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New findings What is the central question of this study? The study aimed to establish a novel model to study the chronic obstructive pulmonary disease (COPD)-related cardiopulmonary effects of dynamic hyperinflation in healthy subjects. What is the main finding and its importance? A model of expiratory resistance breathing (ERB) was established in which dynamic hyperinflation was induced in healthy subjects, expressed both by lung volumes and intrathoracic pressures. ERB outperformed existing methods and represents an efficacious model to study cardiopulmonary mechanics of dynamic hyperinflation without potentially confounding factors as present in COPD. Abstract Dynamic hyperinflation (DH) determines symptoms and prognosis of chronic obstructive pulmonary disease (COPD). The induction of DH is used to study cardiopulmonary mechanics in healthy subjects without COPD-related confounders like inflammation, hypoxic vasoconstriction and rarefication of pulmonary vasculature. Metronome-paced tachypnoea (MPT) has proven effective in inducing DH in healthy subjects, but does not account for airflow limitation. We aimed to establish a novel model incorporating airflow limitation by combining tachypnoea with an expiratory airway stenosis. We investigated this expiratory resistance breathing (ERB) model in 14 healthy subjects using different stenosis diameters to assess a dose-response relationship. Via cross-over design, we compared ERB to MPT in a random sequence. DH was quantified by inspiratory capacity (IC, litres) and intrinsic positive end-expiratory pressure (PEEPi, cmH2 O). ERB induced a stepwise decreasing IC (means (95% CI): tidal breathing: 3.66 (3.45-3.88), ERB 3 mm: 3.33 (1.75-4.91), 2 mm: 2.05 (0.76-3.34), 1.5 mm: 0.73 (0.12-1.58) litres) and increasing PEEPi (tidal breathing: 0.70 (0.50-0.80), ERB 3 mm: 11.1 (7.0-15.2), 2 mm: 22.3 (17.1-27.6), 1.5 mm: 33.4 (3.40-63) cmH2 O). All three MPT patterns increased PEEPi, but to a far lesser extent than ERB. No adverse events during ERB were noted. In conclusion, ERB was proven to be a safe and efficacious model for the induction of DH and might be used for the investigation of cardiopulmonary interaction in healthy subjects.

Background COPD patients suffer from respiratory symptoms and limitations in daily life. We aimed to characterize the impact of disease on overall health, daily life, and perceived well-being in COPD outpatients. Methods We conducted a national, cross-sectional study among pulmonologists and general practitioners (GPs). The St. George's Respiratory Questionnaire for COPD patients (SGRQ-C) was used. Inclusion criteria were a physician's diagnosis of COPD and age ≥40 years. Subjects with a history of lung surgery, lung cancer or COPD exacerbation within the last four weeks were excluded. Results Sixty-seven pulmonologists and 6 GPs enrolled 1175 COPD patients. Two hundred forty-eight of those did not fulfill GOLD criteria for COPD (FEV1/FVC

The second-generation ALK tyrosine kinase inhibitor brigatinib has recently been approved in the European Union for use after crizotinib treatment in patients with EML4-ALK-rearranged lung cancer. In the current study, brigatinib was investigated as second-line or later-line treatment in 35 patients who had developed resistance to crizotinib, ceritinib, or alectinib. Most patients (68.6%) received brigatinib as second or third line (range: second to 12th line). In the total cohort, complete and partial responses were obtained for 9.1 and 75.8%, respectively. Overall median progression-free survival was 9.9 months, whereas the largest treatment cohort (brigatinib after crizotinib failure) showed a median progression-free survival of 8.4 months. Fifty-four percent of patients with baseline brain metastases responded to brigatinib treatment. Brigatinib was highly effective after crizotinib and ceritinib failure. Six patients had received alectinib as monotherapy, second-line, or third line before brigatinib; of these, four experienced partial responses and two progressed responses. Brigatinib treatment was well tolerated.

Background Serological tests are widely used in various medical disciplines for diagnostic and monitoring purposes. Unfortunately, the sensitivity and specificity of test systems is often poor, leaving room for false positive and false negative results. However, conventional methods used to increase specificity decrease sensitivity and vice versa. Using SARS-CoV-2 serology as an example, we propose here a novel testing strategy: the "Sensitivity Improved Two-Test" or "SIT2" algorithm. Methods SIT2 involves confirmatory re-testing of samples with results falling in a predefined retesting-zone of an initial screening test, with adjusted cut-offs to increase sensitivity. We verified and compared the performance of SIT2 to single tests and orthogonal testing (OTA) in an Austrian cohort (1,117 negative, 64 post-COVID positive samples) and validated the algorithm in an independent British cohort (976 negatives, 536 positives). Results The specificity of SIT2 was superior to single tests and non-inferior to OTA. The sensitivity was maintained or even improved using SIT2 when compared to single tests or OTA. SIT2 allowed correct identification of infected individuals even when a live virus neutralization assay could not detect antibodies. Compared to single testing or OTA, SIT2 significantly reduced total test errors to 0.46% (0.24-0.65) or 1.60% (0.94-2.38) at both 5% or 20% seroprevalence. Conclusion For SARS-CoV-2 serology, SIT2 proved to be the best diagnostic choice at both 5% and 20% seroprevalence in all tested scenarios. It is an easy to apply algorithm and can potentially be helpful for the serology of other infectious diseases.

