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Type 2 inflammation in asthma and other airway diseases

Jorge Maspero, Yochai Adir, Mona Al-Ahmad, Carlos A. Celis-Preciado, Federico D. Colodenco, Pedro Giavina-Bianchi, Hani Lababidi, Olivier Ledanois, Bassam Mahoub, Diahn-Warng Perng, Juan C. Vazquez, Arzu Yorgancioglu
ERJ Open Research 2022 8: 00576-2021; DOI: 10.1183/23120541.00576-2021
Jorge Maspero
1Fundacion CIDEA (Centro de Investigacion de Enfermedades Alergicas y Respiratorias), University of Buenos Aires, Buenos Aires, Argentina
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  • For correspondence: jorge.maspero@fundacioncidea.org.ar
Yochai Adir
2Pulmonary Division, Lady Davis Carmel Medical Center, Faculty of Medicine, The Technion, Institute of Technology, Haifa, Israel
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Mona Al-Ahmad
3Microbiology Dept, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
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Carlos A. Celis-Preciado
4Pulmonary Unit, Internal Medicine Department, Hospital Universitario San Ignacio, Bogota, Colombia
5Faculty of Medicine, Pontificia Universidad Javeriana, Bogota, Colombia
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Federico D. Colodenco
6Pulmonology, Hospital De Rehabilitación Respiratoria María Ferrer, Buenos Aires, Argentina
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Pedro Giavina-Bianchi
7Clinical Immunology and Allergy Division, University of Sao Paulo, Sao Paulo, Brazil
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Hani Lababidi
8King Fahad Medical City, Riyadh, Saudi Arabia
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Olivier Ledanois
9Sanofi Genzyme, Paris, France
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Bassam Mahoub
10Dept of Pulmonary Medicine and Allergy and Sleep Medicine, Rashid Hospital, Dubai, United Arab Emirates
11Dept of Medicine and Chest Disease, University of Sharjah, Sharjah, United Arab Emirates
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Diahn-Warng Perng
12Taipei Veterans General Hospital, Taipei, Taiwan
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Juan C. Vazquez
13Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
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  • ORCID record for Juan C. Vazquez
Arzu Yorgancioglu
14Dept of Chest Diseases, Faculty of Medicine, Manisa Celal Bayar University, Manisa, Turkey
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Figures

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  • FIGURE 1
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    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
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    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

  • Figures
  • TABLE 1

    Airway diseases driven by type 2 inflammation [17–24, 26–41]

    Evidence of type 2 inflammationProportion of type 2 patientsComorbid 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-4IL-13IL-5
      Th2 cell differentiationGoblet cell hyperplasiaEosinophil 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/contractility
        Inflammatory cell trafficking to the tissue
        IgE production
        Goblet cell hyperplasia/mucus production
        Barrier dysfunction
        Tissue remodelling
        Microbiome alterations
        Inflammatory cell trafficking to the tissue
        IgE production
        Goblet cell hyperplasia/mucus production
        Barrier dysfunction

        IL: 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 years
          US indication:
          patients with severe eosinophilic asthma aged ≥6 years
          EMA indication:
          patients with severe refractory eosinophilic asthma aged ≥6 years
          US indication: patients with severe eosinophilic asthma aged ≥18 years
          EMA indication: patients with severe refractory eosinophilic asthma aged ≥18 years
          US indication: patients with severe eosinophilic asthma aged ≥12 years
          EMA indication: patients with severe refractory eosinophilic asthma aged ≥18 years
          US 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 years
          US indication:
          patients with severe asthma aged ≥12 years
          Approval (CRSwNP)Approved EU and US CRSwNP inadequately controlledEMA indication: inadequately controlled severe CRSwNP
          US indication: inadequately controlled CRSwNP [143]
          Phase 3 recruiting
          CRS with elevated eosinophils
          Phase 3 complete
          severe symptomatic bilateral nasal polyps
          Approved EU and US
          CRSwNP inadequately controlled
          Phase 3 recruiting
          Approval (COPD)Phase 2 withdrawn
          Lack of eligible COPD subjects with elevated IgE
          Phase 3 complete
          COPD with elevated eosinophil count
          Phase 3 complete
          COPD with exacerbation history
          Phase 3 recruiting
          Moderate-to-severe COPD with type 2 inflammation
          Phase 2a recruiting [144]
          Approval (other)Chronic idiopathic urticariaEosinophilic granulomatosis with polyangiitis
          Hypereosinophilic syndrome
          Atopic 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.

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          Type 2 inflammation in asthma and other airway diseases
          Jorge Maspero, Yochai Adir, Mona Al-Ahmad, Carlos A. Celis-Preciado, Federico D. Colodenco, Pedro Giavina-Bianchi, Hani Lababidi, Olivier Ledanois, Bassam Mahoub, Diahn-Warng Perng, Juan C. Vazquez, Arzu Yorgancioglu
          ERJ Open Research Jul 2022, 8 (3) 00576-2021; DOI: 10.1183/23120541.00576-2021

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          Type 2 inflammation in asthma and other airway diseases
          Jorge Maspero, Yochai Adir, Mona Al-Ahmad, Carlos A. Celis-Preciado, Federico D. Colodenco, Pedro Giavina-Bianchi, Hani Lababidi, Olivier Ledanois, Bassam Mahoub, Diahn-Warng Perng, Juan C. Vazquez, Arzu Yorgancioglu
          ERJ Open Research Jul 2022, 8 (3) 00576-2021; DOI: 10.1183/23120541.00576-2021
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          • Article
            • Abstract
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            • Epidemiology
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            • Type 2 inflammation: pathophysiology
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            • Management of severe asthma and other airway diseases with type 2 inflammation
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