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Introduction: The standard of care (SoC) for unresectable stage III non-small-cell lung cancer (NSCLC) is durvalumab maintenance therapy after concurrent chemoradiation in patients with PD-L1 > 1%. However, the concurrent approach is only amenable for about one-third of patients due to co-morbidities. Although sequential regimens are usually not regarded as curative, these schedules applied in a dose-escalated manner may be similarly radical as SoC. As combining high-dose radiation and durvalumab remains a question of debate this retrospective bi-center study aims to evaluate pulmonary toxicity after high-dose chemoradiotherapy beyond 70 Gy compared to SoC. Patients and Methods: Patients with NSCLC stage III received durvalumab after either sequential high-dose chemoradiation or concomitant SoC. Chemotherapy consisted of platinum combined with either pemetrexed, taxotere, vinorelbine, or gemcitabine. The primary endpoint was short-term pulmonary toxicity occurring within six months after the end of radiotherapy (RT). Results: A total of 78 patients were eligible for this analysis. 18F-FDG-PET-CT, cranial MRT, and histological/cytological verification were mandatory in the diagnostic work-up. The high-dose and SoC group included 42/78 (53.8%) and 36/78 (46.2%) patients, respectively, which were matched according to baseline clinical variables. While the interval between the end of RT and the start of durvalumab was equal in both groups (p = 0.841), more courses were administered in the high-dose cohort (p = 0.031). Pulmonary toxicity was similar in both groups (p = 0.599), whereas intrathoracic disease control was better in the high-dose group (local control p = 0.081, regional control p = 0.184). Conclusion: The data of this hypothesis-generating study suggest that sequential high-dose chemoradiation followed by durvalumab might be similar to SoC in terms of pulmonary toxicity and potentially more effective with respect to intra-thoracic disease control. Larger trials with a prospective design are warranted to validate these results.

Bronchiectasis (BE) might be frequently present in COPD but masked by COPD symptoms. We studied the relationship of clinical signs of bronchiectasis to the presence and extent of its radiological signs in patients of different COPD severity. Visit 4 data (GOLD grades 1-4) of the COSYCONET cohort was used. Chest CT scans were evaluated for bronchiectasis in 6 lobes using a 3-point scale (0: absence, 1: ≤50%, 2: >50% BE-involvement for each lobe). 1176 patients were included (61%male, age 67.3y), among them 38 (3.2%) with reported physicians' diagnosis of bronchiectasis and 76 (6.5%) with alpha1-antitrypsin deficiency (AA1D). CT scans were obtained in 429 patients. Within this group, any signs of bronchiectasis were found in 46.6% of patients, whereby ≤50% BE occurred in 18.6% in ≤2 lobes, in 10.0% in 3-4 lobes, in 15.9% in 5-6 lobes; >50% bronchiectasis in at least 1 lobe was observed in 2.1%. Scores ≥4 correlated with an elevated ratio FRC/RV. The clinical diagnosis of bronchiectasis correlated with phlegm and cough and with radiological scores of at least 3, optimally ≥5. In COPD patients, clinical diagnosis and radiological signs of BE showed only weak correlations. Correlations became significant with increasing BE-severity implying radiological alterations in several lobes. This indicates the importance of reporting both presence and extent of bronchiectasis on CT. Further research is warranted to refine the criteria for CT scoring of bronchiectasis and to determine the relevance of radiologically but not clinically detectible bronchiectasis and their possible implications for therapy in COPD patients.

The COPD Assessment Test (CAT) is in widespread use for the evaluation of patients with chronic obstructive pulmonary disease (COPD). We assessed whether the CAT items carry additional information beyond the sum score regarding COPD characteristics including emphysema. Patients of GOLD grades 1 to 4 from the COPD cohort COSYCONET (German COPD and Systemic Consequences - Comorbidities Network) with complete CAT data were included (n = 2270), of whom 493 had chest CT evaluated for the presence of emphysema. Comorbidities and lung function were assessed following standardised procedures. Cross-sectional data analysis was based on multiple regression analysis of the single CAT items against a panel of comorbidities, lung function, or CT characteristics (qualitative score, 15th percentile of mean lung density), with age, BMI and gender as covariates. This was supported by exploratory factor analysis. Regarding the relationship to comorbidities and emphysema, there were marked differences between CAT items, especially items 1 and 2 versus 3 to 8. This grouping was basically confirmed by factor analysis. Items 4 and 5, and to a lower degree 1, 2 and 6, appeared to be informative regarding the presence of emphysema, whereas the total score was not or less informative. Regarding comorbidities, similar findings as for the total CAT score were obtained for the modified Medical Research Council scale (mMRC) which was also informative regarding emphysema. Our findings suggest that the usefulness of the CAT can be increased if evaluated on the basis of single items which may be indicating the presence of comorbidities and emphysema.

