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Seit sechs Jahren hat sich in der Therapie der Patienten mit Mukoviszidose (Cystische Fibrose, CF) etwas grundlegend verandert. Zunachst wurde fur einen kleinen Teil der CF Betroffenen (ca. 1-4% der Patienten) ein mutationsspezifisches Medikament (CFTR-Modulator, Ivacaftor) entwickelt und die Wirkung war enorm. Die Betroffenen sind fast symptomfrei und konnen ein weitestgehend "normales" Leben fuhren. In der Zukunft gibt es CFTR-Modulatoren fur fast 90% aller CF-Betroffenen, je fruher die Modulatoren eingesetzt werden, umso weniger Symptome treten noch auf. Damit ist ein Durchbruch in der Forschung und Versorgung von Patienten mit CF gelungen. Trotzdem bleibt die Basistherapie mit Physiotherapie, Inhalationen, Sport und Medikamenten zur Fettverdauung bestehen, da es zu diesen Aspekten noch keine Ergebnisse aus Langzeitstudien gibt.

In cystic fibrosis (CF) the phenotypic expression of complaints varies widely. Genotypes with sufficient pancreatic function (PS) exhibit milder lung disease compared to CF patients with insufficient pancreatic function (PI). The purpose of this study was to evaluate structural lung disease (SLD) in CF patients with differing pancreatic status but similar results on pulmonary function testing using a pulmonary magnetic resonance imaging score (MR-CF score). In this retrospective study, 20 patients in our single-center CF database were included: 10 with PS (mean age 12.5 years; six male; BMI 17.4 kg/m Patients with CF-PS had overall statistically significant lower MR-CF scores (p = 0.024), and therefore milder SLD, compared to CF-PI. The differences were most significant for bronchiectasis (p = 0.0042) and air trapping (p = 0.0304). SLD was more severe in the upper lobes in all patients. However, differences between CF-PS and CF-PI patients were present in both the upper and lower lung areas (p = 0.0247 and p = 0.0196, respectively). Our results demonstrated that CF patients with impaired pancreatic function show more severe lung pathology detected by MRI, especially bronchiectasis and air trapping. · Pulmonary MRI offers morphological and functional details without using ionizing radiation. · CF patients with pancreatic insufficiency show more severe pulmonary structural impairment. · Bronchiectasis and air trapping are the most common structural lung changes with predominance in the upper lung lobes..· Kraus MS, Teufel M, Esser M et al. Differing Pulmonary Structural Abnormalities Detected on Pulmonary MR Imaging in Cystic Fibrosis Patients with Varying Pancreatic Function. Fortschr Röntgenstr 2020; 192: 567 - 575.ZIEL: Die Multisystemerkrankung zystische Fibrose (CF) zeigt phänotypisch eine große Symptomvarianz, wobei Genotypen mit suffizienter Pankreasfunktion (PS) eine mildere Lungenbeeinträchtigung aufzuweisen scheinen im Vergleich zu pankreasinsuffizienten (PI) CF-Patienten. Ziel dieser Studie war die Evaluation von strukturellen Lungengerüstveränderungen (SLD) bei CF-Patienten mit unterschiedlicher Pankreasfunktion mittels pulmonalem MRT-Score (MR-CF-Score). 20 CF-Patienten wurden in diese retrospektive monozentrische Studie eingeschlossen: 10 PS-CF-Patienten (mittleres Alter 12,5 Jahre; 6 männlich; BMI 17,4 kg/m CF-PS-Patienten zeigten einen signifikant niedrigeren MR-CF-Gesamtscore (p = 0,024) und damit mildere Lungengerüstveränderungen. Die größten kategorischen Unterschiede waren bezüglich Bronchiektasien (p = 0,0042) und Überblähung (p = 0,0304) zu beobachten. SLD waren insbesondere in den Lungenoberfeldern am deutlichsten, jedoch zeigten sich signifikante Unterschiede in Bezug auf die Pankreasfunktion in sowohl den Lungenober- als auch -unterfeldern (p = 0,0247 und p = 0,0196). Unsere Ergebnisse zeigen signifikante Unterschiede bezüglich SLD und Pankreasstatus bei CF-Patienten mit identischen Lungenfunktionswerten. Pankreasinsuffiziente Patienten zeigten hierbei deutlich schwerere Lungengerüstveränderungen im MRT, insbesondere Bronchiektasien und Überblähung. · Pulmonales MRT ermöglicht eine morphologische und funktionelle Diagnostik ohne Einsatz ionisierender Strahlung.. · CF-Patienten mit insuffizienter Pankreasfunktion zeigen ausgeprägtere strukturelle Lungengerüstveränderungen im Vergleich zu pankreassuffizienten Patienten bei gleicher Lungenfunktion.. · Bronchiektasien und Überblähung sind die häufigsten strukturellen Lungengerüstveränderungen mit Betonung der Lungenoberfelder..

