In the first article, Huang and coworkers [1] describe a carefully performed double-blind, placebo-controlled study that shows convincingly that during the first 48 hours after hospitalization for asthma, theophylline, when added to albuterol and methylprednisolone, produces more rapid and sustained improvement in airflow rates than the same regimen lacking theophylline.

In the second, Shannon [2] describes theophylline overdose in 249 consecutive patients referred to the Massachusetts Poison Control System with a peak serum theophylline concentration of 167 µmol/L (30 mg/L) or greater to identify risk factors for major toxicity. In this select population, major toxicity occurred in 62 patients and caused death in 13. It is important to note that 37% of the patients with toxicity had been inadvertently overmedicated while receiving long-term theophylline therapy and that major toxicity was more common in this group than in those with acute (presumably intentional) overdosage. Although the study shows that peak level is the most important risk factor for major toxicity in acute overdosage, advancing age is the most critical factor in chronic overdosage. The study design does not allow investigation of the reasons for this disparity, but the findings indicate that different patient populations have clinically important variability in response to theophylline administration. In the important subset of older patients who are receiving theophylline for management of chronic asthma, toxicity can be inadvertent and serious. Shannon also cites previous evidence that up to 21% of patients receiving long-term theophylline therapy may have at least some toxic manifestations. In fact, the long-standing controversy over theophylline use has centered not only on the question of its effectiveness when compared with other, more modern drugs but also on its narrow therapeutic range.

There is no dearth of data indicating that theophylline is a relatively weak bronchodilator when compared with ß₂-agonists and inhaled ipratropium bromide. Even in combination with other bronchodilators, some studies have suggested that the addition of theophylline increases side effects without improving bronchodilatation [3]. Although these studies appear to be valid, concentrating on bronchodilatation alone may be a too-restrictive assessment of theophylline, which has multiple actions.

In order to come to rational conclusions regarding the use of theophylline, we must examine exactly what we are trying to accomplish in light of a new understanding of the pathophysiology of the disease and our current understanding of the actions of theophylline. Asthma is now viewed as a series of separate but inter-related pathophysiologic steps consisting of acute asthmatic reaction, late asthmatic reaction, and nonspecific bronchial hyper-reactivity. Clinically, chronic asthma is a combination of all three of these steps. The acute asthmatic reaction depends on preformed and rapidly synthesized mediators elaborated and released by mast cells. Degranulation of mast cells initiates arachidonic acid metabolism and the generation of leukotrienes and prostaglandins. Mast cell mediators cause bronchospasm, increased vascular permeability, mucus hyper secretion, and autonomic activation. Acute asthmatic reactions are anaphylactic phenomena that occur rapidly in response to inhaled antigens and dissipate within 1 to 3 hours. Inflammation, defined as the accumulation of inflammatory cells and their products, is not a feature of the acute asthmatic reaction. Pretreatment of asthmatic patients with ß₂-agonists can block an acute asthmatic reaction, but pretreatment with steroids cannot [4].

Approximately half of the patients experiencing an acute asthmatic reaction develop a late asthmatic reaction within 3 to 4 hours. The connection between acute asthmatic reaction and late asthmatic reaction most likely occurs through the chemotactic effects of mediators released at the time of mast cell degranulation. Bronchoalveolar lavage studies and transbronchial biopsies, done in asthmatic patients during quiescent and active phases of the disease, have greatly enhanced our knowledge about the inflammatory process. These studies have shown that the late asthmatic reaction is characterized by accumulation and activation of inflammatory cells including eosinophils, lymphocytes, pulmonary alveolar macrophages, and polymorphonuclear leukocytes. Activation of these cells leads to the release of a myriad of cytokines as well as bronchoactive and vasoactive substances. Chemotactic and cell adhesive agents released by pulmonary alveolar macrophages, eosinophils, and mast cells magnify and sustain the inflammatory character of the late asthmatic reaction. In fact, chronic asthma, even in its mild form, is probably characterized by persistent inflammation.

