Treatment of aspirin-intolerant asthma with antileukotrienes.

Abstract

Intolerance to aspirin and related nonsteroidal antiinflammatory drugs (NSAIDs) is a significant clinical problem among subjects with asthma (reviewed in References 1 and 2). Aspirin-intolerant asthmatics often suffer from a particularly severe form of asthma (2). Characteristically, in adult life the subjects develop chronic rhinosinusitis and recurrent polyposis, asthma, and intolerance to aspirin-like drugs. Ingestion of NSAIDs precipitates acute bronchoconstriction, which is often severe and persistent. Extrapulmonary symptoms such as nasal congestion, ocular injection, flush, heat rash, perspiration, and occasionally gastrointestinal symptoms may accompany the airway obstruction, in isolation or in combination. In severe cases the reaction can progress into shock and respiratory arrest. While there are no in vitro tests available for routine clinical diagnosis, the lysine-aspirin bronchoprovocation introduced by Bianco and coworkers (3), has proven useful in identifying aspirin-intolerant patients with asthma. In a prospective comparative study the lysine-aspirin bronchoprovocation was found to be as sensitive as the oral provocation with respect to detection of airway obstruction (4). In that study, 22 consecutive patients with a history and/or clinical findings (asthma, rhinorrhea, nasal polyposis) suggestive of aspirin intolerance were challenged by both routes at least 2 wk apart. Ten of the subjects developed significant bronchoconstriction (≥ 20% drop in forced expiratory volume in 1 s [FEV 1 ]) during either challenge, with the same absolute sensitivity for both tests (9 of 10). The bronchial provocations evoked reactions that developed more promptly, were limited to the airways, caused a lesser degree of airway obstruction, and were more easily reversed. The differences in challenge methods are summarized in Table 1. In 19 aspirin-tolerant control subjects with the same baseline pulmonary function, inhalation of lysine-aspirin caused no significant changes in FEV 1 , supporting the specificity of the test. Although the oral administration is necessary for detection and investigation of extrapulmonary reactions, the bronchial challenge has characteristics supporting it as the first choice both in routine clinical practice and in mechanistic investigations. For the latter purpose, safety aspects and high repeatability (5) provide a considerable advantage over the oral challenge, particularly because a significant proportion of aspirin-intolerant individuals with asthma suffer from severe asthma. The time course of an inhalation challenge with lysine-aspirin is exemplified in Figure 1. It is well established that cyclooxygenase inhibition is central in the chain of events leading to aspirin-elicited reactions (1). Plasma concentrations of acetylsalicylic acid (ASA), measured at the time of reaction following oral provocations, are of the magnitude (3-30 μM) (6) that has been established to inhibit cyclooxygenases in various test systems (7). Salicylic acid (SA), the main metabolite of ASA, is found at much higher concentrations (20-250 μM) (6). However, SA is not responsible for the intolerance reactions, because provocations with sodium salicylate with commonly used doses (0.5-1.0 g) yield much higher plasma concentrations of SA that are tolerated by NSAID-sensitive individuals (6).