[CF Lung Disease - a German S3 Guideline: Module 2: Diagnostics and Treatment in Chronic Infection with Pseudomonas aeruginosa]. / S3-Leitlinie: Lungenerkrankung bei Mukoviszidose ­ Modul 2: Diagnostik und Therapie bei der chronischen Infektion mit Pseudomonas aeruginosa.

Cystic Fibrosis (CF) is the most common autosomal-recessive genetic disease affecting approximately 8000 people in Germany. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the epithelial lining fluid which leads to chronic inflammation of the airways. Recurrent infections of the airways as well as pulmonary exacerbations aggravate chronic inflammation, lead to pulmonary fibrosis and tissue destruction up to global respiratory insufficiency, which is responsible for the mortality in over 90 % of patients. The main aim of pulmonary treatment in CF is to reduce pulmonary inflammation and chronic infection. Pseudomonas aeruginosa (Pa) is the most relevant pathogen in the course of CF lung disease. Colonization and chronic infection are leading to additional loss of pulmonary function. There are many possibilities to treat Pa-infection. This is a S3-clinical guideline which implements a definition for chronic Pa-infection and demonstrates evidence-based diagnostic methods and medical treatment for Pa-infection in order to give guidance for individual treatment options.

[Emergencies in adult mucoviscidosis patients]. / Notfälle bei erwachsenen Mukoviszidosepatienten.

Cystic fibrosis is an inherited autosomal recessive metabolic disease caused by mutations on the CFTR gene. This leads to defective chloride channels on epithelial cell membranes and causes various disorders of the respiratory, gastrointestinal, and urogenital tracts.As a result, all exocrine glands produce a viscous secretion, leading to pulmonary symptoms such as chronic cough, secretion retention, recurring infections as well as bronchiectasis and obstructive lung emphysema. Gastrointestinal effects include exocrine and often also endocrine pancreatic insufficiency with chronic diarrhea and maldigestion syndrome as well as pancreoprivic diabetes mellitus; biliary cirrhosis occurs in 10% of cases. Additional effects include reduced fertility in women and infertility in men.Life-threatening complications include bleeding from the bronchial arteries, pneumothorax, and distal intestinal obstruction syndrome (DIOS), previously known as meconium ileus equivalent. Treatment requires rapid diagnosis and should be carried out in experienced centres, since the mortality rate can otherwise be up to 50%.

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

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

[MRI-based flow measurements in the main pulmonary artery to detect pulmonary arterial hypertension in patients with cystic fibrosis]. / MRT-basierte Flussmessungen im Truncus pulmonalis zur Detektion einer pulmonal-arteriellen Hypertonie in Patienten mit zystischer Fibrose.

PURPOSE: Development of pulmonary arterial hypertension (PH) is a common problem in the course of patients suffering from cystic fibrosis (CF). This study was performed to evaluate MRI based flow measurements (MR(venc); Velocity ENCoding) to detect signs of an evolving PH in patients suffering from CF. MATERIALS AND METHODS: 48 patients (median age: 16 years, range: 10 - 40 years, 25 female) suffering from CF of different severity (mean FEV (1): 74% +/- 23, mean Shwachman-score: 63 +/- 10) were examined using MRI based flow measurements of the main pulmonary artery (MPA). Phase-contrast flash sequences (TR: 9.6 ms, TE: 2.5 ms, bandwidth: 1395 Hertz/Pixel) were utilized. Results were compared to an age- and sex-matched group of 48 healthy subjects. Analyzed flow data where: heart frequency (HF), cardiac output (HZV), acceleration time (AT), proportional acceleration time related to heart rate (ATr), mean systolic blood velocity (MFG), peak velocity (Peak), maximum fow (Fluss(max)), mean flow (Fluss(mitt)) and distensibility (Dist). RESULTS: The comparison of means revealed significant differences only for MFG, Fluss(max) and Dist, but overlap was marked. However, using a scatter-plot of AT versus MFG, it was possible to identify five CF-patients demonstrating definite signs of PH: AT = 81 ms +/- 14, MFG = 46 +/- 11 cm/s, Dist = 41% +/- 7. These CF-patients where the most severely affected in the investigated group, two of them were listed for complete heart and lung transplantation. The comparison of this subgroup and the remaining CF-patients revealed a highly significant difference for the AT (p = 0.000001) without overlap. CONCLUSION: Screening of CF-patients for the development of PH using MRvenc of the MPA is not possible. In later stages of disease, the quantification of AT, MFG and Dist in the MPA may be useful for the detection, follow-up and control of therapy of PH. MR(venc) of the MPA completes the MRI-based follow-up of lung parenchyma damage in patients suffering from CF.

