ΠΝΕΥΜΩΝ PNEUMON. ΑΘΗΝΑ. Cited in: Εmbase Copernicus Index Google Scholar doaj ISSN X. e-issn ATHENS

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1 ΠΝΕΥΜΩΝ PNEUMON VOL. 27 No 4 OCTOBER-DECEMBER 2014 ΠΝΕΥΜΩΝ ΤΟΜΟΣ 27 ΤΕΥΧΟΣ 4 ΟΚΤΩΒΡΙΟΣ-ΔΕΚΕΜΒΡΙΟς 2014 ΠΝΕΥΜΩΝ/PNEUMON ΤΟΜΟΣ/VOL. 27 ΤΕΥΧΟΣ/No 4 ΟΚΤΩΒΡΙΟΣ/OCTOBER - ΔΕΚεμβρΙΟΣ/DECember 2014 ΤΡΙΜΗΝΗ ΙΑΤΡΙΚΗ ΕΚΔΟΣΗ ΕΛΛΗΝΙΚΗ ΒΡΟΓΧΟΛΟΓΙΚΗ ΕΤΑΙΡΕΙΑ GREEK BRONCHOLOGIC SOCIETY PNEUMON ΕΛΛΗΝΙΚΗ ΠΝΕΥΜΟΝΟΛΟΓΙΚΗ ΕΤΑΙΡΕΙΑ HELLENIC THORACIC SOCIETY QUARTERLY MEDICAL JOURNAL ISSN X e-issn Αριθμός Άδειας 4/2007 ôåχíïãñáììámed Λ. Μεσογείων Áãßá ÐáñáóêåõÞ AÖÌ: ΠΛΗΡΩΜΕΝΟ ΤΕΛΟΣ Ταχ. Γραφείο ΚΕΜΠ Αθηνών Cited in: S CO P U S Εmbase Copernicus Index Google Scholar doaj ΑΘΗΝΑ ATHENS

2 ΠΝΕΥΜΩΝ ΤΡΙΜΗΝΗ ΙΑΤΡΙΚΗ ΕΚΔΟΣΗ PNEUMON ΕΛΛΗΝΙΚΗ ΕΛΛΗΝΙΚΗ ΒΡΟΓΧΟΛΟΓΙΚΗ ΕΤΑΙΡΕΙΑ ΠΝΕΥΜΟNOΛΟΓΙΚΗ ΕΤΑΙΡΕΙΑ GREEK BRONCHOLOGIC HELLENIC THORACIC SOCIETY SOCIETY QUARTERLY MEDICAL JOURNAL ÅËËÇÍÉÊÇÓ ÐÍÅÕÌÏÍÏËÏÃÉÊÇÓ ÅÔÁÉÑÅÉÁÓ ΕΠΙΣΗΜΟ ΕΠΙΣΤΗΜΟΝΙΚΟ ΟΡΓΑΝΟ ÅËËÇÍÉÊÇÓ ÂÑÏÃ ÏËÏÃÉÊÇÓ ÅÔÁÉÑÅÉÁÓ Ιδιοκτήτης: ΕΛΛΗΝΙΚΗ ΒΡΟΓΧΟΛΟΓΙΚΗ ΕΤΑΙΡΕΙΑ ISSN X e-issn ΔΙΕΥΘΥΝΣΗ Περιοδικό ΠΝΕΥΜΩΝ Μεσογείων 152 Αθήνα Νοσοκομείο Νοσημάτων Θώρακος Αθηνών "Η Σωτηρία" Τηλ.: , FREE ONLINE ACCESS ΕΤΗΣΙΕΣ ΣΥΝΔΡΟΜΕΣ Eσωτερικού Μέλη ΕΠΕ - ΕΒΕ Ειδικευόμενοι - Φοιτητές Εταιρείες - Οργανισμοί Βιβλιοθήκες Εξωτερικού Εκτύπωση: ΤΕΧΝΟΓΡΑΜΜΑ Λ. Μεσογείων 380, Αγία Παρασκευή Τηλ: , fax: techn@hol.gr Εκδότης: Μ. Στεφανάκης Διευθυντής Σύνταξης: Βοηθοί σύνταξης: Διεθνής Συντακτική Επιτροπή Philippe Astoul (France) Bruno Balbi (Italy) Peter J. Barnes (UK) Robert Baughman (USA) Semra Bilaceroglou (Turkey) Philippe Camus (France) John Catravas (USA) Carlos Robalo Cordeiro (Portugal) Ulrich Costabel (Germany) Vincent Cotin (France) Claudio Donner (Italy) Elisabeth Fireman (Israel) Patricia Haslam (UK) Kazuhiro Ito (UK) Talmadge King (USA) Meinhard Kneussl (Austria) Richard Light (USA) Fernando Martinez (USA) Dario Olivieri (Italy) Paco Panadero (Spain) Panos Pantelidis (UK) Martin Petrek (CZ) Vesna Petrovic (Serbia) Udaya Prakash (USA) Ganesh Raghu (USA) Steven Rennard (USA) Paola Rotoli (Italy) Cuneyt Tetikkurt (Τurkey) Theocharis Theocharides (USA) Argyris Theophilopoulos (USA) George Tselepis (USA) Athol Wells (UK) ΣυντακτικH ΕπιτροπH Δημοσθένης Μπούρος Κώστας Κωστίκας Στέλιος Λουκίδης Πέτρος Μπακάκος Ιωάννης Πνευματικός Γεώργιος Σταθόπουλος Joanna Floros PhD (USA) Μέλη Εθνικής Συντακτικής Επιτροπής Αντώνης Αντωνιάδης (Σέρρες) Νικόλαος Γαλάνης (Θεσ/νίκη) Δημήτριος Γεωργόπουλος (Ηράκλειο) Μίνα Γκάγκα (Αθήνα) Κώστας Γουργουλιάνης (Λάρισα) Γεώργιος Δημόπουλος (Αθήνα) Κώστας Ζαρογουλίδης (Θεσ/νίκη) Κωνσταντίνος Κατής (Αθήνα) Γεώργιος Κολιός (Αλεξανδρούπολη) Επαμεινώνδας Κοσμάς (Αθήνα) Νικόλαος Κουλούρης (Αθήνα) Αντωνία Κουτσούκου (Αθήνα) Σταύρος Κωνσταντινίδης (Αλεξανδρούπολη) Κώστας Κωνσταντίνου (Αθήνα) Σταύρος Κωνσταντόπουλος (Ιωάννινα) Κατερίνα Μαλαγάρη (Αθήνα) Αργύρης Μιχαλόπουλος (Αθήνα) Γεώργιος Μπαλτόπουλος (Αθήνα) Παναγιώτης Μπεχράκης (Αθήνα) Γεώργιος Νάκος (Ιωάννινα) Σπύρος Παπίρης (Αθήνα) Βλάσης Πολυχρονόπουλος (Αθήνα) Κώστας Πρίφτης (Αθήνα) Αντώνης Ρασιδάκης (Αθήνα) Νικόλαος Σιαφάκας (Ηράκλειο) Μιχάλης Τουμπής (Αθήνα) Μάριος Φρουδαράκης (Αλεξανδρούπολη)