Rationale: Metabolic syndrome (MetS), in particular increased central obesity is associated with cardiovascular events but also lung function (LF) impairment. The aim was to investigate whether LF impairment is associated with increased levels of visceral adipose tissue (VAT). Methods: Data was obtained from the Austrian LEAD Study, an observational, population-based cohort study. Adults aged 25-82 years with valid LF and metabolic data, including waist circumference (WC) for central obesity, and DXA Scans for VAT (n=9.157) were included in this analysis. LF was assessed by spirometry pre- and post-bronchodilation (BD). Abnormal LF was defined as FEV1 pre BD Results: Table 1 shows odds ratios of MetS components and VAT associated with impaired LF pattern. Increased VAT was associated with both, obstructive (OR 1.5 [1.3-1.8]) and restrictive (OR 2.4 [1.8-3.0]) LF pattern, while increased WC was not. Conclusion: VAT showed a consistent association with LF impairment independent of the type of impairment, in contrast to the different components of the MetS.

Background In the context of the COVID-19 pandemic, numerous new serological test systems for the detection of anti-SARS-CoV-2 antibodies rapidly have become available. However, the clinical performance of many of these is still insufficiently described. Therefore, we compared 3 commercial CE-marked, SARS-CoV-2 antibody assays side by side. Methods We included a total of 1154 specimens from pre-COVID-19 times and 65 samples from COVID-19 patients (≥14 days after symptom onset) to evaluate the test performance of SARS-CoV-2 serological assays by Abbott, Roche, and DiaSorin. Results All 3 assays presented with high specificities: 99.2% (98.6–99.7) for Abbott, 99.7% (99.2–100.0) for Roche, and 98.3% (97.3–98.9) for DiaSorin. In contrast to the manufacturers’ specifications, sensitivities only ranged from 83.1% to 89.2%. Although the 3 methods were in good agreement (Cohen’s Kappa 0.71–0.87), McNemar tests revealed significant differences between results obtained from Roche and DiaSorin. However, at low seroprevalences, the minor differences in specificity resulted in profound discrepancies of positive predictive values at 1% seroprevalence: 52.3% (36.2–67.9), 77.6% (52.8–91.5), and 32.6% (23.6–43.1) for Abbott, Roche, and DiaSorin, respectively. Conclusion We found diagnostically relevant differences in specificities for the anti-SARS-CoV-2 antibody assays by Abbott, Roche, and DiaSorin that have a significant impact on the positive predictive values of these tests.

There is growing interest in blood eosinophil counts in the management of chronic respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD). Despite this, typical blood eosinophil levels in the general population, and the impact of potential confounders on these levels have not been clearly defined.We measured blood eosinophil counts in a random sample of 11 042 subjects recruited from the general population in Austria. We then: 1) identified factors associated with high blood eosinophil counts (>75th percentile); and 2) excluded subjects with these factors to estimate median blood eosinophil counts in a “healthy” sub-population (n=3641).We found that: 1) in the entire cohort, age ≤18 years (OR 2.41), asthma (OR 2.05), current smoking (OR 1.72), positive skin prick test (OR 1.64), COPD (OR 1.56), metabolic syndrome (OR 1.41), male sex (OR 1.36) and obesity (OR 1.16) were significantly (pversus 100 (30–310) cells·µL−1, respectively) and did not change with age.Median blood eosinophil counts in adults are considerably lower than those currently regarded as normal, do not change with age beyond puberty, but are significantly influenced by a variety of factors which have an additive effect. These observations will contribute to the interpretation of blood eosinophil levels in clinical practice.

Background Based on biological and behavioural diversity sex and gender may affect comorbidities associated with prediabetes and diabetes. Besides evaluating the prevalence of prediabetes and diabetes (using fasting plasma glucose and HbA1(c) levels), the primary aim of the study is to investigate sex and gender differences in the prevalence of comorbidities in subjects with prediabetes and diabetes and to identify possible risk factors associated with prediabetes and diabetes.Design This observational, population-based cohort study included 11.014 subjects aged 6-80 years. Examinations included blood samples, ankle-brachial index, ECG, dual-energy X-ray absorptiometry scan and an interviewer-administered questionnaire.Results Across all ages, prevalence of prediabetes was 20.2% (male 23.6%; female 17.1%), and 5.4% for diabetes (male 7.3%; female 3.7%). The prevalence of prediabetes ranged from 4.4% (6

