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Treatment With the Immunomodulator AM3 Improves the Health-Related Quality of Life of Patients With COPD*

Posted on: Wednesday, 27 April 2005, 03:00 CDT

Background: COPD has a severe impact on patient quality of life. AM3 is an orally effective immunomodulator that can normalize the defective antimicrobial functions of the immune system effector cells of COPD patients.

Objectives: We analyzed the effect of AM3 on exacerbation frequency and health-related quality of life (HRQL) of COPD patients with moderate disease.

Design: A randomized, double-blind, placebo-controlled trial.

Setting: Outpatient departments of 21 hospitals.

Methods: A total of 253 COPD patients with a mean age of 67.7 years (SD, 8.1 years) and mean FEV^sub 1^ percentage of predicted of 49.6% (SD, 10.2%) were evaluated. Patients received (orally) either 3 g/d AM3 or a matched placebo for 180 consecutive days. Patient quality of life was measured using the St. George's Respiratory Questionnaire (SGRQ).

Results: There were no differences in the exacerbation frequency of the two groups (0.82 episodes per patient in the AM3 arm vs 0.84 in the placebo arm), and 55.3% of patients were exacerbation free in the AM3 arm compared to 48.8% in the placebo arm (p = 0.11). At the end of treatment, quality of life was significantly better in the AM3 arm than in the placebo arm (SGRQ total score, 32.9; SD, 16.4, compared to 37.5; SD, 17.5 [p < 0.05]: activity score, 47.5; SD, 22.4, compared to 54.6; SD, 20.5 [p < 0.05]). The improvements in total SGRQ scores were 8.9 U (SD, 13.4 U) in the AM3 arm and 5.6 U (SD, 15.9 U) in the placebo arm (p = 0.076). Improvements on the symptoms subscale were 15.9 U (SD, 20.7 U) for the AM3 arm and 10.2 U (SD, 21.3 U) for the placebo arm (p < 0.05). Both AM3 and the placebo were clinically, biochemically, and hematologically well tolerated.

Conclusions: AM3 is a safe, easily tolerated, effective treatment that improves the quality of life of COPD patients as measured by SGRQ scores. This effect was observed with no significant reduction in the frequency of exacerbations. (CHEST 2005; 127:1212-1218)

Key words: AM3; clinical trial; COPD; health-related quality of life; St. George's Respiratory Questionnaire

Abbreviations: BMI = body mass index; HRQL = health-related quality of life; SGRQ = St. George's Respiratory Questionnaire

COPD is one of the most common respiratory diseases and one of the main causes of morbidity worldwide. It is now the fourth most common cause of death, and its burden on public health budgets is increasing.1,2

Exacerbations are a frequent event in the natural history of the disease. Patients with frequent exacerbations experience an accelerated decline in lung function3 and health-related quality of life (HRQL).4,5 Treatments that reduce the frequency of exacerbations may eventually reduce the rate of decline of HRQL.6 This has been observed with inhaled corticosteroids, although some of the improvements seen are probably explained by the pharmacologic effect of the drug rather than a reduction in the number of exacerbations.7

In addition to its impact on patient life span and health-care costs, there is growing concern over the impact of COPD on HRQL. HRQL has been used as an independent predictor of hospitalization and mortality,8 and there is evidence that it is already reduced in the initial phases of the disease.9 The importance of improving HRQL is addressed in consensus documents on COPD therapy.10 HRQL in COPD patients appears to depend on multiple factors, including the so- called "systemic effects" of the disease, such as systemic inflammation, skeletal muscle dysfunction, and nutritional problems leading to weight loss.11

Chronic inflammation of the airways plays an essential pathogenic role in COPD. Its relationship with the degree of airflow obstruction and with susceptibility to periods of exacerbation is well established.3 In addition to local inflammation in the lungs, there is growing evidence that systemic inflammatory events occur, which may be involved in HRQL impairment.12,13

The effects of standard respiratory medication (ie, different combinations of oral and inhaled bronchodilators and antiinflammatory drugs) on HRQL in patients with stable COPD are controversial. Although positive results on HRQL have been obtained with long-acting β^sub 2^-adrenergic agonists,14 long-acting anticholinergic drugs,15 and inhaled corticosteroids,16 there is evidence that the use of multiple drugs is associated with poorer quality of life in COPD patients.17

AM3 is a commercially available immunomodulator with a low toxicity profile. Its active ingredient is a polysaccharide/protein compound purified from Candida utilis. AM3 has been shown to recover and normalize the phagocytic deficits of polymorphonuclear cells and macrophages, and to correct the lytic activity of natural killer cells in patients with stable COPD.18 Clinical studies19,20 have shown the efficacy of AM3 as a vaccine adjuvant in both healthy and immunocompromised subjects. This article reports a randomized, double-blind, placebo-controlled, clinical trial to assess the effects of AM3 treatment on exacerbation frequency and HRQL in stable COPD patients receiving standard respiratory medication.