In cystic fibrosis (CF), 85% to 90% of patients develop exocrine pancreatic insufficiency. Despite enzyme substitution, low pancreatic phospholipase A2 (sPLaseA2-IB) activity causes fecal loss of bile phosphatidylcholine and choline deficiency. We report on a female patient who has CF and progressive hepatosteatosis from 4.5 y onward. At 22.3 y, the liver comprised 27% fat (2385 mL volume) and transaminases were strongly increased. Plasma choline was 1.9 µmol/L (normal: 8-12 mol/L). Supplementation with 3×1g/d choline chloride decreased liver fat and volume (3 mo: 8.2%; 1912 mL) and normalized transaminases. Plasma choline increased to only 5.6 µmol/L upon supplementation, with high trimethylamine oxide levels (12-35 µmol/L; normal: 3 ± 1 mol/L) proving intestinal microbial choline degradation. The patient was homozygous for rs12325817, a frequent single-nucleotide polymorphism in the PEMT gene, associated with severe hepatosteatosis in response to choline deficiency. Resolution of steatosis required 2 y (4.5% fat). Discontinuation/resumption of choline supplementation resulted in rapid relapse/resolution of steatosis, increased transaminases, and abdominal pain.

Background: Choline is essential for the synthesis of liver phosphatidylcholine (PC), parenchymal maintenance, bile formation, and lipoprotein assembly to secrete triglycerides. In choline deficiency, the liver accretes choline/PC at the expense of lung tissue, thereby impairing pulmonary PC homoeostasis. In cystic fibrosis (CF), exocrine pancreas insufficiency results in impaired cleavage of bile PC and subsequent fecal choline loss. In these patients, the plasma choline concentration is low and correlates with lung function. We therefore investigated the effect of choline supplementation on plasma choline/PC concentration and metabolism, lung function, and liver fat. Methods: 10 adult male CF patients were recruited (11/2014&ndash, 1/2016), and orally supplemented with 3 &times, 1 g choline chloride for 84 (84&ndash, 91) days. Pre-/post-supplementation, patients were spiked with 3.6 mg/kg [methyl-D9]choline chloride to assess choline/PC metabolism. Mass spectrometry, spirometry, and hepatic nuclear resonance spectrometry served for analysis. Results: Supplementation increased plasma choline from 4.8 (4.1&ndash, 6.2) &micro, mol/L to 10.5 (8.5&ndash, 15.5) &micro, mol/L at d84 (p &lt, 0.01). Whereas plasma PC concentration remained unchanged, D9-labeled PC was decreased (12.2 [10.5&ndash, 18.3] &micro, mol/L vs. 17.7 [15.5&ndash, 22.4] &micro, mol/L, p &lt, 0.01), indicating D9-tracer dilution due to higher choline pools. Supplementation increased Forced Expiratory Volume in 1 second percent of predicted (ppFEV1) from 70.0 (50.9&ndash, 74.8)% to 78.3 (60.1&ndash, 83.9)% (p &lt, 0.05), and decreased liver fat from 1.58 (0.37&ndash, 8.82)% to 0.84 (0.56&ndash, 1.17)% (p &lt, 0.01). Plasma choline returned to baseline concentration within 60 h. Conclusions: Choline supplementation normalized plasma choline concentration and increased choline-containing PC precursor pools in adult CF patients. Improved lung function and decreased liver fat suggest that in CF correcting choline deficiency is clinically important. Choline supplementation of CF patients should be further investigated in randomized, placebo-controlled trials.