Physical exercise training is an evidence-based treatment in chronic obstructive pulmonary disease, and patients' peak work rate is associated with reduced chronic obstructive pulmonary disease mortality. We assessed whether supplemental oxygen during exercise training in nonhypoxemic patients with chronic obstructive pulmonary disease might lead to superior training outcomes, including improved peak work rate.This was a randomized, double-blind, controlled, crossover trial. Twenty-nine patients with chronic obstructive pulmonary disease (aged 63.5 ± 5.9 years; forced expiratory volume in 1 second percent predicted, 46.4 ± 8.6) completed 2 consecutive 6-week periods of endurance and strength training with progressive intensity, which was performed 3 times per week with supplemental oxygen or compressed medical air (flow via nasal cannula: 10 L/min). Each session of electrocardiography-controlled interval cycling lasted 31 minutes and consisted of a warm-up, 7 cycles of 1-minute intervals at 70% to 80% of peak work rate alternating with 2 minutes of active recovery, and final cooldown. Thereafter, patients completed 8 strength-training exercises of 1 set each with 8 to 15 repetitions to failure. Change in peak work rate was the primary study end point.The increase in peak work rate was more than twice as high when patients exercised with supplemental oxygen compared with medical air (0.16 ± 0.02 W/kg vs 0.07 ± 0.02 W/kg; P.001), which was consistent with all other secondary study end points related to exercise capacity. The impact of oxygen on peak work rate was 39.1% of the overall training effect, whereas it had no influence on strength gain (P.1 for all exercises).We report that supplemental oxygen in nonhypoxemic chronic obstructive pulmonary disease doubled the effect of endurance training but had no effect on strength gain.

Background: Short-term, indoor exposure to environmental tobacco smoke (ETS) is still highly prevalent; however, little is known about the acute lung response in adult asthma. Objectives: We investigated whether acute, experimental ETS exposure influences symptoms, lung function, and inflammatory parameters. Methods: Human subjects with asthma (n = 23) were exposed for 180 min to either room air or ETS at 250, 450, or 850 µg/m3. Respiratory symptoms, lung function, and exhaled nitric oxide (FeNO) were measured. Additionally, blood samples were analyzed for pro- and anti-inflammatory cytokines. Results: Humans with asthma demonstrate an increase in respiratory symptoms at all levels of ETS exposure, while the forced expiratory volume in 1 s (FEV1) and FeNO decrease with increasing ETS. The anti-inflammatory cytokine interleukin (IL)-10 increases at intermediate ETS concentrations, whereas tumor necrosis factor (TNF)-α and IL-8 increase only at the highest ETS concentration. Conclusion: Following 180 min of acute, experimental ETS exposure, we observed a significant increase in respiratory symptoms, a decrease in lung function, and an increase in inflammatory cytokines, indicating an acute lung response in asthma.

This study investigated whether different breathing conditions during exercise testing will influence measures of exercise capacity commonly used for training prescription in chronic obstructive pulmonary disease. Twenty-seven patients with chronic obstructive pulmonary disease (forced expiratory volume in 1 sec = 45.6 [9.4]%) performed three maximal exercise tests within 8 days, but at least 48 hrs apart. Subjects were thereby breathing either room air through a tightly fitting face mask like during any cardiopulmonary exercise test (MASK), room air without mask (No-MASK), or 10 l/min of oxygen via nasal cannula (No-MASK + O2). Cycling protocols were identical for all tests (start = 20 watts, increment = 10 males/5 females watts/min). Maximal work rate (90.4 [33.8], 100.3 [34.8], 107.4 [35.9] watts, P < 0.001) and blood lactate at exhaustion (4.3 [1.5], 5.2 [1.6], 5.0 [1.4] mmol/l, P < 0.001) were lowest for MASK when compared with No-MASK and No-MASK + O2, respectively, whereas maximal heart rate did not differ significantly. Submaximal exertion (Borg rating of perceived exertion = 12-14) was perceived at lower intensity (P = 0.008), but higher heart rate (P = 0.005) when MASK was compared with No-MASK and No-MASK + O2. Different breathing conditions during exercise testing resulted in an 18.8% difference in maximal work rate, likely causing underdosing or overdosing of exercise in chronic obstructive pulmonary disease. Face masks reduced whereas supplemental oxygen increased patients' exercise capacity. For accurate prescription of exercise in chronic obstructive pulmonary disease, breathing conditions during testing should closely match training conditions.

