[Adults with cystic fibrosis. It's not just about longevity]. / Erwachsene mit Mukoviszidose. Es geht um mehr als die Lebensdauer.

Cystic fibrosis (CF) is one example of serious disorders for which medical progress and the integration of chronic treatment into the patients' daily routines have led to markedly better longevity. Formerly known as a 'killer disease' of childhood, CF is now considered a disorder with childhood onset, but is well known in adult medicine. Since 2009, for the first time CF adults have made up the majority of patients in the German CF registry. The drawbacks of improved longevity are long-term complications (e.g., CFRD, osteoporosis) that were rarely seen before. In particular, unwanted effects of treatments that today are performed for decades rather than years are becoming pressing problems. Unwanted effects as well as the ever-increasing treatment burden must be carefully weighed against the expected benefits of treatment. However, CF medicine has always been aware that it is not just about longevity, but that prolonged life has to have meaning. Therefore, the marked increase in longevity is also a psychosocial challenge. So far, empirical data suggest that the majority of people with CF courageously struggle for a normal life.

Resting energy expenditure before and after treatment for Pseudomonas aeruginosa infection in patients with cystic fibrosis.

To investigate whether metabolic rates change after antipseudomonal treatment, resting energy expenditure (REE) was measured in 29 patients with cystic fibrosis (CF) aged 5-27 y before and after a 2-wk course of intravenous antibiotics for the treatment of chronic Pseudomonas aeruginosa infection. Before therapy, mean (+/- SD) REE was increased to 119.0 +/- 11.4% of the predicted normal value (REE%). Seventeen of the 29 patients were classified as having increased baseline REE% (> 115% of predicted, group I), whereas 12 patients had resting energy expenditures within the normal range (group N). After antipseudomonal therapy, mean REE% decreased significantly by 6.2% of predicted. This decline was negatively correlated with the baseline REE% (r = 0.70, P < 0.001). It was most pronounced (-11.3%) in group I whereas patients of group N showed no major changes. These results suggest that antipseudomonal therapy can reduce increased energy requirements of moderately ill CF patients with chronic Pseudomonas aeruginosa infection.

Management of mycotic rupture of the ascending aorta after heart-lung transplantation.

A 19-year-old woman underwent heart-lung transplantation for obstructive bronchiolitis. Eleven days later mycotic rupture of the ascending aorta occurred. Emergency cardiopulmonary bypass was instituted via the femoral vessels and the chest was reopened under cardiac massage. Perforation of the aorta at the site of insertion of the cardioplegic cannula in the donor aorta was seen. Under circulatory arrest the infected area was excised, a pericardial patch plasty was performed, and the region was covered with a muscle flap. Postoperatively, Candida albicans was found in the excised specimen of the aorta, in drainage fluid, and in the bronchoalveolar lavage. High doses of antimycotics were administered intravenously and for irrigation of the mediastinum, which resulted in an eradication of fungi in all cultures 7 days later. Six weeks after reoperation the patient was discharged home, and she remains well 9 months postoperatively.

Comparative hygienic surveillance of contamination with pseudomonads in a cystic fibrosis ward over a 4-year period.

In order to study the long-term distribution and population dynamics of Pseudomonas aeruginosa strains in a highly contaminated hospital environment, two 4-week epidemiological studies, with an interval of 4 years, were carried out in the cystic fibrosis (CF) ward of the Paediatric Clinic of the Medical School of Hannover. Out of the 1948 specimens taken, P. aeruginosa was mainly identified in those from moist, inanimate sources (200 isolates) and hospitalized CF patients (168 isolates). A correlation was established between the frequency with which P. aeruginosa-positive patients came into contact with hospital facilities and the rate of contamination of these facilities. Rooms reserved for colonized patients were more frequently contaminated with P. aeruginosa in contrast to function rooms in the same ward and the outpatient clinic. However, no direct exchange between patients' strains and the inanimate hospital environment was detected. Out of the 11 genotypes of P. aeruginosa found in 1989 and the 13 genotypes found in 1993, four genotypes were present on both occasions. The most predominant clone was found in tap-water, sinks, wash-basins and creams with an incidence of 34 and 68% in the environmental isolates. The strains seemed to have spread into the adjacent control ward during the 4-year interval. Thus, the separation of colonized and non-colonized patients was undermined through the transfer of strains from a highly contaminated environment without additional hygiene precautions.

Cystic fibrosis: the impact of analytical technology for genotype-phenotype studies.

