Cardiopulmonary Exercise Testing Provides Prognostic Information in Advanced Cystic Fibrosis Lung Disease.

Rationale: Cardiopulmonary exercise testing (CPET) provides prognostic information in cystic fibrosis (CF); however, its prognostic value for patients with advanced CF lung disease is unknown. Objectives: To determine the prognostic value of CPET on the risk of death or lung transplant (LTX) within 2 years. Methods: We retrospectively collected data from 20 CF centers in Asia, Australia, Europe, and North America on patients with a forced expiratory volume in 1 second (FEV1) ⩽ 40% predicted who performed a cycle ergometer CPET between January 2008 and December 2017. Time to death/LTX was analyzed using mixed Cox proportional hazards regression. Conditional inference trees were modeled to identify subgroups with increased risk of death/LTX. Results: In total, 174 patients (FEV1, 30.9% ± 5.8% predicted) were included. Forty-four patients (25.5%) died or underwent LTX. Cox regression analysis adjusted for age, sex, and FEV1 revealed percentage predicted peak oxygen uptake ([Formula: see text]o2peak) and peak work rate (Wpeak) as significant predictors of death/LTX: adjusted hazard ratios per each additional 10% predicted were 0.60 (95% confidence interval, 0.43-0.90; P = 0.008) and 0.60 (0.48-0.82; P < 0.001). Tree-structured regression models, including a set of 11 prognostic factors for survival, identified Wpeak to be most strongly associated with 2-year risk of death/LTX. Probability of death/LTX was 45.2% for those with a Wpeak ⩽ 49.2% predicted versus 10.9% for those with a Wpeak > 49.2% predicted (P < 0.001). Conclusions: CPET provides prognostic information in advanced CF lung disease, and Wpeak appears to be a promising marker for LTX referral and candidate selection.

Cardiopulmonary Exercise Testing Provides Additional Prognostic Information in Cystic Fibrosis.

RATIONALE: The prognostic value of cardiopulmonary exercise testing (CPET) for survival in cystic fibrosis (CF) in the context of current clinical management, when controlling for other known prognostic factors, is unclear. OBJECTIVES: To determine the prognostic value of CPET-derived measures beyond peak oxygen uptake ( V. o2peak) following rigorous adjustment for other predictors. METHODS: Data from 10 CF centers in Australia, Europe, and North America were collected retrospectively. A total of 510 patients completed a cycle CPET between January 2000 and December 2007, of which 433 fulfilled the criteria for a maximal effort. Time to death/lung transplantation was analyzed using Cox proportional hazards regression. In addition, phenotyping using hierarchical Ward clustering was performed to characterize high-risk subgroups. MEASUREMENTS AND MAIN RESULTS: Cox regression showed, even after adjustment for sex, FEV1% predicted, body mass index (z-score), age at CPET, Pseudomonas aeruginosa status, and CF-related diabetes as covariates in the model, that V. o2peak in % predicted (hazard ratio [HR], 0.964; 95% confidence interval [CI], 0.944-0.986), peak work rate (% predicted; HR, 0.969; 95% CI, 0.951-0.988), ventilatory equivalent for oxygen (HR, 1.085; 95% CI, 1.041-1.132), and carbon dioxide (HR, 1.060; 95% CI, 1.007-1.115) (all P < 0.05) were significant predictors of death or lung transplantation at 10-year follow-up. Phenotyping revealed that CPET-derived measures were important for clustering. We identified a high-risk cluster characterized by poor lung function, nutritional status, and exercise capacity. CONCLUSIONS: CPET provides additional prognostic information to established predictors of death/lung transplantation in CF. High-risk patients may especially benefit from regular monitoring of exercise capacity and exercise counseling.

Repaglinide versus insulin for newly diagnosed diabetes in patients with cystic fibrosis: a multicentre, open-label, randomised trial.

