A104-04 Time-variable Associations Between Interferon-associated Mediators and Outcomes in Critically Ill Covid-19 Patients

Abstract Rationale Interferons and their inducible mediators have been associated with COVID-19 severity in ICU patients. However, it is unknown whether the illness phase (early vs. late) modifies associations between these mediators and outcomes. Determining how the immune response to viral infection changes over the illness course is essential to defining the type and timing of novel therapeutics. Methods We analyzed data from two ICU cohorts that enrolled COVID-19 patients: CHROme (n = 101, 3 hospitals) and SARI-Prep (n = 263, 7 hospitals). We measured Type I, II, and III interferon levels and a panel of 7 interferon-inducible mediators from plasma samples collected at ICU admission. Five of the mediators (IFN-L, IFN-G, CCL5, CXCL10, PD-L1) met QC standards and were carried forward. Our primary analysis used multivariable proportional odds logistic regression models adjusted for age, sex, and race to estimate pooled ORs for associations between mediators and day 14 NIH ordinal scale scores (no o2=4, supplemental o2=5, HFNC/NIPPV=7, IMV/ECMO=7, death=8). Results Enrolled subjects were admitted to the ICU a median of 4 days following SARS-CoV-2 positivity (Panel A). Higher CXCL10 and sPD-L1 levels at ICU admission were associated with worse day 14 clinical status, but higher CCL5 levels were associated with better outcomes (Panel B). The timing of enrollment in the course of infection modified associations between IFN-lambda or sPD-L1 and the primary outcome. Higher levels of these mediators tracked with worse outcomes in early enrollment (≤4d), but with better outcomes in late enrollment (4d) (Panel C). Higher levels of CCL5 at admission were associated with lower viral load (via nasal swab PCR), whereas higher levels of sPD-L1 were associated with higher viral load (Panel D). In serially-sampled subjects still admitted and alive 14 days after ICU admission (n = 130), persistent elevation of PD-L1 was associated with death in the next 2 weeks, whereas rising levels of CCL5 were associated with survival (Panel E). Conclusions We identified associations between ICU admission plasma levels of multiple interferon-associated mediators and day 14 clinical status, however we posit these associations differ by phase of illness. Higher levels of the NK and T cell chemokine CCL5 on admission were associated with lower viral load, and increases during the first 2 weeks of hospitalization were associated with 28d survival. Our findings suggest CCL5 may have a robust protective role in severe COVID-19, and that phase-of-viral-illness is a key variable that should be accounted for in future ICU studies of interferon-associated mediators. This abstract is funded by: None