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Stephan Budweiser1, Rudolf A Jörres2, Michael Pfeifer1,31Center for Pneumology, Hospital Donaustauf, Donaustauf, Germany; 2Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig-Maximilians-University, Munich, Germany; 3Department of Internal Medicine II, Division of Respirology, University of Regensburg, Regensburg, GermanyAbstract: Patients with advanced COPD and acute or chronic respiratory failure are at high risk for death. Beyond pharmacological treatment, supplemental oxygen and mechanical ventilation are major treatment options. This review describes the physiological concepts underlying respiratory failure and its therapy, as well as important treatment outcomes. The rationale for the controlled supply of oxygen in acute hypoxic respiratory failure is undisputed. There is also a clear survival benefit from long-term oxygen therapy in patients with chronic hypoxia, while in mild, nocturnal, or exercise-induced hypoxemia such long-term benefits appear questionable. Furthermore, much evidence supports the use of non-invasive positive pressure ventilation in acute hypercapnic respiratory failure. It application reduces intubation and mortality rates, and the duration of intensive care unit or hospital stays, particularly in the presence of mild to moderate respiratory acidosis. COPD with chronic hypercapnic respiratory failure became a major indication for domiciliary mechanical ventilation, based on pathophysiological reasoning and on data regarding symptoms and quality of life. Still, however, its relevance for long-term survival has to be substantiated in prospective controlled studies. Such studies might preferentially recruit patients with repeated hypercapnic decompensation or a high risk for death, while ensuring effective ventilation and the patients’ adherence to therapy.Keywords: respiratory failure, COPD, mechanical ventilation, non-invasive ventilation long-term oxygen therapy, chronic hypercapnic respiratory failure, oxygen

Smoking is known to be linked to skin ageing and there is evidence for premature senescence of parenchymal lung fibroblasts in emphysema. To reveal whether the emphysema-related changes in cellular phenotype extend beyond the lung, we compared the proliferation characteristics of lung and skin fibroblasts between patients with and without emphysema. Parenchymal lung fibroblasts and skin fibroblasts from the upper torso (thus limiting sun exposure bias) were obtained from patients without, or with mild, or with moderate to severe emphysema undergoing lung surgery. We analysed proliferation rate, population doublings (PD), staining for senescence-associated beta-galactosidase (beta-gal) and gene expression of IGFBP-3 and IGFBP-rP1. Population doubling time of lung fibroblasts differed between control, mild, and moderate to severe emphysema (median (IQR) 29.7(10.0), 33.4(6.1), 44.4(21.2) h; p=0.012) and staining for beta-gal was elevated in moderate to severe emphysema. Compared to control subjects, skin fibroblasts from patients with emphysema did not differ with respect to proliferation rate, PD and beta-gal staining, and showed a lower abundance of mRNA for IGFBP-3 and -rP1 (p

Background The combined measurement of diffusing capacity of the lung for nitric oxide (Dlno) and diffusing capacity of the lung for carbon monoxide (Dlco) is a simple, noninvasive tool, but methodologic factors might influence results and reproducibility. We thus quantified the influence of breath-hold time on Dlco and Dlno in subjects with or without airway disease. Methods Simultaneous single-breath measurements of Dlco and Dlno were performed in 10 patients with cystic fibrosis (CF) [mean ± SD age, 33 ± 9 years; FEV 1 , 69 ± 28% of predicted] and 10 healthy subjects (age, 31 ± 9 years; FEV 1 , 108 ± 8% of predicted), using the Masterscreen PFT (Viasys/Jaeger; Hochberg, Germany), with 45 ppm of inspired nitric oxide (NO), and breath-hold times of 4 s, 6 s, 8 s, and 10 s. The last two of three consecutive measurements were used for analysis. Results In healthy subjects but not patients with CF, Dlno, and Dlco differed significantly (p Conclusions Single-breath determinations of dlno and dlco showed no difference between breath-hold times of 6 s and 8 s in subjects with or without airway obstruction, and reproducibility was acceptable. Standardization of breath-hold time for Dlno measurements seems important for clinical and research comparisons.

Objectives Histamine and cysteinyl leukotrienes play an important role in early (EAR) and late (LAR) allergen reactions. Although protection by anti-histamines and anti-leukotrienes has been studied extensively, little is known about the effect of their combination. We, therefore, assessed the effect of clinically recommended doses of azelastine and montelukast alone and in combination on EAR and LAR. Methods Seventeen patients (mean age 31 years, 14 m/3 f) with asthma and proven EAR and LAR received an oral dose of 4 mg azelastine twice daily, or 10 mg montelukast once daily, or both for 1 week, in a double-blind, double-dummy, cross-over fashion. FEV1 was measured after single-dose allergen challenges during EAR (0–2 h) and LAR (2–9 h). Results Azelastine, montelukast and their combination protected against both EAR and LAR ( p 0.004 , each) by 46% and 43%, 76% and 59%, and 89% and 78%, respectively. Azelastine was not as effective during EAR but equally effective to montelukast during LAR. The combination was superior to each drug alone during both EAR and LAR ( p 0.05 , each). Conclusion The combination of azelastine and montelukast in clinically recommended doses has a greater effect in suppressing early and late allergen reactions than each drug alone.

SummaryBackgroundPatients with severe COPD suffer from impairments of exercise capacity which affects daily activity. Conversely, activity might exert effects on the functional state. We studied whether a short-term intervention by regular phone calls caused an increase in activity at home and whether this resulted in a gain in exercise capacity.MethodsOver a 2-week period (P1) normal daily activity was assessed in 21 patients with stable severe COPD (GOLD III/IV). After this, the individual setting was explored in a short home visit. The subsequent 2-week period (P2) involved phone calls every other day to raise home-based activity (target: 3×15min daily at 75% of maximum dyspnea). During the study, patients wore an actograph plus pedometer and kept a diary. Before P1 and after P2, 6-min walking distance (6MWD), lung function, the Borg score and quality of life (SF-36, SGRQ) were determined.ResultsCompared to P1, actograph counts (p

Background: The 6-min walk distance (6-MWD) is a global marker of functional capacity and prognosis in chronic obstructive pulmonary disease (COPD), but less explored in other chronic respiratory diseases. Objective: To study the role of 6-MWD in chronic hypercapnic respiratory failure (CHRF). Methods: In 424 stable patients with CHRF and non-invasive ventilation (NIV) comprising COPD (n = 197), restrictive diseases (RD; n = 112) and obesity-hypoventilation-syndrome (OHS; n = 115), the prognostic value of 6-MWD for long-term survival was assessed in relation to that of body mass index (BMI), lung function, respiratory muscle function and laboratory parameters. Results: 6-MWD was reduced in patients with COPD (median 280 m; quartiles 204/350 m) and RD (290 m; 204/362 m) compared to OHS (360 m; 275/440 m; p < 0.001 each). Overall mortality during 24.9 (13.1/40.5) months was 22.9%. In the 424 patients with CHRF, 6-MWD independently predicted mortality in addition to BMI, leukocytes and forced expiratory volume in 1 s (p < 0.05 each). In COPD, 6-MWD was strongly associated with mortality using the median [p < 0.001, hazard ratio (HR) = 3.75, 95% confidence interval (CI): 2.24–6.38] or quartiles as cutoff levels. In contrast, 6-MWD was only significantly associated with impaired survival in RD patients when it was reduced to 204 m or less (1st quartile; p = 0.003, HR = 3.31, 95% CI: 1.73–14.10), while in OHS 6-MWD had not any prognostic value. Conclusions: In patients with CHRF and NIV, 6-MWD was predictive for long-term survival particularly in COPD. In RD only severely reduced 6-MWD predicted mortality, while in OHS 6-MWD was relatively high and had no prognostic value. These results support a disease-specific use of 6-MWD in the routine assessment of patients with CHRF.

