and narrowing. Placement of a tracheal stent will improve symptoms by reducing airway collapse. Tracheobronchoplasty could be considered in some patients.

Connective tissue disorders, particularly rheumatoid arthritis and Sjögren’s syndrome, predispose to the development of bronchiectasis, although the exact mechanism is unknown. Symptoms of bronchiectasis occur years after the diagnosis of the underlying condition is made. In one study, the frequency of an abnormal CFTR allele was increased in patients with bronchiectasis and rheumatoid arthritis relative to patients with rheumatoid arthritis but without bronchiectasis and normal controls. Bronchiectasis is a rare complication of other connective tissue disorders, especially systemic lupus erythematosus (SLE) and Marfan’s syndrome. Bronchiectasis is also associated with Crohn’s disease, ulcerative colitis, and yellow nail syndrome. It is assumed that optimal treatment of the underlying systemic disease will prevent the deterioration of bronchiectasis, although there are no studies supporting this assumption.

Alpha 1 antitrypsin (A1AT) deficiency is associated with bronchiectasis. A1AT deficiency is discussed in Chapter 6. Adult polycystic kidney disease (APKD), which is an autosomal dominant disease, occurs because of defective cilia and ciliary protein expression of polycystin‐1 and polycystin‐2, with the formation of renal cysts. Patients with APKD are more likely to develop bronchiectasis.

Congenital hypogammaglobulinaemia and selective immunoglobulin deficiencies present with recurrent upper and lower respiratory tract infections in childhood and, if undetected, will result in bronchiectasis. Hypogammaglobulinaemia may be associated with thymoma. Common variable immunodeficiency (CVID) results in small airway changes and bronchiectasis. It is not clear whether an isolated IgG subclass deficiency, for example, IgG₂ deficiency, can result in bronchiectasis as the levels of these vary greatly in normal adults. Investigation for bronchiectasis includes measurement of IgG, IgA, and IgM with serum electrophoresis and other specialist immunology assessments as indicated. Immunoglobulin deficiencies can be managed with intravenous or subcutaneous immunoglobulin replacement therapy, vaccination as well as prompt treatment of infections.

To evaluate the patient’s response to infection, baseline specific antibody levels to tetanus toxoid and the capsular polysaccharides of Streptococcus pneumonia and Haemophilus influenza type b should be measured. If baseline levels are low, the adequacy of the humoral response should be assessed by immunisation with the appropriate vaccines and re‐measurement of antibody levels after four weeks.

Immunoglobulin deficiency can occur because of haematological malignancies, such as lymphoma and myeloma. Human immunodeficiency virus (HIV) also predisposes to recurrent bacterial infections and bronchiectasis.

Primary ciliary dyskinesia (PCD) is a rare, inherited abnormality of the cilium which will be discussed later in this chapter.

Abnormally viscid mucus, as occurs in cystic fibrosis (CF), is a cause of severe bronchiectasis and will be discussed later in this chapter.

Diagnosis of bronchiectasis

A careful history of presenting complaints, childhood infections, past medical history and family history should be taken. A meticulous clinical examination is essential. Box 12.2 lists the common symptoms and signs of bronchiectasis. Patients usually present with chronic, productive cough, recurrent chest infections, and minor haemoptysis. Information about hearing loss, sinusitis, gastrointestinal symptoms, and infertility should be ascertained. Only 2% of patients with bronchiectasis will have finger clubbing, although the majority will have coarse crackles on auscultation.

Table 12.2 lists the investigations that are routinely carried out to make a diagnosis of bronchiectasis and the investigations that should be done if PCD, immunodeficiency or CF is suspected.

The diagnosis of bronchiectasis is made on clinical history and radiological appearance. In early, mild, disease the CXR may appear normal. If the clinical presentation suggests bronchiectasis, then a high resolution computed tomography (HRCT) or multi‐detector computed tomography (MDCT) scan of the thorax should be done which will be more sensitive at detecting changes. Expiratory scans best demonstrate air trapping and mosaic attenuation.

Box 12.3 lists the characteristic radiological finding in bronchiectasis, the abnormalities typically affecting the lower lobes (Figure 12.3, Figure 12.4, Figure 12.5). Airway dilatation results in the appearance of parallel lines, referred to as tram lines, and ring shadows when the airway is seen in cross‐section. When the diameter of the airway is more than 1.5 times greater than the diameter of the adjacent blood vessel, this is termed cylindrical bronchiectasis. With severe bronchiectasis there is the formation of cysts, and this is termed cystic bronchiectasis.

Bronchiectasis predominantly affecting the upper lobes of the lungs suggests post‐tuberculous bronchiectasis or CF, whereas a middle lobe distribution is consistent with PCD (Box 12.3). A tree in bud appearance is often seen with non‐tuberculous mycobacterial infection. This is discussed in Chapter 8.

Nitric oxide (NO) levels can be measured quite simply by blowing into a NO monitor. Levels of NO are increased in patients with bronchiectasis because of airway inflammation, although raised exhaled NO is not diagnostic. Very low levels <77 nl min⁻¹ in a patient with bronchiectasis is consistent with PCD and should prompt the doctor to do ciliary studies.

Lung function tests will show obstruction, with a reduced forced expiratory volume in one second (FEV₁) and a reduced FEV₁/FVC ratio. The severity of clinical disease correlated well with HRCT changes and poor lung function in several studies. Individuals with severe bronchiectasis may develop type 1 respiratory failure, with hypoxia and normocapnia on arterial blood gas measurement.

The result of the shuttle walking test correlates well with the severity of bronchiectasis and may be of prognostic value. Shuttle walking test can be used to monitor the response to treatment and is used as an end‐point in many trials. A validated respiratory questionnaire, for example, the St. George’s Respiratory Questionnaire (SGRQ), can be used to monitor the patient’s response to treatment. The details of these investigations are discussed in Chapter 4.

Differential diagnoses of bronchiectasis

The differential diagnosis of bronchiectasis includes other conditions which cause bronchial wall dilatation. Chronic obstructive pulmonary disease (COPD) can have a similar presentation to bronchiectasis, with chronic sputum production and frequent exacerbations but with a history of cigarette smoking. A quarter of patients with alpha 1 antitrypsin deficiency (A1AT) present with daily, chronic sputum production, and the majority have radiological evidence of bronchiectasis. It is therefore recommended that testing for A1AT deficiency is carried out in patients presenting with bronchiectasis with no obvious underlying cause.

Allergic bronchopulmonary aspergillosis (ABPA), which results in proximal bronchiectasis, with dilatation of central airways, develops in patients with asthma and is caused by an allergic reaction to the fungus Aspergillus fumigatus. COPD, A1AT deficiency, and ABPA are discussed in more detail in Chapter 6. Traction bronchiectasis describes stretching and distortion of bronchi due to pulmonary fibrosis, and is discussed in Chapter 7.

Management of bronchiectasis

The management of bronchiectasis depends on the underlying cause. For example, bronchiectasis that occurs due to immunodeficiency will respond to intravenous or subcutaneous immunoglobulin therapy. However, there are several evidence‐based treatments that improve symptoms, reduce the frequency of infections, thus preventing further bronchial wall damage. The management is summarised in Box 12.4.