at SciVerse ScienceDirect

Pulmonary Pharmacology & Therapeutics 26 (2013) 218e228

Contents lists available

Pulmonary Pharmacology & Therapeutics

journal homepage: www.elsevier .com/locate/ypupt

Project PriMo: Sharing principles and practices of bronchodilator therapymonitoring in COPDA consensus initiative for optimizing therapeutic appropriateness among Italianspecialists

Mario Cazzola a,*, Vito Brusasco b, Stefano Centanni c, Isa Cerveri d, Fausto De Michele e,Giuseppe Di Maria f, Paolo Palange g, Riccardo Pellegrino h, Mario Polverino i, Andrea Rossi j, Alberto Papi k

aUnità di Farmacologia Clinica Respiratoria, Dipartimento di Medicina dei Sistemi, Università di Roma ‘Tor Vergata’, Via Montpellier 1, 00133 Rome, ItalybDipartimento di Medicina Interna, Università di Genova, Genoa, ItalycClinica Malattie Respiratorie, Dipartimento della Salute, Università degli Studi di Milano, Milan, ItalydUO di Fisiopatologia Respiratoria, Fondazione IRCCS Policlinico San Matteo, Pavia, ItalyeUOC di Pneumologia e Fisiopatologia Respiratoria, A.O.R.N. ‘A. Cardarelli’, Napoli, ItalyfClinica Pneumologica, Dipartimento di Biomedicina Clinica e Molecolare, Università di Catania, Catania, ItalygUOC di Medicina Interna I e UOS di Diagnosi e Terapia delle Disfunzioni Respiratorie, Università di Roma ‘La Sapienza’, Rome, ItalyhAllergologia e Fisiopatologia Respiratoria, Azienda Sanitaria Ospedaliera ‘S. Croce e Carle’, Cuneo, Italyi Polo Pneumologico Provinciale, ASL Salerno, ItalyjUOC di Pneumologia, D.A.I. Cardiovascolare-Toracico, A.O.U Integrata, Verona, ItalykClinica Pneumologica, Università degli Studi di Ferrara, Ferrara, Italy

a r t i c l e i n f o

Article history:Received 1 May 2012Received in revised form1 October 2012Accepted 30 October 2012

Keywords:COPDBronchodilatorsDelphi process

* Corresponding author.E-mail address: mario.cazzola@uniroma2.it (M. Ca

1094-5539/$ e see front matter � 2012 Elsevier Ltd.http://dx.doi.org/10.1016/j.pupt.2012.10.010

a b s t r a c t

Background: Even after publication of the 2011 update of GOLD report, some fundamental questions inthe management of COPD are still open and this may weaken the applicability of these guidelines ineveryday clinical practice.Objective: To assess the level of consensus amongst Italian respirologists on different topics related todiagnosis, monitoring and role of bronchodilator therapy in COPD, by using the Delphi technique.Methods: A Delphi study was undertaken between July and November 2011, when two questionnaireswere consecutively sent to a panel of experts to be answered anonymously. After each round, the datawere aggregated at group level of question topics and structured feedback was given to the panel.Results: A first-round questionnaire was sent to 208 pulmonologists randomly selected from differentItalian regions. The132 respondents (63%of those initially selected)were fromnorthern (53%), central (19%)and southern (28%) Italy. A second-round questionnaire was sent to all the first-round respondents, anda response was received from 110 of them (83%). The main topics that reached the pre-defined cut off forconsensus (67% or more) were: a) bronchodilator therapy with long-acting bronchodilators could bebeneficial in patients with airflow limitation even in the absence of symptoms, b) in patients not fullycontrolled with one long-acting bronchodilator, maximizing bronchodilation (i.e. adding another bron-chodilator with a different mechanism of action) is the preferable option; and c) the use of inhaled corti-costeroids (ICSs) as add on therapy should be considered in severe patients with frequent exacerbations.Conclusions: Italian specialists agree on several aspects of the diagnosis and treatment of COPD andexpert opinion could support everyday decision process in the management of COPD.

� 2012 Elsevier Ltd. All rights reserved.

1. Introduction

Chronic obstructive pulmonary disease (COPD) is defined as “acommon preventable and treatable disease, characterized by

zzola).

All rights reserved.

persistent airflow limitation that is usually progressive and asso-ciated with an enhanced chronic inflammatory response in theairways and the lung to noxious particles or gases” [1].

GOLD report has long recommended adopting an initial step-wise approach in COPD management, based on the severity ofairflow limitation, where bronchodilators are the mainstaytreatment [2]. The original therapeutic decision is then adjusted to

M. Cazzola et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 218e228 219

patient’s response to treatment [2]. In the 2011 update of GOLDreport [1], lung function (FEV1) leadership in addressing phar-macological treatment is downgraded and it becomes one of the 3parameters taken into account when recommending treatment,along with severity of symptoms and frequency of exacerbations.This major change leaves many important areas in the manage-ment of COPD unanswered or without recommendations. Eventhe updated COPD guidelines recently released by the AmericanCollege of Physicians (ACP), the American College of ChestPhysicians (ACCP), the American Thoracic Society (ATS), and theEuropean Respiratory Society (ERS) [3] fail to provide completeanswers to several important questions. For instance, they indi-cate that spirometry should be used to identify symptomaticpatients with airflow obstruction who may benefit from phar-macotherapy and recommend regular inhaled bronchodilatortreatment in patients who have respiratory symptoms and FEV1values less than 60% of predicted. However, there are no recom-mendations for symptomatic patients with moderate airflowlimitation (FEV1 60e80% of predicted) [3]. In addition, there is noindication about whether to use long-acting b2-agonists (LABAs)or long-acting antimuscarinic drugs (LAMAs) when long-actingbronchodilator treatment is recommended. Moreover, there isno guidance on when to combine two bronchodilators withdifferent mechanisms of action or use triple therapy, adding aninhaled corticosteroid (ICS) [3].

The fact that fundamental questions in themanagement of COPDremain unanswered and that no recommendations exist weakensthe applicability of these guidelines in everyday clinical practice.

The use of formal consensus techniques inmedicine is becomingincreasingly frequent. Formal consensus techniques can be helpfulin making decisions in situations where no gold standard exists,potentially reducing bias and resulting in a better decision. Avarietyof formal methods are available when conducting a consensusprocess [4]. One such method is the Delphi technique, a validatedconsensus-building process to build consensus and make group-based decisions in a variety of fields. This is an iterative processwhere experts are polled individually using a series of question-naires and receive anonymous group feedback between iterations[5]. The Delphi method has been widely used in respiratory medi-cine for epidemiological purposes and to set up and define health-care protocols and procedures, including treatment [6e10].

In this study we used the Delphi process to evaluate the level ofconsensus amongst Italian respirologists on the role and the posi-tioning of bronchodilator therapy in COPD.

StartDefinition

of the problem

Determination of necessary

expertise

Selectionof

experts

No

Comparison of final replies and drafting of a report

Yes

Has a consensus been

reached?

Fig. 1. Phases in the

2. Methods

The study was conducted among Italian specialists in respira-tory medicine.

