Golniški simpozij 2011 Zbornik povzetkov

Golnik
Symposium
2011
Congress
Bled, Slovenia, October 7-8, 2011
Book of abstracts

Publisher
University Clinic of Respiratory
and Allergic Diseases Golnik
Editor
Izidor Kern, Urøka Bidovec Stojkoviœ
Prepress
Trajanus d.o.o., Kranj
Printing
Pro Grafika d.o.o., Æabnica
Printed
200 copies
Bled, Slovenia, October 7-8, 2008
CIP - Kataloæni zapis o publikaciji
Narodna in univerzitetna knjiænica, Ljubljana
616.2(082)
GOLNIK Symposium (2011 ; Bled)
Book of abstracts / Golnik Symposium, 2011, Bled, Slovenia,
October 7-8, 2011 ; [editor Izidor Kern, Urøka Bidovec Stojkoviœ].
- Golnik : University Clinic of Respiratory and Allergic Diseases,
2011
ISBN 978-961-6633-30-7
1. Kern, Izidor
257761536
BOLNIØNICA GOLNIK - KLINIŒNI ODDELEK ZA PLJUŒNE BOLEZNI IN ALERGIJO
UNIVERSITY CLINIC OF RESPIRATORY AND ALLERGIC DISEASES GOLNIK
Golnik 36, 4204 Golnik, Slovenija T: +386 (0)4 25 69 100 F: +386 (0)4 25 69 117
E: kopa.tajnistvo@klinika-golnik.si W: www.klinika-golnik.si

Content
Oral presentations
Kadivec S Coordination of discharge in COPD 9
Joøt M, Morgan T Improving medication management on a hospital level - 10
our experience
Meøko Brguljan P Patient safety – the preanalytical impact on quality 12
of laboratory reports
Muøiœ E Current concept on pathomechanism of Idiopathic 14
pulmonary fibrosis
Poster presentations
Meøko Brguljan P, Benedik B Quality indicators of the preanalytical phase 20
in blood gas analysis
Meøko Brguljan P, Bratoæ S Licensing of medical laboratories in Slovenia 21
Œebron Lipovec N, Mrhar A, Knez L, Impact of pharmacists interventions on the frequency 22
Farinha H, Amaral J,
of medication errors in patients
Parola A, Falcão F
with enteral feeding tubes
Knez L, Reæonja R, Øuøkoviœ S, Comprehensive medication history: the need for the 24
Koønik M, Mrhar A
implementation of medication reconciliation processes
Knez L, Øuøkoviœ S, Primoæiœ A, Implementation of a medication reconciliation service 25
Laaksonen R, Joøt M,
at hospital admission: results
Koønik M, Mrhar A
from a randomised control study
Lunder U, Furlan M Communication in palliative care: challenge 27
for healthcare providers
Ziherl K, Øarc I, Gabrijelœiœ J Patients referred to Laboratory for sleep related 28
breathing disorders: our 5 year experience
Hafner T, Øorli J Pulmonary rehabilitation program – our results 30
Adamiœ K, Lalek N, Øtupnik T Videothoracoscopic resection of giant 31
emphysema bullae
Zabret M, Boneø U, Øarc I, Koønik M, Electrocardiogram analysis of patients with chronic 33
Øuøkoviœ S, Lainøœak M
obstructive pulmonary disease
Øarc I, Tomiœ V, Lainøœak M, Implications of sputum bacteriology in acute 34
Ziherl K, Jeriœ T,
exacerbations of chronic obstructive
Koønik M, Øuøkoviœ S
pulmonary disease
Boneø U, Øarc I, Ziherl K, Zabret M, Antibiotic treatment during hospitalization due 36
Jeriœ T, Tomiœ V, Koønik M,
to acute exacerbation of chronic
Øuøkoviœ S, Lainøœak M
obstructive pulmonary disease
3

Nastasijeviå Borovac D, Pejœiå T, Examination of resistance of bacteria isolated 37
Radjenoviå Petkoviå T,
from sputum and partial broncoalveolar
Djordjeviå I, Ranœiå M
lavage in Clinic for lung disease, Knez Selo
Adamiœ K, Polajnar M, Pneumococcal bacteriemia in adults with 39
Øifrer F, Tomiœ V
community-acquired pneumonia
Jeriœ T, Kern I, Svetina Øorli P Aspergillosis 41
Luænik D, Stokiå J, Tomiœ V, Øifrer F Use of multiplex PCR for detection of bacterial 42
respiratory tract pathogens
Øinkovec K, Luænik D, Carriage rate of extended-spectrum b-lactamase 43
Œernivec J, Tomiœ V
producing Enterobacteriaceae and methicillinresistant
Staphylococcus aureus in elderly
on admission to the nursing home
Øinkovec K, Luænik D, Methicillin-resistant Staphylococcus aureus 44
Œop Z, Tomiœ V
and extended-spectrum b-lactamase producing
Enterobacteriaceae in house pets
Svetina Øorli P, Pivk K, Jakelj A Screening of persons after contact with a TB patient 45
in the Shelter for the homeless
Koren Pucelj N, Hudoklin I Occurrence of tuberculosis in largest Slovenian 46
correctional facility ZPKZ Dob in the period
from 2000 to 2008
Toni J, Œebron Lipovec N, Pharmacist’s role in the treatment of patients 48
Svetina Øorli P
with tuberculosis – our positive experience
Æolnir Dovœ M, Fajfar N, Plesec I, A nation-wide study of nontuberculous mycobacteria 50
Petroviœ Æ, Øorli Peranoviœ N in Slovenia
Bidovec Stojkoviœ U, Æolnir Dovœ M The importance of pre-analytic factors 52
in Quantiferon-TB Gold test
Fajfar N, Bidovec Stojkoviœ U, Evaluation of GeneXpert MTB/RIF assay for detection 54
Æolnir Dovœ M
of Mycobacterium tuberculosis and rifampicin
resistance in a routine laboratory setting in Slovenia
Bidovec Stojkoviœ U, Fajfar N, Nation-wide evaluation of three molecular genotyping 55
Æolnir Dovœ M
methods in Slovenia
Unk M, Kern I, Œufer T Primitive neuro-ectodermal tumour of the lung- 56
a case report
Zukiå E, Keser D, Premalignant lesions among coal miners 58
Jusufoviå E, Sejdinoviå R
Lalek N, Adamiœ K, Øtupnik T Videothoracoscopic lung lobectomy in patients 59
over 75 years of age
Sodja E, Knez L, Ovœariœek T, Clinical impact of ERCC1 protein expression 60
Kern I, Koønik M, Sadikov A, Œufer T in small-cell lung cancer patients treated
with platinum-based chemotherapy
Kontiå M, Stojøiå J, Jovanoviå D, Quantitative Methylation Profiles of Multiple Genes 61
Bunjevacki V, Puumala S,
in Patients with Non-Small Cell Lung Cancer And its
Nelson HH
Association with Clinicopathological Correlations
Jusufoviå E, Rijavec M, Keser D, Anti-angiogenic miRNAs let-7b and miR-126 63
Sodja E, Koønik M, Koroøec P are down-regulated in tumour and tumour surrounding
in NSCLC lung tissue
Knez L, Ovœariœek T, Sadikov A, MDR1 polymorphisms G2677T/A and C3435T 65
Sodja E, Kern I, Koønik M, Œufer T are independent predictive markers in small-cell
lung cancer patients treated with chemotherapy
Øumer TT, Œufer T Changing to another TKI in treatment 66
of metastatic NSCLC
Kern I, Kovaœeviå M, Sodja E, Œufer T Topoisomerase II in small cell lung carcinoma 67
4

Turnøek N, Mohorœiœ K, Neutropenia in lung cancer patients treated 68
Sadikov A, Œufer T with chemotherapy in a routine clinical practice –
an institutional experience
Mlakar J, Œufer T, Triller N, Safety and efficiency of treatment of advanced 70
Sadikov A, Øumer TT
NSCLC with non-squamous histology with pemetrexed
and platinum derivate combination in routine clinical
practice; experience at University Clinic Golnik
Ivaniøeviå J, Kotur Stevuljeviå J, Blood oxidative stress markers and lipid status 72
Stefanoviå A, Jeliå Ivanoviå Z, in sarcoidosis
Spasiå S, Videnoviå Ivanov J,
Vuœiniå Mihailoviå V, Iliå J
Videnoviå Ivanov J, Results of 18 F FDG PET scan in patients 74
Sobiå Øaranoviå D,
with chronic sarcoidosis
Vuœiniå Mihailoviå V, Zugiå V,
Filipoviå S
Øumer TT, Æagar I, Gaøperøiœ N The significance of PET CT in diagnosis 75
of Takayasu arteritis – a case study
Osolnik K, Rijavec M, Koroøec P Diagnostic value of pulmonary 76
NKT CD3 + CD16/56 + cells
Rijavec M, Osolnik K, Peripheral invariant NKT cells and factors involved 77
Koønik M, Koroøec P
in the development of iNKT cells in sarcoidosis patients
Dimitrijeviå J, Vegnuti M, Adamiœ K, Side-effects of specific immunotherapy: 78
Bajroviå N, Eræen R, Koønik M, our experience – KOPA Golnik
Muøiœ E, Zidarn M
Mumoviå G, Hoœevar Bolteæar I, Allergy in patients with vocal fold nodules 79
Popov Dragin O
Balantiœ M, Rijavec M, Kavalar M, ORMDL3 gene polymorphism is associated 81
Øilar M, Koønik M, Koroøec P with asthma risk and severity in Slovenian children
Øilar M, Pevec B, Rijavec M, Expression profiles of regulatory genes after venom 82
Eræen R, Koønik M,
immunotherapy
Stipiå Markoviå A, Koroøec P
Œelesnik N, Kopaœ P, Eræen R, Baseline serum tryptase is not associated 83
Øilar M, Koønik M, Koroøec P with the risk for severe anaphylactic reactions
in honey bee venom allergy
Œelesnik N, Eræen R, Øilar M, Diagnosis of double sensitized Hymenoptera venom 84
Mittermann I, Valenta R,
allergic patients with recombinant species-specific
Zidarn M, Koønik M, Koroøec P major allergens used in basophil activation test
Zidarn M, Koønik M, Øilar M, Rhinitis symptoms caused by grass pollen 85
Grahek A, Koroøec P
are associated with elevated basophil allergen
sensitivity and a larger grass-specific IgE fraction
Kopaœ P, Gentinetta T, Rudin M, Continuous apple consumption induces oral tolerance 86
Gerber R, Pichler C, Hausmann O, in birch-pollen associated apple allergy
Schnyder B, Pichler WJ
Eræen R, Øilar M, Comparison of basophil activation test and inhibition tests 88
Koroøec P, Koønik M
in double positive Hymenoptera venom allergic patients
Perin P, Berce V, Potoœnik U Association analysis of polymorphisms in selected 89
candidate genes in slovenian children with astma
Workshop / Delavnica – organizirajoœa pljuœnica
Kern I Organizirajoœa pljuœnica – histopatoloøka entiteta 92
Poæek I Organizirajoœa pljuœnica – spekter radioloøkih vzorcev 94
Osolnik K Organizirajoœa pljuœnica – kliniœni problem 96
5

ORAL PRESENTATIONS
7

Coordination
of discharge in COPD
Saøa Kadivec
University Clinic of Respiratory and Allergic Diseases Golnik
Healthcare is facing a number of factors that are reducing the inpatient length of stay and have influence
on the intensity of the treatment of hospitalized patients. The average age of patients is increasing,
and so is the complexity of their problems and needs due to the chronic nature of their
illnesses. Many patients are discharged from the hospital while still receiving treatment. These results
in a greater amount and diversity of their needs after discharge, and also in the amount of pressure
that is put on health care services and providers as well as other services that help patients perform
daily and other life activities.
The importance of discharge is still underestimated in daily practice, because discharge is still perceived
as a conclusion of medical treatment and not as a part of integrated treatment. Timely recognition
of patients’ needs after discharge during their hospital stay is often lacking and insufficient
due to short hospitalization, staff work overload due to acute treatment and insufficient and/or ineffective
communication.
In order to solve the problem with the discharge process, the University Clinic of Respiratory and Allergic
Diseases Golnik has implemented a case manager who is a missing link between the integrated
patient treatment and patients’ needs for further treatment at home or in institutional care. A case manager
enables not only the continuity of treatment but also those patients, their families and providers of
health and social care on all levels of treatment get more information. He/she coordinates work, communicates
with the patient the first week after hospital discharge and informs them about the activities
related to discharge, consults them and is in regular contact with their GP and community nurse.
A case manager is included in the treatment of patients that meet the following criteria:
• They have a chronic disease (COPD, TB, asthma, chronic heart conditions, neoplasm) and
• They have been admitted or discharged as at least category II according to demands of hospital
nursing care.
How to develop the role of a case manager in the future?
We believe that case managers could work in nurse-led outpatient units, as heads of registers and
in telemedicine.
In 2009, we started a project of work evaluation of case managers. The purpose of the study was to evaluate
the influence of the case manager’s work on the treatment of patients with chronic obstructive pulmonary
disease (COPD) with a prospective randomized clinical study. Patients are divided into two
equally large groups: an intervention group and a control group. The case manager only works with the
intervention group. Patients from the intervention group are treated according to the principle of good
clinical practice. Data collection was made using a number of tools (different questionnaires).
9

Improving medication management
on a hospital level - our experience
Maja Joøt, Tina Morgan
University Clinic of Respiratory and Allergic Diseases Golnik
The rough beginnings
The story of a comprehensive medicine management on a hospital level began with the decision of
top hospital management to implement clinical pharmacy. Before that the major task of hospital pharmacists
was to provide wards with medicines, at a reasonable time and price. The first step towards
better medicine management was made by the identification of drawbacks in the existing process.
Present state
Quality, effective and safe medicines are the base for successful treatment. Therefore it was essential
to assure proper storage conditions and to establish suitable transport within our hospital (e.g.
cold chain). Stability of diluted solutions and compatibility of admixtures was revised according to the
literature. Special focus was put on safe, centralized preparation of high risk medications (e.g. cytostatics).
A progress was made in the perspective of medicines reaching the patient. Accessibility was upgraded
by ensuring a continuous and controlled access to medicine stocks in the hospital pharmacy.
Rare and expensive medicines are now dispensed per patient for pre-defined medical
indications. Drug administration was unified among wards.
Further on, recommendations and protocols for the treatment of certain diseases or with certain drugs
(e.g. LMWH, chemotherapy) were prepared and implemented in routine clinical practice. This was
upgraded with new pharmacy services: chemotherapy prescription screening and provision of a
medication history for each patient, starting cancer drug therapy.
Substantial improvements in the continuity of care of patients with certain diseases (e.g. TB) was
made: pharmacists perform medication reconciliation at admission, medication review during hospitalization,
patient counselling before discharge and provide patients with medicines for home treatment.
For all other patients, these services are offered to a various extent on some of the wards or
for selected patients.
The definition, identification and monitoring of high risk medications and patients at a high risk for adverse
drug events are objectives of a high priority, on-going process, led by a pharmacist.
Where to?
Medicine management is now being improved in a systematic way to ensure continuity of care for
all patients. The emphasis should be given on the safety, efficacy and quality of drug treatment. A
logistic reorganization of drug dispensing, guaranteeing efficient, safe and recordable unit dose dis-
10

pensing should be undertaken in order to allow pharmacist to focus on more clinically oriented activities
and make the best use of their expertise.
References
1. Knez L, Joøt M, Toni J, Triller N, Œufer T. Implementing new clinical pharmacy services parallel to the introduction
of centralized preparation of anti-cancer drugs. Zdravstveno varstvo 2011; 50:12-23.
2. Guchelaar H-J, Colen HBB, Kalmeijer MD, et al. Medication Errors Hospital Pharmacist perspective. Drugs
2005; 65:1735-46.
11

Patient safety – the preanalytical
impact on quality of laboratory reports
Pika Meøko Brguljan
University Clinic for Respiratory Diseases and Allergy Golnik, Clinical Chemistry Department, Golnik,
Slovenia
Patient safety, the freedom from accidental or unnecessary harm due to adverse events occurring in
any healthcare setting, directly affects the quality of care. The Institute of Medicine (IOM) report, To err
is human, dramatically increased level of concern about adverse events and patient safety in healthcare,
including errors in laboratory medicine (1). Even a low incidence of laboratory mistakes among
the billions of tests performed every day worldwide could have important public health and patient
safety implications. While the IOM report presented few data on errors in laboratory medicine, it has
wide-reaching implications for all disciplines. The IOM report, Crossing the quality chasm (2), stressed
the concept of patient-centered care and the fact that complex systems are characterized by specialization
and interdependency. The evidence reported can be translated into a better understanding of
the importance of the total testing process (TTP) – preanalytical, analytical and postanalytical, as the
right framework for patient safety in laboratory medicine. The TTP consists of a series on interrelated
processes, each involving a series of a process step, every one of which can result in an error (3).
In the last years, in our laboratory many strategies are used to reduce errors, such as improved laboratory
technology, internal quality control procedures, external quality assurance programs, educational
programs, licensing of laboratory professionals, certification of laboratory (as the part of our
clinic’s ISO 9001:2000 and DNV accreditation certificates). Laboratory also fulfil the Slovenian regulatory
requirements in laboratory medicine and gain the working license in the year 2009. In the
past, the preanalytical phase has been often overlooked as a source of errors, evidence from recent
studies shows that a large percentage of laboratory errors occur in the preanalytical steps (4). In the
laboratory several steps have already been taken to increase awareness and establish a governance
of the preanalytical aspect of laboratory processes. Standardization and monitoring of the most common
preanalytical errors have been implemented in the every-day work in the laboratory. Quality indicators
and the error monitoring system of the preanalytical phase are tools that can be used to
supervise the activity carried out in the laboratory and activities in relation to the clinical laboratory.
Till the data are collected and corrective actions, such as education of staff on preanalytical issues,
have been taken, a big improvement in fulfilment of the quality specifications have been detected.
The interdisciplinary approach to manage the quality of the preanalytical phase is a good approach
to avoid and reduce laboratory errors in TTP. In the future our aim is to integrate more effective error
tracking and quality indicator reporting system to our laboratory informaton system (LIS). Continuous
actions for all involved in the processes and move from error reporting to risk managament is of extreme
importance for patient safety.
12

References
1. Plebani M. Errors in laboratory medicine and patient safety: the road ahead. Clin Chem Lab Med 2007;45:700-
707.
2. Institute of Medicine. Crossing the quality chasm: a new health care system for the 21st century. Washington,
DC: National Academy Press, 2001.
3. Boone DJ. Is it safe to have a laboratory test? Accred Qual Assur 2004; 10:5-9.
4. Lippi e tal.:Preanalytical quality improvement: from dream to reality. Clin Chem Lab Med 2011;49(7):1113-
1126.
13

Current concept on pathomechanism
of Idiopathic pulmonary fibrosis
Ema Muøiœ
Previously it was anticipated that idiopathic pulmonary fibrosis (IPF) reflects an inflammatory driven
alveolitis form of lung fibrosis. But the frustrated experience in IPF is that steroids and immunosuppressants
are of little help. A more recent hypothesis puts the alveolar type II cell (P II) at the centre
of the concept, according to which chronic epithelial damage is the underlying trigger mechanism
in IPF. Proliferation of pneumocyte type II cells (P II) is induced to overcome the loss of epithelium
and the factor released may largely induce the uncontrolled proliferation of fibroblasts and the excessive
deposition of extracellular matrix, mostly collagen. IPF patients experience a progressive
dyspnoea due to loss of regularly structured alveolar units and concomitant scarring of the lung.
Quality of life gradually decreases and patients usually die within 3-5 years after diagnosis. No approved
treatment was available, but newly some studies are bringing hope with new approach
against the fibroproliferation.
Figure1. From fibroblast foci with collagen production to honey combing of the lung seen on HRCT.
(courtesy of Izidor Kern and Rok Cesar)
The pathomechanism of IPF is yet not totally understood. Previously, it was anticipated that the disease
reflects another inflammatory driven form of lung fibrosis. However, the frustrating experience
in IPF is that steroids and immunosuppressants are of little help, if at all. A more recent and increasingly
favoured hypothesis puts the alveolar type II cell at the centre of a unifying concept, according
to which chronic epithelial damage is the underlying trigger mechanism for the development
14

of lung fibrosis. In more detail, misfolding or defective processing of proteins (e.g. surfactant protein
C), altered lysosomal transport or processing or chronic DNA damage have already been proven to
induce alveolar epithelial apoptosis. Proliferation of P II are induced to overcome the loss of epithelium
and the factors released may in a paracrine fashion largely induce the uncontrolled proliferation
of fibroblasts and the excessive deposition of extracellular matrix, mostly collagen.
What is the triggering event in IPF?
The P II are thought to be at the centre of a pathomechanistic concept for sporadic or familial IPF, but
also for other diffuse interstitial lung diseases (DILD), such as the Hermansky-Pudlack syndrome, amiodarone-induced
pneumonitis, or irradiation-induced lung fibrosis. Both, enhanced PII cell apoptosis
and hyperplasia ultimately induce distorted epithelial-mesenchymal cross-talk, resulting in enhanced
fibroblast activation and extracellular matrix (ECM) synthesis. Ultrastructural studies have revealed the
existence of proliferative alveolar epithelial cells immediately adjacent to injured epithelial cells, suggesting
that epithelial apoptosis, proliferation and hyperplasia occur simultaneously during the process
of fibrosis. In detail, chronic endoplasmic reticulum (ER) or lysosomal stress has been reported to induce
PII apoptosis and thus set the stage for the development of lung fibrosis. In detail, mutations in
the surfactant protein C (SFTPC) and telomerase genes (TR/TERT) in familial forms IPF provided initial
evidence that apoptosis of PII cells may represent an important pathogenetic trigger event.
In parallel, activation of endoplasmatic reticulum (ER) stress pathway components and activating
transcription factor 6 (ATF) was observed in IPF and NSIP, and found to result in a persistent and overwhelming
ER stress response and induction of epithelial apoptosis via DNA damage inducible transcript
(DDIT) 3. Also, respiratory infections represent a common phenomenon in IPF, which not only
seem to frequently antecede the clinical appearance of the disease, but also to accelerate its clinical
course. Consistent with these observations, bacterial, and – even more compelling – viral infections
can induce severe ER-stress. Thus, an intriguing and unifying concept for sporadic and familial
IPF would consist of a genetic predisposition to an epithelial injury, a modifying environmental stimulus
and a common downstream pathway resulting in fibrosis based on ER stress (or DNA damage)
induced PII cell apoptosis. Other diseases resulting in chronic APII cell injury, such as Hermansky
Pudlak Syndrome, amiodarone- or irradiation-induced lung fibrosis, might similarly result in epithelial
apoptosis and subsequent fibrosis, and could thus be integrated into this concept.
What are the mediators of distorted epithelial-mesenchymal interactions (cross-talk) in lung
fibrosis?
Balanced epithelial-mesenchymal interactions are of the utmost importance for proper lung development,
in particular for regular definition of a proximal-distal axis and dichotomous branching. In the
adult lung, mesenchymal-epithelial interactions warrant proper lung function and are a prerequisite
for the maintenance of the trophic alveolar unit, but impaired epithelial-mesenchymal crosstalk between
PII cells and subepithelial fibroblasts, as well as dysregulated precursor cell recruitment, have
recently been shown to contribute to the pathobiology of IPF.
It has been proposed that the PII cell, by action of cyclooxygenase 2, releases PGE2, which then binds
to the EP-2 receptor on fibroblasts, increases cAMP levels in the fibroblast and thereby inhibits the proliferation
and transactivation of this cell. In addition, several growth factors are released by the PII cell
that controls the fibroblast phenotype, such as members of the Wnt, BMP, or TGF-b superfamilies. In
particular, enhanced secretion and/or activity of Wnt and TGF-b superfamily members have been documented
in IPF. The fibroblast itself is a rich source of factors like FGF-7, FGF-10, and HGF. HGF will
be released by fibroblasts in dependency of cAMP levels and must be activated by extracellular serine
proteases such as the HGF activator. FGF-7, FGF-10, as well as HGF are known to exert a marked
influence on PII cell proliferation, migration and survival, and at least HGF has been shown to be released
to a much weaker extent from IPF fibroblasts as compared to fibroblasts from healthy lungs.
What is the origin of activated (myo-) fibroblasts in IPF?
While the initial injury in IPF is most likely affecting the PII cell (see above), it is well accepted that the
interstitial fibroblast / activated myofibroblast represents the key effector cell responsible for the in-
15

creased ECM deposition that is characteristic for this disease. The number of smooth muscle actinpositive,
activated (myo-) fibroblasts is significantly increased in multiple forms of pulmonary fibrosis
including IPF, but their origin remains to be elucidated.
Currently, three major theories attempt to explain this hallmark of maladaptive cell activation:
1. It has been demonstrated that resident pulmonary fibroblasts proliferate in response to fibrogenic
cytokines and growth factors (see below), thereby increasing the local fibroblast pool via local fibroproliferation.
2. In addition, several recent studies have shown that bone marrow-derived circulating fibrocytes
traffic to the lung during experimental lung fibrosis, and serve as progenitors for interstitial fibroblasts.
In particular, collagen I-positive fibrocytes have been shown to traffic to injured lungs in a
chemokine-dependent fashion, integrate into the lung ECM, and contribute to enhanced collagen
synthesis in fibrosis.
3. It was recently proposed that PII cells are capable of undergoing the process of epithelial-to-mesenchymal
transition (EMT), the phenotypic, reversible switching of epithelial to fibroblast-like cells,
which is initiated by an alteration of the transcriptional and proteomic profile of P2 cells. The orchestrated
series of events initiating EMT include remodelling of epithelial cell-cell and cell-matrix
adhesion contacts, reorganization of the actin cytoskeleton, and induction of mesenchymal gene
expression.
EMT is a highly controlled process initially discovered and described in embryonic development and
morphogenesis. In addition, EMT has gained wide recognition as a mechanism that facilitates cancer
progression and metastasis, as well as the development of chronic degenerative fibrotic disorders
of the kidney, liver, and lung. Transforming growth factor (TGF)-b is a main inducer and regulator
of EMT in multiple organ systems.
What are the major signalling pathways for matrix remodelling in the lung?
As a kind of primary wound healing response, activation of the coagulation cascade and suppression
of the fibrinolysis system has been observed in patients with IPF, and the cellular origin of these
coagulation factors (alveolar macrophages and P II cells) has been disclosed. Analysis of bronchoalveolar
lavage fluids (BALF) revealed substantial activation of the extrinsic coagulation pathway
(tissue factor VII), alongside with pronounced suppression of antithrombotic (activated protein C) or
fibrinolytic (plasminogen activator inhibitor 1) activities. These changes promote alveolar and interstitial
fibrin deposition, forming a provisional matrix and thereby contributing to lung fibrosis. Moreover,
several procoagulant serine proteases such as TF/FVII, factor X and thrombin induce fibrotic
events via the Protease activated receptors PAR-1 and PAR-2. In response to the activation of this
G-protein coupled receptor, increased ECM production, secretion and induction of profibrotic growth
factors such as TGF-b and PDGF can be observed. Vice versa, the urokinase system has repeatedly
been shown to exert strong antifibrotic activity, most likely due to the activation of HGF and the removal
of fibrin and ECM.
With respect to scar formation as aberrant alveolar/interstitial wound healing response, there is currently
no doubt that the Transforming Growth Factor (TGF)-b family represents the pivotal mediator
system. In vitro, TGF-b induces fibroblast chemotaxis, proliferation and transdifferentiation into myofibroblasts,
and it largely promotes the production and secretion of extracellular matrix compounds,
mainly collagen. Application of TGF-b encoding adenoviral vectors to the distal lung induces a progressive
and severe lung fibrosis. Likewise, application of these vectors to the pleural space induces
pleural fibrosis and subpleural lung fibrosis as seen in IPF. Increased TGF-b signalling is also observed
in other animal models of lung fibrosis, such as the bleomycin model, where collagen deposition
is reduced by TGF-b antibodies and soluble TGF-b receptors. In lungs of IPF patients, increased
expression of TGF-b has been observed in close proximity to areas of increased ECM deposition.
Apart from TGF-b, there are also other growth factors such as PDGF (platelet-derived growth factor),
CTGF (connective tissue growth factor), members of the Wnt pathway, or IGF-I (insulin-like growth
factor I) and endothelin, which may significantly
contribute to the pathogenetic sequelae of IPF.
16

