Christina Smaczny

Non-invasive measurement of liver and pancreas fibrosis in patients with cystic fibrosis.

BACKGROUND Patients with cystic fibrosis (CF) have a relevant morbidity and mortality caused by CF-related liver-disease. While transient elastography (TE) is an established elastography method in hepatology centers, Acoustic-Radiation-Force-Impulse (ARFI)-Imaging is a novel ultrasound-based elastography method which is integrated in a conventional ultrasound-system. The aim of the present study was to evaluate the prevalence of liver-fibrosis in patients with CF using TE, ARFI-imaging and fibrosis blood tests. METHODS 106 patients with CF were prospectively included in the present study and received ARFI-imaging of the left and right liver-lobe, ARFI of the pancreas TE of the liver and laboratory evaluation. RESULTS The prevalence of liver-fibrosis according to recently published best practice guidelines for CFLD was 22.6%. Prevalence of significant liver-fibrosis assessed by TE, ARFI-right-liver-lobe, ARFI-left-liver-lobe, Fibrotest, Fibrotest-corrected-by-haptoglobin was 17%, 24%, 40%, 7%, and 16%, respectively. The best agreement was found for TE, ARFI-right-liver-lobe and Fibrotest-corrected-by-haptoglobin. Patients with pancreatic-insufficiency had significantly lower pancreas-ARFI-values as compared to patients without. CONCLUSIONS ARFI-imaging and TE seem to be promising non-invasive methods for detection of liver-fibrosis in patients with CF.

BIIL 284 reduces neutrophil numbers but increases P. aeruginosa bacteremia and inflammation in mouse lungs

BACKGROUND A clinical study to investigate the leukotriene B(4) (LTB(4))-receptor antagonist BIIL 284 in cystic fibrosis (CF) patients was prematurely terminated due to a significantly increased risk of adverse pulmonary events. We aimed to establish the effect of BIIL284 in models of Pseudomonas aeruginosa lung infection, thereby contributing to a better understanding of what could have led to adverse pulmonary events in CF patients. METHODS P. aeruginosa DNA in the blood of CF patients during and after acute pulmonary exacerbations and in stable patients with non-CF bronchiectasis (NCFB) and healthy individuals was assessed by PCR. The effect of BIIL 284 treatment was tested in an agar bead murine model of P. aeruginosa lung infection. Bacterial count and inflammation were evaluated in lung and other organs. RESULTS Most CF patients (98%) and all patients with NCFB and healthy individuals had negative P. aeruginosa DNA in their blood. Similarly, the P. aeruginosa-infected mice showed bacterial counts in the lung but not in the blood or spleen. BIIL 284 treatment decreased pulmonary neutrophils and increased P. aeruginosa numbers in mouse lungs leading to significantly higher bacteremia rates and lung inflammation compared to placebo treated animals. CONCLUSIONS Decreased airway neutrophils induced lung proliferation and severe bacteremia in a murine model of P. aeruginosa lung infection. These data suggest that caution should be taken when administering anti-inflammatory compounds to patients with bacterial infections.

High Variability in Oral Glucose Tolerance among 1,128 Patients with Cystic Fibrosis: A Multicenter Screening Study

Background In cystic fibrosis, highly variable glucose tolerance is suspected. However, no study provided within-patient coefficients of variation. The main objective of this short report was to evaluate within-patient variability of oral glucose tolerance. Methods In total, 4,643 standardized oral glucose tolerance tests of 1,128 cystic fibrosis patients (median age at first test: 15.5 [11.5; 21.5] years, 48.8% females) were studied. Patients included were clinically stable, non-pregnant, and had at least two oral glucose tolerance tests, with no prior lung transplantation or systemic steroid therapy. Transition frequency from any one test to the subsequent test was analyzed and within-patient coefficients of variation were calculated for fasting and two hour blood glucose values. All statistical analysis was implemented with SAS 9.4. Results A diabetic glucose tolerance was confirmed in 41.2% by the subsequent test. A regression to normal glucose tolerance at the subsequent test was observed in 21.7% and to impaired fasting glucose, impaired glucose tolerance or both in 15.2%, 12.0% or 9.9%. The average within-patient coefficient of variation for fasting blood glucose was 11.1% and for two hour blood glucose 25.3%. Conclusion In the cystic fibrosis patients studied, a highly variable glucose tolerance was observed. Compared to the general population, variability of two hour blood glucose was 1.5 to 1.8-fold higher.