2.1. Delphi process

The study (Fig. 1) was undertaken between July and November2011, when two consecutive questionnaires were emailed (thesecond questionnaire after six weeks from the first one) to a panelof experts and completed anonymously. After each round,following the collection of the filled in questionnaires, data entryand statistical analysis of these results, data were aggregated atgroup level and structured feedback was given to the panel. Thismethodology was used as it provides a useful way of identifyingandmeasuring uncertainty in medical and health services research.

2.2. First round e questionnaire 1 (Q1)

For this specific project, a small group of specialists (the 11 co-authors of the present article) examined scientific literature onthe topic (bronchodilators & COPD) and developed a 22-itemquestionnaire (Q1; see Table 1), plus 4 initial demographic ques-tions. The questions were divided into four main chapters (Defi-nition/Classification/Diagnosis; Bronchodilator therapy; Follow-up;Outcomes & Biomarkers). For each question, spacewas provided forcomments.

The questionnaire was given to respirologists and COPDspecialists, who were requested to complete it within 2 weeks.

Panellist specialists were identified amongst the Italian Heads ofRespiratory Units (Hospital or University based) or Chiefs ofRespiratory Healthcare Structures. A geographic distribution, toinclude all Italian areas/regions was also adopted.

For the majority of questions in Q1 (13 out of 22), the respon-dents used a scale of 0 (total disagreement) to 9 (complete agree-ment) while for the others they were asked to rank a set of optionsprovided in order of importance in their clinical opinion, or tocomplete open-ended questions.

To better analyze the results, the answers were divided into twocategories for the questions with a 0e9 response scale:

� Score of 0e4: negative answer;� Score of 5e9: positive answer

Drafting of the

questionnaire

Distribution of the

questionnaire

Collection of completed

questionnaires

Inclusion of replies in a new questionnaire

Delphi method.

Table 1Questionnaire 1. Answers are expressed as percentage of all responses. The cut-off level for consensus is two-thirds (67%) of agreement of effective answers.

Question % All options % Combinedoptions(0e4/5e9)or Rank

Consensus

Definition/Classification/Diagnosis5. Do you think that the definition of COPD as “a disease of the respiratory tract characterized

by chronic and never fully reversible obstruction of the airflow. Obstructive ventilatorydefect is the main cause of the progressive nature of the disease” e is this correct?

Yes

0 Total disagreement 0.00% 15.9%/84.1%1 0.76%2 5.30%3 3.79%4 6.06%5 8.33%6 16.67%7 13.64%8 21.97%9 Complete agreement 23.48%6. Do you think it is essential to consider respiratory function parameters

in the diagnosis of the disease?Yes

0 Total disagreement 0.00% 0.8%/99.2%1 0.00%2 0.00%3 0.00%4 0.76%5 0.00%6 1.52%7 8.33%8 12.88%9 Complete agreement 76.52%7. Do you think that the presence of airflow obstruction parameters is sufficient to diagnose

COPD in patients at risk (smokers)?No

0 Total disagreement 6.25% 43.0%/57.0%1 12.50%2 5.47%3 8.59%4 10.16%5 9.38%6 10.16%7 10.94%8 9.38%9 Complete agreement 17.19%8. If not, would you include:a. The presence of cough with sputum and/or dyspnea 62.6%b. The presence of dyspnea 32.1%c. Others 5.3%9. Do you think that a single diagnostic parameter (forced expiratory volume

in 1 second [FEV1]) is sufficient to characterize functional changes?Yes

0 Total disagreement 30.00% 80.8%/19.2%1 21.54%2 15.38%3 7.69%4 6.15%5 10.77%6 2.31%7 3.08%8 0.77%9 Complete agreement 2.31%10. If not, would you include:a. Inspiratory capacity (IC) 29.8%b. Carbon monoxide diffusing capacity (DLco) 28.9%c. Residual volume (RV) 28.1%d. 6-Minute Walk Test (6-MWT) 13.2%11. In clinical practice, in addition to FEV1, do you use other functional parameters for the

clinical and therapeutic choices?Yes

0 Total disagreement 3.08% 6.2%/93.8%1 0.77%2 0.00%3 0.77%4 1.54%5 6.92%6 2.31%7 12.31%8 23.85%9 Complete agreement 48.46%

M. Cazzola et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 218e228220

Table 1 (continued )

Question % All options % Combinedoptions(0e4/5e9)or Rank

Consensus

12. If the answer to the question above is affirmative, would you include:a. IC 25.8%b. DLCO 22.7%c. RV 19.5%d. 6-MWT 17.9%e. Clinics 14.0%f. Arterial blood gas analysis 14.0%g. FEV1/forced vital capacity (FVC) 10.9%Bronchodilator therapy in COPD13. Do you agree that bronchodilators are the mainstay of COPD pharmacological treatment? Yes0 Total disagreement 0.00% 3,1%/96.9%1 0.76%2 0.00%3 0.00%4 2.29%5 1.53%6 3.05%7 9.16%8 27.48%9 Complete agreement 55.73%14. Do you think it is useful to start the therapy with long-acting bronchodilators in the

presence of bronchial obstruction even in the absence of symptoms?Yes

0 Completely useless 3.08% 24.6%/75.4%1 5.38%2 4.62%3 6.15%4 5.38%5 3.85%6 4.62%7 21.54%8 16.92%9 Fully useful 28.46%15. Do you think it is useful to increase the dose of a bronchodilator to better

control your COPD patients?No

0 Completely useless 7.63% 39.7%/60.3%1 6.11%2 7.63%3 6.11%4 12.21%5 12.98%6 8.40%7 14.50%8 9.16%9 Fully useful 15.27%16. In patients who are not controlled with a single bronchodilator, do you believe that

maximal bronchodilation (e.g. more drugs with different mechanisms of action) isfundamental to achieve an adequate therapeutic response?

Yes

0 Total disagreement 1.55% 8.5%/91.5%1 1.55%2 1.55%3 1.55%4 2.33%5 2.33%6 7.75%7 6.98%8 28.68%9 Complete agreement 45.74%17. Do you think that inhaled steroids in severe patients with repeated exacerbations and

only after regular use of one or more bronchodilators can be useful?Yes

0 Completely useless 0.76% 3.8%/96.2%1 0.00%2 0.00%3 0.00%4 3.03%5 1.52%6 8.33%7 11.36%8 24.24%9 Fully useful 50.76%

(continued on next page)

M. Cazzola et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 218e228 221

Table 1 (continued )

Question % All options % Combinedoptions(0e4/5e9)or Rank

Consensus

18. Do you agree on the use of inhaled steroids associated withlong-acting bronchodilators in patients with mild but symptomatic obstruction?