Apart from the proliferation of fibroblasts, the excessive deposition of matrix is a key feature of IPF
and, most likely, is the result of excessive production of ECM compounds and a local imbalance between
the matrix metalloproteinases (MMP) and their inhibitors (TIMP).
In general, increased TIMP expression and virtual absence of the collagen I specific MMP-1 has
been observed in the lungs of IPF patients, thus contributing to collagen deposition. In view of the
coexistence of fibrotic scars and honeycomb cysts in the lungs of IPF subjects, it is yet not settled,
if a spatial disarrangement of the collagenases (largely MMP-1) and the TIMPs may be the primary
reason for the development of this structural heterogeneity. In contrast, the two gelatinases MMP 2
und 9, known for their ability to destruct the basement membrane and thus to impair epithelial regeneration,
were found to be increased in lung fibrosis. Finally, matrilysin (MMP-7) was also found
to be highly upregulated in IPF and MMP-7 knock out mice were protected from the bleomycin induced
lung fibrosis, thus supporting an important role of this MMP.
Treatment of lung fibrosis - translational approaches
The therapeutic approach to patients with IPF has not changed dramatically over the last 10 years.
But in 2011 Pirfenidone (targeting the TGF-b pathway), as well as bosentan (targeting the endothelin
pathway), have provided initial hope. Pirfenidon was registered in Europa in februar 2011 as the
first medicament for the treatment of IPF. Also N-acetyl cysteine was tested against placebo and
was found out to attenuate the loss of lung function. In the meantime, an encouraging increase in clinical
trials in the field of IPF can be observed. Most of these studies are addressing secondary
processes forwarding fibrosis per se. An overview is given in the figure 2 outlined below.
Figure 2. The cytokine oriented targets of promising drugs for IPF
Conclusions
We are at the entrance to a new time with knowledge, that inflammation is not needed to precede lung
fibrosing but there are multiple, microepithelial injuries, followed by activatoin and formation of fibroblast-myofibroblast
foci, which evolve to fibrosis. The genetic background for abnormal repair of
epithelial damage is of importance. IPF is an epithelial-fibroblastic disease and not a postinflammatory
fibrosing process.
It is the answer why the antiinflammatory, including steroid therapy was not successful in IPF. And
now antifibrotic oriented drugs are already evidence based promising.
17

References
1. Moises Selman, King T.E.,Pardo A: idioppathic pulmonary fibrosis: Prevailing and Evolving Hypotheses about
its Pathogenesis and Implications for therapy. Ann Intern Med 2001;134.136-151
2. Moises Selman, Pardo A:The epithelial/fibroblasic pathway in the pathogenesis of Idiopathic Pulmonary fibrosis.
American Journal of respiartory Cell and Molecular Biology 2003;29: S93-S97
3. 52. Kongress der DGP in Dresden-Symposium 8.4.2011: Idiopathische Lungenfibrose (IPF): Neue Erkenntnisse,
neue Hoffnung für den Patienten.
18

POSTER PRESENTATIONS
19

Quality indicators of the preanalytical
phase in blood gas analysis
Pika Meøko Brguljan, Barbara Benedik
University Clinic of Respiratory Diseases and Allergy Golnik
Background
The preanalytical phase is often overlooked as a major source of errors in whole-blood analysis, especially
in blood gasses. Arterial blood samples are very sensitive because of the physiological properties
of blood and the changes after the sampling. Quality indicators of the preanalytical phase are
tools that can be used to supervise the activity carried out in the laboratory and activities in relation
to the clinical laboratory.
Methods
Sampling of the arterial blood for whole blood analysis is performed by nursing staff on the wards,
the analysis are performed by laboratory staff in the clinical laboratory. The standard procedure for
sampling and the importance of the preanalytical phase with the aim to avoid errors in laboratory reports,
has been prepared by both, the laboratory and the nursing staff. Six quality indicators, based
on most common preanalytical errors, have been defined. These were sample volume, mixing of
samples, air bubbles in samples, transportation time, identification of the sample and electronic request
form, transfer of electronic request form from hospital information system to laboratory information
system,. The data are collected 14 days per year for all samples, received by the laboratory.
Results
Till the year 2007 the data were collected and corrective actions, such as education of nursing staff
on preanalytical issues, have been taken. A big improvement in fulfilment of the quality specifications
goals have been detected. By the end of the 2010 99,6% fullfil the criteria on sample volume, 98,2%
on mixing of samples, 97,8% on air bubbles in the samples, 93,8% on transportation time, 98,9% on
identification issues, and 98,9% on appropriate electronic request procedure.
Conclusions
The interdisciplinary approach to manage the quality of the preanalytical phase is a good approach
to avoid laboratory errors in whole-blood testing. Process has already proved benefits. Continuous
actions for all involved in the processes, including new staff, are needed to further improve the quality
of the preanalytical phase.
20

Licensing of medical laboratories
in Slovenia
Pika Meøko Brguljan 1 , Saøa Bratoæ 2
1
University Clinic for Respiratory Diseases and Allergy, Golnik
2
University Medical Centre Ljubljana
Background
Accreditation of medical laboratories in Slovenia is not yet implemented. Nevertheless the concept
of laboratory accreditation defined by ISO/IEC as formal recognition that the testing laboratory is
competent to carry out specific tests was implemented by a different model of licensing. In order to
assure quality and competence in laboratory medicine the National Bylaw for medical laboratories
based on ISO 15189 was adopted.
Methods
Laboratory applies for certification of its professional activity (clinical chemistry, microbiology, transfusiology
or pathology /cytopatholgy) at Ministry of Health. The complyment to the requirements is verified
by commissions appointed by the Ministry. Members of commissions are professionals of the
scientific fields trained for auditing. In principle a commission consists of three members but in case
those laboratories carry out analyses from diffrent fields, a specialist of the relevant field joins the
audit. The special fields often overlap and that as a rule provokes disagreement over professional
competences.
Results
By the end of the 2010 55 out of 102 registered medical biochemistry laboratories were audited, 49
laboratories complied with the requirements and gained the license, 6 laboratories got a suspense
of 6 months due to minor nonconformities.
At microbiology 15 laboratories were audited 3 out of these have to correct deficiencies. Transfusiologists
audited all 16 centers and ordered suspense for two, while at pathology/cytopatholgy one
out of 19 got suspense and two were found not complying.
Conclusions
Process has already proved benefits; laboratories have their quality systems set up, are committed
to continuous quality improvement which will eventually result in accreditation.
21

Impact of pharmacists interventions
on the frequency of medication errors
in patients with enteral feeding tubes
Nanœa Œebron Lipovec 1 , Aleø Mrhar 2 , Lea Knez 1 , H Farinha 3 , J Amaral 3 , A Parola 3 , F Falcão 3
1
University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia
2
Faculty of Pharmacy, University of Ljubljana, Slovenia
3
Hospital de Egas Moniz – CHLO EPE, Lisbon, Portugal
Background
In the last decade, the use of enteral feeding has expanded due to its advantages over parenteral
nutrition. The choice and administration of medications through enteral feeding tubes (EFT) represents
a challenge since it often requires crushing tablets and off-label use which can cause adverse
drug events (ADE). Purpose of our study was evaluation of prescription, dispensing and administration
of medications to patients with EFT and assessment of the impact of pharmacist interventions
on the frequency of medication errors (ME) and preventable ADE.
Methods
A prospective randomised control trial including 60 patients with EFT was performed in July and August
2010 in a general hospital in Lisbon. In the intervention group, the appropriateness of drug therapy
was assessed daily by the researcher according to selected literature on medication
administration via EFT and specific interventions were suggested by pharmacists. Patients in the observation
group were subjected to usual drug therapy check. For both groups, identified medication
errors were recorded and compared ans potential ADEs assessed.
Results
Figure 1. Comparison of main clinical outcomes between control and intervention group
Incorrect doses administrated
(N, mean per patient per day)
151 (0.6) 19 (0.1) p < 0.01
Non-doubtful ADEs
(N, per 100 patients)
8 (27) 1 (3) p < 0.01
ADEs of at least moderate severity
(N, per 100 patients)
8 (27) 0 (0) p < 0.01
* The results are based on 100 % interventions acceptance rate. In practice, acceptance rate was 77 %.
22
Control group Intervention group* Statistical analysis
Prescribing errors (N, %) 20/183 (11 %) 15/190 (8 %) p = 0.49
Dispensing errors (N, %) 13/183 (8 %) 1/190 (0.5 %) p < 0.01

The intervention group had a significantly lower number of dispensing errors (t-test, p

Comprehensive medication history:
the need for the implementation
of medication reconciliation processes
Lea Knez 1 , Renata Reæonja 1,2 , Stanislav Øuøkoviœ 1 , Mitja Koønik 1 , Aleø Mrhar 2
1
Faculty of Pharmacy, University of Ljubljana
2
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
Comprehensive medication history (CMH) is of outmost importance for patient evaluation and prescription
of drug treatment upon hospital admission. The aim of this study was to assess the need
for the implementation of medication reconciliation processes into clinical practice.
Method
Patients admitted to a teaching hospital in Slovenia were randomly selected and included in the
study. For every patient a CMH was obtained by a research pharmacist using different sources of information.
Next, medication history in the hospital medical record was reviewed. Prescription of medicines
was assessed for completeness of information and discrepancies between both medication
histories were recorded and classified.
Results
Overall, 108 patients with a median age of 73 years were included. The research pharmacist recorded
the use of 651 medicines, of which 94.9% provided all relevant details for drug identification and administration.
Less medicines (464) were recorded in the hospital medical record as compared to the
CMH (paired t-test, p>0.001) and only 42.0% of these medicines were evaluated as complete. When
comparing the medication history in the medical record with the CMH, at least one discrepancy was
detected in 72.4% of medicines and was often present in the medication order on the drug chart
(76.2%) and in the discharge letter (69.9%). Discrepancies often arose due to medicine’s omission
(20.9%) and medicine’s commission (6.5%).
Conclusions
The high rate of discrepancies between the recorded drug history and CMH reported in our study
shows the need for implementation of medication reconciliation practices. Pharmacists’ participation
in admission reconciliation, as described in this study, led to more complete and accurate drug
histories. In the study hospital, pharmacist-led CMH have been introduced in a research framework
within which the benefits of this service for the reduction of medication errors and adverse drug
events are being studied against routine practice in a randomised trial.
24

Implementation of a medication
reconciliation service at hospital
admission: results from
a randomised control study
Lea Knez 1 , Stanislav Øuøkoviœ 1 , Anja Primoæiœ 2 ,
Raisa Laaksonen 3 , Maja Joøt 1 , Mitja Koønik 1 , Aleø Mrhar 2
1
University Clinic of Respiratory and Allergic Diseases, Golnik
2
Faculty of Pharmacy, University of Ljubljana
3
Faculty of Pharmacy, University of Helsinki
Background
Medication errors (ME) resulting from poor communication when patients are transferred across the
healthcare interface are a frequent cause of adverse drug events (ADE). Medication reconciliation: the
process of verifying medication use, identifying variances, and preventing errors, has been introduced
as a measure to improve patient safety. This randomised controlled study was undertaken to assess the
effects of a medication reconciliation service at hospital admission on the reduction of MEs and ADEs.
Methods
Patients admitted to an internal medical ward were randomly selected and randomised to the intervention
group, offered a medication reconciliation service within the first four days of hospital admission, or
to the control group, offered routine clinical practice. A comprehensive medication history (CMH) was obtained
for every patient, and the number of ME, defined as any unintentional discrepancies between the
CMH and the prescribed drug therapy, the resulting ADE and their severity was determined as a consensus
of a medical doctor and a clinical pharmacist, blinded for patient’s group allocation.
Results
A total of 120 patients (60 per group), of higher age (72 years) and with a median of seven medicines
in their CMH were included in the study. In both groups, a discrepancy with a patient’s CMH was
recorded for over 60% of drugs, prescribed on the second day of hospitalisation, and around 30%
of these discrepancies represented a ME. For patients in the intervention group, the treating clinician
was notified of all identified ME and reconciliation of prescribed therapy was proposed; however, this
did not result in a significant reduction in the number of ME present on the fourth day of hospitalisation
(in both groups around 65% of prescribed drugs presented a discrepancy, of which around 25%
represented a ME), nor in the number and severity of ADE, experienced by patients. In both groups,
around 20% of recorded ME resulted in an actual ADE that required temporary treatment.
Conclusions
The high number of MEs and ADEs resulting from poor CMH highlights the prosperity of this problem
for patient safety. The implementation of medication reconciliation at hospital admission within
25

a study setting did not reduce the number of ME nor ADE: the sole provision of the service cannot
succeed in tackling this problem without its recognition and commitment by all the members of the
healthcare team.
26

Communication in palliative care:
challenge for healthcare providers
Urøka Lunder 1 , Maja Furlan 2
1
University Clinic of Respiratory and Allergic Diseases Golnik
2
Faculty of Arts, University of Ljubljana
Background
Effective communication is essential component of end-of-life care. The role of health care providers
is considered to be as experts in their professional field and effecitve communicators who should explain,
most often in layman’s terms, the situation to patients and their relatives. Open communication
has gained increasing importance in recent years and sharing of prognostic information is now common
place. Good communication skills are therefore of vital importance. In this study different health
care professionals were surveyed about their communication skills. We examined whether health
care providers are trained to break bad news and what are the challenges they face in their current
practice of breaking bad news.
Methods
56 health care providers filled out a survey before the effective communication workshop.
Results
Majority of participants were physicians and nurses, with average age of 38 years. 57% had 15 years
or less of work experience. More than half of the participants break bad news at least once a week,
yet 79% of them have never received any training. Management of patients’ emotional reactions and
answering difficult questions were two most common areas of difficulty, with hurting the patient and
getting emotionally attached to the patient being two most common fears while communicating bad
news.
Conclusions
Results suggest knowledge (practical as well as theoretical), organizational resources and personal
growth and development are required to be competent in breaking bad news. Besides the challenges
covered in our survey, participants highlited the burdensome residuals of open communication
with patients, e. g. feelings of guilt and emotional attachement to the patient.
27

Patients referred to Laboratory
for sleep related breathing disorders:
our 5 year experience
Kristina Ziherl, Irena Øarc, Jasmina Gabrijelœiœ
University Clinic of Respiratory and Allergic Diseases Golnik
Background
Sleep-disordered breathing (SDB) is a common medical condition affecting at least 5% of population
and by some studies up to 20%. SDB is associated with much co-morbidity, especially with cardiovascular
disease (CVD) and metabolic syndrome. There are no epidemiological studies of SDB
in Slovenia. Aim of study was to describe basic characteristics of patients referred to laboratory for
SDB and comparison of characteristics between patients without SDB and patients with obstructive
sleep apnea syndrome (OSAS) and obesity hypoventilation syndrome (OHS).
Methods
We screened all initial diagnostic hospitalizations in laboratory for SDB, University Clinic Golnik, between
October 2005 and October 2010. Medical records were reviewed for clinical characteristics
and laboratory results. Statistical analysis was performed by SPSS 17.0.
Results
During five years of the study we performed diagnostic polisomnography in 1102 patients (age 53+/-
11 years, 22% women). ESS score was significant (>10 points) in 51% of patients. 91% patients had
BMI ≥25 kg/m 2 and 62% ≥ 30 kg/m 2 . Men were younger, had lower BMI, higher ESS and AHI and
women more often had hypothyrosis, depression and asthma (p

tients with OHS were treated with CPAP (69%), BiPAP (14%) and LTOT (12% alone and 8% in combination
with CPAP). Average CPAP pressure in patients with OSAS was 10.24 +/- 2.8 cmH2O and
in patients with OHS 11.62 +/- 2.7 cmH2O (p

Pulmonary rehabilitation program –
our results
Tomaæ Hafner, Jurij Øorli
University Clinic of Respiratory and Allergic Diseases Golnik
Background
Chronic obstructive pulmonary disease (COPD) is a chronic disease which through systemic inflammation
and physical inactivity because of dyspnea leads to muscle wasting and atrophy. Rehabilitation
improves patients’ physical performance and consequently their ability to perform everyday
tasks and their quality of life. That is why physical rehabilitation of COPD patients is very important
in long term management of COPD. In our hospital we have four week long pulmonary rehabilitation
program (PRP) for COPD patients.
Methods
We retrospectively searched through medical records of patients who underwent our PRP from years
2006-2010 for results of maximal inspiratory and expiratory pressure (MIP & MEP), distance walked
on shuttle and 6 minute walk tests (SWT & 6MWT) before and after PRP. Not all patients performed
all tests. Data are presented as mean, standard deviation and p value from paired-samples T test.
We wondered how efficient our PRP was and how much patients physically improved.
Results
71 patients (46 man and 25 women) with average age of 65,8 +/- 9,0 years were included in this
study. They were mostly COPD stage 3 and 4 according to GOLD with average FEV1 33,8% +/-
14,1%. Average MIP before PRP was 62,8 +/- 22,2 cm H2O. After PRP increased to 73,9 +/- 22,4 cm
H2O which reached statistical significance with p 0,024. Average MEP before PRP was 107,4 +/-
47,4 cm H2O. After PRP increased to 126,0 +/- 46,5 cm H2O with p 0,009. Achieved walking distance
on SWT before PRP was 224,3 +/ -120,3 m. After PRP increased to 263,5 +/- 139,0 m with p 0,000.
Achieved walking distance on 6MWT before PRP was 287,6+/-124,8m. After PRP increased to 353,3
+/- 133,6 m with p 0,000.
Conclusions
Physical rehabilitation of COPD patients importantly increases their measurable physical performance
which consequently improves their everyday functionality and quality of life.
30

Videothoracoscopic resection
of giant emphysema bullae
Katja Adamiœ 1 , Nika Lalek 1 , Tomaæ Øtupnik 2
1
University Clinic of Respiratory and Allergic Diseases Golnik
2
Clinical Department of Thoracic Surgery, University Medical Centre Ljubljana
Background
The most common indications for resection of giant emphysema bullae (GEB - large bulla occupying
at least 30 percent of the hemithorax) are severe dyspnoea, compression of the surrounding normal
lung and secondary spontaneous pneumothorax. Excision of a GEB reduces airway resistance,
functional residual capacity and physiologic dead space. Physiologic outcome after surgery is determined
mostly by the size of the bulla (preferably > 50% of the hemithorax) and the severity of the
underlying emphysema as the patients with severe generalized emphysema tend to have a worse
outcome. The surgical risk is increased when forced expiratory volume in first second (FEV1) is less
than 40% of the predicted (FEV1 < 20% is an absolute contraindication for surgery) (1, 2).
GEB can be removed using open or videothoracoscopic technique (VATS). VATS is technically more
complex, but provides the best preservation of lung function in early postoperative period, thus it is
most beneficial for patients with reduced pulmonary reserve (3).
Methods
In 2010, we have used the three-incision VATS technique on two patients with GEB. All bullae were
opened longitudinally and resected at their base using a 60 mm long endoscopic stapler.
Clinical case 1. A 57-year old male with a non-small cell lung cancer in the left upper lobe
(cT2bN1M0) and a GEB in the apex of the right upper lobe (FEV1 61%, forced vital capacity (FVC)
101%) had undergone an uncomplicated VATS left upper lobectomy Several months later the GEB
grew to almost 50% of the hemithorax and the patient became severely dyspnoeic (Medical Research
Council dyspnea score (MRC) 4, FEV1 46%, FVC 61%). The bulla was resected eight months
after the lobectomy without any further complications. Two weeks after surgery, the patient was capable
of normal efforts (MRC 1, FEV1 65%, FVC 79%).
Clinical case 2. A 53-year old female presented with the first spontaneous pneumothorax and was
initially treated with a chest tube. Computed tomography revealed severe centrilobular emphysema
and two GEBs in the left upper and lower lobe. Two weeks after discharge the pneumothorax recurred.
Chest tube was inserted to relieve severe dyspnoea and she was scheduled for surgery two
days later. Both GEBs were resected using the VATS technique and a mechanical pleurodesis was
performed. Postoperative recovery was uneventful. A month after surgery, she is capable of normal
efforts (MRC 1) with improved pulmonary function: FEV1 from 25% to 50% and FVC from 51% to
60%.
31

Conclusions
VATS resection of GEB using modern 60 mm staplers is a relatively easy and very effective technique.
In our patient with synchronous lung cancer and a GEB, reverse order of the interventions would
have been more appropriate: removal of the GEB on the right side followed by a lobectomy on the
left side a month later. The patient with secondary spontaneous pneumothorax should have been
scheduled for surgery at her first occurrence of pneumothorax.
References
1. Nickoladze GD. Functional results of surgery for bullous emphysema. Chest 1992; 101:119.
2. FitzGerald MX, Keelan PJ, Cugell DW, Gaensler EA. Long– term results of surgery for bullous emphysema. J
Thorac Cardiovasc Surg 1974; 68:566.
3. Wakabayashi A. Thoracoscopic technique for management of giant bullous lung disease. Ann Thorac Surg
1993; 56:708.
32

Electrocardiogram analysis
of patients with chronic obstructive
pulmonary disease
Miha Zabret, Urøa Boneø, Irena Øarc, Mitja Koønik, Stanislav Øuøkoviœ, Mitja Lainøœak
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
Morbidity and mortality from chronic obstructive pulmonary disease (COPD) is increasing worldwide
and cardiovascular disease contributes significantly. Standard electrocardiogram (ECG) provides
wealth of general and COPD specific information which can serve for patient risk stratification. We
aimed to assess the presence of ECG changes and to analyze potential associations with long-term
mortality.
Methods
This retrospective cohort study included 1001 patients with COPD, hospitalized in University clinic
Golnik between years 2002-2007. ECGs were analyzed by three independent investigators. Next to
standard assessment and measurements, particular attention was given to COPD associated
changes (e.g. P-pulmonale, right heart axis, right ventricular hypertrophy and right bundled branch
block) and parameters associated with prognosis (prolonged QTc interval - 120ms). The survival was ascertained with Central population registry and the database was
censored on November 1st, 2008.
Results
Most of our patients had severe or very severe COPD (63%). They were mostly male (72%), aged 70
± 9 years on average. At least one COPD typical ECG change was present in 33% of patients (P-pulmonale
9%, right heart axis 11%, right ventricular hypertrophy 17%, right bundle branch block 8%)
and correlated with GOLD stage (p

Implications of sputum bacteriology
in acute exacerbations of chronic
obstructive pulmonary disease
Irena Øarc, Viktorija Tomiœ, Mitja Lainøœak,
Kristina Ziherl, Tina Jeriœ, Mitja Koønik, Stanislav Øuøkoviœ
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
Pathogenic bacteria have been implicated as a causative agent in majority of episodes of acute exacerbation
of COPD (AECOPD). We aimed to investigate sputum bacteriology and prognostic implications
of sputum results in AECOPD.
Methods
We conducted a retrospective study of consecutive patients admitted to University Clinic Golnik with
AECOPD from 2002 to 2007. The diagnosis of COPD, sputum bacteriology and clinical characteristics
of patients were confirmed with detailed review of complete medical records. Only the initial hospitalization
of patients with quality sputum was included in the study. Vital status was obtained from
Central Population Registry.
Results
Final sample consisted of 697 patients (age 70 ±9 years, 75% men, 65% GOLD III/IV). Most frequently
isolated pathogens were H.influenzae (19.4%), P. aeroginosa (14.9%) and S. pneumoniae (11.8%). The
isolation of S. pneumoniae (p=0.009), P. aeroginosa (p=0.01), non-fermenting Gram negative bacilli
(p

of COPD but not in the severity of exacerbation. Isolation of multiple pathogens was associated with
negative outcomes at 6 months.
35

Antibiotic treatment during
hospitalization due to acute
exacerbation of chronic obstructive
pulmonary disease
Urøa Boneø, Irena Øarc, Kristina Ziherl, Miha Zabret, Tina Jeriœ,
Viktorija Tomiœ, Mitja Koønik, Stanislav Øuøkoviœ, Mitja Lainøœak
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
Antibiotic treatment during acute exacerbation of chronic obstructive pulmonary disease (AECOPD)
remains controversial. Due to lack of information about antibiotic use in clinical practice, this study
investigated therapeutic pattern and association with prognosis.
Methods
In our retrospective cohort study, we screened all consecutive discharges between 2002 and 2007.
We reviewed medical charts for presence of AECOPD, sputum sample and in-hospital management.
The survival was ascertained with Central population registry.
Results
We included 679 patients (age 70 ±9 years, 75% men, 65% GOLD III/IV). Antibiotics were prescribed
to 560 (80%) patients, who had more advanced COPD stage (GOLD III/IV 69% vs. 57%, p

Examination of resistance of bacteria
isolated from sputum and partial
broncoalveolar lavage in Clinic
for lung disease, Knez Selo
Nastasijeviå Borovac Desa, Tatjana Pejœiå,
Tatjana Radjenoviå Petkoviå, Djordjeviå Ivanka, Ranœiå Milan
Clinic for lung disease, Knez Selo, Clinical Center Niø, Serbia
Background
Due to irrational antibiotic use, a growing bacterial resistance has been noted worldwide, including
our environment. Resistant and multiresistant bacterial strains pose one of the greatest therapeutic
problems. The aim of this study was to present the sensitivity and resistance of bacteria isolated from
sputum and partial broncholaveolar lavage of patients treated in the Clinic for Lung Diseases, Knez
Selo, Serbia, in the period April 1, 2010 - April 1, 2011.
Methods
Resistance was examined by disk diffusion method. The results are shown in percents, by groups
including at least 40 isolated bacteria.
Results
From 2012 sputum samples were isolated 403 (20,03%) bacteria, and 49(12,44%) bacteria from 394
partial broncholaveolar lavage. The following bacteria were isolated: Pseudomonas aeruginosa 87
(19,24%), Staphylococcus (aureus, epidermidis) 67 (14,83%), Serratia 60 (13,28%), Streptococcus
(pyogenes, faecalis, and haemoliticus) 45 (9,96%), Streptococcus pneumoniae 42 (9,3%), Escherichia
coli 40 (8,85%). Other bacteria (Providencia, Proteus, Acinetobacter, Citrobacter, Haemophyllus
influencae, Klebsiela, Enterobacter, Moraxella catarralis) were isolated in a number insufficient
for statistical processing. Gram-negative bacteria were isolated in 65,92% of cases. P.aeruginosa
showed high resistance to cefotaksim (94,25%), trimetoprim-sulfametoksazol (86,04%) and sensitivity
to ciprofloxacin (84,9%), ceftazidim (75,8%) and amikacin (74,7%). Staphylococcus showed preserved
sensitivity to cefuroksim (96,6%), trimetoprim-sulfametoksazol (88,7%), ciprofloxacin (83,3%)
and eritromicin (74,6%), but high resistance to penicillin G (88,7%) and sinacillin (82,9%). Serratia
showed high resistance to amikacin (57,8%) and ceftrikson (50,0%), lower resistance to ciprofloksacin
(29,6%), and high sensitivity to carbapenems (93,1%). Streptococcus (pyogenes, faecalis, and
haemoliticus) was sensitive to penicillin G (97,6%), cefuroksim (97,36%), and ciprofloksacin (95,8%)
but highly resistant to trimetoprim-sulfametoksazol (97,22%). Streptococcus pneumoniae was sensitive
to penicillin G (100%), cefuroksim (97,36%), but resistance to eritromicin (51,3%) and trimetoprim-sulfametoksazol
(86,6%). Escherichia coli was sensitive to ciprofloksacin (89,19%),
trimetoprim-sulfametoksazol (89,5%) and ceftazidim (75,0%), but resistance to ceftriakson (32,5%)
and amikacin (61,1%). Gram-negative bacteria dominated among the isolates. A growing resistance
37

of gram-positive bacteria to macrolides was noted, but also the resistance of gram-negative bacteria
to aminoglycosides, penicillins and cephalosporines.
Conclusions
Since Serbia is not an active member of EARSS (European Antibiotic Resistance Surveillance System),
knowing the local resistance can considerably affect a modality of empirical therapy.
38

Pneumococcal bacteriemia in adults
with community-acquired pneumonia
Katja Adamiœ, Mateja Polajnar, Franc Øifrer, Viktorija Tomiœ
University Clinic for Respiratory and Allergic Diseases, Golnik
Background
Streptococcus pneumoniae (SP) is the most common cause of community-acquired pneumonia
(CAP). Complications of CAP are pleural effusion, empyema, lung abscess and metastatic infection
in patients with bacteremia. Appropriate antibiotic therapy should be initiated as soon as possible
after diagnosis. To establish SP as an aetiologic agent of CAP cultivation and isolation of the bacterium
from patients’ blood cultures (BC) and respiratory specimens should be performed. Also detection
of the pneumococcal antigen (Ag-SP) in urine samples can be used.
Methods
We performed a retrospective analysis of hospital records of patients with pneumococcal bacteremia
admitted to University Clinic Golnik between January 1, 2003 and December 31, 2009. We collected
demographic data, signs and symptoms on admission, laboratory results (C-reactive protein (CRP),
white blood count (WBC), urea, creatinine, etc), microbiological testing results, smoking habits, associated
diseases, antibiotic therapy, use of steroids, vaccination status.
Results
Pneumonia with pneumococcal bacteremia was observed in 139 patients (79 men and 60 women),
mean age was 66 years (range 19 to 95 years). Seventy-five percent of patients had at least one associated
chronic disease, mainly hypertension (43%), diabetes type 2 (24%) and COPD (20%). Eighteen
patients had associated malignant diseases and 2 had confirmed HIV infection. Twelve percent
were alcohol dependent, 26% active smokers, 22% former smokers. Fourteen percent of patients
were receiving inhaled or systemic steroids. No patient had documented information on vaccination
against SP, one patient was advised vaccination at discharge. Most commonly reported sings and
symptoms at admission were cough, dispnea, chest pain, fever and chills with 8% of patients having
haemoptysis. Sixty-three percent of patients were hypoxemic and 25% were hypotensive. Average
admission values of laboratory tests were CRP 260mg/L, WBC 14x10 9 /L (less than 4.0x109/L in
12 patients), haemoglobin (Hb) 124g/L, glucose 8.2 mmol/L, urea 11.3 mmol/L, creatinine 125 µmol/L.
In 10% of patients SP was isolated from sputum, in 9% urine Ag-SP was positive. In 14% of patients
pleural effusion was present (empyema in 5 patients). As empirical antibiotic treatment 51% of patients
received amoxicillin with clavulanic acid, 7% received co-amoxiclav and macrolide, 4% penicillin
and 17% respiratory quinolones. In 30% of patients the empiric antibiotic treatment was changed
to penicillin on account of microbiological results. Twenty-three percent of patients needed haemo-
39

dynamic support with dopamine, 12% had to be intubated and mechanically ventilated. Average duration
of hospitalization was 15 days with 31% of patients treated in the intensive care unit (ICU) for
an average of 9 days. From 139 patients 15% died during hospitalization, 7% during the first 3 days.
Conclusions
According to the national recommendations for the treatment of patients with CAP, patients with
pneumococcal bacteremia who meet the criteria for severe CAP 1 should be initially treated in ICU.
In our retrospective analysis 31% of patients were treated in ICU. To curb the development of pneumococcal
resistance replacement of empirically introduced antibiotic with penicillin after receiving
the microbiological test results should be encouraged. Patients with certain associated diseases and
clinical conditions 1 should be advised to receive pneumococcal vaccine after they recover from CAP.
Literature:
1. E. Muøiœ, K.Osolnik, V. Tomiœ, R. Eræen, M. Koønik et al: Recommendations for the Management of Community-acquired
Pneumonia in Adults (Updated and revised Edition, 2010), Zdrav Vestn 2010;79: 245–264
40

