© 2004 American Thoracic Society
Phenotypes in AsthmaUseful Guides for Therapy, Distinct Biological Processes, or Both?Department of Medicine National Jewish Center for Immunology Denver, Colorado Webster's New Collegiate Dictionary defines the word "phenotype" as "the visible properties of an organism that are produced by the interaction of genotype and the environment" (1). This definition of phenotypes would appear to be highly applicable to the various subtypes of asthma recently described. Asthma heterogeneity has long been appreciated, and over the years, a number of "visible properties" (clinical, allergic, and, more recently, pathophysiologic) have been applied to describe subtypes of asthma. Yet, by definition, these subtypes likely cannot be termed phenotypes until there is an appreciation for if and how these visible characteristics link to differences in "genetic makeup" of the patients. Further, as the definition of phenotypes suggests, "environmental stimuli" (allergens, viruses, and just as importantly, various pharmacologic agents) differentially interact with this genetic makeup of the individual to produce the clinical, immunologic, and/or pathophysiologic phenotype that we observe. Hence, a better understanding of phenotype will likely be accompanied by improved insights into the genetic and environmental factors involved with complex diseases such as asthma. In recent years, several severe asthma phenotypes have been described. However, few studies have taken the next step to evaluate their usefulness in understanding mechanistic processes associated with asthma, improving evaluation of asthma genetics, or designing specific phenotype-driven asthma therapy trials. In addition, national and international guidelines for asthma therapy generally use a "one size fits all" approach, so that phenotypic details (beyond loosely defined severity levels) are not used in treating patients (2, 3). In most instances, this approach is adequate, as commonly used asthma therapies, including corticosteroids (CS) and ß agonists, work well in the majority of patients. However, when an asthma patient reaches a specialist, it is often because the response to "commonly used asthma therapies" has not been adequate. At this point, a better understanding of the complexities of the disease and its presentation are required. Clearly, this most urgently applies to patients with severe asthma. In severe or difficult to treat asthma, several different phenotypes have been proposed, some based on clinical and physiologic parameters, others on pathology. Brittle asthma has been used to describe a subset of asthma that deteriorates catastrophically in a short period of time with or without normal lung function in between episodes (4). Aspirin-sensitive asthma, linked to an overproduction of cysteinyl leukotrienes, has long been described as a phenotype associated with severe asthma groups (5). Finally, pathologic elements have also been proposed to define asthma phenotypes. In particular, the persistence of lung eosinophils despite high dose CSs has been used to describe a phenotype of severe asthma associated with a thickened subepithelial basement membrane, certain inflammatory and physiologic markers, and risk for near fatal events (6, 7). Inasmuch as there is a subset of severe asthma with eosinophils, the opposite, i.e., no or limited evidence for eosinophils in the lungs, is also likely to exist. The presence of "non-eosinophilic asthma" has been supported by several groups (8). Although this subset has been associated with increased pulmonary neutrophils, this has not always been the case (6, 9). Focusing on the predictive value of these two pathologic subsets toward clinical outcomes, studies in milder asthma suggest these phenotypes predict (1) exacerbations that require and respond to CSs (eosinophilic phenotype) or (2) a general lack of response to CSs (neutrophilic phenotype) (9, 10). In the article by ten Brinke and colleagues published in this issue of the Journal (pp. 601–605), the authors produce further evidence that the presence of persistent sputum eosinophils in patients with severe asthma on high dose inhaled and even oral CSs predicts a favorable response to very high doses of a systemic CSs (11). The authors demonstrate that for nearly every parameter measured, improvement is seen after treatment with 120 mg of intramuscular triamcinolone. This information suggests that an attempt at measuring lung eosinophils (likely sputum-based) should be undertaken by physicians treating severe asthma, once numerous other issues, including compliance/adherence and the possibility for other diseases, have been addressed. If eosinophils are present, then a trial of higher, and probably systemic CSs, should be initiated, with the caveat that there are also substantially greater side effects from this approach to treatment. Unfortunately, a limitation of this study is that it did not comparably evaluate the effect of high dose CSs on a similar group of subjects with severe asthma without eosinophils in sputum. Therefore, it is impossible to know specifically whether the absence of an eosinophilic phenotype at baseline would have predicted a lesser response to high dose CSs. However, clinical experience at our institution (unpublished data) would suggest the response is likely to be less in the noneosinophilic phenotype. As noted, the definition of phenotype is based on the visible manifestation of genetic and environmental factors. The authors of the referenced article suggest that because the group of subjects with severe asthma with persistent eosinophils responded to high dose CSs, the concept that they are a separate "phenotype" is negated. As the definition of phenotype also involves response to environmental factors (including therapeutic agents), it is not clear why this clearly blunted response to CSs negates the concept of a different phenotype. Although these individuals responded to CSs, the doses required were dramatically higher than needed in a milder population, suggesting that poorly understood genetic (or less likely, environmental) factors are contributing to the diminished response, thereby producing the "visible" phenotypic element of eosinophilia. Clearly, the authors selected these patients from a larger group of subjects with severe asthma in whom eosinophils were not consistently present. As noted above, a comparable study of CS efficacy was not performed in these "noneosinophilic" subjects. Therefore, at this point it is not possible to suggest these patient/subjects with or without eosinophils are all part of the same pathobiological phenotype. Until further data are forthcoming, the eosinophilic "phenotype" of severe asthma should remain both a marker for differing pathobiological processes, as well as a potentially helpful clue to appropriate treatment. Further studies are required to determine whether genetic and environmental elements can now be used to better predict and define these phenotypic characteristics. FOOTNOTES Conflict of Interest Statement: S.E.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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