Rationale: It is well known, that normal values of blood eosinophil counts (EOSb) have a broad range, which is age/sex dependent in general populations (GP). The longitudinal consistency of EOSb in a GP is scarcely investigated. Methods: We investigated the consistency of EOSb in the Austrian LEAD study, a single-centred, observational, population-based cohort from 6-80 years. We analysed EOSb in 7774 participants (total cohort; tGP) and in 2720 participants with non EOS-associated disease (no allergy, asthma, COPD,metabolic syndrome/obesity, current smoking, HES reported - healthy subgroup; HSP) at baseline and at follow up after 4 years. EOSb were categorized in low (0-99 cells/µl), medium (100-299 cells/µl) and high (>300 cells/µl). The individual upper/lower limit of normal (ULN/LLN) was calculated for baseline and follow up EOSb by using the LMS-method and the calculation of z-scores. Proportion of probands were expressed as ULN. Results: In the tGP 27.25% had low EOSb, 59.26 % medium EOSb, and 13.49% high EOSb; in HSP, 34.6 % had low EOSb, 55.5% medium EOSb, and 9.83% high EOSb. Changes from ULN happened only in 6.18% of tGP/ 4.35% of HSP and from>ULN to

Background: In the general population the prevalence of PRISM is high and associated with higher cardiovascular (CV) mortality. Carotid-femoral pulse wave velocity (PWV), a direct measure of arterial stiffness (AS), is the most important risk factor for CV-diseases. Rationale: We wondered, whether CV diseases and diabetes are more prevalent in PRISM and whether AS is increased in PRISM. Methods: CV diseases (hypertension, coronary artery disease) and diabetes were self-reported (doctor´s diagnosis, medication) and PWV were measured non-invasively in the Austrian LEAD study, a single-centred, observational, population based cohort from 18-80 years. We divided the study population into three groups according to spirometry: normal (n=6954; FEV1/FVC ≥0.7, FEV1 ≥80%), PRISM (n=509; FEV1/FVC ≥0.7, FEV1 <80%) and obstruction (n=419; FEV1/FVC ≥0.7, FEV1 <80%). Results: Hypertension (16.0% vs 20.6%; p<0.008; vs 23.4%; p<0.001), coronary artery disease (1.5% vs 3.5%; p<0.002; vs 4.3%; p<0.001), and diabetes (4.2% vs 8.4%; p<0.001; vs 9.6%; p< 0.001) were significantly more prevalent in PRISM and obstruction compared to normal. Figure 1 presents PWV values and regression lines for the three groups. PWV increased with age; however, the increase is more pronounced in PRISM and obstruction compared to normal. Summary: In PRISM, CV diseases and diabetes are more prevalent and AS is increased compared to individuals with normal lung function.

Background SARS-CoV-2 antibody tests have undergone a remarkable improvement in performance. However, due to the low seroprevalence in several areas, very high demands are made on their specificity. Furthermore, the low antibody-response in some individuals requires high test sensitivity to avoid underestimating true seroprevalence. Optimization of testing has been reported through lowering manufacturer cut-offs to improve SARS-CoV-2 assay sensitivity or by combining two tests to improve specificity at the cost of sensitivity. However, these strategies have thus far been used in isolation of each other. Methods To increase sensitivity, cut-offs of three commercially available SARS-CoV-2 automated assays (Roche, Abbott, and DiaSorin) were reduced according to published values in a pre-pandemic specificity cohort (n=1117) and a SARS-CoV-2 positive cohort (n=64). All three testing systems were combined in an orthogonal approach with a confirmatory test, which was one of the remaining automated assays or one of two commercial ELISAs directed against the spike protein receptor binding-domain (RBD) or the nucleocapsid antigen (NP). Results The modified orthogonal test strategy resulted in an improved specificity of at least 99.8%, often even 100%, in all 12 tested combinations with no significant decline in sensitivity. In our cohort, regardless of whether the assays were used for screening or confirmation, combining Roche and Abbott delivered the best overall performance (+~10% sensitivity compared to the single tests and 100% specificity). Conclusion Here we propose a novel orthogonal assay strategy that approaches 100% specificity while maintaining or even significantly improving the screening test's sensitivity.

