Long-term treatment with oral N-acetylcysteine: affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial.

PURPOSE: To evaluate the effects of oral N-acetylcysteine (NAC), which replenishes systemic glutathione, on decreasing inflammation and improving lung function in CF airways. METHODS: A multicenter, randomized, double-blind proof of concept study in which 70 CF subjects received NAC or placebo orally thrice daily for 24 weeks. ENDPOINTS: primary, change in sputum human neutrophil elastase (HNE) activity; secondary, FEV(1) and other clinical lung function measures; and safety, the safety and tolerability of NAC and the potential of NAC to promote pulmonary hypertension in subjects with CF. RESULTS: Lung function (FEV(1) and FEF(25-75%)) remained stable or increased slightly in the NAC group but decreased in the placebo group (p=0.02 and 0.02). Log(10) HNE activity remained equal between cohorts (difference 0.21, 95% CI -0.07 to 0.48, p=0.14). CONCLUSIONS: NAC recipients maintained their lung function while placebo recipients declined (24 week FEV1 treatment effect=150 mL, p<0.02). However no effect on HNE activity and other selected biomarkers of neutrophilic inflammation were detected. Further studies on mechanism and clinical outcomes are warranted.

Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in pseudohypoaldosteronism.

BACKGROUND: Active sodium absorption is the dominant mechanism of ion transport in airway epithelium, but its role in pulmonary physiology and airway host defense is unknown. To address this question, we studied the function of airway epithelial cells and determined the frequency of pulmonary symptoms in patients with systemic pseudohypoaldosteronism, a salt-losing disorder caused by loss-of-function mutations in the genes for the epithelial sodium channel. METHODS: In nine patients 1.5 to 22 years of age who had systemic pseudohypoaldosteronism, we tested for mutations in the genes for the epithelial sodium channel, estimated the rate of sodium transport in the airway, determined the volume and ion composition of airway surface liquid, reviewed clinical features, collected laboratory data pertinent to pulmonary function, and, in three adults, measured mucociliary clearance. RESULTS: The patients with systemic pseudohypoaldosteronism had loss-of-function mutations in the genes for the epithelial sodium-channel subunits, no sodium absorption from airway surfaces, and a volume of airway surface liquid that was more than twice the normal value. The mean (+/-SE) mucociliary transport rate was higher in the 3 adult patients than in 12 normal subjects (2.0+/-0.7 vs. 0.5+/-0.3 percent per minute, P=0.009). Young patients (those five years of age or less) all had recurrent episodes of chest congestion, coughing, and wheezing, but no airway infections with Staphylococcus aureus or Pseudomonas aeruginosa. Older patients (those more than five years of age) had less frequent respiratory symptoms. CONCLUSIONS: Patients with systemic pseudohypoaldosteronism fail to absorb liquid from airway surfaces; the result is an increased volume of liquid in the airways. These results demonstrate that sodium transport has a role in regulating the volume of liquid on airway surfaces.

Clinical spectrum in homozygotes and compound heterozygotes inheriting cystic fibrosis mutation 3849 + 10kbC > T: significance for geneticists.

We describe patients inheriting cystic fibrosis (CF) mutation 3849 + 10kb > T as homozygotes or compound heterozygotes. Three unrelated homozygotes for this mutation were all pancreatic-sufficient and sweat test-negative or inconclusive. Among the compound heterozygotes, both pancreatic sufficiency and insufficiency, as well as positive and negative/inconclusive sweat test results are reported, expanding the range of clinical expression associated with inheritance of this mutation. 3849 + 10kbC > T is one of several CF mutations that can result in atypical or variant forms of CF. For geneticists, the diagnosis of variant CF has implications for recurrence risk and prognosis counseling of the families of affected individuals, and possibly for CF carrier screening in the general population.

Binding of Pseudomonas aeruginosa to respiratory epithelial cells from patients with various mutations in the cystic fibrosis transmembrane regulator.

OBJECTIVE: To determine whether there is an association between mutations of the cystic fibrosis transmembrane regulator (CFTR) and the predilection of patients with cystic fibrosis (CF) for Pseudomonas aeruginosa infection. METHOD: We quantified the adherence of P. aeruginosa PA01, labeled with sulfur 35-methionine, to epithelial monolayers derived from nasal scrapings of patients with specific CFTR mutations, and of carriers and normal subjects. RESULTS: Adherence of P. aeruginosa to epithelial cells from patients with CF was significantly greater than to cells from either carriers (t = 2.94; p = 0.009) or normal subjects (t = 3.32; p = 0.004). Adherence to epithelial cells from patients with CF who were homozygous for the delta F508 mutation ranged from 12% to 35% (mean, 23.7%) of the added inoculum, which was significantly greater than the binding to cells from patients with other mutations, which ranged from 3% to 18% (mean, 9.4%; t = 3.71; p = 0.002), from heterozygote carriers (3% to 11%; mean, 7.9%; t = 4.87; p = 0.002), or from normal subjects (2% to 10%: mean, 7.0%; t = 5.21; p = 0.002). CONCLUSION: Adherence to P. aeruginosa can be correlated with homozygosity for the delta 508 mutation; CFTR dysfunction may be one of the factors involved in the pathogenesis of pulmonary infection in CF.

Cystic fibrosis.

While the care of cystic fibrosis (CF) patients has been mainly the province of pediatricians, great improvements in the therapy and life span of CF patients often results in their transition to care by adult physicians. In this review of CF, we begin with an overview of the epidemiology and genetics of the disease, with a discussion of the recently found ion abnormalities that lead to the clinical manifestations. This is followed by a discussion of the pathophysiology. Methods of diagnosis, ranging from the gold standard, the sweat test, to recent advances based on a greater understanding of the genetics of the disease are reviewed. This is followed by a discussion of therapy primarily geared to the treatment of the respiratory complications, as they are the most common lethal factors of the disease. We point out controversies where they exist. Newer forms of therapy such as lung transplantation are discussed, and we finish with a discussion about future therapeutic modalities, some of which are being approved as the paper is in print.

Detection of three rare frameshift mutations in the cystic fibrosis gene in an African-American (CF444delA), an Italian (CF2522insC), and a Soviet (CF3821delT).

We have identified three new frameshift mutations in the CFTR gene in patients with cystic fibrosis (CF). The first one involves the deletion of an adenine nucleotide in exon 4 in an African-American patient (CF444delA), the second involves the insertion of a cytosine nucleotide in exon 13 in an Italian patient (CF2522insC), and the third results from the deletion of a thymidine nucleotide in exon 19 in a Soviet patient (CF3821delT). Each mutation is predicted to result in premature termination of the CFTR protein.