Inflammatory biomarker kinetics in COVID-19

ABSTRACT

RATIONALE Biomarkers such as procalcitonin (PCT), ferritin, and D-dimer are widely used to guide the management of COVID-19. In particular, PCT has been utilized as an indicator for secondary bacterial infection, and D-dimer for venous thromboembolism. To better understand the clinical significance of these biomarkers, we studied their kinetics in two contrasting populations patients with mild versus fulminant disease. METHODS: We conducted a retrospective cohort study of 739 adult patients hospitalized at Yale-New Haven Hospital with COVID-19 infection. Patients with mild disease were defined by recovery and eventual discharge;those with fulminant disease were defined by death during hospitalization. Patients were systematically tested for PCT, ferritin, and D-dimer;each was measured at least once every 30h on average. Biomarker data was subjected to transformation to satisfy the assumptions for linear regression analysis. The Mann-Whitney U test was used for comparison throughout given non-normal data distributions. RESULTS: Upon admission, PCT and D-dimer levels were significantly higher in patients admitted to the intensive care unit (median 0.21 ng/mL and 1.30 mg/L FEU) than in those admitted to general medical wards (median 0.10 ng/mL and 0.92 mg/L FEU) (p<0.001;p<0.001). Terminal PCT values during admission were 11.9 times higher in patients with fulminant versus mild disease (p<0.001) and terminal D-dimer values were 3.5 times higher (p<0.001). Linear regression analysis was used to assess the dynamics of PCT and D-dimer over time. During the first 21 days, both biomarkers decreased markedly in patients with mild disease (negative slopes of -0.12 ng/mL/day and -0.10 mg/L FEU/day) and increased in those with fulminant disease (positive slopes of 0.13 ng/mL/day and 0.51 mg/L FEU/day) (p<0.01;p<0.001). Rather than demonstrating divergent patterns determined by complications such as bacterial superinfection and thromboembolism, all three biomarkers trended closely together, as PCT correlated with both ferritin (R=0.39) and D-dimer (R=0.31). CONCLUSION: Our analysis of biomarker kinetics suggests that PCT, ferritin, and D-dimer may represent general indices of COVID-19 severity rather than specific markers of secondary complications. These results are consistent with decades of studies in sepsis, which have shown nonspecific elevation of inflammatory biomarkers. Further research is necessary to clarify their clinical relevance and diagnostic utility in COVID-19. ∗Nota bene AC and GC contributed equally to this work and therefore may be listed in either order.