Diabetes in Cystic Fibrosis: Multicenter Screening Results Based on Current Guidelines

Background Published estimates on age-dependent frequency of diabetes in cystic fibrosis (CF) vary widely, and are based mostly on older data. However, CF treatment and prevention of comorbidities changed over recent years. In many studies, definition of cystic fibrosis-related diabetes (CFRD) is not in line with current guideline recommendations. Therefore, we evaluated age-dependent occurrence of glucose abnormalities and associated risk factors in CF patients who participated in a multicenter screening program using oral glucose tolerance tests (OGTT). Methods Between 2001 and 2010, 43 specialized CF centers from Germany and Austria serially performed 5,179 standardized OGTTs in 1,658 clinically stable, non-pregnant CF patients with no prior steroid medication or lung transplantation. Age-dependent occurrence of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG+IGT, one (DGT) or two consecutive (CFRD) diabetic OGTTs was analyzed, using Kaplan Meier curves. Cox proportional-hazards models were created to elucidate the influence of sex or underweight. Results At baseline/last OGTT, median age was 15.9 years/18.2 years and 30.6%/31.8% of patients were underweight. 25% of patients showed IFG at age 14.3 years; IGT at age 16.3 years; IFG+IGT combined at age 17.7 years. DGT was observed in 25% of patients at age 22.6 years; CFRD at age 34.5 years. Females had a 3.54 [95% CI 1.23–10.18] times higher risk for CFRD; risk for DGT was 2.21 [1.22–3.98] times higher. Underweight was a risk factor for IGT (HR [95% CI]: 1.38 [1.11–1.71]) and IFG+IGT (1.43 [1.11–1.83]), and in males also for DGT (1.49 [1.09–2.04]). Conclusions/Significance If confirmation of diabetes by a second test is required, as recommended in current guidelines, age at CFRD diagnosis was higher compared to most previous studies. However, known risk factors for glucose abnormalities in CF were confirmed. Confirmation of diabetic OGT by a repeat test is important for a consistent diagnosis of CFRD.

Pro-resolving lipid mediator Resolvin D1 serves as a marker of lung disease in cystic fibrosis.

Background Cystic fibrosis (CF) is an autosomal recessive genetic disorder that affects multiple organs, including the lungs, pancreas, liver and intestine. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) locus lead to defective proteins and reduced Cl- secretion and Na+ hyperabsorption in the affected organs. In addition, patients suffering from CF display chronic inflammation that contributes to the pathogenesis of CF. Recent work suggests that CF patients have a reduced capacity to biosynthesize specialized pro-resolving lipid mediators (SPMs), which contributes to the development and duration of the unwanted inflammation. Alterations in the metabolism of arachidonic acid (AA) and docosahexaenoic acid (DHA) to specialized pro-resolving mediators (SPMs), like lipoxins (LXs), maresins (MaRs), protectins (PDs) and resolvins (Rvs), may play a major role on clinical impact of airway inflammation in CF. Methods In this study, our aims were to detect and quantitate Resolvin D1 (RvD1) in sputum and plasma from patients with CF and compare levels of RvD1 with biomarkers of inflammation and lung function. We studied 27 CF patients aged 6 to 55 years (median 16 years) in a prospective approach. Results DHA can be found in the plasma of our CF patients in the milligram range and is decreased in comparison to a healthy control group. The DHA-derived pro-resolving mediator Resolvin D1 (RvD1) was also present in the plasma (286.4 ± 50 pg/ mL, mean ± SEM) and sputum (30.0 ± 2.6 pg/ mL, mean ± SEM) samples from our patients with CF and showed a positive correlation with sputum inflammatory markers. The plasma concentrations of RvD1 were ten times higher than sputum concentrations. Interestingly, sputum RvD1/ IL-8 levels showed a positive correlation with FEV1 (rs = 0.3962, p< 0.05). Conclusions SPMs, like RvD1, are well known to down-regulate inflammatory pathways. Our study shows that the bioactive lipid mediator RvD1, derived from DHA, was present in sputum and plasma of CF patients and may serve as a representative peripheral biomarker of the lung resolution program for CF patients.