3 ΠΝΕΥΜΩΝ ΤΡΙΜΗΝΗ ΙΑΤΡΙΚΗ ΕΚΔΟΣΗ PNEUMON ΕΛΛΗΝΙΚΗ ΕΛΛΗΝΙΚΗ ΒΡΟΓΧΟΛΟΓΙΚΗ ΕΤΑΙΡΕΙΑ ΠΝΕΥΜΟNOΛΟΓΙΚΗ ΕΤΑΙΡΕΙΑ GREEK BRONCHOLOGIC HELLENIC THORACIC SOCIETY SOCIETY QUARTERLY MEDICAL JOURNAL THE HELLENIC THORACIC SOCIETY (HTS) OFFICIAL JOURNAL THE GREEK BRONCHOLOGIC SOCIETY (GBS) Owner: GREEK BRONCHOLOGIC SOCIETY ISSN X e-issn Address: PNEUMON Medical Journal Athens Chest Hospital (Sotiria) 152 Messogion Ave. Athens Greece Tel.: pneumon@hts.org.gr FREE ONLINE ACCESS Annual Subscriptions Inland Members of HTS and GBS Interns-Medical Students Medical Societies Medical Libraries Abroad Publisher: Technogramma 380 Messogion Ave., Athens - Greece Tel.: , Fax: techn@hol.gr Editor-in-Chief: Associate Editors: Demosthenes Bouros, MD, PhD, FCCP Kostas Kostikas, MD, FCCP Stelios Loukidis, MD, FCCP Petros Bakakos, MD International Board Philippe Astoul (France) Bruno Balbi (Italy) Peter J. Barnes (UK) Robert Baughman (USA) Semra Bilaceroglou (Turkey) Philippe Camus (France) John Catravas (USA) Carlos Robalo Cordeiro (Portugal) Ulrich Costabel (Germany) Vincent Cotin (France) Claudio Donner (Italy) Elisabeth Fireman (Israel) Patricia Haslam (UK) Kazuhiro Ito (UK) Talmadge King (USA) Meinhard Kneussl (Austria) Richard Light (USA) Fernando J. Martinez (USA) Dario Olivieri (Italy) Paco Panadero (Spain) Panos Pantelidis (UK) Martin Petrek (CZ) Vesna Petrovic (Serbia) Udaya Prakash (USA) Ganesh Raghu (USA) Steven Rennard (USA) Paola Rotoli (Italy) Cuneyt Tetikkurt (Τurkey) Theocharis Theocharides (USA) Argyris Theophilopoulos (USA) George Tselepis (USA) Athol Wells (UK) EDITORIAL BOARD Ioannis Pneumatikos, MD, FCCP Georgios Stathopoulos, MD Joanna Floros PhD (USA) National Board Antonis Antoniadis (Serres) George Baltopoulos (Athens) Panagiotis Behrakis (Athens) George Dimopoulos (Athens) Marios Froudarakis (Alexandroupolis) Mina Gaga (Athens) Nikolaos Galanis (Thessaloniki) Demetrios Georgopoulos (Heraklion) Kostas Gourgoulianis (Larisa) Konstantinos Katis (Athens) George Kolios (Alexandroupolis) Stauros Konstantinidis (Alexandroupolis) Kostas Konstantinou (Athens) Stavros Konstantopoulos (Ioannina) Epameinondas Kosmas (Athens) Nikolaos Koulouris (Athens) Antonia Koutsoukou (Athens) Katerina Malagari (Athens) Argyris Michalopoulos (Athens) George Nakos (Ioannina) Spyros Papiris (Athens) Vlasis Polychronopoulos (Athens) Kostas Priftis (Athens) Antonis Rassidakis (Athens) Nikolaos Siafakas (Heraklion) Michael Toumbis (Athens) Kostas Zarogoulidis (Thessaloniki)

4 ΠΝΕΥΜΩΝ ΤΡΙΜΗΝΗ ΙΑΤΡΙΚΗ ΕΚΔΟΣΗ ΕΛΛΗΝΙΚΗ ΕΛΛΗΝΙΚΗ ΒΡΟΓΧΟΛΟΓΙΚΗ ΕΤΑΙΡΕΙΑ ΠΝΕΥΜΟNOΛΟΓΙΚΗ ΕΤΑΙΡΕΙΑ GREEK BRONCHOLOGIC HELLENIC THORACIC SOCIETYPNEUMON SOCIETY QUARTERLY MEDICAL JOURNAL Άρθρα Σύνταξης Περιεχόμενα Θεραπευτικό πρωτόκολλο για την ιδιοπαθή πνευμονική ίνωση Δ. Μπούρος, Ε.Δ. Μάναλη, Σ.Α. Παπίρης, Κ.Μ. Αντωνίου Παχυσαρκία και πνευμονία. Μια περίπλοκη σχέση Π. Στειρόπουλος, Δ. Μπούρος Αντιμετώπιση Πνευμονικής Εμβολής. Νέες Ευρωπαϊκές Κατευθυντήριες Οδηγίες Σ. Κωνσταντινίδης, Γ. Χαλικιάs Σύνδρομο αλληλοεπικάλυψης βρογχικού άσθματος ΧΑΠ: ACOS, CAOS ή CHAOS; Σ. Λουκίδης, Π. Μπακάκος, Κ. Κωστίκας Ανασκόπηση Ανασκόπηση βιβλιογραφίας για τη χρήση του flutter σε άτομα με βρογχεκτασίες. Ο ρόλος του flutter στην αναπνευστική λειτουργία και στην κάθαρση των πύελών σε ασθενείς με βρογχεκτασίες Μ.-Ε. Κλώνη, Α. Κλώνης, Κ. Μπενίδης Ερευνητική Εργασία Γνώσεις και πρακτικές των εργαζομένων στο νοσοκομείο για τη φυματίωση Α. Χαρίσης, Α. Τατσιώνη, Α. Γόγαλη, Α. Ευθυμίου, Γ. Δασκαλόπουλος, Σ. Κωνσταντόπουλος, Α. Κωνσταντινίδης Παρουσίαση Περιστατικων Αλλεργική Βρογχοπνευμονική Ασπεργίλλωση οφειλόμενη σε Aspergillus niger. Περιγραφή δύο περιστατικών στην Ελλάδα και ανασκόπηση της βιβλιογραφίας Ε. Μάναλη, Χ. Τριανταφυλλίδου, Ε.-Δ. Ιωαννίδου, Π. Λυμπερόπουλος, Α. Καρακατσάνη, Μ. Γιαννάκη, Λ. Κολιλέκας, Κ. Καγκουρίδης, Σ.Α. Παπίρης Συνήθης διάμεση πνευμονία σε ασθενή με κοιλιοκάκη και πολυενδοκρινικό σύνδρομο ΙΙΙΑ Λ. Κολιλέκας, Ε.Δ. Μάναλη, Μ. Πέππα, Θ. Χαμογεωργάκης, A. Παπαδοπούλου, Χ. Τριανταφυλλίδου, Κ. Καγκουρίδης, Δ. Ροντογιάννη, Α. Καρακατσάνη, Σ.Α. Παπίρης Εικόνες στην Πνευμονολογία Αποφολιδωτική Διάμεση Πνευμονία Π. Ντόλιος, Θ. Καραμπιτσάκος, Δ. Μπούρος Μονήρης όζος πνεύμονα οφειλόμενος σε πνευμονική αρτηριοφλεβώδη δυσπλασία Ε. Χαΐνη, Η. Παπανικολάου, Ε. Περούλη, Θ. Δημητρίου, Κ. Παγκράτης ΠΝΕΥΜΩN Τόμος 27, Τεύχος 4 Οκτώβριος - Δεκέμβριος 2014

5 ΠΝΕΥΜΩΝ ΤΡΙΜΗΝΗ ΙΑΤΡΙΚΗ ΕΚΔΟΣΗ ΕΛΛΗΝΙΚΗ ΕΛΛΗΝΙΚΗ ΒΡΟΓΧΟΛΟΓΙΚΗ ΕΤΑΙΡΕΙΑ ΠΝΕΥΜΟNOΛΟΓΙΚΗ ΕΤΑΙΡΕΙΑ GREEK BRONCHOLOGIC HELLENIC THORACIC SOCIETYPNEUMON SOCIETY QUARTERLY MEDICAL JOURNAL Editorials Contents Therapeutic protocol for idiopathic pulmonary fibrosis D. Bouros, E.D. Manali, S.A. Papiris, K.M. Antoniou Obesity and pneumonia. A complex relationship P. Steiropoulos, D. Bouros Management of Pulmonary Embolism. The New European Guidelines S. Konstantinides, G. Chalikias The asthma COPD overlap syndrome: ACOS, CAOS or CHAOS? S. Loukides, P. Bakakos, K. Kostikas Review A review investigating the flutter s effects in people with bronchiectasis Flutter s effect in pulmonary function and sputum clearance in bronchiectasis M.-E. Kloni, A. Klonis, K. Benidis Original Paper Attitudes, knowledge, and practices of hospital employees on tuberculosis. Α structured questionnaire survey A. Charisis, A. Tatsioni, A. Gogali, A. Efthymiou, G. Daskalopoulos, S.H. Constantopoulos, A.K. Konstantinidis Case Reports Allergic Bronchopulmonary Aspergillosis due to Aspergillus niger Report of two cases in Greece and review of the literature E.D. Manali, C. Triantafillidou, E.-D. Ioannidou, P. Lyberopoulos, A. Karakatsani, M. Giannaki, L. Kolilekas, K. Kagouridis, S.A. Papiris Usual interstitial pneumonia in a patient with celiac disease and polyglandular syndrome IIIA L. Kolilekas, E.D. Manali, M. Peppa, T. Chamogeorgakis, A. Papadopoulou, C. Triantafillidou, K. Kagouridis, D. Rontogianni, A. Karakatsani, S.A. Papiris Images in Pneumonology Desquamative Interstitial Pneumonia P. Ntolios, T. Karampitsakos, D. Bouros Solitary pulmonary nodule due to pulmonary arteriovenous malformation E. Haini, I. Papanikolaou, E. Perouli, T. Dimitriou, K. Pagratis PNEUMON Vol. 27, No 4 October - December 2014

