I read with interest the article by Hanania et al (1) in September 2003, where the combination of fluticasone proprionate (250 [micro]g)/salmeterol (50 [micro]g bid) was found to improve FE[V.sub.1] better than salmeterol in COPD. Moreover, fluticasone alone improved FE[V.sub.1]. I am concerned that the article has inadvertently allowed the inclusion of asthmatic patients who were mislabeled as "COPD."

1. Patients' ages were [greater than or equal to] 49 years. Moderate-to-severe COPD is rare below the age of 50 years. (2)

2. The exclusion criteriae removed patients with "current diagnosis of asthma". This implies that patients who had asthma in the past were recruited. And who decided they were no more asthmatic? Over a hundred doctors at 76 investigative sites across the United States, where the standards of clinical judgment vary.

3. The patients recruited where classified as "reversible" and "nonreversible." The mean percentage increase of FE[V.sub.1] in the reversible group--after administering 400 [micro]g of albuterol--was 30% (range not given). As the inclusion criteriae included patients with baseline FE[V.sub.1] < 65%, it is very likely that many patients in the reversible group had achieved an FE[V.sub.1] of > 86% after albuterol, which takes them out of the definition of COPD. (3)

4. The patients' response to medications is typical of asthma in that fluticasone was effective at a small dose. Several previous studies on COPD have failed to demonstrate such effect even though larger doses of inhaled corticosteroids were used. (4) In addition, the response to fluticasone was manifest 24 h only after the initiation of treatment. This is too quick a response for patients with COPD outside acute exacerbation.

My concern is highlighted by the fact that differentiation between asthma and COPD can sometimes be difficult. (3) Also, a metaanalysis (5) of eight articles showed that inhaled corticosteroids had improved FE[V.sub.1] in patients with COPD. (5) The same analysis--after excluding the articles that included patients with asthma/COPD--showed no such effect. (4) The inclusion of a few asthmatic cases can tip the balance towards response.

Feisal A. El-Kassimi, FRCP, FCCP

King Saud University

Riyadh, Saudi Arabia

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Feisal A. El-Kassimi, FRCP, FCCP, Consultant Pulmonologist, Professor of Medicine, Medical Department (38), College of Medicine, King Saud University, PO Box 2925, Riyadh 11461, Saudi Arabia

REFERENCES

(1) Hanania NA, Darken P, Horstman D, et al. The Efficacy and safety of fluticasone propionate (250 [micro]g)/salmeterol (50 [micro]g) combined in the Diskus Inhaler for the treatment of COPD. Chest 2003; 124:834-843

(2) Lacasse Y, Brooks D, Goldstein RS. Trends in the epidemiology of COPD in Canada, 1980 to 1995: COPD and Rehabilitation Committee of the Canadian Thoracic Society. Chest 1999; 116:306-313

(3) Global Initiative for Chronic Obstructive Pulmonary Disease: NHLBI/WHO workshop report. Bethesda, MD: National Institutes of Health, 2001; publication No. 2701

(4) Highland KB, Strange C, Heffner JE. Long-term effects of inhaled corticosteroids on FE[V.sub.1] in patients with chronic obstructive pulmonary disease: a metaanalysis. Ann Intern Med 2003; 138:969-973

(5) Sutherland ER, Allmers H, Ayas NT, et al. Inhaled corticosteroids reduce the progression of airflow limitation in chronic obstructive pulmonary disease: a metaanalysis. Thorax 2003; 58:937-941

To the Editor:

We sincerely appreciate Dr. El-Kassimi's interest in our article. (1) While the inclusion criteria for our study may appeal to be broad, they were designed to select patients with COPD as defined by both the American Thoracic Society (ATS) (2) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) (3) guidelines. We agree with Dr. El-Kassimi that COPD is rare in patients 40 to 50 years old; however, it does exist. (4) In this study, only 53 patients (7%) were < 50 years of age.