Patients with cystic fibrosis (CF) lung disease have chronic airway inflammation driven by disrupted balance of T-cell (Th17 and Th2) responses. Regulatory T cells (Tregs) dampen T-cell activation, but their role in CF is incompletely understood.To characterize numbers, function, and clinical impact of Tregs in CF lung disease.Tregs were quantified in peripheral blood and airway samples from patients with CF and from lung disease control patients without CF and healthy control subjects. The role of Pseudomonas aeruginosa and CF transmembrane conductance regulator (CFTR) in Treg regulation was analyzed by using in vitro and murine in vivo models.Tregs were decreased in peripheral blood and airways of patients with CF compared with healthy controls or lung disease patients without CF and correlated positively with lung function parameters. Patients with CF with chronic P. aeruginosa infection had lower Tregs compared with patients with CF without P. aeruginosa infection. Genetic knockout, pharmacological inhibition, and P. aeruginosa infection studies showed that both P. aeruginosa and CFTR contributed to Treg dysregulation in CF. Functionally, Tregs from patients with CF or from Cftr(-/-) mice were impaired in suppressing conventional T cells, an effect that was enhanced by P. aeruginosa infection. The loss of Tregs in CF affected memory, but not naive Tregs, and manifested gradually with disease progression.Patients with CF who have chronic P. aeruginosa infection show an age-dependent, quantitative, and qualitative impairment of Tregs. Modulation of Tregs represents a novel strategy to rebalance T-cell responses, dampen inflammation, and ultimately improve outcomes for patients with infective CF lung disease.

To evaluate the applicability of a semiquantitative MRI scoring system (MR-CF-S) as a prognostic marker for clinical course of cystic fibrosis (CF) lung disease. This observational study of a single-centre CF cohort included a group of 61 patients (mean age 12.9 ± 4.7 years) receiving morphological and functional pulmonary MRI, pulmonary function testing (PFT) and follow-up of 2 years. MRI was analysed by three raters using MR-CF-S. The inter-rater agreement, correlation of score categories with forced expiratory volume in 1 s (FEV1) at baseline, and the predictive value of clinical parameters, and score categories was assessed for the whole cohort and a subgroup of 40 patients with moderately impaired lung function. The inter-rater agreement of MR-CF-S was sufficient (mean intraclass correlation coefficient 0.92). MR-CF-S (−0.62; p 3%/year) and normal course were only significant for MR-CF-S (p

Background/Aims: Several recent clinical studies revealed an accumulation of ceramide in bronchial epithelial cells of patients with cystic fibrosis (CF). Degradation of ceramide concentrations in lungs of CF patients employing the functional acid sphingomyelinase inhibitor amitriptyline revealed a benefit in lung function, weight and exacerbation rates. Methods: To test for a beneficial effect of amitriptyline in vivo, we performed two phase II randomised, double-blind, placebo-controlled studies. CF patients were treated with 25 mg amitriptyline twice daily, i.e. a total dose of 50 mg/d. After those two studies part of the patients used amitriptyline in an off-lable-use for routine treatment. These patients were observed after one, two and three years after continuous use of amitriptyline and were matched with those patients who were not treated. These patients were used as a control group. Results: After one year of treatment, forced expiratory volume in 1 sec predicted (FEV1) increased significantly by 7.6±7.0%, p=

Background Staphylococcus aureus is an important pathogen in cystic fibrosis (CF). However, it is not clear which factors are associated with worse lung function in patients with persistent S. aureus airway cultures. Our main hypothesis was that patients with high S. aureus density in their respiratory specimens would more likely experience worsening of their lung disease than patients with low bacterial loads. Methods Therefore, we conducted an observational prospective longitudinal multi-center study and assessed the association between lung function and S. aureus bacterial density in respiratory samples, co-infection with other CF-pathogens, nasal S. aureus carriage, clinical status, antibiotic therapy, IL-6- and IgG-levels against S. aureus virulence factors. Results 195 patients from 17 centers were followed; each patient had an average of 7 visits. Data were analyzed using descriptive statistics and generalized linear mixed models. Our main hypothesis was only supported for patients providing throat specimens indicating that patients with higher density experienced a steeper lung function decline (p

