Long-term effects of a partially supervised conditioning programme in cystic fibrosis.

Little is known about the long-term persistence of positive effects induced by a physical conditioning programme in cystic fibrosis. Therefore, this study determined the effects of a 6-month conditioning programme on peak oxygen uptake (primary outcome) and other markers of fitness, physical activity, anthropometry, lung function and quality of life (secondary outcomes), 18 and 24 months after the programme was initiated. Patients with cystic fibrosis aged 12-40 yrs were randomly assigned to an intervention (n = 23) and a control (n = 15) group. The intervention group consented to add 3 h of sports per week for > or =6 months to their previous activities. Controls were asked to maintain their level of activity for 12 months. Patients were seen at baseline and after 3, 6, 12, 18 and 24 months. There was no significant difference between groups at baseline. The intervention induced positive effects on peak oxygen uptake (difference in changes from baseline to the 18- and 24-month assessments between groups: 3.72+/-1.23 mL.min(-1).kg(-1); p<0.01), maximal workload (0.37+/-0.11 W.kg(-1); p<0.01), vigorous physical activity (1.63+/-0.82 h.week(-1); p<0.05), forced vital capacity (6.06+/-2.87% predicted; p<0.05) and perceived health (9.89+/-4.72; p<0.05). A home-based partially supervised physical conditioning programme can improve physical fitness, lung function and perceived health long after the intervention has ended.

Tobramycin once- vs thrice-daily for elective intravenous antipseudomonal therapy in pediatric cystic fibrosis patients.

PURPOSE: We hypothesized that a single intravenous (iv) tobramycine infusion (treatment B) would have equivalent anti-infectious efficacy in chronic Pseudomonas aeruginosa (PA) infection in cystic fibrosis (CF) as the commonly performed treatment of three doses (treatment A) . Toxicity and practicability may even be improved in the single-dose regimen. METHODS: This was a randomized crossover study comparing outcome after 14 and 35 days. The primary end-point was a decrease in the leukocyte count, and the secondary end-points were clinical and lung function parameters, Pseudomonas quantification in sputum, and inflammation markers (immunoglobulin G, C-reactive protein) in serum. 30 patients (20 female, mean age 11.2 years, mean age range 1.7-18.1 years) received elective 14-day courses of treatments A or B, followed by the alternative treatment after a mean interval of 37 (+/- 21) weeks. RESULTS: With the exception of PA density, there were no significant differences between both treatment strategies after 14 days of treatment. After 35 days of treatment, there were no significant changes in the leukocyte count and inflammation markers. Both treatment strategies reduced the bacterial load in the airways, as reflected by a decreased PA density in sputum. Nephrotoxicity was equal in both groups, with a transient slight elevation of urinary N-acetyl-beta-glucosaminidase concentrations. Standard audiometry tests revealed no evidence of a hearing impairment in any patient following therapy. Mean body weight increased during the study period by 0.5 kg. Forced expiratory volume increased by approximately 5% of the predicted volume, forced vital capacity increased by 2% of predicted capacity, and forced mid expiratory flow rate increased by 7% (A) or 4% (B) of the predicted normal value, although these changes were not statistically significant. CONCLUSION: We conclude that tobramycin given in a daily single dose (with the advantage of being more practical in a home environment) has an efficacy equal to that of three daily doses in terms of elective antipseudomonal therapy in clinically stable patients with CF.

Continuous vs thrice-daily ceftazidime for elective intravenous antipseudomonal therapy in cystic fibrosis.

