Le Comorbilità BPCO: Documenti e linee guida a confronto Mogliano Veneto (TV) 31 gennaio 2014 Le Comorbilità dr. Stefano Calabro Dr. Stefano Calabro REGIONE VENETO – AZIENDA U.L.S.S. n.3 Ospedale S. Bassiano - Bassano del Grappa Dipartimento di Medicina Struttura Complessa di Pneumologia Dr. Rolando Negrin REGIONE VENETO – AZIENDA U.L.S.S. n.6 Ospedale S. Bortolo - Vicenza Dipartimento di Area Medica II Unità Operativa Complessa di Pneumologia Ultima revisione 28.01.2014. 1

Un caso di instabilità terminologica nel vocabolario medico: comorbidità, comorbilità, comorbosità Comorbidità e comorbilità sono due forme lessicali – entrambe attestate negli usi linguistici medico-scientifici italiani, a volte anche in grafia non univerbata (cioè con il trattino) – usate dagli specialisti in maniera intercambiabile: negli stessi contesti, con gli stessi significati, per indicare quindi uno stesso concetto o grappolo di concetti. Questa oscillazione fra comorbidità e comorbilità negli usi specialistici si spiega, più che in termini di sinonimia, come compresenza nel vocabolario medico italiano attuale di forme alternative e concorrenti, in competizione fra di loro per designare sostanzialmente la stessa cosa. Si tratta, dunque, di un caso di instabilità terminologica, accentuata dall’alternanza con una terza forma, comorbosità, che, sebbene meno frequente – e probabilmente per questo non menzionata nelle domande – è tuttavia attestata e registrata.

Definizione di comorbidità “The existence or occurrence of any distinct additional entity during the Clinical course of a patient who has the index disease under study”. “l’esistenza o la presenza di ogni entità patologica distinta addizionale durante il decorso clinico di una patologia oggetto di studio”.

Comorbidity constructs Valderas JM, Starfield B, Sibbald B, et al. Defining Comorbidity: Implications for Understanding Health and Health Services. Ann Fam Med 2009;7:357-363. doi:10.1370/afm.983.

BroncoPneumopatia Cronica Ostruttiva Complicanze Comorbilità

Malattie croniche Number of chronic disorders by age-group Barnett K, Mercer SW, Norbury M, et al. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Published online May 10, 2012 DOI:10.1016/S0140-6736(12)60240-2.

Malattie croniche Invecchiamento (modificazioni strutturali organo-specifiche, sistemiche e immunologiche in senso proinfiammatorio) fattori di rischio (es. fumo, inquinamento, iperdislipidemia, obesità) Invecchiamento, infiammazione sistemica e malattie croniche complesse Franceschi C, Pauletto P, Incalzi RA, Fabbri LM Invecchiamento, infiammazione sistemica e malattie cliniche complesse Italian Journal of Medicine 2011;5S: S3—S13.

The guideline with the highest coverage of comorbidities was that of the Global Initiative for Chronic Obstructive Lung Disease (GOLD).

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Comorbidity Prevalence in COPD (%) Patel AR, Hurst JR. Extrapulmonary comorbidities in chronic obstructive pulmonary disease: state of the art. Expert Rev Respir Med. 2011; 5:647-62.

Valutazione della gravità Diagnosi fattori di rischio sintomi spirometria Valutazione della gravità gravità dei sintomi grado di ostruzione bronchiale rischio di riacutizzazioni numero e gravità delle comorbidità

Relation between lung function and death due to cardiovascular disease, lung cancer, and respiratory failure Sin DD, Anthonisen NR, Soriano JB, et al. Mortality in COPD: role of comorbidities. Eur Respir J 2006; 28: 1245–57.

Cardiovascular diseases (CVD) Vascular and heart diseases are among the most important comorbidities observed in COPD, because they have a direct impact on patient survival. The pathophysiological mechanisms underlying the vascular alterations observed in COPD appear to be mainly mediated by endothelial dysfunction and coagulopathy.

Relationship Between Reduced Lung Function and Cardiovascular Mortality There is strong epidemiologic evidence to indicate that reduced FEV1 is a marker for cardiovascular mortality independent of age, gender, and smoking history.

