[en] BACKGROUND: The precise mechanism of action of theophylline in asthma is not fully understood but recent data have drawn attention to its potential anti-inflammatory effect. OBJECTIVE: The purpose of this study was to assess the effect of theophylline on sputum eosinophilia and sputum eosinophil chemotactic activity in steroid-naive asthmatics. METHOD: We performed a 4-week randomized double-blind, placebo-controlled, parallel group study in 21 mild to moderate steroid-naive asthmatics whose sputum eosinophilia was found twice > 5% during the run in period. Eleven subjects received 600 mg/24 h theophylline for the first 2 weeks and 900 mg/24 h for the last 2 weeks while 10 subjects took a placebo for 4 weeks. Sputum was induced after 2 and 4 weeks of treatment and 1 week after stopping the treatment. The sputum samples were compared for their cell counts, eosinophil cationic protein (ECP) levels and eosinophil chemotactic activity using micro-Boyden chambers. RESULTS: Serum theophylline concentrations reached 7 and 11 microg/mL at V3 and V4, respectively. Intragroup comparisons showed that theophylline, but not placebo, caused a significant reduction in sputum eosinophil counts at V3 (62 +/- 10% from baseline, P < 0.01) and a strong trend at V4 (67 +/- 16% from baseline, P = 0.07) when compared to baseline. The intergroup difference obtained after comparing the area under the curve over the 4 week treatment period only approached the statistical significance (P = 0.08). At baseline the fluid phase of the sputum contained a significant eosinophil chemotactic activity which was inhibited after a 4-week treatment by theophylline (P < 0. 01) but not by placebo. The mean sputum theophylline levels after 4 weeks of treament (1.7 microg/mL) was lower than that required to cause significant inhibition of eosinophil chemotaxis in vitro. CONCLUSION: Theophylline decreases the natural sputum eosinophil chemotactic activity present in asthmatics. However, when using a small sample size, the 35% reduction in sputum eosinophilia achieved by theophylline failed to reach statistical significance when compared to that seen after placebo.
Disciplines :
Cardiovascular & respiratory systems
Author, co-author :
Louis, Renaud ; Université de Liège - ULiège > Département des sciences cliniques > Pneumologie - Allergologie
Bettiol, J.
Cataldo, Didier ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement - Département des sciences biomédicales et précliniques
Sele, Jocelyne ; Centre Hospitalier Universitaire de Liège - CHU > Pneumologie-Allergologie
1 Weinberger M, Hendeles L. Theophylline in asthma. N Engl J 1996; 334:1380-8.
2 Piafsky KM, Ogilvie RI. Dosage of theophylline in bronchial asthma. N Engl J Med 1975; 292:1218-22.
3 Aubier M, De Troyer A, Sampson M, Macklem PT, Roussos C. Aminophylline improves diaphragmatic contractility. N Engl J Med 1981; 305:249-52.
4 Barnes PJ, Pauwels RA. Theophylline in the management of asthma: time for reappraisal? Eur Respir J 1994; 7:579-91.
5 Djukanovic R, Roche W, Wilson J, Beasley R, Twentymann O, Howarth P et al. Mucosal inflammation in asthma. Am Rev Respir Dis 1990; 142:434-57.
6 Gleich G. The eosinophil in asthma: current understanding. J Allergy Clin Immunol 1990; 85:422-36.
7 Adelroth E, Barnes N, Chung K, Davies R, Poulter L. Drug Trials. Eur Respir J 1998; 11 (Suppl.) 26:36-8.
8 Pauwels R, van Renterghem D, Van der Straeten M, Johannsson N, Persson CGA. The effect of theophylline and enprofylline on allergen-induced bronchoconstriction. J Allergy Clin Immunol 1985; 76:583-90.
9 Mapp C, Boshetto P, Dal Veccho L, Crescioli S, de Marzo N, Paleari D et al. Protective effect of anti-asthma drugs on late asthmatic reactions and increased airway responsiveness induced by toluene diisocyanate in sensitized subjects. Am Rev Respir Dis 1987; 136:1403-7.
10 Crescioli S, Spinazzi A, Plebani M, Pozzani M, Mapp C, Boschetto P et al. Theophylline inhibits early and late asthmatic reactions induced by allergens in asthmatic subjects. Ann Allergy 1991; 66:245-51.
12 Sullivan P, Bekir S, Jaffar Z, Page C, Jeffery P, Costello J. Anti-inflammatory effects of low-dose oral theophylline in asthma. Lancet 1994; 343:1006-8.
13 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; 151:1907-14.
14 Finnerty JP, Lee C, Wilson S, Madden J, Djukanovic R, Holgate ST. Effects of theophylline on inflammatory cells and cytokines in asthmatic subjects: a placebo-controlled parallel group study. Eur Respir J 1996; 9:1672-7.
15 Pin I, Gibson R, Kolendowicz A, Girgis-Gabardo Denburg J, Hargreave F et al. Use of induced sputum cell counts to investigate airway inflammation in asthma. Thorax 1992; 47:25-9.
