Mukoviszidose Literaturservice Ausgabe 4 / 2006 an apparent greater contribution of inspiratory rib cage INHALT muscles to inspiratory pressure zu PubMed Lunge...........................................................1 Predictors of pulmonary exacerbations in patients Entzündung................................................6 with cystic fibrosis infected with multi-resistant P. aeruginosa.............................................9 organisms Block JK et al. Thorax ,2006 Andere Bakterien.....................................11 Ernährung, Körperzusammensetzung.13 Background: This study examined characteristics of adult Gastrointestinaltrakt, Diabetes mellitus15 and adolescent cystic fibrosis patients to determine factors Genetik, Basisdefekt...............................17 that would be associated with an increased risk of pulmonary Konsensus, Leitlinien..............................24 exacerbations. Methods: We recruited 249 cystic fibrosis Register, Screening, Überleben............26 patients who were infected with multi-drug resistant bacteria Psychosoziale Themen..........................30 and prospectively followed them for up to 4.5 years until Fertilität, Schwangerschaft.....................32 they experienced a pulmonary exacerbation severe enough to Osteoporose.............................................32 require intravenous antibiotics. Multivariable regression Transplantation........................................33 analyses were used to compare characteristics of patients who experienced an exacerbation with those who did not. Sonstige....................................................34 Results: Among the 249 patients, 124 (50%) developed a pulmonary exacerbation during the first year and 154 (62%) experienced an exacerbation during the 4.5 year study Lunge period. Factors predictive of exacerbations in a multivariable survival model were younger age (OR 0.98, 95% CI 0.96- Sex differences in thoracic adaptation to pulmonary 0.99), female gender (OR 1.45, 95% CI 1.07-1.95), lower hyperinflation in cystic fibrosis FEV1 (OR 0.98, 95% CI 0.97-0.99), and previous history of Bellemare F, Jeanneret A. Eur Respir J ,2006 multiple pulmonary exacerbations (OR 3.16, 95% CI 1.93- 5.17). Chronic use of inhaled corticosteroids was associated Sex differences in thoracic adaptation were reported in with an increased risk of exacerbation (OR 1.92, 95% CI patients with cystic fibrosis (CF). We investigated the 1.00-3.71) during the first study year. Conclusions: Patients interplay between the pattern of thoracic adaptation and the who experience pulmonary exacerbations are more likely to function of the respiratory muscles in male and female CF be younger, female, using inhaled steroids, have a lower patients with pulmonary hyperinflation.Thoracic dimensions FEV1 and a history of multiple previous exacerbations. and diaphragm length were measured at residual volume, Knowledge of these risk factors will allow better functional residual and total lung capacities using chest x- identification and closer monitoring of patients who are at rays in 23 CF (12 males) and 18 normal subjects (11 males). high risk of exacerbations Respiratory muscle recruitment during resting breathing was zu PubMed assessed by recording intra-thoracic and an intra-abdominal pressures.In female CF patients rib cage expansion was AMorphometric Study of Mucins and Small Airway predominant, tending to preserve diaphragm length. In male Plugging in Cystic Fibrosis CF patients thoracic configuration was normal and Burgel PR et al. Thorax ,2006 diaphragm shortening consequently greater. Rib cage cross- section area for a given rib inclination was greater in CF Rationale: Little knowledge exists on structural changes and patients indicating a structural expansion of the rib cage 2.5 plugging in small airways in cystic fibrosis (CF). times greater in females than males. The contribution of OBJECTIVE: To characterize the extent of plugging and inspiratory rib cage muscles was also greater relative to the contribution of secreted mucins to the plugs. METHODS: diaphragm in the CF group.A structural expansion of the rib Small airways in CF subjects at transplantation (n=18) were cage occurs in CF patients with lung hyperinflation that is compared to control non-smokers (n=10). Tissue sections greater in females than males and which is associated with were stained with Alcian blue (AB)/PAS, for mucins MUC5B and MUC5AC, and for neutrophils and its Bibliographie CF Roche Q4_2006.doc, 11. Oktober 2006 Seite 2 von 38 chemoattractant IL-8. EGFR and its ligand pro-TGF-alpha CONCLUSION: This pilot study shows that evaluation of were also identified using immunohistochemistry. Epithelial nebulisers based on tobramycin renal excretion is feasible in and luminal contents were assessed morphometrically. young children with cystic fibrosis RESULTS: Plugs occupying more than 50% of total luminal zu PubMed volume were found in 147 of 231 (63.6%) airways in CF subjects, but only in 1 of 39 (2.6%) airways in controls. In High-resolution computed tomography (HRCT) CF epithelium, AB/PAS-, MUC5B-, and MUC5AC-stained should not be considered as a routine assessment volume densities were increased ten-fold (P<0.01), method in cystic fibrosis lung disease indicating increased mucin production. In airway lumens, Cooper P, Maclean J. Paediatr Respir Rev 7:197-201,2006 staining for mucins was also increased in CF, indicating increased mucin secretion. In CF epithelium, neutrophil High-resolution computed tomography (HRCT) scanning of numbers were markedly increased and were inversely the chest should not be considered a routine clinical correlated with volume densities of mucous glycoconjugates investigation in the management of CF. Although it (r=-0.66, P<0.005). IL-8 staining was increased in CF demonstrates the detection of early lung damage in children epithelium and colocalized with mucins. Stained for EGFR with cystic fibrosis (CF), before HRCT can be considered and for pro-TGF-alpha were increased in CF epithelium; for routine clinical use in CF it needs to be shown that the positive correlations were found between benefit from the information obtained will out-weigh zu PubMed potential risks. There is insufficient evidence for the benefit of HRCT for its inclusion into routine care. Moreover, in the Mucoid impaction: An unusual form of allergic absence of information resulting in change in management, bronchopulmonary aspergillosis in a patient with HRCT has the potential to increase anxiety for both cystic fibrosis clinicians and families. In order to advocate for Cakir E et al. Pediatr Pulmonol 41:1103-1107,2006 incorporating this technology into routine CF care, further support for its role in management decisions is needed We reported a child with cystic fibrosis (CF) who developed zu PubMed mucoid impaction related to allergic bronchopulmonary aspergillosis (ABPA). This is the first reported case of Physical activity in patients with cystic fibrosis: a mucoid impaction related to ABPA in CF described to date new variable in the health-status equation in the literature. The case was successfully treated by unravelled? corticosteroids and itraconazole therapy, but relapsed 6 Decramer M, Gosselink R. Eur Respir J 28:678-679,2006 months later. During exacerbation therapy, cataract zu PubMed formation complicated the corticosteroid treatment. We want Effect of Allergic Broncho-pulmonary Aspergillosis to emphasize that 6-months therapy may be inadequate for on Lung Function in Children with Cystic Fibrosis the treatment of ABPA, and it is important to monitor for Kraemer R et al. Am J Respir Crit Care Med ,2006 possible complications of corticosteroids therapy. Pediatr Pulmonol. 