Risk for cardiovascular disease in COPD patients and matched controls Prevalence of all cardiovascular diseases was higher in the COPD group than in the comparison group. * *P<0.05 for between-group difference MI = myocardial infarction CHF = congestive heart failure CVD = cardiovascular disease * * * * * * Curkendall SM, DeLuise C, Jones JK, et al. Cardiovascular disease in patients with chronic obstructive pulmonary disease, Saskatchewan Canada cardiovascular disease in COPD patients. Am J Epidemiol. 2006;16:63-70. 15

Cardiovascular disease in COPD patients 300 control subjects COPD group Control group Ischemic heart disease 12.5% 4.7%; P <0.0001 Cerebrova-scular disease 10% 2% Peripheral vascular disease 16.4% 4.1% P <0.001 COPD Compared with the control group, the COPD group showed a significantly higher prevalence of ischemic heart disease, cerebrovascular disease, and peripheral vascular disease In the univariate risk analysis, COPD, hypertension, diabetes, obesity, and dyslipidemia were risk factors for ischemic heart disease In the multivariate analysis adjusted for the remaining factors, COPD was still an independent risk factor (odds ratio: 2.23; 95% confidence interval: 1.18–4.24; P = 0.014) COPD patients show a high prevalence of cardiovascular disease, higher than expected given their age and the coexistence of classic cardiovascular risk factors de Lucas-Ramos P, Izquierdo-Alonso JL, Moro JM, et al. Chronic obstructive pulmonary disease as a cardiovascular risk factor. Results of a case–control study (CONSISTE study) Int J Chron Obstruct Pulmon Dis. 2012;7:679-686.

The mechanistic links between COPD and cardiovascular disease are complex, multifactorial, and not entirely understood Decramer M, Janssens W. Chronic obstructive pulmonary disease and comorbidities. Lancet Respir Med. 2013;1:73-83.

Cardiovascular diseases (CVD) Systemic venous thromboembolism During COPD exacerbations, VTE is found in 3–29% of cases Gunen H, Gulbas G, In E, et al. Venous thromboemboli and exacerbations of COPD. Eur Respir J 2010; 35: 1243–1248. Pulmonary artery disease : pulmonary hypertension Coronary heart disease Heart failure Heart arrhythmia

Prevention of Thrombosis Prevention of VTE in Nonsurgical Patients Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines 2012 Prevention of Thrombosis For acutely ill hospitalized medical patients at increased risk of thrombosis, we recommend anticoagulant thromboprophylaxis with low-molecular-weight heparin [LMWH], low-dose unfractionated heparin (LDUH) bid, LDUH tid, or fondaparinux (Grade 1B). For acutely ill hospitalized medical patients at low risk of thrombosis, we recommend against the use of pharmacologic prophylaxis or mechanical prophylaxis (Grade 1B). In acutely ill hospitalized medical patients who receive an initial course of thromboprophylaxis, we suggest against extending the duration of thromboprophylaxis beyond the period of patient immobilization or acute hospital stay (Grade 2B). During COPD exacerbations, VTE is found in 3–29% of cases In chronically immobilized persons residing at home or at a nursing home, we suggest against the routine use of thromboprophylaxis (Grade 2C).

Increased risk of thrombosis Prevention of VTE in Nonsurgical Patients Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines 2012 Increased risk of thrombosis Risk Factors for VTE in Hospitalized Medical Patients Risk Factor Points Active cancer 3 Previous VTE (with the exclusion of superfi cial vein thrombosis) Reduced mobility Already known thrombophilic condition Recent (< 1 mo) trauma and/or surgery 2 Elderly age ( > 70 y) 1 Heart and/or respiratory failure Acute myocardial infarction or ischemic stroke Acute infection and/or rheumatologic disorder Obesity (BMI > 30) Ongoing hormonal treatment In the Padua Prediction Score risk assessment model, high risk of VTE is defined by a cumulative score 4 points.

