Severe Adult Asthmas: Integrating Clinical Features, Biology, and Therapeutics to Improve Outcomes

Abstract

Evaluation and effective management of asthma, and in particular severe asthma, remains at the core of pulmonary practice. Over the last 20-30 years, there has been increasing appreciation that "severe asthma" encompasses multiple different subgroups or phenotypes, each with differing presentations. Using clinical phenotyping, in combination with rapidly advancing molecular tools and targeted monoclonal antibodies (human knockouts), the understanding of these phenotypes, and our ability to treat them, have greatly advanced. Type-2 (T2)-high and -low severe asthmas are now easily identified. Fractional exhaled nitric oxide and blood eosinophil counts can be routinely employed in clinical settings to identify these phenotypes and predict responses to specific therapies, meeting the initial goals of precision medicine. Integration of molecular signals, biomarkers, and clinical responses to targeted therapies has enabled identification of critical molecular pathways and, in certain phenotypes, advanced them to near-endotype status. Despite these advances, little guidance is available to determine which class of biologic is appropriate for a given patient, and current "breakthrough" therapies remain expensive and even inaccessible to many patients. Many of the most severe asthmas, with and without T2-biomarker elevations, remain poorly understood and treated. Nevertheless, conceptual understanding of "the severe asthmas" has evolved dramatically in a mere 25 years, leading to dramatic improvements in the lives of many.

Keywords: asthma; biologic therapy; cytokines; eosinophils; type 2 asthma.

Figure 1.

(A) Suggested flow diagram for the initial assessment of a patient with difficult asthma, before confirmation of diagnosis of severe asthma, based on current or previous evidence for airway obstruction, with or without reversibility. (B) Suggested flow diagram for the initial evaluation of a patient after confirming a diagnosis of severe asthma. Each algorithm includes initial and continued assessment and treatment of risk factors and comorbid conditions, as well as prescription of and adherence to standard therapies at each step. Fe_NO-Hi is characterized by >24 ppb, and Eos-Hi is characterized by 300 cells/μl, although in some cases, ≥150 cells/μl may be sufficient (see text for further details). ACO = asthma–COPD overlap; AG = asthmatic granulomatosis; COPD = chronic obstructive pulmonary disease; CRP = C-reactive protein; CT = computed tomography; EGPA = eosinophilic granulomatosis with polyangiitis; Eos = eosinophils; eval = evaluation; Fe_NO = fraction of exhaled NO; Hi = high; HP = hypersensitivity pneumonitis; HS = Hi-sensitivity; LAMA = long-acting muscarinic antagonist; Lo = low; Neg = negative; OCS = oral corticosteroid; Pos = positive; pred = predicted; T2 = type 2; VATS = video-assisted thoracoscopic surgery.

Figure 1.

(A) Suggested flow diagram for the initial assessment of a patient with difficult asthma, before confirmation of diagnosis of severe asthma, based on current or previous evidence for airway obstruction, with or without reversibility. (B) Suggested flow diagram for the initial evaluation of a patient after confirming a diagnosis of severe asthma. Each algorithm includes initial and continued assessment and treatment of risk factors and comorbid conditions, as well as prescription of and adherence to standard therapies at each step. Fe_NO-Hi is characterized by >24 ppb, and Eos-Hi is characterized by 300 cells/μl, although in some cases, ≥150 cells/μl may be sufficient (see text for further details). ACO = asthma–COPD overlap; AG = asthmatic granulomatosis; COPD = chronic obstructive pulmonary disease; CRP = C-reactive protein; CT = computed tomography; EGPA = eosinophilic granulomatosis with polyangiitis; Eos = eosinophils; eval = evaluation; Fe_NO = fraction of exhaled NO; Hi = high; HP = hypersensitivity pneumonitis; HS = Hi-sensitivity; LAMA = long-acting muscarinic antagonist; Lo = low; Neg = negative; OCS = oral corticosteroid; Pos = positive; pred = predicted; T2 = type 2; VATS = video-assisted thoracoscopic surgery.

Figure 2.

Distal lung (VATS) tissue from a patient with physiologically defined T2-Hi severe asthma with background autoimmune thyroid and inflammatory bowel disease, potentially representing T2 complex asthma. (A) Evidence of severe eosinophilic and profoundly lymphocytic airway disease with goblet-cell hyperplasia. (B) Concurrent scattered interstitial perivascular mononuclear inflammatory-cell aggregates (identified by arrows). (C) Lymphocytic pleuritic inflammation characteristic of autoimmune lung disease (the asterisk identifies the inflammation). Scale bars, 200 μm. Hi = high; T2 = type 2; VATS = video-assisted thoracoscopic surgery.

Figure 3.

Schematic representation of the potential mechanisms defining the clinical–molecular phenotype of early-onset T2-Hi (or T2-Lo) asthma. Question marks and dashed arrows represent speculative relationships. The more bold dashed line represents the boundary of a lymph node. APC = antigen-presenting cell; Hi = high; iNOS = inducible nitric oxide synthase; Lo = low; T2 = type 2; Tfh = T-follicular helper cell; Th0 = T-helper cell type 0; Th2 = T-helper cell type 2.

Figure 4.

Schematic representation of the potential mechanisms defining the clinical–molecular phenotype (or perhaps endotype) of late-onset T2-Hi asthma, showing the central roles of epithelial cells, ILC2s, and mast cells. Question marks represent speculation. 15LO1 = 15 lipoxygenase-1; Hi = high; ILC2 = T2 innate lymphoid cell; iNOS = inducible nitric oxide synthase; ST2 = IL-33 receptor; T2 = type 2; TSLP = thymic stromal lymphopoietin.