2006, 41:1103-1107. (c) 2006 Wiley-Liss, Inc Rationale. The relationship between sensitization to A. zu PubMed fumigatus (Af) and progression of pulmonary function is not Nebulisers comparison with inhaled tobramycin in yet established in cystic fibrosis (CF). Objectives. We aimed young children with cystic fibrosis to evaluate onset of Af-sensitization and development of Clavel A et al. J Cyst Fibros ,2006 allergic broncho-pulmonary aspergillosis (ABPA), as well as to determine the physiological factors of lung function BACKGROUND: This randomised cross-over pilot study influencing these mechanisms in CF. Methods. Serial annual was undertaken in 10 cystic fibrosis children aged 10 to 63 lung function tests performed in 122 CF-children (62 males; months to describe lung absorption of tobramycin delivered 60 females; age: 6-18 y), provided data pertaining to by the PariLC+/PariTurboboyN (Pari GmbH) and the functional residual capacity (FRCpleth), lung clearance disposable NL9M/AtomisorBoxPlus (Diffusion Technique index (LCI), volume of trapped gas (VTG), effective Francaise) nebulising systems. METHODS: Each child specific airway resistance (sReff), and forced expiratory inhaled 300 mg tobramycin delivered with one or the other indices (FEV1, FEF50). Specific IgE to recombinant Af apparatus via a facemask in two separate and standardised allergens rAspf1 and rAspf3, served as marker for sessions. Urine was collected for 6 h. Tobramycin sensitization, and to rAspf4 and rAspf6 as indication for a concentrations determined by immunoprecipitation were serological ABPA, clinically diagnosed (Nelson criteria). By expressed in mg per g of creatinine and compared by a linear mixed-effect model analysis 5 patient groups, (i) not Wilcoxon test for matched pairs. The influences of age, sensitized and free from P. aeruginosa (PA), (ii) weight and Brasfield score on this parameter were evaluated intermittently PA-colonized, (iii) chronically PA-infected, by correlation tests, and those of sex, previous nebulisation (iv) sensitized, and (v) ABPA, were retrospectively treatment, and crying or coughing were evaluated by evaluated. Measurements and Main Results. Af sensitization Student's t-test. RESULTS: The amount of tobramycin was best reflected by increased rAspf1+3-specific IgE measured in urines was low and variable. Median values for levels, whereas in most patients sensitization was preceded urinary tobramycin concentration were 47.6 mg/g (14.9- by PA infection. ABPA patients demonstrated the most 79.6) with the PariLC+ and 42.6 mg/g (6.3-112.8) with the severe progression in all lung function parameters, and NL9M (p=0.6). PariLC+ delivered tobramycin in 22 min and FEF50, VTG and sReff were the best predictor (p<0.0001). NL9M in 12 min (p=0.005). Crying or coughing However, regarding distinction between sensitization to Af dramatically reduced the amount of tobramycin collected. and development of ABPA in the course of CF, chronic PA Bibliographie CF Roche Q4_2006.doc, 11. Oktober 2006 Seite 3 von 38 infection has to be taken into account. Conclusions. Airway relate to safety, in particular increased risk of bleeding from narrowing, gas trapping and small airway disease are the ahypertrophied bronchial circulation. The aim of this major targets for functional derangement in ABPA retrospective study was to compare the safety of EBB in zu PubMed children with CF and those with other conditions, the most frequent of which included primary ciliary dyskinesia and Immediate Changes in Blood-Gas Tensions During recurrent lower respiratory tract infections. Case notes of all Chest Physiotherapy With Positive Expiratory children undergoing EBB in our institution between Pressure and Oscillating Positive Expiratory February 2003 and May 2004 were reviewed. EBB was Pressure in Patients With Cystic Fibrosis performed during 45 bronchoscopies in 42 CF patients (19 Lagerkvist AL et al. Respir Care 51:1154-1161,2006 males, group mean age 7.13 +/- 4.48 years) and in 39 controls (20 males, group mean age 6.59 +/- 4.48 years). OBJECTIVE: To assess and compare immediate effects of There were no significant differences between disease chest physiotherapy with positive expiratory pressure (PEP) groups in the number, type, or severity of complications versus oscillating PEP on transcutaneously measured blood- occurring during or in the first 12 hr after the procedure. We gas tensions in patients with cystic fibrosis. METHODS: conclude that EBB performed as part of fibreoptic Fifteen patients (mean age 12.5 y, range 6.9-21.5 y) bronchoscopy (FOB) under general anaesthesia can be participated. The treatments were randomized and performed performed safely in children with CF, when both on 2 separate occasions, 8 weeks apart. Spirometry was bronchoscopist and anaesthetist are suitably experienced. conducted before and after each treatment. We Studies of such samples would allow us to determine the transcutaneously measured oxygen tension (P(tO(2)) early pathological changes in the CF airway and possibly zu PubMed find new treatments to prevent the progression to bronchiectasis and end stage airway destruction. Pediatr Hyperpolarized (3)helium magnetic resonance Pulmonol. 2006, 41:1021-1024. (c) 2006 Wiley-Liss, Inc ventilation imaging of the lung in cystic fibrosis: zu PubMed comparison with high resolution CT and spirometry Association between mannan-binding lectin and McMahon CJ et al. Eur Radiol ,2006 impaired lung function in cystic fibrosis may be age-dependent The purpose of this study was to compare hyperpolarized Muhlebach MS et al. Clin Exp Immunol 145:302-307,2006 (3)helium magnetic resonance imaging ((3)He MRI) of the lungs in adults with cystic fibrosis (CF) with high-resolution An association between mannan-binding lectin (MBL) status computed tomography (HRCT) and spirometry. Eight and severity of lung function impairment in cystic fibrosis patients with stable CF prospectively underwent (3)He MRI, (CF) has been found in several studies, but not in others. To HRCT, and spirometry within 1 week. Three-dimensional explore the possible basis for discrepancies in the literature, (3D) gradient-echo sequence was used during an 18-s we related both MBL and L-ficolin concentrations to lung breath-hold following inhalation of hyperpolarized (3)He. function and examined the results in relation to the age of Each lung was divided into six zones; (3)He MRI was the patients. For patients under 15 years of age, those with scored as percentage ventilation per lung zone. HRCT was MBL < 200 ng/ml had better lung function than those with scored using a modified Bhalla scoring system. Univariate MBL > 200 ng/ml [median forced expiratory volume in 1 s (Spearman rank) and multivariate correlations were (FEV(1)), 99% versus 83%; P = 0.05]. For patients over 15 performed between (3)He MRI, HRCT, and spirometry. years of age, those with MBL < 200 ng/ml had poorer lung Results are expressed as mean+/-SD (range). Spirometry is function than those with MBL > 200 ng/ml (median FEV(1), expressed as percent predicted. There were four men and 44% versus 55%; P = 0.1). Also, for the over 15-year-olds, four women, mean age=31.9+/-9 (20-46). Mean forced the proportion of patients with FEV(1) values below the expiratory volume in 1 s (FEV)(1)=52%+/-29 (27-93). Mean median was greater in the MBL-insufficient subgroup (P < (3)He MRI score=74%+/-25 (55-100). Mean HRCT 0.04). In other words, relative deficiency of MBL appears to score=48.8+/-24 (13.5-83). The correlation between(3)He accelerate the age-related decline in lung function in CF MRI and HRCT was strong (R=+/-0.89, p<0.001). patients. No corresponding relationships could be found Bronchiectasis was the only independent predictor of (3)He between L-ficolin concentration and lung function. These MRI; (3)He MRI correlated better with FEV(1) and forced findings and interpretation lend support to the potential vital capacity (FVC) (R=0.86 and 0.93, p<0.01, respectively) value of MBL replacement therapy in a small minority of than HRCT (R=+/-0.72 and +/-0.81, p<0.05, respectively). cystic fibrosis patients This study showed that (3)He MRI correlates strongly with zu PubMed structural HRCT abnormalities and is a stronger correlate of spirometry than HRCT in CF Airway surface liquid volume regulates ENaC by zu PubMed altering the serine protease-protease inhibitor balance: a mechanism for sodium hyperabsorption Safety of endobronchial biopsy in children with in cystic fibrosis cystic fibrosis Myerburg MM et al. J Biol Chem 281:27942-27949,2006 Molina-Teran A et al. Pediatr Pulmonol 41:1021-1024,2006 Efficient clearance of mucus and inhaled pathogens from the There is little found in the published literature regarding the lung is dependent on an optimal airway surface liquid (ASL) use of endobronchial biopsy (EBB) in children with cystic volume, which is maintained by the regulated transport of fibrosis (CF). One concern over the use of the technique may sodium and chloride across the airway epithelium. Bibliographie CF Roche Q4_2006.doc, 11. Oktober 2006 Seite 4 von 38 Accumulating evidence suggests that impaired mucus was reported after NPPV and CPAP than after mask PEP. clearance in cystic fibrosis (CF) airways is a result of ASL CONCLUSIONS: There were no differences in sputum depletion caused by excessive Na(+) absorption through the clearance or pulmonary-function measures between mask epithelial sodium channel (ENaC). However, the cellular PEP and short-term administration of either CPAP or NPPV mechanisms that result in increased ENaC activity in CF combined with directed cough. After mask PEP these airways are not completely understood. Recently, proteases patients felt more tired than after CPAP or NPPV secretion- were shown to modulate the activity of ENaC, but the clearance therapy relevance of this mechanism to the physiologic regulation of zu PubMed ASL volume is unknown. Using primary human airway epithelial cells, we demonstrate that: (i) protease inhibitors Proton MRI appearance of cystic fibrosis: are present in the ASL and prevent the activation of near- Comparison to CT silent ENaC, (ii) when the ASL volume is increased, Puderbach M et al. Eur Radiol ,2006 endogenous protease inhibitors become diluted, allowing for proteolytic activation of near-silent channels, and (iii) in CF, Cystic fibrosis (CF) is the most frequent inherited disorder the normally present near-silent pool of ENaC is leading to premature death in the Caucasian population. As constitutively active and the alpha subunit undergoes life expectancy is limited by pulmonary complications, increased proteolytic processing. These findings indicate that repeated imaging [chest X-ray, multislice high-resolution the ASL volume modulates the activity of ENaC by computed tomography (MS-HRCT)] is required in the modification of the serine protease-protease inhibitor follow-up. Magnetic resonance imaging (MRI) of the lung balance and that alterations in this balance contribute to parenchyma is a promising new diagnostic tool. Its value for excessive Na(+) absorption in cystic fibrosis imaging lung changes caused by CF compared with CT is zu PubMed demonstrated. MRI performs well when compared with CT, which serves as the gold standard. Its lack in spatial Chest physiotherapy with positive airway pressure: resolution is obvious, but advantages in contrast and apilot study of short-term effects on sputum functional assessment compensate for this limitation. Thus, clearance in patients with cystic fibrosis and MRI is a reasonable alternative for imaging the CF lung and severe airway obstruction should be introduced as a radiation-free modality for follow- Placidi G et al. Respir Care 51:1145-1153,2006 up studies in CF patients. For further evaluation of the impact of MRI, systematic studies comparing MRI and BACKGROUND: The periodic administration of positive conventional imaging modalities are necessary. Furthermore, airway pressure combined with directed cough could aid the value of the additional functional MRI (fMRI) mucus clearance in patients with cystic fibrosis (CF) and information has to be studied, and a scoring system for the severe airway obstruction. OBJECTIVE: To compare the morphological and functional aspect of MRI has to be short-term effect of positive expiratory pressure (PEP) established physiotherapy via mask (mask PEP), continuous positive zu PubMed airway pressure (CPAP), and noninvasive positive-pressure ventilation (NPPV) physiotherapies on amount of sputum Classifying severity of cystic fibrosis lung disease collected. METHODS: Directed cough was standardized for using longitudinal pulmonary function data each patient and used as the control treatment. We studied Schluchter MD et al. Am J Respir Crit Care Med 174:780- 17 patients with CF (mean +/- SD age 28 +/- 7 y) and severe 786,2006 airway obstruction (forced expiratory volume in the first second 25 +/- 6% of predicted) admitted for pulmonary Rationale: The study of genetic modifiers in cystic fibrosis exacerbation. Mask PEP, CPAP, NPPV, and the control (CF) lung disease requires rigorous phenotyping. One type treatment (directed cough) were administered in a random of genetic association study design compares sequence. Each patient received each treatment twice a day polymorphisms in patients at extremes of phenotype, (in 70-min sessions) for 2 consecutive days. We measured requiring accurate classification of pulmonary disease at the wet and dry weight of sputum collected and the number varying ages. Objective: To evaluate approaches to quantify of directed and spontaneous coughs during each session. severity of pulmonary disease and their ability to Spirometry and pulse oximetry were conducted before and discriminate between patients with CF at the extremes of after each session. For mask PEP, CPAP, and NPPV, each phenotype. Methods: DeltaF508 homozygotes (n = 828) patient gave a subjective score for the efficacy and were initially classified as "severe" (approximate lowest tolerability of the treatment, compared to the control quartile of FEV(1) (% pred) for age, 8-25 yr) or "mild" treatment. RESULTS: There was no statistically significant disease (highest quartile of FEV(1) for age, >/= 15 yr). difference in the dry weight of sputum collected: mask PEP FEV(1) measurements from the 5 yr before enrollment (total 0.9 +/- 0.6 g, CPAP 0.8 +/- 0.4 g, NPPV 0.9 +/- 0.6 g, =18,501 measurements; average 23 per subject) were control treatment 1.0 +/- 0.8 g. There was a statistically analyzed with mixed models, and patient-specific estimates significant difference in the wet weight of sputum collected: of FEV(1) (% pred) at ages 5, 10, 15, 20, and 25 yr and mask PEP 15.8 +/- 5.5 g, CPAP 13.7 +/- 5.5 g, NPPV 13.2 slope of FEV(1) versus age were examined for their ability +/- 5.0 g, control treatment 14.0 +/- 5.0 g (p < 0.05), but that to discriminate between groups using receiver operating difference became nonsignificant when we took into account characteristics (ROC) curve areas. Results: Logistic the number of spontaneous coughs. There were no