Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study.

OBJECTIVE: To determine whether the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is involved in human insulin secretion by assessing the metabolic impact of the new CFTR corrector-ivacaftor. METHODS: This open-label pilot study was conducted in CF patients with the G551D mutation given new prescriptions for ivacaftor. At baseline and 4 wk after daily ivacaftor therapy, intravenous glucose tolerance tests (IVGTT) and oral glucose tolerance tests (OGTT) were performed. RESULTS: Five patients aged 6-52 were studied. After 1 month on ivacaftor, the insulin response to oral glucose improved by 66-178% in all subjects except one with long-standing diabetes. OGTT glucose levels were not lower in the two individuals with diabetes or the two with normal glucose tolerance (NGT), but the glucose tolerance category in the subject with impaired glucose tolerance (IGT) improved to NGT after treatment. In response to intravenous glucose, the only patient whose acute insulin secretion did not improve had newly diagnosed, untreated CFRD. The others improved by 51-346%. Acute insulin secretion was partially restored in two subjects with no measurable acute insulin response at baseline, including the one with IGT and the one with long-standing diabetes. CONCLUSIONS: This small pilot study suggests there is a direct role of CFTR in human insulin secretion. Larger, long-term longitudinal studies are necessary to determine whether early initiation of CFTR correction, particularly in young children with CF who have not yet lost considerable ß-cell mass, will delay or prevent development of diabetes in this high-risk population.

Socioeconomic status and the likelihood of antibiotic treatment for signs and symptoms of pulmonary exacerbation in children with cystic fibrosis.

OBJECTIVE: To determine whether socioeconomic status (SES) influences the likelihood of antibiotic treatment of pulmonary exacerbations in patients with cystic fibrosis (CF). STUDY DESIGN: We used data on 9895 patients ≤ 18 years old from the Epidemiologic Study of CF. After establishing an individual baseline of clinical signs and symptoms, we ascertained whether antibiotics were prescribed when new signs/symptoms suggested a pulmonary exacerbation, adjusting for sex, presence of Pseudomonas aeruginosa, the number of new signs/symptoms, and baseline disease severity. RESULTS: In a 12-month period, 20.0% of patients <6 years of age, 33.8% of patients 6 to 12 years of age, and 41.4% of patients 13 to 18 years of age were treated with any (oral, intravenous (IV), or inhaled) antibiotics; the percentage receiving IV antibiotics was 7.3%, 15.2%, and 20.9%, respectively. SES had little effect on treatment for pulmonary exacerbation with any antibiotics, but IV antibiotics were prescribed more frequently for patients with lower SES. CONCLUSIONS: SES-related disparities in CF health outcomes do not appear to be explained by differential treatment of pulmonary exacerbations.

A pre-post retrospective study of patients with cystic fibrosis and gastrostomy tubes.

OBJECTIVES: The aim of the study was to assess the efficacy of gastrostomy tube (GT) placement on improving nutritional status and pulmonary function in patients with cystic fibrosis (CF). PATIENTS AND METHODS: Data were collected from the Minnesota Cystic Fibrosis Database. Subjects with at least 5 percent-predicted forced expiratory volume in 1 second (ppFEV1) and 1 BMI percentile (pBMI) measurements before and after GT placement were included. Median pBMI values were compared 2 years before and 1, 2, and 4 years after GT placement using a signed rank test. Longitudinal mixed model analysis was used to assess the effect of GT placement on ppFEV1. To assess the effect of ppFEV1 at GT placement on efficacy, the estimated ppFEV1 change was regressed against the ppFEV1 level at placement. RESULTS: Forty-six subjects with CF who met entry criteria were identified. Mean estimated step changes in ppFEV1 at placement for men, women, boys, and girls were 2.16% (P = 0.52), 0.43% (P = 0.92), 0.99% (P = 0.65), and -0.91% (P = 0.74), respectively. Mean estimated slope changes of ppFEV1 after GT placement were 5.01% (P = 0.02), 4.48% (P = 0.07), 1.49% (P = 0.23), and 4.02% (P = 0.01) per year for men, women, boys, and girls, respectively. Median change in pBMI in the second year after GT placement was 13.3% (P ≤ 0.0001). Estimated coefficients for the effect of ppFEV1 level at placement on the ppFEV1 step and slope change were -0.041 (P = 0.28) and -0.005 (P = 0.84), respectively. CONCLUSIONS: GT placement in patients with CF results in significant improvement in both pBMI and ppFEV1, except in women. The change in lung function after GT placement is not dependent on the level of lung function at placement.

