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Dr. Bernstein is Clinical Professor of Medicine and Environmental Health Sciences, University of Cincinnati.
Correspondence to: I. Leonard Bernstein, MD, Clinical Professor of Medicine and Environmental Health Sciences, University of Cincinnati, 231 Bethesda Ave, M.L. 0563, Cincinnati, OH 45267-0563; e-mail: bernstil{at}email.uc.edu
Despite the significant contributions of inhaled synthetic sympathomimetic agonists to the therapeutic armamentarium of asthma, the benefit/risk ratio of these agents evoked controversy throughout the last half of the 20th century. Concern about possible serious adverse effects first emerged from the United Kingdom, Australia, and New Zealand in the mid-1960s, when a sudden increase in asthma mortality was attributed to overuse of a short-acting, dose-fortified formulation of isoproterenol.1 A recurrent rise in mortality occurring a decade later in New Zealand appeared to be associated specifically with regular use of inhaled fenoterol, a more selective, relatively short-acting ß2-agonist (SABA).2 A Canadian retrospective case-control analysis3 of pressurized SABAs in patients with asthma suggested that increased asthma mortality was not necessarily due to fenoterol alone but also occurred after overuse of any pressurized SABA of the same class. A subsequent meta-analysis4 of six similar surveys not only failed to confirm this conclusion but found that mortality was increased to a slight extent only in patients who used nebulized SABAs on a regular basis. Although this first generation controversy vis-à-vis SABAs and mortality still engenders debate, the current consensus about mortality attributed to SABAs is most likely based on overdosage and/or abuse by poorly controlled patients.
The first-generation epidemiologic controversies stimulated more intensive exploration of the nonbronchodilator activities of SABAs and also long-acting ß2-agonists (LABAs) soon after they became available. The interactive effects of these agents and their respective enantiomers have been studied extensively, utilizing in vitro assays of isolated smooth muscle, purified cells, cloned ß2 receptors, intracytoplasmic signaling cascades, and gene transcription.5 6 Such investigations have revealed a complex and often contradictory array of biological activities that encompass both proinflammatory and anti-inflammatory properties. As examples of anti-inflammatory effects, ß2-agonists are known to attenuate release of mediators from mast cells, suppress airway smooth-muscle growth, and inhibit the function of immunocompetent lymphocytes.7 8 9 By contrast, proinflammatory effects of these agents include suppression of interleukin-12 production in antigen-presenting cells, intensification of the T-helper type 2 immune response, augmentation of eosinophil survival, and enhancement of the late allergic response.10 11 12 SABAs may also favor the synthesis of receptors associated with neurogenic inflammation that could play a role in the phenomenon of increased airway hyperresponsiveness (AHR) that has been noted after long-term use of these agents.6
The ambivalent characteristics of SABAs in the early 1990s set the stage for the current second-generation controversy concerning whether proinflammatory or anti-inflammatory properties of LABAs would determine the overall pharmacodynamics of these agents. Indeed, the early concerns about LABAs were particularly relevant, inasmuch as the lipophilic nature of these agents would enable them to partition into the outer phospholipid layer of cell membranes, where they have better access to receptors and downstream signaling cascades. Fortunately, down-regulation of ß2-agonist receptors on smooth muscle was not clinically relevant, presumably because of their overabundant distribution and relative refractoriness to tachyphylaxis in this tissue site.
Ultimately, the balance between salutary and adverse effects of both SABAs and LABAs must be evaluated in vivo by well-controlled clinical investigations in asthmatic patients. Such effects have been assessed by two clinical designs: (1) laboratory-based allergen challenges, and (2) double-blinded, placebo- controlled trials of efficacy and safety. In the allergen challenge experiments, markers of inflammation included bronchial secretions and biopsy specimens while long-term clinical studies focused chiefly on indexes of AHR, as measured by dose-response effects on airway caliber induced by histamine, methacholine, or adenosine monophosphate (AMP), and exhalation of nitrogen oxide (ENO).
Because a number of clinical studies in the mid-1980s and early 1990s demonstrated that regular use of SABAs increased AHR and actually worsened asthma control, guidelines of asthma management recommended against the regular use of these agents.13 14 When LABAs became available, similar concerns were initially expressed. Indeed, several early clinical trials15 16 reported that either short-term or long-term use of LABAs dampened the ß2-agonist protective effect against methacholine-induced bronchoconstriction without evidence of smooth-muscle tachyphylaxis. However, more recent studies17 18 demonstrated that the LABA-induced protective effect against AHR was unimpaired after relatively long-term, continuous use of LABAs without evidence of a rebound effect after cessation of therapy. These discordant results have been ascribed to patient-specific differences in sensitivity to the deleterious effects of bronchodilators, variability of allergic status among patient groups, or a masking activity of ß2-agonists.19 The latter effect might occur because these agents inhibit only the early allergic response and might exacerbate the ongoing inflammation associated with the late allergic response.