No

0 Total disagreement 13.64% 52.3%/47.7%1 11.36%2 9.09%3 9.85%4 8.33%5 8.33%6 9.09%7 11.36%8 5.30%9 Complete agreement 13.64%Follow-up19. What should be the frequency of follow-up visits in patients with

stable COPD?a. 3 months 11.68%b. 6 months 37.96%c. 12 months 8.76%d. Depending on the severity of the patient 41.61%20. What functional tests do you use in the follow-up in addition to FEV1

for therapeutic decisions?ScoreD Rank

a. Lung volumes 641 1b. Ergometric test 212 5c. DLCO 379 4d. 6-MWT 552 2e. IC 540 3f. Total lung capacity 164 621. What parameters do you use to evaluate the efficacy of therapeutic

intervention?ScoreD Rank

a. Symptoms 719 1b. FEV1 426 3c. Frequency of exacerbations 563 2d. FVC 288 5e. IC 368 4f. Pulmonary function test 237 622. If the patient is uncontrolled with current therapy, how important

is it to assess patient compliance to therapy before increasing thedosage or changing it?

Yes

0 Completely useless 0.78% 1.6%/98.4%1 0.00%2 0.00%3 0.00%4 0.78%5 0.78%6 3.88%7 6.98%8 20.16%9 Fully useful 66.67%23. In the follow-up, what measures do you use when a patient, already under

treatment with a single bronchodilator, returns with persistent symptoms?a. I increase the dose of bronchodilator in use if possible 14.43%b. I add a bronchodilator 51.24%c. I add an inhaled steroid 26.87%d. I add a theophylline 7.46%24. In the follow-up, do you add an additional bronchodilator to basal

bronchodilator treatment if there is:ScoreD Rank

a. Unsatisfactory clinical response (worsening of dyspnea) 413 1b. Partial functional response (possible further reduction of obstruction and hyperinflation) 266 3c. Patient with major clinical and functional severity 295 2d. Patient with poor functional response to a single bronchodilator 258 425. In the follow-up, you add an inhaled steroid to basal bronchodilator treatment in a: ScoreD Ranka. Severe patient with frequent exacerbations 476 1b. Patient with major functional impairment 324 2c. Chronic bronchitis phenotype 283 3d. Emphysema phenotype 126 4Outcomes & Biomarkers26. The main objective of therapeutic intervention in COPD isa. Improving FEV1 10.53%b. Improving transition dyspnea index (TDI) 8.61%c. Reducing dyspnea 45.45%d. Reducing exacerbations 35.41%

M. Cazzola et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 218e228222

Table 1 (continued )

Question % All options % Combinedoptions(0e4/5e9)or Rank

Consensus

27. Do you agree on the use of biomarkers in clinicalpractice for clinical decisions in COPD?

No

0 Total disagreement 16.94% 61.3%/38.7%1 8.87%2 17.74%3 12.10%4 5.65%5 11.29%6 8.87%7 6.45%8 6.45%9 Complete agreement 5.65%

M. Cazzola et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 218e228 223

2.3. Second round e questionnaire 2 (Q2)

A second round was deemed necessary and a second ques-tionnaire (Q2) was prepared on the grounds that a number of itemsfrom Q1 were unclear. Q2 included items from Q1 for whichconsensus recommendations were unclear, accompanied bya summary of the original responses to Q1. The questions weredivided in the same way (four main chapters) as in Q1. Some newquestions were formulated to further examine some points. Finally,the items found to be ambiguous were detailed. The expert panelwas given 2 weeks to complete the questionnaire. Q2 was given tothe same experts and the replies were collected and processed inthe same way.

After each round, the level of agreement was evaluateddepending on the percentage of positive answers to each question.To reach consensus, a cut-off level of two-thirds (67%) of agreement(for positive or negative answers) was required for both rounds(Q1 and Q2).

For the questions that asked for listed options to be ranked inorder of importance (for example from 1 to 4), each “1” (meaning“first in order of importance”) was given a value of 4, “2” a value of3, “3” a value of 2 and “4” a value of 1. The total score of each optionis an indicator of the degree of preference by the experts. Only theoptions reaching a pre-defined threshold of 50% of the maximumscore were considered and reported.

3. Results

Q1 was sent to 208 pulmonologists randomly selected from 208different Respiratory Units (Hospital or University based) or Respira-toryHealthcare Structures. The132 respondents (63%of those initiallyselected)were fromnorthern (53%), central (19%) and southern (28%)Italy. Q2 was sent to all the Q1 respondents, and a response wasreceived from 110 of them (83%). The percentage breakdown ofrespondents for each question is shown in Tables 1 and 2.

The following statements reached the pre-defined cut off forconsensus (67% or more):

3.1. Definition/Diagnosis of COPD

1. COPD can be defined as a disease characterized by persistentairflow limitation that is never fully reversible and is usuallyprogressive. (Q1-5)

2. The evaluation of respiratory functional parameters is essentialfor the diagnosis of the disease. (Q1-6)

3. Forced expiratory volume in 1 second (EV1) cannot beconsidered the only evaluation parameter for lung function inCOPD. Diffusing capacity of the lung for carbon monoxide

(DLco) and residual volume (RV) should be also considered.(Q1-9; Q2-1)

4. In clinical practice the overall approach for COPD patients takesinto account different parameters in addition to FEV1, such asFEV1/forced vital capacity (FVC), RV, arterial blood gas analysisand inspiratory capacity (IC). (Q1-11; Q2-2)

3.2. Therapy

5. Bronchodilators are the mainstay of COPD pharmacologicaltreatment. (Q1-13)

6. Bronchodilator therapy with long-acting bronchodilators couldbe beneficial in patients with airflow limitation and no symp-toms. (Q1-14)

7. In patients not fully controlled with one long-acting broncho-dilator, maximizing bronchodilation (i.e. adding anotherbronchodilator with a different mechanism of action) may beuseful to achieve clinical improvement. (Q1-16)

8. The use of ICSs as add-on therapy in patients receiving one ormore long-acting bronchodilators may be useful in severepatients with frequent exacerbations. (Q1-17)

3.3. Follow-up

9. Follow-up visits of patients with stable COPD should be per-formed at varying intervals depending on the severity of thedisease. (Q1-19; Q2-4)

10. In the follow up the assessment of lung volumes, 6-MinuteWalk Test (6-MWT) and IC, in addition to FEV1, may be usefulfor a clinical re-evaluation. (Q1-20; Q2-5)

11. The efficacy of a pharmacological treatment should be assessedthrough the evaluation of the following parameters: symp-toms, frequency of exacerbation, FEV1. (Q1-21; Q2-6)

12. When the expected efficacy is not achieved, patients’ compli-ance to a treatment should be considered. (Q1-22)

13. In the follow up, when a patient receiving a long-acting bron-chodilator continues to be symptomatic, the first measure totake is adding a second bronchodilator with a differentmechanism of action. (Q1-23; Q2-7)

14. A second long-acting bronchodilator with a different mecha-nism of action should be added to regular bronchodilatortherapy in case of unsatisfactory clinical and lung functionresponses. (Q1-24; Q2-8)

15 In the follow-up, an inhaled corticosteroid should be added tobasal bronchodilator therapy in patients suffering from severeCOPD and frequent exacerbations. (Q1-25; Q2-9)

Table 2Questionnaire 2 answers are expressed as percentage of all responses. The cut-off level for consensus is two-thirds (67%).

