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1 MRM _def:Layout 1 12/04/10 11:08 Pagina 154 vol. 5 n.2/april 2010: Associazione Scientifica Interdisciplinare per lo Studio delle Malattie Respiratorie volume 5 number 2 april 2010 Multidisciplinary Respiratory Medicine Poste Italiane Spa - Spedizione in Abbonamento Postale - D.L. 353/2003 (convertito in L. 27/02/2004 n. 46) art. 1 comma 1, DCB MILANO Sarioglu N, Alpaydin AO, Coskun AS, Celik P, Ozyurt BC, Yorgancioglu A Relationship between BODE index, quality of life and inflammatory cytokines in COPD patients Correlazione tra indice BODE, qualità di vita e citochine infiammatorie nei pazienti con BPCO Basyigit I, Sahin M, Sahin D, Yildiz F, Boyaci H, Sirvanci S, Ercan F Anti-inflammatory effects of montelukast on smoke-induced lung injury in rats Effetto antinfiammatorio del montelukast sul danno polmonare indotto da fumo nel ratto Magni C, Chellini E, Zanasi A Cough variant asthma and atopic cough Asma variante con tosse e tosse atopica Donner CF (ed.) Conference: "COPD a social disease: inappropriateness and pharmaco-economics. The role of the specialist: present and future", Venice, April 21-22, 2010: long summaries Conferenza: "BPCO una malattia sociale: inappropriatezze ed aspetti farmacoeconomici. Il ruolo dello specialista: presente e futuro", Venezia, aprile 21-22, 2010: riassunti estesi Indexed and Abstracted in: Science Citation Index Expanded (SciSearch ), Journal Citation Reports/Science Edition, and Scopus Elsevier Bibliographic Databases anno 5 - n. 2 - Reg.Trib. Novara n.120 dell 11/11/2005 ISSN X Medicine Respiratory Multidisciplinary

2 MRM _def:Layout 1 08/04/10 15:47 Pagina 77 MULTIDISCIPLINARY RESPIRATORY MEDICINE OFFICIAL SCIENTIFIC JOURNAL OF AIMAR An Italian scientific journal of AIMAR dedicated to the advancement of knowledge in all fields of respiratory medicine. MRM publishes - in Italian and English - original articles, new methodological approaches, reviews, points of view, editorials, states of the art, position papers and congress proceedings. Editors Fernando De Benedetto, Chieti Claudio F. Donner, Borgomanero (NO) Claudio M. Sanguinetti, Roma Managing Editor Gianfranco Sevieri, Viareggio (LU) Editorial Office Manager Stefano Nardini, Vittorio Veneto (TV) Editorial Board Coordinator: Mario Polverino, Cava de Tirreni (SA) Sabina Antoniu, Iasi, Romania Alberto Braghiroli, Veruno (NO) Mauro Carone, Veruno (NO) Lucio Casali, Terni Mario Cazzola, Roma Stefano Centanni, Milano George Cremona, Milano Roberto Dal Negro, Bussolengo (VR) Filippo De Marinis, Roma Francesco Ioli, Veruno (NO) Giovanni Paolo Ligia, Cagliari Rasmi Magadle, Baka El-Garbia, Israel Riccardo Pela, Ascoli Piceno Luca Richeldi, Modena Roberto Torchio, Torino International Advisory Board Isabella Annesi-Maesano, Paris, France Antonio Anzueto, San Antonio, TX, USA Peter J. Barnes, London, UK Panagiotis Behrakis, Athens, Greece Peter M.A. Calverley, Liverpool, UK Richard Casaburi, Los Angeles, CA, USA Bartolome Celli, Boston, MA, USA Ronald Dahl, Aarhus, Denmark Roger Goldstein, Toronto, Canada Peter Howard, Sheffield, UK Günseli Kilinç, Istanbul, Turkey Marc Miravitlles, Barcelona, Spain Stephen I. Rennard, Omaha, NE,USA Nikolaos Siafakas, Heraklion, Crete, Greece Samy Suissa, Montreal, Canada Martin Tobin, Maywood, IL, USA Jadwicha Wedzicha, London, UK Emiel Wouters, Maastricht, The Netherlands Jan Zielinski, Warsaw, Poland Richard ZuWallack, Hartford, CT, USA AIMAR Scientific Committee Coordinator: Luigi Allegra (MI) Allergology and Environmental Medicine: Gennaro D Amato (NA) Cardiac Surgery: Mario Viganò (PV) Cardiology: Nazzareno Galié (BO), Alessandro Palmarini (MI) Endocrinology: Aldo Pinchera (PI) Epidemiology: Fernando Romano (CH) Formation and Quality: Maurizio Capelli (BO), Piera Poletti (PD) Gastroenterology: Gabriele Bianchi Porro (MI), Lucio Capurso (RM) General Medicine: Claudio Cricelli (FI) Geriatrics: Emanuele Tupputi (BA), Stefano M. Zuccaro (RM) Imaging: Alessandro Carriero (NO), Francesco Schiavon (BL) Immunology: Giuseppe Montrucchio (TO) Infectivology: Ercole Concia (VR) Intensive Care: Marco Ranieri (TO) Internal Medicine: Roberto Corinaldesi (BO) Microbiology: Giancarlo Schito (GE) Neurology: Luigi Ferini Strambi (MI) Occupational Medicine: Plinio Carta (CA), Giacomo Muzi (PG) Oncology: Filippo De Marinis (RM), Cesare Gridelli (AV) Otolaryngology: Michele De Benedetto (LE), Desiderio Passali (SI) Pediatrics: Angelo Barbato (PD), Fernando M. De Benedictis (AN) Pharmacology: Ilario Viano (VC) Pneumology: Francesco Blasi (MI), Lucio Casali (TR), Mario Cazzola (RM), Giuseppe U. Di Maria (CT), Giuseppe Girbino (ME), Carlo Grassi (MI), Dario Olivieri (PR), Pier Luigi Paggiaro (PI), Paolo Palange (RM), Riccardo Pela (AP), Mario Polverino (Cava de Tirreni, SA). Relationships with Patients Organizations: Mariadelaide Franchi (RM) Thoracic Surgery: Francesco Sartori (PD) Associazione Scientifica Interdisciplinare per lo Studio delle Malattie Respiratorie Multidisciplinary Respiratory Medicine Editorial Office Novamedia s.r.l. Via Monsignor Cavigioli, Borgomanero (NO) Tel Fax Lilia Giannini Elisa Rossi Editorial Supervision Rosemary Allpress, Alberto Braghiroli Marketing & Advertising Gaudenzio Nidasio Tel MRM 77

3 MRM _def:Layout 1 08/04/10 15:47 Pagina 78 Associazione Scientifica Interdisciplinare per lo Studio delle Malattie Respiratorie Certificazione ISO N. IT Modulo di Iscrizione da inviare alla segreteria Nome:* Cognome:* Specialità:* Ente/Azienda Ospedaliera: N. B.: i dati indicati di seguito verranno utilizzati per il recapito di tutta la corrispondenza e le riviste. Indirizzo:* N. Città:* CAP:* Provincia:* Regione:* Stato:* Tel. privato: Tel. lavoro: Tel. mobile: Fax: * La quota per l anno 2010 è: t per pneumologi t per non pneumologi Modalità di pagamento - barrare l opzione desiderata: * campi obbligatori - si prega di compilare la scheda in stampatello contanti assegno: Banca Carta di credito: intestata a: numero carta: scadenza: / codice di sicurezza (cw2) (il codice è riportato sul retro della carta): Il codice di sicurezza (cw2) a tre cifre è riportato sul retro, in corsivo, immediatamente sopra il riquadro dela firma. Far riferimento alle illustrazioni a lato a seconda del tipo di carta posseduta. Bonifico Bancario Banca d'appoggio: Banca Intesa San Paolo - Filiale di Borgomanero (NO) IBAN IT67Y Intestato a: Associazione Scientifica Interdisciplinare per lo Studio delle Malattie Respiratorie (AIMAR) Firma:* Data: Le ricordiamo che collegandosi al sito potrà accedere a tutti i servizi offerti ai Soci di AIMAR. Segreteria: Via Monsignor Cavigioli, Borgomanero (NO) Tel Fax Informativa art. 13, d. lgs 196/2003 I Suoi dati saranno trattati, con modalità anche informatiche, da AIMAR - titolare del trattamento - Via Monsignor Cavigioli 10, Borgomanero (NO) - per gestire la Sua iscrizione ad AIMAR e, laddove richiesto, per attivare la casella di posta elettronica, e per attività a ciò strumentali. Inoltre, previo consenso, i Suoi dati saranno trattati per l'invio di newsletter periodiche. Le categorie di soggetti incaricati del trattamento dei dati per le finalità suddette sono gli addetti alla registrazione, modifica ed elaborazione dati, al confezionamento e spedizione di nostre riviste e newsletter, all'amministrazione, alla segreteria soci. Ai sensi dell'art. 7, d. lgs 196/2003 può esercitare i relativi diritti fra cui consultare, modificare, aggiornare o cancellare i Suoi dati, nonché richiedere elenco aggiornato dei responsabili del trattamento rivolgendosi al titolare al succitato indirizzo.

4 MRM _def:Layout 1 08/04/10 15:47 Pagina 79 Editoriale / Editorial Accettazione della vaccinazione antinfluenzale Certezze, limiti, perplessità Acceptance of the influenza vaccine Certainties, limits, doubts 82 Gesualdo Agati Original Articles / Articoli Originali Relationship between BODE index, quality of life and inflammatory cytokines in COPD patients Correlazione tra indice BODE, qualità di vita e citochine infiammatorie nei pazienti con BPCO 84 Nurhan Sarioglu, Aylin Ozgen Alpaydin, Aysın Sakar Coskun, Pınar Celik, Beyhan Cengiz Ozyurt, Arzu Yorgancioglu INDICE / INDEX Anti-inflammatory effects of montelukast on smoke-induced lung injury in rats Effetto antinfiammatorio del montelukast sul danno polmonare indotto da fumo nel ratto 92 Ilknur Basyigit, Murat Sahin, Deniz Sahin, Fusun Yildiz, Hasim Boyaci, Serap Sirvanci, Feriha Ercan Review / Rassegna Cough variant asthma and atopic cough Asma variante con tosse e tosse atopica 99 Chiara Magni, Elisa Chellini, Alessandro Zanasi Long summaries / Riassunti estesi Conference: "COPD a social disease: inappropriateness and pharmaco-economics. The role of the specialist: present and future", Venice, April 21-22, 2010: long summaries Conferenza: "BPCO una malattia sociale: inappropriatezze ed aspetti farmacoeconomici. Il ruolo dello specialista: presente e futuro", Venezia, aprile 21-22, 2010: riassunti estesi 104 Edited by Claudio F. Donner Rationale and structure of the conference Razionale e struttura della Conferenza 104 Claudio F. Donner Future of NHS in the welfare state Il futuro del Servizio Sanitario Nazionale nel welfare state 106 Maurizio Sacconi The growing role of rehabilitation and chronic care Il ruolo crescente della riabilitazione e del trattamento cronico 108 Daniela Carraro The institutions Le Istituzioni 111 Giovanna Laurendi MRM 79

5 MRM _def:Layout 1 08/04/10 15:47 Pagina 80 Role of patients associations Il ruolo delle Associazioni di pazienti 112 Fausta Franchi Primary care Medicina di base 112 Giovanni Invernizzi Role of the respiratory specialist Il ruolo dello specialista di ambito respiratorio 113 Stefano Nardini Long term oxygen therapy: a critical re-evaluation of current guidelines Ossigenoterapia a lungo termine: una rivalutazione critica delle linee guida attuali 115 Antonio Corrado, Teresa Renda Lessons from large international clinical trials Le lezioni dei trial clinici internazionali 117 Antonio Anzueto The situation in North America: view from Canada La situazione in Canada 119 Rick Hodder The situation in North America: view from the United States La situazione negli USA 121 Robert A. Wise The situation in Europe La situazione in Europa 123 Marc Miravitlles The situation in Europe: Scandinavia La situazione in Europa: Scandinavia 126 Ronald Dahl The situation in Italy La situazione in Italia 127 Roberto W. Dal Negro AGE.NA.S: national system for guidelines AGE.NA.S: il sistema nazionale per le linee guida 128 Bruno Rusticali Prevention Prevenzione 129 Isabella Annesi-Maesano Diagnosis Diagnosi 131 Isa Cerveri Treatment Trattamento 132 Bartolome R. Celli Follow up Follow up 135 Francesco G. Salerno, Mauro Carone 80 MRM

6 MRM _def:Layout 1 08/04/10 15:47 Pagina 81 Pathogenesis of COPD: an innovative approach Patogenesi della BPCO: un approccio innovativo 136 Marco Chilosi, Andrea Rossi COPD management: an integrated approach La gestione della BPCO: un approccio integrato 137 Josep Roca A comprehensive approach to COPD Un approccio onnicomprensivo alla BPCO 139 Claudio F. Donner ATP Corner / L Angolo dell ATP Società Italiana di Tabaccologia Perché la salute non vada in fumo Italian Tobaccology Society To stop health going up in smoke 141 Biagio Tinghino AIMAR Newsletter 144 RUBRICHE From the CFC Bulletin 146 L'Angolo della Cultura (non solo Medicina...) L inquieto fantasma della letteratura italiana The haunting spirit of Italian literature 148 Francesco Iodice Meeting Calendar 151 Avviso importante ai Soci Si rammenta a tutti i Soci che, come più volte comunicato negli scorsi numeri di MRM, la rivista non sarà più inviata senza la regolarizzazione dell'iscrizione ad AIMAR. Le modalità di pagamento della quota societaria per l'anno 2010 sono riportate a pagina 78. MRM 81

7 MRM _def:Layout 1 08/04/10 15:47 Pagina 82 Editoriale / Editorial Accettazione della vaccinazione antinfluenzale Certezze, limiti, perplessità Acceptance of the influenza vaccine Certainties, limits, doubts Gesualdo Agati Direttore Unità Operativa di Pneumologia, AO Bianchi-Melacrino-Morelli, Reggio Calabria Dopo 35 anni di professione come medico ospedaliero sono arrivato alla consapevolezza che la medicina non è una scienza esatta - e non sono il solo ad affermarlo - ma è una scienza dinamica fatta di varie componenti: competenza scientifica, esperienza, arte, filosofia e talvolta anche affari economici. La ricerca scientifica medica dimostra ancora oggi di non essere assolutamente autosufficiente: fa talvolta errori, lascia dubbi, mostra aspetti lacunosi su molte malattie e spesso è scollata dall esperienza della pratica clinica quotidiana. È innegabile che l esperienza è la vera madre di tutte le scienze e la pratica clinica mette spesso a dura prova l innovazione della ricerca. Entro nel merito del mio dire e mi riferisco alla campagna di allarmismo psicologico sul presunto nuovo flagello della pandemia influenzale. Grossi dubbi e perplessità ha suscitato anche nei medici e la conferma viene proprio dalla scarsa accettazione della campagna vaccinale. Dati imprecisi, lacunosi sui meccanismi di adesione, di moltiplicazione dei virus influenzali, sui tempi e modi di contagiosità e su molti altri aspetti delle infezioni virali respiratorie sono a monte di questo fenomeno. Un informazione allarmistica sui giornali, in televisione e su altri mezzi di comunicazione crea sempre una psicosi di fronte a un presunto nuovo flagello, che si chiami influenza suina AH1N1, SARS, ecc. Nonostante questo allarmismo gran parte dei medici di famiglia, medici ospedalieri, altri specialisti in genere non hanno ritenuto di prescrivere il vaccino antinfluenzale contro l influenza suina a tutti i loro pazienti, ai loro familiari, né loro stessi lo hanno fatto, forse forti di esperienze precedenti non sempre positive o scientificamente poco adeguate in merito ad una indicata vaccinazione antinfluenzale di massa. La medicina si deve distinguere in una medicina preventiva, di massa, rivolta alla popolazione sana o a rischio in generale, e una medicina curativa individuale, che deve tenere conto di tante situazioni, di tante variabili, di patologie croniche preesistenti nel singolo paziente, anche per trattamenti preventivi come nella fattispecie della vaccinazione antinfluenzale. Altrimenti diventa una medicina empirica, forfettaria, superficiale e non scientificamente corretta. Una sanità competente, scientificamente supportata, scrupolosa non può non bene interpretare i problemi pratici che una presunta emergenza sanitaria può scatenare nella popolazione. Le autorità statali istituzionali non solo non hanno ben gestito le informazioni tecnico-scientifiche sulla presunta pandemia, ma hanno consentito alle testate giornalistiche nazionali e locali di diffondere notizie allarmistiche sulla necessità di vaccinare larghe fasce della popolazione compresi gli anziani, i malati terminali, i malati gravi neoplastici, scompensati, pazienti cardiorespiratori con instabilità emodinamica, immunocompromessi, ecc., perché più esposte a gravi complicazioni influenzali. E guarda caso sono questi proprio i pazienti che sono stati vaccinati contro l influenza AH1N1, contro la stagionale e che hanno avuto i maggiori problemi postvaccinali. A tale riguardo mi pare opportuno invitare i responsabili istituzionali della sanità locale, regionale, nazionale a condurre studi clinici e a rilevare dati statistici sui molti e complessi aspetti delle conseguenze della vaccinazione antinfluenzale in determinate tipologie di pazienti, e sui molti e incerti aspetti clinici relativi alle infezioni virali delle vie respiratorie. Molte sono le problematiche e le conseguenze post + Gesualdo Agati Direttore Unità Operativa di Pneumologia, AO Bianchi-Melacrino-Morelli Via Torrione 32 C, Reggio Calabria, Italia Multidisciplinary Respiratory Medicine 2010; 5(2): MRM

8 MRM _def:Layout 1 08/04/10 15:47 Pagina 83 vaccinali nei pazienti immunocompromessi respiratori o sistemici. In particolare quanti di essi hanno avuto complicazioni cliniche? Quanti hanno dovuto fare ricorso al ricovero ospedaliero? Quanti costi socio-sanitari hanno comportato queste conseguenze? Quanti costi per farmaci, per assistenza sanitaria? Quanti problemi per le famiglie? Si ritiene opportuno e utile confrontare i dati tra i pazienti gravi non vaccinati e quelli vaccinati, considerato che patologie gravi preesistenti avrebbero potuto porre delle limitazioni alla vaccinazione stessa. Allo stesso modo sarebbe opportuno poter valutare gli indici statistici di mortalità nei 2-3 mesi prima e dopo la vaccinazione, specie nei pazienti con gravi patologie di base. Ci si chiede se le valutazioni fin qui segnalate sono state mai studiate anche negli anni precedenti dopo altri procurati allarmi su presunte precedenti pandemie, per cercare di capire se i risultati clinici siano positivi o negativi in merito alla consigliata vaccinazione antinfluenzale che erroneamente viene assimilata ad altre tipologie di vaccinazioni di organi interni (per esempio quella contro l epatite). Essa, invece, è di tipo mucosale con caratteristiche e meccanismi di risposta immunitaria diversificati in quanto la prima barriera di difesa delle alte e basse vie respiratorie è proprio alla superficie delle mucose stesse, che sono esposte 24 ore su 24 ad agenti lesivi esogeni (virus, batteri, fattori inquinanti, ecc.). Comunque sembra che la risposta immunitaria locale di potenziamento dell effetto barriera di difesa sia più efficace, a livello respiratorio, dell immunità conseguente a vaccinazione parenterale, proprio perché l effetto barriera e le IgA secretorie rappresentano la principale difesa locale antinfettiva delle vie respiratorie. C è forse in atto una grande confusione e disorganizzazione nell ambito della sanità territoriale e ospedaliera. Le vaccinazioni dovrebbero servire a tutelare i cittadini, i pazienti, selezionandoli in base alle patologie da cui sono affetti. La prescrizione della vaccinazione antinfluenzale dovrebbe richiedere una severità scientifica nella selezione dei pazienti applicando in tutti i casi il detto primum non nocere, non dimenticando, quindi, che ogni farmaco, ogni trattamento può essere allo stesso tempo un rimedio, ma anche un danno, un veleno. Sorgono, dunque, spontanee alcune domande di carattere scientifico e socio-sanitario che possono suscitare risposte utili a chiarire quanto più possibile le incertezze e i dubbi relativi alle vaccinazioni antinfluenzali: 1) Esiste una differenza tra i vaccini obbligatori e i vaccini facoltativi? Questi ultimi vanno consigliati solo selezionando i pazienti e indicando le limitazioni e controindicazioni? 2) Esiste una differenza tra i vaccini tessutali di organi interni e i vaccini mucosali, cioè come quelli destinati all apparato respiratorio? Che risposta immunologica diversificata e più complessa viene richiesta ai vaccini antinfluenzali? 3) Vale sempre il concetto scientifico che i vaccini facoltativi, come quelli antinfluenzali, vanno fatti ai pazienti immunocompetenti o presunti tali? 4) È un dato scientifico che l impiego di un vaccino deve tendere all eradicazione della malattia e che questo obiettivo può essere ottenuto soltanto se vengono raggiunti livelli elevati di immunizzazione compresi tra l 85% e il 95%? Questi livelli di immunizzazione si possono raggiungere con la vaccinazione antinfluenzale attuale? Che tipi di vaccini dovremmo usare? Per che via andrebbero somministrati? A che livello dovrebbero agire? Che tipo di risposta immunologica prevalente dovremmo ottenere: di tipo locale, mucosale ad effetto barriera, cellulare, umorale? 5) Viene consigliato il vaccino ad una popolazione di massa, indicando alcune fasce più esposte, in apparente contraddizione con la nozione che il vaccino antinfluenzale non è indicato in pazienti particolari con gravi patologie specie acute o subacute, con episodi infettivi recenti o con patologie croniche gravemente riacutizzate? 6) I vaccini antinfluenzali provocano flogosi nelle vie respiratorie, anche se minimale, iperreattività bronchiale o possono accentuarla se già preesistente, come negli asmatici, nei broncopatici cronici ostruttivi, nei bronchiectasici, ecc.? Che può succedere in questi pazienti in cui esiste già una flogosi cronica delle vie broncopolmonari aggiungendo flogosi alla flogosi, iperreattività all iperreattività o facilitando il risveglio di colonizzazioni batteriche croniche delle vie respiratorie silenti o in fase di stabilità clinica e batteriologica? Esiste una correlazione tra flogosi delle vie respiratorie, anche da antigeni vaccinali, e maggiore adesione batterica per caduta dell effetto barriera a livello dell epitelio respiratorio? 7) Come si giustifica che molti cittadini, molti pazienti, molti medici non hanno avuto fiducia nella campagna di informazione sulle vaccinazioni antinfluenzali tanto che su una previsione di oltre 40 milioni di dosi vaccinali sono state utilizzate solo 35 mila dosi? Si è trattato di boicottaggio della campagna di vaccinazione oppure molti dubbi, incertezze, sfiducia hanno indotto prima di tutto gli stessi medici a non vaccinarsi? 8) Esiste un consenso informato che ogni vaccinato dovrebbe sottoscrivere e anche un dissenso informato che dovrebbe sottoscrivere chi rifiuta la vaccinazione; perché non vengono richiesti? Sarebbe il caso che lo Stato nominasse una commissione di esperti della sanità per la ricerca di vaccini antinfluenzali più mirati ed efficaci e senza alcun rischio per i pazienti. Nel campo della salute l investimento prioritario di risorse economiche deve essere sempre diretto verso il malato. G Agati Editoriale - Editorial MRM 83

9 MRM _def:Layout 1 08/04/10 15:47 Pagina 84 Original Article / Articolo Originale Relationship between BODE index, quality of life and inflammatory cytokines in COPD patients Correlazione tra indice BODE, qualità di vita e citochine infiammatorie nei pazienti con BPCO Nurhan Sarioglu 1, Aylin Ozgen Alpaydin 1, Aysın Sakar Coskun 1, Pınar Celik 1, Beyhan Cengiz Ozyurt 2, Arzu Yorgancioglu 1 1 Celal Bayar University, Medical Faculty, Pulmonary Diseases, Manisa, Turkey 2 Celal Bayar University Medical Faculty, Public Health, Manisa, Turkey ABSTRACT Background and aims: Recently a multidimensional grading system based on the body mass index (B), degree of airflow obstruction (O), dyspnea (D) and exercise capacity (E) - the BODE index - has begun to be used increasingly for the evaluation of chronic obstructive pulmonary disease (COPD) patients. The aim of our study was to investigate the relationship between the BODE index and disease duration, annual exacerbation and hospitalization rates, health related quality of life and systemic inflammatory markers like C-reactive protein (CRP), tumor necrosis factor (TNF)-α and interleukin (IL)-8. Materials and methods: In 88 stable COPD patients we evaluated the body-mass index, pulmonary function tests, Modified Medical Research Council dyspnea scale and sixminute walk test (6MWT). BODE scores were determined. Disease duration, number of exacerbations and hospitalization in the previous year were recorded. We also performed arterial blood gases analysis, administered the St. George s Respiratory Questionnaire (SGRQ) and measured serum levels of CRP, TNF-α, IL-8. Results: According to BODE score 52% of patients were BODE 1, 21% BODE 2, 15% BODE 3 and 12% were BODE 4. There was a significant relationship between BODE index and COPD stage as classified according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) (p < 0.001). Correlations between BODE score and disease duration (p = 0.011), number of exacerbations (p < 0.001) and hospitalizations (p < 0.001) in the last year were also observed. SGRQ symptom, activity, emotion scores and total scores were found to be significantly correlated to BODE (p < 0.001). Serum CRP levels and BODE were also correlated (p = 0.014); however, no correlation was found between serum levels of TNF-α and IL-8 and BODE. Conclusions: As the BODE index shows a strong correlation with various prognostic and follow up parameters of COPD and systemic inflammation, its use should be considered for the evaluation of COPD patients. Keywords: Biomarkers, BODE index, COPD, quality of life. RIASSUNTO Razionale e scopi: Nella valutazione dei pazienti con broncopneumopatia cronica ostruttiva (BPCO) è recentemente invalso l uso in modo crescente di un sistema multidimensionale di misura basato su indice di massa corporea (B), entità dell ostruzione funzionale respiratoria (O), dispnea (D) e capacità di esercizio fisico (E): l indice BODE. Scopo del nostro studio era valutare la correlazione tra l indice BODE e la storia di malattia, il numero di riacutizzazioni annue e il tasso di ospedalizzazioni, la qualità della vita legata alla salute e marker infiammatori sistemici come la proteina C reattiva (PCR), il fattore di necrosi tumorale (TNF)-α e l interleuchina (IL)-8. Materiali e metodi: Abbiamo valutato in 88 pazienti con BPCO stabile l indice di massa corporea, le prove di funzionalità respiratoria, la scala Modified Medical Research Council della dispnea ed il test del cammino di 6 minuti (6MWT). Sono stati calcolati i punteggi BODE. Sono state registrate la durata della malattia, il numero di riacutizzazioni e di ospedalizzazioni nell anno precedente. Inoltre sono state effettuate l emogasanalisi, il St. George s Respiratory Questionnaire (SGRQ) e determinati i livelli serici di PCR, TNF-α e IL-8. Risultati: Secondo il punteggio BODE 52% dei pazienti erano + Aylin Ozgen Alpaydin Celal Bayar University, Medical Faculty, Department of Pulmonary Diseases Manisa, Turkey Data di arrivo del testo: 08/09/2009 Accettato dopo revisione: 17/12/2009 Multidisciplinary Respiratory Medicine 2010; 5(2): MRM

10 MRM _def:Layout 1 08/04/10 15:47 Pagina 85 BODE 1, 21% BODE 2, 15% BODE 3 e 12% erano BODE 4. La correlazione era significativa (p < 0,001) tra indice BODE e stadio della BPCO determinato secondo la stadiazione del Global Initiative for Chronic Obstructive Lung Disease (GOLD). Erano significative anche le correlazioni tra punteggio BODE e durata di malattia (p = 0,011), numero di riacutizzazioni (p < 0,001) e ospedalizzazioni (p < 0,001) nell ultimo anno. Il punteggio totale del SGRQ e dei campi sintomi, attività e emozioni era significativamente correlato al BODE (p < 0,001). Anche i livelli serici di PCR e il BODE erano correlati (p = 0,014), mentre non si è rilevata alcuna correlazione tra TNF-α e IL-8 con il BODE. Conclusioni: Dal momento che l indice BODE mostra una forte correlazione con vari indici di prognosi, di follow up ed infiammatori nella BPCO, una sua applicazione sistematica dovrebbe essere presa in considerazione nella valutazione dei pazienti con BPCO. Parole chiave: Biomarker, BPCO, indice BODE, qualità di vita. INTRODUCTION Currently, chronic obstructive pulmonary disease (COPD) is regarded as a systemic disease causing structural and functional changes in many organs as well as in the lung. Malnutrition, weight loss, and peripheral muscle weakness are some of the systemic manifestations of COPD that seriously affect the health related quality of life and exercise capacity of patients [1,2]. Advances in understanding the systemic nature of COPD have given rise to the development of a combined index of multiple mortality predictors for this disease known as the BODE index. The components of the index are: body mass index (BMI), airway obstruction (O), dyspnea (D) and exercise capacity (E). The BODE index includes both symptoms and physiological measurements and it has been reported as a better mortality predictor than forced expiratory volume in 1 second (FEV 1 ) [3]. It predicts mortality from any cause as well as respiratory causes and gives more comprehensive information than the FEV 1 -based staging system described in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) [3-5]. In view of the systemic nature of COPD, other tools such as quality of life questionnaires (QoLQ) have been developed to establish the systemic impacts of the disease. It has been recommended to administer QoLQs to determine disease severity and treatment responses in collaboration with physiological measurements [6]. St. George s Respiratory Diseases Questionnaire (SGRQ) was designed specifically for COPD patients and demonstrates the impact of the disease on daily life [6,7]. Since systemic inflammation has been recognized as an indisputable component of COPD, the role of inflammatory cytokines has also been widely investigated in the natural history of COPD [8]. It has been shown that C-reactive protein (CRP) levels are elevated in the serum of COPD patients even in stable disease [9]. In a follow up study of 8 years, basal CRP levels significantly predicted overall mortality, cardiovascular disease-related mortality and cancer-related mortality in patients with mild and moderate COPD. FEV 1 loss was shown to be correlated to CRP levels [1] and CRP was found to be a specific marker of COPD exacerbations [10]. Increased levels of tumor necrosis factor (TNF)-α have been found in serum, induced sputum and bronchial biopsies of COPD patients, especially those in whom COPD was associated with weight loss [11-13]. Also, interleukin (IL)-8, a strong selective neutrophil chemo-attractant, showed increased levels in serum of COPD patients with respect to healthy controls [8]. Currently, clinical outcomes and biomarkers are two parameters being used to determine the pulmonary function and systemic effects of COPD. We think that evaluating COPD, a multicomponent disease, functionally and systemically will improve understanding of this disease. In our study we hypothesized that a composite index of clinical outcomes, the BODE index, was a better predictor of health status and systemic inflammation in COPD than FEV 1 alone and aimed to investigate the relationship of the components of BODE and the BODE index itself with systemic inflammatory biomarkers and quality of life as well as with prognostic factors like disease duration and annual exacerbation and hospitalization rates. MATERIALS AND METHODS Eighty-eight stable COPD patients diagnosed according to GOLD guidelines in our pulmonary diseases outpatient clinic were included in the study consecutively between November 2006 and May The study was approved by the human-research Ethical Review board and all patients provided written informed consent. Inclusion criteria were: COPD patients in stable conditions (no exacerbations due to any reason in the last 6 weeks). COPD was defined as a history of smoking of more than 20 pack-years and a FEV 1 /forced vital capacity (FVC) ratio of less than 70% after 20 minutes after salbutamol administration [14]. Exclusion criteria were: patients with other inflammatory diseases (inflammatory bowel disease, rheumatologic diseases, vasculitis), interstitial lung diseases, active pulmonary tuberculosis, presence of atopy, history of myocardial infarction in the last 6 months, decompensated cardiovascular disease and walking disability. Demographic features and medical history of the patients were recorded. Emergency service visits due to acute exacerbations and hospitalization to general ward or intensive care unit in the last year were investigated. Weight, height, dyspnea severity were measured and the six-minute walking test (6MWT), pulmonary function tests (PFT) were performed. SGRQ, arterial blood gases (ABG) analysis and measurement of serum levels of inflammatory cytokines (CRP, TNF-α, IL-8) were also performed. Pulmonary Function Tests: PFT were performed with the Jaeger Master Screen Pneumo device. The best test from three consecutive tests was accepted. FEV 1, FVC, FEV 1 /FVC were measured according to ATS criteria. COPD staging was done according to N Sarioglu, AO Alpaydin, AS Coskun, P Celik, BC Ozyurt, A Yorgancioglu BODE index, quality of life and inflammatory markers in COPD Indice BODE, qualità di vita e marker infiammatori nella BPCO MRM 85

11 MRM _def:Layout 1 08/04/10 15:47 Pagina 86 Multidisciplinary Respiratory Medicine 2010; 5(2): GOLD 2006 [14]. Body Mass Index: BMI was calculated according to the formula weight (kg) / height (m) 2 [15]. Dyspnea Severity: The Modified Medical Research Council (MMRC) scale was used for the evaluation of dyspnea [16]. Six-minute walking test: 6MWT was performed in a 35 m long corridor. Patients were motivated to walk at the fastest speed they could. Oxygen saturation was measured before and after the test and the distance walked was recorded [17]. BODE index: The overall index was calculated according to BMI, FEV 1, 6MWT, MMRC by summing the points as shown in Table I. Further subgroupings like BODE 0, 1, 2, 3 were made, as defined in the formula [3]. Quality of Life Questionnaire: The Turkish translation of the St. George s Respiratory Diseases Questionnaire (SGRQ) was used to determine the quality of life [18]. Arterial Blood Gases Analysis: ABG samples were obtained from the radial artery with heparinized injectors and studied with a Roche Diagnostics GmbH OMNI C, Mannheim (Germany) device with original reactive analyzers. Measurement of CRP, TNF-α, IL-8 levels: Venous blood samples were centrifuged and serums were separated and preserved at -20 C to be analyzed together. Serum CRP levels were studied with original reactive analyzers (Beckman Coulter Inc. Unicel DxC 800 Synchron Clinical Systems Galway, Ireland). Serum TNF-α and IL-8 levels were studied according to the manufacturer s recommendations (BioSource Europe S.A Nivelles, Belgium) with the Enzyme Linked-Immuno-Sorbent Assay (ELISA) method. Intra-assay variation coefficient (%CV) values for IL-8 kit were 3.9% for 74.9 pg/ml, 2.6% for pg/ml, 5.3% for pg/ml while the inter-assay variation coefficients were 5% for 89.8 pg/ml, 5.5% for pg/ml, 7.8% for pg/ml. Lowest measurement level for IL-8 kit was < 5.0 pg/ml. Intra-assay variation coefficient values for TNF-α kit were 5.2% for 8 pg/ml, 4.1% for 167 pg/ml, 3.9% for 459 pg/ml, while the inter-assay variation coefficients were 8.5% for 47 pg/ml, 8.2% for 170 pg/ml, 5.9% for 438 pg/ml. Lowest measurement level for TNF-α kit was 1.7 pg/ml. IL-8 and TNF-α levels were measured in only 65 of the patients, and CRP levels in 86 patients according to a table of random numbers, due to an inadequate number of kits. Statistical analysis Data were analyzed by the SPSS 15.0 package programme. Spearman s rank correlations and Pearson correlations were used to analyze comparisons. RESULTS Demographic characteristics of the 88 patients are shown in Table II. Duration of the disease ranged widely, from 6 months to 40 years, in the study population. Sixteen of the patients (18%) were non smokers but had a history of passive exposure while 72 (82%) were current smokers. Most patients (53%) had comorbid diseases like hypertension, congestive heart failure and diabetes mellitus. Fiftyone (58%) patients had had no exacerbation and 65 (74%) had not been hospitalized in the previous 12 months. Functional parameters and serum cytokine levels of the study population are shown in Table III. Of the 88 patients, 16% were stage I, 42% were stage II, 27% were stage III, and 15% were stage IV according to GOLD guidelines. When patients were classified with respect to BODE score, 52% were BODE 1, 21% were BODE 2, 15% were BODE 3 and 12% were BODE 4. BODE scores and disease stages of the patients according to GOLD were significantly correlated, as expected (p < 0.001) (Figure 1). Each single BODE component and the BODE index itself were compared with disease duration, number of exacerbations and number of hospitalizations in the last year, separately. BMI was not found to be correlated with any of these parameters. A significant relationship was found between MMRC and disease duration (p = 0.003), number of exacerbations (p = 0.008) and number of hospitalizations (p = 0.001). 6MWT was found to be correlated with disease duration (p = 0.041) and number of hospitalizations (p = 0.002). As for FEV 1, a significant correlation was observed for disease duration (p = 0.001) and number of exacerbations (p < 0.001). The BODE index itself was found to be correlated with all these parameters, showing the strongest correlation for number of exacerbations and number of hospitalizations in the last year (p < for both). Among the single components of the BODE index, BMI was the one that showed the least correlation (p = 0.020) with BODE (p < 0.001). Components of BODE index including BMI, MMRC dyspnea scale, 6MWT and pulmonary function parameters (FEV 1, FVC and FEV 1 /FVC) were also compared. There was a significant relationship between BMI and FEV 1 /FVC (p = 0.011). MMRC and 6MWT were also significantly correlated with FEV 1 (p < for both), FVC (p < for both) and FEV 1 /FVC (p = 0.016, p = respectively). All components of BODE index and the BODE index itself were found to be significantly correlated with arterial PO 2 (p < 0,05). The correlation was determined negative for BODE and PaO 2, while it was positive for BODE and PaCO 2 (p < 0.001). A significant correlation was observed between MMRC, 6MWT, FEV 1 and SGRQ total score (p < respectively). Also, BODE index and SGRQ symptom, emotion, activity and total scores were found to be significantly correlated (p < 0.001, respectively) (Figure 2). When inflammatory markers were compared with BODE index, CRP levels were shown to have a weak but statistically significant correlation (r = 0.2, p = 0.014) (Figure 3) while TNF-α and IL-8 did not show a correlation. CRP was not found to be correlated with FEV 1, FVC and FEV 1 /FVC. However, a significant relationship was found between CRP 86 MRM

