Linda Pedder

Predictors of pulmonary exacerbations in patients with cystic fibrosis infected with multi-resistant bacteria

Background: This study examined characteristics of adult and adolescent patients with cystic fibrosis (CF) to determine factors associated with an increased risk of pulmonary exacerbations. Methods: 249 patients with CF infected with multidrug resistant bacteria were recruited and prospectively followed for up to 4.5 years until they experienced a pulmonary exacerbation severe enough to require intravenous antibiotics. Multivariable regression analyses were used to compare the characteristics of patients who experienced an exacerbation with those who did not. Results: 124 of the 249 patients (50%) developed a pulmonary exacerbation during the first year and 154 (62%) experienced an exacerbation during the 4.5 year study period. Factors predictive of exacerbations in a multivariable survival model were younger age (OR 0.98, 95% CI 0.96 to 0.99), female sex (OR 1.45, 95% CI 1.07 to 1.95), lower forced expiratory volume in 1 second (FEV1) (OR 0.98, 95% CI 0.97 to 0.99), and a previous history of multiple pulmonary exacerbations (OR 3.16, 95% CI 1.93 to 5.17). Chronic use of inhaled corticosteroids was associated with an increased risk of exacerbation (OR 1.92, 95% CI 1.00 to 3.71) during the first study year. Conclusions: Patients who experience pulmonary exacerbations are more likely to be younger, female, using inhaled steroids, have a lower FEV1, and a history of multiple previous exacerbations. It is hoped that knowledge of these risk factors will allow better identification and closer monitoring of patients who are at high risk of exacerbations.

Treatment of Aspergillus fumigatus in Patients with Cystic Fibrosis: A Randomized, Placebo-Controlled Pilot Study

Background Many patients with cystic fibrosis develop persistent airway infection/colonization with Aspergillus fumigatus, however the impact of A. fumigatus on clinical outcomes remains unclear. The objective of this study was to determine whether treatment directed against Aspergillus fumigatus improves pulmonary function and clinical outcomes in patients with cystic fibrosis (CF). Methods We performed a double-blind randomized placebo-controlled pilot clinical trial involving 35 patients with CF whose sputum cultures were chronically positive for A. fumigatus. Participants were centrally randomized to receive either oral itraconazole 5 mg/kg/d (N = 18) or placebo (N = 17) for 24 weeks. The primary outcome was the proportion of patients who experienced a respiratory exacerbation requiring intravenous antibiotics over the 24 week treatment period. Secondary outcomes included changes in FEV1 and quality of life. Results Over the 24 week treatment period, 4 of 18 (22%) patients randomized to itraconazole experienced a respiratory exacerbation requiring intravenous antibiotics, compared to 5 of 16 (31%) placebo treated patients, P = 0.70. FEV1 declined by 4.62% over 24 weeks in the patients randomized to itraconazole, compared to a 0.32% improvement in the placebo group (between group difference = −4.94%, 95% CI: −15.33 to 5.45, P = 0.34). Quality of life did not differ between the 2 treatment groups throughout the study. Therapeutic itraconazole blood levels were not achieved in 43% of patients randomized to itraconazole. Conclusion We did not identify clinical benefit from itraconazole treatment for CF patients whose sputum was chronically colonized with A. fumigatus. Limitations of this pilot study were its small sample size, and failure to achieve therapeutic levels of itraconazole in many patients. Trial Registration ClinicalTrials.gov NCT00528190

Inflammatory and growth factor response to continuous and intermittent exercise in youth with cystic fibrosis

BACKGROUND Children with cystic fibrosis (CF) tend to suffer from chronic systemic inflammation and may have impaired growth associated with muscle catabolism. Therefore, investigating which type of exercise can elicit an anabolic response with minimal inflammation is of clinical value. METHODS Twelve children with CF (mean±SD; age: 14.7±2.3 years, predicted FEV(1): 90.0±21.6%) and biological age-matched controls (age: 13.9±2.1 years) completed moderate-intensity, continuous exercise (MICE) and high-intensity, intermittent exercise (HIIE) on separate days. During each exercise, blood was drawn at various time points and analyzed for immune cells, inflammatory cytokines, and growth mediators. RESULTS At rest, children with CF had higher concentrations of neutrophils and IL-6 compared with controls. In children with CF, HIIE did not affect immune cell subsets or cytokines: TNF-α, IL-6, and tumor necrosis factor-like weak inducer of apoptosis (TWEAK). All immune cell subsets and IL-6 increased significantly with MICE in both groups. Growth hormone (GH) increased with both types of exercise, with a greater change from rest during MICE. CONCLUSIONS HIIE was a sufficient stimulus to increase GH in children with CF, without affecting systemic inflammation.

Sedentary Time and Screen-Based Sedentary Behaviors of Children With a Chronic Disease

The objectives of this study were to (i) assess sedentary time and prevalence of screen-based sedentary behaviors of children with a chronic disease and (ii) compare sedentary time and prevalence of screen-based sedentary behaviors to age- and sex-matched healthy controls. Sixty-five children (aged 6-18 years) with a chronic disease participated: survivors of a brain tumor, hemophilia, type 1 diabetes mellitus, juvenile idiopathic arthritis, cystic fibrosis, and Crohns disease. Twenty-nine of these participants were compared with age- and sex-matched healthy controls. Sedentary time was measured objectively by an ActiGraph GT1M or GT3× accelerometer worn for 7 consecutive days and defined as less than 100 counts per min. A questionnaire was used to assess screen-based sedentary behaviors. Children with a chronic disease engaged in an average of 10.2 ± 1.4 hr of sedentary time per day, which comprised 76.5 ± 7.1% of average daily monitoring time. There were no differences between children with a chronic disease and controls in sedentary time (adjusted for wear time, p = .06) or in the prevalence of TV watching, and computer or video game usage for varying durations (p = .78, p = .39 and, p = .32 respectively). Children with a chronic disease, though relatively healthy, accumulate high levels of sedentary time, similar to those of their healthy peers.