Question % All options % Combinedoptions (0e4/5e9)or Rank

Consensus

Definition/Classification/Diagnosis1. If you do NOT think that a single parameter (FEV1) is sufficient to characterize

the functional changes, would you include: (rank 1e4)Scoreþ Rank

a. IC 298 2b. DLCO 229 3c. VR 309 1d. 6 MWT 201 42. If in clinical practice, in addition to FEV1, you use other clinical and functional

parameters for clinical and therapeutic choices, would you include: (rank 1e7)

Scoreþ Rank

a. IC 413 5b. DLCO 345 7c. VR 439 3d. 6 MWT 360 6e. Clinics 583 1f. EGA 437 4g. FEV1/FVC 471 2Bronchodilator therapy in COPD3. In order to gain better control of COPD patients, it is appropriate to increase

the dose of a bronchodilator.No

0 Total disagreement 8.26% 45.9%/54.1%1 10.09%2 9.17%3 9.17%4 9.17%5 16.51%6 6.42%7 11.93%8 6.42%9 Complete agreement 12.84%Follow-up4. What should be the frequency of follow-up visits in patients with stable COPD?a. At fixed 3-monthly intervals 14.16%b. At fixed 6-monthly intervals 29.20%c. At fixed 12-monthly intervals 7.08%d. Depending on the severity of the patient 49.56%5. What functional tests do you use in the follow-up in addition to FEV1 for

therapeutic decisions? (rank 1e5)ScoreD Rank

a. Lung volumes 418 1b. Ergometric test 160 5c. DLCO 243 4d. 6 Minutes walking test 353 2e. IC 337 36. What parameters do you use to evaluate the efficacy of therapeutic

intervention? (rank 1e5)ScoreD Rank

a. Symptoms 485 1b. FEV1 308 3c. Frequency of exacerbations 387 2d. FVC 220 5e. IC 187 47. In the follow-up, what is the first measure you use when a patient, already receiving a

single bronchodilator, returns because symptoms persist? (only one option)a. I increase the dose of bronchodilator in use, if possible 8.85%b. I add a second bronchodilator with a different mechanism of action 77.88%c. I add an inhaled steroid 12.39%d. I add a theophylline 0.88%8. In the follow-up, you add a second bronchodilator with a different mechanism of

action to basal bronchodilator therapy if there is: (only one option)a. Unsatisfactory clinical response 37.04%b. Unsatisfactory functional response 0.00%c. Both of the above 62.96%9. In the follow-up, you add an inhaled steroid to basal bronchodilator

treatment in a: (only one option)a. Severe patient with frequent exacerbations 78.95%b. Patient with major functional impairment 8.77%c. Chronic bronchitis phenotype 12.28%d. Emphysema phenotype 0.00%Outcomes & Biomarkers10. The main objective of therapeutic intervention in COPD is:a. Improving FEV1/slowing down its decline 20.37%b. Reducing dyspnea 30.86%c. Improving exercise tolerance 17.90%d. Reducing exacerbations 30.86%

M. Cazzola et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 218e228224

Table 2 (continued )

Question % All options % Combinedoptions (0e4/5e9)or Rank

Consensus

11. Do you think the use of bronchodilators is effective in the prevention ofexacerbations?

Yes

0 No e total disagreement 1.80% 22.5%/77.5%1 0.90%2 3.60%3 6.31%4 9.91%5 8.11%6 15.32%7 20.72%8 14.41%9 Yes e complete agreement 18.92%

M. Cazzola et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 218e228 225

3.4. Outcomes & Biomarkers

16. The main therapeutic goals in COPD treatment are theimprovement of dyspnea and reduction of exacerbation rate.(Q1-26; Q2-10)

17. The use of bronchodilators should be considered effective forpreventing exacerbations (Q2-11)

4. Discussion

The Delphi process is a recognized method to determine andquantify group consensus [5e10].

This study, conducted amongst 132 Italian lung specialists,showed that there is large consensus onmost of the items proposedand related to the role and relevance of bronchodilator therapy inCOPD. Only 4 questions from Q1 and 1 from Q2 (a minority) did notreach the predefined level of consensus. It must be mentioned thatmany of the panellists’ answers were consistent with the currentupdated GOLD guidelines [1].

The following are some of the most important vs. debatableresults:

4.1. Lung function

There was consensus that lung function is essential in thediagnosis of COPD, but also that other parameters in addition toFEV1 should be considered for a better functional characterizationof the disease, such as DLCO and RV. In clinical practice, whentreating the disease, clinical presentation is considered importantalong with a more precise functional characterization that includesFEV1/FVC, RV, blood gases, and IC in addition to FEV1. Consensus onthese aspects indicates the need to include several pieces ofinformation to fully characterize COPD patients, including clinicalpresentation. The need to have a multidimensional approach is inline with the recently revised GOLD classification of severity ofCOPD, where apart from FEV1, clinical presentation (symptoms)and frequency of exacerbation are taken into account to groupCOPD patients [1]. However, our expert panel did not reacha consensus on the question whether the presence of airflowobstruction parameters is sufficient to diagnose COPD in smokers.Tobacco smoking is the main risk factor for COPD, and spirometry isthe best tool to diagnose and stage COPD [1e3]. Nonetheless,a broad spectrum of other disorders, including asthma, bronchi-ectasis, upper airway lesions, bronchiolar diseases, and someinterstitial lung diseases, are associated with airflow obstructionand many patients suffering from these disorders are smokers [11].It is obvious, therefore, that clinicians should remember that the

differential diagnosis in patients with obstructive lung diseases isbroad and heterogeneous.

4.2. Initiation of treatment with bronchodilators

The specialists agreed that regular therapy with long-actingbronchodilators should be started in obstructed patients both inthe presence and absence of symptoms. This is a debatable issue.Recent ACP/ACCP/ATS/ERS guidelines conclude that no sufficientevidence exists to support bronchodilator treatment in asymp-tomatic patients [3]. Thus, the result of the Delphi methodology inthis specific matter appears to be an expert opinion rather than anevidence-based assertion. Nonetheless, some studies report thatmild and even moderate airflow obstruction can occur withoutcomplaints or symptoms [12] and several surveys revealed a cohortof COPD patients with “silent obstruction” who had no chroniccough, phlegm, and/or dyspnea, although they had airflow limita-tion in spirometry tests [13e15]. After all this is not a surprise, giventhe weak correlation between the severity of complaints and theseverity of airway obstruction [16]. Early intervention mightpossibly avoid/delay the onset of symptoms and other clinicalmanifestations, such as exacerbations, and their long term conse-quences [17,18]. This hypothesis needs to be tested in appropriateprospective studies.

4.3. Combining different bronchodilators

Although there was not a consensus on the usefulness ofincreasing the dose of a bronchodilator to better control COPDpatients, several panellists believed that this is an appropriateaction. This was not a surprise because, in real life, a dyspneicpatient who has only a single bronchodilator available oftenassumes additional doses of his/her bronchodilator in the hope ofrelieving dyspnea when he/she is unable to perceive bronchodila-tion or must perform an exercise [19]. However, almost all panel-lists concurred that patients not controlled by a singlebronchodilator, should be given two bronchodilators with differentmechanisms of action. Certainly, this seems to be a good choicebecause using multiple drugs in combination may lower doses ofindividual agents, decrease adverse effects, simplify medicationregimens and improve compliance [20].

