[Guidance to the Interpretation of Cardiopulmonary Exercise Testing]. / Spiroergometrie kompakt ­ Physiologie, Durchführung und Auswertung.

Cardiorespiratory fitness has been established as an independent overall predictor of morbidity and mortality. However, patients' symptoms or stated levels of exercise intolerance correlate only poorly with resting functional and imaging tests. Cardiopulmonary exercise testing (CPET) is the gold standard for the integrative assessment of the cardiocirculatory, pulmonary and metabolic response to exercise and can help identify the source of exercise limitation, monitor disease progression, evaluate treatment responsiveness and inform about prognosis. Though CPET offers more valuable and pertinent information with slightly more expenditure of time compared to other methods even at submaximal exercise levels, it remains underutilized for various reasons such as costs, reimbursement and expertise. CPET can be seen as a complex, but not necessarily difficult tool. The objective of this review was to provide a description of the underlying principles of physiology, and an easy-to-follow guidance to indications, methodology, and interpretative strategies of CPET.

[Use of a lung function screening device for identifying patients at risk for COPD in general practice]. / COPD-Screening in der hausärztlichen Praxis mit einem Lungenfunktions-Schnellmessgerät.

BACKGROUND: Screening measures can facilitate the diagnosis of chronic obstructive pulmonary disease (COPD) and help save costs and time. We examined whether use of a lung function screener (Vitalograph copd-6™) can help general practitioners to identify patients at risk for COPD. METHODS: In 17,856 patients aged > 40 years (smokers/ex-smokers with cough and/or exertional dyspnoea) general practitioners measured prebronchodilator FEV1 [% of predicted] and FEV1/FEV6 with the lung function screening device. In addition, the general practitioners completed a questionnaire on symptoms, history and planned measures and estimated whether or not the patient was at risk for COPD. RESULTS: In 2927 patients (16.7 %) an FEV1/FEV6 < 70 % was measured; 88.2 % of these were classed by the doctors as being at risk for COPD. The total number of all patients with suspected COPD was considerably greater (10,000; 56 % of the total population); in only 25.3 % was an FEV1/FEV6 < 70 % documented. Compared with patients without a suspicion of COPD, patients judged to be at risk for COPD in spite of an FEV1/FEV6 ≥ 70 % were more often male, had more cigarette pack years and more often had dyspnoea, but less often cough, as main symptom. They had more concomitant diseases and previous hospitalisations, more prescriptions for bronchodilators, glucocorticoids and antibiotics in the past year and lower FEV1 values. In 61.3 % of the patients with suspected COPD the general practitioners planned further evaluation by spirometry, in 39.9 % referral to a pulmonologist as alternative or additional procedures were suggested. CONCLUSION: Most patients with an FEV1/FEV6 < 70 % measured with the lung function screener Vitalograph copd-6™ were classed by the general practitioners as being at risk for COPD. Even in patients with unremarkable FEV1/FEV6 values the diagnosis of suspected COPD was often made if clinical signs or symptoms or a reduced FEV1 pointed to such a suspicion.

[Early treatment of COPD with tiotropium]. / Evidenz für eine frühzeitige Therapie der COPD mit Tiotropium.

BACKGROUND: In a prespecified subgroup analysis of the 4-year trial "Understanding Potential Long-term Impacts on Function with Tiotropium", the efficacy of tiotropium versus control in patients with moderate COPD (GOLD II) was examined and compared with the pooled results of patients with more severe disease (GOLD III/IV). METHODS: Randomised, multicentre, double-blind, placebo-controlled, parallel-group study in 5993 patients over a period of 4 years. Patients received either tiotropium 18 µg or placebo once-daily. The study endpoints were the annual FEV1 decline as well as lung function parameters, health status, exacerbations and all-cause mortality. RESULTS: 46 % of the patients had moderate disease (GOLD II; tiotropium: n = 1384, control group: n = 1355) with a mean postbronchodilator FEV1 of 1.63 (0.37) L (59 % predicted). In these patients with moderate COPD, tiotropium significantly improved the absolute FEV1 values (pre-bronchodilator FEV1: 101 - 119 ml, post-bronchodilator FEV1: 52 - 82 ml, p < 0.001) and the postbronchodilator FEV1 decline compared with the control patients (43 (2) vs. 49 (2) ml/year; p = 0.024). In addition, there was a statistically significant improvement in the annual exacerbation rate (tiotropium: 0.56, control: 0.7; p < 0.0001), the time to first exacerbation (tiotropium: 23.09, control: 17.47 months; p < 0.0001) and health status (tiotropium vs. control: minus 2.7 - 4 units; p < 0.0001) in the tiotropium group.  CONCLUSIONS: The results of this subgroup analysis support current guideline recommendations and indicate that already patients with moderate COPD (GOLD stage II) benefit clinically from treatment with tiotropium.