regression of severity group on mixed model (empirical statistically significant changes in the spirometry and pulse- Bayes) estimates of intercept and slope of FEV(1) (% pred) oximetry values. The patients' subjective efficacy scores versus age discriminated better than did classification using were similar for mask PEP, CPAP, and NPPV. Less fatigue FEV(1) slope alone (ROC area = 0.995 vs. 0.821) and was Bibliographie CF Roche Q4_2006.doc, 11. Oktober 2006 Seite 5 von 38 equivalent to using estimated FEV(1) at 20 yr of age as a in one second (FEV(1)) percent of predicted and age in single discriminator. The estimated survival percentile from short-term studies, and FEV(1) percent predicted and gender ajoint survival/longitudinal model provided equally good in long-term studies were statistically important in predicting classification (ROC area = 0.994). Conclusions: In CF, respiratory AE rates. Although these variables were estimated FEV(1) (% pred) at 20 yr of age and the estimated statistically significant, the models' predictive abilities were survival percentile are useful indices of pulmonary disease low, with adjusted R(2)'s of 0.06 and 0.12 in the short- and severity long-term studies, respectively. Combining placebo-subject zu PubMed AEdata recorded from multiple CF clinical trials yields better estimates of true rates of occurrence in the CF Cough frequency and patterns of cough in cystic population. The tables published from this study can be used fibrosis to assist those charged with safety monitoring in CF clinical Smith JA. J R Soc Med 99 Suppl 46:17-22,2006 trials zu PubMed zu PubMed Intravenous injection of pharmaceutical tablets Chest computed tomography scans should be presenting as multiple pulmonary nodules and considered as a routine investigation in cystic declining pulmonary function in an adolescent with fibrosis cystic fibrosis Tiddens HA. Paediatr Respir Rev 7:202-208,2006 Smith KJ et al. Pediatrics 118:e924-e928,2006 Cystic fibrosis (CF) patients demonstrate lung inflammation Here we present the unusual case of an adolescent with and infection beginning early in life. Both inflammation and cystic fibrosis presenting with declining pulmonary function infection lead to irreversible structural lung damage, and diffuse micronodular pulmonary disease. This case primarily as bronchiectasis and fibrosis. The course of CF illustrates the radiographic and pathologic findings varies widely between patients due to genotypic and associated with the intravenous injection and pulmonary environmental differences. The primary aim of CF therapy is arterial embolization of insoluble pharmaceutical-tablet to prevent or delay structural damage and conserve lung constituents. The number of first-time users reporting function. Adequate monitoring of CF lung disease is nonmedical use of prescription pain relievers is increasing paramount to tailoring treatment to a patient's need. dramatically, especially in adolescents. Recognition of both Pulmonary function tests (PFTs) are important in monitoring the diagnostic imaging features and histologic features on lung function. PFTs, however, are only an indirect measure lung biopsy are critical steps for early diagnosis, of lung structure and are insensitive to localised or early intervention, and potential prevention of sudden death in damage. By contrast, computed tomography (CT) is these at-risk patients currently the most sensitive tool to monitor lung structure. zu PubMed As up to 50% of patients will have discordant staging of lung disease when PFTs are compared to CT findings, both Respiratory adverse event profiles in cystic fibrosis methods are needed to adequately assess a patient's placebo subjects in short- and long-term inhaled pulmonary condition and tailor the treatment strategy to the therapy trials patient's needs Sucharew H et al. Contemp Clin Trials ,2006 zu PubMed The frequency and nature of adverse events (AEs) are Assessment of lung disease in children with cystic important safety endpoints in clinical trials of therapies for fibrosis using hyperpolarized 3-Helium MRI: cystic fibrosis (CF) subjects, yet published tables of comparison with Shwachman score, Chrispin- background AE rates in the CF population are not readily Norman score and spirometry available. Our objective in this study was to produce tables van Beek EJ et al. Eur Radiol ,2006 of respiratory AE rates for placebo subjects (pediatric and adult) for inhaled therapy trials in CF subjects. Respiratory This study assesses the feasibility of hyperpolarized 3- AE rates in inhaled therapy trials were computed by Helium MRI in children with cystic fibrosis (CF) and combining data on placebo subjects from early-phase dosing correlates the findings with standard clinical parameters studies and middle/late-phase studies, where placebo based on chest radiograph (CXR) and pulmonary function consisted of 4 or 5 mL of inhaled saline solution. AE rates tests (PFT). An uncontrolled, observational study in eighteen were computed as number of events divided by number of children with cystic fibrosis aged 5 - 17 years (median 12.1 placebo-subject days of observation, and 95% confidence years), with different severity of disease was carried out. All intervals were computed based on a Poisson model. AEs subjects underwent routine clinical assessment including were categorized as both broad (e.g., respiratory, reactive PFT and standard auxology; CXR was obtained and airway disease) and specific (e.g., cough, chest tightness, Shwachman and Chrispin-Norman scores calculated. hemoptysis). In short-term studies, respiratory AE rates Hyperpolarized 3-He magnetic resonance imaging (MRI) (95% confidence interval) were 1.1(0.7, 1.6)/person-week was carried out using a spin-exchange polarizer and a whole and 1.0(0.7, 1.4)/person-week in pediatric and adult subjects, body 1.5 T scanner. Ventilation distribution images were respectively. In long-term studies, respiratory AE rates were obtained during a 21-second breath-hold and scored 1.7(1.6, 1.8)/person-month and 2.2(2.1, 2.3)/person-month in according to previously defined criteria. Spearman's non- pediatric and adult subjects, respectively. Stepwise Poisson parametric correlations test was performed to assess for models were fit to determine if baseline covariates were statistical significance at the p<0.05 level. The children important in predicting AE rates. Forced expiratory volume tolerated the procedure well. No desaturation events were Bibliographie CF Roche Q4_2006.doc, 11. Oktober 2006 Seite 6 von 38 observed during 3-He MRI. A significant, albeit moderate, concentrations in neutrophils. Sputum taurine correlates with correlation was found between MRI score and FEV1% respiratory exacerbations of cystic fibrosis. Seventeen predicted (r=-0.41; p=0.047) and FVC% predicted (r=-0.42; patients with cystic fibrosis were each assigned to three p=0.04), while there were trends of correlations between sequential 10-day periods including first, aerosol therapy of Shwachman score and MRI score (r=-0.38; p=0.06) and 5ml saline solution bid; second, aerosol therapy of 250 mg Shwachman score and FEV1% predicted (r=0.39; p=0.055). Prolastin bid; third, no aerosol therapy. On days 8, 9 and 10 The feasibility of hyperpolarized 3-He MRI in children with of each period, early morning sputum was collected for the CFwas demonstrated. MRI appears to be able to quantification of alpha1-PI, neutrophil elastase activity, IL-8 demonstrate functional lung changes, although correlations and taurine. RESULTS: During Prolastin therapy, a 3-fold with routine clinical