Reduced fat oxidation rates during submaximal exercise in boys with cystic fibrosis

BACKGROUND Exercise is a viable form of therapy for children with cystic fibrosis (CF). Understanding the energy sources used during exercise would aid CF patients in obtaining proper nutrition in order to sustain an active lifestyle. METHODS Six boys with CF (mean age ± SD: 14.8 ± 2.3 yrs, FEV1: 99 ± 18% predicted) and six matched controls (14.0 ± 2.2 yrs) completed a session of two 30 min bouts of cycling at an intensity set at 50% peak mechanical power. Rates of total fat and carbohydrate (CHO) oxidation were calculated from expired gases. Plasma insulin, glucose and free fatty acid (FFA) were determined before, during and at the end of the exercise. RESULTS Rates of fat oxidation (expressed in mean mg × kg body weight(-1) × min(-1) ± SD) were significantly lower in children with CF (5.7 ± 1.6) compared to controls (8.6 ± 1.8, p < 0.05). Children with CF also had lower values than controls in amount of fat oxidized (CF: 17.3 ± 5.0 g, controls: 26.1 ± 5.9 g, p < 0.05) and percent of total energy expenditure from fat (CF: 32 ± 6%, controls: 43 ± 7%, p < .0.05), but a higher contribution from CHO (CF: 68 ± 6%, controls: 57 ± 7% p < .0.05). Plasma FFA was significantly lower in children with CF compared to controls during (CF: 252.5 ± 117.9 μM, controls: 602.2 ± 295.6) and at the end of exercise (CF: 430.9 ± 180.6, controls: 1147.5 ± 473.5). There were no differences in the rates of CHO oxidation, insulin or glucose between groups. CONCLUSION Fat metabolism during exercise is impaired in boys with CF and may be attributed to an inability to mobilize FFA.

The Sweat Metabolome of Screen-Positive Cystic Fibrosis Infants: Revealing Mechanisms beyond Impaired Chloride Transport

The sweat chloride test remains the gold standard for confirmatory diagnosis of cystic fibrosis (CF) in support of universal newborn screening programs. However, it provides ambiguous results for intermediate sweat chloride cases while not reflecting disease progression when classifying the complex CF disease spectrum given the pleiotropic effects of gene modifiers and environment. Herein we report the first characterization of the sweat metabolome from screen-positive CF infants and identify metabolites associated with disease status that complement sweat chloride testing. Pilocarpine-stimulated sweat specimens were collected independently from two CF clinics, including 50 unaffected infants (e.g., carriers) and 18 confirmed CF cases. Nontargeted metabolite profiling was performed using multisegment injection–capillary electrophoresis–mass spectrometry as a high throughput platform for analysis of polar/ionic metabolites in volume-restricted sweat samples. Amino acids, organic acids, amino acid derivatives, dipeptides, purine derivatives, and unknown exogenous compounds were identified in sweat when using high resolution tandem mass spectrometry, including metabolites associated with affected yet asymptomatic CF infants, such as asparagine and glutamine. Unexpectedly, a metabolite of pilocarpine, used to stimulate sweat secretion, pilocarpic acid, and a plasticizer metabolite from environmental exposure, mono(2-ethylhexyl)phthalic acid, were secreted in the sweat of CF infants at significantly lower concentrations relative to unaffected CF screen-positive controls. These results indicated a deficiency in human paraoxonase, an enzyme unrelated to mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) and impaired chloride transport, which is a nonspecific arylesterase/lactonase known to mediate inflammation, bacterial biofilm formation, and recurrent lung infections in affected CF children later in life. This work sheds new light into the underlying mechanisms of CF pathophysiology as required for new advances in precision medicine of orphan diseases that benefit from early detection and intervention, including new molecular targets for therapeutic intervention.

The effects of resting and exercise serum from children with cystic fibrosis on C2C12 myoblast proliferation in vitro

Chronic systemic inflammation is a clinical symptom in children with cystic fibrosis (CF), but the effects on skeletal muscle development are unknown. The aims of this study were to determine (1) the effects of systemic factors from children with CF and healthy controls on myoblast proliferation, and (2) whether exercise serum can have an effect on proliferation in vitro. Eleven children with CF and 11 biological age‐matched controls completed two 30‐min bouts of cycling at an intensity set at 50% peak mechanical power. Serum samples were collected before exercise (REST), immediately following exercise (EX), and after 60 min of recovery (REC). Serum samples prepared in group‐specific pools were used for cell culture experiments. C2C12 myoblasts were incubated in 5% serum and media for 1 h and then immediately harvested for protein and mRNA analysis, or incubated in growth media for 2 days to examine proliferation. C2C12 myoblasts treated with CF serum displayed greater proliferation phenotype than myoblasts treated with control serum. Proliferation did not change with EX or REC serum from children with CF compared to CF REST serum, while proliferation was increased with EX and REC serum from control compared to control REST serum. These findings suggest that systemic factors from children with CF at rest and after exercise can alter myoblast proliferation responses when compared to systemic factors from healthy children, which may have implications on skeletal muscle development.