Background and objective Cardiovascular risk is substantially increased in patients with COPD and can be quantified via arterial stiffness. The PDE-IV inhibitor roflumilast revealed a potential reduction of COPD-related cardiovascular risk. We aimed to investigate the effects of roflumilast on arterial stiffness by quantification of pulse wave velocity (PWV) in stable COPD. Methods In this randomized placebo-controlled trial, 80 COPD patients received roflumilast or placebo for 24 weeks. The primary outcome was the change in cf-PWV. Secondary outcomes comprised markers of vascular function (e.g. Aix and RHI), systemic inflammation (e.g. IL-6 and TNF-α) and clinical characteristics of COPD (e.g. CAT and 6MWT). Results A total of 33 and 34 patients completed the roflumilast and placebo arm, respectively (age, median (IQR): 64.5 (61-69.5) vs 64.5 (56-72) years; FEV1 , median (IQR): 34.5 (25.5-48.6) vs 35.3 (27-46.8) % predicted; 6MWT, median (IQR): 428 (340-558) vs 456 (364-570) m). Change from baseline PWV did not show a significant difference between roflumilast and placebo (+5.0 (95% CI: -2.0 to +13.0) vs 0.0 (95% CI: -7.0 to +7.0)%, P = 0.268). Roflumilast did not improve markers of vascular function or systemic inflammation. We observed a significant improvement in change from baseline 6MWT with roflumilast versus placebo (+53.0 (95% CI: +19.1 to +86.9) vs -0.92 (95% CI: -35.1 to +33.3) m, P = 0.026). Conclusion Our study revealed no beneficial effects of roflumilast on arterial stiffness. Further studies are needed to test a potential improvement of exercise capacity with roflumilast in COPD.

Background Acquired epidermal growth factor receptor (EGFR) T790M mutation is the primary resistance mechanism to first-generation EGFR tyrosine kinase inhibitors (TKIs) used in advanced, EGFR mutation-positive non-small-cell lung cancer (NSCLC). Available data, predominantly in Asian patients, suggest that this mutation is also the major cause of resistance to the irreversible ErbB family blocker, afatinib. For EGFR T790M-positive patients who progress on EGFR TKI therapy, osimertinib is an effective treatment option. However, data on osimertinib use after afatinib are, to date, scarce. Objective To identify the prevalence of EGFR T790M mutations in predominantly Caucasian patients with stage IV EGFR mutation-positive NSCLC who progressed on afatinib, and to investigate the subsequent response to osimertinib. Patients and Methods In this single-center, retrospective analysis, EGFR T790M mutation status after afatinib failure was assessed using liquid biopsy and tissue rebiopsy. EGFR T790M-positive patients subsequently received osimertinib. Results Sixty-seven patients received afatinib in the first-, second-, or third-line (80.6%, 14.9%, and 4.5%, respectively). After afatinib failure, the T790M mutation was identified in 49 patients (73.1%). Liquid biopsy and tissue rebiopsy were concordant in 79.4% of cases. All patients with T790M-positive tumors received osimertinib (73.5% after first-line afatinib); 37 (75.5%) of these had an objective response (complete response: 22.4%; partial response: 53.1%). Response rate was independent of T790M copy number. Conclusion EGFR T790M mutation is a major mechanism of acquired resistance to afatinib. Osimertinib confers high response rates after afatinib failure in EGFR T790M-positive patients and its use in sequence potentially allows extended chemotherapy-free treatment.

Introduction Osimertinib is standard treatment for patients with advanced EGFR T790M-mutated non–small-cell lung cancer who have been pre-treated with EGFR–tyrosine kinase inhibitors (TKIs). We studied whether cell-free plasma DNA for T790M detection can be used to select patients for osimertinib treatment in the clinical routine. Methods From April 2015 to November 2016, we included 119 patients with advanced EGFR -mutated non–small-cell lung cancer who had progressed under treatment with an EGFR-TKI. The T790M mutation status was assessed in cell-free plasma DNA by droplet digital polymerase chain reaction in all patients and by tissue analyses in selected patients. Results T790M mutations were detected in 85 (93%) patients by analyses of cell-free plasma DNA and in 6 (7%) plasma-negative patients by tumor re-biopsy. Eighty-nine of 91 T790M-positive patients received osimertinib. Median progression-free survival (PFS) was 10.1 months (95% confidence interval [CI]: 8.1–12.1). Median survival was not reached and the 1-year survival was 64%. The response rate was 70% in T790M-positive patients (n = 91) in the intention-to-treat population. PFS trended to be shorter in patients with high T790M copy number (≥10 copies/mL) compared to those with low T790M copy number ( p = 0.09). A comparable trend was observed for overall survival (hazard ratio for overall survival = 2.16, 95% CI: 0.89–5.25, p = 0.09). No difference in response rate was observed based on T790M copy numbers. Conclusion Plasma genotyping using digital polymerase chain reaction is clinically useful for the selection of patients who had progressed during first-line EGFR-TKI therapy for treatment with osimertinib.

Lessons Learned Conventional medicine and homeopathy work well together. Quality of life improves with additive homeopathy in patients with non-small cell lung cancer (NSCLC). Survival improves with additive homeopathy in patients with NSCLC. Background Patients with advanced non-small cell lung cancer (NSCLC) have limited treatment options. Alongside conventional anticancer treatment, additive homeopathy might help to alleviate side effects of conventional therapy. The aim of the present study was to investigate whether additive homeopathy might influence quality of life (QoL) and survival in patients with NSCLC. Methods In this prospective, randomized, placebo-controlled, double-blind, three-arm, multicenter, phase III study, we evaluated the possible effects of additive homeopathic treatment compared with placebo in patients with stage IV NSCLC, with respect to QoL in the two randomized groups and survival time in all three groups. Treated patients visited the outpatients' centers every 9 weeks: 150 patients with stage IV NSCLC were included in the study; 98 received either individualized homeopathic remedies (n = 51) or placebo (n = 47) in a double-blinded fashion; and 52 control patients without any homeopathic treatment were observed for survival only. The constituents of the different homeopathic remedies were mainly of plant, mineral, or animal origin. The remedies were manufactured by stepwise dilution and succussion, thereby preparing stable Good Manufacturing Practice grade formulations. Results QoL as well as functional and symptom scales showed significant improvement in the homeopathy group when compared with placebo after 9 and 18 weeks of homeopathic treatment (p < .001). Median survival time was significantly longer in the homeopathy group (435 days) versus placebo (257 days; p = .010) as well as versus control (228 days; p < .001). Survival rate in the homeopathy group differed significantly from placebo (p = .020) and from control (p < .001). Conclusion QoL improved significantly in the homeopathy group compared with placebo. In addition, survival was significantly longer in the homeopathy group versus placebo and control. A higher QoL might have contributed to the prolonged survival. The study suggests that homeopathy positively influences not only QoL but also survival. Further studies including other tumor entities are warranted.