SummaryBackgroundNatriuretic peptides are considered as reliable indicators of left-heart failure (HF) and are useful for differential diagnosis of dyspnoea.AimWe evaluated the clinical significance of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with chronic hypercapnic respiratory failure (CHRF).MethodsIn 60 patients with CHRF, plasma concentrations of NT-proBNP were assessed at baseline and after treatment including non-invasive ventilation (NIV). The relationship of NT-proBNP to disease severity and its predictive value for survival were evaluated up to 4 years.ResultsNT-proBNP levels were markedly elevated in patients with CHRF (n=60; geometric mean (SD) 546.4 (4.9)pg/mL; p722pg/mL (67th percentile) and no adherence to NIV displayed poor prognosis (hazard ratio=0.21; 95%-CI=0.022–0.580; p=0.0091).ConclusionsNT-proBNP was highly elevated in patients with CHRF and correlated with the degree of respiratory impairment and exacerbation. Correspondingly, treatment including NIV led to reduction of NT-proBNP. These data indicate a potential role of NT-proBNP in assessing disease severity, treatment efficacy and prognosis in CHRF.

Allergic occupational asthma is frequent in farming populations. As educational interventions can improve disease management, the short-term effect of an educational intervention in asthmatic farmers was evaluated on the basis of spirometric indices and exhaled nitric oxide fraction (F(eNO)). Farmers with occupational asthma (n = 81), mostly sensitised against cow dander and storage mites, participated in a 1-day educational programme. Outcome measures were assessed at baseline and after 4-6 weeks, using F(eNO), lung function and a questionnaire. Results were compared with those of a control group without intervention (n = 24). In the educational group, the proportion of subjects reporting work-related symptoms was reduced after the intervention. The F(eNO) decreased from a geometric mean of 28.2 to 25.7 ppb, and, in subjects with an elevated (>35 ppb) baseline F(eNO) (n = 32), from 59.7 to 49.2 ppb. The corresponding changes in the control group were 25.6 versus 27.7 ppb and 49.5 versus 48.1 ppb. Spirometric results were unaltered in the two groups. Thus exhaled nitric oxide fraction, a marker of allergic airway inflammation, indicated a beneficial effect of a short-term educational intervention in farmers with occupational asthma. This suggests a potential for exhaled nitric oxide fraction in assessing the efficacy of preventive measures within a short time with higher sensitivity than spirometry.

Patients with COPD and chronic hypercapnic respiratory failure (CHRF) are at high risk, and noninvasive ventilation at home is increasingly being used. Knowledge of prognostic parameters under these conditions is limited but may be clinically helpful and highlight the role of noninvasive ventilation.In 188 patients with COPD (mean +/- SD FEV1, 31.0 +/- 9.6% of predicted; PaCo2, 56.3 +/- 9.4 mm Hg) discharged from the hospital receiving NIV between July 1994 and July 2004, the prognostic value of body mass index (BMI), lung function, laboratory parameters, and blood gas levels was assessed by univariate and multivariate Cox regression analyses. Moreover, the impact of changes in risk factors on mortality assessed 6.7 +/- 2.8 months after the initiation of noninvasive ventilation was evaluated.Overall, the mortality rate during follow-up (duration, 32.2 +/- 24.3 months) was 44.7%, with 1-year, 2-year, and 5-year survival rates of 84.0%, 65.3%, and 26.4%. Deaths resulted predominantly from respiratory causes (73.8%). Univariate regression analyses revealed age, BMI, hemoglobin, FEV1, specific airway resistance, residual volume (RV)/total lung capacity (TLC), pH, and base excess (BE) to be associated with prognosis (p0.01 each), whereas multivariate analysis identified only age, BMI, RV/TLC, and BE as independent predictors (p0.05). In patients at risk (BMI25 km/m2, RV/TLCor= 73%, or BEor= 9 mmol/L), changes in these predictors were also associated with survival.In patients with COPD and CHRF, nutritional status, hyperinflation, and BE, which turned out to be reliable and consistent markers in CHRF, were independent prognostic factors for mortality. These data favor a multidimensional approach in these patients, including the use of noninvasive ventilation.

While malnutrition, especially fat-free mass index (FFMI), is a predictor for mortality in chronic obstructive pulmonary disease (COPD), less information on prevalence and mechanisms is available in patients with chronic respiratory failure (CRF) due to restrictive thoracic diseases (RTD).Cross-sectional study of patients consecutively admitted to an in-patient primary pulmonary centre.One hundred and thirty-two patients (30% RTD; 70% COPD) with CRF and intermittent non-invasive positive pressure ventilation.Malnutrition was quantified by bioelectrical impedance analysis or body mass index (BMI), and its relationship to laboratory, lung function, inspiratory muscle and blood gas parameters and 6-min walking distance (6-MWD) was assessed.Malnutrition in terms of BMI20 kg/m(2) occurred in 16.1% of patients with COPD but none of those with RTD. FFMI17.4 (15.0 in female patients) kg/m(2) was found in 35.4 and 30.7%, respectively. FFMI was correlated with airway obstruction (sR(aw), r = -0.50; FEV(1)/VC, r = -0.28; Por = 0.01 each) and lung hyperinflation (intrathoracic gas volume, r = -0.41; total lung capacity (TLC), r = -0.50; Por = 0.001 each) in COPD, and with lung restriction in RTD (TLC, r=0.40; P=0.011). Furthermore, malnourished patients showed a higher inspiratory load (P (0.1)) and reduced 6-MWD in both groups. In COPD, only hyperinflation and P (0.1) were independently related to FFMI.Malnutrition as indicated by low FFMI was similarly prevalent in patients with CRF and COPD or RTD, but inadequately represented by BMI. The correlations between lung function impairments specific for the disease and FFMI emphasized the link between malnutrition and respiratory mechanical load irrespective of its aetiology.