BACKGROUND/AIM: We hypothesized that a continuous 24-h infusion of 100 mg/kg per day ceftazidime (treatment C) would result in equivalent or even superior anti-infectious efficacy in chronic Pseudomonus aeruginosa (PA) infection in patients with cystic fibrosis (CF) in comparison to the usual application of 200 mg/kg per day ceftazidime in three doses (treatment T). METHODS: This was a randomized crossover study comparing outcome after 14 days and 35 days. Tobramycin administered once daily (10 mg/kg per day) was administered concomitantly in both groups. The primary end-point was a decrease in the leukocyte count, and the secondary endpoints were clinical and lung function parameters, Pseudomonas quantification in sputum, and inflammation markers (immunogloblulin [Ig] G, C-reactive protein [CRP]) in serum. All patients received antibiotics electively as 14-day courses on a regular basis, not for acute exacerbations. RESULTS: Fifty-six patients (29 females, mean patient age 14.4 years, age range 5-37) initially received treatments C or T, followed by the alternative treatment after a mean interval of 37 (+/- 21) weeks. After 2 weeks of antibiotic treatment, the overall study group showed significant improvements compared to baseline for body weight, leukocyte counts, CRP, forced expiratory volume in 1 s (FEV(1)), FVC (forced vital capacity), and bacterial load in the airways, with no significant differences between treatment groups. Both regimens were well tolerated. Three weeks after cessation of antimicrobial therapy, leukocytes and PA density had returned to pre-treatment values. CONCLUSION: We conclude that continuous or thrice-daily dosing of intravenous ceftazidime, both combined with once-daily tobramycin, are equally effective application regimens for elective antipseudomonal therapy in clinically stable patients with CF.

[Lung transplantation in cystic fibrosis--a position paper]. / Lungentransplantation bei Mukoviszidose--ein Positionspapier.

Lung transplantation in cystic fibrosis is an established therapy, due to the fact that vast majority of adult CF patients will develop respiratory failure. Even adolescents and children can be transplanted successfully today. Lung transplantation in cystic fibrosis requires special consideration concerning candidate selection, surgery and postoperative follow-up care. Due to a donor shortage and increasing waiting time, early referral to transplant centres of potential candidates is crucial. In the process of candidate selection, assumed improvements in quality of life and survival benefit should be weighed against contraindications. Centre-based follow-up and close cooperation with local physicians are key factors for success. During follow-up care, the transplantation team should be contacted immediately in the case of any problem or change in medication.

Respiratory viral infections within one year after pediatric lung transplant.

To characterize epidemiology and risk factors for respiratory viral infections (RVI) in pediatric lung transplant recipients within the first post-transplant year, a retrospective multicenter study of pediatric lung transplant recipients from 1988 to 2005 was conducted at 14 centers in the United States and Europe. Data were recorded for 1 year post transplant. Associations between RVI and continuous and categorical risk factors were assessed using Wilcoxon's rank-sum and chi(2) tests, respectively. Associations between time to RVI and risk factors or survival were assessed by multivariable Cox proportional hazards models. Of 576 subjects, 79 subjects (14%) had 101 RVI in the first year post transplant. Subjects with RVI were younger than those without RVI (median ages 9.7, 13; P<0.01). Viruses detected included adenovirus (n=25), influenza (n=9), respiratory syncytial virus (n=21), parainfluenza virus (n=19), enterovirus (n=4), and rhinovirus (n=22). In a multivariable model for time to first RVI, etiology other than cystic fibrosis (CF), younger age, and no induction therapy were independently associated with risk of RVI. Cytomegalovirus serostatus and acute rejection were not associated with RVI. RVI was independently associated with decreased 12-month survival (hazard ratio 2.6, 95% confidence interval 1.6-4.4). RVI commonly occurs after pediatric lung transplantation with risk factors including younger age and non-CF diagnosis. RVI is associated with decreased 1-year survival.

Transient correction of the basic defect in sweat glands in an individual with cystic fibrosis carrying the complex CFTR allele F508del-R553Q.

The molecular pathology of mutant F508del CFTR is partially corrected in vitro by the secondary amino acid substitution R553Q in the ABC signature motif. An individual with the CFTR genotype R553X/F508del-R553Q showed the typical symptoms and electrophysiological anomalies of cystic fibrosis in the airways and intestine. Sweat chloride concentrations were normal early in life, but were later raised into the range that is diagnostic for cystic fibrosis, suggesting that R553Q could temporarily correct the basic defect in sweat glands. R553Q caused a delay in diagnosis because of false negative sweat tests but was not a disease reverting suppressor mutation as had been inferred from cellular models.

A novel sidestream ultrasonic flow sensor for multiple breath washout in children.