12 MRM _def:Layout 1 08/04/10 15:47 Pagina 87 TABLE I: SCORING FOR THE COMPONENTS OF THE BODE INDEX: BODY-MASS INDEX, DEGREE OF AIRFLOW OBSTRUCTION, DYSPNEA, AND EXERCISE CAPACITY and SGRQ total score (p = 0.015). When the patients were divided into two groups according to the presence of comorbid diseases, there was no statistically significant difference with respect to dyspnea severity, 6MWT and CRP levels between the two groups. DISCUSSION The most recently discussed topic in COPD in the last few years is its inflammatory and systemic nature. Several clinical tests and biomarkers have been developed for the evaluation of systemic effects of the disease [1]. A weak correlation has been defined between pulmonary function tests, especially FEV 1 and clinical outcomes including the severity of dyspnea and other symptoms, mortality, health status, quality of life and frequency of exacerbations [18,19]. The BODE index has been suggested as a new follow up tool for the evaluation of COPD patients [3]. CRP is another systemic biomarker that has been widely used for inflammatory diseases like COPD [8]. In our study, among the 88 COPD patients we found a correlation between BODE index and COPD stages according to GOLD; this was surely due to the impact of FEV 1 in both GOLD staging and BODE index. Points on BODE Index Parameter Body mass index (kg/m²) > FEV 1 (% predicted) minute walking distance (m) MMRC dyspnea scale (score) Definition of abbreviation: FEV 1, forced expiratory volume in 1 st second; MMRC, Modified Medical Research Council. BODE groups are classified as: 1-2 points: BODE 0; 2-4 points: BODE 1; 4-7 points: BODE 2; 7-10 points: BODE 3. Ong et al. found the BODE index and number of emergency visits related in their study of 16 months follow up, and also showed a significant but lower grade relationship between number of emergency visits and FEV 1 [20]. In another study, the BODE index was shown to be more significant for determining the severity of COPD exacerbations with respect to FEV 1 [21]. In our study, we similarly found the BODE index to be related to annual rate of hospitalizations (p < 0.001), but this relationship was not observed for FEV 1. However, both BODE and FEV 1 had the same significant relationship for number of exacerbations (p < for both). In the light of these results, we consider that FEV 1 is an important marker in determining exacerbations within the other components of BODE, while for hospitalizations other components of BODE than FEV 1 are more important. Weight loss is one of the common systemic effects of COPD. In a retrospective study of 400 patients Schols et al. reported increased mortality in severe COPD patients with chronic hypoxemia and a BMI < 25 kg/m 2 [22]. Another study showed a significant correlation between fat free mass index (FFMI) and MRC, FEV 1, FEV 1 /FVC. BMI and FFMI were found to be related to 6MWT, but there was no correlation between BMI and disease severity. It was suggested that FFMI showed a better correlation with disease N Sarioglu, AO Alpaydin, AS Coskun, P Celik, BC Ozyurt, A Yorgancioglu BODE index, quality of life and inflammatory markers in COPD Indice BODE, qualità di vita e marker infiammatori nella BPCO TABLE II: DEMOGRAPHIC CHARACTERISTICS OF STUDY POPULATION (N = 88) Age (mean ± SD) 63.6 ± 10.5 Sex (female/male) 12/76 Disease duration, median (25 th to 75 th percentile) 5 (2-10) years Smoking history, median (25 th to 75 th percentile) 40 (20-60) pack/year Number of exacerbations, median (25 th to 75 th percentile) 0 (0-1) /last year Number of hospitalizations, median (25 th to 75 th percentile) 0 (0-1) /last year Comorbid diseases (present/absent) 47/41 Oxygen therapy (present/absent) 8/80 Maintenance therapy with inhaled steroid (present/absent) 49/39 MRM 87

13 MRM _def:Layout 1 08/04/10 15:47 Pagina 88 Multidisciplinary Respiratory Medicine 2010; 5(2): TABLE III: SUMMARY OF FUNCTIONAL PARAMETERS AND SERUM CYTOKINE LEVELS FOR THE STUDY POPULATION Number (n) Mean ± SD Minimum Maximum BMI (kg/m²) ± FEV 1 (L) ± FEV 1% predicted ± FEV 1/FVC ± MMRC ± MWT (m) ± BODE index ± Number (n) Median ± IQR (25 th - 75th) Minimum Maximum SGRQ total score (31-62) CRP (pg/ml) ( ) TNF-α (pg/ml) (15-21) IL-8 (pg/ml) (8-23) Definition of abbreviations: BMI, body mass index; CRP, C-reactive protein; FEV 1 (L), forced expiratory volume in 1 second, liter; FVC, forced vital capacity; MMRC, Modified Medical Research Council; 6MWT, 6-minute walking test; SGRQ, St. George s Respiratory Disease Questionnaire; TNF-α, tumor necrosis factor-α; IL-8, interleukin 8. severity than BMI [23]. In our study, mean BMI of the patients was 25.7 kg/m 2 and a significant positive correlation was found only with FEV 1 /FVC. No correlation was determined between BMI and disease severity according to GOLD. Also, the relationship between BMI and BODE index was the least with respect to the other components. This result leads us to consider that BMI has little contribution in determining disease severity. Dyspnea, one of the major symptoms of COPD, is a subjective symptom with perception differences depending on age or individual characteristics. Many dyspnea measurement scales have been developed and MMRC is one of the most widely accepted. Pulmonary function and dyspnea severity have been reported to be correlated in some studies; however in other studies dyspnea has been found uncorrelated with obstruction degree [24-27]. In our study, MMRC and FEV 1, FVC, FEV 1 /FVC were found to be related. In addition, a difference of our study with respect to other studies was the relationship between MMRC and disease duration, annual exacerbation and hospitalization rates and disease severity as well as arterial blood gas parameters (PaO 2, PaCO 2 ). 6MWT utilization has recently been increased in the evaluation of functional status and exercise performance of COPT patients. In our study, similarly to Marin s findings [28], 6MWT was found correlated with MMRC, COPD stage according to GOLD and PFT parameters. There was also a significant re- FIGURE 1: RELATIONSHIP BETWEEN BODE INDEX AND COPD STAGE ACCORDING TO GOLD FIGURE 2: RELATIONSHIP BETWEEN BODE INDEX AND SGRQ TOTAL SCORES BODE score * BODE score Stage Box and plot showing median, 25 th and 75 th percentiles. Definition of abbreviations: COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease p < 0.001; r = SGRQ total score Definition of abbreviation: SGRQ, St. George s Respiratory Diseases Questionnaire. 88 MRM

14 MRM _def:Layout 1 08/04/10 15:47 Pagina 89 FIGURE 3: RELATIONSHIP BETWEEN BODE INDEX AND SERUM CRP (PG/ML) LEVELS BODE score CRP levels pg/ml p = 0.014, r = Definition of abbreviation: CRP, C-reactive protein. lationship between 6MWT and age, disease duration, and annual hospitalization rates. A distinctive finding of our study was the correlation between 6MWT and arterial blood gas parameters. In addition, 6MWT and SGRQ symptom, emotion, activity and total scores were found to be significantly related. In view of these data, 6MWT is suggested as a first step test for demonstrating the unfavorable effects of COPD on quality of life and reflecting daily activities of the patients. Recent studies have reported that functional parameters like FEV 1 are insufficient to determine the health status in COPD, and quality of life measurements have gradually become more important for COPD [29]. In a study of COPD patients in which the relationship between BODE index and SGRQ was investigated, the BODE index was found to increase as SGRQ scores increased. There was a moderate and high relationship between BODE index and SGRQ; however COPD stage according to GOLD had a mild correlation with SGRQ [30]. In another study, a relationship between SGRQ total score and BODE severity scores was demonstrated; however this relationship was not observed between SGRQ total score and disease severity by GOLD stages [31]. In our study, we also found significant correlations between symptom, emotion, activity and total scores of SGRQ and BODE, and a weak correlation between all the SGRQ scores and COPD stage. These results suggest that the BODE index reflects the effects of disease on quality of life better than the GOLD stages do. Several serum biomarkers have been defined in COPD. Among them, CRP, fibrinogen, interleukins (IL-6, IL-8), TNF-α and leucocytes are the ones most studied. Even in stable conditions, all these biomarkers have been shown to be elevated in COPD patients [8]. In our study, CRP, IL-8 and TNF-α levels were investigated. In a study by Wu et al., sputum/serum CRP levels and pulmonary function tests of 30 COPD patients were compared and an inverse relationship was observed between sputum/serum CRP levels and FEV 1, and FEV 1 /FVC levels [32]. Broekhuizen et al. found lower post bronchodilator FEV 1 levels in patients with high CRP levels in a group of 102 stable stage II and IV COPD patients. SGRQ scores were high and exercise capacity evaluated by 6MWT was low in this group of patients also [33]. Garrod et al. demonstrated that COPD patients with high CRP levels had lower quality of life and exercise capacity and a greater decline in lung functions [34]. In our study, unlike other studies in similar case series, CRP and pulmonary function tests were not found to be correlated. However, SGRQ and CRP were found to be inversely correlated, while there was a positive relationship between BODE index, COPD stage and CRP. Nearly half of the patients in our study population had comorbid diseases like hypertension, congestive heart failure and diabetes mellitus related to systemic inflammation and this might have interfered with CRP levels, although these comorbidities had to be under control as an inclusion criterion. In an observational cohort study, in which moderate to severe COPD patients and two control groups without COPD (smokers and non-smokers) were tested using a high sensitivity CRP (hs-crp) test, CRP levels were found to be elevated in patients with COPD independent of clinically significant ischemic heart disease and cigarette smoking [35]. Emerging laboratory and epidemiologic data have demonstrated that hs-crp levels are associated with impaired insulin sensitivity and the development of type 2 diabetes [36]. Hence, diabetes mellitus might not be the cause of the high CRP levels in our study. However, we analyzed the CRP levels according to the presence or not of comorbidities and no statistically significant difference was observed between the two groups. Many studies have shown a relationship between high TNF-α levels and weight loss in COPD [37,38]. In our study, we did not find a correlation between TNF-α levels and body mass index nor with the BODE index. IL-8 is another important biomarker in COPD and some studies have shown high levels of IL-8 in COPD patients [39], but also here we were not able to show any correlation between BODE index and IL-8. In conclusion, in this study all components of BODE and the BODE index itself were compared with most of the clinical outcomes and biomarkers used in the evaluation of COPD. The most powerful correlation was observed between 6MWT, MMRC dyspnea scale and FEV 1. The BODE index is a comprehensive, feasible and simple clinical scoring system in the evaluation of COPD. It also reflects the quality of life and is correlated with CRP, one of the biological markers of systemic inflammation, while there is not a similar relationship with TNF-α and IL-8. Therefore, BODE is a clinical test which evaluates the pulmonary and extrapulmonary effects of N Sarioglu, AO Alpaydin, AS Coskun, P Celik, BC Ozyurt, A Yorgancioglu BODE index, quality of life and inflammatory markers in COPD Indice BODE, qualità di vita e marker infiammatori nella BPCO MRM 89

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Does the multidimensional grading system (BODE) correspond to differences in health status of patients with COPD? Int J Chron Obstruct Pulmon Dis 2006;1: Medinas Amorós M, Mas-Tous C, Renom-Sotorra F, Rubí- 90 MRM

16 MRM _def:Layout 1 08/04/10 15:47 Pagina 91 Ponseti M, Centeno-Flores M, Gorriz-Dolz M. Health-related quality of life is associated with COPD severity: a comparison between the GOLD staging and the BODE index. Chron Respir Dis 2009;6: Wu SJ, Chen P, Jiang XN, Liu ZJ. C-reactive protein level and the correlation between lung function and CRP levels in patients with chronic obstructive pulmonary disease. Zong Nan Da Xue Xue Bao Yi Xue Ban 2005;30: Broekhuizen R, Wouters EF, Creutzberg EC, Schols AM. Raised CRP levels mark metabolic and functional impairment in advanced COPD. Thorax 2006;61: Garrod R, Marshall J, Barley E, Fredericks S, Hagan G. The relationship between inflammatory markers and disability in chronic obstructive pulmonary disease (COPD). Prim Care Respir J 2007;16: Wouters EF, Creutzberg EC, Schols AM. Systemic effects in COPD. Chest 2002;121(5 Suppl):127S-130S. 36. Pinto-Plata VM, Müllerova H, Toso JF, Feudjo-Tepie M, Soriano JB, Vessey RS, Celli BR. C-reactive protein in patients with COPD, control smokers and non-smokers. Thorax 2006;61: Ndumele CE, Pradhan AD, Ridker PM. Interrelationships between inflammation, C-reactive protein, and insulin resistance. J Cardiometab Synd 2006;1: Di Francia M, Barbier D, Mege JL, Orehek J. Tumor necrosis factor alpha levels and weight loss in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1994:150: Kanazawa H, Kurihara N, Otsuka T, Fujii T, Tanaka S, Kudoh S, Hirata K, Takeda T. Clinical significance of serum concentration of interleukin 8 in patients with bronchial asthma or chronic pulmonary emphysema. Respiration 1996; 63: N Sarioglu, AO Alpaydin, AS Coskun, P Celik, BC Ozyurt, A Yorgancioglu BODE index, quality of life and inflammatory markers in COPD Indice BODE, qualità di vita e marker infiammatori nella BPCO MRM 91

17 MRM _def:Layout 1 08/04/10 15:47 Pagina 92 Original Article / Articolo Originale Anti-inflammatory effects of montelukast on smoke-induced lung injury in rats Effetto antinfiammatorio del montelukast sul danno polmonare indotto da fumo nel ratto Ilknur Basyigit 1, Murat Sahin 2, Deniz Sahin 3, Fusun Yildiz 1, Hasim Boyaci 1, Serap Sirvanci 4, Feriha Ercan 4 1 Department of Pulmonary Diseases, School of Medicine, Kocaeli University, Kocaeli, Turkey 2 Department of Pulmonary Diseases, Kocaeli Government Hospital, Turkey 3 Department of Physiology, School of Medicine, Kocaeli University, Kocaeli, Turkey 4 Department of Histology and Embryology, School of Medicine, Marmara University, Istanbul, Turkey ABSTRACT Aim: To evaluate the effects of montelukast in smokeinduced lung injury. Methods: 28 Wistar-Albino rats were enrolled into 4 groups with 7 rats per group. The healthy control group was exposed to fresh air while all rats in the 3 experimental groups were exposed to cigarette smoke for 20 weeks for 2 hours per day. After histopathological verification of smoke induced lung injury, montelukast (0.1 mg/kg) dissolved in Na 2CO 3 was given in one group (MON), Na 2CO 3 only was given in another group (MON control) and placebo was injected in the third group (COPD control) intraperitoneally for 21 days. At the end of this period blood samples were obtained for serum TNF-α assessment and light and electron microscopy analyses were performed on the lung tissues of sacrificed rats. Results: Serum TNF-α levels in the MON group were significantly lower than in the MON control and COPD control groups (38.84 ± 4.9 pg/ml, 77.5 ± 5.8 pg/ml and 79.2 ± 6.9 pg/ml respectively, p < 0.05). Furthermore there was no statistically significant difference between the MON group and healthy controls with respect to serum TNF-α levels (38.84 ± 4.9 pg/ml vs ± 3.6 pg/ml, p > 0.05). Light and electron microscopic evaluation of the lungs demonstrated that the total histopathological damage score of the lung samples was significantly lower in the MON group than in MON controls and COPD controls (5.14 ± 0.5, 8.4 ± 0.6 and 8.7 ± 0.4 respectively, p < 0.05), while there was no significant difference between the MON group and healthy controls (5.1 ± 0.6 vs 2.3 ± 0.2, p > 0.05). Conclusion: These findings suggest that montelukast might have a protective effect on smoke-induced lung injury in rats both from a histopathological and inflammatory point of view. Keywords: Chronic bronchitis, inflammation, montelukast, smoking. RIASSUNTO Scopo: Valutare gli effetti del montelukast sui danni polmonari indotti dal fumo. Metodi: 28 ratti Wistar-Albino sono stati suddivisi in 4 gruppi di 7 ratti per gruppo. Il gruppo di controlli normali è stato esposto ad aria pura, mentre tutti i ratti dei 3 gruppi sperimentali sono stati esposti a fumo di sigaretta per 20 settimane per 2 ore al giorno. Dopo la verifica istopatologica del danno polmonare indotto da fumo ad un gruppo è stato somministrato montelukast (0,1 mg/kg) disciolto in Na 2CO 3 (MON), ad un altro gruppo è stato somministrato il solo Na 2CO 3 (controlli MON) e nel terzo gruppo è stato iniettato placebo (controlli COPD) per via intraperitoneale per 21 giorni. Al termine di questo periodo sono stati effettuati prelievi di sangue per il dosaggio del TNF-α serico e sul tessuto polmonare dei ratti sacrificati sono state effettuate analisi al microscopio ottico ed elettronico. Risultati: I livelli serici di TNF-α nel gruppo MON erano significativamente inferiori ai controlli MON e ai controlli COPD (38,84 ± 4,9 pg/ml, 77,5 ± 5,8 pg/ml e 79,2 ± 6,9 pg/ml rispettivamente; p < 0,05). non vi erano inoltre differenze statisticamente significative tra il gruppo MON ed i controlli sani nei livelli serici di TNF-α (38,84 ± 4,9 pg/ml vs. 29,5 ± 3,6 pg/ml, p > 0,05). La valutazione al microscopio ottico ed elettronico dei tessuti polmonari dimostravano che lo score complessivo di danno istopatologico dei campioni di polmone era significativamente minore nel gruppo MON rispetto ai controlli MON e ai controlli COPD (5,14 ± 0,5, 8,4 ± 0,6 and 8,7 ± 0,4 rispettivamente, p < 0,05), mentre non vi erano differenze si- + Ilknur Basyigit Kocaeli University, School of Medicine, Department of Pulmonary Disease Umuttepe, Kocaeli, Turkey Data di arrivo del testo: 07/12/2009 Accettato dopo revisione: 19/1/2010 Multidisciplinary Respiratory Medicine 2010; 5(2): MRM

18 MRM _def:Layout 1 08/04/10 15:47 Pagina 93 gnificative tra il gruppo MON ed i controlli sani (5,1 ± 0,6 vs 2,3 ± 0,2; p > 0,05). Conclusioni: Questi risultati suggeriscono che il montelukast possa avere un effetto protettivo sul danno polmonare indotto da fumo nei ratti sia dal punto di vista istopatologico che da quello infiammatorio. Parole chiave: Bronchite cronica, fumo, infiammazione, montelukast. BACKGROUND Cigarette smoking induces an abnormal inflammatory response in the airways which is now increasingly acknowledged in the pathogenesis of chronic obstructive pulmonary disease (COPD) [1]. Smoking classically causes neutrophil predominant inflammation in the airways with the increase of neutrophil chemotactic cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-8, and leukotriene (LT)B4 [2-4]. Leukotrienes are generated from the metabolism of arachidonic acid and have significant effects on bronchoconstriction, mucus hypersecretion and airway inflammation [4]. Montelukast is a cysteinyl leukotriene receptor antagonist (LTRA) and widely used as an anti-inflammatory agent in the treatment of asthma [5-7]. Recent studies conducted in smoker and non-smoker asthmatics have shown that inhaled beclomethasone increased forced expiratory volume in 1 sec (FEV 1 ) levels only in non-smoker asthmatics; on the other hand montelukast increased morning peak flow values only in smoker asthmatics [8]. These data suggested that smoke-induced lung injury might be resistant to inhaled steroids and that LTRA may have possible effects in this setting. The bronchodilator effects of LTRA in patients with COPD has previously been demonstrated [9,10]. In a recent meta-analysis, Nguyen et al. reviewed 4 placebo-controlled trials investigating the effects of LTRA in the treatment of COPD and concluded that LTRA is associated with significant improvements in FEV 1 levels [11]. The anti-inflammatory effect of montelukast has mostly been investigated in animal models of asthma; therefore data is limited about its effects on smoke-induced inflammation [12,13]. However possible protective effects on smoke-induced lung injury have been previously reported [14]. In this study, our aim was to investigate the possible anti-inflammatory effects of montelukast in rats with smoke-induced chronic bronchitis. Serum TNF-α level was used as a marker of inflammation and a histopathological evaluation of the lung was performed with both light and electron microscopy. METHODS Animals Male Wistar-Albino rats, weighing g, were used in this study (n = 28). The rats were kept under standard conditions (stainless-steel cages, o C, 55-60% relative humidity, and 12 hours light/dark cycles). Standard chow in tablet form and water were available ad libitum. All animals were free from infections. Rats were exposed to passive cigarette smoke for 20 weeks in order to develop COPD [15] and were decapitated 24 hours after the last injection of the agents; 4 ml of blood was taken intra-cordially for the measurement of serum TNF-α levels. Rat lung tissues were dissected after intra cardiac perfusion. The present study was performed in accordance with the Guiding Principles for the Care and Use of Laboratory Animals; all procedures were approved by the ethics committee of Kocaeli University. Smoke exposure machine A special smoke exposure machine based on Chen s definition and Walton s modification was prepared in the Experimental Medicine Research Laboratory of Kocaeli University [16]. Briefly, the machine consisted of three separate chambers connected to each other. The first chamber was a generation chamber where smoke was generated, the second was a residence chamber where smoke was diluted and the third was an exposure chamber where rats were exposed to smoke. Fans between the chambers were used to conduct smoke from one chamber to another, operating at a speed of 5.2 L/min. Standardized nicotine and cigarette tar were used for exposure 2 hours per day for 20 weeks. Study population The rats were divided into four groups; smoke exposure and injections were performed in three of the groups while the group of rats without smoke exposure constituted the healthy controls. All injections were performed each day at 09:00 am after development of COPD and continued for 21 days. The study groups and doses of injections were as follows: 1. MON group: 7 rats received 0.1 mg/kg montelukast (Sigma-Aldrich, Italy) dissolved in 1 ml Na 2 CO 3 (sodium bicarbonate) intraperitoneally. 2. MON control: 7 rats received 1 ml Na 2 CO 3 (Sigma-Aldrich, Italy) intraperitoneally (control group for montelukast). 3. COPD control: 7 rats received 1 ml physiological serum intraperitoneally. 4. Healthy control: the 7 rats in this group were not exposed to smoke; however they were kept in the same machine for 2 hours daily with clean air in order to provide exposure to similar stress. Histopathological evaluation Light microscopy: After the perfusion of 2.5% glutaraldehyde, lung tissue specimens were dehydrated in a graded series of ethanol (70%, 80%, 90% and 100%), cleared in toluene and embedded in paraffin. Section paraffin blocks at 5 µm thickness were stained with hematoxylin and eosin (H&E) and evaluated with an Olympus BH2 photomicroscope (Tokyo, Japan). Light microscopic results were scored for four I Basyigit, M Sahin, D Sahin, F Yildiz, H Boyaci, S Sirvanci, F Ercan Montelukast and smoke-induced lung injury Montelukast nel danno polmonare da fumo MRM 93

19 MRM _def:Layout 1 08/04/10 15:47 Pagina 94 Multidisciplinary Respiratory Medicine 2010; 5(2): histopathological categories; 1) dilatation of respiratory tract, 2) infiltration of inflammatory cells, 3) proliferation of respiratory epithelium, and 4) vascular congestion. The first three categories were scored from 0 to 3, 0 indicating no pathology and 3 the most severe damage, using a semi-quantitative scale; the last category was scored from 0 to 1 with respect to absence or presence of vascular congestion. The total histopathological score of the lung was calculated as the sum of the scores given for each criterion [17]. Electron microscopic evaluation: After the perfusion of 2.5% glutaraldehyde, lung tissue specimens were post-fixated with 1% osmium tetroxide (0.1 M, ph 7.2), dehydrated in a graded series of ethanol (70%, 80%, 90% and 100%), cleared in toluene and embedded in Epon812 for 24h at 60 o C. Semithin sections of 1 µm were cut, stained with toluidine blue and viewed with the light microscope for proper orientation. Tissues were then thin sectioned (60 nm), stained with uranyl acetate and lead citrate and evaluated in a JEOL 1200 SX transmission electron microscope [18]. FIGURE 1: LIGHT MICROSCOPIC FINDINGS OF LUNG TISSUE FROM MONTELUKAST (MON) CONTROL GROUP a Serum TNF-α measurement Blood samples were taken intra-cordially in dry tubes. After centrifugation, serum was aspirated and TNF-α was measured with the ELISA method (Biosource Rat TNF-α kit, CA, USA). TNF-α measurement level was pg/ml. Statistical analysis All data were analyzed using the SPSS program version The results were expressed as mean ± standard error (SE). Kruskall-Wallis test was used for statistical comparison of the groups and a p < 0.05 was considered as statistically significant. RESULTS We found dilatation in alveolar duct and respiratory bronchioles, proliferation of alveolar epithelial cells, inflammatory cell infiltration and vascular congestion in the MON control and COPD control groups. The number of type 2 pneumocyte cells and surfactant levels was increased in electron microscope specimens of both groups (Figures 1 and 2). In the MON group, on the other hand, dilatation of alveolar duct was seen less prominently, and there was a decrease in the inflammatory cell infiltration, respiratory epithelial cell proliferation and vascular congestion (Figure 3). Electron microscopic findings were found to be less improved with montelukast therapy where surfactant deposition and an increase in the number of macrophages were observed (Figure 4). The total histopathological score was significantly lower in the healthy control group (2.3 ± 0.2) compared to COPD control and MON control groups (p < 0.001). However, there was also a significant difference between the montelukast group (MON) and both COPD controls and MON controls (5.1 ± 0.6 in MON vs. 8.4 ± 0.6 in MON controls and 8.7 b Evidence can be seen of (1a) alveolar duct dilatation (*), respiratory epithelial proliferation ( ), and (1b) increased inflammatory cell infiltration ( ) (H&E, 1a:X100; 1b:X200). ± 0.4 in COPD controls, p < 0.05). There was no significant difference between the healthy control group and the MON group (Figure 5). All four categories included in the total histopathological score were also evaluated separately (Table I). We found the inflammatory cell infiltration, respiratory epithelial proliferation and respiratory tract dilatation to be decreased in the smoke-exposed rat lungs of the montelukast group compared to the MON control and COPD control groups. Vascular congestion was found to be less affected by the montelukast treatment. Smoke exposure caused a significant elevation of serum TNF-α levels in COPD controls and MON controls. However montelukast decreased this elevation to a level comparable with the healthy controls; no significant difference was found between the montelukast group and healthy controls (38.84 ± 4.9 pg/ml vs ± 3.6 pg/ml respectively, p > 0.05) (Figure 6). DISCUSSION This study demonstrated that montelukast has protective effects on both inflammatory and histopathological aspects of smoke-induced lung 94 MRM

20 MRM _def:Layout 1 08/04/10 15:47 Pagina 95 FIGURE 2: LIGHT AND ELECTRON MICROSCOPIC FINDINGS OF COPD CONTROL GROUP a b 2a: showing inflammatory cell infiltration ( ) and airway wall edema (o) (H&E, X100). 2b: showing increase in surfactant deposition ( ) and increase in the number of macrophages ( ) (X6000). FIGURE 3: LIGHT MICROSCOPIC EVALUATION OF LUNG TISSUE FROM MONTELUKAST GROUP (MON) a b 3a: showing alveolar duct dilatation (*) and decrease in respiratory epithelial proliferation ( ). 3b: showing decrease in inflammatory cell infiltration ( ) and arterial wall edema (o) (H&E, 1acX100; 1d:X400). I Basyigit, M Sahin, D Sahin, F Yildiz, H Boyaci, S Sirvanci, F Ercan Montelukast and smoke-induced lung injury Montelukast nel danno polmonare da fumo injury. The effects of smoke exposure in the lung parenchyma was evaluated with light and electron microscopes and montelukast was found to decrease the inflammatory cell infiltration, respiratory cell proliferation, and alveoli-bronchiolar dilatation in smoke-exposed rat lungs. The effects on surfactant deposition and macrophage recruitment in the alveolar space were less prominent; however serum TNF-α levels were shown to be suppressed significantly with montelukast treatment. Smoke-induced increase in leukotriene levels and associated changes in the airways such as recruitment of inflammatory cells, vascular congestion, mucus hypersecretion and bronchoconstriction have been shown previously [1,19,20]. In addition, our study displayed significant alveolar dilatation, inflammatory cell infiltration, vascular congestion and surfactant deposition in the smoke exposed rat lung and indicated some beneficial effects of montelukast on such alterations. Yüksel et al. investigated the effects of montelukast on smoke-induced lung injury in rats [14]. They performed morphometric examinations of lung tissues and counted mast cell numbers in lung parenchyma besides histopathological evaluation. Using a digital computerized system adapted to a light microscope, they measured linear intercept of alveolar septa as an indicator of airspace dilatation and volume density of alveolar septa and the density of alveolar surface area as indicators of tissue loss. Smoke exposure was found to be associated with alveolar dilatation and tissue loss though significant improvements were noted in the montelukast treated rats. The authors also reported that histopathological alterations such as airspace enlargements, alveolar distortion and visceral pleural thickening were more severe in the smoke-exposed controls than in the montelukast treated group [14]. In our study, a histopathological scoring system was used to evaluate lung parenchyma and, although the methods are not quite the same as those in the study of Yüksel et al., we also demonstrated several protective effects of montelukast on smoke-induced lung injury. In addition, we found a significant decrease in the serum levels of TNF-α in the montelukast treated rats. TNF-α which is known as a neutrophil chemotactic cytokine has been found to be elevated in human MRM 95

21 MRM _def:Layout 1 08/04/10 15:47 Pagina 96 Multidisciplinary Respiratory Medicine 2010; 5(2): FIGURE 4: ELECTRON PHOTOMICROGRAPH OF LUNG TISSUE FROM MONTELUKAST GROUP (MON) a FIGURE 5: HISTOPATHOLOGICAL SCORE OF THE LUNG TISSUE SPECIMEN Histopatological Score ** Healthy control * MON group MON control COPD control * p < 0.05; MON group vs. MON control and COPD control groups. ** p < 0.001; healthy controls vs. MON control and COPD control groups. b 4a showing: increase in surfactant deposition in the type 2 pneumocyte ( ). 4b: showing increase in the number of macrophages ( ) (X6000). smokers and it is thought to have an important role in the pathogenesis of COPD since animal models of smoke exposure showed a strong correlation between serum TNF-α levels and airspace dilatation [21]. Montelukast has been shown to inhibit several proinflammatory cytokines in animal models of asthma [12,13]. Maeba et al. reported an inhibitory effect of montelukast on the lipopolysaccharide induced production of IL-1β, IL-6, TNF-α and MCP-1 from peripheral blood mononuclear cells, while Can et al. showed a decrease in serum TNF-α levels in pediatric asthmatics with montelukast treatment [22,23]. Our study demonstrated the inhibitory effect of montelukast on smoke-induced elevation of serum TNF-α in rats. This finding suggests that, besides its anti-inflammatory effects in asthma, montelukast might also suppress smoke induced inflammation. Recent studies have reported that smoking may affect the response to anti-inflammatory therapy since smoker asthmatics get less benefit from treatment with inhaled corticosteroid, and have recommended leukotriene antagonists as an alternative anti-inflammatory agent in the treatment of smoker asthmatics [8]. On the other hand, COPD has a distinct association with smoking and is thought to have different inflammatory characteristics from asthmatics. The bronchodilator effects of leukotriene modifiers have been investigated in clinical studies of COPD and TABLE I: HISTOPATHOLOGICAL SCORE FOR SINGLE PARAMETERS AND TOTAL SCORE Groups Histopathological categories Grade range Healthy control MON group MON control COPD control Dilatation of respiratory tract ± ± ± ± 0.3 Infiltration of inflammatory cells ± ± ± ± 0.1 Proliferation of respiratory epithelium ± ± ± ± 0.2 Vascular congestion ± ± ± ± 0.1 Total histopathological score ± 0.2** 5.1 ± 0.6* 8.4 ± ± 0.4 * p< 0.05; MON group vs. MON control and COPD control groups. ** p< 0.001; healthy control vs. MON control and COPD control groups. 96 MRM

22 MRM _def:Layout 1 08/04/10 15:47 Pagina 97 FIGURE 6: SERUM TNF-α LEVELS OF STUDY GROUPS TNF-α (pg/ml) * Healthy control ** MON group MON control *p < 0.01; healthy control vs. MON control and COPD control groups. ** p < 0.05; MON group vs. MON control and COPD control groups. COPD control improvements in FEV 1 levels were reported [9-11]. Montelukast was also shown to be associated with symptom relief, improvements in the quality of life scores, decrease in the use of inhaled cortico - steroids and bronchodilators, and a reduction in exacerbations and hospitalization rates [9,24]. However data are limited about the anti-inflammatory effects of montelukast in smoke-induced inflammation. Celik et al. studied the effects of montelukast on pulmonary function tests and quality of life scores in COPD patients; in this controlled study sputum samples were also obtained for the evaluation of inflammation, which it was possible to examine in 24 patients. Compared to the control group, a significant decrease in neutrophilic inflammation was observed in the montelukast treated group [9]. Although we did not count an exact number of inflammatory cells, our study also demonstrated a significant decrease in inflammatory cell infiltration in the lung parenchyma and a reduction in serum TNF-α, which is thought to be an indicator of neutrophilic inflammation. There are some limitations of our study as a model of airway inflammation; one may be the lack of inflammatory marker levels in bronchial secretions and the other may be the lack of differential inflammatory cell counts. Nevertheless, we thought that serum levels of TNF-α is an important marker for inflammation in COPD and demonstrating its reduction with montelukast therapy is quite an interesting finding. In conclusion, treatment with montelukast in smoke-exposed rats is shown to be associated with the suppression of serum TNF-α levels as well as with improvements in histopathological alterations incurred by smoke exposure. Further studies are needed to investigate the use of montelukast as an anti-inflammatory agent in smoke-induced lung diseases. CONFLICT OF INTEREST STATEMENT: None of the authors has any conflict of interest to declare in relation to the subject matter of this manuscript. I Basyigit, M Sahin, D Sahin, F Yildiz, H Boyaci, S Sirvanci, F Ercan Montelukast and smoke-induced lung injury Montelukast nel danno polmonare da fumo References 1. Carpagnano GE, Kharitonov SA, Foschino-Barbaro MP, Resta O, Gramiccioni E, Barnes PJ. Increased inflammatory markers in the exhaled breath condensate of cigarette smokers. Eur Respir J 2003;21: Tetley TD. Inflammatory cells and chronic obstructive pulmonary disease. Curr Drug Targets Inflamm Allergy 2005;4: Barnes PJ. 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Respirology 2004;9: Lazarus SC, Chinchilli VM, Rollings NJ, Boushey HA, Cherniack R, Craig TJ, Deykin A, DiMango E, Fish JE, Ford JG, Israel E, Kiley J, Kraft M, Lemanske RF Jr, Leone FT, Martin RJ, Pesola GR, Peters SP, Sorkness CA, Szefler SJ, Wechsler ME, Fahy JV; National Heart Lung and Blood Institute's Asthma Clinical Research Network. Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am J Respir Crit Care Med 2007;175: Celik P, Sakar A, Havlucu Y, Yuksel H, Turkdogan P, Yorgancioglu A. Short-term effects of montelukast in stable patients with moderate to severe COPD. Respir Med 2005;99: Nannini LJ Jr, Flores DM. Bronchodilator effect of zafirlukast in subjects with chronic obstructive pulmonary disease. Pulm Pharmacol Ther 2003;16: Nguyen M, Woo D. Beyond asthma: a meta-analysis of leukotriene antagonists in the treatment of COPD (abstract). Chest 2008;134:p Wu Y, Zhou C, Tao J, Li S. Montelukast prevents the decrease of interleukin-10 and inhibits NF-kappaB activation in inflammatory airway of asthmatic guinea pigs. Can J Physiol Pharmacol 2006;84: Harrison S, Gatti R, Baraldo S, Oliani KL, Andre E, Trevisani M, Gazzieri D, Saetta M, Geppetti P. Montelukast inhibits inflammatory responses in small airways of the Guinea-pig. Pulm Pharmacol Ther 2008;21: Yüksel H, Ozbilgin K, Coskun S, Tuglu I. Protective effects of leukotriene receptor antagonist montelukast on smokinginduced lung injury in Wistar rats. Acta Med Okayama MRM 97