Background: Chronic obstructive pulmonary disease (COPD) is often considered to be related to premature ageing but adequate, clinically feasible markers are lacking. We compared three molecular/biochemical markers and one set of phenomenological markers and determined their relationship to the disease state. Methods: Within the COSYCONET National COPD cohort, 127 patients from the study centre LMU Munich were investigated by comprehensive functional and clinical assessments, measurements of advanced glycation endproducts (AGE), the peptide LL-37 and telomere length (T/S ratio, qPCR) in blood, as well as scoring of facial wrinkling via coded photos. A binary CT emphysema score was available in 39 patients and predicted in 122 patients via a function based on functional parameters. Results: The percentages of COPD stages 0-IV were 5, 20, 35, 20, and 20%. Stages were not related to age or T/S ratio, but associated with lung function and the age excess (estimated–factual age) estimated from skin scoring. The predicted emphysema score also depended on age excess, lung function indices and BMI. Logistic regression analyses indicated that the association with age excess was robust. AGEs were mostly dependent on the comorbidity diabetes and LL-37 was affected by smoking. Conclusions: The results support the notion that COPD and emphysema are related to premature ageing. In particular biological excess age estimated from facial photos correlated with stages of COPD and (predicted) emphysema and was superior to blood markers of ageing. Supported by German Federal Ministry of Education and Research, Kompetenznetz Asthma/COPD, and by Friedrich-Baur-Stiftung, LMU Munchen.

Background: Relationship between comorbidities and lung disorder could depend on the type of lung disorder (parenchymal vs airway). Aim: Determine whether CT scans available from clinical routine assessments can be made comparable for developing a prediction function to estimate the probability of lung disorder types from functional data. Methods: Within the COSYCONET cohort study, 2,741 patients with COPD were recruited in 30 study centers. Assessments included spirometry, body plethysmography and diffusing capacity for CO. CT scans from 24 centres were evaluated regarding the type of lung disorder. Using logistic/linear regression analyses, associations between categorical/continuous measures of CTs and lung function were assessed. Results: 342 CT scans could be used in patients of categories GOLD 0-IV (mean (SD) age 65 (8) y; 34% female; 8% GOLD 0; 40% I/II; 52% III/IV). Regarding the binary emphysema score, FEV1/FVC, TLCO%pred, TLC%pred, specific airway resistance sRaw and absolute FEV1 were identified as predictors, resulting in 76% of patients correctly categorized (sensitivity for emphysema 78%). Analyses of the continuous scores lung density, 15-percentile of density and emphysema index were consistent with these findings. Conclusion: Results indicate that rather heterogeneous chest CT scans can be brought to a level of comparability that is sufficient to reveal meaningful associations between emphysema scoring and functional parameters. The functions will be used to investigate the impact of the type of lung disorder in the total COPD cohort. Competence Network Asthma/COPD funded by German Federal Ministry of Education and Research.

Background: COPD may influence different aspects of health-related quality of life (HRQL). Disease-specific HRQL instruments focus on symptoms and functional impairments while generic HRQL instruments cover a broader view on health. Aims: To compare HRQL assessment by the generic EQ-5D and two disease-specific HRQL questionnaires (Saint George9s Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT)) and to describe generic and COPD-specific HRQL in different COPD severity grades. Methods: This study is a cross-sectional analysis of the baseline data from the German COPD cohort COSYCONET. Correlations between EQ-5D utility index, SGRQ total score, CAT score and GOLD grade or BODE index as clinical measures of COPD severity were examined by Spearman correlation coefficients. Mean HRQL scores were compared by linear regression models adjusting for age, sex, education. Results: 2,288 subjects in COPD grade 1-4 (mean age 65 yrs, 61% males, 56% basic education, mean BODE 2.3) were included for analyses. Correlation between EQ-5D utility and SGRQ score (-0.56, p Conclusions: Generic and disease-specific HRQL instruments yield complementary information when aiming at a comprehensive picture of HRQL impairments in COPD.

Ultrafine particles (UFP) are emitted from laser printers in varying quantities during operation. However, their possible impact on human health is controversially discussed. We investigated effects of a 75-minute exposure of 52 volunteers to emissions from low emitting (LE) and high emitting (HE) laser printers. 23 healthy subjects, 14 patients with light, stable asthma and 15 persons with self-reported symptoms associated with laser printer exposure were exposed to LE (∼3,000 Particles/cm3; background with negligible LE contribution) and HE (∼100,000 UFP/cm3) in a standardised, randomised, cross-over manner. Examinations before and after exposures included whole-body plethysmography (WBP), transfer factors for CO and NO (TLCO, TLNO), bronchial and alveolar NO, biomarkers in serum and nasal secretions (IL-1β, IL-5, IL-6, IL-8, GM-CSF, IFNγ, TNFα) and symptom questionnaires. Overall, no significant changes were found for WBP measures and bronchial or alveolar NO. We observed a decrease in volume-related TLNO that was more pronounced in HE than LE (p Observed changes were low and do not suggest clinically relevant differential effects of HE and LE in terms of UFP/cm3 although we included subjects who might be regarded as particularly sensitive based on anamnesis or physiological considerations. Supported by the German Statutory Accident Insurance (FP294).

Rationale: The 6-Minute-Walk-Distance (6MWD) is an important instrument to assess patient-related outcomes in COPD. Conversely, the Timed-Up-and-Go (TUG) test is widely used as measure of physical mobility in the elderly but data in COPD are rare. Whether peripheral artery disease (PAD) has an impact on these parameters in patients with COPD has not been studied so far. Aims: To determine the association between PAD and 6MWD and TUG test in a large cohort of patients with COPD. Methods: Baseline characteristics, 6MWD and TUG test were assessed in 2,233 patients with COPD enrolled in the COSYCONET cohort study. Ankle-brachial index (ABI) was used to define PAD (ABI≤0.9). Characteristics were compared between patients with and without PAD and adjusted for age, gender, height, weight and FEV 1 . Results: 2,233 patients with COPD (60.9% male, age 64.9 [8.4] yrs, FEV 1 55.5 [19.7]% pred, GOLD stage I, II, III, IV: 12.6%, 43.9%, 34.6%, 8.9%) were included for analyses. Patients with PAD (n=184, 8.2%, GOLD stage I, II, III, IV: 4.6%, 7.5%, 10.5%, 8.1%) had a shorter 6MWD (355 [108] vs 423 [104] m, p Conclusions: Patients with COPD and comorbid PAD had worse functional capacity compared to those without PAD. Further studies are needed to evaluate the impact of concomitant PAD on the response to interventions. Funded by the German Federal Ministry of Education and Research, FZK 01GI0881; SW was supported by Lung Foundation Netherlands (3.4.10.015) and GSK (SCO115406).