BACKGROUND: As survival among patients with cystic fibrosis has improved in recent decades, complications have become increasingly relevant. The most frequent complication is cystic-fibrosis-related diabetes. The recommended treatment is injected insulin, but some patients are treated with oral antidiabetic drugs to ease the treatment burden. We assessed the efficacy and safety of oral antidiabetic drugs. METHODS: We did a multicentre, open-label, comparative, randomised trial in 49 centres in Austria, France, Germany, and Italy. Eligible patients had cystic fibrosis, were older than 10 years, and had newly diagnosed diabetes. We used a central randomisation schedule derived from a Geigy random number table to assign patients 1:1 to receive insulin or repaglinide, stratified by sex and age (10-15 years or >15 years). The primary outcome was glycaemic control assessed by mean change in HbA1c concentration from baseline after 24 months of treatment. Differences between groups were assessed by linear models. The primary and safety analyses were done in the modified intention-to-treat population (including patients who stopped treatment early because of lack of efficacy). This trial is registered with ClinicalTrials.gov, number NCT00662714. FINDINGS: We enrolled 34 patients in the repaglinide group and 41 in the insulin group, of whom 30 and 37, respectively, were included in the analyses. At 24 months, glycaemic control was similar in the repaglinide and insulin groups (mean change in HbA1c concentration from baseline 0·2% [SD 0·7%], 1·7 mmol/mol [8·1 mmol/mol] with repaglinide vs -0·2% [1·3%], -2·7 mmol/mol, [14·5 mmol/mol] with insulin; mean difference between groups -0·4%, (95% CI -1·1 to 0·2 [-4·4 mmol/mol, -11·5 to 2·7], p=0·15). The most frequent adverse events were pulmonary events (43 [40%] of 107 in the repaglinide group and 60 [45%] of 133 in the insulin group), and the most frequent serious adverse events were pulmonary events leading to hospital admission (five [50%] of ten and seven [54%] of 13, respectively). INTERPRETATION: Repaglinide for glycaemic control in patients with cystic-fibrosis-related diabetes is as efficacious and safe as insulin. FUNDING: Mukoviszidose eV, Vaincre la Mucoviscidose, ABCF Association, and Novo Nordisk.

Quality of life is associated with physical activity and fitness in cystic fibrosis.

BACKGROUND: Health-related and disease-specific quality of life (HRQoL) has been increasingly valued as relevant clinical parameter in cystic fibrosis (CF) clinical care and clinical trials. HRQoL measures should assess - among other domains - daily functioning from a patient's perspective. However, validation studies for the most frequently used HRQoL questionnaire in CF, the Cystic Fibrosis Questionnaire (CFQ), have not included measures of physical activity or fitness. The objective of this study was, therefore, to determine the cross-sectional and longitudinal relationships between HRQoL, physical activity and fitness in patients with CF. METHODS: Baseline (n = 76) and 6-month follow-up data (n = 70) from patients with CF (age ≥12 years, FEV1 ≥35%) were analysed. Patients participated in two multi-centre exercise intervention studies with identical assessment methodology. Outcome variables included HRQoL (German revised multi-dimensional disease-specific CFQ (CFQ-R)), body composition, pulmonary function, physical activity, short-term muscle power, and aerobic fitness by peak oxygen uptake and aerobic power. RESULTS: Peak oxygen uptake was positively related to 7 of 13 HRQoL scales cross-sectionally (r = 0.30-0.46). Muscle power (r = 0.25-0.32) and peak aerobic power (r = 0.24-0.35) were positively related to 4 scales each, and reported physical activity to 1 scale (r = 0.29). Changes in HRQoL-scores were directly and significantly related to changes in reported activity (r = 0.35-0.39), peak aerobic power (r = 0.31-0.34), and peak oxygen uptake (r = 0.26-0.37) in 3 scales each. Established associates of HRQoL such as FEV1 or body mass index correlated positively with fewer scales (all 0.24 < r < 0.55). CONCLUSIONS: HRQoL was associated with physical fitness, especially aerobic fitness, and to a lesser extent with reported physical activity. These findings underline the importance of physical fitness for HRQoL in CF and provide an additional rationale for exercise testing in this population. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00231686.

Effect of supervised training on FEV1 in cystic fibrosis: a randomised controlled trial.