With intensified antibiotic therapy and longer survival, patients with cystic fibrosis (CF) are colonized with a more complex pattern of bacteria and fungi. However, the clinical relevance of these emerging pathogens for lung function remains poorly defined. The aim of this study was to assess the association of bacterial and fungal colonization patterns with lung function in adolescent patients with CF. Microbial colonization patterns and lung function parameters were assessed in 770 adolescent European (German/Austrian) CF patients in a retrospective study (median follow-up time: 10years). Colonization with Pseudomonas aeruginosa and MRSA were most strongly associated with loss of lung function, while mainly colonization with Haemophilus influenzae was associated with preserved lung function. Aspergillus fumigatus was the only species that was associated with an increased risk for infection with P. aeruginosa. Microbial interaction analysis revealed three distinct microbial clusters within the longitudinal course of CF lung disease. Collectively, this study identified potentially protective and harmful microbial colonization patterns in adolescent CF patients. Further studies in different patient cohorts are required to evaluate these microbial patterns and to assess their clinical relevance.

Individuals with cystic fibrosis (CF) receive antibiotics continuously throughout their entire life which leads to drug resistant microbial lung infections which are difficult to treat. Nitric oxide (NO) gas possesses antimicrobial activity against a wide variety of microorganisms in vitro, in vivo in animal models and a phase I study in healthy adults showed administration of intermittent 160 ppm NO to be safe. We assessed feasibility and safety of inhaled NO in eight CF patients who received 160 ppm NO for 30 min, three times daily for 2 periods of 5 days. The NO treatment was safe and in none of the patients were serious drug-related adverse events observed which caused termination of the study. The intention-to-treat analysis revealed a significant mean reduction of the colony forming units of all bacteria and all fungi, while mean forced expiratory volume 1 s % predicted (FEV1) relative to baseline increased 17.3 ± 8.9 % (P = 0.012). NO treatment may improve the therapy of chronic microbial lung infections in CF patients, particularly concerning pathogens with intrinsic or acquired resistance to antibiotics.

Background and Objectives: Fungi, particularly Aspergillus and Candida species, are increasingly found in cystic fibrosis (CF) airway fluids. However, their association with other CF pathogens, medications and lung function, especially in CF children, remains elusive. We analyzed the relationship of fungal colonization to microbiological and clinical parameters of pediatric CF patients. Methods and Results: Fungal colonization and long-term clinical parameters like BMI and lung function were retrospectively studied in over 500 CF patients. Colonization was defined based on Chotirmall et al. (Chest 2010). Candida albicans (CA) was the most prevalent fungus detected in CF airway fluids, followed by C. non-albicans > Aspergillus fumigatus (AF) > A. non-fumigatus species. We found an association between fungal colonization and (among other parameters) bacterial co-colonization, lung function, BMI and antibiotic therapy. Conclusion: This study suggests that colonization with CA or AF is affected by bacterial co-colonization and may modulate the disease severity already in pediatric CF patients.