Whole-body plethysmography (WBP) with bronchial challenge testing to measure the (specific) airway resistance, (s)R(AW), is considered to be a more sensitive diagnostic procedure than spirometry, which can only measure the forced expiratory volume in one second (FEV1). The evidence for the added diagnostic value of WBP is not yet conclusive.In a prospective diagnostic study, we carried out WBP with bronchial challenge testing as well as a bronchodilation test in 400 patients with suspected asthma from June 2010 to October 2011. The bronchial provocation test was considered positive if the FEV1 fell by at least 20% and/or the airway resistance doubled, with an increase of the sR(AW) to at least 2.0 kPA × s and/or of the R(AW) to 0.5 kPA × s/L. Follow-up evaluation was performed one year later.The prevalence of asthma in the 302 patients who completed follow-up was 27.5%. The sensitivity of WBP with sR(AW) measurement for asthma was 95.2% (95% confidence interval [CI] 88.3%-98.1%), and its specificity was 81.7% (95% CI 76.1%-86.3%). The sensitivity of FEV1 was 44.6% (95% CI 34.4%-55.3%), and its specificity was 91.3% (95% CI 86.6%-94.4%). The negative predictive value (NPV) of WBP with sR(AW) measurement was 97.8% (95% CI 94.5%-99.1%), while that of FEV1 was 81.3% (95% CI 76.0%-85.7%). The positive predictive value (PPV) of WBP with sR(AW) measurement was 66.4% (95% CI 57.5%-74.2%), while that of FEV1 was 66.1% (95% CI 53.0%-77.1%).With sR(AW) measurement, asthma can be ruled out with high certainty. Improving the positive predictive value of testing for asthma remains a challenge, however, as sR(AW) measurement does not yield any increase in specificity.

Budweiser S, Moertl M, Jorres RA, Windisch W, Heinemann F, Pfeifer M. Respiratory muscle training in restrictive thoracic disease: a randomized controlled trial. Objective To investigate the effects of respiratory muscle training (RMT) in patients with restrictive thoracic disorders and intermittent noninvasive positive-pressure ventilation (NPPV). Design Prospective randomized controlled trial. Setting Home-based RMT, with assessment in a primary care pulmonary center. Participants Thirty patients with restrictive thoracic disorders; 28 patients completed the trial. Intervention Three months of RMT by isocapnic hyperpnea or sham training. Main Outcome Measures Respiratory muscle strength and endurance, lung function, exercise performance, and health-related quality of life (HRQOL). Results After RMT, maximal inspiratory mouth pressure was increased (27.6%±36.5%, P =.013). In patients who could perform cycle ergometer testing (n=17), peak oxygen consumption (2.24±3.39mL·kg −1 ·min −1 vs −1.71±2.54mL·kg −1 ·min −1 , P =.014) and maximal work rate (9.4±14.8W vs −5.1±10.8W, P =.043) increased relative to a control group. Similar differences occurred regarding changes of HRQOL (physical performance, 3.3±11.4 score vs −6.6±9.0 score; P =.012) and time of ventilator use (−0.6±1.2h/d vs 0.4±0.5h/d, P =.010). Lung volumes, 12-second maximum voluntary ventilation, 6-minute walking distance, and blood gases were unchanged. Conclusions In patients with restrictive thoracic disorders and NPPV, RMT improved inspiratory muscle strength. Exercise performance and HRQOL were improved when the 2 groups were compared. RMT was practicable and safe despite severe respiratory impairment. Further evaluation, including different training intensities and modalities, seems warranted.

Background: The interleukins IL-4 and IL-13 play a key role in the pathophysiology of asthma. The interleukin receptor IL-13Rα2 is believed to act as a decoy receptor, but until now, the functional significance of IL-13Rα2 remains vague. Methods: Bronchial reactivity was quantified in murine lung slices by digital video microscopy and acetylcholine (ACH)-induced Ca2+ signaling was measured in human airway smooth muscle cells (ASMC) using fluorescence microscopy. Results: IL-4 or IL-13 up to 50 ng/ml induced bronchial hyperreactivity. But after incubation with 100 ng/ml this effect was lost and bronchial responsiveness was again comparable to the control level. The effects of IL-4 and IL-13 on bronchial reactivity were paralleled by the effects on ASMC proliferation. Fifty nanograms per milliliter of IL-4 and IL-13 increased the Ca2+ response of human ASMC to ACH. At 100 ng/ml, however, the effects of the cytokines on the Ca2+ response were no longer evident. The expression of IL-13Rα2 increased with increasing concentrations of IL-4 or IL-13, reaching its maximum at 100 ng/ml. Blocking IL-13Rα2, the loss of the effect of IL-4 and IL-13 at 100 ng/ml on human ASMC proliferation and the ACH-induced Ca2+ response were no longer present. Conclusions: IL-4 and IL-13 induce bronchial hyperreactivity by changing the Ca2+ homeostasis of ASMC. These effects are counteracted by IL-13Rα2. The biological significance of IL-13Rα2 might be a protective function by regulating IL-13- and IL-4-mediated signal transduction and thereby limiting pathological alterations in Th2-mediated inflammatory diseases.

The present study aimed to investigate, whether short-term experimental exposure to high levels of welding fumes would be capable of exerting acute effects in healthy subjects. Specifically, we assessed cardiovascular function in terms of heart rate variability (HRV) as well as the concentrations of inflammatory mediators and hemostatic proteins in blood as outcome measures. Twenty subjects without a history of airway and cardiovascular diseases were exposed to either control air or welding fume for 1 h on 2 separate days under standardized conditions. The median concentration of the alveolar particle fraction during welding was 3.5 mg/m(3 )(quartiles: 1.4-6.3 mg/m(3); range 1.0-25.3 mg/m(3)). Five hours later a panel of clinical assessments was performed, including HRV measurement and drawing of blood samples. There were no changes in symptom ratings or lung function after welding fume exposure. Exposures did also not differ regarding effects on time- and frequency-domain parameters of HRV. Similarly, blood leukocyte numbers, cell differentials and the blood levels of fibrinogen, C-reactive protein, antithrombin III, factor VIII, von Willebrand factor, ristocetin cofactor, sICAM-1, tumor necrosis factor alpha, interleukin 6, interleukin 8 and epithelial neutrophil activating peptide 78 were not altered by welding fume inhalation. However, there was a significant fall in the level of endothelin-1 (P0.01). In conclusion, the data did not indicate effects of clinical significance of a short-term high-level exposure to welding fumes on HRV or a set of blood hemostatic and acute inflammatory parameters in healthy subjects. The small but statistically significant effect on endothelin levels demonstrated that measurable effects could be elicited even in these individuals. Overall, welding fumes are not likely to exert acute cardiovascular effects in healthy individuals.