Oral glucose tolerance testing in children with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) related diabetes is the most common comorbidity in persons with CF. International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines recommend annual oral glucose tolerance testing (OGTT) screening starting at age 10. The OGTT might be recommended in younger children if, as in adults, it provided clinically relevant prognostic information. A database review was performed to determine whether OGTT findings in children with CF predict subsequent clinical course. METHODS: A retrospective matched-pair cohort study was based on OGTTs performed during 1998-2003. Children aged 6-9 were classified as having normal glucose tolerance (NGT) or abnormal glucose tolerance (AGT). Children with AGT were matched by age and gender to those with NGT. Clinical status was assessed at baseline and 5 yr later. In a separate investigation, diabetes and prior AGT status of children aged 10-18 were used to assess predictions derived from the cohort study. RESULTS: In 1998-2003, 39 of 94 children had AGT. Of these, 31 had sufficient follow-up data to be included. Both at baseline and 5 yr later there was no significant difference in height, weight, body mass index (BMI) or lung function between AGT and NGT. Diabetes developed in 13 AGT (42%) and one NGT (3%) [odds ratio (OR) 11, p = 0.0009]. Age of diabetes onset was 12 ± 1 yr in boys and 11 ± 1 yr in girls, compared to approximately 23 yr in the general CF population. Fifteen current children age 10-18 who had AGT before age 10 have diabetes, close to the prediction of 19. CONCLUSIONS: AGT in children with CF age 6-9 yr identifies those at high risk for progression to early onset diabetes.

An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5 years (KLIMB).

BACKGROUND: KIWI (NCT01705145) was a 24-week, single-arm, pharmacokinetics, safety, and efficacy study of ivacaftor in children aged 2 to 5 years with cystic fibrosis (CF) and a CFTR gating mutation. Here, we report the results of KLIMB (NCT01946412), an 84-week, open-label extension of KIWI. METHODS: Children received age- and weight-based ivacaftor dosages for 84 weeks. The primary outcome was safety. Other outcomes included sweat chloride, growth parameters, and measures of pancreatic function. RESULTS: All 33 children who completed KIWI enrolled in KLIMB; 28 completed 84 weeks of treatment. Most adverse events were consistent with those reported during KIWI. Ten (30%) children had transaminase elevations >3 × upper limit of normal (ULN), leading to 1 discontinuation in a child with alanine aminotransferase >8 × ULN. Improvements in sweat chloride, weight, and body mass index z scores and fecal elastase-1 observed during KIWI were maintained during KLIMB; there was no further improvement in these parameters. CONCLUSIONS: Ivacaftor was generally well tolerated for up to 108 weeks in children aged 2 to 5 years with CF and a gating mutation, with safety consistent with the KIWI study. Improvements in sweat chloride and growth parameters during the initial 24 weeks of treatment were maintained for up to an additional 84 weeks of treatment. Prevalence of raised transaminases remained stable and did not increase with duration of exposure during the open-label extension.

Decreased Pseudomonas aeruginosa detection in children after separation of pediatric from adult cystic fibrosis clinics: A single center experience.

