Pathophysiology of Severe Asthma

Severe asthma is described in the 2021 Global Initiative for Asthma (GINA) guideline as asthma that is uncontrolled despite adherence with maximal optimized high-dose inhaled corticosteroid and long-acting β2-agonist combination therapy, including worsening when such treatment is decreased. However, importantly, severe asthma symptoms resulting from poor adherence to therapy are not classified as severe asthma. Although severe asthma may present with many of the symptoms associated with other forms of asthma, including wheezing, shortness of breath, chest tightness, cough of varying intensity, and variable expiratory airflow limitation, severe asthma has specific features that may differ from other types of asthma. Certain phenotypes and biomarkers are associated with severe asthma including higher eosinophil counts, atopy, and allergic asthma. These are all features associated with type 2 inflammation. Recognizing these features and associated biomarkers may aid in the diagnosis of severe asthma.1


APC = antigen-presenting cell; CRTh2 = chemoattractant receptor-homologous molecule expressed on Th2 cells; Ig = immunoglobulin; IL = interleukin; iNOS = induced nitric oxide synthase; PGD2 = prostaglandin D2; TGF = tumor growth factor; Th = T helper; TSLP = thymic stromal lymphopoietin. Wenzel SE. Nat Med. 2012;18:715-725.

  • Asthma is characterized by inflammation3
  • Cytokines produced: interleukin (IL)-3, IL-4, IL-5, IL-13, IL-333
  • IL-3: Regulates eosinophil and basophil differentiation, migration, and survival4
  • IL-4: Important for T helper (Th) 2 cell differentiation and immunoglobulin (Ig) E production4
  • IL-5: Involved in eosinophil differentiation, maturation, recruitment, and survival4
  • IL-13: Involved in lung inflammation, mucus hypersecretion, subepithelial fibrosis, and eotaxin production4
  • IL-33: IL-33 receptor (ST2) is a marker for Th2 and activates Th2 cells4
  • IL-25 and thymic stromal lymphopoietin: Potential to induce features of Th2-type response such as eosinophilia and the production of IL-4, IL-5, IL-13, and anti-IgE
  • Allergen challenge results in influx of activated Th2 cells into the airway in addition to an increase of Th2 cytokines and recruitment of eosinophils3,4
  • Number of Th2 cells in airway correlates with disease severity
  • Reduction of specific Th2 responses can treat disease without causing generalized immmunosupression



Non-Th2 Asthma Phenotype2

DAMP = danger-associated molecular pattern; GRO = growth-regulated oncogene; IFN = interferon; IL = interleukin; PAMP = pathogen-associated molecular pattern; Th = T helper; TLR = toll-like receptor. Wenzel SE. Nat Med. 2012;18:715-725.



  1. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. Updated 2021 (
  2. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18:715-725. doi:10.1038/nm.2678
  3. Lloyd CM, Hessel EM. Functions of T cells in asthma: more than just T(H)2 cells. Nat Rev Immunol. 2010;10:838-848. doi:10.1038/nri2870
  4. Bosnjak B, Stelzmueller B, Erb KJ, et al. Treatment of allergic asthma: modulation of Th2 cells and their responses. Respir Res. 2011;12:114. doi:10.1186/1465-9921-12-114