6 Άρθρο Σύνταξης Θεραπευτικό πρωτόκολλο για την ιδιοπαθή πνευμονική ίνωση Δημοσθένης Μπούρος 1, Ευφροσύνη Δ. Μάναλη 2, Σπύρος Α. Παπίρης 2, Κατερίνα Μ. Αντωνίου 3 1 Α Πνευμονολογική Κλινική, Νοσοκομείο Νοσημάτων Θώρακος Αθηνών, Ιατρική Σχολή Αθηνών, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών 2 Β Πνευμονολογική Κλινική, Γενικό Νοσοκομείο Αθηνών «Αττικόν», Ιατρική Σχολή Αθηνών, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών 3 Πνευμονολογική Κλινική, Πανεπιστημιακό Νοσοκομείο Ηρακλείου, Τμήμα Ιατρικής, Πανεπιστήμιο Κρήτης Λέξεις κλειδιά - Ιδιοπαθής Πνευμονική Ίνωση - Θεραπεία - Πιρφενιδόνη - NIntedanib - Θεραπευτικά πρωτόκολλα Αλληλογραφία Δημοσθένης Μπούρος Πανεπιστημιακή Κλινική ΝΝΘΑ «Σωτηρία» Μεσογείων 152, Αθήνα ΤΚ debouros@med.uoa.gr, debouros@gmail.com Η Ιδιοπαθής Πνευμονική Ίνωση (ΙΠΙ) είναι μία χρόνια, μη αναστρέψιμη, προοδευτικά εξελισσόμενη και τελικά θανατηφόρα ινωτική πνευμονική νόσος αγνώστου αιτιολογίας, με διάμεση επιβίωση που εκτιμάται στα 3 έτη μετά τη διάγνωση 1,2. Τα ποσοστά 5ετούς επιβίωσης των ασθενών με ΙΠΙ αναφέρονται κοντά στο 30%, ποσοστά σαφώς χειρότερα από συνήθεις νεοπλασίες όπως του μαστού ή του προστάτη και παρόμοια με αυτά του καρκίνου του πνεύμονα 3. Η ανάγκη διαχείρισης και θεραπευτικής αντιμετώπισης των ασθενών αυτών είναι επιτακτική και επείγουσα λόγω της υψηλής θνησιμότητας της νόσου. Η μόνη μέχρι σήμερα θεραπευτική προσέγγιση που αύξανε την επιβίωση ήταν η μεταμόσχευση πνεύμονα 1,2. Το θεραπευτικό πρωτόκολλο που περιλάμβανε τον συνδυασμό τριπλής θεραπείας με κορτικοειδή, ακετυλ-κυστεΐνη (NAC) και αζαθειοπρίνη έχει κριθεί ιδιαίτερα επιβλαβές για τους ασθενείς με ΙΠΙ, καθώς η interim ανάλυση της μελέτης Panther ανέδειξε αυξημένη πιθανότητα θανάτου, νοσηλείας, παροξύνσεων και άλλων μειζόνων επιπλοκών της νόσου στην ομάδα της τριπλής θεραπείας σε σχέση με την ομάδα με το εικονικό φάρμακο 4. Σημειώνεται ότι με βάση τη μελέτη αυτή η τριπλή θεραπεία δεν συνιστάται ήδη σε χώρες της Ευρώπης, όπως η Γαλλία, Γερμανία, Ολλανδία, Αυστρία, Σουηδία, Ηνωμένο Βασίλειο, Δανία και Ιρλανδία. Αντίθετα από το 2011 έχει εγκριθεί από τον ΕΜΑ (European Medical Agency) η πιρφενιδόνη (Esbriet) ως η μοναδική, μέχρι στιγμής, θεραπεία για την ΙΠΙ. Τον Οκτώβριο του 2014 η πιρφενιδόνη (Esbriet) πήρε έγκριση κυκλοφορίας και στις ΗΠΑ (FDA approval). Στην Ελλάδα το Esbriet χαρακτηρίζεται «ορφανό» φάρμακο, εμπίπτει στις διατάξεις της 12 2 του Ν.3816/2010, και ανήκει στην κατηγορία Β της Υ.Α.28822/ Συγκεκριμένα η πιρφενιδόνη έχει λάβει άδεια κυκλοφορίας για τη θεραπεία της ΙΠΙ τόσο από τον EMA [Ένδειξη: ήπιας/ μέτριας βαρύτητας ΙΠΙ, δηλαδή μέγιστη ζωτική χωρητικότητα FVC 50% pred και διαχυτική ικανότητα του μονοξειδίου του άνθρακα 35% pred] όσο και από τον FDA [Ένδειξη: ΙΠΙ ανεξαρτήτως βαρύτητας]. Πρόκειται για ένα φάρμακο με αντι-ινωτική, αντιφλεγμονώδη και αντιοξειδωτική δράση που επιβραδύνει την εξέλιξη της νόσου. Οι σχετικές μελέτες (CAPACITY και ASCEND) έδειξαν ένα ασφαλές προφίλ με πιο συχνές ανεπιθύμητες ενέργειες τις γαστρεντερικές διαταραχές, τη φωτοευαισθησία και τις διαταραχές της ηπατικής βιοχημείας. Η συγκεντρωτική ανάλυση των αποτελεσμάτων των ως άνω μελετών έδειξε