The generalized exocrinopathy cystic fibrosis (CF) is the most common severe genetic disease in Caucasian populations. A panel of more than 700 chromosomes from German and Turkish CF patients was screened for disease-causing mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene by chemical cleavage of mismatch, single strand conformation polymorphism, restriction analysis and direct sequencing of genomic DNA amplified by polymerase chain reaction. Besides the major 3-bp deletion, delta F508 that was found on 73% of German CF chromosomes, more than 50 other missense, nonsense, frame-shift, and splice-site mutations have already been identified. In general, a CFTR mutation is linked with a single 10-marker haplotype which indicates that in most cases a particular mutation spread from a common ancestor. The comparison of mutation genotypes with the disease phenotype emphasized the causative role of the type and localization of the CFTR mutation for clinical course and prognosis. Pancreatic status and the risk of colonization of airways with opportunistic pathogens are genetically determined. Most patients who are harbouring mutations in the nucleotide binding folds were suffering from severe CF disease. Mild or even aberrant forms of CF were observed for many missense mutations located in the putative transmembrane domains or for mutations that are expected to result in a truncated protein of half of wild-type CFTR.

Bronchial sensitivity to inhaled histamine in healthy, nonatopic children.

Bronchial reactivity was determined in 38 healthy children by histamine inhalation challenge using forced expiratory and body plethysmographic methods. The histamine concentrations which produced a 20% decrease in forced expiratory volume in 1 second (PC20,FEV1), were comparable to the concentrations producing a 60% fall in specific airway conductance (PC60,SGaw). There was a significant difference in bronchial reactivity between the healthy children and a group of 29 asthmatic children (P less than 0.001), although there was some overlap. Bronchial reactivity in healthy children was found to be much higher than expected from surveys of adults. External influences or intrinsically increased bronchial reactivity in childhood are discussed as possible explanations.

Effect of endotracheal tube leakage on functional residual capacity determination by nitrogen washout method in a small-sized lung model.

The determination of functional residual capacity (FRC) would be extremely helpful for the controlled adjustment of mechanical ventilation in sick neonates and infants. However, these patients have small lung volumes and usually have been intubated by uncuffed endotracheal tubes (ETT). Therefore, the open-circuit nitrogen washout technique (N2wo) may give false FRC values if the inspired oxygen concentration (FIO2) is high and leakage around the ETT is present. We evaluated the N2wo as supplied by the Pediatric Pulmonary System 2600 (Sensor-Medics) in a small-sized lung model by 570 measurements using five different ventilator settings, an FIO2 increasing up to 0.9, different bypass flows between 0 and 12 L/min, and various patterns of leakage, either during inspiration or exhalation, or both. We found the most reliable results (error, 0.6%; CV, 0.7%) with a bypass flow of 6 L/min. Absolute N2 volumes as small as 14 mL could be measured using an FIO2 as high as 0.9 with only slight loss of accuracy (error, 4%; CV, 2.8%). During leakage, FRC had been underestimated with a very strong correlation to the total amount of leakage over the measurement period, which was irrespective of the ventilatory parameters (r = 0.9, P < 0.001). The regression equation could, therefore, be used for FRC correction in the lung model. However, most of the miscalculation was due to N2 loss during expiratory leakage, which quite simply and reliably can be excluded by an end-inspiratory occlusion test.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of salbutamol delivery from a metered dose inhaler versus jet nebulizer on dynamic lung mechanics in very preterm infants with chronic lung disease.

Treatment of chronic lung disease of prematurity requires effective aerosol delivery of different therapeutic agents. Aerosols can be generated by a metered dose inhaler (MDI) or a jet nebulizer. An MDI combined with a spacer device is easier to use and avoids undesirable effects noted in conjunction with jet nebulization. We compared the clinical effectiveness of 200 micrograms (2 puffs) salbutamol delivered from an MDI in conjunction with a valved spacer device (Aerochamber), and 600 micrograms given via jet nebulizer (PariBaby) on 2 consecutive days, the order being randomized. Thirteen spontaneously breathing very preterm infants [mean (SD) gestational age 27.2 (1.8) weeks; birth weight 0.90 (0.34) kg] were studied at a corrected age of 37 (2.3) weeks. Mean (SD) study weight was 1.83 (0.38) kg. Dynamic lung compliance and resistance were determined from measurements of flows, volumes, and transpulmonary pressures, using a pneumotachometer and a small esophageal microtransducer catheter before and 20 min after salbutamol application. Baseline values before salbutamol administration were similar on both occasions: the mean (SD) compliance was 7.7 (3.0) mL.kPa-1.kg-1 pre-MDI plus-spacer and 8.4 (3.1) pre-jet nebulizer; the resistance was 10.4 (4.0) kPa.L-1.s pre-MDI plus-spacer and 9.7 (3.4) pre-jet nebulizer. Following salbutamol, compliance did not change significantly with either MDI plus spacer or jet nebulizer. Resistance fall significantly with MDI plus spacer (mean -2.2; 99.9% CI -0.35, -4.35) and jet nebulizer (-2.4; 99% CI -0.39, -4.42). We conclude that even in small preterm infants 200 micrograms salbutamol via MDI plus spacer improves dynamic resistance as effectively as 600 micrograms via jet nebulizer and may therefore be a preferable mode of aarosol administration.