Lipopolysaccharide Binding Protein, Cytokine Production in Whole Blood, and Lipoproteins in Cystic Fibrosis

According to the endotoxin lipoprotein hypothesis, lipoproteins may down-regulate cytokine production by neutralizing lipopolysaccharide (LPS) binding protein (LBP) complexes. We investigated the correlation between lipoproteins, LBP, cytokine production, and clinical status in Delta F 508 (homozygous) individuals. Cystic fibrosis patients with mild disease were compared with those with more severe disease and age-matched controls. LBP, IL-8, and tumor necrosis factor-α, using a chemiluminescent immunometric assay, and fat intake, as well as serum triglycerides, cholesterol, very low density lipoprotein, LDL, and HDL were measured. In more severe disease there was a correlation between maximum expiratory flow at 25% of vital capacity and HDL. To adjust for the influence of colonization with Pseudomonas aeruginosa, those who were colonized with P. aeruginosa were analyzed separately. There was a significant correlation between LBP and forced expiratory volume in 1 s. Lipoproteins may have a modulating effect in more advanced disease and are not influenced by fat intake. LBP correlates those who were colonized with P. aeruginosa (Psa+) with clinical status as well as lung function and may be a critical molecule regulating LPS-induced inflammation.

Repaglinide versus insulin for newly diagnosed diabetes in patients with cystic fibrosis: a multicentre, open-label, randomised trial

BACKGROUND As survival among patients with cystic fibrosis has improved in recent decades, complications have become increasingly relevant. The most frequent complication is cystic-fibrosis-related diabetes. The recommended treatment is injected insulin, but some patients are treated with oral antidiabetic drugs to ease the treatment burden. We assessed the efficacy and safety of oral antidiabetic drugs. METHODS We did a multicentre, open-label, comparative, randomised trial in 49 centres in Austria, France, Germany, and Italy. Eligible patients had cystic fibrosis, were older than 10 years, and had newly diagnosed diabetes. We used a central randomisation schedule derived from a Geigy random number table to assign patients 1:1 to receive insulin or repaglinide, stratified by sex and age (10-15 years or >15 years). The primary outcome was glycaemic control assessed by mean change in HbA1c concentration from baseline after 24 months of treatment. Differences between groups were assessed by linear models. The primary and safety analyses were done in the modified intention-to-treat population (including patients who stopped treatment early because of lack of efficacy). This trial is registered with ClinicalTrials.gov, number NCT00662714. FINDINGS We enrolled 34 patients in the repaglinide group and 41 in the insulin group, of whom 30 and 37, respectively, were included in the analyses. At 24 months, glycaemic control was similar in the repaglinide and insulin groups (mean change in HbA1c concentration from baseline 0·2% [SD 0·7%], 1·7 mmol/mol [8·1 mmol/mol] with repaglinide vs -0·2% [1·3%], -2·7 mmol/mol, [14·5 mmol/mol] with insulin; mean difference between groups -0·4%, (95% CI -1·1 to 0·2 [-4·4 mmol/mol, -11·5 to 2·7], p=0·15). The most frequent adverse events were pulmonary events (43 [40%] of 107 in the repaglinide group and 60 [45%] of 133 in the insulin group), and the most frequent serious adverse events were pulmonary events leading to hospital admission (five [50%] of ten and seven [54%] of 13, respectively). INTERPRETATION Repaglinide for glycaemic control in patients with cystic-fibrosis-related diabetes is as efficacious and safe as insulin. FUNDING Mukoviszidose eV, Vaincre la Mucoviscidose, ABCF Association, and Novo Nordisk.

Airway inflammation in mild cystic fibrosis

BACKGROUND Airway infection and inflammation play major roles in the progression of cystic fibrosis (CF) lung disease. In patients with mild disease, airway inflammation is a clinically relevant and often underdiagnosed feature. Lung function, sputum cell counts, and cytokine profiles in CF with mild disease might be different in patients with and without involvement of small airway disease (SAD). METHODS Patients with mild CF (n=32) and 22 healthy controls were enrolled in this study. Patients with CF were assigned to two groups: (1) patients without SAD (n=19, median age 12.3years, MEF25>50% predicted), and (2) patients with SAD (n=13 median age, 13.2years, MEF25<50% predicted). Lung function parameters were measured, cells in induced sputum were counted, and cytokines/chemokines (IL-1β, IL-6, IL-8, TNF-α) were analyzed by real-time quantitative PCR (qRT-PCR) and cytometric bead array (CBA). RESULTS Patients with CF had significant elevated levels of pro-inflammatory genes in qRT-PCR and secreted gene products in CBA compared to controls. Patients with CF and SAD had significantly increased trapped air (RV/TLC) and pronounced airway inflammation compared to controls as indicated by elevated levels of sputum biomarkers like total cells, neutrophils, and IL6. CONCLUSIONS Our study demonstrated that patients with CF with mild disease defined by lung function might be further endotyped according to their involvement of SAD. In patients with CF and SAD, airway neutrophilic inflammation is more pronounced and is in part distinct from that seen in patients without SAD.