Matthias Helmut Urban,1 Philipp Eickhoff,2 Georg-Christian Funk,1 Otto Chris Burghuber,1 Michael Wolzt,3 Arschang Valipour1 1Department of Respiratory and Critical Care Medicine, Ludwig-Boltzmann Institute for COPD and Respiratory Epidemiology, Otto Wagner Hospital, Vienna, Austria; 2Department of Obstetrics and Gynecology, St. Josef Hospital, Vienna, Austria; 3Department of Clinical Pharmacology, Medical University Vienna, Vienna, Austria Background: Chronic obstructive pulmonary disease (COPD) is associated with an increased cardiovascular risk. However, the mechanisms for this association are yet unclear. The aim of this study was to investigate the relationship between brachial intima-media thickness (B-IMT), an independent predictor of cardiovascular risk, systemic inflammation, and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, in patients with COPD and respective controls. Methods: The study sample consisted of 60 patients with stable COPD, free from overt cardiovascular disorders, as well as 20 smoking and 20 nonsmoking controls. Ultrasound assessment of B-IMT, spirometry, venous blood sampling for quantification of inflammatory markers and ADMA levels were carried out, and individual cardiovascular risk was calculated via the Framingham risk score. Results: Patients with COPD showed significantly higher B-IMT compared to smoking (P=0.007) and nonsmoking controls (P=0.033). COPD patients with elevated B-IMT had a twofold increased calculated 10-year risk for cardiovascular events compared to those below the recommended cutoff (P=0.002). B-IMT was significantly associated with systemic inflammation (interleukin-6 [IL-6]; r=0.365, P=0.006) and ADMA (r=0.331, P=0.013) in COPD. Multivariate linear regression revealed male sex and ADMA as independent predictors of B-IMT in this study sample. Conclusion: B-IMT is significantly increased in patients with COPD and is associated with systemic inflammation and ADMA levels. Keywords: cardiovascular risk, chronic obstructive pulmonary disease, comorbidity, subclinical atherosclerosis, biomarker

In the setting of pseudo-progression in a cancer patient who receives immunotherapeutic treatment, discontinuation of therapy is recommended if the patient is symptomatic. Here, we present two patients with advanced adenocarcinoma of the lung who developed massive tumor growth after initiation of treatment with the anti-PD-1 antibody pembrolizumab. Even though clinical deterioration occurred in the form of severe dyspnea and weight loss, pembrolizumab therapy was continued, as the speed of tumor growth suggested pseudo-progression and the tumors showed marked PD-L1 expression. This approach was successful, and both patients experienced impressive treatment responses within a few weeks.

Background: Impaired left ventricular diastolic function is common in patients with chronic obstructive pulmonary disease (COPD). Among several potential mechanisms dynamic hyperinflation might affect left ventricular filling through mechanical constraint on the heart and right to left ventricular interaction. Aims: We aimed to investigate the isolated effects of induced dynamic hyperinflation on left ventricular filling in healthy males in order to exclude other potential mechanisms. Methods: In a randomized cross-over interventional study we induced dynamic hyperinflation by the novel method Expiratory Stenosis Breathing (ESB) combining tachypnea and expiratory stenosis in healthy males (n=14). Dynamic hyperinflation was verified by intrinsic positive end-expiratory pressure (PEEPi). The effects on diastolic filling were measured by echocardiographic assessment of E/A-ratio and E/e9-ratio. Results: During ESB peak A-velocity increased and E/A-ratio adjusted for heart rate 60/min decreased from 1,90 (1,66 to 2,14) during spontaneous breathing (SB) to 1,63 (1,49 to 1,77) during maximum ESB (p=0,009). Septal E/e9-ratio increased from 6,2 (5,7 to 6,8) during SB to 7,1 (6,2 to 8,0) during maximum ESB (p=0,023). Higher PEEPi was correlated with lower E/A-ratio (p=0,001). Conclusions: Dynamic hyperinflation altered left ventricular filling in healthy males through increases in late diastolic filling during atrial systole and left ventricular filling pressure. This could be the result of increased constraint on the heart by the hyperinflated lungs. Our observations underline the role of dynamic hyperinflation as a determinant of left ventricular filling in patients with COPD.

