© 2003 American Thoracic Society
Do Complex Conditions Require Complex Treatment?McMaster University Hamilton, Ontario, Canada Approximately 30 years ago, inhaled corticosteroids were introduced for the management of asthma. Since this time, there has been a great deal of original research concerning this condition (almost 70,000 published articles). Much of this research has been aimed at increasing our understanding of the underlying mechanisms giving rise to the airway dysfunction that is ultimately responsible for disability in the affected patients. Clearly, the underlying aim in this effort (by both the researchers and their sources of support) is to either eradicate the condition or at least develop treatment strategies that are superior to those currently available. In this issue of AJRCCM (pp. 50–56), Kibe and coworkers (1) have added to our understanding of the basis of the asthmatic condition by addressing which, of several, interleukin (IL)-13 induced effects on the mouse airway are sensitive to corticosteroids. An interest in IL-13 is clearly warranted, given previous observations that IL-13 is increased in asthmatic airways (2, 3) and is associated with both airway hyper-responsiveness (4, 5) and several aspects of airway remodeling (5, 6) in animal models. In the mouse airway, Kibe and coworkers observed that exogenous IL-13 induced production of the eosinophil chemokine, eotaxin, and eosinophilia were prevented by prior corticosteroid treatment. However, IL-13 induced airway hyperresponsiveness and markers of goblet cell hyperplasia were unaffected by corticosteroid treatment. This appears to be an illustration of fundamentally different mechanisms underlying downstream events after exposure of the mouse airway to IL-13. The final conclusion reached by these authors is that further investigation of the corticosteroid-resistant effects of IL-13 is called for, as this may ultimately lead to improved management of the patient with asthma. This conclusion is in keeping with what I believe to be our underlying aim in asthma research—improving patient management. Care must be taken in the interpretation of this study, which at first glance apparently demonstrates potential limitations in the efficacy of corticosteroid therapy. Although the authors are no doubt correct that corticosteroid treatment can suppress only a limited number of IL-13–mediated events, there are several sources that suggest that corticosteroids may prevent the increase in IL-13 observed in patients with asthma. Prednisolone treatment reduces levels of IL-13 messenger RNA levels in airway biopsies from patients with asthma (7), and dexamethsone suppresses release of IL-13 from a variety of inflammatory cells including mast cells and monocytes (8, 9). This evidence may make the findings of Kibe and coworkers, despite being scientifically correct, clinically irrelevant (i.e., if corticosteroids can prevent increases in IL-13, does it really matter whether they can also suppress downstream effects?). The suggestion of Kibe and coworkers (1) to perform further research to uncover the mechanisms of IL-13-mediated effects is at first glance entirely logical. If, through the use of animal models and clinical research, we can determine all the mechanisms underlying asthmatic and other allergic conditions, then presumably we should be able to prevent them all, achieving our ultimate goal of either curing the disease or at least optimizing therapy. In light of increasing evidence supporting the effectiveness of inhaled steroids, however, at some point we need to address to what extent new, complicated, specific mechanism-based treatments will benefit the patient with asthma. Inhaled corticosteroid treatment is highly efficacious in reducing the burden of disease in patients with asthma, particularly when used in more severe cases in conjunction with long-acting ß-agonists (10). Moreover, there is recent evidence that the efficacy can be improved when corticosteroid treatment is introduced early in the course of the disease (11). Although it is difficult to put a number to it, a strong argument can be made that most of the current burden of asthma (both to the individual patient and to society) could be eliminated if currently available therapy could be provided to all those who need it, and used correctly by them, once it is provided. Although I am not suggesting that the type of research done by Dr. Kibe and coworkers is not appropriate (indeed, I am actively involved in similar lines of research), I believe that we need to be more aware that a possibly more difficult task than developing new and improved therapy for asthma will be to ensure that it is delivered to and received by all the patients who need it. If a method could be found to deliver inhaled corticosteroids, with or without additional therapy, to all those who require them, then this would likely achieve a level of effectiveness in asthma therapy that requires no bettering. Although finding such a method would not be easy (low-level nebulization in shopping malls would likely meet more public opposition than fluoride in drinking water), it may ultimately prove more cost-effective than developing new therapies. REFERENCES
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