Although bronchospasm is a clinical manifestation of both the acute and the late asthmatic reaction, the effects of inflammation dominate the pathophysiology of the late asthmatic reaction [5]. Chronic inflammatory activity damages the respiratory epithelium and causes sloughing of sheets of ciliated epithelium into the bronchial lumen. The damage is primarily caused by the release of major basic protein by degranulating eosinophils. In persons with chronic asthma, recurrent episodes of inflammation cause peribronchial fibrosis [6], which has previously been described as thickening of the basement membrane. Chronic bronchial narrowing caused by this fibrosis magnifies the intermittent exacerbations of bronchospasm in chronic asthma because minor degrees of change in the luminal radius can have substantial effects on resistance to airflow. Any therapeutic agent that interferes with inflammation or promotes bronchodilatation is likely to be helpful in the late asthmatic reaction. Denuding of the respiratory epithelial surface appears to contribute to the development of bronchial hyper-reactivity by several possible, but poorly understood mechanisms. A postulated but unproven bronchodilating effect of epithelium-derived relaxing factor may be lost when the respiratory surface is disrupted. In addition, irritation of subepithelial neural plexuses may play a role.

Theophylline appears to have several types of activity against asthma, but the most obvious is its primary bronchodilating effect. This appears to be a direct effect on bronchial smooth muscle, although the way in which it is achieved is not known; older theories regarding phosphodiesterase inhibition have been discarded for lack of scientific support.

A growing body of evidence indicates that theophylline also has anti-inflammatory actions in addition to its bronchodilating effects. The suppression of activity of a broad range of inflammatory cells by theophylline administration is of considerable interest but is as yet poorly understood.

The role of theophylline as an immunomodulator has recently received increasing attention because of the obvious importance of T-cell activity in the release of cytokines [7]. These substances play a pivotal role in the attraction, activation, and persistence of eosinophils and other participants in the inflammatory process such as neutrophils [8]. In fact, the number of eosinophils found in bronchoalveolar lavage fluid of asthmatics correlates with the severity of symptoms, the level of bronchospasm, and the degree of bronchial hyper-reactivity [9, 10]. The finding that slow-release theophylline increases suppressor T-cell counts in the peripheral blood of antigen-challenged asthmatics suggests such an immunomodulator effect.

Finally, the effectiveness of theophylline depends on how it is given, because of the chronobiology of asthma [11]. It is now well established that there is a diurnal variation in bronchial tone, with the lowest flow rates occurring in early morning, around 4 a.m., and the highest occurring in late afternoon, around 4 p.m. These changes in bronchial tone appear to be due to circadian rhythms in epinephrine, adenosine monophosphate, histamine, cortisol, and vagal tone as well as other possible factors. Sustained-release theophylline has been shown to be superior to a long-acting ß₂-agonist in the management of nocturnal asthma.

Taking all this information into account, how should theophylline be used? Currently, it seems clear that theophylline should not be a first-line drug for treatment of very mild, intermittent asthma because the acute asthmatic reaction is most effectively managed by more powerful and rapidly acting ß₂-agonists. Conversely, suppression of inflammatory precursors of the late asthmatic reaction is best achieved by administration of inhaled steroids. In more severe asthma, there appears to be an increasing role for the use of theophylline that is supported by most of the current literature. Particularly in patients with nocturnal symptoms, long-term theophylline therapy has a clear role in amelioration of the disease process. Despite the lack of evidence that theophylline provides bronchodilator advantage in the emergency room setting, the study by Huang and coworkers [1] lends credence to the concept that hospitalized patients benefit from early administration of the drug. Because advancing age increases the likelihood of toxicity, theophylline should be used with care in elderly patients and should be accompanied by frequent measurements of blood levels (even in the apparently stable patient). Although it is obvious that the role of theophylline has changed with better understanding of the drug and better understanding of asthma, the multiple actions of theophylline make it useful in a way the more specific drugs are not. As better drugs become available to control the inflammatory pathways that lead to chronic asthma, we can expect that the role of theophylline will shift, but for the moment, it continues to be a valuable drug with toxicity that can be avoided with appropriate attention to blood levels and careful choice of patients to whom it is administered.