Pseudomonas aeruginosa persists in patients with cystic fibrosis (CF) and drives CF lung disease progression. P. aeruginosa potently activates the innate immune system, mainly mediated through pathogen-associated molecular patterns, such as flagellin. However, the host is unable to eradicate this flagellated bacterium efficiently. The underlying immunological mechanisms are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells generated in cancer and proinflammatory microenvironments and are capable of suppressing T cell responses. We hypothesized that P. aeruginosa induces MDSCs to escape T cell immunity. In this article, we demonstrate that granulocytic MDSCs accumulate in CF patients chronically infected with P. aeruginosa and correlate with CF lung disease activity. Flagellated P. aeruginosa culture supernatants induced the generation of MDSCs, an effect that was 1) dose-dependently mimicked by purified flagellin protein, 2) significantly reduced using flagellin-deficient P. aeruginosa bacteria, and 3) corresponded to TLR5 expression on MDSCs in vitro and in vivo. Both purified flagellin and flagellated P. aeruginosa induced an MDSC phenotype distinct from that of the previously described MDSC-inducing cytokine GM-CSF, characterized by an upregulation of the chemokine receptor CXCR4 on the surface of MDSCs. Functionally, P. aeruginosa–infected CF patient ex vivo–isolated as well as flagellin or P. aeruginosa in vitro–generated MDSCs efficiently suppressed polyclonal T cell proliferation in a dose-dependent manner and modulated Th17 responses. These studies demonstrate that flagellin induces the generation of MDSCs and suggest that P. aeruginosa uses this mechanism to undermine T cell–mediated host defense in CF and other P. aeruginosa–associated chronic lung diseases.

Background Chitinases have recently gained attention in the field of pulmonary diseases, particularly in asthma and chronic obstructive pulmonary disease, but their potential role in patients with cystic fibrosis (CF)–associated lung disease remains unclear. Objective The aim of this study was to assess chitinase activity systemically and in the airways of patients with CF and asthma compared with healthy subjects. Additionally, we assessed factors that regulate chitinase activity within the lungs of patients with CF. Methods Chitinase activities were quantified in serum and bronchoalveolar lavage fluid from patients with CF, asthmatic patients, and healthy control subjects. Mechanistically, the role of CF airway proteases and genetic chitinase deficiency was assessed. Results Chitinase activity was systemically increased in patients with CF compared with that in healthy control subjects and asthmatic patients. Further stratification showed that chitinase activity was enhanced in patients with CF colonized with Candida albicans compared with that in noncolonized patients. CF proteases degraded chitinases in the airway microenvironment of patients with CF. Genetic chitinase deficiency was associated with C albicans colonization in patients with CF. Conclusion Patients with CF have enhanced chitinase activation associated with C albicans colonization. Therefore chitinases might represent a novel biomarker and therapeutic target for CF-associated fungal disease.

A genome-wide association study identified interferon-related development regulator-1 (IFRD1), a protein expressed by neutrophils, as a key modifier gene in cystic fibrosis (CF) lung disease. Here, we investigated the expression and regulation of IFRD1 in CF neutrophils. IFRD1 expression was quantified in peripheral blood and airway neutrophils from patients with CF, patients with non-CF lung disease, and healthy control subjects. The regulation of IFRD1 expression was analyzed using isolated neutrophils and ex vivo stimulation assays with CF airway fluids. IFRD1 single-nucleotide polymorphisms (SNPs) were analyzed in a CF cohort (n = 572) and correlated with longitudinal lung function and IFRD1 expression. Patients with CF expressed higher protein levels of IFRD1 in peripheral blood neutrophils compared with healthy or non-CF disease control subjects. Within patients with CF, IFRD1 protein expression levels in neutrophils were lower in airway fluids compared with peripheral blood. High IFRD1 expression was positively associated with the production of reactive oxygen species (ROS) in CF neutrophils. In vitro regulation studies showed that CF airway fluid and the CF-characteristic chemokines CXCL8 and CXCL2 down-regulated IFRD1 expression in neutrophils, an effect that was mediated through CXCR2. Genetic analyses showed that three IFRD1 SNPs were associated with longitudinal declines in lung function, and modulated IFRD1 expression. These studies demonstrate that IFRD1 expression is systemically up-regulated in human CF neutrophils, is linked to the production of ROS, and is modulated by chemokines in CF airway fluids, depending on the IFRD1 genotype. Understanding the regulation of IFRD1 may pave the way for novel therapeutic approaches to target neutrophilic inflammation in CF.