BACKGROUND: The impact of separating the adult from pediatric patients on Pseudomonas aeruginosa (P. aeriginosa) detection in the respiratory cultures of patients was examined at the University of Minnesota CF Center. METHODS: This study was a retrospective review using data recorded in the University of Minnesota CF Database between 1995 and 2010. Respiratory culture results obtained during routine University of Minnesota Cystic Fibrosis (CF) Center. CF clinic encounters of two cohorts of pediatric and adult CF patients (pre- and post-separation) were analyzed for presence of P. aeruginosa. RESULTS: The odds of a pediatric patient having P. aeruginosa were significantly less if the first culture was obtained after separation of pediatric and adult clinics. Being diagnosed by newborn screening or introduction of inhaled tobramycin did not affect this outcome. This reduction in P. aeruginosa was not detected in the adult cohort. CONCLUSIONS: Separation of pediatric and adult CF clinics has contributed to decrease in P. aeruginosa detection in pediatric patients.

Risk factors for rate of decline in forced expiratory volume in one second in children and adolescents with cystic fibrosis.

OBJECTIVES: To characterize the rate of decline of forced expiratory volume in 1 second (FEV(1)) in children and adolescents with cystic fibrosis and to identify and compare risk factors associated with FEV(1) decline. STUDY DESIGN: The rate of decline in FEV(1)% predicted over 3 to 6 years in 3 different age groups was determined. Risk factors for decline were identified and compared among and within age groups as a function of disease severity with repeated-measures, mixed-model regression. RESULTS: Mean (+/-SD) baseline FEV(1)% predicted was 88.4% +/- 20.5% for 6- to 8-year-olds (n = 1811), 85.3% +/- 20.8% for 9- to 12-year-olds (n = 1696), and 78.4% +/- 22.0% for 13- to 17-year-olds (n = 1359). Decline in FEV(1)% predicted/year was -1.12, -2.39, and -2.34, respectively. High baseline FEV(1) and persistent crackles were significant independent risk factors for decline across all age groups. Female sex, Pseudomonas aeruginosa infection, low weight-for-age, sputum, wheezing, sinusitis, pulmonary exacerbations treated with intravenous antibiotics, elevated liver test results, and pancreatic insufficiency were also identified as independent risk factors in some age groups. CONCLUSIONS: This study identifies risk factors for FEV(1) decline in children and adolescents with cystic fibrosis. Clinicians should not be reassured by high lung function, particularly in young children, because this factor, among others, is independently associated with steeper decline in FEV(1).

Presence of methicillin resistant Staphylococcus aureus in respiratory cultures from cystic fibrosis patients is associated with lower lung function.

The prevalence of methicillin resistant Staphylococcus aureus (MRSA) infections is increasing in both the general population and cystic fibrosis (CF) patients. We hypothesized that MRSA infection of the conductive airways as seen in CF would be associated with more severe disease than that seen with methicillin sensitive S. aureus (MSSA). To test this hypothesis, we used data from the Epidemiologic Study of Cystic Fibrosis (ESCF), a large observational study of CF patients in North America, to compare CF patients with MRSA in their respiratory tract cultures to those with MSSA. During a 1-year time period from January 1, 2001 to December 31, 2001, data from 20,451 patients were collected by the ESCF, and 1,834 (7.5%) patients had respiratory tract cultures that were positive for S. aureus only. Compared to patients with MSSA only, patients with MRSA only had significantly more airflow obstruction, as measured by forced expiratory volume in 1 sec (FEV1). The mean FEV1 for patients 6-17 years old with MRSA was 80.7% predicted compared to 89.4% in the MSSA group (P<0.001). The likelihood of hospitalization and treatment with oral, inhaled, and intravenous antibiotics were all significantly increased in patients with MRSA compared to those with MSSA. Similar results were seen in patients >or=18 years old. The results of our study highlight the growing clinical impact of MRSA infections in CF patients.

Oral manifestations of a possible new periodic fever syndrome.