Hypertonic saline aerosol can elicit airway obstruction in patients with moderate or severe COPD. In the present study we assessed whether cetirizine dihydrochloride is capable of modulating this response. After a screening visit, 20 patients with COPD (mean FEV(1) 49% pred) were treated with cetirizine 10mg daily or placebo over 1 week in a randomized, double-blind, cross-over fashion and measurements performed at the end of treatment periods. At each visit, patients were challenged by 3% saline aerosol (screening: 0.9%) over 5 min after prior inhalation of salbutamol, and 45 min later sputum was obtained after inhalation of 0.9% saline. Lung function was quantified in terms of forced expiratory (FEV(1)) and inspiratory (FIV(1)) volumes. Spirometric values did not differ between visits and salbutamol-induced bronchodilation was not altered by cetirizine. Compared to baseline or post-salbutamol values, the saline-induced fall in FEV(1) was smallest at screening (P

This study aimed to test the utility of the ozone challenge model for profiling novel compounds designed to reduce airway inflammation. The authors used a randomized, double-dummy, double-blind, placebo-controlled 3-period crossover design alternating single orally inhaled doses of fluticasone propionate (inhaled corticosteroids, 2 mg), oral prednisolone (oral corticosteroids, 50 mg), or matched placebo. At a 2-week interval, 18 healthy ozone responders (>10% increase in sputum neutrophils) underwent a 3-hour ozone (250 ppb)/intermittent exercise challenge starting 1 hour after drug treatment. Airway inflammation was assessed at 2 hours (breath condensate) and 3 hours (induced sputum) after ozone challenge. Compared to placebo, pretreatment with inhaled corticosteroids or oral corticosteroids resulted in a significant reduction (mean [95% confidence interval]) of sputum neutrophils by 62% (35%, 77%) and 64% (39%, 79%) and of sputum supernatant myeloperoxidase by 55% (41%, 66%) and 42% (25%, 56%), respectively. The authors conclude that an optimized ozone challenge model (including ozone responders and ensuring adequate drug levels during exposure) may be useful for testing novel anti-inflammatory compounds in early development.

In Deutschland haben Rehabilitations- und Trainingsprogramme zur klinischen und funktionellen Verbesserung von Patienten mit chronisch-obstruktiven Atemwegserkrankungen eine lange Tradition. Dies gilt insbesondere fur stationare Programme. Aufbauend auf Erfahrungen des Auslandes wird jedoch inzwischen ambulanten oder hauslichen Programmen zunehmend Beachtung geschenkt. Ein zentraler Bestandteil der Programme ist korperliches Training. Dahinter steht die Erwartung, mit relativ geringem Aufwand den klinischen Zustand, sowie Lebensqualitat, Krankheitsverlauf und Prognose des Patienten verbessern zu konnen. Erste Erfahrungen liegen - neben dem Asthma bronchiale - insbesondere bei der COPD vor. Die Daten legen nahe, dass korperliches Training die Exazerbationsraten senken kann und dieser Effekt mit minimalem Betreuungsaufwand erreichbar ist. Vordringliches Ziel kunftiger Untersuchungen scheint daher die Entwicklung und Evaluierung praxisnaher, minimal aufwendiger Trainingsprogramme. Inwieweit diese Programme auf andere Lungenerkrankungen ubertragbar sind, sollte ebenfalls gepruft werden. In Germany there is a long tradition of rehabilitation and exercise training programs to improve the clinical state and physical function of patients with chronic obstructive pulmonary diseases. This is particularly true regarding inpatient rehabilitation. Based on experiences gained in other countries, outpatient and home-based programs are currently getting more attention. One of the key components of pulmonary rehabilitation is exercise training which can be expected to exert direct and indirect beneficial effects on physical performance, health-related quality of life and even the progress of the disease. Most of the available experience refers to patients with COPD - besides those with bronchial asthma. The data available so far suggest that exercise training programs can reduce exacerbation rates and that this effect is achievable by minimal personal assistance. Thus the most important aim of future studies seems to be the development and evaluation of training programs which are efficient but also easy to implement and minimally expensive. Furthermore it needs to be studied whether such programs can be transferred to pulmonary disorders other than obstructive airway diseases.

Emphysema is characterised by a loss of alveolar structure, as reflected in elastic recoil and gas exchange. As fibroblasts play a key role in the maintenance of structure, the current authors hypothesised that their proliferation might be constitutively impaired in lung emphysema. Using explant cultures, lung fibroblasts were obtained from resected lungs of 10 patients with emphysema (median forced expiratory volume in one second (FEV1) 40% predicted) and 10 control patients (FEV1, 95% pred). The doubling time (DT) was measured over 4 days under standard conditions (10% foetal calf serum) prior and after cryopreservation. Additionally, in seven samples per group the total population doubling level (PDL) was determined. In emphysema, mean+/-sem DT was 33.6+/-2.8 h compared with 24.8+/-1.4 h in controls. The differences in DT were preserved after cryopreservation. Groups also differed in the initial slope of the PDL plot during long-term culture (up to 35 days). However, the median (range) maximum PDL did not differ significantly between groups (13.8 (7.4-22.6) versus 20.2 (11.2-25.5)). The current authors, therefore, suggest that the reduced proliferation rate in vitro of lung fibroblasts from patients with emphysema reflects a persistent, intrinsic failure of cellular replacement and maintenance in this disease, possibly in relation to pre-term aging.

Whether leukotriene receptor antagonists exhibit adequate anti-inflammatory effects in the treatment of asthma is still a controversial issue. The aim of the present study was to perform a direct comparison of the effects of a 4-week treatment with either montelukast (10 mg, once a day) or low-dose inhaled fluticasone (100 microg b.i.d.) on functional and inflammatory parameters in steroid-naïve patients with moderate asthma. Forty patients (forced expiratory volume in one second (FEV1), 60-80% predicted) were studied in a double-blind, randomised, crossover design. Treatment periods were separated by 3-8 weeks of washout. At the beginning and end of each period, FEV1, airway responsiveness to inhaled methacholine (provocative concentration causing a 20% fall in FEV1 (PC20)), the level of exhaled nitric oxide (NO) and sputum differential cell counts were determined. Only short-acting beta2-agonists were allowed for relief of symptoms. FEV1 increased by 0.50+/-0.07 L (mean+/-SEM) after fluticasone and by 0.37+/-0.07 L after montelukast (p0.001, each), and PC20 by 1.33+/-0.13 (p0.001) and 0.15+/-0.17 (NS) doubling doses, respectively. Correspondingly, percentages of sputum eosinophils were reduced by factor 2.7 (p0.01) and 1.4 (nonsignificant (NS)), and the levels of exhaled NO (at 50 mL x s(-1)) by factor 2.1 (p0.01) and 1.1 (NS). These data indicate a comparable bronchodilator action of montelukast and fluticasone in patients with moderate asthma, but additional attenuation of airway inflammation by fluticasone as detectable through noninvasive methods.