tests are only moderate to poor. This increase in sputum alpha1-PI was observed (P = 0.002). non-ionising radiation technique could be useful for Baseline values of sputum alpha1-PI correlated with the monitoring lung disease and assessing therapy in this patient values obtained after Prolastin aerosol (R = 0.77, P < 0.01). population Sputum neutrophil elastase activity remained unchanged but zu PubMed taurine decreased after Prolastin therapy (during therapy P = 0.052, after therapy P = 0.026). Prolastin aerosol therapy had no adverse effect on pulmonary function. CONCLUSIONS: Aerosol therapy with Prolastin in patients with cystic Entzündung fibrosis leads to a progressive decrease in sputum taurine. This suggests that even in the absence of sustained elastase inhibition, Prolastin aerosol therapy may have a beneficial Expression and antimicrobial function of effect on airway inflammation in patients with cystic fibrosis bactericidal permeability-increasing protein in zu PubMed cystic fibrosis patients Aichele D et al. Infect Immun 74:4708-4714,2006 Free 3-nitrotyrosine in exhaled breath condensates of children fails as a marker for oxidative stress in In cystic fibrosis (CF), the condition limiting the prognosis stable cystic fibrosis and asthma of affected children is the chronic obstructive lung disease Celio S et al. Nitric Oxide 15:226-232,2006 accompanied by chronic and persistent infection with mostly mucoid strains of Pseudomonas aeruginosa. The majority of 3-Nitrotyrosine (3-NT) is considered as a marker of CF patients have antineutrophil cytoplasmic antibodies oxidative stress, which occurs during inflammation. Since 3- (ANCA) primarily directed against the bactericidal NT levels in exhaled breath condensate (EBC) are very low, permeability-increasing protein (BPI) potentially interfering we applied a specific and sensitive gas chromatography- with antimicrobial effects of BPI. We analyzed the negative ion chemical ionization-mass spectrometry (GC- expression of BPI in the airways of patients with CF. In their NICI-MS) method and high performance liquid sputum samples or bronchoalveolar lavage specimens, chromatography (HPLC) with electrochemical detection for nearly all patients expressed BPI mRNA and protein, which the analysis of free 3-NT in EBC. A total of 42 children were mainly products of neutrophil granulocytes as revealed (aged 5-17 years) were enrolled in this study, including by intracellular staining and subsequent flow cytometry. children with asthma (n=12), cystic fibrosis (n=12), and Repeated measurements revealed consistent individual BPI healthy controls (n=18). Additionally, 14 healthy non- expression levels during several months quantitatively smoking adults (aged 18-59 years) were included. An correlating with interleukin-8. In vitro, P. aeruginosa isolates EcoScreen system was used for the collection of EBC from CF patients initiated the rapid release of BPI occurring samples. Free 3-NT levels in EBC ranged from 0.54-6.8nM. independently of protein de novo syntheses. Furthermore, Median (interquartile range) concentrations (nM) were purified natural BPI as well as a 27-mer BPI-derived peptide similar in all groups: 1.46 (0.97-2.49) in healthy adults, 2.51 displayed antimicrobial activity against even patient-derived (1.22-3.51) in healthy children, 1.46 (0.88-2.02) in children mucoid P. aeruginosa strains and bacteria resistant against with asthma, and 1.97 (1.37-2.35) in CF children, all antibiotics tested. Thus, BPI that is functionally active respectively (p=0.24, Kruskall-Walis test). No difference against mucoid P. aeruginosa strains is expressed in the was found between the children with airway disease and airways of CF patients but may be hampered by age-matched healthy controls. In healthy subjects, there was autoantibodies, resulting in chronic infection no effect of age on 3-NT concentrations. HPLC analyses zu PubMed provided similar concentration ranges for EBC 3-NT when compared with GC-NICI-MS. Our study has clearly Prolastin aerosol therapy and sputum taurine in demonstrated that free 3-NT in EBC fails as a marker for cystic fibrosis oxidative stress in children with stable CF and asthma Cantin AM et al. Clin Invest Med 29:201-207,2006 zu PubMed BACKGROUND: Neutrophil elastase in the cystic fibrosis Anew model of cystic fibrosis pathology: Lack of airways inhibits opsonophagocytosis and induces the transport of glutathione and its thiocyanate expression of interleukin-8, a neutrophil chemoattractant. conjugates Prolastin is a therapeutic preparation of alpha-1 proteinase Childers M et al. Med Hypotheses ,2006 inhibitor (alpha1,-PI), a neutrophil elastase inhibitor. The objective of this study was to determine the effects of Many of the symptoms of cystic fibrosis are not explained Prolastin aerosol therapy on airway inflammation in cystic by the current disease mechanisms. Therefore, the authors fibrosis. METHODS: The primary endpoint of this study conducted an extensive literature review and present a new was sputum taurine, an amino-acid present in high Bibliographie CF Roche Q4_2006.doc, 11. Oktober 2006 Seite 7 von 38 model of cystic fibrosis pathology, which is the culmination ofthis research. Understanding that the cystic fibrosis Rationale: Relatively few studies have characterized mucous transmembrane conductance regulator (CFTR) is responsible cells or mucins in detail in cystic fibrosis, and the for glutathione (GSH) transport, the authors hypothesize that relationship between mucous cell abnormalities and mutations of the CFTR, which create abnormal GSH neutrophilic inflammation is uncertain. Objectives: To transport, will lead to aberrations of GSH levels in both the characterize mucous cell phenotypes and mucin profiles in intracellular as well as the extracellular milieu. These cystic fibrosis and to determine if neutrophils accumulate alterations in normal cellular GSH levels affect the redox around goblet cells in the epithelium and gland acini in the state of the cell, thereby affecting the intracellular stress submucosa. Methods: Bronchial biopsies were collected protein, metallothionein. The authors describe how this from 7 subjects with cystic fibrosis and 15 controls, and the disruption of the redox state caused by excess cellular GSH, morphology of mucous cells was measured. Immunostains will naturally prevent the delivery of zinc as a cofactor for for gel-forming mucins and neutrophil elastase were various enzymatic processes, and how these disruptions in quantified. Measurements and Main Results: Goblet cell size normal redox may cause alterations in both humoral and was increased in cystic fibrosis (p=0.004), but the number of cell-mediated immunity. Moreover, the symptom of thick goblet cells was normal. The volume of submucosal glands sticky mucus in these patients might be explained through was four-fold higher than normal (p=0.031), but the the understanding that oversulfation of mucus is a direct proportion of mucous and serous cells in CF glands was result of elevated cellular GSH and cysteine. The issues of normal. The patterns of expression of gel-forming mucins in hyperinflammation, altered pH and the imbalance of fatty epithelial and submucosal compartments in CF were similar acids that are typical in cystic fibrosis are addressed-all of to normal. Although neutrophil elastase immunostaining was which may also be linked to disruptions in GSH intense in the epithelium in CF, neutrophils were largely homeostasis. Additionally, this new model of cystic fibrosis absent around gland acini in the submucosa. Conclusion: pathology, clarifies