BACKGROUND: Long-term exercise interventions have been shown to improve vital capacity in cystic fibrosis (CF). Yet, no data are available indicating positive effects of long-term exercise training on FEV1. METHODS: 39 Swiss patients with CF were randomly divided into strength training (ST, n=12), endurance training (AT, n=17) and controls (CON(CH), n=10), and also compared with age-matched Swiss (n=35) and German (n=701) CF registry data. A partially supervised training of 3×30 min/week for 6 months took place with measurements at baseline and after 3, 6, 12 and 24 months. Primary outcome was FEV1 at 6 months. RESULTS: FEV1 increased significantly in both training groups compared with CON(CH) (AT:+5.8±0.95, ST:+7.4±2.5, CON(CH):-11.5±2.7% predicted, p<0.001) and both registry groups at 6 months. At 24 months, changes in favour of the training groups persisted marginally compared with CONCH, but not compared with registry data. CONCLUSIONS: A partially supervised training over 6 months improved FEV1 but effects were basically gone 18 months off training. Regular long-term training should be promoted as essential part of treatment in CF.

Epidemiology and survival of patients with hepatocellular carcinoma in Southern Germany.

Hepatocellular carcinoma (HCC) belongs to the most frequent tumors worldwide with an incidence still rising. Patients with cirrhosis are at the highest risk for cancerogenesis and are candidates for surveillance, and here, as well as for the choice of potential forms of treatment, identification of suitable parameters for estimating the prognosis is of high clinical importance. The aim of this study was to describe the etiology of underlying liver disease and to identify predictors of survival in a large single center cohort of HCC patients in Southern Germany. Clinicopathologi-cal characteristics and survival rates of 458 patients (83.6% male; mean age: 62.5+/-11.2 years) consecutively admitted to a University Hospital between 1994 and 2008 were retrospectively analyzed. The results indicate that chronic alcohol abuse was the most common risk factor (57.2%), followed by infection with hepatitis B and C viruses (HBV: 10.9% and HCV: 20.5%). Overall median survival was 19.0 months, and higher OKUDA, CHILD and CLIP scores correlated negatively with prognosis. Of these, only the CLIP Score was an independent predictor in multivariate analysis. We conclude that chronic alcohol abuse is frequently associated with HCC in low hepatitis virus endemic areas, such as Germany. Our study suggests the CLIP score as a valuable prognostic marker for patients' survival, particularly of patients with alcohol related HCC.

Risks associated with exercise testing and sports participation in cystic fibrosis.

BACKGROUND: Severe adverse reactions (SARs) associated with physical exercise have not been systematically studied in cystic fibrosis (CF). METHODS: Two surveys were conducted to assess the incidence of exercise-related SARs: a caregiver survey asking for complications associated with exercise testing and in-hospital training therapy and a web-based patient survey asking for problems with exercise. RESULTS: 78 of 107 CF facilities caring for 4208 patients responded to the caregiver survey, 256 patients answered the web-based survey. No SARs were reported for 713 exercise tests. With in-hospital training, the yearly incidence of exercise-related SARs such as pneumothorax, cardiac arrhythmia, injury or hypoglycaemia was <1% each, the respective lifetime incidences reported by the patients were 0.8-6.3%. 67% of the patients reported no SARs with exercise. CONCLUSIONS: Exercise testing is safe in patients with CF. Despite the limitations in quality of data, the incidence of exercise-related SARs appears low in this population.

Persistence of Candida species in the respiratory tract of cystic fibrosis patients.

It is still controversial as to whether Candida spp. are transient or persistent colonizers of the respiratory tract of cystic fibrosis (CF) patients. We conducted a prospective study of 56 CF patients over a 30 month period to assess the distribution and persistence of different Candida spp. In vitro antifungal susceptibility testing was performed and the C. albicans isolates were typed with CARE-2 hybridization and other Candida spp. by RAPD-PCR for persistence and transmission. We found that the mean persistence of the most frequent Candida spp. was >or= 9 months. In patients from whom more than 10 isolates were recovered, we noted that at least 30% were genetically related and transmission of C. albicans in siblings was observed. The majority of all isolates were susceptible to all antifungals tested. We concluded that there was long-term persistence of Candida in the respiratory tract of CF patients and that transmission between siblings may be one possible means of acquisition. Whether long-term colonization with Candida strains can contribute to the chronic infection and inflammation in the CF lung requires further investigation.

Molecular typing and colonization patterns of Aspergillus fumigatus in patients with cystic fibrosis.

