Denufosol tetrasodium in patients with cystic fibrosis and normal to mildly impaired lung function.

RATIONALE: Intervention for cystic fibrosis lung disease early in its course has the potential to delay or prevent progressive changes that lead to irreversible airflow obstruction. Denufosol is a novel ion channel regulator designed to correct the ion transport defect and increase the overall mucociliary clearance in cystic fibrosis lung disease by increasing chloride secretion, inhibiting sodium absorption, and increasing ciliary beat frequency in the airway epithelium independently of cystic fibrosis transmembrane conductance regulator genotype. OBJECTIVES: To evaluate the efficacy and safety of denufosol in patients with cystic fibrosis who had normal to mildly impaired lung function characteristic of early cystic fibrosis. METHODS: A total of 352 patients greater than or equal to 5 years old with cystic fibrosis who had FEV(1) greater than or equal to 75% of predicted normal were randomized to receive inhaled denufosol, 60 mg, or placebo three times daily in a Phase 3, randomized, double-blind, placebo-controlled, 24-week trial. MEASUREMENTS AND MAIN RESULTS: Main outcome measures included change in FEV(1) from baseline to Week 24 endpoint and adverse events. Mean change from baseline to Week 24 endpoint in FEV(1) (primary efficacy endpoint) was 0.048 L for denufosol (n = 178) and 0.003 L for placebo (n = 174; P = 0.047). No significant differences between groups were observed for secondary endpoints including exacerbation rate and other measures of lung function. Denufosol was well tolerated with adverse event and growth profiles similar to placebo. CONCLUSIONS: Denufosol improved lung function relative to placebo in cystic fibrosis patients with normal to mildly impaired lung function. Clinical trial registered with www.clinicaltrials.gov (NCT00357279).

Variant cystic fibrosis phenotypes in the absence of CFTR mutations.

BACKGROUND: Cystic fibrosis is a life-limiting autosomal recessive disorder with a highly variable clinical presentation. The classic form involves characteristic findings in the respiratory tract, gastrointestinal tract, male reproductive tract, and sweat glands and is caused by loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR ) gene. Nonclassic forms of cystic fibrosis have been associated with mutations that reduce but do not eliminate the function of the CFTR protein. We assessed whether alteration in CFTR function is responsible for the entire spectrum of variant cystic fibrosis phenotypes. METHODS: Extensive genetic analysis of the CFTR gene was performed in 74 patients with nonclassic cystic fibrosis who had been referred by 34 medical centers. We evaluated two families that each included a proband without identified mutations and a sibling with nonclassic cystic fibrosis to determine whether there was linkage to the CFTR locus and to measure the extent of CFTR function in the sweat gland and nasal epithelium. RESULTS: Of the 74 patients studied, 29 had two mutations in the CFTR gene, 15 had one mutation, and 30 had no mutations. A final genotype of two mutations was more common among patients who had been referred after screening for common cystic fibrosis-causing mutations identified one mutation than among those who had been referred after screening had identified no such mutations (26 of 34 patients vs. 3 of 40 patients, P<0.001). Comparison of clinical features and sweat chloride concentrations revealed no significant differences among patients with two, one, or no CFTR mutations. Haplotype analysis in the two families revealed no linkage to CFTR. Although each of the affected siblings had elevated sweat chloride concentrations, measurements of cyclic AMP-mediated ion and fluid transport in the sweat gland and nasal epithelium demonstrated the presence of functional CFTR. CONCLUSIONS: Factors other than mutations in the CFTR gene can produce phenotypes clinically indistinguishable from nonclassic cystic fibrosis caused by CFTR dysfunction.

Gender differences in health-related quality of life of adolescents with cystic fibrosis.