MATERIALS AND METHODS

Study Design

The aims of this double-blind, controlled study were to determine the effect of AM3 on the prevention of exacerbations of COPD in patients receiving treatment with standard respiratory medication over a 6-month period, and to assess the impact of treatment with AM3 on HRQL, as measured by the St. George's Respiratory Questionnaire (SGRQ). It was estimated that a sample size of 360 patients would be needed to detect a significant reduction of 20% in the number of exacerbations at the 95% significance level with 80% power. The recruited patients were assigned to receive either 3 g/d (1 g tid) AM3 or a placebo, both administered orally, for 180 days. The study had a random four-block design. Exacerbations were defined as having at least two of the following: worsening productive cough, increasing production of purulent sputum, or increasing dyspnea.

The trial was approved by the clinical research ethics committees of all the participating centers. All patients gave their written, informed consent to be included.

Patients

COPD patients, both smokers and ex-smokers (at least 20 pack- years), were recruited at the outpatient departments of 21 hospitals during the vear 2000. All recruited patients had chronic, irreversible airflow limitation defined as an FEV^sub 1^ of 35 to 70% of the predicted value, and an FEV^sub 1^/FVC ratio < 70%. Patients with salbutamol (200 g) response showing an FEV^sub 1^ > 15% and > 200 mL were excluded. At least two episodes of acute respiratory exacerbation during the previous year were required for inclusion. All patients were clinically stable and had no history of infection or exacerbation of their illness in the 4 weeks prior to the trial.

Patients with bronchiectasias, active pulmonary tuberculosis, lung cancer, cancer of any other organ, cystic fibrosis, restrictive lung disease, heart failure (New York Heart Association functional class ≥ III), advanced kidney failure (serum creatinine > 4 mg/ dL), or uncompensated liver disease (Child-Pugh stage B or C) were excluded. Patients receiving treatment with immunosuppressors, immunomodulators. cimetidine, or any other drug that might modify the immune response were also excluded, as were those treated with systemic corticoids in the 2 weeks prior to the study.

Throughout the study, all patients received conventional respiratory medication (bronehodilators, antiinflammatory agents, oxygen therapy, etc.) for their underlying condition as their physicians saw fit. Inhaled steroids were administered equivalent to ≤ 800 g/d of budesonide. Systemic corticosteroids were administered in cases of exacerbation for no longer than 2 weeks at a time.

At the time of inclusion, the nutritional status of all patients was determined by calculating body mass index (BMI). All patients underwent forced spirometry before and after bronchodilation with salbutamol, arterial blood gas analysis, chest radiography, and an ECG, and all completed the SGRQ. At the end of the study, the BMIs were calculated again, the spirometry test was retaken, and the SGRQ completed once more. Patients attended scheduled monthly visits during which investigators recorded the incidence of exacerbations and the possible appearance of adverse effects of AM3 treatment. Patients were also instructed to contact the researchers by telephone if they had exacerbation symptoms.

Determination of HRQL

HRQL was measured using the validated Spanish version of the SGRQ.21 This questionnaire, specific for respiratory disease, contains 76 questions that collect information on three components: the frequency and severity of respiratory symptoms (symptoms), activities caused by or limited by dyspnea (activity), and changes in social and psychosocial functions caused by the disease (impact). The scores for each component and the total score are based on a 0 to 100 scale (from no effect to maximum deterioration). Therefore, any reduction in SGRQ score reflects an improvement in HRQL. The variation in score required for a minimum clinical difference to be accepted has been established as four points.22

Statistical Analysis

Intragroup comparisons of the numberof exacerbations and SGRQ scores (symptoms, activity, impact, and total score) were performed using the Wilcoxon paired-sample test. The nonparametric Mann- Whitney U test was used for intergroup comparisons. Proportions were compared using χ^sup 2^ test. Significance was set at p < 0.05.