Pulmonary hypertension (PH) Haemodynamic definitions of pulmonary hypertension a All values measured at rest. c High CO can be present in cases of hyperkinetic conditions such as systemic-to-pulmonary shunts (only in the pulmonary circulation),anaemia, hyperthyroidism, etc. CO = cardiac output; PAP = pulmonary arterial pressure; PH = pulmonary hypertension; PWP = pulmonary wedge pressure; TPG = transpulmonary pressure gradient (mean PAP – mean PWP). ECS/ERS Guidelines 2009

Pulmonary hypertension (PH) Most studies have indicated that COPD tends to produce relatively modest hemodynamic alterations at rest, relative to other forms of PH, such as idiopathic pulmonary arterial hypertension or PH associated with connective tissue diseases. Typical hemodynamic alterations include mild elevations in mPAP, right atrial pressure (RAP), and pulmonary vascular resistance (PVR). PH in COPD typically occurs in patients with more advanced compromise in respiratory function (FEV1 < 30% predicted) and low PaO2. Pulmonary hypertension in COPD: a review of the literature Minai OA www.pvrireview.org

Pulmonary Hypertension in COPD PH is mild to moderate but it may be severe and could be observed without major airflow limitation This latter condition has been termed ‘‘out-of- proportion’’ PH (may be defined by mPAP > 35–40 mmHg and a mild-to- moderate airflow limitation) Mean pulmonary artery pressure in a hospital-based cohort of 998 COPD patients with a mild to very severe airflow limitation Chaouat A, Bugnet AS, Kadaoui N, et al. Severe pulmonary hypertension and chronic obstructive pulmonary disease Am J Respir Crit Care Med 2005; 172: 189–194

Prognostic impact of PH in patients with COPD Chronic obstructive pulmonary disease patients with a mPAP > 25 mmHg (– – – –) at the beginning of long-term oxygen therapy have a significantly (p < 0.001) shorter life expectancy compared with patients with mPAP < 25 mmHg (––––) Oswald-Mammosser M, Weitzenblum E, Quoix E, et al Prognostic factors in COPD patients receiving long-term oxygen therapy. Importance of pulmonary artery pressure Chest 1995; 107: 1193–1198

Prevalence of COPD ranges from 20-32% in CHF CHF & COPD Heart failure is a complex clinical syndrome with many features in common with COPD, particularly the cardinal symptoms of dyspnea and fatigue. Prevalence of COPD ranges from 20-32% in CHF Risk ratio of developing CHF is 4.5 in COPD Heart failure (HF) has been defined by the European Society of Cardiology (ESC) as “clinical symptoms and objective evidence of cardiac dysfunction (systolic and/or diastolic). Rutten FH, Cramer MM, Lammers JJ, et al. Heart failure and chronic obstructive pulmonary disease: an ignored combination. Eur J Heart Fail 2006;8:706-711. O'Connor CM, Stough WG, Gallup DS, et al. Demographics, clinical characteristics, and outcomes of patients hospitalized for decompensated heart failure: observations from the IMPACT-HF registry. J Card Fail 2005;11:200-205. Gustafsson F, Torp-Pedersen C, Burchardt H, et al. Female sex is associated with a better longterm survival in patients hospitalized with congestive heart failure. Eur Heart J. 2004;25:129-315.

BPCO e Scompenso cardiaco – mortalità 12 24 36 48 60 72 0.5 0.6 0.7 0.8 0.9 1.0 Time (Months) Survival COPD + Heart failure COPD GOLD + Heart Failure COPD COPD GOLD primary care patients with COPD ≥ 65 years (n=404) follow up for a mean duration of 4.2 (SD 1.4) years. HF doubles mortality of patients with COPD: adjusted HR 2.1 (1.2–3.6 C.I.) Boudestein LC, Rutten FH, Cramer MJ, et al. The impact of concurrent heart failure on prognosis in patients with chronic obstructive pulmonary disease. Eur J Heart Fail 2009;11:1182–1188.

Heart failure (HF) The combination of heart failure and chronic obstructive pulmonary disease presents many therapeutic challenges. The cornerstones of therapy are beta-blockers and beta-agonists, respectively. Their pharmacological effects are diametrically opposed, and each is purported to adversely affect the alternative condition.