Aspergillus fumigatus is a chronic colonizer of the respiratory tract of patients with cystic fibrosis (CF). A total of 204 A. fumigatus isolates from 36 CF patients from three different medical centers, collected over a period of four months till 9.5 years, were genotyped using the short tandem repeat panel for A. fumigatus (STRAf assay). Four different colonization patterns were observed. Colonization patterns with only unique genotypes were found in 36% of the patients. In contrast 17% of the patients were chronically colonized with a single genotype. The remaining patients showed a predominant genotype or genotypes that succeed each other. In this collection no relation was found between colonization patterns and allergic bronchopulmonary aspergillosis.

Hypertonic saline inhibits luminal sodium channels in respiratory epithelium.

Physical exercise with increased ventilation leads to a considerable rise in water loss from the airways. The mechanisms underlying the regulation of transepithelial fluid transport necessary to compensate for these losses are unknown but may include changes in luminal ion channel conductance. The present study was designed to examine the effects of an increase in luminal chloride and sodium concentrations which may locally occur during hyperventilation on luminal ion conductance in the respiratory epithelium of healthy controls and patients diagnosed with cystic fibrosis (CF). Changes in luminal chloride and sodium conductance were inferred by recording nasal potential difference in eight healthy subjects and 10 patients with CF, using superfusing solutions based on isotonic saline (150 mM) on one occasion and solutions based on hypertonic saline (300 mM) on the other. Switching from isotonic to hypertonic saline superfusion decreased potential difference in controls and CF patients significantly. Amiloride induced a decrease of potential difference which was larger with isotonic than with hypertonic saline (controls 9.5 +/- 6.1 vs. 3.7 +/- 4.6 mV; CF 17.2 +/- 7.2 vs. 9.8 +/- 7.6 mV). Chloride conductance stimulated with solutions low in chloride and containing isoproterenol was not significantly changed by hypertonic saline solutions compared with isotonic solutions in both groups. The findings indicate a significant inhibition of luminal sodium conductance by high luminal sodium concentrations. This mechanism may be involved in the regulation of fluid transport across the respiratory epithelium during exercise and in the improvement of mucociliary clearance and lung functions with inhalation of hypertonic saline in CF.

Oxygen uptake kinetics are slowed in cystic fibrosis.

PURPOSE: There are conflicting reports on the kinetics of oxygen uptake at the onset of exercise in patients with cystic fibrosis (CF). The objective of the present study was, therefore, to compare oxygen uptake (VO(2) kinetics in patients with CF with those of healthy controls (CON). METHODS: Eighteen CF patients (FEV1 37-98% predicted) and 15 CON aged 10-33 yr completed two to four transitions from low-intensity cycling (stage 1, 20 W) to cycling at 1.3-1.4 W.kg(-1) body weight (stage 2). There was no difference between groups in heart rate at stages 1 and 2 or in relative exercise intensity, as expressed as percent VO(2peak) or percentage of ventilatory threshold. However, oxygen saturation (SpO(2)) was lower in the patients with CF during both stages. VO(2) data were interpolated second by second, time-aligned, and averaged. Monoexponential equations were used to describe phase II VO(2) responses. RESULTS: Although there were no differences between CF and CON in amplitude (10.9 +/- 1.8 vs 10.2 +/- 1.6 mL O2.W(-1)) of phase II VO(2) response, the time constant tau was significantly prolonged in CF compared with CON (36.8 +/- 13.6 vs 26.4 +/- 9.1 s). When tau was adjusted for the effects of FEV1 or SpO(2) during submaximal exercise, the difference between CF patients and controls disappeared. CONCLUSION: VO(2) kinetics are slowed in CF, which may, in part, be attributed to an impairment of oxygen delivery.

Assessment of human pulmonary function using oxygen-enhanced T(1) imaging in patients with cystic fibrosis.

Indirect qualitative MRI of pulmonary function is feasible using the paramagnetic effects of oxygen physically dissolved in blood. In this study, a more quantitative oxygen-enhanced pulmonary function test based on the slope of a plot of R(1) vs. oxygen concentration-the oxygen transfer function (OTF)-was developed and tested in a pool of five healthy volunteers and five patients with cystic fibrosis (CF). The lung T(1) relaxation rate, R(1), under normoxic conditions (room air, 21% O(2)), and the response to various hyperoxic conditions (40%-100% O(2)) were studied. Lung T(1) in healthy volunteers showed a relatively homogeneous distribution while they breathed room air, and a homogeneous decrease under hyperoxic conditions. Lung T(1) in CF patients showed an inhomogeneous distribution while they breathed room air, and the observed lung T(1) decrease under hyperoxia depended on the actual state of the diseased lung tissue. In the selected group of CF patients, areas with reduced OTF also showed reduced perfusion, as confirmed by qualitative contrast-enhanced MR pulmonary perfusion imaging. The results demonstrate that this completely noninvasive oxygen-enhanced pulmonary function test has potential for clinical applications in the serial diagnosis of lung diseases such as CF. .