Chronic obstructive pulmonary disease prevalence rates are still high. However, the majority of subjects are not diagnosed. Strategies have to be implemented to overcome the problem of under-diagnosis. Questionnaires could be used to pre-select subjects for spirometry and thereby help reducing under-diagnosis. We report a brief, simple, self-administrable and validated chronic obstructive pulmonary disease questionnaire to increase the pre-test probability for chronic obstructive pulmonary disease diagnosis in subjects undergoing confirmatory spirometry. In 2005, we completed the Austrian Burden of Obstructive Lung Disease-study in 1258 subjects aged >40 years. Post-bronchodilator spirometry was performed, and non-reversible airflow limitation defined by FEV1/FVC ratio below the lower limit of normal. Questions from the Salzburg chronic obstructive pulmonary disease screening-questionnaire were selected using a logistic regression model, and risk scores were based on regression-coefficients. A training sub-sample (n = 800) was used to create the score, and a test sub-sample (n = 458) was used to test it. In 2008, an external validation study was done, using the same protocol in 775 patients from primary care. The Salzburg chronic obstructive pulmonary disease screening questionnaire was composed of items related to “breathing problems”, “wheeze”, “cough”, “limitation of physical activity”, and “smoking”. At the >=2 points cut-off of the Salzburg chronic obstructive pulmonary disease screening questionnaire, sensitivity was 69.1% [95%CI: 56.6%; 79.5%], specificity 60.0% [95%CI: 54.9%; 64.9%], the positive predictive value 23.2% [95%CI: 17.7%; 29.7%] and the negative predictive value 91.8% [95%CI: 87.5%; 95.7%] to detect post bronchodilator airflow limitation. The external validation study in primary care confirmed these findings. The Salzburg chronic obstructive pulmonary disease screening questionnaire was derived from the highly standardized Burden of Obstructive Lung Disease study. This validated and easy to use questionnaire can help to increase the efficiency of chronic obstructive pulmonary disease case-finding., Chronic obstructive pulmonary disease: Questionnaire for pre-screening potential sufferers Scientists in Austria have developed a brief, simple questionnaire to identify patients likely to have early-stage chronic lung disease. Chronic obstructive pulmonary disease (COPD) is notoriously difficult to diagnose, and the condition often causes irreversible lung damage before it is identified. Finding a simple, cost-effective method of pre-screening patients with suspected early-stage COPD could potentially improve treatment responses and limit the burden of extensive lung function (‘spirometry’) tests on health services. Gertraud Weiss at Paracelsus Medical University, Austria, and co-workers have developed and validated an easy-to-use, self-administered questionnaire that could prove effective for pre-screening patients. The team trialed the five-point Salzburg COPD-screening questionnaire on 1258 patients. Patients scoring 2 points or above on the questionnaire underwent spirometry tests. The questionnaire seems to provide a sensitive and cost-effective way of pre-selecting patients for spirometry referral.

Background Childhood exposure to a farm environment has been shown to protect against the development of inflammatory diseases, such as allergy, asthma, and inflammatory bowel disease. Objective We sought to investigate whether both exposure to microbes and exposure to structures of nonmicrobial origin, such as the sialic acid N-glycolylneuraminic acid (Neu5Gc), might play a significant role. Methods Exposure to Neu5Gc was evaluated by quantifying anti-Neu5Gc antibody levels in sera of children enrolled in 2 farm studies: the Prevention of Allergy Risk factors for Sensitization in Children Related to Farming and Anthroposophic Lifestyle (PARSIFAL) study (n = 299) and the Protection Against Allergy Study in Rural Environments (PASTURE) birth cohort (cord blood [n = 836], 1 year [n = 734], 4.5 years [n = 700], and 6 years [n = 728]), and we associated them with asthma and wheeze. The effect of Neu5Gc was examined in murine airway inflammation and colitis models, and the role of Neu5Gc in regulating immune activation was assessed based on helper T-cell and regulatory T-cell activation in mice. Results In children anti-Neu5Gc IgG levels correlated positively with living on a farm and increased peripheral blood forkhead box protein 3 expression and correlated inversely with wheezing and asthma in nonatopic subjects. Exposure to Neu5Gc in mice resulted in reduced airway hyperresponsiveness and inflammatory cell recruitment to the lung. Furthermore, Neu5Gc administration to mice reduced the severity of a colitis model. Mechanistically, we found that Neu5Gc exposure reduced IL-17+ T-cell numbers and supported differentiation of regulatory T cells. Conclusions In addition to microbial exposure, increased exposure to non–microbial-derived Neu5Gc might contribute to the protective effects associated with the farm environment., published version, peerReviewed