Aspergillosis
Tina Jeriœ, Izidor Kern, Petra Svetina Øorli
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
Aspergillus species are ubiquitous in nature and inhalation of infectious conidia is a common event.
Aspergillus causes a spectrum of disease, from colonization to hypersensitivity reactions to chronic
necrotizing infections to rapidly progressive angioinvasion, often resulting in death. Tissue invasion
is uncommon and occurs most frequently in patient with immunosuppression (neutropenia, transplanted
organ). Aspergillus fumigatus is the most common etiological agent of human aspergillosis.
Case report
We present a case of 55 years old male, ex smoker, with asthma and emphysema, who was treated
with inhaled corticosteroids for at least 10 years. On his last admission to our hospital he presented
with shortness of breath, fever, productive cough, and bilateral apical inifiltrates on chest X-ray. Despite
aggressive empiric antibiotic treatment systemic inflammatory response syndrom developed
and the patient died because of cardiorespiratory failure. Post mortem besides pulmonary thrombembolia
chronic necrotizing pulmonary aspergillosis was found.
Conclusions
Aspergillus conidia are frequently inhaled into the airways but in most cases do not cause the disease
because of the effective clearance. Culture isolation of Aspergillus species from the airway
does not necessarily indicate disease. The diagnosis of invasive aspergillosis is based upon both isolating
the organism and the probability that is the cause of disease. Culture of Aspergillus species
in combination with the histopathological demonstration of tissue invasion provides definite evidence
for invasive aspergillosis. So although invasive Aspergillus infection is rare it should be considered
when the disease is resistant to broad-spectrum antibiotics in immunocompromised patient.
41

Use of multiplex PCR for detection of
bacterial respiratory tract pathogens
Dane Luænik, Judit Stokiå, Viktorija Tomiœ, Franc Øifrer
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
To investigate the usefulness of multiplex polymerase chain reaction (mPCR) to detect Mycoplasma
pneumoniae, Legionella pneumophila, and Chlamydophila pneumoniae in patients with suspected
atypical community-acquired pneumonia and to assess the prevalence of Streptococcus pneumoniae
and Haemophilus influenzae detection.
Methods
We evaluated retrospectively the results of mPCR in 210 patients asigned to 3 groups: patients with
suspected atypical pneumonia (n = 110), patients with asthma (n = 27), and patients with diseases
other than infection (heart failure, malignancy, pulmonary embolism, allergic reactions) (n = 73) admitted
to University Clinic of Respiratory and Allergic Diseases Golnik between January 2010 and January
2011.
Results
An atypical pathogen was detected only in the 26 patients in suspected atypical pneumonia group
(23.6%). L. pneumophila was detected in 4 patients (3.6%), M. pneumoniae in 21 (19%), and C.
pneumoniae in 1 patient (0.9%). No pathogen could be detected by mPCR in 24 (21.8%), 2 (7.4%),
and 49 (67%) patients in suspected atypical pneumonia group, asthma, and other diseases group,
respectively. In patients with suspected atypical pneumonia S. pneumoniae and H. influenzae were
detected 61.8% and 30% patients, respectively. In asthmatic patients S. pneumoniae and H. influenzae
were detected in 81.5% and 51.8%, respectively. In patients with other diseases S. pneumoniae
and H. influenzae were detected in 31.5% and 23%, respectively.
Conclusions
mPCR can increase the number of microbiological detection of atypical pathogens in patients with
suspected community-acquired pneumonia. Clinical relevance of positive mPCR for S. pneumoniae
and H. influenzae is questionable since it cannot distinguish between colonization and infection and
thus, further studies are needed.
42

Carriage rate of extended-spectrum b-
lactamase producing Enterobacteriaceae
and methicillin-resistant Staphylococcus
aureus in elderly on admission to the
nursing home
Katja Øinkovec 1 , Dane Luænik 2 , Jelka Œernivec 3 , Viktorija Tomiœ 2
1
Faculty for Biotechnology, Ljubljana – Department of Microbiology,
2
University Clinic of Respiratory and Allergic Diseases, Golnik,
3
Nursing Home Danice Vogrinec, Maribor
Background
Resistant bacteria are a major public health concern. With population aging more people are admitted
to nursing homes which are presumed to be reservoirs of resistant bacteria. Reports on prevalence
of extended-spectrum b-lactamase producing Enterobacteriaceae (ESBL-E) and
methicillin-resistant Staphylococcus aureus (MRSA) are few in number. We wanted to determine the
carriage rate of both pathogens in elderly on admission to the largest nursing home in Slovenia.
Methods
A survey was conducted prospectively from January 10 to June 1, 2011 in the Danica Vogrinec nursing
home in Maribor which has 809 beds. All future residents were screened for carriage of ESBL-E
and MRSA on admission. To assess carriage of MRSA nose, throat, rectal, wound (when present)
swabs and for carriage of ESBL-E rectal, wound (when present) swabs and urine samples (when urinary
catheter was inserted) were collected. All swabs were inoculated into brain-heart infusion broth.
After 24 h of incubation, broths were subcultured onto BBL CHROMagar MRSA (BD, USA) and Brilliance
ESBL agar (Oxoid, UK). Urine samples were inoculated directly onto Brilliance ESBL agar plates.
Suspected colonies of MRSA and ESBL-E were identified by standard laboratory procedures.
Results
Screening samples were collected from 87 elderly future residents, 62 females (71.%) and 25 males
(28.7%). Mean age was 79 years (range 35 – 97 years). We detected 14 residents (16%) colonized with
ESBL-E (11 female and 3 male) residents and no resident colonized with MRSA on admission. Mean
age of colonized residents was 79.5 years (range 68 – 89 years). Twenty-seven future residents (31%)
were transfered from hospitals, 15 (17%) were transfered from other nursing homes and 45 (52%) were
admitted from home environment. Of the 14 colonized residents 2 (14.3%) were admitted from home,
9 (64.3%) were transfered from hospital and 3 (21.6%) were transfered from other nursing homes.
Conclusions
Due to implemented infection control program to control the spread of MRSA in hospitals MRSA is
not our primary problem anymore. More efforts should be directed to control the spread of ESBL-E
in hospitals, nursing homes as well as in the community.
43

Methicillin-resistant Staphylococcus
aureus and extended-spectrum b-
lactamase producing
Enterobacteriaceae in house pets
Katja Øinkovec 1 , Dane Luænik 2 , Zlata Œop 3 , Viktorija Tomiœ 2
1
Department of Microbiology, Faculty for Biotechnology, University of Ljubljana
2
University Clinic of Respiratory and Allergic Diseases, Golnik
3
Veterinary Clinic, Lesce
Background
Resistant bacteria are a major public health concern. Methicillin-resistant Staphylococcus aureus
(MRSA) is a major pathogen in human medicine and has become a recognized problem in farm animals
(e.g. pigs). Pet owners as well as veterinary doctors and assistants can be colonized with
MRSA and/or with entended-spectrum b-lactamase producing Enterobacteriaceae (ESBL-E) and
they could transfer the pathogens to their pets through direct contact. We wanted to determine the
carriage rate of both pathogens in house pets attending a busy veterinary clinic in Lesce (NW Slovenia).
Methods
A survey was conducted prospectively from February 1 to May 1, 2011 Veterinary Clinic Lesce.
House pets, mainly cats and dogs were screened for carriage of ESBL-E and MRSA on a visit to the
clinic. To assess carriage of MRSA nose and rectal swabs and for carriage of ESBL-E only rectal
swabs were collected. All swabs were inoculated into brain-heart infusion broth. After 24 h of incubation,
broths were subcultured onto BBL CHROMagar MRSA (BD, USA) and Brilliance ESBL agar
(Oxoid, UK). Suspected colonies of MRSA and ESBL-E were identified by standard laboratory procedures.
Results
Screening samples were collected from 100 house pets, 42 cats (42%), 57 dogs (57%) and 1 guinea
pig. Also nasal screening swabs for MRSA detection were collected from 6 veterinary workers (2 veterinary
doctors and 4 assistants). We detected only 1 cat colonized with ESBL-E and no house pets
colonized with MRSA. All screened employees of the veterinary clinic were free of MRSA.
Conclusions
Carriage of resistant bacteria in screened group of house pets was minimal. Since resistant bacteria
can be easily transferred from owners to pets and vice versa periodic surveillance would seem
reasonable.
44

Screening of persons after contact
with a TB patient in the Shelter
for the homeless
Petra Svetina Øorli, Katja Pivk, Andraæ Jakelj
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
To prevent spreading the infection with tuberculosis (TB) in countries with low incidence of TB it is
very important to screen people who were in contact with a TB patient. A contact person is defined
as a person who was in close contact with a patient during his active phase of TB. 10% of infected
contact persons will develop an active TB. Risk factors for infection are alcoholism, smoking, addiction
to intravenous drugs, cachexia, chronic illnesses, and congenital or acquired imunnodeficiency.
Methods
We analyzed the data obtained from homeless persons who were several weeks in daily contact with
a microscopically positive pulmonary TB patient living in the shelter for the homeless. The goal was
to determine the incidence of both latent TB infection (LTBI) and active disease. This data was compared
to the data from a Slovene retrospective study of contact persons in which the incidence of
LTBI was 15% and of active disease 0.7%. 22 homeless people who were in contact with a TB patient
were invited for an examination. Sputum samples for M. tuberculosis were obtained and physical
exam, chest X-ray and QuantiFERON test (QFT) were done.
Results
18 (82%) out of 22 invited homeless person from the shelter actually came for the examination. They
were all unemployed and had never been treated for TB. Cough was present in 3 persons, other
were symptomless. Only 2 chest X-rays were not normal. From each person sputum was obtained
and they were all microscopically negative for TB. Only one (5.5%) person had culture-positive TB
and standard antituberculosis therapy was initiated. In other 17 persons without TB QFT was done
and in 10 (55.5%) of them latent TB infection was confirmed and 3 months chemoprofilactic therapy
was initiated.
Conclusions
Only one (5.5%) of examined homeless contact person from the shelter had culture-positive pulmonary
TB and was treated with standard regime of anti-TB therapy. In 10 (55.5%) of examined persons
LTBI was confirmed. The number of patients with latent infection and active disease in homeless
contact persons is higher than in general population of contact persons. In order to detect and prevent
spreading the infection with M. tuberculosis examination of persons with history of contact with
a TB patient, especially from high risk groups of the population, is very important.
45

Occurrence of tuberculosis in largest
Slovenian correctional facility ZPKZ
Dob in the period from 2000 to 2008
Nadja Koren Pucelj 1 , Irena Hudoklin 2
1
University Medical Centre, Ljubljana
2
Out-patient Practice for Respiratory Diseases, Trebnje
Background
Inmates are known to be more vulnerable to infection with tuberculosis (TB) compared to general population
(crowded environment, presence of persons of low socioeconomic status, foreign-born individuals,
users of illicit substances, persons with human immunodeficiency virus infection). According
to the Slovenian national central register TB did not occur often in correctional facilities until 2000 (1-
2 cases annually).
Methods
In 2000, after first symptomatic case was found, altogether four cases of pulmonary TB were detected
in epidemiological investigation in largest Slovenian correctional facility ZPKZ Dob (ZPKZ
Dob) with 345 male long term inmates. ZPKZ Dob had been overcrowded for many years (official capacity
is 233 persons). As incidence of TB in general population was 18.9 per 100,000 inhabitants
in the same year, the need for enhanced surveillance for TB in this correctional facility was recognized.
Results
From beginning of 2001 until the end of 2008 all new inmates were screened for symptoms of TB and
had tuberculin skin test and chest x-ray carried out. On average 162 (min 118, max 210, SD 29,1)
new inmates were examined annually (altogether 1251 in 8 years). All were male, on average 36,2
years old (min 19, max 77, SD 10,4). In the period of eight years two cases of pulmonary TB (in 2002
and in 2004) and one person with inactive TB and documented history of adequate treatment for TB
were found. Furthermore 169 cases of latent TB infection, with tuberculin skin test more or equal 10
mm, were detected. Both cases of active and 95,4% cases of latent TB infection (161 of 169) were
treated with standard regimens for active and latent infection respectively.
Conclusions
We believe that the danger of outbreaks of TB in ZPKZ Dob was greatly reduced with treatment of
active and latent TB among new inmates. We also recognize the need to implement the surveillance
protocol for infection with TB among new inmates, already incarcerated inmates and correctional officers
in all correctional facilities in Slovenia because the risk of TB is known to be higher in correctional
facilities compared to general population. This is even more relevant for our country as for
46

many years correctional facilities have been overcrowded and in last ten years 11-16% of inmates
have been foreign-born (including those born in countries with high prevalence of TB and multidrugresistant
TB).
47

Pharmacist’s role in the treatment of
patients with tuberculosis – our
positive experience
Janez Toni, Nanœa Œebron Lipovec, Petra Svetina Øorli
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
Tuberculosis as a disease demands long-term multidrug treatment. These drugs can cause serious
adverse drug reactions, mostly hepatotoxicity, that can affect the course of therapy. Moreover,
antituberculotic drugs interact with a variety of drugs, OTC preparations and food, all of
which can significantly alter the effectiveness of patient’s antituberculotic and/or chronic therapy.
Patient’s compliance and patient-tailored therapy are thus crucial for achieving effective
treatment.
Methods
In the University Clinic Golnik, clinical pharmacists are included in the treatment of patients with tuberculosis.
They teach patients on correct drug use and instruct them on the management of possible
adverse drug events and perform drug therapy reviews. These most frequently include counseling
on clinically important drug-drug interactions as well as recommendations on adjustments of drug
doses according to patient’s renal and hepatic function. In 2011, the collaboration of clinical pharmacists
in the treatment of tuberculosis in our hospital was supported by the Health Insurance Institute
of Slovenia.
Results
From June to August 2011 clinical pharmacists performed 29 drug therapy reviews on the tuberculosis
department. The most frequent interventions included recommendations on drug-drug interactions.
One of the most clinically important interactions of antituberculotic drugs occurs with
warfarin: its effectiveness can be significantly reduced in concomitant use with rifampicin, requiring
regular INR measurements and possibly a 2 to 5 fold increase in warfarin dose. Oral calcium
preparations reduce the absorption of antituberculotic drugs from the GIT, whereas concomitant use
of rifampicin and levothyroxine reduces the effectiveness of levothyroxine and requires regular
measurement of thyroid hormones levels and possibly dose adjustment. The detected interactions
and adjusted therapy were documented in the hospital electronic clinical files as well as in the patients’
discharge documentation. This allowed the patient’s GP and local pulmonologist to be informed
about the therapy adjustments and the need for readjustments at the end of antituberculotic
treatment. Clinical pharmacists also performed individual patient counseling on correct drug use,
adverse drug reactions, their prevention and treatment. In the selected period 17 individual counselings
were performed.
48

Conclusions
The collaboration of different healthcare professional in the healthcare team at the University Clinic
Golnik aims at ensuring high quality patient care. At the tuberculosis department, clinical pharmacists
counsel to patients and advise on the management of clinically important interactions on a daily
basis and thus constantly improve the high quality of patient care.
49

A nation-wide study of nontuberculous
mycobacteria in Slovenia
Manca Æolnir Dovœ 1 , Nataøa Fajfar 1 , Irena Plesec 1 , Æiva Petroviœ 2 , Nada Øorli Peranoviœ 1
1
University Clinic of Respiratory and Allergic Diseases, Golnik
2
Institute of Public Health, Centre for Microbiology, Maribor
Background
Nontuberculous mycobacteria (NTM) are ubiquitous bacteria and are isolated from many environmental
sources, most often from water and soil. They are capable of infecting and causing disease
(mycobacteriosis) in both immunocompetent and immunocompromised hosts. HIV infection,
previous chronic lung disease, cystic fibrosis, work in mining industry, advanced age, and male
sex are the most frequent risk factors for the disease reported in several studies. Human infections
caused by NTM have four major clinical manifestations: pulmonary disease, lymphadenitis, disseminated
disease, and skin or soft tissue infections. The frequency of NTM diseases differs with
regard to different geographical regions of the world. In general, cases of mycobacteriosis are on
the rise in the last years. The aim of this study was to analyze laboratory diagnostics of NTM and
NTM disease in the last eleven years (2000-2010) and to detect any changes in distribution of
NTM in Slovenia.
Methods
Between 2000 and 2010, there were 3-6 laboratories in Slovenia that were performing laboratory diagnostics
of tuberculosis and NTM in humans. In the majority of laboratories, cultures were grown on
solid and in liquid media. All clinical isolates of mycobacteria were sent for identification to the National
Reference Laboratory for Mycobacteria Golnik. GenoType Mycobaterium CM/AS assays (Hain
Lifescience, Nehren, Germany), AccuProbe tests (GenProbe, San Diego, USA), classical biochemical
tests and/or colony morphology of NTM on transparent medium were used for identification of mycobacteria.
Results
A total of 2238 (1.6%) isolates of NTM were isolated from 140,001 clinical specimens in Slovenia
in the period 2000-2010. Mycobacterium (M.) xenopi (27.5%) was the most frequently isolated
species followed by M. avium complex (22.6%), M. gordonae (16.3%), M. kansasii (8.1%) and M.
fortuitum (6.7%). In contrast, M. kansasii and M. avium complex were found to be the most common
disease-causing mycobacteria in our country in the last 11 years. Mycobacteriosis has been
observed in at least 115 persons in the same period. Eight of them were children aged between
1.5 and 4 years, all had lymphadenitis caused by M. avium complex and all were detected in the
period 2006-2010.
50

Conclusions
NTM are not very often isolated from human specimens in Slovenia. M. xenopi is the most frequently
isolated mycobacteria and M. kansasii the most common disease-causing mycobacteria in our country.
Mycobacterioses are being detected more often in the last years, but are still relatively rare. Lymphadenitis
in children, “an expected novelty”, appeared in 2006, a year and a half after non-selective
BCG vaccination was stopped in our country.
51

The importance of pre-analytic factors
in Quantiferon-TB Gold test
Urøka Bidovec Stojkoviœ, Manca Æolnir Dovœ
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
Addition of a third (mitogen, M) tube to Nil (N) and Antigen (A) tubes in QuantiFERON - TB Gold intube
(QFT-IT) test represented an important step as the test gained a new value; the result of M tube
can give information about immune status of a person or incorrect transport of blood to the laboratory.
QFT-IT is used in our laboratory since 2004. Mitogen tube was introduced into daily routine in
2008. The aim of our study was to evaluate the influence of pre-analytic factors on the percentage of
indeterminate results.
Methods
A total of 4185 samples obtained between 2008 and 2010 were analyzed in this study. Only data obtained
with all three tubes (N, A and M) were used. In 2009 and 2010, all (100%) samples were collected
into all three tubes while in 2008, 822 samples (73.4%) included all three tubes. Approximately
1.4% of blood samples were rejected by the laboratory due to errors in transport (time of transport
exceeding 16 hours, incorrect transport at 4°C, blood collected in wrong type of tubes). In 256 cases
(6.1%), the result was indeterminate while in 709 (17.0%) cases the result was positive. Negative result
was found in 75.8%.
Results
Detailed insight into indeterminate results per year revealed 93 (11.3%), 82 (5.9%) and 81 (4.1%) indeterminate
results in 2008, 2009 and 2010, respectively. The samples collected in one hospital
showed a particularly high number of indeterminate results, 17% in the first half of 2009. The hospital
has a large number of immunocompromised patients; nevertheless, the percentage was still very
high. The communication with the head nurse responsible for the samples led to improved results
(11% of indeterminate samples; unchanged until present).
Conclusions
Pre-analytical steps of QFT-IT importantly affect the result of QFT-IT test. In our case, the implementation
of QFT-IT into daily laboratory routine started with large number of activities to assure good
quality of the results, including practical and theoretical education of nurses responsible for the collection
of blood, reducing the number of places where blood is collected, well organized transport,
written instructions and providing information and instructions over the phone. As a consequence of
using the third (M) tube and occurrence of indeterminate results, the laboratory has introduced even
52

more serious measures in pre-analytical steps, e.g. more strict control over transport, recommendation
on shorter transport time (4 hours if possible) and communication with people responsible for
the transport of samples. These measures helped to improve the results of QFT-IT test and the number
of indeterminate results significantly decreased.
53

Evaluation of GeneXpert MTB/RIF
assay for detection of Mycobacterium
tuberculosis and rifampicin resistance
in a routine laboratory setting in
Slovenia
Nataøa Fajfar, Urøka Bidovec Stojkoviœ, Manca Æolnir Dovœ
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
Nucleic acid amplification tests have improved tuberculosis diagnostics considerably. The latest development
in the field of molecular diagnosis of tuberculosis is a quick fully automated real-time PCR
diagnostic test, the Cepheid GeneXpert MTB/RIF assay (GX), for the detection of Mycobacterium tuberculosis
and the detection of rifampicin resistance. The aim of our prospective study was to evaluate
the performance of GX in comparison to the Gen-Probe Amplified M. tuberculosis Direct test
(MTD), using culture as a reference method.
Methods
A total of 63 specimens (56 pulmonary and 7 extra-pulmonary) from 55 untreated patients for whom
there was high clinical suspicion of tuberculosis were included in our study.
Results
42 of 63 specimens were culture positive and 21 culture negative. 35 specimens were positive and
22 negative by GX and MTD. 6 specimens were positive by GX only. From 42 culture positive specimens
MTD did not detect M. tuberculosis in 7 specimens but GX did not detect M. tuberculosis in
only one culture positive specimen with only 1 colony grown on Loewenstein-Jensen medium which
indicates really high sensitivity of the GX test. In comparison to culture, the sensitivity, specificity,
positive predictive value and negative predictive value were 97.7%, 100%, 100% and 95.5%, respectively,
for the GX; the corresponding values were 85.7%, 100%, 100% and 75.0%, respectively,
for the MTD. From 41 GX M. tuberculosis positive specimens all of them were rifampicin sensitive by
phenotypic drug susceptibility testing method, but GX test showed 39 rifampicin sensitive specimens
and detected 1 rifampicin resistance and 1 result was indeterminate. After repeat testing GX
test did not detect rifampicin resistance.
Conclusions
The GX test is rapid and has produced better results than MTD; it is more sensitive with significantly
higher sensitivity and negative predictive value. It is suitable for routine detection of M. tuberculosis
in specimens from untreated patients in small laboratories. Thus it can be easily included in our clinical
laboratory in Slovenia. Further studies are needed to evaluate the performance of the GX test for
the detection of rifampicin resistance since no rifampicin resistant specimens were included in this
study.
54

Nation-wide evaluation of three
molecular genotyping methods
in Slovenia
Urøka Bidovec Stojkoviœ, Nataøa Fajfar, Manca Æolnir Dovœ
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
High discriminatory power of genotyping method is of great importance however some other requirements
such as low cost and timeliness are also relevant. The aim of our one year nation-wide
study was to evaluate three different methods for genotyping Mycobacterium (M.) tuberculosis on all
culture positive isolates in Slovenia in year 2008. All MDR strains in the period 1996 and 2009 were
also evaluated in this study. We tried to determine discriminatory power of different genotyping methods.
Methods
A total of 212 Slovenian M. tuberculosis isolates were typed by three different genotyping methods:
IS6110-RFLP (RFLP), 24 loci MIRU-VNTR (MIRU-VNTR) and spoligotyping. Analysis of typing results
was performed with BioNumerics program ver. 5.1 (Applied Maths, Belgium) and Hunter-Gaston discriminatory
index (HGDI) was calculated as well. 190 isolates were obtained from 190 TB patients registered
in 2008 at Slovenian Central Registry for TB Golnik. Additional 22 MDR strains were included
in the study and they represent all (100%) MDR cases in the period 1996-2009.
Results
Among 212 M. tuberculosis isolates 160, 157, 63 distinct patterns; 135 (63.7%), 126 (59.4%), 36
(17.0%) unique isolates; 77 (36.3%), 86 (40.6%), 176 (83%) clustered isolates; 25, 31, 27 clusters
were found with RFLP, MIRU-VNTR and spoligotyping method, respectively. Number of isolates per
cluster was 2-8, 2-7, 2-46 for RFLP, MIRU-VNTR and spoligotyping, respectively. HGDI showed even
more surprising results since we obtained discriminatory index 0.9947, 0.9953, 0.9183 for RFLP,
MIRU-VNTR and spoligotyping, respectively. Evaluation of MDR strains gave us some interesting information.
Among 22 M. tuberculosis MDR isolates 9, 11 and 8 distinct patterns were found in RFLP,
MIRU-VNTR and spoligotyping, respectively.
Conclusions
Our one year nation-wide study showed that the highest discriminatory power has RFLP method.
Nevertheless MIRU-VNTR has shown very high discriminatory power as well, in some cases even
higher than RFLP (MDR isolates). Spoligotyping method showed very low discriminatory power but
has its advantage in recognizing some important strains lineage (Beijing, Haarlem, LAM type…).
55

Primitive neuro-ectodermal tumour
of the lung- a case report
Mojca Unk, Izidor Kern, Tanja Œufer
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
A rare case of a pulmonary primitive neuro-ectodermal (PNET) tumour in an adult is presented here.
In this case due to the rapid aggressive progression of the tumour, which is the characteristic of disease,
the patient died within few days after the diagnosis.
Case report
A 36-years old male, hypertonic, non smoker was admitted to hospital with febrile state, cough and
haemoptysis. CT scan of the thorax confirmed several bilateral nodular masses in the lung with pleural
involvement, enlarged lymph nodes in the mediastinum and right hilus. Bronchoscopy with transbronchial
biopsy was performed and the samples were suspicious for lymphoproliferative disease.
Biopsy of the bone marrow revealed extensive (20%) lymphoid bone marrow infiltration, without infiltrates
or pools of malignant cells, cells were scattered and TIA-1 positive. There was a diagnostic
dilemma of possible NK cell lymphoma. Sixth day after admission to hospital the patient became
febrile, dyspnoeic, tachycardic, anaemia worsened and chest x-ray revealed massive pleural effusion
right. Pleural thoracocentesis revealed haematothorax. He died 13 days after admission due to
unknown malignant disease. Post-mortem examination showed tumour masses in both lungs and on
the parietal pleura, some homogenous, some haemorrhagic and necrotic, haematothorax bilaterally,
enlarged subcarinal lymph node. The rest of the examination showed no pathological changes. Histological
examination showed highly cellular discohesive necrotic tumour growth, tumour cells were
of medium size, with high mitotic index and blastic morphology. They stained positive for vimentin,
CD99, CD68 (not strongly, but CD163 negative), synaptophysin (focally positive, less than 10%),
actin (nuclear positivity, collagen IV (focal positivity around each cell). All the epithelial, mesenchymal,
lymphoma and other markers (desmin, NSE, CD56, EBV, MPO) were negative. Based on morphology
and immunohistochemistry several diagnoses were proposed: high grade undifferentiated
round cell malignant tumour, granulocytic sarcoma. Second opinion obtained from abroad suggested
PNET/Ewing sarcoma. Cytogenetic analysis for reciprocal translocation of the long arms of chromosomes
11 and 22 was negative.
Conclusions
PNETs are exceedingly rare in the adult population, with very few documented cases of primary lung
PNET in the literature, first reported from Askin. Over the last decade, diagnosis has greatly improved
with the introduction of an array immunohistochemical markers, PNETs stain positive for CD99 and
56

NSE and negative for cytokeratins and desmin. In cases where morphology is inconclusive, cytogenetic
analysis has rapidly become the standard for confirming the diagnosis. PNET lesions are aggressive
and usually lethal; they should be considered in the differential diagnosis of thoracic tumours
regardless of the age of the patient. Once a diagnosis of PNET has been made, early wide excision
of the tumour, if possible, along with multimodality chemo- and radiotherapy, should be undertaken
to offer any hope of a long-term cure.
57

