The genetic influence on the development of non-CF bronchiectasis is the subject of ongoing research, often on the role of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most common mutation of this gene, ΔF508 (F508del), is associated with severe CF (see Chapter 44). Numerous other mutations have been identified and associated with a milder clinical phenotype. As a consequence, late first presentation of CF has been described in patients who would otherwise have been considered to have idiopathic non-CF bronchiectasis. It is now recognized that mutations of the CFTR gene are more frequently observed in patients with bronchiectasis and a normal sweat chloride test than in the general population. Studies show that the spectrum of CFTR genotypes is associated with a continuum of CFTR dysfunction in the airways. Phenotypes range from patients with bronchiectasis, normal sweat test, and no other features suggestive of CF to those with classic CF. Also, some evidence suggests the CFTR mutations are associated with non-CF bronchiectasis and rheumatoid arthritis. Therefore, CFTR dysfunction can be identified as a cause of bronchiectasis in patients previously diagnosed with idiopathic non-CF bronchiectasis, but without fulfilling the diagnostic criteria for CF. How this affects patient management is currently unknown.

Establishing a cause for bronchiectasis depends on an accurate recollection of events by patients, making it difficult to establish a direct cause and effect in most patients. Nonetheless, an infective insult undoubtedly plays a role in establishing and maintaining the pathologic changes seen in bronchiectasis. This is demonstrated by the falling incidence since the widespread use of antibiotic therapy and immunizations in childhood. The role of infection is further emphasized by the association between the immune defects, and therefore increased susceptibility to infection, and the development of bronchiectasis.

The “vicious cycle” hypothesis of bronchiectasis suggests an initial failure or overwhelmed host defenses, leading to a host-mediated chronic inflammatory response, which in turn causes new or further impairment of mucociliary clearance and defenses, amplifying the problem. This interaction between chronic infection and excessive inflammation, which is predominantly neutrophilic, ensures ongoing damage to the airways and the development and maintenance of the features seen in bronchiectasis. Inflammatory mediators such as the neutrophil chemoattractant interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α) are found in bronchial mucosal biopsies and secretions from bronchiectatic airways, in addition to tissue neutrophilia. This initiation of the inflammatory reaction results in the recruitment of phagocytes, dendritic cells, and lymphocytes, which contribute to the adaptive response (Figure 45-2).

Figure 45-2 Infectious inflammatory cycle of bronchiectasis. Damage to airway results in impaired mucociliary clearance, leading to bacterial colonization, which stimulates neutrophilic inflammation. This not only damages the tissues further, but also disturbs the local immune status, resulting in establishment and maintenance of colonization. Neutrophilic proteinases damage immunoglobulins, reduce antibacterial properties, reduce ciliary beat frequency, and damage airway epithelium, all leading to increased bacterial adherence and retention.

Clinical Features

The severity of clinicopathologic events varies widely in patients with bronchiectasis. At the milder end of the spectrum, patients may have occasional exacerbations, with little or no intervening sputum production. Others have frequent exacerbations with chronic production of purulent sputum, even in the stable state. Symptoms can include hemoptysis, especially during exacerbations, and breathlessness, characterized by mild to moderate airflow obstruction, lethargy, and reduced health status. Hemoptysis may be only a minor problem, although erosion of mucosal neovascular arterioles during an acute exacerbation can result in massive hemoptysis. Quantitative analysis of HRCT scanning in bronchiectasis shows that the airflow obstruction is primarily linked to disease of small and medium-sized airways and not to bronchiectatic abnormalities in large airways, emphysema, or retained endobronchial secretions. Nonspecific chest pain varying in severity is also reported with increased frequency in bronchiectatic patients.

Clinical Signs

Finger (digital) clubbing has long been recognized as a sign of chronic suppurative lung disease. Despite previous reports of being frequently encountered in bronchiectasis, clubbing is much less common in more recent studies, perhaps because of a lower threshold for diagnosis of bronchiectasis. Studies report that the prevalence of clubbing is 1% to 2%, both in patients who develop symptoms as adults or in childhood and in adult patients. Overall, this suggests that finger clubbing is now seen only in a minority of patients with non-CF bronchiectasis.

