Genetics of CFTR and male infertility.

Cystic fibrosis (CF) is a rare autosomal-recessive disorder manifested as multisystem organ dysfunction. The cystic fibrosis transmembrane conductance regulator (CFTR) protein functions as an ion transporter on the epithelium of exocrine glands, regulating secretion viscosity. The CFTR gene, encoded on chromosome 7, is required for the production and trafficking of the intact and functional CFTR protein. Literally thousands of human CFTR allelic mutations have been identified, each with varying impact on protein quality and quantity. As a result, individuals harboring CFTR mutations present with a spectrum of symptoms ranging from CF to normal phenotypes. Those with loss of function but without full CF may present with CFTR-related disorders (CFTR-RDs) including male infertility, sinusitis, pancreatitis, atypical asthma and bronchitis. Studies have demonstrated associations between higher rates of CFTR mutations and oligospermia, epididymal obstruction, congenital bilateral absence of the vas deferens (CBAVD), and idiopathic ejaculatory duct obstruction (EDO). Genetic variants are detected in over three-quarters of men with CBAVD, the reproductive abnormality most classically associated with CFTR aberrations. Likewise, nearly all men with clinical CF will have CBAVD. Current guidelines from multiple groups recommend CFTR screening in all men with clinical CF or CBAVD though a consensus on the minimum number of variants for which to test is lacking. CFTR testing is not recommended as routine screening for men with other categories of infertility. While available CFTR panels include 30 to 96 of the most common variants, complete gene sequencing should be considered if there is a high index of suspicion in a high-risk couple (e.g., partner is CFTR mutation carrier). CF treatments to date have largely targeted end-organ complications. Novel CFTR-modulator treatments aim to directly target CFTR protein dysfunction, effectively circumventing downstream complications, and possibly preventing symptoms like vasal atresia at a young age. Future gene therapies may also hold promise in preventing or reversing genetic changes that lead to CF and CFTR-RD.

Improved pulmonary and growth outcomes in cystic fibrosis by newborn screening.

BACKGROUND: Newborn screening for cystic fibrosis (CF) is effective in improving long-term growth outcomes. However, there is conflicting evidence that early diagnosis maintains normal pulmonary function. Our goal was to determine if newborn screening results in improved longitudinal growth and maintenance of normal pulmonary function. METHODS: A retrospective study of individuals with CF born in Connecticut between 1983 and 1997 was conducted by medical record and CF Foundation Registry review. Growth, pulmonary function and bacterial acquisition/colonization data, from diagnosis through July 1, 2005, were compared in those diagnosed by newborn screen (n = 34) to those diagnosed by sweat test after symptom appearance (n = 21). RESULTS: Screened individuals demonstrated greater weight and height for age at diagnosis (P = 0.01 and 0.01) and through 15 years of age (P = 0.0002 and 0.01). Body mass index was higher in screened individuals (21 vs. 18 kg/m(2)) at 15 years of age (P = 0.01). At 15 years of age, screened individuals had a clinically higher forced expiratory volume in 1 second (FEV(1)) and forced vital capacity (FVC; 90% and 104% predicted) than non-screened individuals (74% and 91% predicted; P = 0.08 and 0.10). Over a 9-year period, from ages 6 to 15, percent predicted FEV(1) and FVC increased by 4% and 13% in screened individuals; and declined by 14% and 5% respectively in non-screened individuals (P = 0.01 and 0.02). Acquisition/colonization of Pseudomonas aeruginosa was similar between groups (P = 0.23). CONCLUSIONS: In this CF cohort, individuals diagnosed by newborn screening have improved growth and preservation of normal pulmonary function without increased risk of Pseudomonas aeruginosa colonization.

The influence of pulmonary function testing on the management of asthma in children.

OBJECTIVE: To assess how often in a single encounter that pulmonary function tests (PFTs) influenced management decisions in children with asthma, beyond what was obtained from history and physical examination alone. STUDY DESIGN: Children with asthma (n = 367, age 4 to 18 years) performed spirometry before clinical evaluation. Physicians and nurse practitioners in the outpatient pulmonary office evaluated the children and made initial treatment recommendations before reviewing the spirometry results. Any changes based on the test results were documented. RESULTS: Spirometry was abnormal in 45% of the visits, related to underlying asthma severity but not to clinical findings. PFT results changed management decisions in 15% of visits. This frequency was not affected by the patient's age, disease severity, symptom control, or exam findings. When spirometry did not change treatment decisions, the provider was more likely to maintain therapy (58%) than to increase (17%) or decrease (24%) therapy. In contrast, when spirometry did change treatment decisions, the provider was more likely to increase therapy (75%) than to maintain (20%) or decrease (5%) therapy. CONCLUSION: Without PFTs, providers often overestimated the degree of asthma control. This incorrect assessment could have resulted in suboptimal therapy.

Airway physiology, autogenic drainage, and active cycle of breathing.

Airway clearance techniques are used to aid in mucus clearance in a variety of disease states. Autogenic drainage and active-cycle-of-breathing technique are 2 such modalities that rely heavily on basic airway physiology to enhance clearance. In this review I discuss the equal pressure point, huffing, and asynchronous and collateral ventilation, and review the literature and theory regarding autogenic drainage and active cycle of breathing. Selection of airway clearance techniques is discussed in the light of evidence-based medicine.