Premalignant lesions
among coal miners
Edin Zukiå 1 , Dragan Keser 1 , Edin Jusufoviå 1 , Rifat Sejdinoviå 2
1
Polyclinic for lung diseases, Healthcare Center Tuzla, Bosnia and Herzegovina
2
General Hospital Teøanj, Bosnia Hercegovina
Background
Similar to other malignant disease the lung cancer in some cases develops after a sequence of premalignant
lesions. Sequential changes of the bronchial epithelia include hyperplasia, metaplasia,
dysplasia, carcinoma in situ, which eventually turn to invasive cancer. In previous studies coal miners
have been confirmed to have increased incidence of lung cancer. Goal of this research was to
determine the frequency of preneoplastic lung lesions among coal miners.
Methods
We examined a total of 89 coal miners, 51 employed in surface mining, and 38 in underground mining.
The control group consisted of 33 patients without serious lung conditions that could lead to
preneoplastic lesions. Videobronhoscopy with NBI light source, followed by cytological analysis was
used to detect preneoplastic lesions.
Results
Metaplasia was detected in 42 of the 89 coal miners (47,19%), and in 8 of the 33 patients in the control
group (24,24%). Significantly higher incidence of metaplasia was detected among coal miners
compared to the control group (p=0,037), taking into account the smoking habits.
Conclusions
Preneoplastic lesions represent an important factor in the development of invasive lung cancer among
coal miners.
58

Videothoracoscopic lung lobectomy
in patients over 75 years of age
Nika Lalek 1 , Katja Adamiœ 1 , Tomaæ Øtupnik 2
1
University Clinic of Respiratory and Allergic Diseases Golnik
2
Clinical Department of Thoracic Surgery, University Medical Centre Ljubljana
Background
Videothoracoscopic (VATS) lobectomies are now routinely performed to treat patients with earlystage
lung cancer. In comparison to open lobectomies, VATS lobectomies are associated with less
postoperative pain, lower rate of postoperative complications, shorter length of hospital stay and
faster return to full activity. Age is a known independent risk factor for minor and major postoperative
complications after open and VATS lung lobectomy (1,2).
Methods
We have made a retrospective study of all lung lobectomies done over a 3 year period (2008-2010)
in patients older than 75 years. Propensity score matching with genetic search algorithm was used
to balance groups for known independent risk factors such as: tumor size, comorbidities, age and
location of the tumor.
Results
A total of 39 lobectomies were performed in patients over 75-years of age (9.9% of all lobectomies
performed at our department): 28 open lobectomies (OL) and 11 VATS lobectomies (VL).
The rate of minor complications (air leak > 5 days, arrhythmia) was 45% in VL and 63% in OL group
(p = 0.05). The rate of major complications (pneumonia, empyema, death) was 9% in VL and 17%
in OL group (p = 0.23). The mean length of hospital stay was 7.1 days in VL and 10.7 days in the OL
group (p = 0.01).
Conclusions
VL are associated with a significantly lower rate of postoperative complications and significantly
shorter hospital stay than OL and are thus a highly recommended way to treat early-stage lung cancer
in a subset of older patients.
References
1. Flores RM, Park BJ, Dycoco J, Aronova A et al. Lobectomy by video-assisted thoracic surgery (VATS) versus
thoracotomy for lung cancer. J Thorac Cardiovasc Surg. 2009 Jul;138(1):11-8.
2. Cattaneo SM, Park BJ, Wilton AS, Seshan VE et al. Use of video-assisted thoracic surgery for lobectomy in the
elderly results in fewer complications. Ann Thorac Surg. 2008 Jan;85(1):231-5.
59

Clinical impact of ERCC1 protein
expression in small-cell lung cancer
patients treated with platinum-based
chemotherapy
Eva Sodja 1 , Lea Knez 1 , Tanja Ovœariœek 2 , Izidor Kern 1 ,
Mitja Koønik 1 , Aleksander Sadikov 3 , Tanja Œufer 1
1
University Clinic of Respiratory and Allergic Diseases Golnik, Golnik
2
University Clinic Maribor, Maribor
3
Faculty of Computer and Information Science, University of Ljubljana
Background
The protein excision repair cross complementing 1 (ERCC1) may decrease the sensitivity to platinum
agents. The relationship between low ERCC1 expression and better response to platinum
agents has already been confirmed in non-small-cell lung cancer (NSCLC), while the data on possible
predictive value of ERCC1 in small-cell lung cancer (SCLC) is still very limited.
Methods
This retrospective study evaluated the impact of ERCC1 levels in primary tumour on response to
platinum-based chemotherapy and on survival of SCLC patients treated in a routine clinical practice
at the University Clinic Golnik, between years 2001 and 2007. ERCC1 expression was determined
immunohistochemically in FFPE tumour tissue. The criteria for ERCC1 IHC evaluation was based on
the percentage of cells with positive nuclear staining (0=none, 1=1-9%, 2=10-49%, 3= 50%) and intensity
of staining (0=none, 1=weak staining, 2=strong staining). FFPE tumour tissue samples presenting
with 50% of strongly stained tumour cells were considered as ERCC1 positive. Medical
charts were reviewed for classical clinico-pathological characteristics and for treatment outcome.
Results
269 SCLC patients were enrolled in this study, but only 86 patients had sufficient amount and well preserved
tumour tissue corresponding to SCLC histology for IHC staining. Of those, 64 patients received platinumbased
chemotherapy and were included in further analysis. ERCC1 protein was positive in 38/64 (59%) of
the SCLC patients. No significant difference in overall survival between ERCC1 positive and negative patients
was observed (median survival 12.1 vs. 11.7 months, respectively). There was no significant difference
between ERCC1 positive and negative patients in response to platinum-based chemotherapy (the
percent of patients who obtained either complete or partial response was 80.8% vs. 76.3%, respectively).
Conclusions
In our limited group of 64 SCLC patients ERCC1 protein expression was not found to correlate with
either overall survival or response to platinum-based chemotherapy. To get a definitive answer on the
predictive value of ERCC1 in SCLC a larger prospective trial is mandatory.
60

Quantitative Methylation Profiles
of Multiple Genes in Patients
with Non-Small Cell Lung Cancer
And its Association
with Clinicopathological Correlations
Milica Kontiå 1 , Jelena Stojøiå 1 , Dragana Jovanoviå 1 ,
Vera Bunjevacki 2 , Susan Puumala 3 , Heather H Nelson 4
1
Pulmonology Clinic, Clinical Centre of Serbia, Medical Faculty, University in Belgrade, Serbia
2
Institute for Human Genetics, Oncogenetics Department, Medical Faculty, University in Belgrade, Serbia
3
Sanford Research/ Sanford School of Medicine of the University of South Dakota, USA
4
CancerCentre, Minneapolis, University of Minnesota, USA
Background
Systemic methylation changes may be a diagnostic marker for tumor development or prognosis.
Many genes have been reported as epigenetically aberrant in non-small cell lung cancer. Further, it
has been suggested that DNA methylation changes that occur in lung tumors may be detectable in
circulating blood leading to a clinical tool for screening or relapse. Here, we investigate the relationship
between gene methylation in lung tumors relative to normal lung tissue, and whether DNA
methylation changes can be detected in paired blood samples.
Methods
Sixty five patients were enrolled in a surgical case series of non-small cell lung cancer (NSCLC) at
a single institution. Using bisulfite pyrosequencing, CpG methylation was quantified at five genes
(RASSF1A, CDH13, MGMT, ESR1 and DAPK) in lung tumor, pathologically normal lung tissue, and
circulating blood from enrolled cases.
Results
Three genes had significantly higher methylation in tumors compared to normal lung tissue (CDH13,
RASSF1A and DAPK), and two of the tested genes were not significantly different (ESR1 and MGMT).
To determine whether the aberrantly methylated genes could be detected in circulating blood, we
stratified cases according to their tumor status for CDH13, RASSF1A and DAPK. However, average
DNA methylation in circulating blood was similar among the tumors positive for methylation and those
that were negative, indicating a low feasibility of detecting lung cancer using these genes in a bloodbased
test. Lastly we probed whether tumor methylation was associatied with clinical and demographic
traits of the cases. Histology and gender were associated with methylation at the CDH13
gene, while stage was associated with methylation at MGMT.
Conclusions
Our results demonstrate that elevated methylation at the RASSF1A, CDH13, and DAPK genes are
specific to lung tumors relative to pathologically normal lung. However, we did not observe these
61

same see methylation changes in blood samples from patients with NSCLC indicating they are poorly
suited to a screening test.
62

Anti-angiogenic miRNAs let-7b
and miR-126 are down-regulated
in tumour and tumour surrounding
in NSCLC lung tissue
Edin Jusufoviå 1, 2 , Matija Rijavec 3 , Dragan Keser 1, 2 , Eva Sodja 3 , Mitja Koønik 2, 3 , Peter Koroøec 3
1
Polyclinic for Pulmonary Diseases, Health Medical Centre Tuzla, Bosnia and Herzegovina
2
Medical Faculty, University in Tuzla, Bosnia and Herzegovina
3
University Clinic of Respiratory and Allergic Diseases Golnik
Background
Lung cancer development represents complex molecular events. Angiogenic processes seem to be
crucial for tumor invasiveness and metastatic potential. Micro RNAs (miRNA) might be important in
regulating tumor angiogenesis.
Methods
A total of 50 patients with pathologically proven non small cell lung cancer (NSCLC) (32 squamous
cell lung carcinoma and 18 lung adenocarcinoma) and a control group of 45 healthy individuals were
included in this study. The expression of four angiogenic miRNAs (let-7b, miR-9, miR-19a and miR-
126) was detected by quantitative real-time RT-PCR in formalin fixes and paraffin embedded tissue
samples. Three different tissue samples of NSCLC patients (tumor tissue, tumor surroundings and
healthy lung tissue) as well as lung tissue of healthy individuals were compared.
Results
Expression of anti-angiogenic let-7b and miR-126 were significantly lower (p

Conclusions
In NSCLC patients we observed down-regulation of let-7b and miR-126 in tumor tissue as well as in
tumor surroundings. The level of expression of anti-angiogenic let-7b and miR-126 was similar in
tumor and tumor surrounding. Our results confirm the possible role of those two miRNas in lung cancer
angiogenesis and suggest the potential new target cancer therapy in controlling tumor angiogenesis.
64

MDR1 polymorphisms G2677T/A
and C3435T are independent predictive
markers in small-cell lung cancer
patients treated with chemotherapy
Lea Knez 1 , Tanja Ovœariœek 2 , Aleksander Sadikov 3 ,
Eva Sodja 1 , Izidor Kern 1 , Mitja Koønik 1 , Tanja Œufer 1
1
University Clinic of Respiratory and Allergic Diseases, Golnik
2
University Clinic Maribor
3
Faculty of Computer and Information Sciences, University of Ljubljana
Background
Multiple drug resistance limits the efficacy of chemotherapy treatment and, consequently, survival of
patients with small-cell lung cancer (SCLC). The protein multiple drug resistance 1 (MDR1) has an
important role in this process and variability in its gene may affect treatment outcomes.
Methods
This study evaluated the associations between MDR1 polymorphisms G2677T/A and C3435T with
progression free survival (PFS) and overall survival (OS) in 177 SCLC patients, treated with cisplatinetoposide
or cyclophosphamide-epirubicin-vincristine chemotherapy in a routine clinical practice at
a teaching hospital in Slovenia, between the years 2002 and 2007. To determine the MDR1 genotype,
allelic specific TaqMan® probes were used in a RT-PCR reaction.
Results
Patients, homozygotes for the G2677T/A variant allele (42/174; 24,1%) or harbouring at least one
C3435T variant allele (127/177; 71,8%) had a longer PFS (Log-rank, p=0,050 and p=0,036, respectively)
which persisted also when adjusted for age, sex, stage and PS in multivariate analysis (Coxregression,
p=0,028 and p=0,037, respectively). Moreover, patients with at least one C3435T variant
allele had a longer OS (Log-rank, p=0,021), the association being significant also in multivariate
analysis (Cox-regression, p=0,028).
Conclusions
Our study indicates that MDR1 polymorphisms G2677T/A and C3435T are independent predictive
markers for longer PFS (both polymorphisms) and OS (only C3435T) in Caucasian patients with
SCLC. However, their use to support decisions on chemotherapy treatment in routine clinical practice
requires further validation.
65

Changing to another TKI
in treatment of metastatic NSCLC
Tijana Taja Øumer, Tanja Œufer
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
Epidermal growth factor receptor (EGFR) gene mutations predict for a good response to EGFR directed
therapy with TKIs (gefitinib, erlotinib) in lung adenocarcinoma. There are available data pointing
out that treatment with erlotinib can be effective in patients with prior exposure to gefitinib. Hereby,
we report on three female patients (age 56-79 yr, median age 67 yr) with activating EGFR mutations
in primary tumor those received two subsequent lines of TKI therapy in a routine clinical practice.
Patients
The youngest patient was smoker, the other two never smoked. In the first patient maintenance treatment
with erlotinib resulted in 25 moths of partial response (PR). Gefitinib was initiated as second line
TKI therapy and resulted in PR that still lasts after 17 months. In another case PR of 31 months was
achieved by first line erlotinib therapy. After 5 months without therapy CT scan showed progression
and gefitinib was introduced. After 15 months of follow up she has a stable disease. In the third patient
(ex smoker) stagnation of the disease lasting for 6 months was achieved by first line gefitinib
treatment. Erlotinib was introduced as second line therapy and she is now in observation period for
5 months without signs of progression.
Conclusions
These limited data from our cases suggest that patients with EGFR gene mutations may benefit from
second line TKI after progression instead of immediate chemotherapy introduction.
66

Topoisomerase IIa in small cell lung
carcinoma
Izidor Kern, Mile Kovaœeviå, Eva Sodja, Tanja Œufer
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
Small cell lung carcinoma (SCLC) is very sensitive to chemotherapy. Topoisomerase IIa (TOP2A)
has important role in DNA replication. Cytostatic drugs used to treat SCLC work by blocking the enzyme.
The aim of this study was to determine the TOP2A gene and protein expression and gene amplification
in SCLC.
Methods
We performed analysis of 29 archived bronchial biopsies samples diagnosed as SCLC. Immunohistochemical
staining (monoclonal antibody clone 3F6) was evaluated semi quantitatively by determing
the intensity of reaction in tumor nuclei (negative, weak, marked). Dual silver in situ
hybridization was performed for gene amplification analysis. Signals were counted in 40 preserved
nuclei to detect a ratio between TOP2A gene copy numbers and CEP 17, while polisomy was considered
when at least 40% cells with at least 4 copies of TOP2A gene were observed. Total RNA
was extracted from sections of formalin-fixed and paraffin-embedded tumor tissue. Relative quantification
was performed by real-time polymerase chain reaction using intron-spanning primer-probe
sets.
Results
All 29 samples showed positive immunohistochemical nuclear reaction for TOP2A (16 weak, 13
marked). Four samples showed polisomy, while ratio TOP2A /CEP 17 value was 1,08 - 1,56. Most
samples showed trisomy (22 of 29), while normosomy was detected in 3 samples. Only 11 out of 13
samples were successfully amplified. Median relative gene expression value was 0,901 (0,277-2,902,
SD=0,73).
Conclusions
This study revealed that, although the majority of the samples expressed TOP2A positive immunohistochemical
nuclear staining, it is not possible to correlate it with neither TOP2A gene expression
nor amplification.
67

Neutropenia in lung cancer patients
treated with chemotherapy in a routine
clinical practice – an institutional
experience
Nina Turnøek 1 , Katja Mohorœiœ 1 , Aleksander Sadikov 2 , Tanja Œufer 1
1
University Clinic of Respiratory and Allergic Diseases, Golnik
2
Faculty of Computer and Information Sciences, University of Ljubljana
Background
Chemotherapy is the standard treatment for advanced small-cell (SCLC) and non-small cell lung
cancer (NSCLC). Mielosuppression is a very common side-effect, compromising clinical outcome and
efficacy of the treatment with chemotherapy (ChT), and predisposes patients to serious infections.
Febrile neutropenia (FN) as the most serious side-effect is associated with dose reductions and delays
and serious complications, sometimes even with death. The use of antibiotics, G-CSF and need
for hospitalization are associated with substantial escalation of costs.
Methods
We performed a retrospective analysis of 190 patients with advanced lung cancer (SCLC and
NSCLC), treated with ChT in a routine clinical practice at University Clinic Golnik from January 2009
until March 2011. The rate and severity of neutropenia, the rate of febrile neutropenia, treatment
strategies and the impact of neutropenia and its treatment on patient’s outcome were evaluated. Majority
of patients received platinum based ChT schemes (cisplatin 64.7%, carboplatin 20.0%), smaller
amount of patients received schemes containing other cytotoxics in combination or monotherapy
(15.3%). The frequency of SCLC and NSCLC was in concordance with their incidence (71.1% of patients
had NSCLC, 28.9% had SCLC). Majority of patients received 6 cycles of ChT (46.3%, range
2-6 cycles). Most of our patients received first line ChT (86.8%), only 13.2% received ChT in second
or third line.
Results
Neutropenia was recorded in 100/190 (52.6%) of all patients, and 60/190 (31.6%) patients suffered
severe neutropenia grade 3 or 4. No correlation was found between occurence of neutropenia and
histological type of the tumor or line of ChT. Neither there was a correlation between occurence of
neutropenia and cisplatin- vs carboplatin- based ChT. In majority of the patients neutropenia developed
after the first three cycles of ChT (76.0%), FN also developed mostly after first three cycles of
ChT (81.3%). FN was recorded in 16/190 (8.4%) of patients. No correlation between FN and other
tumor or treatment characteristics was done due to the small number of patients. Prophylactic G-CSF
was used in 14/190 (7.4%) of all our patients, 8 of them received G-CSF after the episode of FN, and
6 of them due to higher grade neutropenia without FN. One patient received primary prophylaxis
with G-CSF, all the others secondary prophylaxis. Therapeutic G-CSF received 6 patients. All pa-
68

tients with FN received antibiotic treatment; however no one of our patients received prophylactic antiobiotic
treatment. One patient died due to FN.
Conclusions
The rate of neutropenia observed in our patients was expected, though the rate of FN was quite low.
The reported rate of FN in lung cancer patients treated with comparable cytotoxic schemes is 10-
20%. The number of patients that received G-CSF is relatively high, especially because G-CSF was
mostly used as secondary prophylaxis. The reason for low rate of FN can be due to relatively high
amount of G-CSF used as secondary prophylaxis. On the other hand, we must be aware of the fact,
that this is a retrospective analysis, where there was no clinical examination and blood analysis during
ChT cycles while our patients were at home. Nevertheless, such a result can also be due to well
chosen indication and well conducted ChT. There is a need to conduct prospective analysis to closely
define this situation.
69

Safety and efficiency of treatment of
advanced NSCLC with non-squamous
histology with pemetrexed
and platinum derivate combination
in routine clinical practice; experience
at University Clinic Golnik
Jernej Mlakar 1 , Tanja Œufer 1 , Nadja Triller 1 , Aleksander Sadikov 2 , Tijana Taja Øumer 1
1
University Clinic of Pulmonary and Allergic Diseases, Golnik
2
Faculty of Computer and Information Science, University of Ljubljana
Background
On the basis of results of a study published in 2008 by Scaggliotti et al, pemetrexed and a platinum
derivate combination has become the standard treatment of advanced non-small cell lung carcinoma
with non-squamous histology. In Slovenia, pemetrexed has become available in the second half
of 2009. We have studied the safety and efficacy of this regimen in our group of patients.
Methods
37 patients with advanced non-small cell lung carcinoma with non-squamous histology, treated with
pemetrexed and platinum derivate from September 2009 to August 2011 were included in a retrospective
study. Previous surgery, radiotherapy or chemotherapy was permitted. At the time of treatment
with pemetrexed and platinum derivate all patients had advanced disease and did not receive
any other treatment modality. Performance status (PS), treatment response and adverse effects were
defined according to the ECOG standards, RECIST 1.1 criteria and CTCAE v4.0, respectively. Time
to disease progression was defined as the time from the start of treatment with pemetrexed and platinum
derivate to disease progression or death and estimated with a Kaplan-Meier method.
Results
31 (83,8%) patients received pemetrexed and cisplatin and 6 (16,2%) patients received pemetrexed
and carboplatin. As a consequence of a small patient number, analysis by chemotherapy regimen
was not possible. Therefore all results represent the entire 37-patient group. Median age was 57
years (range 38-76 years). 7 (18,9%) patients had a PS 0 at the start of treatment with pemetrexed
and a platinum derivate, 26 (70,3%) patients had PS 1, 3 (8,1%) patients had PS 2 and 1 (2,7%) patient
had PS 3. All 37 patients (100%) had adenocarcinoma. The majority of patients (29 or 78,4%)
received pemetrexed and platinum derivate as a first line of treatment, 4 (10,8%) patients received
it as a second line and 4 patients (10,8%) as a third line of treatment. Median number of received
chemotherapy cycles was 5 (range 1-8). Treatment response could be assessed in 35 of 37 patients.
None of the patients achieved complete response, 17 (45,9%) patients achieved partial response
(PR) and 7 (18,9%) patients achieved stable disease. 11 (29,7%) experienced disease progression
during treatment. It was not possible to asses the duration of response due to lack of stringency in
performing regular radiological evaluations. Most of adverse effects (AE) were of grades 1 and 2. Proportions
of patients with individual non-hematologic grade 1 and 2 AE were: nausea 70,2%, vomit-
70

ing 45,9%, elevated liver enzymes 59,5%, stomatitis 5,4%, rash 13,5%, neuropathy 13,5%, elevated
BUN 8,1%, diarrhea 2,7%. Among grade 3 AE neuropathy was present in 2,7% and elevated liver enzymes
in 5,4% of cases. Hematologic AE analysis revealed the following: 29 (24,3%) patients developed
grade 1/2 neutropenia, 5 (13,5%) patients developed grade 3 neutropenia. Grade 1/2
thrombocytopenia developed in 7 (18,9%) patients and grade 1/2 anemia in 24 (64,9%) patients.
Grade 3/4 thrombocytopenia and/or anemia were not detected. Febrile state without neutropenia
(with or without a known localization of infection) occurred in 7 (18,9%) patients. Febrile neutropenia
did not occur. Progression free survival (PFS) of 7,9 months (95%CI, 5,6-10,3 months) was observed
after a median observation time of 11,1 months (95% CI, 4,7 – 17,6 months). Overall survival could
not be estimated due to a short observation time.
Conclusions
According to results of our study we might conclude that pemetrexed and platinum based chemotherapeutic
treatment was safe and active in our group of routinely treated patients. Comparison of results
with the reference study by Scagliotti and colleagues surprisingly showed even better treatment
response (46% vs. 30%), longer PFS (7,9 m vs. 5,3 m) and less AE (especially non-hematologic) in
patients treated in clinical practice than those treated in the trial. Because of the inclusion of patients
with less favorable characteristics, we attribute this discrepancy to a less rigorous response evaluation
and AE assessment in our routine clinical practice. Pemetrexed and a platinum derivate
chemotherapy regimen seem to be safe and effective in clinical practice, however, for a more trustworthy
conclusion to be made, more rigorous evaluation procedures and side effects measurements
need to be performed in routine clinical practice. In addition, a more relevant conclusion on the outcome
of our patients will be possible after a longer follow up period, when overall survival estimation
will be done.
71

Blood oxidative stress markers
and lipid status in sarcoidosis
Jasmina Ivaniøeviå 1 , Jelena Kotur Stevuljeviå 1 , Aleksandra Stefanoviå 1 , Zorana Jeliå Ivanoviå 1 ,
Slavica Spasiå 1 , Jelica Videnoviå Ivanov 2 , Violeta Vuœiniå Mihailoviå 2 , Jasmina Iliå 3
1
Department for Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Serbia
2
Clinic for Pulmonary Diseases, Clinical Centre of Serbia, Belgrade, Serbia
3
Health Centre „St. Luka“, Smederevo, Serbia
Background
Sarcoidosis is an inflammatory disease with enhanced production of reactive oxygen species (ROS)
and alterations in lipid profile suggested to play a role in its pathogenesis. However, current knowledge
about the significance of blood oxidative stress/antioxidant defense as well as lipid status parameters
measurement in sarcoidosis is very limited. Therefore, the aim of our study was to assess
these parameters and to estimate their value for disease prediction.
Methods
The parameters of oxidative stress [malondialdehyde (MDA), superoxide anion (O 2
.-
), total oxidant status
(TOS), prooxidant-antioxidant balance (PAB)] and antioxidant defense [superoxide dismutase
(SOD), total sulfhydryl (SH) groups, total antioxidant status (TAS)] were determined in serum and
erythrocytes and lipid status parameters [total cholesterol (TC), LDL-cholesterol (LDL-c), HDL-cholesterol
(HDL-c) and triglycerides] were assessed in serum of 213 treated sarcoidosis patients and
90 control subjects. Significant difference was set at P

stress and lipid status showed potential to discriminate sarcoidosis from healthy subjects with pronounced
contribution of oxidative stress status parameters. The joint action of these parameters also
suggests certain risk for the development of atherosclerosis.
Grant support
The authors appreciate the financial support from the Ministry of Science and Technological Development,
Republic of Serbia (Project number 175035).
73

Results of 18 F FDG PET scan
in patients with chronic sarcoidosis
Jelica Videnoviå Ivanov, D Sobiå Øaranoviå, Violeta Vuœiniå Mihailoviå, V Zugiå, S Filipoviå
Clinic for lung diseases and tuberculosis, CC Serbia, Belgrade
Background
Sarcoidosis is rare disorder with non-caseating granulomas as main findings. A systemic disease with
predominantly chronic course is another caracteristics. Relapses occur. Aim of work was to analyze
the potential role of 18 F FDG PET scan as marker of activity.
Methods
Results
Among 40 patients with chronic course of sarcoidosis, only one was not treated with corticosteroid
therapy. Positive scan (hypermetabolism) was obtained in 32 patients. The main findings were enlarged
lymph nodes predominantly in mediastinum but higher uptake were also obtained in lung
parenchyma and accidently findings were in non-pulmonary organs.
Conclusions
According to obtained results 18 F FDG-PET scan can represent as the potential diseases activity
marker.
74

The significance of PET CT in diagnosis
of Takayasu arteritis – a case study
Taja Tijana Øumer 1 , Ivana Æagar 2 , Nataøa Gaøperøiœ 3
1
University Clinic of Respiratory and Allergic diseases, Golnik
2
Department of Nuclear Medicine, Institute of Oncology, Ljubljana
3
Department of Rheumatology, University Medical Centre Ljubljana
Background
PET/CT (positron emission tomography with computer tomography) has been shown to be useful for
assessing the location and extent of cancer. It has also been suggested that PET/CT is useful in evaluating
the presence and extent of vasculitis.
Case
A 59-year old female underwent a long diagnostic procedure in another hospital because of undefined
high inflammatory markers (sedimentation rate over 120mm/h, C-reactive protein 131 mg/l),
microcytic anemia (hemoglobin 82 g/l , ferritin 2420 mcg/l). Her leading symptoms were muscle pain,
weight loss and generally very bad state of health. In 1990 she was treated for of pulmonary embolism
of unknown origin. Acute inflammatory or autoimmune disease, malignant disease or other probable
reasons for her health condition were excluded by extensive diagnostic workout. The only important
finding was a small nodule in left thyroid lobe, which was cytologically proven to be benign, without
evidence of inflammation. As she did not meet criteria for any of rheumatologic diseases, the exact
diagnosis remained unclear.
Results
The patient was referred for PET/CT to exclude occult malignant disease. The examination revealed
diffuse and slightly irregular pathologic 18-F-FDG (fluordeoksyglucose) uptake in the aortic wall along
the entire aorta from its arch to bifurcation, with SUV max
3.6. Pathologic accumulation has also been
detected in the wall of both subclavian and carotid arteries and was suggestive of large vessel vasculitis.
The patient was treated with glucocorticoids according to the scheme for Takayasu arteritis.
During a 1,5 year follow-up she is now without any symptoms and signs of the disease .
Conclusions
18
F-FDG-PET is proving to be a sensitive and specific tool for detection of active vascular wall inflammation
and should be taken into account in diagnosis of Takayasu arteritis. Clinical criteria for
Takayasu arteritis are probably not sufficient. New diagnostic technologies should be evaluated in
such unusual cases.
75

Diagnostic value of pulmonary NKT
CD3 + CD16/56 + cells
Katarina Osolnik, Matija Rijavec, Peter Koroøec
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
Natural killer T (NKT) cells, a unique subgroup of T cells, may be implicated in the pathogenesis of
interstitial lung diseases (ILDs).
Methods
We used multi-parameter flow cytometry with antibodies to CD3, CD4, CD8, CD14, CD45 and
CD16/56 in BAL fluid (BALF) to examine the diagnostic relevance of pulmonary CD3 + CD16/56 + NKT
cells and to compare them with NK cell frequencies and CD4/CD8 index. We selected and analysed
only BALF of patients with initial increased (> 8%) frequency of CD3 + CD16/56 + NKT cells.
Results
Of 88 selected patients with increased frequencies, 25 patients were diagnosed as hypersensitivity
pneumonitis (HP) and 35 as sarcoidosis (SA), 14 patients demonstrated diffuse ILDs, 7 had malignant
diseases and 7 patients had bacterial infection. The uppermost frequencies of BALF
CD3 + CD16/56 + NKT cells were demonstrated in patients with HP (median of 16%, range 8% to 52%),
and those values were significantly higher as CD3 + CD16/56 + frequencies observed in patients with
SA (10%, range 8% to 19%) or diffuse ILDs (10.5%, range 8% to 17%; P