7 286 ΠΝΕΥΜΩΝ Τεύχος 4ο, Τόμος 27ος, Οκτώβριος - Δεκέμβριος 2014 στατιστικά σημαντική μείωση της θνητότητας από κάθε αιτία κατά 48% (p=0.01) και στατιστικά σημαντική μείωση της θνησιμότητας από ΙΠΙ κατά 68% (p=0.006) σε σύγκριση με αυτούς που έλαβαν εικονικό φάρμακο 5-7. Στις 15 Οκτωβρίου 2014 έλαβε έγκριση από τον FDA και το nintedanib για τη θεραπεία της ΙΠΙ ασχέτως βαρύτητας. Πρόκειται για τριπλό αναστολέα των τυροσινικών κινασών. Η έγκριση από τον FDA στηρίχθηκε στα αποτελέσματα δύο μελετών φάσης ΙΙΙ (IMPULSIS-1, IMPULSIS-2) 8 που έδειξαν, στην πρώτη ότι η ετήσια μείωση της FVC ήταν 114,7 ml στην ομάδα του nintedanib, ενώ στην ομάδα του placebo ήταν 239,9 ml (διαφορά, ml; 95% CI, 77.7 to 172.8; p<0.001), ενώ στη δεύτερη μελέτη ήταν ml και ml αντίστοιχα (διαφορά, 93.7 ml per year; 95% CI, 44.8 to 142.7; p<0.001). Μόνο στην IMPULSIS II βρέθηκε σημαντική διαφορά όσον αφορά τον χρόνο εμφάνισης της πρώτης οξείας παρόξυνσης της νόσου (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; p = 0.005). Υπό το φως των παραπάνω αποτελεσμάτων και επιστημονικών δεδομένων κρίνεται αναγκαία η αναθεώρηση του θεραπευτικού πρωτοκόλλου για την ΙΠΙ που ισχύει μέχρι σήμερα ως εξής: Σε ασθενείς με ήπια και μέτρια ΙΠΙ (FVC 50% pred και DL CO 35% pred) κρίνεται σκόπιμη η έναρξη αγωγής με πιρφενιδόνη, επί απουσίας αντενδείξεων. Η εφαρμογή αυτής της θεραπείας πρέπει να γίνεται από ιατρό πνευμονολόγο εξειδικευμένο στην αντιμετώπιση ασθενών με ΙΠΙ και απαιτεί συστηματική παρακολούθηση της κλινικής ανοχής και αποτελεσματικότητας του φαρμάκου. Πρέπει να γίνεται σύσταση για την ανάγκη αποφυγής κατά έκθεσης στον ήλιο, ενώ δεν θα πρέπει να χορηγείται σε ασθενείς που λαμβάνουν ταυτόχρονα φλουβοξαμίνη, καθώς και σε ασθενείς με σοβαρή ηπατική και νεφρική δυσλειτουργία. Ενημέρωση του ασθενούς για δυνατότητα πρώιμης πρόσβασης στο nintedanib, μέσω ειδικού προγράμματος, και μέχρι της αναμενόμενης έγκρισης από τον ΕΜΑ. Συνιστάται ακόμα: η διάγνωση και κατάλληλη αντιμετώπιση των συννοσηροτήτων (π.χ. γαστρο-οισοφαγική παλινδρόμηση, σύνδρομο άπνοιας στον ύπνο, κατάθλιψη, καρδιαγγειακή νόσος, νεοπλάσματα) Η χρόνια οξυγονοθεραπεία σε ασθενείς με χρόνια αναπνευστική ανεπάρκεια Η πνευμονική αποκατάσταση επί των κατάλληλων ενδείξεων Η προληπτικός εμβολιασμός έναντι της γρίπης και του πνευμονιοκόκκου Ο προμεταμοσχευτικός έλεγχος και η ένταξη σε λίστα για μεταμόσχευση πνευμόνων επί των κατάλληλων ενδείξεων Η ενημέρωση των ασθενών και η δυνατότητα ένταξης σε κλινικές δοκιμές για νέα θεραπευτικά σχήματα (φάρμακα, κυτταρική θεραπεία-βλαστοκύτταρα). Επισημαίνεται η ανάγκη ακριβούς διεπιστημονικής διάγνωσης και παρακολούθησης από ομάδα ειδικών (multidisciplinary approach) σε κέντρα αναφοράς, με την έννοια που προτείνεται γενικά για όλα τα σπάνια νοσήματα, όπως είναι η ιδιοπαθής πνευμονική ίνωση. Η ομάδα πρέπει να αποτελείται από έμπειρο ειδικό πνευμονολόγο, καθώς και ειδικό ακτινολόγο και παθολογοανατόμο θώρακος, προς αποφυγήν λανθασμένων διαγνώσεων, βλαπτικών θεραπειών και οικονομικής σπατάλης 9. Βιβλιογραφία Βλέπε αγγλικό κείμενο.

8 Editorial Therapeutic protocol for idiopathic pulmonary fibrosis Demosthenes Bouros 1, Effrosyni D. Manali 2, Spyros A. Papiris 2, Katerina M. Antoniou st Department of Pneumonology, Medical School, National and Kapodistrian University of Athens, Greece 2 2 nd Department of Pneumonology, Medical School, National and Kapodistrian University of Athens, Greece 3 Department of Pneumonology, Medical School, University of Crete, Heraklion, Greece Key words - Idiopathic Pulmonary Fibrosis - Pirfenidone - Nintedanib - Treatment Correspondence to: Prof. Demosthenes Bouros MD, PhD, FERS, FCCP Hospital for Diseases of the Chest SOTIRIA, Messogion 152, Athens 11527, Greece debouros@med.uoa.gr, debouros@gmail.com Idiopathic pulmonary fibrosis (IPF) is a chronic irreversibly progressive fibrosing lung disease of unknown etiology leading to death all patients affected with a reported median survival of 3 years post diagnosis 1,2. Five year survival of IPF patients is estimated at 30%, much worse than that of many common neoplasms such as breast and prostate cancer and similar to that of lung cancer 3. The need for appropriate management and treatment of IPF patients appears imperative and urgent due to the high mortality rate of the disease. Up to now the only therapeutic approach proved to increase survival was lung transplantation 1,2. The therapeutic strategy with triple combination with steroids, azathioprine and n-acetyl cysteine proved harmful for the treatment of IPF patients as shown by the interim analysis of the PANTHER trial that demonstrated significant increase of the risk of death, hospitalizations, exacerbations and other major complications at the treated group compared to the placebo arm of the study 4. Based on the above mentioned data, triple therapy is not recommended anymore in many European countries, such as France, Germany, the Netherlands, Austria, Sweden, the United Kingdom, Denmark and Ireland. On the other hand, since 2011 the European Medical Agency (EMA) has approved of pirfenidone (Esbriet) as the only up to now treatment for the management of IPF patients. In October 2014, pirfenidone (Esbriet) obtained official authorization for use in IPF patients by FDA approval in the United States of America as well. In Greece Esbriet is characterized as an orphan drug coming under the provisions of paragraph 12 2 of the law Ν.3816/2010 and belongs to the category B of the Ministry Decision Υ.Α.28822/ More precisely, pirfenidone has obtained circulation authorization for the treatment of IPF both from EMA [indication: mild/moderate IPF, that is Forced Vital Capacity (FVC) 50% predicted and Diffusing capacity of the lung for carbon monoxide (DLCO SB) 35% predicted] and by the FDA (IPF independently of severity status, that is for mild/moderate and severe disease). Pirfenidone is a drug with anti-fibrotic, anti-inflammatory and antioxidative properties proven to slow down the progression of the disease. The main phase III trials for pirfenidone (CAPACITY and ASCEND) demonstrated that the drug has a safe profile with the most common side effects related to gastrointestinal tract complications, photosensitivity and liver

9 288 PNEUMON Number 4, Vol. 27, October - December 2014 enzyme disturbances. The pooled analysis of the results of the above mentioned studies showed a statistically significant 48% decrease of all-cause mortality (p=0.01) and a statistically significant 68% decrease of IPF-related mortality (p=0.006) for the treated patients in comparison with the placebo arm of the study 5-7. In October 15 th, 2014 FDA authorized the use of another agent: nintedanib, for IPF treatment independently of the disease severity status. Nintedanib is a triple tyrosine kinase inhibitor. Approval was based on the results of two phase III trials (IMPULSIS-1, IMPULSIS-2) 8, the first showing that the adjusted annual rate of change in FVC was ml with nintedanib versus ml with placebo (difference, ml; 95 %CI, 77.7 to 172.8; p<0.001) and the second showing that the adjusted annual rate of change in FVC was ml with nintedanib versus ml with placebo (difference, 93.7ml; 95% CI, 44.8 to 142.7; p<0.001). In IMPULSIS -2 only there was a significant benefit with nintedanib versus placebo in the time to the first exacerbation (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; p=0.005). Under the light of the above mentioned data and scientific evidence, the review of the therapeutic protocol for IPF in Greece is considered mandatory as follows: IPF patients with mild and moderate disease (FVC 50% pred and DL CO 35% pred) should initiate treatment with pirfenidone unless contraindicated. The application of the therapeutic treatment should be undertaken by a pulmonary medicine physician specialized in the management of IPF patients and demands the systematic follow-up of the patients for issues of drug tolerance and effectiveness. Patients should be advised to avoid sun exposure and the drug should not be administered to patients already taking fluvoxamine as well to patients with significant hepatic and renal function disturbances. Patients should be informed about the possibility of having access to early treatment access with nintedanib before its awaited EMA approval, through the application of a specific program. It is furthermore recommended that: IPF co-morbidities such as gastro-eosophageal reflux, obstructive sleep apnea syndrome, depression, cardiovascular disease, neoplastic disease, should be properly diagnosed and adequately treated Patients with chronic respiratory failure should receive long term oxygen therapy as indicated Pulmonary rehabilitation should be applied as indicated IPF patients should systematically undergo prophylactic vaccination against influenza virus and pneumococcal disease IPF patients should be evaluated for lung transplantation and prescribed in lung transplant lists as indicated IPF patients should be informed about the possibility of participating in clinical trials for new therapeutic options (new drugs under investigation, stem cell therapy) It is of major importance to note that patients with IPF should be managed and followed-up by a specialized team of physicians through the multidisciplinary approach in referral centers, just like it is the case for every rare disease like IPF is. This team should include an experienced specialized pulmonary medicine doctor as well as a specialized thoracic radiologist and pathologist, in order to diminish as far as possible the possibility of wrong diagnosis, harmful treatments and inappropriate economic waste 9. REFERENCES 1. Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183: Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013;188: Vancheri C, Failla M, Crimi N, et al. Idiopathic pulmonary fibrosis: a disease with similarities and links to cancer biology. Eur Respir J 2010; 35: Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ; Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 2012; 366: Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; 377: Bouros D. Pirfenidone for idiopathic pulmonary fibrosis. Lancet 2011; 377: King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: Bouros D. Idiopathic pulmonary fibrosis: the dawn of a new era. PNEUMON 2014; 27:115-9.

