1 annual report lbi for copd and pulmonary epidemiology 2015 · chronic obstructive pulmonary...

1 Annual Report LBI for COPD and Pulmonary Epidemiology 2015

Ludwig Boltzmann Institute for

COPD and Pulmonary Epidemiology

LBI - COPD AND PE

Clinical and translational science at the

Department of Respiratory and Critical Care Medicine

Otto Wagner Hospital

Sanatoriumstraße 2

1140 Vienna

Austria

Contact information

Head of Institute: Otto Chris Burghuber, MD, FCCP, Prof.

P: +43 1 91060 41007

F: +43 1 91060 41839

M: [email protected]


Content

INTRODUCTION 3

INSTITUTION 4

Career (Scientific Group Leader; alphabetical order) 5

Location 8

General Scientific Approach 8

Funding 8

Partner 10

SCIENTIFIC PROGRAM LINES 11

1. Program Line 1: Pulmonary Epidemiology 11

2. Program Line 2: Systemic effects of COPD 15

3. Program Line 3: Therapeutic interventions in COPD 25

PUBLICATIONS (ORIGINAL ARTICLES) 37

REVIEWS, EDITORIALS, GUIDELINES, BOOKS 47


Introduction

Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of morbidity and

mortality worldwide, resulting in both an increasing economic and social burden.

COPD prevalence, morbidity, and mortality vary across countries but, in general are directly

related to the prevalence of tobacco smoking. The prevalence and burden of COPD are

projected to increase in the coming decades due to continued exposure to COPD risk factors

and the changing age structure of the world’s population with more people living longer, and

thus reaching the age at which COPD normally develops. The Global Burden of Disease

Study has projected that COPD will become the third leading cause of death worldwide by

2020. Furthermore, epidemiological data predict COPD becoming the fifth leading cause of

loss of Disability Adjusted Life Years (DALY´s) worldwide in 2020, following ischemic heart

diseases, major depression, traffic accidents, and cerebrovascular diseases.

However, the “Natural history of COPD”, commonly described with the natural decline of lung

function, is under-evaluated. To understand the natural history of early development and

decline in health and disease of the respiratory tract is a number one priority in current

respiratory research. However, in Austria there have been no investigations on this research

priority until 2011. Therefore the program line 1 “Pulmonary Epidemiology” was set up in

2011 to investigate the natural history of COPD as well as phenotyping of COPD to raise

information on the phenotyping presentation of this disease.

In addition, pathogenesis and clinical manifestations of COPD are not restricted to the lungs.

A number of recent studies have demonstrated important systemic alterations and organ

dysfunctions associated and/or caused by COPD. These extra-pulmonary effects of COPD

have been a major focus of clinical and basic research within the last years. Therefore, the

program line 2 “systemic effects of COPD” was initiated in 2007 to investigate the prevalence

and effects of systemic inflammation in stable COPD as well as in COPD exacerbations.

Individual burden of disease in COPD is well known as mentioned before. Hyperinflation is a

main feature in high grade COPD and an important determinant of airflow obstruction,

exercise limitation, and dyspnea in patients with high-grade COPD. Treatment options

include non-invasive and invasive therapy and objecting to reduce hyperinflation as well as

the accompanying individual symptoms and outcomes. Therefore, the program line 3

“therapeutic interventions” in COPD was set up in 2008 and number of investigations on this

topic has been enlarged continuously from the beginning.

The current report will give an overview about the organisation, the research within the

institute, and the scientific output since 2011 in particular.


Institution

LEADING STAFF

Head of Institute

Otto C. Burghuber, MD, FCCP, Prof. of Medicine

Scientific Group leader and Key researcher:

Marie-Kathrin Breyer, MD, PhD

Robab Breyer-Kohansal, MD

Georg-Christian Funk, MD, Assoc. Prof.

Sylvia Hartl, MD, MBA

Matthias Urban, MD

Arschang Valipour, MD, Assoc. Prof.

SCIENTIFIC STAFF

Scientific fellows, study nurses, and associates:

Program Line 1

Katarina Ahlberg, BSc.

Jasmin Ernst

Martina Koppi, Bakk.

Verena Lang, BSc.

Jolanta Maleska-Sobarnia

Denise Mayerhofer

Katharina Portugal, BA

Boban Stamenkovic, Cand.med.

Lucie Stärk

Michael Sturm

Barbara Wimmer

Program Line 2 Sophia Holzer, BSc.

Nicole Kreibich, Maga.

Program Line 3

Christine Abele, MD

Marina Duller

Irene Firlinger, MD

Maria-Anna Grasl, Bakk.

Maria-Christine Leitgeb

Oliver Overheu

Medical students of the Medical University of Vienn a, currently under supervision by

the LBI – COPD and PE for diploma: Canan Dereci, Anna Mayer, and Eldin Selimovic.


Career (Scientific Group Leader; alphabetical order)

Marie Kathrin Breyer, MD, PhD is currently a chest physician at the Department

of Respiratory and Critical Care Medicine, Otto Wagner Hospital, Vienna, Austria. From

2007 till 2013 Dr. Breyer was a PhD student at the Department of Respiratory Medicine,

Maastricht, The Netherlands. She finished successfully her PhD entitled ‘Adiposity in CODP’

in 2013 at the University of Maastricht. During her trainee of becoming a chest physician at

the Department of Respiratory and Critical Care Medicine, Otto-Wagner Hospital, Vienna,

Austria from 2008-2014, she worked as the local secretary of the annual congress of the

Austrian Society of Pneumology from 2010-2013. Since 2008 she is a scientific director of

the Austrian LEAD Study. In 2013 she started her ongoing lectureship at the Medical

University of Vienna.

Robab Breyer-Kohansal, MD is currently a trainee for chest physician at the

Department of Respiratory and Critical Care Medicine, Otto Wagner Hospital, Vienna,

Austria. In 2007 she received a long term fellowship from the European Respiratory Society

at the department of epidemiology and clinical research at the International Centre for

Advanced Respiratory Medicine CIMERA in Spain. She worked as the local secretary of the

annual congress of the Austrian Society of Pneumology from 2010-2013. Since 2008 she is

a scientific director of the Austrian LEAD Study (Research line Epidemiology) and started in

2013 an ongoing lectureship at the Medical University of Vienna. Since 2014 she is

additionally as a key researcher to support the administrative management of the institute.

Otto C. Burghuber, MD, FCCP, Prof. of Medicine is head of the Department of

Respiratory and Critical Care Medicine Otto Wagner Hospital, Vienna, and director of the

Ludwig Boltzmann Institute. He was trained at the University of Vienna Medical School and

the University of Colorado Health Sciences Centre. He has specialized degrees in Internal

Medicine, Cardiology, Respiratory Medicine and Respiratory Intensive Care. From 2007 –

2009 he was President of the Austrian Society of Pneumology. 2009 he served as a local

president the annual congress of the European respiratory society in Vienna. He initiated

the LBI for COPD and PE in 2002. Under his leadership the institute increased its size,

number of program lines, and the scientific output continuously.


Georg-Christian Funk, MD, Assoc. Prof. is currently a senior physician at the

intensive care unit of the Department of Respiratory and Critical Care Medicine, Otto

Wagner Hospital, Vienna, Austria. He started his education at the Medical University in

Vienna and has specialized degrees in Internal Medicine, Respiratory Medicine and Critical

Care Medicine. He is consultant chest physician at the Department of Respiratory and

Critical Care Medicine. In 2010 he has received the “venia docendi” for Internal Medicine at

the Medical University of Vienna. He is currently the general secretary of the Austrian

Society of Pneumology and since 2010 he has an ongoing lectureship at the Medical

University and is the PhD supervisor of Dr. Urban. Moreover, he supervised 6 medical

student taking diploma since 2010. Since 2008 he enlarged his specific scientific work on

patients with COPD and respiratory failure and is a group leader in the research line

Sylvia Hartl, MD, MBA is a senior physician at the competence centre for

weaning and rehabilitation of the Department of Respiratory and Critical Care Medicine,

Otto Wagner Hospital, Vienna, Austria. She was currently announced to head of the

department for Respiratory and Critical Care Medicine and infectious diseases, Otto

Wagner Hospital, Vienna, Austria. From 2011 – 2013 she was the President of the Austrian

Society of Pneumology and since 2013 she is in the executive committee of the Society.

Since 2008 she is deputy principal investigator of the Austrian LEAD Study. Moreover she

enlarged specific scientific work on patients with COPD and respiratory failure and she is a

group leader in the research line “pulmonary epidemiology”, “Systemic effects of COPD”,

and “interventions in COPD”.

Matthias Urban, MD is a trainee for chest physician at the Department of

Respiratory and Critical Care Medicine, Otto Wagner Hospital, Vienna, Austria. In 2010 he

started a PhD programme on “Vascular Biology” at the Medical University of Vienna under

supervision of Assoc. Prof. Funk and Prof. Burghuber. By 2015 he will finish his PhD thesis.

Moreover, he supervises a medical student taking diploma since January 2015. Based on

his PhD he enlarged his specific scientific work on a) studying different aspects of COPD as

a systemic disease with its substantial comorbidities, particularly focusing on cardiovascular

diseases und the underlying metabolic and inflammatory mechanisms; b) identifying

pharmacological as well as non-pharmacological treatment options to improve

comorbidities, quality of life and functional capacity in patients with COPD. Since 2008 he is

at the scientific work group of the Austrian LEAD Study.


Head of institute and scientific group leaders are staff members at the Department of

Respiratory and Critical Care Medicine and employees of the City of Vienna. Because of

specific scientific interest in the various aspects of COPD and pulmonary Epidemiology the

leading staff is complimentary working for the LBI – COPD.

Most of the other LBI contracted researchers developed sincere interest in clinical research

at the institution over the past years, thereby gaining both scientific training and clinical

expertise in a translational research environment. The LBI - COPD and PE opened a wide

range of career opportunities for its researchers, some of which continued international post-

doc fellowships in cooperation with the LBI, whereas others pursued their medical careers

after a short time employment with the LBI - COPD and PE.

Arschang Valipour , MD, Assoc. Prof. is a Consultant Physician and Intensive

Care Specialist at the Department of Respiratory and Critical Care Medicine, Otto-Wagner-

Spital, Vienna. He conducted a research fellowship at the University College London

Hospitals with Prof. Steven Spiro between 1999 and 2000. He became a specialist in

General Medicine (2001), in Pulmonary Medicine (2006), and in Intensive Care Medicine

(2009). Dr. Valipour was further appointed Associate Professor in Pulmonology in 2010. He

has been the Head of the CME program of the Austrian Society of Pneumology for several

years, and is a member of the Executive and Congress Committee of the national society.

He further served as a Secretary to the Sleep and Breathing working group of the European

Respiratory Society. He is conducting clinical research as a Group Leader at the LBI -

COPD and PE. His main research interests include interventional COPD treatment (lung

volume reduction), cardiopulmonary interaction and physiology, and Sleep Medicine. He is

the Principal Investigator of a number of ongoing clinical trials in the field of COPD

management and emphysema therapy.


Location

The Ludwig Boltzmann Institute for COPD (LBI – COPD), initiated in 2002, is located at the

Department of Respiratory and Critical Care Medicine, Otto Wagner Hospital, Vienna, with

the aim to encourage clinical and translational research within the Competence Center of

Pulmonology in Vienna.

In 2011 an additional program line (“Pulmonary Epidemiology”) was initiated investigate the

natural history of COPD as well as phenotyping of COPD and the insititution was re-named

in the LBI for COPD and Pulmonary Epidemiology (LBI – COPD and PE).

The LBI - COPD and PE was successfully approbated by international reviewers in 2008 and

2011. Since the last evaluation the institute`s number of investigations, scientific output, and

members (staff) increased considerably. Since the last evaluation, the institute received more

than 250m2 extra laboratory spaces within the Otto Wagner Hospital for the Austrian LEAD

Study.

General Scientific Approach

a) To study different aspects of COPD as a systemic disease with its substantial

comorbidities, particularly focusing on cardiovascular diseases, metabolic diseases, and

sleep.

b) To identify non - pharmacological treatment options to improve the burden of COPD.

c) To provide information about the natural history of lung function (lung development and

decline) in health and disease and its interactions of environmental and socioeconomic

factors.

Funding

Funding of the LBI – COPD and PE stems mainly from donations (unrestricted scientific

grants) by pharmaceutical and non-pharmaceutical companies (see below). Additional

funding was provided by grant applications (Fonds zur Förderung der Bekämpfung der

Tuberkulose und anderer Lungenkrankheiten and Fonds des Bürgermeisters der Stadt

Wien), from peer reviewed government-based, non-profit organizations supporting clinical


research activities in Austria. In addition, from 2007 – 2014 the Ludwig Boltzmann Society

promote the institution with 100.000.- Euro/annually. After internal revision the amount was

increased due to the increased scientific output of the LBI - COPD and PE with 200.000.-

Euro/annually, beginning in 2015.