An experimental basis for these hypotheses was supported by several allergen challenge studies. Most compelling was an investigation that demonstrated not only an increase of tolerance against the ß2-agonist protective effects on allergen-induced bronchoconstriction but also an increase in nonspecific AHR after regular use of an SABA.12 It was postulated that this phenomenon was due to down-regulation of mast cell ß2 receptors with subsequent enhanced release of mediators from these cells. Consistent with this explanation is the fact that ß2-agonist–induced tolerance against AMP bronchoconstriction, an in vivo surrogate of mast cell-mediator release, is more pronounced than the corresponding effect on methacholine challenge.20 Subsequently, several other allergen challenge experiments utilizing a spectrum of inflammatory markers in BAL and bronchial biopsies failed to show a consistent pattern of proinflammatory effects due to LABAs.21 22 Yet another dimension to this controversy occurred when a clinical study23 comparing addition of a LABA (salmeterol) to a higher dose of inhaled glucocorticosteroid revealed a greater improvement in symptoms after the addition of the LABA. Similar clinical results were obtained in other independent trials.24 Mechanistically, the clinical efficacy of combined use of inhaled LABAs and glucocorticosteroids has been attributed to some of the previously cited anti-inflammatory effects of LABAs, modulation of airway sensory nerves by LABAs, mutual complementary effects of LABAs and glucocorticosteroids, or reciprocal reversal of the deleterious effects of each agent.6
The apparent paradoxical data emanating from controlled laboratory challenges and long-term effects on clinical responses with or without concomitant glucocorticosteroids poses a dilemma for the primary care health professional. This is compounded by the fact that these studies are often based on variable experimental designs that may not have predetermined statistical power. In an attempt to resolve this controversy, Prieto et al (see page 798 in this issue of CHEST) performed a 6-week, controlled (placebo vs salmeterol) study that utilized a well-defined allergic phenotype of mild asthma (ie, pollen sensitive asthmatics), a well-defined exposure period (ie, a grass pollen season), direct and indirect measures of AHR (ie, methacholine and AMP), and ENO as a marker of airway inflammation.25 Airway caliber (FEV1), AHR indexes (methacholine, AMP) and ENO were measured before the administration of salmeterol or placebo and at midseason. Concurrent glucocorticosteroids were not permitted to avoid the confounding effects of these agents. As expected, patients receiving salmeterol experienced significant protection against a fall in FEV1 during the height of the allergy season, as compared to placebo. Under natural allergen exposure conditions, a significant increase in methacholine-induced AHR was observed only in the placebo group, while patients receiving salmeterol exhibited a small, insignificant increase. This result emphasizes the difference between natural exposure and a single experimental allergen challenge that was found to induce a greater increase in AHR. Particularly striking was a failure to detect a significant difference in AMP-induced AHR between salmeterol-treated and placebo-treated patients when they were challenged with this agent during the height of the pollen season. Since the AMP indirect challenge reflects bronchoconstriction caused by mast cell mediators, long-term salmeterol did not attenuate the chronic effects of mediators during the season and therefore did not function as an anti-inflammatory agent. Finally, ENO levels were increased in both treatment arms during the height of the pollen season, but there was neither an augmentative nor inhibitory effect in the salmeterol group. Taken together, these data, accumulated after long-term administration of salmeterol in pollen-allergic asthmatic patients during a well-defined period of seasonal exposure to pollen, confirm the safety profile of LABAs with respect to possible inflammatory or increased AHR effects. At the same time, however, based on the AMP challenge and the ENO results, the data also indicate that long-term use of an LABA alone will not provide a clinically effective anti-inflammatory effect. As the authors stipulate, possible mitigating variables, such as the time interval between the last dose of medication and pulmonary measurements, ß2-agonist polymorphisms, or the complementary effects of inhaled glucocorticosteroid, were not fully addressed and may warrant further investigation. Nevertheless, this study reinforces the postulate that clinical management paradigms should be based on evidence derived from trials that closely simulate the natural course of disease.
References
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