© 2002 American Thoracic Society
On Theophylline, Leukocytes, and Chicken SoupLeiden University Medical Center Leiden, The Netherlands Albrecht Karl Ludwig Martin Leonhard Kossel would have been pleased and surprised to see a report on theophylline for the treatment of chronic obstructive pulmonary disease (COPD) published 114 years after his presentation at the Deutsche Chemische Gesellschaft in Berlin (1). This surprise arises because Kossel witnessed the diverse use of the drug as a diuretic and an antiangina and vasodilator agent, but it was not until 1922, five years before Kossel's death, that the bronchodilator effect was described. What Kossel did not witness was the widespread use of theophylline for asthma and COPD in the second half of the 20th century nor its steady decline in use after the introduction of inhaled steroids and long-acting bronchodilators and the constant concern over side-effects (2). At some point, it seemed that the diversity of its actions proved also one of its biggest problems: a substance that can do many things but nothing really well. Over the years, 25,714 publications have appeared on theophylline, including 1,833 clinical trials. Scientifically solid and long-term trials are surprisingly rare, and the precise mechanism of action is still a matter of debate. Nevertheless, it is newsworthy and still exciting when new approaches are tested and presented (3, 4). In this context, I have read with interest the article by Culpitt and coworkers (5) in this issue of AJRCCM (pp. 1371–1376). The study follows earlier reports that demonstrated anti-inflammatory effects of low doses of theophylline in patients with asthma. In the new study, 25 patients with a diagnosis of COPD were included in a placebo-controlled, randomized, double-blind, crossover trial. Patients were treated with theophylline for 4 weeks, resulting in a serum theophylline concentration between 9 and 11 mg/L. The endpoint was fortunately not the change in lung function but rather the number of inflammatory cells in induced sputum, particularly neutrophils, and the levels of the chemokine interleukin-8, myeloperoxidase, and lactoferrin. The chemotactic response to chemoattractants such as N-formyl-methionyl-leucyl-phenylalanine was also assessed. The findings can be summarized as showing a significant decrease in the absolute numbers of inflammatory cells in sputum and a significant decrease in sputum neutrophils after theophylline. This decrease in cells was accompanied by a decrease in sputum interleukin-8 levels and a decreased chemotactic response of sputum neutrophils. Why is the article so interesting? COPD is a common disease and is believed to result from an abnormal inflammatory response where neutrophils play a significant role in long-term progression and exacerbations. Existing medications, including inhaled steroids, have not been conclusively shown to interfere with this inflammatory response (6, 7). This leaves treating physicians only the choice of intense antismoking counseling (we all know the problems), bronchodilator therapy, and the use of steroids in those known to have frequent exacerbations (2). Why is the article worth reading? It is an interesting approach, a good study design, and it is typically written as if the consequences for the long-term treatment of COPD were obvious. Is this a definite report? COPD is a heterogeneous disorder, and the 11 active smokers among subjects probably confound data interpretation because smoking itself has chronic and acute effects on neutrophils. Are data from these 25 patients sufficient to make any clinical claims? I doubt it. In planning a solid clinical trial such as this one, estimates of sample size are a bit of a gamble because we do not know what represents a clinically significant difference. What is the meaning of 800,000 less neutrophils per milliliter of sputum, and what is the relevance of 6% less neutrophils with a range of 52 to 94%? I do not know, and I do not believe that anyone does. What is worthwhile in these types of studies is that they make us think. For example, what is the mechanism of action? Is it inhibition of phosphodiesterase that would ultimately result in the elevation of cAMP in neutrophils? Then this effect might also be achieved with ß adrenoreceptor agonists and, probably more interestingly, with novel selective phosphodiesterase 4 inhibitors, targeting the neutrophil more selectively, where novel clinical data are now accumulating (8). I am sure this article will stimulate discussions, but it does not provide us with the information we yet need. Rigid studies are needed that are of the same scientific quality as the study by Culpitt and coworkers in larger number of patients and definitely over a longer period of time to provide solid advice to physicians on the role of theophylline for COPD, as they undoubtedly will not measure inflammatory markers in sputum. For longer term studies in patients with COPD and significant comorbidity, compliance and side-effects will be of great importance. In this context, I was definitely surprised that 20% of subjects complained of nausea with low-dose theophylline. We should remember that chemotaxis of neutrophils to the very same stimulus N-formyl-methionyl-leucyl-phenylalanine can be inhibited by other remedies, including chicken soup (9), which undoubtedly has potential for fewer adverse events, although in this case, long-term trials and health economic assessments are also still outstanding. The article of Culpitt and associates undoubtedly adds to the current literature and addresses the urgent clinical question of how to deal with inflammation in COPD. What the article cannot do is provide evidence that low-dose theophylline is of any clinical benefit for patients with COPD. The only way to prove that this form of treatment is clinically superior to other remedies, including chicken soup, is performing a long-term clinical trial with theophylline in COPD, something Albrecht Kossel has not yet witnessed in the 114 years since his Berlin presentation in 1888. REFERENCES
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