Reliable antibody tests are an essential tool to identify individuals who have developed an adaptive immune response to SARS-CoV-2. However, attempts to maximize the specificity of SARS-CoV-2 antibody tests have come at the cost of sensitivity, exacerbating the total test error with increasing seroprevalence. Here, we present a novel method to maximize specificity while maintaining or even increasing sensitivity: the “Sensitivity Improved Two-Test” or “SIT²” algorithm.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).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.SIT² proved to be the best diagnostic choice at both 5% and 20% seroprevalence in all tested scenarios. It is an easy algorithm to apply to different available SARS-CoV-2 antibody testing systems and can potentially be helpful for the serology of other infectious diseases.

ZusammenfassungDas vorliegende Dokument ist eine Neufassung und Aktualisierung der Leitlinie zur Diagnostik und Therapie von Patienten mit COPD, die die bisherige Version aus dem Jahr 2007 ablöst. Die Fülle an neuen Erkenntnissen zu Risikofaktoren, Diagnostik, Schweregradeinschätzung, Prävention und medikamentösen sowie nicht medikamentösen Therapiemaßnahmen machten eine umfassende Überarbeitung erforderlich. Die neue Leitlinie baut auf das GOLD-Dokument unter Berücksichtigung von Besonderheiten in Deutschland und Österreich auf.

Patients with lung cancer, who show EML4-ALK translocation are routinely treated with ALK inhibitors (ALKi) as Alectinib, Ceritinib or Crizotinib, but develop resistance over time in the majority of cases. Brigatinib, a new next-generation ALKi, is FDA approved in crizotinib-refractory ALK-positive NSCLC. The role of Brigatinib after Ceritinib or Alectinib failure is unknown in clinical practice. We report about our experience with Brigatinib in EML4-ALK translocated NSCLC patients, who became resistant to Alectinib, Ceritinib or Crizotinib. We treated 35 EML4-ALK translocated NSCLC patients with Brigatinib. Patient characteristics including sex, age, race, presence/ absence of brain metastases and smoking history of ALK+ NSCLC patients were collected. All data were obtained from Otto-Wagner hospital from August 2015 until April 2018. Before receiving Brigatinib, the patients were either only treated with Crizotinib (n = 15), with Crizotinib and then Ceritinib (n = 12), with Alectinib (n=1), with Crizotinib and then Alectinib (n=3), with Crizotinib, then Ceritinib and then Alectinib (n=1) or with Ceritinib and Alectinib (n=3). All patients were treated with daily dose of 180 mg oral Brigatinib after a 7- day lead- in at 90 mg. 27 patients were women and 8 men. 3 patients were smokers ( 8,5%), 9 were former smokers ( 25,7 %) and 23 were never smokers (65,7%). 13 patients had initial brain metastases (31%). 34 of the treated patients are Caucasians and 1 is Asian. 3 of the 35 showed a complete response (9%), 25 a partial response (76%) and 5 a disease progression (15%), 2 were not evaluable. 7 of the 13 patients with brain metastases responded to Brigatinib (54%). The median PFS (progression free survival) was 7.5 months (range 1-21) and treatment of 21 patients is still ongoing. Of the 15 patients, who received only Crizotinib before Brigatinib, 2 patients were complete responders, 12 were partial responders and 1 had disease progression. Of the 12 patients, who received Crizotinib followed by Ceritinib, 1 patient had a complete response, 9 partial response and 2 disease progression. All other patients demonstrated a partial response except two, who had disease progression with Brigatinib following Ceritinib/ Alectinib treatment. Brigatinib was well tolerated overall. Brigatinib was highly effective in these pretreated EML4-ALK translocated NSCLC patients in clinical practice.

This document is a revision of the guideline for diagnosis and treatment of COPD that replaces the version from 2007. A multitude of recent reports regarding risk factors, diagnosis, assessment, prevention and pharmacological as well as non-pharmacological treatment options made a major revision mandatory. The new guideline is based on the GOLD document taking into account specifics in Germany and Austria.