It is true that patients included in our study may have received a previous diagnosis of asthma. Importantly, many patients are often misdiagnosed during the early stages of COPD and we did not want to exclude patients who had clear clinical evidence of the disease. In fact, only three patients in the study reversed to albuterol to > 80% predicted FE[V.sub.1], thus supporting that this was a COPD population. Similar inclusion criteria have been used in many other large COPD studies. In fact, the mean percentage of reversible patients in this study (55 to 56%) was comparable to that seen in clinical trials with salmeterol in COPD (57 to 65%), (5,6) and it was lower than that seen in clinical trials of ipratropium/ albuterol in COPD (68 to 73%). (7)

In Table 3 of our article, lung function response is reported by reversibility. Surprisingly, the difference in predose FE[V.sub.1] between fluticasone propionate/salmeterol combination (FSC) therapy and salmeterol was highest among the nonreversible subgroup. Within the nonreversible subgroup, the change from baseline for FSC was approximately 100 mL greater than that for salmeterol. By comparison, the effect of the combination was higher in the reversible subgroup (328 mL vs 221 mL), but the difference between FSC and salmeterol in this subgroup was smaller (approximately 60 mL). This is counterintuitive to those that expect an inhaled corticosteroid (ICS) to make a greater contribution among reversible patients.

For many years, patients with COPD were defined by having irreversible airflow obstruction and therefore would derive little benefit From treatment with an ICS. This assumption has now been shown to be incorrect. While most studies (8,9) have failed to demonstrate a reduction in the rate of lung function decline with the use of high dose of ICS, several studies (8-10) have demonstrated that ICS therapy improves lung function, reduces the rate of exacerbations, and improves quality of life in patients with COPD. (8-10) In addition, there is now compelling evidence demonstrating the benefits of ICS/long-acting [beta]-agonist (LABA) in combination in COPD with respect to improving lung function and reducing exacerbations. (11-14) In a retrospective study, (15) this combination therapy has also been shown to reduce morbidity and mortality in such patients, although prospective studies are needed to confirm this finding.

There is no evidence of a dose response to ICS in patients with COPD, and therefore there is nothing to support that the response to the medium-dose fluticasone propionate observed in our study was atypical. In fact, in a similarly designed study with a higher dose of fluticasone propionate, the magnitude of response in lung function was comparable to that seen in our study. (11)

The concerns raised by Dr. El-Kassimi underscore an important point: the differential diagnosis between asthma and COPD can sometimes be very difficult. Both diseases involve inflammation and bronchoconstriction and result in airflow obstruction that can lead to similar symptoms of dyspnea, cough, and wheezing. Our results show that similar to asthma, the combination of a long-acting bronchodilator and an antiinflammatory results in a significant improvement in lung function compared with either agent alone, even in a disease which has been historically defined as "irreversible." We believe that reversibility to albuterol should not be a criterion for the diagnosis of COPD, nor should it dictate therapy. This opinion is supported by both GOLD and ATS, and this study demonstrates that ICS/LABA together in the treatment of COPD play a beneficial role and should nut be reserved for patients with COPD with an "asthmatic response."

=========================== REFERENCES

(1) Hanania NA, Darken P, Horstman D, et al. The efficacy and safety of fluticasone propionate (250 [micro]g)/salmeterol (50 [micro]g) combined in the Diskus Inhaler for the treatment of COPD. Chest 2003; 124:834-843

(2) American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995; 152:S77-S121

(3) Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: executive summary--updated 2003. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health, 2003

(4) de Marco R, Accordini S, Cerveri I, et al. An international survey of chronic obstructive pulmonary disease in young adults according to GOLD stages. Thorax 2004; 59:120-125

(5) Mahler DA, Donohue JF, Barbee RA, et al. Efficacy of salmeterol xinafoate in the treatment of COPD. Chest 1999; 115:957-965

(6) Rennard SI, Anderson W, ZuWallack R, et al. Use of a long-acting inhaled [[beta].sub.2]-adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001:163:1087-1092

(7) Combivent Inhalation Aerosol Study Group, In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone: an 85-day multicenter trial. Chest 1994; 105:1411-1419

(8) Burge PS, Calverley PM, Jones PW, et al. Randomised, double-blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000; 320:1297-1303

(9) Lung Health Research Group. Effect of inhaled triamcinolone on the decline, in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 2000; 343:1902-1909

(10) Paggiaro PL, Dahle R, Bakran I, et al. Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. Lancet 1998; 351:773-780

(11) Mahler DA, Wire P, Horstman D, et al. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2092; 166: 1084-1091

(12) Calverley P, Pauwels R, Vestbo J, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary, disease: a randomised controlled trial. Lancet 2003; 361:449-456

(13) Calverley PM, Boonsawat W, Cseke Z, et al. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J 2003; 22:912-919

(14) Szafranski W, Cukier A, Ramirez A, et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J 2003; 21:74-81

(15) Soriano JB, Vestbo J, Pride NB, et al. Survival in COPD patients after regular use of fluticasone propionate and salmeterol in general practice. Eur Respir J 2002; 20:819-825

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