Diagnostic implications and treatment of massive spontaneous atelectasis in childhood.

During a 5-month period five children were treated for spontaneously occurring massive lung atelectasis. In three patients the underlying disease was bronchial asthma; in one patient idiopathic plastic bronchitis; and in another patient, infection with anaerobic Corynebacteria may have been a contributing factor. Types I and III hypersensitivity reactions were not considered to be likely causal factors. The clinical manifestations and management of this relatively rare event are described.

Diabetes mellitus and cystic fibrosis: comparison of clinical parameters in patients treated with insulin versus oral glucose-lowering agents.

The prevalence of cystic fibrosis-related diabetes melltitus (CFRD) is increasing as patients with cystic fibrosis (CF) live longer. Because patients with CFRD are insulin-deficient, the standard medical treatment is exogenous insulin. Sulfonylureas enhance insulin secretion by acting on a specific islet beta cell receptor. No data are available about the outcome of sulfonylurea treatment vs. insulin treatment. In this retrospective study, data from 45 patients with CFRD were analyzed regarding their clinical outcome as it related to the treatment protocol. The duration of DM treatment was 7.6 +/- 4.6 years in the insulin-treated group and 3.5 +/- 2.0 years in the sulfonylurea group (n.s.). The age of CFRD diagnosis was significantly earlier in patients treated with insulin (n = 34) than in the patients treated with sulfonylurea (n = 11) (16.4 +/- 3.6 vs. 24.2 +/- 4.8 years, P < 0.001). No statistical differences were found between the two groups in the time of CF diagnosis, the most recent forced expired volume in 1 sec, forced vital capacity, Shwachman score, hemoglobin A(1C) levels, or weight for height index at the end of the study. Our data suggest that a subgroup of CFRD patients can be managed for a number of years with sulfonylurea, and that the clinical outcome was not different in this group compared with the insulin-treated patients.

Long-term tobramycin aerosol therapy in cystic fibrosis.

The long-term efficacy and safety of aminoglycoside aerosol therapy for Pseudomonas aeruginosa colonization/infection in cystic fibrosis has not been fully investigated. In the present study, 14 patients with cystic fibrosis, ages 8-19 years (mean: 13.3 years), received tobramycin aerosol therapy for a mean duration of 20 months. Eighty milligrams of a tobramycin solution were inhaled twice daily after physiotherapy via a jet nebulizer. After 1 year, weight for height increased significantly by 2.9% of the predicted normal, and the Kraemer clinical score increased by 2.1 points (P less than 0.05). The frequency of hospital admissions decreased from 2.0 to 1.3 per patient, respectively, during the years before and after the study onset. The antibody response to P. aeruginosa elastase, exotoxin A, and alkaline phosphatase showed a reduction in serum titers against one or more enzymes in eight patients. The best long-term results after 12-38 months of treatment were obtained in moderately ill children. No evidence of ototoxicity or renal damage was observed. Although intermittent bacterial resistance occurred in five patients after 10-21 months of tobramycin inhalation, this was not associated with clinical deterioration. The study demonstrates the safety and clinical efficacy of long-term tobramycin aerosol therapy. Double-blind studies with larger patient cohorts are required to determine the value of aminoglycoside inhalation as an adjunct to the established therapeutic regimens.

Placebo-controlled, double-blind, randomized study of aerosolized tobramycin for early treatment of Pseudomonas aeruginosa colonization in cystic fibrosis.