In patients with EGFR-mutant non-small-cell lung cancer (NSCLC), progression inevitably occurs after 9 to 14 months of treatment with EGFR tyrosine kinase inhibitors (TKIs). EGFR T790M mutations have been identified as the most common mechanism of acquired resistance. Analyzes assessing the frequency of acquired T790M mutations have mainly been conducted in patients receiving the first-generation EGFR TKIs erlotinib and gefitinib, however limited data is available on the prevalence of this mutation after failure of the ErbB family blocker afatinib. This retrospective analysis aimed at determining the prevalence of EGFR T790M mutation in patients who had benefitted from afatinib therapy, but ultimately developed progression. Another objective was the assessment of response to the subsequent treatment with the third-generation EGFR TKI osimertinib, which is the treatment of choice for patients who have developed T790M mutations. The analysis included consecutive patients with stage IV adenocarcinoma of the lung and sensitizing EGFR mutations who had progressed on first-, second- or third-line afatinib treatment after experiencing at least 3 months of disease stabilization. Mutation status was assessed using liquid biopsy or both liquid biopsy and tissue re-biopsy. Patients with confirmed T790M mutation received osimertinib. T790M mutations were found in 27 of 48 patients, corresponding to a prevalence rate of 56.3%. The concordance rate between liquid biopsy and re-biopsy was 80%. In the total cohort, the objective response rate (ORR) obtained with afatinib was 89.6%, and in the patients who developed T790M mutation, 92.6%. Complete responses (CR) occurred in 25.0% and 37.0%, respectively, and partial responses (PR) in 64.6% and 55.6%, respectively. In the patients who received osimertinib after the discovery of T790M mutations, ORR was 81.5%, with CR and PR rates of 22.2% and 59.3%, respectively. The prevalence of acquired T790M mutations as assessed in this cohort was consistent with the mutation rates reported for patients who progressed on first-generation EGFR TKI treatment. T790M mutation appears to be the main mechanisms of acquired resistance to afatinib. The development of this mutation was not affected by any baseline characteristics. These real-world data confirm that for patients with advanced, EGFR-positive NSCLC who progressed on afatinib and developed T790M mutations, osimertinib therapy elicited excellent response rates, with a substantial proportion of patients achieving complete remissions.

Zusammenfassung Die Prävalenz von Asthma und COPD ist steigend und das Interesse zur Erforschung von zugrunde liegenden Risikofaktoren sehr hoch. In den letzten Jahren hat sich wissenschaftlich die Methodik zur Erforschung des natürlichen Verlaufes beider Erkrankungen um Komponenten wie Biomarker, Genetik, Metabolomik und Epidemiologie erweitert. Der natürliche Verlauf der Lungenfunktion, beginnend von der Adoleszenz bis zur Seneszenz, spielt eine wesentliche Rolle in der Entwicklung von diesen obstruktiven Atemwegserkrankungen. Risikofaktoren, passiv (familiäre Anamnese, soziales Umfeld, Umwelt etc.), aktiv (Rauchverhalten, Sozioökonomie, Lifestyle etc.) und Genetik nehmen Einfluss auf die Lungenfunktion und damit auf den natürlichen Verlauf der Lungenfunktion. Es bedarf pulmologischer Kohorten, um 1. potenzielle Risikofaktoren zu definieren (durch Quantifizierung der früh-kindlichen Risikofaktoren, wie genetische Prädisposition und Faktoren, welche in utero und postnatal Einfluss nehmen auf die Lungenfunktion, sowie Evaluierung der Risikofaktoren in der Kindheit, welche zur Reduktion der Lungenfunktion führen) und 2. um prospektiv in jüngeren Altersgruppen der COPD frühe Risikofaktoren zu detektieren. Die Austrian LEAD Study wurde 2012 initiiert, um den natürlichen Verlauf der Lungenfunktion in einer repräsentativen österreichischen Population zu untersuchen.

Background In patients with COPD it has been shown that there is a correlation between the degree of lung hyperinflation and subclinical atherosclerosis measured by carotid-femoral PWV (pulse wave velocity-PWV). We wondered wheter we could demonstrate this correlation also in a general population cohort. Methods In an interim analysis of the ongoing Austrian LEAD (Lung hEart sociAl body) study, a single-center, longitudinal, open labeled, observational, population based cohort study, 1147 participants were included (female 54,9%, mean age 52,8 yrs). In addition to PWV also age, parameters of lipid profil (HDL plasma level), systemic inflammation (hsCRP), and lung hyperinflation (RV%/TLC) were measured. Results In total 7,2% (n=83) of participants showed elevated levels of PWV, defined as > 12m/second indicating subclinical atherosclerosis. Compared to participants with normal PWV, those with elevated PWV were older (67,2+/-8,0 vs 51,7+/-15,7; p=0.0051), had higher HDL plasma levels 67,3mg/dl+/-18,6 vs. 62,1mg/dl +/-16,9; p=0.05), higher hsCRP plasma levels (3,2mg/dl +/- 4,4 vs. 2,1mg/dl +/-3,9; p=001), and increased RV%TLC post lysis (40,8% +/-6,8 vs. 34,9%+/-7,7;p=0.000). However, in a multivariant analysis, only age correlated significantly with PWV, possibly due to the small sample size. Conclusion In a general population cohort, subclinical atherosclerosis seems not only be linked to age, lipid profil and systemic inflammation, but also to lung hyperinflation.

