Guideline on the design and conduct of cystic fibrosis clinical trials: the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN).

We describe the rationale for disease specific research networks in general as well as the aims and function of the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) specifically. The ECFS-CTN was founded in 2009 with the aim of improving the quality and quantity of clinical research in the area of cystic fibrosis (CF) in Europe. A network of 18 clinical trial sites in 8 European countries was established according to uniform state-of-the-art quality criteria. To support the ECFS-CTN in the acquisition, planning and conduct of clinical trials, the network is equipped with a coordinating centre, steering and executive committees, and committees for protocol review, standardization, training and networking as well as a data safety monitoring board. A strong partnership with European CF patient parent organizations aims to increase awareness of the need for efficient clinical research and the participation of patients in clinical trials.

Bronchiolitis obliterans organizing pneumonia in a patient with non-Hodgkin's lymphoma following R-CHOP and pegylated filgrastim.

Bronchiolitis obliterans organizing pneumonia (BOOP) presents with fever, dyspnoea, pleuritic chest pain and hypoxia. The diagnosis can be made from radiological appearances on chest radiograph and CT scan correlated with histological findings following biopsy. We present a 52-year-old gentleman undergoing treatment for high grade non-Hodgkin's lymphoma who developed respiratory symptoms during chemotherapy. BOOP was diagnosed and he responded well to oral prednisolone. The cause of BOOP is often not certain. However, in this case we suspect pegylated filgrastim or rituximab as possible agents.

Subjective benefit of inhaled therapies in patients with bronchiectasis: a questionnaire study.

The objectives of this study were to obtain information about the use and subjective benefits of inhaled therapies in patients with bronchiectasis and to determine if these benefits were related to the presence of airflow obstruction. One hundred and twenty patients completed a questionnaire on inhaled therapies and performed spirometry. Inhalers were used daily by 85/120 patients with bronchiectasis and 42/120 patients had a nebuliser. Inhaled therapies were used extensively in patients with (FEV1 < 80%) and without (FEV1 > 80%) evidence of airflow obstruction. The majority of patients reported subjective benefits from their inhaled therapies. Chi2 analysis showed that there was no association between perceived benefits of short acting bronchodilators (SAB), long acting bronchodilators (LAB), corticosteroids or nebulisers and degree of airflow obstruction. This study provides information about the subjective benefits of inhaled therapies which could facilitate a more comprehensive assessment of the net benefit of inhaled therapies in patients with bronchiectasis with and without airflow obstruction.

Burkholderia cepacia complex genomovars and pulmonary transplantation outcomes in patients with cystic fibrosis.

Burkholderia cepacia is a group of organisms that comprises seven genotypically distinct species (B cepacia genomovars I-VII), which are collectively known as the B cepacia complex. Preoperative infection with B cepacia is associated with a poor prognosis in lung transplant recipients with cystic fibrosis. Many centres do not, therefore, offer transplants to these individuals. Our aim was to ascertain whether or not post-transplant mortality is affected by pretransplant genomovar status. We studied archived isolates with PCR-based methods, and recorded excessive mortality in patients infected with B cepacia genomovar III, but not in those infected with other genomovars.

Individuals with cystic fibrosis do not display impaired endothelial function or evidence of oxidative damage in endothelial cells exposed to serum.

Heightened systemic oxidative stress is increasingly recognized as a feature of cystic fibrosis (CF). The consequences of long-term exposure to free radical attack include a predisposition to diseases such as cancer and atherosclerosis. An increased incidence of malignancy among adult patients with CF has been reported, but the absence of atherosclerotic disease is well described. The aim of the present study was to assess endothelial function in vivo and relate this to the potential of serum from patients with CF to induce oxidative-mediated damage in cultured human endothelial cells. A group of 11 CF patients was matched with a group of healthy volunteers with regard to age and sex. Endothelial function was assessed as endothelium-dependent and -independent vasodilation by measuring forearm blood flow in response to infused acetylcholine and sodium nitroprusside respectively. Confluent monolayers of cultured human endothelial cells were exposed to serum from CF patients and control subjects. Following exposure, cell death was assessed by lactate dehydrogenase release, and the degree of lipid peroxidation in the membrane was assessed by measuring the content of lipid hydroperoxides, malondialdehyde and 4-hydroxynonenal. Endothelial monolayers exposed to serum from CF patients released significantly less lactate dehydrogenase following exposure than those exposed to serum from healthy controls (1.8% and 3.0% respectively; mean difference -1.2%; 95% confidence intervals -1.9% to -0.1%; P<0.05) and contained significantly less 4-hydroxynonenal (0.75 and 3.41 micromol/g of protein respectively; mean difference -2.66 micromol/g; 95% confidence intervals -5.10 to -0.22 micromol/g; P<0.05). There was no significant difference between patients and controls in the extent of serum-induced membrane peroxidation, as assessed by malondialdehyde or lipid hydroperoxides, or in endothelial function, as assessed by forearm blood flow. In conclusion, despite evidence for heightened systemic oxidative stress in CF, patients displayed no impairment of endothelial function, and their serum caused significantly less damage to human endothelial cells than that from matched controls.

