[Exercise testing in respiratory medicine]. / Belastungsuntersuchungen in der Pneumologie.

This document replaces the DGP recommendations published in 1998. Based on recent studies and a consensus conference, the indications, choice and performance of the adequate exercise testing method in its necessary technical and staffing setting are discussed. Detailed recommendations are provided: for arterial blood gas analysis and right heart catherterization during exercise, 6-minute walk test, spiroergometry, and stress echocardiography. The correct use of different exercise tests is discussed for specific situations in respiratory medicine: exercise induced asthma, monitoring of physical training or therapeutical interventions, preoperative risk stratification, and evaluation in occupational medicine.

[Differential diagnosis of restrictive lung diseases: utility of cardiopulmonary exercise testing]. / Differenzialdiagnostik restriktiver Ventilationsstörungen: Stellenwert der Spiroergometrie.

Exercise dyspnea is a common symptom of restrictive lung diseases. Not only from the clinical perspective but also from the pathophysiological point of view, restrictive lung disorders represent a very heterogeneous group of diseases. Exercise testing is mandatory because pulmonary function tests at rest are not reliable for the diagnostic evaluation and functional characterisation of these patients. Cardiopulmonary exercise testing (CPET) with measurement of gas exchange is the favoured tool. It is an excellent method to investigate exercise dyspnea, describe altered physiological response to exercise and characterise the involved organ systems heart, lung and muscle. This paper addresses the pathophysiology of restrictive lung diseases and the principles of cardiopulmonary exercise testing, discusses case reports and assesses the clinical value of CPET in patients with restrictive lung disease.

[Asthma and COPD - dosing recommendations at beginning and end of treatment]. / Asthma und COPD - Arzneimittel-Dosierung am Anfang und Ende einer Therapie.

In the treatment of asthma and COPD for two drug classes slowly increasing starting doses or tapering at the end of therapy is required: In the case of allergen specific immunotherapy (desensitisation) with allergen extracts gradual increases of doses are necessary to prevent allergic shock. In the case of prolonged systemic treatment of asthma or COPD with glucocorticoids tapering is necessary to avoid symptoms of adrenal gland insufficiency after drug withdrawal or exacerbation of the underlying disease. In the short term treatment of asthma exacerbations with systemic glucocorticoids tapering is not necessary, for COPD suitable studies are still lacking.

Cost-effectiveness of formoterol and salbutamol as asthma reliever medication in Sweden and in Spain.

This study aimed to evaluate the cost-effectiveness of formoterol (Oxis) Turbuhaler 4.5 microg and salbutamol 200 microg as reliever medications in Sweden and Spain. The study used data on effectiveness (exacerbations and symptom-free days) and resource utilisation from an open, 6-month, parallel-group, multicentre randomised trial with 18,124 asthma patients in 24 countries. Country-specific unit costs for Sweden and for Spain were used to transform resource utilisation data into costs. Total healthcare costs were not significantly different between formoterol and salbutamol dry powder inhalers in Sweden, whereas in Spain, the healthcare costs were 20% higher for formoterol vs. salbutamol pressurised metered dose inhalers. Total healthcare costs increased with disease severity, defined according to the Global Initiative for Asthma guidelines. Compared with salbutamol, formoterol produced statistically significant improvements in effectiveness, less reliever and maintenance medication usage, reduced healthcare resource utilisation, with no increase or a limited increase in healthcare cost.

Formoterol as relief medication in asthma: a worldwide safety and effectiveness trial.