RESULTS

Population

A total of 360 patients entered the study. After randomization, 16 patients dropped out, leaving 344 patients in the two study arms (176 in the AM3 arm and 168 in the placebo arm). No significant differences were seen in the number of patients of either arm who eventually abandoned the trial (42 in the AM3 arm and 43 in the placebo arm). In the AM3 arm, 20 patients failed to undergo the final analysis through voluntary abandonment, and 22 for clinical reasons (including the appearance of possible adverse effects), whereas 24 patients abandoned voluntarily and 19 failed for clinical reasons in the placebo group (Fig 1).

FIGURE 1. Study outline

No significant differences were seen in the baseline demographic characteristics of the patients of either study arm (ie, with respect to the 253 patients who completed the study) [Table 1]. The mean age of the population was 67.6 years (SD, 8.1 years); 92.9% of the patients were men. The mean FEV^sub 1^ percentage of predicted was 48.8% (SD, 10.3%) for the placebo group and 50.2% (SD, 10.1%) for the AM3 group. Patients were classified as Global Initiative for Chronic Obstructive Lung Disease stage II (FEV^sub 1^ percentage of predicted ≥ 50 to < 80%; n = 63 in the AM3 arm and n = 50 in the placebo group) or stage III (FEV^sub 1^ percentage of predicted ≥ 30 to < 50%; n = 69 in the AM3 arm and n = 71 in the placebo group). Nearly all patients (92.3%) received at least one respiratory medication for COPD: 83.4% received β^sub 2^- adrenergic agonists, 66.0% received inhaled steroids, and 62.8% received anticholinergic agents; 38.3% of medicated patients received all three treatments. Theophyllines were also prescribed for 26.5%. No significant differences were seen in the medication prescribed to patients in the two arms of the trial; patient medication did not change significantly during the study period.

Table 1-Demographic and Clinical Characteristics of the Patients Studied*

Table 3-Baseline and Final Evaluation of Patients*

The number of acute exacerbations during the study was lower in both groups compared to the previous year, although there were no significant differences between the median exacerbation rates in the two study arms during the 6 months of treatment (0.82 episodes per patient in the AM3 group vs 0.84 in the placebo group). However, the number of subjects in the AM3 arm that remained free from exacerbations was greater than that in the placebo group, although these differences again just failed to show significance (p = 0.11) [Table 2]. No significant modifications to FEV^sub 1^ or BMI were seen in either the AM3- or placebo-treated groups at 6 months (Table 3).

Table 2-Exacerbations During the 6-Month Treatment Period*

Table 4-Reduction in SGRQ and Symptoms Scores at 6 Months (Compared to Baseline) for Both Groups

Change in HRQL in COPD Patients

No significant differences were seen in the baseline HRQL of patients in either study arm, as determined by the SGRQ. The baseline SGRQ total score and the baseline scores for its three components were similar for the patients of both study arms (Table 3). After 6 months of treatment, the SGRQ total scores for the AM3 and placebo groups were significantly different at 32.9 and 37.5 (p < 0.05), respectively. The improvement in HRQL of the AM3-treated patients was greater than that experienced by the placebo-treated patients (the SGRQ total score was down by 8.9 points in the AM3 group, compared to 5.6 points in the placebo group [p = 0.076]). Analysis of the different SGRQ components showed the improvement in symptoms to be significantly greater (p < 0.05) for the AM3 group than for the placebo group (Table 4). AM3 patients also showed more strongly reduced impact and activity scores than those in the placebo arm, but the differences were not significant.

The effect of AM3 and placebo treatment on HRQL was also determined after stratifying patients according to their respiratory medication. Among patients receiving one or more respiratory drugs, baseline total SGRQ scores were not significantly different between the treatment arms (41.4 [SD, 15.5] in the AM3 group, compared to 43.6 [SD, 17.8] in the placebo group). However, the SGRQ score in the AM3 group was significantly lower than that of the placebo group at the end of the study for patients receiving one or more concomitant drugs (21.1% vs 15.8%, p < 0.05) [Table 5]. We next examined the impact of AM3 on the SGRQ score with respect to individual drugs. Notably, AM3 markedly improved the SGRQ score of patients receiving inhaled steroids: 87 patients in the AM3 arm had a 21.5% improvement, compared to 10.3% for the 80 patients in the placebo group (p < 0.05).

The safety profiles were similar for both study arms. Neither the percentage of patients with adverse reactions nor the number of adverse reactions were significantly different (p = 0.59) [Table 6].