10 Άρθρο Σύνταξης Παχυσαρκία και πνευμονία Μια περίπλοκη σχέση Πασχάλης Στειρόπουλος, MD, PhD, FCCP; Δημοσθένης Μπούρος MD, PhD, FERS, FCCP Πνευμονολογική Κλινική, Ιατρική Σχολή, Δημοκρίτειο Πανεπιστήμιο Θράκης, Αλεξανδρούπολη Λέξεις κλειδιά: - Δείκτης μάζας σώματος - Παχυσαρκία - Πνευμονία Αλληλογραφία: Πασχάλης Στειρόπουλος, MD, PhD, FCCP Πνευμονολογική Κλινική ΔΠΘ Πανεπιστημιακό Γενικό Νοσοκομείο Έβρου Δραγάνα 68100, Αλεξανδρούπολη Τηλ.: pstirop@med.duth.gr Ο επιπολασμός της παχυσαρκίας έχει αυξηθεί σημαντικά κατά τις δύο τελευταίες δεκαετίες 1. Η διάγνωση της παχυσαρκίας βασίζεται στο δείκτη μάζας σώματος (body mass index, ΒΜΙ), ο οποίος υπολογίζεται ως το βάρος σε κιλά διαιρούμενο με το ύψος σε μέτρα στο τετράγωνο (kg/m 2 ). Ως υπέρβαροι θεωρούνται όσοι έχουν BMI 25 kg/m 2 και παχύσαρκοι αυτοί με ΒΜΙ 30 kg/m 2. Η πνευμονία αποτελεί σημαντική αιτία νοσηρότητας και θνησιμότητας σε ενήλικες στις ανεπτυγμένες χώρες 3. Οι διάφοροι παράγοντες κινδύνου για πνευμονία που έχουν αναγνωριστεί είναι η ηλικία >65 ετών 3-5, το κάπνισμα 4, ο αλκοολισμός 5, η ανοσοκαταστολή 5, και χρόνια νοσήματα όπως η ΧΑΠ 6, τα καρδιαγγειακά νοσήματα, ΑΕΕ, η χρόνια ηπατική ή νεφρική νόσος, ο σακχαρώδης διαβήτης και η άνοια 7. Η παχυσαρκία μπορεί επίσης να αυξήσει τον κίνδυνο για πνευμονία για διάφορους λόγους. Η παχυσαρκία έχει συνδεθεί με βλάβες στους μηχανισμούς άμυνας του ξενιστή 8-11, οι οποίες φάνηκε ότι είναι αναστρέψιμες μετά την απώλεια βάρους 11. Επιπλέον, η παχυσαρκία έχει ακόμη αρνητικές επιπτώσεις στο αναπνευστικό σύστημα. Η πρωϊμότερη και συχνότερη διαταραχή της αναπνευστικής λειτουργίας είναι η μείωση του εκπνευστικού εφεδρικού όγκου (expiratory reserve volume, ERV) και της λειτουργικής υπολειπόμενης χωρητικότητας (functional residual capacity, FRC) ενώ η ζωτική χωρητικότητα και η ολική πνευμονική χωρητικότητα είναι μειωμένες σε μικρότερο βαθμό. Για τις διαταραχές αυτές φαίνεται ότι ευθύνονται οι μεταβολές των μηχανικών ιδιοτήτων του θωρακικού τοιχώματος 12. Επιπλέον, η παχυσαρκία προκαλεί αύξηση του έργου της αναπνοής λόγω της μειωμένης διατασιμότητας του αναπνευστικού συστήματος και της αύξησης των αντιστάσεων των αεραγωγών 12. Τέλος, η παχυσαρκία συνδέεται με τον κίνδυνο ανάπτυξης χρόνιων νοσημάτων, όπως ο σακχαρώδης διαβήτης ή καρδιαγγειακά νοσήματα, καταστάσεις οι οποίες συμβάλλουν ανεξάρτητα στην αύξηση του κινδύνου για πνευμονία 13,14. Ωστόσο, τα ευρήματα πρόσφατων μελετών για τη συσχέτιση μεταξύ παχυσαρκίας και τον κίνδυνο ανάπτυξης πνευμονίας ήταν ασαφή 15. Πολλές μελέτες έδειξαν ότι η αύξηση του σωματικού βάρους αυξάνει σημαντικά τον κίνδυνο νοσηλείας με πνευμονία 4,16-19, ενώ άλλες μελέτες δεν ανέδειξαν αυτή τη συσχέτιση Υπάρχουν ακόμη μελέτες που ανέφεραν ότι τα παχύσαρκα άτομα με πνευμονία είχαν χαμηλότερη θνησιμότητα σε σύγκριση

11 290 ΠΝΕΥΜΩΝ Τεύχος 4ο, Τόμος 27ος, Οκτώβριος - Δεκέμβριος 2014 με τα άτομα με πνευμονία και κανονικό βάρος (obesity survival paradox). Συμπερασματικά, τα παχύσαρκα άτομα φαίνεται να διατρέχουν μεγαλύτερο κίνδυνο για πνευμονία. Πρόσθετες προοπτικές μελέτες είναι απαραίτητες ώστε να εξαχθούν ασφαλή συμπεράσματα. ΒΙΒΛΙΟΓΡΑΦΙΑ Βλέπε αγγλικό κείμενο

12 Editorial Obesity and pneumonia A complex relationship Paschalis Steiropoulos, MD, PhD, FCCP; Demosthenes Bouros, MD, PhD, FERS, FCCP Department of Pneumonology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece Key words: - Body mass index - Obesity - Pneumonia Correspondence: Paschalis Steiropoulos, MD, PhD, FCCP Medical School, Democritus University of Thrace Department of Pneumonology, University Hospital of Evros Alexandroupolis, Greece Tel.: pstirop@med.duth.gr In the last two decades, the prevalence of obesity has dramatically increased 1. The diagnosis of obesity is based on body mass index (BMI), calculated as weight in kilograms divided by height in meters squared (kg/ m 2 ). A patient with a BMI 25 kg/m 2 is defined as overweight, and a BMI 30 kg/m 2 as obese. Pneumonia is one of the most common infectious diseases. It has been ranked as the third leading cause of death worldwide 2 and is one of the most common infectious disease in Western societies 3. Several risk factors for pneumonia are recognized, including age >65 years 3-5, smoking 4, alcoholism 5, immunosuppressive conditions 5, and chronic conditions such as COPD, 6 cardiovascular disease, cerebrovascular disease, chronic liver or renal disease, diabetes mellitus and dementia 7. Obesity may increase the risk of pneumonia due to several reasons. First of all, obesity has been associated with impairments in host defense mechanisms 8-11, reversible after weight reduction 11. Additionally, obesity has multiple adverse effects on the respiratory system. Increasing BMI is usually associated with a reduction in forced vital capacity, total lung capacity, functional residual capacity, and expiratory reserve volume 12. In addition, obesity can increase the work of breathing due to reduced chest wall compliance and increased respiratory system resistance 12. Moreover, obesity is also associated with the risk of major chronic conditions such as diabetes, cardiovascular disease and liver diseases, and those diseases may cause an elevated risk of pneumonia 13,14. However, the findings of recent studies on the relationship between excessive weight and risk of pneumonia were inconclusive 15. While some studies indicated that excessive weight gain significantly increased risk of hospitalization with pneumonia 4,16-19, other studies illustrated a reversed relationship In addition, other studies reported that obese subjects with pneumonia had lower mortality compared to normal weight subjects (obesity survival paradox). Οbese individuals maybe at higher risk for pneumonia. Nevertheless, available data are sparse and inconsistent. Additional prospective studies with adjustment for confounding factors are warranted before a safe conclusion can be drawn.

