EFFECTS OF THEOPHYLLINE ON AIRWAY EOSINOPHILS

To the Editor :

I read with interest the recent article by Lim and colleagues that demonstrates in 15 mild stable asthmatics a significant effect of low-dose theophylline as monotherapy on airway eosinophilia, but not on exhaled nitric oxide or bronchial hyperresponsiveness to methacholine (1). These findings are similar to those of Leckie and coworkers, who observed that a marked reduction in airway eosinophilia with a monoclonal antibody to interleukin-5 was not associated with any significant effect on the late asthmatic response or on airway hyperresponsiveness to histamine challenge, questioning the relevance of airway eosinophils as a therapeutic marker (2).

A more relevant question than using theophylline as monotherapy, is whether theophylline has added antiinflammatory effects on top of a low-dose inhaled corticosteroid in patients with mild to moderate persistent asthma. In a recent study of 24 mild to moderate asthmatics using a randomized threeway crossover design, the use of 20 mg of zafirlukast twice daily but not 200-300 mg of theophylline twice daily in combination with 50 µg of HFA-beclomethasone twice daily, produced significant improvements in airway hyperresponsiveness to methacholine, exhaled nitric oxide, FEF_25-75, and peak flow, as compared with beclomethasone monotherapy (3). As bronchial hyperresponsiveness is fundamental to the underlying pathophysiology of asthma, one has to question the role of theophylline on its own or in combination with low-dose inhaled corticosteroid in patients with persistent asthma, especially as there are also several potential drug interactions and the need for therapeutic drug monitoring.

University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland

1. Lim S, Tomita K, Carramori G, Jatakanon A, Oliver B, Keller A, Adcock I, Chung KF, Barnes PJ. Low-dose theophylline reduces eosinophilic inflammation but not exhaled nitric oxide in mild asthma. Am J Respir Crit Care Med 2001; 164: 273-276 [Abstract/Free Full Text].

2. Leckie MJ, ten Brinke A, Khan J, Diamant Z, O'Connor BJ, Walls CM, Mathur AK, Cowley HC, Chung KF, Djukanovic R, et al . . Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000; 356: 2144-2148 [Medline].

3. Fowler SJ, Dempsey OJ, Wilson AM, Lipworth BJ. Effects of adding either a leukotriene receptor antagonist or theophylline to a low or medium dose of inhaled corticosteroid in patients with persistent asthma. J Allergy Clin Immunol 2001; 107: S266-S267 .

From the Authors:

We thank Dr. Lipworth for his comments regarding the effects of theophylline as described in our recent paper (1). He raises two separate issues. First, theophylline as monotherapy: Dr. Lipworth compares the theophylline study to that of our other study of a monoclonal antibody to interleukin-5. The mechanisms of action of these agents are so different that it is difficult to conclude as he does. Theophylline, on the other hand, reduces allergn-induced eosinophil infiltration in the airways (2), and possesses immunomodulatory effects (3, 4).

Second, Dr. Lipworth raises the issue of theophylline as additive therapy to inhaled corticosteroids. We note Dr. Lipworth's preliminary results of his comparative study of zafirlukast versus theophylline added to low dose inhaled beclomethasone. We and others have previously reported several studies that demonstrate additive effects of low-dose theophylline to moderate-to-high dose inhaled corticosteroid therapy, in terms of peak flow and FEV₁ (2, 5-7). We do not understand why this study did not show any effects of added theophylline, unless a mild population of asthmatics that may not need any additional therapies was studied, or that the number of patients were too few. We look forward to seeing his study reported in full.

Even if theophylline had few effects on bronchial hyperresponsiveness or exhaled nitric oxide, it remains a useful additive agent to medium- to high-dose inhaled corticosteroid therapy in persistent asthma, as we have demonstrated. The mechanisms of action of theophylline, despite being in clinical use for more than 60 years, remain unclear, but it is likely to interact with corticosteroids to enhance its molecular effects (8). One disadvantage of theophylline is its relatively low potency, hence the need for a more potent theophylline derivative and for unravelling its mode of action. Using low-dose theophylline obviates the need for therapeutic drug monitoring and reduces potential drug interactions, which limits the clinical use of theophylline at previously used "therapeutic" doses.

National Heart & Lung Institute, Imperial College, London, United Kingdom

1. Lim S, Tomita K, Carramori G, Jatakanon A, Oliver B, Keller A, Adcock I, Chung KF, Barnes PJ. Low-dose theophylline reduces eosinophilic inflammation but not exhaled nitric oxide in mild asthma. Am J Respir Crit Care Med 2001; 164: 273-276 .

2. Sullivan P, Bekir S, Jaffar Z, Page C, Jeffrey P, Costello J. Anti-inflammatory effects of low-dose oral theophylline in atopic asthma. Lancet 1994; 343: 1006-1008 [Medline].

3. Kidney J, Dominguez M, Taylor PM, Rose M, Chung KF, Barnes PJ. Immunomodulation by theophylline in asthma. Demonstration by withdrawal of therapy. Am J Respir Crit Care Med 1995; 151: 1907-1914 [Abstract].

4. Jaffar ZH, Sullivan P, Page C, Costello J. Low-dose theophylline modulates T-lymphocyte activation in allergen-challenged asthmatics. Eur Respir J 1996; 9: 456-462 [Abstract].

5. Ukena D, Harnest U, Sakalauskas R, Magyar P, Vetter N, Steffen H, et al . . Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma. Eur Respir J 1997; 10: 2754-2760 [Abstract].

6. Evans DJ, Taylor DA, Zetterstrom O, Chung KF, O'Connor BJ, Barnes PJ. Theophylline plus low dose inhaled steroid is as effective as high dose inhaled steroid in the control of asthma. N Eng J Med 1997; 337: 1412-1418 [Abstract/Free Full Text].

7. Lim S, Jatakanon A, Gordon D, Macdonald C, Chung KF, Barnes PJ. Comparison of high dose inhaled steroids, low dose inhaled steroids plus low dose theophylline, and low dose inhaled steroids alone in chronic asthma in general practice. Thorax 2000; 55: 837-841 [Abstract/Free Full Text].

8. Ito K, Lim S, Adcock IM, Caramori G, Keller A, Barnes PJ. Effect of low dose theophylline on histone deacetylase activity in patients with mild asthma. Am J Respir Crit Care Med 2000; 161: A614 .