Beyond CRP and SAA: Proteomics reveals a combined CR2 and VSIG4 signature for severity in influenza and COVID-19 pneumonia.

BACKGROUND: Innate immune molecules like CRP and SAA are established biomarkers in bacterial pneumonia, but their role in viral CAP is rarely investigated. METHODS: Untargeted proteomics was analyzed in two discovery cohorts: an influenza-associated severe CAP cohort of 16 patients and 16 controls; and a longitudinal COVID-19-dominant CAP cohort of 15 patients at three time points and 15 controls. Analyses focused on innate immune molecules. Selected candidates were evaluated by ELISA using available samples from the discovery cohorts and further validated in an independent validation cohort of 28 viral CAP patients and 28 HCs. RESULTS: CRP, SAA1, and SAA2 were consistently upregulated across both cohorts. In the COVID-19 cohort stratified by severity, the invasive mechanical ventilation subgroup showed elevated VSIG4 and decreased CR2. ELISA/ROC analyses confirmed SAA1/SAA2 significantly elevated in CAP patients, with excellent diagnostic performance (AUC=1.000) but limited severity discrimination. Public COVID-19 cohorts further supported increased VSIG4 expression in severe and fatal disease. The CR2 and VSIG4 combination showed good performance in distinguishing patients requiring invasive mechanical ventilation from those on oxygen/non-invasive support (AUC=0.854) or no support (AUC=0.969). CONCLUSION: CRP, SAA1, and SAA2 are reliable diagnostic markers for CAP, while CR2 + VSIG4 may aid severity stratification. These findings highlight innate immune molecules as potential biomarker panels for diagnosing and risk assessment in viral respiratory infections.