Pulmonary function, inflammation, exercise capacity and quality of life in cystic fibrosis.

The aim of the study was to determine the extent to which treatment induced changes in exercise capacity and quality of life (QoL) are related to spirometric measures of lung function and other measures of disease impairment. Twenty patients admitted to hospital with an exacerbation of pulmonary disease were recruited. Measures of disease impairment, disability and QoL were obtained at the beginning and end of an intravenous course of antibiotic therapy. Intravenous antibiotic treatment resulted in a significant improvement in all measures of disease impairment, disability and handicap. The only significant predictor of treatment induced change in exercise capacity was C-reactive protein (CRP) and this explained 28% of the variance in change in exercise capacity. In the case of QoL, two predictors (change in exercise capacity and sputum output) contributed significantly to the change in QoL and collectively explained 54% of the variance in QoL. Lung function provides a limited index of treatment outcome. Exercise capacity and quality of life assessment have the potential to make a significant contribution to the decision making process regarding treatment choices in cystic fibrosis and should be measured directly if a comprehensive evaluation of the effect of treatment is required.

Reliability, repeatability, and sensitivity of the modified shuttle test in adult cystic fibrosis.

STUDY OBJECTIVES: The purpose of this study was to investigate the test-retest reliability, repeatability, and sensitivity of the modified shuttle test (MST) in adult patients with cystic fibrosis (CF). DESIGN: : Prospective study. SETTING: Adult CF Unit, Belfast City Hospital. PATIENTS: : Adult patients with CF. INTERVENTIONS: Test-retest reliability-none; sensitivity-inpatient IV antibiotic therapy for an acute exacerbation of respiratory disease. MEASUREMENTS: The test-retest reliability and repeatability of the MST was assessed by comparing performance on two consecutive MSTs performed in 12 patients with CF and stable disease. The sensitivity of the MST was assessed by measuring the change in MST performance after 2 weeks of IV antibiotic therapy in 24 patients admitted to hospital with acute exacerbations of their respiratory disease. RESULTS: In the assessment of test-retest reliability and repeatability (n = 12), there was a significant and strong correlation between trials for distance completed (Pearson's r = 0. 99; p < 0.01), peak heart rate (Pearson's r = 0.99; p < 0.01), peak arterial oxygen saturation (SaO(2); Pearson's r = 0.99; p < 0.01), and peak Borg rating of perceived breathlessness (Pearson's r = 0. 99; p < 0.01). The coefficients of repeatability for these variables were small (coefficient of repeatability: distance completed, 4 shuttles; peak heart rate, 6 beats/min; peak SaO(2), 4%; and peak Borg rating of perceived breathlessness, 0.9). In the assessment of sensitivity (n = 24), the standardized response mean (SRM) for distance completed on MST (SRM = 1.18) was the SRMs for spirometric measures of lung function (FEV(1), SRM = 0.96; FEV(1) percent predicted, SRM = 0.88). CONCLUSIONS: This study demonstrates that the MST is a reliable, repeatable, and sensitive measure of exercise capacity in adult CF. The MST may be of value in determining prognosis, evaluation for lung transplantation, exercise prescription, and establishing the impact of new treatments on the disability associated with CF.

Breath isoprene during acute respiratory exacerbation in cystic fibrosis.

Patients with cystic fibrosis (CF) experience a combination of chronic systemic oxidative stress, generation of free radicals in the lungs due to a hyperimmune response and a diminished ability to scavenge free radicals secondary to malabsorption and increased consumption. The authors asked the question, "Does breath isoprene content reflect systemic oxidative stress?" The study involved 12 CF patients and 12 matched healthy controls. The patients were sampled during acute respiratory exacerbation (increased respiratory symptoms, reduction in forced expiratory volume (FEV1) of >10%, and a decision to treat with intravenous antibiotics) and after two weeks of antibiotic treatment. Blood samples were examined for markers of oxidative stress. Breath samples were analysed for isoprene content. Malondialdehyde (MDA), erythrocyte membrane polyunsaturated fatty acids, protein sulphydryls and protein carbonyls all showed evidence of increased oxidative stress which was moderated by antibiotic treatment. Breath isoprene production rate was significantly lower in patients during exacerbation than in controls with a mean difference of-39 (95% confidence interval (CI) -11-57) pmol.min.kg(-1) and increased to normal values following treatment (mean change 63 (95% CI 42-84) pmol.min.kg(-1)). In conclusion, breath isoprene cannot be considered a reliable marker of oxidative stress.