Reduced airway inflammation in CD26/DPP4-deficient F344 rats is associated with altered recruitment patterns of regulatory T cells and expression of pulmonary surfactant proteins.

INTRODUCTION: CD26 is highly expressed on lung epithelial cells as well as on immune cells. Ovalbumin (OVA)-induced airway inflammation induces a further increase of CD26 expression. CD26-deficient rat strains exhibit blunted clinical courses in models of experimental asthma. OBJECTIVE: (1) To investigate the involvement of regulatory T cells (Tregs) and the surfactant system in a rat model of genetic CD26 deficiency. (2) To investigate regulatory mechanisms dependent on the endogenous CD26 expression. (3) To investigate the impact of CD26 on surfactant protein (SP)-levels under inflammatory conditions. METHODS: Wild-type and CD26-deficient F344 rats were sensitized to and challenged with OVA. Subsequently, airway inflammation, SP levels as well as surface tension of the bronchoalveolar lavage (BAL) fluid were evaluated. RESULTS: CD26 deficiency led to decreased airway inflammation, e.g. reduced numbers of eosinophils and activated T cells in the BAL. Remarkably, the CD26-deficient rats exhibited a significantly increased influx of FoxP3(+) Tregs into the lungs and increased IL-10-secretion/production by draining lymph node cells in culture experiments. Furthermore, in OVA-challenged CD26-deficient rats, the increase of the expression of the collectins SP-A and SP-D as well as of the surface tension-active SP-B was significantly less pronounced than in the CD26-positive strain. Only in the wild-type rats, functional alterations of the surfactant system, e.g. the increased surface tension were obvious after OVA challenge. CONCLUSION: Reduced airway inflammation in CD26-deficient F344 rats appear to be mediated by differences in the recruitment and activity of Tregs. This altered inflammation is associated with differences in the SP expression as well as function.

Statistical analysis of chronic obstructive pulmonary disease exacerbations in clinical studies: expectations and limitations.

Acute exacerbations of chronic obstructive pulmonary disease (COPD) occur more frequently with increasing COPD severity and are associated with increased morbidity, reduced quality of life, and increased risk of mortality. The prevention and assessment of exacerbations, as a clinically and therapeutically relevant parameter, is a central aspect of clinical COPD studies. The aim of this review is to identify pitfalls in the analysis of the parameter of exacerbation and to describe the criteria that need to be considered in the statistical analysis of exacerbation studies.

Surfactant protein D inhibits early airway response in Aspergillus fumigatus-sensitized mice.

