Differences in the inflammatory response and outcome among hospitalized patients during different waves of the COVID-19 pandemic

Violeta Briciu ¹ Daniel Corneliu Leucuta ^2* Monica Muntean ¹ Amanda Radulescu ¹ Cristina Cismaru ¹ Adriana Topan ¹ Lucia Herbel ³ Melinda Horvat ¹ Mirela Flonta ³ Mihai Calin ³ Roxana Dobrota ³ Mihaela Lupse ¹

• ¹ Department of Infectious Diseases and Epidemiology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
• ² Department of Medical Informatics and Biostatistics, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania
• ³ The Clinical Hospital of Infectious Diseases, Cluj-Napoca, Romania

The aim of this study was to evaluate differences in inflammatory biomarkers and association with outcomes in hospitalized patients with COVID-19 during four pandemic waves determined by different SARS-CoV-2 variants of concern. We explored if laboratory biomarkers of inflammation adjusted to patients' comorbidities, age, and vaccination status correlated with severity and mortality. A retrospective study on 8614 consecutive hospitalized COVID-19 patients was conducted in a Romanian hospital on a three years interval (February 2020-May 2023). Data collected included demographics, duration of hospitalization, comorbidities, vaccination status, COVID-19 severity, outcome, and markers of inflammation from first blood test performed at admittance (CRP, fibrinogen, ferritin, lactate dehydrogenase (LDH), procalcitonin (PCT), IL-6, D-dimer, complete blood count). Systemic inflammatory indexes like NLR (neutrophile-to-lymphocyte ratio), derived neutrophile to leucocyte ratio (dNLR), LMR (lymphocyte-to-monocyte ratio), PLR (platelets-tolymphocyte ratio), NPR (neutrophile-to-platelets ratio), SII (Systemic Immune-Inflammation Index) and SIRI (systemic inflammation response index) were calculated. The Delta wave, characterized by the longest hospitalizations and the highest rates of severe cases and mortality, showed significant elevations in inflammatory biomarkers. CRP, fibrinogen, ferritin, IL-6, D-dimer, and LDH increase in their median values from Wuhan to Delta wave, and decrease in Omicron, except PCT which increases from Alpha to Omicron wave. Leucocytes and neutrophils increase in their median values from Wuhan to Delta wave, and decrease in Omicron while an inverse pattern can be observed for lymphocytes, monocytes and basophils. The best inflammatory biomarkers for predicting severe/critical COVID-19 were CRP, dNLR, LDH, and NLR, (cut-off of 3.41 mg/dL, 3.05, 262 U/L and 4.5) while for predicting death outcome were dNLR, NLR, LDH and NPR (cut-off of 3.6, 4.9, 278 U/L and 0.02). For all these biomarkers the AUCs surpassed 0.8. In the multivariate analysis the highest adjusted OR for death were described for dNR (8.46), NLR (7.59), LDH (5.99) and NPR (5.5), while increased lymphocytes decrease the most the odds of death (0.16). The study, underscoring the dynamic nature of COVID-19, brings a detailed analysis on biomarkers trends that could provide valuable information for early identification of patients at risk for severe outcome, allowing for timely interventions.