The aim of the study was to compare the safety and effectiveness of as-needed formoterol with salbutamol in a large international real-life asthma study. Children and adults (n=18,124) were randomised to 6 months as-needed treatment with open-label formoterol 4.5 microg Turbuhaler or salbutamol 200 microg pressurised metered dose inhaler or equivalent. Primary safety variables were asthma-related and nonasthma-related serious adverse events (SAE)s and adverse events (AE)s resulting in discontinuation (DAE)s. The primary efficacy variable was time to first asthma exacerbation. The incidences of AEs, SAEs and DAEs arising from SAEs were not significantly different between treatments. DAEs for nonserious AEs were higher with formoterol. Asthma-related AEs decreased with formoterol (1,098 (12.3%) versus 1,206 (13.5%)), asthma-related SAEs were similar (108 (1.2%) versus 121 (1.4%)) but more asthma-related DAEs occurred in the formoterol group (89 (1.0%) versus 48 (0.5%)). Time to first exacerbation was prolonged (hazard ratio 0.86) and less as-needed and maintenance medication was used with formoterol. Reductions of exacerbations with as-needed formoterol versus salbutamol increased with increasing age and asthma medication level. This real-life study demonstrates that formoterol as-needed has a similar safety profile to salbutamol, and its use as a reliever therapy is associated with fewer asthma symptoms and exacerbations.

A prospective, randomized, multicenter comparative study of clinafloxacin versus a ceftriaxone-based regimen in the treatment of hospitalized patients with community-acquired pneumonia.

In an open-label, phase 3, randomized, multicenter study, clinafloxacin (200 mg/d) was compared to ceftriaxone (2 g/d; with or without erythromycin) in 527 patients with acute community-acquired bacterial pneumonia (CAP). Primary efficacy parameters were clinical cure rate and microbiologic eradication rates (by pathogen and by patient) determined 5-9 d post-therapy (test of cure; TOC). Clinical cure rates at TOC for the 2 treatment groups were equivalent in the intention-to-treat (clinafloxacin 79.3, ceftriaxone 78.6%), clinically evaluable (clinafloxacin 88.1, ceftriaxone 85.0%), modified intention-to-treat (clinafloxacin 82.6, ceftriaxone 86.9%) and microbiologically evaluable populations (clinafloxacin 86.2, ceftriaxone 86.2%). Microbiologic eradication rates were similar in the 2 treatment groups. Both drugs were tolerated. Treatment of hospitalized CAP patients with clinafloxacin is a reasonable choice, especially when a resistant pathogen is anticipated.

A comparative study of levofloxacin and ceftriaxone in the treatment of hospitalized patients with pneumonia.

A multinational, multicentre, open, randomised study in hospitalised patients with pneumonia compared levofloxacin 500 mg twice daily with ceftriaxone 4 g i.v. once daily. Levofloxacin patients started on i.v. treatment and switched to oral on d 3-5 of therapy if signs and symptoms had improved. The minimum treatment duration was 5 d, except for treatment failure, and the median 8 d. The primary efficacy analysis was based on the per-protocol assessment of the clinical cure rate determined 2-5 d after the end of treatment in the per-protocol (PP) population (levofloxacin 127, ceftriaxone 139). Of 625 patients enrolled and randomized, 6 received no treatment, giving an intention-to-treat (ITT) population of 619 (levofloxacin 314, ceftriaxone 305). At the clinical endpoint, 2-5 d after the end of treatment, the cure rates for levofloxacin and ceftriaxone were similar in both the ITT (76% and 75%, respectively) and PP (87% and 86%, respectively) populations. Both drugs were well tolerated. Twice-daily levofloxacin 500 mg, either i.v. or as sequential i.v./oral therapy, was as effective as i.v. once-daily ceftriaxone 4 g in the treatment of hospitalized patients with pneumonia and offers the advantage of sequential therapy.

Protein profile in bronchoalveolar lavage fluid from patients with sarcoidosis and idiopathic pulmonary fibrosis as revealed by SDS-PAGE electrophoresis and western blot analysis.