the relationship between the CFTR and The most prominent pathologic feature in the CF airway is the multi-drug resistance proteins, and the lack of cell- an increase in submucosal gland volume, but serous cell mediated immunity by predicting that the substrate of these transdifferentiation to mucous cells does not occur, nor are proteins is a glutathione adduct of thiocyanate. Finally, a gland acini inflamed with neutrophils. The mechanism for new therapeutic strategy by using isothiocyanates to rectify increased submucosal gland volume in CF deserves further the GSH imbalance and restore the immune system is study suggested for the treatment of cystic fibrosis patients zu PubMed zu PubMed CFTR Expression in human neutrophils and the Use of high-dose ibuprofen in a pediatric cystic phagolysosomal chlorination defect in cystic fibrosis center fibrosis Fennell PB et al. J Cyst Fibros ,2006 Painter RG et al. Biochemistry 45:10260-10269,2006 Despite its apparent benefits, high-dose ibuprofen has been Production of hypochlorous acid (HOCl) in neutrophils, a infrequently applied to children with cystic fibrosis. We critical oxidant involved in bacterial killing, requires have noted a decrease in the use of high-dose ibuprofen at chloride anions. Because the primary defect of cystic fibrosis our pediatric cystic fibrosis center during the past decade. In (CF) is the loss of chloride transport function of the CF this retrospective study, we examined our clinical experience transmembrane conductance regulator (CFTR), we with high-dose ibuprofen and other anti-inflammatory drugs hypothesized that CF neutrophils may be deficient in in cystic fibrosis patients. The medical records of all chlorination of bacterial components due to a limited patients, ages 5 to 18 years, followed at the cystic fibrosis chloride supply to the phagolysosomal compartment. center from 1995 to 2002, were reviewed and children were Multiple approaches, including RT-PCR, classified into two cohorts: ibuprofen-treated and untreated immunofluorescence staining, and immunoblotting, were groups. Patterns of ibuprofen use and pharmacokinetics in used to demonstrate that CFTR is expressed in resting treated patients, and for patients who discontinued neutrophils at the mRNA and protein levels. Probing ibuprofen, the reasons for stopping the medication, including fractions of resting neutrophils isolated by Percoll gradient adverse effects, were assessed. Pulmonary function decline fractionation and free flow electrophoresis for CFTR and hospitalization rates for each group were compared, revealed its presence exclusively in secretory vesicles. The examining both intent to treat and patients who continued CFTR chloride channel was also detected in therapy for at least 4 years. Nearly half of the patients in our phagolysosomes, a special organelle formed after pediatric cystic fibrosis center who were prescribed with phagocytosis. Interestingly, HL-60 cells, a human high-dose ibuprofen discontinued therapy due to adverse promyelocytic leukemia cell line, upregulated CFTR events, not because of poor adherence or patient choice. expresssion when induced to differentiate into neutrophils Neither use of high-dose ibuprofen nor its cessation resulted with DMSO, strongly suggesting its potential role in mature in a significant change in the rate of decline in pulmonary neutrophil function. Analyses by gas chromatography and function or influenced hospitalization rates mass spectrometry (GC-MS) revealed that neutrophils from zu PubMed CF patients had a defect in their ability to chlorinate bacterial proteins from Pseudomonas aeruginosa Characterizing Mucous Cell Remodeling in Cystic metabolically prelabeled with [(13)C]-l-tyrosine, unveiling Fibrosis: Relationship to Neutrophils defective intraphagolysosomal HOCl production. In contrast, Hays SR, Fahy JV. Am J Respir Crit Care Med ,2006 both normal and CF neutrophils exhibited normal extracellular production of HOCl when stimulated with Bibliographie CF Roche Q4_2006.doc, 11. Oktober 2006 Seite 8 von 38 phorbol ester, indicating that CF neutrophils had the normal response. We hypothesized that their expression and/or ability to produce this oxidant in the extracellular medium. function may be altered in cystic fibrosis (CF), a disorder This report provides evidence which suggests that CFTR characterized by an excessive host inflammatory response. channel expression in neutrophils and its dysfunction affect METHODS: PPARalpha, beta and gamma mRNA levels neutrophil chlorination of phagocytosed bacteria were measured in peripheral blood cells of CF patients and zu PubMed healthy subjects via RT-PCR. PPARalpha protein expression and subcellular localization was determined via western blot CFTR inhibition mimics the cystic fibrosis and immunofluorescence, respectively. The activity of inflammatory profile PPARalpha was analyzed by gel shift assay. RESULTS: In Perez A et al. Am J Physiol Lung Cell Mol Physiol ,2006 lymphocytes, the expression of PPARalpha mRNA, but not of PPARbeta, was reduced (-37%; p < 0.002) in CF patients Primary airway epithelial cells grown in air-liquid interface compared with healthy persons and was therefore further differentiate into cultures that resemble native epithelium analyzed. A similar reduction of PPARalpha was observed at morphologically, express ion transport similar to those in protein level (-26%; p < 0.05). The transcription factor was vivo, and secrete cytokines in response to stimuli. mainly expressed in the cytosol of lymphocytes, with low Comparisons of cultures derived from normal and CF expression in the nucleus. Moreover, DNA binding activity individuals are difficult to interpret due to genetic of the transcription factor was 36% less in lymphocytes of differences besides CFTR. The recently discovered CFTR patients (p < 0.01). For PPARalpha and PPARbeta mRNA inhibitor, CFTRinh-172, was used to create a CF model with expression in monocytes and neutrophils, no significant its own control to test if loss of CFTR-Cl(-) conductance differences were observed between CF patients and healthy alone was sufficient to initiate the CF inflammatory persons. In all cells, PPARgamma mRNA levels were below response. Continuous inhibition of CFTR-Cl(-) conductance the detection limit. CONCLUSION: Lymphocytes are for 3-5 days resulted in significant increase in IL-8 secretion important regulators of the inflammatory response by at basal (p = 0.006) and in response to 10(9) Pseudomonas releasing cytokines and antibodies. The diminished (p = 0.0001), a four-fold decrease in Smad3 expression (p = lymphocytic expression and activity of PPARalpha may 0.02), a 3-fold increase in RhoA expression, and increased therefore contribute to the inflammatory processes that are NF-kappaB nuclear translocation upon TNFalpha/IL-1beta observed in CF stimulation (p < 0.000001). CFTR inhibition by CFTRinh- zu PubMed 172 over this period does not increase ENaC activity, so lack of Cl(-) conductance alone can mimic the inflammatory CF Myeloperoxidase promoter polymorphism -463G is phenotype. CFTRinh-172 does not affect IL-8, IL-6 or GM- associated with more severe clinical expression of CSF secretion in two CF phenotype immortalized cell lines: cystic fibrosis pulmonary disease 9/HTEo(-) pCEP-R and 16HBE14o(-) AS, or IL-8 secretion Reynolds WF et al. Mediators Inflamm 2006:36735,2006 in primary CF cells, and inhibitor withdrawal abolishes the increased response, so CFTRinh-172 effects on cytokines The severity of cystic fibrosis (CF) pulmonary disease is not are not direct. Five-day treatment