13 292 PNEUMON Number 4, Vol. 27, October - December 2014 REFERENCES 1. Baskin ML, Ard J, Franklin F, Allison DB. Prevalence of obesity in the United States. Obes Rev 2005; 6: Lopez AD, Murrey CC. The global burden of disease. Nat Med 1998; 4: Welte T, Torres A, Nathwani D. Clinical and economic burden of community-acquired pneumonia among adults in Europe. Thorax 2012; 67: Baik I, Curhan GC, Rimm EB, et al. A prospective study of age and lifestyle factors in relation to community-acquired pneumonia in US men and women. Arch Intern Med 2000; 160: Koivalu I, Sten M, Makela PH. Risk factors for pneumonia in the elderly. Am J Med 1994; 96: Mannino DM, Davis KJ, Kiri VA. Chronic obstructive pulmonary disease and hospitalizations for pneumonia in a US cohort. Respir Med 2009; 103: Polverino E, Torres Marti A. Community-acquired pneumonia. Minerva Anestesiol 2011; 77: Kopelman PG. Obesity as a medical problem. Nature 2000; 404: Stallone DD. The influence of obesity and its treatment on the immune system. Nutr Rev 1994; 52(2 Pt 1): Lamas O, Marti A, Martinez JA. Obesity and immunocompetence. Eur J Clin Nutr 2002;56(Suppl 3):S Τanaka S, Inoue S, Isoda F, et al. Impaired immunity in obesity: suppressed but reversible lymphocyte responsiveness. Int J Obes Relat Metab Disord 1993; 17: Koutsoukou A. Respiratory function abnormalities in morbidly obese subjects and the risk of low lung volume injury. Pneumon 2007; 20: Formiguera X, Canton A. Obesity: epidemiology and clinical aspects. Best Pract Res Clin Gastroenterol 2004; 18: Falagas ME, Kompoti M. Obesity and infection. Lancet Infect Dis 2006; 6: Phung DT, Wang Z, Rutherford S, Huang C, Chu C. Body mass index and risk of pneumonia: a systematic review and metaanalysis. Obes Rev. 2013;14: Kornum JB, Norgaard M, Dethlefsen C et al. Obesity and risk of subsequent hospitalization with pneumonia. Eur Respir J 2010; 36: LaCroix AZ, Lipson S, Miles TP, White L. Prosepective study of pneumonia hospitalizations and mortality of U.S. older people: the role of chronic conditions, health behaviors, and nutritional status. Public Health Rep 1989; 104: Lange P, Vestbo J, Nyboe J. Risk factors for death and hospitalization from pneumonia. A prospective study of a general population. Eur Respir J 1995; 8: Almirall J, Bolibar I, Balanzo X, Gonzalez CA. Risk factors for community-acquired pneumonia in adults: a population-based case-control study. Eur Respir J 1999; 13: Inoue Y, Koizumi A,Wada Y, et al. Risk and protective factors related to mortality from pneumonia among middle-aged and elderly community residents: the JACC study. J Epidemiol 2007; 17: Blumentals WA, Nevitt A, Peng MM, Toovey S. Body mass index and the incidence of influenza-associated pneumonia in a UK primary care cohort. Influenza Other Respi Viruses 2011; 6: Almirall J, Bolivar I, Serra-Prat M, et al. New evidence of risk factors for community-acquired pneumonia: a populationbased study. Eur Respir J 2008; 31: Schnoor H, Klante T, Beckmann M, et al. Risk factors for community-acquired pneumonia in German adults: the impact of children in the households. Epidemiol Infect 2007; 135: King P, Mortensen EM, Bollinger M, et al. Impact of obesity on outcomes for patients hospitalised with pneumonia. Eur Respir J 2013, 41: Kahlon S, Eurich DT, Padwal RS, et al. Obesity and outcomes in patients hospitalized with pneumonia. Clin Microbiol Infect 2013, 19: Singanayagam A, Singanayagam A, Chalmers JD. Obesity is associated with improved survival in community-acquired pneumonia. Eur Respir J 2013; 42: Corrales-Medina VF, Valayam J, Serpa JA, Rueda AM, Musher DM. The obesity paradox in community-acquired bacterial pneumonia. Int J Infect Dis 2011; 15:e Nie W, Zhang Y, Jee SH, Jung KJ, Li B, Xiu Q. Obesity survival paradox in pneumonia: a meta-analysis. BMC Med 2014;12:61.

14 Άρθρο Σύνταξης Αντιμετώπιση Πνευμονικής Εμβολής Νέες Ευρωπαϊκές Κατευθυντήριες Οδηγίες Σταύρος Κωνσταντινίδης 1,2 Γεώργιος Χαλικιάs 1 1 Καρδιολογικό Τμήμα, Δημοκρίτειο Πανεπιστήμιο Θράκης 2 Κέντρο Θρόμβωσης και Αιμόστασης, University Medical Center Mainz, Γερμανία Λέξεις κλειδιά: - Κατευθυντήριες Οδηγίες - Πνευμονική εμβολή - Φλεβική θρόμβωση - Χρόνια θρομβοεμβολική πνευμονική υπέρταση - Διάγνωση - Anticoagulation Αλληλογραφία: Σταύρος Κωνσταντινίδης, MD, FESC Καρδιολογικό Τμήμα, Πανεπιστημιακό Γενικό Νοσοκομείο Δημοκρίτειο Πανεπιστήμιο Θράκης Αλεξανδρούπολη skonst@med.duth.gr Περίληψη. Η οξεία πνευμονική εμβολή (ΠΕ), το τρίτο συχνότερο καρδιαγγειακό σύνδρομο μετά το έμφραγμα του μυοκαρδίου και το αγγειακό εγκεφαλικό επεισόδιο, αποτελεί όχι μόνο απειλή για τη ζωή μεγάλου αριθμού ασθενών αλλά και σημαντικό οικονομικό βάρος για τα συστήματα υγείας σε όλον το κόσμο. Πρόσφατα δημοσιευθέντα δεδομένα επέφεραν σημαντική πρόοδο στη διαχείριση της νόσου και δημιούργησαν μία σταθερή επιστημονική βάση για τις συστάσεις των Κατευθυντηρίων Οδηγιών της Ευρωπαϊκής Καρδιολογικής Εταιρείας που ενημερώθηκαν το Η διαστρωμάτωση κινδύνου των ασθενών με ΠΕ μη υψηλού κινδύνου (χωρίς σοκ ή παρατεταμένη υπόταση) γίνεται με βάση κλινικούς προγνωστικούς κανόνες (scores), ακολουθούμενους από εκτίμηση της δεξιάς καρδιακής λειτουργίας. Στη θεραπεία της ΠΕ, πρόσφατες μεγάλες τυχαιοποιημένες μελέτες έδειξαν ότι τα νέα, μη βιταμινοεξαρτώμενα από του στόματος αντιπηκτικά φάρμακα είναι τουλάχιστον τόσο αποτελεσματικά και πιθανόν ασφαλέστερα (τουλάχιστον ως προς την πρόκληση μειζόνων αιμορραγιών) από ότι η ως τώρα καθιερωμένη αντιπηκτική αγωγή. Στην ΠΕ «υψηλού ενδιαμέσου κινδύνου», οριζόμενη με βάση απεικονιστικές μεθόδους και εργαστηριακούς καρδιακούς βιοδείκτες, ο αιμορραγικός κίνδυνος μίας ενδοφλέβιας θρομβολυτικής αγωγής σε πλήρη δόση φαίνεται να είναι υπερβολικά υψηλός για να δικαιολογήσει τη χρήση της, εκτός εάν εμφανιστούν σημεία επικείμενης αιμοδυναμικής κατάρριψης. Οι νέες Ευρωπαϊκές Κατευθυντήριες Οδηγίες αποτελούν, στο σύνολό τους, μία ολοκληρωμένη προσέγγιση στη νόσο της ΠΕ, τη θεραπεία των οξειών επιπλοκών της, τη διαχείρισή της σε ειδικούς πληθυσμούς ασθενών και τα χρόνια επακόλουθά της όπως η χρόνια θρομβοεμβολική πνευμονική υπέρταση. Ευελπιστούμε ότι θα αποτελέσουν έναν εμπεριστατωμένο και ταυτόχρονα πρακτικό οδηγό για τους κλινικούς γιατρούς κάθε ειδικότητας που αντιμετωπίζουν στην καθημερινή τους πράξη ασθενείς με οξεία ΠΕ. Πνεύμων 2014, 27(4):293. ΒΙΒΛΙΟΓΡΑΦΙΑ Βλέπε αγγλικό κείμενο

