Seminars in respiratory and critical care medicine
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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
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
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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Improved clinical care has led to a dramatic increase in life expectancy for people with cystic fibrosis (CF). As they live longer, people with CF are therefore developing secondary complications. Cystic fibrosis-related diabetes (CFRD) is the commonest extrapulmonary complication of CF. ⋯ Many centers are therefore using continuous glucose monitoring to refine the diagnosis and investigate real-life glycemic control. Future research will hopefully widen our understanding of the pathophysiology of CFRD and therefore the treatment options available. There are clearly some promising results suggesting the use of oral agents may prove beneficial in treating CFRD but insulin should remain the mainstay of treatment until these are further evaluated.
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Semin Respir Crit Care Med · Apr 2015
Airway clearance strategies in cystic fibrosis and non-cystic fibrosis bronchiectasis.
Many patients with cystic fibrosis (CF) and non-CF bronchiectasis present with common symptoms in clinical domains that appear to benefit from airway clearance strategies. These symptoms include chronic productive cough, retention of excessive, purulent mucus in dilated airways, impairment of normal mucociliary clearance (MCC), atelectasis, breathlessness, fatigue, respiratory inflammation, fever, infection, and airflow obstruction. Airway clearance strategies may involve singular and focused interventions for the purpose of removing secretions and improving lung recruitment and gas exchange in patients with atelectasis. ⋯ Currently, a solid evidence base does not exist for airway clearance strategies in CF and non-CF bronchiectasis, and much of airway clearance clinical practice remains in the domain of clinical expertise. The paucity of evidence is partly explained by the relatively immature research machinery in allied health care internationally but is also partly to do with inadequate or inappropriate research designs. This article aims to provide an overview of the nature of, and physiological basis for, the direct and indirect airway clearance strategies in CF and non-CF bronchiectasis with reference to the best available evidence.