In chronic Pseudomonas aeruginosa pulmonary infection of patients with cystic fibrosis (CF), antibiotic therapy generally fails to eradicate the bacterial pathogen. The mucoid bacterial phenotype, high sputum production by the host, and low airway levels of antibiotics seem to be responsible for the observed decrease in antibiotic efficacy. We hypothesized that early antibiotic treatment by inhalation in CF patients may be able to prevent or at least delay airway infection. In a prospective placebo-controlled, double-blind, randomized multicenter study, 22 CF patients received either 80 mg b.i.d. of aerosolized tobramycin or placebo for a period of 12 months shortly after the onset of P. aeruginosa pulmonary colonization. Two patients in the tobramycin and six patients in the placebo group stopped inhalation before the 12 month treatment period. Using life table analysis, the time to conversion from a P. aeruginosa-positive to a P. aeruginosa-negative respiratory culture was significantly shorter in the tobramycin-treated group than in the placebo group (P < 0.05, log rank test). Lung function parameters and markers of inflammation did not change in either group during treatment. The results of this study suggest that early tobramycin inhalation may prevent and/or delay P. aeruginosa pulmonary infection in CF patients.

Multicenter, open-label study of recombinant human DNase in cystic fibrosis patients with moderate lung disease. DNase International Study Group.

Cystic fibrosis is characterized by the accumulation of thick viscous purulent secretions. Recombinant human deoxyribonuclease I (rhDNase) breaks down extracellular DNA, which contributes to the increased viscosity of sputum. A multinational, open-label study was conducted in 974 cystic fibrosis patients with moderate lung disease [forced vital capacity (FVC) 40-70% of predicted values] to examine the safety and efficacy of aerosolized rhDNase, 2.5 mg, once daily over a period of at least 12 weeks. Patients were assessed under conditions reflecting routine clinical practice. During rhDNase therapy, at least one respiratory tract infection (RTI) requiring intravenous antibiotics was experienced by 29.5% of patients. Forced expiratory volume in 1 second (FEV1) and FVC were significantly improved from baseline by a mean of 10.5% and 7.2%, respectively. Voice alteration and pharyngitis were the most frequent rhDNase-related adverse events, but only 2% of all patients discontinued treatment due to adverse events. The results obtained were similar to a subanalysis of data from the first 3 months of a placebo-controlled U.S. study. The patients in the present study had a similar frequency of RTIs and improvement in pulmonary function, and reported fewer rhDNase-related and cystic fibrosis-related adverse events than patients in the U.S. study. We conclude that administration of rhDNase is safe, well tolerated, and effective under conditions reflecting routine clinical practice in patients with cystic fibrosis and moderate lung disease.

Low-dose methotrexate for advanced pulmonary disease in patients with cystic fibrosis.

UNLABELLED: Inflammation is a hallmark in the pathogenesis of pulmonary destruction in cystic fibrosis (CF). There is no proven effective systemic anti-inflammatory treatment for CF patients with advanced pulmonary disease. Methotrexate (MTX) is known as an effective anti-inflammatory treatment in asthma and in juvenile rheumatoid arthritis. The question was: Is an improvement in pulmonary function achievable with low-dose MTX in patients with cystic fibrosis and advanced pulmonary disease.? METHODS: We treated five CF patients with advanced pulmonary disease, who deteriorated in spite of intensive conventional therapy on an individual basis with low-dose MTX. FEV1% and immunoglobulin G (IgG) serum levels were followed from the year before to the year after starting with MTX. RESULTS: In the year before starting with MTX, FEV1% decreased (median: 10% FEV1; range 9-15% FEV1; P<0.005) after starting with MTX, FEV1% increased (median: 9% FEV1; range: 2-15% FEV1; P<0.05). IgG changed (median: -2 g/l; range: 0.2 to -7.3 g/l) in the first year with MTX. CONCLUSION: These preliminary data suggest a beneficial effect of MTX even in advanced pulmonary disease in CF patients and supports the need for a controlled prospective study.

[Changes in the pulmonary vessels during asthma in childhood (author's transl)]. / Veränderungen des Lungengefässbildes bei Asthma bronchiale im Kindesalter.

One hundred and twenty-eight erect radiographs of the thorax in 42 children with bronchial asthma have been analysed. The criterium for inclusion in this study was the demonstration on once occasion at least of hyperinflation of the lung with a low diaphragm, increased size of lung, narrow heart and increase in the retrosternal transparent area. In all patients there was narrowing of the vessels. In addition, the vessels appeared irregular and curved. Other characteristic radiological findings were tram-lines, obstructed bronchi, peribronchial infiltrates and atelectases. Increasing severity of the attack lead to increasing finding of other radiological changes in the thorax, but these have not yet been statistically examined.

Transition of adult patients with cystic fibrosis from paediatric to adult care--the patients' perspective before and after start-up of an adult clinic.