National funding by non-pharmaceutical companies

NÖGUS NÖ Gesundheits- und Sozialfonds

Österreichische Lotterien

International funding by unrestricted research grants 2009 2010 2011 2012 2013 2014

Böhringer Ingelheim GmbH 30.000 80.000 80.000 90.000 50.000 125.550

AstraZeneca Österreich GmbH 18.170 18.170 18.169 80.000

GlaxoSmithKline Pharma GmbH 16.000 35.000 120.000

Chiesi Farmaceutici S.P.A. 50.000 50.000 50.000 50.000

Merck/Sharp/Dome 50.000 50.000 50.000

Bayer Austria GmbH 1.500 5.000

Janssen-Cilag Pharma GmbH 5.000

Actelion Pharmaceuticals 10.000

Emphasys Medical Inc. 10.000

Nycomed 50.000 50.000 50.000 50.000

Ludwig Boltzmann Gesellschaft 100.000 100.000 100.000 100.000 200.000

Novartis Pharma AG 50.000 50.000

Menarini Pharma Ges. 25.000

Almirall GmbH 25.000

Takeda Pharma GmbH 20.000 20.000

Spiration Inc. 16.500 15.000


Partner

During the last years a various number of national and international scientific collaborations

with academic partners and national institutions have been established:

International scientific collaborations

• Aarhus University

• Charite Berlin

• Charles University Prague

• CIBER de Enfermedades Respiratorias (CIBERES)

• Fraunhofer Institute Portugal

• Lungenklinik Hemer

• Politecnico di Milano

• Royal Brompton Hospital

• University of Barcelona

• University of Giessen and Marburg

• UMC Groningen

• University Hannover

• University Heidelberg

• University Kosice

• University Leuven

• University of Melbourne

National scientific collaborations

• Ludwig Boltzmann Society (Ludwig Boltzmann Gesellschaft)

• Austrian Ministry of Health (Bundesministerium für Gesundheit)

• The Viennese hospital association (Winer Krankenanstaltenverbund; KAV)

• City of Vienna (Stadt Wien)

• Medical University of Vienna (MUW)

• Austrian Institute of Technology (AIT)


Scientific Program Lines

1. Program Line 1: Pulmonary Epidemiology

Background

The underlying mechanism of every disease is defined by the natural history of disease.

Understanding normal lung development and ageing in health and disease, both in men and

women, is essential to interpret any therapeutic intervention. In respiratory medicine the

natural history of COPD is defined by the natural decline of lung function from the

adolescence to senescence. The LBI-COPD has enlarged it`s scientific profile, starting

international collaborations with Prof. Alvar Agusti and Dr. Joan Soriano in 2007 and

investigating the natural history of COPD within the Framingham cohort (The natural history

of chronic airflow obstruction revisited. Am J Respir Crit Care Med. 2009). This study was

based on original data collected in Framingham, USA beginning in the 70`s. In addition, the

same investigators published a review of current available data of lung function

measurements (CHEST 2009). Moreover, this review identified main methodological

considerations in epidemiology studies and proposed a number of characteristics that an

“ideal” study on natural history of lung function decline should consider. Based on this and in

consideration of the fact that the “number one priority in current respiratory research” (Guerra

S et al., Lancet Respir Med. 2013) was not present in Austria; the LBI – COPD and PE

opened the program line 1 “Pulmonary Epidemiology” and initiated the Austrian LEAD Study

in 2011.

In addition, the natural history of every disease includes different phenotyping presentations

within the disease in stable phase and in exacerbation. For this purpose the LBI - COPD and

PE participated in 2010 in collaboration with the Austrian Society of Pneumology at the ERS

– COPD Audit, a pilot study to evaluate clinical variability related to outcomes for COPD

hospital admissions across Europe. In total 13 European countries participated in this

prospective, observational, and non-interventional cohort study including 15.195 COPD

patients (Roberts CM et al., Thorax. 2013).

Moreover, in collaboration with the Charles University Prague, the University in Kosice, and

CIBER de Enfermedades Respiratorias (CIBERES) Assoc. Prof. Dr. Valipour started a

multinational, multicentre, prospective, observational, non-interventional registry in COPD

patients in Central and Eastern Europe (the POPE study) as a principal investigator. The

study was initiated in 2014 and is recruitment is ongoing.

Recently, the program line for Pulmonary Epidemiology initiated a novel study for two

medical student taking diploma at the Medical university of Vienna aiming to investigate

whether smoking behaviour is associated with migration background. Results implicate a


strong demand for cessation programs adjusted to cultural background and represent a

potential tool to improve the prevention of COPD and will be part of the diploma thesis.

1.1. The Austrian LEAD Study (Lung, hEart, sociAl, boDy)

A longitudinal study investigating health challenges in Pulmology

Aims: To investigate 1. the normal and pathologic lung growth and development, 2. the risk

of development of major NCD’s as COPD, cardiovascular diseases, metabolic diseases,

osteoporosis, and neuropsychiatric diseases, and 3. the complex presentation of COPD,

including its relationship with several extra-pulmonary manifestations of the disease.

This single-centred health examination survey started in November 2011 and is designed as

a longitudinal, observational, population based cohort. Examinations on 10.000 male and

female, aged from 6 to 80 years (1 urban cohort and 1 rural cohort) from the general

population will include lung function testing (pre- and postbronchodilator spirometry,

bodyplethysmography) cardiovascular examinations (blood pressure, myocardial injury

score by ECG, arterial stiffness by pulse wave velocity, brachial-ankle index and carotid

intima media-thickness measurement by Doppler ultrasound), body composition (fat mass,

fat free mass, and bone mineral density by dual-energy X-ray absorptiometry; DXA) and

metabolic testing (waste circumference, serum levels of glucose, cholesterol, triglycerides,

HDL, LDL, and HbA1c) as well as socioeconomic status (occupation, income, education) and

mental health status (cognitive dysfunction, depression and anxiety). After first round of

examinations (cross sectional analysis) two additional follow up investigations are planned

every 4years (longitudinal approach; 2016 - 2020 and 2020 - 2024). To date, the Austrian

LEAD Study has included over 6.500 participants and first round close up will be in March

2016 with projected 10.000 participant. Every day 20 participants are measured at the LEAD

institute (Vienna, Austria) and >5.000 variables per participants are collected during study

period. In addition, blood samples are collected in Biobank for future analyses. Recently,

collaborations with the environmental agencies of Vienna (urban cohort) and Lower Austria

(rural cohort) have been set up. These agencies will provide individual occupational

information (PM 10, PM 2.5; NO etc) for every participant, both at home and at work place.

1.2. The ERS – COPD Audit

Aims: To develop a core data set that can be used to audit COPD in acute hospital

admissions across Europe with a view to raising the standards of care to a level consistent

with the European management guidelines.


The European COPD Audit was initiated in 2010 by the European Respiratory Society (ERS)

as a pilot study to evaluate clinical practice variability related to outcomes for COPD hospital

admissions across Europe. In total, 13 European countries participated in this prospective,

observational, and non-interventional cohort study including 15.195 COPD patients. In

Austria 26 hospitals/ departments participated including data from 823 patients as well as

organisational data from the given resources of the hospital/ department. In addition, 23

hospitals/ departments participated with organisational data only.

Besides a number of publications of the total European collection, the LBI – COPD

submitted the main outcome parameters (mortality, hospital length of stay, and readmission

rate) from the European collection to the European Respiratory Journal (status: under

revision) and is preparing to publish the Austrian Data in 2015.

1.3. The POPE Study

Phenotypes of COPD in Central and Eastern Europe Study

Aims: To assess the distribution of patients with COPD in clinical practice within the CEE

region according to disease severity, disease category, and disease phenotypes.

The LBI-COPD launched an international collaborative effort to better characterize

phenotypes of COPD across Central and Eastern Europe (CEE). In this context, the POPE

Study is the first of its kind in a scientifically rather underrepresented region of Europe. The

POPE study aims for recruitment of more than 3500 patients from more than 80 different

clinical centers in CEE. This project is a multinational, multicentre, prospective,

observational, non-interventional registry in patients in Central and Eastern Europe, from

2014 – 2015. The infrastructure implemented at the clinical sites may allow additional future

studies to assess both diagnostic and therapeutic aspects of the disease in countries with

different risk factors and health care access.

The participation in the study is offered to all consecutive outpatients with stable COPD in 84

centers if they fulfill the following criteria: age > 40 years, smoking history ≥ 10 pack-years, a

confirmed diagnosis of COPD with post-BD FEV1/FVC<0.7, and absence of COPD

exacerbation ≥ 4 weeks. For each individual COPD patient, clinical, functional and imaging

data will be obtained as available. Co-morbidities of subjects enrolled will be assessed by

detailed interview and review of concomitant medications at the time of inclusion. Pulmonary

function data will be obtained with standard equipment according to ATS/ERS consensus

guidelines. Spirometric values for assessing COPD disease severity will be reported as post-

bronchodilator values. The long-term aims of the POPE study are to educate and raise

awareness for COPD phenotypes amongst physicians and patients alike, in order to support

an individualized patient treatment approach in clinical practice.


1.4. Tobacco addiction and smoking cessation in Austrian migrants

Aims: To investigate whether smoking behaviour is associated with migration background or

not. If so, to identify characteristics of adjusted smoking cessation strategies.

Determinants of smoking behaviour and cessation in smokers with Turkish and Bosnian

migration background compared to smokers without migration background in Austria have

been investigated. Nicotine addiction expressed via the Fagerstrom score was significantly

higher in smokers with migration background vs. those without. Migrants had a higher

willingness to quit but also more previous cessation trials than smokers. Migrants were less

often allocated to counselling than non-immigrant subjects. Finally, we found significant

differences in key determinants of smoking cessation (i.e. preferred location, mother tongue

rather than German, group rather than single counselling). The results implicate a strong

demand for cessation programs adjusted to cultural background and represent a potential

tool to improve the prevention of chronic obstructive pulmonary disease.

Parts of this study were submitted as a diploma thesis at the Medical University of Vienna by

Eldin Selimovic and Canan Dereci.

The full-length manuscript was recently accepted by the BMJ (April 2015).


2. Program Line 2: Systemic effects of COPD

Background

While COPD is primarily defined as a chronic inflammatory disease of the lungs, it is

accompanied by a variety of systemic features such as osteoporosis, muscle weakness,

and/or cardiovascular disease (CVD). The underlying mechanisms of these systemic effects

are unclear, but they are probably interrelated and multifactorial, including inactivity, systemic

inflammation, tissue hypoxia and oxidative stress among others. These systemic effects

adding to respiratory morbidity of the underlying pulmonary disease have to be considered in

clinical assessment as well as in the treatment of COPD patients.

Thus, Program Line 2 investigates important systemic components of COPD:

Cardiovascular effects of COPD

A variety of mechanism may contribute to the link between COPD and CVD, including

hypoxia, systemic inflammation, oxidative stress, and/or activation of the sympathetic

nervous system. In a series of previous studies the LBI - COPD and PE was able to

demonstrate evidence of a link between systemic inflammation and vascular dysfunction in

patients with COPD compared with smoking and non-smoking controls, independent of

traditional cardiovascular risk factors, including smoking, hypertension,

hypercholesterolemia, and/or diabetes mellitus. These findings were recently extended, as to

the LBI – COPD and PE showed that altered glucose metabolism over the course of one

year in patients with stable COPD may - in the absence of diabetes - be associated with the

progression of endothelial dysfunction in COPD. Furthermore, cardiovascular risk markers

are upregulated during acute exacerbations of COPD. In a prospective study of 29 patients

with moderate-to-severe COPD there was evidence of worsening endothelial function and

reduced concentrations of soluble receptor for advanced glycation end-products. Clinical

recovery was associated with partial recovery from these systemic (cardiovascular) effects of

the acute exacerbation.

Sleep in COPD

Patients with COPD frequently report impaired quantity and quality of sleep. Sleep problems

associated with chronic obstructive pulmonary disease may in turn have an important impact

on quality of life, comorbidities, and health outcome measures. Investigations of sleep

profiles and symptoms associated with sleep disorders in patients with stable mild to

moderate COPD in comparison with matched controls have been investigated. . The LBI –

COPD and PE demonstrated evidence of significant differences in both quantity and quality

of sleep between patients with COPD and respective controls. Given the impact of sleep

quality on health outcomes and quality of life measures in COPD, these data should

contribute to raise awareness of sleep problems in patients with COPD.