16 Fahy J, Liu J, Wong H, Boushey H. Cellular and biochemical analysis of induced sputum from asthmatic and from healthy subjects. Am Rev Respir Dis 1993; 147:1126-31.
17 Kips J, Fahy J, Hargreave F, Ind P, in't Veen J. Methods for sputum induction and analysis of induced sputum: a method for assessing airway inflammation in asthma. Eur Respir J 1998; 11 (Suppl.) 26:9-12.
18 Louis R, Shute J, Biaggi S, Stanciu L, Marelli F, Tenor H et al. Cell infiltration, ICAM-1 expression and eosinophil chemotactic activity in asthmatic sputum. Am J Respir Crit Care Med 1997; 155:466-72.
19 Jolley M, Stroupe S, Schwenzer Wang C, Lu-Steffes Hill D, Popelka S, Holen J, Kelso D. Fluoresence polarization immunoassay (FPIA) for theophylline; clinical correlation and reagent stability. Clin Chem 1981; 27:1575-9.
20 Cockcroft DW, Killian DN, Mellon JJ, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy 1977; 7:235-43.
21 Louis R, Bury Th, Corhay JL, Radermecker M. No increase in plasma histamine during PAF-induced airway obstruction in allergic asthmatics. Chest 1993; 104:806-10.
22 Hatzelmann A, Tenor H, Schudt C. Differential effects of nonselective and selective phosphodiesterase inhibitors on human eosinophil function. Br J Pharmacol 1995; 114:821-31.
23 Claman D, Boushey H, Liu J, Wong H, Fahy J. Analysis of induced sputum to examine the effects of prednisone on airway inflammation in asthmatic subjects. J Allergy Clin Immunol 1994; 94:861-9.
24 Reed C, Offord K, Nelson H, Li J, Tinkelman D and the American Academy of Allergy, Asthma and Immunology BeclomethasoneDipropionate-Theophylline Study Group. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild to moderate asthma. J Allergy Clin Immunol 1998; 101:14-23.
25 Tenor H, Hatzelman A, Church M, Schudt C, Shute J. Effects of theophylline and rolipram on leukotriene C4 (LTC4) synthesis and chemotaxis of human eosinophils from normal and atopic subjects. Br J Pharmacol 1996; 118:1727-35.
26 Kraft M, Torwick J, Trudeau J, Wenzel S, Martin R. Theophylline: potential anti-inflammatory effects in nocturnal asthma. J Allergy Clin Immunol 1996; 97:1242-6.
27 Ohta K, Sawamoto S, Nakajima M, Kubota S, Tanaka Y, Miyasaka T et al. The prolonged survival of human eosinophils with interleukin-5 and its inhibition by theophylline via apoptosis. Clin Exp Allergy 1996; 26:10-5.
28 Efthimiadis A, Pizzichini M, Pizzichini E, Dolovich J, Hargreave F. Induced sputum cell and fluid-phase indices of inflammation: comparison of treatment with dithiothreitol vs phosphate-buffered saline. Eur Respir J 1997; 10:1336-40.
29 Louis R, Shute J, Goldring Perks B, Lau LCK, Radermecker M, Djukanovic R. The effect of processing on inflammatory markers in induced sputum. Eur Respir J 1999; 13:660-7.
30 Dutoit J, Salome C, Woolcock A. Inhaled corticosteroids reduce the severity of bronchial hyperresponssiveness in asthma but oral theophylline does not. Am Rev Respir Dis 1987; 136:1174-8.
31 Kirby J, Hargreave F, Gleich J, O'Byrne P. Bronchoalveolar cell profiles in asthmatic and non asthmatic subjects. Am Rev Respir Dis 1987; 136:379-83.
32 Wardlaw A, Dunnette S, Gleich G, Collins J, Kay B. Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma. Am Rev Respir Dis 1988; 137:62-9.
33 Fergusson A, Wong H. Bronchial hyperresponsiveness in asthmatic children: correlation with macrophages and eosinophils in bronchoalveolar lavage fluid. Chest 1989; 96:988-91.
34 Crimi E, Spanavello A, Neri M, Ind P, Rossi G, Brusasco V. Dissociation between airway inflammation and airway hyperresponsiveness in allergic asthma. Am J Respir Crit Care Med 1998; 157:4-9.
35 Gibson P, Denburg J, Dolovich J, Ramsdale E. Chronic cough: eosinophilic bronchitis without asthma. Lancet 1989; 1:1346-8.
36 Louis E, Louis R, Shute J, Lau L, Franchimont D, Lamproye A et al. Bronchial eosinophilic infiltration in Crohn's disease in the absence of pulmonary disease. Clin Exp Allergy 1999; 29:660-7.
37 Uchida D, Ackerman S, Coyle A, Larsen G, Weller P, Freed J et al. The effect of human eosinophil granule major basic protein on airway responsiveness in the rat in vivo. A comparison with polycations. Am Rev Respir Dis 1993; 147:982-8.
38 Fahy J, Boushey H. Effect of low-dose beclomethasone dipropionate on asthma control and airway inflammation. Eur Respir J 1998; 11:240-1247.