Periodic fever syndrome is composed of a group of disorders that present with recurrent predictable episodes of fever, which may be accompanied by: (1) lymphadenopathy; (2) malaise; (3) gastrointestinal disturbances; (4) arthrolgia; (5) stomatitis; and (6) skin lesions. These signs and symptoms occur in distinct intervals every 4 to 6 weeks and resolve without any residual effect, and the patient remains healthy between attacks. The evaluation must exclude: (1) infections; (2) neoplasms; and (3) autoimmune conditions. The purpose of this paper is to report the case of a 41/2- year-old white female who presented with a history of periodic fevers accompanied by: (1) joint pain; (2) skin lesions; (3) rhinitis; (4) vomiting; (5) diarrhea; and (6) an unusual asymptomatic, marked, fiery red glossitis with features evolving to resemble geographic tongue and then resolving completely between episodes. This may represent the first known reported case in the literature of a periodic fever syndrome presenting with such unusual recurring oral findings.

Pulmonary function tests correlated with thoracic volumes in adolescent idiopathic scoliosis.

Scoliosis deformity has been linked with deleterious changes in the thoracic cavity that affect pulmonary function. The causal relationship between spinal deformity and pulmonary function has yet to be fully defined. It has been hypothesized that deformity correction improves pulmonary function by restoring both respiratory muscle efficiency and increasing the space available to the lungs. This research aims to correlate pulmonary function and thoracic volume before and after scoliosis correction. Retrospective correlational analysis between thoracic volume modeling from plain x-rays and pulmonary function tests was conducted. Adolescent idiopathic scoliosis patients enrolled in a multicenter database were sorted by pre-operative Total Lung Capacities (TLC) % predicted values from their Pulmonary Function Tests (PFT). Ten patients with the best and ten patients with the worst TLC values were included. Modeled thoracic volume and TLC values were compared before and 2 years after surgery. Scoliosis correction resulted in an increase in the thoracic volume for patients with the worst initial TLCs (11.7%) and those with the best initial TLCs (12.5%). The adolescents with the most severe pulmonary restriction prior to surgery strongly correlated with post-operative change in total lung capacity and thoracic volume (r2 = 0.839; p < 0.001). The mean increase in thoracic volume in this group was 373.1 cm3 (11.7%) which correlated with a 21.2% improvement in TLC. Scoliosis correction in adolescents was found to increase thoracic volume and is strongly correlated with improved TLC in cases with severe restrictive pulmonary function, but no correlation was found in cases with normal pulmonary function. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:175-182, 2017.

Objective Measurement of Adherence to Out-Patient Airway Clearance Therapy by High-Frequency Chest Wall Compression in Cystic Fibrosis.

BACKGROUND: Objective measures of adherence to high-frequency chest wall compression (HFCWC), a form of airway clearance therapy for patients with cystic fibrosis, are lacking. We used a novel electronic monitoring device integrated into an HFCWC vest to measure adherence compared with self-reported adherence. We determined factors that influenced adherence and how adherence correlated with baseline pulmonary function and pulmonary exacerbations. METHODS: Data were collected by direct measurement of date, time of day, and duration of HFCWC use to determine the number of daily treatments and daily duration of treatments. Chart review provided prescribed airway clearance therapy treatment and demographic and clinical information. Subject and caregiver report of the daily number of airway clearance therapy treatments was obtained by telephone interviews. Analysis used 2-sample and paired t test, analysis of variance, and linear regression. RESULTS: Average adherence was 69%. Adherence was highest in children (82%, P = .02) and those receiving assistance with treatment (82%, P < .001). Subjects overestimated therapy duration from a mean ± SD of 127 ± 169% by adults to 19.2 ± 26.3% by parents or guardians of children. Average adherence decreased with increasing prescribed therapy time (P = .02). Average daily therapy time and adherence had significant positive associations with baseline FEV1 percent of predicted (P = .02 and P = .02, respectively) and negative associations with pulmonary exacerbations during the pre-study period and at baseline (P = .044 and P = .02, respectively). CONCLUSIONS: Greater adherence to HFCWC measured directly by a novel recorder was associated with better baseline pulmonary function and fewer exacerbations in the pre-study and baseline period. Adherence decreased with age and prescribed therapy time and increased with therapy assistance. Self-report overestimation is large and thus not an accurate measure of adherence.

