Sequential Inhalational Tobramycin-Colistin-Combination in CF-Patients with Chronic P. Aeruginosa Colonization - an Observational Study

Background/Aims: In cystic fibrosis (CF), chronic microbial lung infections are difficult to treat and cause morbidity and increased mortality. Methods: In a multicentre, open-label, exploratory, non-interventional study, inhaled tobramycin (300 mg twice daily) and colistin (1 million I.U. twice daily) were sequentially combined with the aim to investigate the effect on 41 CF patients with chronic P. aeruginosa infections for six months (mean age 24 ± 10.8y). Results: Six patients had adverse events that were assessed as being related to treatment. Mucus production and coughing both decreased in 39%, whereas FEV1 absolute and relative to baseline increased by 4.9% and 9.1%, respectively (p = 0.004) in 29 patients, who were definitely treated sequentially. Efficacy of the therapy was rated ‘excellent' or ‘good' by the physicians in 80.5% of the patients. Conclusions: The results indicate that treatment with inhaled antibiotics, sequentially combined, was very well tolerated by most patients and may have a beneficial effect, even if transitory on lung function and respiratory symptoms

Factors associated with worse lung function in cystic fibrosis patients with persistent staphylococcus aureus

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<0.001). Patients with exacerbations (n = 60), S. aureus small-colony variants (SCVs, n = 84) and co-infection with Stenotrophomonas maltophilia (n = 44) had worse lung function (p = 0.0068; p = 0.0011; p = 0.0103). Patients with SCVs were older (p = 0.0066) and more often treated with trimethoprim/sulfamethoxazole (p = 0.0078). IL-6 levels positively correlated with decreased lung function (p<0.001), S. aureus density in sputa (p = 0.0016), SCVs (p = 0.0209), exacerbations (p = 0.0041) and co-infections with S. maltophilia (p = 0.0195) or A. fumigatus (p = 0.0496). Conclusions In CF-patients with chronic S. aureus cultures, independent risk factors for worse lung function are high bacterial density in throat cultures, exacerbations, elevated IL-6 levels, presence of S. aureus SCVs and co-infection with S. maltophilia

Long-Term Pulmonal Therapy of Cystic Fibrosis-Patients with Amitriptyline

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=1 decreased significantly in the control group by 1.8±3.3%, p=0.010, and weight increased by 1.1±2.7kg, p=0.010 (n=14). After two years of treatment, FEV1 increased significantly by 5.6±10.3%, p=0.009, and weight increased by 3.6±2.9kg, p=1 decreased in the control group by 2.1±3.7%, p=0.051 and weight increased by only 0.4±2.9kg, p=0.31 (n=10). After three years of treatment, FEV1 increased significantly by 7.7±8%, p=0.050, and weight increased by 7.3±3.8kg, p=0.016, in the amitriptyline population (n=5), whereas FEV1 decreased in the control group by 1.0±1.3%, p=0.075 and weight increased by 0.4±1.5kg, p=0.29 (n=5). Conclusion: Amitriptyline significantly increases FEV1, reduces ceramide in lung cells and increases weight of CF patients

Choline Supplementation in Cystic Fibrosis—The Metabolic and Clinical Impact

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

Comparison between High-Resolution CT and MRI Using a Very Short Echo Time in Patients with Cystic Fibrosis with Extra Focus on Mosaic Attenuation

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; It would be beneficial to establish pulmonary MRI as a complementary approach to CT for direct visualization of mosaic perfusion, bullae, and emphysema in patients with cystic fibrosis. &lt;b&gt;&lt;i&gt;Objectives:&lt;/i&gt;&lt;/b&gt; The purpose of this study was to compare both modalities, CT and MRI, using the Helbich-Bhalla score with a special focus on reliable detection of a mosaic pattern. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Out of 51 patients examined by MRI on a 1.5-Tesla system during a period of 2 years, 19 patients were scheduled for additional low-dose CT in a clinical context. The MRI protocol comprised a gradient echo (GRE) sequence with a very short echo time (TE = 0.8 ms) in inspiration and expiration, a 3-D GRE sequence in breath hold, and a fast spin echo sequence with respiration and ECG triggering. MDCT was carried out in inspiration and adapted to body weight using 100 or 120 kV, 30-60 mA, 1- and 3-mm slice thicknesses, as well as low and high kernels. Additionally incremental slices in 3 positions were recorded in expiration for distinct detection of air trapping. CT and MRI analyses were performed by two radiologic readers in consensus unaware of the clinical parameters. The Helbich-Bhalla score of both examinations was correlated. Mean difference and accordance were assessed in each category. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; There was a strong correlation between CT and MRI (R = 0.87, p &lt; 0.01). The mean Helbich-Bhalla score for CT was 12.2 (range 1-18) and for MRI it was 11.7 (range 2-19). The mean difference was 0.5 points. Besides this strong correlation for findings (bronchiectasis, mucus plugging, peribronchial thickening, and consolidation) with a prolonged T2 TE in MRI, we could also state a qualitative agreement of 95-100% in the categories with short T2 and low signal intensity in MRI as emphysema, bullae, and mosaic perfusion. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; These results suggest that in our patient group none of the relevant findings were missed by MR imaging and reading.</jats:p