The characteristic clinical finding in bronchiectasis is coarse crackles heard on auscultation, consistently reported in up to 73% of patients in more recent studies. Interestingly, an in-depth study of the phenotypes of bronchiectasis found the frequency of crackles to be much less in patients with adult onset of the symptom of chronic productive cough than in those with childhood onset of symptoms (20% vs. 64%). This difference was also associated with a greater amount of sputum production in the childhood-onset group. The crackles typically heard in bronchiectasis occur in the early and middle phases of inspiration, fading by the end of inspiration. Crackles also are usually present at expiration, which differentiates these from the finer crackles in alveolitis or chronic obstructive pulmonary disease (COPD). Although crackles are profuse, this may be reduced with coughing and expectoration. The location and extent of the crackles on physical examination, however, does not necessarily relate to the extent or area of distribution of bronchiectasis on the CT scan.

Diagnosis and patient assessment

Radiology

Chest radiography is often the first imaging modality used to investigate patients with suspected bronchiectasis. However, radiographs are insensitive as a diagnostic tool for bronchiectasis and suggest the diagnosis in less than 50% of cases in some studies. There is also little evidence for the use of chest radiographs in monitoring patients with bronchiectasis with no change in symptoms.

HRCT is the radiologic modality of choice for establishing the diagnosis of bronchiectasis, although its reported sensitivity and specificity vary. It is difficult to assess fully the accuracy of HRCT in diagnosing all patients with bronchiectasis, but it is believed to be highly specific for the diagnosis of moderate or severe disease. However, the features of early bronchiectasis with bronchial wall thickening are also seen in other conditions (e.g., COPD, asthma), suggesting its specificity is less for frank bronchiectasis. Furthermore, a comparison of thin-section CT with bronchography demonstrated that although bronchial wall thickening is often seen, bronchography shows this is not always bronchiectatic in origin. The increasing use of multi-detector CT scanners, which allow for greater variance in section thickness compared to standard HRCT (sections obtained only at 10-mm intervals), may lead to improved detection of bronchiectasis, although this has yet to be assessed for early disease. However, this must be weighed against an increased radiation burden, and at present, standard HRCT remains the recommended investigation for the diagnosis of bronchiectasis.

Blood Tests

Inflammatory markers include white blood cell (WBC) count, neutrophil count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) and can be used as nonspecific tests of disease activity and exacerbation severity. These tests can also be used to guide the need for and response to antibiotics in the absence of changes in clinical state or symptomatology of bronchiectatic patients (Box 45-2).

Immunoglobulins

Immunoglobulins (IgA, IgG, and IgM) are often elevated in a significant proportion of patients with bronchiectasis, which reflects chronic bronchial infection. Hypogammaglobulinemia as a recognized cause of bronchiectasis and antibody deficiency or an inadequate antibody response has been reported in 8% of patients in a large study into causative factors in bronchiectasis. This supports the need for antibody levels (IgA, IgG, IgM) to be checked in patients because they may influence treatment. The role of IgG subclasses is less clear because normal ranges for each subclass have been difficult to establish, and absence or deficiency of a subclass can be found in otherwise healthy individuals, as can IgA deficiency. The inability to produce a response to immunization with a polysaccharide antigen despite normal levels of serum immunoglobulin also suggests a causative but specific immunodeficiency.

Current guidelines recommend that evaluation of antibody deficiency in bronchiectasis should include a universal or targeted assessment of a specific baseline antibody response to peptide and polysaccharide antigens. Routinely, tetanus toxoid, Streptococcus pneumoniae and Haemophilus influenzae type B are used. If these are low, immunization should occur with the appropriate antigen and levels should be remeasured approximately 21 days later. Whether a response affects the subsequent clinical course remains unknown, and in some cases seems illogical, especially as the H. influenzae lung infections are nontypeable H. influenzae, not type B.

Allergic bronchopulmonary aspergillosis (ABPA) has been recognized as a cause of bronchiectasis, usually affecting atopic patients and caused by an allergy to Aspergillus species. The proximal bronchiectasis, usually affecting the upper lobes, associated with Aspergillus is IgG and type 3 immune reaction–related. When ABPA is clinically suspected, elevated total blood eosinophils and IgE suggest an allergic response. Specific IgE in addition to precipitating IgG to Aspergillus should be checked.

Rheumatoid factor (RF) is also found to be elevated in some patients in isolation and is a nonspecific finding. However, high RF values can be important in some patients, related to a true arthritic etiology and small airways disease. Nonspecific arthralgia can also be a feature of the exuberant inflammatory reaction related to airway colonization. Treatment of the arthritis or bacterial load can lead to improvement in the related feature.

Alpha₁-antitrypsin levels should be guided by clinical suspicion of bronchiectasis, as should genetic testing for CF or its variants (Box 45-2).