Objective The effects of passive smoke exposure on respiratory health are still under debate. Therefore, we examined the risk of respiratory symptoms related to passive smoke exposure among German adults within the European Community Respiratory Health Survey. Methods The questionnaire data of the population-based sample (n = 1,890) were analyzed. Multiple logistic regression models were carried out for current asthma (asthma symptoms or medication), chronic bronchitis (cough with phlegm for ≥ 3 months per year), and wheezing as dependent variables, and self-reported exposure to passive smoke at home and at the workplace as independent variables after adjusting for city, age, gender, active smoking, and socioeconomic status as well as occupational exposure to dusts and/or gases. Results The relative odds for chronic bronchitis were significantly higher in subjects reporting involuntary tobacco smoke exposure in the workplace (odds ratio [OR], 1.90; 95% confidence interval [CI], 1.16 to 3.11). Likewise, the adjusted OR for asthma was slightly elevated (OR, 1.51; 95% CI, 0.99 to 2.32). The risk of chronic bronchitis (OR, 3.07; 95% CI, 1.56 to 6.06), asthma (OR, 2.06; 95% CI, 1.07 to 3.97), and wheezing (OR, 2.12; 95% CI, 1.25 to 3.58) increased significantly with a daily exposure of > 8 h. Conclusion The control of passive smoke exposure in the workplace might reduce the risk of respiratory symptoms independently of exposure to other airborne contaminants.

Although hyperlipidemia is common in COPD, its relationship to comorbidities, risk factors and lung function in COPD has not been studied in detail. Using the baseline data of the COSYCONET cohort we addressed this question. Data from 1746 COPD patients (GOLD stage 1-4; mean age 64.6 y, mean FEV1%pred 57%) were evaluated, focusing on the comorbidities hyperlipidemia, diabetes and cardiovascular complex (CVC; including arterial hypertension, cardiac failure, ischemic heart disease). Risk factors comprised age, gender, BMI, and packyears of smoking. The results of linear and logistic regression analyses were implemented into a path analysis model describing the multiple relationships between parameters. Hyperlipidemia (prevalence 42.9%) was associated with lower intrathoracic gas volume (ITGV) and higher forced expiratory volume in 1 second (FEV1) when adjusting for its multiple relationships to risk factors and other comorbidities. These findings were robust in various statistical analyses. The associations between comorbidities and risk factors were in accordance with previous findings, thereby underlining the validity of our data. In conclusion, hyperlipidemia was associated with less hyperinflation and airway obstruction in patients with COPD. This surprising result might be due to different COPD phenotypes in these patients or potential anti-inflammatory effects of hyperlipidemia-related medication.

Background E-cigarettes are coming into wider use. They are advertised as an aid to smoking cessation, but there is concern that they may also serve as a gateway drug for cigarette smoking. Method The authors systematically searched the PubMed database for relevant publications on the mechanism of action of e-cigarettes, the nature of their emissions, their assessment by potential users, their efficacy in smoking cessation, and their potential for addiction. Results There have been many reports of epidemiologically uninformative case series in which smokers were helped to stop smoking by the use of e- cigarettes. Only two controlled trials have shown that e-cigarettes have approximately the same effect as nicotine substitution therapy when used as an aid to smoking cessation. The effect is nearly independent of nicotine content. E-cigarettes are also consumed, to a small extent, by nonsmokers. As far as can be estimated toxicologically at present, the danger to active and passive smokers of e-cigarettes is presumably orders of magnitude less than that of tobacco smokers, although the variable composition of the fluids used in e-cigarettes introduces a degree of uncertainty. Conclusion Preclinical and initial clinical data, including some data from randomized controlled trials, indicate that e-cigarettes may be useful as an aid to smoking cessation or as a means of lowering risk in high-risk groups. In contrast to the demonstrated efficacy of multimodal smoking-cessation programs with pharmacological and psychotherapeutic support, the efficacy of e-cigarettes in smoking cessation has not yet been satisfactorily shown. Valid and informative clinical trials are urgently needed. These should also be designed to determine what predisposition(s), if any, might make the use of e-cigarettes more or less successful than that of other aids to smoking cessation. Moreover, e-cigarettes might be a gateway drug for cigarette smoking; thus, no clear recommendation about their use can be made at present.

Hintergrund: Flugpersonal kann in regularer Flughohe in Maschinen ohne Ozonkonverter intermittierend Ozonkonzentrationen bis ca. 0,25 ppm ausgesetzt sein. Eine Analyse moglicher adverser Effekte insbesondere auf die Lungenfunktion steht aus; hierbei scheint eine verlasliche Abschatzung nur anhand experimenteller Daten moglich. Fragestellung: Kann mittels einer Meta-Analyse der Lungenfunktionsdaten in experimentellen Ozon-Studien ein Dosis-Wirkungs-Modell entwickelt werden, mit dem erwartbare akute Effekte bei realistischen Expositionsszenarien abgeschatzt werden konnen? Methoden: Gemas Systematic Review/Meta-Analyse wurden publizierte Studien mit experimentellen Expositionen von Probanden gesucht. Diese wurden entsprechend der Qualitat der Angaben zu Exposition, Ventilation, FEV1 und FVC in eine zentrale Gruppe 0 („Kern“) sowie in weitere 7 Gruppen („Schalen“) kategorisiert. Die Ergebnisse in der Kerngruppe wurden mittels der anderen Gruppen per Sensitivitatsanalyse auf Anderungen uberpruft. Ergebnisse: 223 Studien mit 4356 Expositionen wurden identifiziert (Gruppe 0: n = 16). Standard- und Meta-Regressionsanalysen ergaben die Ozonkonzentration als starksten und die Ventilation pro Korperoberflache (BSA) als zweitstarksten Pradiktor; daher galt die Dosisleistung (Konzentration*Ventilation) als Hauptpradiktor. Wurden verschiedene Gleichungen fur Ventilationsraten von 5 und 10 L/min/BSA auf die erwartbaren Ozonprofile angewandt, lagen die nach den Modellen erwartbaren Anderungen von FEV1 und FVC i.d.R. bei 1 – 2% und unter 5%, also im Bereich der Messvariabilitat. Fur Symptome und zellulare Effekte war nur eine qualitative Beschreibung moglich. Schlussfolgerung: Der systematische Literaturreview zu den Effekten von Ozon auf die Lungenfunktion erlaubte es, Anderungen von FEV1 und FVC in Abhangigkeit von zu erwartenden Ozonexpositionen abzuschatzen. Dies ist von Bedeutung fur die evidenzgestutzte Gefahrdungsbeurteilung fur Flugpersonal. Unterstutzt von Lufthansa Cargo AG

The present study aimed at delineating the mechanisms underlying the adverse response to hypertonic saline inhalation in patients with chronic obstructive pulmonary disease (COPD). Twenty patients (age, 48-70 yr; FEV(1), 29-58 %pred) inhaled, on two different days in randomized order, 200 microg salbutamol from an MDI and 20 min later either 0.9% or 3% saline from an ultrasonic nebulizer for a maximum of four consecutive 5-min periods. Forced expiratory (FEV(1)) and inspiratory (FIV(1)) volumes, inspiratory capacity (IC), intrathoracic gas volume (ITGV), and specific airway resistance (SRaw) were measured. Significant changes occurred in FEV(1), FIV(1), IC, ITGV, and SRaw with both concentrations (p < 0.05, each) and effects were stronger with 3% as compared with 0.9% saline (p < 0.05, each). The increase in dyspnea was associated with the changes in FIV(1), FEV(1), IC, and ITGV, in contrast to its decrease during bronchodilation, where only FIV(1) was important. Sputum analysis showed elevated concentrations of histamine after 3% as compared with 0.9% saline. These data indicate that the adverse lung function response to hypertonic saline is common in patients with moderate to severe COPD, involves both bronchoconstriction and lung hyperinflation, and could be mediated, at least partially, through activation of mast cells.