Exercise testing and training in German CF centers.

Physical exercise is increasingly recognized as a valuable diagnostic and therapeutic modality for patients with cystic fibrosis (CF). We sought to characterize the use of exercise testing and training as well as the attitude toward both issues through a national survey. A questionnaire was sent to 107 specialized CF centers (caring for a total of 5,231 patients) and 7 inpatient rehabilitation institutions. Answers were available from 62 specialized centers caring for 3,580 patients and from 4 rehabilitation centers with 520 treatment episodes per year. Sixty percent of specialized centers performed some sort of exercise testing at an average frequency of 1 in 2.3 years for patients aged 8 and above. However, protocols and indication criteria were often unstandardized or not specified at all. Equipment availability was no major problem, and the majority of tests were conducted by a physician alone. Nineteen centers had adopted exercise testing as part of their diagnostic routine. Two thirds of caregivers advised their patients to engage in physical activity, but failed to discuss specific modalities and potential hazards. Nevertheless, physical exercise was viewed as "extremely important" or "very important" by 87%. In a rehabilitation setting, an exercise test was conducted 1.1 times per patient stay, and a training program offered in 100% of cases. In conclusion, standardized exercise testing and training programs appear to be underused in German CF centers, despite a high degree of interest in the topic. Supplementary material for this article can be found on the Pediatric Pulmonology website (http//www.interscience.wiley.com/jpages/8755-6863/suppmat).

Quantitative perfusion mapping of the human lung using 1H spin labeling.

PURPOSE: To evaluate the feasibility and reproducibility of a noninvasive, rapid and quantitative pulmonary perfusion mapping method using a two-compartment tissue model in combination with a (1)H spin labeling technique. MATERIALS AND METHODS: Ten healthy volunteers and three patients with cystic fibrosis (CF) were examined on a 1.5-T whole-body scanner. Global and selective lung T(1) maps based on an inversion recovery Snapshot FLASH technique were acquired from each subject with breath-holds at end-expiration. For comparison, corresponding Gd-DTPA-enhanced (1)H MR perfusion images were also obtained from each CF patient. RESULTS: Quantitative perfusion maps were calculated from the global and selective T(1) maps. The measured perfusion rates of the upper right lung in volunteers ranged from 400 to 600 mL/100 g/minute. The method showed a high intra-study reproducibility and low relative errors. In CF-patients, perfusion defects detected using Gd-DTPA-enhanced MR imaging were also detected using the spin labeling method. The perfusion rates of diseased lung tissues were less than 200 mL/100 g/minute. CONCLUSION: Noninvasive, robust and quantitative (1)H MR mapping of pulmonary perfusion was successfully performed using a rapid lung T(1) mapping in combination with spin labeling within the imaging slice. The proposed method has the potential to provide both important qualitative functional information and quantitative pulmonary perfusion rates in various lung diseases at various stages without the need of contrast agents.

Magnetization transfer short inversion time inversion recovery enhanced 1H MRI of the human lung.

The unique characteristics of the human lung arising from low proton density and multiple air-tissue interfaces of the alveoli cause difficulty in 1H lung magnetic resonance imaging. In addition, the dominating signal from sources such as the thoracic muscle and subcutaneous fat hampers the visualization of the lung parenchyma. In this contribution, an efficient tissue suppression technique is presented which allows one to significantly enhance lung parenchyma visibility. A short inversion time inversion recovery (STIR) experiment combined with a magnetization transfer (MT) experiment was used for magnetization preparation in order to suppress the signal from muscle. A half-Fourier single-shot turbo spin-echo sequence was used as acquisition module. This approach was used to perform lung anatomical imaging in eight healthy human subjects and five patients with cystic fibrosis. The results obtained demonstrate that with MT-STIR approach high quality human lung images can be obtained and that this approach has the potential for the evaluation of lung pathologies.