Diagnosis and treatment

Bronchiectasis should be suspected in children who present with chronic productive cough, airway obstruction, and recurrent infections. The diagnosis is made by high-resolution CT scans, which can classify the bronchiectasis as focal or diffuse, cylindrical, varicose, or saccular.

Treatment goals are to reduce the number of exacerbations and improve quality of life. Therapeutic strategies are largely derived from CF. All patients with bronchiectasis should have a microbiological examination (spontaneous/induced sputum or bronchoalveolar lavage) for routine bacterial and non-tuberculosis mycobacteria (NTM). About one-third of patients with non-CF bronchiectasis are chronically colonized with Pseudomonasaeruginosa. Patients with P. aeruginosa experience an accelerated decline in lung function and more frequent exacerbations [8]. Maintenance therapy with inhaled tobramycin has shown a microbiological benefit in two studies [1,9] but those studies were not powered to detect a clinical benefit. Antimicrobial, anti-inflammatory, airway clearance therapies, and immunization are the mainstays of therapy.

Etiology

Common variable immunodeficiency should be considered, as the age at diagnosis shows two peaks, between 6 and 10 years of age, and in young adulthood [10].

Bare lymphocyte syndrome is an autosomal recessive disorder [11] characterized by the absence of constitutive and inducible expression of major histocompatibility complex class II (MHCII) genes [12,13], which affect all cell types. An additional immune deficiency associated with pulmonary manifestations is that of Del-1 (developmental endothelial locus-1), which is an anti-adhesive factor that interferes with leukocyte-endothelial adhesion dependent on the integrin lymphocyte function-associated antigen-1 (LFA-1). Endothelial Del-1 deficiency increases LFA-1-dependent leukocyte adhesion and transmigration into the lungs, leading to excessive neutrophilic lung inflammation and bronchiectasis [14].

Post-infectious bronchiectasis secondary to NTM may occur in children with CF or HIV infection and in middle-aged Caucasian women without pre-existing conditions [15]. Of interest, in one study 36% of these females carried mutations in the CF transmembrane regulator (CFTR) gene [16].

Diagnosis

Primary ciliary diskenesia (PCD) is characterized by bronchiectasis, rhinosinusitis, ear infections, and infertility. Approximately one-half of the patients with PCD have situs inversus totalis or heterotaxy [17]. Eight genes have been linked with PCD: two outer dynein arm (ODA) genes, intermediate chain (DNAI1) and heavy chain (DNAH5), have been found to be mutated in approximately 30-38% of affected families [18-21]. Mutations in other ODA genes (TXNDC3 and DNAI2) have been noted in a small fraction (approximately 2%) of PCD patients [22]. Lately, mutations in ktu, which is required for the dynein complex assembly, have been described in approximately 12% of PCD patients with defects in both the ODA and inner dynein arm (IDA) [23]. Recently, mutations in radial spoke head protein genes RSPH9 and RSPH4A have been shown to cause central-microtubular-pair abnormalities in seven consanguineous Pakistani families in the UK [24]. Digital high-speed videomicroscopy has been used to detect more subtle abnormalities in ciliary beat pattern and has demonstrated that some of these patterns are associated with specific ultrastructural defects: immotile or limited flickering for ODA defects; low-amplitude stiff beat for isolated IDA defects or radial spoke defects; and circular, whip-like beat for central microtubular defects such as transposition [25]. The nasal nitric oxide method was shown to be a bona fide diagnostic test, as in PCD nasal and exhaled nitric oxide values are lower than normal, for reasons that are still unclear [26].

Treatment

There is no evidence base or consensus on the treatment of non-CF bronchiectasis [27]. Anwar et al. [28] recently reported the efficacy of long-term, oral, low-dose azithromycin in non-CF bronchiectasis patients. Beneficial effects were demonstrated on exacerbation frequency, sputum microbiology, FEV1 (forced expiratory volume in 1 second) testing, and sputum volume. This therapy was recommended for the management of difficult-to-control bronchiectasis. The mechanism of action of azithromycin is not fully elucidated, but studies suggest potential immunomodulatory effects. Azithromycin significantly reduces bronchoalveolar lavage neutrophilia and interleukin-8 mRNA [29]. It is also known to have prokinetic effects on the gut and has been associated with lower levels of aspiration markers. The anti-pseudomonal effect of azithromycin may represent an inhibitory effect on quorum sensing (a phenomenon whereby the accumulation of signaling molecules enables a single cell to sense the number of bacteria according to the local density of their population), biofilm formation, production of immunostimulatory exoproducts, and the inflammatory response to this organism [30].

There is an ongoing debate about the efficacy of inhaled corticosteroids in CF and non-CF bronchiectasis [31]. Mucoactive agents such as hypertonic saline 7% are beneficial in patients with CF [32]. Few reports are available on hypertonic saline in non-CF bronchiectasis. Mannitol in a dry powder inhaler has been used as a hyperosmolar stimulus to increase mucociliary clearance in bronchiectatic subjects [33].

Two case reports documented the usefulness of short-term use of dornase alfa in treating PCD [34]. As DNAH5 mutations in PCD patients are nonsense mutations, pharmacogenetic therapies such as PTC124 that are designed to read through premature stop codons may potentially correct the primary defect in these PCD patients.

Allergic bronchopulmonary aspergillosis (ABPA) treatment involves long-term attenuation of the inflammatory and immunological activity with corticosteroids and reduction of the antigen burden from fungal colonization with antifungal agents. High-dose intravenous pulse methylprednisolone was found to be an effective treatment for ABPA in CF with relatively minor side effects [35]. Omalizumab, a humanized monoclonal antibody directed against IgE, has a potential role as adjuvant therapy for CF patients that are corticosteroid-dependent [36].

Prognosis

Lung function usually stabilizes in children with non-CF bronchiectasis [27] if diagnosed early and a consequent long-term treatment plan is followed. Surgery and lung transplantation are rarely required for non-CF bronchiectasis.