23 MRM _def:Layout 1 08/04/10 15:47 Pagina 98 Multidisciplinary Respiratory Medicine 2010; 5(2): ;57: Wright JL, Churg A. Animal models of cigarette smokeinduced COPD. Chest 2002;122(6 Suppl):S301-S Chen BT, Weber RE, Yeh HC, Lundgren DL, Snipes MB, Mauderly JL. Deposition of cigarette smoke particles in the rat. Fundam Appl Toxicol 1989;13: Sener G, Topaloğlu N, Sehirli AO, Ercan F, Gedik N. Resveratrol alleviates bleomycin-induced lung injury in rats. Pulm Pharmacol Ther 2007;20: Akgun S, Tekeli A, Isbir SC, Civelek A, Ak K, Sirvanci S, Arbak S, Yaylim I, Arsan S. FK506 to prevent lung injury after hindlimb ischemia and reperfusion in a rat model: an electron microscopic study. Surg Today 2004;34: Fauler J, Frölich JC. Cigarette smoking stimulates cysteinyl leukotriene production in man. Eur J Clin Invest 1997;27: Busse WW, McGill KA, Horwitz RJ. Leukotriene pathway inhibitors in asthma and chronic obstructive pulmonary disease. Clin Exp Allergy 1999;29(Suppl 2): Churg A, Cosio M, Wright JL. Mechanisms of cigarette smoke-induced COPD: insights from animal models. Am J Physiol Lung Cell Mol Physiol 2008;294:L612-L Maeba S, Ichiyama T, Ueno Y, Makata H, Matsubara T, Furukawa S. Effect of montelukast on nuclear factor kappab activation and proinflammatory molecules. Ann Allergy Asthma Immunol 2005;94: Can M, Yüksel B, Demirtaş S, Tomaç N. The effect of montelukast on soluble interleukin-2 receptor and tumor necrosis factor alpha in pediatric asthma. Allergy Asthma Proc 2006;27: Rubinstein I, Kumar B, Schriever C. Long-term montelukast therapy in moderate to severe COPD - a preliminary observation. Respir Med 2004;98: MRM

24 MRM _def:Layout 1 08/04/10 15:47 Pagina 99 Review / Rassegna Cough variant asthma and atopic cough Asma variante con tosse e tosse atopica Chiara Magni 1, Elisa Chellini 1, Alessandro Zanasi 2,3 1 Dipartimento di Medicina Interna, Malattie dell Apparato Respiratorio e Terapie Cellulari, Università di Firenze 2 UO Pneumologia, S. Orsola-Malpighi, Bologna 3 Presidente AIST (Associazione Italiana per lo Studio della Tosse) ABSTRACT Chronic cough has been reported to be the fifth most common complaint seen by primary care physicians in the world, the third in Italy. Chronic cough in non-smoking, non-treated with ACE-inhibitor adults with normal chest radiogram could be a symptom of asthma and can be sub-classified into: cough-variant asthma, atopic cough, and eosinophilic bronchitis. This review discusses the differential diagnosis of these three disorders. Keywords: Atopic cough, bronchial hyperresponsiveness, cough-variant asthma, eosinophilic bronchitis. RIASSUNTO La tosse cronica è la quinta causa che induce a consultare il proprio medico di famiglia nel mondo, in Italia è la terza. La tosse cronica in un adulto non fumatore che non assume ACEinibitori ed ha una Rx torace nella norma può essere un sintomo indicatore di asma in una delle sue tre varianti: asma variante con tosse, tosse atopica e bronchite eosinofila. La diagnosi differenziale di queste tre patologie è oggetto di questa rassegna. Parole chiave: Asma variante con tosse, bronchite eosinofila, iperreattività bronchiale, tosse atopica. In some patients cough is a chronic unremitting symptom leading to a marked decrement in quality of life [1,2]. Chronic cough has been reported to be the fifth most common complaint seen by primary care physicians [3]. For instance, in USA up to 38% of a pulmonologist s outpatient practice is accounted for by persistently troublesome chronic cough [4]. In Japan, cough is the most frequent reason (11.7% of all) why patients visit clinics [5]. In Italy, cough is the third most common cause of medical visits with about 25 million consultancies for cough per year of which 5 million for the acute problem and 2 million for the chronic one (Dal Negro, personal communication). According to questionnaire surveys, the prevalence of chronic cough in the general population, including children, may vary from 9 to 33% [6]. Chronic cough is present in older subjects as may be seen from the average age of patients seen in cough clinics (Table I). The most common causes worldwide of chronic cough in non-smoking, non-treated with ACE-inhibitor adults with normal chest radiogram include the upper airway cough syndrome (UACS), gastroesophageal reflux disease (GERD) and asthma syndromes [4,7-15]. This indicates a group of related airway disorders including the classic asthma, the so-called cough variant asthma, nonasthmatic eosinophilic bronchitis (NAEB), and atopic cough. However, even if the guidelines on cough diagnosis and management [16-18] are followed in detail, the cause of chronic cough may remain unexplained in up to 33-46% of cases [6,19]. The prevalence of UACS, GERD and asthma syndromes varies in different reports [4,7-15]. This suggests the necessity of further examination to elucidate cough mechanisms and etiology [20]. The differences in prevalence may depend upon racial and life style differences, access to specialists or differences in the definition of some cough causes [21,22]. For instance, in the United Kingdom and Australia the two most common causes of cough are rhinitis for both (24% and 93% respectively), followed by asthma in UK (17.6%) and GERD in Australia (70%) [11,23]. In Turkey, eosinophilic bronchitis is the cause of chronic cough in 33.3% of patients, while postnasal drip syndrome and GERD are each responsible for chronic cough in 22.2% of patients [24]. In Japan, cough variant asthma and atopic cough are + Alessandro Zanasi UO Pneumologia, S. Orsola-Malpighi Via Massarenti 9, Bologna (Italia) Data di arrivo del testo: 22/01/ Accettato per la pubblicazione: 07/02/2010 Multidisciplinary Respiratory Medicine 2010; 5(2): MRM 99

25 MRM _def:Layout 1 08/04/10 15:47 Pagina 100 Multidisciplinary Respiratory Medicine 2010; 5(2): TABLE I: COMMONEST CAUSES OF CHRONIC COUGH IN PATIENTS INVESTIGATED IN SPECIALIST CLINICS Author Patients' mean age Diagnosis (% of total) in years (range) Asthma syndrome GERD Rhinitis Most common other causes Irwin et al [38] 50.3 (17-88) Chronic bronchitis (12) Poe et al [39]? (15-89) Postinfectious (27) Poe et al [7] 44.8 (19-79) Idiopathic (12) Irwin et al [4] 51 (6-83) Chronic bronchitis (5) Hoffstein 1994 [40] Postinfectious (21) O Connell et al [41] 49 (19-83) Idiopathic (22) Smyrnios et al [42] 58 (18-86) Chronic bronchitis (11) Mello et al [43] 53.1 (15-83) Bronchiectasis (4) Marchesani et al [44] Chronic bronchitis (16) McGarvey et al [10] 47.5 (18-77) Idiopathic (18) Palombini et al [13] 57 (15-81) Bronchiectasis (18) Brightling et al [11] * Postviral (13) Definition of abbreviation: GERD, gastroesophageal reflux disease. *No figures given for the total sample but mean age of 12/91 patients with eosinophilic bronchitis given as 52 (28-76) years. major causes of isolated chronic non-productive cough [25]. Gastro-esophageal reflux-associated cough and post-nasal drip-induced cough, which are major causes of chronic cough in Western countries [26], are very rare in Japan [27]. Chronic cough can arise in asthma in various clinical settings, and is not always associated with airflow obstruction, wheezing or dyspnea. In addition, asthma may predominantly present with cough, which is often nocturnal; the diagnosis is supported by the presence of bronchial hyper-responsiveness [28]. Elderly people with asthma can also present with a history of chronic cough, with little or no wheezing. Cough is often the symptom most report- TABLE II: COUGH CAUSED BY EOSINOPHILIC AIRWAY DISEASES Asthma Cough variant Atopic Eosinophilic asthma cough bronchitis Symptoms Cough, breathlessness, Cough only Cough only Cough and sputum wheeze Atopy Common Common Common As in general population Variable airflow obstruction + ± - - Airway hyper-responsiveness Capsaicin cough hyper-responsiveness ± ± - + Bronchodilator response Corticosteroid response Response to H 1 antagonist ± ± + NK Progression to asthma n/a 30% rare 10% Sputum eosinophilia (> 3%) Frequent Frequent Frequent Always (by definition) Submucosal eosinophils BAL eosinophilia Mast cells in ASM NK Basement membrane thickness NK Definition of abbreviations: ASM, airway smooth muscle; BAL, bronchoalveolar lavage; n/a, not applicable; NK, not known. + = often present. ± = sometimes present. = not present. = increased. = not increased. 100 MRM

26 MRM _def:Layout 1 08/04/10 15:47 Pagina 101 ed by patients with chronic asthma, despite the fact they have achieved good asthma control with inhaled corticosteroids [29]. Finally, cough can be the first sign of worsening of asthma; doctors should look for a fall in early morning peak flows [30]. As mentioned above, three asthma-related conditions, which are accompanied by chronic cough, have been described: cough-variant asthma, atopic cough, and eosinophilic bronchitis (Table II) [30]. Whether atopic cough represents a self-standing airway disease is still the object of debate [31]. In 1992 Fujimura and others proposed the existence of a bronchodilator-resistant non productive chronic cough associated with atopy which they termed atopic cough [32]. According to the authors [31], the pathological characteristics of atopic cough include eosinophilic tracheobronchitis without broncho - alveolar lavage (BAL) eosinophilia, and the physiological characteristics of atopic cough include cough hypersensitivity without bronchial hyper - responsiveness (BHR) [33]. Conversely, cough variant asthma [34] appears to be similar to asthma, with mild BHR and eosinophilic inflammation of central and peripheral airways, and a cough responsive to bronchodilator treatment [28]. Until the 1970s cough was commonly associated with episodic wheezing and dyspnea in symptomatic asthmatic patients. Corrao et al. [28] studied six patients with chronic persistent cough as the sole manifestation of bronchial asthma as diagnosed according to the criteria of the American Thoracic Society [35]: all had persistence for an average of six months, inducible diffuse airway broncho - constriction and disappearance of cough with specific bronchodilator therapy. The return of cough when bronchodilators were discontinued, the disappearance of cough with the re-institution of this medication and the subsequent development of wheezing in two patients further supported the authors contention that these cases represented a variant group of asthma [28]. Some years later Braman and Corrao [3] re-studied patients diagnosed with cough variant asthma and found that 37% of these patients had developed intermittent wheezing. As nearly 30% of patients with cough variant asthma have been found to develop typical asthma, cough variant asthma has been considered a precursor of typical asthma. However, the evolution of atopic cough, particularly with regard to its progression to typical asthma, has not been elucidated [31]. Determining whether atopic cough is a precursor of asthma may be important [36] in terms of the possibility of early intervention in asthma therapy. In 2003 Fujimura et al. [31] examined retrospectively the onset of typical asthma, defined as wheezing and/or a dyspneic attack responding to inhaled β 2 -agonists, in 82 patients with atopic cough (with probable or definite diagnosis) and in 55 patients affected by cough variant asthma with or without long term treatment with inhaled steroids. The median follow up period for patients with atopic cough and cough variant asthma was 4.8 and 3.7 years, respectively. The diagnosis of atopic cough was made according to the following criteria proposed by the Japanese Cough Research Society: 1. Non-productive cough lasting for more than 8 weeks without wheezing or dyspnea. 2. Presence of one or more findings indicative of an atopic constitution, including a past history and/or complications of allergic diseases excluding asthma, peripheral blood eosinophilia ( 6% or 400 cells/ml), raised total IgE level in serum ( 200 IU/mL), positive specific IgE antibody to aeroallergens and positive allergen skin test and/or induced sputum eosinophilia ( 2.5%). 3. No bronchial reversibility, defined as less than a 10% increase in forced expiratory volume in 1 sec (FEV 1 ) after inhalation of 300 µg salbutamol sulphate. 4. Normal bronchial responsiveness (positive responsiveness being the provocative concentration of methacholine causing a 20% fall in FEV 1 (PC 20 ) < 10 mg/ml). 5. Increased cough reflex sensitivity (capsaicin concentration eliciting five or more coughs (C5) 3.9 mmol/l). 6. Cough resistant to bronchodilator therapy (oral clenbuterol 40 mg/day plus inhaled procaterol or salbutamol at bedtime and on demand for 1 week). 7. No abnormal findings indicative of cough etiology on chest X-ray. 8. Normal FEV 1 ( 80% of predicted value), forced vital capacity (FVC) ( 80% of predicted value), and FEV 1 /FVC ratio ( 70%). When all criteria were satisfied, a definite diagnosis of atopic cough was made. If one or more criteria were not satisfied (or assessed), a diagnosis of probable atopic cough was made when all of the following were present: i) non-productive cough lasting more than 8 weeks without wheezing or dyspnea; ii) cough resistant to bronchodilator therapy; iii) presence of one or more findings indicative of atopic constitution as a global feature described above and/or induced sputum eosinophilia ( 2.5%); and iv) complete relief of cough after treatment with histamine H1-antagonists and/or corticosteroid therapy. The complete relief of cough within 2 months of treatment was an important factor in making a probable diagnosis of atopic cough even if 2 3 weeks of oral corticosteroids were required for severe patients. The diagnosis of cough variant asthma was made according to the following criteria proposed by the Japanese Cough Research Society: i) isolated chronic non-productive cough lasting more than 8 weeks; ii) absence of a history of wheeze or dyspnea, and no adventitious lung sounds on physical examination; iii) absence of postnasal drip to account for the cough; iv) FEV 1, FVC, and FEV 1 /FVC ratio within normal limits; v) presence of bronchial hyper - responsiveness (PC 20 < 10 mg/ml); vi) cough reflex sensitivity within normal limits (C5 > 3.9 mmol/l); vii) no abnormal findings indicative of cough etiol- C Magni, E Chellini, A Zanasi Cough variant asthma and atopic cough - Asma variante con tosse e tosse atopica MRM 101

27 MRM _def:Layout 1 08/04/10 15:47 Pagina 102 Multidisciplinary Respiratory Medicine 2010; 5(2): ogy on chest radiograph; and viii) relief of cough with bronchodilator therapy. The efficacy of bronchodilator therapy was assessed according to the following criteria: i) excellent when cough was totally resolved; ii) good when sleep and daytime quality of life were improved; iii) fairly good when severity and frequency of cough were somewhat decreased; and iv) poor when the cough was unchanged. An assessment of excellent or good was judged as effective. When all criteria were satisfied, a definite diagnosis of cough variant asthma was made. If one or more criteria were not satisfied (or assessed), a diagnosis of probable cough variant asthma was made when all of the following were present: i) cough without wheezing lasting 8 weeks or more and no wheezes on auscultation; ii) no upper respiratory tract infection within 8 weeks; and iii) relief of cough with bronchodilator therapy. The results showed that in patients with cough variant asthma the onset of typical asthma occurred in 5.7% of patients in the group treated with inhaled corticosteroid therapy and in 30% of patients in the group not treated. In patients with atopic cough the onset of typical asthma was confirmed in only 1.2% of the total. The onset of typical asthma was thus significantly less prevalent in patients with atopic cough than in those with cough variant asthma. In addition, long term inhaled steroids significantly decreased the development of typical asthma in patients with cough variant asthma. If mild asthma benefits from early intervention with long term inhaled steroids, it will be also useful for cough variant asthma. As atopic cough differs from cough variant asthma with regard to both outcome and pathophysiological features, the authors recommended that atopic cough be recognized as a new clinical entity characterized by isolated chronic non-productive cough [31]. Morice and McGarvey [37] in a letter to Fujimura and collegues expressed their dismay at reading the paper [31]. The diagnosis of atopic cough, they claimed, would succeed only in adding further unnecessary complexity to the cough-related conditions [37]. The evidence to support a new clinical entity atopic cough they felt was tenuous and further hampered by the extremely vague term probable atopic cough, that merely described atopic individuals with cough predominant asthma. Such diagnostic imprecision may yet have therapeutic consequences but Morice and McGarvey claimed that the authors did not provide sufficient information in the paper to conclude that these patients had failed to respond to steroids, and claimed that the response to bronchodilators was tested in neither a randomized nor a controlled way [37]. The absence of transformation to typical asthma was considered too heavily to differentiate atopic cough from asthmatic cough [37]. The lack of progression to typical asthma is well described both in atopic cough and in cough variant asthma, so it cannot be used to support the proposition that atopic cough is unique [37]. Summing up, Morice and McGarvey believe their clinical understanding of asthmatic cough is enhanced by the recognition that an individual patient may show different features of the disease process. The unnecessary subdivision into an arbitrarily defined disease such as atopic cough (or, indeed, eosinophilic bronchitis) is not helpful either diagnostically or therapeutically. In conclusion, the confusion or lack of consensus in cough-related disorders may be affecting the etiology of chronic cough reported from various countries [21]. Issues such as site of inflammation, mediators involved, and allergens in atopic causes for these entities remain to be clarified in more detail in future studies [45]. CONFLICT OF INTEREST STATEMENT: None of the authors has any conflict of interest to declare in relation to the subject matter of this manuscript. 102 MRM References 1. French CL, Irwin RS, Curley FJ, Krikorian CJ. Impact of chronic cough on quality of life. Arch Intern Med 1998;158: Birring SS, Prudon B, Carr AJ, Singh SJ, Morgan MD, Pavord ID. Development of a symptom specific health status measure for patients with chronic cough: Leicester Cough Questionnaire (LCQ). Thorax 2003;58: Braman SS, Corrao WM. Chronic cough. Diagnosis and treatment. Prim Care 1985;12: Irwin RS, Curley FJ, French CL. Chronic cough. The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis 1990;141: Yamada T, Yoshimura M, Nago N, Asai Y, Koga Y, Inoue Y, Hamasaki K, Mise J, Lamberts H. What is the Common Diseases and Common Health Problems? The use of ICPC in the community-based project. Jpn J Prim Care 2000;23: Chung KF, Pavord ID. Prevalence, pathogenesis and causes of chronic cough. Lancet 2008;371: Poe RH, Harder RV, Israel RH, Kallay MC. Chronic persistent cough. Experience in diagnosis and outcome using an anatomic diagnostic protocol. Chest 1989;95: Pratter MR, Bartter T, Akers S, DuBois J. An algorithmic approach to chronic cough. Ann Intern Med 1993;119: French CL, Irwin RS, Curley FJ, Krikorian CJ. Impact of chronic cough on quality of life. Arch Intern Med 1998;158: Mc Garvey LP, Heaney LG, Lawson JT, Johnston BT, Scally CM, Ennis M, Shepherd DR, MacMahon J. Evaluation and outcome of patients with chronic non-productive cough using a comprehensive diagnostic protocol. Thorax 1998;53: Brightling CE, Ward R, Goh KL, Wardlaw AJ, Pavord ID. Eosinophilic bronchitis is an important cause of chronic cough. Am J Respir Crit Care Med 1999;160: Kastelik JA, Aziz I, Ojoo JC, Thompson RH, Redington AE, Morice AH. Investigation and management of chronic cough using a probability-based algorithm. Eur Respir J

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Chest 2006;129(1 Suppl):220S-221S. 20. Grabczak EM, Dabrowska M, Krenke R, Domeracka- Kolodziej A, Domagala-Kulawik J, Arcimowicz M, Hamera M, Chazan R. Does the established cause of chronic cough depend on diagnostic approach? J Physiol Pharmacol 2008;59(Suppl 6): Niimi A. Geography and cough aetiology. Pulm Pharmacol Ther 2007;20: Morice AH. Epidemiology of cough. Pulm Pharmacol Ther 2002;15: Carney IK, Gibson PG, Murree-Allen K, Saltos N, Olson LG, Hensley MJ. A systematic evaluation of mechanisms in chronic cough. Am J Respir Crit Care Med 1997;156: Ayik SO, Başoğlu OK, Erdínç M, Bor S, Veral A, Bílgen C. Eosinophilic bronchitis as a cause of chronic cough. Respir Med 2003;97: Fujimura M. Cough variant asthma and related disorders: atopic cough. Arerugi no rinsho 1996;16: Irwin RS, Boulet LP, Cloutier MM, Fuller R, Gold PM, Hoffstein V, Ing AJ, McCool FD, O'Byrne P, Poe RH, Prakash UB, Pratter MR, Rubin BK. Managing cough as a defense mechanism and as a symptom. 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29 MRM _def:Layout 1 08/04/10 15:47 Pagina 104 Long summaries / Riassunti estesi COPD a social disease: inappropriateness and pharmaco-economics. The role of the specialist: present and future Venice, Italy, April 21-22, 2010 Conference: "COPD a social disease: inappropriateness and pharmaco-economics. The role of the specialist: present and future", Venice, April 21-22, 2010: long summaries Conferenza: "BPCO una malattia sociale: inappropriatezze ed aspetti farmacoeconomici. Il ruolo dello specialista: presente e futuro", Venezia, aprile 21-22, 2010: riassunti estesi Edited by Claudio F. Donner Rationale and structure of the conference Razionale e struttura della Conferenza Claudio F. Donner Mondo Medico, Multidisciplinary and Rehabilitation Outpatient Clinic, Borgomanero (NO), Italy Chronic respiratory diseases (CRDs), with particular regard to COPD, constitute an epidemic in the full sense of the term, though they still go underdiagnosed and undertreated. COPD is one of the major health problems worldwide, negatively affecting patients and their families, the employment sector, the institutional network and, hence, society as a whole. Its epidemiological, clinical, social and socio-economic impact is on the rise and there are no signs of any change to this trend. The Global Alliance against chronic Respiratory Diseases (GARD) of the World Health Organisation (WHO) - of which AIMAR has been a partner since 2005 [1] - was launched in 2006 as a voluntary alliance of national and international organizations, institutions and agencies committed to the vision of a world where all people can breathe freely [2,3]. The goal of GARD is to improve global lung health by promoting a comprehensive approach to fight CRDs within the framework of the WHO strategic measures [4]. GARD has formulated the following working re - commendations: - to develop national programs of prevention and control of CRDs, with the double aim of defining the most pertinent strategies and healthcare + Claudio F. Donner Mondo Medico, Multidisciplinary and Rehabilitation Outpatient Clinic Via Monsignor Cavigioli 10, Borgomanero (NO), Italy Multidisciplinary Respiratory Medicine 2010; 5(2): MRM

30 MRM _def:Layout 1 08/04/10 15:47 Pagina 105 actions and raising political and social awareness about this public health priority. The first step to attain this goal are health education campaigns and data collection on: the frequency of these diseases, their impact, and the relative risk factors; - to provide training and continuing education on prevention and treatment of CRDs, disseminating the existing guidelines; - to facilitate access to essential treatments and favour adherence to long term treatment, including drug treatment and pulmonary rehabilitation, particularly amongst disadvantaged sectors of the population. Besides GARD recommendations to create synergies on prevention and control between CRDs and other chronic diseases, the final outcome should be country-specific initiatives tailored to local needs. Therefore, after the first phase, from 2006 to 2008, devoted to building a global network, consolidating objectives and creating tools and resources, the second phase (started in 2008 and due to end in 2015) has as its aim to launch GARD national organizations in each country [5]. Pre-requisites for developing a GARD national body are as follows: 1. a prior analysis of the situation of surveillance, prevention and control of chronic respiratory diseases in that country; 2. invitation to the Ministry of Health to participate in the development of the GARD national body; 3. a similar invitation to the WHO Regional Office and WHO country representative. In Italy, all three pre-requisites were fulfilled in June 2009 when GARD-Italy was launched in Rome, during a meeting addressed by the Minister of Health, Ferruccio Fazio [6] in which a Document of Strategy [7] was signed by all the major medical and patients societies and associations attending the meeting. AIMAR signed this document and viewed it as the first endpoint of numerous initiatives carried out by AIMAR to implement GARD in Italy (seminars, learning courses, conferences, documents, recommendations, all aimed at emphasising the importance of respiratory diseases and disseminating the existing guidelines for their management). Among the actions which a GARD national body is urged by WHO-GARD to carry out, one is to re - commend affordable and effective strategies for the management of CRDs based on the latest evidence [8]. Another is to provide training and continuing education on the prevention and treatment of CRDs, disseminating the existing guidelines, while emphasizing the sustainability of all the recommended actions. In face of the need to reconcile the limited available References 1. Donner CF, Nardini S. Multidisciplinary Respiratory Medicine 2006;2(2): European Federation of Allergy and Airways Diseases Patients Associations. Annual Report int/respiratory/publications/beijing%20meeting%20report economic resources with the increasing demand for well-being, the health services of industrialized countries are at present devoting much attention to the costs generated by healthcare in their own territories. CRDs, in particular, concern a large number of subjects and generate important health and social costs. The global impact of these diseases, in particular COPD, has been the subject of an increasing number of pharmaco-economic studies published in the literature in recent years. Although these studies had different experimental designs, they all confirm the growing impact of COPD in all countries, both from the perspective of the patient and patient s family, and that of society as a whole. The findings that emerge reveal that the attitude towards COPD management is still largely inadequate. This Top Seminar, starting from the above scenario, focuses on the role that the pulmonary specialist can play in detecting inappropriateness in the clinical course of COPD and in providing the basis for a correct assessment of pharmaco-economic issues. Given the increasing social impact of COPD, the meeting fits in perfectly with the goals and recommendations of GARD. COPD a social disease: inappropriateness and pharmaco-economics. The role of the specialist: present and future has been organized by AIMAR under the umbrella of the Year of the Lung 2010 promoted worldwide by the Forum of International Respiratory Societies and within Europe by the European Respiratory Society. AIMAR has designed this new Top Seminar as a moment for all the stakeholders (Ministry of Health, health district managers, patient organizations and specialists in respir - atory medicine) to come together and reflect on the pharmaco-economic issues related to the clinical course of COPD. The Seminar will be divided into four sessions: 1. From scientific to social and institutional recognition: comparing different experiences. 2. Pharmaco-economics. 3. Inappropriateness at different steps of management. 4. A new decade of COPD. In each session, leading international scholars of COPD will discuss with the other stakeholders not only the scientific issues, but also the impact - present and future - of COPD from the point of view of the patient, their family and society as a whole. The Seminar will produce a series of documents (e.g. a short report to be published in Respiratory Medicine, and full proceedings in Multidisciplinary Respiratory Medicine, AIMAR s official journal) which will be useful for GARD-I to plan and implement actions so as to make Italy a country where all people can breathe freely. %20FINAL%2 0layout%2026_12_2006.pdf 3. World Health Organization. Surveillance, prevention and control of chronic respiratory diseases: a comprehensive approach. Bousquet J, Khaltaev N, eds. int/gard/publications/gard%20book% pdf CF Donner (ed.) Summaries, COPD: inapropriateness and pharmaco-economics, Venice, April 2010 Riassunti, BPCO: inappropriatezze e farmacoeconomia, Venezia, aprile 2010 MRM 105

31 MRM _def:Layout 1 08/04/10 15:47 Pagina 106 Multidisciplinary Respiratory Medicine 2010; 5(2): World Health Organization Action Plan for the Global Strategy for the Prevention and Control of Noncommunicable Diseases. publications/ncd_action_plan_en.pdf 5. Nardini S, Donner CF. 3 rd GARD World Assembly, Istanbul, May 2008: implications for Italy. Multidisciplinary Respiratory Medicine 2008;3: Donner CF, De Benedetto F, Sanguinetti CM, Nardini S. GARD-Italy launched in Rome on June Future of NHS in the welfare state Il futuro del Servizio Sanitario Nazionale nel welfare state Maurizio Sacconi Minister of Labour and Welfare, Rome, Italy Multidisciplinary Respiratory Medicine 2009;4: Ministero del Lavoro, della Salute e delle Politiche Sociali. GARD-I: Documento di strategia. Multidisciplinary Respiratory Medicine 2009;4: World Health Organization. Action plan of the Global Alliance against Chronic Respiratory diseases, NAL.pdf The National Health Service (NHS) has up till now guaranteed health care to all citizens along with a constant rise both of the average life expectancy and of individual wellbeing. In a certain sense, however, the NHS is today a victim of its own self: in the last fifty years following progress in medicine and in the organization of the social state Italy (as other developed countries) has seen a radical change in what constitute the prevalent diseases and main causes of death, and this change has thrown the NHS into crisis. The chronic invalidating diseases that dominate the scene today cannot be managed with the old hospital-centered model that was based on the need to respond to acute situations: the system has to be readapted to the actual epidemiological situation today. The health care provided for chronic broncho - pulmonary diseases, lung cancer and cancer in general, for diabetes and heart diseases (to mention just a few of the most frequent and important diseases) is becoming increasingly costly (as new pharmacological and rehabilitative therapies are introduced and patients survive longer) and the number of people affected by these diseases is destined to rise substantially as the average age of the population rises. These tendencies could in the medium term render the cost of health unsustainable and, in the absence of corrective re-equilibrating measures, health costs might more than double by For this reason a radical change in the organization of the NHS is necessary, in harmony with a change in the role played by the state. In the 19 th and first part of the 20 th century, the prevalent diseases were infective diseases of an epidemic nature (such as cholera, tuberculosis, poliomyelitis) and the role of the state was in the first place to guarantee drinkable water, sewage disposal and improved living conditions, and successively to help defend the population through programs of mass vaccination against diseases not eliminated by the improved public hygiene. Today the diseases are linked to life styles chosen on an individual basis, not to collective living conditions, and hence the role of the state is no longer to choose and implement the best health options on behalf of citizens but rather to help citizens themselves choose the best options, through education, health information and the provision of integrated services of primary, secondary and tertiary prevention. The future of the NHS will thus be focused on primary prevention (helping citizens to prevent the onset of diseases) and early diagnosis and rehabilitation (helping citizens to reduce the invalidating consequences of already existing diseases with the least possible impact on the community). It goes without saying that the need for a radical change in health care for reasons of sustainability, already announced in previous years, has now become absolutely urgent with the heavy crisis that has recently hit the world economy. These changes in the NHS will take place within the context of an overall change in the whole welfare system, centered on the idea that people first try to develop their own resources to respond to their needs, that people live in a free and responsible manner and respond to their own uncertainties. In other terms, in the new welfare, the concession of protection and subsidies will be subject, where possible, to the citizen s active participation in society through a path that ensures opportunities while stimulating the individual s own responsibility. The link between health and social wellbeing is indissoluble: just as health promotion reduces poverty, emargination and social distress and increases work productivity, employment rates and overall economic growth, so too does an increase in the quality of work and work opportunities over a longer life span, and a context that favours employability and social mobility - whatever the individual s starting point - translate into greater health and psycho-physical wellbeing. The new welfare must orient people towards active behaviours and responsible lifestyles, preventing situations of need due to physiological (infancy, materni- 106 MRM

32 MRM _def:Layout 1 08/04/10 15:47 Pagina 107 ty, old age) or pathological (disease, accident, disability) events or to particular economic situations (business or employment crises, unemployment, termination of work). In this context, health does not mean simply treating the disease but rather a priori promoting wellbeing and developing personal capacities, taking into account the different conditions of each individual. The citizen s active participation, a correct information and health culture, essential in an era of great changes, a renewed relationship of trust between family doctor and patient, are the premises for promoting healthy life in the active society (which also is not by chance the title of the white book on the future of the social model recently produced by the Ministry. The physical setting in which the changes described above will take place is the local community, i.e. the place where the integrated, preventive responses to people s real and potential needs are put into effect, where the policies designed to guarantee the continual employability of people are implemented, so preventing their exclusion from the employment market; and, finally, where the social-health services aimed at prevention, early diagnosis, primary care, and home care are developed. What will have to be achieved as rapidly as possible is a unified management of the homogeneous socio-health-welfare services at local level, able to create a continuum between systems for health care and those for social protection; a unified management that sees the socio-health districts as the citizens center of reference and the place where this integration occurs in effect. In the NHS, one will have to go beyond the concept of integration between hospital and local community in favour of a new interdisciplinary and interprofessional approach with the person at the center of the treatment process (which must flow without interruptions), utilizing a personal electronic dossier that contains all relevant information about the person. In this vision, the hospital will return to its historical role as a provider of emergency and acute care while the general practitioner (GP), operating no longer as a soloist but in association with other professionals in a collaborative network, will be the stable point of reference for the patient throughout the course of the day and week. Addressing an international audience of respiratory specialists, I cannot but conclude with some remarks of particular reference to specialists, focused on the application of the new model of welfare to respiratory medicine. I greatly appreciate the fact that the title of your Seminar is related to the social aspects of the most important chronic respiratory disease and that you particularly wish to examine the specialist s role in the appropriateness of interventions and in the pharmaco-economics of management. Respiratory diseases constitute an emergency. In Italy, all together (including also lung cancer) they represent the second most important cause of death and their frequency and diffusion is probably far greater than we actually realize, given that they are widely under-diagnosed. Underdiagnosis has not only epidemiological but also clinical consequences: as little attention is paid to respiratory diseases by the individual and by the community, those affected receive late and non optimal treatment. A further consequence of the poor visibility that up to now has characterized respiratory diseases is that insufficient consideration is given to the specialist hospital structures dedicated to them. However, signs of the new importance now being attributed to respiratory diseases are the fact that the Italian National Health Plan placed chronic respiratory diseases among its four top health priorities and that the Ministry of Health launched in when I myself was Minister of Health - GARD-Italy, the Italian part of the Global Alliance against Chronic Respiratory Diseases (GARD) of the World Health Organization (WHO), a volountary alliance of national and international organizations, institutional bodies and agencies that has as its goal to reduce the global burden of chronic respiratory diseases. It is precisely this recognized importance that prompts us to denounce the critical situation that exists at present. Patients suffering from chronic pulmonary diseases are treated in a discontinuous and non integrated mode: this leads to inappropriateness of the caring procedures. This inappropriateness represents a cost that is not negligible. The Institute for the Innovation and Improvement of the NHS in Britain evidenced, for example, that GBP 1.3 billion are spent each year in visits to Emergency Care for patients with 18 diseases (www.healthcarecommission.gov.uk). These include up to three or four visits per year by the same patient. Not by chance, occupying first place in the list of diseases is chronic obstructive pulmonary disease (COPD), with more than 106,000 admissions and an annual cost of 253 million, while in third place, after angina pectoris, comes asthma with more than 61,000 admissions and a cost of 64 million. Varying percentages of these admissions resulted inappropriate at a retrospective analysis. An optimal management of the above diseases would not only reduce the crowding of Emergency Care facilities and lower the global health costs, but it would improve also the conditions of life of those affected. At the organizational level, the health care for chronic respiratory diseases will be similar to that for diabetics. One must achieve a greater possibility of self management for the patient, give more responsibility to the GP, with an opportune use of telemedicine and home care built into the plan. In the field of pulmonology, the NHS must undertake in each ULSS to: 1. prevent respiratory disease developing through a consistent reduction of the number of smokers in the community; 2. improve COPD diagnosis, in particular through a more widespread use of spirometric tests; 3. help patients to self manage their own disease, CF Donner (ed.) Summaries, COPD: inapropriateness and pharmaco-economics, Venice, April 2010 Riassunti, BPCO: inappropriatezze e farmacoeconomia, Venezia, aprile 2010 MRM 107