with CFTRinh-172 does directly related to CFTR genotype but depends upon several not affect cells deleteriously as evidenced by LDH, trypan parameters, including neutrophil-dominated inflammation. blue, ciliary activity, EM histology, and inhibition Identification of agents modulating inflammation constitutes reversibility. Our results support the hypothesis that lack of arelevant goal. Myeloperoxidase (MPO) is involved in both CFTR activity is responsible for the onset of the microbicidal and proinflammatory neutrophil activities. The inflammatory cascade in the CF lung. Key words: aim of this study was to evaluate whether the -463GA MPO inflammation, CFTR, cytokines, Pseudomonas, ENaC promoter polymorphism is linked to clinical severity of CF- zu PubMed associated pulmonary inflammation. This polymorphism significantly affects the level of MPO gene expression in New insights into pulmonary inflammation in cystic leukocytes and the G allele is more expressing than the A fibrosis allele. We show that MPO genotype significantly influences Rao S, Grigg J. Arch Dis Child 91:786-788,2006 the severity of pulmonary disease in early stages, prior to the development of chronic lung infections, with GG genotype Persistent lower airway infection with inflammation is the being associated with more severe CF disease. Our findings major cause of morbidity and mortality in cystic fibrosis. indicate that the level of MPO gene expression influences This review examines the recent advances in the the CF pathogenesis, presumably reflecting cellular damage understanding of airway inflammation in cystic fibrosis, and by MPO-generated oxidants or other activity of MPO in focuses on the evidence that pulmonary inflammation is, airway inflammation under some circumstances, disassociated from infection, and zu PubMed the potential implications for therapeutic intervention zu PubMed Free radicals in exhaled breath condensate in cystic fibrosis and healthy subjects Peroxisome proliferator-activated receptor alpha Rosias PP et al. Free Radic Res 40:901-909,2006 (PPAR alpha) down-regulation in cystic fibrosis lymphocytes Many markers of airway inflammation and oxidative stress Reynders V et al. Respir Res 7:104,2006 can be measured non-invasively in exhaled breath condensate (EBC). However, no attempt has been made to BACKGROUND: PPARs exhibit anti-inflammatory directly detect free radicals using electron paramagnetic capacities and are potential modulators of the inflammatory resonance (EPR) spectroscopy. Condensate was collected in Bibliographie CF Roche Q4_2006.doc, 11. Oktober 2006 Seite 9 von 38 14 children with cystic fibrosis (CF) and seven healthy could be misleadingly skewed. OBJECTIVE: To assess the subjects. Free radicals were trapped by 5,5-dimethyl-1- degree of bias introduced into a hospital antibiogram by pyrroline-N-oxide. EPR spectra were recorded using a combining cystic fibrosis (CF) and non-CF isolates of Bruker EMX spectrometer. Secondly, to study the source of Pseudomonas aeruginosa to produce one hospital-wide oxygen centered radical formation, catalase or hydrogen percent susceptible figure for each tested antibiotic. peroxide was added to the condensate. Radicals were METHODS: A retrospective analysis was conducted of an detected in 18 out of 21 condensate samples. Analysis of academic, tertiary care medical center's microbiology spectra indicated that both oxygen and carbon centered database. We examined quarterly and annual susceptibility radicals were trapped. Within-subject reproducibility was data from 2004, comparing non-CF data with combined good in all but one subject. Quantitatively, there was a trend susceptibility data for 10 antibiotics within each quarter, as towards higher maximal peak heights of both oxygen and well as those reported in the annual antibiogram. Differences carbon centered radicals in the children with CF. Catalase were assessed for statistical significance using chi(2) testing completely suppressed the signals in condensate. Addition of with Bonferroni correction. RESULTS: Large differences hydrogen peroxide resulted in increased radical signal were observed between non-CF and combined percent intensity. Detection of free radicals in EBC of children with susceptible data in the 4 quarters (aminoglycosides 3% vs CF and healthy subjects is feasible using EPR spectroscopy 20%, fluoroquinolones 2% vs 18%, respectively) and when zu PubMed comparing annual non-CF (n = 191) with annual combined (n = 266) data. With the annual figures, these differences Cystic fibrosis and normal human airway epithelial were frequently statistically significant (70% vs 58%, 91% cell response to influenza a viral infection vs 83%, 85% vs 70%, and 72% vs 60% for gentamicin, Xu W et al. J Interferon Cytokine Res 26:609-627,2006 tobramycin, amikacin, and gatifloxacin/levofloxacin, respectively; all p </= 0.01). CONCLUSIONS: Combining Viral infections produce severe respiratory morbidity in CF and non-CF P. aeruginosa susceptibility into one percent children with cystic fibrosis (CF). CF cells are more susceptibility value for all isolates may produce figures that susceptible to virus in part because of impaired airway underestimate the activity of some antibiotic classes against epithelial activation of signal transducer and activator of non-CF isolates. Clinicians may make less than optimal transcription 1 (Stat1). As Stat1 is a fundamental regulator empiric antibiotic selection choices based on such data of antiviral defenses, we hypothesized that there may be zu PubMed multiple alterations in the antiviral defense of CF epithelium compared with normal (NL). To obtain a comprehensive Once-daily tobramycin in cystic fibrosis: better for view of mucosal host responses to influenza and characterize clinical outcome than thrice-daily tobramycin but the difference between CF and NL responses to influenza, more resistance development? gene expression profiles of primary human airway epithelial Burkhardt O et al. J Antimicrob Chemother 58:822-829,2006 cells (HAEC) were evaluated using an interferon (IFN)- stimulated genes/AU/double-stranded RNA (dsRNA) OBJECTIVES: Once-daily administration of microarray or quantitative real-time polymerase chain aminoglycosides in cystic fibrosis (CF) patients is reaction (PCR) following influenza A infection. Gene considered equally efficacious and potentially less expression was significantly modified by influenza in NL nephrotoxic than dosing three times a day. However, the (228 genes) and CF (101 genes), with a similar pattern of choice of the most suitable PK/PD index (C(max)/MIC gene response but with overall less numbers of responsive versus AUC(24)/MIC) to ensure optimum clinical outcome genes in CF (p < 0.05). Moreover, CF cells had less IFN- in this patient population is not clear. PATIENTS AND related antiviral gene induction at 24 h but greater METHODS: In a single-centre, open, randomized, inflammatory cytokine gene induction at 1 h after infection. controlled, non-blinded study 33 adult CF patients (20 Taken together, the lesser antiviral and greater early females, 19-37 years) were treated with intravenous inflammatory response likely contribute to the severe tobramycin (10 mg/kg/day) for 14 days given either as single respiratory illness of CF patients with viral infections dose once a day (Q24; 17 patients) or divided into three zu PubMed equal doses every 8 h (Q8; 16 patients). Tobramycin serum concentrations and MICs for Pseudomonas aeruginosa were determined on days 1 and 14. The clinical outcome parameter, correlated to PK/PD indices, was the percentage