So far bronchoalveolar lavage (BAL)-protein in interstitial lung disease (ILD) is evaluated by measuring concentrations of single proteins. Due to the high dilution of most proteins in BAL, analysis of protein profile has been disappointing. This study describes a new method to overcome this problem and to reveal a highly differentiated picture of BAL proteins. Eighteen patients with pulmonary sarcoidosis, 18 patients with idiopathic pulmonary fibrosis (IPF) and 22 patients with no clinical, roentgenologic or functional evidence of ILD underwent BAL. Total and differential cell count was performed. Normal values for the control group, a lymphocytic alveolitis in sarcoidosis and a granulocytic alveolitis in IPF-patients were found. Median total protein concentration in sarcoidosis showed an increase five times higher than that of the controls (150 mg 1(-1) and 27 mg 1(-1), respectively) with p < 0.001, IPF protein concentration (58 mg 1(-1)) exceeded twice the control values (0.01 > p > 0.001). Analysis of electrophoretic protein profile in controls with Western blot analysis and the biotin/streptavidin staining system revealed a highly differentiated range of bands. Staining with immunoglobulin antibody identified six bands. Four proteins with molecular weight < 21.000 dalton were present only in sarcoidosis patients. These proteins may be identical with fragmented serum proteins or different cell mediators detected in alveolar cell supernatants. Furthermore, in sarcoidosis the intensity and number of bands with molecular weight more than 67.000 dalton was increased. This gives strong evidence for an injury of the alveolar membrane integrity in the alveolitis during the course of sarcoidosis.(ABSTRACT TRUNCATED AT 250 WORDS)

B-lymphocyte response in peripheral blood of patients with pulmonary sarcoidosis.

Sarcoidosis is a granulomatous disorder which can be characterized by various immunologic abnormalities including lymphocyte dysfunctions. The purpose of this study was to investigate the B-lymphocyte reactivity in the peripheral blood of 29 various patients with pulmonary sarcoidosis. A significant decrease in the production of IgG, IgM and IgA in supernatants of cultivated sarcoidosis B-cells both after stimulation with a T-cell dependent polyclonal B-cell activator (pokeweed mitogen) and with a T-cell independent polyclonal B-lymphocyte activator (Klebsiella pneumoniae) was seen, which suggested a disturbance in the B-cell differentiation of sarcoidosis patients. Those patients which were known to have a clinically active disease or a high intensity alveolitis in the bronchoalveolar lavage fluid showed a greater reduction in the B-cell differentiation response. Further evaluation of Ig-G subclasses displayed a significant decrease in the secretion of IgG1, IgG3 and IgG4. In contrast to the differentiation, the proliferation response of sarcoidotic peripheral blood lymphocytes to different mitogens did not differ from healthy controls.

Recovery of proteins from the broncho-alveolar lavage fluid proposal for a standardisation.

In this study various precipitation methods have been used to concentrate the proteins from broncho-alveolar-lavages. The highest percentage of proteins was recovered from the broncho-alveolar-lavages using the method of Wessel & Flügge (Anal. Biochem. 138 (1984) 141-143). The recovered proteins were further analysed by SDS-polyacrylamide gel electrophoresis. Except for low molecular mass proteins, the method of Wessel & Flügge proved to be the most effective for the recovery of individual proteins. In general, the method of Wessel & Flügge seems to be the superior method for concentrating proteins of broncho-alveolar-lavages for further analysis.

Increased expression of growth factor genes for macrophages and fibroblasts in bronchoalveolar lavage cells of a patient with pulmonary histiocytosis X.

Pulmonary histiocytosis X is the local manifestation of a systemic disorder of unknown cause characterised by infiltration of Langerhans cell like histiocytes and parenchymal fibrosis. In a male smoker with histologically proved histiocytosis X and functional impairment bronchoalveolar lavage showed an increase in CD-1/OKT-6 antigen positive histiocytes to 8%. Northern blot analysis of RNA from bronchoalveolar lavage cells showed an exaggerated expression of the M-CSF gene and of the c-fms gene encoding for the corresponding receptor. An increased level of c-sis RNA, which encodes the B chain of platelet derived growth factor, was also found. Diffuse reticulonodular infiltrates on the chest radiograph resolved with glucocorticoid treatment and CD-1/OKT-6 antigen positive histiocytes fell to 3%. Macrophage colony stimulating factor, c-fms and c-sis gene expression were reduced almost to normal after treatment. The results suggest that macrophage colony stimulating factor and platelet derived growth factor may have a role in the initiation or maintenance of pathological reactions in pulmonary histiocytosis X.

