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Eosinophilia induced by blocking the IL-4/IL-13 pathway. Potential mechanisms and clinical outcomes

Olaguibel JM1, Sastre J2, Rodríguez JM3, del Pozo V4

1Servicio de Alergología, Hospital Universitario de Navarra. CIBER de Enfermedades Respiratorias (CIBERES). Pamplona, Spain
2Allergy Service, Fundación Jiménez Díaz. CIBER de Enfermedades Respiratorias (CIBERES). Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
3Department of Immunology, IIS-Fundación Jiménez Díaz and CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain
4Department of Immunology, IIS-Fundación Jiménez Díaz; CIBER de Enfermedades Respiratorias (CIBERES) and Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain

J Investig Allergol Clin Immunol 2022; Vol. 32(6)
doi: 10.18176/jiaci.0823

Currently, five biological drugs for uncontrolled severe asthma treatment are marketed. They all block type 2 inflammatory pathways, either by targeting IgE (omalizumab), the IL-5 pathway (mepolizumab, reslizumab, benralizumab), or the IL-4/13 pathway (dupilumab). Hypereosinophilia has been observed in between 4% and 25% of patients treated with dupilumab, being transient in most cases, but persistent cases of symptomatic hypereosinophilia consistent with eosinophil granulomatosis with polyangiitis (EGPA), eosinophilic pneumonia, eosinophilic vasculitis or sudden worsening of asthma symptoms have been described. Cases of EGPA have been described with all biologics, including anti-IL-5, and with leukotriene receptors antagonists in publications or in the Eudravigilance database. In many cases of EGPA, it appears during systemic steroids tapering or after switching from an anti-IL-5 biologic to Dupilumab, suggesting that systemic steroids or the anti IL-5 were masking the vasculitis. This review aims to substantiate the plausible mechanisms of dupilumab-induced hypereosinophilia and review symptomatic hypereosinophilia cases associated with dupilumab therapy. Blockade of the IL-4/IL-13 pathway cause a reduction of eosinophil migration and blood accumulation by inhibiting eotaxin-3, VCAM-1, and TARC without simultaneously inhibiting eosinophilopoiesis in the bone marrow. When choosing the optimal biologic, it seems necessary to consider the presence of hypereosinophilia (>1,500/mL), where an anti-IL-5/IL-5R is preferable. Also, when changing from an anti-IL-5/5R to an anti-IL-4/13R. Close monitoring of blood eosinophils and clinical evolution seems justified in these situations. Nevertheless, dual therapy with anti-IL-5/5R and anti-IL4/IL-13R may be needed for optimal control since both IL-5, and IL-4/13 pathways can simultaneously contribute to airway inflammation. 

Key words: Asthma, Biologic treatment, Eosinophil granulomatosis with polyangiitis, Eosinophilia