15 Editorial Management of Pulmonary Embolism The New European Guidelines Stavros Konstantinides 1,2, George Chalikias 1 1 Department of Cardiology, Democritus University of Thrace, Greece 2 Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Germany Key words: - Guidelines - Pulmonary embolism - Venous thrombosis - Chronic thromboembolic pulmonary hypertension - Diagnosis - Anticoagulation SUMMARY. Acute pulmonary embolism (PE) is the third most frequent acute cardiovascular syndrome, threatening the life of many patients worldwide and imposing a substantial economical burden on health systems. Recent evidence has led to significant progress in the management of the disease and provided a solid basis for the recommendations included in the 2014 update of the European Society of Cardiology Guidelines 2014 (endorsed by the European Respiratory Society). Advanced risk stratification of normotensive patients with non-high-risk PE places an emphasis on clinical prediction rules and assessment of right ventricular function. In PE treatment, recently completed randomised trials using new oral (non-vitamin K-dependent) anticoagulants showed that these agents are at least as effective and probably cause less major bleeding than standard regimens. For intermediate-high-risk PE defined on the basis of imaging tests and laboratory biomarkers, the bleeding risks of full-dose thrombolytic treatment appear too high to justify its use unless clinical signs of haemodynamic decompensation appear. Overall, the new European Guidelines represent a comprehensive, multidisciplinary approach to PE, its acute complications, its management in specific patient populations, and its chronic sequelae such as chronic thromboembolic pulmonary hypertension. They provide a thorough and evidence-based, and at the same time practical and user-friendly guide to physicians involved in the management of PE. Pneumon 2014, 27(4): Correspondence to: Stavros V. Konstantinides, MD, FESC Department of Cardiology Democritus University of Thrace University General Hospital Alexandroupolis, Greece skonst@med.duth.gr Acute pulmonary embolism (PE), represents a major threat for the health, the well-being and, in severe cases, the life of a large number of patients worldwide. With its acute and long-term complications, it also poses a substantial economical burden on national health systems. In 2014, the results of landmark clinical trials and cohort studies were included in the update of the European Society of Cardiology (ESC) Guidelines on the management of PE 1. In the 2014 ESC Guidelines, which were endorsed by the European Respiratory Society (ERS), several recommendations regarding

16 PNEUMON Number 4, Vol. 27, October - December diagnostic strategies and algorithms were confirmed and extended. In parallel, new data extending our knowledge with regard to optimal risk assessment and risk-adapted patient treatment led to major revisions in the recommendations within these areas, and new sections on the long-term sequelae of PE as well as its management in specific patient populations such as pregnant patients and those with active cancer were added (reviewed in 2 ). The present article summarises and highlights the most relevant new aspects of the 2014 version as compared with the previous European guidelines published in Diagnosis: clinical prediction rules and D-dimer testing Despite the limited sensitivity and specificity of individual symptoms, signs, and common baseline clinical tests, the combination of findings evaluated by clinical judgement or by the use of standardised prediction rules allows us to classify patients with suspected PE into distinct categories of clinical, or pre-test, probability of the disease. Recently, both the Wells and the revised Geneva clinical prediction rule were simplified in order to increase their practicability and adoption into clinical practice 3,4, and the simplified versions were externally validated 5,6. Whichever rule or version is used, the proportion of patients with confirmed PE can be expected to be approximately 10% in the low-probability category, 30% in the intermediate-probability category, and 65% in the high-clinical probability category when using the three-level classification 7. If a two-level classification is used, the proportion of patients with confirmed PE in the PE-unlikely category is around 12% 7. The specificity of a positive D-dimer test in suspected PE decreases steadily with age, to almost 10% in patients >80 years 8. Using age-adjusted cut-offs may improve the performance of D-dimer testing in the elderly. In a recent meta-analysis, age-adjusted cut-off values (age x 10 μg/l above 50 years) allowed increasing specificity from 34 46% while keeping the sensitivity above 97% 9. A multicentre, prospective management study evaluated this age-adjusted cut-off level in a cohort of 3346 patients. Patients with a normal age-adjusted D-dimer value did not undergo imaging tests for PE; instead, they were left untreated and followed over a three-month period. On the basis of D-dimer, using the age-adjusted cut-off (instead of the standard 500 μg/l cut-off) increased the number of patients in whom PE could be excluded from 43 (6.4%; 95% CI %) to 200 (29.7%; 95% CI %), without any additional false-negative findings 10. Subsegmental and incidental pulmonary embolism The clinical significance of isolated subsegmental PE on computed tomographic (CT) pulmonary angiography is controversial. It is likely that a single subsegmental defect does not have the same clinical relevance as multiple, subsegmental thrombi. The positive predictive value is low and inter-observer agreement is poor at this distal level 11. Compression ultrasound of the leg veins may be helpful in this situation, as the exclusion of proximal deep vein thrombosis in a patient with isolated sub-segmental PE would support a decision against anticoagulation treatment; such cases should be managed on an individual basis, taking into account the clinical probability and the bleeding risk. The incidental discovery of clinically unsuspected PE on CT is an increasingly frequent problem, arising in 1 2% of all thoracic CT examinations, most often in patients with cancer, but also among those with paroxysmal atrial fibrillation, or heart failure and history of atrial fibrillation No robust data exist to guide the decision on how to manage unsuspected PE, but most experts agree that patients with cancer and those with clots at the lobar or more proximal level should be treated with anticoagulants. Risk stratification of pulmonary embolism For prediction of early (in-hospital or 30-day) outcome in patients with acute PE, both the PE-related risk and the patient s clinical status and comorbidities should be taken into consideration. Generally, patients presenting without shock or hypotension, i.e. the vast majority of patients with acute PE, are not at high risk of an adverse early outcome. However, further risk stratification should be considered in these patients after the diagnosis of PE has been confirmed, as this may influence the therapeutic strategy (particularly the need for monitoring and rescue thrombolytic therapy) and possibly the duration of hospitalisation. The 2014 PE Guidelines recommend beginning advanced risk assessment of normotensive patients with confirmed PE with a validated clinical prognostic score, preferably the Pulmonary Embolism Severity Index (PESI) 15

17 296 PNEUMON Number 4, Vol. 27, October - December 2014 or its simplified version (spesi) 16, to distinguish between intermediate and low risk (of an adverse early outcome). Approximately one-third of PE patients are at low risk of an early adverse outcome as indicated by a PESI Class I or II, or an spesi of 0. On the other hand, patients in PESI Classes III V have a 30-day mortality rate of up to 24.5% 15, and those with a simplified PESI 1 up to 11% 16. Accordingly, normotensive patients in PESI Class III or higher, or a spesi of 1 or higher, constitute an intermediaterisk group. Within this category, further risk assessment should be considered, encompassing the status of the right ventricle (RV) to detect PE-induced acute pressure overload and dysfunction. Patients who display evidence of both RV dysfunction (by echocardiography or CT angiography) and elevated cardiac biomarker levels in the circulation (particularly a positive cardiac troponin test indicating myocardial injury) should be classified into an intermediate-high risk category. On the other hand, patients in whom the RV is normal on echocardiography or CT angiography, and/or have normal cardiac biomarker levels, belong to an intermediate-low risk group. The therapeutic implications of this classification are displayed in Figure 1 and discussed below. Treatment and secondary prophylaxis with new oral anticoagulants In patients with acute PE, anticoagulation effectively prevents both early death and recurrent symptomatic or fatal VTE. The duration of anticoagulation should cover at least 3 months. Within this period, the standard regimen of acute-phase treatment consists of administering parenteral anticoagulation (unfractionated heparin, low molecular weight heparin, or fondaparinux) over the A/C = anticoagulation; CT = computed tomographic pulmonary angiography; PE = pulmonary embolism; PESI = Pulmonary embolism severity index; RV = right ventricular; spesi = Simplified Pulmonary embolism severity index. Figure 1. Risk-adjusted management strategies in acute PE (adapted from 1 ).