33 MRM _def:Layout 1 08/04/10 15:47 Pagina 108 Multidisciplinary Respiratory Medicine 2010; 5(2): through pulmonary rehabilitation; 4. integrate the care of patients affected by COPD, i.e. link specialist care to primary care, and extend end of life treatment from the oncological to the respiratory sphere. Within the strictly hospital setting, the role of Pneumology will be similar to that of modern cardiology: intensive management of acute respiratory problems and consultancy and specialist guidance provided within the local community. In terms of this project each Operational Unit will have to organize itself. On this subject, I would like to cite an experiment that is underway in the area I come from. It is an initiative in pulmonary rehabilitation on patients affected by COPD, which involves, besides respiratory specialists and GPs, also sports physicians and graduates in motor science. This initiative is being carried out completely in the local community and has so far enrolled 50 patients, who have been offered the possibility of strength re-education. What is news for you who are specialists in the field is not so much the fact that all the participants have increased their performance and improved their quality of life, but that this has all occurred through a multidisciplinary effort and completely outside of the hospital setting. I hope that this Seminar will bring other significant gains to help individual specialists better understand the existing problems and better define their own role. The growing role of rehabilitation and chronic care Il ruolo crescente della riabilitazione e del trattamento cronico Daniela Carraro General Manager, Health & Social Welfare District 21, Legnago (VR), Italy Definition and background Pulmonary rehabilitation is an evidence-based, multidisciplinary and comprehensive intervention for patients with chronic respiratory diseases who are symptomatic and often have decreased daily life activities. Integrated into the individualized treatment of the patient, pulmonary rehabilitation is designed to reduce symptoms, optimize functional status, increase participation, and reduce health care costs through stabilizing or reversing systemic manifestations of the disease [1]. Extensive rehabilitation: Complex welfare activity for patients who have superceded the acute and immediate post-acute phase and require interventions to ensure further functional recovery in a defined time (DRG 398/2000). Rehabilitative maintenance activities: Assistance activities aimed at patients with stabilized outcome from psycho-physical disease requiring interventions to keep any residual capacity functional or to contain the damage (DRG 398/2000). Aim Specific aims of pulmonary rehabilitation are to reduce symptoms, teaching patients to deal successfully with their disease, to maintain an active and independent lifestyle, to maximize functional abilities, to reduce the consumption of healthcare resources and, where possible, to improve survival [2-4]. Materials and methods Pulmonary rehabilitation programs involve patient assessment, exercise training, education, nutritional intervention and psychosocial support. Pulmonary rehabilitation includes a spectrum of interventional strategies integrated into the lifelong management of patients with chronic respiratory disease and involves a dynamic, active collaboration among the patient, family and health care providers. These strategies address both the primary and the secondary impairments associated with the respiratory disease [1]. The rehabilitation program includes optimizing the drug therapy, education, chest physiotherapy, exercise training, respiratory muscle training, selective muscle group training, occupational therapy, reducing workload of the respiratory muscles, long-term oxygen therapy, psychosocial and nutritional programs [5,6]. These programs are aimed at patients with the following diseases: COPD, asthma, cystic fibrosis, bronchiectasis, chronic respiratory failure (CRF) from any cause, severe acute respiratory patients with CRF, restrictive syndromes from neuromuscular and chest wall diseases, pulmonary fibrosis and other interstitial disease, pre- and post-surgery, outcomes of chest injury, respiratory sleep disorders, outcomes of pulmonary embolism, chronic pulmonary heart disease, preparation and management of lung transplantation [7-9]. Pulmonary rehabilitation programs can be performed: - at home: usually they follow the inpatient and outpatient programs; interventions are designed to keep the patient at the highest level of sufficiency; - in day hospital and/or the outpatient setting: activities that tend to reduce impairments report- 108 MRM

34 MRM _def:Layout 1 08/04/10 15:47 Pagina 109 ed by the subject consequent to an acute event; - in hospital: patients with no or limited mobility who need continuous monitoring and invasive maneuvers, or with transport difficulties. An example: COPD (Figure 1). Patients with COPD are a group of high consumers of healthcare resources in terms of drugs, hospital admissions and days spent in hospital: in a study conducted in Italy on moderate to severe COPD patients hospitalized due to exacerbation, health care rehabilitative treatment was only 42 per patient/year, i.e. 0.9% of all direct costs. Despite this, one of the potential benefits of rehabilitation would be to reduce episodes of exacerbations and, as a result, health spending [9-10]. Rehabilitation programs have been shown to reduce hospitalizations and home visits and the number of exacerbations [11]. Clini has demonstrated that a cycle of rehabilitation included in a shorter hospitalization stay resulted in the same physiological effects as a longer cycle in day-hospital, but had lower costs [12]. FIGURE 1: COPD TREATMENT BASED ON DISEASE STAGE I: Mild FEV 1 /FVC < 0.7 FEV 1 80% pred. FEV 1 /FVC < % FEV 1 < 80% pred. Organization, setting While many protocols have been evaluated to render respiratory rehabilitation more efficient in various lung diseases, few studies have focused on the optimal composition of the staff, organization of the place of care and equipment [13]. Respiratory rehab - ilitation is a multidisciplinary intervention, in which the following health professionals collaborate: - pulmonologist, who should have the role of program director - nursing staff - rehabilitation therapists (nine different types re - commended). Areas of rehabilitation treatment and types of patients: 1. Respiratory Intensive Care Unit and general ICU 2. Pulmonary diseases department 3. Pulmonary rehabilitation in pre- and post-thoracic and abdominal surgery 4. Pulmonary rehabilitation in pre- and post-transplant of thoracic and abdominal organs (lung, heart, liver, etc.) 5. Respiratory rehabilitation in diseases characterized by muscle weakness (neuromuscular disorders) 6. Respiratory disease in children [14]. Existing models At present the organizational models and the rehab - ilitation programs are not very uniform. 1. The model used in some foreign countries (USA, Canada, Brazil) and in some Italian hospitals is that physiotherapists form a functional team with the other professionals; they are always present, in ICU and in the Emergency Room, covering the entire day, every day of the week and (only abroad) with shifts even at night. 2. Another organizational model, often found in Italy, provides for the presence of physiotherapists within a single department, or throughout the II: Moderate III: Severe IV: Very severe FEV 1 /FVC < % FEV 1 < 50% pred. FEV 1 /FVC < 0.7 FEV 1 < 30% pred. o FEV 1 < 50% pred. + chronic respiratory failure Active reduction of risk factors; flu vaccination, anti-pneumococcal vacc. Add short-acting bronchodilators (when needed) Add as regular therapy one or more (when needed) long-acting bronchodilators; add rehabilitation Add inhaled corticosteroids in the case of repeated exacerbations Add long term oxygen therapy in the case of respiratory failure. Consider surgery World COPD Project CF Donner (ed.) Summaries, COPD: inapropriateness and pharmaco-economics, Venice, April 2010 Riassunti, BPCO: inappropriatezze e farmacoeconomia, Venezia, aprile 2010 Tratto da [15] mod. MRM 109

35 MRM _def:Layout 1 08/04/10 15:47 Pagina 110 Multidisciplinary Respiratory Medicine 2010; 5(2): entire hospital, especially if this is dedicated to specific diseases. Here the physiotherapist carries out his/her duties, often working alongside other professionals with activities during the day for 5 days/week. These structures also provide out - patient treatment for external or discharged patients (e.g. regional centers for cystic fibrosis and other centers dedicated to pediatric, orthopedic, neuromuscular disease, and many rehabilitation centers in agreement with the National Health System). 3. A third model envisages a pyramid structure, in which physical therapists address all needs; it provides all the benefits of rehabilitation "on demand" as requested by the other operating units. Rehabilitation treatment is interrupted when the patient is discharged, and the physiotherapist moves on to deal with a new case that is assigned [14]. Results and conclusions Pulmonary rehabilitation is undergoing great development. Since the publication of previous recommendations there has been significant progress in both techniques and outcome assessment [13]. The new data give further support for: - the benefits of training in improving lower limb dyspnea and quality of life. There are no definitive studies on the effect on survival, costs and utilization of resources; - other studies have evaluated upper limb training as a means to obtain benefits in daily living activities, but the results do not offer sufficient evidence for its introduction as a routine practice; Data are also emerging on the effects of rehabilitation on respiratory diseases other than COPD. Important areas for future research concern [13]: - the length of the programs and strategies to maintain the benefits obtained; - more efficient use of scarce resources; - individualization of the program to different phenotypes of clinical COPD; - better definition of optimal training schemes; - the supplementation of oxygen in various situations of hypoxemia (resting, stress, night); - the use of non-invasive ventilation; - nutritional supplementation; - electrical stimulation of muscles and peripheral respiratory muscles; - the role of exacerbation to influence results of rehabilitation and viceversa. References 1. Nici L, Donner C, Wouters E, Zuwallack R, Ambrosino N, Bourbeau J, Carone M, Celli B, Engelen M, Fahy B, Garvey C, Goldstein R, Gosselink R, Lareau S, MacIntyre N, Maltais F, Morgan M, O'Donnell D, Prefault C, Reardon J, Rochester C, Schols A, Singh S, Troosters T; ATS/ERS Pulmonary Rehabilitation Writing Committee. American Thoracic Society/European Respiratory Society statement on pulmonary rehabilitation. Am J Respir Crit Care Med 2006;173: Reardon J, Awad E, Normandin E, Vale F, Clark B, ZuWallack RL. The effect of comprehensive outpatient pulmonary rehabilitation on dyspnea. Chest 1994;105: Fishman AP. Pulmonary rehabilitation research. Am J Respir Crit Care Med 1994;149: Cambach W, Chadwick-Straver RV, Wagenaar RC, van Keimpema AR, Kemper HC. The effects of a communitybased pulmonary rehabilitation programme on exercise tolerance and quality of life: a randomized controlled trial. Eur Respir J 1997;10: Rampulla C, Ambrosino N. Riabilitazione nelle malattie respiratorie. Torino, UTET, British Thoracic Society Standards of Care Subcommittee on Pulmonary Rehabilitation. BTS Statement. Pulmonary rehabilitation. Thorax 2001;56: Ambrosino N, Vitacca M. Rampulla C. Percorsi riabilitativi nelle malattie respiratorie. Rassegna di Patologia dell Apparato Respiratorio 1996,11: Ambrosino N, Foglio K. Selection criteria for pulmonary rehabilitation. Respir Med 1996;90: Lucioni C, Donner CF, De Benedetto F, Lusuardi M, Mazzi S, Paggiaro PI, Sanguinetti CM. I costi della broncopneumopatia cronica ostruttiva in Italia: la fase prospettica dello studio ICE. Presentazione della prima fase dello studio ICE. Pharmacoeconomics Italian Research Articles 2005,7, Griffiths TL, Phillips CJ, Davies S, Burr ML, Campbell IA. Cost effectiveness of an outpatient multidisciplinary pulmonary rehabilitation programme. Thorax 2001;56: Ambrosino N, Bellone A. Raccomandazioni sulla riabilitazione respiratoria. Rassegna di Patologia dell Apparato Respiratorio 2001;16: Clini E, Foglio K, Bianchi L, Porta R, Vitacca M, Ambrosino N. In-hospital short-term training program for patients with chronic airway obstruction. Chest 2001;120: Pasqua F, Garuti G. Raccomandazioni sulla riabilitazione respiratoria. Rassegna di Patologia dell Apparato Respiratorio 2007;22: Morlini G. I percorsi della riabilitazione respiratoria. Ambiti di trattamento riabilitativo e tipologie di malati ulto.pdf 15. International Guidelines on Rhinitis, Asthma and COPD. Global Initiatives ARIA, GINA and GOLD/ATS/ERS. 110 MRM

36 MRM _def:Layout 1 08/04/10 15:47 Pagina 111 Session I: From scientific to social and institutional recognition: comparing different experiences Sessione I: Dal riconoscimento scientifico a quello sociale ed istituzionale: comparazione di diverse esperienze The institutions Le Istituzioni Giovanna Laurendi Department of Health Prevention, Ministry of Health, Labour and Welfare, Rome, Italy The incidence of chronic respiratory disease has increased steadily over the past several years and currently constitutes a serious public health problem. Chronic respiratory diseases are often underdiagnosed. Many patients are not diagnosed until the chronic respiratory disease is so severe as to prevent normal daily activities, including attendance at school or work. The prevention of chronic disease, particularly of chronic respiratory diseases, and the reduction of their social and individual impacts is based on the modification of environmental and social factors, and the improvement of diagnosis and treatment. Today, many risk factors have been identified: tobacco smoke, allergens, occupational agents, indoor air pollution and outdoor pollution. Prevention of these risk factors will have a significant impact on morbidity and mortality. In a country such as Italy, where life expectancy is continuously rising, it is important to set up respiratory disease preventive measures, in order to achieve better health conditions and preserve the population s quality of life. The Italian Ministry of Health has made respiratory disease prevention a top priority and has been gradually putting in place a comprehensive strategy. It has a role in the implementation of policies against tobacco smoking, indoor and outdoor pollution, obesity, and communicable diseases. Presently, these actions are not well integrated, and this poor coordination is an important limitation for the Ministry of Health. Therefore, the GARD initiative is a great opportunity for the Ministry of Health which may play a role in coordinating GARD in Italy. Following the WHO-GARD guidelines, we have collaborated in the creation of the Italian GARD. The main objective is to discuss the development of a global chronic respiratory disease program in Italy. Effective prevention implies setting up a health policy with the support of health care professionals and citizen associations at the national, regional, and district levels. What is required is a true interinstitutional synergy: prevention of respiratory diseases cannot and should not be the responsibility of doctors alone, but should involve politicians/policy makers, as well as the media, local institutions, school, and food producers. GARD could be a significant experience and a great opportunity for Italy, and a means to implement the GARD vision of a world where all people can breathe freely. References 1. World Health Organization. World Global Report Preventing chronic diseases: a vital investment. World Health Organization (WHO) Asaria P, Chisholm D, Mathers C, Ezzati M, Beaglehole R. Chronic disease prevention: health effects and financial costs of strategies to reduce salt intake and control tobacco use. Lancet 2007;370: Ministero della Salute. Sito Web 4. ISTAT. Stime preliminari della mortalità per causa nelle regioni italiane - anno CF Donner (ed.) Summaries, COPD: inapropriateness and pharmaco-economics, Venice, April 2010 Riassunti, BPCO: inappropriatezze e farmacoeconomia, Venezia, aprile 2010 MRM 111

37 MRM _def:Layout 1 08/04/10 15:47 Pagina 112 Multidisciplinary Respiratory Medicine 2010; 5(2): Role of patients associations Il ruolo delle Associazioni di pazienti Fausta Franchi Vice President, Italian Association of COPD Patients, Rome, Italy The right to health, as defined in the Italian Republic Constitution, is one of the fundamental rights of an individual. The search for different, new equilibria in which it is the individual, and not the disease, at the centre of the system, requires a greater responsibility on the part of all the players involved, including the patients, to achieve the goal of preventing or delaying the development of complications. Therefore, interventions must be coordinated among scientific societies, professional associations, volunteer organisations, and public and private institutions. It is thus necessary to develop assistential profiles based on a multidisciplinary approach and ensure continuity among actions of prevention, treatment and rehabilitation, with intersectorial interventions, both medical and social, able to involve also the family and volunteer organisations. In the approach to chronic diseases in general, and to COPD in particular, we must work to empower the people, i.e. make them able to participate actively in the therapeutic choices that concern them and in the decisional processes aimed at improving their quality of life and reducing complications. Patients must be helped to obtain ability through acquiring knowledge about the disease and treatments available. Indeed, knowledge is essential to obtain a good level of healthcare that places the patient at its centre. On the other hand, it is also necessary that the health care system and social services are aware of people s needs, and are able to work together to trigger a process of improvement, that respects the rights and freedom of the individual. Primary care Medicina di base Giovanni Invernizzi Tobacco Control Unit, Istituto Nazionale dei Tumori/SIMG Italian College GPs, Milan, Italy Due to its increasing prevalence, COPD is considered a social disease which warrants special attention at primary care level. General practitioners (GPs) have a central role in disease prevention, detection, treatment, and management. This applies also to COPD. Smoking cessation intervention is the cornerstone for preventing COPD: GPs attitude towards offering brief advice to every smoker in the office is becoming a rule, as well as their awareness to belong to the wider network of anti-smoking services. The manifold contacts on a yearly basis with their patients who smoke allow GPs to carry out early detection by means of spirometry, and to collaborate with pneumolgists if needed. COPD treatment should be based on regular therapy with inhaled drugs (long-acting bronchodilators and steroids) to ensure a good quality of life. Prevention and treatment of exacerbations is of the utmost importance: avoiding airborn pollutants (environmental tobacco smoke and urban pollution) is mandatory, while early recognition of an exacerbation, and starting oral steroids and antibiotics courses, are the cornerstone of good practice by GPs. Finally, COPD management is based on planning regular clinical and functional follow up. References 1. Stratelis G, Mölstad S, Jakobsson P, Zetterström O.The impact of repeated spirometry and smoking cessation advice on smokers with mild COPD. Scand J Prim Health Care 2006;24: Lai DT, Cahill K, Qin Y, Tang JL. Motivational interviewing for smoking cessation. Cochrane Database Syst Rev 2010;1:CD MRM

38 MRM _def:Layout 1 08/04/10 15:47 Pagina 113 Role of the respiratory specialist Il ruolo dello specialista di ambito respiratorio Stefano Nardini Pulmonary and TB Unit, General Hospital, Vittorio Veneto (TV), Italy Respiratory diseases constitute an emergency. Altogether (including lung cancer) they represent the 2 nd major cause of mortality and are likely even more frequent than we know given the under-diagnosis that today exists [1-2]. The future trend is for a still further increase, although differentiated for the different diseases [3]. As for other chronic diseases, we need to re-think the organization of health care provided for respiratory diseases. Specialists need ongoing training not only on the technical front but also on health care planning, and must be informed about management and systemic issues based on solid epidemiological data or estimates. Background: respiratory diseases Cancerous diseases. Lung cancer is everywhere one of the primary causes of cancer mortality [4]. Life expectancy at the time of diagnosis is low and has not substantially modified in the last decades due in part to the lack of procedures for early diagnosis [5]. Chronic obstructive diseases. These diseases (in particular, COPD and asthma) rank amongst the foremost causes of death and invalidity. COPD is very widespread, affecting at least 10-15% of the adult population [6]. It is estimated that COPD will rank 3 rd as a cause of morbidity and 6 th as a cause of mortality in 2020 [7]. The prevalence of asthma shows a wide variation among the different countries, ranging from 2-4% in the large Asian countries to 15%-20% in England, Canada, Australia and New Zealand [8]. In Italy, its prevalence is about 7% in children [9]. Asthma is moreover the most frequent occupational disease. Infective respiratory diseases. In contrast to other specialist disciplines like gastroenterology, last century did not see a reduction in the morbidity due to infective respiratory diseases (pneumonia and tuberculosis being the most important). Today, the incidence of pneumonia ranges from 4.7 per 1000 inhabitants/year in the U.K. general population to 14 cases in the more elderly populations in Spain [10-11]; some countries have recently witnessed a rise in hospitalizations [12]. Tuberculosis is, after HIV infection, the 2 nd most frequent cause of death from infective disease in the world [13]. Obstructive apneas. Obstructive sleep apnea syndrome (OSAS) is very widespread. The estimated prevalence in Italy is 2.7% of the adult population, though among males aged > 40 years it is 12% and for professional drivers it is 17% [14]. One of its consequences is daytime sleepiness that can cause accidents, in particular driving accidents (22% of which are due to eccessive sleepiness). Cigarette smoking. The two most important respiratory diseases (lung cancer and COPD) are in the overwhelming majority of cases caused by cigarette smoking, which also worsens the disease course. Smoking is both a risk factor and a disease in itself. With variations between the different countries, smoking affects on average ¼ to 1 /5 of the population [15]. The specialist is involved in both its prevention and treatment. Economic and social costs of respiratory diseases The total cost of respiratory diseases in Europe is more than 100 billion per year. COPD contributes to at least half of this figure, followed by asthma, pneumonia, lung cancer and tuberculosis. In general, inpatient hospital services represent 17.5% of the total cost, outpatient care 8.9%, pharmaceutical drugs 6.6%, mortality and rehabilitation 19.6%, and lost work days 47.4% [16]. The annual cost for medical treatment alone (direct healthcare costs) for a patient affected by COPD has been calculated in France to exceed 4,300, almost half of which is related to hospital admissions and one third to pharmaceutical drugs. The overall cost of COPD for France (based on a prevalence of 1.3%, and hence only very approximate, see below) has been estimated at 3.5 billion, i.e. 3.5% of the total medical expenditure [17]. Also the cost for the employer is elevated [17-19]. The social impact of COPD is very high, particularly in the phase of respiratory failure when the social life of the patient, now invalid, is reduced to zero. The direct costs of asthma constitute 1-2% of overall healthcare costs in Italy. Indirect costs (concerning work and family) represent 60% of the overall costs. The cost/year of an adult asthmatic (aged years) is estimated at 800 (with an incidence on family income between 2 and 8%). 11% of adult asthmatics and 19% of child asthmatics will be hospitalized at least once for asthma, and 19% and 31%, respectively, will require an emergency visit. Asthma in children is responsible for absence from school (31% of total school absences are related to asthma) and absence from work for the family. Trends in respiratory disease Besides active smoking as the cause of the principal respiratory diseases, these latter are also linked to indoor and outdoor pollution (in the home, public places and workplace). Estimated trends over the CF Donner (ed.) Summaries, COPD: inapropriateness and pharmaco-economics, Venice, April 2010 Riassunti, BPCO: inappropriatezze e farmacoeconomia, Venezia, aprile 2010 MRM 113

39 MRM _def:Layout 1 08/04/10 15:47 Pagina 114 Multidisciplinary Respiratory Medicine 2010; 5(2): next few years are for: - a rise in COPD (due to the increase of the average age and a decline in underdiagnosis), asthma (due to reasons not yet fully clear), and OSAS (due to an increase in the average body weight and a decline in underdiagnosis). - stable trend for smoking (with country to country variations), lung cancer (in decline amongst males but on the rise amongst females), tuberculosis (dependent on the migratory flows), and pneumonia. Role of the specialist in healthcare planning To deal with chronic respiratory diseases and optimize their management, there is need for a global approach that can define, on the basis of solid epidemiological data, the best care for the patient throughout the course of the disease, in a way that is sustainable for the community. Numerous initiatives and studies are under way everywhere. One of these, which for reasons of space we will focus on here, is the Global Alliance against chronic Respiratory Diseases (GARD), an ensemble of national and international organizations guided and coordinated by the World Health Organization (WHO): GARD s strategies and corresponding actions [20] delineate the role of the specialist at global and national level. For example, in Italy, the Ministry of Health which defined chronic respiratory diseases as a priority of the national Health Program and hence finalized, with the National Agency for Regional Healthcare Services (AGE.NA.S) the national guidelines for COPD launched in 2009 GARD-Italy. [21]. Respiratory specialists participate in the central planning phase of all these initiatives, while other specialists participate in the peripheral phase of implementation. Successively, these same specialists verify the applicability in the real world and the final efficacy of what has been planned and implemented. Following we will see how. Role of the specialist in implementing healthcare strategies Today patients affected by chronic pulmonary diseases are managed in a discontinuous and non integrated mode with inappropriate care procedures as a consequence. In turn, the prevention of these diseases is neither systematized nor integrated. Inappropriateness costs both the individual and the community. It has been calculated that GBP 1.3 billion are spent each year in the U.K. for Emergency Care visits for patients with 18 diseases (and 3-4 visits per individual patient). Occupying first place in the list of diseases is COPD and in third place is asthma. Varying percentages of these visits resulted inappropriate at a retrospective analysis [22]. An optimal management of the above diseases would not only reduce the crowding of Emergency Care facilities and the global healthcare costs, but would also improve the conditions of life of those affected. The long term goal must be to reduce the incidence of respiratory diseases while the short- and medium-term goal is to reduce - in an economically sustainable way the social and economic consequences of the diseases already present, through a greater appropriateness. The specialist thus has a role to play in primary prevention, early diagnosis and rehabilitation, as guide or coordinator or consultant depending on the type of intervention. The interventions to promote are [23]: 1.to prevent respiratory disease developing through a consistent reduction of the number of smokers in the community and total control of risk factors; 2.to improve and anticipate diagnosis, in particular of COPD and asthma, through a more widespread use of spirometric tests and specialist expertise; 3.to help patients self manage their own disease, through health education and pulmonary rehabilitation; 4.to integrate the care of patients affected by respiratory diseases, through linking specialist care to primary care, and extending end of life treatment from the oncological to the respiratory sphere. In concrete terms, the specialist will build up a network in which the Operational Unit functions as the junction for the whole vine of respiratory care that begins with primary prevention and goes right through to palliative care, e.g. according to the following scheme of action: - in primary prevention: - implement smoking cessation in prevention and treatment - increase the opportunity for screening for obstructive sleep apnea - in secondary prevention: - increase accessibility to lung function assessment - experiment screening models for lung cancer - in improvement of patient management: - expand and rationalize semi-intensive treatment - further reduce hospitalization through integration with services available in the local community, e.g. home hospitalization monitoring of patients with chronic respiratory failure health education telemedicine - experiment a model of pulmonary rehabilitation provided in the local community - experiment the extension of palliative care to patients with severe respiratory failure. Conclusions Healthcare planning for respiratory diseases must undertake a whole re-think of its mission and a reorganization of the specialist network based on a redefinition of the role of the specialist. The goal is to achieve greater possibilities of self-management for the patient, greater responsibilization of primary care givers, through use of telemedicine, optimal crisis management, and greater options for dedicated and planned home care. The model for the hos- 114 MRM

40 MRM _def:Layout 1 08/04/10 15:47 Pagina 115 pital pulmonary unit is similar to that of modern cardiology (i.e. intensive management of the acute crisis and of the immediate post-acute period in hospital) while that for the local community is akin to that of the services of diabetology (i.e. specialist consultation and guidance) with particular focus on self-management and pulmonary rehabilitation for patients with respiratory failure. The hospital specialist, who needs to be part of a Specialist Unit in order to have full knowledge of all the aspects, maintains the direct management of emergencies. For this the Pulmonology Unit must be an integral part of the critical area and not of the medical area, and its role in activities of non invasive respiratory intensive care needs to be recognized and promoted. References 1. Horton R. The neglected epidemic of chronic disease. Lancet 2005;366: Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino DM. Global burden of COPD: systematic review and meta-analysis. Eur Respir J 2006;28: Mannino D. Chronic obstructive pulmonary disease in 2025: where are we headed? Eur Respir J 2005;26: Alberg AJ, Samet JM. Epidemiology of lung cancer. Chest 2003;123:21S-49S. 5. Spiro SG, Tanner NT, Silvestri GA, Janes SM, Lim E, Vansteenkiste JF, Pirker R. Lung cancer: progress in diagnosis, staging and therapy. Respirology 2010;15: Viegi G, Pedreschi M, Baldacci S, Chiaffi L, Pistelli F, Modena P, Vellutini M, Di Pede F, Carrozzi L. Prevalence rates of respiratory symptoms and diseases in general population samples of North and Central Italy. Int J Tuberc Lung Dis 1999;3: Murray CJ, Lopez AD. Regional patterns of disability-free life expectancy and disabilityadjusted life expectancy: global Burden of Disease Study. Lancet 1997;349: Subbarao P, Mandhane PJ, Sears MR. Asthma: epidemiology, etiology and risk factors. CMAJ 2009;181:E Corbo GM, Forastiere F, De Sario M, Brunetti L, Bonci E, Bugiani M, Chellini E, La Grutta S, Migliore E, Pistelli R, Rusconi F, Russo A, Simoni M, Talassi F, Galassi C; Sidria-2 Collaborative Group. Wheeze and asthma in children: associations with body mass index, sports, television viewing, and diet. Epidemiology 2008;19: Woodhead M. The European vision of community-acquired pneumonia. Semin Respir Crit Care Med 2009;30: Vila-Corcoles A, Ochoa-Gondar O, Rodriguez-Blanco T, Raga-Luria X, Gomez-Bertomeu F; EPIVAC Study Group. Epidemiology of community-acquired pneumonia in older adults: a population-based study. Respir Med 2009;103: Trotter CL, Stuart JM, George R, Miller E. Increasing hospital admissions for pneumonia, England. Emerg Infect Dis 2008;14: Glaziou P, Floyd K, Raviglione M. Global burden and epidemiology of tuberculosis. Clin Chest Med 2009;30: Lévy P, Pépin JL, Arnaud C, Tamisier R, Borel JC, Dematteis M, Godin-Ribuot D, Ribuot C. Intermittent hypoxia and sleep-disordered breathing: current concepts and perspectives. Eur Respir J 2008;32: van Zyl Smit RN, Pai M, Yew WW, Leung CC, Zumla A, Bateman ED, Dheda K. Global lung health: the colliding epidemics of tuberculosis, tobacco smoking, HIV and COPD. Eur Respir J 2010;35: Loddenkemper R (ed). European Lung White Book. ERS Journals Ltd, Sheffield, Chapman KR, Mannino DM, Soriano JB, Vermeire PA, Buist AS, Thun MJ, Connell C, Jemal A, Lee TA, Miravitlles M, Aldington S, Beasley R. Epidemiology and costs of chronic obstructive pulmonary disease. Eur Respir J 2006;27: Detournay B, Pribil C, Fournier M, Housset B, Huchon G, Huas D, Godard P, Voinet C, Chanal I, Jourdanne C, Durand-Zaleski I; SCOPE Group. The SCOPE study: healthcare consumption related to patients with chronic obstructive pulmonary disease in France. Value Health 2004;7: Nurmagambetov T, Atherly A, Williams S, Holguin F, Mannino DM, Redd SC. What is the cost to employers of direct medical care for chronic obstructive pulmonary disease? COPD 2006;3: Donner CF, De Benedetto F, Sanguinetti CM, Nardini S. GARD-Italy launched in Rome on June Multidisciplinary Respiratory Medicine 2009;4: Nardini S. Schiarire l aria: uno studio nazionale sulla broncopneumopatia cronica ostruttiva. Multidisciplinary Respiratory Medicine 2007;2(1): De Benedetto F, Donner CF, Nardini S, Sanguinetti CM. La BPCO, la medicina respiratoria e i cambiamenti in corso nell assistenza sanitaria. Multidisciplinary Respiratory Medicine 2007;2(1): Long term oxygen therapy: a critical re-evaluation of current guidelines Ossigenoterapia a lungo termine: una rivalutazione critica delle linee guida attuali Antonio Corrado, Teresa Renda Respiratory Intensive Care Unit, Careggi Hospital, Florence, Italy CF Donner (ed.) Summaries, COPD: inapropriateness and pharmaco-economics, Venice, April 2010 Riassunti, BPCO: inappropriatezze e farmacoeconomia, Venezia, aprile 2010 Oxygen therapy represents an essential part of treatment in the care of COPD patients with chronic respiratory failure. The evidence supporting the large use of oxygen therapy and the current indications of international documents are based on the two landmark clinical trials (prospective and randomized) - MRM 115

41 MRM _def:Layout 1 08/04/10 15:47 Pagina 116 Multidisciplinary Respiratory Medicine 2010; 5(2): NOTT and MRC - published more than 25 years ago [1,2]. These studies showed that stable COPD patients, recruited according to pre-established inclusion criteria, live longer when they receive domiciliary long term oxygen therapy (LTOT) for more than 15 hours/day. The effectiveness of LTOT in improving survival has been documented only in COPD patients with severe chronic hypoxemia (PaO 2 less than 55 mm Hg (7.3 kpa) or PaO 2 ranging from 56 to 59 mmhg ( kpa) in the presence of signs of cor pulmonale, hematocrit > 55%). The LTOT indications (based on NOTT and MRC) were established in a very selected and limited number of patients that are unlikely to represent the heterogeneity of the COPD population. These recommendations have been subsequently extended, albeit without solid evidence, to COPD patients with moderate hypoxemia (55 < PaO 2 < 65 mmhg), and to patients with decreased oxygen saturation (SaO 2 < 90%) during exercise or sleep [3-7]. Increased life expectancy in the general population will lead into an increase in the numbers of patients surviving beyond age 70 with chronic diseases, like COPD. Comorbidities are very likely to affect both prognosis and health outcomes in COPD patients but clinical practice guidelines do not provide adequate guidance for patients in LTOT with complex chronic diseases. It has been reported that reassessment of the indication for LTOT after some months of clinical stability reduced significantly the number of patients who would be eligible for LTOT soon after an episode of exacerbation [6]. The stability of underlying chronic disease before commencing LTOT is crucial. Actually, many COPD patients are prescribed oxygen therapy because they are hypoxemic at discharge from hospital after exacerbation of an underlying respiratory disease, despite an absence of data to support short- or long-term benefits of oxygen therapy. After acute exacerbations of COPD approximately 30-38% of patients improved PaO 2 values merely by optimizing medical management to the extent that they no longer fulfilled the selection criteria for LTOT [8]. In order to optimize oxygen use it is advisable that patients should be reassessed, both at 3 months and at approximately one year after commencing oxygen therapy [9]. Furthermore, it is generally accepted without evidence that LTOT in clinical practice is warranted in other forms of chronic respiratory failure such as pulmonary fibrosis, kyphoscoliosis, and cystic fibrosis when arterial blood gas criteria are similar to those established for COPD patients. Given the increasing numbers of patients receiving supplemental oxygen as treatment and the high costs incurred in providing oxygen therapy, a critical revision of the actual indications for LTOT is needed, particularly for COPD patients with comorbidities, mild-moderate hypoxemia, and exercise and sleep desaturation. Nevertheless, the high overall cost of LTOT is an argument in favour of prescribing it only for patients in whom there is a reasonable expectation of clinical benefit. References 1. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med 1980;93: Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Report of the Medical Research Council Working Party. Lancet 1981;1: National Collaborating Centre for Chronic Conditions. Chronic obstructive pulmonary disease. National clinical guideline on management of chronic obstructive pulmonary disease in adults in primary and secondary care. Thorax 2004;59(Suppl. 1): Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, Zielinski J; Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007;176: Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23: McDonald CF, Crockett AJ, Young IH. Adult domiciliary oxygen therapy. Position Statement of the Thoracic Society of Australia and New Zealand. Med J Aust 2005;182: Murgia A, Scano G, Palange P, Corrado A, Gigliotti F, Bellone A, Clini EM, Ambrosino N. Gruppo di Studio Riabilitazione Respiratoria. Linee Guida per l Ossigenoterapia a Lungo Termine. Aggiornamento anno Rassegna di Patologia dell Apparato Respiratorio 2004;19: Eaton TE, Grey C, Garret JE. An evaluation of short-term oxygen therapy: the prescription of oxygen to patients with chronic lung disease hypoxic at discharge from hospital. Respir Med 2001;95: Guyatt GH, Nonoyama M, Lacchetti C, Goeree R, McKim D, Heels-Ansdell D, Goldstein R. A randomized trial of strategies for assessing eligibility for long-term domiciliary oxygen therapy. Am J Respir Crit Care Med 2005;172: MRM