OBIETTIVI A BREVE TERMINE OBIETTIVI A LUNGO TERMINE Terapia dell’insufficienza cardiaca OBIETTIVI A BREVE TERMINE Riduzione sintomatologia DIURETICI VASODILATATORI DIGITALE Prolungamento sopravvivenza OBIETTIVI A LUNGO TERMINE I b – bloccanti migliorano in modo marcato la sintomatologia e la sopravvivenza dei pazienti con scompenso ACE- INIBITORI b – BLOCCANTI INIBITORI RECETTORIALI A II ANTIALDOSTERONICI INIBITORI NEURO-UMORALI

Differenze farmacologiche dei β-bloccanti approvati per lo scompenso cardiaco Blocco Blocco Blocco ISA ß1 ß2 α1 Carvedilolo +++ +++ +++ - Metoprololo +++ - - - Bisoprololo +++ - - - Nebivololo +++ - - - ISA attività simpaticomimetica intrinseca

Heart disease - COPD Le linee guida della Società Europea di Cardiologia dicono che la BPCO non rappresenta una controindicazione all'utilizzo dei beta-bloccanti. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Eur Heart J 2008;29:2388-442

Beta-bloccanti – BPCO/scompenso cardiaco I beta-bloccanti migliorano in maniera altamente significativa i sintomi e la sopravvivenza nei pazienti con scompenso cardiaco. La BPCO (anche se moderata o grave) non costituisce una controindicazione per i beta-bloccanti. Va raccomandato un inizio a basso dosaggio e incrementi progressivi graduali. Un aspetto fondamentale è la cardioselettività: sono permessi nella BPCO metoprololo, bisoprololo e nebivololo.

Beta bloccanti e BPCO What this study adds β blockers (predominantly cardioselective) reduced mortality and COPD exacerbations when added to stepwise inhaled therapy for COPD (including long acting β agonists and antimuscarinics) in addition to the benefits attributable to addressing cardiovascular risk. The benefits observed occurred without adverse effects on pulmonary function. These data support the use of β blockers in patients with COPD. Kaplan-Meier estimate of probability of survival among patients with COPD by use of β blockers Adjusted hazard ratios for all cause mortality among patients with COPD in reference to the control group (who received only inhaled therapy with short acting β agonists or antimuscarinics) Short PM, Lipworth, SIW, Elder DHJ, et al. Effect of β blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study. BMJ 2011;342:bmj.d2549

Heart failure (HF) Are beta2-agonists responsible for increased mortality in heart failure? Bermingham M, O'Callaghan E, Dawkins I, et al. Eur J Heart Fail 2011; 13: 885-891. Data were available for 1294 patients (age 70.6 ± 11.5 years) of whom 64% were male and 22.2% were taking B2As. β2-Agonist users were older, more likely to be male, to have smoked, to have chronic obstructive pulmonary disease (COPD) and asthma. When adjusted for age, sex, medication, co-morbidity, smoking, COPD, and BNP differences, overall mortality rates were similar [HR 1.043, 95% CI (0.771–1.412), P= 0.783]. Unlike previous reports, this retrospective evaluation of β2-agonist therapy in HF patients shows no relationship with long-term mortality when adjusted for population differences including BNP.  Large, prospective studies are required to define the risk/benefit ratio of β2-agonists in patients with heart failure.

Broncodilatatori – BPCO/scompenso cardiaco Anche se trial clinici randomizzati e controllati hanno stabilito la sicurezza dei beta-agonisti a lunga durata d'azione nei pazienti con BPCO, restano zone d'ombra riguardo la sicurezza nei pazienti con asma. Nessuno studio prospettico ha valutato la sicurezza dei beta-agonisti a lunga durata d'azione nei pazienti con BPCO e asma concomitante. Un broncodilatatore anticolinergico a lunga durata d'azione (tiotropio) si è dimostrato efficace sia nella BPCO che nell'asma; per tale agente è stata evidenziata una sicurezza cardiovascolare. . I pazienti con SC e BPCO concomitante che hanno bisogno di un'assunzione regolare di broncodilatatori per via inalatoria a lunga durata d'azione potrebbero iniziare con un agente anticolinergico piuttosto che con un beta-agonista a lunga durata d'azione. Hawkins NM, Petrie MC, MacDonald MR, et al. Heart Failure and Chronic Obstructive Pulmonary Disease: The Quandary of Beta-Blockers and Beta-Agonists. J Am Coll Cardiol.2011; 57: 2127-2138. Chowdhury BA, Dal PG. The FDA and safe use of long-acting betaagonists in the treatment of asthma. N Engl J Med 2010;362:1169-71.