Mucociliary Function

Mucociliary function is assessed in adult patients with suspected primary ciliary dyskinesia (PCD). This needs consideration in patients with a history of chronic rhinitis, sinusitis, otitis media, neonatal respiratory symptoms, or situs inversus viscerum (a feature of only 50% of patients with PCD). Male infertility and subfertility in females are also features. PCD is best assessed using the saccharin method or nasal nitric oxide measurements as first-line investigations. Cilia can be obtained for direct examination in patients who require further investigation when these initial investigations are abnormal, although secondary abnormalities can be found in the nasal and bronchial tissues, especially in the patient with chronic infection in the region tested.

Neutrophil Function

Neutrophil-dominant inflammation is a central feature in bronchiectasis. Neutrophils aggregate quickly at the site of infection. Phagocytosis occurs when the neutrophil moves in response to chemotactic stimuli to the site of bacterial colonization or infection. In particular, leukotriene B₄ (LTB₄) and IL-8 are major chemoattractants identified, with IL-8 playing a crucial role during acute exacerbations.

The granule proteins of the neutrophil release antibacterial proteins and cytolytic enzymes on activation. Excessive degranulation and activity of cytolytic enzymes such as myeloperoxidase and elastase have been implicated most in host tissue damage and thus may be central to the establishment or amplification of the vicious cycle. The neutrophils also produce reactive oxygen species (ROS) directed at bacterial killing. The release of uncontrolled ROS by neutrophils, however, may also lead to damage to the surrounding tissues, again exacerbating the lung-destructive process. With the genetic defect of chronic granulomatous disease, patients develop a variety of inflammatory complications, including bronchiectasis, as a result of an exaggerated inflammatory response; are unable to produce ROS; and manifest recurrent life-threatening bacterial infections and granuloma formation.

Tests of neutrophil function are not routinely performed in patients with bronchiectasis. However, some studies of immune function have shown oxidative burst to be lower in patients with bronchiectasis. The significance of this abnormality remains to be identified.

Sputum Microbiology

An assessment of lower respiratory tract microbiology is imperative in the investigation and management of bronchiectasis. Table 45-1 summarizes the most common organisms isolated from the respiratory tract and their frequency in adults with bronchiectasis.

Table 45-1 Organisms Isolated in Bronchiectasis

Organism	Frequency
Haemophilus influenzae	14%-35%
Pseudomonas aeruginosa	9%-31%
Staphylococcus aureus	0%-14%
Streptococcus pneumoniae	2%-13%
Moraxella (Branhamella) catarrhalis	0%-20%
Possibly “nonpathogenic organisms” Corynebacterium spp., Neisseria spp., coagulase-negative Staphylococcus, β-hemolytic Streptococcus	5%-60%

Bronchiectasis is associated with frequent bacterial colonization of the airway. As such, patients, even in the stable state, often produce sputum daily as part of the host defense response. Sputum may be mucopurulent to purulent in appearance, dependent on the neutrophil content. Development or increasing purulence of sputum is often indicative of a bacterial exacerbation. Purulent sputum color can be graded visually and is associated with activity of the underlying markers of bronchial inflammation, such as myeloperoxidase, IL-8, and leukocyte elastase. These factors are central in the ongoing neutrophil-derived inflammation, which, when overexuberant or ineffective, can impair even the competence of lung defenses. Patients with purulent sputum are more frequently found to be colonized than those with persistently mucoid sputum.

The role of quantitative bacterial culture has been important in establishing increased airway inflammation and exacerbation in patients with chronic sputum production. An increase in the bacterial load of more than 10⁶ colony forming units (CFUs) is associated with increasing airway neutrophils and inflammation, with a reduction in bacterial load as the exacerbation resolves. Similarly, even in the presence of a background of 10⁶ organisms, a further increase in the load may be confirmatory of a change in the bronchiectatic patient’s clinical status, requiring intervention even in the absence of other clinical or biochemical markers.

Therefore, identification of colonizing organism is important in patients with bronchiectasis, but quantitative microbiology remains a vital tool for identifying exacerbation status and is a surrogate marker of inflammation that correlates with degree of sputum purulence. Although clinically useful, this is not routinely employed and requires further study and validation.

exacerbations

Acute Exacerbation

As discussed earlier with microbiologic identification of bronchiectasis exacerbation, presence of bacteria alone does not necessarily indicate an exacerbation requiring antibiotic therapy, in view of the prevalence of colonization in the stable clinical state. A worsening of symptoms from baseline and acute deterioration with a change in bacterial load, however, indicate the need to introduce or add further antibiotics. Box 45-3 lists other symptoms suggestive of an acute bacterial exacerbation.