42 MRM _def:Layout 1 08/04/10 15:47 Pagina 117 Lessons from large international clinical trials Le lezioni dei trial clinici internazionali Antonio Anzueto Pulmonary Medicine and Critical Care, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, Texas, USA COPD is a major cause of morbidity and mortality worldwide. Airflow obstruction is variable and results in hyperinflation, the hallmark of COPD physiological impairment. Besides the decline in lung function, COPD patients experience significant limitation in their daily life including dyspnea, exercise capacity, frequent exacerbations and hospitalizations. Long acting bronchodilators including β-agonists and anticholinergics with or without inhaled corticosteroids have been shown to impact these factors. Published studies over the last several years of pharmacotherapy have demonstrated improvements in lung function, dyspnea, decreases in exacerbations, improvements in health-related quality of life (HRQoL), and decreased mortality. Bronchodilators have also been associated with a reduction of dynamic hyperinflation, increased inspiratory capacity (by reducing the functional residual capacity), decreased work of breathing, improved ventilatory capacity and less dyspnea during activity and formal exercise testing. The longterm efficacy and safety of these medications were demonstrated in several multi-center, double-blind, 1-4 year long clinical trials. Tiotropium, the first medication in the new class of long acting anticholinergics, exhibits a longer duration of action and has more specific muscarinic receptor antagonism. Its mode of action allows the medication to be given once a day, and further studies have shown that its half-life can be up to 36 hours. Clinical studies of long-acting bronchodilators, long-acting β-agonists (formoterol, salmeterol and recently indacaterol) and long-acting anti-muscarinic agents (tiotropium) showed significant improvement in trough, peak FEV 1 (range, L) and average FEV 1 (range, L) compared to a decline in placebo-treated patients (short-acting β-agonists, salmeterol and/or ipratropium). Comparable results were achieved with FVC measurements. In order to compare the efficacy between these long-acting bronchodilators, Donohue et al. conducted a 6-month, placebo controlled, parallel group study of tiotropium vs. salmeterol in patients with COPD. Both active treatments resulted in significant improvement in trough, average (0 to 12 hours), and peak FEV 1 compared with placebo (p < 0.001). At the end of 24 weeks however, trough, average, and peak FEV 1 improved significantly more with respect to placebo in the tiotropium group than in the salmeterol. Clinical studies evaluated the use of combination of tiotropium and long acting β 2 agonists showing that there is a synergistic effect of the combination therapy and further improvement in lung function. This combination therapy will be suitable for patients with severe disease. The sustained improvement in lung function seen in these studies suggests that long active bronchodilators may slow the decrease in lung function over time and subsequently change the clinical course of the disease. Furthermore, the impact of combination therapy (fluticasone propionate/salmeterol, and formoterol/budesonide) on patients mortality, frequency of exacerbations and long-term effects on lung function has been reported. The TORCH (Towards a Revolution in COPD Health) trial is a large study that prospectively investigated the potential for combination therapy (fluticasone propionate/salmeterol) to impact survival in patients with COPD. TORCH was a three year, multicenter, randomized, double-blind, parallel group, placebo controlled study. Approximately 6,112 patients were randomized into 4 study groups: placebo, salmeterol, fluticasone propionate (500 µg), and fluticasone propionate/salmeterol (500/50 µg). The primary end point was the reduction in all-cause mortality, comparing fluticasone propionate/salmeterol with placebo. Secondary end points included COPD morbidity (rate of exacerbations) and quality of life assessment. The study showed a 17% relative reduction in mortality over three years for patients receiving fluticasone propionate/salmeterol as compared with placebo (p = 0.052); a 25% reduction in exacerbations compared with placebo; and significant improvement in quality of life measured by the St. George s Respiratory Questionnaire (SGRQ). Taken together, existing data suggest that a fixed combination of long-acting β-agonists (LABA)/ inhaled corticosteroid therapy has a significant impact in COPD by improving lung function, symptoms and HRQoL, as well as reducing exacerbations. Importantly, this therapy may also alter the course of the disease by reducing mortality. The UPLIFT study results were recently reported. UPLIFT was a randomized, double-blind, placebocontrolled, parallel group trial designed to assess range of clinical parameters, including the rate of decline of lung function, quality of life, exacerbation frequency, rate of hospitalization and mortality in COPD patients (GOLD Stages II, III and IV) treated for 4 years with tiotropium 18 mcg inhalation capsule once daily. The study was conducted at 600 centers and involved over 6,000 patients. Findings showed that tiotropium compared with standard bronchodilator care resulted in a superior broncho - CF Donner (ed.) Summaries, COPD: inapropriateness and pharmaco-economics, Venice, April 2010 Riassunti, BPCO: inappropriatezze e farmacoeconomia, Venezia, aprile 2010 MRM 117

43 MRM _def:Layout 1 08/04/10 15:47 Pagina 118 Multidisciplinary Respiratory Medicine 2010; 5(2): dilator effect, less dyspnea, superior health scores, and fewer COPD exacerbations and hospitalizations. Tiotropium was also shown to be safe with significant less cardiac related events. Except for dry mouth incidence in tiotropium, adverse events were comparable with placebo. These data suggest that tiotropium has a significant role in COPD therapy. Clinical studies using triple therapy - tiotropium and fixed combination of long-acting bronchodilator and inhaled corticosteroid have demonstrated an enhanced improvement in lung function, and reduction of exacerbations as compared with any product alone. Several of these studies also showed improvements in morning and daytime symptoms, nighttime awakenings, reliever use, and HRQoL. In COPD patients with severe and very severe disease triple therapy is highly effective. Regardless of whether the treatment paradigm is driven by symptoms or spirometry, an important issue is whether regular treatment with long-acting bronchodilators and/or the combination of LABAinhaled corticosteroids should be initiated at earlier stages of the disease. Recent reports of a sub-analysis of TORCH and UPLIFT studies show that patients with moderate disease will benefit from these therapies. These studies showed significant increase in trough FEV 1, peak FEV 1, dyspnea score, and HRQoL measured by the SGRQ. Notably, patients also have a significant reduction in exacerbations. Roflumilast, an investigational selective phospho - diesterase 4 inhibitor, taken orally once daily targets the inflammation that is a hallmark of the disease. Participants in several 6- and 12-month studies who received roflumilast alone or in combination with salmeterol and/or tiotropium had a significant improvement in lung function, quality of life and reduction in exacerbations. Adverse events were mostly mild in nature. The two most frequent in the roflumilast group were diarrhea and weight loss. This medication is awaiting approval by the regulatory agencies. In COPD patients, both airflow limitation and deconditioning lead to reduced exercise tolerance. Pulmonary rehabilitation (PR) has been shown to improve exercise tolerance, as well as dyspnea. A placebo-controlled trial tested the hypothesis that improvements in ventilatory mechanics resulting from tiotropium use would permit enhanced ability to train muscles of ambulation and, therefore, augment exercise tolerance benefits of PR. Tiotropium in combination with PR improved endurance in a constant work rate treadmill task and produced clinically meaningful improvements in dyspnea and health status compared with PR alone. Furthermore, following PR completion, improvements with tiotropium were sustained for 3 months. These data demonstrate that using long-acting bronchodilators will enhance the benefits of PR. In conclusion, as the incidence of COPD increases, the need for agents that reduce associated morbidity and mortality is ever-growing. Long-acting broncho - dilators alone and in combination with inhaled corticosteroids signify a major advancement in the management of COPD. These medications have been shown to improve lung function, quality of life and exercise performance, decrease exacerbations, and reduce hospitalizations. Recent long term studies (3 to 4 years) showed sustained improvement in lung function, decreased mortality, and safety of these medications. Several new long-acting bronchodilators are under investigation in clinical trials and will become available in the years to come. Selected references: 1. ATS/ERS Standards for the diagnosis and management of patients with COPD. Available at: COPD/. Accessed June 1, van Noord JA, Smeets JJ, Custers FL, Korducki L, Cornelissen PJ. Pharmacodynamic steady state of tiotropium in patients with chronic obstructive pulmonary disease. Eur Respir J 2002;19: Casaburi R, Mahler DA, Jones PW, Wanner A, San PG, ZuWallack RL, Menjoge SS, Serby CW, Witek T Jr. A longterm evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J 2002;19: O Donnell DE, Flüge T, Gerken F, Hamilton A, Webb K, Aguilaniu B, Make B, Magnussen H. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J 2004;23: van Noord JA, Bantje TA, Eland ME, Korducki L, Cornelissen PJ. A randomised controlled comparison of tiotropium and ipratropium in the treatment of chronic obstructive pulmonary disease. The Dutch Tiotropium Study Group. Thorax 2000;55: Donohue JF, van Noord JA, Bateman ED, Langley SJ, Lee A, Witek TJ Jr, Kesten S, Towse L. A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. Chest 2002;122: Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 2003;58: Cazzola M, Di Marco F, Santus P, Boveri B, Verga M, Matera MG, Centanni S. The pharmacodynamic effects of single inhaled doses of formoterol, tiotropium and their combination in patients with COPD. Pulm Pharmacol Ther 2004;17: GOLD: Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease - Updated November 2009, accessed January 12, Anzueto A, Tashkin D, Menjoge S, Kesten S. One-year analysis of longitudinal changes in spirometry in patients with COPD receiving tiotropium. Pulm Pharmacol Ther 2005;18: 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: Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356: Adams SG, Anzueto A, Briggs DD, Menjoge SS, Kesten S. 118 MRM

44 MRM _def:Layout 1 08/04/10 15:47 Pagina 119 Tiotropium in COPD patients not previously receiving maintenance respiratory medications. Respir Med 2006;100: Cooper C. The connection between chronic obstructive pulmonary disease symptoms and hyperinflation and its impact on the exercise and function. Am J Med 2006;119(10 Suppl 1): Decramer M, Celli B, Tashkin DP, Pauwels RA, Burkhart D, Cassino C, Kesten S. Clinical trial design considerations in assessing long-term functional impacts of tiotropium in COPD: the UPLIFT trial. COPD 2004;1; Niewoehner DE, Rice K, Cote C, Paulson D, Cooper JA Jr, Korducki L, Cassino C, Kesten S. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Ann Intern Med 2005;143: Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, Decramer M; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359: Welte T, Miravitlles M, Hernandez P, Eriksson G, Peterson S, Session II: Pharmaco-economics Sessione II: Farmacoeconomia The situation in North America: view from Canada La situazione in Canada Polanowski T, Kessler R. Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009;180: Jenkins CR, Jones PW, Calverley PM, Celli B, Anderson JA, Ferguson GT, Yates JC, Willits LR, Vestbo J. Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomized, placebo-controlled TORCH study. Respir Res 2009;10: Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP; UPLIFT investigators. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet 2009;374: Fabbri LM, Calverley PM, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ, Rabe KF; M2-127 and M2-128 study groups. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long acting bronchodilators: two randomised clinical trials. Lancet 2009;374: Rick Hodder Division of Pulmonary and Critical Care, University of Ottawa, The Ottawa Hospital, Canada The BOLD survey [1] estimated the prevalence of COPD in persons aged 40 years or older in Canada to be 11.1% (Stage I), 7.3% (Stage II) and 0.9% (Stage III-IV) or about 3.3 million. This is considerably higher than the official estimate of 750,000 Canadians with COPD that is based on reported physician diagnosis [2]. Clearly, as in other countries, there is a very large undiagnosed COPD population in Canada [3]. Despite this, respiratory diseases rank fourth in Canada in terms of the proportion of healthcare costs [2]. Hidden COPD in Canada is like a tsunami gaining strength, but which has yet to wreck on the shores of Canada s healthcare system, a system largely unprepared for the huge stresses that threaten to overwhelm our infrastructure, healthcare personnel, and financial resources. This in turn will prevent us from providing the comprehensive health care that these patients will need. Healthcare in Canada is funded by each of our 10 provinces and 3 territories, with some additional federal funding transfers. Approximately 70% of total healthcare expenditure is financed by government (provincial, territorial, federal) taxation [4]. All hospitalizations, physician visits and home care services are covered by the public purse. Patients do not have to pay for their assessments and there are no co-payment requirements, which allows Canadians to access a physician more easily than in many other countries. Primary care providers (PCP) are usually the first point of care for patients with COPD and the majority of physicians (PCPs and specialists) are paid on a fee-for-service basis according to the provincial fee schedule. Consultation by specialists, including respirologists is generally arranged through a PCP, because services for non-referred patients are paid at a lower rate. The cost of delivering COPD care in Canada has been assessed [5-8]. The Canadian RUSIC study [5] estimated that acute exacerbations of COPD (AECOPD) requiring a medication change plus a visit to an outpatient facility including an emergency department had a mean cost of $641 (CAN 2006 $), whereas the mean cost of an AECOPD CF Donner (ed.) Summaries, COPD: inapropriateness and pharmaco-economics, Venice, April 2010 Riassunti, BPCO: inappropriatezze e farmacoeconomia, Venezia, aprile 2010 MRM 119

45 MRM _def:Layout 1 08/04/10 15:47 Pagina 120 Multidisciplinary Respiratory Medicine 2010; 5(2): requiring hospitalization was $9,557. In 2003, data from the Confronting COPD Survey were used to estimate that the annual direct cost of COPD care including laboratory tests and visits to PCPs and specialists, was almost $2000 per patient, with about half of the costs due to hospitalization [7]. The estimated economic burden of COPD through work loss was $1,198 per patient, giving an annual societal cost of $3,195 per patient. Costs increased in direct proportion to the severity of COPD as measured either by FEV 1 or MRC dyspnea score. Clearly, any therapy that will reduce the frequency of AECOPD, improve symptoms and slow down the age-related loss of FEV 1 in COPD should reduce associated healthcare costs over time. There is no universal drug plan in Canada, and private payments are required for many citizens for medications, medical devices, some investigations and alternative practitioners such as chiropractors and optometrists. These payments are split between out-of-pocket expenses (15%), and private health insurance (12%), with the remaining 3% of payments provided by social services, charities and workmen s compensation benefits [4]. Provinces pay for medications for senior citizens (age 65 and over) and those on social services, but the medications provided come from a restricted list, which varies from province to province. This can be problematic in that the provincial drug formularies often favour generic versions of low cost drugs [9]. Thus while the Canadian [3] and other [10] clinical practice guidelines (CPG) for COPD recommend a longacting anticholinergic bronchodilator or a LABA as first line treatment and combinations of long-acting bronchodilators (LABD) with or without inhaled corticosteroids (ICS) for more advanced disease, these restrictive provincial formularies act as barriers to physicians who wish to follow the CPGs. For example, only 3 of 10 provinces fully funded tiotropium for COPD, while the remainder placed restrictions on its use, such as requiring that the physician provide spirometric documentation of advanced airflow obstruction and evidence of treatment failure on high dose ipratropium, before granting funding for the long-acting anticholinergic agent [9]. Similar restrictions exist for the combination LABA/ICS inhalers for COPD. A recent survey of Canadian PCP practice patterns in COPD in the provinces of Ontario and Quebec (CAGE study) observed that pharmacologic treatment that matched Canadian CPGs was present in only 34% of practices [11]. Non-prescription of LABDs for patients with moderate and severe COPD occurred in 27% and 21% of cases respectively and prescription of two LABDs for advanced COPD occurred only 49% of the time. A recent attempt [12] has been made to perform a cost effectiveness analysis of the Canadian [3] and GOLD [10] CPG COPD pharmacotherapy recommendations based on the results from the Canadian OPTIMAL trial [13]. This trial demonstrated that triple therapy with tiotropium plus fluticasone plus salmeterol (TFS) was superior to tiotropium plus salmeterol (TS), or to tiotropium alone with respect to lung function, frequency of AECOPD requiring hospitalization and quality of life. The cost effectiveness analysis demonstrated that the incremental cost per exacerbation avoided with TFS was $6,510 (CAN) and the incremental cost per quality adjusted life year (QUALY) gained was $243,180 (CAN) [12]. Put in the context of what is considered an acceptable (to society) cost per QUALY gained and per AECOPD avoided, the authors of this analysis concluded that neither TFS nor TS were economically attractive alternatives compared with monotherapy with tiotropium for moderate-to-severe COPD [12]. It remains to be seen whether governments and third party payers will begin to consider requiring this type of cost effectiveness analysis when constructing lists of which drugs to support financially. Also yet to be considered is the price to society of increased longevity in COPD, such as that suggested recently in response to sustained bronchodilator therapy with expensive long-acting bronchodilators, with or without ICS [14-16]. Non-pharmacologic COPD therapies such as pulmonary rehabilitation (PR) have also undergone cost/benefit analysis in the Canadian context [6]. An economic analysis of a 2-month inpatient followed by 4-month outpatient PR program in Canada in 1997 estimated that it cost $11,597 (CAN) to achieve clinically significant gains in dyspnea, emotional function, and mastery, with more than 90% of the costs being due to the inpatient phase of the program [6]. This data ignores potential cost savings resulting from fewer hospitalizations for COPD patients successfully completing a PR program [17]. It also emphasizes the value and potential cost-effectiveness of developing smaller outpatient and home-based PR programs [18]. A recent review has suggested that the most significant gains in COPD healthcare utilization have been realized by collaborative self-management education (SME) interventions [19]. A Canadian randomized controlled trial comparing case manager-driven SME versus usual care demonstrated a 40% reduction in the need for COPD patients to access healthcare resources including hospitalizations, emergency department visits and unscheduled clinic visits [20]. A cost-effectiveness analysis of this trial demonstrated significant net savings of $2,148 (CAN) per patient, provided the case manager supervised 50 or more patients per year [8]. Canada is the first country to have certified respiratory educators (CRE), although many of these individuals are not fully employed. This reflects an under appreciation of the benefits of a collaborative self-management education approach to COPD care, which has led to under funding for such individuals. However, the situation is beginning to change as many provinces are moving towards a restructuring of primary care into multidisciplinary teams which are given financial incentives to provide comprehensive care including CRE-facilitated SME and whose physicians often forfeit fee-for-service remuneration in return for a salary and a less bottom line -driven lifestyle [21]. 120 MRM

46 MRM _def:Layout 1 08/04/10 15:47 Pagina 121 References 1. Buist A, McBurnie M, Vollmer W, Gillespie S, Burney P, Mannino DM, Menezes AM, Sullivan SD, Lee TA, Weiss KB, Jensen RL, Marks GB, Gulsvik A, Nizankowska-Mogilnicka E; BOLD Collaborative Research Group. International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study. Lancet 2007;370: Life and Breath: Respiratory Disease in Canada. Public Health Agency of Canada O'Donnell DE, Aaron S, Bourbeau J, Hernandez P, Marciniuk D, Balter M, Ford G, Gervais A, Goldstein R, Hodder R, Maltais F, Road J; Canadian Thoracic Society. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease Can Respir J 2003;10(Suppl A):11A-65A. 4. Kaplan A. Systems for the management of respiratory disease in primary care - an international series: Canada. Prim Care Respir J 2008;17: Mittmann N, Kuramoto L, Seung S, Haddon JM, Bradley- Kennedy C, Fitzgerald JM. The cost of moderate and severe COPD exacerbations to the Canadian healthcare system. Respir Med 2008;102: Goldstein RS, Gort EH, Guyatt GH, Feeny D. Economic analysis of respiratory rehabilitation. Chest 1997;112: Chapman K, Bourbeau J, Rance L. The burden of COPD in Canada: results from the Confronting COPD survey. Respir Med 2003;97: Bourbeau J, Collet J, Schwartzman K, Ducruet T, Nault D, Bradley C. Economic benefits of self-management education in COPD. Chest 2006;130: Canadian Lung Association Chronic Obstructive Pulmonary Disease (COPD): A National Report Card 2005; 10. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. Bethesda, National Institute of Health, National Heart, Lung,and Blood Institute 2003; NHLBI/WHO Workshop Report. 11. Bourbeau J, Sebaldt R, Day A, Bouchard J, Kaplan A, Hernandez P, Rouleau M, Petrie A, Foster G, Thabane L, Haddon J, Scalera A. Practice patterns in the management of chronic obstructive pulmonary disease in primary practice: The CAGE study. Can Respir J 2008;15: Najafzadeh M, Marra CA, Sadatsafavi M, Aaron SD, Sullivan SD, Vandemheen KL, Jones PW, Fitzgerald JM. Cost effectiveness of therapy with combinations of long acting bronchodilators and inhaled steroids for treatment of COPD. Thorax 2008;63: Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, Balter M, O'Donnell D, McIvor A, Sharma S, Bishop G, Anthony J, Cowie R, Field S, Hirsch A, Hernandez P, Rivington R, Road J, Hoffstein V, Hodder R, Marciniuk D, McCormack D, Fox G, Cox G, Prins HB, Ford G, Bleskie D, Doucette S, Mayers I, Chapman K, Zamel N, FitzGerald M; Canadian Thoracic Society/Canadian Respiratory Clinical Research Consortium. Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone- Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease: A Randomized Trial. Ann Intern Med 2007;146: Celli B, Decramer M, Kesten S, Liu D, Mehra S, Tashkin DP; UPLIFT Study Investigators. Mortality in the 4-Year Trial of Tiotropium (UPLIFT) in Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2009;180: Tashkin D, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, Decramer M; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359: Suissa S, Ernst P, Vandemheen K, Aaron SD. Methodological issues in therapeutic trials. Eur Respir J 2008;31: Rea H, McAuley S, Stewart A, Lamont C, Roseman P, Didsbury P. A chronic disease management programme can reduce days in hospital for patients with chronic obstructive pulmonary disease. Intern Med J 2004;34: Maltais F, Bourbeau J, Shapiro S, Lacasse Y, Perrault H, Baltzan M, Hernandez P, Rouleau M, Julien M, Parenteau S, Paradis B, Levy RD, Camp P, Lecours R, Audet R, Hutton B, Penrod JR, Picard D, Bernard S; Chronic Obstructive Pulmonary Disease Axis of Respiratory Health Network, Fonds de recherche en santé du Québec Effects of homebased pulmonary rehabilitation in patients with chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2008;149: Clark N, Dodge J, Partridge M, Martinez FJ. Focusing on outcomes: Making the most of COPD interventions. Int J Chron Obstruct Pulmon Dis 2009;4: Bourbeau J, Julien M, Maltais F, Rouleau M, Beaupré A, Bégin R, Renzi P, Nault D, Borycki E, Schwartzman K, Singh R, Collet JP; Chronic Obstructive Pulmonary Disease axis of the Respiratory Network Fonds de la Recherche en Santé du Québec. Reduction of hospital utilization in patients with chronic obstructive pulmonary disease: a disease-specific self-management intervention. Arch Intern Med 2003;163: Rosser W, Colwill J, Kasperski J, Wilson L. Patient-centered medical homes in Ontario. N Engl J Med 2010;362:e7. The situation in North America: view from the United States La situazione negli USA Robert A. Wise Asthma and Allergy Center, Johns Hopkins University, Baltimore, USA COPD is a highly prevalent and morbid condition affecting million United States citizens. COPD is the fourth leading cause of death in the U.S. with more than 125,000 deaths annually. In 2010, the direct health care costs of COPD are projected to total $29.5 billion [1]. Of these costs, $13.2 billion are hospital care costs, $5.5 billion are physician costs, $5.8 billion are outpatient prescription drug costs, $1.3 billion are home health care costs, and $3.7 billion are nursing home care. CF Donner (ed.) Summaries, COPD: inapropriateness and pharmaco-economics, Venice, April 2010 Riassunti, BPCO: inappropriatezze e farmacoeconomia, Venezia, aprile 2010 MRM 121

47 MRM _def:Layout 1 08/04/10 15:47 Pagina 122 Multidisciplinary Respiratory Medicine 2010; 5(2): Moreover, long-term oxygen therapy costs Medicare more than $2 billion per year for COPD and the cost is growing by 12-18% per year [2]. In addition, there are $20.4 billion in indirect costs due to lost productivity from death and disability. Lung volume reduction surgery and lung transplantation, although costly procedures, are infrequently used in COPD, so they do not presently account for substantial healthcare costs [3]. The primary goals of treating COPD are to improve functional status, reduce morbidity, and prolong survival. However, because substantial costs of COPD are related to health care use for exacerbations, it is a reasonable goal to consider therapy in terms of reduction in health care costs as well as direct expense for the drugs. The current status of pharmacoeconomic evaluations of COPD has recently been critically reviewed and, while a number of methodologic flaws were found, the results were generally concordant [4]. Three older retrospective analyses have shown that the anticholinergic bronchodilator ipratropium in early stage COPD and a combination anticholinergic-β-agonist in more advanced COPD are associated with lower overall healthcare costs, largely because of reduction in exacerbations requiring hospital care [5]. Another retrospective analysis compared costs of COPD treatment with ipratropium vs. theophylline [6]. Although the direct drug costs for ipratropium were greater, the overall healthcare costs were 28% lower in those patients treated with ipratropium, mainly because of reduction in exacerbations. An analysis of healthcare costs from a health maintenance organization database showed that monotherapy with ipratropium was associated with a reduction in healthcare costs compared to monotherapy with either a β-agonist, inhaled steroid, or theophylline in the first six months following a COPD diagnosis. Subsequent treatment with combination therapy with ipratropium and a β-agonist were also lower than other therapy groups [7]. These observational studies were supported by an economic analysis of two clinical trials of ipratropium-albuterol combination compared to ipratropium or albuterol alone [8]. Both of the ipratropium arms of the study indicated lower direct healthcare costs than albuterol alone. Again, the main component of the reduced expenditures was related to fewer exacerbations and fewer hospitalizations. Long-acting β-agonists (LABA) as monotherapy for COPD are effective in reducing exacerbations compared to placebo, and a review of two clinical trials indicates that this translates into a reduction in healthcare expenditures, although these studies did not provide a comparison to other bronchodilator monotherapies [9]. Monotherapy with an inhaled corticosteroid, fluticasone, assessed in a placebocontrolled trial was found to be associated with a reduction in both direct healthcare expenditures as well as indirect healthcare costs from days of incapacitation [10]. A clinical trial comparing the longacting anticholinergic tiotropium to ipratropium demonstrated a 26% reduction in exacerbations and 46% reduction in hospitalizations associated with tiotropium. Calculations of costs using standard costs in The Netherlands indicated that the use of tiotropium, although more effective, was associated with increased healthcare costs for tiotropium due to the increased cost of drug acquisition. The cost-effectiveness of tiotropium vs. ipratropium is sensitive, however, to the relative costs of drugacquisition compared to hospitalization and may have demonstrated a different effect on healthcare costs in the United States where the costs and charges for hospitalization are substantially higher than in The Netherlands [11]. This is further supported by a Spanish modeling study using outcome data from clinical trials comparing cost-effectiveness of monotherapy with salmeterol, ipratropium, and tiotropium. All three treatments were cost-effective in terms of clinical outcomes, but the most effective and highest cost monotherapy treatment was tiotropium [12]. Different strategies for initiation of inhaled corticosteroid therapy (ICS) in COPD were analyzed using a Markov chain model and using the assumption that ICS cause an initial increment in lung function but no change in the rate of subsequent decline. This analysis, which is highly dependent upon the assumptions regarding frequency of exacerbations and transition between different stages of COPD, suggested that the costeffectiveness of ICS was greater in the most severely impaired individuals [13]. Three economic analyses of the TORCH trial have been published. TORCH compared salmeterol-fluticasone combinations (SFC) to the individual components and placebo. In one study using the United States cost structure, salmeterol was the most costeffective drug ($20,792/QALY) and SFC was second most cost-effective ($33,865/QALY). Fluticasone alone, which did not improve survival in TORCH was not considered cost-effective [14]. A similar Markov-chain analysis of the TORCH trial, using different cost assumptions, found that SFC was the most cost-effective ($52,046/QALY), followed by salmeterol monotherapy ($56,519/QALY) and fluticasone monotherapy ($56,519) [15]. In a third analysis of TORCH, using a multinational approach to cost structure, SFC was also found to be most cost effective with a cost of $43,600 per QALY, compared to $197,00 for salmeterol monotherapy and $78,000 per QALY for fluticasone monotherapy. The cost-effectiveness was considerably lower for SFC in the United States ($77,100/QALY) compared to Western Europe ($24,200/QALY) [16]. Analysis of a Medicare HMO database using actual healthcare expenditures compared the costs of initial maintenance therapy for COPD using FSC, ipratropium monotherapy, ipratropium-albuterol monotherapy, and tiotropium. In this retrospective comparison, SFC was associated with slightly more cost savings than tiotropium ($110/year), and ipratropium-albuterol ($295/year), but substantially better than ipratropium alone ($1235/year) [17]. In conclusion, a review of pharmacoeconomic 122 MRM

48 MRM _def:Layout 1 08/04/10 15:48 Pagina 123 studies for COPD demonstrates that the analytic approach and baseline assumptions can lead to substantial differences in the conclusions that are reached. Nonetheless, there does appear to be substantial evidence that maintenance therapy in COPD is cost-effective and is comparable to the cost-effectiveness of treatments for other chronic diseases. But the most effective therapies may exceed the threshold of willingness to pay by third-parties compared to management approaches in other chronic diseases. There are still substantial gaps in our knowledge of the comparative cost-effectiveness of other therapeutic strategies for COPD, particularly the combinations of therapies from different classes. In addition, we need to know better how the severity of COPD and clinical expression of the disease might influence the cost-effectiveness of comparative treatments. References 1. National Heart, Lung, and Blood Institute. Morbidity and mortality: 2009 chart book on cardiovascular, lung, and blood diseases. docs/2009_chartbook.pdf. Accessed January 18, Croxton TL, Bailey WC. Long-term oxygen treatment in chronic obstructive pulmonary disease: recommendations for future research: an NHLBI workshop report. Am J Respir Crit Care Med. 2006;174: Ramsey SD, Berry K, Etzioni R, Kaplan RM, Sullivan SD, Wood DE; National Emphysema Treatment Trial Research Group. Cost effectiveness of lung-volume-reduction surgery for patients with severe emphysema. N Engl J Med 2003;348: D'Souza AO, Smith MJ, Miller LA, Kavookjian J. An appraisal of pharmacoeconomic evidence of maintenance therapy for COPD. Chest 2006;129: Hilleman DE, Dewan N, Malesker M, Friedman M. Pharmacoeconomic evaluation of COPD. Chest 2000;118: Jubran A, Gross N, Ramsdell J, Simonian R, Schuttenhelm K, Sax M, Kaniecki DJ, Arnold RJ, Sonnenberg FA. Comparative cost-effectiveness analysis of theophylline and ipratropium bromide in chronic obstructive pulmonary disease A three-center study. Chest 1993;103: The situation in Europe La situazione in Europa 7. Sclar DA, Legg RF, Skaer TL, Robison LM, Nemic NL. Ipratropium bromide in the management of chronic obstructive pulmonary disease: effect on health service expenditures. Clin Ther 1994;16: Friedman M, Serby CW, Menjoge SS, Wilson JD, Hilleman DE, Witek TJ Jr. Pharmacoeconomic evaluation of a combination of ipratropium plus albuterol compared with ipratropium alone and albuterol alone in COPD. Chest 1999;115: Jones PW, Wilson K, Sondhi S. Cost-effectiveness of salmeterol in patients with chronic obstructive pulmonary disease: an economic evaluation. Respir Med 2003;97: Ayres JG, Price MJ, Efthimiou J. Cost-effectiveness of fluticasone propionate in the treatment of chronic obstructive pulmonary disease: a double-blind randomized, placebo-controlled trial. Respir Med 2003;97: Oostenbrink JB, Rutten-van Molken MP, Al MJ, Van Noord JA, Vincken W. One-year costeffectiveness of tiotropium versus ipratropium to treat chronic obstructive pulmonary disease. Eur Respir J 2004;23: Rutten-van Mölken MP, Oostenbrink JB, Miravitlles M, Monz BU. Modelling the 5-year cost effectiveness of tiotropium, salmeterol and ipratropium for the treatment of chronic obstructive pulmonary disease in Spain. Eur J Health Econ 2007;8: Sin DD, Golmohammadi K, Jacobs P. Cost-effectiveness of inhaled corticosteroids for chronic obstructive pulmonary disease according to disease severity. Am J Med 2004;116: Earnshaw SR, Wilson MR, Dalal AA, Chambers MG, Jhingran P, Stanford R, Mapel DW. Cost-effectiveness of fluticasone propionate/salmeterol (500/50 microg) in the treatment of COPD. Respir Med 2009;103: Oba Y. Cost-effectiveness of salmeterol, fluticasone, and combination therapy for COPD. Am J Manag Care 2009;15: Briggs A, Glick H, Lozano-Ortega G, Spencer M, Calverley PM, Jones P, Vestbo J; TOwards a Revolution in COPD Health (TORCH) investigators. Is treatment with ICS and LABA cost-effective for COPD? Multinational economic analysis of the TORCH study. Eur Respir J 2010;35: Dalal AA, Petersen H, Simoni-Wastila L, Blanchette CM. Healthcare costs associated with initial maintenance therapy with fluticasone propionate 250 mug/salmeterol 50 mug combination versus anticholinergic bronchodilators in elderly US Medicare-eligible beneficiaries with COPD. J Med Econ 2009;12: Marc Miravitlles Fudació Clínic, Institut d Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Catalonia, Spain Obstructive lung diseases, particularly COPD are one of the main causes of morbidity and mortality in developed countries. In Spain, the prevalence of COPD was 9% in adults between 40 and 70 years of age in 1999, although only 22% are diagnosed. In another population-based study performed ten years later, the observed prevalence was 10.2% and the underdiagnosis persisted, with only 27% of CF Donner (ed.) Summaries, COPD: inapropriateness and pharmaco-economics, Venice, April 2010 Riassunti, BPCO: inappropriatezze e farmacoeconomia, Venezia, aprile 2010 MRM 123

49 MRM _def:Layout 1 08/04/10 15:48 Pagina 124 Multidisciplinary Respiratory Medicine 2010; 5(2): TABLE I. COMPARISON OF THE COSTS PUBLISHED FOR COPD IN DIFFERENT COUNTRIES IN EUROPE Reference Country Focus Costs Cost/patient/year Global cost /year Morera, 1992 [4] Spain Top-down Direct and indirect 959 Direct 319 M Indirect 541 M Jacobson, 2000 [9] Sweden Top-down Direct and indirect Direct 109 M Indirect 541 M Rutten van Mölken, 2000 [6] Netherlands Top-down Direct $876 Dal Negro, 2001 [10] Italy Bottom-up Direct Stage I = 151 Stage II = 3,001 Stage III = 3,912 Jansson, 2002 [11] Sweden Bottom-up Direct and indirect $1,284 $871 M Miravitlles, 2003 [5] Spain Bottom-up Direct Stage I = 1, M Stage II = 1,640 Stage III = 2,333 Masa, 2004 [12] Spain Bottom-up Direct M Cross-sectional Izquierdo, 2004 [13] Spain Bottom-up Direct Stage I = 1,657 Stage II = 2,425 Stage III = 3,303 Borg, 2004 [14] Sweden Top-down Direct and indirect Direct costs GOLD I = 92 GOLD IIA = 631 GOLD IIB = 2,144 GOLD III = 8,678 Detournay, 2004 [15] France Bottom-up Direct and indirect Direct costs 3,500 M GOLD II = 1,904 GOLD III = 2,683 GOLD IV = 6,357 Lucioni, 2005 [16] Italy Bottom-up Direct and indirect Direct costs 4,645 Koleva, 2007 [17] Italy Bottom-up Direct costs GOLD I = 1,046 GOLD II = 2,319 GOLD III = 3,572 GOLD IV = 5,033 Dal Negro, 2008 [18] Italy Bottom-up Direct costs Mild = 1,314 Moderate-severe= 5,451 De Miguel, 2008 [19] Spain Bottom-up Direct costs 1,922 $ = costs in U.S. dollars; M = million. individuals with COPD having a previous diagnosis of the disease. Considering its high prevalence and the chronic and progressive course of COPD, it is easy to understand that this disease will represent a high societal and economic burden. Studies performed in different European and American countries have tried to estimate the healthcare costs associated with the management of COPD patients. Costs obtained may differ in numbers, but in all cases they represent a significant proportion of the healthcare costs in each country. Studies of costs of COPD have been performed in different countries and differ in their approach and methodology. In order to compare results among studies it is important to verify how the study has been designed. Basically, the differences derive from the inclusion or not of indirect costs. These refer to the morbidity and mortality caused by the disease. They measure the impact which the disease studied may have on national production. The most common method of calculation is based on human capital in which days off work, whether because of disease or death, are transformed into monetary units by the application of the mean returns. This method has been extensively criticized, one of the reasons being that it does not include the impact on the collectives which are not integrated in the labor market such as children, the elderly, housewives, etc. In contrast, the direct costs are those related to the detection, treatment, prevention and rehabilitation of the disease studied. Most studies of this type concentrate on the analysis of the costs incurred by the hospital, ambulatory and pharmacologic care related to the disease in question. Other direct costs apart from health care, such as social services, are usually not included due to the lack of information. Another source of variation is the type of analysis. 124 MRM

