Inhaled Glucocorticoids and Acute Asthma
Therapeutic Breakthrough or Nonspecific Effect?

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If ever there was a magic potion that should resolve the symptoms of an affliction, it is the use of glucocorticoids in asthma. Since their first clinical application, there has been uniform agreement that the anti-inflammatory activities of the corticosteroids make them ideal agents to stabilize this disease during periods of increasing symptoms. So ingrained is this tenet that to suggest otherwise is nothing short of heresy. Unfortunately, such faith has its downside, and it has led practitioners of all stripes into an intellectual trap. The problem is that the unquestionably favorable effects seen with steroids in the chronic and subacute phases of this illness have produced expectations that have been inappropriately extended to emergency situations; and it is here that our beliefs have been battered. Despite almost half a century of clinical use, and intense research, such fundamental issues as the quantities of glucocorticoids required to induce a rapid remission, the existence of dose-response effects, and the patient populations likely to require, or respond, to this therapy in emergency situations remain areas of considerable uncertainty. Equally disappointing, the literature is replete with claim and counterclaim of alleged benefits that have subsequently failed to withstand critical examination (1). Everyone accepts that the drugs work, but as investigator after investigator has discovered, little in medicine has proven more difficult to establish than the utility of corticosteroids in acute asthma (1).

When viewed from this background, the findings of Rodrigo and Rodrigo (2) in the present issue of the Journal are noteworthy. These investigators report for the first time that inhaled steroids speed the resolution of acute bronchoconstriction. Their study incorporated a randomized, double-blind protocol in which 1 mg of flunisolide and 400 µg of salbutamol were administered every 10 min for 3 h. The control arm consisted of salbutamol and a placebo. At the end of 90 min of treatment, and throughout the remainder of the period of observation, the flunisolide group had better lung function. The PEFR was approximately 50 L/min higher, and somewhat later, the between-group variance in the FEV₁ reached 0.3 L. These effects represent about a 20% improvement over the ₂ agonist alone. The dose of flunisolide was quite large (18 mg), but the study design was flawless, the number of subjects appropriate (n = 94), and the results straightforword.

On the surface, these observations appear to set the stage for a therapeutic breakthrough, and this may ultimately prove to be the case; however, because so many investigators, including Rodrigo and Rodrigo (3), have unsuccessfully attempted to find such events using other routes of administration (1), a critical reflection seems to be in order. The reliability of the data in the study under review is not in question, just their ultimate interpretation. The issues that need to be addressed for future reference are whether the speed of onset and the size of the response derive from a primary action of flunisolide on the cellular and immunologic factors producing the airway narrowing in asthma, or whether they represent a nonspecific generic phenomenon common to topical steroids in general.

The available data demonstrate that the benefits of glucocorticoids are slow to develop and require a minimum of 6 to 12 h to be manifest in acute situations (1, 4). Neither the routes of administration, the quantities of glucocorticoids used, nor the agents employed have made any differences in outcome. Although it is true that a great deal of flunisolide was applied directly to the tracheobronchial tree by Rodrigo and Rodrigo (2), these two factors (dose and delivery per se) are unlikely to account for the results, if the findings of previous studies (1), and/or the current model of steroid activity in asthma are correct (5). (As will be discussed subsequently, the absolute dose of flunisolide may be important, but not in the context of interfering with the immunopathologic aspects of asthma.) Infused steroids have not produced the results recorded herein, yet this route provides quite rapid delivery to the site of need. Glucocorticoids can be detected in bronchoalveolar lavage fluid within a few minutes of intravenous instillation (6), and truly enormous doses have been given in carefully designed studies without showing the short-term effects (1, 7) seen by Rodrigo and Rodrigo (2).

