Eosinophilia Induced by Blocking the IL-4/IL-13 Pathway: Potential Mechanisms and Clinical Outcomes

Five biological drugs are currently marketed for treatment of uncontrolled severe asthma. They all block type 2 inflammatory pathways by targeting IgE (omalizumab), the IL-5 pathway (mepolizumab, reslizumab, benralizumab), or the IL-4/IL-13 pathway (dupilumab). Hypereosinophilia has been observed in 4%-25% of patients treated with dupilumab and is transient in most cases, although there have been reports of persistent cases of symptomatic hypereosinophilia consistent with eosinophilic granulomatosis with polyangiitis (EGPA), eosinophilic pneumonia, eosinophilic vasculitis, and sudden worsening of asthma symptoms. Cases of EGPA have been reported with all biologics, including anti-IL-5 agents, and with leukotriene receptor antagonists in publications or in the EudraVigilance database. In many cases, EGPA appears during tapering of systemic corticosteroids or after switching from an anti-IL-5 biologic to dupilumab, suggesting that systemic corticosteroids or the anti-IL-5 agent were masking vasculitis. This review investigates plausible mechanisms of dupilumab-induced hypereosinophilia and review cases of symptomatic hypereosinophilia associated with dupilumab. Blockade of the IL-4/IL-13 pathway reduces eosinophil migration and accumulation of blood by inhibiting eotaxin-3, VCAM-1, and TARC without simultaneously inhibiting eosinophilopoiesis in bone marrow. When choosing the optimal biologic, it seems necessary to consider the presence of hypereosinophilia (>1500/μL), in which case an anti-IL-5/IL-5R agent is preferable. Furthermore, when switching from an anti-IL-5/5R to an anti-IL-4/13R agent, blood eosinophils and clinical progress should be closely monitored. Nevertheless, dual therapy with anti-IL-5/5R and anti-IL4/IL-13R agents may be needed for optimal control, since both the IL-5 and the IL-4/IL-13 pathways can simultaneously contribute to airway inflammation. This approach can prevent the development of EGPA and other types of symptomatic hypereosinophilia while maintaining control of nasal polyposis. In the near future, it will be possible to use a new generation of biological therapies for the treatment of severe asthma. These act at a higher level of the inflammatory cascade, as is the case of the antialarmins tezepelumab and itepekimab.