OBJECTIVE: Inert gas multiple breath washout (MBW) for measuring Lung Clearance Index using mass spectrometry and 4% sulfur hexafluoride (SF(6)) as the tracer gas has been shown to be sensitive for detecting early Cystic Fibrosis (CF) lung disease. However, mass spectrometry requires bulky equipment and is expensive to buy and maintain. A novel sidestream ultrasonic device may overcome this problem. The aims of this study were to assess the feasibility and clinical validity of measuring lung volume (functional residual capacity, FRC) and the LCI using the sidestream ultrasonic flow sensor in children and adolescents with CF in relation to spirometry and plain chest radiographs. PATIENTS AND METHODS: MBW using the sidestream ultrasonic device and conventional spirometry were performed in 26 patients with CF and 22 healthy controls. RESULTS: In the controls (4.7-17.7 years) LCI was similar to that reported using mass spectrometry (mean (SD) 6.7 (0.5)). LCI was elevated in 77% of the CF children (6.8-18.9 years), whereas spirometry was abnormal in only 38.5%, 61.5%, and 26.9% for FEV(1), MEF(25), and FEV(1)/FVC, respectively. This was more marked in children <10 years. LCI correlated with the Crispin-Norman score, whereas FEV(1) did not. CONCLUSIONS: Sidestream ultrasonic MBW is a valid and simple alternative to mass spectrometry for assessing ventilation homogeneity in children.

Diversity of the basic defect of homozygous CFTR mutation genotypes in humans.

BACKGROUND: Knowledge of how CFTR mutations other than F508del translate into the basic defect in cystic fibrosis (CF) is scarce due to the low incidence of homozygous index cases. METHODS: 17 individuals who are homozygous for deletions, missense, stop or splice site mutations in the CFTR gene were investigated for clinical symptoms of CF and assessed in CFTR function by sweat test, nasal potential difference and intestinal current measurement. RESULTS: CFTR activity in sweat gland, upper airways and distal intestine was normal for homozygous carriers of G314E or L997F and in the range of F508del homozygotes for homozygous carriers of E92K, W1098L, R553X, R1162X, CFTRdele2(ins186) or CFTRdele2,3(21 kb). Homozygotes for M1101K, 1898+3 A-G or 3849+10 kb C-T were not consistent CF or non-CF in the three bioassays. 14 individuals exhibited some chloride conductance in the airways and/or in the intestine which was identified by the differential response to cAMP and DIDS as being caused by CFTR or at least two other chloride conductances. DISCUSSION: CFTR mutations may lead to unusual electrophysiological or clinical manifestations. In vivo and ex vivo functional assessment of CFTR function and in-depth clinical examination of the index cases are indicated to classify yet uncharacterised CFTR mutations as either disease-causing lesions, risk factors, modifiers or neutral variants.

Cystic fibrosis in 65- and 67-year-old siblings. Clinical feature and nasal potential difference measurement in patients with genotypes F508del and 2789+5G-->A.

Cystic fibrosis (CF) is a recessive genetic disease caused by defects of the cystic fibrosis trans-membrane regulator (CFTR) gene with a median survival of less than 35 years. This work reports on the oldest living German siblings with CF. Besides clinical history, CF genotype and nasal potential difference (NPD) measurement results, the remarkably high exercise activity of the siblings is discussed as a disease-modifying factor. Both male patients have an overall mild pulmonary manifestation. They have suffered from abdominal symptoms since their early childhood, including recurrent pancreatitis and diffuse symptoms leading to partial gastric resection. They were diagnosed as having CF with positive sweat tests at the advanced ages of 45 and 43 years, respectively. Later on genotyping revealed compound heterozygosity for F508del and 2789+5G-->A. Using NPD we demonstrated a CF-typical inhibition of the NPD by the Na channel blocker amiloride, although in both siblings the remaining CFTR function and alternate chloride channel function were detected during superfusion of the nasal epithelium with isoproterenol and ATP. Long-term survival with CF is basically influenced by the CFTR genotype. The patients' genotype was discussed as a mild one with remaining CFTR function. We demonstrated this residual CFTR function in both siblings using NPD. Additionally the siblings' continuous healthy lifestyle and their engagement in a remarkably high level of exercise activities from early childhood to the present possibly have an important effect on the long-term outcome of CF as disease-modifying factors. In this regard this report can encourage CF patients to maintain a high level of physical activity in their daily lives.