DISCUSSION

In this randomized, double-blind, placebo-controlled, clinical trial, AM3 treatment improved the HRQL of COPD patients treated with standard respiratory medications. The clinical impact of AM3 on HRQL was additive or synergic to the effects of established treatments for GOPD, particularly that involving inhaled corticosteroids. The beneficial effect of AM3 on the symptoms score, which is directly related to clinical manifestations of the disease, was particularly noticeable. Patient tolerance to AM3 was excellent; no important adverse effects were recorded, in agreement with that recorded in unrelated clinical studies.18-20 These results on the impact of AM3 on HRQL were obtained in patients with moderate or severe COPD (Global Initiative for Chronic Obstructive Lung Disease stages II and III), a clinically and epidemiologically important subgroup of patients. Future studies will determine whether patients with very severe disease (FEV^sub 1^ < 35%) can also benefit from AM3 treatment.

Table 5-Effect of Respiratory Medication on the Reduction of SGRQ Scores in Both Treatment Groups*

Table 6-Treatment-Related Adverse Events*

The pharmacologic treatment of COPD has reached a point where different pathogenic mechanisms can be somewhat ameliorated. The control of airway inflammation, of the functional phenomena associated with the hypersecretion of mucus, and of the increased contractility of bronchial smooth muscle now achieves clinical benefits.23 It is well established that long-acting β^sub 2^- adrenergic agonists and long-acting anticholinergic agents improve the HRQL in COPD patients, as determined by the SGRQ.12-13 It has also been found that inhaled steroids can delay the progression of HRQL impairment in COPD patients.24 However, it is clear that the medical treatment of this disease needs to be optimized.25 Attempts to definitively modify the natural history of the disease, other than smoking cessation, have not been as successful as expected. The improvement of HRQL in COPD patients is therefore still a therapeutic goal. Interestingly, the beneficial effect of AM3 was particularly remarkable in patients receiving inhaled steroids as part of their usual respiratory medication. It has been demonstrated that inhaled steroids have poor antimflammatory effects on stable COPD.26 This corticosteroid resistance has been related to increased oxidative stress and peroxynitrite formation, which reduces the antiinflammatory action of corticosteroids.27 It has been shown28 that AM3 inhibits inducible nitric oxide synthetase in response to inflammatory signals. This might play a role in the marked improvement of HRQL in COPD patients treated with inhaled steroids. In the present trial, we also found an improvement in SGRQ scores in the placebo group: this has been observed by other authors and might be due to the frequent and close follow-up of the patients during the study.5

Treatment with AM3 failed to lead to a reduction in the number of exacerbations. Studies45 have demonstrated that longer periods of observation are required for any effect on the number of exacerbations to be seen. Only a nonsignificant trend toward a higher number of patients free of exacerbations during the 6-month follow-up was observed. This lack of statistical significance in the reduction of exacerbations in the AM3-treated group might be due to the number of patients studied being smaller than expected (only 253 of 360 patients entered completed study). We cannot exclude, however, that this nonsignificant reduction in exacerbations observed in the AM3 group might be involved in the demonstrated improvement in HRQL. If confirmed in larger studies, this could mean that AM3 may prevent exacerbations in patients with mild disease, who usually have infrequent exacerbations. To evaluate the possible effect of AM3 in preventing exacerbations in patients with severe disease would require larger populations and extended follow-up times.

According to the present results, the effect of AM3 on HRQL cannot be explained by a reduction in exacerbations. In contrast, Spencer et al7 report that the beneficial effect of inhaled corticosteroids on HRQL of COPD patients is largely due to their effect on exacerbation frequency. However, there was a small effect of the treatment on HRQL that was independent of its effect on exacerbations. This could be due to the pharmacologic effect of the drug per se. Similarly, the impact on HRQL induced by AM3 treatment may be related to its immunomodulatory and antimflammatory effect, independent of any impact on exacerbation frequency.

