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Severe asthma and its phenotypes

Sally E. Wenzel, MD
University of Pittsburgh Medical Center NW
Pittsburgh, PA, United States

Asthma has long been appreciated to be a heterogeneous disease, but the identification of specific phenotypes has been difficult. Severe asthma represents a group of patients with an extreme form of the disease where phenotype characterization may be easier. Additionally, severe asthma itself is likely to be more heterogeneous than milder asthma. Approaches to identifying phenotypes of severe asthma have ranged from biased clinical impressions to searches for biomarkers to relatively unbiased statistical approaches. Perhaps surprisingly, there is considerable overlap among the approaches.

One of the earliest attempts at phenotyping of asthma was the breakdown into allergic/extrinsic and intrinsic (less allergic) forms of asthma. Although this fell out of favor years ago, recent studies have strongly supported a very similar approach based on age at onset of disease. Similar to the previous differentiation, early onset disease (before the age of 12) represents a very homogeneous, highly atopic/allergic phenotype. This phenotype represents the large majority of all asthmatics, but perhaps only 50-60% of severe asthmatics. This early onset, allergic phenotype has been identified using both biased and unbiased approaches. In this subgroup, there appears to be a strong relationship between genetics, duration of disease and additional “hits” in determining the progression of the disease.

In contrast, later onset asthma (12 or older) represents a much more heterogeneous group of asthmatics. These groups of asthmatics are surprisingly more likely to be severe asthmatics and less likely to be allergic/atopic. These individuals range from women with an age at onset around the time of menopause, to aspirin sensitive asthmatics to post infectious, as well as allergic and occupational asthmatics.

The inflammatory process associated with each of these phenotypes differs, with increasing severity of early onset disease associated with increasing neutrophilic inflammation. In contrast, the inflammatory pattern in late onset disease may help to identify specific phenotypes, less dependent on severity. While these distinct immuno-inflammatory phenotypes help to identify specific groups of patients which do, in fact, appear to respond differently to different therapies, it is likely that some commonalities exist as well. Whether these underlying similarities will tie in the common themes of airway reversibility, obstruction and bronchial hyperresponsiveness remain to be determined.

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