Effects of gender and age at diagnosis on disease progression in long-term survivors of cystic fibrosis.

RATIONALE: Long-term survivors of cystic fibrosis (CF) (age > 40 yr) are a growing population comprising both patients diagnosed with classic manifestations in childhood, and nonclassic phenotypes typically diagnosed as adults. Little is known concerning disease progression and outcomes in these cohorts. OBJECTIVES: Examine effects of age at diagnosis and gender on disease progression, setting of care, response to treatment, and mortality in long-term survivors of CF. METHODS: Retrospective analysis of the Colorado CF Database (1992-2008), CF Foundation Registry (1992-2007), and Multiple Cause of Death Index (1992-2005). MEASUREMENTS AND MAIN RESULTS: Patients with CF diagnosed in childhood and who survive to age 40 years have more severe CFTR genotypes and phenotypes compared with adult-diagnosed patients. However, past the age of 40 years the rate of FEV(1) decline and death from respiratory complications were not different between these cohorts. Compared with males, childhood-diagnosed females were less likely to reach age 40 years, experienced faster FEV(1) declines, and no survival advantage. Females comprised the majority of adult-diagnosed patients, and demonstrated equal FEV(1) decline and longer survival than males, despite a later age at diagnosis. Most adult-diagnosed patients were not followed at CF centers, and with increasing age a smaller percentage of CF deaths appeared in the Cystic Fibrosis Foundation Registry. However, newly diagnosed adults demonstrated sustained FEV(1) improvement in response to CF center care. CONCLUSIONS: For patients with CF older than 40 years, the adult diagnosis correlates with delayed but equally severe pulmonary disease. A gender-associated disadvantage remains for females diagnosed in childhood, but is not present for adult-diagnosed females.

Ivacaftor in cystic fibrosis with residual function: Lung function results from an N-of-1 study.

BACKGROUND: Ivacaftor shows benefit in patients with cystic fibrosis (CF) and CFTR mutations associated with residual CF transmembrane conductance regulator (CFTR) function. Here we further assess the effect of ivacaftor in such patients using an N-of-1 study design. METHODS: Patients aged ≥12 years with CF with clinical or molecular evidence of residual CFTR function were randomized to 1 of 4 treatment sequences for two 4-week, double-blind crossover cycles (each divided into 2 weeks of ivacaftor treatment and placebo) followed by 8 weeks of open-label ivacaftor treatment. The primary endpoint was absolute change from cycle baseline of percent predicted forced expiratory volume in 1 s (ppFEV1) after 2 weeks of treatment with ivacaftor relative to placebo. RESULTS: Absolute change (SD) from study baseline in ppFEV1 favored ivacaftor by 2.3 (1.0) percentage points (95% credible interval, 0.4-4.1) after 2 weeks of treatment. Absolute mean change (SD) from open-label baseline (defined as day 1 of the open-label ivacaftor treatment period) in ppFEV1 after 8 weeks of treatment was 4.7 (4.2) percentage points (P<.0001). Safety of ivacaftor was consistent with that observed in prior studies. CONCLUSIONS: Ivacaftor improved lung function during the double-blind and open-label treatment periods in patients with CF and CFTR mutations associated with residual CFTR function (ClinicalTrials.gov, NCT01685801).

Urine lipoarabinomannan as a marker for low-risk of NTM infection in the CF airway.

BACKGROUND: Individuals with Cystic fibrosis (CF) are the most vulnerable population for pulmonary infection with nontuberculous mycobacteria (NTM). Screening, diagnosis, and assessment of treatment response currently depend on traditional culture techniques, but sputum analysis for NTM in CF is challenging, and associated with a low sensitivity. The cell wall lipoarabinomannan (LAM), a lipoglycan found in all mycobacterial species, and has been validated as a biomarker in urine for active Mycobacterium tuberculosis infection. METHODS: Urine from a CF cohort (n = 44) well-characterized for NTM infection status by airway cultures was analyzed for LAM by gas chromatography/mass spectrometry. All subjects with positive sputum cultures for NTM had varying amounts of LAM in their urine. No LAM was detected in subjects who never had a positive culture (14/45). One individual initially classified as NTM sputum negative subsequently developed NTM disease 657 days after the initial urine LAM testing. Repeat urine LAM testing turned positive, correlating to her positive NTM status. Subjects infected with subspecies of M. abscessus had greater LAM quantities than those infected with M. avium complex (MAC). There was no correlation with disease activity or treatment status and LAM quantity. A TB Capture ELISA using anti-LAM antibodies demonstrated very poor sensitivity in identifying individuals with positive NTM sputum cultures. CONCLUSION: These findings support the conclusion that urine LAM related to NTM infection may be a useful screening test to determine patients at low risk for having a positive NTM sputum culture, as part of a lifetime screening strategy in the CF population.