18 PNEUMON Number 4, Vol. 27, October - December first 5 10 days. Parenteral heparin should overlap with the initiation of a vitamin K antagonist. In some cases, extended anticoagulation beyond the first 3 months, or even indefinitely, may be necessary for secondary prevention, after weighing the individual patient s risk of recurrence versus bleeding risk. The results of the trials using the new, non-vitamin K-dependent oral anticoagulants (NOACs) dabigatran 17,18, rivaroxaban 19,20, apixaban 21 or edoxaban 22 in the treatment of VTE indicated, both individually and in a meta-analysis 23, that these agents are non-inferior (in terms of efficacy) and possibly safer (particularly in terms of major bleeding) than the standard heparin/vka regimen. As a result, NOACs are recommended in the 2014 PE Guidelines as an alternative to standard treatment. Currently, rivaroxaban, dabigatran and apixaban are approved for treatment of VTE in the European Union; edoxaban is under regulatory review. Experience with NOACs in clinical practice is accumulating at an increasing pace. Three NOACs, dabigatran 24, rivaroxaban 20, and apixaban 25, have also been evaluated in the extended treatment of patients with VTE. To be included in the extended studies, patients needed to have completed the initial and long-term anticoagulation phase. Taken together, the results of the trials using NOACs in the extended treatment of VTE are in line with those of the studies that tested these agents in the acute-phase treatment and standard duration of anticoagulation after PE or VTE. They indicate that NOACs are both effective (in terms of prevention of symptomatic or fatal recurrence of VTE) and safe (particularly in terms of major bleeding), probably safer than standard VKA regimens. Accordingly, the 2014 PE Guidelines recommend that treatment with a NOAC should be considered as an alternative to the use of a vitamin K antagonist if extended secondary prophylaxis is deemed necessary. major non-intracranial bleeding 26. Accordingly, systemic thrombolysis is not routinely recommended as primary treatment for patients with intermediate-high-risk PE; instead, these patients should be monitored for approximately hours and rescure thrombolysis should be considered if clinical signs of haemodynamic decompensation appear. Surgical pulmonary embolectomy or percutaneous catheter-directed treatment may be considered as alternative rescue procedures for patients with intermediate-high-risk PE, in whom haemodynamic decompensation appears imminent and the anticipated bleeding risk under systemic thrombolysis is high 27. Early discharge and home (outpatient) treatment of carefully selected patients Recent multicentre clinical trials investigated the three-month clinical outcome of patients with PE who were discharged early or treated entirely as outpatients. Overall, the proportion of screened patients who were identified as eligible for home treatment varied widely, ranging from 13 to 51% 28. In a meta-analysis of 14 (mostly small) studies, the pooled incidence rates of recurrent VTE, major bleeding and total mortality did not differ significantly between outpatients, patients discharged early, and those treated as inpatients 29. Based on the encouraging available data, low-risk patients in the PESI Class I or II, and probably those with spesi of 0, should be considered for early discharge and outpatient treatment, if this appears feasible based on the patient s anticipated compliance as well as his/her family and social background. Further management trials are necessary to better define the criteria that will permit early discharge and home treatment of low-risk patients with acute PE. Reperfusion treatment for intermediaterisk pulmonary embolism As already mentioned, an echocardiogram or CT scan indicating RV dysfunction in combination with a positive cardiac troponin test classifies a normotensive patient with PE into an intermediate-high-risk group. In a large multicentre investigator-initiated European trial, full-dose systemic thrombolytic therapy effectively prevented potentially life-threatening haemodynamic decompensation or collapse in these patients, but this benefit was counterbalanced by a high risk of haemorrhagic stroke or A new, risk-adapted management algorithm for pulmonary embolism A risk-adapted management algorithm for acute PE, as proposed in the 2014 PE Guidelines, is shown in Figure 1. Chronic thromboembolic pulmonary hypertension Chronic thromboembolic pulmonary hypertension (CTEPH) is a debilitating disease caused by chronic obstruction of major pulmonary arteries. CTEPH is assumed

19 298 PNEUMON Number 4, Vol. 27, October - December 2014 to be a long-term complication of PE, with a reported cumulative incidence of % within the first two years after a symptomatic PE event 30. The 2014 PE Guidelines specify that CTEPH should be ruled out in PE survivors with persistent dyspnoea, but routine screening for CTEPH in asymptomatic survivors of PE is currently not recommended. In all patients with diagnosed CTEPH, the assessment of operability and decisions regarding other treatment strategies should be made by a multidisciplinary team of experts. Lifelong anticoagulation is recommended in all patients with CTEPH, and surgical pulmonary endarterectomy (PEA) should be performed in those patients who are considered operable by a CTEPH team including at least one experienced PEA surgeon. Medical treatment with the recently approved agent riociguat is recommended in symptomatic patients who have been classified as having persistent/recurrent CTEPH after surgical treatment, or those with inoperable disease as judged by an expert CTEPH team (see above). An emerging interventional treatment option for inoperable patients percutaneous balloon pulmonary angioplasty is also mentioned in the updated CTEPH management algorithm but it is not yet formally recommended. Pulmonary embolism in specific patient populations The 2014 PE Guidelines emphasize that suspicion of PE in pregnancy warrants formal diagnostic assessment with validated methods, exactly as suspected in non-pregnant patients. Venous compression ultrasonography may be considered in order to avoid unnecessary irradiation, as a diagnosis of proximal deep vein thrombosis confirms PE. Perfusion scintigraphy, which exposes the mother s breast to lower radiation doses compared to CT angiography, may be deemed to rule out suspected PE in pregnant women with normal chest X-ray. A weight-adjusted dose of low molecular weight heparin (not fondaparinux) is the recommended therapy during pregnancy in patients without shock or hypotension. Importantly, NOACs are contraindicated in pregnant patients. The overall risk of venous thromboembolism in patients with cancer is four times as great as in the general population 31. Although the largest absolute numbers of VTE episodes occur in patients with lung, colon, and prostate cancer, the relative risk for VTE is highest in multiple myeloma, brain, and pancreatic cancer (46-, 20-, and 16-fold increased vs. healthy controls, respectively) 32. Patients receiving chemotherapy have a six-fold increase in the adjusted risk ratio for VTE compared with a healthy population 31. Nevertheless, prophylactic anticoagulation is not routinely recommended during ambulatory anti-cancer chemotherapy, with the exception of thalidomide- or lenalidomide-based regimens in multiple myeloma 33,34. The risk of VTE increases over 90-fold in the first 6 weeks after cancer surgery, compared with that in healthy controls, and is second only to the risk of VTE after hip or knee replacement surgery. For patients with PE and cancer, weight-adjusted subcutaneous low molecular weight heparin should be considered for the first 3 6 months; evidence with new oral anticoagulants is still limited in this early time period. For patients with PE and cancer, extended -oral or parenteral- anticoagulation (beyond the first 3 6 months) should be considered for an indefinite period, or until the cancer is cured. Conclusions Considerable progress in the diagnosis, treatment and secondary prevention of venous thromboembolism could be made in the past few years, and management concepts continue to evolve at a rapid pace. Thanks to the joint efforts of experts nominated by the ESC and the ERS in close collaboration, the new (2014) European Pulmonary Embolism Guidelines represent a contemporary multidisciplinary approach to acute PE. The Guidelines Task Force took every effort to issue impartial, evidencebased recommendations, while at the same time providing a practical guide to physicians being involved in the management of pulmonary embolism. References 1. Konstantinides S, Torbicki A, Agnelli G, et al ESC Guidelines on the diagnosis and management of acute pulmonary embolism: The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)Endorsed by the European Respiratory Society (ERS). Eur Heart J 2014;35: Konstantinides SV, Torbicki A. Management of pulmonary embolism: recent evidence and the new European guidelines. Eur Respir J 2014;44: Gibson NS, Sohne M, Kruip MJ, et al. Further validation and simplification of the Wells clinical decision rule in pulmonary embolism. Thromb Haemost 2008;99: Klok FA, Mos IC, Nijkeuter M, et al. Simplification of the revised Geneva score for assessing clinical probability of pulmonary

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