Peripheral invariant NKT cells and
factors involved in the development
of iNKT cells in sarcoidosis patients
Matija Rijavec, Katarina Osolnik, Mitja Koønik, Peter Koroøec
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
Invariant natural killer T (iNKT) cells, with restricted Va24-Ja18-Vb11 T cell receptor, might contribute
to the amplified and prolonged T-cell immune response that characterizes sarcoidosis. Their exact
role as well as factors involved in regulating the development and recruitment of iNKT cells is still to
be determined. SAP-dependent signalling as well as specific miRNAs might be involved in iNKT cell
development. The aim of the study was to analyze the numbers of invariant NKT cells, mRNA and
miRNA expression profiles of factors that might be involved in SAP-dependent signalling in the whole
blood of corticosteroid-naïve patients in comparison with healthy individuals.
Methods
We used multi-parameter flow cytometry, with antibodies to CD3, Vb11 and 6B11 in combination with
beads, to examine the absolute counts of iNKT cells. Total RNA and miRNA was extracted from peripheral
blood, it was reverse transcribed to cDNA and Real time PCR for the mRNA/miRNA of interest,
was performed. We included 31 newly diagnosed sarcoidosis patients and 28 healthy subjects.
Results
We have found striking reduction in absolute numbers of CD3+CD4+ but not CD3+CD4– Va24-Ja18-
Vb11 iNKT cells as well as significantly decreased expression of SAP, SLAMF1, SLAMF6 and Fyn and
increased expression of miR-21 in patients with sarcoidosis in comparison to healthy subjects.
Conclusions
These results suggest that the deficiency of iNKT cells might be crucial for the development and
course of sarcoidosis. Furthermore, we imply on the involvement of SAP-dependent signalling pathway
as well as specific miRNAs in the development of iNKT cells.
77

Side-effects of specific
immunotherapy: our experience –
KOPA Golnik
Jasmina Dimitrijeviå, Miljana Vegnuti, Katja Adamiœ,
Nissera Bajroviå, Renato Eræen, Mitja Koønik, Ema Muøiœ, Mihaela Zidarn
University Clinic of Respiratory and Allergic Diseases Golnik
Background
Immunotherapy celebrated 100 years of efficiency in management of allergic asthma, Allergic rhinitis/conjunctivitis
and stinging insect hypersensitivity. In our Clinic, we perform specific immunotherapy
(SIT) for such group of patients for almost 40 years.
Methods
We performed a retrospective study to compare side effects of immunotherapy to different allergens.
We included 1774 patients that were treated with SIT (2 day ultra-rush protocol for venom immunotherapy
(VIT) and 6 week dose-increase protocol with modified aeroallergen extracts). The aim
of our retrospective study was to show the frequency and degree as well as the type of allergic reaction
during the course of Immunotherapy.
Results
In our study 1449 patients received venom immunotherapy and 465 patients received inhaled allergen
immunotherapy. The overall prevalence of side effects was 29,2%. In venom immunotherapy
prevalence was 30% and for the aero-allergen group 25%. In group of patients receiving VIT, side
effects appeared more frequently in the dose-increase phase and in the other group patients showed
more side effects in the maintenance phase. The majority of systemic reactions were mild. Only eight
patients in both groups had a life-threatening reaction after immunotherapy followed by fall of blood
pressure and/or loss of consciousness which was treated with adrenalin. We had no fatal outcomes
due to immunotherapy during all years of clinical experience. Large local reactions were present in
20.4% in both groups in dose-increase phase and 24.8% in maintenance phase with no significant
difference between the allergens.
Conclusions
In our study we came to conclusion that even though systemic reactions are not rare during the
course of Immunotherapy, they are mild in the most cases and well tolerated. Like in foreign literature,
the group with highest risk for having side effects was the group of patients receiving venom
immunotherapy, first of all – honeybee extract.
78

Allergy in patients
with vocal fold nodules
Gordana Mumoviå 1 , Irena Hoœevar Bolteæar 2 , Olga Popov-Dragin 1
1
University Department of Otorhinolaryngology, Novi Sad, Serbia
2
Department of Otorhinolaryngology and Head & Neck Surgery, University Medical Center, Ljubljana,
Slovenia
Background
Vocal fold nodules (VFN) are results of voice misuse and abuse. The incidence of allergy in patients
with benign vocal fold lesions was found to be higher than in the general population. It is possible
that allergy makes the mucosa of vocal folds more susceptible for mechanical trauma during vocal
fold vibration in aggressive phonation. The aim of the study was to find out whether there are some
differences in the voice quality in patients with VFN with allergy versus those without allergy.
Methods
Fifty consecutive patients with VFN and allergy and 20 patients with VFN and without allergy were included
in the study. The allergy was proven by history and skin prick tests. In all patients acoustic
analysis of voice samples (vowel /a/ at habitual pitch and loudness) was performed. The following parameters
were analyzed: fundamental frequency (F0), jitter, shimmer, minimal and maximal voice intensity,
normalized noise energy (NNE) and harmonic-to-noise ratio (HNR) with the use of Dr. Speech
(TIGER DRS) software. The voice characteristics hoarse, harsh and breathy were also determined in
comparison with the software’s database. A comparison of voice characteristics between the patients
with allergy and without it was done using SPSS statistical package, Version 18.
Results
There were 20 men and 30 women in the allergy group and 9 men and 11 women in the control group
(p=0.791). Their age range was 12-65 years, mean 32.26 years. Thirty-four patients had allergy on
house dust and 33 patients on different pollens. Allergy on other allergens (fungi, animal fur) was
found in less than 10 patients. The patients with allergy had significantly louder minimal (p=0.043)
and maximal voice intensity (p=0.021) and less favorable NNE (p=0.017) than the patients without
allergy. There were no significant differences regarding voice characteristics hoarse, harsh and
breathy.
Conclusions
The results of the study showed that patients with VFN and allergy were louder and had less favorable
noise presence in their voices than the patients without allergy. We suppose that hyperplastic
rhinitis and Eustachian tube dysfunction were the reasons for greater loudness in allergic patients.
79

Anyhow, allergy appears to be one of the important factors which must be considered in the treatment
of patients with VFN.
References
1. Curr Opin Otolaryngol Head Neck Surg. 2009; 17(6):420-3.
2. Curr Opin Otolaryngol Head Neck Surg. 2003; 11(6):456-61.
3. J Voice. 2007; 21(2):151-6.
80

ORMDL3 gene polymorphism is
associated with asthma risk and
severity in Slovenian children
Mateja Balantiœ 1 , Matija Rijavec 1 , Maja Kavalar 2 , Mira Øilar 1 , Mitja Koønik 1 , Peter Koroøec 1
1
University Clinic of Pulmonary and Allergic Diseases, Golnik
2
University Clinical Centre Maribor
Background
Genome-wide association study identified ORM1-like 3 (ORMDL3) as an asthma candidate gene.
ORMDL3 encodes a 4-transmembrane domain-containing protein that is localized to the endoplasmic
reticulum membrane. Although current knowledge of ORMDL3 function is limited, it was associated
with asthma in different population samples. Rs7216389 was one of the most studied SNPs in
ORMDL3 and it was associated with asthma in numerous studies. There is much less data about
rs4795405 C>T, which was missing in majority of above mentioned studies. Therefore we evaluate
rs4795405 allele frequencies in Slovenian children with different severity (severe, moderate, mild)
and healthy controls.
Methods
All subjects came from the East-North region and were genotyped with Real Time TaqMan allelic
discrimination assay, using DNA isolated from blood specimens.
Results
We clearly showed that SNP rs4795405 was significantly associated with asthma risk and severity in
our study groups. The frequency of risk allele C was significantly higher in asthmatic patients than in
healthy controls. Patients with severe asthma had higher C allele frequency, compared to moderate
and mild. Groups of patients with severe and moderate asthma had significantly different allele C frequency.
Conclusions
Finally we can summarize that SNP rs4795405 might be an important asthma genetic marker. It is not
only associated with asthma development, but also with asthma severity in Slovenian children. Therefore
it is necessary to replicate our study on bigger population samples, to additionally confirm its involvement
in asthma.
81

Expression profiles of regulatory
genes after venom immunotherapy
Mira Øilar 1 , Branko Pevec 2 , Matija Rijavec 1 , Renato Eræen 1 ,
Mitja Koønik 1 , Asja Stipiå Markoviå 2 , Peter Koroøec 1
1
University Clinic of Respiratory and Allergic Diseases, Golnik
2
Clinical Hospital Sveti Duh, Department of Clinical Immunology, Pulmonology and Rheumatology,
Zagreb, Croatia
Background
The aim of our study was to investigate the ex vivo gene expression profiles of transcription factors
involved in the regulation of Treg, Th1 and Th2 cells, namely FOXP3, T-BET and GATA-3, and the efficacy
of venom immunotherapy (VIT).
Methods
For the purpose of the study we have included 5 groups of subjects. First group included 24 Hymenoptera
sting allergic patients, whose samples were taken before starting VIT. In second group
28 patients were on VIT for 1 year and sampling was done just before the next maintenance dose.
The third group represents 22 patients after completed VIT, which lasted from 3 to 5.5 years. The sampling
was done just before sting challenge. Sting challenge was performed with the insects implicated
by the VIT. The fourth group consisted of 25 healthy control subjects and the last study group consisted
of 20 atopic patients with mite allergy and allergic rhinitis. Total RNA was isolated from peripheral
blood, reverse transcribed to cDNA and the expression was analyzed with Real time PCR
using the DDCt method.
Results
Expression levels of FOXP3, T-BET and GATA-3 were significantly higher in patients with successfully
completed VIT (negative sting challenge) compared to Hymenoptera venom allergic patients before
VIT, after 1 year of VIT and also to healthy controls. Expression level of T-BET was also
significantly higher in comparison to atopic subjects, but that was not the case for FOXP3 and GATA-
3. Levels of all those markers were also higher compared to the patient who has positive sting challenge
after completed VIT.
Conclusions
Our results suggest that increased expression of FOXP3 might be significantly associated with successfulness
of VIT and long term allergen tolerance.
There was no change of transcription factor expression after one year of immunotherapy. This finding
could explain why short lasting immunotherapy has no long term effect.
82

Baseline serum tryptase is not
associated with the risk for severe
anaphylactic reactions in honey bee
venom allergy
Nina Œelesnik, Peter Kopaœ, Renato Eræen, Mira Øilar, Mitja Koønik, Peter Koroøec
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
An elevated level of tryptase outside anaphylaxis in Hymenoptera allergy has not yet been fully elucidated.
The aim of our study was to evaluate whether a baseline tryptase level predicts the severity
of anaphylactic reaction in honey bee venom allergy.
Methods
We included 184 Hymenoptera venom allergic patients with established honey bee venom allergy.
The study group consisted of patients with large local reaction - LLR (11%), Mueller grade I (8%), II
(18%), III (40%) and IV (23%) after a honey bee field sting. Furthermore all recruited patients had positive
sIgE for honey bee venom and negative for wasp venom. Diagnostic evaluations occurred at
least 14 days after the field sting by ImmunoCAP (Phadia). The value of 11.4 µg/L was considered
to be elevated.
Results
Baseline serum tryptase values were highly comparable between different subgroups of patients.
The comparison between the subgroups clearly did not show any significant differences in elevated
baseline serum tryptase levels, as 5% of LLR and 0%, 3%, 4% and 7% of Mueller grade I, II, III and
IV subgroups exceeded the value for normal baseline tryptase value.
Conclusions
The results of our study indicate that there is no significant association between an elevated serum
tryptase and severe anaphylaxis in honey bee venom allergy. Previous findings observed an elevated
baseline serum tryptase significantly more often in wasp venom than in honey bee venom allergic
patients, which may elucidate our findings.
83

Diagnosis of double sensitized
Hymenoptera venom allergic patients
with recombinant species-specific
major allergens used in basophil
activation test
Nina Œelesnik 1 , Renato Eræen 1 , Mira Øilar 1 , Irene Mittermann 2 ,
Rudolf Valenta 2 , Mihaela Zidarn 1 , Mitja Koønik 1 , Peter Koroøec 1
1
University Clinic of Respiratory and Allergic Diseases, Golnik
2
Christian Doppler Laboratory for Allergy Research, Center for Physiology and Pathophysiology,
Dept. of Pathophysiology/Division of Immunopathology, Medical University of Vienna, Vienna, Austria
Background
Double positivity to honey bee and wasp venom necessitates supplementary testing to distinguish
genuine double sensitization from cross-reactivity in patients, who are unable to identify the culprit
insect. Our aim was to define their primary sensitization.
Methods
We included 14 Hymenoptera venom allergic patients with double-positive sIgE to both venoms. Furthermore
all recruited patients had double-positive basophile activation test as well. The culprit insect
responsible for their anaphylactic reaction remained unidentified. Additional testing was
performed with recombinant species-specific major allergens rApi m1, rApi m2 and rVes V5.
Results
With the use of recombinant species-specific allergens in basophile activation testing we were able
to identify 4 patients with unambiguous wasp venom sensitization, 5 patients with antibodies to wasp
venom and cross-reactive hyaluronidase and 1 patient with cross-reactive antibodies exclusively to
hyaluronidase. One the other hand the remaining 3 patients were displaying a genuine double sensitization
to both species-specific major allergens. In one patient, who did not react with any of the
species-specific major allergens, additional measurements with OSR and MUX from bromelain, revealed
his true sensitization to cross-reactive carbohydrate determinants.
Conclusions
Our results demonstrate the usefulness of species-specific recombinant allergens in elucidating double-positivity
in Hymenoptera venom allergy. Determining the primary sensitizing insect is crucial for
selection of appropriate venom immunotherapy, as it is unlikely that immunotherapy with the second
venom would be of any additional benefit.
84

Rhinitis symptoms caused by grass
pollen are associated with elevated
basophil allergen sensitivity and a
larger grass-specific IgE fraction
Mihaela Zidarn, Mitja Koønik, Mira Øilar, Andrej Grahek, Peter Koroøec
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
The mechanisms responsible for the difference between clinically irrelevant IgE sensitization and allergic
rhinitis are not fully understood. For that reason, we evaluated the humoral and cellular mechanisms
that may be associated with the presence of allergic rhinitis symptoms.
Methods
We selected 26 of 33 subjects with positive grass pollen skin tests, elevated sIgEs specific for Timothy
(g6) and the major grass allergen r Phl p 1, 5b. Fourteen of those patients reported a history of
allergic rhinitis. During winter, we performed a grass pollen CD63 basophil activation test using four
log allergen concentrations, followed by a grass nasal provocation test (NPT). In the subsequent pollination
season, we obtained symptom scores.
Results
We showed that the subjects with a positive NPT have significantly higher CD63 basophil grass pollen
responsiveness then NPT-negative subjects, preferably at sub-maximal allergen concentrations,
which represent cellular sensitivity. Moreover, basophil sensitivity positively correlated with the size
of the grass-specific IgE fraction in relation to total IgE levels, and it was highly predictive of allergic
rhinitis symptoms in the following pollination season.
Conclusions
Allergic rhinitis symptoms are significantly associated with allergen basophil sensitivity, and this cellular
allergen sensitivity correlates with the percentage of grass pollen-specific IgE antibodies relative
to total IgE antibody levels. In vitro evaluation of basophil sensitivity should prove useful for
distinguishing clinical phenotype of allergic sensitization.
85

Diagnosis of double sensitized
Hymenoptera venom allergic patients
with recombinant species-specific
major allergens used in basophil
activation test
Peter Kopaœ 1,2,3 , T. Gentinetta 1,2 , M. Rudin 2 , R. Gerber 2 ,
C. Pichler 2 , O. Hausmann 2 , B. Schnyder 2 , W.J. Pichler 1,2
1
ADR-AC GmbH, Holligenstrasse 91, CH-3008 Bern
2
Division of Allergology, Clinic for Rheumatology and Clinical Immunology/Allergology, Inselspital,
University of Bern, CH-3010-Bern, Switzerland,
3
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
Patients with birch pollen allergy (major allergen: Bet v1) have often an associated oral allergy syndrome
(OAS) to apple, which contain the cross-reactive allergen Mal d1. As successful birch pollen
immunotherapy does not consistently improve apple related OAS symptoms, we evaluated if regular
apple consumption has an effect on apple associated OAS and immune parameters of Mal d1 or
Bet v1 allergy.
Methods
40 patients with a clear history of birch pollen rhino-conjunctivitis and associated OAS to apple were
included into randomized, controlled clinical trial. 13 patients remained untreated (control group),
while 27 patients (active group) consumed daily small amounts of apple (“Golden Delicius” strain with
high content of Mal d1 (6,2 ug/g)). Starting dose was the smallest dose, causing not yet or only very
minor OAS, determined by oral provocation tests (OPT). The dose was increased gradually and was
doubled every 2-3 weeks, always aiming to remain free of symptoms in spite of eating more apples.
In vivo (OPT, intradermal tests (ITD) with Bet v1 and Mal d1, conjunctival provocation test (CPT) with
Bet v1) and in vitro tests (sIgE, sIgG4, basophil activation test (BAT) with both allergens) were performed
at the beginning and after 8 months.
Results
5/27 patients in the active group withdrew (2 experienced local mild gastrointestinal side effects, 3
because personal reasons). After approximately 20 weeks (17-30 weeks) of regular apple consumption,
17/27 patients in the active group could tolerate a whole apple (~ 200g) without OAS. The
dose of apple tolerated at OPT increased from 4g to 128g (p: 0.00001) after 8 months; A few patients
could also tolerate some cross-reactive food. 5/27 patients of the active group could not successfully
reach maintenance dose despite trying eating apple. Stop of apple consumption lead to rapid
reappearance of symptoms. All (13/13) patients in control group had an unchanged reactivity to
apple at the beginning and at the end of the study. In vivo (ITD, CPT) and in vitro (sIgE, sIgG4 levels,
BAT) tests were not significantly altered in the active vs. control group.
86

Conclusions
We provide a protocol of oral desensitization to apple, which was safe and highly successful in clinical
terms, while no clear change of immunological parameters was seen in the 8 months of “apple
therapy”. The procedure proposed seems to induce similar effects as drug desensitization, and may
be transient and only affect the oral mucosa.
87

Comparison of basophil activation test
and inhibition tests in double positive
Hymenoptera venom allergic patients
Renato Eræen, Mira Øilar, Peter Koroøec, Mitja Koønik
University Clinic of Respiratory and Allergic Diseases, Golnik
Background
In Hymenoptera venom allergic patients double positive tests are frequently found. Distinguishing between
double sensitization and cross reactivity is crucial for choosing proper venom for specific immunotherapy.
In diagnostic procedure of double positive patients inhibition tests are helpful. In our
analysis we compared the results of inhibition tests and BAT in evaluating double sensitization and
cross reactivity.
Methods
Patients with a history of anaphylactic reaction after Hymenoptera sting are included into study. Double
positivity was diagnosed with skin prick tests and specific IgE (FEIA, Uppsala, Sweden). FEIA inhibition
tests and BAT were performed in all patients.
Results
26 double positive patients were included into study. 92.3% experienced anaphylactic reaction Muller
grade IV and 7.7% Muller grade III. The culprit insect was honeybee in 38.4% of the patients, wasp
in 30.8% of patients and unknown in 30.8% of patients. In 73.2% of patients the results of inhibition
tests and BAT matched and showed double sensitization. In 15.4% BAT showed double sensitization
while inhibition tests cross reactivity. In 7.6% inhibition tests showed double sensitization while
in BAT only sensitization with one culprit was confirmed.
Conclusions
In distinguishing double sensitization and cross reactivity inhibition tests and BAT are complementary.
Cross-reactive hyaluronidase with proven cross-reactivity in inhibition tests could result in double
positive BAT. Interpretation of results requires careful reassessment and correlation with
anamnestic data.
88

Association analysis of polymorphisms
in selected candidate genes
in slovenian children with astma
Petra Perin 1,2 , Vojko Berce 3 , Uroø Potoœnik 1,2
1
Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of
Maribor, Maribor
2
Laboartory for Biochemistry Molecular Biology and Genomics, Faculty of chemistry and chemical
tehnology, University of Maribor, Maribor
3
Department of Pediatrics, University Medical Centre Maribor
Background
Many candidate genes initially associated with asthma or asthma phenotypes were not confirmed as
asthma genes in the follow up independent studies in different populations. In most association studies,
candidate genes were compared between controls and all asthma patients in one group. The aim
of our study was the association analysis of selected genes in Slovenian asthmatic children.
Methods
We analyzed candidate genes in all asthmatics and separately in the group of atopic asthmatics and the
group of non-atopic asthmatics. In addition, we have analyzed the correlation between selected polymorphisms
(SNPs), clinical parameters and response to therapy with glucocorticoids. Using bioinformatics
tools nine single nucleotide polymorphisms (SNPs) in nine different candidate genes were selected.
We have genotyped 247 children with asthma and 186 healthy controls. Genotyping was performed by
polymerase chain reaction (PCR) and by the restriction fragment length polymorphism (RFLP) analysis.
Results
We have found significant association of genes CCR5, IL13 and RANTES and asthma. In addition, we found
that non-atopic asthmatics with CC or CT genotype for SNP 159C/T in CD14 gene have increased bronchial
hyperreactivity measured by PC20 of methacholine (0.41 mg/ml, compared to 1.50 mg/ml in patients with
TT genotype, p = 0.018). The same SNP is also associated with FEV1/FVC ratio as a measure of bronchial
obstruction in sub-group of non-atopic patients. Carriers of at least one allele T for SNP -159C/T have a
lower FEV1/FVC ratio (87.4%), compared to 91.8% in patients with CC genotype (p=0.017). In atopic asthmatics
we found that IL12B gene influences the bronchial obstruction (p = 0.006). In addition, we are the
first ones who associated CTLA4 and ORMDL3 with response to asthma therapy with glucocorticoids.
Conclusions
Our results contribute to our understanding of the asthma pathogenesis. SNPs which we have identified
as associated with asthma, asthma phenotypes, severity or response to therapy may in future
serve as diagnostic and prognostic biomarkers and lead to better management of asthma patients.
89

WORKSHOP
DELAVNICA – ORGANIZIRAJOŒA PLJUŒNICA
91

Organizirajoœa pljuœnica –
histopatoloøka entiteta
Izidor Kern
Univerzitetna klinika za pljuœne bolezni in alergijo Golnik
Za organizirajoœo pljuœnico (OP) je znaœilna razrast granulacijskega tkiva v svetlini malih dihalnih
poti in okolnih alveolarnih prostorih. Gre za nespecifiœen, pogost odgovor pljuœnega tkiva na razliœne
etioloøke dejavnike z vzorcem intraluminalne fibroplazije z organizacijo vnetnega eksudata. Zaradi
moæne soœasne histoloøko spremenjene strukture stene malih dihalni poti je sinonim za OP tudi obliterantni
bronhiolitis z organizirajoœo pljuœnico (BOOP), kar vnaøa zmedo in ga zato opuøœamo.
Spremembe so v pljuœih razporejene æariøœno (tabela 1). Osnovna arhitektura pljuœnega parenhima
je v celoti ohranjena. Izstopa proliferacija rahlega veziva, granulacijskega tkiva distalno v pljuœih (v
svetlinah malih dihalnih poti, alveolarnih vodov in okolnih alveolov), kar imenjemo tudi Massonovi
poganjki. Gre za œasovno unimorfne bronhiolocentriœne spremembe. Vezivo je bogato z mukopolisaharidi
in ne vsebuje zrelega kolagena, zato ga lahko prikaæemo s specialnimi barvanji (slika 1). V
vezivnih œepih so lahko prisotni fibrin, siderofagi in vnetnice. Blaga do zmerna vnetnoceliœna infiltracija
zajame tudi alveolarne septe. V vnetnem infiltratu so limfociti in plazmatke. Izraæene so reaktivne
spremembe alveolarnega epitela s hiperplazijo pnevmocitov tipa 2. V alveolih se kopiœijo penasti
makrofagi. V intersticiju ni pomembne fibroze. Ni razvitega granulomskega vnetja. Prav tako je pomembna
odsotnost eozinofilcev, nevtrofilcev, oblikovanja abscesov, nekroze, hialinih membran, fibrina.
Tabela 1. Znaœilnosti histoloøkega vzorca OP.
Vedno prisotno Lahko prisotno Odsotno
1. æariøœne spremembe
2. bronhiolocentriœna
razporeditev
3. fibroblastni œepi
4. blaga kroniœna vnetnoceliœna
intersticijska infiltracija
5. arhitektura parenhima
ohranjena
1. Obliterantni bronhiolitis 1. izrazita eozinofilija
2. pomembna intersticijska
fibroza
3. granulomi
Vzorec OP pogosto sreœujemo sekundarno zaradi razliœnih vzrokov (tabela 2). Iz histopatoloøke slike
vzorca OP ne moremo zanesljivo sklepati o moæni etiologiji. V primerih, da so razen vzorca OP izraæene
øe druge histopatoloøke spremembe, se diferencialno diagnostiœne moænosti zelo razøirijo (tabela 3
in 4). Pomembno je, da vzorec OP najdemo tudi pri lokaliziranih, nodularnih spremembah v pljuœih.
Te se lahko kliniœnoradioloøko kaæejo kot pljuœni tumor, zato je bolnik lahko kirurøko zdravljen.
92

Tabela 2. Moæni vzroki vzorca OP
idiopatsko
okuæbe
zdravila
Sistemske vezivnotkivne bolezni
Kriptogena organizirajoœa pljuœnica
bakterije (klamidija, mikoplazma, nokardija, streptokok, stafilokok, …),
virusi (herpes, HIV, gripa, parainfluenca),
glive (kriptokok, pnevmocista)
Amiodaron, bleomicin, busulfan, soli zlata, sulfasalazin,…
Revmatoidni artritis, Sjoegrenov sindrom, sistemski lupus eritemetodes,
sistemska skleroza, idiopatske vnetne miopatije
Tabela 3. Histopatoloøke entitete z vzorcem OP
OP
OP je ena od histopatoloøkih sprememb
OP je nespecifiœna reakcija
Idiopatsko (kriptogena OP)
Sekundarno (glej tabelo 2)
Preobœutljivostni pnevmonitis, Wegenerjeva granulomatoza,
eozinofilna pljuœnica
Perifokalna sprememba ob abscesu, tumorju, infarktu
Aspiracija
Vaskulitis
Tabela 4. Diferencialna diagnoza histopatoloøkega vzorca OP
Difuzna alveolarna okvara v organizaciji
Obiœajna intersticijska pljuœnica (UIP)
Nespecifiœna intersticijska pljuœnica (NSIP)
Preobœutljivostni pnevmonitis
Wegenerjeva granulomatoza
Eozinofilna pljuœnica v organizaciji
Akutna fibrinozna in OP
Konstriktivni bronhiolitis - sekundarno
Organizacija alveolarne krvavitve
Organizacija infekcijske pljuœnice
Organizacija obstrukcijskega pnevmonitisa
Prizadetost pljuœ zaradi zdravil
Prizadetost pljuœ zaradi vdihovanja ali izpostavljenosti toksinom
Prizadetost pljuœ v sklopu sistemskih vezivnotkivnih bolezni
Prizadetost pljuœ pri kroniœnih vnetnih œrevesnih boleznih
Organizacija ob robu drugih procesov (infarkt, absces, tumor,…)
Kriptogena organizirajoœa pljuœnica
Slika 1. Intraluminalna proliferacija mladega veziva (Giemsa)
93

Organizirajoœa pljuœnica –
spekter radioloøkih vzorcev
Igor Poæek
Univerzitetna klinika za pljuœne bolezni in alergijo, Golnik
Organizirajoœa pljuœnica (OP) je histopatoloøki vzorec in predstavlja stopnjo nespecifiœnega odgovora
na poøkodbo pljuœ zaradi razliœnih vzrokov (glej predavanje dr. Kerna – tabela2). OP je tudi kliniœna
entiteta, ki se kaæe z nespecifiœnimi simptomi in razliœnimi radioloøkimi spremembami in je lahko
primarna – kriptogena (COP) ali sekundarna. Radioloøke spremembe pri OP so øtevilne. Opisani
bodo najpogostejøi in øele pred kratkim opisani radioloøki vzorci OP. Pogosto je hkrati prisotnih veœ
vzorcev, nekateri vzorci si œasovno sledijo. Zunaj-pljuœne spremembe so vidne v manjøem odstotku
in zajemajo plevralni izliv ter blago do zmerno poveœane mediastinalne bezgavke.
Klasiœni radioloøki vzorci OP
Migrirajoœe multifokalne periferne konsolidacije. Veœina, pribliæno ¾ pacientov s COP ima v pljuœih
multifokalne infiltrate oz. konsolidacije, ki leæijo najveœkrat periferno in spreminjajo lokacijo v poteku
nekaj tednov. Na CT-ju imajo infiltrati viden zraœni bronhogram, veœkrat jih obdajajo zgostitve mleœnega
stekla. Pogosteje so prizadeti spodnji deli pljuœ, œeprav nekateri avtorji ugotavljajo enakomerno razporeditev
sprememb v vseh pljuœnih poljih. Spontan regres in migracija infiltratov zoæita diferencialno
diagnozo sprememb na pljuœih na COP, eozinofilno pljuœnico, krvavitev in vaskulitis.
Bronhocentriœni vzorec se pojavlja pri cca 1/3 pacientov. Okoli veœjih bronhovaskurarnih snopov so
vidne trakaste konsolidacije, ki so pogostejøe v spodnjih delih pljuœ in lahko segajo do periferije oz.
subplevralno. Pogosto so pridruæene zgostitve mleœnega stekla ali nodularne spremembe.
Neobiœajni vzorci
Solitarna fokalna masa/tumor ali nodul. Gre za fokalno zgostitev, ki ne vsebuje zraœnega bronhograma
in je ne moremo loœiti od pljuœnega tumorja oz. malignoma, œeprav je najveœkrat bolj ovalne
ali romboidne oblike. Pogosteje se nahaja v zgornjih reænjih. Obiœajno kopiœi FDG na PET-u, kar ne
omogoœa razloœevanja od pljuœnega raka.
Nodularen vzorec je lahko viden pri cca 1/3 pacientov, najveœkrat so pridruæeni øe drugi radioloøki
vzorci. Noduli so obiœajno acinarne velikosti (cca 6-10 mm), œeprav so lahko vidni tudi mikronoduli
(< 4 mm). Obiœajno leæijo peribronhovaskularno ali periferno, redko tudi centrilobularno ali v obliki
vejic s popki, kar je znaœilnost eksudativnega bronhiolitisa.
94