Staphylococcal alpha-toxin causes increased tracheal epithelial permeability.

Staphylococcus aureus is an important cause of pulmonary infections. The role of S. aureus alpha-toxin as a virulence factor is unclear. We hypothesized that airway epithelium is a target of S. aureus alpha-toxin and that exposure of airway epithelium to alpha-toxin results in damage to the airway epithelium. To examine the hypothesis that alpha-toxin is capable of independently producing airway epithelium damage as measured by permeability and morphometry, an isolated whole mouse trachea test apparatus was developed. In vitro epithelial permeability (P) was calculated and digital micrographs were analyzed morphometrically. Purified S. aureus alpha-toxin produced a significant increase in tracheal epithelial P (P < 0.05). Morphometric analysis revealed the ratio of adherent tracheal epithelium attached to the basement membrane divided by the total length of the basement membrane decreased in a dose-dependent manner with 1 microg/ml alpha-toxin and 10 microg/ml alpha-toxin (P < 0.05). We developed a novel isolated whole mouse trachea test apparatus for the measurement of tracheal epithelium damage. Increased P and separation of the tracheal epithelium from the basement membrane occurred after S. aureus alpha-toxin exposure. We conclude that mammalian airway epithelium is a target of S. aureus alpha-toxin.

Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study.

BACKGROUND: Ivacaftor has been shown to be a safe, effective treatment for cystic fibrosis in patients aged 6 years or older with a CFTR gating mutation. We aimed to assess the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in children aged 2-5 years. METHODS: In the two-part KIWI study, we enrolled children aged 2-5 years weighing 8 kg or more with a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the USA, UK, and Canada. Participants received oral ivacaftor 50 mg (if bodyweight <14 kg) or 75 mg (if bodyweight ≥14 kg) every 12 h for 4 days in part A (to establish the short-term safety of doses for subsequent assessment in part B), and then for 24 weeks in part B (to assess safety and longer-term pharmacodynamics). Children could participate in both or just one part of the study. Primary outcomes were pharmacokinetics and safety, analysed in all patients who received at least one dose of ivacaftor. Secondary outcomes were absolute change from baseline in sweat chloride concentrations and bodyweight, body-mass index (BMI), and height Z scores, and pharmacokinetic parameter estimation of ivacaftor. This study is registered with ClinicalTrials.gov, number NCT01705145. FINDINGS: Between Jan 8, 2013, and March 1, 2013, nine patients were enrolled onto part A of the study, all of whom completed the 4 day treatment period, and eight of whom took part in part B. Between June 28, 2013, and Sept 26, 2013, 34 patients were enrolled in part B, 33 of whom completed the 24 week treatment period. All patients received at least one dose of ivacaftor. Results of ivacaftor pharmacokinetics suggested that exposure was similar to that reported in adults (median Cmin were 536 ng/mL for the 50 mg dose; 580 ng/mL for the 75 mg dose; median ivacaftor AUC values were 9840 ng × h/mL and 10 200 ng × h/mL, respectively). Common adverse events in part B included cough (in 19 [56%] of 34 patients) and vomiting (in ten [29%]). Five (15%) patients had liver function test (LFT) results that were more than eight times higher than the upper limit of normal, four of whom had study drug interrupted, and one of whom had study drug discontinued. Six (18%) of 34 patients had seven serious adverse events; a raised concentration of transaminases was the only serious adverse event regarded as related to ivacaftor and the only adverse event that resulted in study treatment discontinuation. At week 24, in patients for whom we had data, sweat chloride had changed from baseline by a mean of -46·9 mmol/L (SD 26·2, p<0·0001), weight Z score by 0·2 (0·3; p<0·0001), BMI Z score by 0·4 (0·4, p<0·0001), and height Z score by -0·01 (0·3; p=0·84). INTERPRETATION: Ivacaftor at doses of 50 mg and 75 mg seems to be safe in children aged 2-5 years with cystic fibrosis with a gating mutation followed up for 24 weeks, although the frequency of elevated LFTs suggests that monitoring should be frequent in young children, particularly those with a history of elevated LFTs. Results of an ongoing extension study assessing durability of these effects and longer-term safety are warranted. FUNDING: Vertex Pharmaceuticals Incorporated.

