Prediction of mortality in adolescents with cystic fibrosis.

INTRODUCTION: Lung function, nutritional status, and parameters of exercise capacity are known predictors of mortality in patients with cystic fibrosis (CF). The aim of the current study was to use these important parameters to develop a multivariate model to predict mortality in adolescent patients with CF. METHODS: A total of 127 adolescents with CF (57 girls) with a mean age of 12.7 ± 0.9 yr and a mean percentage of predicted forced expired volume in 1 s (FEV1% predicted) of 77.7% ± 15.6% were included. Cardiopulmonary exercise testing-derived parameters, nutritional status, and resting lung functions were dichotomized according to the criterion value determined using receiver operating characteristic curves. Body mass index (BMI), FEV1%predicted, predicted peak oxygen uptake corrected for body weight (VO2 peak/kg%predicted), peak minute ventilation (VE peak), peak VE/VO2, peak VE/VCO2, and breathing reserve were included in a multivariate model. The Cox proportional hazards model was used to determine the combination of parameters that best predicted mortality and/or lung transplantation. RESULTS: The mean duration of follow-up was 7.5 ± 2.7 yr, during which, nine of the 127 patients (7.1%) died and six (4.7%) underwent lung transplantation. Mortality in this population was best predicted by the model that included FEV1%predicted (hazard ratio, 17.13; 95% confidence interval (CI), 3.76-78.06), peak VE/VO2 (hazard ratio, 5.92; 95% CI, 1.27-27.63), and BMI (hazard ratio, 5.54; 95% CI, 1.82-16.83). CONCLUSIONS: The currently developed model consisting of BMI, FEV1%predicted, and VE/VO2 is a strong predictor of mortality rate in adolescents with CF. This prediction equation may be useful in clinical practice to detect patients with a high risk of mortality and to provide them with additional therapy earlier.

Chronic inflammation and infection associate with a lower exercise training response in cystic fibrosis adolescents.

Considerable heterogeneity among training-induced effects is observed in patients with cystic fibrosis (CF). We previously showed that longitudinal changes in exercise capacity in adolescents with CF were negatively associated with Pseudomonas aeruginosa (P. aeruginosa) colonization and total immunoglobulin G (IgG) levels, independent of age, pulmonary function and bodyweight. This is the first study investigating whether chronic inflammation and infection also associate with the exercise training response in adolescents with CF. Participants performed a home-based exercise training program for 12 weeks. Pulmonary function, anthropometrics, exercise capacity, markers of inflammation and P. aeruginosa colonization status were measured at baseline. Exercise training-induced changes in pulmonary function and exercise capacity were compared between patients with a low and high inflammation-infection status. Participants with CF with high total IgG levels and P. aeruginosa colonization improved significantly less from the exercise training program, with regard to maximal oxygen consumption. These observations support the hypothesis that chronic systemic inflammation and infection leads to devastating effects on skeletal muscles, hampering skeletal muscle tissue to improve from regular physical exercise. Data further suggest that patients with CF should preferentially be encouraged to engage in regular physical exercise when inflammation and infection status is low (e.g. at a young age).

Effect of long-term voluntary exercise wheel running on susceptibility to bacterial pulmonary infections in a mouse model.

Regular moderate exercise has been suggested to exert anti-inflammatory effects and improve immune effector functions, resulting in reduced disease incidence and viral infection susceptibility. Whether regular exercise also affects bacterial infection susceptibility is unknown. The aim of this study was to investigate whether regular voluntary exercise wheel running prior to a pulmonary infection with bacteria (P. aeruginosa) affects lung bacteriology, sickness severity and phagocyte immune function in mice. Balb/c mice were randomly placed in a cage with or without a running wheel. After 28 days, mice were intranasally infected with P. aeruginosa. Our study showed that regular exercise resulted in a higher sickness severity score and bacterial (P. aeruginosa) loads in the lungs. The phagocytic capacity of monocytes and neutrophils from spleen and lungs was not affected. Although regular moderate exercise has many health benefits, healthy mice showed increased bacterial (P. aeruginosa) load and symptoms, after regular voluntary exercise, with perseverance of the phagocytic capacity of monocytes and neutrophils. Whether patients, suffering from bacterial infectious diseases, should be encouraged to engage in exercise and physical activities with caution requires further research.

Optimal complement-mediated phagocytosis of Pseudomonas aeruginosa by monocytes is cystic fibrosis transmembrane conductance regulator-dependent.

Cystic fibrosis (CF) is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and is characterized by chronic pulmonary infections. The mechanisms underlying chronic infection and inflammation remain incompletely understood. Mutant CFTR in nonepithelial tissues such as immune cells has been suggested to contribute to infection, inflammation, and the resultant lung disease. However, much controversy still exists regarding the intrinsic role of CFTR in immune cells, especially phagocytes. Therefore, we investigated CFTR expression and function in neutrophils and monocytes isolated from human peripheral blood. CFTR function was assessed by comparing non-CF and CF cells, before and after the chemical inhibition of CFTR. We found CFTR protein expression in monocytes, but this expression was limited or undetectable in neutrophils. Furthermore, the phagocytosis and intracellular killing of Pseudomonas aeruginosa was reduced in CF monocytes, and impaired phagocyte effector mechanisms were phenocopied in non-CF monocytes upon the pharmacological inhibition of CFTR. Reduced phagocytosis in CF monocytes relied on the complement-dependent opsonization of Pseudomonas aeruginosa, and was also observed in the context of latex particles labeled with purified C3b. In mechanistic terms, we observed that CFTR function in monocytes is required for the optimal expression of CD11b. We observed no role for CFTR in neutrophil-mediated phagocytosis. These data support an intrinsic role for CFTR in monocytes, and suggest that CFTR-dependent alterations in complement-mediated interactions between Pseudomonas aeruginosa and monocytes may contribute to enhanced susceptibility to infection in patients with CF.

Supramaximal verification of peak oxygen uptake in adolescents with cystic fibrosis.

PURPOSE: To study whether peak oxygen uptake ((Equation is included in full-text article VO2 peak), attained in traditional cardiopulmonary exercise testing (CPET) in adolescents with cystic fibrosis (CF), could be verified by a supramaximal exercise test. METHODS: Sixteen adolescents with CF (forced expiratory volume in 1 second as % of predicted [range, 45%-117%]) volunteered and successively performed CPET and a supramaximal test (Steep Ramp Test [SRT] protocol). RESULTS: Cardiopulmonary exercise testing and the SRT resulted in comparable cardiorespiratory peak values. We found no significant difference in oxygen uptake ((Equation is included in full-text article VO2 peak/kg) between CPET and the SRT (38.9 ± 7.4 and 38.8 ± 8.5 mL min kg, respectively; P = .81). We found no systemic bias for CPET and SRT measurements of (Equation is included in full-text article VO2 peak/kg and no differences between CPET and SRT (Equation is included in full-text article VO2 peak values within and between the maximal and non-maximal effort groups (P > .4). CONCLUSION: The (Equation is included in full-text article VO2 peak measured in CPET seems to reflect the true (Equation is included in full-text article.)O2 peak in adolescents with CF.