Adiposity in COPD

Earlier on, every COPD patient was thought to be characterized by a homogenous systemic

low-grade inflammation. Taken recent data into account one third of COPD patients does not

have any elevated systemic inflammatory biomarkers. Furthermore this group of patients

seems to have a better survival rate compared to the ‘inflamed’ ones. Dr. Marie-Kathrin

Breyer from the LBI – COPD and COPD started in 2007 her PhD in the Netherlands under

supervision of Prof. Emiel Wouters from University of Maastricht. This collaboration ended in

2013 successfully with the thesis “Adiposity in COPD”. A number of investigations, all

published in peer – reviewed journals, have revealed in summary that a) abdominal fat mass

could be one of the contributing sources of systemic low-grade inflammation, b) abdominal

fat produces and secrets various pro-, and anti-inflammatory mediators, c) a gender-

dependent dysregulated adipokine metabolism in relation to systemic inflammatory

biomarkers is present in COPD, d) physical inactivity has been associated with increased

levels of systemic inflammatory biomarkers in COPD patients, and that d) the metabolic

syndrome is more prevalent in overweight and obese COPD patients and contributes to

patients’ co-morbid status.

The investigations of Program Line 2 may generate new hypotheses concerning the

pharmacological and therapeutic means of preventing systemic complications associated

with COPD.


2.1. Cardiovascular effects of COPD

2.1.1. ADMA

Intima media thickness and asymmetric dimethylarginine in patients with

stable COPD

Aims: To investigate structural markers subclinical atherosclerosis in patients with stable

COPD compared to healthy controls.

Brachial intima-media thickness (B-IMT), a promising predictor of future vascular events, has

not been studied in COPD so far. Hence, we assessed B-IMT in COPD patients compared to

healthy control subjects. We further investigated parameters systemic inflammation, lung

function, and an endogenous inhibitor of nitric oxide synthase named asymmetric dimethyl

arginine (ADMA). We enrolled 60 stable COPD patients and 40 smoking and non-smoking

control subjects. Measurement of B-IMT was performed by ultrasound and blood specimen

were taken to quantify ADMA and markers of systemic inflammation. Our study showed

substantially higher B-IMT in COPD. B-IMT was correlated with parameters of airway

obstruction, levels of inflammatory markers and ADMA. These data suggest B-IMT as a valid

marker of subclinical atherosclerosis in patients with COPD and characterized ADMA as a

potential determinant of COPD related atherosclerosis. Preliminary data from this study were

presented in form of an abstract at the National Society Meeting of the European Respiratory

Society in 2010 and the Austrian Society of Pneumology in 2011.

The manuscript entitled “Increased brachial intima-media thickness is associated with

circulating levels of asymmetric dimethylarginine in patients with COPD” in currently being

reviewed by the co-authors for publication in form of an original research article.

The study will be submitted as part of the PhD-thesis at the Medical University of Vienna by

Matthias Urban.

2.1.2 The ELASTIC Trial

Effects of ROFLUMILAST on markers of subclinical atherosclerosis in stable

COPD

Aims: To determine the effects of the phosphodiesterase-4 inhibitor Roflumilast on

surrogates of subclinical atherosclerosis and markers of systemic inflammation in COPD.

Chronic obstructive pulmonary disease is associated with a low grade systemic inflammatory

process. Systemic inflammation is hypothesized to maintain cardiovascular morbidity and


mortality in COPD. Early changes of vascular integrity can be detected via markers of

subclinical atherosclerosis. Selective inhibition of phosphodiesterase subtype 4 describes a

promising therapeutic option in COPD with beneficial impact on lung function and

exacerbation rate. Moreover, an anti-inflammatory effect of phosphodiesterase-4 inhibition

was confirmed by recent data. The aim of this study will be to determine the effects of the

phosphodiesterase-4 inhibitor Roflumilast on firstly surrogates of subclinical atherosclerosis

and secondly markers of systemic inflammation in the peripheral circulation of patients with

stable chronic obstructive pulmonary disease. To investigate these circumstances, we are

planning to enrole patients with diagnosed COPD pulmonary disease at GOLD-stage III or IV

and history of at least one COPD exacerbation in the previous year. Subjects will be

randomized to one of the two treatment arms receiving either Roflumilast or placebo for a

study period of six months. Prior to initiation of study medication and after the treatment

period patients will undergo measurements of arterial stiffness, systemic inflammation and

lung function. The primary endpoint is defined as a significant improvement of arterial

stiffness quantified by means of the so called carotid femoral-Pulse Wave Velocity (cf-PWV).

Secondary endpoints include beneficial impacts of study medication on further markers of

vascular functional and structural state (i.e. Augmentation Index [Aix], Flow-Mediated Dilation

[FMD], brachial artery Intima-Media Thickness [ba-IMT], Matrix Metalloproteinase-9 [MMP-9],

asymmetric dimethylarginine [ADMA]) and markers of systemic inflammation (Tumor

NecrosisFactor a [TNF-a], C-reactive Protein [CRP]). The study protocol was approved by

local Ethics Committee/Institutional Review Board and enrolment started in 2011.

So far, 78 of the 80 scheduled patients were enrolled and completion of data assessment as

well as submission of the manuscript for publication is expected by the end of 2015.

2.1.3. Endothelial dysfunction and systemic inflammation in patients

with acute exacerbations of COPD

Aims: To determine associations between the clinical entity of exacerbation, markers of

systemic inflammation and endothelial dysfunction.

Cumulating data suggest that the inflammatory reaction associated with COPD is not

restricted to the lungs but has a systemic component. Additionally patients with COPD have

increased cardiovascular morbidity and mortality. The suspected link between increased

cardiovascular mortality and systemic inflammation is endothelial dysfunction, which has

been demonstrated in patients with COPD. Furthermore there is a close correlation between

endothelial dysfunction in coronary and peripheral vessels, which allows assessing Flow-

Mediated Dilation (FMD) in the brachial artery via high resolution ultrasound as an early

predictor of atherosclerosis. Moreover, systemic inflammatory markers correlate with


endothelial dysfunction in patients with stable COPD. Exacerbations of COPD are episodes

of worsening symptoms characterized by increased airway and systemic inflammation. The

soluble receptor for advanced glycation end-products (sRAGE), a novel circulating biomarker

for cardiovascular risk, has recently been shown to be decreased in patients with stable

COPD compared to healthy controls. If systemic inflammation is a cause of endothelial

dysfunction in COPD, endothelial function as well as sRAGE levels would be suspected to be

further impaired during exacerbation and recover thereafter. The study has been approved

by the institutional ethics committee and 29 patients have been enrolled and followed up. We

observed a significant improvement of endothelial dysfunction as well as sRAGE levels from

acute exacerbation clinical recovery. Our study was the first to suggest decreased sRAGE as

a potential mediator for endothelial dysfunction during acute exacerbation of COPD.

Moreover, novel insights were given into the role of acute exacerbation as a determinant of

endothelial dysfunction and therefore morbidity and mortality. Our data favoured sRAGE as a

potential link between acute exacerbations and the excess occurrence of cardiovascular

events in COPD.

After completion of recruitment the manuscript entitled „Soluble receptor of advanced

glycation end-products and endothelial dysfunction in COPD“ was published in forms of an

original research article (Respir Med. 2014).

This study will be included in the PhD-thesis of Matthias Urban at the Medical University of

Vienna.

2.1.4. Longitudinal study of endothelial function in COPD

Aims: Longitudinal follow up of the original project studies systemic vascular function,

markers of systemic inflammation and lung function in patients with stable COPD and

appropriate controls free from traditional cardiovascular risk factors (“Determinants of

systemic vascular function in patients with stable chronic obstructive pulmonary disease,

AJRCCM 2008).

In order to assess the disease course of subclinical cardiovascular disease in our study

population, a longitudinal follow-up study was initiated in a subset of patients with COPD

from the previously described cohort. In this study we determined systemic vascular function,

circulating inflammatory markers, lung function parameters, and markers of glucose

metabolism at baseline and after 12 months. We observed worsening of endothelial

dysfunction and altered glucose metabolism in the presence of preserved lung function

values, indicating progression of cardiovascular risk within this cohort. Noteworthy, there was

a significant relationship between changes in endothelial function and insulin resistance,

suggesting an important role for altered glucose metabolism in the development of


cardiovascular disease. Results of this study have been accepted for presentation at various

national and international congress meetings including the European Respiratory Society

(Eur Respir J Suppl 2008) and the American Thoracic Society (Am J Respir Crit Care Med

2010 Suppl).

The manuscript entitled “Insulin resistance may contribute to systemic vascular dysfunction

in patients with stable COPD: a longitudinal pilot study” has successfully been published in

2014 (Wien Klin Wochenschr. 2014) and will be submitted as part of the PhD Thesis of

Matthias Urban.

2.1.5. Diastolic dysfunction and dynamic hyperinflation

Aims: To investigate the impact of dynamic hyperinflation on diastolic dysfunction in COPD

patients without history of cardiovascular diseases.

COPD is associated with an access cardiovascular comorbidity. Diastolic dysfunction of the

left ventricle is a frequent condition among patients with COPD. A recent study showed the

prevalence of diastolic dysfunction to 90% in patients with severe stable COPD. The distinct

mechanisms for this observation are not fully understood. Dynamic hyperinflation was

suggested as a potential determinant of diastolic dysfunction in patients with COPD.

However, potential cofactors like arterial hypertension, hypoxia, reduced exercise capacity

airflow obstruction and ventricular interdependence could confound the association of

dynamic hyperinflation and diastolic dysfunction in patients with COPD. Via metronome-

paced tachypnoea, dynamic hyperinflation can be induced in patients with airflow obstruction

as well as in healthy subjects. Consequently, we are planning a randomized cross-over trial

investigating the impact of dynamic hyperinflation on diastolic dysfunction via metronome-

paced tachypnoea in 10 subjects free from cardiorespiratory diseases. Results from this

study will provide further insight into a potential association between altered respiratory

mechanics and cardiovascular comorbidities in COPD.

Parts of this study will subsequently be submitted as a diploma thesis at the Medical

University of Vienna by Anna Mayer.


2.2. Sleep in COPD

2.2.1. Sleep profiles in COPD patients with different severity

Aims: To identify differences in symptom profile and in patients with stable COPD and

controls without airflow obstruction.

Patients with COPD have a higher prevalence of obstructive sleep apnea (OSA), insomnia,

nightmares and daytime sleepiness than the general population. These sleep disturbances

contribute to the nonspecific daytime symptoms of chronic fatigue, lethargy and overall

impairment in quality of life described by these patients. Unfortunately, sleep impairment is

an aspect of COPD that is frequently ignored by many physicians, even in research protocols

designed to assess the impact of COPD on quality of life. Primary aim of this research line

was therefore 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. Using polysomnography in 72 patients

with stable mild-moderate COPD we detected a 28% prevalence of obstructive sleep apnea.

After exclusion of patients with OSA, we observed that patients with COPD only had overall

lower sleep efficiency, a lower total sleep time, and lower mean overnight oxygen saturation

compared with controls. Patients with COPD were furthermore significantly more likely to

report symptoms such as insomnia and difficulty in initiating and maintaining sleep. Thus our

results indicate clinically relevant impairment in both quantity and quality of sleep in patients

with stable mild to moderate chronic obstructive pulmonary disease. The results of this report

have been recently published (Sleep Med 2011).

A variety of therapeutic modalities exist to treat sleep disordered breathing. While continuous

positive airway pressure therapy has become the standard treatment of OSA, many patients

suffer from local side-effects at the nose or face, or discomfort due to the mask. Moreover,

CPAP does not allow for a permanent resolution of respiratory disturbances during sleep, but

only suppresses them while using the devices. Therefore, many patients look for more

comfortable or curative treatment options. Both conservative and surgical alternative

therapeutic approaches have been described. However, there is a need to discuss the

scientific evidence for these therapies. Thus, the LBI - COPD and PE (A.Valipour) joined a

European Respiratory Society Task Force initiative with the aim of screening the scientific

literature on non-positive-pressure therapies, evaluating the studies according to the criteria

of the evidence-based medicine, and giving recommendations for use in sleep disordered

breathing patients. First results of this Task Force have been published (Eur Respir J 2011).


2.2.2. VASA Study

Validation of the ApneaScan Algorithm for the detection of Sleep Disordered

Breathing in patients with stable symptomatic chronic heart failure

Aims: To validate the ApneaScan algorithm as a screening tool in chronic heart failure.

The purpose of this prospective, multinational, multicentre study is to validate of the

ApneaScan algorithm (integrated in ICD and CRT-D devices) for the screening of sleep

disordered breathing in patients with stable symptomatic chronic heart failure, using portable

polygraphy monitoring and polysomnography as a reference. Secondary objectives are the

detection of severe SDB in patients with clinically indicated in-laboratory polysomnography,

as well as correlations of AHI detected by ApneaScan with other clinical endpoints including

morbidity and mortality data. For this purpose 200 consecutive patients with moderate-to-

severe stable heart failure who receive an ICD or CRT-D implantation with the ApneaScan

algorithm will be enrolled in Austria, Germany, and Japan. The algorithm of the ApneaScan

is based on significant changes of the intrathoracic impedance (defined by a decrease of

thoracic impedance >30% during >10 sec) as detected between the cardiac lead and the ICD

device itself, correlating to the airflow during sleep.