Butyrfentanyl overdose resulting in diffuse alveolar hemorrhage.

Butyrfentanyl is a potent short-acting opioid and a fentanyl analog with uncertain clinical effects. A review of the literature reveals no human case reports of butyrfentanyl overdose. As the use of analog and synthetic drugs continues to increase, clinicians are often faced with tremendous uncertainty when they encounter patients exposed to these synthetic drugs. We describe, to our knowledge, the first case of a butyrfentanyl overdose that resulted in clinically significant hemoptysis, acute lung injury, hypoxic respiratory failure, and diffuse alveolar hemorrhage. Complicating this case was a false-positive urine drug screen for fentanyl. Clinicians who encounter fentanyl exposures should be aware they may in fact be dealing with butyrfentanyl. As little is known of butyrfentanyl and our patient suffered a significant pulmonary hemorrhage, those who encounter butyrfentanyl exposures should monitor for hemorrhagic complications.

Antibiotic treatment of signs and symptoms of pulmonary exacerbations: a comparison by care site.

BACKGROUND: Antibiotic treatment of cystic fibrosis pulmonary exacerbations is inconsistent. Previous research has indicated that intravenous antibiotics are used more frequently at sites with better pulmonary function but it is not clear under what circumstances they are prescribed. METHOD: Pediatric care sites enrolled in the Epidemiologic Study of Cystic Fibrosis were ranked by median FEV1 % predicted of children they followed. Reported presence of new signs and symptoms of a pulmonary exacerbation (PEx) and antibiotic treatment within 21 days were compared between those in the highest vs. those in the other quartiles, and adjusted for sociodemographic and clinical characteristics of patients. RESULT: Highest quartile sites had a total of 2,454 children eligible for this analysis; lower quartile sites had a total of 5,487. The odds of having a PEx at highest vs. lower sites varied with how the PEx was defined, but high quartile sites were uniformly more likely to treat PEx with antibiotics. The adjusted odds ratio for treatment with any antibiotics of a PEx defined by the occurrence of one or two new signs and symptoms was 1.24 (95% CI 1.10, 1.40); for treatment of a PEx defined by the occurrence of three or four new signs and symptoms was 1.50 (95% CI 1.06, 2.11); and for treatment of a PEx defined by a drop of FEV(1) by ≥-15% was 1.33 (1.10, 1.60). The adjusted OR for treatment of these PEx with IV antibiotics was 1.11 (0.94, 1.32), 1.90 (1.32, 2.72), and 1.33 (1.10, 1.60), respectively. CONCLUSION: ESCF care sites in the highest quartile for FEV(1) were more likely to prescribe antibiotics when patients present with either mild or overt evidence of PEx. While this may not be the only reason that their patients have superior median FEV(1), it is likely an important contributor.

Pulmonary exacerbations in cystic fibrosis.