In anycase, current international recommendations (GOLD2011)point out that the combined use of LABAs and antimuscarinics maybe considered if symptomsdonot improvewith single agents [1]. Anincreasing body of evidence suggests that the LABA/LAMA combi-nation appears to play an important role in maximizing broncho-dilation, with studies to date indicating that combining differentclasses of bronchodilators may result in significantly greater

M. Cazzola et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 218e228226

improvements in lung function compared to the use of a single drug,and that these combinations are well tolerated in patients withmoderate-to-severe COPD [21]. The nature of interaction betweenthe two systems is not yet fully understood [22]. Though expected inlight of potential pharmacological potentiation, the effects ofmaximizing bronchodilation with two different bronchodilatorsneed to be properly tested in prospective studies.

4.4. ICSs and triple therapy in COPD

There was consensus that ICSs should be prescribed in additionto bronchodilators in patients with severe COPD and repeatedexacerbations [1]. Indeed, exacerbations represent a relevantoutcome where the addition of ICS proved superior to long-actingbronchodilators alone [23,24]. In the last version of the GOLDreport [1], the use of ICS/LABA combinations in the treatment ofCOPD is recommended for patients at high risk of exacerbation (�2exacerbations/year or FEV1 < 60% predicted), but about half of ourpanel experts believed that inhaled corticosteroids associated withlong-acting bronchodilators are useful also in patients with mildbut symptomatic obstruction, although the evidence that cansupport this clear over-prescription is truly modest [25]. In anycase, a recent multicentre, cross-sectional, observational study thatwas carried out in 49 Italian Pulmonary Units evenly distributedthroughout the Country showed that in Italy there is a poor rela-tionship between the recommendations of the GOLD internationalguidelines and current clinical practice [26]. Apparently, the pres-ence and the number of exacerbations represented an importanttrigger for over-prescription in mild COPD [26].

Triple therapy, i.e. the addition of a LABA plus an ICS to a LAMA,has inadequate scientific support. Preliminary data from a limitednumber of studies suggest the beneficial effect of “triple therapy”over monotherapy with a long-acting bronchodilator in severe andvery severe COPD patients [27].

4.5. Follow-up

There was consensus that for patients with stable COPD, follow-up visits should be performed at varying intervals according to theseverity of the disease: the greater the severity, the shorter theintervals. A recent Australian study reported that three-monthlyspirometry and regular medical check-ups by general practi-tioners are not associated with any significant improvement inquality of life or other health outcomes for COPD patients [28].However, Canadian population-based data suggested that follow-up visits are effective in reducing early relapses in patients whohave been recently treated in emergency departments for COPD[29]. Intriguingly, the majority of panellists believed that the use ofbiomarkers is not useful in clinical practice for clinical decisions inCOPD. In effect, although there is increasing interest in usingpulmonary biomarkers for a more complete and clinically relevantassessment of COPD and a plethora of biomarkers are becomingavailable, there is a lack of well-validated biomarkers that can beused for monitoring disease activity, predicting future clinicaloutcomes and the effect of therapeutic interventions [30].

GOLD report has always recommended monitoring symptomsand objectively measuring airflow limitation to adjust therapy [31].In particular, it suggested monitoring the effectiveness of thecurrent regime in controlling symptoms, side effects of treatment,dosages of various medications, adherence to the regimen andinhalation technique [31]. Non-adherence to medication regimensis a significant problem in the management of COPD as non-adherence rates are high in these populations [32]. There isstrong consensus amongst the experts participating this study thatwhen a patient is not controlled with his/her current therapy, it is

important to assess whether he/she adheres to therapy beforeincreasing its dosage or changing it.

4.6. Goals of COPD treatment

The panellists of this Delphi process agreed that themain goal ofstarting therapy in COPD is the reduction in symptoms (dyspnea)and exacerbation frequency. Therewas consensus on the efficacy ofbronchodilators in preventing exacerbations. These opinions arewidely supported by literature: A) long-acting bronchodilatorsreduce hyperinflation and improve dyspnea and exercise endur-ance [33]; B) long-acting bronchodilators, alone or combinedwith ICSs, reduce the rate of exacerbations in patients with COPD[34e36].

4.7. Limitations of the study

Some limitations of this study should be acknowledged. A) Theuse of multiple-choice questions may have limited responses orinduced bias [37]. B) All the panellists participating in the studywere Italian and practice in Italy, thus their responses may reflectgeographically-driven practices and biases. However, it should bepointed out that all of the panel members are experts in the fieldand have likely used the latest information in their responses.

5. Conclusion

In conclusion, this Delphi study revealed that Italian specialistsagree on several aspects of the diagnosis and treatment of COPD. Inparticular, our panellists believe that bronchodilator therapy withlong-acting bronchodilators could be beneficial in patients withairflow limitation even in the absence of symptoms. Moreover, inpatients not fully controlled with one long-acting bronchodilator,maximizing bronchodilation (i.e. adding another bronchodilatorwith a different mechanism of action) is the preferable option. Theuse of ICSs as add on therapy should be considered in severepatients with frequent exacerbations.

These consensus statements should be considered the expertopinion on some of the questions in the management of COPD thatremain unanswered, as previously discussed in detail, to supporteveryday decision process in the management of COPD and couldhelp overcoming the shortage of some crucial information that stillexists in several reports/guidelines. For this reason, we believe thata multinational survey would support the consensus scenario andoffer a strong opinion for the issues incompletely addressed byguidelines.

Conflict of interest statement

Novartis Italia has given support to the scientific committee tofinance the development of field work for the Delphi survey part ofthe study, without taking part in the design, collection of infor-mation, data analysis, or preparation of this article.

Acknowledgments

Wewish to thank the 132 specialists on the panel of experts (seelist in Appendix) and ThinkTank, a Milan-based Delphi Methodconsultant agency, for its methodological and logistic support.

All of the authors were significantly involved in the design, datacollection, and manuscript preparation concerning this research.