Background In recent years, studies have shown a protective effect of being raised in a farm environment on the development of hay fever and atopic sensitization. Inconsistent data on the relation of farming to asthma and wheeze have raised some doubt about a true protective effect. Objective We sought to study the differential effects of farm-associated exposures on specific asthma-related health outcomes. Methods The cross-sectional Prevention of Allergy Risk Factors for Sensitization in Children Related to Farming and Anthroposophic Lifestyle study included 8263 school-age children from rural areas in 5 European countries. Information on farm-related exposures and health outcomes was obtained by using questionnaires. In subsamples allergen-specific IgE and RNA expression of CD14 and Toll-like receptor genes were measured, and dust from children's mattresses was evaluated for microbial components. Results Inverse relations with a diagnosis of asthma were found for pig keeping (odds ratio [OR], 0.57; 95% CI, 0.38-0.86), farm milk consumption (OR, 0.77; 95% CI, 0.60-0.99), frequent stay in animal sheds (OR, 0.71; 95% CI, 0.54-0.95), child's involvement in haying (OR, 0.56; 95% CI, 0.38-0.81), and use of silage (OR, 0.55; 95% CI, 0.31-0.98; for nonatopic asthma) and in Germany for agriculture (OR, 0.34; 95% CI, 0.22-0.53). Protective factors were related with higher expression levels of genes of the innate immunity. Potential risk factors for asthma and wheeze were also identified in the farm milieu. Levels of endotoxin and extracellular polysaccharides were related to the health outcomes independently of the farm exposures. Conclusions The protective effect of being raised in a farm environment was ascribed to distinct exposures. Clinical implications The development of atopic sensitization and atopic and nonatopic asthma is most likely determined by different environmental factors, possibly reflecting distinct pathomechanisms.

The objective of our asthma management program is to optimize the disease management and the quality of life of children and adolescents with asthma. An improvement in coping with asthma should be achieved by teaching theoretical aspects and practical skills. The training is performed in small groups of children and adolescents of similar age, going for 10 sessions each lasting 90 minutes. Additionally, in 1999 and 2000, the program was also offered as a two-week workshop in the summer holidays. The goal of this study was the assessment of parental satisfaction with the outpatient asthma management program for children and adolescents. We developed a short questionnaire and assessed the following aspects: general parental satisfaction with the training, judgement of the children's knowledge about asthma, coping skills and recommendation of the training. All parents (n = 138) whose children/adolescents attended the training between 1999 and 2002 were invited to take part in this study. 106 parents (76.8%) returned the questionnaire. The results showed that most parents (95%) were highly satisfied with this asthma management program. They equally positively rated their children's coping skills (87% classified them as "much better") and their knowledge (96% rated it as "very good" resp. "good") about asthma after the training. Almost all parents (97%) recommended our program. The results were very helpful for planning the recently started, prospective case-control study on outcome evaluation of this program.

Background: Chronic obstructive pulmonary disease (COPD) is a major public health burden and profoundly affects individuals suffering from the disease. However, the majority of subjects with COPD are still undiagnosed. Objectives: To evaluate COPD prevalence and detection strategies for COPD in the primary-care setting. Methods: The study was conducted in a random sample of general practitioner (GP) offices in Salzburg (Austria). A questionnaire and post-bronchodilator (PBD) spirometry was administered to patients aged ≥40 years. Nonreversible airway obstruction was considered when PBD FEV1/FVC was Results: 60 GP offices were randomly selected for study participation, however only 30 (50.0%) were willing to participate. 1,230 of 9,820 (12.52%) patients consented to the protocol. Quality of PBD spirometry was evaluated, and 882 (71.7%) met ATS/ERS quality criteria. 7.5% (95% CI: 5.7-9.4%) of the patients had COPD grade II+ (FEV1/FVC 1 Conclusion: COPD in the primary-care setting is as prevalent and underdiagnosed as reported recently for the BOLD study. The surprisingly low participation rate of GPs and patients indicates that prevention of COPD is not a health priority, and that awareness for COPD has to heightened before case-finding strategies will be successful.