From the Department of Pediatrics, University of California, San Francisco, San Francisco, CA.
Correspondence to: Dennis W. Nielson, MD, PhD, Department of Pediatrics, University of California, San Francisco, 521 Parnassus Ave, San Francisco, CA 94143-0632; e-mail: email@example.com
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The cystic fibrosis (CF) protein forms an anion channel in epithelial cells, and the absence or defective function of this channel results in the clinical manifestations of CF. CF is an autosomal recessive disorder, and its many disease-causing mutations divide into five or six classes. There are 10 known class 3 gating mutations, the most common of which is G551D. Ivacaftor is a drug that in vitro increases open time and transepithelial chloride transport in all 10 gating mutations, but it is approved for use only in patients with the G551D mutation. We report complete normalization of sweat chloride concentration and rapid clinical improvement over 6 weeks of treatment with ivacaftor in a patient with CF with the gating mutation S549N. The findings suggest that ivacaftor should be considered for use in patients with any of the known gating mutations.
Ten known cystic fibrosis (CF) mutations result in a gating (class 3) defect in CF channel function.1 In affected cells, the channel is present and has normal conductivity but does not open. Ivacaftor increases open time, which increases transepithelial chloride transport. G551D is the most common CF gating mutation, occurring in 4% of patients. The remaining nine gating mutations affect 1% of patients. All gating mutations are associated with a severe phenotype. Ivacaftor is approved only for patients with the G551D mutation, but in vitro, it potentiates the function of all 10 gating mutations.1 We report our experience with ivacaftor in a patient with CF with the S549N gating mutation.
The patient is a 12-year-old girl with rapidly advancing CF lung disease who has the gating mutation S549N. Her second mutation, 1811+1.6kbA>G, is a severe class 1 mutation that results in no CF transmembrane conductance regulator (CFTR) protein production.2 Since diagnosis, she has been hospitalized 19 times for pulmonary exacerbations, including eight admissions (117 days) over the past 2 years. Her lung function deteriorated in spite of aggressive CF treatment (Fig 1), and in October 2012 we prescribed ivacaftor 150 mg bid. Because it was covered by public insurance, the prescription was approved and dispensed for off-label use without questions or delay.
Prior to ivacaftor, the patient’s sweat chloride level was 95 mmol. After 2 and 4 weeks of treatment, it was 19 and 20 mmol, respectively. Her productive cough cleared completely in 3 weeks. Previously unable to walk 1 block, the patient was able to engage in normal school exercise classes by 4 weeks. She changed her high-calorie, high-fat diet to a normal diet because of rapid weight gain (Table 1). Her chest radiograph and lung function improved significantly (Fig 2, Table 1). The 39% increase in FVC and 87% in FEV1 resulted in her best lung function in >3 years.
There was no change in any other medication or treatment during the course. FEF25%-75% = forced expiratory flow, midexpiratory phase.
CF is an autosomal recessive disorder that results in the absence or dysfunction of the CF anion channel in respiratory epithelia, causing abnormal transport of salt and water and leading to the respiratory problems typical of CF.3 There are five or six functional classes of mutations. Class 1 mutations result in no protein production. Class 3 mutation channels transport little chloride because the channels remain closed most of the time. The patient has severe CF, which is typical of heterozygous patients with class 1 and 3 mutations.
Ivacaftor4-6 is a first-of-its-kind drug approved by the Food and Drug Administration for patients with CF and at least one copy of the G551D mutation. Ivacaftor increases by sixfold the open time of the G551D CFTR protein. This increase in open time increases the movement of salt and water across the affected epithelium, which in patients with the G551D mutation results in an average decrease in sweat chloride concentration of 40 to 50 mmol.4-6 Ivacaftor treatment of patients with the G551D mutation also results in an average increase in FEV1 of 8.7%, a decrease in the frequency of pulmonary exacerbations and spontaneous weight gain.4-6 Improvement is sustained indefinitely, and ivacaftor accomplishes these beneficial changes without serious side effects.
Cells transfected with S549 respond to ivacaftor with a 99-fold increase in open probability that results in chloride transport equal to wild-type cells,1 and in the present patient, the in vivo response to ivacaftor was rapid and remarkable, consistent with the in vitro response of S549N.1 If the improvement in her clinical status is sustained, as it has been in patients with the G551D mutation,7 ivacaftor will have dramatically improved the course and quality of life of a 12-year-old girl with rapidly progressing and life-threatening CF lung disease.
Pharmacologic correction of mutant CFTR protein function currently offers the greatest promise for a major advance in the treatment of CF. Ivacaftor is a first-of-its-kind corrector currently available to patients with CF. Its effects in patients with the G551D mutation and now in the present patient with the S549N mutation strengthen the argument that correction of defective CFTR function is therapeutic, but the correlation of the magnitude of the sweat chloride decrease with clinical response in CF is uncertain.8 However, accumulating experience, including this case report, suggests that clinicians should consider ivacaftor treatment of all patients with CF and a gating mutation. Whether all such patients will respond well to ivacaftor remains to be demonstrated, and significant barriers to off-label use of this costly new drug likely will arise.
Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Other contributions:CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
cystic fibrosis transmembrane conductance regulator
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