Introduction:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces strong innate immune responses and sustained inflammation, which may promote immune exhaustion via PD-1-PD-L1/PD-L2 and LAG-3-MHC pathways. The longitudinal dynamics and prognostic significance of soluble immune checkpoint molecules in moderate to severe COVID-19 remain unclear. Therefore, we assessed whether markers of immune exhaustion are associated with disease severity and recovery.

Material and Methods:
We analyzed 51 hospitalized patients (36 males and 15 females) with moderate to severe COVID-19 on day 1 of hospitalization, day 8, and on days 40-50. Laboratory tests, including complete blood count (CBC), C-reactive protein, fibrinogen, D-dimers, and ferritin concentration in sera, were routinely performed in the hospital diagnostic unit using applicable diagnostic automated methods. Soluble exhaustion markers, including sPD-L1, sPD-L2, and sLAG-3, were assessed by ELISA.

Results:
sPD-L2 and sLAG-3 levels were elevated at the time of admission. sPD-L2 and sLAG-3 levels decreased in the course of the disease. LAG-3 concentrations had decreased by day 8 and remained lower on days 40-50. PD-L2 levels decreased only in the recovery phase. Decreases of sPD-L2 and sLAG-3 were associated with clinical improvement and declining inflammatory parameters.

Conclusions:
High serum levels of sPD-L2 and sLAG-3 characterize the early phase of COVID-19, may be associated with active infection with SARS-CoV-2, and may reflect disease activity. Declining levels of markers of immune exhaustion have potential prognostic value for recovery from COVID-19.