Chronic obstructive pulmonary disease (COPD) represents a major global health problem; however, there are no data regarding clinical phenotypes of these patients in Austria. This was an analysis from the Austrian cohort of the cross-sectional Phenotypes of COPD in Central and Eastern Europe (POPE) study, which was offered to patients with stable COPD in a real-life setting. Patients were recruited at 5 different outpatient facilities in 3 different provinces in Austria. All consecutive patients aged ≥40 years with a diagnosis of COPD confirmed by a post-bronchodilator forced expired volume in 1 s/forced vital capacity (FEV1/FVC) ratio

Background: COPD is associated with an excess atherosclerotic risk. Both, COPD and atherosclerosis are mediated by systemic inflammation. Roflumilast, as an anti-inflammatory drug, revealed potential atheroprotective effects in patients with COPD. Aims: To investigate the effects of Roflumilast on subclinical atherosclerosis (i.e. arterial stiffness, endothelial dysfunction) and a potential association with systemic inflammation in COPD. Methods: 80 COPD patients were randomized to receive Roflumilast or placebo for 24 weeks. Arterial stiffness was measured by pulse wave velocity (PWV) and augmentation index (AIx). Endothelial dysfunction was assessed via reactive hyperemia index (RHI), circulating levels of asymmetric dimethylarginine (ADMA) and matrix metalloproteinase-9 (MMP-9). Systemic inflammation was quantified by C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). Results: 67 patients completed the study, 33 of which received Roflumilast and 34 received placebo. The primary endpoint, change from baseline PWV, did not show a significant difference between Roflumilast and placebo (1.07 [95% CI 0.98 – 1.17] vs. 0.99 [95% CI 0.91 – 1.08], p = 0.214). Roflumilast did not improve AIx or markers of endothelial dysfunction (RHI, ADMA, MMP-9) and systemic inflammation (CRP, IL-6, TNF-alpha). We observed a significant improvement of 6-minute walking test with Roflumilast compared to placebo (59.2 [95% CI 18.3 – 100] vs. 0.69 [95% CI -39.7 – 42.1], p = 0.045). Conclusions: Our study does not support an atheroprotective effect of Roflumilast. However, there might be an improvement of exercise capacity with Roflumilast in patients with COPD.

Background Maintenance therapy (MT) with pemetrexed has been shown to improve overall and progression-free survival of patients with non-squamous non-small cell lung cancer (NSCLC), without impairing patients’ health-related quality of life (HRQOL) substantially. Comprehensive data on HRQOL under real-life conditions are necessary to enable informed decision-making. This study aims to (1) assess HRQOL during first-line chemotherapy and subsequent MT and (2) record patients’ and physicians’ reasons leading to clinical decisions on MT. Methods Patients treated for NSCLC at three Austrian medical centres were included. HRQOL was assessed at every chemotherapy cycle using the EORTC QLQ-C30/+LC13 questionnaire. Semi-structured interviews were conducted before MT initiation and at the time of discontinuation to evaluate patients’ and physicians’ reasons for treatment decisions. Longitudinal QOL analysis was based on linear mixed models. Results Sixty-one (73%) out of 84 patients were considered for MT. Thirty-six patients (43%) received MT and 29 (35%) discontinued therapy. Decisions on MT initiation (in 20 cases by the physician vs 4 by the patient) and discontinuation (19 vs 10) were mainly voiced by the physician. Treatment toxicity of first-line chemotherapy was the main reason for rejection of MT in patients with stable disease and was more often indicated by patients than clinicians. HRQOL data were collected from 83 patients at 422 assessment time points and indicated significantly lower symptom severity during MT compared with first-line therapy for nausea and vomiting (p = 0.006), sleep disturbances (p

Patients with chronic obstructive pulmonary disease (COPD) are at an increased cardiovascular risk; however, the underlying mechanisms for this relationship are ill defined. Altered glucose metabolism may increase cardiovascular risk via impaired endothelial function.We conducted a longitudinal pilot study to assess the interrelationship between systemic vascular function, glucose metabolism, and lung function in patients with COPD. Eighteen non-smoking patients with stable moderate-to-severe COPD [67 % male; median (first to third quartiles) Forced Expiratory Volume in 1 second (FEV1) % predicted: 38 % (28-55 %); body mass index: 26 kg/m(2) (24-28 kg/m(2))] free from cardiovascular risk factors were evaluated. Systemic vascular function was assessed by means of flow-mediated dilation technique of the brachial artery. Laboratory measurements included fasting blood glucose levels, circulating concentrations of insulin, C-reactive protein, and fibrinogen. Homeostatic model assessment of insulin resistance (HOMA-IR) was determined. Measurements were performed at baseline and were repeated after 12 months.Flow-mediated dilation significantly decreased from 13.5 % (11-15 %) at baseline to 9.8 % (6-12 %; p = 0.002) at the follow-up visit, whereas both fasting blood glucose concentrations and HOMA-IR increased from 94 mg/dl (86-103 mg/dl) to 102 mg/dl (94-111 mg/dl; p = 0.027) and from 1.2 (0.8-2.1) to 1.7 (1.2-3.0; p = 0.023), respectively. There was a significant relationship between changes in endothelial function and changes in fasting serum glucose (r = - 0.483, p = 0.009), HOMA-IR (r = - 0.441, p = 0.019), and FEV1 (r = 0.336, p = 0.05).Altered glucose metabolism may be associated with progression of endothelial dysfunction in patients with COPD.