Multiple mase ali veœji noduli. Ob prisotnosti veœih tumorskih mas je pomembna izkljuœitev metastaz,
limfoma ali multicentriœnega adenokarcinoma. Pri razloœevanju nam najveœkrat pomaga hkratna
prisotnost drugih vzorcev, pogost o je vsaj mestoma viden zraœni bronhogram. Pri imunokompromitiranem
bolniku ima podobno sliko lahko invazivna aspergiloza.
Progresivno fibrozni vzorec. Na mestu perifernih konsolidacij se postopoma pojavljajo retikularne,
mreæaste spremembe s spremenjeno arhitekturo pljuœ , podroœja mleœnega stekla, noduli in vœasih
satasta pljuœa, kar spominja na fibrozno obliko NSIP.
Perilobularen vzorec je opisan pri veœ kot polovici pacientov s COP, obiœajno je viden skupaj z
drugimi vzorci in ima zato pomembno diagnostiœno vrednost. Predstavlja prizadetost pljuœ na obrobju
sekundarnega pljuœnega lobulusa, ki se kaæe kot neostro omejena poligonalno oblikovana trakasta
podroœja konsolidacij na periferiji pljuœ, obiœajno subplevralno, med katerimi so normalno prezraœena
pljuœa.
Parenhimski traœki predstavljajo trakasta podroœja konsolidacij øirine veœ kot 8 mm, ki potekajo do
plevre, ki ni zadebeljena in vsebujejo enojen zraœni bronhogram, po œemer jih loœimo od trakastih
atelektaz.
Vzorec obrnjenega haloja (reversed halo) ali atolni vzorec. Polkroæna ali obroœasta konsolidacija,
ki obdaja zgostitve mleœnega stekla v sredini je bila najprej opisana pri pacientih z OP in sicer pri cca
20% pacientov. Kasneje je bil vzorec opisan øe pri nekaterih drugih boleznih (sarkoidoza, Wegenerjeva
granulomatoza, ..), kar je nekoliko zmanjøalo njegovo diagnostiœno vrednost.
Crazy paving. Zgostitve mleœnega stekla so vidne pri veœini pacientov z OP, predvsem kot ostanki
prej vidnih konsolidacij pa tudi samostojno. Zadebeljena interlobularna septa so pogosto vidna na
obrobju konsolidacij, vendar obiœajno niso izrazita. Kombinacija mleœnega stekla in zadebeljenih interlobularnih
sept da vzorec »crazy paving«, ki je bil opisan pri OP kot posledica jemanja nekaterih
zdravil.
95

Organizirajoœa pljuœnica –
kliniœni problem
Katarina Osolnik
Univerzitetna klinika za pljuœne bolezni in alergijo, Golnik
S kliniœnega staliøœa o diagnozi organizirajoœe pljuœnice z gotovostjo lahko govorimo øele po prejemu
histoloøkega izvida biopsije pljuœ. Seveda je odloœitev o napotitvi bolnika na invazivno diagnostiko
(bronhoskopija s transbronhialno biopsijo in bronhoalveolarno lavaæo, kirurøka pljuœna biopsija) v
rokah klinika. Le-ta se mora na podlagi anamnestiœnih podatkov, kliniœnih ugotovitev, izvidov radioloøkih
preiskav (rentgenska slika in visokoloœljivostna raœunalniøka tomografija - HRCT), laboratorijskih
preiskav krvi, meritev pljuœne funkcije in upoøtevaje bolnikovo stanje, odloœiti za najprimernejøi
naœin ugotovitve etiologije infiltratov v pljuœih.
Kliniœno obravnavo bolnika z organizirajoœo pljuœnico delimo lahko na dva dela.
Prvi del predstavlja obravnavo bolnika s pljuœnimi infiltrati razliœnih vrst: od bilateralnih intersticijskih
in alveolarnih zgostitev, nesimetriœno razporejenih infiltratov in solitarnih infiltratov v kateremkoli delu
pljuœ pred pridobitvijo histoloøkega izvida – organizirajoœa pljuœnica, ki je nespecifiœna in pogosta
reakcija pljuœnega tkiva na razliœne vzroœne dejavnike. Natanœna anamneza z vsebovanimi demografskimi
podatki, poklicnimi in okoljskimi izpostavitvami, natanœnim popisom jemanja trenutne in
pretekle terapije, epidemioloøkimi podatki, natanœen kliniœni pregled, rentgenska slika, preiskava
pljuœne funkcije vkljuœno z difuzijsko kapaciteto za CO, osnovne laboratorijske preiskave (KKS, CRP,
retenti, urin) in visokoloœljivostni CT so zaœetni in temeljni postopki obravnave.
Vzorec HRCT zoæi diagnostiœno paleto, v veœini primerov pa HRCT ni specifiœen in kliniku v teku diagnostike
obiœajno sugerira vsaj dve, lahko tudi veœ moænosti, ki jih mora z vodenjem nadaljnjega
postopka diagnostike - invazivnimi postopki - razreøiti.
Na podlagi retrogradnih analiz naøih bolnikov ugotavljamo, da so najpogostejøi simptomi in znaki:
kaøelj, dispneja, zviøana temperatura, znojenje, hemoptize, v avskultatornem izvidu nad pljuœi pa inspiratorni
poki. Velika veœina bolnikov prejema kot ustaljeno terapijo veœ razliœnih zdravil, obiœajno
so zdravljeni æe pred zaœetkom pulmoloøke obravnave z vsaj enim antibiotikom. Pri veliki veœini naøih
bolnikov smo histoloøko diagnozo organizirajoœe pljuœnice postavili s transbronhialno biopsijo ob
bronhoskopiji z upogljivim bronhoskopom.
Pred zaœetkom invazivne diagnostike se mora klinik opredeliti do okuæbe kot moænega vzroka radioloøko
vidnih sprememb. Pri bolnikih s kliniœnimi in laboratorijskimi znaki okuæbe je potrebno odvzeti
96

kuænine: hemokulture pri bolnikih s srednje teæko in teæko kliniœno sliko, in sicer pred uvedbo ali menjavo
antibiotiœnega zdravljenja, œe bolnik izkaøljuje, kultiviramo izmeœek na patogene bakterije. Ob
posebnih epidemioloøkih in anamnestiœnih podatkih odvzamemo kuænine za dokazovanje atipiœnih
povzroœiteljev pljuœnic: izmeœek ali bris ærela za dokazovanje atipiœnih in virusnih povzroœiteljev z
metodo veriæne reakcije (PCR) in urin za dokazovanje antigena legionele in pnevmokoka.
Øe pred nadaljevanjem z invazivno diagnostiko je potrebno posebno pozornost posvetiti zdravilom,
ki jih je ali jih trenutno bolnik prejema. V kolikor obstaja po zdruæitvi anamnestiœnih, kliniœnih in radioloøkih
preiskav verjetnost, da gre za preobœutljivostno reakcijo za doloœeno zdravilo, je le-to
potrebno takoj ukiniti.
Podatek o sistemskih vezivno tkivnih boleznih, ki so pri bolniku æe diagnosticirane, mora klinika
nenehno spremljati in usmerjati v iskanje moænih povezav s spremembami na pljuœih.
Drugi del kliniœne obravnave sledi po pridobitvi histoloøkega izvida-organizirajoœa pljuœnica, ki za
klinika pogosto lahko pomeni zaœetek iskanja vzroka. Najpogostejøi vzroki sekundarne organizirajoœe
pljuœnice so bakterijske (veœkrat atipiœne), virusne (influenca) in gliviœne okuæbe, zdravila (amiodaron,
citostatiki, sulfasalazin, soli zlata) in sistemske vezivnotkivne bolezni, pri katerih je lahko pojav
sprememb na pljuœih prva manifestacija do tedaj øe nepoznane sistemske vezivnotkivne bolezni.
Glede na to, je skupino bolezni potrebno pri bolnikih z organizirajoœo pljuœnico aktivno iskati oziroma
s seroloøkimi preiskavami izkljuœevati.
Œe vzroka ne najdemo, govorimo o kriptogeni organizirajoœi pljuœnici.
Za klinika je nujno poznavanje dejstva, da je organizirajoœa pljuœnica lahko samo ena od histopatoloøkih
sprememb pri preobœutljivostnem pnevmonitisu, Wegenerjevi granulomatozi in eozinofilni
pljuœnici in da lahko predstavlja samo nespecifiœno reakcijo ob abscesu, tumorju, pljuœnem infarktu,
vaskulitisih in aspiracijskih pljuœnicah. Iz teh dejstev mora klinik izhajati pri odloœitvi, kdaj se s pridobitvijo
histoloøkega izvida organizirajoœe pljuœnice diagnostiœni postopek zakljuœi, kdaj pa se z diagnostiko
nadaljuje.
Organizirajoœo pljuœnico uspeøno zdravimo s sistemskimi steroidi, ki so terapija izbora. Pri sekundarni
organizirajoœi pljuœnici soœasno zdravimo spremljajoœo vezivnotkivno bolezen, okuæbo, pri z zdravili
povzroœeni, zdravilo za katerega menimo, da je vzroœno povezano s pojavom organizirajoœe
pljuœnice, ukinemo.
Ni ugotovljenih razlik med pogostostjo relapsov in smrtnostjo pri kriptogeni in sekundarni organizirajoœi
pljuœnici. Prognoza kriptogene organizirajoœe pljuœnice je v primerjavi s sekundarno boljøa.
Pri slednji je odvisna od spremljajoœe bolezni-slabøa pri sistemskih vezivnotkivnih boleznih.
97

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105

PARTNERS
Congress was supported by Slovenian Research Agency
(Javna agencija za raziskovalno dejavnost Republike Slovenije)
SPONSORS
Astra
Glaxo SmithKline
Medis
Novartis
Boehringer Ingelheim
Bayer HealthCare
Eli Lilly
Ewopharma
IRIS
Johnson &Johnson
Krka
LKB
MEDA Pharma
MSD
Nycomed
Olimpus
Pfizer
Providens
Remas
Roche
Sanofi Aventis
Sapio plini
Torrex Chiesi
106

RAZMISLIMO
Boehringer Ingelheim je predan raziskovanju
novih substanc na področju:
ONC 01/marec 2011 Samo za strokovno javnost
inhibicije angiogeneze tumorja
inhibicije signalne poti
kontrole celičnega cikla
UKREPAJMO
ONKOLOGIJA BOEHRINGER INGELHEIM

Najbolj predpisovano zdravilo za vzdræevalno zdravljenje KOPB 1 ,
ki bolnikom æe 8 let lajπa dihanje in ohranja aktivno æivljenje 3,4
ZGODNEJ©E ZDRAVLJENJE 2 aktivnejπi jutri 3,4
SKRAJ©AN POVZETEK GLAVNIH ZNA»ILNOSTI ZDRAVILA
Samo za strokovno javnost.
SPIRIVA 18 mikrogramov praπek za inhaliranje, trde kapsule
Kakovostna in koliËinska sestava: 1 kapsula vsebuje 22,5 µg tiotropijevega bromida monohidrata, kar ustreza 18 µg tiotropija. Terapevtske indikacije: Vzdræevalno bronhodilatacijsko zdravljenje, ki zmanjπa simptome pri bolnikih
s kroniËno obstruktivno pljuËno boleznijo (KOPB). Odmerjanje in naËin uporabe: Inhalacija vsebine ene kapsule 1-krat na dan ob enakem Ëasu z vdihovalnikom HandiHaler. Bolnikov mlajπih od 18 let ne smemo zdraviti s Spirivo.
Kontraindikacije: preobËutljivost za tiotropijev bromid, atropin ali njune derivate, npr. ipratropij ali oksitropij ter za pomoæno snov laktozo monohidrat. Posebna opozorila in previdnostni ukrepi: Tiotropijev bromid je bronhodilatator
za vzdræevalno zdravljenje z enim odmerkom na dan in ga ne smemo uporabljati za zaËetno zdravljenje akutnih epizod bronhospazma oz. kot reπevalno zdravilo. Po dajanju tiotropijevega bromida v obliki praπka za inhaliranje se lahko
pojavijo takojπnje preobËutljivostne reakcije. Tiotropijev bromid je treba previdno uporabljati pri bolnikih z glavkomom zaprtega kota, hiperplazijo prostate ali zaporo vratu seËnega mehurja. Pri zdravilih za inhaliranje lahko inhalacija
sproæi bronhospazem. Pri bolnikih z zmerno do hudo ledviËno okvaro smemo uporabiti tiotropijev bromid samo, kadar je priËakovana korist zdravljenja veËja od morebitnega tveganja. Pri pojavu znakov in simptomov glavkoma
zaprtega kota morajo bolniki tiotropijev bromid prenehati jemati in se nemudoma posvetovati s specialistom. Suha usta so lahko dolgoroËno povezana z zobnim kariesom. Bolniki z redko dedno intoleranco za galaktozo, laponsko
obliko zmanjπane aktivnosti laktaze ali malabsorbcijo glukoze/galaktoze ne smejo jemati tega zdravila. Interakcije: Pri soËasni uporabi tiotropijevega bromida v obliki praπka za inhaliranje in drugih zdravil niso zasledili kliniËnih znakov
interakcij. Ta zdravila so bila simpatikomimetiËni bronhodilatatorji, metilksantini ter peroralni in inhalacijski steroidi, ki jih pogosto uporabljamo v zdravljenju KOPB. SoËasnega zdravljenja s tiotropijevim bromidom in drugimi zdravili,
ki vsebujejo antiholinergik, niso raziskovali, zato ga ne priporoËamo. NoseËnost in dojenje: ©tudije na æivalih so pokazale vpliv na sposobnost razmnoæevanja, povezano s toksiËnimi uËinki pri samici. Moæno tveganje za ljudi ni znano.
Spirivo smemo med noseËnostjo uporabljati samo, kadar je jasno indicirana. Spirive med dojenjem ne priporoËamo. Tiotropijev bromid je dolgodelujoËa spojina. Pri odloËitvi o nadaljevanju ali prenehanju dojenja oziroma nadaljevanju ali
ukinitvi zdravljenja s Spirivo je treba presoditi med koristjo dojenja za otroka in koristjo zdravljenja matere. Neæeleni uËinki: Pogost neæeleni uËinek so suha usta. ObËasni neæeleni uËinki so: omotica, glavobol, motnje okuπanja, meglen
vid, fibrilacija preddvorov, kaπelj, faringitis, disfonija, stomatitis, slabost, gastroezofagealna refluksna bolezen, zaprtje, izpuπËaj, dizurija, zastoj seËa. Redki neæeleni uËinki so: nespeËnost, poveËan oËesni tlak, glavkom, tahikardija,
palpitacije, supraventrikularna aritmija, epistaksa, bronhospazem, laringitis, sinusitis, zapora Ërevesa, tudi paralitiËni ileus, gingivitis, glositis, orofaringealna kandidoza, disfagija, urtikarija, pruritus, druge oblike preobËutljivosti (tudi
takojπnje reakcije), okuæba seËil. Neæeleni uËinki neznane pogostnosti so: dehidracija, zobni karies, koæna okuæba in koæna razjeda, suha koæa, angionevrotiËni edem, sklepna oteklina. NaËin in reæim izdaje: Rp. Imetnik dovoljenja za
promet: Boehringer Ingelheim International GmbH, Binger Straße 173, D-55216 Ingelheim am Rhein, NemËija.Za podrobnejπe informacije glejte Povzetek glavnih znaËilnosti zdravila, z dne 09.10.2009.
Spirivo je razvilo podjetje Boehringer Ingelheim. Sopromovirata jo podjetji Boehringer Ingelheim in Pfizer.
Literatura
1. IMS podatki 2010. 2. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention
of chronic obstructive pulmonary disease. Dopolnjeno 2009. http://www.goldcopd.org/Guidelineitem.asp?l1=2&l2=1&intId=2003.
Dostop: april 2010. 3. Tashkin DP, Celli B, Senn S s sod.; on behalf of the UPLIFT ® (Understanding Potential Long-term Impacts on Function
with Tiotropium) study investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359:1543-
1554. 4. Casaburi R, Kukafka D, Cooper CB, Witek TJ Jr, Kesten S. Improvement in exercise tolerance with the combination of tiotropium and
pulmonary rehabilitation in patients with COPD. Chest. 2005;127:809-817.
@ivljenje. Se nadaljuje.
Pfizer Luxembourg SARL, Podruænica Ljubljana, Letaliπka 3c, Ljubljana
Boehringer Ingelheim RCV, Podruænica Ljubljana, ©landrova 4b, Ljubljana
Spiriva 8/september 2011

PAH je redka in huda kronina bolezen pljunih krvnih žil, za katero je znailno
progresivno poveanje vaskularne rezistence. e bolezni ne zdravimo, povzroi
popušanje desne strani srca in prezgodnjo smrt. 1 PAH je lahko klasificirana kot idiopatska
(iPAH) ali v povezavi z nekaterimi drugimi boleznimi, kot so bolezni vezivnega
tkiva, prirojene srne napake in pri bolnikih z okužbo z virusom HIV. Povpreno preživetje
nezdravljene napredujoe iPAH je po podatkih iz literature 2,8 let po postavitvi
diagnoze, kar je primerljivo s prognozo napredujoih malignih bolezni. 2, 3
V zgodnjih fazah PAH bolniki obiajno nimajo simptomov ali pa imajo blage netipine
simptome (npr. pomanjkanje zraka), ki so lahko napano diagnosticirani (npr. kot
astma). 4 Dispneja, še posebej ob naporu, je najpogostejši simptom, ki se pojavi
pri skoraj vseh bolnikih in napreduje z napredovanjem bolezni. Od drugih simptomov
navajajo utrujenost in splošno slabotnost, redkeje pa sinkopo ali anginozno
boleino. Simptomi v mirovanju so prisotni le v napredujoi fazi bolezni. 1 Zaradi slabe
prognoze in visoke umrljivosti je izjemno pomembno im prej postaviti diagnozo
in zaeti zdravljenje. Zaradi nespecifinih simptomov je postavljanje tone diagnoze
pogosto oteženo. 5
Ob sumu na PAH ima kljuno vlogo transtorakalni ehokardiografski pregled, saj
omogoa vpogled v stanje desne strani srca in doloanje pljunega arterijskega
tlaka (PAP, pulmonary arterial pressure). Kateterizacija desne strani srca je zlati standard
za potrditev PAH. 6
Pred predpisovanjem zdravila Tracleer ® preberite Povzetek glavnih znailnosti zdravila, ki ga dobite pri naših strokovnih
sodelavcih.
Samo za strokovno javnost
Ni astma.
Ni anemija.
Ni KOPB.
Prepoznajte
pljuno arterijsko
hipertenzijo
(PAH).
www.pah-info.com www.medis.si
(bosentan)
Tracleer® temelj zdravljenja pljune arterijske hipertenzije (PAH)
Srednji pljuni arterijski
tlak 25 mmHg
Pljuni zagozditveni
tlak 15 mmHg
Minutni volumen srca
normalen ali zmanjšan
Prilagojeno po Galiè et al; European Heart Journal (2009)
Reference
1. Galié N, Torbicki A, Barst R et al. Eur Heart J 2004; 25: 2243–2278. 2. D’Alonzo GE, Barst RJ, Ayres SM et al. Ann
Intern Med 1991; 115: 343–9. 3. Kato I, Severson RK, Schwartz AG. Cancer 2001; 92: 2211–2219. 4. Hamilton N, Elliot
C. Hosp Pharm 2006; 13: 7–9. 5. McLaughlin VV, Shillington A, Rich S. Circulation 2002; 106 (12): 1477–1482. 6. Galié
N, Hoeper MM, Humbert M et al. Eur Heart J 2009; 30 (20): 2493–537.

z
b
f
160 µg/4,5 µg/odmerek

SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVIL
SYM 18/11 P
Symbicort Turbuhaler 80 mikrogramov/4,5 mikrograma na odmerek prašek za inhaliranje
Symbicort Turbuhaler 160 mikrogramov/4,5 mikrograma na odmerek prašek za inhaliranje
Symbicort Turbuhaler 320 mikrogramov/9 mikrogramov na odmerek prašek za inhaliranje
SESTAVA: Vsak inhalator Symbicort Turbuhaler 80 µg/4,5 µg na odmerek vsebuje 120 odmerkov. Vsak oddani odmerek (tisti, ki
pride iz ustnika) vsebuje naslednji učinkovini: budezonid, in sicer 80 µg na vdih, in formoterolijev fumarat dihidrat, 4,5 µg na vdih.
Vsak inhalator Symbicort Turbuhaler 160 µg/4,5 µg na odmerek vsebuje 120 odmerkov. Vsak oddani odmerek vsebuje naslednji
učinkovini: budezonid, in sicer 160 µg na vdih, in formoterolijev fumarat dihidrat, 4,5 µg na vdih. Vsak inhalator Symbicort
Turbuhaler 320 µg/9 µg na odmerek vsebuje 60 odmerkov. Vsak oddani odmerek vsebuje naslednji učinkovini: budezonid, in sicer
320 µg na vdih, in formoterolijev fumarat dihidrat, 9 µg na vdih.
INDIKACIJE: Zdravilo Symbicort Turbuhaler 80 µg/4,5 µg na odmerek je indicirano za redno zdravljenje astme, ko je primeren način
zdravljenja kombinacija zdravil (inhalacijski glukokortikoid in dolgodelujoči agonist receptorjev beta2). Zdravilo Symbicort Turbuhaler
80 µg/4,5 µg na odmerek ni primerno za bolnike s hudim astmatičnim obolenjem. Zdravili Symbicort Turbuhaler
160 µg/4,5 µg na odmerek in 320 µg/9 µg na odmerek sta indicirani za redno zdravljenje astme, ko je primeren način zdravljenja
kombinacija zdravil (inhalacijski glukokortikoid in dolgodelujoči agonist receptorjev beta2), in simptomatsko zdravljenje bolnikov s
hudo obliko KOPB (FEV1 < 50 % predvidenega normalnega FEV1) ob ponavljajočih se poslabšanjih v anamnezi, ko se kljub
zdravljenju z dolgodelujočimi bronhodilatatorji pojavljajo izraziti simptomi.
ODMERJANJE IN NAČIN UPORABE: Inhalator Symbicort Turbuhaler se aktivira pri vdihu, kar pomeni, da ob bolnikovem vdihu
skozi ustnik vdihan zrak odnese učinkovini v dihalne poti. Zaradi majhne količine zdravila v posameznem vdihu bolnik pri uporabi
inhalatorja Turbuhaler morda sploh ne bo okusil ali začutil zdravila.
ASTMA: Odmerjanje je individualno. Vzdrževalno zdravljenje (vse jakosti): bolnikom je potrebno svetovati, da imajo hitrodelujoči
bronhodilatator vedno na razpolago. Odrasli (18 let ali več): Symbicort Turbuhaler 80 µg/4,5 µg na odmerek in 160 µg/4,5 µg na
odmerek: 1–2 vdiha dvakrat na dan. Pri nekaterih bolnikih bodo potrebni tudi do največ 4 vdihi dvakrat na dan. Symbicort
Turbuhaler 320 µg/9 µg na odmerek: 1 vdih dvakrat na dan. Pri nekaterih bolnikih bosta potrebna tudi do največ 2 vdiha dvakrat na
dan. Mladostniki (12–17 let): 1–2 vdiha dvakrat na dan oz. 1 vdih dvakrat na dan (Symbicort Turbuhaler 320 µg/9 µg na odmerek).
Otroci (6 let ali več): 2 vdiha dvakrat na dan (samo Symbicort Turbuhaler 80 µg/4,5 µg na odmerek). Zdravila Symbicort ne
priporočamo pri otrocih, mlajših od 6 let. Vzdrževalno in olajševalno zdravljenje (Symbicort Turbuhaler 80 µg/4,5 µg na odmerek in
Symbicort Turbuhaler 160 µg/4,5 µg na odmerek): bolniki redno jemljejo dnevni vzdrževalni odmerek zdravila Symbicort, ob pojavu
simptomov pa po potrebi dodatne odmerke zdravila. Bolnikom je potrebno svetovati, da imajo zdravilo Symbicort kot olajševalec
vedno pri sebi. Priporočeni odmerki: odrasli (18 let in več): priporočen vzdrževalni odmerek je 2 vdiha na dan, bodisi 1 vdih zjutraj
in 1 vdih zvečer bodisi 2 vdiha zjutraj oziroma 2 vdiha zvečer. Za nekatere bolnike je primerno odmerjanje 2 vdiha dvakrat dnevno
(Symbicort Turbuhaler 80 µg/4,5 µg na odmerek ali Symbicort Turbuhaler 160 µg/4,5 µg na odmerek). Ob pojavu simptomov se po
potrebi naredi še 1 dodaten vdih. Če so simptomi po nekaj minutah še vedno prisotni, se doda še 1 vdih. Naenkrat ni dovoljeno
narediti več kot 6 vdihov. Celotni dnevni odmerek, večji od 8 vdihov, v normalnih okoliščinah ni potreben. Kljub temu je lahko v
določenih omejenih časovnih obdobjih celotni dnevni odmerek 12 vdihov. Vzdrževalno in olajševalno zdravljenje za otroke in
mladostnike do 18. leta ni priporočljivo.
KOPB: Priporočeni odmerki za odrasle: Symbicort Turbuhaler 160 µg/4,5 µg na odmerek 2 vdiha dvakrat na dan in Symbicort
Turbuhaler 320 µg/9 µg na odmerek 1 vdih dvakrat na dan.
KONTRAINDIKACIJE: Preobčutljivost za budezonid, formoterol ali laktozo.
POSEBNA OPOZORILA IN PREVIDNOSTNI UKREPI: Priporočamo, da ob prekinitvi zdravljenja odmerek zmanjšujete postopoma in
zdravljenja ne prekinete nenadoma. Če bolnik ugotavlja, da je zdravljenje neučinkovito ali če preseže največji priporočeni
odmerek zdravila Symbicort, mora poiskati zdravniško pomoč. Bolnikom je treba naročiti, naj imajo olajševalec vedno pri sebi. Tako
kot pri drugih inhalacijskih zdravilih se lahko tudi po uporabi tega zdravila pojavi paradoksni bronhospazem. Pri uporabi vseh
inhalacijskih kortikosteroidov se lahko pojavijo sistemski učinki, še posebno če so bili predpisani veliki odmerki za dlje časa. Med
možnimi sistemskimi učinki so Cushingov sindrom, supresija nadledvične žleze, zastoj rasti pri otrocih in mladostnikih, zmanjšanje
mineralne gostote kosti, katarakta in glavkom. Priporočljivo je redno spremljanje višine otrok, ki se dalj časa zdravijo z
inhalacijskimi glukokortikoidi. Da bi čim bolj zmanjšali tveganje orofaringealne kandidoze, je treba bolniku naročiti, da si mora po
inhaliranju vzdrževalnega odmerka usta sprati z vodo. Zdravilo Symbicort predpisujte previdno pri bolnikih s hudimi
kardiovaskularnimi boleznimi, tirotoksikozo, feokromocitomom, sladkorno boleznijo, nezdravljeno hipokaliemijo. Za ostala
posebna opozorila in previdnostne ukrepe glejte celoten povzetek.
INTERAKCIJE: Zaviralci receptorjev beta (vključno s kapljicami za oko) lahko oslabijo ali zavrejo delovanje formoterola. Sočasna
uporaba močnih zaviralcev CYP P450 3A4 lahko poveča plazemski nivo budezonida. Za ostale interakcije glejte celoten povzetek.
NOSEČNOST IN DOJENJE: V času nosečnosti se sme zdravilo Symbicort predpisovati le, če koristi zdravila presegajo morebitna
tveganja. Zdravilo Symbicort se sme doječi ženski predpisati le, če pričakovana korist za mater presega morebitno tveganje za
otroka.
GLAVNI NEŽELENI UČINKI: Pogosti: palpitacije, glavobol, tremor, okužbe s kandido v ustnem delu žrela, blago draženje žrela,
kašelj, hripavost. Občasni: tahikardija, navzeja, mišični krči, omotičnost, agitacija, nemir, razdražljivost, motnje spanja, modrice.
Redki: atrijska fibrilacija, supraventrikularna tahikardija, ekstrasistole, eksantem, urtikarija, pruritus, dermatitis, angioedem,
anafilaktična reakcija, hipokaliemija, bronhospazem.
REŽIM IZDAJE ZDRAVILA: Zdravilo se izdaja le na recept.
IMETNIK DOVOLJENJA ZA PROMET: AstraZeneca AB, Kvarnbergagatan 12, SE-151 85 Södertälje, Švedska
DATUM PRIPRAVE INFORMACIJE: avgust 2010
Pred predpisovanjem, prosimo, preberite celoten povzetek glavnih značilnosti zdravila.
Dodatne informacije so na voljo pri družbi AstraZeneca UK Limited, Podružnica v Sloveniji, Verovškova 55, Ljubljana.
1. Welte T et al. Am J Respir Crit Care Med 2009; 180: 741-750

