Eosinophil-derived neurotoxin suggests early eosinophil activation may be involved in COVID-19-related immune exhaustion

Background: Upregulation of PD-L1 (B7-H1, CD274) on eosinophils (Eos) discriminates moderate/severe (MOD) and mild forms of COVID-19. PD-L1 is a ligand of PD-1 (CD279), a coinhibitory receptor (immune checkpoint) expressed by T cells and thus a gatekeeper for broad adaptive immune suppression. Outside COVID-19, PD-L1/PD-1-mediated synapses enable Eos to downregulate T cell responses, mainly in the context of Eos activation and degranulation. We sought to determine Eos activation during COVID-19.Method: Eosinophil-derived neurotoxin (EDN), a granular RNase specific of Eos, was measured with an experimental fluoroimmunoenzyme assay in the serum of 79 COVID-19 patients (PCR-confirmed) at 0–180 days post-symptom onset (PSO) and of 15 PCR-negative controls. Serum (s) EDN, Eos blood counts and the EDN/blood Eos ratio were analyzed as a function of COVID-19 severity and time PSO. Results are expressed as median and interquartile range (IQR).Results: Patients experienced mild (60) or MOD (19) COVID-19. The former received outpatient care. Moderate (MOD) required hospitalization and oxygen but not intensive care. MOD (59.41–71) were older than controls (32.24–54) but not mild (39.26–51). Overall, sEDN levels in mild COVID-19 at any time PSO were lower than in controls or MOD: 49 (25–75), 69 (36–98) and 78 (54–125) µg/L, p < 0.05. sEDN decreased in mild COVID-19 as early as the first 24h PSO, remained significantly lower until day 22, and was still lower, albeit not significantly, after 6 months. Eos counts dropped in MOD (median