Treatments for COPD may positively affect morbidity Treatment of chronic obstructive pulmonary disease and its comorbidities Treatments for COPD may positively affect morbidity and mortality linked to comorbidities of COPD Treatments for comorbidities may positively affect morbidity and mortality linked to COPD Luppi F, Franco F, Beghé B, et al. Treatment of chronic obstructive pulmonary disease and its comorbidities Proc Am Thorac Soc 2008;5:848-856.

Predictors of Early and Late Mortality in Hospitalized Patients with Acute Exacerbation of COPD Adapted from Singanayagam A, Schembri S, Chalmers JD. Predictors of mortality in hospitalized adults with acute exacerbation of chronic obstructive pulmonary disease. Ann Am Thoracic Soc 2013, 10:81–89.

Changing paradigms in cardiovascular risk management Volpe M, Erhardt LR, Williams B. Managing cardiovascular risk: the need for change. J Hum Hypertens 2008; 22: 154–157.

Valutazione del rischio cardiovascolare nel paziente BPCO Età Sesso (prima della menopausa) Familiarità per coronaropatia o morte improvvisa: positiva se coronaropatia o morte improvvisa Attività fisica: livello di attività sia al lavoro che extra Fumo: 1) numero di sigarette fumate al giorno e durata della abitudine al fumo 2) se ex fumatore, da quando ha smesso e per quanto tempo ha fumato 3) esposizione passiva Peso corporeo e distribuzione del grasso: 1) anamnesi familiare/personale 2) peso, altezza con calcolo dell’IMC( > 25 Kg/m2 sovrappeso, > 30 Kg/m2 obesità) 3) circonferenza vita (adiposità addominale > 102cm per uomo, > 88cm per donna, adiposità addominale borderline > 94 cm per uomo e > 80 cm per donna) Pressione arteriosa Sindrome metabolica, intolleranza glucidica, diabete, Lipidi plasmatici (colesterolo, HDL colesterolo, LDL colesterolo, trigliceridi) Sindrome delle apnee ostruttive nel sonno Malattie renali croniche Valutazione dei fattori di rischio

Effects of statins on the cholesterol biosynthesis pathway . De Loecker I and Preiser J-C Statins in the critically ill Annals of Intensive Care 2012, 2:19.

Pleiotropic effects of statins . De Loecker I and Preiser J-C Statins in the critically ill Annals of Intensive Care 2012, 2:19.

Effect of statins on mortality and exacerbation in COPD 1,687 patients (mean age 70.6 years) 596 statin users - 1,091 non-users Hazard ratios calculated for statin users versus statin non-users for all-cause mortality over follow-up of up to 4 years. Statin use is associated with a 30% reduction in all-cause mortality at 3-4 years after first admission for COPD, irrespective of a past history of cardiovascular disease and diabetes. Lawes CM, Thornley S, Young R,et al. Statin use in COPD patients is associated with a reduction in mortality: a national cohort study. Prim Care Respir J 2012, 21:35–40. 21_1_35_40COPD 1465-9921-10-45COPD Statins (HMG-CoA reductase inhibitors) lower plasma cholesterol and are used as part of the prevention and management of cardiovascular disease (CVD). However, laboratory-based and animal research has shown that statins have a diverse range of ‘pleiotropic effects’ including antiinflammatory actions, anti-thrombotic properties, anti-oxidant effects, and immunomodulatory effects. 1) This study found a 30% reduction in all-cause mortality in those prescribed statins. _________________________________________________________________________________________________ 2) Association of prior outpatient use of statins and angiotensin converting enzyme (ACE) inhibitors on mortality for subjects ≥ 65 years of age hospitalized with acute COPD exacerbations. Use of statins and ACE inhibitors prior to admission is associated with decreased mortality in subjects hospitalized with a COPD exacerbation. Randomized controlled trials are needed to examine whether the use of these medications are protective for those patients with COPD exacerbations We identified 11,212 subjects with a mean age of 74.0 years, 98% were male, and 12.4% of subjects died within 90-days of hospital presentation. In this cohort, 20.3% of subjects were using statins, 32.0% were using ACE inhibitors or angiotensin II receptor blockers (ARB). After adjusting for potential confounders, current statin use (odds ratio 0.51, 95% confidence interval 0.40–0.64) and ACE inhibitor/ARB use (0.55, 0.46–0.66) were significantly associated with decreased 90-day mortality. Mortensen EM, Copeland LA, Pugh MJ, et al. Impact of statins and ACE inhibitors on mortality after COPD exacerbations. Respiratory Research 2009, 10:45 doi:10.1186/1465-9921-10-45 Proportion of surviving patients hospitalized with COPD exacerbation by use of statin versus non-use (p < 0.0001).