The adaptations of a quality of life questionnaire for routine use in clinical practice: the Chronic Respiratory Disease Questionnaire in cystic fibrosis.

The assessment of quality of life (QoL) is necessary to monitor the course of disease and to assess the effect of new and existing interventions in clinical practice. This will only be achieved if QoL can be measured accurately and routinely. The aim of this study was to demonstrate the methodology involved in the adaptation and shortening of the Chronic Respiratory Disease Questionnaire (CRDQ) in a population of adults with cystic fibrosis (CF). A single interviewer administered the CRDQ to a sample of 45 adult patients (32 males) with CF prior to assessment of spirometric measures of lung function. Those patients whose lung function was stable at the time of study and who could attend for a retest within 14 days were asked to complete the questionnaire at a subsequent visit (n = 10). The mean interval between visits was 7 days (range 5-14 days). Correlations between spirometry and CRDQ dimensions ranged from -0.003 to 0.426. The fatigue, emotion and mastery dimensions showed high internal consistency and adequate construct validity. In the small number of patients suitable for retest, the results indicated that the dimensions exhibited adequate test-retest reliability. In contrast, low internal consistency was demonstrated for the dyspnoea dimension. The fatigue, emotion and mastery dimensions could be reduced, in terms of their number of items, without a substantial loss in explanatory power. This study suggests that QoL measurement can be made convenient and, thus, more easily accessible for routine clinical assessment.

Oxidative stress during acute respiratory exacerbations in cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis experience chronic systemic oxidative stress. This is coupled with chronic inflammation of the lung involving bronchial polymorphonuclear neutrophil accumulation and activation. We hypothesised that, during periods of acute respiratory exacerbation, free radical activity and consequent damage would be most marked and that intensive treatment of the infection would result in improvement towards values found during stable periods. METHODS: Plasma and red blood cells were collected from 12 healthy normal volunteers and from 12 patients with cystic fibrosis with an acute respiratory exacerbation (increased respiratory symptoms, reduction in forced expiratory volume in one second (FEV1) of more than 10%, and a decision to treat with intravenous antibiotics). Further samples were collected from patients following two weeks of treatment. Samples were analysed for inflammatory markers, markers of free radical damage, and aqueous and lipid phase scavengers. RESULTS: During respiratory exacerbations FEV1 and forced vital capacity (FVC) were lower than in controls (mean differences -2.82 (95% CI -2.12 to -3.52) and -3. 79 (-3.03 to -4.55) l, respectively) but improved following treatment (mean change 0.29 (95% CI 0.18 to 0.40) and 0.33 (0.23 to 0.43) l, respectively). Inflammatory markers during exacerbations were significantly higher in patients than in controls with the following mean (95% CI) differences: C reactive protein (CRP), 46 (17 to 75) g/l; neutrophil elastase alpha1-antiprotease complexes (NEAPC), 4.4 (1.77 to 7.07) mg/l; white cell count (WCC), 5.3 (4.7 to 5.9) x 10(9)/l. These markers decreased significantly following treatment with the following mean (95% CI) changes: CRP -26 (-10 to -42) g/l; NEAPC -3.1 (-1.3 to -4.9) mg/l; WCC -1.5 (-1.3 to -1.7) x 10(9)/l. Malondialdehyde (MDA) as a marker of free radical activity was significantly higher in patients during exacerbations than in controls with a mean (95% CI) difference of 193 (107 to 279) which improved with treatment (mean change -56 (95% CI -28 to -84) nmol/mmol cholesterol). Red blood cell polyunsaturated fatty acids were significantly lower in patients than in controls with a mean difference of -4.4(95% CI -2.6 to -6.2) moles percent, but did not improve significantly after treatment. Protein carbonyls during exacerbations were not different from controls but did increase with treatment compared with levels during the exacerbation (mean change 0.39 (95% CI 0.11 to 0.67) micromol/g protein). Aqueous and lipid phase scavengers in patients during exacerbations were significantly lower than in controls with the following mean (95% CI) differences: ascorbate, -19.0 (-2.7 to -35.3) micromol/l; sulphydryls, -122 (-77 to -167) micromol/l; retinol, -237 (-47 to -427) nmol/mmol cholesterol; beta-carotene, -52.8 (-11.8 to -93.8) nmol/mmol cholesterol; luteine, -50.4 (-10.4 to -90.4) nmol/mmol cholesterol; lycopene, -90.1 (-30.1 to -150.1) nmol/mmol cholesterol. Treatment resulted in improvement with the following mean (95% CI) changes: sulphydryls, 50 (32 to 68) micromol/l; retinol, 152 (47 to 257) nmol/mmol cholesterol; alpha- and beta-carotene, 0.6 (0.0 to 1.2) and 7.6 (0.0 to 15.2) nmol/mmol cholesterol, respectively; alpha-tocopherol, 839 (283 to 1405) nmol/mmol cholesterol; and lycopene, 8.2 (0.0 to 16.2) nmol/mmol cholesterol. CONCLUSIONS: Abnormalities of markers of inflammation, free radical activity, and radical scavengers were significantly more extreme during acute respiratory exacerbations and showed improvement with treatment. The need to provide protection from inflammation and free radical damage should therefore be dynamic and related to the inflammatory and oxidative processes.