BACKGROUND: Female patients with cystic fibrosis (CF) have consistently poorer survival rates than males across all ages. To determine if gender differences exist in health-related quality of life (HRQOL) of adolescent patients with CF, we performed a cross-section analysis of CF patients recruited from 2 medical centers in 2 cities during 1997-2001. METHODS: We used the 87-item child self-report form of the Child Health Questionnaire to measure 12 health domains. Data was also collected on age and forced expiratory volume in 1 second (FEV1). We analyzed data from 98 subjects and performed univariate analyses and linear regression or ordinal logistic regression for multivariable analyses. RESULTS: The mean (SD) age was 14.6 (2.5) years; 50 (51.0%) were female; and mean FEV1 was 71.6% (25.6%) of predicted. There were no statistically significant gender differences in age or FEV1. In univariate analyses, females reported significantly poorer HRQOL in 5 of the 12 domains. In multivariable analyses controlling for FEV1 and age, we found that female gender was associated with significantly lower global health (p < 0.05), mental health (p < 0.01), and general health perceptions (p < 0.05) scores. CONCLUSION: Further research will need to focus on the causes of these differences in HRQOL and on potential interventions to improve HRQOL of adolescent patients with CF.

Association of Medical School Pediatric Department Chairs Principles of Lifelong Learning in Pediatric Medicine.

Pediatric general and subspecialty care requires continuous effort to maintain knowledge and competencies in clinical practice. Equally important are efforts by investigators and educators to maintain knowledge and competencies in the conduct of research and training. The Association of Medical School Pediatric Department Chairs initiated a survey in July 2015 to define principles of lifelong learning in pediatric medicine and determine the approaches and strategies used by chairs to assess knowledge and competence across the care, research, and teaching missions. A total of 101 of 142 chairs (71%) completed the survey. Six of 7 proposed principles were endorsed by 84% to 96% of Association of Medical School Pediatric Department Chairs members. The focus areas included individual accountability, individually relevant activities, use of evidence-based guidelines/national standards, gaining cognitive expertise, learning as a continuous effort, affordability, and focus on individual understanding. The chairs endorsed a requirement for evidence of lifelong learning, competence, and compliance by all faculty members in clinical (n = 89 [88%]), research (n = 63 [62%]), and educational (n = 85 [84%]) practice. The survey identified the strategies to assess lifelong learning and faculty competence and compliance in clinical, research, and educational roles. Across missions, chairs endorsed an expectation for individual responsibility supplemented by formal evaluation practices and institutional and regulatory office oversight. While chairs endorsed an important role for the American Board of Pediatrics in assessing and verifying lifelong learning, knowledge, and competence in general and specialty certification, most (n = 91 [90%]) endorsed a need to revise current board requirements to better emphasize closing gaps in knowledge and using approaches that are evidence-based. This study provides the perspectives of pediatric department chairs on principles for lifelong learning and strategies and approaches used to assess faculty competence and commitment to lifelong learning across missions.

Efficiency of pulmonary administration of tobramycin solution for inhalation in cystic fibrosis using an improved drug delivery system.

STUDY OBJECTIVES: To determine whether tobramycin solution for inhalation (TSI) can be administered safely and more efficiently with a new-generation aerosol device, the AeroDose 5.5 RP inhaler (Aerogen; Mountain View, CA) than with the approved PARI LC PLUS nebulizer (PARI Respiratory Equipment; Monterey, CA) with Pulmo-Aide compressor (DeVilbiss Corp; Somerset, PA). Second, we wanted to ascertain which AeroDose-delivered tobramycin dose is equivalent to the standard 300-mg dose administered with the PARI LC PLUS. DESIGN: Open-label, randomized, multicenter, single-dose, three-period, four-treatment, active- control, crossover trial. SETTING: Nine US cystic fibrosis (CF) centers. PATIENTS: Fifty-three patients >or= 12 years of age with a confirmed diagnosis of CF, the ability to expectorate sputum, and FEV(1) of >or= 40% of predicted. METHODS: Subjects inhaled three single doses of TSI at 1-week intervals, as follows: conventional control treatment, 300 mg via the PARI LC PLUS; and two of three experimental treatments, 30, 60, or 90 mg via the AeroDose. FEV(1) was measured before and after dosing. After each dose, sputum and serum samples were collected at various intervals for 8 h, and urine was collected for 24 h to estimate lung and systemic tobramycin delivery. RESULTS: There were no significant differences between treatments in the change in FEV(1) 30 min after dosing or in the frequency of adverse events. Sputum and serum levels of tobramycin produced by the AeroDose 90-mg dose treatment approximated those achieved with the PARI LC PLUS 300-mg dose treatment. Nebulization times using the AeroDose inhaler were < 50% those of the PARI LC PLUS. CONCLUSIONS: Compared with the standard nebulizer, the AeroDose safely achieved an approximately threefold greater efficiency in the delivery of TSI to the lungs in less than half the time.

