Novel outcome measures for clinical trials in cystic fibrosis.

Cystic fibrosis (CF) is a common inherited condition caused by mutations in the gene encoding the CF transmembrane regulator protein. With increased understanding of the molecular mechanisms underlying CF and the development of new therapies there comes the need to develop new outcome measures to assess the disease, its progression and response to treatment. As there are limitations to the current endpoints accepted for regulatory purposes, a workshop to discuss novel endpoints for clinical trials in CF was held in Anaheim, California in November 2011.

Reduced sodium transport with nasal administration of the prostasin inhibitor camostat in subjects with cystic fibrosis.

Background: Prostasin, a trypsin-like serine protease, is a channel-activating protease and major regulator of epithelial sodium channel-mediated sodium absorption. Its direct inhibition by camostat represents a potential approach to inhibiting sodium transport in cystic fibrosis (CF).

Methods: To determine whether a topical formulation of camostat represents an efficacious and tolerable approach to reducing Na+ transport in the CF airway, we conducted a two-part randomized, double-blind, placebo-controlled, crossover, ascending single-dose study to evaluate the pharmacodynamics, safety, and pharmacokinetics of camostat administered through a nasal spray pump in subjects with CF.

Inhaled amiloride and tobramycin solutions fail to eradicate Burkholderia dolosa in patients with cystic fibrosis.

Background: Burkholderia dolosa can result in chronic airway infection and rapid decline in lung function in patients with cystic fibrosis (CF). Amiloride has antibacterial properties that may be synergistic with aminoglycosides against other species belonging to the Burkholderia cepacia complex (Bcc). We attempted to eradicate B.

Role of bacteriocins in mediating interactions of bacterial isolates taken from cystic fibrosis patients.

Pseudomonas aeruginosa (Pa) and Burkholderia cepacia complex (Bcc) lung infections are responsible for much of the mortality in cystic fibrosis (CF). However, little is known about the ecological interactions between these two, often co-infecting, species. This study provides what is believed to be the first report of the intra- and interspecies bacteriocin-like inhibition potential of Pa and Bcc strains recovered from CF patients.

MDCT evaluation of the prevalence of tracheomalacia in children with mediastinal aortic vascular anomalies.

Objective: The purpose of this study is to determine the prevalence of tracheomalacia (TM) associated with different types of mediastinal aortic vascular anomalies in symptomatic children using paired inspiratory-expiratory multidetector computed tomography (MDCT).

Materials And Methods: The study group consisted of 15 consecutive symptomatic pediatric patients (12 males/3 females; mean age of 4.4 y; age range of 2 wk to 16 y) with mediastinal aortic vascular anomalies, who were referred for paired inspiratory-expiratory MDCT during a 35-month time period.

The impact of incident methicillin resistant Staphylococcus aureus detection on pulmonary function in cystic fibrosis.

The incidence of methicillin resistant Staphylococcus aureus (MRSA) infection is increasing in cystic fibrosis (CF), but the impact of MRSA detection on clinical outcomes is unclear. Our objective was to determine whether incident detection of MRSA is associated with a change in pulmonary function over time in CF patients. We analyzed data from the Epidemiologic Study of Cystic Fibrosis (ESCF), a prospective observational study of CF patients in North America.

MDCT assessment of tracheomalacia in symptomatic infants with mediastinal aortic vascular anomalies: preliminary technical experience.

Background: Mediastinal aortic vascular anomalies are relatively common causes of extrinsic central airway narrowing in infants with respiratory symptoms. Surgical correction of mediastinal aortic vascular anomalies alone might not adequately treat airway symptoms if extrinsic narrowing is accompanied by intrinsic tracheomalacia (TM), a condition that escapes detection on routine end-inspiratory imaging. Paired inspiratory-expiratory multidetector CT (MDCT) has the potential to facilitate early diagnosis and timely management of TM in symptomatic infants with mediastinal aortic vascular anomalies.

Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: a randomized placebo-controlled phase 2B trial.

