Clinical entities, phenotypes, causation, and endotypes based on selected asthma publications.

Patients with complex chronic disorders, such as asthma, present clinicians with important management problems. The identification of a clinical syndrome usually leads to the diagnosis of the disease entity. The next concern involves classification and a choice as to whether to use a few inclusive categories or multiple exclusive categories. Patients with asthma have multiple clinical syndromes, and these can be described as phenotypes. The use of cluster analysis allows investigators to identify phenotypes with less clinical bias. However, the identification of a particular phenotype does not necessarily provide much insight into the underlying pathogenesis. In asthma, the pathogenetic events are complex and multiple and require a classification based on endotypes. This difficulty introduces the idea of causation and models for causation. Asthma probably does not have a single universal necessary cause. However, it does have multiple sufficient component causes. Understanding these components and their interactions potentially leads to better treatment trials and more focused drug therapy. Clinicians need to identify asthmatic patients and classify them into particular phenotypes; they should also wonder about causation. Clinical investigators need to use these phenotypes to identify more homogenous groups of patients to study the underlying pathogenesis and establish endotypes. Focusing on causation can improve our understanding of disease entities, disease classification, and disease causation. This review outlines ideas relevant to causation in nearly all diseases.