Validity of a modified shuttle test in adult cystic fibrosis.

BACKGROUND: The purpose of this study was to provide some evidence of the validity of a modified shuttle test (MST) by comparing performance on the MST with peak oxygen consumption (VO2peak) measured during a treadmill test in a group of adult patients with cystic fibrosis. METHOD: Twenty patients with stable cystic fibrosis performed a ramped maximal treadmill test (STEEP protocol) and the MST using a randomised balanced design. RESULTS: The relationship between the distance achieved on the MST and VO2peak was strong (r = 0.95, p<0.01) with 90% of the variance in VO2peak explained by the variance in MST distance. The relationship was represented by the regression equation (with 95% confidence intervals) VO2peak = 6.83 (2.85 to 10.80) + 0.028 (0.019 to 0.024) x MST distance. CONCLUSION: This study provides evidence of the construct validity of the MST as an objective measure of exercise capacity in adults with cystic fibrosis.

The management of young adults with cystic fibrosis: 'genes, jeans and genies'.

Cystic fibrosis is now an adult disease. The understanding of the basic pathophysiology of this disease has increased considerably over the past decade. This has resulted in effective management protocols and the development of innovative approaches to therapy. Management of young adults is complex and requires expert medical care delivered in a sensitive and appropriate way. The daily treatment schedule for many adults involves physiotherapy; nebulized, oral and i.v. drugs; exercise and nutritional supplements. Adherence to such treatment while living a busy school, work and social life is extremely difficult for patients. The psychological implications of having a disease with very significant morbidity and mortality also has an enormous impact on individuals with CF. Many of these issues have evolved as survival has increased and the next few decades may produce more unexpected 'genies'. These may be from the disease itself or from some of the exciting new treatments currently being developed. It is important that individuals with CF are fully involved in decisions relating to their treatment and that CF teams provide optimal and appropriate care to enable these young adults to enjoy their lives to the fullest extent.

Misleading experiments.

Everyone, including myself, wants to see advances in medical research, but animal experiments, because other species differ from humans, are intrinsically unreliable and misleading, and therefore dangerous. They are also inhumane and sickeningly cruel.

The pharmacokinetics of sulphasalazine in young and elderly patients with rheumatoid arthritis.

The clinical pharmacokinetics of enteric-coated sulphasalazine (Salazopyrin-EN) were studied after acute and chronic dosing in 20 patients with 'active' rheumatoid arthritis. 12 elderly (mean age 74.4 +/- 1 yr; range 71-83) and 8 young (mean age 40.5 +/- 1.4 yr; range 35-46) patients were given a single 2 g oral dose of sulphasalazine after an overnight fast. Serum and urine samples were collected at regular intervals over a 96 hour period for estimation of concentrations of sulphasalazine, sulphapyridine and its metabolites. This procedure was repeated after 17 days of continuous treatment with salazopyrin-EN 2 g daily in order to compare the drug's kinetics at 'steady-state'. Whilst the interindividual variation in kinetic parameters was large, age and acetylator status had a significant influence on a number of factors. The elimination half-life of sulphasalazine was prolonged in the elderly whilst renal clearance was increased in slow acetylators at 'steady-state'. The tmax and apparent volume of distribution of sulphapyridine were increased in the elderly after a single drug dosage but these differences disappeared with regular dosing. The Cmax, elimination half-life, 'steady-state' serum concentration, apparent volume of distribution and total clearance of sulphapyridine were all affected by acetylator status. We conclude that old age has only a minor effect on the body's handling of sulphasalazine and sulphapyridine but that acetylator phenotype plays a significant role in determining the 'steady-state' serum concentrations of sulphapyridine. This is likely to have practical implications with regard to some of the drug's adverse effects.