Previous studies have demonstrated that delivery of a recombinant adeno-associated virus (AAV) vector encoding the complete human cystic fibrosis transmembrane regulator (CFTR) cDNA (tgAAVCF) to the nose, sinus, and lungs of subjects with cystic fibrosis (CF) was safe and well tolerated. In a small randomized, double-blind study of three doses of aerosolized tgAAVCF or placebo at 30-day intervals, encouraging but non-significant trends in pulmonary function and induced sputum interleukin 8 (IL-8) levels were seen at early time points. This larger study was conducted to verify these trends.

Oral corticosteroid therapy in cystic fibrosis patients hospitalized for pulmonary exacerbation: a pilot study.

Background: We hypothesized that adding 5 days of prednisone to standard therapy for acute pulmonary exacerbations in patients with cystic fibrosis (CF) would result in a more rapid and greater increase in lung function.

Methods: CF patients with an acute pulmonary exacerbation were randomized to receive oral placebo or prednisone, 2 mg/kg/d up to 60 mg, on days 1 to 5 in addition to standard therapy. Study evaluations on days 1 to 6, 14, and 42 included spirometry, glucose measurements, sputum analysis, and symptom scores.

Duration of treatment effect after tobramycin solution for inhalation in young children with cystic fibrosis.

Rationale: Among young children with cystic fibrosis (CF), Pseudomonas aeruginosa (Pa) airway infection is associated with increased morbidity and mortality. Early intervention strategies include tobramycin solution for inhalation (TSI), which can eradicate lower airway Pa from cultures obtained at the end of 28 days of treatment in young children.

Methods: We conducted an open label, sequential cohort study of TSI in young children with CF to investigate duration of antimicrobial treatment effect.

Membranous obliterative bronchitis: a proposed unifying model.

Three adults with cystic fibrosis (one after lung transplantation) presented with fever, chest pain, and acute radiographic changes. The changes included a cavitary lesion of the lung, acute dense infiltrates, and lobar collapse. After failing conventional antibiotic therapy, the patients underwent flexible bronchoscopy.

Impact of Burkholderia dolosa on lung function and survival in cystic fibrosis.

Rationale: Chronic infection with Burkholderia cepacia complex bacteria in cystic fibrosis is associated with accelerated decline in pulmonary function and increased mortality. Clinical implications of the recently characterized genomovar VI, B. dolosa, are unknown.

Cutaneovisceral angiomatosis with thrombocytopenia.

We describe 10 children with multiple vascular lesions of the skin and gastrointestinal tract associated with sustained, minor thrombocytopenia. In some children, there was involvement of the lung (n = 5), bone (n = 2), liver (n = 1), spleen (n = 1), and muscle (n = 1). The cutaneous lesions were congenital, multifocal, discrete, red-brown and variably blue macules and papules; in 3 children, a large dominant plaque was also present.

Tracheomalacia and tracheobronchomalacia in children and adults: an in-depth review.

Tracheomalacia and tracheobronchomalacia are disorders that are encountered in both pediatric and adult medicine. Despite increasing recognition of these disease processes, there remains some uncertainty regarding their identification, causes, and treatment. This article is intended to be a comprehensive review of both the adult and pediatric forms of the diseases, and includes sections on the historical aspects of the disorders, and their classification, associated conditions, histopathology, and natural history.

Population-based newborn screening for genetic disorders when multiple mutation DNA testing is incorporated: a cystic fibrosis newborn screening model demonstrating increased sensitivity but more carrier detections.

Objectives: Newborn screening for cystic fibrosis (CF) provides a model to investigate the implications of applying multiple-mutation DNA testing in screening for any disorder in a pediatric population-based setting, where detection of affected infants is desired and identification of unaffected carriers is not. Widely applied 2-tiered CF newborn screening strategies first test for elevated immunoreactive trypsinogen (IRT) with subsequent analysis for a single CFTR mutation (DeltaF508), systematically missing CF-affected infants with any of the >1000 less common or population-specific mutations. Comparison of CF newborn screening algorithms that incorporate single- and multiple-mutation testing may offer insights into strategies that maximize the public health value of screening for CF and other genetic disorders.

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.