320 µg/9 µg/odmerek

SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVIL
SYM 07/11 P
Symbicort Turbuhaler 80 mikrogramov/4,5 mikrograma na odmerek prašek za inhaliranje
Symbicort Turbuhaler 160 mikrogramov/4,5 mikrograma na odmerek prašek za inhaliranje
Symbicort Turbuhaler 320 mikrogramov/9 mikrogramov na odmerek prašek za inhaliranje
SESTAVA: Vsak inhalator Symbicort Turbuhaler 80 µg/4,5 µg na odmerek vsebuje 120 odmerkov. Vsak oddani odmerek (tisti, ki pride
iz ustnika) vsebuje naslednji učinkovini: budezonid, in sicer 80 µg na vdih, in formoterolijev fumarat dihidrat, 4,5 µg na vdih. Vsak
inhalator Symbicort Turbuhaler 160 µg/4,5 µg na odmerek vsebuje 120 odmerkov. Vsak oddani odmerek vsebuje naslednji učinkovini:
budezonid, in sicer 160 µg na vdih, in formoterolijev fumarat dihidrat, 4,5 µg na vdih. Vsak inhalator Symbicort Turbuhaler 320 µg/9 µg
na odmerek vsebuje 60 odmerkov. Vsak oddani odmerek vsebuje naslednji učinkovini: budezonid, in sicer 320 µg na vdih, in
olijev fumarat dihidrat, 9 µg na vdih.
INDIKACIJE: Zdravilo Symbicort Turbuhaler 80 µg/4,5 µg na odmerek je indicirano za redno zdravljenje astme, ko je primeren način
zdravljenja kombinacija zdravil (inhalacijski glukokortikoid in dolgodelujoči agonist receptorjev beta2). Zdravilo Symbicort Turbuhaler
80 µg/4,5 µg na odmerek ni primerno za bolnike s hudim astmatičnim obolenjem. Zdravili Symbicort Turbuhaler 160 µg/4,5 µg na
odmerek in 320 µg/9 µg na odmerek sta indicirani za redno zdravljenje astme, ko je primeren način zdravljenja kombinacija zdravil
(inhalacijski glukokortikoid in dolgodelujoči agonist receptorjev beta2), in simptomatsko zdravljenje bolnikov s hudo obliko KOPB
(FEV1 < 50 % predvidenega normalnega FEV1) ob ponavljajočih se poslabšanjih v anamnezi, ko se kljub zdravljenju z dolgodelujočimi
bronhodilatatorji pojavljajo značilni simptomi.
ODMERJANJE IN NAČIN UPORABE: Inhalator Symbicort Turbuhaler se aktivira pri vdihu, kar pomeni, da ob bolnikovem vdihu skozi
ustnik vdihan zrak s sabo potegne učinkovini v dihalne poti. Zaradi majhne količine zdravila v posameznem vdihu bolnik pri uporabi
inhalatorja Turbuhaler morda sploh ne bo okusil ali začutil zdravila.
ASTMA: Odmerjanje je individualno. Vzdrževalno zdravljenje (vse jakosti): bolnikom je potrebno svetovati, da imajo hitrodelujoči
bronhodilatator vedno na razpolago. Odrasli (18 let ali več): Symbicort Turbuhaler 80 µg/4,5 µg na odmerek in 160 µg/4,5 µg na
odmerek: 1–2 vdiha dvakrat na dan. Pri nekaterih bolnikih bodo potrebni tudi do največ 4 vdihi dvakrat na dan. Symbicort Turbuhaler
320 µg/9 µg na odmerek: 1 vdih dvakrat na dan. Pri nekaterih bolnikih bosta potrebna tudi do največ 2 vdiha dvakrat na dan. Mladostniki
(12–17 let): 1–2 vdiha dvakrat na dan oz. 1 vdih dvakrat na dan (Symbicort Turbuhaler 320 µg/9 µg na odmerek). Otroci (6 let ali več):
2 vdiha dvakrat na dan (samo Symbicort Turbuhaler 80 µg/4,5 µg na odmerek). Zdravila Symbicort ne priporočamo pri otrocih, mlajših
od 6 let. Vzdrževalno in olajševalno zdravljenje (Symbicort Turbuhaler 80 µg/4,5 µg na odmerek in Symbicort Turbuhaler 160 µg/4,5 µg
na odmerek): bolniki redno jemljejo dnevni vzdrževalni odmerek zdravila Symbicort, ob pojavu simptomov pa po potrebi dodatne
odmerke zdravila. Bolnikom je potrebno svetovati, da imajo zdravilo Symbicort kot olajševalec vedno pri sebi. Priporočeni odmerki:
odrasli (18 let in več): priporočen vzdrževalni odmerek je 2 vdiha na dan, bodisi 1 vdih zjutraj in 1 vdih zvečer bodisi 2 vdiha zjutraj
oziroma 2 vdiha zvečer. Za nekatere bolnike je primerno odmerjanje 2 vdiha dvakrat dnevno (Symbicort Turbuhaler 160 µg/4,5 µg na
odmerek). Ob pojavu simptomov se po potrebi naredi še 1 dodaten vdih. Če so simptomi po nekaj minutah še vedno prisotni, se doda
še 1 vdih. Naenkrat ni dovoljeno narediti več kot 6 vdihov. Celotni dnevni odmerek, večji od 8 vdihov, v normalnih okoliščinah ni
potreben. Kljub temu je lahko v določenih omejenih časovnih obdobjih celotni dnevni odmerek 12 vdihov.
KOPB: Priporočeni odmerki za odrasle: Symbicort Turbuhaler 160 µg/4,5 µg na odmerek 2 vdiha dvakrat na dan in Symbicort Turbuhaler
320 µg/9 µg na odmerek 1 vdih dvakrat na dan.
KONTRAINDIKACIJE: Preobčutljivost za budezonid, formoterol ali inhalirano laktozo.
POSEBNA OPOZORILA IN PREVIDNOSTNI UKREPI: Priporočamo, da ob prekinitvi zdravljenja odmerek zmanjšujete postopoma in
zdravljenja ne prekinete nenadoma. Če bolnik ugotavlja, da je zdravljenje neučinkovito ali če preseže največji priporočeni odmerek
zdravila Symbicort, mora poiskati zdravniško pomoč. Bolnikom svetujte, naj imajo inhalator kot olajševalec vedno pri sebi, ali Symbicort
(za bolnike, ki uporabljajo Symbicort za vzdrževalno in olajševalno zdravljenje) ali samostojni hitrodelujoči bronhodilatator (za bolnike,
ki uporabljajo Symbicort le za vzdrževalno zdravljenje). Symbicort kot olajševalec se uporablja v primerih, ko se pojavijo simptomi, ne
pa redno v profilakticne namene. Pri uporabi vseh inhalacijskih glukokortikoidov se lahko pojavijo sistemski učinki, še posebno če so
bili predpisani veliki odmerki za dlje časa, vendar pa so sistemski učinki veliko manj verjetni pri inhalacijskem zdravljenju kakor pri
uporabi peroralnih glukokortikoidov. Med možnimi sistemskimi učinki so na primer supresija nadledvične žleze, zastoj rasti pri otrocih
in mladostnikih, zmanjšanje kostne mineralne gostote, katarakta in glavkom. Priporočljivo je redno spremljanje višine otrok, ki se dalj
časa zdravijo z inhalacijskimi glukokortikoidi. Zdravilo Symbicort predpisujte previdno pri bolnikih s hudimi kardiovaskularnimi
boleznimi, tirotoksikozo, feokromocitomom, sladkorno boleznijo, nezdravljeno hipokaliemijo. Za ostala posebna opozorila in
previdnostne ukrepe glejte celoten povzetek.
INTERAKCIJE: Zaviralci receptorjev beta (vključno s kapljicami za oko) lahko oslabijo ali zavrejo delovanje formoterola. Sočasna
uporaba močnih zaviralcev CYP P450 3A4 lahko poveča plazemski nivo budezonida. Za ostale interakcije glejte celoten povzetek.
NOSEČNOST IN DOJENJE: V času nosečnosti se sme zdravilo Symbicort predpisovati le, če koristi zdravila presegajo morebitna
tveganja. Zdravilo Symbicort se sme doječi ženski predpisati le, če pričakovana korist za mater presega vsakršno morebitno tveganje
za otroka.
GLAVNI NEŽELENI UČINKI: Pogosti: palpitacije, glavobol, tremor, okužbe s kandido v ustnem delu žrela, blago draženje grla, kašljanje,
hripavost. Občasni: tahikardija, navzeja, mišični krči, omotičnost, agitacija, nemir, razdražljivost, motnje spanja, modrice. Redki: atrijska
fibrilacija, supraventrikularna tahikardija, ekstrasistole, eksantem, urtikarija, pruritus, dermatitis, angioedem, anafilaktična reakcija,
hipokaliemija, bronhospazem. Zelo redki: angina pektoris, znaki ali simptomi sistemskih učinkov glukokortikoidov, hiperglikemija,
motnje okusa, depresija, vedenjske motnje, spremembe krvnega tlaka.
REŽIM IZDAJE ZDRAVILA: Zdravilo se izdaja le na recept.
IMETNIK DOVOLJENJA ZA PROMET: AstraZeneca UK Limited 15 Stanhope Gate, London, W1K 1LN, Velika Britanija
Pred predpisovanjem, prosimo, preberite celoten povzetek glavnih značilnosti zdravila.
Dodatne informacije so na voljo pri družbi AstraZeneca UK Limited, Podružnica v Sloveniji, Verovškova 55, Ljubljana.
DATUM PRIPRAVE INFORMACIJE: junij 2010
SAMO ZA STROKOVNO JAVNOST
1. Welte T et al. Am J Respir Crit Care Med 2009; 180: 741-750

SAMO ZA STROKOVNO JAVNOST.

SKRAJŠAN POVZETEK GLAVNIH ZNAČILNOSTI
ZDRAVILA
IME ZDRAVILA
SERETIDE DISKUS 50 mikrogramov/100 mikrogramov/odmerek
prašek za inhaliranje, odmerjeni
SERETIDE DISKUS 50 mikrogramov/250 mikrogramov/odmerek
prašek za inhaliranje, odmerjeni
SERETIDE DISKUS 50 mikrogramov/500 mikrogramov/odmerek
prašek za inhaliranje, odmerjeni
KAKOVOSTNA IN KOLIČINSKA SESTAVA
SERETIDE DISKUS 50 mikrogramov/100 mikrogramov/odmerek
prašek za inhaliranje, odmerjeni
En odmerek (en vdih) vsebuje 50 mikrogramov
salmeterola (v obliki 72,5 mikrogramov salmeterolijevega
ksinafoata) in 100 mikrogramov flutikazonpropionata.
SERETIDE DISKUS 50 mikrogramov/250 mikrogramov/odmerek
prašek za inhaliranje, odmerjeni
En odmerek (en vdih) vsebuje 50 mikrogramov
salmeterola (v obliki 72,5 mikrogramov salmeterolijevega
ksinafoata) in 250 mikrogramov flutikazonpropionata.
SERETIDE DISKUS 50 mikrogramov/500 mikrogramov/odmerek
prašek za inhaliranje, odmerjeni
En odmerek (en vdih) vsebuje 50 mikrogramov
salmeterola (v obliki 72,5 mikrogramov salmeterolijevega
ksinafoata) in 500 mikrogramov flutikazonpropionata.
Pomožne snovi:
Laktoza monohidrat
En odmerek zdravila SERETIDE DISKUS (ne glede na
jakost) vsebuje največ do 11,8 mg laktoze.
KLINIČNI PODATKI
Terapevtske indikacije
ASTMA
Če je uporaba kombiniranega zdravila (kombinacije
dolgodelujočega agonista adrenergičnih receptorjev
beta-2 in inhalacijskega kortikosteroida) primerna,
je zdravilo SERETIDE DISKUS indicirano za redno
zdravljenje astme pri:
- bolnikih, katerih simptomi astme z uporabo inhalacijskega
kortikosteroida in občasno uporabo
(po potrebi) kratkodelujočega inhalacijskega
agonista adrenergičnih receptorjev beta-2 niso
zadostno nadzorovani,
ali
- bolnikih, katerih simptomi astme so že zadostno
nadzorovani z uporabo obeh, inhalacijskega
kortikosteroida in dolgodelujočega agonista
adrenergičnih receptorjev beta-2.
KRONIČNA OBSTRUKTIVNA PLJUČNA BOLE-
ZEN (KOPB)
Zdravilo SERETIDE DISKUS je indicirano za simptomatsko
zdravljenje bolnikov s KOPB (forsirani
ekspiracijski volumen v 1. sekundi; FEV1 < 60 %
pričakovane normalne (pre-bronhodilatorne) vrednosti)
in anamnezo ponavljajočih se poslabšanj, ki
imajo signifikantne simptome bolezni kljub rednemu
zdravljenju z bronhodilatatorjem.
Odmerjanje in način uporabe
Zdravilo SERETIDE DISKUS je namenjeno izključno
za inhaliranje.
Bolnikom je treba pojasniti, da bo optimalna korist
zdravila SERETIDE DISKUS dosežena le, če ga bodo
uporabljali vsakodnevno, tudi takrat, ko nimajo simptomov
bolezni.
Bolniki morajo biti pod rednim zdravniškim nadzorom,
da bi tako jakost zdravila SERETIDE DISKUS, ki
ga uporabljajo, ostala optimalna ves čas zdravljenja.
Jakost zdravila SERETIDE DISKUS lahko spremeni le
zdravnik. Odmerek je treba postopno zmanjševati
do najmanjšega odmerka, ki še zagotavlja
učinkovito nadzorovanost simptomov bolezni.
Če se nadzorovanost simptomov vzdržuje z
uporabo najmanjše jakosti kombinacije dvakrat
na dan, se lahko v naslednji fazi zdravljenja
poskusi z uporabo inhalacijskega kortikosteroida
samega. Bolnikom, ki potrebujejo zdravljenje z
dolgodelujočim agonistom adrenergičnih receptorjev
beta-2 se alternativno lahko predpiše uporaba zdravila
SERETIDE DISKUS enkrat na dan, če zdravnik
meni, da bo s takšno uporabo nadzorovanost bolezni
ostala zadovoljiva. V primeru uporabe zdravila enkrat
na dan mora bolnik, ki ima simptome predvsem ponoči,
uporabiti odmerek zdravila zvečer, bolnik, ki pa
ima simptome predvsem podnevi, pa mora odmerek
zdravila uporabiti zjutraj.
Bolnikom je treba predpisati jakost zdravila SERETI-
DE DISKUS, ki vsebuje odmerek flutikazonpropionata,
primeren resnosti bolezni. Zdravniki morajo upoštevati,
da je pri bolnikih z astmo flutikazonpropionat
tako učinkovit kot drugi inhalacijski kortikosteroidi
že v približno polovičnem mikrogramskem dnevnem
odmerku. Na primer, odmerek 100 mikrogramov
flutikazonpropionata je približno enakovreden odmerku
200 mikrogramov beklometazondipropionata
(z vsebnostjo CFC) ali budezonida. Če posamezen
bolnik potrebuje zdravljenje z odmerkom, ki je
izven priporočenega režima odmerjanja, mu je treba
predpisati primeren odmerek agonista adrenergičnih
receptorjev beta in/ali kortikosteroida.
Priporočeni odmerki
ASTMA
• Odrasli in mladostniki, stari 12 let in starejši
- En odmerek (en vdih) 50 mikrogramov salmeterola
in 100 mikrogramov flutikazonpropionata
dvakrat na dan,
ali
- en odmerek (en vdih) 50 mikrogramov salmeterola
in 250 mikrogramov flutikazonpropionata
dvakrat na dan,
ali
- en odmerek (en vdih) 50 mikrogramov salmeterola
in 500 mikrogramov flutikazonpropionata
dvakrat na dan.
Pri odraslih ali mladostnikih z zmerno persistentno
astmo (bolniki z vsakodnevnimi simptomi, vsakodnevno
uporabo olajševalca in zmernim do hudim
zmanjšanjem pretoka zraka), pri katerih je nujno
treba doseči hitro nadzorovanost astme, se lahko
razmisli o kratkotrajni poskusni uporabi zdravila
SERETIDE DISKUS kot začetnega vzdrževalnega
zdravljenja. V takšnih primerih je priporočeni začetni
odmerek ena inhalacija 50 mikrogramov salmeterola
in 100 mikrogramov flutikazonpropionata dvakrat
na dan. Ko je dosežena nadzorovanost astme, je
treba zdravljenje ponovno ovrednotiti in presoditi
o primernosti zmanjšanja odmerka in zdravljenju z
inhalacijskim kortikosteroidom samim. Bolniki, pri
katerih se odmerek zmanjša ali uvede zdravljenje z
inhalacijskim kortikosteroidom samim, morajo biti
pod rednim zdravniškim nadzorom.
V primeru odsotnosti enega ali dveh kriterijev za
opredelitev nadzora bolezni očitna korist pri začetnem
vzdrževalnem zdravljenju, v primerjavi z uporabo
inhalacijskega flutikazonpropionata samega,
ni bila dokazana. Pri večini bolnikov inhalacijski
kortikosteroidi na splošno ostajajo zdravila prvega
izbora. Zdravilo SERETIDE DISKUS ni namenjeno
začetnemu zdravljenju blage astme. Jakost zdravila
SERETIDE DISKUS 50/100 mikrogramov ni primerna
za odrasle in otroke s hudo astmo. Pri bolnikih s hudo
astmo je pred uvedbo katerekoli fiksne kombinacije
priporočljivo določiti ustrezni odmerek inhalacijskega
kortikosteroida.
• Otroci, stari od 4 do 11 let
- En odmerek (en vdih) 50 mikrogramov salmeterola
in 100 mikrogramov flutikazonpropionata
dvakrat na dan.
Največji dovoljeni odmerek flutikazonpropionata, ki
ga lahko prejmejo otroci z zdravilom SERETIDE DIS-
KUS je 100 mikrogramov dvakrat na dan.
• Otroci, mlajši od 4 let
Podatki o uporabi zdravila SERETIDE DISKUS pri otrocih,
mlajših od 4 let, niso na voljo.
KOPB
• Odrasli
- En odmerek (en vdih) 50 mikrogramov salmeterola
in 500 mikrogramov flutikazonpropionata
dvakrat na dan.
Posebne skupine bolnikov
Pri starejših bolnikih in bolnikih z okvaro ledvic
odmerka ni treba prilagajati. Podatki o uporabi
zdravila SERETIDE DISKUS pri bolnikih z okvaro jeter
niso na voljo.
Uporaba zdravila SERETIDE DISKUS
Bolnike je treba natančno poučiti o pravilni uporabi
naprave DISKUS.
Bolnik DISKUS najprej odpre in ga s premikom vzmeti
pripravi za uporabo. Ustnik nato vstavi med ustnici.
Med inhalacijo se iz naprave DISKUS sprosti prašek,
ki ga bolnik skozi usta vdihne v pljuča. Po uporabi
mora bolnik DISKUS ustrezno zapreti. Števec odmerkov
na napravi DISKUS kaže število preostalih
odmerkov.
Kontraindikacije
Preobčutljivost za zdravilni učinkovini ali katerokoli
pomožno snov.
Posebna opozorila in previdnostni ukrepi
Običajno mora zdravljenje astme potekati po stopenjskem
programu. Bolnikov odziv je treba nadzirati
tako klinično kot s testi pljučne funkcije.
Zdravila SERETIDE DISKUS se ne sme uporabljati
za zdravljenje akutnih simptomov astme. V takšnih
primerih morajo bolniki uporabiti kratkodelujoči
bronhodilatator s hitrim začetkom delovanja. Bolnike
je treba poučiti, da morajo imeti svoj medicinski pripomoček
za lajšanje akutnih astmatičnih napadov
(akutnih poslabšanj astme) vedno na razpolago.
Zdravljenja z zdravilom SERETIDE DISKUS se ne sme
uvesti med akutnim poslabšanjem astme oziroma če
bolezen pomembno in hitro napreduje.
Med zdravljenjem z zdravilom SERETIDE DISKUS
se lahko pojavijo resni neželeni učinki, povezani z
astmo, in poslabšanja astme. Bolnikom je treba pojasniti,
da naj v takšnih primerih nadaljujejo z uporabo
zdravila, vendar pa naj poiščejo zdravniško pomoč, če
simptomi astme ostanejo nenadzorovani ali se po začetku
uporabe zdravila SERETIDE DISKUS poslabšajo.
Pogostejša uporaba kratkodelujočih bronhodilatatorjev
za lajšanje simptomov kaže na slabšo nadzorovanost
bolezni. Takšni bolniki potrebujejo ustrezno
zdravniško obravnavo.
Nenadno in progresivno poslabšanje nadzorovanosti
astme je lahko smrtno nevarno. Takšni bolniki potrebujejo
urgentno zdravniško oskrbo. Morda bo potrebno
zdravljenje z večjim odmerkom kortikosteroida.
Bolnik potrebuje zdravniški pregled tudi, če trenutni
odmerek zdravila SERETIDE DISKUS ne zagotavlja zadostne
nadzorovanosti astme. Pri bolnikih z astmo ali
KOPB bo morda potrebno uvesti dodatno zdravljenje
s kortikosteroidi.
Ko je dosežena nadzorovanost simptomov astme je
treba presoditi o primernosti postopnega zmanjšanja
odmerka zdravila SERETIDE DISKUS. Pomembno je,
da so bolniki po zmanjšanju odmerka pod rednim
zdravniškim nadzorom. Uporablja naj se najnižji še
učinkoviti odmerek zdravila SERETIDE DISKUS.
Pri bolnikih z astmo se zaradi nevarnosti poslabšanj
zdravljenje z zdravilom SERETIDE DISKUS ne
sme prekiniti nenadoma. Odmerek zdravila je treba
zmanjševati postopoma, pod zdravniškim nadzorom.
Tudi pri bolnikih s KOPB je opustitev zdravljenja lahko
povezana s simptomatsko dekompenzacijo in mora
zato potekati pod zdravniškim nadzorom.
Tako kot vsa inhalacijska zdravila, ki vsebujejo kortikosteroide,
je treba tudi zdravilo SERETIDE DISKUS
uporabljati previdno pri bolnikih, ki imajo pljučno
tuberkulozo.
Zdravilo SERETIDE DISKUS lahko pri visokih terapevtskih
odmerkih v redkih primerih povzroči aritmije,
npr. supraventrikularno tahikardijo, ekstrasistole in
atrijsko fibrilacijo ter blago prehodno zmanjšanje
serumskega kalija. Zdravilo SERETIDE DISKUS je
treba zato uporabljati previdno pri bolnikih, ki imajo
hujšo kardiovaskularno bolezen, vključno z motnjami
srčnega ritma, sladkorno bolezen, hipertiroidizem
(tirotoksikozo), nezdravljeno hipokaliemijo ali predispozicijo
za nizke vrednosti serumskega kalija.
Zelo redko so poročali o povečanih vrednostih glukoze
v krvi, kar je treba upoštevati pri predpisovanju
zdravila bolnikom, ki imajo v anamnezi sladkorno
bolezen.
Tako kot pri zdravljenju z drugimi inhalacijskimi
zdravili se lahko tudi pri zdravljenju z zdravilom SE-
RETIDE DISKUS pojavi paradoksni bronhospazem, ki
se kaže s pojavom piskajočega dihanja takoj po uporabi
odmerka. Uporabo zdravila SERETIDE DISKUS je
treba nemudoma opustiti, opraviti ponoven pregled
bolnika in po potrebi uvesti alternativno zdravljenje.
Pri prehodu na zdravljenje z zdravilom SERETIDE DI-
SKUS je potrebna previdnost, še posebej pri bolnikih,
pri katerih obstaja kakršenkoli sum na oslabljeno
delovanje nadledvične žleze zaradi predhodnega
zdravljenja s sistemskimi kortikosteroidi.
Sistemski učinki se lahko pojavijo pri zdravljenju s
katerimkoli inhalacijskim kortikosteroidom, še posebej
v primeru velikih odmerkov, predpisanih za daljše
obdobje. Verjetnost pojava sistemskih učinkov pa je
vendarle veliko manjša kot pri zdravljenju s peroralnimi
kortikosteroidi. Možni sistemski učinki vključujejo
Cushingov sindrom in z njim povezane značilnosti,
supresijo nadledvične žleze, zastoj rasti pri otrocih in
mladostnikih, zmanjšanje kostne gostote, katarakto
in glavkom. Pomembno je torej, da so bolniki pod
rednim zdravniškim nadzorom, in da se odmerek
inhalacijskega kortikosteroida zmanjša do
najmanjšega odmerka, ki še zagotavlja učinkovito
nadzorovanost bolezni.
Pri otrocih, ki se dolgotrajno zdravijo z inhalacijskim
kortikosteroidom, je priporočljivo opravljati redne
meritve telesne višine.
Dolgotrajno zdravljenje bolnikov z visokimi odmerki
inhalacijskih kortikosteroidov lahko posledično povzroči
supresijo nadledvične žleze in akutno adrenalno
krizo. Še posebno tveganje lahko obstaja pri otrocih
in mladostnikih, mlajših od 16 let, ki se zdravijo z
visokimi odmerki flutikazonpropionata (običajno
≥ 1.000 mikrogramov/dan). Zelo redko so poročali
tudi o primerih pojava supresije nadledvične žleze in
akutne adrenalne krize pri bolnikih, ki so se zdravili
s flutikazonpropionatom v odmerkih od 500 do <
1.000 mikrogramov. Okoliščine, v katerih lahko pride
do pojava akutne adrenalne krize, vključujejo travmo,
kirurški poseg, okužbo ali kakršnokoli nenadno
zmanjšanje odmerka. Simptomi so običajno nejasni
in lahko vključujejo anoreksijo, abdominalno bolečino,
hujšanje, utrujenost, glavobol, navzeo, bruhanje,
hipotenzijo, zmanjšano stopnjo zavesti, hipoglikemijo
in epileptične napade. Med obdobjem stresa ali načrtovanega
kirurškega posega bo morda potrebno
dodatno zdravljenje s sistemskimi kortikosteroidi.
Zaradi koristi zdravljenja z inhalacijskim flutikazonpropionatom
se zmanjša potreba po zdravljenju
s peroralnimi kortikosteroidi. Pri bolnikih, ki so se
predhodno zdravili s peroralnimi kortikosteroidi, pa
lahko tveganje za okvarjeno adrenalno rezervo traja
še znaten čas. Tveganje obstaja tudi pri bolnikih, ki so
v preteklosti nujno potrebovali zdravljenje z visokimi
odmerki kortikosteroidov. Takšno možnost rezidualne
okvare je potrebno vedno upoštevati pri urgentnih
in načrtovanih okoliščinah, ki lahko izzovejo stres.
Morda bo potrebno ustrezno kortikosteroidno zdravljenje.
Pred načrtovanimi posegi bo o obsegu okvare
nadledvične žleze morda potrebno pridobiti mnenje
ustreznega specialista.
Ritonavir lahko znatneje poveča koncentracijo flutikazonpropionata
v plazmi. Sočasni uporabi se je torej
potrebno izogibati, razen v primerih, ko morebitna
korist za bolnika prevlada nad tveganjem za pojav
sistemskih kortikosteroidnih neželenih učinkov. Večje
tveganje za pojav sistemskih neželenih učinkov obstaja
tudi pri uporabi flutikazonpropionata v kombinaciji
z drugimi močnimi zaviralci CYP3A4.
V študiji TORCH pri bolnikih s KOPB, ki so prejemali
zdravilo SERETIDE DISKUS 50/500 mikrogramov
dvakrat na dan v primerjavi s placebom, v študijah
SCO40043 in SCO100250 pa pri bolnikih, ki so
prejemali nižji odmerek zdravila SERETIDE DISKUS
50/250 mikrogramov dvakrat na dan v primerjavi
s 50 mikrogramov salmeterola dvakrat na dan, so
pogosteje poročali o infekcijah spodnjih dihal (še
zlasti o pljučnici in bronhitisu). (glejte poglavji 4.8 in
5.1). Podobno incidenco pljučnice so opazili pri vseh
študijah v skupini, ki je prejemala zdravilo SERETIDE
DISKUS. V študiji TORCH so pri starejših bolnikih, pri
bolnikih z nižjim indeksom telesne mase (< 25 kg/m 2 )
in pri bolnikih z zelo resno obliko bolezni (pričakovan
FEV1 < 30 % ) opazili največje tveganje za pojav
pljučnice ne glede na zdravljenje. Pri bolnikih s KOPB
morajo biti zdravniki pozorni na možen pojav pljučnice
in drugih infekcij spodnjih dihal, saj se klinični
znaki takih infekcij in poslabšanja osnovne bolezni
pogosto prekrivajo. V primeru, da je bolnik s hudo
obliko KOPB prebolel pljučnico, je potrebno zdravljenje
z zdravilom SERETIDE DISKUS ponovno oceniti.
Podatki iz obsežnega kliničnega preskušanja (SMART;
“The Salmeterol Multi-Center Asthma Research Trial”)
kažejo, da pri bolnikih afroameriškega porekla
obstaja večje tveganje za pojav resnih respiratornih
dogodkov ali smrtnih izidov pri uporabi salmeterola
v primerjavi s placebom (glejte poglavje 5.1). Povezava
s farmakogenetskimi ali drugimi dejavniki ni
znana. Bolnikom črnega afriškega ali afrokaribskega
izvora je treba pojasniti, da naj nadaljujejo z uporabo
zdravila, vendar pa naj poiščejo zdravniško pomoč,
če simptomi astme ostanejo nenadzorovani ali se
med uporabo zdravila SERETIDE DISKUS poslabšajo.
Sočasna uporaba sistemskega ketokonazola bistveno
poveča sistemsko izpostavljenost salmeterolu.
To lahko poveča incidenco sistemskih učinkov (npr.
podaljšanja intervala QTc in palpitacij). Sočasnemu
zdravljenju s ketokonazolom ali drugimi močnimi
zaviralci CYP3A4 se je zato treba izogibati, razen če
koristi odtehtajo možno povečano tveganje sistemskih
neželenih učinkov zdravljenja s salmeterolom.
Zdravilo SERETIDE DISKUS vsebuje laktozo (do 11,8
miligramov/odmerek). Pri osebah, intolerantnih za
laktozo, takšna količina običajno ne povzroča težav.
Bolniki z redko dedno intoleranco za galaktozo,
laponsko obliko zmanjšane aktivnosti laktaze ali
malabsorpcijo glukoze/galaktoze ne smejo jemati
tega zdravila.
Medsebojno delovanje z drugimi zdravili in
druge oblike interakcij
Izogibati se je treba uporabi tako neselektivnih kot
selektivnih antagonistov adrenergičnih receptorjev
beta, razen v primerih, ko je njihova uporaba utemeljena
in nujno potrebna.
Sočasna uporaba drugih zdravil z beta adrenergičnim
delovanjem ima lahko aditiven učinek.
Flutikazonpropionat
V običajnih okoliščinah so po inhalacijskem odmerjanju
dosežene zelo nizke koncentracije flutikazonpropionata
v plazmi, kar je posledica znatne presnove
prvega prehoda in visokega sistemskega očistka s
citokromom P450 3A4 v črevesju in jetrih. Klinično
pomembne interakcije s flutikazonpropionatom so
zato malo verjetne.
Pri zdravih osebah, ki so v študiji medsebojnega
delovanja z drugimi zdravili prejemale flutikazonpropionat
intranazalno, so ugotovili, da so se zaradi
ritonavirja (zelo močan zaviralec citokroma P450
3A4) v odmerku 100 mg dvakrat na dan plazemske
koncentracije flutikazonpropionata povečale
za več stokrat, serumske koncentracije kortizola pa
posledično znatno zmanjšale. Za inhalacijski flutikazonpropionat
podatki sicer niso na voljo, vendar pa
lahko pričakujemo znatno povečane vrednosti flutikazonpropionata
v plazmi. Poročali so o primerih Cushingovega
sindroma in supresije nadledvične žleze.
Sočasni uporabi flutikazonpropionata in ritonavirja
se je torej potrebno izogibati, razen v primerih, ko
morebitna korist za bolnika prevlada nad povečanim
tveganjem za pojav sistemskih glukokortikoidnih
neželenih učinkov.
Pri zdravih prostovoljcih, ki so bili vključeni v manjšo
študijo, so ugotovili, da se je zaradi ketokonazola (nekoliko
manj močan zaviralec CYP3A4 izpostavljenost
flutikazonpropionatu po eni sami inhalaciji slednjega
povečala za 150 %. To je imelo za posledico močnejše
zmanjšanje kortizola v plazmi kot pa pri uporabi
flutikazonpropionata samega. Pri sočasnem zdravljenju
z drugimi močnimi zaviralci CYP3A4, kot je itrakonazol
se tudi pričakuje, da se bosta sistemska izpostavljenost
flutikazonpropionatu in tveganje za pojav
sistemskih neželenih učinkov povečala. Priporočamo
previdnost. Če je le možno, se je dolgotrajnemu zdravljenju
s tovrstnimi zdravili potrebno izogibati.
Salmeterol
Močni zaviralci CYP3A4
Sočasna 7-dnevna uporaba ketokonazola (400
mg peroralno enkrat na dan) in salmeterola (50
mikrogramov v inhalaciji dvakrat na dan) je pri 15
zdravih preiskovancih bistveno povečala plazemsko
izpostavljenost salmeterolu (1,4-kratno povečanje
Cmax in 15-kratno povečanje AUC). To lahko poveča
incidenco drugih sistemskih učinkov zdravljenja s salmeterolom
(npr. podaljšanja intervala QTc in palpitacij)
v primerjavi z zdravljenjem samo s salmeterolom
ali samo s ketokonazolom.
Klinično pomembnih učinkov na krvni tlak, srčno
frekvenco in koncentracijo glukoze ali kalija v krvi ni
bilo. Sočasna uporaba s ketokonazolom ni podaljšala
eliminacijskega razpolovnega časa salmeterola in
tudi ni povečala kopičenja salmeterola po večkratnem
odmerjanju.
Sočasni uporabi ketokonazola se je treba izogniti,
razen če koristi odtehtajo možno večje tveganje
sistemskih neželenih učinkov zdravljenja s salmeterolom.
Verjetno obstaja podobno tveganje medsebojnega
delovanja z drugimi močnimi zaviralci CYP3A4
(npr. z itrakonazolom, telitromicinom, ritonavirjem).
Zmerni zaviralci CYP3A4
Sočasna 6-dnevna uporaba eritromicina (500 mg
peroralno trikrat na dan) in salmeterola (50 mikrogramov
v inhalaciji dvakrat na dan) je pri 15 zdravih
preiskovancih malenkostno, statistično nepomembno
povečala izpostavljenost salmeterolu (1,4-kratno
povečanje Cmax in 1,2-kratno povečanje AUC). Med
sočasno uporabo z eritromicinom ni bilo nobenih
resnih neželenih učinkov.
Nosečnost in dojenje
Nosečnost
O uporabi salmeterola in flutikazonpropionata pri
nosečnicah in doječih materah je premalo podatkov,
da bi lahko podali oceno o možnih škodljivih učinkih.
Pri študijah na živalih so se po uporabi agonistov
adrenergičnih receptorjev beta-2 in glukokortikosteroidov
pojavile anomalije plodov.
Zdravilo SERETIDE DISKUS se sme nosečnicam predpisati
le, če pričakovana korist za mater prevlada nad
kakršnimkoli možnim tveganjem za plod.
Nosečnicam se sme predpisati le najmanjši še učinkovit
odmerek flutikazonpropionata, ki še zagotavlja
zadovoljivo nadzorovanost astme.
Dojenje
Podatkov o izločanju zdravila z materinim mlekom ni.
Tako salmeterol kot flutikazonpropionat se izločata
z mlekom pri doječih podganah. Zdravilo SERETIDE
DISKUS se sme doječim materam predpisati le, če pričakovana
korist za mater prevlada nad kakršnimkoli
možnim tveganjem za dojenega otroka.
Vpliv na sposobnost vožnje in upravljanja
s stroji
Študij o vplivu na sposobnost vožnje in upravljanja
s stroji niso izvedli.
Neželeni učinki
Zdravilo SERETIDE DISKUS vsebuje salmeterol (v
obliki salmeterolijevega ksinafoata) in flutikazonpropionat,
zato lahko pričakujemo vrsto in resnost
neželenih reakcij, ki so povezane z vsako posamezno
učinkovino. Zaradi sočasne uporabe obeh zdravilnih
učinkovin, se dodatni neželeni učinki niso pojavili.
Neželeni učinki, ki so bili povezani z uporabo salmeterola/flutikazonpropionata
so navedeni v nadaljevanju
glede na organski sistem in pogostnost.
Pogostnost je navedena kot: zelo pogosti (≥ 1/10),
pogosti (≥ 1/100 do < 1/10), občasni (≥ 1/1.000
do < 1/100), redki (≥ 1/10.000 do < 1/1.000), zelo
redki (< 1/10.000) ter neznani (ni mogoče oceniti
iz razpoložljivih podatkov). Podatki o zelo pogostih,
pogostih in občasnih učinkih so bili pridobljeni s kliničnimi
raziskavami, pri čemer pojavnost pri placebu
ni upoštevana. Podatki o zelo redkih učinkih so bili
pridobljeni s pomočjo spontanih poročil med spremljanjem
zdravila po pridobitvi dovoljenja za promet.
Zelo pogosti: glavobol 1 , nazofaringitis 2,3
Pogosti: kandidoza ustne votline in žrela, pljučnica
1,3 , bronhitis 1,3 , hipokalijemija 3 , tremor , palpitacije,
draženje žrela, hripavost/disfonija, sinuzitis 1,3 , kontuzije
1,3 , mišični krči, zlomi kosti zaradi poškodb 1,3
Občasni: preobčutljivostne kožne reakcije, tahikardija
Zelo redki: angioedem (predvsem edem obraza in
orofaringealni edem), respiratorni simptomi (dispneja
in/ali bronhospazem), anafilaksijske reakcije,
vključno z anafilaktičnim šokom, Cushingov sindrom
in z njim povezane značilnosti 4 , supresija nadledvične
žleze 4 , zastoj rasti pri otrocih in mladostnikih 4 , zmanjšanje
mineralne gostote kosti 4 , katarakta 4 , glavkom 4 ,
hiperglikemija 4 , anksioznost, motnje spanja in
vedenjske spremembe, vključno s hiperaktivnostjo
ter razdražljivostjo (predvsem pri otrocih), aritmije
(vključno z atrijsko fibrilacijo, supraventrikularno
tahikardijo in ekstrasistolami), paradoksni bronhospazem
4 , artralgija, mialgija.
1. Pogosta poročila pri placebu, 2. Zelo pogosta poročila
pri placebu, 3. Poročila v 3 letih v študiji pri bolnikih
s KOPB, 4. Glejte poglavje: Posebna opozorila in
previdnostni ukrepi
Opis izbranih neželenih učinkov
Poročali so o farmakoloških neželenih učinkih zdravljenja
z agonisti adrenergičnih receptorjev beta-2,
kot so tremor, palpitacije in glavobol. Običajno so
bili prehodni in so se pri rednem zdravljenju ublažili.
Zaradi flutikazonpropionata se lahko pri posameznih
bolnikih pojavi hripavost in kandidoza (soor) ustne
votline in žrela. Oboje, hripavost in pojavnost kandidoze
se lahko ublaži z izpiranjem ustne votline z
vodo po uporabi zdravila. Simptomatska kandidoza
se lahko, ob sočasnem nadaljevanju zdravljenja z
zdravilom SERETIDE DISKUS, zdravi s topikalnimi
protiglivičnimi zdravili.
Pediatrična populacija
Možni sistemski učinki vključujejo Cushingov
sindrom in z njim povezane značilnosti, supresijo
nadledvične žleze in zastoj rasti pri otrocih in mladostnikih.
Pri otrocih se lahko pojavijo anksioznost,
motnje spanja in vedenjske spremembe vključno s
hiperaktivnostjo ter razdražljivostjo.
Preveliko odmerjanje
Podatkov o primerih prevelikega odmerjanja zdravila
SERETIDE DISKUS med kliničnimi preskušanji ni, vendar
pa so v nadaljevanju podani podatki o prevelikem
odmerjanju posamezne zdravilne učinkovine.
Znaki in simptomi prevelikega odmerjanja salmeterola
so tremor, glavobol in tahikardija. Prednostni
antidot je kardioselektivni antagonist adrenergičnih
receptorjev beta, ki pa ga je pri bolnikih z bronhospazmom
v anamnezi potrebno uporabljati previdno.
Če se mora zdravljenje z zdravilom SERETIDE DISKUS
prekiniti zaradi prevelikega odmerjanja agonista
adrenergičnih receptorjev beta, bo morda potrebno
zagotoviti ustrezno nadomestno zdravljenje s kortikosteroidom.
Lahko se pojavi tudi hipokaliemija, zato
bo morda potrebno nadomeščanje kalija.
Akutno: Akutna uporaba inhalacijskega flutikazonpropionata
v odmerkih, ki so večji od priporočenih,
lahko povzroči začasno supresijo nadledvične žleze.
Nujni ukrepi zaradi tega običajno niso potrebni, saj
se delovanje nadledvične žleze v nekaj dneh povrne,
kar se lahko ugotovi z merjenjem koncentracije
kortizola v plazmi.
Za kronično preveliko odmerjanje inhalacijskega
flutikazonpropionata glejte podatke o tveganju za
supresijo nadledvične žleze v poglavju 4.4. Morda bo
potreben nadzor adrenalne rezerve. V primeru prevelikega
odmerjanja flutikazonpropionata se lahko
zdravljenje z zdravilom SERETIDE DISKUS nadaljuje,
in sicer z odmerki, ki zadoščajo za nadzorovanje
simptomov.
Inkompatibilnosti
Navedba smiselno ni potrebna.
Vrsta ovojnine in vsebina
Škatla vsebuje napravo iz lite plastike (DISKUS), ki
je sestavljena iz zunanjega ohišja, ustnika, vzmeti in
števca preostalih odmerkov. Prašek za inhaliranje se
enakomerno razporejen v odmerke nahaja med dvema
plastema odmernega traku v notranjosti naprave.
Zdravilo SERETIDE DISKUS je na voljo v treh jakostih,
vsaka izmed njih zadošča za 60 odmerkov.
IMETNIK DOVOLJENJA ZA PROMET
GSK d.o.o., Ljubljana, Knezov štradon 90, 1000 Ljubljana,
Slovenija
DATUM ZADNJE REVIZIJE BESEDILA
11. 06. 2010
Pred predpisovanjem, prosimo, preberite celoten
povzetek glavnih značilnosti zdravila.
Predpisovanje in izdaja zdravila je le na recept.
Za vse morebitne neadaljne informacije o tem zdravilu
se lahko obrnete na imetnika dovoljenja za promet
z zdravilom:GSK d.o.o.,Ljubljana, knezov štradon 90,
1000 Ljubljana, Tel:+ 386(0) 1 280 25 00, medical.x.si@
gsk.com.
Seretide ® in Diskus ® sta zaščiteni blagovni znamki skupine
družb GlaxoSmithKline. © 2010 GlaxoSmithKline. Vse
pravice pridržane.
Datum priprave materiala: September 2011.
Veljavnost 1 leto.
Literatura:
1. Dalal AA in sod., Chest 2009; 136(4): 89s-90s and
poster presented at the meeting of the American
College of Chest Physicians, San Diego 2009 (P428).
2. Povzetek temeljenih značilnosti zdravila Seretide.
SLO/SFC/0002/11