A review of previous microbiology, and thus any change from the stable state, is essential before initiating antibiotic therapy, and ideally, sputum should be obtained for culture, preferably before antibiotic therapy, to guide antibiotic choice.

Recurrent Exacerbation

Patients with frequent exacerbations may require longer-term antibiotic therapy. The principle of treatment is to reduce the microbial load and thereby modulate the persistent inflammation characteristic of bronchiectasis, that is, an attempt to break the vicious cycle of bronchiectasis previously described. The aim is to improve the symptoms and subsequent poor health status and quality of life for these patients and reduce the number of exacerbations. The generally accepted cutoff for considering long-term antibiotic therapy is more than three exacerbations in 1 year. This particularly applies to patients colonized with Pseudomonas aeruginosa, which is associated with more hospital admissions, poorer quality of life, and more rapidly declining lung function.

Pseudomonas aeruginosa frequently persists in the airways of patients with bronchiectasis after its initial isolation. One feature of P. aeruginosa that enhances its ability to colonize the lungs is its ability to form biofilms. A biofilm is a community of bacterial cells irreversibly attached to a surface or each other and embedded in a matrix of extracellular polymeric substance (EPS). Existing in biofilms enhances the ability of bacteria to colonize and to evade antimicrobial therapies, thus making it difficult to eradicate these organisms from the lungs of chronically infected patients. The formation of biofilms is multifactorial, but one influential bacterial behavior is quorum sensing, a complex cell-to-cell signaling mechanism well characterized in P. aeruginosa that modulates bacterial functions, including metabolism, expression of virulence factors, and biofilm formation. This ability to regulate bacterial behavior also enhances the ability of P. aeruginosa to invade and colonize the host. Because this pathogen frequently colonizes the lungs of patients with bronchiectasis, its significance in this condition merits further investigation.

Furthermore, the clinical problems associated with P. aeruginosa may be further exacerbated by the development of antibodies that reduce bacterial killing. Studies in the 1970s and 1980s of CF patients colonized with P. aeruginosa identified a blocking factor in serum that inhibited killing of Pseudomonas, subsequently shown to be an IgG₂ subclass. Recent work supports the role of inhibitory antibodies in the ability of other bacteria to establish infection within the host. This may partly contribute to the failure of the host to control infection, and although the role of this mechanism has yet to be established in bronchiectasis, it is worthy of study. However, this ability of organisms to survive will establish ongoing inflammation as a frustrated attempt by the host to eradicate them, leading to proteolytic damage and perpetuation of the vicious cycle illustrated in Figure 45-2. For these reasons, patients should receive longer-term antibiotic therapy as appropriate, if the cycle can be broken (i.e., sputum purulence disappears).

Antibiotic Therapy

Figure 45-3 provides a decision-making algorithm for antibiotic therapy of the patient with bronchiectasis.

Figure 45-3 The degree of purulence of stable-state sputum must be considered when treating bronchiectasis exacerbation. Patients who relapse quickly or frequently (>3 times in 1 year) with mucoid or mucopurulent sputum are usually managed with short courses (10-14 days) of appropriate antibiotics but may need longer-term preventive therapy. Patients with chronic purulent sputum usually require higher-than-conventional doses of antibiotics and would have a lower threshold for consideration of long-term nebulized antibiotic therapy.

Patient with Acute Exacerbation

Prompt antimicrobial therapy is required once an acute exacerbation is identified, guided by the most up-to-date microbiology results and local guidelines. There are not randomized, placebo controlled trials evaluating the effectiveness of antibiotics in exacerbations in bronchiectasis, but in general high-dose, targeted antibiotics are required for effective treatment. The British Thoracic Society guidelines recommend that many patients with bronchiectasis should receive 14 days of antibiotics rather than the conventional dose. The antibiotics most often used for exacerbations have a broad spectrum of activity. Amoxicillin remains the initial choice for many organisms, especially in the UK, but patterns of resistance need to be recognized and management adapted appropriately. H. influenzae is usually sensitive to amoxicillin, but the production of β-lactamase or changes in penicillin-binding proteins increase resistance, and the presence of resistant strains varies from country to country. Moraxella (Branhamella) catarrhalis also produces β-lactamase. Antibiotic choices based on current UK guidelines are shown in Table 45-2, but local guidelines should be considered.

Table 45-2 Antibiotic Guidelines for Bronchiectasis Exacerbation

Organism	Antiobiotic/Dose
Streptococcus pneumoniae
β-lactamase −ve Haemophilus influenzae	Amoxicillin 500 mg three times daily orally (higher doses may be required in some patients)