Seminars in respiratory and critical care medicine
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Semin Respir Crit Care Med · Apr 2015
ReviewLung transplantation for cystic fibrosis: results, indications, complications, and controversies.
Survival in patients with cystic fibrosis (CF) has improved dramatically over the past 30 to 40 years, with mean survival now approximately 40 years. Nonetheless, progressive respiratory insufficiency remains the major cause of mortality in CF patients, and lung transplantation (LT) is eventually required. Timing of listing for LT is critical, because up to 25 to 41% of CF patients have died while awaiting LT. ⋯ Determining which patients are candidates for LT is difficult, and survival benefit remains uncertain. In this review, we discuss when LT should be considered, criteria for identifying candidates, contraindications to LT, results post-LT, and specific complications that may be associated with LT. Infectious complications that may complicate CF (particularly Burkholderia cepacia spp., opportunistic fungi, and nontuberculous mycobacteria) are discussed.
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Semin Respir Crit Care Med · Apr 2015
ReviewFungi in cystic fibrosis and non-cystic fibrosis bronchiectasis.
Bronchiectasis is a pathologic bronchial dilatation with loss of function that can result from multiple inflammatory and infectious injuries to the conducting airways of the lung. Molds, particularly the filamentous fungus Aspergillus fumigatus, have been implicated as a common cause of both cystic fibrosis (CF) and non-CF bronchiectasis, the latter primarily in patients with severe asthma. The pathogenesis of mold-associated bronchiectasis is usually due to atopic sensitization to mold allergens in the presence of active chronic endobronchial fungal infection with host innate and adaptive immune deviation to a Th2-dominated inflammation, a condition known as allergic bronchopulmonary aspergillosis (ABPA) (or allergic bronchopulmonary mycosis if a non-Aspergillus mold is implicated). Diagnostic criteria of ABPA continue to evolve, while treatment relies upon downregulation of the allergic inflammatory response with immunomodulatory agents and antifungal pharmacotherapy.
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Semin Respir Crit Care Med · Apr 2015
ReviewGenotypes and phenotypes in cystic fibrosis and cystic fibrosis transmembrane regulator-related disorders.
Cystic fibrosis (CF) is characterized by remarkable variability in severity, rate of disease progression, and organ involvement. In spite of the considerable amount of data collected on the relationship between genotype and phenotype in CF, this is still a challenging matter of debate. Barriers to the interpretation of this connection are the large number of mutations in the CF transmembrane regulator (CFTR) gene, the difficulties in attributing several of them to a specific mode of dysfunction, and a limited number of the almost 2,000 mutations so far detected, which have been clinically annotated. ⋯ The phenotype variability extends to conditions, named CFTR-related disorders, which are connected with CFTR dysfunction, but do not satisfy diagnostic criteria for CF. The current level of knowledge does not allow use of the CFTR genotype to predict individual outcome and cannot be used as an indicator of CF prognosis. This might change with the development of treatments targeting specific mutations and possibly capable of changing the natural history of the disease.
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Semin Respir Crit Care Med · Apr 2015
ReviewCystic fibrosis transmembrane conductance regulator modulators: the end of the beginning.
Cystic fibrosis (CF) represents one of the success stories of modern medicine with sustained incremental increases in the survival from one of childhood death to one of adult survival into the middle decades over the past 30 years. Improving survival has focused on multidisciplinary management centered on treating the consequences of this genetic disease. It has been firmly established for more than 20 years that mutations in the CF transmembrane conductance regulator (CFTR) gene result in a defective protein that normally functions as a chloride channel on epithelial cell surfaces. ⋯ This review highlights the evidence to date on efforts to modulate CFTR and restore robust functional protein to the cell surface. This approach has now led to the licensing of one CFTR potentiator, which has been shown to have significant clinical improvements in a subset of CF patients. This success represents the beginning for CFTR modulation and further research is ongoing which aims to broaden the applicability of these techniques.
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Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder of cilia structure, function, and biogenesis leading to chronic infections of the respiratory tract, fertility problems, and disorders of organ laterality. The diagnosis can be challenging, using traditional tools such as characteristic clinical features, ciliary function, and ultrastructural defects and newer screening tools such as nasal nitric oxide levels and genetic testing add to the diagnostic algorithm. There are 32 known PCD-causing genes, and in the future, comprehensive genetic testing may screen young infants before developing symptoms, thus improving survival. ⋯ As with cystic fibrosis (CF), standardized care at specialized centers using a multidisciplinary approach likely improves outcomes. In conjunction with the CF foundation, the PCD foundation, with experienced investigators and clinicians, is developing a network of PCD clinical centers to coordinate the effort in North America and Europe. As the network grows, clinical care and knowledge will improve.