^AS ZA ŽIVLJENJE.
DOKAZANO PODALJŠA PREŽIVETJE PRI BOLNIKIH:
z lokalno napredovalim ali metastatskim
nedrobnoceli~nim rakom plju~ 1
z metastatskim rakom trebu{ne slinavke 1
1
Povzetek glavnih značilnosti zdravila TARCEVA, www.ema.europa.eu

SKRAJ[AN POVZETEK GLAVNIH ZNA^ILNOSTI ZDRAVILA
Samo za strokovno javnost.
Ime zdravila: Tarceva 25 mg/100 mg/150 mg filmsko obložene
tablete
Kakovostna in koli~inska sestava: Ena filmsko obložena tableta
vsebuje 25 mg, 100 mg ali 150 mg erlotiniba (v obliki erlotinibijevega
klorida).
Terapevtske indikacije: Nedrobnoceli~ni rak plju~: Zdravilo Tarceva
je indicirano za samostojno vzdrževalno zdravljenje bolnikov z lokalno
napredovalim ali metastatskim nedrobnoceli~nim rakom plju~ s stabilno
boleznijo po 4 ciklih standardne kemoterapije na osnovi platine v prvi
liniji zdravljenja. Zdravilo Tarceva je indicirano tudi za zdravljenje
bolnikov z lokalno napredovalim ali metastatskim nedrobnoceli~nim
rakom plju~ po neuspehu vsaj ene predhodne kemoterapije. Pri
predpisovanju zdravila Tarceva je treba upo{tevati dejavnike, povezane
s podalj{anim preživetjem. Koristnega vpliva na podalj{anje preživetja
ali drugih klini~no pomembnih u~inkov zdravljenja niso dokazali pri
bolnikih z EGFR-negativnimi tumorji. Rak trebu{ne slinavke: Zdravilo
Tarceva je v kombinaciji z gemcitabinom indicirano za zdravljenje
bolnikov z metastatskim rakom trebu{ne slinavke. Pri predpisovanju
zdravila Tarceva je treba upo{tevati dejavnike, povezane s podalj{anim
preživetjem. Koristnega vpliva na podalj{anje preživetja niso dokazali
za bolnike z lokalno napredovalo boleznijo.
Odmerjanje in na~in uporabe: Zdravljenje z zdravilom Tarceva
mora nadzorovati zdravnik z izku{njami pri zdravljenju raka. Zdravilo
Tarceva vzamemo najmanj eno uro pred zaužitjem hrane ali dve uri po
tem. Kadar je potrebno odmerek prilagoditi, ga je treba zmanj{evati v
korakih po 50 mg. Pri so~asnem jemanju substratov in modulatorjev
CYP3A4 bo morda potrebna prilagoditev odmerka. Pri dajanju zdravila
Tarceva bolnikom z jetrno okvaro je potrebna previdnost. ^e se pojavijo
hudi neželeni u~inki, pride v po{tev zmanj{anje odmerka ali prekinitev
zdravljenja z zdravilom Tarceva. Uporaba zdravila Tarceva pri bolnikih s
hudo jetrno ali ledvi~no okvaro ter pri otrocih ni priporo~ljiva. Bolnikom
kadilcem je treba svetovati, naj prenehajo kaditi, saj so plazemske
koncentracije erlotiniba pri kadilcih manj{e kot pri nekadilcih.
Nedrobnoceli~ni rak plju~: Priporo~eni dnevni odmerek zdravila Tarceva
je 150 mg. Rak trebu{ne slinavke: Priporo~eni dnevni odmerek zdravila
Tarceva je 100 mg, v kombinaciji z gemcitabinom. Pri bolnikih, pri
katerih se kožni izpu{~aj v prvih 4 do 8 tednih zdravljenja ne pojavi,
je treba ponovno pretehtati nadaljnje zdravljenje z zdravilom Tarceva.
Kontraindikacije: Preob~utljivost za erlotinib ali katero koli pomožno
snov.
Posebna opozorila in previdnostni ukrepi: Mo~ni induktorji
CYP3A4 lahko zmanj{ajo u~inkovitost erlotiniba, mo~ni zaviralci
CYP3A4 pa lahko pove~ajo toksi~nost. So~asnemu zdravljenju s temi
zdravili se je treba izogibati. Bolnikom, ki kadijo, je treba svetovati, naj
prenehajo kaditi, saj so plazemske koncentracije erlotiniba pri kadilcih
zmanj{ane v primerjavi s plazemskimi koncentracijami pri nekadilcih.
Verjetno je, da je velikost zmanj{anja klini~no pomembna. Pri bolnikih,
pri katerih se akutno pojavijo novi in/ali poslab{ajo nepojasnjeni
plju~ni simptomi, kot so dispneja, ka{elj in vro~ina, je treba
zdravljenje z zdravilom Tarceva prekiniti, dokler ni znana diagnoza.
Bolnike, ki se so~asno zdravijo z erlotinibom in gemcitabinom, je
treba skrbno spremljati zaradi možnosti pojava toksi~nosti, podobni
intersticijski bolezni plju~. ^e je ugotovljena intersticijska bolezen
plju~, zdravilo Tarceva ukinemo in uvedemo ustrezno zdravljenje. Pri
približno polovici bolnikov, ki so se zdravili z zdravilom Tarceva, se
je pojavila driska (vklju~no z zelo redkimi primeri, ki so se kon~ali s
smrtnim izidom). Zmerno do hudo drisko zdravimo z loperamidom.
V nekaterih primerih bo morda potrebno zmanj{anje odmerka. V
primeru hude ali dolgotrajne driske, navzeje, anoreksije ali bruhanja,
povezanih z dehidracijo, je treba zdravljenje z zdravilom Tarceva
prekiniti in dehidracijo ustrezno zdraviti. O hipokaliemiji in ledvi~ni
odpovedi so poro~ali redko. Posebno pri bolnikih z dejavniki tveganja
(so~asno jemanje drugih zdravil, simptomi, bolezni ali drugi dejavniki,
vklju~no z visoko starostjo) moramo, ~e je driska huda ali dolgotrajna
oziroma vodi v dehidracijo, zdravljenje z zdravilom Tarceva prekiniti
in bolnikom zagotoviti intenzivno intravensko rehidracijo. Dodatno je
treba pri bolnikih s prisotnim tveganjem za razvoj dehidracije spremljati
ledvi~no delovanje in serumske elektrolite, vklju~no s kalijem. Pri
uporabi zdravila Tarceva so poro~ali o redkih primerih jetrne odpovedi.
K njenemu nastanku je lahko pripomogla predhodno obstoje~a jetrna
bolezen ali so~asno jemanje hepatotoksi~nih zdravil. Pri teh bolnikih je
treba zato premisliti o rednem spremljanju jetrnega delovanja. Dajanje
zdravila Tarceva je treba prekiniti, ~e so spremembe jetrnega delovanja
hude. Bolniki, ki prejemajo zdravilo Tarceva, imajo ve~je tveganje za
razvoj perforacij v prebavilih, ki so jih opazili ob~asno (vklju~no z
nekaterimi primeri, ki so se kon~ali s smrtnim izidom). Pri bolnikih, ki
so~asno prejemajo zdravila, ki zavirajo angiogenezo, kortikosteroide,
nesteroidna protivnetna zdravila (NSAID) in/ali kemoterapijo na osnovi
taksanov, ali so v preteklosti imeli pepti~ni ulkus ali divertikularno
bolezen, je tveganje ve~je. ^e pride do tega, je treba zdravljenje z
zdravilom Tarceva dokon~no ukiniti. Poro~ali so o primerih kožnih
bolezni z mehurji in lu{~enjem kože, vklju~no z zelo redkimi primeri,
ki so nakazovali na Stevens-Johnsonov sindrom/toksi~no epidermalno
nekrolizo in so bili v nekaterih primerih smrtni. Zdravljenje z zdravilom
Tarceva je treba prekiniti ali ukiniti, ~e se pri bolniku pojavijo hude
oblike mehurjev ali lu{~enja kože. Zelo redko so poro~ali o primerih
perforacije ali ulceracije roženice; opazili so tudi druge o~esne bolezni.
Zdravljenje z zdravilom Tarceva je treba prekiniti ali ukiniti, ~e se pri
bolnikih pojavijo akutne o~esne bolezni, kot je bole~ina v o~eh, ali se lete
poslab{ajo. Tablete vsebujejo laktozo in jih ne smemo dajati bolnikom
z redkimi dednimi stanji: intoleranco za galaktozo, laponsko obliko
zmanj{ane aktivnosti laktaze ali malabsorpcijo glukoze/galaktoze.
Medsebojno delovanje z drugimi zdravili in druge oblike
interakcij: Erlotinib se pri ljudeh presnavlja v jetrih z jetrnimi
citokromi, primarno s CYP3A4 in v manj{i meri s CYP1A2. Presnova
erlotiniba zunaj jeter poteka s CYP3A4 v ~revesju, CYP1A1 v plju~ih
in CYP1B1 v tumorskih tkivih. Z zdravilnimi u~inkovinami, ki se
presnavljajo s temi encimi, jih zavirajo ali pa so njihovi induktorji,
lahko pride do interakcij. Erlotinib je srednje mo~an zaviralec CYP3A4
in CYP2C8, kot tudi mo~an zaviralec glukuronidacije z UGT1A1 in vitro.
Pri kombinaciji ciprofloksacina ali mo~nega zaviralca CYP1A2 (npr.
fluvoksamina) z erlotinibom je potrebna previdnost. V primeru pojava
neželenih u~inkov, povezanih z erlotinibom, lahko odmerek erlotiniba
zmanj{amo. Predhodno ali so~asno zdravljenje z zdravilom Tarceva
ni spremenilo o~istka prototipov substratov CYP3A4, midazolama in
eritromicina. Inhibicija glukoronidacije lahko povzro~i interakcije z
zdravili, ki so substrati UGT1A1 in se izlo~ajo samo po tej poti. Mo~ni
zaviralci aktivnosti CYP3A4 zmanj{ajo presnovo erlotiniba in zve~ajo
koncentracije erlotiniba v plazmi. Pri so~asnem jemanju erlotiniba in
mo~nih zaviralcev CYP3A4 je zato potrebna previdnost. ^e je treba,
odmerek erlotiniba zmanj{amo, {e posebno pri pojavu toksi~nosti.
Mo~ni spodbujevalci aktivnosti CYP3A4 zve~ajo presnovo erlotiniba in
pomembno zmanj{ajo plazemske koncentracije erlotiniba. So~asnemu
dajanju zdravila Tarceva in induktorjev CYP3A4 se je treba izogibati.
Pri bolnikih, ki potrebujejo so~asno zdravljenje z zdravilom Tarceva in
mo~nim induktorjem CYP3A4, je treba premisliti o pove~anju odmerka
do 300 mg ob skrbnem spremljanju njihove varnosti. Zmanj{ana
izpostavljenost se lahko pojavi tudi z drugimi induktorji, kot so fenitoin,
karbamazepin, barbiturati ali {entjanževka. ^e te zdravilne u~inkovine
kombiniramo z erlotinibom, je potrebna previdnost. Kadar je mogo~e, je
treba razmisliti o drugih na~inih zdravljenja, ki ne vklju~ujejo mo~nega
spodbujanja aktivnosti CYP3A4. Bolnikom, ki jemljejo kumarinske
antikoagulante, je treba redno kontrolirati protrombinski ~as ali INR.
So~asno zdravljenje z zdravilom Tarceva in statinom lahko pove~a
tveganje za miopatijo, povzro~eno s statini, vklju~no z rabdomiolizo;
to so opazili redko. So~asna uporaba zaviralcev P-glikoproteina, kot sta
ciklosporin in verapamil, lahko vodi v spremenjeno porazdelitev in/ali
spremenjeno izlo~anje erlotiniba. Za erlotinib je zna~ilno zmanj{anje
topnosti pri pH nad 5. Zdravila, ki spremenijo pH v zgornjem delu
prebavil, lahko spremenijo topnost erlotiniba in posledi~no njegovo
biolo{ko uporabnost. U~inka antacidov na absorpcijo erlotiniba niso
prou~evali, vendar je ta lahko zmanj{ana, kar vodi v nižje plazemske
koncentracije. Kombinaciji erlotiniba in zaviralca protonske ~rpalke se je
treba izogibati. ^e menimo, da je uporaba antacidov med zdravljenjem
z zdravilom Tarceva potrebna, jih je treba jemati najmanj 4 ure pred ali
2 uri po dnevnem odmerku zdravila Tarceva. ^e razmi{ljamo o uporabi
ranitidina, moramo zdravili jemati lo~eno: zdravilo Tarceva je treba vzeti
najmanj 2 uri pred ali 10 ur po odmerku ranitidina. V {tudiji faze Ib
ni bilo pomembnih u~inkov gemcitabina na farmakokinetiko erlotiniba,
prav tako ni bilo pomembnih u~inkov erlotiniba na farmakokinetiko
gemcitabina. Erlotinib pove~a koncentracijo platine. Pomembnih
u~inkov karboplatina ali paklitaksela na farmakokinetiko erlotiniba ni
bilo. Kapecitabin lahko pove~a koncentracijo erlotiniba. Pomembnih
u~inkov erlotiniba na farmakokinetiko kapecitabina ni bilo.
Neželeni u~inki: Zelo pogosti neželeni u~inki so kožni izpu{~aj
in driska, kot tudi utrujenost, anoreksija, dispneja, ka{elj, okužba,
navzea, bruhanje, stomatitis, bole~ina v trebuhu, pruritus, suha koža,
suhi keratokonjunktivitis, konjunktivitis, zmanj{anje telesne mase,
depresija, glavobol, nevropatija, dispepsija, flatulenca, alopecija,
okorelost, pireksija, nenormalnosti testov jetrne funkcije. Pogosti
neželeni u~inki so krvavitve v prebavilih, epistaksa, keratitis, paronihija,
fisure na koži. Ob~asno so poro~ali o perforacijah v prebavilih,
hirzutizmu, spremembah obrvi, krhkih nohtih, odstopanju nohtov od
kože, blagih reakcijah na koži (npr. hiperpigmentacija), spremembah
trepalnic, hudi intersticijski bolezni plju~ (vklju~no s smrtnimi primeri).
Redko pa so poro~ali o jetrni odpovedi. Zelo redko so poro~ali o Stevens-
Johnsonovem sindromu/toksi~ni epidermalni nekrolizi ter o ulceracijah
in perforacijah roženice.
Režim izdaje zdravila: H/Rp. Imetnik dovoljenja za promet: Roche
Registration Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7
1TW, Velika Britanija. Verzija: 2.0/10. Informacija pripravljena:
avgust 2011.
DODATNE INFORMACIJE SO NA VOLJO PRI:
Roche farmacevtska družba d.o.o.
Vodovodna cesta 109, 1000 Ljubljana.
Povzetek glavnih zna~ilnosti zdravila je dosegljiv
na www.roche.si ali www.onkologija.si.
025-11-TAR