Physical activity is independently related to aerobic capacity in cystic fibrosis.

It is unclear whether a relationship between physical activity (PA) and maximal oxygen uptake (V'(O2,max)) exists in cystic fibrosis (CF) and, if so, whether the relationship reflects a direct effect or is mediated by the effects of confounding variables, such as pulmonary or muscle function. The objective of the present study was to determine the relationship between PA and V'(O2,max) in CF while adjusting for possible influences of confounding factors. In total, 36 female and 35 male patients with CF from Germany and Switzerland (aged 12-40 yrs, forced expiratory volume in one second (FEV1) 25-107% predicted) were studied. A Wingate test was employed to measure muscle power. PA was monitored for 7 days and expressed in two ways: 1) average daily accelerometer count (ADAC) and 2) time spent in moderate-to-vigorous PA (MVPA). V'(O2,max) was determined during an incremental cycle exercise test to volitional fatigue. PA was positively related to V'(O2,max). In a multiple linear regression analysis, height, sex, FEV1, muscle power and ADAC (additionally explained variance 2.5%) or time spent in MVPA (additionally explained variance 3.7%) were identified as independent predictors of V'(O2,max). In conclusion, high levels of physical activity in addition to good muscular and pulmonary functions are associated with a high aerobic capacity in cystic fibrosis.

New criteria for impaired fasting glucose and screening for diabetes in cystic fibrosis.

Cystic fibrosis-related diabetes mellitus (CFRD) is the most frequent comorbidity in cystic fibrosis. Its clinical relevance is stressed by the association with increased mortality, and decreased pulmonary and nutritional status. An annual oral glucose tolerance test (OGTT) is recommended as a screening test for CFRD, but this is often not realised because of its time- and resource-consuming nature. Therefore, alternative approaches are welcome. In 2003, the American Diabetes Association (ADA) lowered the cut-off point separating normal from elevated fasting plasma glucose from <6.1 mmol x L(-1) to <5.6 mmol x L(-1), suggesting the performance of an OGTT only in those with impaired fasting glucose (IFG; range 5.6-6.0 mmol x L(-1)). The current authors tested whether this approach was reliable for the early identification of patients with CFRD. OGTTs from 1,128 patients (53% males; 47% females; median age 17.1 yrs) were available for analysis. A total of 101 (8.9%) OGTTs were classified as diabetic. The new ADA criteria for IFG increased the sensitivity to 82% (versus 65%) and decreased the specificity to 70% (versus 94%) compared with the old criteria used to identify patients with diabetic OGTTs. In conclusion, the American Diabetes Association approach of using impaired fasting glucose as an indication for performing selective oral glucose tolerance tests is definitely unsuitable when aiming at the early identification of patients with cystic fibrosis-related diabetes mellitus, and it cannot replace annual oral glucose tolerance tests.

[Isolation measurements for cystic fibrosis patients]. / Hygienemassnahmen für Patienten mit Cystischer Fibrose.

BACKGROUND: Respiratory tract infections significantly contribute to morbidity and mortality of cystic fibrosis patients. METHODS: We conducted a systematic literature review (Pubmed 01/1966 up to 09/2003) in order to present recommendations for the isolation of CF patients colonized with Burkholderia cepacia spp., Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Alcaligenes spp. Evidence and quality of 64 publications dealing with pathogen transmission or isolation measurements of colonized patients were evaluated. RESULTS: B. cepacia spp. was dealt most often with and 35 of 36 authors recommended the isolation of patients colonized with this pathogen. Isolation of patients colonized with P. aeruginosa was proposed by 21 of 25 authors. Only 5 studies concerned S. maltophilia or Alcaligenes spp. CONCLUSIONS: A) B. cepacia spp. colonized patients need to get a single room for their own. B) P. aeruginosa colonized CF patients should be separated from non-colonized CF patients. C) Patients harbouring even multi drug resistant P. aeruginosa, S. maltophilia or Alcaligenes spp. may not share their room with immunocompromised patients and should also be isolated when treated in intensive care units.