Lungentransplantation bei Mukoviszidose – ein Positionspapier

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

Medikamentöse Behandlung von Mukoviszidose: Kostenstruktur und Einsparpotenzial der ambulanten Behandlung

ZusammenfassungHintergrund und Ziel:Die medikamentöse Behandlung erwachsener Mukoviszidosepatienten ist mit hohen Kosten verbunden. Als Beitrag zur Sicherung einer adäquaten und nachhaltigen Behandlung erörtert die vorliegende Untersuchung die ambulanten Arzneimittelkosten von Mukoviszidosepatienten in Deutschland. Dabei werden Hauptkostentreiber ebenso identifiziert wie das Potenzial für Kosteneinsparungen durch Aut-idem-Präparatsubstitution und die Summe lebenslanger Medikationskosten.Methodik:Die Analyse basiert auf einem umfassenden Datensatz aller Arzneimittelverordnungen für erwachsene Mukoviszidosepatienten (n = 124) aus der Spezialambulanz der Universitätsklinik Frankfurt am Main im Jahr 2007. Die jährlichen Arzneimittelkosten wurden auf Basis der Preise der Roten Liste ermittelt. Einsparmöglichkeiten gemäß Aut-idem-Präparatsubstitution wurden mit Hilfe des ABDATA Pharma-Daten-Service berechnet.Ergebnisse:Die ambulanten Arzneimittelkosten für einen erwachsenen Mukoviszidosepatienten betragen durchschnittlich 17.219 € pro Jahr, welche im Falle einer zusätzlichen i.v.-Therapie auf 21.782 € ansteigen. Die lebenslangen Medikationskosten eines CF-Patienten mit einer mittleren Lebenserwartung bei Geburt von 39,7 Jahren belaufen sich auf 824.159 € (Bezugsjahr 2007, Inflationsrate 2,7%, Diskontierungsrate 3%). Bei Ausschöpfung sämtlicher Substitutionsmöglichkeiten mit günstigeren Präparaten gemäß Aut idem lassen sich die jährlichen Arzneimittelausgaben um 4,1% senken.Schlussfolgerung:Die vorliegenden Ergebnisse spiegeln die hohen Therapiekosten der Mukoviszidose nachvollziehbar sowohl pro Jahr als auch über die Lebenszeit eines Patienten wider. Dabei fällt das Potenzial für Kosteneinsparungen durch Aut-idem-Substitution gering aus. Vielmehr stellt die Identifikation einiger weniger kostentreibender Medikamente einen soliden Beitrag zur Beurteilung verschiedener Therapieoptionen und Finanzierungsstrukturen dar, um eine angemessene und tragfähige Behandlung von Mukoviszidose sicherzustellen.AbstractBackground and Purpose:Drug treatment of cystic fibrosis (CF) is associated with significant costs. To help ensure sustainable care, this study assesses the costs associated with outpatient treatment of adult CF patients in Germany. It identifies main cost drivers, evaluates the potential for cost savings from “aut idem” substitution and presents a projection of lifelong medication costs.Methods:The analysis is based on a complete set of prescriptions for adult CF patients from the outpatient clinic of the university hospital of Frankfurt am Main during 2007 (n = 124 patients). Annual treatment costs were calculated on the basis of the “Rote Liste”, while the potential for cost savings from “aut idem” drug substitution was obtained through ABDATA Pharma Data Service.Results:The annual outpatient drug costs for an adult patient with CF averages € 17,219 (n = 124), which increases to € 21,782 if i.v. therapies are included. With an average life expectancy at birth of 39.7 years, total lifetime drug treatment costs amount to € 824,159 (reference year 2007, inflation rate 2.7%, 3% discount rate). “Aut idem” substitution with cheaper drugs could reduce pharmaceutical expenditures by 4.1%.Conclusion:Our results confirm the costly nature of drug treatment for CF patients, both on an annual and in particular on a lifelong basis. At the same time, the potential for cost savings through “aut idem” substitution with cheaper drugs remains limited. The added transparency around a small set of costdriving drugs, which is offered in this study, represents a solid contribution to assess treatment choices and financing options to help secure adequate yet sustainable care for CF patients.