[New concepts of pathophysiology and therapy in cystic fibrosis]. / Neue Konzepte zur Pathophysiologie und Therapie der Mukoviszidose.

Today, the majority of cystic fibrosis (CF) patients treated in Germany have reached adulthood. However, with increasing age the morbidity and frequency of severe pulmonary complications continues to rise. Further optimization of conventional therapy alone will be insufficient to compensate for this development. In recent years, there has been impressive progress in our understanding of the molecular basis of the CF gene and its product, the cystic fibrosis transmembrane conductance regulator (CFTR). This knowledge can now be applied to develop new therapeutic strategies. However, important questions remain to be solved, i. e., little is known about the pathways that link the malfunctioning of the CFTR protein with the observed clinical phenotype. This review briefly touches on CF genetics as it applies to lung disease and will focus on the current hypotheses of CFTR (dys)function and its impact on pulmonary fluid homeostasis. New treatment options that target the molecular basis of the disease will be discussed.

Sex steroids and body composition in men with cystic fibrosis.

OBJECTIVE: Delayed sexual maturation and low body weight is common in cystic fibrosis (CF). Concomitant data on sex hormones and concomitant body composition are lacking in men with CF. DESIGN: Cross-sectional study. SUBJECTS AND METHODS: Serum levels of testosterone, 17beta-oestradiol (E(2)), 25-hydroxyvitamin D (25(OH)D), sex hormone-binding globulin (SHBG) and LH were measured by RIA and total and regional lean body mass (LBM), fat body mass (FBM), bone mineral content and bone mineral density (BMD) were assessed by dual-energy X-ray absorptiometry, in men with CF (n=40; age 24.7+/-5.4 years) and age-matched healthy controls (n=28; age 25.7+/-3.7). Only men without acute disease exacerbation or systemic glucocorticoid treatment were included. RESULTS: Mean levels of hormonal serum parameters differed significantly between healthy controls (testosterone=20.2+/-5.5 nmol/l; E(2)=95.0+/-20.2 pmol/l; 25(OH)D=62.8+/-28.3 nmol/l) and patients (testosterone=15.9+/-4.1 nmol/l; E(2)=60.7+/-19.4 pmol/l; 25(OH)D=39.5+/-17.8 nmol/l; P<0.001) while no difference was found for SHBG or LH. Eleven (for E(2), 19 of 40, for 25(OH)D, 20 of 40) out of 40 patients had serum testosterone levels 2 s.d. below the mean of normal. Men with CF showed a relative shift from FBM to LBM and a different body fat distribution compared with healthy controls (P<0.01). Testosterone was not correlated with weight, total or regional LBM or FBM, but significantly with BMD (r=0.32; P<0.05) independently from body height and 25(OH)D levels. E(2) was correlated with regional and total FBM (r=0.48; P<0.05). In a multiple regression analysis of the joint effect of testosterone and body components on E(2), a testosterone-independent effect was found for FBM. CONCLUSIONS: CF patients with stable disease have moderately reduced serum testosterone levels. This might already imply detrimental effects on bone. The change in LBM of patients appears to have no direct association with sex hormone levels while low FBM might cause reduced net conversion of serum testosterone to E(2) with possible effects on FBM distribution.

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

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

Lack of transmission of mycobacterium abscessus among patients with cystic fibrosis attending a single clinic.

We retrospectively analyzed 1062 respiratory specimens from 214 patients with cystic fibrosis, of whom 5 patients had 36 cultures positive for M. abscessus. Results of molecular typing demonstrated that each of these 5 patients carried a single unique strain (genotype), which suggests that it may not be necessary to segregate patients with CF who are colonized or infected with M. abscessus from those who are not.

[Cost comparison of hospital and ambulatory i.v. therapy in adult cystic fibrosis patients. Results of a controlled prospective study]. / Kostenvergleichsanalyse der stationären und ambulanten Intervalltherapie bei erwachsenen Mukoviszidosepatienten. Ergebnisse einer prospektiven kontrollierten Studie.