Objectives Pseudomonas aeruginosa in the airways of CF-patients restricts the efficacy of antibiotics leading to chronic infections which have a large impact on morbidity and mortality. Antibiotic combination therapy might be more efficient than single antibiotics to combat lung infections in CF. Methods In an observational pilot study CF patients, suffering from chronic P. aeruginosa lung infection, pre-treated either with tobramycin or colistin, were inhalatively treated for 28 days with 300 mg tobramycin in combination with colistin (1 Mio IU) and meropenem 250 mg twice daily. Lung function expressed as expiratory volume in 1 second (FEV 1 ), bacterial cfu and adverse events were determined before and after treatment. Results 15 adult CF patients (mean age 27.9±9.4 years) inhaled b-sympathomimetics prior to the triple antibiotic solution which was well tolerated by all patients. FEV1 increased significantly by 7.8±5.7% absolute and 11.6±10% relative to baseline (p = 0.001) since only one patient showed no benefit after 28 days of inhalation. P. aeruginosa decreased significantly by 1.46±1.4 log cfu/ml (p = 0.042). No adverse reactions were found. Conclusion For the first time administered, the efficacy of an inhalative triple antibiotic solution with meropenem, tobramycin and colistin suggest, that this combination therapy seems to be safe and efficient to increase lung function and decrease chronic Pseudomonas infection in CF patients. This alternative combination of inhalative antibiotics has to be investigated in further trials.

WS6.2 Anti-inflammatory pulmonal therapy of CF patients with amitriptyline and placebo − a randomised, double-blind, placebo-controlled Phase IIb multicenter cohort study C. Adams1, J.G. Mainz2, L. Naehrlich3, C. Engel4, G. Herrmann4, V. Icheva4, U. Graepler-Mainka4, S. Heyder5, M. Stern4, G. Doring6, E. Gulbins1, J. Riethmueller4. 1University of Duisburg-Essen, Dept. of Molecular Biology, Essen, Germany; 2University of Jena, Childrens Hospital, Jena, Germany; 3University of Giessen, Childrens Hospital, Giessen, Germany; 4University of Tubingen, Childrens Hospital, Tubingen, Germany; 5Klinik Schillerhohe, Gerlingen, Germany; 6University of Tubingen, Tubingen, Germany

Objectives: Fungi, particularly Aspergillus and Candida species, are increasingly found in cystic fibrosis (CF) airway fluids. However, their relationship to other CF pathogens, medications and lung function, especially in CF children, remains poorly understood. To address this question, we analyzed the associations of fungal colonization with microbiological and clinical parameters of pediatric CF patients. Methods: Fungal colonization was categorized in n = 128 CF patients based on Chotirmall et al. (Chest 2010). Candida albicans (CA) was the most prevalent fungus detected in CF airway fluids, followed by C. non-albicans > Aspergillus fumigatus (AF) > A. non-fumigatus species. Colonization with CA correlated positively with age, inhaled antibiotic use, and Aspergillus species, while an inverse correlation with Haemophilus and no association with S. aureus or Pseudomonas was found. Colonization with AF correlated positively with age, inhaled antibiotics, Pseudomonas, Stenotrophomonas, atypical mycobacteria and CF-related diabetes and inversely with Haemophilus. ABPA showed no correlation with AF colonization, but with non-fumigatus species and use of azithromycin. Colonization with AF or CA correlated inversely with cross-sectional FEV1, but not with MEF25. Colonization with AF correlated with longitudinal FEV1 decline. Conclusion: This study suggests that colonization with CA or AF is affected by bacterial co-colonization and may modulate lung function already in pediatric CF.

J. Hentschel1, M. Jager1, N. Beiersdorf1,2, F. Doht1, R. Michl1, U.R. Markert2, K. Boer3, P. Keller4, M.W. Pletz5, J.G. Mainz1. 1Jena University Hospital, CF-Centre, Paediatrics, Jena, Germany; 2Jena University Hospital, Department of Obstetrics, Placenta Laboratory, Jena, Germany; 3Jena University Hospital, Institute for Clinical Chemistry and Laboratory Diagnostics, Jena, Germany; 4Jena University Hospital, Institute of Medical Microbiology, Jena, Germany; 5Jena University Hospital, Center for Infectious Diseases and Infection Control, Jena, Germany