Introduction Smoking is the main preventable cause of premature death and the main risk factor for chronic obstructive pulmonary disease. According to the Eurobarometer 2010, the prevalence of ever smoking in Austrian is higher compared to other European countries (57% vs. 51%, respectively). An underlying cause might be the failure of national smoke ban actions. Objective and methods We aimed to investigate the prevalence of active and second hand smoking in Austrian male and female participants of the Austrian LEAD study, an ongoing, longitudinal, observational, population based cohort study. Results Interim analysis (n=1.314; male 47%; age 51.9±17 years) showed that in Austrian male and female participants ever smoking (65% and 56%; respectively) as well as second hand smoking (70% and 70.8%; respectively) in childhood and/or adulthood are highly prevalent. Second hand smoke in adulthood lasts on average 17.4±13.3 years and happens predominantly at work (20.6%). Interestingly, ever-smokers have a higher prevalence of second hand smoking compared to never smokers in both, childhood and adulthood (p<0.01). Conclusion Active smoking and second hand smoking are highly prevalent in Austria and national smoke ban actions have to be executed more strictly in order to reduce smoking itself as well as smoking related morbidity and mortality.

Introduction Although recommended, most lung function studies in the general population abandon bronchodilation when defining airflow obstruction and evaluating the prevalence of chronic obstructive lung diseases. The aim of the present study was to evaluate the prevalence of airflow obstruction pre and post bronchodilation in a general population. Methods The ongoing Austrian LEAD study intends to investigate the natural decline in lung function in a general population. Participant9s lung function was assessed pre and post bronchodilation. Airflow obstruction was defined as FEV1/FVC Results In total 1268 participants (male: 46%, age: 53±17 years) were included. Airflow obstruction was diagnosed pre and post bronchodilation in 15.3% and 10.4%, respectively (p Conclusion When defining airflow obstruction in the general population, lung function including bronchodilation should be performed in order to accurately evaluate the prevalence of chronic obstructive lung diseases.

s The Central European Journal of Medicine

Objectives: Recent studies suggest reduced cardiac filling pressures in patients with COPD due to hyperinflation. A reduction in cardiac preload may result in unloading of baroreceptors. We thus investigated spontaneous baroreceptor sensitivity, an independent predictor of cardiovascular morbidity and mortality, in patients with COPD and controls. Methods: 33 patients with severe airflow obstruction but free from clinical cardiovascular disease (age 64±7yrs, BMI 23±4 kg/sqm, FEV1 27±7%, TLC 140±19%) and 12 age, gender, and body-weight matched controls without airflow obstruction were studied. Spontaneous baroreceptor activity was measured using the sequence method during resting conditions. The baroreceptor effectiveness index was calculated from the total number of baroreceptor sequences divided by the total number of systolic blood pressure ramps. Results: The mean slope of spontaneous baroreceptor sequences (7.0±4.7msec/mmHg vs. 13.5±6.4msec/mmHg, p<0.01) and the baroreceptor effectiveness index (71±54 vs. 103±34, p<0.05) were significantly lower in patients with COPD than controls. There was a significant inverse relationship between the slope of baroreceptor sensitivity (r = -0.302, p < 0.05) and baroreceptor effectiveness index (r = - 0.391, p < 0.01) with RV/TLC ratio. There were no such associations with airflow obstruction. Conclusions: Our findings indicate a link between hyperinflation and baroreceptor function in patients with COPD.

Das Vorhandensein einer bronchopleuralen Fistel ist mit einem erhöhtem Morbiditäts- und Mortalitätsrisiko verbunden. Die Therapie umfasst neben intrathorakaler Drainage und Antibiose den Fistelverschluss, welcher im Regelfall eine chirurgische Domäne darstellt. Bei Pat. mit eingeschränkter Lungenfunktion ist in vielen Fällen eine minimal-invasive Alternative wünschenswert bzw. erforderlich. Wir berichten über eine 62-jährige Pat. mit schwerer COPD, die aufgrund eines Lungenabszesses zur Aufnahme gelangte und eine bronchopleurale Fistel entwickelte. Die Behandlung umfasste neben einer antibiotischen Therapie die Implantation endobronchialer Einwegventile, welche zum Fistelverschluss und schließlich zur Rekonvaleszenz führte.