50 MRM _def:Layout 1 08/04/10 15:48 Pagina 125 One option would be to calculate the cost of disease starting with total figures at a national level for all the diseases together and, thereafter, reach the level at which the disease studied lies through a disaggregation process: this is called a top-down analysis. The second option would be to start by taking a group of subjects with the disease analyzed together as a base for the calculation and study the consumption of resources used during the time period considered. The national total may be determined by extrapolation of the costs of this subset of the population: this is called a bottom-up analysis. An example of the variation that can be observed in the calculation of costs is provided by the analysis of different studies in the same country, as in Spain. Top-down estimates have been carried out on the costs generated by COPD in Spain using statistical and epidemiological data. These studies have reported figures of around 800 million annually in 1994 including both direct and indirect costs. In a microeconomic study performed in 1,510 patients with ambulatory COPD followed over one year (bottom-up), the average annual cost per patient was $1, With this study the approximate direct annual cost generated by COPD in Spain may be calculated from the focus of prevalence. If we take into account data obtained in the IBERPOC population-based epidemiological study, the prevalence of COPD was estimated to be 9% in the year age group, of which only 22% were diagnosed and received treatment of some kind. Therefore, a total of 270,000 subjects would be diagnosed and treated for COPD multiplied by the annual average obtaining a total of $ million annually in direct health care costs generated by COPD. This figure is greater than that obtained with the previous focus which may be due to methodological differences and also, in part, to differences in the management of the disease during the period from 1994 to 1999 when information for the last study was collected. It is interesting to compare the distribution of the costs estimated in both models. In the top-down calculation the hospital costs constituted 36.3%, the expenses attributed to drugs 42.2% and the clinical consultations and diagnostic tests 22.5%. In the study using the bottom-up focus the hospital costs represented 43% of the total, drugs 40% and consultations and complementary tests 17%. Despite the differences observed in the absolute values between the two types of studies, the distribution of the costs was very similar. If the total direct cost of COPD is divided between the total of the country population, health care for COPD costs each citizen $13.32 annually. To put this figure into perspective, a study carried out in The Netherlands reported a cost of $23 per capita in the association of asthma and COPD. The differences may be due to the inclusion of asthma in the last study and a lower index of underdiagnosis in The Netherlands, among others. Other studies carried out regarding the cost of COPD in different European countries are shown in Table I. All estimates indicate that the situation will not improve in the near future. The impact of aging and changes in smoking habits is responsible for an estimated increase of more than 60% of total life years loss and an increased loss of 75% of disabilityadjusted life years (DALYs) from 1990 to 2020 in The Netherlands [20]. New projections performed until 2025 provide similar results with an increase in prevalence and costs of COPD despite the campaigns against tobacco smoking [21]. References 1. Peña VS, Miravitlles M, Gabriel R, Jiménez-Ruiz CA, Villasante C, Masa JF, Viejo JL, Fernández-Fau L. Geographic variations in prevalence and underdiagnosis of COPD: results of the IBERPOC multicentre epidemiological study. Chest 2000;118: Miravitlles M, Soriano JB, García-Río F, Muñoz L, Duran- Taulería E, Sánchez G, Sobradillo V, Ancochea J. Prevalence of COPD in Spain: impact of undiagnosed COPD on quality of life and daily life activities. Thorax 2009;64: Chapman KR, Mannino DM, Soriano JB, Vermeire PA, Buist AS, Thun MJ, Connell C, Jemal A, Lee TA, Miravitlles M, Aldington S, Beasley R. Epidemiology and costs of chronic obstructive pulmonary disease. Eur Respir J 2006;27: Morera Prat J. Enfermedad pulmonar obstructiva crónica. Magnitud del problema. En: Enfermedad pulmonar obstructiva crónica. Conceptos Generales. Vol. 1 Eds MCR. Barcelona 1992: Miravitlles M, Murio C, Guerrero T, Gisbert R on behalf of the DAFNE study group. Costs of chronic bronchitis and COPD. A one year follow-up study. Chest 2003;123: Rutten van Mölken MP, Postma MJ, Joore MA, Van Genugten ML, Leidl R, Jager JC. Current and future medical costs of asthma and chronic obstructive pulmonary disease in the Netherlands. Respir Med 2000;93: Feenstra TL, van Genugten ML, Hoogenveen RT, Wouters EF, Rutten van Mölken MP. The impact of aging and smoking on the future burden of chronic obstructive pulmonary disease: a model analysis in the Netherlands. Am J Respir Crit Care Med 2001;164: Hoogendoorn M, Rutten-van Mölken MP, Hoogenveen RT, van Genugten ML, Buist AS, Wouters EF, Feenstra TL. A dynamic population model of disease progression in COPD. Eur Respir J 2005;26: Jacobson L, Hertzman P, Löfdahl CG, Skoogh BE, Lindgren B. The economic impact of asthma and chronic obstructive pulmonary disease (COPD) in Sweden in 1980 and Respir Med 2000;94: Dal Negro R, Berto P, Tognella S, Quareni L, on behalf of GOLD study Group. Cost-ofillness of lung disease in the TriVeneto Region, Italy: the GOLD Study. Monaldi Arch Chest Dis 2002;57: Jansson SA, Andersson F, Borg S, Ericsson A, Jönsson E, Lundbäck B. Costs of COPD in Sweden according to disease severity. Chest 2002;122: Masa JF, Sobradillo V, Villasante C, Jiménez-Ruiz CA, Fernández-Fau L, Viejo JL, Miravitlles M. Costs of chronic obstructive pulmonary disease in Spain: Estimation from a population-based study. Arch Bronconeumol 2004;40: Izquierdo-Alonso JL, de Miguel-Díez J. Economic impact of pulmonary drugs on direct costs of stable chronic obstructive pulmonary disease. Journal of COPD 2004;1: Borg S, Ericsson A, Wedzicha J, Gulsvik A, LundbÑack B, Donaldson GC, Sullivan SD. A computer simulation model of the natural history and economic impact of chronic CF Donner (ed.) Summaries, COPD: inapropriateness and pharmaco-economics, Venice, April 2010 Riassunti, BPCO: inappropriatezze e farmacoeconomia, Venezia, aprile 2010 MRM 125

51 MRM _def:Layout 1 08/04/10 15:48 Pagina 126 Multidisciplinary Respiratory Medicine 2010; 5(2): obstructive pulmonary disease. Value Health 2004;7: Detournay B, Pribil C, Fournier M, Housset B, Huchon G, Huas D, Godard P, Voinet C, Chanal I, Jourdanne C, Durand- Zaleski I; SCOPE Group. The SCOPE study: health-care consumption related to patients with chronic obstructive pulmonary disease in France. Value Health 2004;2: Lucioni C, Donner CF, De Benedetto F, Lusuardi M, Mazzi S, Paggiaro PL, Sanguinetti C. I costi della broncopneumopatia cronica ostruttiva: la fase prospettica dello studio ICE (Italian Costs for Exacerbations in COPD). Pharmacoeconomics Italian Research Articles 2005;7: Koleva D, Motterlini N, Banfi P, Garattini L. Healthcare The situation in Europe: Scandinavia La situazione in Europa: Scandinavia Ronald Dahl Department of Respiratory Diseases, Aarhus University Hospital, Denmark costs of COPD in Italian referral centres: a prospective study. Respir Med 2007;101: Dal Negro RW, Tognella S, Tosatto R, Dionisi M, Turco P, Donner CF. Costs of chronic obstructive pulmonary disease (COPD) in Italy: The SIRIO (Social Impact of Respiratory Integrated Outcomes). Respir Med 2008;102: De Miguel Diez, Carrasco Garrido P, García Carballo M, Gil de Miguel A, Rejas Gutierrez J, Bellón Cano JM, Hernandez Barrera V, Jimenez García R. Determinants and predictors of the cost of COPD in primary care: A Spanish perspective. Int J COPD 2008;4: The cost of pharmacological treatment is steadily increasing in all European countries. The main reasons are expensive, new hospital treatments with biological drugs and medications for cancer. The other main reason is that the population segment of elderly people is widening and with that the number of people with common chronic diseases including COPD. The cost of COPD in Denmark amounts to 10% of all health care costs. The annual cost of pharmacological treatment in Scandinavia is today around 100 per inhabitant (from newborn to old age included). The cost in Denmark rose from about 2 billion in 2004 to 3 billion in This huge cost is mainly covered by the public health system, some private insurance and to a minor degree by the patients themselves. This immediately results in several interested parties involved in the actual use and choice of medication: i) health professionals (especially doctors and nurses as well as clinicians and clinical pharmacologists), ii) the patients and patient organizations, iii) the administrative systems with administrators, health economists and politicians, iv) the pharmaceutical industry, and v) public opinion with journalists and lobbyists. A regulation by central guidelines, specific rules and norms seems justified. There are massive differences between regions in the prescribing pattern of drugs with the same effect and side effect profiles but in some cases a 10-fold difference in cost. Such unnecessary expense is obviously unwarranted because the treatment effect is the same for a less expensive drug. A correct treatment can have an unacceptably high cost. Regional guidelines are therefore produced for the usual choice of a medication in a specific class of drugs (inhaled cortico - steroid and bronchodilators, anti-tnf, ACE inhibitors, etc). These guidelines are publicized in different ways and discussed with the health professionals. Other actions can be taken, e.g. withdrawal of the reimbursement from specific drugs, which makes the cost for the patient unacceptably high, or imposing rules such as disallowing renewal of the driver s license to elderly people treated with benzodiazepines. In special cases an audit and personal discussion with a doctor is arranged. The general guidelines for handling a disease entity are usually formulated by the scientific society, and agreement about the general use of medication by classes based on a step wise approach according to severity is usually reached without problems among specialists. However, when it comes to the specific choice of a brand name, large differences in opinion often flare up. This may be caused by personal opinion about the effects of a specific medication and/or by a lack of interest in the economic aspect of drug use or the influence of the pharmaceutical industry. This is the background for the establishment of local pharmaceutical committees that explicitly choose labelled drugs in a prioritized sequence. This often occurs in the form of compromises between specialists with different opinions that have to find arguments for their choices. A regulated practice has developed by law for pharmaceutical substitution in the pharmacy. This means that the pharmacy shall deliver another and cheaper medication to the patient than the one written on the prescription form, if the drugs contain the same active substance, in the same amount and are used in the same way. These are synonymous drugs and the practice is possible as the National Medical agency has made an evaluation. This means that the pharmacy gives the cheapest medication in almost all cases only with a few exceptions (allergy to constituents, the explicit wish of the patient or the prescriber for a certain drug, if the cost difference is trivial). 126 MRM

52 MRM _def:Layout 1 08/04/10 15:48 Pagina 127 The situation in Italy La situazione in Italia Diseases increase in incidence and prevalence with age, which makes the presence of comorbidities very frequent. COPD is a very good example of a disease with one or more comorbidities on account of age and smoking as a common risk factor (osteoporosis, cardiovascular diseases, cancer) and complications (depression and bronchiectasis). This is the reason why patients are treated with polypharmacy, that carries with it the risk of drug inter - actions. Patients with more than 5 drugs in their treatment should have their medication explained and reviewed for interactions. Patients on inhaler treatment are all offered an evaluation of their inhaler technique and instruction in correct inhaler use, in order to improve the efficacy of inhaled medications and avoid waste due to ineffective inhaler technique. Each country in Scandinavia has developed its own reimbursement system, that comprises a common part which applies to everybody and special rules for patients in specific circumstances. The common reimbursement scheme in Denmark is, roughly speaking, that the first 115 spent for the purchase of pharmaceutical drugs is not reimbursed (however, for age < 18 years, there is a 60% reimbursement also of this cost segment provided). The % reimbursement increases gradually to 85% with purchases above 400 in all age groups. However, persons with chronic diseases pay up to a maximum of 450 out of their own pocket, and will have all additional cost covered. In special cases it is possible to apply for reimbursement of specific drug treatments, to have additional cost cover if the personal economic situation requires, or special support for terminal care and treatments. A special group of people are the illegal immigrants, who have no public or private insurance. They experience serious problems when falling ill. They can in principle only be treated for acute severe disease and transported to their homeland as soon as possible, whereas management of the cost of chronic diseases is at their own total expense. References 1. Bilde L, Rud Svenning A, Dollerup J, Baekke Borgeskov H, Lange P. The cost of treating patients with COPD in Denmark - a population study of COPD patients compared with non-copd controls. Respir Med 2007;101: Danish Medicines Agency. Annual report on the inspection of retail sale of OTC medicines dkma.dk/1024/visuklsartikel.asp?artikelid= DanBio. Annual report Danish Medical Agency workshop Brug medicinen bedre (Better use of medicines) Delafuente JC. Understanding and preventing drug interactions in elderly patients. Crit Rev Oncol Hematol 2003;48: Roberto W. Dal Negro Department of Respiratory Diseases, ULSS22 Veneto Region, Orlandi Hospital, Bussolengo, Verona, Italy FISAR National Center for Studies in Respiratory Pharmacoeconomics and Pharmaco-epidemiology (CESFAR), Verona, Italy In Italy, as well as in other industrialised countries, COPD still represents a major cause of morbidity and mortality, and exerts a substantial burden on health and the health care system. The pharmacoeconomic era started around the end of the last century and corresponded to the overall need for accountability, and the economic evaluation of interventional strategies progressively became the crucial point aimed to support decision makers in allocating the ever diminishing health care resources. From 1979 to 2009, when compared to overall international and European studies, the Italian scientific literature in pharmacoeconomics of COPD gradually increased from 2.0% to 4.1%, and from 6.9 to 10.7% respectively. At present, while USA is producing the highest number of studies in this field (43.2%), Italy ranks 7 th in the international seeding (3.4%), and 4 th in Europe (8.1%), preceded by The Netherlands, UK and Spain. In Italy, the cost-of-illness of COPD was calculated in 2002 for the first time: data were collected from 28 Lung Units, and the cost-of-illness analysis was carried out within the framework of the NHS [1]. Mean cost/patient/year ranged from 1,500 to 3,912 according to the illness severity, and direct costs (in particular, hospitalizations and ER admissions) represented the main driver of cost. Moreover, unacceptable levels for underdiagnosis and mistreatment of COPD were also confirmed in that study. In a further investigation [2], the mean societal cost of COPD was 1308/p/y: as 75% of cost was due to hospitalizations, a more effective strategy for managing and controlling COPD exacerbations was further strongly recommended in order to alleviate the burden of the disease in Italy. A few years later, the economic value of different therapeutic interventions (which were regarded as appropriate according to the most accepted guide- CF Donner (ed.) Summaries, COPD: inapropriateness and pharmaco-economics, Venice, April 2010 Riassunti, BPCO: inappropriatezze e farmacoeconomia, Venezia, aprile 2010 MRM 127

53 MRM _def:Layout 1 08/04/10 15:48 Pagina 128 Multidisciplinary Respiratory Medicine 2010; 5(2): lines) was investigated by means of a markovian model on the basis of their effectiveness in outcome optimization [3]. The key message emerging was that both a prompt diagnosis of disease and disease exacerbations, together with an appropriate and long-term therapeutic approach to COPD patients, represent the most effective strategy to optimize all outcomes related to the disease, and to substantially reduce the impact of COPD on patient, healthcare institutions and society as a whole. Two years ago, health resources consumption and costs generated in 12 months by COPD were calculated on a national basis, in a real-life setting for a 1-year duration, and according to a bottom-up, observational, prospective multicentric study. At the end of the survey, outcomes were compared with those of the previous year [4]. A total of 748 patients were recruited, and 561 were defined as eligible by the Steering Committee; the proportion of moderate and severe COPD was 53.7 and 16.8%, respectively. Mean total cost/p/y was 2,723.7, ranging 913-5,452 according to the disease severity. At the end of the survey, requirement of health services had dropped significantly compared to baseline: GP visits by 57.4%; ER use by 12.5%; hospitalizations by 18.4%. Furthermore, even if direct costs remained the main driver of cost, the mean total cost per patient dropped by 21.7% (p < 0.002), mainly due to a much more appropriate interventional and therapeutic strategy. When compared to previous studies, these data pinpointed that the mean total cost/p/y of COPD doubled in a 5-year period in Italy: this trend has also been registered in different countries (such as USA) over the same period. Quite similar figures were found in another study carried out on 268 COPD patients from different lung units [5]. Data from a recent cross-sectional study carried out on COPD patients with different severity support the evidence that also moderate COPD represents a substantial economic burden for health care systems, and strongly indicate both the clinical and the economic convenience of an earlier, long-term therapeutic intervention in these circumstances [6]. To identify more incisive strategies for controlling COPD and minimizing related health care expenditure, cost-effectivenes and cost-utility models with a longer time-horizon should be adopted in future studies. References 1. Dal Negro R, Berto P, Tognella S, Quareni L; Global Outcomes in Lung Disease Study Group. Cost-of-illness of lung disease in the TriVeneto region, Italy: the GOLD Study. Monaldi Arch Chest Dis 2002;57: Dal Negro R, Rossi A, Cerveri I. The burden of COPD in Italy: results from the Confronting COPD survey. Respir Med 2003;97(Suppl C):S43-S Dal Negro R. Optimizing economic outcomes in the management of COPD. Int J Chron Obstruct Pulmon Dis 2008;3: Dal Negro RW, Tognella S, Tosatto R, Dionisi M, Turco P, Donner CF. Costs of chronic obstructive pulmonary disease (COPD) in Italy: the SIRIO study (social impact of respiratory integrated outcomes). Respir Med 2008;102: Koleva D, Motterlini N; Banfi P; Garattini L; Study Group BIC. Healthcare costs of COPD in Italian referral centres: a prospective study. Respir Med 2007;101: Dal Negro RW, Bonadiman L, Turati C, Turco P. Clinical and pharmacoeconomic profile of COPD patients with FEV % predicted: pilot study on the impact of the extended indication of ICS/LABA. Ther Adv Respir Dis 2009;3: AGE.NA.S: national system for guidelines AGE.NA.S: il sistema nazionale per le linee guida Bruno Rusticali Scientific Coordinator of Guidelines, AGE.NA.S (National Agency for Regional Health Services), Rome, Italy The AGE.NA.S (National Agency for Regional Health Services) has, among its other activities, the responsibility at national level for the elaboration and dissemination of clinical and organizational guidelines. The strategic use of guidelines permits the evaluation of the quality of the services based on scientifically valid principles, recognizable by operators and decision makers. In fact guidelines constitute a primary source for the identification of indicators which can contribute in the assessment of appropriateness and they are a means of communication among professionals and of information to citizens. Guidelines have been criticized for how they rate the quality of evidence and the strength of recommendations, although with the development of systems such as GRADE - Grading of Recommendations Assessment, Development and Evaluation - this limit has been overcome. Concerns now remain about the necessity of elaborating ad-hoc initiatives for the correct implementation of guidelines at national and local (regional) level. For some clinical conditions limited information is available about current practice patterns and significant deviations 128 MRM

54 MRM _def:Layout 1 08/04/10 15:48 Pagina 129 between current practice and guidelines regarding the use and selection of treatments have been found. Alongside this comes the razionalization of the use of health resources and the choice of diagnostic and therapeuthic paths according to priorities which should be established on the basis of the best available evidence. Therefore, in the development of guidelines efforts should be addressed to the examination and selection of interventions with a costeffective profile. Session III: Inappropriateness at different steps of COPD management Sessione III: Inappropriatezza nei differenti passaggi della gestione della BPCO Prevention Prevenzione Isabella Annesi-Maesano Epidemiology, Allergic & Respiratory Diseases Department, INSERM, Faculty of Medicine Saint-Antoine, Paris, France Reports estimate that, by the year 2020 COPD will have moved up, becoming the third leading cause of death worldwide. These astonishing statistics make it extremely important to identify risk factors associated with COPD and seek early treatment if symptoms arise. This is crucial as presently most people are not diagnosed until they are in their late 50s when a decline in their respiratory lung function has already set in [1]. Recognizing COPD risk factors and advocating lifestyle changes is the best way to maintain optimal respiratory health and prevent this devastating, lifethreatening illness. Population-based and clinical studies have identified risk factors for COPD [2]. These can be divided into factors responsible for COPD exacerbations and factors responsible for COPD development. However, some factors are responsible for both the development and the exacerbations. Factors responsible for lung function impairment (which starts already during lung function growth), a main feature of COPD, have also to be taken into account. Lifestyle modifications that can help prevent COPD, or improve lung function in COPD patients, include: quitting smoking, avoiding respiratory irritants and infections, avoiding allergens, maintaining good nutrition, drinking lots of fluids, avoiding excessively low or high temperatures and very high altitudes, maintaining proper weight, and exercising to increase muscle tone. However, data are insufficiently evidence-based for some factors. Robust data exist, although to different extents, on active and secondhand tobacco smoke exposure, occupational exposure and outdoor and indoor air pollution [3]. Smoking is the leading cause of COPD. For instance, the American Lung Association estimates that 80 to 90% of those diagnosed with COPD are chronic smokers. The amount an individual smokes as well as how long they have been smoking can increase the probability of developing the disease and intensify its severity. Risk factors are not only prevalent in those who smoke regular cigarettes, but exist for pipe and cigar smokers as well. Quitting smoking is the most important thing that one can do to prevent or slow damage to the lungs. Although it is not possible to undo the damage that smoking has already caused, further lung damage can be prevented by quitting. In terms of disease progression, other factors of COPD besides direct smoking that may also influence the course of the disease and its eventual health outcomes as well as the development, include secondhand smoke (SHS) exposure and occupational exposures [3]. Actually, an estimated 25-45% of patients with COPD have never smoked. The burden of non-smoking COPD is therefore much higher than previously believed. Avoiding conditions that may irritate the lungs can reduce breathing problems in people with COPD. These conditions include indoor and outdoor air pollution; smog; cold, dry air; hot, humid air; or high altitudes. SHS exposure is an important factor influencing disease severity and health status in COPD [4]. Previous studies suggest that SHS exposure may be a cause of new-onset COPD or impaired pulmonary function. The effect of SHS exposure on persons with established COPD, however, has received little attention. Because SHS is a modifiable risk factor, clinicians should assess SHS exposure in their COPD patients and counsel its avoidance. In public health terms, the effects of SHS exposure on the vul- CF Donner (ed.) Summaries, COPD: inapropriateness and pharmaco-economics, Venice, April 2010 Riassunti, BPCO: inappropriatezze e farmacoeconomia, Venezia, aprile 2010 MRM 129

55 MRM _def:Layout 1 08/04/10 15:48 Pagina 130 Multidisciplinary Respiratory Medicine 2010; 5(2): nerable subpopulations including COPD patients should provide a further rationale for laws prohibiting smoking in public. Various studies have reported that exposure to toxic gases in the workplace, grain dust in farms, and dust and fumes in factories is strongly associated with COPD. In 2003, results of a systematic epidemiological review into occupational factors associated with COPD by the American Thoracic Society showed that about 15% of COPD cases might be attributable to workplace exposure [5]; and a subsequent follow up provided similar estimates [6]. Use of appropriate protective gear (e.g. face mask) in the workplace to avoid inhaling hazardous substances has also been documented as potentially relevant. Exposure to indoor and outdoor air pollutants continues to be a major contributing factor to augmented morbidity, healthcare resources utilization and higher mortality among patients with COPD [7], particularly in the elderly [8], subsequently impacting public health, but there are few studies on whether air pollution is a key factor in the development of this disease. About 3 billion people, half the world s population, are exposed to smoke from biomass fuel compared with 1.01 billion people who smoke tobacco, which suggests that exposure to biomass smoke might be the biggest risk factor for COPD globally. Byproducts of oxidative stress found in air pollutants are common initiators or promoters of the damage produced in such chronic diseases. Such air pollutants include: ozone, sulfur oxides, carbon monoxide, nitrogen oxides, and particulate matter. Interaction between oxidative stress byproducts and certain genes may modulate the expression of COPD. Strong evidence exists also for infections as a trigger of COPD exacerbations. Avoiding respiratory illnesses, such as influenza and pneumonia, can decrease the risk of COPD worsening [9]. Although clinical trial data are limited, vaccinations can prevent some of the infections that cause COPD exacerbations and should be administered to all patients with COPD. Vaccines do not cause exacerbations of COPD. Patient and physician barriers to vaccination have to be overcome with targeted education and system-wide interventions. Lastly, physical activity has been shown to improve lung health [10]. Airflow obstruction leads to progressive hyperinflation, activity limitation and physical deconditioning. Thus physical inactivity is an important therapeutic target in COPD. Targeting the airflow obstruction with therapy in conjunction with a supervised exercise prescription is currently the most effective therapeutic intervention in earlier COPD. Other important manifestations of skeletal muscle dysfunction include muscle atrophy and weakness. However, data on these physical effects are still scant. The challenge we will all face in the next few years will be to obtain more robust data on risk factors for COPD development, progression and exacerbation and to implement cost-effective prevention and management strategies to stem the tide of this disease and its cost. References 1. Annesi-Maesano I. Epidemiology of chronic obstructive pulmonary disease. Eur RespirMon 2006;38: Annesi-Maesano I, Gulsvick A, Viegi G (ed). Respiratory Epidemiology in Europe. Eur Respir Mon 2000;15: Viegi G, Maio S, Pistelli F, Baldacci S, Carrozzi L. Epidemiology of chronic obstructive pulmonary disease: health effects of air pollution. Respirology 2006;11: Eisner MD, Balmes J, Katz PP, Trupin L, Yelin EH, Blanc PD. Lifetime environmental tobacco smoke exposure and the risk of chronic obstructive pulmonary disease. Environ Health 2005,4:7. 5. Balmes J, Becklake M, Blanc P, Henneberger P, Kreiss K, Mapp C, Milton D, Schwartz D, Toren K, Viegi G: Environmental and Occupational Health Assembly, American Thoracic Society. American Thoracic Society Statement: Occupational contribution to the burden of airway disease. Am J Respir Crit Care Med 2003,167: Blanc PD, Torén K. Occupation in chronic obstructive pulmonary disease and chronic bronchitis: an update. Int J Tuberc Lung Dis 2007;11: Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in non-smokers. Lancet 2009; 29;374: Viegi G, Maio S, Simoni M, Baldacci S, Annesi-Maesano I. The epidemiological link between ageing and respiratory diseases. Eur Respir Mon 2009;43: Varkey JB, Varkey AB, Varkey B. Prophylactic vaccinations in chronic obstructive pulmonary disease: current status. Curr Opin Pulm Med 2009;15: Cooper CB. Airflow obstruction and exercise. Respir Med 2009;103: MRM

56 MRM _def:Layout 1 08/04/10 15:48 Pagina 131 Diagnosis Diagnosi Isa Cerveri Respiratory and Pathophysiology Unit, Respiratory Diseases Division, University of Pavia, IRCCS Policlinico San Matteo, Pavia, Italy While the diagnosis of asthma requires symptoms, the diagnosis of COPD has often been based only on spirometry, given the presence of a provoking factor such as smoking or atmospheric pollution or occupational exposure [1]. Recently, the importance of adding medical history data to spirometry has been emphasized as there is still considerable underpresentation and underdiagnosis of COPD and also as family physicians focus on presented symptoms. Thus, diagnostic guidelines should stress the importance of persistent cough and phlegm to support timely diagnosis of COPD in family practice [2]. Another important point is that the GOLD Committee suggested the use of a fixed FEV 1 /FVC cut-off of 0.70 instead of the more appropriate statistically defined lower limit of normal (LLN), claiming that the fixed ratio is easy to remember and to apply and not dependent on the choice of reference equation. Many recent papers have documented that the fixed cut-off of 0.70 significantly overestimates airflow obstruction in older people leading to misdirection of resources, unnecessary costs, and individual and societal harm [3-5]. On the other hand, it underestimates airflow obstruction among young adults leading to a missed opportunity for an early diagnosis of COPD in patients who are more likely to benefit from intervention [3]. Since diagnostic confusion between COPD and asthma appears common, bronchodilatation performed after spirometry may help to reduce the chance of misclassification. The complexity and heterogeneity of the disorders encompassed by the term COPD with the overlap of different phenotypes have recently led to recommendations: i) that a new taxonomy is required to better define the disorders of airways obstruction and, consequently, ii) that clinical assessment should become increasingly multidimensional [6-7]. Among lung function parameters, besides FEV 1 /FVC, lung volumes should always be included in the diagnosis of COPD as evaluation of hyper - inflation is an important criterion in the phenotyping of COPD patients. References 1. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management and Prevention of COPD (Update 2008) Medical Communications Resources, Inc, De Marco R, Accordini S, Cerveri I, Corsico A, Antó JM, Künzli N, Janson C, Sunyer J, Jarvis D, Chinn S, Vermeire P, Svanes C, Ackermann-Liebrich U, Gislason T, Heinrich J, Leynaert B, Neukirch F, Schouten JP, Wjst M, Burney P. Incidence of chronic obstructive pulmonary disease in a cohort of young adults according to the presence of chronic cough and phlegm. Am J Respir Crit Care Med 2007;175: Cerveri I, Corsico AG, Accordini N, Niniano R, Ansaldo E, Antó JM, Künzli N, Janson C, Sunyer J, Jarvis D, Svanes C, Gislason T, Heinrich J, Schouten JP, Wjst M, Burney P, de Marco R. Underestimation of airflow obstruction among young adults using FEV 1/FVC < 70% as a fixed cut-off: a longitudinal evaluation of clinical and functional outcomes. Thorax 2008;63: Vollmer WM, Gíslason T, Burney P, Enright PL, Gulsvik A, Kocabas A, Buist AS.Comparison of spirometry criteria for the diagnosis of COPD: results from the BOLD study. Eur Respir J 2009;34: Swanney MP, Ruppel G, Enright PL, Pedersen OF, Crapo RO, Miller MR, Jensen RL, Falaschetti E, Schouten JP, Hankinson JL, Stocks J, Quanjer PH. Using the lower limit of normal for the FEV 1/FVC ratio reduces the misclassification of airway obstruction. Thorax 2008,63: Friedlander AL, Lynch D, Dyar LA, Bowler RP. Phenotypes of chronic obstructive pulmonary disease. COPD 2007;4: Weatherall M, Travers J, Shirtcliffe PM, Marsh SE, Williams MV, Nowitz MR, Aldington S, Beasley R. Distinct clinical phenotypes of airways disease defined by cluster analysis. Eur Respir J 2009;34: CF Donner (ed.) Summaries, COPD: inapropriateness and pharmaco-economics, Venice, April 2010 Riassunti, BPCO: inappropriatezze e farmacoeconomia, Venezia, aprile 2010 MRM 131

57 MRM _def:Layout 1 08/04/10 15:48 Pagina 132 Multidisciplinary Respiratory Medicine 2010; 5(2): Treatment Trattamento Bartolome R. Celli Pulmonary Critical Care Medicine, Brigham and Women s Hospital, Boston, MA, USA It is generally accepted that COPD is not only preventable but also treatable. This change in concept from a previously nihilistic treatment paradigm based on smoking cessation being the only possible treatment for COPD has occurred over the last 2 decades as a consequence of several large trials including not only pharmacological agents but - equally important - pulmonary rehabilitation and even surgery (lung volume reduction surgery). It is inherent to these trials that patients be included only if they have COPD and by and large are free of concomitant morbidities that can impact negatively on the trial outcome, thus restricting the value of the results as the population is highly selected. On the other hand, once the results of the trials become available and, usually out of necessity, the findings permeate the larger community and patients get treated whether they meet the original inclusion and exclusion criteria or not. It is in this stage of the implementation of therapies on a greater scale that treatments have to be monitored as to their safety and their likelihood to provide efficacy, thereby avoiding undue side effects and negative consequences. In the specific case of COPD, the problem is compounded by the fact that these patients are frequently afflicted by multiple co-morbid problems. Heart disease, osteoporosis, peripheral muscle weakness and dysfunction, anemia, depression, anxiety and lung cancer are more frequent in patients with COPD than in the population at large. It is then imperative that safety be carefully determined in observational registries so that in the end a composite analysis of trial results is interpreted in the light of empirical usage. Following is an overview of the available evidence for the most frequently used treatments. Pharmacological treatments Recently there has been concern that the long-term use of inhaled bronchodilators commonly used in the treatment of COPD, including long-acting β 2 -agonist (LABA) and anticholinergic drugs, may increase the risk of cardiovascular complications. However, prospective data on the relative risk of therapy in patients with sufficient symptoms to be offered treatment with these drugs has, until recently, been lacking. Anticholinergics The safety profile of inhaled anticholinergics has been studied for many years. The short acting ipra - tropium bromide has been available to patients for over 20 years, and tiotropium since An association between ipratropium and cardiovascular mortality was noted in an earlier report from the Lung Health Study. However, a re-analysis of the same data by Lanes et al. showed that the increased risk of cardiovascular morbidity and mortality in that study was concentrated among patients who were randomized to the ipratropium group but who did not take ipratropium. Several reports have retrospectively examined safety data using different approaches with somewhat conflicting results regarding a possible association between inhaled anticholinergics, including tiotropium, and adverse cardiovascular consequences. In the first one, Lee et al. examined the association between various respiratory medications and risk for death in newly diagnosed COPD patients based on a retrospective nested case-control study using various databases. The authors concluded that ipratropium was associated with increased cardiovascular deaths, whereas inhaled corticosteroids were associated with reduced risk. The authors were limited by the data available to them, which did not include information on smoking or lung function. All-cause mortality risk ratio was 1.02 for ipratropium. The second analysis, by Singh et al., selected randomized controlled trials of any inhaled anticholinergic for treatment of COPD that had at least 30 days of treatment, and reported on cardiovascular events. The primary outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The secondary outcome was all-cause mortality. While the report describes ipratropium and tiotropium trials both combined and separately, no differences in any cardiovascular effects would be expected between the two compounds based on their pharmacology. Singh et al. concluded that inhaled anticholinergics significantly increased the risk of the composite cardiovascular endpoint, myocardial infarction and cardiovascular death without a statistically significant increase in the risk of stroke. The analysis did not take into account differential discontinuation (i.e. in most of the trials, more patients in the placebo group prematurely discontinued the study than did patients taking active medication and were therefore followed for briefer periods of time during which adverse events were reported) and differences in exposure. The recent analysis of the large tiotropium database and the findings of the prospective UPLIFT study indicate a reduced risk for mortality from cardiovascular events and even overall mortality in patients receiving tiotropium. The mechanism by which tiotropium may reduce these events and improve survival cannot be precisely determined in the pooled clinical trial database but 132 MRM

58 MRM _def:Layout 1 08/04/10 15:48 Pagina 133 an association with respiratory events must be considered given the significant reductions in exacerbations and hospitalizations observed. In the pooled analysis of 30 trials, tiotropium treatment also resulted in significant reductions in serious adverse events under the cardiac and respiratory organ systems. There are recognized limitations to pooling of clinical trial data. There are differences in populations, study design, duration of trials, collection of data and the ability to adjust for differences in exposure. β-agonists Like the antimuscarinic agents, β-agonists have the potential to precipitate cardiac rhythm disturbances and other cardiac events; however, this has not been regarded as important in clinical practice until recently. Unfortunately, unlike the situation for cardiovascular disease, most studies of drug treatment in COPD have been relatively brief (1 year and less) and have only reported on-treatment data. As the TORCH study was conducted in a patient group likely to be prescribed inhaled LABAs, that dataset addresses some of the problems inherent in these earlier analyses. TORCH is the largest and longest prospective trial to examine the role of an inhaled LABA and an inhaled corticosteroid in COPD. Half of the over 6,000 patients were randomised to a regime containing SAL and, allowing for dropouts, this provided 7,231 patient-years of exposure to these agents. Over the 3 years, approximately 1 in 5 patients experienced a cardiovascular AE. The event rate was lowest in those receiving SAL in combination with FP, and not different from those patients treated with placebo or with LABA monotherapy. A SAE requiring hospitalization and new cardiovascular ischaemic events were approximately half as common as the total cardiovascular event rate, but there was a similar pattern across treatment groups. Seven percent of patients had a history of previous MI. In this group the cardiovascular event rate, as would be expected, was higher. Again, no trend was seen for more AEs in those patients randomized to treatment with SAL in combination with FP. However the data for SAL alone are inconclusive, possibly due to the small sample size in this smaller subgroup of patients. Unlike other COPD studies, TORCH developed a rigorous methodology for determining the likely cause of death, which was adjudicated by an expert panel blinded to the study medication. Moreover, there was effectively complete follow up of the vital status of all patients 3 years after randomisation. The patients randomised to LABA alone had the lowest rate of cardiovascular death, while those who received placebo had the largest number of events. The number of on-treatment deaths, analogous to data included in earlier COPD studies, showed a similar pattern across treatments. A range of predictable factors increase the cardiovascular event rate, including: greater age, a history of previous cardiac disease, and worse lung function. None of these factors interacted with treatment to identify a specific at risk group. Inhaled corticosteroids If cardiovascular events are the most feared complications of patients receiving treatment with anticholinergics or β-agonists, the recent documentation that the risk of pneumonia is increased in patients receiving inhaled fluticasone has arisen from well controlled randomized trials. Based on the findings reported in the TORCH trial Ernst and colleagues reported the results of a nested casecontrol study within a cohort of nearly 176,000 patients with COPD that examined ICS use and the risk of hospitalization for pneumonia. Compared with non-ics users within the past year, patients receiving at least 1,000 mcg/day of FP equivalent had a rate ratio for pneumonia hospitalization of 2.25 (95% CI ). In addition, the length of pneumonia hospitalization was similar whether or not patients were current users of ICS (mean 11.7 days vs days), as was all-cause mortality within 30 days of being hospitalized for pneumonia for patients dispensed ICS in the prior 2 months (8.2% of 18,005 patients) compared with those who were not dispensed ICS (7.4% of 5,937 patients). The careful review of all deaths reported in the large TORCH trial showed no difference in pneumonia mortality between patients receiving inhaled corticosteroids and those not receiving them. What is very remarkable in the whole arena of pharmacological therapy is how much we have learned in the process. Medications have been shown to improve lung function, health status, decrease exacerbations and perhaps even impact on mortality but this has come at a price. Indeed, there is not only an economic cost but also the development of side effects that need careful monitoring over time. Fortunately, society has developed mechanisms by which the effect of drugs is monitored closely and even if not all problems can be prevented, it has made the agents available much safer to use. Non-pharmacological therapies The implementation of the National Emphysema Trial (NETT) was a first for the evaluation of surgical therapies. NETT represented the first surgical procedure subjected to a randomized trial using a medical comparator, in this case optimal medical therapy including pulmonary rehabilitation. Perhaps the greatest teaching to be derived from this study related to the initial report from the group. That publication dealt with the characterization of patients who had poor outcome when subjected to lung reduction surgery. Indeed, in the initial evaluation and follow up of the patients included in NETT, it became evident that a very low FEV 1 and diffusion capacity for carbon monoxide (DL CO ) were associated with a very poor outcome. Indeed, these observations had important consequences for the field because they became reasons to exclude patients from consideration for lung volume reduction procedures. This report underscores the value of careful CF Donner (ed.) Summaries, COPD: inapropriateness and pharmaco-economics, Venice, April 2010 Riassunti, BPCO: inappropriatezze e farmacoeconomia, Venezia, aprile 2010 MRM 133

