title: Asthma Was Talking, But We Weren't Listening. Missed or Ignored Signals That Have Slowed Treatment Progress.
abstract: The discovery that eosinophilia and steroid responsiveness are dominant signals in patients with asthma led to the conclusion that inflammation characterized by up-regulation of the type 2 cytokines that mediate eosinophilia (IL -4, -5, and -13) (type 2 inflammation) is central to asthma pathogenesis in all patients and resulted in a singular emphasis on animal models of type 2 inflammation to unravel disease mechanisms. This in turn led to great progress in identifying drug targets and in developing inhibitors of type 2 inflammation. Despite this significant and clinically important progress, there has been a growing body of evidence that airway type 2 inflammation is not a ubiquitous pathologic feature of asthma and a growing acceptance that the type 2-centric asthma paradigm has held back understanding of mechanisms of disease in patients who do not have type 2 inflammation (helper T-cell type 2 [Th2]-low asthma). This "tyranny of the dominant paradigm" effect means that asthma clinicians have no effective controller treatments to offer their many patients with Th2-low asthma. It also means that asthma researchers are struggling to understand the mechanisms of disease that operate in Th2-low asthma and how these mechanisms might be modeled in vitro and in vivo to identify novel drug targets and provide a broader range of asthma treatments.
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California.
authors.forename: John V
authors.identifier: http://orcid.org/0000-0001-5427-9308
authors.initials: JV
authors.lastname: Fahy
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016207:Cytokines / Q000378:metabolism*; D018450:Disease Progression; D004802:Eosinophilia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000473:pathology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D016207:Cytokines
keywords: Th2-high; Th2-low; asthma; asthma paradigm; exacerbation; type 2 inflammation