BACKGROUND: The surfactant protein SP-D has been reported to reduce bronchial hyper-responsiveness, blood eosinophilia, and T-helper type 2 cytokines in models of allergic asthma. However, little is known about the functional effect of SP-D on the early airway response upon allergen inhalation, which is an important feature of this disease. OBJECTIVE: We investigated whether SP-D is able to reduce the immediate allergen-induced mediator release and the early bronchial obstruction in addition to its effects on airway inflammation and bronchial hyperresponsiveness in an Aspergillus fumigatus mouse asthma model. METHODS: A. fumigatus-sensitized mice were treated with a recombinant fragment of human SP-D or placebo. Lung functions were measured in orotracheally intubated, spontaneously breathing animals using body plethysmography. In addition, passively sensitized precision-cut lung slices (PCLS) were used to determine the effect of SP-D on allergen-induced histamine release. RESULTS: SP-D inhibited the allergen-induced early airway response and reduced airway hyperresponsiveness compared with placebo. Eosinophilia in bronchoalveolar lavage and lung tissue was reduced after SP-D treatment, possibly by reducing eotaxin levels in the lung. Furthermore, SP-D treatment reduced the allergen-induced histamine release from PCLS. CONCLUSION: These data suggest that SP-D not only reduces allergen-induced eosinophilic inflammation and airway hyperresponsiveness but also provides protection against early airway obstruction by inhibition of early mediator release.

[Guideline-conformity of outpatient COPD management by pneumologists]. / COPD-Management nach aktuellen Leitlinien bei niedergelassenen Pneumologen.

BACKGROUND: Several evidenced-based clinical guidelines are available for COPD which is the most frequent chronic respiratory disease. The purpose of this study was to evaluate the outpatient COPD management of pneumologists based on current national and international guidelines for the first time and to identify any deviations. METHODS: A nationwide prospective cross-sectional survey was performed as a multiple-choice questionnaire sent to 863 pneumologists in Germany. The product-neutral questions focused on the knowledge about, acceptance of and practical experience with current national and international COPD guidelines. RESULTS: 359 pneumologists (41.6 %) participated in the survey. 60.4 % of the participants preferred the GOLD guideline over the German COPD guideline (33.4 %). 54.3 % considered bodyplethysmography as the diagnostic standard, followed by spirometry (38.4 %). However, only about 80 % were able to cite the correct spirometric criteria for classifying COPD severity. It is remarkable that many physicians still oriented to the outdated GOLD classification of 2001. The two most important treatment goals cited were to improve quality of life (82.2 %) and prevent exacerbations (63 %). Except for the criteria for the use of steroids and the implementation of pulmonary rehabilitation measures, treatment of COPD based on severity class was largely in compliance with the guidelines. However, a significant percentage of the pneumologists incorrectly assessed the evidence-based clinical benefits of various therapeutic measures. CONCLUSION: The results of this survey show that most pneumologists adhere to guideline recommendations in daily practice and prefer the GOLD over the national COPD guideline. However, deficiencies in guideline conformity still exist with regard to severity classification and treatment of COPD.

[Guideline conformance for outpatient management of COPD in Germany]. / Leitlinienkonforme ambulante COPD-Behandlung in Deutschland.

BACKGROUND AND OBJECTIVE: Primary care physicians (PCPs) are the ones mainly responsible for the initial diagnosis and outpatient care of patients with COPD. The aim of the present survey was to investigate their initial management of COPD in Germany based on current guidelines and to identify any deviations. METHODS: A prospective cross-sectional survey was conducted as a multiple-choice questionnaire sent out to 1836 PCPs in seven Federal States of Germany (one large town and surrounding country in each). The product-neutral questions focused on the key aspects of current national and international (GLOBAL) COPD guidelines. RESULTS: 486 physicians participated in the study (response rate 26.5%). 66.5% of the physicians used the German COPD guidelines, 20.8% used GOLD guidelines, and only 11.7% observed no guidelines. The physicians were aware of the epidemiological and public health significance of COPD. 76.5% saw spirometry as the diagnostic standard: it was available in 90.1% of the practices. However, only 60-65% were able to cite the correct spirometric criteria for classifying severity of the disease. Educational measures to help patients quit smoking and the teaching and monitoring of patients' inhalation technique were inadequately implemented. The two most important therapeutic goals cited were to improve quality of life (69.1%) and prevent exacerbations (53.1%). Except for the criteria for the use of steroids and the implementation of pulmonary rehabilitation measures, treatment of COPD based on severity class was largely in compliance with the guidelines. However, a significant percentage of the physicians incorrectly assessed the evidence-based clinical benefits of various therapeutic measures. CONCLUSION: The study shows that, despite the high regard in which COPD guidelines are held, deficiencies exist with regard to the diagnosis and treatment of COPD and the practical implementation of educational measures.

