Longitudinal Analysis of Traditional Inflammatory Markers (IL‐6, CRP) Juxtaposed With Heparin‐Binding Protein (HBP) and Serum Amyloid A Protein Component (SAA) During Acute Infection and Convalescence From COVID‐19 Infection in the Context of Initial

<b>Purpose:</b> Characterization of immune system heterogeneity in COVID-19 patients by comparing the inflammatory markers heparin-binding protein (HBP), serum amyloid A protein (SAA), IL-6, and C-reactive protein (CRP) in relation to viral burden, immune response, and tissue damage. Also, determine if prolonged elevations in these markers are associated with long-term symptoms of COVID-19. <b>Methods:</b> This study enrolled 106 hospitalized patients with PCR-confirmed diagnoses of COVID-19. Blood samples were collected within 24 h of admission (<i>t</i> _24h), at 48 h (<i>t</i> _48h), 7 days (<i>t</i> _7d), and long-term, greater than 1 month, post discharge (<i>t</i> _LongTerm). Serum levels of HBP, SAA, IL-6, and CRP were measured using a commercial point-of-care device. Viral burden was assessed via serum viral spike S-protein serum levels and specific immunoglobulins G, M, and D against S&N proteins, and SARS-CoV-2 proteins were quantified. Tissue injury was evaluated by measuring HMGB-1 levels. Clinical data were reviewed retrospectively. Healthy individual samples served as controls. <b>Results:</b> COVID-19 patients exhibited significantly elevated serum HBP and SAA compared to healthy controls. SAA levels normalized over 1 month, whereas HBP, CRP, and IL-6 remained persistently elevated. Patients requiring intensive care unit (ICU) admission, endotracheal intubation, or extracorporeal membrane oxygen (ECMO) demonstrated higher CRP, IL-6, and HBP at initial assessment. However, after 48 h, only IL-6 was elevated in patients who subsequently expired. No significant correlations emerged between serum HBP levels and HMGB-1, viral spike protein levels, or antibodies against SARS-CoV-2 proteins. Pre-existing or acquired comorbidities did not significantly influence HBP or SAA concentrations. An analysis of biomarker profiles identified four distinct patient clusters, each characterized by unique inflammatory patterns that remained stable over time. Specifically, Cluster 1 exhibited low IL-6 with high SAA and CRP. Cluster 2 had low HBP with the highest IL-6. Cluster 3 demonstrated low SAA and CRP levels, and Cluster 4 exhibited robust inflammatory responses across all markers except IL-6. <b>Conclusions:</b> The persistence of inflammatory markers suggests ongoing inflammatory responses post-COVID-19 infection. Significant heterogeneity observed in inflammatory responses upon admission indicates multiple distinct inflammatory phenotypes, which may have implications for clinical outcomes and management strategies.