M. Cazzola et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 218e228 227

Appendix. Specialists participating in the study

Stefano Aiolfie S.C. di Pneumologiae A.O. Maggiore di Crema eCrema (LO); Carlo Albera e Ospedale San Luigi Gonzaga e Orbas-sano (TO); Michele Albergati e Medicina Riabilitativa e Ospedale“SS. Trinità” e Romano di Lombardia (BG); Arnaldo Alessandrini eU.O. di Broncopneumologia ed Allergologia e Ospedale di Abbia-tegrasso e Abbiategrasso (MI); Antonio Alfieri e U.O. di Pneumo-logia e P.O. Nocera Inferiore (SA); Mario Alma e U.O. II diBroncopneumologia e A.O. S. Camillo e Forlanini e Roma; SandroAmaducci e S.C. di Pneumologia e Ospedale San Carlo e Milano;Giuseppe Anzalonee U.O. di Pneumologiae Ospedale Misericordiae Dolce ASL4 e Prato (PO); Luisa Arcangeli e S.C. di Pneumologia e

A.O. Ospedale Niguarda e Ca’ Granda e Milano; Antonio Aufiero e

Pneumologia e Ospedale Eremo di Miazzina e Cambiasca (VB);Gennaro Baldi e Centro di Medicina Respiratoria e ASL SA2 e

Salerno; Pasquale Barone e Divisione di Pneumologia e EnteEcclesiastico Cardinale Panico e Tricase (LE); Vincenzo Bellia e

Pneumologia II e Ospedale Vincenzo Cervello e Palermo; FulvioBenassi e U.O. II di Broncopneumologia e A.O. S. Camillo e For-lanini e Roma; Elisabetta Bertocco e Ospedale di MontecchioMaggiore e Montecchio Maggiore (VI); Alessandra Besozzi e

Medicina Interna e Ospedale di Treviglio e Treviglio (BG); Gian-carlo Bosio e U.O. di Pneumologia e A.O. “Istituti Ospitalieri diCremona” e Cremona; Luigi Brancaccio e Centro Anti Fumo e

U.O.S. Prevenzione Malattie Respiratorie e A.O. Monaldi e Napoli;Rolando Braschi e Ospedali ASL AL e Ovada (AL); Paolo Bulgheronie S.C. di Pneumologia e A.O. Ospedale Niguarda e Ca’ Granda e

Milano; Concetta Buonaiuto e Cardiopneumologia e Casa di CuraMontevergine e Mercogliano (AV); Stefano Calabro e Ospedale S.Bassiano e Bassano del Grappa (VI); Piero Candoli e OspedaleUmberto I e Lugo (RA); Walter Canonica e Divisione di Pneumo-logia e Allergologia e Ospedale S. Martino e Genova; DamianoCapaccio e U.O.A. di Pneumologia e Ospedale Maria SS. Addoloratae Eboli (SA); Mario Caputi e Clinica Pneumologica II SUN e

Ospedale Monaldi e Napoli; Roberto Carbone e Pneumotisiologiae Ospedale Regionale Aosta e Aosta; Stefano Carlone e Ospedale S.Giovanni Addolorata e Roma; Maria Antonietta Ceccon e Unità H1e P.T.P. Rocca Priora e Rocca Priora (RM); Mariano Celano e Divi-sione di Pneumologia e Ospedale San Carlo e Potenza; EnricoChiaravalli e Ospedale di Circolo di Varese e Varese; Enrico Clini eU.O. Pneumologia e Riabilitazione Respiratoria e Ospedale VillaPineta e Pavullo n/F (MO); Roberto Cogo e Pneumologia e Ospe-dale A. Zappatoni e Cassano d’Adda (MI); Fausto Colombo e

Pneumologia e Ospedale di Circolo e Fondazione Macchi di Varesee Varese (VA); Marco Confalonieri e S.C. di Pneumologia e Ospe-dale di Cattinara e Trieste; Giovanni Coniglio e U.O. di Pneumo-logia e Ospedale San Donato e Arezzo; Paolo Conti e Pneumologiae Ospedale S. Andrea ASL VC e Vercelli; Antonio Cotellucci e Ser-vizio di Broncopneumologia e Ospedale di Gavardo e Gavardo(BS); Carlo Cozzi e Pneumologia e Ospedale di Saronno e Saronno(VA); Paolo Crepaldi e Lungodegenza e Ospedale Eremo di Miaz-zina e Cambiasca (VB); Roberto Dal Negroe U.O. di Pneumologia eOspedale di Bussolengo e Bussolengo (VR); Rossano Dallari e

Modulo di Pneumologia e Ospedale di Sassuolo e Sassuolo (MO);Fernando De Benedetto e U.O.C. di Pneumologia e A.O. S. CamilloDe Lellis e Chieti; Francesco De Blasio e Unità Funzionale di Ria-bilitazione Respiratoria e Casa di Cura Clinic Center Spa e Napoli;Claudio De Michelis e P.O. di Imperia e Imperia; Filippo De Padovae Ospedale Specializzato Antonio e Carlo Cartoni e Frascati (RM);Giuseppe De Simone e Divisione di Riabilitazione Respiratoria e

Clinica Privata Villa Margherita e Benevento; Cimino Del Bufalo e

Servizio di Terapia Intensiva e Medicina Respiratoria e Casa di CuraSan Pier Damiano Hospital e Faenza (RA); Saverio Desiderio e

Ospedale degli Infermi e A.U.S.L. Rimini e Rimini; Giulio Donazzan

e Divisione di Pneumologia e Ospedale di Bolzano e Bolzano (BZ);Enzo FaccinieU.O. di PneumologiaeOspedale di DoloeDolo (VE);Giuseppe Failla e Ospedale Regina Apostolorum e Albano Laziale(RM); Andrea Fanti e U.O. II di Broncopneumologia e A.O. S.Camillo Forlanini e Roma; Mauro Ferliga e U.O.S. FisiopatologiaRespiratoria e A.O. M. Mellini e Chiari (BS); Luigi Ferri e Riabili-tazione Respiratoria e Casa di Cura San Raffaele e Cassino (FR);Luigi Ferritto e Medicina e Casa di Cura Athena Villa dei Pini ePiedimonte Matese (CE); Alfeo Fiore-Donati e U.O. di Pneumologiae A.S.L. 4 Terni e L’Aquila; Antonio Foresi e Servizio di Pneumo-logia e Fisiopatologia Respiratoriae P.O. Sesto San Giovannie SestoSan Giovanni (MI); Dario Fornari e Ospedale di Montichiari e

Montichiari (BS); Luigi Frigieri e Reparto di Pneumologia e Ospe-dale S. Giovanni Battista e Foligno (PG); Raffaele Fusco e U.O.S.Pneumologia e P.O. di Maddaloni eMaddaloni (CE); Diego Gatta e

Ospedale di Esine e Esine (BS); Felice Gozzelino e U.O.A. Pneu-mologia e Ospedale degli Infermie Biella; Pietro Greco e OspedaleS. Barbara e Iglesias (CA); Gabriella Guarnieri e Servizio diMedicina del Lavoro e A.O. di Padova e Padova; Enrico Guffanti eUnità di Pneumologia Riabilitativa e Ospedale INRCA-IRCCS e

Casatenovo (LC); Carlo Gulotta e Ospedale San Luigi Gonzaga e

Orbassano (TO); Giuseppe Idotta e Ospedale di Cittadella e Cit-tadella (PD); Giovanni Ligia e Pneumologia IV e Ospedale Binaghie Cagliari; Vittorino Lo Giudice e Pneumologia e OspedaleMariano Santo e Cosenza; Bruno Macciocchi e Ospedale SantaScolastica e Cassino (FR); Claudia Madaschi e Unità Respiratoria e