P. aeruginosa predicted forced expiratory volume in 1 s (FEV(1)% pred.). RESULTS: FEV(1)% pred. improved significantly for both treatments. There was a log-linear relationship between Consequences of Combining Cystic Fibrosis- and C(max)/MIC and FEV(1)% pred. and AUC/MIC and Non-Cystic Fibrosis-Derived Pseudomonas FEV(1)% pred. for both treatments. For equal values of aeruginosa Antibiotic Susceptibility Results in AUC24/MIC, however, Q24 treatment provided better Hospital Antibiograms (November) improvement in lung function than Q8 dosing, whereas Bosso JA et al. Ann Pharmacother ,2006 C(max)/MIC did not show any dosing interval dependence. Astatistically significant increase was observed for MIC BACKGROUND: In preparing hospital antibiograms for (day 1) versus MIC (day 14) for Q24 treatment, however, no individual organisms and antibiotics, laboratories often such difference was observed for Q8 treatment. combine susceptibility data for isolates from a variety of CONCLUSIONS: The most important PK/PD parameter for sources and patient types. If results from patients with clinical outcome in CF patients was C(max)/MIC. Outcome known resistance patterns that vary from normal are prediction of AUC(24)/MIC was dependent on the regimen. included, the overall susceptibility value for the institution Bibliographie CF Roche Q4_2006.doc, 11. Oktober 2006 Seite 10 von 38 The increase of P. aeruginosa resistance after once-daily Antibiotic use in cystic fibrosis administration is linked to a long dosing interval. More and Kelly HW, Lovato C. Ann Pharmacother 40:1424-1435,2006 larger studies are needed to optimize the dosing regimen for zu PubMed maximum clinical outcome with minimum resistance development Pharmacokinetic profile of once daily intravenous zu PubMed tobramycin in children with cystic fibrosis Massie J, Cranswick N. J Paediatr Child Health 42:601- Cystic fibrosis. Pseudomonas aeruginosa infection 605,2006 Chang AL. Ceylon Med J 51:34-35,2006 zu PubMed AIM: Once-daily tobramycin in patients with cystic fibrosis (CF) is a more convenient dosing regimen than thrice daily Measurement of urinary N-acetyl-b-d- dosing. There are limited data on the pharmacokinetic (PK) glucosaminidase in adult patients with cystic profile for once-daily tobramycin in patients with CF. The fibrosis: Before, during and after treatment with aim of this study was to define the PK parameters for once- intravenous antibiotics daily tobramycin in children with CF and develop an Etherington C et al. J Cyst Fibros ,2006 algorithm for therapeutic drug monitoring dosing. METHODS: CF patients admitted to hospital were BACKGROUND: Patients with cystic fibrosis (CF) are at commenced on once-daily intravenous tobramycin (12 high risk from the nephrotoxic effects of intravenous mg/kg/day) and ticarcillin/clavulinic acid. Serum tobramycin antibiotics due to repeated and prolonged courses of therapy. levels were taken at 30 min, 2-4 h and 12 h post dose. Data Routine methods of monitoring renal injury are insensitive. points for the PK model included: age, sex, weight, N-acetyl-b-d-glucosaminidase (NAG) is a lysosomal enzyme tobramycin dose, time of tobramycin doses and levels, present in the renal proximal tubular cells, with increased tobramycin levels. WinNonMix was used to obtain the PK excretion an indicator of renal tubular dysfunction. parameters. RESULTS: Forty-four children with 86 METHODS: Urinary NAG, creatinine, serum creatinine, admissions who were aged 9 months-20 years were electrolytes and BUN were measured on days 1, 14 and at included. A one-compartment intravenous infusion model the first out-patient visit following treatment with with first order elimination kinetics produced the best model. tobramycin or colistin. Urinary NAG levels were corrected Population parameters were: volume of distribution (V(d)) = for urinary creatinine and expressed as a NAG ratio. Patients 0.267 L/kg (95% confidence interval (CL) 0.260-0.272), who received >1 course of intravenous antibiotics during the clearance (CL) 0.103 L/kg/h (95% CI 0.098-0.107) and half- study period were included in a separate analysis of the life (t(1/2)) 1.82 (95% CI 1.77-1.88) h. Once the population cumulative effect of treatment. RESULTS: 88 patients (44 model was established post hoc analysis was used to female, 31 with CFRD) completed a single course of calculate individual subject predictions. Plots of individual intravenous antibiotics. 71 patients had urinary NAG levels prediction curves agreed well with observed values. at follow-up. The median time to follow-up was 50 days. CONCLUSION: This study has established an algorithm for Serum electrolytes, creatinine and BUN were normal routine monitoring of once-daily tobramycin in children with throughout. A 3.5-fold increase in urinary NAG excretion CF. Satisfactory serum levels of tobramycin were obtained was observed between day 1 and 14 and 46% of patients had with a dose of 12 mg/kg/day and a regimen algorithm that an elevated NAG level at follow-up. A highly significant uses only one measurement to monitor the plasma difference in NAG excretion was observed on day 14 for concentration is suggested tobramycin vs. colistin (median 2.24 vs. 0.98, p<0.001). A zu PubMed significant difference in NAG excretion was seen in patients with CFRD at all measured time points. Patients with CFRD Development of a diagnostic test for the Midlands 1 had a significantly worse clinical status and had received cystic fibrosis epidemic strain of Pseudomonas more days of intravenous antibiotics over the previous 6 aeruginosa years. In 20 (80%) of 25 patients who received >1 course of Smart CH et al. J Med Microbiol 55:1085-1091,2006 treatment during the study period, baseline NAG levels were significantly higher in subsequent courses (p<0.001). There In a previous study of isolates from cystic fibrosis (CF) was a significant correlation between previous exposure to patients in England and Wales, the Midlands 1 strain of colistin and baseline NAG levels (r=0.389, p<0.001). Pseudomonas aeruginosa was identified as the second most CONCLUSIONS: Both tobramycin and colistin cause acute common clone, representing 10% of isolates and found in renal tubular injury with a significant rise in urinary NAG nearly one-third of all CF centres [Scott, F. W. & Pitt, T. L. excretion. Patients with CFRD seem to be at greatest risk of (2004). J Med Microbiol 53, 609-615]. Using suppression renal tubular damage. Cumulative damage is evident with subtractive hybridization, 54 sequences were identified as repeated dosing. Previous exposure to nephrotoxic present in a Midlands 1 strain but were absent from strain antibiotics, especially colistin, is associated with elevated PAO1. The distribution of 14 of these sequences amongst baseline NAG levels. We recommend that colistin is representatives of Midlands 1, other CF epidemic strains and reserved for patients with resistant Pseudomonas aeruginosa unrelated P. aeruginosa CF isolates was determined using or those who are intolerant to tobramycin. Serial longitudinal PCR assays. Using these data, a PCR-based test was NAG measurements may be useful in patients with CF, developed that was specific for the Midlands 1 clone, which especially those with CFRD, to identify patients at risk of was confirmed using dot-blot hybridization. By applying the developing renal disease test to CF isolates from a CF centre in Liverpool, a Midlands zu PubMed 1clone was identified. The identity was confirmed using typing by PFGE. The PCR test should facilitate a greater Bibliographie CF Roche Q4_2006.doc, 11. Oktober 2006