Precision medicine for the discovery of treatable mechanisms in severe asthma

Abstract

Although the complex disease of asthma has been defined as being heterogeneous, the extent of its endophenotypes remains unclear. The pharmacological approach to initiating treatment has, until recently, been based on disease control and severity.The introduction of antibody therapies targeting the Type 2 inflammation pathway for patients with severe asthma has resulted in the recognition of an allergic and an eosinophilic phenotype, which are not mutually exclusive. Concomitantly, molecular phenotyping based on a transcriptomic analysis of bronchial epithelial and sputum cells has identified a Type 2 high inflammation cluster characterized by eosinophilia and recurrent exacerbations, as well as Type 2 low clusters linked with IL-6 trans-signalling, interferon pathways, inflammasome activation and mitochondrial oxidative phosphorylation pathways. Systems biology approaches are establishing the links between these pathways or mechanisms, and clinical and physiologic features.Validation of these pathways contributes to defining endotypes and treatable mechanisms. Precision medicine approaches are necessary to link treatable mechanisms with treatable traits and biomarkers derived from clinical, physiologic and inflammatory features of clinical phenotypes. The deep molecular phenotyping of airway samples along with noninvasive biomarkers linked to bioinformatic and machine learning techniques will enable the rapid detection of molecular mechanisms that transgresses beyond the concept of treatable traits. K E Y W O R D Seosinophilic asthma, precision medicine, severe asthma, systems biology

Progress in understanding hypersensitivity reactions to nonsteroidal anti‐inflammatory drugs

“…The elucidation of the genetic variants associated with NSAIDs hypersensitivity could help us prevent and evaluate potential risks through genetic testing, guiding precision medicine. 29,[173][174][175] However, despite recent advances, including high-throughput sequencing technologies development, individual predisposing factors remain unknown. 176 In addition to the difficulties to shed light on the genetics of complex diseases, another important drawback in NSAIDs hypersensitivity is the heterogeneity of phenotypes, and potential differences in their definition.…”

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

“…Another perspective from omics sciences is the rising concept of "treatable mechanisms" to replace phenotypes. Indeed, omics sciences have highlighted numerous up-or downregulated pathways that represent potential robust biomarkers bearing enough precision necessary for 4P medicine to better model asthma and provide "care and cure" at the level of a single patient and thus move from dissociated fingerprints to integrative handprints (Figures 1, 4) (99,100). Though, one must bear in mind that omic (i.e., molecular phenotype) approach provide association between phenotype and molecular pathways.…”

Management of Severe ARDS: New Strategies and Ongoing Challenges

“…ARDS, as defined by the Berlin criteria, 16 is a heterogeneous syndrome, and each patient is a unique case. Personalized or precision medicine is expanding in multiple domains of medicine, [17][18][19] including the identification of ARDS subphenotypes that may respond differently to treatments. 20 Another theoretical example is the recent re-analysis of the ART trial, 21 identified with cluster analysis.…”