Simvastatin Therapy for Moderate and Severe COPD (STATCOPE) To determine the effect of daily administration of 40 mg simvastatin taken for at least 12 months (range 12-36 months) on the frequency of exacerbations of chronic obstructive lung disease (COPD) in patients with moderate to severe COPD who are prone to exacerbations and do not have other indications for statin treatment. Estimated Study Completion Date: January 2014 Simvastatin therapy for moderate and severe COPD (STSTCOPE).: United States National Institute of Health; http://clinicaltrials.gov/ct2/show/NCT01061671

BPCO e Diabete mellito . Kannel WB and McGee DL Diabetes and cardiovascular disease.The Framingham study Jama 1979, 241:2035-2038 Large population studies show that there is an increased prevalence of diabetes among COPD patients (relative risk 1.5– 1.8), even in patients with mild disease. Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension, and cardiovascular disease in chronic obstructive pulmonary disease Eur Respir J 2008; 32: 962–269.

BPCO e Diabete mellito Mortality in COPD Pts Discharged from Hospital (AECOPD) - Role of Comorbidity 416 patients Follow-up 24 months 122 (29.3%) of the 416 patients died . Kaplan-Meier survival curve in patients with and without diabetes Patients with diabetes had an increased mortality rate [HR = 2.25 (1.28–3.95)] Gudmundsson G, Gislason T, Lindberg E, et al. Mortality in COPD patients discharged from hospital: the role of treatment and co-morbidity Respiratory Research 2006, 7:109.

Corticosteroidi inalatori Effetti collaterali Inhaled corticosteroids and the risk of diabetes Current use of inhaled corticosteroids was associated with a 34% increase in the rate of diabetes (rate ratio [RR] 1.34; 95% confidence interval [CI], 1.29-1.39) and in the rate of diabetes progression (RR 1.34; 95% CI, 1.17-1.53). The risk increases were greatest with the highest inhaled corticosteroid doses, equivalent to fluticasone 1000 μg per day or more (RR 1.64; 95% CI, 1.52-1.76 and RR 1.54; 95% CI, 1.18-2.02; respectively). *Individuals who entered the cohort after the age of 55 years and without mention of asthma during a hospitalization. Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and the risks of diabetes onset and progression Am J Med 2010;123:41001-1006.

Corticosteroidi inalatori Effetti collaterali Inhaled corticosteroids and the risk of diabetes 388,584 patients 30,167 had diabetes onset during 5.5 years of follow-up (incidence rate 14.2/1000/year), and 2099 subsequently progressed from oral hypoglycemic treatment to insulin (incidence rate 19.8/1000/year). Adjusted rate ratio of diabetes incidence associated with inhaled corticosteroid use, as a function of the current dose converted to fluticasone equivalents (in g), along with the corresponding 95% confidence limits for the fitted dose-response curve. Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and the risks of diabetes onset and Progression Am J Med 2010;123:41001-1006.

List of potential risk factors of osteoporosis Smoking Increased alcohol intake Vitamin D levels Genetic factors Treatment with corticosteroids Reduced skeletal muscle mass and strength Low BMI and changes in body composition Hypogonadism Reduced levels of insulin-like growth factors Chronic systemic inflammation Ionescu AA, Schoon E. Osteoporosis in chronic obstructive pulmonary disease. Eur Respir J Suppl. 2003;46:64s-75s.

Osteoporosis - COPD Osteoporosis is highly prevalent in patients with COPD, irrespective of gender. Langhammer A, Forsmo S, and Syversen U. Long-term therapy in COPD: any evidence of adverse effect on bone? Int J Chron Obstruct Pulmon Dis. 2009; 4: 365–380.

Osteoporosis – Fractures – ICS - COPD Inhaled corticosteroid use is associated with a modest but statistically significant increase in the risk of fractures in patients with COPD. Meta-analysis of inhaled corticosteroids versus controls for fractures in observational studies Loke YK, Cavallazzi R, Singh S. Risk of fractures with inhaled corticosteroids in COPD: systematic review and meta-analysis of randomised controlled trials and observational studies. Thorax 2011;66:699-708.

