Non-cystic fibrosis bronchiectasis: review and recent advances
Meyer Children's Hospital, Rambam Medical Center, Haifa 31092, Israel
The electronic version of this article is the complete one and can be found at: http://F1000.com/Reports/Medicine/content/1/67
Bronchiectasis is an abnormal dilatation of bronchi and bronchioles associated with repeated cycles of airway infection and inflammation. This review will focus on non-cystic fibrosis bronchiectasis in children, with regard to etiology, diagnosis, treatment options, and recent advances.
Introduction and context
Although the frequency of childhood bronchiectasis has been reduced in western countries, it remains a common problem in poorer countries and among certain demographic groups (native Alaskan children in the USA, in Pacific Islanders, and in New Zealand Maori). Additionally, non-cystic fibrosis (non-CF) bronchiectasis is now being identified more often by high resolution computed tomography (CT).
Bronchiectasis results when inflammatory and infectious damage to the bronchial and bronchiolar walls leads to a vicious cycle of airway injury  and airway and lung parenchyma destruction . Sputum analyses and bronchial mucosal biopsy specimens from bronchiectasis patients have shown increased concentrations of elastase , interleukin-8 , tumor necrosis factor , and prostanoids . Hence, anatomic factors, chronic infection and inflammation, and host defense all play important, yet poorly understood, roles in the development of bronchiectasis .
Bronchiectasis is categorized as focal or diffuse. All patients with focal bronchiectasis require bronchoscopy and/or high resolution CT to evaluate the airways, while patients with diffuse bronchiectasis should be assessed for underlying systemic abnormalities. Focal bronchiectasis can be secondary to airway obstruction such as bronchial atresia/malacia/stenosis, vascular ring/sling, following foreign body aspiration, extrinsic compression, airway tumors, necrotizing pneumonia, or congenital parenchymal malformation. The etiologies of diffuse non-CF bronchiectasis are presented in Table 1. Even after thorough evaluation, diagnosis remains idiopathic in the majority of patients. The relative frequency of each etiology varies, but idiopathic, post-infectious, and immune deficiencies are probably the commonest etiologies.
Etiologies of non-cystic fibrosis bronchiectasis
|Idiopathic||Should be classified after a thorough evaluation|
|Post-infection||Post measles, pertussis, adenovirus, tuberculosis||Decreasing frequency in western countries. Non-progressive bronchiectasis|
|Genetic disease||CF, primary ciliary dyskenesia*, alfa 1 anti-trypsin (AAT) deficiency||Atypical CF has been increasingly recognized. AAT causes bronchiectasis only in adulthood|
|Aspiration/ gastroesophageal reflux||Impaired gag reflex, impaired esophageal motility, esophageal atresia + fistula, convulsions, cleft palate||Barium swallow, pH metry, and swallowing mechanisms should be evaluated|
|Immune deficiency||Severe combined immune deficiency, Omenn's syndrome, hypogammaglobulinemia, hyper-IgE chronic granulomatous disease, common variable hypogamma*, ataxia telangiectasia, bare lymphocyte syndrome*, DEL1*, Wiskott-Aldrich syndrome, HIV, immunosuppressive treatment [corticosteroids, irradiation, organ and bone marrow transplants, biologic agents (for example, infliximab, etanercept)]||This group has increased due to descriptions of new immune deficiencies and increased iatrogenic immunodeficiency. Refer for immunological evaluation|
|Collagen vascular disorders||Systemic lupus erythematosus, rheumatoid arthritis|
|Inflammatory bowel diseases||Ulcerative colitis, Crohn's disease|
|Miscellaneous||Sarcoidosis, Young syndrome, Mounier-Kuhn syndrome, Ehler-Danlos syndrome, Marfan syndrome, yellow nail syndrome|
|ABPA||CF, asthma||New treatment options*|
*See text for recent advances. AAT, alfa 1 anti-trypsin; ABPA, allergic bronchopulmonary aspergillosis; CF, cystic fibrosis; DEL-1, developmental endothelial locus-1.
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 . 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.
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 .
Bare lymphocyte syndrome is an autosomal recessive disorder  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 .
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 . Of interest, in one study 36% of these females carried mutations in the CF transmembrane regulator (CFTR) gene .
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 . 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 . 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) . 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 . 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 . 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 .
There is no evidence base or consensus on the treatment of non-CF bronchiectasis . Anwar et al.  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 . 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 .
There is an ongoing debate about the efficacy of inhaled corticosteroids in CF and non-CF bronchiectasis . Mucoactive agents such as hypertonic saline 7% are beneficial in patients with CF . 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 .
Two case reports documented the usefulness of short-term use of dornase alfa in treating PCD . 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 . Omalizumab, a humanized monoclonal antibody directed against IgE, has a potential role as adjuvant therapy for CF patients that are corticosteroid-dependent .
Lung function usually stabilizes in children with non-CF bronchiectasis  if diagnosed early and a consequent long-term treatment plan is followed. Surgery and lung transplantation are rarely required for non-CF bronchiectasis.
Implications for clinical practice
Non-CF bronchiectasis in childhood is still a common cause of childhood morbidity. Identifying and treating the underlying disease is essential to prevent the progression of bronchiectasis. New diagnostic tools such as the nasal nitric oxide test, immunological tests for bare lymphocyte syndrome and DEL-1, and culture for NTM, may aid in specific diagnosis. Therapeutic strategies are largely derived from CF bronchiectasis and include antimicrobial, anti-inflammatory, and airway clearance therapies, and immunization. Pulse steroids and omalizumab may offer a better control for ABPA. Azithromycin, as an immuno-modulator agent, should be considered in patients with severe bronchiectasis. The role of new mucoactive agents should be further explored.
The authors declare that they have no competing interests.
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