The study has commenced in 2012 and is actively enrolling patients. First results are

expected during the course of 2016.

2.3. Adiposity in COPD

2.3.1. Systemic inflammation in patients with chronic obstructive

pulmonary disease: results from the COSMIC study

Aims: To investigate the association of host-related factors on systemic inflammation in

COPD.

Age, gender, and body composition (body mass index, BMI; fat-free mass index, FFMI; fat

mass index, FMI) were related to inflammatory biomarkers: CRP, fibrinogen, TNFα, and its

soluble receptors (s)TNFαR1 and sTNFαR2. Furthermore, forced expiratory volume in the

first second (FEV1), BMI, FFMI, and FMI were stratified by quartiles to elucidate the influence

on inflammatory biomarkers. Monovariate and multivariate regression analyses were

performed for associations between inflammatory biomarkers. Positive correlations were

found for FFMI with sTNFαR1, FMI with CRP and age with TNFα, sTNFαR1 and sTNFαR2

(p<0.01). FEV1 was not correlated with body composition and inflammatory markers. Mono-


and multivariate analysis showed weak correlations between the acute phase markers and

the TNFα system after correcting for multiple co-variants. In conclusion this study highlights

the modest role of age and body composition on levels of systemic inflammatory biomarkers

in COPD. Results show the degree of airflow limitation does not affect systemic

inflammation. Last, a weak relationship between acute phase markers and markers of the

TNFα system is present in COPD.

The full length article has been published in Open Journal of Respiratory Diseases 2012.

2.3.2. Gender differences in the adipose secretome system in COPD

Aims: To investigate gender related differences in the adipokine metabolism in relation to

systemic inflammatory biomarkers in clinically stable subjects with COPD.

The role of circulating leptin and other adipokines in the involvement of the systemic

inflammation in COPD is only studied scarcely. This study investigated besides other factors

plasma concentration of the adipokines (leptin, adiponectin and resistin) and systemic

inflammatory biomarkers C-reactive protein (CRP), interleukin 6 (IL-6), tumor necrosis factor

α (TNFα), and its soluble receptors 55 and 75 (sTNFα-R55, R75) in patients with COPD and

healthy controls. In conclusion men with clinically stable COPD, leptin, adiponectin and

resistin appear to be physiologically regulated, while in women, leptin metabolism is altered.

Leptin secretion is increased in COPD women when compared to healthy women and

compared to COPD men, and to a greater extent in overweight women with COPD.

The full length article has been published in Respir Med. 2011.

2.3.3. Dysregulated adipokine metabolism in COPD

Aims: To investigate the adipokine metabolism in relation to systemic inflammatory

biomarkers and to evaluate gender related differences in the adipokine metabolism in COPD.

Research concerning the involvement of body composition and systemic inflammatory

markers in adipokine metabolism in COPD is still limited. 186 subjects with COPD and 113

controls, matched for age, gender, and body composition were selected from the ECLIPSE

cohort. COPD patients had higher levels of CRP, IL-6, fibrinogen and adiponectin. After

stratification for gender, men with COPD had higher CRP, IL6 and fibrinogen levels

compared to male controls, while women with COPD had higher levels of CRP and

fibrinogen compared to the female controls. Moreover, in both female controls and COPD

patients, leptin correlated with CRP and fibrinogen, while leptin only correlated with CRP in

male controls. Adiponectin correlated negatively with CRP, only in COPD patients. Body

mass index and gender were the strongest determinants for both leptin and adiponectin. The


study shows a gender dependent dysregulation of adipokine metabolism in COPD patients

and suggests a more prominent role of adiponectin in the systemic response of COPD.

The full length article has been published in Eur J Clin Invest. 2012.

2.3.4. Prevalence of metabolic syndrome in COPD patients and its

consequences

Aims: To investigate the prevalence of metabolic syndrome in COPD patients.

The prevalence of metabolic syndrome in COPD and its impact on patient related outcomes

has been little studied. In this investigation metabolic syndrome was present in 57% of the

COPD patients and 40% of healthy control subjects. In summary, metabolic syndrome is

more prevalent in overweight or obese COPD patients than in BMI matched healthy subjects,

while comparable frequencies were observed in normal weight patients and healthy subjects.

Metabolic syndrome did not additionally impact patients’ related outcomes, like functional

parameters, but did impact the prevalence of co-morbidities. The long-term impact of

metabolic syndrome in COPD needs further studies.

The full length article has been published in PLoS One. 2014.


3. Program Line 3: Therapeutic interventions in COPD

Background

Chronic disease management aims to improve morbidity and mortality of patients by

pharmacological and non-pharmacological therapeutic strategies. Utilization of health

resources is limited and therefore needs understanding of the effects of interventions on

health status with respect to quality of life but also quantifying the impact of interventions.

Non-pharmacologic treatment options in COPD include smoking cessation, pulmonary

rehabilitation, oxygen therapy, ventilatory support, surgical treatments (lung volume reduction

surgery, lung transplantation) and nutritional support.

The LBI – COPD and PE continuous to be involved in the development of novel non-

pharmaceutical techniques in the treatment of moderate-to-severe COPD.

Non-pharmacologic treatment options as ventilatory support have been investigated by the

LBI – COPD and PE within the last years. Although the concept of non – invasive

mechanical ventilation, a ventilator treatment option in severe COPD patients with

hypercapnia is very convincing in acute on chronic respiratory failure in COPD, showing clear

beneficial effects of positive endexspiratory pressure levels on dynamic hyperinflation,

reduction of dyspnea and work of breathing, noninvasive ventilation in stable COPD patients

remains controversial.

While over the past 5 years the focus of interventional COPD treatment was dedicated to

safety and efficacy of lung volume reduction for severe hyperinflation associated with

emphysema, more recent projects aim at appropriate patient selection and treating patients

with the bronchitic phenotype of the disease. In this context, the LBI-COPD has moved from

a purely participatory into a pro-active role initiating and leading multi-center international

collaborations. The reputation of the clinical program of the institute further allows to extend

the research line beyond COPD and to touch other areas of interest in the field of

Respiratory Medicine, such as lung cancer treatment.

Endobronchial methods designed to perform lung volume reduction are being pursued as a

less invasive means to achieve the benefits associated with surgical intervention. The

Endobronchial Valve for Emphysema Palliation Trial (VENT study) was a multi-centre,

prospective, randomised, controlled study conducted at 31 clinical sites in the USA and 23

sites in Europe to evaluate safety and effectiveness of endobronchial valve (EBV) therapy

compared with optimal medical management. In a collaborative effort with key-opinion

leaders in the field we were able to demonstrate statistically significant, but clinically modest

improvements in lung function, exercise capacity and symptoms in patients who underwent


unilateral lobar volume reduction using EBV treatment. Using quantitative image analysis

using the combined US and European data set we identified lobar exclusion and interlobar

fissure integrity as the most important predictors of target lobe volume reduction. Patients

with higher target lobar volume reduction in turn demonstrated not only statistically, but also

clinically relevant benefits in COPD related outcomes, including the BODE index. The results

of these studies have contributed to improving patient selection for EBV therapy, both in

clinical practice and in future research efforts in this particular field. Consequently, a series of

prospective, randomized controlled trials have been launched.

There is increasing recognition in respiratory research that the relationship between many

surrogate outcomes (i.e. physiological and/or anatomical outcomes) and outcomes that

matter to patients (i.e. “patient-centred” or “patient-important” outcomes, such as dyspnoea,

quality of life, frequency of exacerbations, frequency of hospitalisations, and mortality) is

modest at best, and interventions that improve surrogate outcomes frequently do not affect

patient-centred outcomes. As a result international respiratory societies call for an increasing

emphasis on 1) using patient-centred outcomes in clinical research, and 2) finding high-

quality surrogate outcomes that reliably predict patient-centred outcomes. In this context,

there is an increased interest in integrated care or disease management programs.

Integrated care programs in COPD include patient self-education, coordinated care, self-

management, home care, and interventions that address the rehabilitative and psychological

aspects of the disease, with or without support via information technologies. The LBI –

COPD and PE acknowledges the importance of this plea and thus has decided to set-up a

new research focusing on patient self-management and disease management.

Consistent with the affiliated clinical expertise at the site of the LBI – COPD and PE, Program

Line 3 was launched with a focus on major non-pharmacological treatment options in COPD,

which are discussed further in detail.

3.1. Non-invasive ventilation in COPD

3.1.1. The NIVEX Trial

Ventilatory support in COPD patients who remain hypercapnic after one

episode of acute respiratory failure requiring mechanical ventilation

Aims: To evaluate the efficacy of nocturnal non-invasive ventilation in chronic respiratory

failure: withdrawal of non-invasive home ventilation in stable hypercapnic COPD patients.


NIVEX was a controlled study recruiting COPD patients after acute on chronic respiratory

failure being ventilated for emergency reasons. NIVEX follows clinical stabilization of a

severe group of COPD patients - who had to be ventilated because of severe acute on

chronic respiratory failure and remained hypercapnic after recompensation - after hospital

discharge by noninvasive nocturnal ventilation for 6 month. After this period randomized

withdrawal of ventilation is performed (intervention group) or non-invasive ventilation

continued (control group). The LBI – COPD and PE showed that withdrawal of non-invasive

ventilation decreased the time to clinical worsening and decreased the six-minute walking

distance. Therefore, acute respiratory failure in COPD patients with sustained hypercapnia

non-invasive ventilation has to be considered in optimal treatment for COPD patients.

The full length article has been published in "Respiratory Medicine" in 2011 (Respiratory

Medicine 2011). However, the effects of this promising treatment option on mortality of could

not be analyzed due to patient number. Therefore the LBI – COPD and PE started with an

international consortium a multi-center trial (see 3.1.2.).

3.1.2. The Multicenter NIV Study

Aims: To investigate the effect of long-term non-invasive positive pressure ventilation

targeted to markedly reduce hypercapnia, on survival in patients with advanced, stable

hypercapnic COPD.

The NIV Study is an European (German- Austrian- Swiss) investigator-initiated, prospective,

multicentre, randomised, controlled clinical trial enrolling patients with stable severe COPD

and hypercapnia. The effects of non-invasive ventilatory support on mortality have been

analyzed and showed that long-term non-invasive ventilatory support in addition to standard

treatment improves survival of patients with hypercapnic, stable COPD when non-invasive

ventilatory support is targeted to greatly reduce hypercapnia.

The full length article has been published in Lancet Respiratory Medicine in 2014 (Lancet

Respir Med. 2014).

3.1.3. Predictive Markers for Long-Term Outcome in COPD Patients

treated with Invasive or Non-Invasive Ventilation for Acute

Hypercapnic Failure

Aims: To define predictive markers for long-term outcome in COPD patients requiring non-

invasive ventilation after failure.


COPD patients who survive an episode of acute hypercapnic respiratory failure (AHRF)

requiring non-invasive ventilation (NIV) with or without secondary invasive ventilation (IV)

have a dismal prognosis. Knowledge of the factors preceding recurrent respiratory failure

would enable early identification of those patients who may benefit from frequent control

visits, early rehabilitation and domiciliary non-invasive ventilation. A better estimation of the

prognosis may also be helpful for establishing end-of-life decision in time. We plan a

retrospective record review study to explore predictive markers for long-term outcome in

COPD patients requiring NIV with or without secondary IV for AHRF. A cohort of more than

500 COPD patients with AHRF surviving to hospital discharge after treatment with NIV +/-

secondary IV will be assessed. Outcome parameters will be the time to recurrent hospital

admission for respiratory reasons, the time to recurrent ICU admission and mechanical

ventilation, and the time to death. Risk factors will be various clinical variables obtained

during and after the index admission. Publication is expected for 2015.

3.1.4. Prevalence and Prognosis of Chronic Obstructive Pulmonary

Disease in Critically ill Patients between 1998 and 2008

Aims: To investigate prognosis and accompanied factors of COPD patients with respiratory

failure.

A retrospective review of prospectively collected data from 121 Austrian intensive care units

(ICU) between 1998 and 2008 with regard to the incidence, severity and outcome of ICU

admissions who had a co-morbidity of COPD or who were admitted to the ICU because of

acute respiratory failure due to COPD were analysed. COPD was present in 9% of all ICU

patients. The risk-adjusted mortality of patients with COPD was higher compared to patients

without COPD. A mixed logistic model was calculated to identify factors associated with

mortality. The presence of COPD was an independent risk factor for increased mortality and

was associated with prolonged mechanical ventilation and prolonged weaning. Twenty-four

percent of the patients with COPD were admitted to the ICU because of acute respiratory

failure due to COPD. During the course of the 11 years, the incidence of acute respiratory

failure due to COPD increased by about two thirds, and the use of non-invasive ventilation

within the COPD cohort more than doubled. Simultaneously, the risk-adjusted mortality of

patients with COPD improved. In conclusion, the presence of COPD is an independent risk

factor for mortality and morbidity in critically ill patients. The increasing incidence of acute

respiratory failure due to COPD was accompanied by a decrease in the risk-adjusted

mortality.