Osteoporosis - Prednisolone Adjusted odds ratio for fracture risk at different sites by daily dose of prednisolone in UK General Practice Research Database (GPRD) and Danish large register studies. Langhammer A, Forsmo S, and Syversen U. L ong-term therapy in COPD: any evidence of adverse effect on bone? Int J Chron Obstruct Pulmon Dis. 2009; 4: 365–380.

Skeletal Muscle Atrophy - COPD no impairment muscle atrophy semistarvation cachexia Schols AM, Broekhuizen R, Weling-Scheepers CA, et al. Bodycomposition and mortality in chronic obstructive pulmonary disease. Am J Clin Nutr 2005; 82: 53–59.

Proposed Mechanisms of Skeletal Muscle Dysfunction in COPD Kim HC, Mofarrahi M, Hussain SN. Skeletal muscle dysfunction in patients with chronic obstructive pulmonary disease. Int J Chron Obstruct PulmonDis 2008, 3:637–658.

Targets of Exercise Training as Part of a Pulmonary Rehabilitation Program for Patients with COPD Casaburi R, ZuWallack R. Pulmonary rehabilitation for management of chronic obstructive pulmonary disease. N Engl J Med 2009;360:1329-1335.

Variables Associated With Depression and Anxiety in Patients With COPD Physical disability Long-term oxygen therapy Low body mass index Severe dyspnea Percentage of predicted FEV1 50% Poor quality of life Presence of comorbidity Living alone Female gender Current smoking Low social class status Maurer J, Rebbapragada V, Borson S, et al. Anxiety and depression in COPD: current understanding, unanswered questions, and research needs. Chest 2008; 134: 43S–56S.

Anaemia Anaemia is defined by a haemoglobin concentration of < 13 g.dL-1 for males and 12 g.dL-1 for females. Anaemia was recently identified as a comorbidity of COPD. Hypoxaemic smokers would actually be expected to exhibit polycythaemia, but studies that have reported haematological values show that anaemia is more common than polycythaemia, with a prevalence ranging from 12.3% to 23% for anaemia and of 6% for polycythaemia. Chatila WM, Thomashow BM, Minai OA, Criner GJ, Make BJ. Comorbidities in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2008;5:549–555.

Epstein AA. A Contribution to the study of the chemistry of blood serum. J Exp Med. 1912;16:719–731. Weber FP. The prognostic significance of secondary polycythaemia in cardio-pulmonary cases. Proc R Soc Med. 1913;6:83–98. COPD has long been recognized as an important cause of secondary polycythemia. Early reports include that of Epstein in 1912, which described polycythemia occurring in cases of “respiratory embarrassment”, including emphysema, while an association between the presence of polycythemia and increased risk of mortality was observed by Weber in 1913.

Anaemia in COPD and chronic respiratory failure (CRF) 185 patients with CRF; 18.4% anaemia . *Potential contributions for anaemia: low folic acid or vitamin B12 levels (two patients); GFR< 60 ml/min (three patients); uncontrolled diabetes (two patients); toxic causes (two patients); missing values of TSAT (two patients). ACD, anaemia of chronic disease; IDA, iron deficiency anaemia Schneckenpointner R, Jörres RA, Meidenbauer N, et al. The clinical significance of anaemia and disturbed iron homeostasis in chronic respiratory failure. Int J Clin Pract 2014;68:130-138.

In 1978, Bernice Cohen, discussing her findings on familial aggregation of chronic obstructive pulmonary disease (COPD) and lung cancer, stated that “a common predisposition to pulmonary dysfunction in families of COPD and lung cancer probably precedes, rather than merely accompanies, both neoplastic and non neoplastic disease”. Following such a hypothesis, she proposed a model in which impaired pulmonary function, irrespective of its causation (either genetically or environmentally mediated), could lead to many disorders including COPD and lung cancer. Cohen BH. Is pulmonary dysfunction the common denominator for the multiple effects of cigarette smoking? Lancet 1978 ;2 (8098 ): 1024 – 1027.