UNLABELLED: Although most patients with cystic fibrosis (CF) survive into adulthood, many CF centres are still run by paediatricians. A transition programme from the paediatric CF unit to a newly established CF clinic at the Department of Internal Medicine was carried out for the whole group of patients > or =18 years. We aimed to evaluate our patients' opinion of the transition by analysing the results of two surveys performed before and after the transition. Nine months before the transition, we mailed an anonymous questionnaire. Statements regarding the forthcoming transition were to be answered on scales from 1 to 4, and the patients had to check a list of adjectives describing the current treatment in the paediatric CF centre as well as the presumed care in the adult unit. Fifteen months after the transition, a second survey with similar questions was carried out. RESULTS: 44 of 68 patients (65%) aged 18 to 33 years replied to the first and 56% of patients to the second questionnaire. Mean duration of treatment at the paediatric CF centre was 7.5 years (range: 1 to 22 years). Twelve patients each were classified as supporters or opponents of the transition, the remaining patients as intermediates. Older patients and those who had not required hospitalisation during the preceding year had a more positive attitude to the transition (p <0.05). There was a linear relationship between the transition attitude score and the presumed quality of care in the Internal Medicine Department (r = 0.62, p <0.001), but no relation to the quality of present paediatric care (r = -0.09, p = 0.59). In the second survey, patients rated the quality of care in the adult CF unit better than prior to the transition. CONCLUSIONS: The transition from paediatric to a newly established adult CF centre was accepted by most adult CF patients. Thorough training of all staff of the new adult unit and a close co-operation between both departments are pre-requisites to guarantee a smooth transition of all patients.

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.

[Socioeconomic evaluation of the effect of rhDNase on the cost of treating infections of the respiratory tract in patients with cystic fibrosis]. / Sozioökonomische Evaluation des Einflusses von rhDNase auf die Kosten der Behandlung von Infektionen der Atemwege bei Patienten mit zystischer Fibrose.

BACKGROUND: Data from a multicenter, placebo-controlled, double-blind, parallel clinical trial on the use of aerosolized recombinant human DNase (rhDNase), known as Pulmozyme produced by Genentech, about the treating of respiratory-tract infections among patients with cystic fibrosis (CF), has been used to evaluate possible economic effects by identifying the direct medical costs. To calculate the cost an intention-to-treat approach has been used. PATIENTS AND METHOD: The patients were randomly placed in one of three treatment groups. The first group was treated with a 2.5 mg dose of rhDNase and one dose of placebo daily, the second group with placebo twice a day. The third patient group (treated with a 2.5 mg dose of rhDNase twice a day) was not included in this study. RESULTS: The main measurements of resource utilization of services for treatment of respiratory-tract infections were the number of hospitalizations in the follow-up period of 24 weeks (0.41 rhDNase once daily, 0.56 placebo), the number of total days in hospital (4.9 rhDNase, 6.4 placebo), the number of total days of outpatient intravenous antibiotic therapy (2.9 rhDNase, 4.4 placebo), the number of total days of inpatient intravenous antibiotic therapy (4.8 rhDNase, 6.2 placebo), the number of total days of outpatient oral antibiotic therapy (23.5 rhDNase, 25.2 placebo) and the number of total days of inpatient oral antibiotic therapy (0.59 rhDNase, 0.55 placebo). From a health insurance perspective the total direct cost based on a weighted per diem for German CF-centres was 5,879 DM (rhDNase) vs 7,849 DM (placebo) per patient respectively. Costs of antibiotics were estimated using all available information on the consumption of antibiotic drugs revealing 2,954 DM per patient in the rhDNase-group and 4,213 DM in the placebo-group. The large cost differences remain also true in a sensitivity analysis introducing minima and maxima as key factors. CONCLUSION: As a result of this study we conclude that the use of rhDNase in treatment of respiratory-tract infections in patients with cystic fibrosis is cost saving and less burdened for the patients. However, all cost estimates do not include the cost of rhDNase itself, which are DM 9,094 for the period of follow-up.

Long-term tobramycin aerosol therapy of chronic Pseudomonas aeruginosa infection in patients with cystic fibrosis.

Fourteen cystic fibrosis patients (aged 9 to 20 years), chronically infected with Pseudomonas aeruginosa (PA), inhaled 80 mg (2 ml) tobramycin twice daily, because a significant clinical deterioration had occurred. Mean duration of aerosol therapy was 20.3 months (range, 11 to 38 months). There were no toxic side effects and no significant systemic absorption, 50 of 70 tobramycin serum levels being below the minimal detectable value of 0.1 mg/l. After 12 months of therapy there was an improvement of lung function, Po2, and weight. The frequency of intravenous therapy was reduced. Tobramycin resistance occurred in 5.8% of all PA strains after 10 to 29 months and did not represent a clinical problem. In a few patients PA was eradicated from sputum.