Characteristics, phenotypes, mechanisms and management of severe asthma

Abstract

Severe asthma is "asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic corticosteroids) to prevent it from becoming 'uncontrolled' or which remains 'uncontrolled' despite this therapy." The state of control was defined by symptoms, exacerbations and the degree of airflow obstruction. Therefore, for the diagnosis of severe asthma, it is important to have evidence for a diagnosis of asthma with an assessment of its severity, followed by a review of comorbidities, risk factors, triggers and an assessment of whether treatment is commensurate with severity, whether the prescribed treatments have been adhered to and whether inhaled therapy has been properly administered. Phenotyping of severe asthma has been introduced with the definition of a severe eosinophilic asthma phenotype characterized by recurrent exacerbations despite being on high dose ICS and sometimes oral corticosteroids, with a high blood eosinophil count and a raised level of nitric oxide in exhaled breath. This phenotype has been associated with a Type-2 (T2) inflammatory profile with expression of interleukin (IL)-4, IL-5, and IL-13. Molecular phenotyping has also revealed non-T2 inflammatory phenotypes such as Type-1 or Type-17 driven phenotypes. Antibody treatments targeted at the T2 targets such as anti-IL5, anti-IL5Rα, and anti-IL4Rα antibodies are now available for treating severe eosinophilic asthma, in addition to anti-immunoglobulin E antibody for severe allergic asthma. No targeted treatments are currently available for non-T2 inflammatory phenotypes. Long-term azithromycin and bronchial thermoplasty may be considered. The future lies with molecular phenotyping of the airway inflammatory process to refine asthma endotypes for precision medicine.

Figure 1

Airway epithelium interactions with environmental factors to induce innate and adaptive immune and inflammatory responses with the release of TSLP, IL-33, and IL-25. Generation of Th2 cells and ILC2s leads to the elaboration of IL-4, IL-5, and IL-13, inducing an allergic eosinophilic inflammation with eosinophil recruitment and activation, and IgE production. Activation of Th1 and Th17 cells may contribute to neutrophilic inflammation. Airway wall remodeling and repair driven by epithelial-mesenchymal transformation and the effects of ILs on airway structural cells such as airway smooth muscle cells and epithelial cells contribute to chronic airflow obstruction and bronchial hyper-responsiveness. Targets for interleukin intervention against IL-4, IL-5, and IL-13 are shown. B7-2: Also known as cluster of differentiation 86 (CD86); GM-CSF: Granulocyte-macrophage colony-stimulating factor; IFN γ: Interferon γ; IgE: Immunoglobulin E; IL: Interleukin; ILC2: Type 2 innate lymphoid cells; MHC II: Major histocompatibility complex; RANTES: Regulated upon activation, normal T cell expressed and presumably secreted; TCR: T-cell receptor; T2: Type 2 inflammation; TGFβ: Transforming growth factor β; Th0: T helper 0; Th1: T helper 1; Th2: T helper 2; Th17: T helper 17; TNFα: Tumor necrosis factor α; TSLP: Thymic stromal lymphopoietin.

Figure 2

Three transcriptomic-associated clusters (TAC) obtained from hierarchical clustering of differentially expressed genes obtained by comparing the transcriptome of sputum cells obtained from eosinophil-high and eosinophil-low sputum from patients with severe asthma. Each of the lower boxes represent the genes or class of genes that characterize each TAC signature, the salient clinical features and the sputum granulocytic inflammation. CCR3: CC chemokine receptor 3; FEV₁: Forced expiratory volume in one second; IFN: Interferon; IL-33R: Interleukin 33 receptor; TNF: Tumor necrosis factor; T2: Type 2 inflammation; TSLPR: Thymic stromal lymphopoietin receptor; U-BIOPRED: Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes.

Figure 3

Management algorithm for severe asthma. After confirming the diagnosis of severe asthma, Type-2 (T2) biomarkers which are currently based on blood eosinophil count, fractional exhaled nitric oxide (FeNO) and total serum immunoglobulin E (IgE) and presence of allergies can be used to diagnose severe eosinophilic or severe allergic asthma. Those with high-T2 biomarker and regular exacerbations of asthma can be offered biologic anti-T2 treatments. Those with low T2-biomarker will need to have a reduction in oral corticosteroid dosage (OCS) in case the steroids are suppressing the level of T2-biomarkers. Trial of long-term azithromycin or bronchial thermoplasty may be considered. IL: Interleukin; IL4Rα: Interleukin 4 receptor alpha; IL5Rα: Interleukin 5 receptor alpha; ppb: Part per billion; SPT: Skin prick tests; sIgE: Specific immunoglobulin E.

Figure 4

Therapeutic antibodies targeting type 2 cytokines, IL-4, IL-5, and IL-13, and anti-IgE. IgE: Immunoglobulin E; IL: Interleukin; IL4Rα: Interleukin 4 receptor alpha; IL5Rα: Interleukin 5 receptor alpha; T2: Type 2 inflammation.