Several pathogenic mechanisms appear to be involved in the impairment of HRQL in COPD patients. COPD-relat\ed lung inflammation has been associated with immune system disturbances, which may play an important role in the predisposition of patients to infectious and noninfectious exacerbations.29 These immune alterations are also thought to be involved in the maintenance and progression of bronchial inflammatory lesions and in the impairment in lung function.30,31 It is recognized that COPD is also associated with a systemic inflammatory response, identified by the increased serum levels of proinflammatory cytokines and disturbances in peripheral blood immune cell subsets. This systemic inflammatory stage might be also involved in the impairment of HRLQ in these patients. The beneficial effects of AM3 on HRQL might be due to its wide range of effects on the immune system. We have recently reported that in COPD patients, AM3 activates and normalizes the effector functions of the neutrophils, monocytes, and natural killer cells involved in defense against bacteria and viruses.18 AM3 is also able to inhibit the production of proinflammatory cytokines, particularly tumor necrosis factor-α.32 These antiinflammatory effects of AM3 might be involved in the observed improvement of HRQL, and might explain the impressive impact of AM3 treatment on the SGRQ symptoms score. Among the noninfectious mechanisms triggering inflammation in COPD patients, the strenuous demand and functional disturbance of the respiratory muscles has been implicated in the generation of systemic inflammation, negatively affecting HRLQ.33 In this regard, AM3 has been shown to protect against muscle damage induced by strenuous demand in players of competitive sport.34 This protective effect might also occur in COPD patients and be involved in the improvement of HRQL.

The pharmacologic treatment of COPD remains a therapeutic goal. The present work shows that AM3 is able to improve HRQL in COPD patients (as determined by SGRQ), and to improve the results obtained with respiratory medication, particularly inhaled corticosteroids.

* From the Department of Medicine (Dr. Alvarez-Mon), CSIC R&D Associated Unit, Hospital Prncipe de Asturias, Alcal University, Alcal de Henares, Madrid; Respiratory Department (Dr. Miravitlles), Hospital Clinic (IDIBAPS), Barcelona; Respiratory Department (Dr. Morera), Hospital German Trias i Pujol, Badalona; Respiratory Department (Dr. Callol), Hospital Central de la Defensa, Complutense University, Madrid; and Respiratory Department (Dr. Alvarez-Sala), Hospital Clnico San Carlos, Complutense University, Madrid, Spain.

ACKNOWLEDGMENT: The authors thank Dr. A. de la Hera for editorial and scientific review of the article, and Dr. F. Ruis tor statistical assistance.

REFERENCES

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3 Donaldson GC, Seemungal TAR, Bhowmik A, et al. Relationship between exacerbations frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002; 57:847-852

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5 Miravitlles M, Ferrer M, Pont A, et al, for the IMPAC Study Group. Effect of exacerbations on quality of life in patients with chronic obstructive pulmonary disease: a 2-year follow-up study. Thorax 2004; 59:387-395

6 Jones PW, Willits LR, Burge PS, et al. Disease severity and the effect of fluticasone propionate on chronic obstructive pulmonary disease exacerbations. Eur Respir J 2003; 21: 68-73

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11 Agusti AG, Noguera A, Sauleda J, et al. Systemic effects of chronic obstructive pulmonary disease. Eur Respir J 2003; 21:347- 360

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15 Brusasco V, Hodder R, Miravitlles M, et al. Health outcomes following six months treatment with once daily tiotropium compared to twice daily salmeterol in patients with COPD. Thorax 2003; 58:399- 404

16 Spencer S, Calverley PM, Sherwood Burge P, et al. Health status deterioration in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 163:122-128

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18 Prieto A, Reyes E, Bernstein ED, et al. Defective natural killer and phagocytic activities in chronic obstructive pulmonary disease are restored by glycophosphopeptical (Inmunoferon). Am J Respir Crit Care Med 2001; 163:1578-1583

19 Sanchez L, Pea E, Civantos A, et al. AM3, an adjuvant to hepatitis B revaccination in non-responder healthy persons [letter]. J Hepatol 1995; 22:119-121

20 Perez-Garcia R, Perez-Garcia A, Verbeelen D, et al. AM3 (Inmunoferon) as an adjuvant to hepatitis B vaccination in hemodialysis patients. Kidney Int 2002; 61:1845-1852

21 Ferrer M, Alonso J, Prieto L, et al. Validity and reliability of the St George's Respiratory Questionnaire after adaptation to a different language and culture: the Spanish example. Eur Respir J 1996; 9:1160-1166

22 Jones PW. Interpreting thresholds for a clinically significant change in health status in asthma and COPD. Eur Respir J 2002; 19:398-404

23 Barnes P. Medical progress: chronic obstructive pulmonary disease. N Engl J Med 2000; 343:269-280

24 Burge PS, Calverley PMA, Jones PW, et al. Randomized, 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

25 de Miguel Diez J, Izquierdo Alonso JL, Rodriguez Gonzlez-Moro JM, et al. Drug treatment of chronic obstructive pulmonary disease on two levels of patient care: degree of compliance with recommended protocols [in Spanish]. Arch Bronconeumol 2003; 39:195-202