The full length article has been published in “European Respiratory Journal” (Eur Respir J.

2013).


3.1.5. Determining the Causes of prolonged weaning from mechanical

ventilation

Aims: To investigate underlying prognostic factors for prolonged weaning in COPD patients

with mechanical ventilation.

Prolonged weaning from mechanical ventilation is a substantial medical, ethical and financial

problem. Knowledge of the underlying causes of weaning failure (e.g. respiratory muscle

weakness, heart failure) is valuable for expediting successful weaning. It is unknown,

whether an intensive cardiopulmonary diagnostic workup is superior to clinical estimation of

the causes of weaning failure. We hypothesize that an intensive cardiopulmonary diagnostic

workup is superior to clinical estimation of the causes of weaning failure.

Study endpoints are 1. Sensitivity and specificity of the clinical assessment for cause(s) of

weaning failure, and 2. Incidence of the various causes of weaning failure.

Data collection is ongoing (close up in 2016).

3.2. Interventional COPD Treatment

3.2.1. Treatment of emphysema using vapor ablation

Aims: To determine the efficacy and safety profile of Bronchoscopic thermal vapor ablation

(BTVA) in COPD patients with emphysema.

BTVA uses heated water vapour to produce a thermal reaction leading to an initial localized

inflammatory response followed by permanent fibrosis and atelectasis. The remodeling

results in reductions in tissue and air volume of the targeted regions of the hyperinflated lung.

Given the mechanism of action BTVA appears to be an alternative for patients with severe

emphysema who are not eligible or do not benefit from valve treatment. A prospective, non-

randomized, multi-center trial was initiated to determine the efficacy and safety profile of

BTVA in patients with emphysematous type of COPD. BTVA therapy at a vapor dose of 10

cal/g was administered unilaterally to one upper lobe in 44 patients with heterogeneous

emphysema. The procedure was completed in all patients without procedure-related adverse

events. After 6 months, HRCT measurement of lobar volume was reduced by 48%.

Physiological changes included improvements in airflow and reductions with hyperinflation.

These improvements were clinically relevant, as demonstrated by patient-reported outcomes

of quality of life (reductions in the SGRQ and mMRC dyspnoea scores). Reduced symptoms

were supported by more functional outcomes, such as improvements in exercise tolerance.

Consecutive analysis demonstrated that patients with higher upper-to-lower lobe

heterogeneity and those with more prominent respiratory symptoms in the first 30 days


following BTVA therapy experience greater efficacy. The latter phenomenon is a surrogate of

a local inflammatory response reaction, which appears to predict a successful remodeling

process of the lung and thus effective volume reduction. On the basis of these results, future

studies have been launched aiming to further improve safety and efficacy of this novel

approach.

Multiple full length articles have been published continuously since 2012 (Eur Respir J. 2012,

Respiration. 2012, Int J Chron Obstruct Pulmon Dis. 2012, and Respiration. 2013).

3.2.2. Treatment of emphysema using emphysematous lung sealant

Aims: To determine the efficacy and safety profile of Emphysematous lung sealant (ELS) in

COPD patients with emphysema.

ELS is a liquid foam sealant that functions at the small airway and alveolar level, and is

designed to produce volume reduction by flowing into the lung periphery and blocking

conducting airways and collateral ventilation channels independent of collateral ventilation. In

order to ensure appropriate patient selection for this novel therapy, the effects of ELS

therapy on lobar and total lung volumes, gas trapping, spirometry, functional capacity and

health-related quality of life were studied in patients with advance upper lobe predominant

emphysema with and without complete fissures. In this prospective, non-randomized, multi-

center trial patients were treated at two to four subsegmental sites over one or two treatment

sessions. We were able to demonstrate lung volume reduction and clinical benefits in treated

patients at 3 months, irrespective of the presence or absence of interlobar fissures. Similar

results have been observed in patients with homogeneous emphysema. Thus, to further

understand the physiological basis for that observation, we developed a computer model to

simulate the effects of upper and lower lobe lung volume reduction on hyperinflation and lung

recoil in homogeneous emphysema. We observed that increases in transpulmonary pressure

subsequent to volume reduction increased the ratio of residual volume to total lung capacity

in upper lobe alveoli, while caudal shifts in airway closure decreased this ratio in lower lobe

alveoli. Consequently, segmental or subsegmental upper lobe treatment in homogeneous

emphysema eliminates apical alveoli with high RV/TLC values, while it lowers the average

RV/TLC of the lung. Conversely, lower lobe treatment eliminates caudal alveoli with low

RV/TLC values, has less effect. Thus, our findings provide a scientific physiological rationale

for regional differential effects of ELS treatment in patients with homogeneous emphysema.

Full length articles have been published in 2012 (Front Physiol. 2012, Thorax. 2012).


3.2.3. Pneumothorax management in patients with COPD

Aims: To determine the efficacy and safety profile one-way endobronchial valves in COPD

patients with emphysema.

The use of endoscopically placed one-way endobronchial valves for the treatment of

emphysema is increasing. With better patient selection, there is also an increased likelihood

of complications associated with the procedure, such as postprocedural pneumothorax.

Many of these patients suffer from prolonged alveolar-pleural fistula. There is, however, little

evidence of pneumothorax management in patients with severe COPD and emphysema. In a

series of clinical studies we have investigated the outcome and the management of patients

with post-procedural pneumothorax after endoscopic valve placement for lung volume

reduction in patients with moderate-to-severe, emphysematous type of COPD. As a result of

these studies an expert recommendation has been developed to outline pneumothorax

management after valve placement to inform physicians and patients of the risk-benefit

profile and to assist them in decision making. Skilled and aggressive pneumothorax

management is necessary in this patient population, and by following these

recommendations traumatic scenarios, prolonged drainage, extended hospitalizations,

and/or surgery might be avoided in many cases. We have furthermore developed a novel

diagnostic and therapeutic approach for prolonged air leaks using digital air leak flow

monitoring to assess the effects of unidirectional valve placement to block ventilation to the

pleural surface. Consequently, the duration of chest tube drainage and hospital stay of these

patients can be reduced, thus potentially contributing to reduced morbidity and mortality as a

result of alveolar-pleural fistula.

Full length articles have been published continuously since 2013 (Respiration. 2014, Eur

Respir J. 2014, Respiration. 2014, Ann Thorac Surg. 2013, Pneumologie. 2013).

3.2.4. Airflow-1

Sequential Two Phase Multicenter, Randomized Study to Optimize Dose

Selection and Evaluate Safety After Treatment with the Holaira Lung

Denervation System in Patients with Moderate to Severe COPD

Aims: To investigate targeted lung denervation as a treatment in moderate to severe COPD.

Parasympathetic pulmonary nerves release acetylcholine that induces smooth muscle

constriction. Disruption of parasympathetic pulmonary nerves may improve lung function and

COPD symptoms. This research investigates 'targeted lung denervation' (TLD), a novel

bronchoscopic therapy based on ablation of parasympathetic pulmonary nerves surrounding


the main bronchi, as a potential therapy for patients with COPD. In a one year prospective

multi-centre pilot study, the LBI – COPD and PE and collaborators demonstrated safety and

feasibility of TLD in patients with moderate-to-severe COPD. Secondary efficacy data

demonstrated improvements in lung function and quality of life, thus prompting future

research in this field (Slebos DJ et al. Thorax 2015). Hence, a two-phase study has been

initiated to further test safety and feasibility of the TLD System at two energy levels with an

improved delivery device in order to establish the optimal energy dose. In the second phase

of the study, the LBI – COPD and PE and collaborators aiming to compare the safety and

feasibility outcomes between the TLD System vs. a Sham-control group (patients and follow-

up team) utilizing the optimal energy dose.

This ongoing project (2014 – 2017) is a prospective, multicenter, multinational, randomized,

double-blind trial of patients with moderate-to-severe-COPD with international collaborations

(UMC Groningen, Royal Brompton Hospital, and University Leuven).

3.2.5. IMPACT

A Multi-center, Prospective, Randomized, Controlled Investigation of

Endobronchial Valve Therapy vs. Standard of Care in Homogeneous

Emphysema

Aims: To investigate the effects of endobronchial valve treatment in COPD patients with

homogenous emphysema.

Fifty-six subjects with homogeneous emphysema will be recruited from 8 centers in Europe.

Potential subjects with bilateral homogeneous emphysema will initially be identified by visual

read of a high-resolution computer tomography scan by the investigator. Homogeneity will be

confirmed in a core-lab using computerized software. Only those subjects where there is a

heterogeneity index (difference in destruction scores between potential target and ipsilateral

lobes) of < 15% will be considered for enrolment into the study. The target lobe for valve

placement will be determined by perfusion scanning by identifying the lung zone with the

lowest perfusion and patients with greater than 20% difference in perfusion between the left

and right lung will be excluded. All potential study candidates will then undergo a real-time

assessment to determine the extent of collateral ventilation between the target and adjacent

lobes. Subjects will be followed up for a period of 12 months following randomization.

Assessments will be performed at 30 days (valve group only), 3, 6, and 12 months post

enrolment. Subjects in the standard of care arm will be offered valves after completing the 6

months follow-up.


This ongoing project (2014 – 2016) is a prospective, multicenter, multinational, randomized,

controlled trial in patients with emphysematous type of moderate-to-severe-COPD with

international collaborations (University of Heidelberg, UMC Groningen, and Charite Berlin).

3.2.6. STEP-UP

Segmental Treatment of Emphysema with Upper Lobe Predominance

Aims: To investigate the effects of bilateral vapor ablation in addition to standard medical

management in COPD.

Vapor ablation can be used to target specifically the most diseased (emphysematous)

segments of each upper lobe. The STEP-UP trial (Valipour A. BMC Pulm Med. 2014)

compares patients receiving standard medical management alone against patients receiving

bilateral vapor ablation in addition to standard medical management. By dividing the

procedure into two sessions, there is potential to increase the total volume treated per patient

but reduce volume treated and energy delivered per session. This is expected to correlate

with improvements in vapor ablation's safety and efficacy profiles. Sixty nine subjects will be

randomized at a 2:1 (treatment arm: control arm) ratio. The primary endpoints are the

change in FEV1%predicted and St. George Respiratory Questionnaire (SGRQ) score

between the treatment and control arm at 12 months. Adverse events will be monitored as

secondary endpoints along with other efficacy outcomes at 6 and 12 months.

This ongoing project (2013 – 2015) is a randomized, controlled, multinational, multicenter,

open-label, 12 month study of patients with upper lobe predominant emphysema with

international collaborations (University of Melbourne, University of Heidelberg).

3.2.7. Intrabronchial Valve System 9mm European Evaluation Study

Aims: To evaluate the performance of the Intrabronchial Valve System in COPD patients.

This is a multicenter, prospective study designed to evaluate the performance of the

Intrabronchial Valve System in patients with at least one airway with the intention to be

treated with a 9 mm valve. The study is expected to enroll up to 30 patients with up to 15

patients per site. The primary endpoint is the mean change in target lobe volume from

baseline to 180 days post procedure and the number of adverse device effects through 180

days. The treatment algorithm is complete occlusion of one lobe of the lung by using valves

to occlude all segments of the lobe. The lobe will be selected based on imaging with high

resolution computed tomography. The lobe to be treated will have severe heterogenous

emphysema based on visual exam. The selected lobe will also have an intact fissure

separation with the ipsilateral lobe. An intact fissure will be estimated visually to be ≥ 90%


complete after viewing the HRCT in 3 dimensions. If more than one lobe meets criteria, the

investigator will determine a primary lobe to treat based on fissure completeness,

heterogeneity, disease severity, and the anatomy of the airways that will be treated.

This ongoing project (2015 – 2016) is a binational, multicenter, open-label, 6 month study of

patients with upper lobe predominant emphysema with international collaborations

(University of Heidelberg, Lungenklinik Hemer).

3.2.8. Effects of lung volume reduction recoil procedure on Cardiac

function and exercise capacity in patients with emphysematous type

of COPD

Aims: To determine the treatment effects of lung volume reduction recoil procedure on

cardiac function and exercise capacity.

The Lung Volume Reduction Coil procedure is a minimal invasive approach designed to

compress the areas of lung parenchyma most damaged by emphysema. This compression

reduces air flow to treated portions of the lung allowing enhanced airflow to healthier

untreated portions of the lung. Additionally, by gathering up the loose parenchyma of the

most severely damaged segments, the Coil restores elasticity and recoil to the whole lung,

improving expiratory flow rates, lessening small airway collapse with air trapping, and

reducing dynamic hyperinflation. The objective of this study is to determine the treatment

effects on improvement of cardiac function and exercise capacity. We hypothesize that the

reduction in dynamic hyperinflation results in improvement of non-invasively obtained, real

time, beat-to-beat cardiovascular measurements, including cardiac output, baroreceptor

sensitivity, and heart rate and blood pressure variability. For this purpose 25 patients with

moderate-to-severe, emphysematous type of COPD will be prospectively studied for

eligibility. Patients included will undergo comprehensive pulmonary and cardiac assessment

prior to and 3 to 6 months after bilateral coils therapy.