In patients with non-small-cell lung cancer, the presence of brain metastases requires specific treatment due to the unfavourable overall impact of these lesions. Treatment with the tyrosine kinase inhibitor afatinib was shown to induce complete and long-lasting remissions in the five patients described here. All of them had multiple brain lesions and presented with symptoms. Study evidence suggests beneficial effects of afatinib in this respect, underlining these clinical observations. Afatinib might be incorporated into current treatment algorithms, allowing for the omission of radiotherapy, provided that larger phase III trials confirm the potential of epidermal growth factor receptor tyrosine kinase inhibitors in this respect.

Background Sleep problems associated with chronic obstructive pulmonary disease may have an important impact on quality of life and health outcome measures in patients. The aim of this study was to prospectively assess differences in symptom profile and polysomnographic parameters in patients with stable mild to moderate COPD and age, gender, and body-mass-index matched controls without airflow obstruction. Methods The Sleep Disorders Questionnaire was administered to both patients and controls prior to clinical and polysomnographic evaluation. Responses obtained from the questionnaire were used to construct four independent symptom scales: sleep apnea, periodic limb movement syndrome, psychiatric sleep disorder, and narcolepsy. Associations between each diagnostic scale and sleep parameters were considered by means of multiple analyses of covariance. Results Fifty-two patients with mild-to-moderate COPD (age 62 ± 8 years, BMI 29 ± 7 kg/sqm) and 52 age, gender, and body-weight matched controls without COPD were studied. Patients with COPD had overall lower sleep efficiency, a lower total sleep time, and lower mean overnight oxygen saturation compared to controls. Patients with COPD were significantly more likely to report symptoms such as insomnia and difficulty in initiating and maintaining sleep, resulting in overall higher psychiatric sleep disorder scale scores in patients compared with controls. Minimum oxygen saturation was an independent predictor for all symptom scales. After correcting for potentially confounding factors, including pack/years of smoking, total sleep time, sleep efficiency, arousal index, mean and minimum oxygen saturation, and apnea–hypopnea-index, the between group-differences for both the periodic limb movement and psychiatric sleep disorder scale scores remained statistically significant. Conclusions We observed significant differences in both quantity and quality of sleep between patients with stable mild to moderate chronic obstructive pulmonary disease and respective controls.

Summary Background In healthy elderly and adults, lower physical activity level in daily life has been associated with lower socio-economic level and non-Caucasian race. The objective of this study was to determine if this is also applicable in chronic obstructive pulmonary disease (COPD) by comparing physical activity levels in daily life in stable patients from two countries (Austria and Brazil) with different socio-economic and ethnic characteristics. Methods Physical activity in daily life was objectively assessed in 40 Austrian and 40 Brazilian COPD patients. Groups were matched for age, gender, body mass index, disease severity, smoking history, presence of concomitant heart disease, lung function, dyspnea and functional exercise capacity. In addition, climatic conditions were similar during the period of data collection in the two groups. Results In comparison to Brazilian patients, Austrian patients had a significantly lower walking time ( p =0.04), higher sitting time ( p =0.02) and lower movement intensity ( p =0.0001). The proportion of patients who did not reach an average of 30min of walking per day was 48% in the Austrian group and 23% in the Brazilian group. Conclusions Austrian patients with COPD showed a significantly lower daily physical activity level in comparison to matched Brazilian patients. Socio-economic and ethnic factors appear to influence stable COPD patients differently than described in previous studies including healthy subjects.

Impaired vascular reactivity is an important factor in the pathogenesis of cardiovascular disease.We sought to assess vascular reactivity in patients with chronic obstructive pulmonary disease (COPD) and respective control subjects, and to investigate the relation between vascular function and airflow obstruction and systemic inflammation.We studied 60 patients with stable COPD; 20 smokers with normal lung function matched for age, sex, and body weight; and 20 similarly matched nonsmokers. Patients with cardiovascular comorbidities were excluded. The endothelium-dependent and endothelium-independent function of the vasculature was measured using flow-mediated and nitrogen-mediated dilation of the brachial artery, respectively. Systemic inflammatory markers, including C-reactive protein, fibrinogen, and interleukin (IL)-6, were determined in serum.Both flow-mediated and nitrogen-mediated dilation of the brachial artery were significantly lower in patients with stable COPD than in smoking and nonsmoking control subjects. Levels of inflammatory mediators such as IL-6 and fibrinogen were higher in patients than they were in control subjects. In patients with COPD, stepwise multiple regression analysis showed that age, sex, baseline brachial artery diameter, C-reactive protein level, leukocyte count, blood glucose level, and percentage of predicted forced expiratory volume in 1 s were independent predictors of flow-mediated dilation. There was no relation between flow-mediated dilation and pack-years of smoking. Baseline brachial artery diameter was the only independent predictor of nitrogen-mediated dilation in patients with COPD.Both endothelium-dependent and endothelium-independent vasodilation is significantly impaired in patients with stable COPD. Airflow obstruction and systemic inflammation may increase the risk of cardiovascular disease in patients with COPD.