BACKGROUND: The regular i.v.-therapy of adults with cystic fibrosis (CF) on an in-patient basis is regarded as expensive. Home treatment is supposed to be cheaper. During a prospective controlled study to compare in-patient treatment (SIT) with home i.v.-treatment (HIT) in regard to clinical, psychosocial and economic parameters, delivered health services and costs in the German setting were evaluated in a comparable manner. PATIENTS AND METHODS: During the study period 4/95 to 9/96 45 patients with altogether 56 hospital and 40 home i.v.-courses of approximately 14 days were included in the study. Principal instruments to record the resource consumption were documentation sheets kept by the medical staff and the patients. In addition, pharmacy accounts in HIT and patient records and hospital controlling data in SIT were used. RESULTS: The average costs of a course were 14,038 DM for HIT and 18,702 DM for SIT. Striking are the large differences in medication costs. Two main reasons could be identified for the cost difference: 1, the use of a mobile infusion system in HIT and 2, the much higher prices of pharmaceuticals in the ambulatory care sector compared to the hospital sector, where extremely high profits of the home care service firms or the pharmacy can be supposed. The social costs of HIT (when antibiotics are valued to opportunity costs) are estimated at less than 10,500 DM. From a societal perspective HIT is preferable, from the perspective of the statutory health insurance funds hospital therapy is preferable. CONCLUSIONS: 1. The widely accepted hypothesis that ambulatory care is cheaper than hospital care is--at least in the German setting--not a-priori true. 2. In the treatment of CF patients incentive failures exist which induce unnecessary and avoidable hospital stays if the perspective of the statutory sickness funds is dominant. 3. Changes in system conditions as e.g. the permission of mail-order pharmacies might help to implement a more rational allocation of resources.

["Since when have you had mucoviscidosis?" Comment on as yet rarely recognized disease entity in internal medicine]. / "Seit wann haben Sie Mukoviszidose?". Anmerkungen zu einem in der Inneren Medizin noch wenig bekannten Krankheitsbild.

In Germany, many adult patients with cystic fibrosis are still treated by pediatricians. There are still not enough specialists for internal medicine (and particularly pulmonologists) with sufficient knowledge about cystic fibrosis for the treatment of estimated 2000 adult CF-patients. The knowledge about the three basic principles of cystic fibrosis therapy--regular high-dose antibiotics, high-energy and high-fat nutritional support and specific physiotherapy--has to be transferred to adult medicine in order to assure competent care for this "new" group of patients. Cystic fibrosis is also becoming more and more and more important in the field of intensive care medicine and transplantation. Specific diagnostic procedures are important in adult respiratory medicine in order to confirm or exclude late manifestations of the disease. Understanding of the genetic basis of cystic fibrosis and the correlations between genotype and phenotype is beginning to emerge.

[Why do adults with mucoviscidosis refuse a medically recommended course of intravenous antibiotic therapy?]. / Weshalb verweigern Erwachsene mit Mukoviszidose eine ärztlich empfohlene intravenöse Antibiotikatherapie?

BACKGROUND: Regular courses of intravenous antibiotics are recommended for the treatment of chronic Pseudomonas aeruglnosa (PA) infection in patients with cystic fibrosis. We report the results of interviews performed to evaluate why a subgroup of patients vote against regular intravenous (i.v.) antibiotic treatment. METHODS: Structured interviews covering a) the individual's perception of chronic PA infection, b) the patient's expectations regarding the effectiveness of i.v. treatment, c) the patient's personal reasons for refusal of i.v. treatment. STUDY COHORT: 16 out of 18 adult patients treated in the adult CF outpatient clinic at Hannover Medical School who had voted against the physician's recommendation to receive regular i.v. therapy twice a year. RESULTS: More than one half of the patients did not regard chronic PA infection as important due to the lack of specific symptoms. A subgroup of patients had no idea of what their clinical status should be if i.v. antibiotics would be necessary; these patients reported prior experience of treatment courses which had been ineffective and had been instituted after talking into the patients. The most frequent reasons against IV treatment were not being sick enough and fear of adverse drug effects. ASSESSMENT: The results are being discussed considering the physician-patient relationship. The reasons why patients refuse help should be extensively explored rather than simply addressing this attitude as "non-compliance". Patients, too, come to reasonable decisions, and it is important to know their thoughts and reasoning if one intends to influence them.