The reasons for the gradual onset of activity is likely related to the fact that the mechanism of action of corticosteroids requires ligand-dependent activation of glucocorticoid receptor transcriptional functions (5). The initial cellular interaction is likely to be immediate, but the ultimate expressions of the desired physiologic, or therapeutic, consequences lag long behind because of the need to induce and secrete new proteins. On activation by the steroid, the cytosolic receptor moves into the nucleus and interacts with responsive elements on DNA which then in turn either inhibit or stimulate transcription in target genes involved in immunoregulation (5). For example, glucocorticoids inhibit the transcription of some of the interleukins (IL-1, IL-3, IL-4, IL-6, and IL-8), tumor necrosis factor-, and granulocyte-macrophage colony-stimulating factor. They also inhibit the synthesis of cytokine receptors (8) and the inducible form of nitric oxide synthase (9). Alternatively, steroids increase the expression of neural endopeptidase (10). The net effect is to reduce airway blood flow, plasma exudation, and mucus production while limiting the migration of inflammatory cells and the release of bioactive mediators. It is possible that glucocorticoids may stop such processes in relatively short order, but even if they did, the ultimate clinical expression of these activities, as determined by symptomatic improvement and the elimination of obstruction, do not occur concurrently. The attack may terminate from a molecular and biochemical standpoint, but considerable time is still required to resolve the insults to the airway that have already transpired. In approximately 20 to 30% of patients presenting for immediate care, this process can take several days (11). In the remainder, the airflow limitation disseminates quickly without the need for steroids. In contrast, although there are limited data in stable patients that suggest that large doses of inhaled agents may transiently increase pulmonary function 3 to 4 h after administration (12), it usually takes many days to weeks to show persistent improvements, even though there is less airway disorders to control (13). Given this information, it seems reasonable to ask why aerosolized glucocorticoids should then produce more rapid effects in the most pressing of circumstances?

One possibility, of course, is that the molecular and cell biology of these compounds changes as a function of the route of delivery. For the reasons listed above, this does not seem very probable. Another is that the dose used amplified a nonimmunologic anti-inflammatory event such as vasoconstriction. Several recognized areas of steroid pharmacology that are usually not factored into their effects in asthma are the inhibition of edema formation and the constriction of the microcirculation (14). Although these activities exist to a minor degree in the compounds usually given orally and parenterally (e.g., hydrocortisone, prednisolone, and dexamethasone), they are major features of the locally acting drugs (14). In fact, the intensity of skin blanching in humans after topical application is a standard tool to assess potency, as well as a means of developing site-selective glucocorticoid analogues for aerosol use (16). On a scale of relative strengths, flunisolide is approximately 330 times more active in this regard than is dexamethasone (16), and large amounts have quantitatively greater consequences than do smaller ones.

Because vascular congestion, edema formation, and plasma exudation are important pathophysiologic elements in the production of the bronchial narrowing associated with acute asthma (17), it is possible that the dose of flunisolide used caused significant vasoconstriction that modified these factors in a clinically important way. It was this effect that then produced the changes seen by Rodrigo and Rodrigo, and the transcriptional events, and their subsequent cascades, had not yet made their appearance. In this scenario, the dilatation of the bronchial smooth muscle brought about by salbutamol would have been augmented by the accelerated removal of the intraluminal and submucosal contributions to the narrowing without changing the asthmatic inflammatory milieu. Given that vasoactive compounds are known to improve lung function in asthmatics, as well as attenuate induced obstruction from a number of sources (18), this notion does not seem farfetched. Right or wrong, it can be tested by comparing the results of flunisolide to those of a nonsteroidal compound with vascular activity. If the postulate is incorrect, then a new era of treatment has begun and we reevaluate the way steroids work in asthma. If it is correct, then the search goes on for ways to assess steroid behavior in emergent situations. In either event, we have Rodrigo and Rodrigo to thank for a stimulating series of observations.

Division of Pulmonary and Critical Care Medicine
University Hospitals and the Department of Medicine
Case Western Reserve University School of Medicine
Cleveland, Ohio

	Footnotes

Correspondence and requests for reprints should be addressed to E. R. McFadden, Jr., M.D., Division of Pulmonary and Critical Care Medicine, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106-5067.

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Acknowledgments: Supported in part by Specialized Center of Research Grant HL-37117 from the National Heart, Lung, and Blood Institute and by General Clinical Research Center Grant MO1-RR0080 from the National Center for Research Resources.

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