Comparison of non-invasive measures of cholinergic and allergic airway responsiveness in rats.

AIM: Non-invasive analysis of tidal expiratory flow parameters such as Tme/TE (time needed to reach peak expiratory flow divided by total expiratory time) or midexpiratory tidal flow (EF50) has been shown useful for phenotypic characterization of lung function in humans and animal models. In this study, we aimed to compare the utility of two non-invasive measures, EF50 and Tme/TE, to monitor bronchoconstriction to inhaled cholinergic and allergic challenges in Brown-Norway rats. METHODS: Non-invasive measurements of Tme/TE and EF50 were paralleled by invasive recordings of Tme/TE, EF50 and pulmonary conductance (GL). RESULTS: First, dose-response studies with acetylcholine were performed in naive rats, showing that EF50 better than Tme/TE reflected the dose-related changes as observed with the classical invasive outcome parameter GL. The subsequent determination of allergen-specific early airway responsiveness (EAR) showed that ovalbumin-sensitized and -challenged rats exhibited airway inflammation and allergen-specific EAR. Again, EF50 was more sensitive than Tme/TE in detecting the allergen-specific EAR recorded with invasive and non-invasive lung function methods and agreed well with classical GL measurements. CONCLUSION: We conclude that non-invasive assessment of EF50 is significantly superior to Tme/TE and serves as a suitable and valid tool for phenotypic screening of cholinergic and allergic airway responsiveness in rats.

[Use of beta blockers in cardiovascular diseases and bronchial asthma/COPD]. / Einsatz von beta-Blockern bei kardiovaskulären Erkrankungen und Asthma bronchiale/COPD.

Numerous extensive, randomized clinical trials of beta-blockers have shown significant reduction of total mortality in patients with myocardial infarction and chronic heart failure. The life-saving therapy of myocardial infarction or chronic heart failure with beta-blockers, however, is often withheld from patients with COPD/asthma. Several studies demonstrate that especially patients with COPD would benefit from such a therapy due to their high cardiovascular risk profile. Recent meta-analyses show that cardioselective beta-blockers are well tolerated by these patients without causing relevant limitations in lung function. Present findings suggest that the mortality reduction of beta-blocker therapy may outweigh the risks in patients with COPD and possibly even in patients with mild asthma. Contraindications for beta-blockers include acute exacerbations and severe forms of COPD as well as moderate to severe asthma and the regular use of beta(2)-sympathomimetics. beta-Blocker therapy should be given with low initial doses on an individual basis after careful consideration of the benefit to risk ratio, preferably using cardioselective substances with proven mortality benefits for myocardial infarction and chronic heart failure.

Effect of anti-nerve growth factor on early and late airway responses in allergic rats.

BACKGROUND: The increased production of nerve growth factor (NGF) has been associated with allergen-induced airway hyperresponsiveness and enhanced airway inflammation in experimental models of asthma. The aim of this study was to investigate whether a local application of anti-NGF to the lungs may affect the allergen-specific early (EAR) and late (LAR) airway responses to ovalbumin (Ova) of Ova-sensitized brown Norway rats. METHODS: Rats were sensitized systemically with Ova and were boosted twice intratracheally with Ova aerosol using a microsprayer. Two hours before every boost, the animals were pretreated either with aerosolized anti-NGF or with a control antibody. On day 21, all animals were challenged with inhalational Ova aerosol and pulmonary resistance was recorded in anesthetized, orotracheally intubated animals during the early and late asthmatic responses. In addition, differential cell counts from bronchoalveolar lavage and serum immunoglobulin E (IgE) levels were determined 48 h post-Ova challenge. RESULTS: Pretreatment with anti-NGF significantly attenuated the EAR but had no significant effect on the LAR. Serum IgE levels and inflammatory cell influx into the lungs were not affected by anti-NGF pretreatment. CONCLUSION: The data from this study suggest that NGF is directly involved in the development of the EAR without affecting the inflammatory airway response or LAR.

