Highlights from

European Respiratory Society

Congress 2018

Paris 15-19 September 2018

Treatments targeting type2-inflammation

Asthma management has gradually evolved from a ‘’one-size-fits-all’’ concept into a more personalised approach [1]. While the majority of patients with mild-to-moderate and uncomplicated asthma reach optimal control with ICS-containing therapy, a significant minority with more severe disease fails to reach (optimal) control with ICS as a result of the underlying immuno-patho(physio)logy requiring a personalised approach with targeted therapy guided by biomarkers [39,43,44].

Interestingly, guidelines for severe asthma management do not yet insist on standard evaluation of the airway inflammatory components to guide treatment, although the nature of the airway inflammation clearly drives the choice of targeted therapy [1].

For type2 asthma, several add-on treatments targeting different inflammatory pathways are currently available, while several new drugs are in different stages of clinical development (Figure 2) [44]. For patients with a strong allergic component (history and serum IgE ≥30 IU/mL), apart from environmental or life style adjustments, add-on therapy with anti-IgE monoclonal antibodies is recommended for managing asthma (omalizumab is currently the only registered anti-IgE therapy), while for distinct patients with uncontrolled disease and house dust mite allergy, specific sublingual therapy may be considered [1].

More recently, anti-IL-5 targeting monoclonal antibodies have been added to the stepwise approach for management of severe eosinophilic asthma [1]. To guide treatment, eosinophilia is preferably confirmed by induced sputum analysis (sputum eosinophils ≥3%) or by blood eosinophils as a surrogate marker. For blood eosinophils, different cut-offs have been applied across different studies and usually start at least ≥150 cells/µL (to over 300 cells/µL) [45]. Currently, there are three anti-IL-5 monoclonal antibodies available to treat severe adult asthma: mepolizumab, reslizumab, and (more recently) benralizumab. These agents have a slightly different target (IL-5 or its receptor), reflected by a different pharmacological profile, and offer a substantial reduction in asthma exacerbations and oral steroid intake independent of comorbid allergies [46].

Furthermore, various other monoclonal antibodies to treat asthma are currently under investigation. While targeting IL-13 proved less effective in phase 3 studies, blocking the joint IL-4/IL-13 pathway by targeting the IL-4R alpha with dupilumab showed promising effects on several health-related outcomes in type2 diseases including atopic dermatitis, chronic rhinosinusitis with nasal polyps (CRSwNP), and severe asthma, irrespective of eosinophilia [47-49]. Fractionated exhaled nitric oxide (FeNO ≥25 ppb) is the best currently available biomarker to identify patients responding to IL-4/IL-13 targeted therapy [49]. Importantly, as systemic formulations, targeted therapies also showed beneficial effects on other aspects of asthma, such as comorbidities (e.g. CRSwNP, allergic rhinitis, atopic dermatitis) and may potentially also prove effective for small airways disease.

Future type2 asthma treatments targeting alarmins (e.g. TSLP, IL-33), kinases (e.g. JAK, PI3K), and CRTH2/DP2 seem promising in distinct subsets and the results of phase 3 clinical trials are awaited [10].

Figure 2: Inflammatory pathways and biomarkers underlying type2 asthma and targeted therapies (approved and in clinical development) [44]

ERS 2018 - asthma: Figure 2 Inflammatory pathways


  • Chronic airway inflammation is a key feature of asthma and a risk factor of (severe) asthma exacerbations with subsequent accelerated lung function decline
  • Asthma comprises abnormalities at several different levels (including comorbidities and small airways) which should be explored, evaluated, and adequately treated to achieve optimal control
  • Severe asthma (5-10% of asthma population), is difficult to control and accounts for >80% of the total healthcare costs
  • Severe asthma is a heterogeneous disease, roughly consisting of non-eosinophilic and eosinophilic inflammatory phenotypes – the latter being more frequently associated with more severe exacerbations and accelerated lung function decline
  • Eosinophilic severe asthma can be either ‘’allergic’’ or ‘’non-allergic’’ – both being driven by type2 (T2) inflammatory pathways including cytokines IL-5, IL-4, and IL-13.
  • Although eosinophilic asthma usually responds well to treatment with inhaled corticosteroids, non-allergy-driven T2 asthma (e.g. with chronic rhinosinusitis with nasal polyposis, NERD) is often corticosteroid-subsensitive.
  • Several therapies targeting T2 inflammation have been developed.
  • Presently available biomarkers of T2 inflammation comprise: sputum and blood eosinophils, FeNO, IgE, and periostin
  • Non-type2 asthma is less well-defined in terms of underlying mechanisms and biomarkers.
  1. Global Strategy for Asthma Management and Prevention. 2018 GINA Report.
  2. Israel E, Reddel HK. New Engl J Med. 2017;377(10):965-76.
  3. Mukherjee M, et al. Curr Opin Pulm Med. 2017;23(1):78-88.
  4. Albano GD, et al. J Allergy Clin Immunol. 2015;135(5):1144-53.e1-9.
  5. Svenningsen S, Nair P. Front Med. 2017;4:158.
  6. Cosmi L, et al. J Allergy Clin Immunol. 2010;125(1):222-30.e1-4.
  7. Haldar P, et al. Am J Respir Crit Care Med. 2008;178(3):218-24.
  8. Parulekar AD, et al. Curr Opin Pulm Med. 2018;24(1):50-5.
  9. Yancey SW, et al. J Allergy Clin Immunol. 2017;140(6):1509-18.
  10. Farne HA, et al. Cochrane Database Syst Rev. 2017;9:Cd010834.
  11. Bachert C, et al. JAMA. 2016;315(5):469-79.
  12. Wang FP, et al. J Dermatol Sci. 2018;90(2):190-8.
  13. Castro M, et al. N Engl J Med. 2018;378(26):2486-96.

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