Impact of recent pulmonary exacerbations on quality of life in patients with cystic fibrosis.

OBJECTIVE: To compare the health-related quality of life (HRQOL) of people with cystic fibrosis (CF) to the general population, and to determine the relationship between HRQOL and clinical and demographic factors. DESIGN: Cross-sectional analysis of observational cohort. SETTING: Outpatient clinics of a Midwestern CF center. SUBJECTS: One hundred sixty-two subjects with CF aged 5 to 45 years. MAIN OUTCOME MEASURES: Physical and psychosocial summary scores and individual scale scores for the Child Health Questionnaire and Short Form-36. RESULTS: Compared with the general population, people with CF reported similar scores for most psychosocial measures, but lower scores for most physical measures, with the lowest scores on the general health perceptions scale. In multivariable analyses, pulmonary exacerbations in the past 6 months were strongly associated with the physical (p = 0.001) and psychosocial (p = 0.0003) scores. The physical score fell, on average, 6 points per exacerbation and the psychosocial score fell 3 points. Lung function, nutrition, 6-min walk distance, age, gender, and insurance status were not significantly associated with HRQOL in this study population. Those who declined to participate had significantly lower FEV(1) percent predicted and nutritional indexes. Our findings may not be generalizable to the entire CF population. CONCLUSION: Recent pulmonary exacerbations have a profound negative impact on HRQOL that is not explained by differences in lung function, nutritional status, or demographic factors.

Differences between adolescents' and parents' reports of health-related quality of life in cystic fibrosis.

Our objective was to determine the magnitude and direction of differences between adolescents with cystic fibrosis (CF) and their parents' reports of the adolescents' health-related quality of life (HRQOL) as measured by the adolescent and parent versions of the Child Health Questionnaire (CHQ). Sixty-two adolescents (mean age, 13.7 years; 46% female; mean forced expired volume in 1 sec, 73%) completed the 87-item adolescent form, and their parents (79% mothers; 77% working full or part time) completed the 50-item parent form of the CHQ during a routine clinic visit. For each scale, ANOVA was used to determine pairwise differences between adolescent and parent scale scores. For scales in which a significant parent-adolescent difference existed, ANCOVA was used to determine disease and demographic factors independently associated with differences in scores. Finally, responses for each pair were compared only on similarly worded items within each scale. For the full CHQ scales, adolescents rated their HRQOL significantly better than did their parents with regard to General Health (mean difference, 12.4 points), Role Function/Physical (mean difference, 9.0 points), Behavior (mean difference, 4.8 points), and Physical Function (mean difference, 4.0 points). No demographic or health factor was associated consistently with differences in parent-adolescent scores. When only similarly worded items were compared, adolescents still tended to rate their HRQOL better, but the difference was significant only for General Health (P = 0.0005), where adolescents rated themselves less susceptible to illness and less worried about their health than their parents. In conclusion, optimal measurement of adolescent HRQOL will likely require determining both parent and adolescent perceptions of HRQOL.

Perceptions of value of routine care among patients with cystic fibrosis and their families.

Routine quarterly visits are an integral part of effective disease management for patients with cystic fibrosis (CF), regardless of the patient's age. The objective of this study was to explore the relationship between perceptions of the value of routine visits and perceived overall quality of care. The population in this study consisted of 194 patients at a single CF center. Telephone interviews were completed with 162 parents of children or adult patients (response rate, 84%) in May-June 2000. Among other satisfaction-related questions, respondents were asked to rate: 1) overall quality of care, 2) importance of routine clinic visits in providing good preventative care, and 3) helpfulness of routine clinic visits in providing knowledge for CF care. They were also asked open-ended questions concerning the reasons for their ratings. Perceived helpfulness and importance of routine visits were negatively associated with patient age and positively associated with perceived overall quality of care, especially for parents of teenage patients. The most common reason for low importance ratings was that the patient's health is perceived to be good, making routine clinic visits unnecessary. The most common reasons for low helpfulness ratings were that the visits are too repetitive or routine, and the family learns nothing new from them. In conclusion, tailoring routine visits to respond to different age-based needs and making routine visits less repetitive may add value to routine visits, which could result in increased perceived overall quality of care, especially for parents of teenage patients.

