Clinical Pearls & Morning Reports
Published June 4, 2019
Cystic fibrosis is a recessive genetic disease that is caused by mutations in both alleles of the CFTR gene, which encodes the cystic fibrosis transmembrane conductance regulator (CFTR). The CFTR protein forms a chloride channel that is critical to efficient mucus transport. Mutations in CFTR disrupt sodium absorption, chloride secretion, and water transport, leading to the development of viscous mucus that adheres to the airway and impairs bacterial clearance. There are close to 2000 recognized CFTR mutations, and each one confers a different degree of diminished chloride ion transport. Read the latest NEJM Case Records of the Massachussetts General Hospital here.
Q: What are some of the causes of bronchiectasis?
A: Bronchiectasis is characterized by irreversible damage of the airways that results in dilatation. Many lung infections can result in the development of bronchiectasis, including those caused by Mycobacterium tuberculosis and Bordetella pertussis. Bronchiectasis may develop in patients with a history of recurrent pneumonia, particularly those with chronic aspiration. Patients with immunodeficiency syndromes are at high risk for the development of bronchiectasis. In some people, inhalation of Aspergillus fumigatus provokes a brisk allergic response that is characterized by eosinophilia and a high level of IgE antibodies. A hypersensitivity response, known as allergic bronchopulmonary aspergillosis, may ensue, leading to a cycle of bronchial inflammation, mucoid impaction, and bronchial obstruction that results in bronchiectasis.
Q: Describe features of primary ciliary dyskinesia.
A: Primary ciliary dyskinesia is a congenital, autosomal recessive disorder that is characterized by immotile or dyskinetic cilia. In addition to impaired airway clearance, fertility problems can arise in males as a result of impaired spermatozoa motility and in females as a result of impaired ciliary function in the oviduct. Primary ciliary dyskinesia can also cause left–right asymmetry. In the primitive streak of an embryo, in a region called the node, cilia on cells create “nodal flow” that controls developmental symmetry. Therefore, nodal ciliary dysfunction can produce dextrocardia, situs inversus totalis, and situs ambiguus.
A: The primary defect that is caused by the Phe508del mutation is that the CFTR protein is synthesized but misfolded, which keeps it from reaching the cell surface. This is the target of action of the drugs lumacaftor and tezacaftor. The D1152H mutation is considered to be a partial-function mutation that results in diminished ion transport. This type of mutation is the target of the drug ivacaftor, which restores partial ion transport. In 2017, the qualifying mutations for the administration of ivacaftor were expanded to include D1152H.
A: Management of cystic fibrosis is focused on a combination of airway clearance by means of mechanical and pharmacologic methods (chest physiotherapy, inhaled human recombinant dornase alfa therapy, and the administration of hypertonic saline), pancreatic-enzyme replacement in patients with pancreatic insufficiency, nutritional supplementation, suppressive antibiotic therapy (e.g., inhaled tobramycin), and early recognition of pulmonary exacerbations. With the administration of these treatments at cystic fibrosis–specific treatment centers, median survival has increased from 33.3 years (interquartile range, 31.0 to 35.1) in 2000 to 41.7 years (interquartile range, 38.5 to 44.0) in 2015.