Abstract
The heterogeneity of asthma in relation to clinically significant outcomes, including response to treatment, has been established beyond any doubt. However, current treatment guidelines for asthma ignore disease heterogeneity and causal pathways. Extended heterogeneous disease-related metabolic, inflammatory, immunological, and remodeling pathways have been described, and a repetitive pattern is defined as a disease endotype. The response to targeted and non-targeted interventions in asthma may vary among individuals or for the same individual in relation to outcome measures (dissociated effect). Targeted treatment should be both biomarker-driven and outcome-driven. The ideal biomarker should be pathway-specific, reproducible, easily measurable, and affordable. Biomarker research in asthma is increasingly shifting from the assessment of the value of single biomarkers to multidimensional approaches, in which the clinical value of a combination of various markers is studied. Translation of biomarkers into pathway-specific diagnostic tests is essential and should guide the design of future large clinical trials, incorporating both longitudinal and mechanism-tailored endpoints. The selection of outcome measure is difficult, as it must reflect the mechanistic intervention and should be relevant for both the asthmatic population in general and the particular individual with asthma. While endotype-driven therapeutic strategies are increasingly successful, the issues of dissociated effect and drug efficacy at the target site remain unresolved. Efforts needed to move the field forward include profiling of Th2-low inflammation, incorporation of new targets, such as airway smooth muscle and epithelial components of asthma or epigenetics modifications, as well as application of systems pharmacology.
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