[Bronchoalveolar lavage in Wegener's granulomatosis]. / Bronchoalveoläre Lavage bei Wegenerscher Granulomatose.

Bronchoalveolar lavage was performed in 14 patients suffering from histologically confirmed Wegener's granulomatosis who also showed x-ray signs of lung involvement. Cell distribution and immunophenotypical characterisation of lymphocytes and alveolar macrophages of patients suffering from Wegener's granulomatosis were compared with the findings obtained from 10 controls. The bronchoalveolar lavage of the granulomatosis patients showed a significant increase of the total cell count, signalling inflammatory involvement of the lung. Differential cytgological analysis showed a significant increase in the total number of granulocytes in the lavage fluid of the Wegener's granulomatosis patients (in one case up to 40%). The median granulocyte count was increased fivefold compared with the control. The increase of the granulocyte count was mainly conditioned by an increase in the number of neutrophilic granulocytes but there was also a significant increase in eosinophilic granulocytes. There was also a slight but significant increase in the lymphocyte count in the bronchoalveolar lavage fluid of patients with Wegener's granulomatosis. The number of CD-3-positive lymphocytes was significantly higher than with the controls. No significant differences were noted for the CD-4-positive, CD-8-positive and CD-19-positive lymphocytes. Immunophenotyping of the alveolar macrophages with monoclonal differentiation markers of the Ki-M-Series showed that the alveolar macrophages of patients with Wegener's granulomatosis resembled an immunophenotype that was close to that of monocytes. The number of proliferating macrophages was also higher than with the controls.

Ofloxacin in lower respiratory tract infections.

In order to determine the efficacy and safety of the new quinolone ofloxacin in the treatment of chronic lower respiratory disease, 674 patients (353 with chronic bronchitis, 212 with community-acquired pneumonia and 109 with hospital-acquired pneumonia) were treated with ofloxacin 200 mg twice a day. In total, 627 patients (93%) showed a satisfactory clinical response, and 47 patients (7%) had no change or deterioration. Neither severe side effects nor interactions between ofloxacin and coadministered theophylline were seen. This is important in patients suffering from chronic obstructive airways disease. The antibiotic spectrum of ofloxacin covers nearly all bacterial pathogens causing infectious respiratory disease; furthermore, ofloxacin reaches high concentrations in pulmonary secretions and tissue. Ofloxacin is a proven antibiotic substance useful in the treatment of lower respiratory tract infections.

[Bronchoalveolar lavage in diseases of rheumatic origin]. / Die bronchoalveoläre Lavage bei Erkrankungen aus dem rheumatischen Formenkreis.

The cells recovered by bronchoalveolar lavage reflect the cellular composition of the interstitial lung tissue. Inflammatory and fibrosing interstitial lung disorders, often accompanying rheumatic diseases, can be detected by this diagnostic procedure.

Proliferation, macrophage colony-stimulating factor, and macrophage colony-stimulating factor-receptor expression of alveolar macrophages in active sarcoidosis.

Alveolar macrophages (AM) in sarcoidosis display an enhanced mitotic activity. Immunocytochemical detection of the proliferation-associated Ki-67 antigen revealed significant increase in the number of proliferating AM in active sarcoidosis as compared with inactive stages of disease. Macrophage proliferation may provide an additional marker of disease activity. Since growth of macrophages is regulated by hematopoietic growth factors, we examined the expression of macrophage colony-stimulating factor (M-CSF), granulocyte M-CSF, and interleukin-3 by bronchoalveolar lavage cells in active sarcoidosis. Expression of granulocyte M-CSF or interleukin-3 genes could not be detected. AM in active sarcoidosis displayed M-CSF RNA to a comparable level like normal AM. They differed, however, in about 50% of cases analyzed, from normal AM by an enhanced level of c-fms proto-oncogene (M-CSF-receptor) expression. The enlarged proportion of proliferating AM in active sarcoidosis may be the result of an increased influx of strongly fms expressing macrophage precursors into the alveoli and autostimulation of macrophages by M-CSF.