59 MRM _def:Layout 1 08/04/10 15:48 Pagina 134 Multidisciplinary Respiratory Medicine 2010; 5(2): assessment of new technologies, in this case for patients with COPD. Perhaps a word of caution must be raised because alerting to the negative effects of a treatment prior to a full evaluation of the pros and cons of treatments may lead to premature killing of good ideas and therapies. The last therapy that has generated great interest is that of pulmonary rehabilitation. Several modest size trials have been conducted but they have all emphasized the beneficial consequences of the therapy with very little information regarding bad outcomes or side effects. Perhaps, the most relevant information related to negative outcome is that of providing a picture of patients who do not want to participate in rehabilitation and, equally important, of how many do not complete the programs. The percentage of patients who do not join programs hovers around a very high 60% and out of those that join close to 30% fail to complete the program. Unfortunately very little has been done to better characterize those patients and evaluate the factors that lead to lack of compliance and uptake. Conclusions Much has been learned about the inappropriateness of therapies through the implementation of the scientific method. Even though it may seem slow and complex, it is evident that application of these concepts in the area of treatment has enhanced our knowledge about the therapies that we provide to patients. As we enhance our armamentarium, it is important to remember that our current approach has served us well. We have indeed gained know - ledge and confidence that the most frequently used therapies are safe and effective while we continue to investigate newer avenues to further empower our patients with a better future. References 1. Barnes PJ, Celli BR. Systemic manifestations and co-morbidities of COPD. Eur Respir J 2009;33: Sin DD, Man SF. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation 2003;107: Mannino DM, Aguayo SM, Petty TL, Redd SC. Low lung function and incident lung cancer in the United States: data from the First National Health and Nutrition Examination Survey follow-up. Arch Intern Med 2003;163: Johnston AK, Mannino DM, Hagan GW, Davis KJ, Kiri VA. Relationship between lung function impairment and incidence of recurrence of cardiovascular events in a middleaged cohort. Thorax 2008;63: Anthonisen NR. Prognosis in chronic obstructive pulmonary disease: results from multicenter clinical trials. Am Rev Resp Dis 1989;140;S95-S Lange P, Nyboe J, Appleyard M, Jensen G, Schnohr P. Relation of ventilatory impairment and of chronic mucus hypersecretion to mortality from obstructive lung disease and from all causes. Thorax 1990;45: Curkendall SM, DeLuise C, Jones JK, Lanes S, Stang MR, Goehring E Jr, She D. Cardiovascular disease in patients with chronic obstructive pulmonary disease, Saskatchewan Canada cardiovascular disease in COPD patients. Ann Epidemiol 2006;16: Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. JAMA 2008;300: Lee TA, Pickard AS, Au DH, Bartle B, Weiss KB. Risk of death associated with medications for recently diagnosed chronic obstructive pulmonary disease. Ann Intern Med 2008;149: Gershon A, Wang L, To T, Luo J, Upshur RE. Survival with tiotropium compared to longacting beta-2-agonists in chronic obstructive pulmonary disease. COPD 2008;5: Macie C, Wooldrage K, Manfreda J,Anthonisen N. Cardiovascular morbidity and the use of inhaled bronchodilators. Int J Chron Obstruct Pulmon Dis 2008;3: Lanes S, Golisch W, Mikl J. Ipratropium and lung health study. Am J Respir Crit Care Med 2003;167: Fishman A, Martinez F, Naunheim K, Piantadosi S, Wise R, Ries A, Weinmann G, Wood DE; National Emphysema Treatment Trial Research Group. A randomized trial comparing lung-volume reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003;348: Lanes SF, Jara M. The INSPIRE study: influence of prior use and discontinuation of inhaled corticosteroids. Am J Respir Crit Care Med 2008;178: Salpeter SR. Bronchodilators in COPD: impact of beta-agonists and anticholinergics on severe exacerbations and mortality. Int J Chron Obstruct Pulmon Dis 2007;2: Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, Decramer M; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359: Sin DD, Man SF. Chronic obstructive pulmonary disease as a risk factor for cardiovascular morbidity and mortality. Proc Am Thorac Soc 2005;2: Anthonisen NR, Skeans MA, Wise RA, Manfreda J, Kanner RE, Connett JE; Lung Health Study Research Group. The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann Intern Med 2005;142: Keistinen T, Tuuponen T, Kivelä SL. Survival experience of the population needing hospital treatment for asthma or COPD at age years. Respir Med 1998;92: Curkendall SM, Lanes S, de Luise C, Stang MR, Jones JK, She D, Goehring E Jr. Chronic obstructive pulmonary disease severity and cardiovascular outcomes. Eur J Epidemiol 2006;21: Johnston AK, Mannino DM, Hagan GW, Davis KJ, Kiri VA. Relationship between lung function impairment and incidence or recurrence of cardiovascular events in a middleaged cohort. Thorax 2008;63: Hole DJ, Watt GC, Davey-Smith G, Hart CL, Gillis CR, Hawthorne VM. Impaired lung function and mortality risk in men and women: findings from the Renfrew and Paisley prospective population study. BMJ 1996;313: Cazzola M, Matera MG, Donner CF. Inhaled beta2-adrenoceptor agonists: cardiovascular safety in patients with obstructive lung disease. Drugs 2005;65: Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of beta-agonists in patients with asthma and COPD: a meta-analysis. Chest 2004;125: Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH investigators. Salmeterol and fluticasone propionate and survival in 134 MRM

60 MRM _def:Layout 1 08/04/10 15:48 Pagina 135 chronic obstructive pulmonary disease. N Engl J Med 2007;356: Ferguson GT, Calverley PMA, Anderson JA, et al. Incidence of cardiac events in COPD patients in the TORCH study (abstr). Am J Respir Crit Care Med 2008,177:A Vestbo J; TORCH Study Group. The TORCH (towards a revolution in COPD health) survival study protocol. Eur Respir J 2004;24: McGarvey LP, John M, Anderson JA, Zvarich M, Wise RA; TORCH Clinical Endpoint Committee. Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax 2007;62: Crim C, Calverley PM, Anderson JA, Celli B, Ferguson GT, Follow up Follow up Jenkins C, Jones PW, Willits LR, Yates JC, Vestbo J. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J 2009;34: Nici L, Donner C, Wouters E, Zuwallack R, Ambrosino N, Bourbeau J, Carone M, Celli B, Engelen M, Fahy B, Garvey C, Goldstein R, Gosselink R, Lareau S, MacIntyre N, Maltais F, Morgan M, O'Donnell D, Prefault C, Reardon J, Rochester C, Schols A, Singh S, Troosters T; ATS/ERS Pulmonary Rehabilitation Writing Committee. American Thoracic Society/European Respiratory Society statement on pulmonary rehabilitation. Am J Respir Crit Care Med. 2006;173: Francesco G. Salerno, Mauro Carone Pulmonary Division, Salvatore Maugeri Foundation IRCCS, Scientific Institute of Cassano delle Murge, Cassano delle Murge, BA, Italy COPD is believed to become, in a few years, the third leading cause of death worldwide. Exacerbations of COPD are a frequent cause of emergency department visits and hospitalizations. An exacerbation of COPD is defined as a change in the patient s baseline dyspnea, cough, and sputum that is beyond day-to-day variations, is acute in onset, and may warrant a change in regular medication [1]. Exacerbations of COPD are common and present a major financial burden for most health care systems. The management of patients experiencing an acute exacerbation varies despite guideline-recommended care. Furthermore, there is little information on how to manage patients after hospitalization for COPD in order to optimize care and reduce the occurrence of a relapse [2]. Indeed, after an emergency department visit for an exacerbation of COPD there is a high probability that a new episode will occur in the first 2 weeks after discharge [3,4]. Exacerbations are not random events but the risk of recurrence is greatest within the first few weeks of the initial event [5]. Several risk factors have been identified that facilitate the occurrence of a new exacerbation, including: number of previous exacerbations, use of oxygen, lung function, absence of a primary caregiver and choice of pharmacological therapy [6,7]. For instance, patients who lack a primary caregiver use emergency care services more frequently than those who have a primary caregiver [8]. The lack of literature makes it impossible to provide specific recommendations for the management of patients after exacerbations of COPD. The use and value of spirometry, the potential benefit of home monitoring and of noninvasive ventilation as well as the value of long-term oxygen therapy, self-management programs and early rehabilitation need to be better investigated. Current guidelines recommend a follow up at 4 6 weeks after hospitalization in order to assess clinical status, inhaler technique, the need for long-term oxygen therapy and FEV 1. It is not clear whether a follow up earlier after discharge could reduce the exacerbation rate. There are few studies comparing the effect of a different frequency of follow up visits on the relapse rate of patients after hospitalization due to a COPD exacerbation. Available data suggest that an early rehabilitation intervention should be included in the follow up program. Rehabilitation is advisable after an acute exacerbation because it reduces the hospitalization rate and improves exercise capacity and quality of life [9]. In conclusion, although the current literature does not provide clear recommendations regarding all the components of a care plan following an exacerbation of COPD, a rehabilitation program should be included. Efforts should be made to improve the availability of rehabilitation for COPD patients in different health care settings. References 1. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management and Prevention of COPD (Update 2008) Medical Communications Resources, Inc, Osthoff M, Leuppi JD. Management of chronic obstructive pulmonary disease patients after hospitalization for acute exacerbation. Respiration 2010;79: Murata GH, Gorby MS, Chick TW, Halperin AK. Use of emergency medical services by patients with decompensated obstructive lung disease. Ann Emerg Med 1989;18: Kim S, Emerman CL, Cydulka RK, Rowe BH, Clark S, Camargo CA. Prospective multicenter study of relapse following emergency department treatment of COPD exacer- CF Donner (ed.) Summaries, COPD: inapropriateness and pharmaco-economics, Venice, April 2010 Riassunti, BPCO: inappropriatezze e farmacoeconomia, Venezia, aprile 2010 MRM 135

61 MRM _def:Layout 1 08/04/10 15:48 Pagina 136 Multidisciplinary Respiratory Medicine 2010; 5(2): bation. Chest 2004;125: Hurst JR, Donaldson GC, Quint JK, Goldring JJ, Baghai- Ravary R, Wedzicha JA. Temporal clustering of exacerbations in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009;179: Murata GH, Gorby MS, Kapsner CO, Chick TW, Halperin AK. A multivariate model for the prediction of relapse after outpatient treatment of decompensated chronic obstructive pulmonary disease. Arch Intern Med 1992;152: Niewoehner DE. Relation of chronic obstructive pulmonary Session IV: A new decade of COPD Sessione IV: Una nuova decade per la BPCO Pathogenesis of COPD: an innovative approach Patogenesi della BPCO: un approccio innovativo disease exacerbations to FEV 1: an intricate tango. Respiration 2009;77: Tsai CL, Griswold SK, Clark S, Camargo CA Jr. Factors associated with frequency of emergency department visits for chronic obstructive pulmonary disease exacerbation. J Gen Intern Med 2007;22: Puhan MA, Scharplatz M, Troosters T, Steurer J. Respiratory rehabilitation after acute exacerbation of COPD may reduce risk for readmission and mortality: a systematic review. Respir Res 2005;6:54. Marco Chilosi 1, Andrea Rossi 2 1 Department of Pathology, University of Verona, Verona, Italy 2 Pulmonary Division, Verona General Hospital, Verona, Italy COPD is a severe multifactorial pulmonary disorder whose pathogenesis is not completely understood. Interestingly, a gradual shift from inflammatorybased pathogenic theories to more complex approaches has occurred in recent years [1]. Striking new evidence regarding the pathogenesis of COPD (in particular, emphysema) relates to its proposed inclusion within the category of diseases of premature aging of the lung, based on strong similarities with diseases characterized by telomere and stem cell dysfunction [2-4]. In the lungs, telo - mere erosion can variably affect the renewal potential of different stem cells, thus causing progressive depletion of relevant parenchymal components eventually culminating in alveolar loss and functional abnormality. Interestingly, evidence is accumulating that also idiopathic interstitial pneumonia (IPF) can be included in the pathological category of diseases characterized by telomere dysfunction [5-7]. Tobacco smoke is a key pathogenic element in both COPD and IPF, and may serve as an environmental co-factor for the development of both diseases [5]. But how can this proposed similarity between the basic pathogenic mechanisms underlying COPD and IPF be reconciled with the obvious diversity of their pathologic and clinical presentations? The explanation could be sought in the heterogeneity of the underlying genetic alterations, as well as in the diversity of specific cell targets. Several reports in fact suggest that in IPF the major target is the alveolar epithelial stem cell (type II pneumocyte) [8] whereas in COPD mesenchymal cells (fibroblasts and endothelial cells) within the alveolar parenchyma represent the Achille s heel [9]. Thus, in COPD, abnormal apoptosis, senescence and loss of function mainly affect cells involved in the production of extracellular matrix proteins (elastin, fibronectin, etc.), with eventual weakening of the mesenchymal structure of the alveoli, leading to a defect in tissue reserve and vanishing of the supporting scaffold for epithelial cells. Although some evidence has been provided of pneumocyte apoptosis, alveolar reparative mechanisms seem to be absent in emphysema, with no evidence of pneumocyte proliferation. The complexity of genetic predisposing features (e.g. telo - mere stricture together with alpha-1-antitrypsin deficiency, VEGF insufficiency, and/or others) working in concert with environmental factors may explain why mesenchymal progenitors are more profoundly affected in these patients. Accordingly, in emphysema tobacco smoke can severely affect mesenchymal function and repair, and senescence related markers are mainly demonstrable in fibro - blasts and endothelial cells. In conclusion, this evolving scenario opens up new possibilities for a better understanding of the pathogenic mechanisms of COPD and also IPF, and may yield new perspectives for alternative treatments of these devastating diseases acting on either pharmacological protection or specific replacement of affected stem cells [10]. ACKNOWLEDGEMENTS: Supported by the European Union FP7 Health Research Grant n HEALTH-F MRM

62 MRM _def:Layout 1 08/04/10 15:48 Pagina 137 References 1. MacNee W, Tuder RM. New paradigms in the pathogenesis of chronic obstructive pulmonary disease I. Proc Am Thorac Soc 2009;6: Ito K, Barnes PJ. COPD as a disease of accelerated lung aging. Chest 2009;135: Savale L, Chaouat A, Bastuji-Garin S, Marcos E, Boyer L, Maitre B, Sarni M, Housset B, Weitzenblum E, Matrat M, Le Corvoisier P, Rideau D, Boczkowski J, Dubois-Randé JL, Chouaid C, Adnot S. Shortened telomeres in circulating leukocytes of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009;179: Houben JM, Mercken EM, Ketelslegers HB, Bast A, Wouters EF, Hageman GJ, Schols AM. Telomere shortening in chronic obstructive pulmonary disease. Respir Med 2009;103: Ly H. Genetic and environmental factors influencing human diseases with telomere dysfunction. Int J Clin Exp Med 2009;2: Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, Lawson WE, Xie M, Vulto I, Phillips JA 3rd, COPD management: an integrated approach La gestione della BPCO: un approccio integrato Josep Roca Hospital Clínic, CIBERES, IDIBAPS, University of Barcelona, Spain A rapidly evolving scenario Ageing of the population together with changes in lifestyle are central factors explaining the increasing prevalence of chronic disorders, which is expected to continue over the next decade leading to further dysfunctions of healthcare systems worldwide [1-3]. The urgent need to introduce substantial changes in the delivery of care for chronic patients is widely acknowledged. The World Health Organization (WHO) has launched the Innovative Care for Chronic Conditions (ICCC) initiative [4] formulating basic principles and strategies to enhance management of chronic patients [5,6]. There is evidence that information and communication technologies (ICT) can play an enabling role over the whole range of services, from life-style and self-management of health to improving health related quality of life of patients and citizens as well as managing chronic disease conditions [7]. Moreover, properly designed innovative health services supported by ICT might have a positive impact on chronic disease modulation and prognosis. Despite the many advances and accepted potential of technology, ICT adoption in healthcare has lagged behind. The barriers originate at different levels and are associated to a multitude of technological, cultural, legal, and market related factors. Adoption of ICT in healthcare is currently a major Lansdorp PM, Greider CW, Loyd JE. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 2007;356: Cronkhite JT, Xing C, Raghu G, Chin KM, Torres F, Rosenblatt RL, Garcia CK. Telomere shortening in familial and sporadic pulmonary fibrosis. Am J Respir Crit Care Med 2008;178: Sisson TH, Mendez M, Choi K, Subbotina N, Courey A, Cunningham A, Dave A, Engelhardt JF, Liu X, White ES, Thannickal VJ, Moore BB, Christensen PJ, Simon RH. Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis. Am J Respir Crit Care Med 2010;181: Kasahara Y, Tuder RM, Cool CD, Lynch DA, Flores SC, Voelkel NF. Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. Am J Respir Crit Care Med 2001;163: Wilson AA, Murphy GJ, Hamakawa H, Kwok LW, Srinivasan S, Hovav AH, Mulligan RC, Amar S, Suki B, Kotton DN. Amelioration of emphysema in mice through lentiviral transduction of long-lived pulmonary alveolar macrophages. J Clin Invest 2010;120: priority in Europe as shown by the major e-health deployment initiatives (e.g. epsos) launched through the Competitiveness and Information framework Program (CIP) [8,9]. From management of crisis to integrated care A recent analysis of the burden of all chronic conditions on tertiary care hospitalizations [10] indicated the need for revisiting managerial aspects of exacerbated chronic patients with a broad scope aimed at enhancing not only efficacy of care during the exacerbations, but also preventing admissions due to severe exacerbations in frail patients. In view of the high social and economic burden generated by hospitalization of patients with chronic disorders, new care modalities aimed at decreasing admissions through patients empowerment and implementation of alternatives to conventional hospitalization have been developed in recent years [11-12]. It is of note, however, that a holistic approach of integrated care in chronic patients should not be focused only on prevention and/or management of crisis. Instead, principal targets should be early diagnosis and prevention together with future personalized care strategies launched at early stages aimed at modulation of disease progress and enhancement of prognosis. Successful strategies to address the current challenges impose CF Donner (ed.) Summaries, COPD: inapropriateness and pharmaco-economics, Venice, April 2010 Riassunti, BPCO: inappropriatezze e farmacoeconomia, Venezia, aprile 2010 MRM 137

63 MRM _def:Layout 1 08/04/10 15:48 Pagina 138 Multidisciplinary Respiratory Medicine 2010; 5(2): a progressive decline of the classical disease management approach towards new patient-oriented strategies including the adoption of a new health paradigm fitting the needs of chronic care, as proposed by the Chronic Care model [1-6]. Changes in lifestyle aimed at disease prevention and promotion of well being, empowerment of patients and relatives in self-management together with share care arrangements among the different levels of care are all necessary elements to improve efficiency of chronic care. There is no doubt that current fragmentation among levels of care and community services constitutes a major limiting factor for a practical adoption of the principles formulated in the Chronic Care model. Moreover, management of comorbidity is a major challenge often overlooked by evidence-based diagnosis and treatment using disease-specific clinical guidelines. Several disease-specific randomized controlled trials undertaken in patients with chronic heart failure, COPD, diabetes and other disease conditions have consistently shown the potential of integrated care to enhance clinical outcomes while generating cost-containment at system level. A common problem in all these pilot studies is that disease-specific trials have shown high internal validity but a questionable external validity because of an elevated rate of exclusion mainly due to severe comorbid conditions (~ 60% of cases) that could potentially be managed through transversal programs addressed to frail patients with multiple severe chronic disorders. The second most important exclusion factor, often present in frail patients, is lack of appropriate social support. As suggested above, there is a strong need to move the focus from the current interest in advanced chronic conditions toward the development of preventive integrated care strategies addressed to early stages of chronic diseases or even to citizens with high risk of developing chronic disorders. The ultimate aim should not be constrained to management aspects, but should be to achieve a positive modulation of the prognosis of chronic disorders. Note, however, that highly standardized interventions together with continuous evaluation of results will be required. In order to face all these challenges, more and more attention is being paid to the evolution of health systems from a provider-centered perspective to a patient-focused approach. In the integrated care scenario being deployed in the NEXES Living healthily at home project, chronic patients included in well standardized care programs are managed through a support center (multimedia call center) to enhance accessibility to the specific type of care needed (Figure 1). Major organizational adjustments of health systems combined with significant educational changes are urgently needed in order to prepare the healthcare professionals for new and evolving roles. Moreover, there needs to be a major adjustment of financial modalities for the services to ensure sustainability of integrated care supported by ICT. Extensive deployment of integrated care service NEXES is the acronym of the project Supporting Healthier and Independent Living for Chronic Patients and Elderly conceived to face the transitional phase from existing pilot experiences to deployment of health/social services targeting selected groups of patients. It supplements and/or represents an alternative to existent conventional approaches. The project grew from the need to unfold previous pilot experiences on innovative healthcare services supported by ICT, already mentioned above. The main objective is to evaluate the potential for generalization of four specific services (see below) targeting citizens at risk and patients with chronic illnesses. NEXES will mainly address patients with one or more of the following chronic conditions: COPD, chronic heart failure and diabetes type II. In this scenario, ICT plays a fundamental support role in the new health model. The services to be validated through randomized controlled trials will be carried out in large scale studies including approximately 5,000 patients. The four types of services indicated below cover the needs of a broad spectrum of health problems, from those affecting citizens at risk or with early disease to those addressing frail patients with advanced chronic disorders. 1) Wellness and rehabilitation aimed at promoting healthy lifestyles in clinically stable chronic patients and enhancing their self-management 2) Enhanced care for frail patients to prevent unplanned hospitalizations 3) Home hospitalization of chronic patients with severe exacerbations aimed at optimization of home hospitalization 4) Support to diagnosis and/or to therapeutic procedures including collaborative tools for professionals working at different healthcare levels to enhance their potential for action in home-based interventions. All services will be assessed at three distinct sites FIGURE 1: INTEGRATED CARE SERVICES AS DEPLOYED IN THE NEXES PROJECT Target patients Management by programs Well standardized interventions Patient-centered care Patient Triage Self-management Remote monitoring Support center providers network 138 MRM

64 MRM _def:Layout 1 08/04/10 15:48 Pagina 139 (Barcelona, Central Norway Region and Athens) notwithstanding some existing differences in the specifics of healthcare organization. The impact of heterogeneities among sites will be evaluated. The differences among sites may offer opportunities for planning of co-developments at cross-border level in the deployment phase. One of the primary objectives of NEXES is to provide robust results to health technology assessment agencies and to decision makers in order to facilitate the extensive deployment of the services and the sustainability of the care model. References 1. Epping-Jordan JE, Galea G, Tukuitonga C, Beaglehole R. Preventing chronic diseases: taking stepwise action. Lancet 2005;366: Horton R. The neglected epidemic of chronic disease. Lancet 2005;366: Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet 1997;349: World Health Organization. Noncommunicable Disease and Mental Health Cluster. Innovative Care for Chronic Conditions: Building Blocks for Action Global Report. World Health Organization, A comprehensive approach to COPD Un approccio onnicomprensivo alla BPCO 5. Epping-Jordan JE, Pruitt SD, Bengoa R, Wagner EH. Improving the quality of health care for chronic conditions. Qual Saf Health Care 2004;13: van Weel C, Schellevis FG. Comorbidity and guidelines: conflicting interests. Lancet 2006;367: Blumenthal D. Stimulating the adoption of health information technology. N Engl J Med 2009;360: European Commission. Competitiveness and Innovation Framework Programme (CIP). The European Patients Smart Open Services project (epsos). 9. European Science Foundation. Advancing Systems Biology for Medical Applications. ESF Science Policy Briefing 2008;35: Hernandez C, Jansa M, Vidal M, Nuñez M, Bertran MJ, Garcia-Aymerich J, Roca J. The burden of chronic disorders on hospital admissions prompts the need for new modalities of care: a cross-sectional analysis in a tertiary hospital. QJM 2009;102: Casas A, Troosters T, Garcia-Aymerich J, Roca J, Hernández C, Alonso A, del Pozo F, de Toledo P, Antó JM, Rodríguez- Roisín R, Decramer M; members of the CHRONIC Project. Integrated care prevents hospitalisations for exacerbations in COPD patients. Eur Respir J 2006;28: Hernandez C, Casas A, Escarrabill J, Alonso J, Puig-Junoy J, Farrero E, Vilagut G, Collvinent B, Rodriguez-Roisin R, Roca J; CHRONIC project. Home hospitalisation of exacerbated chronic obstructive pulmonary disease patients. Eur Respir J 2003;21: Claudio F. Donner Mondo Medico, Multidisciplinary and Rehabilitation Outpatient Clinic, Borgomanero (NO), Italy COPD is a multicomponent disease with inflammation at its core, in which patients experience progressively worsening lung function, disease symptoms and quality of life, as well as increasing exacerbations. The therapeutic challenge presented by COPD arises from the need to target all components of the disease. In recent years a number of large clinical trials have been carried out aimed at answering major questions on the long-term management of COPD. These clinical studies have been mainly addressed to clarify the following open questions: - what is the best maintenance therapy from GOLD III to IV treatment? - is earlier intervention important for COPD treatment? - do bronchodilators have an impact on COPD mortality? COPD is a treatable disease and the long-acting inhaled medications for bronchodilation in COPD include long-acting anticholinergics and long-acting β 2 -agonists. Each has shown to improve FEV 1 by a mean of approximately ml more than placebo. These agents also significantly improve health-related quality of life. Meta-analyses have demonstrated that these long-acting inhaled medications are associated with significant reductions (20 26% per year) of acute exacerbations of COPD. In addition to pharmacological therapy, patients with moderate to very severe COPD have been shown to benefit (improved health status, quality of life, and exercise tolerance) from participation in a pulmonary rehabilitation program. In COPD patients with chronic, resting hypoxemia, use of supplemental oxygen for > hours per day has been shown to improve mortality. Finally, very severe COPD patients may benefit from lung volume reduction surgery, which improves health-related quality of life and exercise tolerance in patients with FEV 1 < 30% predicted and mortality in carefully selected patients with upper lobe bullae and low exercise capacity. Lung transplantation is another potential option for COPD patients without significant comorbidities but with extremely limited functional status, to improve quality of life (QoL). CF Donner (ed.) Summaries, COPD: inapropriateness and pharmaco-economics, Venice, April 2010 Riassunti, BPCO: inappropriatezze e farmacoeconomia, Venezia, aprile 2010 MRM 139

65 MRM _def:Layout 1 08/04/10 15:48 Pagina 140 Multidisciplinary Respiratory Medicine 2010; 5(2): COPD is a reversible disease if patients receive appropriate therapy. The reversibility relates to exercise capacity and QoL. High on the list of specific complaints that contribute to poor QoL in COPD patients is intolerance concerning everyday activities (due to abnormalities in lung mechanics and gas exchange, and to dysfunction of the ambulation muscles). Bronchodilator therapy and supplemental oxygen have been shown to improve exercise tolerance in the COPD patient and pulmonary rehabilitation is acknowledged to be the most successful intervention for improving exercise capacity. A recently published evidence-based analysis concluded that the highest grade of evidence supports the inclusion of endurance and strength training as well as upper extremity exercise and that rehabilitation programs reduce dyspnea and improve QoL. Current research is seeking to find ways to increase the duration of benefit of pulmonary rehabilitation and to determine whether rehabilitation imparts a survival benefit. Another important issue is the role played by early intervention. In fact COPD in its early stages (stages I and II) is usually not recognized, diagnosed or treated, and therefore it may not be included as a diagnosis in a patient s medical record. Earlier intervention therefore refers to early recognition, diagnosing, and treating of all COPD patients requiring management (i.e. treatment) according to international recommendations. Why intervene earlier? Because significant lung damage may exist even in early disease, as defined by lung function, when patients may be impaired but deny or under-perceive their symptoms and functional impairment. Treatment can be shown to improve function in patients when disease is at an earlier stage and it can impact the clinical course of COPD About the impact of bronchodilators on COPD mortality, the TORCH study showed a reduction in death from all causes among patients with COPD in the combination therapy group, though this did not reach the predetermined level of statistical significance. The UPLIFT study showed that tiotropium improves the natural history of COPD patients reducing mortality by approximately 11-16% and FEV 1 decline in GOLD stage II patients. In conclusion, the experience emerging from large clinical trials carried out in recent years in over 40,000 COPD patients per year/experience indicates a sustained improvement in lung function, quality of life, exercise capacity, decreased frequency of exacerbations and mortality through the long term use of bronchodilators. In addition to these data we have further evidence that long acting bronchodilators should be used in patients with moderate (GOLD II) disease, improving lung function and impacting the clinical course of the disease. References 1. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, Zielinski J; Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007;176: Casaburi R, Mahler DA, Jones PW, Wanner A, San PG, ZuWallack RL, Menjoge SS, Serby CW, Witek T Jr. A longterm evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J 2002;19: Vincken W, van Noord JA, Greefhorst AP, Bantje TA, Kesten S, Korducki L, Cornelissen PJ; Dutch/Belgian Tiotropium Study Group. Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium. Eur Respir J 2002;19: Hanania NA, Darken P, Horstman D, Reisner C, Lee B, Davis S, Shah T. The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPD. Chest 2003;124: Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, Decramer M; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008,359; Sin DD, McAlister FA, Man SF, Anthonisen NR. Contemporary management of chronic obstructive pulmonary disease: scientific review. JAMA 2003;290: Fishman A, Martinez F, Naunheim K, Piantadosi S, Wise R, Ries A, Weinmann G, Wood DE; National Emphysema Treatment Trial Research Group. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003;348: Hosenpud JD, Bennett LE, Keck BM, Edwards EB, Novick RJ. Effect of diagnosis on survival benefit of lung transplantation for end-stage lung disease. Lancet 1998;351: Nici L, Donner C, Wouters E, Zuwallack R, Ambrosino N, Bourbeau J, Carone M, Celli B, Engelen M, Fahy B, Garvey C, Goldstein R, Gosselink R, Lareau S, MacIntyre N, Maltais F, Morgan M, O'Donnell D, Prefault C, Reardon J, Rochester C, Schols A, Singh S, Troosters T; ATS/ERS Pulmonary Rehabilitation Writing Committee. American Thoracic Society/European Respiratory Society statement on pulmonary rehabilitation. Am J Respir Crit Care Med 2006;173: Nici L, ZuWallack R, Wouters E, Donner CF. On pulmonary rehabilitation and the flight of the bumblebee: the ATS/ ERS Statement on Pulmonary Rehabilitation. Eur Respir J 2006;28: Drummond MB, Dasenbrook EC, Pitz MW, Murphy DJ, Fan E. Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and metaanalysis. JAMA 2008;300: Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356: MRM

66 MRM _def:Layout 1 08/04/10 15:48 Pagina 141 ATP Corner / L Angolo dell ATP EDITED BY /A CURA DI MARIO POLVERINO Prosegue su Multidisciplinary Respiratory Medicine la pubblicazione dell ATP corner, per le comunicazioni dell Alleanza per le Malattie Toraco-Polmonari (ATP) e per la presentazione delle Società aderenti a questa nuova Associazione, primo progetto (ambizioso) di una condivisione e diffusione federativa delle mission e attività specifiche delle numerose Società scientifiche operanti in Italia con interessi nella medicina respiratoria. RUBRICA Presentazione di SITAB (Società Italiana di Tabaccologia) Presentation of SITAB (Italian Society of Tobaccology) Prosegue la presentazione delle Società che hanno aderito all ATP. Con questo numero è la volta della SITAB (Società Italiana di Tabaccologia), Società scientifica per lo studio del Tabacco, del Tabagismo e delle patologie fumo-correlate. La SITAB è una realtà ben radicata nel panorama delle Società scientifiche italiane, con un articolato sito web (http://www.tabaccologia.org/), numerose aree tematiche scientifiche (a parte la pneumologia, di cui è referente Margherita Neri, si annoverano: ricerca e documentazione, batteriologia, studio tosse, tossicologia e farmacologia, cardiologia, legislazione e giurisprudenza, ostetricia e ginecologia, epidemiologia, servizi per le dipendenze legali e tossicodipendenze, medicina generale, andrologia, oncologia, prevenzione, medicina estetica, medicina dello sport, patologia del cavo orale, anatomia patologica, gastro-enterologia), un organizzazione territoriale con referenti regionali. Siamo certi che il suo contributo di settore sarà un sicuro punto di riferimento nel panorama della medicina respiratoria. Mario Polverino Società Italiana di Tabaccologia Perché la salute non vada in fumo Italian Tobaccology Society To stop health going up in smoke Biagio Tinghino Presidente Società Italiana di Tabaccologia L idea di curare i fumatori per la loro dipendenza da tabacco è in Italia piuttosto recente, se paragonata alla sensibilità storica per altre dipendenze, per esempio quella da alcol. I primi interventi risalgono alla metà degli anni 70. Essi sono dovuti al volontariato della Lega Vita e Salute, che percorre l Italia col Piano dei cinque giorni per smettere di fumare, un progetto costituito da una serie di serate informative e motivazionali, durante le quali le persone sono aiutate a smettere senza farmaci, col supporto di conduttori esperti. Le istituzioni, com è noto, si muovono su un piano tecnico di MRM 141