As known from studies in animal and human subjects, ozone can exert effects on the immune response including allergic sensitisation and allergen responsiveness. The objective of the present study was to assess the changes in lymphocyte subsets in bronchoalveolar lavage fluid (BALF) after single and repeated ozone exposures. Twenty-three healthy subjects underwent single exposures to 200 ppb ozone or filtered air (FA), as well as repeated exposures to 200 ppb ozone on four consecutive days, each during 4 h of intermittent exercise. Bronchoalveolar lavage was performed 20 h after the single exposure or the last of the repeated exposures. Lymphocytes were identified by sideward scatter and CD45 expression, and their subsets by eight different panels of antibodies. Checksums were calculated to assess the validity of the results. The percentage and the absolute number of lymphocytes, mostly comprising T-lymphocytes (CD2+; overall mean 98.8%), increased after single (P < 0.05; each), but not after repeated ozone exposure, compared with FA (7.4 vs 5.8 vs 6.5%; 680 vs 419 vs 301 × 103). In addition, we observed small but statistically significant changes in the proportions of lymphocyte subpopulations. The percentage of CD4+ lymphocytes increased after single (P < 0.05) and repeated ozone exposure (P < 0.01), whereas the percentage of CD8+ cells decreased after repeated exposure (P < 0.05). The proportion of activated lymphocytes (CD25+) was elevated after repeated, compared with single, ozone exposure (P < 0.01), and the percentages of natural killer (NK) cells were decreased after both single (P < 0.05) and repeated (P < 0.01) exposures. Our data suggest that single but not repeated ozone exposures cause a change in absolute numbers of lymphocytes in BALF, whereas the proportions of lymphocyte subsets are affected by single as well as repeated exposures.

Hydrogen peroxide (H2O2) is known to be detectable in exhaled air. The present study aimed to determine whether the concentration of exhaled H2O2 depends on expiratory flow rate in order to make inferences on the site of its production within the lung. Breath condensate was collected in cooled Teflon tubes, at three different expiratorv flow rates, in 15 healthy or mild asthmatic subjects. Tests were repeated 2-5 times to assess reproducibility. Mean+/-SEM concentrations of H2O2 at flow rates of 140, 69 and 48 mL.s(-1) were 0.12+/-0.02, 0.19+/-0.02 and 0.32+/-0.03 microM, respectively. These values differed significantly from each other (p0.001). For comparison, average coefficients of variability within repeated measurements at each of the three flow rates were 68, 62 and 82%, respectively. These data demonstrate that the concentration of exhaled hydrogen peroxide depends on expiratory flow rate. Since flow dependence is an indicator of production within the airways, this result suggests that, to a large extent, the exhaled hydrogen peroxide originates within the airways. However, even under strictly controlled conditions, a high degree of variability persists, which may limit the usefulness of exhaled hydrogen peroxide as a marker of airway inflammation.

Previous studies have shown higher prevalences of bronchial hyperresponsiveness (BHR), respiratory symptoms and atopic sensitization among adults in Western Germany than in Eastern Germany. One of the aims of the joint project INGA (INdoor Factors and Genetics in Asthma) is to assess incidence, prevalence and trends for asthma, BHR and atopic diseases over a time period of 11 years (1990–2001) in the former West (Hamburg) and East Germany (Erfurt), with special reference to indoor exposure.INGA was designed as a case-control study following a cross-sectional study performed from 1990 to 1992 within the European Community Respiratory Health Survey (ECRHS). The database consisted of 1159 subjects in Hamburg and 731 subjects in Erfurt from the ECRHS (age 20–44). In 1995–1996, 107 cases (diagnosed asthma, positive specific serum IgE, positive skin prick or PD20FEV1≤2·0 mg methacholine at ECRHS) and 106 controls (none of the previous findings) participated in Hamburg (115 cases and 109 controls in Erfurt). The methodology was identical to the ECRHS and dose–response slopes (DRS) of the methacholine challenge were calculated as an index of responsiveness.In the control group, median values of DRS were 0·028% mg−1(1990–1992) and 0·044 (1995–1996) (P

The objectives of the study were to assess the magnitude of the effect of the leukotriene receptor antagonist, zafirlukast, against cold air-induced bronchoconstriction following the first dose and to assess magnitude and duration after 5 days of dosing. Nineteen patients with asthma were included. In a randomized cross-over design, either zafirlukast 20 mg or 80 mg b.d. or placebo were given over 5 days. Challenges were performed 3 h post first dose and 3, 8, 12 and 24 h post last dose. The authors assessed the provocative ventilation rate necessary to achieve a 10% (PV10) and 20% (PV20) fall in forced expiratory volume in one second. The median PV20 3 h post first dose was 69.1 L x min-1 for zafirlukast 80 mg compared to 40 L x min-1 for placebo (p=0.004). The corresponding median value for zafirlukast 20 mg was 59.9 L x min-1 (p=0.06). At steady state the differences in PV20, between zafirlukast 80 mg and placebo were significant at 8 h and 12 h post last dose. The corresponding difference for zafirlukast 20 mg was statistically significant at 8 h post last dose. The analysis of PV10 yielded compatible results. There was no significant protection 24 h after last dose. This study has demonstrated that zafirlukast offers significant protection against cold air-induced bronchoconstriction in asthma. The degree and duration of protection were dose-dependent. However, there was a large interindividual variability for the protective effect of this leukotriene receptor antagonist.

