Needs for Systems Approaches to Better Treat Individuals With Severe Asthma: Predicting Phenotypes and Responses to Treatments

Abstract

Asthma is a frequent heterogeneous multifactorial chronic disease whose severe forms remain largely uncontrolled despite the availability of many drugs and educational therapy. Several phenotypes and endotypes of severe asthma have been described over the last two decades. Typical type-2-immunity-driven asthma remains the most frequent phenotype, and several targeted therapies have been developed and are now available. On the contrary, non-type-2 immunity-driven severe asthma is less understood and still requires efficient innovative therapies. A personalized approach would allow improving asthma control with the help of robust biomarkers able to predict phenotypes/endotypes, exacerbations, response to targeted treatments and, in the future, possible curative options. Some data from large multicenter cohorts have emerged in recent years, especially in transcriptomics. These data have to be integrated and reproduced longitudinally to provide a systems approach for asthma care. In this focused review, the needs for such an approach and the available data will be reviewed as well as the next steps for achieving personalized medicine in asthma.

Keywords: 4P medicine; asthma; biologics; omics sciences; system medicine; type 2 inflammation.

Figure 1

Systems medicine approach for asthma.

Figure 2

Current paradigm of asthma endotypes and related therapies. (A) Eosinophilic asthma is depicted as the most current clinical presentation. Driven by Th2 cytokines (IL-5, IL-4, IL-13), eosinophils chronically infiltrate bronchi and cause bronchial remodeling. Many biotherapies targeting those pathways (red-circled star) have been developed in recent decades. (B) Non-eosinophilic asthma physiopathology is poorly understood. Immune cells (mostly neutrophils and Th1 lymphocytes), cytokines (IL-17A and related molecules) and the immune pathway (inflammasome) seem to be involved, though their precise role remains unclear, restraining the development therapeutic drug targets (orange-circled star). Bronchial smooth muscle is an important therapeutic non-drug target because of bronchial thermoplasty (green-circled star). Subepithelial inflammatory cytokines (alarmins such as IL-33, IL-25, and TSLP) are of growing interest in both endotypes since they are far upstream of the inflammatory cascade (yellow-circled star).

Figure 3

Algorithm for asthma management from primary care to the asthma clinic inspired by the 2018 GINA recommendations, “From difficult to treat to severe asthma.” ICS, inhaled corticosteroids; LABA, long-acting beta agonist; OCS, oral corticosteroids.

Figure 4

In the past, asthma was considered a single disease. Treatment was centered only on obtaining control. Today, asthma care, especially for severe asthmatic patients, takes into account phenotypes and endotypes in treatment decisions. The future for asthma care is an integrative approach with a personalized profile leading to specific care.