67 MRM _def:Layout 1 08/04/10 15:48 Pagina 142 maggiore copertura del territorio, ma spesso sono lente a recepire i bisogni, rispondono solo a cambiamenti culturali già consolidati. I primi ambulatori dedicati al tabagismo sorgono infatti intorno al Si cerca, con queste iniziative, di aggregare gruppi di specialisti (per lo più pneumologi, medici del SERT e psicologi) attorno ad un problema che da subito si comprende essere complesso. In quegli anni si sviluppano i Corsi per Smettere di Fumare della Lega Italiana per la Lotta ai Tumori, che da quel momento dimostrerà un impegno costante in questo campo. La grande svolta avviene nel La disponibilità del bupropione, un altro farmaco (oltre alla nicotina) per trattare i fumatori, è probabilmente l occasione per destare l attenzione sul problema. Non a caso il primo convegno nazionale sul tabagismo di Padova si intitola A fuoco il fumo. Il Veneto era, d altra parte, da sempre un laboratorio privilegiato di idee e progetti, che contava su tanti professionisti di eccellenza. Il 1999 è anche l anno dello sviluppo esponenziale dei Centri Antifumo e della nascita della Società Italiana di Tabaccologia (SITAB). Primo presidente è Giacomo Mangiaracina, con una squadra composta da tutti i maggiori esperti italiani del settore. Si sente l esigenza di dare dignità al lavoro pionieristico svolto, di fornire uno strumento di condivisione della ricerca, della formazione e dell aggiornamento nel campo della dipendenza da tabacco. D altra parte si comprende che la posta in gioco è molto alta, dal momento che si parla di una addiction che coinvolge circa un quarto della popolazione e costituisce il Primo rischio di morte evitabile in Occidente (WHO). Nel 2000 a Monza viene organizzato il primo convegno della SITAB ed è l occasione per raccogliere, con l adesione del presidente Robert Molimard, la partnership della Société Française de Tabacologie (SFT). Nel 2001, due anni dopo, si prova a costituire una rete di alleanze tra associazioni, società, enti non governativi, con la Consulta Nazionale sul Tabagismo. L iniziativa parte questa volta dall Emilia Romagna, grazie alla tessitura di Maurizio Laezza, e riceve subito il sostegno della SITAB, della LILT e di tutte le altre sigle italiane. Si giunge a raccogliere più di cento fra enti ed associazioni. Dalla Consulta prende le mosse un Comitato Tecnico delle Regioni, che intende creare un raccordo tra il mondo delle istituzioni e quello degli enti non governativi. Si profilano in questo modo le maggiori espressioni attuali di impegno nell area del tabagismo. La Società Italiana di Tabaccologia concentra, nei primi anni di vita, le sue energie sulla comunicazione. Nasce Tabaccologia, The Italian Journal of Tobaccology, una rivista scientifica che però si propone di raggiungere ampi e diversi target, anche quelli meno impegnati nella ricerca. È un modo di fare editoria che rispecchia soprattutto l urgenza di sensibilizzare e cambiare i modelli culturali degli operatori. Lo sforzo continua con le iniziative divulgative, il coinvolgimento di testimonial contro il fumo (ad es. le partecipanti al concorso di bellezza Miss Universo ), la formazione dei medici, la presenza sui mass-media. La società consolida le alleanze, sottoscrive protocolli di intesa, entra a far parte dell ATP (Alleanza per le Malattie Toraco-Polmonari), attraverso i suoi componenti dialoga con altre società scientifiche, con l Istituto Superiore di Sanità, con il Ministero e il CCM. Nel 2008 la SITAB ospita a Roma il convegno internazionale della Society for Research on Nicotine and Tabacco (SRNT) e il sottoscritto prende la guida della società, in una linea di continuità con le strategie precedenti. L entusiasmo e la creatività si alleano nell impegno per la programmazione, la pragmatica progettualità, lo sviluppo dei gruppi di lavoro e delle aree specifiche. Le linee di indirizzo della società, divulgate ai primi di quest anno, includono sei obiettivi strategici, su cui si stanno concentrando i nostri sforzi e che stanno raccogliendo un consenso fattivo sempre più ampio. Esse possono essere così sintetizzate. 1. Promuovere la ricerca nel campo della dipendenza del tabacco, dei suoi meccanismi fisiologici, della sua diffusione, dei fattori che causano suo tramite malattie. È nato un gruppo di ricerca, che ha avuto l adesione di diversi centri italiani, coordinato dal Prof. Christian Chiamulera, che è anche l attuale presidente di SRNT Europe. 2. Fornire alla comunità strumenti di formazione continua e di aggiornamento. Il piano di offerta formativa della SITAB si avvale di una rete di formatori su tutto il territorio nazionale, la cui esperienza e didattica è certificata dalla società, con criteri standardizzati e pacchetti formativi collaudati. I progetti formativi predisposti sono multilivello e diversificati a seconda dei destinatari. 3. Incrementare le pratiche di smoking cessation e contribuire a rimuovere gli ostacoli che ne limitano la diffusione. Questo obiettivo strategico è stato definito alla luce delle innumerevoli difficoltà che il trattamento del tabagismo ancora oggi incontra, sia da un punto di vista organizzativo che degli approcci clinici. Non a caso il convegno nazionale del 2010, che quest anno si terrà a Torino nel mese di maggio, è centrato su questo tema e sarà il luogo privilegiato per la discussione degli ostacoli e lo scambio delle esperienze efficaci collaudate sul territorio. 4. Supportare i centri o qualsiasi altro interlocutore nella stesura di progetti condotti con standard e metodologie scientificamente valide. La SITAB offre l assistenza di un Ufficio progetti, presso la presidenza, che permette ai soci di essere consigliati nello sviluppo delle attività cliniche e di prevenzione. Esiste, inoltre, una rete dei Centri per il Trattamento del Tabagismo, a cui aderiscono quasi 120 centri del territorio nazionale, che è stata creata per favorire scambio di informazioni, aiuto reciproco, aggiornamento. I soci, oltre alla rivista, ricevono una newsletter mensile di rassegna bibliografica internazionale su temi legati alla dipendenza da tabacco, con abstract in chiaro. 142 MRM

68 MRM _def:Layout 1 08/04/10 15:48 Pagina Favorire lo sviluppo di progetti rivolti a target specifici di utenza fumatrice: giovani, donne, portatori di patologie fumo-correlate. 6. Integrarsi con piani rivolti alla diffusione di sani stili di vita e alla riduzione dei fattori di rischio sulla salute. È una progettazione ambiziosa, anche se puntuale e dettagliata. Siamo consci delle difficoltà che un programma così ampio comporta, ma non possiamo neanche negare che il fumo di tabacco rappresenta ancora un problema sottostimato dai politici, dagli amministratori e purtroppo anche dagli operatori sanitari. Nonostante l impegno, dobbiamo ricordare che i trattamenti per il tabagismo non sono inseriti nei LEA nazionali, i farmaci di provata efficacia non vengono rimborsati dal SSN, la percentuale di medici che fuma è altissima, solo poche persone smettono perché aiutate con approcci evidence based. Questo è il motivo per cui la Società Italiana di Tabaccologia (www.tabaccologia.org) si mette a disposizione e si propone per fornire un contributo a questa sfida. Sono personalmente convinto che servono sforzi congiunti, umiltà nel mettere da parte visioni particolaristiche, entusiasmo. Ma sopra ogni cosa entusiasmo. MRM 143

69 MRM _def:Layout 1 08/04/10 15:48 Pagina 144 RUBRICA AIMAR Newsletter / Notiziario AIMAR EDITED BY /A CURA DI STEFANO NARDINI Associazione Scientifica Interdisciplinare per lo Studio delle Malattie Respiratorie Il periodo che è iniziato nel 2006 con l inclusione delle malattie respiratorie nelle quattro priorità del Piano Sanitario Nazionale può a buon diritto essere identificato come il punto di partenza di una nuova crescita della specialità di malattie respiratorie in Italia. Tuttavia il riconoscimento dell importanza epidemiologica delle malattie respiratorie, se da un lato ha conferito maggiore visibilità e attenzione alla nostra disciplina, non si può dire abbia trovato la specialità del tutto pronta ad affrontare le nuove sfide. Le domande che gli interlocutori istituzionali hanno via via rivolto alla nostra disciplina non hanno sempre trovato risposte adeguate. Notevoli difformità nella dotazione di UO tra Regione e Regione, differenze significative nel prodotto delle singole UO, anche all interno della stessa Regione, per non parlare del clima da capponi di Renzo tra alcune delle principali società scientifiche di area, hanno finora impedito di cogliere appieno le opportunità che la nuova attenzione alla disciplina ha offerto. Peraltro, nonostante alcune nostre arretratezze, l attenzione alla problematica delle malattie respiratorie è continuata, anzi, se possibile, è anche aumentata. Negli anni successivi al 2006, l Agenzia Nazionale per i Servizi Sanitari (AGE.NA.S) ha iniziato la produzione di linee guida istituzionali per la BPCO, il Piano Nazionale della Prevenzione ha dato nuova importanza alle malattie respiratorie, è stata impostata e infine varata la sezione italiana dell Alleanza Globale contro le malattie respiratorie (GARD-Italia). Come è stato più volte sottolineato, tutte queste iniziative costituiscono un opportunità per la crescita culturale e organizzativa della disciplina, ma, d altro canto, pongono precise e pesanti responsabilità in capo agli specialisti pneumologi e alle loro società, che quindi non dovrebbero esitare nel rispondere adeguatamente alle richieste degli interlocutori istituzionali. A tal proposito, nelle righe seguenti si dà estesamente conto - per farne partecipi tutti gli associati - della seconda assemblea generale della GARD- Italia (GARD-I), svoltasi il giorno 3 marzo 2010 a Roma presso il Ministero della Salute. È bene che i nostri Associati conoscano quanto si sta mettendo in cantiere presso la GARD-I, in quanto le relative iniziative contribuiranno a disegnare il futuro della nostra specialità. Come ricorderanno i lettori di questa rivista, la partecipazione italiana alla GARD è stata varata formalmente il giorno 11 giugno 2009 [1], in occasione della quarta assemblea della GARD mondiale [2] che ha avuto luogo a Roma. Hanno aderito - all atto della costituzione - molte società scientifiche (oltre alle tre maggiori) di area e alcune società di Pazienti e successivamente altre entità hanno manifestato la loro volontà di adesione. Sotto la guida della Direzione della prevenzione del Ministero, la GARD-I ha rapidamente prodotto un documento di strategia [3] e un regolamento, che sono stati approvati dalla prima assemblea GARD-I. Cinque progetti operativi, inseriti in cinque linee di lavoro della GARD-I, sono stati presentati e approvati dall Assemblea generale il giorno 3 marzo. L assemblea è stata aperta dalla commemorazione di Mariadelaide Franchi, scomparsa di recente e ricordata anche attraverso queste colonne [4]. La dr.ssa Franchi aveva profuso moltissime delle sue energie proprio per la costituzione della GARD-I, che vedeva come un passo fondamentale per il miglioramento dell assistenza ai pazienti affetti da malattie respiratorie. Successivamente sono stati presentati i progetti e decise le funzioni di coordinamento di ciascuno e condivisi i gruppi di lavoro che si dovranno occupare della loro realizzazione. Il progetto numero 1 riguarda il programma di prevenzione per le scuole dei rischi indoor per malat- 144 MRM

70 MRM _def:Layout 1 08/04/10 15:48 Pagina 145 tie respiratorie e allergiche. I risultati attesi sono la produzione di una serie di documenti tecnici e linee guida volti a supportare l attuazione del documento dal titolo Schema di linee di indirizzo per la realizzazione nelle scuole di un programma di prevenzione dei fattori di rischio indoor per allergie e asma, attualmente all esame della Conferenza stato-regioni. Responsabili sono stati nominati la dott. ssa Anna De Martino per il Ministero e il dott. Giovanni Rossi, presidente SIMRI. Il progetto numero 2, denominato Fumo e ambiente domestico, prevede la redazione di linee guida per migliorare la qualità dell aria indoor attraverso il controllo del fumo in ambiente domestico, in quanto maggiore inquinante ambientale. Prevede inoltre la progettazione di campagne di informazione ed educazione sanitaria rivolte alle famiglie per favorire l adozione di comportamenti in grado di contrastare l abitudine al fumo. Responsabili del progetto sono i dott. Daniela Galeone e Lorenzo Spizzichini per il Ministero e il Prof. Stefano Centanni, presidente SIMeR. Il progetto numero 3, denominato Sviluppi di Medicina Predittiva nell ambito delle malattie respiratorie, si propone di individuare quali screening di popolazione siano utilizzabili per predirne l insorgenza, secondo criteri e caratteristiche di appropriatezza. Il prodotto finale sarà un rapporto basato sulla valutazione della letteratura esistente sui test in grado di definire il rischio individuale di malattie respiratorie. Una volta individuato il test, verrà definito un progetto pilota di applicazione di un percorso diagnostico di medicina respiratoria predittiva. Responsabili del progetto saranno la dott. ssa Giovanna Laurendi per il Ministero e il dott. Franco Falcone, Presidente AIPO. Il progetto numero 4, denominato Implementazione della diagnosi precoce attraverso percorsi di formazione rivolti ad operatori sanitari, prevede la produzione di un documento di formazione, redatto sull analisi delle criticità esistenti e sulla revisione delle buone pratiche. Responsabili del progetto saranno la dott. ssa Giovanna Laurendi per il Ministero e il dott. Claudio F. Donner, presidente AIMAR. Il progetto numero 5, denominato Continuità assistenziale, porterà alla produzione di un documento di raccomandazioni sulle appropriatezze diagnostiche e terapeutiche nell assistenza ai soggetti con patologia respiratoria e all indicazione di modelli di gestione integrata tra i servizi. Responsabili del progetto saranno le dott. sse Paola Pisanti e Giovanna Laurendi per il Ministero e il Prof. Stefano Centanni per SIMeR e il dott. Antonino Mangiacavallo per FIMPST. Per quest ultimo progetto è stata anche auspicata la partecipazione di Medici delle società di Medicina Generale (vedi sotto). Nel corso dell Assemblea sono state poi ufficializzate le nuove adesioni a GARD-I: oltre a società scientifiche di Medici di Medicina Generale, anche la Fondazione Italiana Salute, Ambiente e Respiro (FISAR), la ONLUS - Impresa sociale che spesso ha operato in iniziative coordinate con AIMAR. Se così esteso è il contributo di AIMAR come società (oltre alla stessa associazione e alla partecipazione in ATP - di cui AIMAR è componente e che è pure parte della GARD-I - anche la Fondazione vicina ad AIMAR) quale può essere il contributo di ciascuno degli associati di AIMAR a GARD-I? L attuale importanza della medicina respiratoria non è solo legata al peso epidemiologico della patologia, sempre più rilevante, ma anche al numero sempre maggiore di conoscenze e strumenti tecnici a disposizione, che ogni professionista dovrebbe, in maggiore o minor misura, secondo la propria collocazione, padroneggiare. Ma gli aspetti tecnici non esauriscono i doveri di noi professionisti che dobbiamo anche essere aggiornati sugli aspetti gestionali e sistemici della nostra vita professionale. Oggi il miglioramento della diagnosi e del trattamento delle malattie respiratorie non riposa solo sulla capacità tecnica degli specialisti o sulle loro dotazioni materiali, ma anche sulla costruzione di alleanze, la creazione di un database per le malattie respiratorie, la sensibilizzazione della comunità e su prevenzione, gestione della cronicità, implementazione di politiche di intersettorialità. Cioè proprio quanto GARD-I si propone di fare. Allora ciascuno degli associati AIMAR può impegnarsi per la creazione - per esempio - di una rete locale con la Medicina Generale e con il Distretto di Prevenzione, per iniziare un percorso comune che diffonda la diagnosi precoce delle malattie croniche respiratorie, oppure l implementazione, con settori locali interessati al controllo del fumo, di iniziative di disassuefazione dal fumo per la prevenzione primaria delle pneumopatie, ovvero ancora la costruzione di percorsi di pneumologia riabilitativa sul territorio. Oppure ancora, ciascuno degli associati può segnalare criticità nell assistenza ai soggetti pneumopatici, di cui sia a conoscenza. E forse chissà, molti Colleghi avranno già in corso alcune di queste iniziative. Non sarebbe male se ne informassero attraverso questo giornale, attraverso questa rubrica, tutti gli iscritti AIMAR e fornissero in tal modo un utilissimo feed-back alla GARD-Italia. Bibliografia 1. Donner CF, De Benedetto F, Sanguinetti CM, Nardini S. Gard-Italy launched in Rome on June Multidisciplinary Respiratory Medicine 2009;4: Nardini S Year of the Lung: la IV Assemblea mondia - le della GARD dell Organizzazione Mondiale della Sanità (OMS). Multidisciplinary Respiratory Medicine 2009;4: Ministero del Lavoro, della Salute e delle Politiche Sociali. GARD-I: Documento di strategia. Multidisciplinary Respiratory Medicine 2009;4: Neri M. In ricordo di Lalli. Multidisciplinary Respiratory Medicine 2010;5:2-3. MRM 145

71 MRM _def:Layout 1 08/04/10 15:48 Pagina 146 RUBRICA From the CFC Bulletin / Notiziario CFC Prosegue su Multidisciplinary Respiratory Medicine, a fronte della collaborazione tra AIMAR e Collegio Federativo Cardiologia (CFC), la pubblicazione di estratti del bollettino CFC, mensile di informazione e aggiornamento del Collegio. CUORE E METABOLISMO APPROCCIO AL DIABETE: MEGLIO SE PRECOCE Al momento della diagnosi di diabete, il 50% della capacità funzionale delle beta cellule pancreatiche è già andata perduta. Il dato viene dall Associazione medici diabetologi italiani (AMD) che, nel corso del Congresso EASD (European Association for the Study of Diabetes), Vienna 2009, sottolinea l importanza di un approccio terapeutico precoce nei confronti della patologia. Nei pazienti con glicemia compresa tra mg/dl e con HbA1c 7% - 8% l intervento va iniziato subito, monitorando frequentemente il paziente. La riduzione di un punto dell emoglobina glicata si traduce in una diminuzione del 25% delle complicanze. Quest effetto è amplificato se il target terapeutico è raggiunto molto precocemente rispetto all instaurarsi della malattia. Si evita, così, la comparsa di danni irreversibili alle cellule vascolari. Vanno presi subito in carico anche i soggetti a rischio, con glicemia normale, ma con familiarità per la malattia, figli di peso superiore ai 4 kg alla nascita e assetti lipidici poco favorevoli quali bassi livelli di HDL-C. In presenza di un evento cardiovascolare, nei pazienti a rischio, l esecuzione della curva da carico va eseguita al più presto. In assenza di fattori di rischio, invece, la glicemia andrebbe controllata una volta ogni 3 anni. EASD, Vienna SCOMPENSO CARDIACO RELAZIONE TRA HbA1c E MORTALITÀ NELLO SCOMPENSO CARDIACO Lo studio ha valutato retrospettivamente una coorte di pazienti presi dal database dei Veterans Affairs medical centers con diabete mellito e scompenso cardiaco. L associazione tra HbA1c e scompenso è risultato a forma di U con il più basso rischio di morte in quei pazienti con modesto controllo glucidico (7,1% < HbA1c < 7,8%). Si ritengono necessari futuri ulteriori studi per definire il trattamento ottimale in questi pazienti. Allo stato attuale vi sono, comunque, buone ragioni per continuare ad ottimizzare il compenso glucidico considerate le evidenze relative ad una riduzione delle complicanze microvascolari con un trattamento spinto e personalizzato. J Am Coll Cardiol 2009;54: UN CONSUMO RILEVANTE DI CAFFÉ NON AUMENTA IL RISCHIO DEGLI UOMINI SCOMPENSATI Studi precedenti avevano trovato che 5 o più tazze di caffé al giorno fossero associate con un aumentato rischio di scompenso cardiaco. Lo studio oggetto di questa pubblicazione ha, pertanto, valutato tra il primo gennaio 1998 ed il 31 dicembre 2006 il consumo di caffé in uomini senza storia di IM, diabete o scompenso cardiaco. I risultati dello studio non hanno supportato l ipotesi che larghe dosi di caffé siano associate ad un aumentato rischio di ospedalizzazione o mortalità negli scompensati. Am Heart J 2009;158: ARITMOLOGIA E CARDIOSTIMOLAZIONE DISTURBI RESPIRATORI DEL SONNO E ARITMIE La ricerca clinica Triggering of Nocturnal Arrhythmias by Sleep-Disordered Breathing Events ha analizzato in registrazioni polisonnografiche la presenza di FA e di TVNS. In 57 soggetti sono state registrate 62 aritmie (di cui 76% sono state TVNS). L Odds ratio per un aritmia è stato 17,5 subito dopo un disturbo del sonno rispetto al respiro normale. La frequenza assoluta di aritmie durante OSAS è stata comunque bassa (1 per ) MRM

72 MRM _def:Layout 1 08/04/10 15:48 Pagina 147 PREVENZIONE ANCORA SUL FUMO PASSIVO La meta-analisi Cardiovascular Effect of Bans on Smoking in Public Places condotta su 11 report e 10 studi sugli effetti della proibizione del fumo nei locali pubblici tra il gennaio 2004 e l aprile 2009 ha confermato il ruolo del fumo passivo ed ha permesso di dimostrare come la proibizione del fumo in pubblico ha condotto ad una riduzione del 17% di IMA, con l effetto più marcato sui giovani e sui non fumatori. L IRR è calato in modo incrementale del 26% per anno di osservazione. Tali risultati confortano i dati italiani già pubblicati negli anni passati per l Italia. abstract/54/14/1249 RIDURRE IL COLESTEROLO LDL, E IN MODO MARCATO, SERVE, E SERVE ANCHE NEL GRANDE ANZIANO Lo studio di coorte retrospettivo condotto su oltre veterani ad alto rischio cardiovascolare, con almeno una determinazione del col-ldl prima dell evento e successivi altri controlli, è descritto nell articolo Cardiovascular Benefit of Magnitude of Low-Density Lipoprotein Cholesterol Reduction - A Comparison of Subgroups by Age. La riduzione del Col-LDL è stata classificata in assente (< 10 ml/dl), modesta (10-40 ml/dl), moderata (40-70 ml/dl) e marcata (>70 ml/dl). In tutti i gruppi d età la riduzione del Col-LDL è risultata proporzionale con la riduzione degli eventi CV. Nel gruppo con riduzione marcata, in tutti i gruppi d età si è raggiunta un importante riduzione del rischio. abstract/120/15/1491 PREVENZIONE CARDIOVASCOLARE ANDANDO A LAVORARE L AHA Policy Statement pubblicato questa settimana dal titolo Worksite Wellness Programs for Cardiovascular Disease Prevention, analizza il ruolo della prevenzione CV sui luoghi di lavoro. Infatti l esperienza ha dimostrato che programmi di salute sui posti di lavoro rappresentano un importante strategia per la prevenzione dei maggiori fattori di rischio CV come il fumo, l obesità, l ipertensione, la dislipidemia, l inattività ed il diabete. I programmi di maggior successo si estendono anche ai familiari che sono esposti alla modificazione favorevole dello stile di vita del dipendente e in definitiva si estendono allo stato di salute dell intera comunità. extract/120/17/1725 CARDIOPATIA ISCHEMICA MRN E CRT La risonanza magnetica offre da sola l opportunità di valutare la dissincronia del ventricolo di sinistra e l estensione della cicatrice miocardica in un unica sessione. Tale tecnica è quindi rilevante in quanto entrambi questi parametri sono importanti predittori della risposta ecocardiografica alla CRT. European Heart Journal 2009;30: FREQUENZA CARDIACA NOTTURNA ED EVENTI CARDIOVASCOLARI 457 ipertesi trattati sono stati sottoposti ad iniziale monitoraggio pressorio circadiano e quindi seguiti per 6 anni. La morbilità/mortalità rilevata è stata posta in relazione con l andamento della frequenza cardiaca notturna. Ne é risultato che i pazienti nei quali la frequenza cardiaca non si riduceva almeno del 10% rispetto alla media diurna presentavano un rischio di eventi di 2,4 volte superiore a coloro che presentavano il calo notturno, indipendentemente dall andamento e dal livello della pressione arteriosa o dalla presenza di diabete mellito. Lo studio propone quindi che, per meglio valutare il rischio reale del paziente iperteso, nella lettura del monitoraggio non ci si limiti solo all osservazione della presenza o meno del calo pressorio notturno, ma venga anche considerato il calo (dipping) della frequenza cardiaca. Kazuo et al. Nocturnal dipping of heart rate predicts cardiovascular events in hypertensive patients. J Hypertens 2009;27: IPERTENSIONE USO MODERATO DI ALCOOL ED INFARTO Sono stati analizzati gli eventi coronarici nei medici maschi ipertesi seguiti dal 1982 al 2008 nel Physicians Health Study. In 623 soggetti si è verificato un infarto miocardico. Nell analisi condotta dopo aggiustamento per i diversi fattori di rischio è stato appurato che il rischio di necrosi miocardica era inversamente proporzionale alla quantità di alcool consumata. In particolare l incidenza di infarto risultava inferiore fino al 40% nei soggetti che consumavano >8 drink a settimana rispetto ai non bevitori. Un drink è all incirca equivalente a due bicchieri di vino. Per il dato sono suggerite diverse ipotesi. Fermo restando che nel paziente iperteso l obiettivo fondamentale rimane sempre il controllo pressorio, viene confermato che un moderato consumo di alcool può essere di beneficio nella prevenzione cardiovascolare. Relation of Alcohol Consumption and Coronary Heart Disease in Hypertensive Male Physicians (from the Physicians Health Study) Britton et al. Am J Cardiol 2009;104: Tratto da Bollettino CFC, anno 2, numero 5, novembre 2009, pubblicato da Edizioni Internazionali srl, Div. EDIMES, Pavia. MRM 147

73 MRM _def:Layout 1 08/04/10 15:48 Pagina 148 RUBRICA L'Angolo della Cultura (non solo Medicina...) A CURA DELLA REDAZIONE La redazione intende lasciare questo spazio a disposizione per la presentazione di contributi culturali, anche non strettamente inerenti l'area medica. Gli interessati possono pertanto sottoporre alla redazione qualunque contributo (articolo, poesia, ecc.) che possa essere di interesse per i lettori e/o stimolare una riflessione ed un eventuale dibattito culturale. L inquieto fantasma della letteratura italiana The haunting spirit of Italian literature Francesco Iodice Già Direttore U.O. s.c. di Fisiopatologia Respiratoria, Ospedale A. Cardarelli, Napoli convinzione del principe Salina e del principe Lampedusa che gli arabi abbiano trovato la Sicilia così, nelle stesse condizioni in cui la trova il prefetto di Vittorio Emanuele II Leonardo Sciascia, cap. Il Gattopardo in Pirandello e la Sicilia Fra i grandi romanzi pubblicati nel Novecento, ce n è uno di cui non si troverà mai una copia con dedica autografa. Impossibile, perché quando il libro uscì in prima edizione da Feltrinelli, l autore da più di un anno era morto di tumore in una clinica romana. Infatti, poche ore dopo la mezzanotte del 23 luglio 1957, Giuseppe Tomasi di Lampedusa moriva nel sonno. È evidente che stiamo parlando de Il Gattopardo, il cui autore passò gli ultimi momenti della sua vita e della sua coscienza nella pena che avessero detto no al suo libro, un romanzo che né Vittorini né altri avevano reputato degno di pubblicazione. E a differenza del caso di Svevo, il no pronunciato dal destino contro l autore vivente era stato definitivo: mai Tomasi avrebbe visto quella copertina gialla dell edizione feltrinelliana che i lettori italiani di libri conoscono tutti. Ma il caso non agisce mai a caso. Elena Croce un po fata, un po dama settecentesca ebbe fra le mani il dattiloscritto e lo lasciò nella portineria dell appartamento romano di Giorgio Bassani, che in quel momento era a capo di una collana di narrativa della Feltrinelli: Bassani lesse il manoscritto e decise di pubblicarlo, anche se alla Feltrinelli pur capendo che il titolo era bellissimo (si riferisce allo stemma del casato dei Salina, che raffigurava un gatto dalla pelliccia leopardata su fondo blu), tutto il resto era un incognita: nessuno sapeva chi diavolo fosse questo Tomasi di Lampedusa che in più aveva l aria di un reazionario mica male, qualifica del tutto sfavorevole per navigare nel mercato letterario italiano dove la sinistra la faceva da padrona. Era sconosciuto perché tutta l esistenza di Tomasi fino ad oltre i 50 anni era rimasta avvolta nel mistero, come se fosse vissuto non nel ventesimo secolo, ma in un passato lontanissimo. Si sa che la sua infanzia fu danneggiata dalla madre che gli impedì di crescere, di avere una vita propria e lo trattò fino alla morte come un bambino, oppure una bambina amatissima. Si sa ancora che era coltissimo: leggeva non come un letterato che ha sempre un saggio o un libro da preparare ma per piacere, curiosità e divertimento, senza nessuna meta nascosta, cercando nei libri quella ricchezza di esperienze e di avventure che la vita non gli aveva dato. Nel 1953 conobbe alcuni giovani palermitani, Francesco Orlando, Mirella Radice, ma soprattutto Gioacchino Lanza Tomasi, che amò moltissimo. Alessandra, la moglie baltica psicologa, chiamava i giovani: Both charming, delightful people e finì assieme al marito per adottarli come figli. Giuseppe Tomasi di Lampedusa. 148 MRM

74 MRM _def:Layout 1 08/04/10 15:48 Pagina 149 La copertina dell edizione feltrinelliana de Il Gattopardo. Alla fine del 1954 Lampedusa cominciò a scrivere Il Gattopardo, non aveva mai tentato nulla di simile, confessava alla moglie che si divertiva a scrivere. Dovette divertirsi moltissimo, perché in poco tempo scrisse un romanzo che non aveva precedenti in nulla di ciò che aveva scritto prima, né nella letteratura italiana. Una prosa memorabile definita d arte, anche se all inizio può rivelarsi fallimentare, svela il suo fascino negli anni, quando scorrendo lo sguardo sopra una fila di vecchi libri, lo si afferra e lo si torna a leggere. Chi affronta oggi Il Gattopardo come un classico, proverà piaceri e sorprese non meno incantevoli di quelli che Lampedusa provò scrivendolo. Il Gattopardo è soprattutto la felice invenzione di un personaggio, il principe Salina, una figura ambigua: colto, ironico, autoritario, animato da un disprezzo tutto intellettuale verso il genere umano, convinto che la Sicilia ed il mondo non cambieranno mai; al massimo, potranno cambiare, ma in peggio, i detentori del potere. Il Gattopardo che tramonta deve far posto a don Calogero Sedara, simbolo della classe emergente di lupi e di sciacalli ; ma non c è solo Sedara nel romanzo, c è anche don Pietro Russo, al quale il principe deve rivolgersi per avere protezione durante i moti garibaldini. E don Pietro in perfetto stile mafioso gli risponde: Villa Salina sarà sicura come una rocca, i piemontesi entreranno con il cappello in mano per riverire le vostre eccellenze. Mafia e politica: è questo il mostro che si alza e cammina proprio in quei giorni, la ferita mai sanata fra Nord e Sud, la nascita della mafia e della politica mafiosa, tutto era stato già raccontato in questo capolavoro inizialmente incompreso. Nel colloquio con l emissario piemontese Chevalley, il principe si concede la più spietata requisitoria mai pronunciata sulla natura dei siciliani: la chiave non è nella prima parte del famoso epitaffio ( eravamo i Gattopardi, ora arrivano i lupi e gli sciacalli ) ma nella seconda: Tutti quanti, gattopardi e sciacalli continueremo a crederci il sale della terra. Tesi d altra parte che Federico De Roberto aveva già ribadito nei Vicerè: Quando c erano i vicerè, gli Uzeda erano vicerè; ora che abbiamo i deputati, lo zio siede in Parlamento. Salina inoltre, è fortissimo, enorme, con la pelle bianca ed i capelli biondi, che sfiora con la testa i lampadari, con le dita accartoccia le monete da un ducato, o tocca con estrema delicatezza i corpi femminili ( i siciliani non vorranno mai migliorare, perché si considerano già perfetti. In loro la vanità è più forte della miseria ): un Ercole Farnese, uno Zeus tedesco - siciliano, un vero vichingo a cui Lampedusa con nascosta vanità intendeva rassomigliare. Ma era soltanto un sogno, una remota proiezione di eleganza e di grandezza per lui inarrivabili (non aveva soprattutto il dono di afferrare e possedere la vita, tipica dello zione ). L autore non fa quasi mai capolino nella vicenda, ma, nella rarità delle intromissioni, la sua idea si esprime attraverso massime ricche di sarcastica verità: attribuire ad altri la propria infelicità è l ultimo ingannevole filtro dei disperati. Quando il libro uscì nell ottobre 1958 (ma portava la data novembre 1958) ebbe un edizione di tremila copie; a tre anni dalla sua pubblicazione il libro aveva venduto quattrocentomila copie; quando uscì a Londra nel 1988, di edizioni italiane ne erano state fatte centoventiquattro; oggi - dopo cinquanta anni - vende ancora quarantamila copie all anno. Ha sempre dato ampio spazio ai dibattiti e alle polemiche il modo in cui Tomasi di Lampedusa usa le parole per dare aria alle pagine, piuttosto che i segni d interpunzione. Aprite Il Gattopardo e immaginate di non trovarli più. Scoprirete come le parole, da sole, facciano da contrappunto alla struttura, come la cadenza sia determinata da un appoggio di voce, da un suono insito nel significato della parola stessa, dal divenire Lo scrittore Tomasi di Lampedusa a sei anni con la la madre. MRM 149

75 MRM _def:Layout 1 08/04/10 15:48 Pagina 150 La lapide che ricorda il soggiorno nelle stanze dell'albergo Trinacria di Giuseppe Garibaldi, che qui avrebbe pronunciato il celebre grido O Roma o morte. della frase. La punteggiatura poi presenta alcune caratteristiche tipiche ed in un certo senso moderne. Lampedusa adopera il punto solo quando ha esaurito per intero un tema; altrimenti preferisce separare i periodi col punto e virgola. L uso di quest ultimo è poi musicale piuttosto che grammaticale, indica la ripresa di fiato e non sempre coincide con l inizio di una coordinata o incidentale, anzi queste ultime sono sovente ignorate dalla punteggiatura. È inevitabile che un libro così famoso abbia qualche curioso retroscena. Nel giugno 1959, dopo il successo del Gattopardo, Feltrinelli pensò di utilizzare l animale come logo editoriale. E ne parlò ad Albe Steiner, consulente editoriale e art director della casa editrice. Ma non se ne fece niente perché mancano notizie della risposta di Steiner, né esistono nel suo archivio bozzetti da collegare all idea di Feltrinelli. Altro episodio bizzarro riguarda Bassani: quando lesse il dattiloscritto ebbe l impressione che fosse incompleto, andò a Palermo, parlò con la moglie che gli mostrò un manoscritto contenente alcuni dei capitoli più belli: Il Ballo e Le vacanze di padre Pirrone. Bassani fece una collazione fra dattiloscritto e manoscritto, affermando in pubblico che non aveva apposto nulla di suo. Ma mentì: nel 68 un criticò riuscì a provare che gli interventi di Bassani c erano stati ed assai numerosi, tanto che per Feltrinelli fu necessario nel 69 stampare una nuova edizione. Sciascia non poté mai soffrire Il Gattopardo, un avversione in parte infondata sulla quale lo stesso scrittore tornò con ammirevole onestà retrospettiva: all inizio aveva detto: Lo considero una specie di 18 aprile della letteratura italiana, ma in seguito cambiò idea e affermò: Oggi, mi affascina, come tutte le cose fatali. Il Gattopardo, definito da qualcuno l inquieto fantasma della storia d Italia, forse aspetta ancora la sua definizione. Scrivendo sul romanzo, Sciascia partì dal famoso dialogo tra don Fabrizio e Chevalley e si convinse che l indifferenza del primo alle ragioni dei contadini era la stessa dell autore, incline a vedere gli umili sempre di sfuggita, come sgradevole manifestazione della condizione umana, incapace di mettersi umilmente al loro servizio ; e concluse: La Sicilia del Gattopardo ha un vizio di astrazione geografico-climatica, in pratica sempre uguale a se stessa e senza tempo. Sciascia aveva un idiosincrasia sociale verso l aristocratico, verso il gran signore che tende ad eliminare dalla propria vita gli aspetti sgradevoli, rappresentati dall oppressione sociale e dalla povertà. Per la verità, non c era solo il motivo dianzi detto, ma anche la constatazione che nel principe non c è neppure la difesa del latifondo aristocratico, ma una nobiltà stanca che non avendo nulla da perdere, né alcuna velleità rampantistica (nonostante l aggressiva figura araldica!): insomma, un raffinato qualunquismo, un disincantato illuminismo che sfocia nell impotenza. A lettura conclusa del Gattopardo come per tutti i grandi romanzi alcuni personaggi restano indelebili nella memoria (Don Fabrizio, Angelica, Tancredi, padre Pirrone, lo spaesato piemontese Aimone Chevalley di Monterzuolo); gli altri vengono subito dimenticati. Tra questi, ingiustamente, Concetta la seconda delle tre figlie del principe invisibile base su cui si poggia tutto l edificio del romanzo: guardiana inflessibile dell onorabilità di casa Salina, è lei che alla fine vince su tutto (sopravvivere a tutto in un romanzo come il Gattopardo è già di per sé una vittoria!), un po come su tutto alla fine prevale ma squallidamente don Abbondio nei Promessi sposi. Non a caso l autore le riserva le pagine conclusive del romanzo. È Concetta ad ordinare di buttare il cane, l ultima grottesca reliquia di una saga imponente; ogni gesto tende a salvare l onore del suo casato, ha commesso il delitto più grave di cui una creatura si possa macchiare: quello di negare la vita a se stessa, vivendo una vita senza vivere e soffocando in sé ogni anelito di amore e di sesso ( L amore? Già, certo, l amore Fuoco e fiamme per un anno, e cenere per trenta ) solo per tenere in piedi il simulacro di una schiatta una volta regnante sui feudi. Dalle descrizioni che Lampedusa dissemina qua e là sappiamo che Concetta ha una bella fronte, occhi azzurri, un riserbo inaccessibile e mani gelide. Tancredi la definisce sorda e crudele, ma Concetta non è né l una, né l altra cosa, è solo la ferrea guardiana del potere in famiglia e nella società: sta qui la sua grandezza, rimane in secondo piano mentre regge su di sé l intero romanzo, come Anna Karenina o Madame Bovary, compare e scompare senza lasciare tracce. Il suo destino assomiglia a quello di Lampedusa che uscì dall oscurità della vita per un momento, parlò perdutamente con dei giovani incantandoli per sempre, scrisse un bellissimo libro e poi ripiombò nelle tenebre. Alla fine, Tomasi spedisce il principe verso bisbigli d immortalità : la bellezza delle stelle immote da contrapporre alle disillusioni della storia. 150 MRM

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