Inhaled Steroids and Obstructive Lung Disease, Not for Asthma Only
ABSTRACT & COMMENTARY
Synopsis: In a group of COPD patients, high-dose inhaled steroids (fluticasone 500 mg twice daily) resulted in fewer severe exacerbations, improved peak flow, spirometry, symptoms, and walking distance.
Source: Paggiaro PL, et al. Lancet 1998;351:773-780.
The concept of chronic obstructive pulmonary disease (COPD) exacerbation is one that is poorly defined and often overlaps with bronchospasm, upper and lower respiratory tract infection, and right and left heart failure. From the clinical perspective, it means patients have reduced exercise tolerance, more dyspnea, increased sputum volume, and change in sputum color. The etiology of "exacerbation" is also unclear but has recently been linked to a downward spiral resulting from the interaction between viral and bacterial infection and chronic inflammation. While inhaled corticosteroids have proven valuable in the management of asthma, the role of these drugs in treatment of COPD where asthma is not as prominent is less certain. Previous studies of oral steroids in COPD have demonstrated only limited value (< 10%) when chronic treatment is initiated. Some investigations have supported the use of intravenous corticosteroids during acute exacerbation. Other studies have shown improved FEV1 after the addition of inhaled corticosteroids to a bronchodilator regimen.1-3 Despite these reports, the use of these agents has generally not been included in most clinical practice guidelines.4
The international COPD study group now provides useful information from a randomized, double-blind, placebo-controlled trial enrolling 218 patients from 15 countries. The patients had moderate-to-severe impairment of pulmonary function and no significant asthma. To be enrolled, patients had to have evidence of the absence of significant asthma (reversibility on bronchodilator of < 15%). At the end of a run-in period, patients enrolled were assigned to either 500 mg twice daily (fluticasone) with two puffs or placebo twice daily via identical metered dose inhalers.
There were significantly fewer patients (P = 0.45) with at least one exacerbation in the fluticasone group. However, the total number of exacerbations was not significantly different. The use of fluticasone also reduced the frequency of moderate-to-severe exacerbations. Peak flows were also increased in the fluticasone group, with a mean difference of approximately 15 L per week by week 24. FEV1 and loop flow rates also improved in the treatment group. The duration of COPD, but not previous steroid use, predicted response to fluticasone. Both cough and sputum volume were also positively effected by the use of inhaled steroids over six months. A six-minute walk increased from 395 to 412 meters at the end of the treatment and was maintained at six months. In addition, breathlessness scores were also reduced. Adverse events were similar between the two groups; however, cortisol concentrations were significantly lower in inhaled steroid-treated patients. This, however, was not associated with any significant clinical effects.
COMMENT BY ALAN M. FEIN, MD
What does this study tell us? As has long been understood by clinicians and recently appreciated by scientists, there is significant overlap between the syndrome of asthma and what has been called chronic obstructive pulmonary disease (COPD). During acute exacerbations of both asthma and COPD, there is enhanced recovery of inflammatory cells and mediators including a variety of cytokines. While the specific components of airway inflammations are somewhat different between the two types of obstructive lung disease, eosinophilic infiltration, in fact, may be associated with some COPD exacerbations. The patients in the study may have had some bronchodilator response, with an average change in FEV1 of approximately 7% in both placebo and fluticasone groups. Previous studies have suggested improved pulmonary function over time when inhaled steroids were added in the COPD patients. However, the precise degree of reversibility was, in many of these studies, not standardized. The present study suggests that long-term improvement in pulmonary function symptoms and exercise performance can be expected in COPD patients who use inhaled steroids over a six-month period. Additionally, the quality of life may be improved by reducing cough and sputum production and reducing number and severity of exacerbations.
It is difficult to understand precisely the pathophysiologic basis of these changes, but they appear to be real and consistent. In addition, this study suggests that, although infection may play a significant role in many cases of exacerbation, underlying inflammation may set the stage for alterations in local host defenses, bacterial adherence, and colonization. While the changes in pulmonary function and exercise tolerance were modest, they do provide hope that the appropriate use of inhaled corticosteroids and antibiotics may result in improved quality of life for patients with advanced lung disease.
References
1. Dompeling E, et al. Ann Intern Med 1993;118:770-778.
2. Kerstjens HAM, et al. N Engl J Med 1992;327: 1413-1419.
3. Fabbri L, et al. Thorax 1993;48:817-823.
4. British Thoracic Society guidelines for the management of chronic obstructive pulmonary disease. Thorax 1997;52 (suppl 5).
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