Precision Medicine for Paediatric Severe Asthma: Current Status and Future Direction

Figures & data

Figure 1 Eosinophilic asthma inflammatory pathways. There are two aetiologies for eosinophilic inflammation in asthma: an allergic pathway triggered by allergens and a non-allergic mechanism triggered by microbes, pollutants and glycolipids. The key mediators in the pathways are depicted below. Eosinophils release cationic proteins,⁵⁷ which lead to bronchial epithelial tissue damage, thus causing airways hyper-responsiveness. Eosinophils also lead to airway smooth muscle cell proliferation through increased eosinophils adhesion caused by the release of cationic proteins and the eosinophilic effect on transforming growth factor-β1 and gene coding of wingless/integrase-1 signaling. IL-13 triggers mucus hyper-secretion. Figure created with BioRender.com.

Abbreviations: IgE, immunoglobulins E; IL, interleukins; ILC2, type 2 innate lymphoid cells; TCR, T-cell receptors; NK, natural killer T cell; TSLPR, thymic stromal lymphopoietin receptor; PG, prostaglandin; ECP, eosinophil cationic protein; EPX, eosinophil protein X; EPO, eosinophil peroxidase; MBP, major basic protein.

Table 1 Licensed Biologics Used for Severe Asthma

Drug	Licensing age Groups	Year of First Approval by US Food and Drug Adminstraion (FDA)	Mechanism of Action	Eligibility Criteria	Published Efficacy Results	Predictors of Response	Off-License Use	Side-Effects	Route and Frequency of Administration	Cost to the NHS
Omalizumab	Age 6 and above	2003	IgE Blocker	IgE serum level between 30UI/mL to 1500 UI/mL	Better symptom control Fewer attacks	High FeNO (≥20 ppb) High blood eosinophils (≥2%) Body mass index (≥25 kg/m^2)	IgE levels higher than 1500 UI/mL Different IgE/bodyweight combinations than on the product monograph	Headache, skin reactions, risk of anaphylaxis- 0.3%	Subcutaneous injection once every 2–4 weeks	£256.15 for a 150-mg vial
Mepolizumab	Age 6 and above	2016	Anti-IL-5	Blood eosinophils of ≥300 cells/µL (within 12 months of dosing) + ≥ 4 attacks needing OCS in last 12 months or daily OCS (≥5mg/day) for last 6 months	Better symptom control Fewer attacks			Pyrexia, headaches, upper abdominal pain, hypersensitivity	Subcutaneous injection once every 4 weeks	£840 per dose
Reslizumab	Age 18 and above	2016	Anti-IL-5	Blood eosinophilia ≥400 cells/μL	Better symptom control Improvement in FEV1			Risk of anaphylaxis, myalgia	Intravenous injection once every 4 weeks	£499.99 per 100-mg vial
Benralizumab	Age 12 and above	2017	Anti-IL-5	Eosinophilic phenotype	Fewer attacks Improvement in FEV1			Pyrexia, headaches and hypersensitivity	Subcutaneous injection once every 4–8 weeks	£1955 per 30-mg pre-filled syringe
Dupilumab	Age 12 and above	2018	Anti-IL-4, Anti- IL-13	FeNO of more than 25 ppb and a concentration of eosinophils of more than 300/mm^3	Better symptom control Fewer attacks			Eye inflammation, eye pruritus, headache, hypersensitivity	Subcutaneous injection once every 2 weeks	£1264.89 per pack of 2×2mL syringes of 150 mg/1 mL solution

Figure 2 Licensed mediator cascade of biologics used in eosinophilic asthma. The figure below shows the targets for the licensed biologics. Omalizumab is an IgE-blocker. Mepolizumab, reslizumab and benralizumab are anti IL-5 agents. Dupilumab is an Anti-IL-4/anti-IL-13 agent. Figure created with BioRender.com.

Abbreviations: IgE, Immunoglobulins E; IL, interleukins; ILC2, type 2 innate lymphoid cells; TCR, T-cell receptors; NK, natural killer T cell; TSLPR, thymic stromal lymphopoietin receptor; PG, prostaglandin.

Malinovschi A, Fonseca JA, Jacinto T, Alving K, Janson C. Exhaled nitric oxide levels and blood eosinophil counts independently associate with wheeze and asthma events in National Health and Nutrition Examination Survey subjects. J Allergy Clin Immunol. 2013;132(4):821–827.e5. doi:10.1016/j.jaci.2013.06.007

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