We studied the role of base excess (BE) as marker of chronic hypercapnia and survival in patients with chronic obstructive pulmonary disease (COPD) and chronic hypercapnic respiratory failure (CHRF). Moreover, it was investigated whether the effects of non-invasive positive pressure ventilation (NPPV) on CHRF were reflected in BE and survival. In 240 (160 without exacerbation) patients with COPD (mean±SD FEV1 30.7±9.7 %pred; PaCO2 56.9±9.9 mmHg) body-mass index (BMI), lung function, respiratory muscle function, blood gases and 6-minute walking distance (6-MWD) were assessed prior to initiation of NPPV. In addition, the changes of risk factors 6.3±2.9 months after initiation of NPPV were evaluated. Overall mortality during the follow-up time (26.0±24.5 months) was 34.6%. Deaths resulted predominantly from respiratory causes (65.1%); among those, respiratory failure was most frequent (85.2%). Univariate analysis revealed BMI, FEV1, maximal inspiratory pressure (PImax), inspiratory load (P0.1), haemoglobin, 6-MWD, hyperinflation (IC/TLC, RV/TLC), blood gases and BE to be associated (p

The aim of this study was to investigate the effect of environmental tobacco smoke (ETS) exposure in the evening on inflammatory changes in bronchoalveolar (BAL) and nasal lavage (NAL) fluid.Ten subjects with mild asthma [mean (+/- SD) age, 25 +/- 2 years, FEV1% pred., 93 +/- 6%, PC20FEV1 0.44 x 5.11 mg/ml methacholine] were exposed to ETS (22.4 +/- 1.2 ppm CO) or ambient air (sham) for 3 h (7.00 to 10.00 p.m). Bronchoscopy was performed the following morning at 7.00 a.m. A visual endoscopic score was assessed, and BAL fluids were analyzed for cellular composition and concentrations of histamine, albumin, eosinophilic cationic protein, myeloperoxidase, hyaluronic acid, tryptase, prostanoids and leukotrienes. Nasal lavages were performed 30 min prior to and 30 min after exposures, and NAL fluids were analyzed for histamine, albumin, eosinophilic cationic protein, myeloperoxidase, hyaluronic acid, and tryptase.There was a significant rise in symptoms after ETS exposure compared with sham (P0.05). Spirometric lung function did not change during or after exposure compared with pre-session values. Visual bronchoscopic scoring revealed no significant effect of ETS exposure, nor did BAL cells and mediators or NAL mediators as compared with pre-challenge or post-sham values.In the subjects tested, a 3-h ETS exposure in the evening appeared not to have an inflammatory effect detectable in BAL or NAL fluid.

Background The purpose of this study was to develop a rapid and safe methacholine provocation protocol equivalent to the standard dosimeter technique. Methods The rapid protocol comprised a short and a long subprotocol. The challenge was started with one of these subprotocols according to the subject's answers to a questionnaire and baseline lung function. If FEV 1 dropped by 10% during the short subprotocol, the test was continued with the long subprotocol. The concentrations of methacholine and numbers of inhalations were chosen to match the concentrations of the standard method as closely as possible. To verify the protocol, we compared both methods in 38 subjects with asthma and 10 control subjects. Results The provocative concentrations of methacholine (PC 20 FEV 1 ) obtained with the standard method and the rapid method were within one doubling concentration in 38 of 40 subjects. None of the subjects who were normoreactive according to the standard method (PC 20 FEV 1 > 8 mg/mL) responded in the rapid protocol. The standard method required, on average (±SD), 34±11 min; the rapid method required 15 ±3 min. Conclusions The rapid provocation protocol is equivalent to the standard method, without loss in precision and safety, but with considerable saving in time. Therefore, it appears to be particularly suited for studies that require comparability with provocative concentrations obtained with the Rosenthal-Chai dosimeter method.

COPD is a multi-component disease that is not sufficiently reflected by FEV1 alone. We studied in patients with very severe COPD, which dimensions of the disease, including co-morbidities, dominate prognosis.In patients with FEV130% predicted, anthropometric, laboratory, spirometric and body plethysmographic data, smoking status, alcohol consumption, the level of dyspnoea and exercise performance were assessed. Co-morbidities were categorized by the Charlson-index and the COPD-specific co-morbidity test (COTE). The prognostic value of multiple dimensions was explored using uni- and multivariate survival analyses regarding death from any or respiratory cause.Among 209 patients included (58/151 female/male; FEV1 25.0 (22.0-26.9)%predicted), arterial hypertension (54.1%), hyperlipidemia (38.3%) and diabetes (19.6%) were most common, 57.9% showing a COTE-index of ≥ 1 point. During follow-up (28 (14-45) months), 121 patients had died, mostly (56.2%) due to respiratory causes. Age, BMI, the ratio of residual volume to total lung capacity (RV/TLC), co-morbidities in terms of the COTE- and Charlson-index, but not FEV1, were significantly associated with all-cause and respiratory mortality. The association of the median values of the Charlson- (HR 1.911 [95%-CI 1.338-2.730]) and COTE-index (HR 1.852 [95%-CI 1.297-2.644], p0.001 each) with mortality was similar and stronger when combined with age. In multivariate analyses, only RV/TLC and co-morbidities were independent risk factors of all-cause mortality (p0.05 each).In very severe COPD, resting hyperinflation and co-morbidities provide the major prognostic information, whereas the association of the recently introduced COTE-index with mortality was similar to that of the established Charlson-index and even stronger when including age.

Summary Objectives To compare the prognostic value of FENO with bronchoprovocation testing when the clinical course within the first year after assessment was taken into account; to compare the prognostic values with respect to eosinophilic versus non-eosinophilic inflammatory pattern. Methods Cross-sectional diagnostic study with a delayed-type reference standard in 393 patients attending a private practice of pneumologists with complaints suspicious of obstructive airway disease. Index test: FENO measurement. Reference standard: ratio FEV 1 /VC or airway resistance assessed by body plethysmography, with additional bronchoprovocation or bronchodilator testing, as well as spontaneous sputum (smear slides). This was combined with a follow-up evaluation by a structured interview after 12 months. Results 302 (76.8%) patients were reached for follow-up. Regarding asthma diagnosis, the area under the curve (AUC) for FENO was 0.603 (95%CI 0.528–0.677) for the whole group. With eosinophilic asthma as target, AUC increased (0.819 (95%CI 0.703–0.934)) and exceeded that of bronchoprovocation (0.711 (95%CI 0.584–0.874)). FENO showed no diagnostic value in non-eosinophilic asthma. In patients reporting wheezing and allergic rhinitis at the initial assessment, its positive predictive value was 90.9% (95%CI 62.3%–98.4) at a cut-off of 45 ppb, and 100% (95%CI 56.6–100%) at 81 ppb. Conclusions FENO bears limited information when measured non-specifically in primary care, but is useful for diagnosing eosinophilic asthma. If sputum is not available, information on wheezing and rhinitis can narrow down the range of patients in whom FENO is informative. Moreover, the evaluation of the clinical value of FENO benefits from taking into account follow-up data to confirm the diagnosis.

Summary Background Anaemia is a frequent, clinically relevant condition in various chronic diseases. It seems also to be prevalent in patients with chronic respiratory failure (CRF). We studied the characteristics of anaemia in CRF and its associations with clinical outcome. Methods In a prospective design, 271 consecutive patients with CRF were evaluated; patients with other conditions often associated with anaemia were excluded. Haematological laboratory and physiological parameters, health-related quality of life (HRQL), dyspnoea and 48-month survival were determined. Anaemia was defined according to WHO [haemoglobin (Hb)