Severe Adult Asthmas: Integrating Clinical Features, Biology, and Therapeutics to Improve Outcomes

Abstract

Evaluation and effective management of asthma, and in particular severe asthma, remains at the core of pulmonary practice. Over the last 20–30 years, there has been increasing appreciation that “severe asthma” encompasses multiple different subgroups or phenotypes, each with differing presentations. Using clinical phenotyping, in combination with rapidly advancing molecular tools and targeted monoclonal antibodies (human knockouts), the understanding of these phenotypes, and our ability to treat them, have greatly advanced. Type-2 (T2)-high and -low severe asthmas are now easily identified. Fractional exhaled nitric oxide and blood eosinophil counts can be routinely employed in clinical settings to identify these phenotypes and predict responses to specific therapies, meeting the initial goals of precision medicine. Integration of molecular signals, biomarkers, and clinical responses to targeted therapies has enabled identification of critical molecular pathways and, in certain phenotypes, advanced them to near-endotype status. Despite these advances, little guidance is available to determine which class of biologic is appropriate for a given patient, and current “breakthrough” therapies remain expensive and even inaccessible to many patients. Many of the most severe asthmas, with and without T2-biomarker elevations, remain poorly understood and treated. Nevertheless, conceptual understanding of “the severe asthmas” has evolved dramatically in a mere 25 years, leading to dramatic improvements in the lives of many.

Immunobiology of Steroid-Unresponsive Severe Asthma

“…Persistence of elevated levels of these typical Th2 cytokines does not necessarily correlate with disease severity in SA (8). Current understanding indicates that the inflammatory phenotypes in SA can be Th2low as well as Th2-high (9)(10)(11). Inflammatory profile that is Th2-low with Th17-high responses, accompanied by dominant neutrophilia, is primarily defined for SA (11)(12)(13)(14).…”

Targeting Airway Smooth Muscle Hypertrophy in Asthma: An Approach Whose Time Has Come

“…Individuals with Th2-high asthma are described as having severe, steroid-dependent disease, and T H 2-low asthma includes the remainder of the allergic asthma group. 2 , 12 Group 2 innate lymphoid cells have a critical role in type 2 immune responses. 2 The Severe Asthma Research Program (SARP) and the Biomarkers for Prediction of Respiratory Disease Outcome (U-BIOPRED) leveraged these T H cell subgroups to characterize disease endotypes and clinical phenotypes according to the molecular mechanisms of allergic asthma.…”

Reply to Yilmaz and Çetin

“…I am delighted by the thoughtful response to my recent article ( 1 ). I believe the overall concept of defining visible and invisible sides of the iceberg is an excellent approach.…”