The clinical characteristics most relevant to the decision to treat for a pulmonary exacerbation with antibiotics in cystic fibrosis patients were determined. Variables including age, increased cough frequency and sputum production, new crackles and wheezing, asthma, symptomatic sinusitis, hemoptysis, decreased lung function, weight loss, and new acquisition of Pseudomonas aeruginosa were collected in a large prospective multicenter database (Epidemiologic Study of Cystic Fibrosis). During a 12-month baseline period, data from 11692 patients were compared with data collected during the subsequent 6-month study period. Because pulmonary function assessments were unavailable for patients <6 years of age, separate analyses were done for those <6 and >or=6 years of age. The outcome of interest was any antibiotic treatment in the 6-month study period reported as indicated for an exacerbation. Characteristics with the most discriminatory power were determined using stepwise multiple logistic regression. For patients <6 years of age, the strongest independent associations with treatment for a pulmonary exacerbation were new crackles, increased cough frequency, decline in weight, and increased sputum production. For those patients >or=6 years of age, the strongest independent associations were a relative decrease in percent predicted forced expired volume in 1 sec, increased cough frequency, new crackles, and hemoptysis. The presence of three or more of these key characteristics was strongly associated with the occurrence of a treated exacerbation. The reproducibility of the model over time was confirmed by application to a subsequent set of data. This model has potential for use as an outcome measure in clinical trials, and to assist in treatment decisions for individual patients.

A phase I randomized, multicenter trial of CPX in adult subjects with mild cystic fibrosis.

CPX (8-cyclopentyl-1,3-dipropylxanthine) is a novel compound currently under development as a potential treatment for cystic fibrosis (CF). The drug has been shown to increase chloride efflux and CFTR trafficking in vitro in CF airway cells. This phase I multicenter, single-dose, placebo-controlled trial was performed at four institutions. Thirty-seven subjects homozygous for the Delta F(508) allele were studied in an escalating dose protocol of seven single-dose cohorts (1, 3, 10, 30, 100, 300, and 1,000 mg) to evaluate the safety, pharmacokinetics, and efficacy of CPX. Efficacy was determined using nasal transepithelial potential difference and sweat chloride measurements prior to dosing and at 1, 2, and 4 hr postdose. The incidence of adverse events in the treatment group was similar to that with placebo, indicating safety of the single doses studied. One serious adverse event (an acute pulmonary exacerbation) occurred 13 days after dosing, and was not considered related to the study drug. The maximal plasma CPX concentration and total amount of CPX absorbed appeared to be linearly related to dose, but was highly variable throughout the dose range studied, suggesting inconsistent absorption. There was no apparent effect of single-dose administration on either nasal transepithelial potential difference or sweat chloride measurements. The positive safety and pharmacokinetic findings of this study support continued development of CPX as a potential therapeutic for CF.

Vitamin D deficiency is associated with pulmonary exacerbations in children with cystic fibrosis.

RATIONALE: Recent literature suggests vitamin D has an effect on lung function and on the lung's ability to fight infection, both important in the cystic fibrosis (CF) population as predictors of morbidity and mortality. OBJECTIVES: Our study assessed associations between vitamin D and % predicted lung function, pulmonary exacerbations, and first Pseudomonas aeruginosa infection in children with CF. We hypothesized that children with CF who have 25-hydroxy vitamin D (25-OHD) levels less than 30 µg/L would have lower % predicted lung function and more pulmonary exacerbations than those with 25-OHD greater than or equal to 30 µg/L. METHODS: This retrospective longitudinal study of 130 children aged 6 to 18 years between 2000 and 2012 examined 25-OHD levels classed in three vitamin D groups: sufficient (≥30 µg/L), insufficient (20-29 µg/L), and deficient (<20 µg/L). Longitudinal models followed individuals' changing vitamin D groups over time to compare numbers of pulmonary exacerbations (defined by hospitalization), incidence of first P. aeruginosa infection, and % predicted lung function. Cross-sectional comparisons between vitamin D groups were performed at ages 8, 12, and 16 years. MEASUREMENTS AND MAIN RESULTS: The prevalence of vitamin D deficiency and insufficiency increased slowly through adolescence. The rate of exacerbations for the deficient vitamin D group, aged 15 to 18 years, was 13.1 per 10 patient-years, significantly higher than 4.3 per 10 patient-years for the insufficient and sufficient vitamin D groups (P < 0.05), which were not significantly different There were no differences between vitamin D groups in pulmonary function or incidence of first P. aeruginosa infection, which was about 2 per 10 patient-years. CONCLUSIONS: Higher 25-OHD levels in children with CF were associated with lower rates of pulmonary exacerbations and, in adolescents, higher FEV1.

