Reply to “Protective effects of eosinophils against COVID-19: More than an ACE(2) in the hole?”

To the Editor:

We would like to thank Drake et al¹ for their valuable comment regarding the antiviral effect of eosinophils, which may explain why patients with type 2 high asthma were protected against severe disease (COVID-19) in our study.² An important aspect that warrants further investigation is to find a mechanistic explanation for high rates of eosinopenia in hospitalized patients with COVID-192, 3, 4 and more importantly, how to speed the recovery of eosinophil counts to properly exhibit their antiviral effects.

Previous data show that bacterial, viral, and parasitic acute inflammation is associated with the decrease in circulating eosinophils due to egress inhibition from the bone marrow.⁵ Eosinopenia in acute inflammation may also result from distribution of eosinophils in the inflamed tissues⁵; however, pulmonary samples from individuals with COVID-19 show a predominant mononuclear inflammatory infiltrate (mostly lymphocytic), without the presence of eosinophils.⁶ Although eosinopenia is not unique to severe acute respiratory syndrome coronavirus (SARS-CoV-2), it was shown to be more prevalent in COVID-19 than it is in acute influenza infection.⁷ Therefore, other mechanisms, perhaps specific to SARS-CoV-2 infection, may explain these findings. It is possible that differences in the cytokine profile of patients with COVID-19 might influence their circulating eosinophils. For example, among the proinflammatory cytokines that are elevated in patients with severe COVID-19,⁸ IFN-γ/TNF-α have been associated with FasL-induced apoptosis of eosinophils.⁹ However, it is not understood which patients are prone to severe disease, eosinopenia, or who are those individuals recovering their eosinophils faster and why. It also remains to be determined if this is an asthma-specific protective effect or a more generalizable finding extending to other conditions.

We show in our study that patients with asthma with prior eosinophilia are more likely to recover their circulating eosinophils during COVID-19 hospitalization, and these patients had subsequently less risk of dying from SARS-CoV-2 infection.² Therefore, individuals with type 2 high asthma appear to have the advantage of pre–COVID-19 eosinophilia. However, it is unclear if this is their main tool in fighting against severe COVID-19 disease, or if other characteristics of these patients (eg, prior Th2 cytokine predominance that might influence the cytokine milieu released during COVID-19, gender differences, certain medications used for asthma control) are also of importance.