[Tracheobronchopathia osteochondroplastica: an uncommon cause of retention pneumonia in an elderly patient]. / Tracheobronchopathia osteochondroplastica: eine ungewöhnliche Ursache einer Retentionspneumonie.

A 79 years old patient without preexisting pulmonary disease was admitted due to pneumonia and hemoptysis. Despite intravenous antibiotic therapy he did not recover and still suffered from fever and dyspnea six days later. Fiberoptic bronchoscopia was performed in order to exclude poststenotic pneumonia. However, macroscopically a "rock-garden" trachea, the characteristic picture of osteochondroplastic tracheobronchopathy, was seen with multiple whitish irregularly shaped nodules in the trachea, except in the pars membranacea, involving both sides of the bronchial system and producing subtotal stenosis. Although cytologic examination suggested adenocarcinoma, histology confirmed the diagnosis of osteochondroplastic tracheobronchopathy. Repeated CT scans as well as control bronchoscopy served as a means of excluding simultaneous carcinoma. The case presented here demonstrates that even progressive tracheobronchopathy may remain asymptomatic for a long time until subtotal stenosis or impaired clearing mechanisms may lead to retention pneumonia. Cytologic examination may give false positive results suggesting malignant disease. However the typical macroscopic picture as well as histology should lead to the correct diagnosis.

Tidal midexpiratory flow as a measure of airway hyperresponsiveness in allergic mice.

A method for the noninvasive measurement of airway responsiveness was validated in allergic BALB/c mice. With head-out body plethysmography and the decrease in tidal midexpiratory flow (EF(50)) as an indicator of airway obstruction, responses to inhaled methacholine (MCh) and the allergen ovalbumin were measured in conscious mice. Allergen-sensitized and -challenged mice developed airway hyperresponsiveness as measured by EF(50) to aerosolized MCh compared with that in control animals. This response was associated with increased allergen-specific IgE and IgG1 production, increased levels of interleukin-4 and interleukin-5 in bronchoalveolar lavage fluid and eosinophilic lung inflammation. Ovalbumin aerosol challenge elicited no acute bronchoconstriction but resulted in a significant decline in EF(50) baseline values 24 h after challenge in allergic mice. The decline in EF(50) to MCh challenge correlated closely with simultaneous decreases in pulmonary conductance and dynamic compliance. The decrease in EF(50) was partly inhibited by pretreatment with the inhaled beta(2)-agonist salbutamol. We conclude that measurement of EF(50) to inhaled bronchoconstrictors by head-out body plethysmography is a valid measure of airway hyperresponsiveness in mice.

Sequential development of airway hyperresponsiveness and acute airway obstruction in a mouse model of allergic inflammation.

BACKGROUND: Mouse models have been established mirroring key features of human bronchial asthma including airway hyperresponsiveness (AHR). Acute airway obstruction in response to an allergen challenge, however, remains to be demonstrated in these models. OBJECTIVE: A mouse model of allergic lung inflammation was employed to analyze the development of specific (allergen-induced) and nonspecific (methacholine-induced) airway obstruction. METHODS: Mice were sensitized to ovalbumin (OVA) and challenged with OVA aerosol twice each week during four weeks. Changes in lung functions were determined by noninvasive head-out body plethysmography. The development of acute airway obstruction after OVA challenge and AHR after methacholine aerosol application were assessed by a decrease in the mid-expiratory flow rate (EF(50)). RESULTS: Two airway challenges were sufficient to induce AHR (5.7 vs. 15 mg/ml methacholine). Further OVA challenges reduced the baseline EF(50) from 1.85 to 1.20 ml/s (4th week) and induced acute airway obstruction. The OVA-induced obstruction was maximal in the 4th week (EF(50) = 0.91 ml/s). CONCLUSION: The development of acute airway obstruction in allergen-sensitized mice was demonstrated by means of head-out body plethysmography. In our model, AHR was observed before the development of airway obstruction.