Pulmonary exacerbations in cystic fibrosis: young children with characteristic signs and symptoms.

BACKGROUND: A standard definition of pulmonary exacerbation based on signs and symptoms would be useful for categorizing cystic fibrosis (CF) patients and as an outcome measure of therapy. The frequently used definition of treatment with intravenous antibiotics varies with practice patterns. One approach to this problem is to use large data sets which include a patient's signs and symptoms along with their clinician's decision to treat with antibiotics for the diagnosis of pulmonary exacerbation. Previous analysis of such a data set, the Epidemiologic Study of Cystic Fibrosis (ESCF), found that new crackles, increased cough, increased sputum, and weight decline were the four clinical characteristics most strongly influencing providers to treat young CF patients for a pulmonary exacerbation. The objectives of this study were to confirm that these four characteristics influence the decision to treat with antibiotics for a pulmonary exacerbation in young CF patients; to evaluate their implications for future nutritional status and lung function; and to assess the effect of antibiotic treatment on these characteristic signs and symptoms. METHODS: This was an observational, longitudinal cohort study of clinical care in children <6 years old cared for at sites participating in ESCF. RESULTS: Using data from children not included in the previous ESCF study, we confirmed that these four characteristics were significantly associated with the likelihood of physicians prescribing antibiotics to treat a pulmonary exacerbation. The number of these characteristics present at a single clinic visit before age 6 predicted hospitalization rate over the next year, the weight-for-age z-score, and the forced expiratory volume in 1 sec (FEV1) percent predicted at age 7. Treatment with antibiotics was associated with a greater decrease in the proportion of children with crackles, cough, and Pseudomonas aeruginosa at a follow-up visit within 6 months. CONCLUSIONS: New crackles, increased cough, increased sputum, and decline in weight percentile at a single clinic visit increase the risk of future malnutrition, hospitalization, and airflow obstruction in young children with CF. Treatment with antibiotics mitigates some of these signs and symptoms by the first follow-up visit. The presence of these four characteristic signs and symptoms is useful to define pulmonary exacerbations in young children with CF that respond to antibiotic treatment in the short-term and influence long-term prognosis.

Oral, inhaled, and intravenous antibiotic choice for treating pulmonary exacerbations in cystic fibrosis.

RATIONALE: Patients with cystic fibrosis (CF) experience frequent pulmonary exacerbations (PExs). Clinicians manage these episodes of worsening signs and symptoms in a variety of ways. OBJECTIVES: To characterize the antibiotic management and associated change in lung function following PExs. METHODS: We used 2003-2005 data from the Epidemiologic Study of Cystic Fibrosis to examine antibiotic treatment and the immediate and long-term lung function change associated with clinician reported PExs. RESULTS: A total of 45,374 PExs were reported in 13,194 unique patients. Most PExs (73%) were treated with oral antibiotics, while 39% were treated IV and 24% were treated with inhaled antibiotics. The likelihood of non-IV versus IV antibiotic treatment was associated with the patient's age, stage of lung disease, and magnitude of lung function drop prior to the PEx. Following treatment, the average improvement in the FEV1 was 3.4 ± 12.2% predicted with a greater (5.1 ± 12.7% predicted) improvement following IV antibiotic treatment than with non-IV treatment (2.0 ± 11.6% predicted). When the best FEV1 from the year before was compared with 180 days following the PEx there was an average fall of 3.8 ± 10.5% predicted with little difference observed between antibiotic treatment routes. Patients with only one exacerbation during the 3-year study had a similar loss of lung function to patients with no reported exacerbations. CONCLUSION: Clinicians treat the majority of PExs with oral antibiotics, particularly in younger, healthier patients. Pulmonary function improves with antibiotic therapy, however, PExs are associated with lung function deterioration over time.