26 Culpitt SV, Maziak W, Loukidis S, et al. Effect of high dose inhaled steroid on cells, cytokines, and proteases in induced sputum in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 160:1635-1639

27 Barnes PJ, Ito K, Adcock MA. Hypothesis: corticosteroid resistance in chronic obstructive pulmonary disease; inactivation of histone deacerylase. Lancet 2004; 363:731-733

28 Majano P, Brieva A, Alonso-Lebrero JL, et al. Modulation of inducible nitric oxide synthase (iNOS) expression by Inmunoferon in an endotoxemic model in rats [abstract]. J Hepatol 2002; 36(suppl 1):72-73

29 Hill AT, Campbell EJ, Hill SL, et al. Association between airway bacterial load and markers of airway inflammation in patients with stable chronic bronchitis. Am J Med 2000; 109:288-295

30 Soler N, Ewig S, Torres A, et al. Airway inflammation and bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease. Eur Respir J 1999; 14:1015-1022

31 Wilkinson TMA, Patel IS, Wilks M, et al. Airway bacterial load and FEV^sub 1^ decline in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 167: 1090-1095

32 Brieva A, Guerrero A, Pivel JP. Inmunoferon, a glycoconjugate of natural origin, regulates the liver response to inflammation and inhibits TNF-α production by an HPA axisdependent mechanism. Int Immunopharmacol 2002; 2:807-813

33 Vassilakopoulos T, Katsaounou P, Karatza MH, et al. Strenuous resistive breathing induces plasma cytokines: role of antioxidants and monocytes. Am J Respir Crit Care Med 2002; 166:1572-1578

34 Cordova A, Martin F, Reyes E, et al. AM3 an immunomodulator, protects competitive sports players from muscular damage [abstract]. Arthritis Rheum 2001; 44(suppl 9):353

Melchor Alvarez-Mon, MD, PhD; Marc Miravitlles, MD, PhD; Josep Morera, MD, PhD; Luis Callol, MD, PhD; and Jos L. Alvarez-Sala, MD, PhD[dagger]

[dagger] See Appendix for a complete list of study participants.

All data acquisition and analysis was completed under the direction of Melchor Alvarez-Mon, MD PhD at the Department of Medicine, Alcal University.

This study was funded by I.F. Cantabria.

Manuscript received July 9, 2004; revision accepted October 26, 2004.

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

Correspondence to: Melchor Alvarez-Mon, MD, PhD, Departmento de Medicina, Universidad de Alcal, Carretera Madrid-Barcelona, Km 33,600, E-28871 Alcal de Henares (Madrid), Spain; e-mail: mams@t\sat.es

APPENDIX

The following persons and institutions participated in this work: Dr. M. Calle (Hospital Clnico San Carlos, Madrid), Dr. A. Garca de Cabo (Hospital Carlos III, Madrid), Dr. A. Valencia (Hospital Carlos Haya, Mlaga), Dr. J. R. Rodrguez (Hospital Clinico Universitario, Santiago de Compostela), Dr. T. Montemayor, Dr. F. Ortega (Hospital Universitario Yirgen del Rocio, Sevilla), Dr. M. Rosales (Hospital Clinico Universitario Virgen de la Victoria, Mlaga). Dr. J. Barrio (Hospital Comarcal Sierrallana, Santander), Dr. J. Lamela, Dr. P. Marcos (Hospital Cristal Pior, Orense). Dr. S. Romero (Hospital General de Alicante), Dr. J. Calvo, Dr. F. Pascual, Dr. M. A. Palma (Hospital la Inmaculada, Almeria), Dr. R. lvarez-Sala (Hospital Universitario La Paz, Madrid), Dr. A. Cceres, Dr. F. J. Garca, Dr. E. Prez (Hospital La Princesa, Madrid), Dr. J. M. Cifrian, Dr. E. Briz (Hospital Marqus de Valdecilla, Santander), Dr. A. Arnedillo (Hospital Puerta del Mar, Cdiz), Dr. L. Borderas (Hospital San Jorge, Huesca), Dr. L. de Teresa (Hospital San Vicente, Alicante), Dr. J. De Miguel (Hospital Universitario de Getafe, Madrid), Dr. J. Muoz (Hospital de Valme, Sevilla).

Copyright American College of Chest Physicians Apr 2005

Source: Chest

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