Mapping Interactions Between Cytokines, Chemokines, Growth Factors, and Conventional Biomarkers in COVID-19 ICU-Patients

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyperinflammation with cytokine and chemokine release, alongside elevations in conventional laboratory biomarkers such as C-reactive protein (CRP), ferritin, and procalcitonin (PCT). However, the interplay between cytokines, chemokines, growth factors (CCGFs), and standard biomarkers remains incompletely understood. Therefore, we aimed to evaluate associations between CCGFs and conventional biomarkers from a broad aspect, utilizing the prospective PronMed cohort of critically ill COVID-19 patients admitted to the intensive care unit (ICU) at Uppsala University Hospital. Plasma concentrations of 92 CCGFs were analyzed in each patient using the Olink Target 96 Cardiovascular II panel and analyzed in relation to conventional biomarkers and peripheral blood cell counts. Associations were evaluated using Spearman rank correlations with Benjamini-Hochberg correction for multiple testing. A total of 114 patients (median age 61 years (IQR: 19), 75% male, median SAPS-3 52 (IQR: 10) were included. Significant correlations confirmed CRP as a robust surrogate of cytokine-driven inflammation. Ferritin was strongly associated with macrophage-related markers, including IL-18, sCD163-related factors, and PARP1. PCT correlated with a wide range of CCGFs, including ADM, PGF, TRAILR2, and IL-6. Blood cell subsets also showed distinct associations with CCGFs, suggesting functional connections between cytokine signaling and hematological disturbances. Our findings demonstrate that conventional biomarkers of inflammation in COVID-19 reflect complex and distinct interaction patterns with cytokines, chemokines, and growth factors. Mapping these associations improves understanding of COVID-19 immunopathology and may inform biomarker-guided risk stratification in critical illness.