The aim of the present study was to assess circulating levels of VEGF (vascular endothelial growth factor), a biomarker with prognostic significance in cardiovascular disease, and markers of systemic inflammation in patients with stable and exacerbated COPD (chronic obstructive pulmonary disease). Lung function parameters, arterial blood gas analysis and circulating levels of VEGF, IL-6 (interleukin-6), TNF-α (tumour necrosis factor-α), CRP (C-reactive protein), fibrinogen and the peripheral blood neutrophil cell count were assessed in 30 patients on admission to the hospital for acute exacerbation of COPD, in 30 age-, gender- and BMI (body mass index)-matched patients with stable COPD, and 30 matched controls with normal lung function. Patients with acute exacerbated COPD had higher circulating concentrations of VEGF (P

Increased right ventricular afterload leads to left ventricular diastolic dysfunction due to ventricular interdependence. Increased right ventricular afterload is frequently present in patients with COPD. The purpose of this study was to determine whether left ventricular diastolic dysfunction could be detected in COPD patients with normal or elevated pulmonary artery pressure (PAP).Twenty-two patients with COPD and 22 matched control subjects underwent pulsed Doppler echocardiography. Left ventricular systolic dysfunction and other causes of left ventricular diastolic dysfunction (eg, coronary artery disease) were excluded in all patients and control subjects. PAP was measured invasively in 13 patients with COPD.The maximal atrial filling velocity was increased and the early filling velocity was decreased in patients with COPD compared to control subjects. The early flow velocity peak/late flow velocity peak (E/A) ratio was markedly decreased in patients with COPD compared to control subjects (0.79 +/- 0.035 vs 1.38 +/- 0.069, respectively; p0.0001), indicating the presence of left ventricular diastolic dysfunction. The atrial contribution to total left diastolic filling was increased in patients with COPD. This was also observed in COPD patients with normal PAP, as ascertained using a right heart catheter. The atrial contribution to total left diastolic filling was further increased in COPD patients with PAP. PAP correlated with the E/A ratio (r = -0.85; p0.0001).Left ventricular diastolic dysfunction is present in COPD patients with normal PAP and increases with right ventricular afterload.

Introduction: Cellular vascular endothelial growth factor (VEGF) expression is increased in response to regional hypoxia, however, contradictory results were reported on the effects of systemic hypoxemia on circulating VEGF levels. This study investigated plasma concentrations of VEGF in patients with a variable degree of overnight hypoxemia due to sleep disordered breathing (SDB).Methods: VEGF levels were assessed by ELISA in non-activated (VEGFbl) and thrombin stimulated platelet rich plasma (VEGFprp) of 45 patients with SDB: Group 1patients with obstructive sleep apnea and an apnea–hypopnea index (AHI) > 15/h; Group 2 subjects with an AHI

In this chapter the concept of the “sick lung circulation informing the heart” is applied to chronic lung diseases. The concept of signals emanating from the injured lung vessels—both precapillary and postcapillary—and influencing the performance of the right and left ventricle by inducing a myocardial microangiopathy, is discussed in the setting of COPD/emphysema, pulmonary fibrosis, and cystic fibrosis and the pertinent literature is reviewed. The concept is supported in COPD patients where right heart dysfunction can occur while significant pulmonary hypertension is absent. In patients with interstitial pulmonary fibrosis, the outcome is more closely related to the right ventricular function than to the pulmonary artery pressure, and there are reports that provide evidence in support of early right heart dysfunction in cystic fibrosis patients.

Little is known about the effects of lung transplantation (LT) on the neural drive to the diaphragm and on the endurance of respiratory muscles in patients with severe chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate these effects of single-lung (SLT) and double-lung transplantation (DLT). The neural drive to the diaphragm was assessed during fatiguing inspiratory threshold loading manoeuvres in six SLT recipients, six DLT recipients and seven patients with severe COPD, by using diaphragmatic surface electromyograms. During threshold loading, the patients had to generate 80% of their maximal transdiaphragmatic pressure with each breath. The endurance of inspiratory muscles was defined as the time from the beginning of a resistive breathing trial until exhaustion (t lim). In DLT recipients and even in SLT recipients (on both sides), neural activation of the diaphragm was significantly lower than in COPD patients (p < 0.05). However, no statistically significant difference in t lim was seen between LT recipients and COPD patients. The data suggest that single-lung and double-lung transplantations cause a significant decrease of the neural drive to the diaphragm, while the endurance of inspiratory muscles is well-preserved in patients with advanced chronic obstructive pulmonary disease. This may contribute to reduced sensation of inspiratory effort during ventilatory stress, thus improving the quality of life.

Background: Because there are few data available on the accuracy of 2D-echocardiography to assess right ventricular (RV) size and function in patients with far-advanced lung disease, in this prospective study, we compared various echocardiographic RV parameters with RV volumes derived from magnetic resonance imaging (MRI). Methods In 32 patients (18 male, 17 female) presenting for lung transplantation, we measured RV end-diastolic and end-systolic area as well as derived RV fractional area change, long-axis diameter, short-axis diameter, tricuspid valve anulus diameter (using 2D apical or sub-costal 4-chamber view), and RV end-diastolic diameter (using M-mode in the parasternal short-axis view). These values were compared with RV end-diastolic and end-systolic volumes derived by MRI, serving as the gold standard. Results Right ventricular end-diastolic area was the most accurate echocardiographic parameter of RV size (correlation to MRI: r = 0.88, p < 0.001), followed by RV end-diastolic short-axis diameter (r = 0.75, p < 0.001), long axis diameter (r = 0.66, p < 0.001), and tricuspid valve anulus diameter (r = 0.63, p < 0.001). In contrast, M-mode measurement of RV end-diastolic diameter was possible in only 24/35 (68%) patients and showed a weak correlation to MRI-derived RV end-diastolic volume (r = 0.56, p = 0.004). Right ventricular fractional area change correlated well with MRI-derivedRV ejection fraction (r = 0.84, p < 0.0001). In a sub-group analysis, patients with vascular lung disease showed best agreement between both methods for RV end-diastolic area and RV fractional area change compared with patients with restrictive or obstructive lung disease. Conclusion This study shows that in patients with far-advanced lung diseases, RV end-diastolic area demonstrated the best correlation with MRI-derived measurement of RV end-diastolic volume, and RV fractional area change compared favorably with MRI-derived ejection fraction. Despite reduced image quality, especially in patients with obstructive lung disease, these parameters can yield clinically valuable information.