Humanitas Gavazzeni e Bergamo; Donato Maiella e U.O.C. Diag-nostica Preventiva e Medicina Sociale e ASL BN1 e Benevento;Mirella Malara Guarna e Pneumologia e A.O. Bianchi MelacrinoMorelli e Reggio Calabria; Mario Malerba e U.O. di Pneumologia e

A.O. Spedali Civili di Brescia e Brescia; Filippo Manzi e U.O.C.Pneumologia ad Indirizzo Oncologico e A.O. Cardarelli e Napoli;Mario Marino e U.O. di Fisiopatologia Respiratoria e A.S.L. RM/BPoliambulatorio e Roma; Serafino Antonio Marsico e ClinicaPneumologia SUN e A.O. Monaldi e Napoli; Anna Maspero e

Pneumologia e Ospedale S. Anna e San Fermo della Battaglia (CO);Michele Mastroberardino e U.O. di Pneumologia e A.O.R.N. SanGiuseppe Moscati e Avellino; Francesco Mazza e S.C. di Pneumo-logia e Ospedale Santa Maria della Misericordia e Pordenone;Antonietta Melchiorre e Reparto di Pneumologia e Ospedale diDesenzano e Desenzano (BS); Antonio Meriggi e Ospedale diCasorate Primo e Casorate Primo (PV); Claudio Micheletto e

Ospedale Mater Salutis e Legnago (VR); Romano Nardelli e Ospe-dale di Arco e Arco (TN); Luigi Negri e U.O. di Pneumologia e A.O.Provincia di Lodi e Lodi; Rolando Negrin e Ospedale S. Bortolo e

Vicenza; Paolo Noceti e U.O. di Pneumologia e Ospedale S. Croce eCarle e Cuneo; Lucia Occhionero e Pneumologia e ASL Asti e Asti;Antonella Papalia e Unita di Riabilitazione Pneumologica e Ospe-dale Morelli e Sondalo (SO); Antonio Pappacoda e Centro Pneu-mologico e Poliambulatorio Brembate Sopra e A.O. Treviglio (BG);Antonio Pasi e U.O. di Pneumologia e Ospedale “Asilo Vittoria” e

Mortara (PV); Franco Pasquae Riabilitazione Respiratoriae Casa diCura San Raffaele e Velletri (RM); Giovanni Passalacqua e U.O.Malattie Apparato Respiratorio e A.O. Papardo e Messina; Vin-cenzo PatellaeU.O.A. di Pneumologiae Ospedale Civile di Agropolie Agropoli (SA); Vincenzo Patruno e Pneumologia Riabilitativa e

Istituto di Medicina Fisica e Riabilitazione e Udine; Riccardo Pela eU.O.C. di Pneumologia e Ospedale C.G. Mazzoni e Ascoli Piceno;Roberto Perra e Reparto di Pneumologia e INRCA e Cagliari;Innocente Piazza e Medicina e Ospedale di Iesolo e Iesolo (VE);Vito Picca e Unità di Pneumologia III e Ospedale San Paolo e Bari;Pavilio Piccioni e U.O. di Pneumologia e C.P.A. Torino e Torino;Pietro Pipitone e Ambulatorio Territoriale di Pneumologia e

A.U.S.L. 6 PA e Distretto Partinico e Partinico (PA); Pietro Pirina e

Clinica Pneumologica e Università di Sassari e Sassari; Massimo

M. Cazzola et al. / Pulmonary Pharmacology & Therapeutics 26 (2013) 218e228228

PistolesieUnità Funzionale di Medicina Respiratoriae A.O. Careggie Firenze; Carlo Pomari e Ospedale di Negrar e Negrar (VR);Giovanni Puglisie U.O. II di Broncopneumologiae A.O. S. Camillo e

Forlanini e Roma; Stefano Putinati e U.O. di Fisiopatologia Respi-ratoria e A.O. Universitaria e Arcispedale S. Anna e Ferrara; Ono-frio Restae U.O. Malattie dell’Apparato Respiratorio UniversitariaeConsorziale Policlinico e Bari; Giangaleazzo Riario Sforza e Riabi-litazione Respiratoria e Istituti Clinici di Perfezionamento e

Milano; Violetta Romano e ASL Roma B e Roma; Anna Rosa e Casadi Cura Ancelle della Caritàe Cremona; Eugenio Sabatoe Divisionedi Pneumologia e Ospedale Ninetto Melli e San Pietro Vernotico(BR); Pasquale Salzillo e U.O. Pneumologia e A.O.R.N. S. Anna e S.Sebastiano e Caserta; Alessandro Sanduzzi Zampanelli e U.O.C.Clinica Pneumologica II e A.O. Monaldi e Federico II e Napoli;Giorgio Santelli e Struttura Complessa di Pneumologia e Ospedale“S. Maria di Ca’ Foncello” e Treviso; Barbara Santini e Unità Fun-zionale e Riabilitazione Respiratoria e Policlinico San Marco e OsioSotto (BG); Carlo Santoriello e U.O. Pneumologia e P.O. di Polla-Sant’Arsenio e Sant’Arsenio (SA); Antonella Sarni e Ospedale S.Maria Goretti e Latina; Mauro Scanferlato e U.O. di Medicina e

Servizio di Pneumologia e Allergologia e Ospedale di San Donà diPiave (VE); Patrizia Scavalli e Hospedale Civita Castellana e Civ-itacastellana (VT); Alfonso Schiavo e U.O. Medicina Interna e P.O.Cava dei Tirreni (SA); Matteo Sofia e U.O.C. Clinica PneumologicaI e A.O. Monaldi e Federico II e Napoli; Battista Squitieri e U.O.Medicina e P.O. di Marcianise eMarcianise (CE); Silvano Subiaco e

A.S.U.R. Z.T. n.5 e Jesi (AN); Cosimo Tarantino e Presidio Pneumo-logico e A.U.S.L. TA/1 e Taranto; Roberto Tazza e U.O. di Pneu-mologia e A.S.L. 4 Terni e Terni; Marcello Ugolini e S.O.C. diPneumologia e Ospedale San Salvatore e Pesaro; Adriano Vaghi eOspedale Salvini di Garbagnate e Garbagnate (MI); Paolo Vanzettoe Servizio di Pneumologia e Ospedale di Castelfranco Veneto e

Castelfranco Veneto (TV); Umberto Vincenzi e U. O. MalattieApparato Respiratorio e Ospedale d’Avanzo e Foggia; FrancoZambotto e Pneumotisiologia e Ospedale Santa Maria del Prato e

Feltre (BL); Claudio Zamprogna e Ospedale Amedeo di Savoia e

Torino; Pietro Zanon e U.O. di Broncopneumologia e Ospedale diCircolo di Busto Arsizio e Busto Arsizio (VA); Maria CristinaZappa e Ospedale S. Pertini e Roma.

References

[1] Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategyfor the diagnosis, management, and prevention of chronic obstructive lungdisease. Revised 2011. http://www.goldcopd.com.

[2] Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategyfor the diagnosis, management, and prevention of chronic obstructive lungdisease. Updated 2010. http://www.goldcopd.com.