Lung cancer COPD is associated with a lung cancer risk that is two to six times that of smokers without COPD. Moreover, COPD was associated with lung cancer in never-smokers; hence, the association is not solely due to smoking. The lung cancer risk seems to be greater in patients with mild to moderate COPD than in those with more severe disease. Proportion of chronic smokers with COPD and healthy lung function who will get lung cancer Lung cancer Young RP, Hopkins RJ, Christmas T, et al. COPD prevalence is increased in lung cancer, independent of age, sex and smoking history. Eur Respir J 2009; 34: 380–86.

The patients’ lung function was not reported in the trial. Recent data from the American National Lung Screening Trial showed a 20% reduction in death due to lung cancer in the group screened using computed tomography compared to the group screened by radiography, among smokers or former smokers aged between 55 years and 74 years with a smoking history of o30 pack-years. The patients’ lung function was not reported in the trial. These epidemiological data suggest that targeted lung cancer screening for COPD patients could be worthwhile. The National Lung Screening Trial Research Team, Aberle DR, Adams AM. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011; 365: 395–409.

U.S. Preventive Services Task Force La USPSTF raccomanda: LO SCREENING ANNUALE CON LDCT NEGLI ADULTI DI ETÀ COMPRESA TRA I 55 E GLI 80 ANNI CHE HANNO UNA STORIA DI FUMO DI ALMENO 30 PACCHETTI-ANNO, E CHE CONTINUANO A FUMARE O HANNO SMESSO DA MENO DI 15 ANNI.

COTE Index 1664 patients with COPD in 5 centers were observed for a median of 51 months, and 79 comorbidities were recorded. Fifteen of 79 comorbidities differed in prevalence between survivors and non-survivors. Of those, 12 predicted mortality: Oncologic (lung, pancreatic, esophageal, and breast cancers) Pulmonary (pulmonary fibrosis) Cardiac (atrial fibrillation/flutter, congestive heart failure, and coronary artery disease) Gastrointestinal (gastric/duodenal ulcer, liver cirrhosis) Endocrine (diabetes with neuropathy) Psychiatric (anxiety) Divo M, Cote C, de Torres JP, et al. Comorbidities and risk of mortality in patients with chronic bstructive pulmonary disease Am. J. Respir. Crit. Care Med. 2012;186:155 -161.

COTE Index COMORBIDITIES AND POINT VALUES USED FOR THE COMPUTATION OF COTE INDEX Increases in the BODE and COTE were independently associated with an increased risk for death. A COTE of 4 points or more increased the risk for death by 2.2-fold (HR, 2.26 - 2.68; P < .001) in all BODE quartiles. Increases in the COTE index were associated with an increased risk for death from both COPD (HR, 1.13; 95% CI, 1.08 - 1.18; P < .001) and causes not related to COPD (HR, 1.18; 95% CI, 1.15 - 1.21; P < .001). Divo M, Cote C, de Torres JP, et al. Comorbidities and risk of mortality in patients with chronic bstructive pulmonary disease Am. J. Respir. Crit. Care Med. 2012;186:155 -161.

William Osler (1849 – 1919) «It is much more important to know what sort of patient has a disease than to know what kind of a disease a patient has»

Co-morbidity: we need a guideline for each patient not a guideline for each disease Dawes M. Co–morbidity: we need a guideline for each patient not a guideline for each disease. Fam Pract 2010, 27:1-2.

Grazie per l’attenzione dr. Stefano Calabro Dr. Stefano Calabro REGIONE VENETO – AZIENDA U.L.S.S. n.3 Ospedale S. Bassiano - Bassano del Grappa Dipartimento di Medicina Struttura Complessa di Pneumologia Dr. Rolando Negrin REGIONE VENETO – AZIENDA U.L.S.S. n.6 Ospedale S. Bortolo - Vicenza Dipartimento di Area Medica II Unità Operativa Complessa di Pneumologia 66

Corticosteroidi inalatori DOSI QUOTIDIANE (in mcg) COMPARATIVE DI CORTICOSTEROIDI PER VIA INALATORIA FARMACO ADULTI $ Dose bassa Dose intermedia Dose Alta Beclometasone Dipropionato HFA 100 – 200 >200 – 400 >400 – 800 Budesonide 200 – 400 >800 – 1600 Ciclesonide 80-160 160-320 320-1280 Flunisolide 500 – 1000 >1000 – 2000 >2000 Fluticasone Propionato 100 – 250 >250 – 500 >500 – 1000 Mometasone furoato 200-400 400-800 800-1200 $ confronto basato sui dati di efficacia