Figures
- FIGURE 1
Key cytokines driving type 2 inflammatory airway diseases [3, 31, 104–106]. S. aureus: Staphylococcus aureus; TSLP: thymic stromal lymphopoietin; IL: interleukin; ILC2: type 2 innate lymphoid cells; Th: T-helper; TARC: thymus and activation-regulated chemokine; CRSwNP: chronic rhinosinusitis with nasal polyps; PGD2: prostaglandin D2.
- FIGURE 2
The Global Initiative for Asthma stepwise approach to control symptoms and minimise future asthma risk in adults and adolescents aged >12 years [1]. ICS: inhaled corticosteroid; SABA: short-acting β-agonist; LAMA: long-acting muscarinic antagonist; IL: interleukin; LABA: long-acting β-agonist; LTRA: leukotriene receptor antagonist; HDM: house dust mite; SLIT: sublingual allergen immunotherapy; OCS: oral corticosteroid; FeNO: exhaled nitric oxide fraction; s.c.: subcutaneous; i.v.: intravenous; CBC: complete blood count; CRP: C-reactive protein; HRCT: high-resolution computed tomography; DLCO: diffusing capacity of the lung for carbon monoxide; ANCA: antineutrophil cytoplasmic antibodies; CT: computed tomography; BNP: brain natriuretic peptide.
Tables
- TABLE 1
Airway diseases driven by type 2 inflammation [17–24, 26–41]
Evidence of type 2 inflammation Proportion of type 2 patients Comorbid disease prevalence Asthma Uncontrolled asthma despite medium- to high-dose ICS Elevated serum IgE
Elevated serum eosinophils
51% + CRSwNP 30–50%
+ Allergic rhinitis >80%
+ COPD [33] ∼13%
+ NSAID-ERD/AERD ∼7%
Severe asthma Elevated sputum eosinophils
Expression of IL-13-inducible genes and Th2 genes in sputum cells
55–70% Difficult asthma despite high-dose ICS Elevated blood eosinophils or FeNO
71% CRSwNP Elevated CLC and IL-13 gene expression
Elevated IL-5 and Th2 gene expression
∼80% + Asthma 50%
+ Allergic rhinitis ∼75%
+ NSAID-ERD/AERD ∼10–20%
COPD Persistent blood eosinophils ≥300 cells·µL−1 or ≥2%
15–37% A subset may also present with asthma [33]
+ Allergic rhinitis ∼7%
+ CRS [42, 43]
Allergic rhinitis IgE-mediated disease driven by type 2 inflammation [10, 37, 38]
100% Comorbid asthma [37] 19–38%
Comorbid CRS [38] ∼67%ICS: inhaled corticosteroids; CRSwNP: chronic rhinosinusitis with nasal polyps; NSAID-ERD: nonsteroidal anti-inflammatory drug-exacerbated respiratory disease; AERD: aspirin-exacerbated respiratory disease; IL: interleukin; Th2: type 2 T-helper; FeNO: exhaled nitric oxide fraction; CLC: Charcot–Leyden crystals; CRS: chronic rhinosinusitis.
- TABLE 2
Central drivers of type 2 inflammation interleukin (IL)-4 and IL-13 have unique and overlapping functions, contributing the pathophysiology of asthma, chronic rhinosinusitis with nasal polyps and allergic rhinitis [3, 31, 92, 93, 93–99]
IL-4 IL-13 IL-5 Th2 cell differentiation Goblet cell hyperplasia Eosinophil differentiation and survival Mucociliary dysfunction Excess mucus production Collagen deposition Smooth muscle proliferation Increased contractility Hyperresponsiveness Neuroimmune dysfunction B-cell isotype switching and IgE production; mast cell and basophil degranulation Mast cell activation and trafficking to tissue Fibrosis and airway remodelling Epithelial barrier dysfunction and microbiome imbalance TARC-induced migration of Th2 cells Activation of macrophages to M2 type Eosinophil recruitment and trafficking to tissue Th2: type 2 T-helper; TARC: thymus and activation-regulated chemokine.
- TABLE 3
Pathophysiological features of type 2 inflammatory airway diseases [3, 31, 92–99]
Asthma (IL-4, IL-13, IL-5) CRSwNP (IL-4, IL-13, IL-5) Allergic rhinitis (IL-4, IL-13, IL-5) Inflammatory cell trafficking to the tissue
IgE production
Goblet cell hyperplasia/mucus production
Barrier dysfunction
Tissue remodelling
Smooth muscle proliferation/contractilityInflammatory cell trafficking to the tissue
IgE production
Goblet cell hyperplasia/mucus production
Barrier dysfunction
Tissue remodelling
Microbiome alterationsInflammatory cell trafficking to the tissue
IgE production
Goblet cell hyperplasia/mucus production
Barrier dysfunctionIL: interleukin; CRSwNP: chronic rhinosinusitis with nasal polyps.
- TABLE 4
Approved biological therapies for type 2 inflammatory airway diseases
Omalizumab
(anti-IgE)Mepolizumab
(anti-IL-5)Reslizumab
(anti-IL-5)Benralizumab
(anti-IL-5R)Dupilumab
(anti-IL-4R)Tezepelumab
(anti-TSLP)Approval (asthma) US indication:
patients with moderate-to-severe persistent allergic asthma aged ≥6 years
EMA indication:
patients with severe persistent allergic asthma aged ≥6 yearsUS indication:
patients with severe eosinophilic asthma aged ≥6 years
EMA indication:
patients with severe refractory eosinophilic asthma aged ≥6 yearsUS indication: patients with severe eosinophilic asthma aged ≥18 years
EMA indication: patients with severe refractory eosinophilic asthma aged ≥18 yearsUS indication: patients with severe eosinophilic asthma aged ≥12 years
EMA indication: patients with severe refractory eosinophilic asthma aged ≥18 yearsUS indication: patients with moderate-to-severe eosinophilic asthma or OCS-dependent asthma aged ≥6 years [142]
EMA indication: patients with severe asthma with type 2 inflammation (elevated FeNO/eosinophils) aged ≥12 yearsUS indication:
patients with severe asthma aged ≥12 yearsApproval (CRSwNP) Approved EU and US CRSwNP inadequately controlled EMA indication: inadequately controlled severe CRSwNP
US indication: inadequately controlled CRSwNP [143]Phase 3 recruiting
CRS with elevated eosinophilsPhase 3 complete
severe symptomatic bilateral nasal polypsApproved EU and US
CRSwNP inadequately controlledPhase 3 recruiting Approval (COPD) Phase 2 withdrawn
Lack of eligible COPD subjects with elevated IgEPhase 3 complete
COPD with elevated eosinophil countPhase 3 complete
COPD with exacerbation historyPhase 3 recruiting
Moderate-to-severe COPD with type 2 inflammationPhase 2a recruiting [144] Approval (other) Chronic idiopathic urticaria Eosinophilic granulomatosis with polyangiitis
Hypereosinophilic syndromeAtopic dermatitis IL: interleukin; TSLP: thymic stromal lymphopoietin; CRSwNP: chronic rhinosinusitis with nasal polyps; US: United States; EMA: European Medicines Agency; OCS: oral corticosteroids; FeNO: exhaled nitric oxide fraction; EU: European Union; CRS: chronic rhinosinusitis.