This ongoing project (2015 – 2017) is a monocentric, non-randomized, uncontrolled

interventional prospective study.

3.2.9. Real-life effects of endobronchial vale treatment in patients

without collateral ventilation in Austria

Aims: To investigate effects of endobronchial vale treatment in COPD patients with

Emphysema and without collateral ventilation.


Multicenter, retrospective analysis patients who underwent endobronchial valve treatment for

severe emphysema with evidence of hyperinflation on lung function and CT scans. Real-life

data from 4 centers in Austria will be collected and analyzed with a follow-up up to two years

from index bronchoscopy. Functional outcomes, complications, and medium-term results will

be evaluated and analyzed to provide the first dataset for valve treatment in an Austrian

population.

This ongoing project (2015 – 2016) is a multicenter, national, retrospective case series with

national collaborations (LKH Vöcklabruck, LKH Natters, KH Elisabethinnen Linz).

3.3. Patient self-management and disease management

3.3.1. SMARTair

Self-Management, gAmified Respiratory Training and dEcision suppoRt for

COPD patients

Aims: To investigate the effects of gamified respiratory training and decision support for

COPD patients.

SMARTair offers a holistic solution for COPD patients supporting their self-management of

the disease. The first phase of the study will be used to collect real-life, continuous health

data (heart rate, oxygen and carbon dioxide saturation, respiration rate, number of steps and

pulmonary function tests) over the course of one year, which will be used for the

development of a novel computer model to predict the clinical worsening of COPD including

acute exacerbations. The second phase of this study will be used to develop modular

solution that eases handling and living with this disease. Therefore, users will receive a

sensor wristband and a newly designed mouthpiece that is blended with a medication

inhaler. All components will be wirelessly connected to the SMARTair mobile application,

which is accessible via personal devices. The sensor wristband includes all necessary

sensors for health data and a new mouthpiece to measure data lung function, the latter can

further be used for inhaler medication. With the help of innovative gamification and

motivation strategies, patients will be further motivated to train frequently which is not only

beneficial for their personal health situation but also generates valuable and comparative

health data to be monitored over time. The mobile application serves as data aggregator and

the main entrance to our major COPD tools for self-managing all aspects of this disease.

This project (2015 – 2018) is prospective, multicenter, two-phase trial in patients with mild-to-

moderate COPD with international collaborations (Austrian Institute of Technology, Charles


University Prague, Politecnico di Milano, Fraunhofer Institute Portugal) has been recently

submitted for the Horizon 2020 European Commission Call.


Publications (Original articles)

1. Petkov V, Mosgöller W, Ziesche R, Raderer M, Stiebellehner L, Vonbank K, Funk GC, Hamilton G, Novotny C, Burian B, Block LH. Vasoactive intestinal peptide as a new drug for tre atment of primary pulmonary hypertension. J Clin Invest. 2003, 111:1339-46.

2. Stiebellehner L, Petkov V, Vonbank K, Funk GC, Schenk P, Ziesche R, Block LH. Long-term treatment with oral sildenafil in additio n to continuous IV epoprostenol in patients with pulmonary arterial hypertension. Chest. 2003, 123:1293-5.

3. Bauer E, Funk GC, Gendo A, Kramer L, Zauner C, Sterz F, Schneider B, Madl C. Electrophysiological assessment of the afferent sen sory pathway in cardiac arrest survivors. Eur J Clin Invest. 2003, 33:283-7.

4. Mc Gown AD, Alwell C, Makker HK, Al-Rawi P, Valipour A, Spiro SG. Measurement of changes in cytochrome oxidase redox state during obstructive sleep apnoea using near infra-red spectroscopy. Sleep 2003, 26:710-716.

5. Valipour A, Cozzarini W, Burghuber OC. Non-invasive pressure support ventilation in patien ts with respiratory failure due to severe acute cardiogenic pulmonary edema. Respiration 2004, 71 (2): 144 – 151.

6. Valipour A, Litschauer B, Mittermayer F, Rauscher H, Burghuber OC, Wolzt M. Circulating plasma levels of vascular endothelial g rowth factor in patients with sleep disordered breathing. Respir Med 2004, 98(12): 1180 – 1186.

7. Funk GC, Doberer D, Heinze G, Madl C, Holzinger U, Schneeweiss B. Changes of serum chloride and metabolic acid-base s tate in critical illness. Anaesthesia. 2004, 59:1111-5.

8. Alt E, Amann-Vesti BR, Madl C, Funk GC, Koppensteiner R. Platelet aggregation and blood rheology in severe s epsis/septic shock: relation to the Sepsis-related Organ Failure Assessment (SOFA) score. Clin Hemorheol Microcirc. 2004, 30:107-15.

9. Hartl S, Heindl W, Lahrmann H, Kink E, Oberwaldner B, Pfleger A, Schreiber, W, Studnicka, M, Wild, M, Zach, M. S. Provisions for long-term at home ventilated patient . Wiener klinische Wochenschrift. 2004;116 Suppl 3:1-20.

10. Block LH, Burghuber OC, Hartl S, Zwick H. Management of chronic obstructive pulmonary disease s (COPD). Wiener klinische Wochenschrift. 2004;116(7-8):268-78.

11. Valipour A, Kreuzer A, Koller H, Koessler W, Burghuber OC. Bronchoscopy guided topical hemostatic tamponade th erapy for the management of life threatening hemoptysis. Chest 2005, 127: 2113-2118.


12. Valipour A, Schneider F, Koessler W, Saliba S, Burghuber OC. Heart rate variability and spontaneous baroreflex s equences in supine healthy volunteers subjected to nasal positive airway press ure. J Appl Physiol 2005, 99(6): 2137-2143.

13. Prebio M, Katz-Papatheophilou E, Heindl W, Gelbmann H, Burghuber OC. Verminderung von Hautdefekten bei Bauchlagerung bei beatmeten Intensivpatienten durch das Prone-Head-Support-Syst em: eine Pilotstudie. Wiener klinische Wochenschrift 2005, 117/3: 98-105.

14. Kramer L, Hofer H, Bauer E, Funk GC, Formann E, Steindl-Munda P, Ferenci P. Relative impact of fatigue and subclinical cognitiv e brain dysfunction on health-related quality of life in chronic hepatitis C infe ction. AIDS. 2005, 19 Suppl 3: 85-92.

15. Funk GC, Doberer D, Osterreicher C, Peck-Radosavljevic M, Schmid M, Schneeweiss B. Equilibrium of acidifying and alkalinizing metaboli c acid-base disorders in cirrhosis. Liver Int. 2005, 25:505-12.

16. Fuhrmann V, Madl C, Mueller C, Holzinger U, Kitzberger R, Funk GC, Schenk P. Hepatopulmonary syndrome in patients with hypoxic h epatitis. Gastroenterology 2006, 131:69-75.

17. Funk GC, Doberer D, Fuhrmann V, Holzinger U, Kitzberger R, Kneidinger N, Lindner G, Schneeweiss B. The acidifying effect of lactate is neutralized by the alkalinizing effect of hypoalbuminemia in non-paracetamol-induced acute li ver failure. J Hepatol. 2006, 45:387-92.

18. Valipour A, Lothaller H, Rauscher H, Zwick H, Burghuber OC, Lavie P. Gender related differences in symptoms of patients with suspected breathing disorders in sleep: a clinical population study usi ng the Sleep Disorders Questionnaire. Sleep 2007, 30: 306-313.

19. Funk GC, Doberer D, Kneidinger N, Lindner G, Holzinger U, Schneeweiss B. Acid-base disturbances in critically ill patients w ith cirrhosis. Liver Int. 2007, 27:901-9.

20. Nava S, Sturani C, Hartl S, Magni G, Ciontu M, Corrado A, Simonds, A. End-of-life decision-making in respiratory intermed iate care units: a European survey. Eur Respir J. 2007;30(1):156-64.

21. Kneidinger N, Lindner G, Fuhrmann V, Doberer D, Dunkler D, Schneeweiss B, Funk GC. Acute phase proteins do not account for unmeasured anions in critical illness. Eur J Clin Invest. 2007, 37:820-5.

22. Eisenburger P, Funk GC, Burda G, Sterz FR, Laggner AN, Herkner H. Gas concentrations in expired air during basic life support using different ratios of compression to ventilation. Resuscitation 2007, 73:115-22.

23. Holzinger U, Kitzberger R, Fuhrmann V, Funk GC, Madl C, Ratheiser K. Correlation of calculated indices of insulin resist ance (QUICKI and HOMA) with the euglycaemic hyperinsulinaemic clamp technique for e valuating insulin resistance in critically ill patients .


Eur J Anaesthesiol. 2007, 24:966-70.

24. Lindner G, Funk GC, Schwarz C, Kneidinger N, Kaider A, Schneeweiss B, Kramer L, Druml W. Hypernatremia in the critically ill is an independe nt risk factor for mortality. Am J Kidney Dis. 2007, 50:952-7.

25. Valipour A, Schreder M, Wolzt M, Saliba S, Kapiotis S, Eickhoff P, Burghuber OC. Circulating vascular endothelial growth factor and systemic inflammatory markers in patients with stable and exacerbated chronic obs tructive pulmonary disease. Clin Sci 2008, 115: 225-232.

26. Funk GC, Lang I, Schenk P, Imkova I, Valipour A, Burghuber OC. Left ventricular diastolic dysfunction in patients with COPD in presence and absence of elevated pulmonary arterial pressure . Chest. 2008 June, 133(6):1354-9.

27. Eickhoff P, Valipour A, Kiss D, Schreder M, Cekici L, Geyer K, Kohansal R, Burghuber OC Determinants of Systemic Vascular Function in Patie nts with Stable COPD. Am J Respir Crit Care Med. 2008; 178: 1211-1218.

28. Vonbank K, Funk GC, Marzluf B, Burian B, Ziesche R, Stiebellehner L, Petkov V, Haber P. Abnormal pulmonary arterial pressure limits exercis e capacity in patients with COPD. Wiener klinische Wochenschrift 2008, 120:749-55.

29. Pitta F, Breyer MK, Hernandes NA, Teixeira D, Sant’Anna TJP, Fontana AD, Probst VS, Brunetto AF, Spruit MA, Wouters EFM, Burghuber OC, Hartl S. Physical activities in daily life in patients with COPD from Central-Europe and South-America: a comparative study. Respir Med. 2009 Mar, 103(3):421-6 .

30. Funk GC, Kirchheiner K, Burghuber OC, Hartl S. BODE index versus GOLD classification for explainin g anxious and depressive symptoms in patients with COPD - a cross-sectional study. Respir Res. 2009 Jan 9, 10(1):1.

31. Kaufmann M, Hartl S, Geyer K, Breyer MK, Burghuber OC. Measuring FEV6 for Detecting Early Airway Obstructi on in the Primary Care Setting: Quality and Utility of the New PiKo-6-Devi ce. Respiration 2009, 78:161-167 .

32. Zwick R, Burghuber OC, Dovjak N, Hartl S, Kössler W, Lichtenschopf A, Müller R, Zwick H. Der Effekt von einem Jahr ambulanter pneumologische r Rehabilitation auf Patienten mit COPD. Wiener klinische Wochenschrift 2009, 121/189-195 .

33. Hartl.S, Breyer MK. Nicht invasive Beatmung (NIV). Wiener klinische Wochenschrift Education. 2009;4(3):113-21.

34. Breyer MK, Spruit MA, Celis AP, Rutten EP, Janssen PP, Wouters EF; CIRO Network: Highly elevated C-reactive protein le vels in obese patients with COPD; a fat chance? Clin Nutr. 2009 Dec, 28(6):642-7.


35. Oschatz E, Prosch H, Kohansal R, Valipour A, Mostbeck GH. COPD and Osteoporosis: detection and grading of ver tebral fractures on lateral chest radiography . J Thorac Imaging 2009, 24:212-215.

36. Cekici L, Valipour A, Kohansal R, Burghuber O. Short-term effects of inhaled salbutamol on autonom ic cardiovascular control in healthy subjects: a placebo-controlled study . Br J Clin Pharmacol 2009, 67, 394-402.

37. Funk GC, Lindner G, Druml W, Metnitz B, Schwarz C, Bauer P, Metnitz PG. Incidence and prognosis of dysnatremias present on ICU admission. Intensive Care Med 2009, 35(2), 232-9.