To evaluate the effect of lung transplantation on right ventricular (RV) and left ventricular (LV) volumes and function, magnetic resonance imaging (MRI) was performed in 11 patients before and 6 to 24 months after single (n = 7) or double (n = 4) lung transplantation as well as in 15 healthy control subjects. Prior to transplantation, RV end-diastolic (RVEDVI, ml/m2) and end-systolic (RVESVI, ml/m2) volume indices were significantly increased in patients compared with those in control subjects. RV ejection fraction (RVEF, %), although within the lower normal range, was significantly reduced. In contrast, LV volume indices (ml/m2) were significantly smaller in patients than in control subjects, whereas LV ejection fraction (LVEF, %) was not different from that in normal subjects. After lung transplantation, MRI revealed a significant reduction in RVEDVI from 73 +/- 29 to 54 +/- 14 (p = 0.03) and RVESVI from 38 +/- 23 to 20 +/- 6 (p = 0.01) with a concomitant significant increase in RVEF from 48 +/- 14 to 63 +/- 6 (p = 0.01). Consecutively, the LV expanded to normal (LVEDVI from 49 +/- 12 to 65 +/- 14, p = 0.01; LVESVI from 23 +/- 9 to 28 +/- 7, p = 0.05), whereas LVEF remained unchanged (55 +/- 9 versus 56 +/- 8).

Terbutaline, a beta 2-adrenergic agonist, has been shown to cause hypokalemia and an increase of plasma glucose and serum insulin concentrations. We considered that terbutaline-induced hypokalemia may be due to the insulin-induced shift of potassium (K+) from the extracellular to the intracellular space. If so, then inhibition of insulin secretion by somatostatin would prevent terbutaline-induced hypokalemia. Further, we wondered whether oral potassium pretreatment could prevent terbutaline-induced hypokalemia. Therefore, 10 healthy volunteers (5 men, 5 women; mean age, 23 yr +/- 3 SD) received either sodium chloride (NaCl) or somatostatin intravenously together with 0.25 mg terbutaline subcutaneously in a double-blind crossover design. On a third test day, they received 39 mval of K+ powder orally before terbutaline injection in an open trial. Terbutaline caused a significant decrease of K+ (from 3.96 +/- 0.08 to 3.3 +/- 0.13 mmol/L +/- SEM; p less than 0.0005), accompanied by a significant increase in plasma glucose (from 83 +/- 3.6 to 101 +/- 4.4 mg/dl +/- SEM; p less than 0.01) and serum insulin concentrations (from 11.7 +/- 0.9 to 19.9 +/- 1.1 microU/ml +/- SEM; p less than 0.001), confirming earlier data. Somatostatin pretreatment inhibited the terbutaline-induced hypokalemia; the small fall of K+ (from 3.7 +/- 0.08 to 3.5 +/- 0.2 mmol/L) was no longer significant. Insulin secretion was completely blocked by somatostatin, leading to an even more pronounced increase of blood glucose. Hypokalemia after terbutaline injection was not prevented by oral potassium pretreatment. In summary, the present findings confirm that terbutaline-induced hypokalemia is associated with increased plasma glucose and insulin levels.(ABSTRACT TRUNCATED AT 250 WORDS)

SummaryBackgroundChronic obstructive pulmonary disease (COPD) is accompanied by an increased cardiovascular risk which is aggravated by the incidence of acute exacerbations (AE). Endothelial function, as well as the soluble receptor for advanced glycation end-products (sRAGE), both markers of cardiovascular risk, has been shown to be decreased in stable COPD.ObjectivesWe aimed to investigate a possible link between sRAGE and endothelial function in AE of COPD. We hypothesize that circulating levels of sRAGE and endothelial function are impaired during AE and improve after clinical recovery, respectively.MethodsWe enrolled patients admitted to hospital due to an AE of COPD without overt cardiovascular comorbidities. Study related procedures comprised spirometry, measurement of plasma sRAGE levels and the quantification of endothelial function by means of the flow-mediated dilation technique (FMD). All measurements were scheduled during hospitalization and after confirmed clinical stability.ResultsWe recruited 29 patients (27% female) with moderate to severe COPD. Median sRAGE concentration was 525 pg/mL (371–770, 1st–3rd quartile) and mean FMD 6.7 ± 3.6% at AE. There was a significant increase of sRAGE levels to 876 pg/mL (633–1371, 1st–3rd quartile, p