Low-dose methotrexate for advanced pulmonary disease in patients with cystic fibrosis.

UNLABELLED: Inflammation is a hallmark in the pathogenesis of pulmonary destruction in cystic fibrosis (CF). There is no proven effective systemic anti-inflammatory treatment for CF patients with advanced pulmonary disease. Methotrexate (MTX) is known as an effective anti-inflammatory treatment in asthma and in juvenile rheumatoid arthritis. The question was: Is an improvement in pulmonary function achievable with low-dose MTX in patients with cystic fibrosis and advanced pulmonary disease.? METHODS: We treated five CF patients with advanced pulmonary disease, who deteriorated in spite of intensive conventional therapy on an individual basis with low-dose MTX. FEV1% and immunoglobulin G (IgG) serum levels were followed from the year before to the year after starting with MTX. RESULTS: In the year before starting with MTX, FEV1% decreased (median: 10% FEV1; range 9-15% FEV1; P<0.005) after starting with MTX, FEV1% increased (median: 9% FEV1; range: 2-15% FEV1; P<0.05). IgG changed (median: -2 g/l; range: 0.2 to -7.3 g/l) in the first year with MTX. CONCLUSION: These preliminary data suggest a beneficial effect of MTX even in advanced pulmonary disease in CF patients and supports the need for a controlled prospective study.

Chloride conductance and genetic background modulate the cystic fibrosis phenotype of Delta F508 homozygous twins and siblings.

To investigate the impact of chloride (Cl(-)) permeability, mediated by residual activity of the cystic fibrosis transmembrane conductance regulator (CFTR) or by other Cl(-) channels, on the manifestations of cystic fibrosis (CF), we determined Cl(-) transport properties of the respiratory and intestinal tracts in Delta F508 homozygous twins and siblings. In the majority of patients, cAMP and/or Ca(2+)-regulated Cl(-) conductance was detected in the airways and intestine. Our finding of cAMP-mediated Cl(-) conductance suggests that, in vivo, at least some Delta F508 CFTR can reach the plasma membrane and affect Cl(-) permeability. In respiratory tissue, the expression of basal CFTR-mediated Cl(-) conductance, demonstrated by 30% of Delta F508 homozygotes, was identified as a positive predictor of milder CF disease. In intestinal tissue, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid-insensitive (DIDS-insensitive) Cl(-) secretion, which is indicative of functional CFTR channels, correlated with a milder phenotype, whereas DIDS-sensitive Cl(-) secretion was observed mainly in more severely affected patients. The more concordant Cl(-) secretory patterns within monozygous twins compared with dizygous pairs imply that genes other than CFTR significantly influence the manifestation of the basic defect.

Diabetes mellitus in patients with cystic fibrosis: the impact of diabetes mellitus on pulmonary function and clinical outcome.

In this multicenter study, the impact of CF-related diabetes mellitus (CFRD) on pulmonary function and clinical outcome has been investigated. To better characterize the relationship between insulin deficiency and clinical outcome we prospectively followed a group of 56 CF patients, 28 with CFRD (group 1) and 28 without diabetes (group 2) for 5 years. The clinical course of the patients was registered at each center. Data included were mortality, pulmonary function, body mass index, in-patient treatment, and CF-typical and diabetes typical complications. At the end of the study nearly twice the number of patients had died in group 1 as compared to group 2, however due to the low patient number this did not reach statistical significance. In patients with diabetes FEV1 and FVC declined significantly over the five year study period, whereas patients without diabetes did not show a significant decline during the study period. Retinopathy, nephropathy, and neuropathy were only observed in diabetic patients. In conclusion, the data presented in this prospective, multicenter study give evidence that insulin deficiency leads to a direct decline in pulmonary function suggesting a cause and effect relationship between insulin deficiency and lung disease.