38. Funk GC, Doberer D, Sterz F, Richling N, Kneidinger N, Lindner G, Schneeweiss B, Eisenburger P. The strong ion gap and outcome after cardiac arrest in patients treated with therapeutic hypothermia: a retrospective study. Intensive Care Med. 2009, 35, 232-9.

39. Kohansal R, Martinez-Camblor P, Agustí A, Buist AS, Mannino DM, Soriano JB. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort. Am J Respir Crit Care Med. 2009 Jul 1, 180(1), 3-10.

40. Walch A, Meshkat M, Reinisch W. Long-term outcome in patients with ulcerative colit is treated with intravenous cyclosporine A is determined by previous exposure t o thiopurines. Journal of Crohn’s and Colitis, 2010 Oct;4(4):398-404.

41. Funk GC, Anders S, Breyer MK, Burghuber OC, Edelmann G, Heindl W, Hinterholzer G, Kohansal R, Schuster R, Schwarzmaier-D'Assie A, Valentin A, Hartl S. Incidence and outcome of weaning from mechanical ve ntilation according to new categories. Eur Respir J 2010;35:88-94.

42. Eickelberg O, Laurent G, Nicod LP, Hartl S , Siafakas NM, ad hoc c. European Respiratory Society MD PhD programme in re spiratory science. Eur Respir J. 2010;36(2):229-30.

43. Breyer MK, Breyer-Kohansal R, Funk GC, Dornhofer N, Spruit MA, Wouters EF, Burghuber OC, Hartl S. Nordic Walking improves daily physical activities i n COPD: a randomised controlled trial. Respir. Res. 2010 Aug. 22, 11:112.

44. Rutten EP, Breyer MK; Spruit MA, Hofstra T, van Melick PP, Schols AM, Wouters EF. Abdominal fat mass contributes to the systemic infl ammation in chronic obstructive pulmonary disease. Clin Nutr. 2010 June 2, Dec; 29 (6): 756-60.

45. Funk GC, Breyer MK, Burghuber OC, Kink E, Kirchheiner K, Kohansal R, Schmidt I, Hartl S. Long-term non-invasive ventilation in COPD after ac ute-on-chronic respiratory failure. Respir. Med. 2010 Nov. 24

46. Funk GC, Lindner G, Druml W, Metnitz B, Schwarz C, Bauer P, Metnitz PG.


Incidence and prognosis of dysnatremias present on ICU admission. Intensive Care Med 2010;36:304-11.

47. Faybik P, Hetz H, Mitterer G, Krenn CG, Schiefer J, Funk GC, Bacher A. Regional citrate anticoagulation in patients with l iver failure supported by a molecular absorbent recirculating system. Crit Care Med 2010;39:273-9.

48. Lindner G, Funk GC, Lassnigg A, Mouhieddine M, Ahmad SA, Scharz C, Hiesmayr M. Intensive care-acquired hypernatremia after major c ardiothoracic surgery is associated with increased mortality. Intensive Care Med 2010;36:1718-23.

49. Randerath WJ, Verbraeckene J. Andreas S, Bettega G, Boudewyns A, Hamans A, Jalbert F, Paoli JR, Sanner B, Smith I, Stuck B, Lacassagne L, Marklund M, Maurer J, Pepin JL, Valipour A, Verse T, Fietze Non-CPAP therapies in Sleep Apnoea. Eur Respir J. 2011 May;37(5):1000-28.

50. Breyer MK, Rutten EP, Vernooy JH, Spruit MA, Dentener MA, van der Kallen C, Vangreevenbroek MM, Wouters EF. Gender Differences in the Adipose Secretome System in Chronic Obstructive Pulmonary Disease (COPD): a Pivotal Role of Leptin. Respir Med. 2011 Jul;105(7):1046-53.

51. Valipour A, Lavie P, Lothaller H, Mikulic I, Burghuber OC. Sleep profile and symptoms of sleep disorders in pa tients with stable mild to moderate chronic obstructive pulmonary disease. Sleep Med 2011 Apr;12(4):367-72.

52. Randerath WJ, Verbraecken J, Andreas S, Bettega G, Boudewyns A, Hamans E, Jalbert F, Paoli JR, Sanner B, Smith I, Stuck BA, Lacassagne L, Marklund M, Maurer JT, Pepin JL, Valipour A, Verse T, Fietze I. Non-CPAP therapies in OSA.

Eur Respir J. 2011; 37(5):1000-28. 53. Valipour A, Lavie P, Lothaller H, Mikulic I, Burghuber OC.

Sleep profile and symptoms of sleep disorders in pa tients with stable mild to moderate chronic obstructive pulmonary disease. Sleep Med 2011; 12(4):367-72.

54. Faybik P, Hetz H, Mitterer G, Krenn CG, Schiefer J, Funk GC, Bacher A. Regional citrate anticoagulation in patients with l iver failure supported by a molecular adsorbent recirculating system. Crit Care Med. 2011;39:273-9

55. Locker GJ, Fuchs EM, Worel N, Bojic A, Heinrich G, Brodowicz T, Clodi M, Funk GC, Knöbl P, Zielinski CC, Köstler WJ. Whole body hyperthermia by extracorporeal circulati on in spontaneously breathing sarcoma patients: hemodynamics and oxygen metabolism . Int J Artif Organs 2011;34:1085-94.

56. Funk GC, Breyer MK, Burghuber OC, Kink E, Kirchheiner K, Kohansal R, Schmidt I, Hartl S. Long-term non-invasive ventilation in COPD after ac ute-on-chronic respiratory failure.


Respir Med 2011;105:427-34. 57. Breyer MK, Rutten EPA, Locantore NW, Watkins ML, Miller BE, Wouters EFM.

Dysregulated adipokine metabolism in chronic obstru ctive pulmonary disease. Eur J Clin Invest. 2012 Sep;42(9):983-91.

58. Breyer MK, Rutten EPA, Spruit MA, Hop WCJ, Postma DS, Wouters EFM. Systemic inflammation in patients with COPD: result s from the COSMIC study. Open Journal of Respiratory Diseases, Vol. 2 No. 3, 2012, pp. 63-72.

59. Snell G, Herth FJ, Hopkins P, Baker KM, Witt C, Gotfried MH, Valipour A, Wagner M, Stanzel F, Egan JJ, Kesten S, Ernst A. Bronchoscopic thermal vapour ablation therapy in th e management of heterogeneous emphysema. Eur Respir J. 2012;39(6):1326-33.

60. Herth FJ, Noppen M, Valipour A, Leroy S, Vergnon JM, Ficker JH, Egan JJ, Gasparini S,

Agusti C, Holmes-Higgin D, Ernst A; International VENT Study Group. Efficacy predictors of lung volume reduction with Z ephyr valves in a European cohort. Eur Respir J. 2012;39(6):1334-42.

61. Magnussen H, Kramer MR, Kirsten AM, Marquette C, Valipour A, Stanzel F, Bonnet R,

Behr J, Fruchter O, Refaely Y, Eberhardt R, Herth FJ. Effect of fissure integrity on lung volume reductio n using a polymer sealant in advanced emphysema. Thorax 2012;67(4):302-8.

62. Gompelmann D, Heussel CP, Eberhardt R, Snell G, Hopkins P, Baker K, Witt C, Valipour A, Wagner M, Stanzel F, Egan J, Ernst A, Kesten S, Herth FJ. Efficacy of bronchoscopic thermal vapor ablation an d lobar fissure completeness in patients Respiration 2012;83(5):400-6.

63. Valipour A, Kramer MR, Stanzel F, Kempa A, Asadi S, Fruchter O, Eberhardt R, Herth FJ, Ingenito EP. Physiological modeling of responses to upper versus lower lobe lung volume reduction in homogeneous emphysema. Front Physiol. 2012;3:387.

64. Herth FJ, Ernst A, Baker KM, Egan JJ, Gotfried MH, Hopkins P, Stanzel F, Valipour A, Wagner M, Witt C, Kesten S, Snell G. Characterization of outcomes 1 year after endoscopi c thermal vapor ablation for patients with heterogeneous emphysema. Int J COPD 2012;7: 397-405.

65. Hartl S. The European COPD Audit: a pilot experience of 16 E uropean countries. Pneumonologia i alergologia polska. 2012;80(6):501-4.

66. Arampatzis S, Lindner G, Irmak F, Funk GC, Zimmermann H and Exadaktylos AK. Geriatric urolithiasis in the emergency department: Risk factors for hospitalisation and emergency management patterns of acute urolithi asis BMC Nephrology 2012;24:117.

67. Arampatzis S, Frauchiger B, Fiedler GM, Leichtle AB, Buhl D, Schwarz C, Funk GC,


Zimmermann H, Exadaktylos AK, Lindner G. Characteristics, Symptoms, and Outcome of Severe Dy snatremias Present on Hospital Admission. Am J Med 2012;125:1125.e1-1125.

68. Fazekas AS, Wewalka M, Zauner C, Funk GC. Carboxyhemoglobin levels in medical intensive care patients: a retrospective, observational study. Crit Care. 2012 Jan 11;16(1):R6.

69. Lindner G, Schwarz C, Funk GC. Osmotic diuresis due to urea as the cause of hypern atraemia in critically ill patients. Nephrol Dial Transplant. 2012;27:962-7.

70. Gompelmann D, Eberhardt R, Ernst A, Hopkins P, Egan J, Stanzel F, Valipour A,

Wagner M, Witt C, Baker KM, Gotfried MH, Kesten S, Snell G, Herth FJ. The Localized Inflammatory Response to Bronchoscopi c Thermal Vapor Ablation. Respiration 2013; 86: 324 – 331.

71. Firlinger I, Stubenberger E, Müller MR, Burghuber OC, Valipour A. Endoscopic one-way valve implantation in patients w ith prolonged air leak and the use of digital air leak monitoring. Ann Thoracic Surgery. 2013 Apr;95(4):1243-9.

72. Lopez-Campos JL, Hartl S, Pozo-Rodriguez F, Roberts CM. European COPD Audit: design, organisation of work a nd methodology. Eur Respir J. 2013;41(2):270-6.

73. Roberts CM, Lopez-Campos JL, Pozo-Rodriguez F, Hartl S. European COPD Audit: European hospital adherence to GOLD recommendations for chronic obstructive pulmonary disease (COPD) ex acerbation admissions. Thorax. 2013;68(12):1169-71.

74. Pfortmueller CA, Funk GC, Marti G, Leichtle AB, Fiedler GM, Exadaktylos AK, Lindner G. Diagnostic performance of high-sensitive troponin T in patients with renal insufficiency. Am J Cardiol. 2013;112:1968-72.

75. Lindner G, Pfortmueller CA, Funk GC, Leichtle AB, Fiedler GM, Exadaktylos AK. High-Sensitive Troponin Measurement in Emergency De partment Patients Presenting with Syncope: A Retrospective Analysis. PLoS One. 2013 Jun 18;8(6):e66470.

76. Kneidinger N, Funk GC, Lindner G, Drolz A, Schenk P, Fuhrmann V. Unmeasured anions are associated with short-term mo rtality in patients with hypoxic hepatitis. Wiener Klinische Wochenschrift 2013;125:474-80.

77. Arampatzis S, Funk GC, Leichtle AB, Fiedler GM, Schwarz C, Zimmermann H, Exadaktylos AK and Lindner G. Impact of diuretic therapy-associated electrolyte d isorders present on admission to the emergency department: a cross-sectional anal ysis BMC Medicine 2013;11:83.

78. Arampatzis S, Gaetcke LM, Funk GC, Schwarz C, Mohaupt M, Zimmermann H,


Exadaktylos AK, Lindner G. Diuretic-induced hyponatremia and osteoporotic frac tures in patients admitted to the emergency department. Maturitas. 2013;75:81-6.

79. Fazekas AS, Funk GC Klobassa DS, Rüther H, Ziegler I, Zander R, Semmelrock HJ. Evaluation of 36 formulas for calculating plasma os molality. Intensive Care Medicine 2013;39:302-8.

80. Lindner G, Schwarz C, Grüssing H, Kneidinger N, Fazekas A, Funk GC. Rising serum sodium levels are associated with a co ncurrent development of metabolic alkalosis in critically ill patients. Intensive Care Med. 2013;39:399-405.

81. Funk GC, Bauer P, Burghuber OC, Fazekas A, Hartl S, Hochrieser H, Schmutz R, Metnitz P. Prevalence and Prognosis of Chronic Obstructive Pul monary Disease in Critically Ill Patients between 1998 and 2008. Eur Respir J. 2013;41:792-9.

82. Breyer MK, Spruit MA, Rutten EPA, Franssen FME, Wouters EFM. Prevalence of metabolic syndrome in COPD patients a nd its consequences PLoS One. 2014 Jun 20;9(6)

83. Vanfleteren LE, Kocks JW, Stone IS, Breyer-Kohansal R, Greulich T, Lacedonia D, Buhl R, Fabbri LM, Pavord ID, Barnes N, Wouters EF, Agusti A. Moving from the Oslerian paradigm to the post-genom ic era: are asthma and COPD outdated terms? Thorax. 2014 Jan;69(1):72-9.