The impact of treatment of pulmonary exacerbations on the health-related quality of life of patients with cystic fibrosis: does hospitalization make a difference?

OBJECTIVES: To investigate the impact of pulmonary exacerbations on the health-related quality of life (HRQOL) of patients with cystic fibrosis (CF) and to elucidate factors that are associated with changes in HRQOL post-exacerbation. STUDY DESIGN: Participants completed questionnaires at a pre-exacerbation visit, at the beginning of the exacerbation, and at the post-exacerbation visit. To measure HRQOL, we used the Child Health Questionnaire-Parent Form (PF-50) and the Medical Outcomes Study Short Form-36 (SF-36). We examined demographic, clinical, and treatment-related predictor variables for association with change in Physical Summary (PhS) and Psychosocial Summary (PsS) HRQOL scores after an exacerbation. RESULTS: We collected data from 48 subjects. Patients experiencing exacerbations who were treated as outpatients had a mean (SD) age of 19.5 (12.7) years and a mean pre-exacerbation forced expiratory volume in 1 second (FEV(1)) of 70% (36%) of predicted; 53% were female. Patients treated as inpatients had a mean age of 14.6 (5.5) years and a mean FEV(1) of 56% (24%); 56% were female. In univariate analyses, exacerbations were associated with a statistically significant decrease in FEV(1) (-10.0%) and PhS scores (-4.5 points). PsS scores did not significantly change with exacerbations (-0.7 points). In multivariable analyses examining change between pre-exacerbation and post-exacerbation visits, no variables were significantly associated with change in PhS scores. However, not being hospitalized for the exacerbation was associated with deterioration in PsS scores, and being hospitalized was associated with improvement in PsS scores (beta coefficient: 9.4; P <.01) by the post-exacerbation visit. Results were similar from the exacerbation to the post-exacerbation visit. CONCLUSION: In patients with CF, on average, pulmonary exacerbations affect physical HRQOL more than psychosocial HRQOL. Being hospitalized for exacerbations is associated with improvement in psychosocial HRQOL after exacerbations, whereas not being hospitalized is associated with deterioration.

High-resolution computed tomography in young patients with cystic fibrosis: distribution of abnormalities and correlation with pulmonary function tests.

OBJECTIVE: To assess pulmonary abnormalities detected by high-resolution computed tomography (HRCT) in young children with cystic fibrosis (CF) and mild to moderate lung disease. STUDY DESIGN: High-resolution computed tomography was performed in 60 children, 6 to 10 years old, with mild to moderate lung disease (forced expiratory volume in 1 minute [FEV(1)], 52-137; mean, 102; SD, 15% predicted). HRCTs were scored by using a system that evaluates each lobe for severity and extent of CF lung disease. Findings of CF lung disease were tabulated in all subjects and in a subgroup with normal pulmonary function tests. HRCT scores were correlated with FEV(1), forced vital capacity (FVC), and forced expiratory flow between 25% and 75% of expired vital capacity (FEF(25-75)) in 57 patients. RESULTS: Bronchiectasis was present in 35% of subjects, mucous plugging in 15%, and air trapping in 63%. No abnormality was detected in 25%. In 37 subjects with FEV(1), FVC, and FEF(25-75) >85% predicted, bronchiectasis was present in 30%. In 17% of these subjects, bronchiectasis was seen in > or =4 lobes. Correlations between HRCT scores and FEV(1) were significant and showed fair to moderate correlation (r=0.36-0.46). CONCLUSIONS: High-resolution computed tomography demonstrated a broad range of pulmonary abnormalities in young patients with CF with mild to moderate lung disease. In this study, abnormalities, including bronchiectasis, were common in young children with CF and normal pulmonary function tests.