[3] Qaseem A, Wilt TJ, Weinberger SE, Hanania NA, Criner G, van der Molen T,et al. Diagnosis and management of stable chronic obstructive pulmonarydisease: a clinical practice guideline update from the American College ofPhysicians, American College of Chest Physicians, American Thoracic Society,and European Respiratory Society. Ann Intern Med 2011;155:179e91.

[4] Murphy M, Sanderson C, Black N. Consensus development methods and theiruse in clinical guideline development. Health Technol Assess 1998;2:1e100.

[5] Fink A, Kosecoff J, Chassin M, Brook RH. Consensus methods: characteristicsand guidelines for use. Am J Public Health 1984;74:979e83.

[6] Wyrwich KW, Fihn SD, Tierney WM, Kroenke K, Babu AN, Wolinsky FD.Clinically important changes in health-related quality of life for patients withchronic obstructive pulmonary disease: an expert consensus panel report.J Gen Intern Med 2003;18:196e202.

[7] Flume PA, Mogayzel Jr PJ, Robinson KA, Rosenblatt RL, Quittell L, Marshall BC.Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysisand pneumothorax. Am J Respir Crit Care Med 2010;182:298e306.

[8] Mahler DA, Selecky PA, Harrod CG, Benditt JO, Carrieri-Kohlman V, Curtis JR,et al. American College of Chest Physicians consensus statement on themanagement of dyspnea in patients with advanced lung or heart disease.Chest 2010;137:674e91.

[9] Schutt AC, Bullington WM, Judson MA. Pharmacotherapy for pulmonarysarcoidosis: a Delphi consensus study. Respir Med 2010;104:717e23.

[10] Upton J, McCutcheon E, Loveridge C, Wiggins J, Walker S, Fletcher M.What provokes experienced COPD clinical practitioners in the UK toinitiate or change medication? A consensus study. Prim Care Respir J2011;20:155e60.

[11] Ryu JH, Scanlon PD. Obstructive lung diseases: COPD, asthma, and manyimitators. Mayo Clin Proc 2001;76:1144e53.

[12] van den Boom G, Rutten-van Mölken MP, Tirimanna PR, van Schayck CP,Folgering H, van Weel C. Association between health-related quality of lifeand consultation for respiratory symptoms: results from the DIMCA pro-gramme. Eur Respir J 1998;11:67e72.

[13] d’Andiran G, Schindler C, Leuenberger P. The absence of dyspnoea, cough andwheezing: a reason for undiagnosed airflow obstruction? Swiss Med Wkly2006;136:425e33.

[14] Shin C, Lee S, Abbott RD, Kim JH, Lee SY, In KH, et al. Respiratory symptomsand undiagnosed airflow obstruction in middle-aged adults: the Koreanhealth and genome study. Chest 2004;126:1234e40.

[15] Lu M, Yao WZ, Zhong NS, Zhou YM, Wang C, Chen P, et al. Asymptomaticpatients of chronic obstructive pulmonary disease in China. Chin Med J 2010;123:1494e9.

[16] Brand PL, Rijcken B, Schouten JP, Koëter GH, Weiss ST, Postma DS. Perceptionof airway obstruction in a random population sample. Relationship to airwayhyperresponsiveness in the absence of respiratory symptoms. Am Rev RespirDis 1992;146:396e401.

[17] Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, Salcedo E,Navarro M, Ochando R. Severe acute exacerbations and mortality in patientswith chronic obstructive pulmonary disease. Thorax 2005;60(11):925e31.

[18] Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationshipbetween exacerbation frequency and lung function decline in chronicobstructive pulmonary disease. Thorax 2002;57(10):847e52.

[19] Cazzola M, Santus P, Castagna F, Di Marco F, Terzano C, Matera MG, et al.Addition of an extra dose of salmeterol Diskus to conventional dose of sal-meterol Diskus in patients with COPD. Respir Med 2002;96:439e43.

[20] Mak G, Hanania NA. New bronchodilators. Curr Opin Pharmacol 2012;12:238e45.

[21] Cazzola M, Tashkin DP. Combination of formoterol and tiotropium in the treat-ment of COPD: effects on lung function. Chronic Obstr Pulm Dis 2009;6:404e15.

[22] Cazzola M, Molimard M. The scientific rationale for combining long-acting b2-agonists and muscarinic antagonists in COPD. Pulm Pharmacol Ther 2010;23:257e67.

[23] Jones PW, Anderson JA, Calverley PMA, Celli BR, Ferguson GT, Jenkins C, et al.Spencer MD and for the TORCH investigators. Health status in the TORCHstudy of COPD: treatment efficacy and other determinants of change. RespirRes 2011;12:71.

[24] Kardos P, Wencker M, Glaab T, Vogelmeier C. Impact of salmeterol/fluticasonepropionate versus salmeterol on exacerbations in severe chronic obstructivepulmonary disease. Am J Respir Crit Care Med 2007;175:144e9.

[25] Ferguson GT. Maintenance pharmacotherapy of mild and moderate COPD:what is the evidence? Respir Med 2011;105:1268e74.

[26] Corrado A, Rossi A. How far is real life from COPD therapy guidelines? AnItalian observational study. Respir Med 2012;106:989e97.

[27] Rodrigo GJ, Plaza V, Castro-Rodríguez JA. Comparison of three combinedpharmacological approaches with tiotropium monotherapy in stablemoderate to severe COPD: a systematic review. Pulm Pharmacol Ther 2012;25:40e7.

[28] Abramson MJ, Schattner RL, Sulaiman ND, Birch KE, Simpson PP, Del Colle EA,et al. Do spirometry and regular follow-up improve health outcomes ingeneral practice patients with asthma or COPD? A cluster randomisedcontrolled trial. Med J Aust 2010;193:104e9.

[29] Sin DD, Bell NR, Svenson LW, Man SF. The impact of follow-up physician visitson emergency readmissions for patients with asthma and chronic obstructivepulmonary disease: a population-based study. Am J Med 2002;112:120e5.

[30] Cazzola M, Novelli G. Biomarkers in COPD. Pulm Pharmacol Ther 2010;23:493e500.

[31] Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy forthe diagnosis, management, and prevention of chronic obstructive pulmonarydisease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease(GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163:1256e76.

[32] Agh T, Inotai A, Meszaros A. Factors associated with medication adherence inpatients with chronic obstructive pulmonary disease. Respiration 2011;82:328e34.

[33] O’Donnell DE. Hyperinflation, dyspnea, and exercise intolerance in chronicobstructive pulmonary disease. Proc Am Thorac Soc 2006;3:180e4.

[34] Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al.Salmeterol and fluticasone propionate and survival in chronic obstructivepulmonary disease. N Engl J Med 2007;356:775e89.

[35] Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, et al. A 4-yeartrial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med2008;359:1543e54.

[36] Wang J, Nie B, Xiong W, Xu Y. Effect of long-acting beta-agonists on thefrequency of COPD exacerbations: a meta-analysis. J Clin Pharm Ther 2012;37:204e11.

[37] Hasson F, Keeney S, McKenna H. Research guidelines for the Delphi surveytechnique. J Adv Nurs 2000;32:1008e15.