84. Urban MH, Ay L, Funk GC, Burghuber OC, Eickhoff P, Wolzt M, Valipour A. Insulin resistance may contribute to vascular dysfu nction in patients with chronic obstructive pulmonary disease. Wiener klinische Wochenschrift 2014 Feb;126(3-4):106-12.

85. Valipour A, Herth FJ, Burghuber OC, Criner G, Vergnon JM, Goldin J, Sciurba F, Ernst A; for the VENT study group. Target lobe volume reduction and COPD outcome measu res after endobronchial valve therapy . Eur Respir J. 2014, 43: 387-396.

86. Gompelmann D, Herth FJ, Slebos DJ, Valipour A, Ernst A, Criner GJ, Eberhardt R.

Pneumothorax following Endobronchial Valve Therapy and Its Impact on Clinical Outcomes in Severe Emphysema. Respiration 2014, 87: 485-491.

87. Kohnlein T, Windisch W, Kohler D, Drabik A, Geiseler J, Hartl S, Karg, O,Laier-Groeneveld, G, Nava, S, Schonhofer, B, Schucher, B, Wegscheider, K, Criee, C. P, Welte, T. Non-invasive positive pressure ventilation for the treatment of severe stable chronic obstructive pulmonary disease: a prospectiv e, multicentre, randomised, controlled clinical trial. Lancet Respir Med. 2014 Sep;2(9):698-705.3.


88. Pfortmueller CA, Funk GC, Leichtle AB, Fiedler GM, Schwarz C, Exadaktylos AK, Lindner

G. Electrolyte Disorders and In-Hospital Mortality dur ing Prolonged Heat Periods: A Cross-Sectional Analysis PLoS One. 2014;9:e92150.

89. Lindner G, Funk GC, Pfortmueller CA, Leichtle AB, Fiedler GM, Schwarz C, Exadaktylos AK, Puig S. D-Dimer to rule out pulmonary embolism in renal ins ufficiency. Am J Med 2014;127:343-7.

90. Lindner G, Doberer D, Schwarz C, Schneeweiss B, Funk GC. Evaporation of free water causes concentrational al kalosis in vitro. Wiener Klinische Wochenschrift 2014;126:201-207.

91. Pfortmueller CA, Funk GC, Leichtle AB, Wiemann C, Exadaktylos AK, Martin G, Lindner G. Hypoglycemia is associated with Increased Mortality in Patients with Acute Decompensated Liver Cirrhosis. J Crit Care. 2014;29:316.e7-12.

92. López-Campos JL, Hartl S, Pozo-Rodriguez F, Roberts CM; European COPD Audit team. Variability of hospital resources for acute care of COPD patients: the European COPD Audit. Eur Respir J. 2014 Mar;43(3):754-62.

93. Gompelmann D, Herth FJ, Slebos DJ, Valipour A, Ernst A, Criner GJ, Eberhardt R. Pneumothorax following endobronchial valve therapy and its impact on clinical outcomes in severe emphysema. Respiration. 2014;87(6):485-91. Epub 2014 Apr 30.

94. Spruit MA, Pitta F, Garvey C, ZuWallack RL, Roberts CM, Collins EG, Goldstein R, McNamara R, Surpas P, Atsuyoshi K, López-Campos JL, Vogiatzis I, Williams JE, Lareau S, Brooks D, Troosters T, Singh SJ, Hartl S, Clini EM, Wouters EF; ERS Rehabilitation and Chronic Care, and Physiotherapists Scientific Groups; American Association of Cardiovascular and Pulmonary Rehabilitation; ATS Pulmonary Rehabilitation Assembly and the ERS COPD Audit team. Differences in content and organisational aspects of pulmonary rehabilitation programmes. Eur Respir J. 2014 May;43(5):1326-37.

95. Urban MH, Valipour A, Kiss D, Eickhoff P, Funk GC, Burghuber OC. Soluble receptor of advanced glycation end-products and endothelial dysfunction in COPD. Respir Med. 2014 Jun;108(6):891-7.

96. Potura E, Lindner G, Biesenbach P, Funk GC, Reiterer C, Kabon B, Schwarz C, Druml

W, Fleischmann E. An Acetate-Buffered Balanced Crystalloid Versus 0.9 % Saline in Patients with End-Stage Renal Disease Undergoing Cadaveric Renal Tran splantation: A Prospective Randomized Controlled Trial Anesth Analg. 2014 Sep 3.


97. Pertl D, Eisenmann A, Holzer U, Renner AT, Valipour A. Effectiveness and efficacy of minimally invasive lu ng volume reduction surgery for emphysema. GMS Health Technol Assess. 2014 Oct 1;10:Doc01.

98. Lindner G, Funk GC, Leichtle AB, Fiedler GM, Schwarz C, Eleftheriadis T, Pasch A, Mohaupt M, Exadaktylos AK, Arampatzis S Impact of proton-pump inhibitor use on magnesium ho meostasis: a cross-sectional study in a tertiary emergency department. International Journal of Clinical Practice, 2014 Nov;68(11):1352-7.

99. Valipour A, Herth FJ, Eberhardt R, Shah PL, Gupta A, Barry R, Henne E, Bandyopadhyay S, Snell G. Design of the randomized, controlled sequential sta ged treatment of emphysema with upper lobe predominance (STEP-UP) study. BMC Pulm Med. 2014 Dec 3;14:190.

100. Slebos DJ, Klooster K, Koegelenberg CF, Theron J, Styen D, Valipour A, Mayse M, Bolliger CT. Targeted lung denervation for moderate to severe COPD: a pilot study. Thorax. 2015 May;70(5):411-9.


Reviews, Editorials, Guidelines, Books

1. Koller HK, Burghuber OC. Diffuse interstitielle Lungenkrankheiten mit besond erer Berücksichtigung des rheumatischen Formenkreises Z Rheumatologie 2003; 62: 122.

2. Block LH, Ziesche R,. Kneussl M, Petkov V,Hesse C, Kähler C, Fruhwald F, Zach M, Burghuber OC, Fugger B. Konsensus-Empfehlung der Arbeitsgruppe pulmonalarte rielle Hypertension der Österreichischen Gesellschaft für Lungenerkrankunge n und Tuberkulose. Wiener klinische Wochenschrift 2003, 115/10: 351.

3. Valipour A, Burghuber OC. Non-invasive pressure support ventilation in patien ts with acute cardiogenic pulmonary edema: a critical appraisal. International Respiratory Care Clinics and Technology. Update in Respiratory Care Technology. Ed 2003-2006, Publisher: Editorial Mason/ GrupoAulamedica.

4. Block LH, .Burghuber OC, Hartl S, Zwick H. Österreichische Gesellschaft für Lungenerkrankungen und Tuberkulose: Konsensus zum Management der chronisch obstruktiven Lungenkrankheiten (COPD) Wiener klinische Wocheneschrift. 2004, 116/7, 268.

5. Burghuber OC. Pulmonary embolism: Clinical features in Principles of Respiratory Medicine. Second edition ed. Albert RK, SG Spiro SG, Jett J Mosby International 2004.

6. Burghuber OC. COPD - State of the Art. Österreichische Ärztezeitung 2005; 9, 36

7. Burghuber OC. Editorial: Chronisch obstruktive Lungenerkrankung. Wiener klinische Wochenschrift. 2005, 155 (5/6), 77.

8. Hartl S, Burghuber OC. Diagnostik der COPD. Wiener klinische Wochenschrift. 2005, 155 (5/6), 90.

9. Schenk, Stiebellehner L, Burghuber OC, Kneussl M, .Lang IM. Untersuchung des Lungekreislaufs mittels Rechtsherz katheter. Positionspapier des Kardiopulmonalen Arbeitskreises der Österreichischen Gesellschaft für Pneumologie und der Österreichischen Gesellschaft für Kardiologie Wiener klinische Wochenschrift . 2005, 117/9, 651.

10. Schneeweiss B, Funk GC. Akute Störungen des Wasser-, Elektrolyt- und Säure- Basen Haushaltes. In P Reuter, editor: Springer Lexikon Diagnose und Therapie. 1.Auflage, Springer Verlag 2006.

11. Hartl S, Schmidt I.

Atemphysiotherapie bei CVI unter Berücksichtigung d er NIV – Optionen.


Nicht-invasive Beatmung - Grundlagen und moderne Praxis / Prof. Dr. Bernd Schönhofer. 1. Auflage 2006 – Bremen: UNI-MED Science, 2006, P178 – 181.

12. Funk GC. Stewart's acid-base approach. Wiener klinische Wochenschrift. 2007, 119(13-14), 390-403.

13. Wouters EFM, Celis MPM, Breyer MK, Rutten EPA, Graat-Verboom L, Spruit MA Co-morbid manifestations in COPD Respiratory Medicine: COPD Update, Vol. 3, Issue 4, Nov. 2007, p.135-151.

14. Valipour A, Ruis M, Burghuber OC Ist das obstruktive Schlafapnoesyndrom ein Risikofa ktor für das metabolische Syndrom? J Hypertonie 2008; 12(2), 31-33.

15. Valipour A. Gender aspects in sleep apnoea. Int J Respir Care 2008, AUTUMN/WINTER 2008, 57 – 61.

16. Kohansal R, Soriano JB, Agusti A. Investigating the natural history of lung function: facts, pitfalls, and opportunities. Chest. 2009 May,135(5),1330-41.

17. Valipour A, Burghuber OC. Schlafatemstörungen. Wiener klinische Wochenschrift, Education 2009.

18. Burghuber OC, Valipour A. Knowing Chronic Obstructive Pulmonary Disease by He art: Cumulating Evidence of Systemic Vascular Dysfunction. Am J Respir Crit Care Med 2009, 180, 487-488.

19. Funk GC. Home ventilation for COPD. In A Esquinas, editor: Yearbook Non-invasive mechanical ventilation – edition 2009 International Association of Non-invasive Mechanical Ventilation (IANIMV).

20. Funk GC. Säure-Basen Störungen. In Smolle/Funk, editors: Wasser-Elektrolyt- und Säure-Basen-Störungen in der Intensiv- und Notfallmedizin. UNIMED Verlag 2010.

21. Valipour A.

Kardiale Komorbidität bei COPD. Atemwegs- und Lungenkrankheiten 2011, 2:37:48-50.

22. Hartl S. Chronic obstructive pulmonary disease exacerbations : better standards--better prognosis? Respiration. 2011;82(4):317-9.

23. Esquinas Rodriguez AM, Scala R, Soroksky A, Bahammam A, de Klerk A, Valipour A, Chiumello D, Martin C, Holland AE. Humidifiers during non-invasive ventilation - key t opics and practical implications. Crit Care 2012;16(1):203.

24. Hartl S, Netz M, Breyer MK, Breyer-Kohansal R. Husten -Atemnot –COPD.


2012, Med Media Verlag, ISBN-978-3-9501-4464-2.

25. Valipour A. Pros and Cons of humidification for CPAP therapy in the treatment of sleep apnea Humidifcation in the Intensive Care Unit, 2012, Part 4, 109 – 113 Ed: Antonio Esquinas, Publisher: Springe Verlag, Heidelberg.

26. Burghuber OC, Breyer MK, GC Funk, Vogelmeier C.

Komorbiditäten bei COPD – Entzündung und antiinflam matorische Therapie 2012, Unimed Verlag, ISBN 978-3-8374-2231-1.

27. Breyer MK

Adiposity in COPD 2013, Maastricht University, the Netherlands, ISBN 978-3-200-03188-3.

28. Esquinas AM, Valipour A. Cardiac performance by noninvasive bilevel positive airway pressure (BiPAP) in acute-on-chronic heart failure: pressure dependence or nervous activity. J Card Fail. 2013 Sep;19(9):661.

29. Funk GC. Ambulante Rehabilitation bei chronisch-obstruktiver Lungenerkrankung. In Versicherungsgeschichte Österreichs, Band XI – Ethik – Nachhaltigkeit – Versicherung. Verlag Tronik Dizajn, Belgrad 2013.

30. Valipour A, Slebos DJ, de Oliveira HG, Eberhardt R, Freitag L, Criner GJ, Herth FJ.

Expert Statement: Pneumothorax Associated with Endoscopic Valve Therapy for Emphysema - Potential Mechanisms, Treatment Algorit hm, and Case Examples. Respiration 2014; 87: 513-521.

31. Valipour A. Ambulatory management of primary spontaneous pneumo thorax: the good is (not always) the enemy of the better (evidence). Eur Resp J 2014 Feb;43(2):334-6.

32. Valipour A. The role of the nose in obstructive sleep apnea: a short review. Pneumologie. 2014 Jun;68(6):397-400.

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