Serum Markers Associated with Disease Severity in a Bosnian Hemorrhagic Fever with Renal Syndrome Cohort

Abstract

Puumala orthohantavirus (PUUV) is endemic in Europe and can cause hemorrhagic fever with renal syndrome (nephropathia epidemica). Disease features include fever, thrombocytopenia, and acute kidney injury (AKI). This retrospective cohort study of forty PUUV patients aims to characterize associations of serum immunological, hemostatic or kidney injury markers to disease severity. While interleukin-18 (IL-18) was significantly increased in severely thrombocytopenic patients (<100 × 109 platelets/L) compared to patients with higher platelet counts, RANTES was significantly decreased in these patients. These data suggest that patients with significant thrombocytopenia might have experienced pronounced Th1 immune responses. When kidney dysfunction was used as the primary disease outcome, recently identified AKI biomarkers (Cystatin C, insulin-like growth factor-binding protein 7, Nephrin, and trefoil factor 3) were significantly upregulated in patients with severe PUUV infection, defined as the estimated glomerular filtration rate (eGFR) below 30 m/min/1.73 m2. The increased expression of these markers specifically indicates pathology in glomeruli and proximal tubuli. Furthermore, E-selectin was significantly higher while interferon gamma-induced protein 10 (IP-10) was significantly lower in PUUV patients with more severe kidney dysfunction compared to patients with higher eGFR-values. Increased E-selectin illustrates the central role of endothelial cell activation, whereas decreased IP-10 could indicate a less important role of this cytokine in the pathogenesis of kidney dysfunction.

Keywords: Puumala virus; hemorrhagic fever with renal syndrome; nephropathia epidemica; orthohantavirus; patient cohort; serum markers; virus neutralization.

Figure 1

Serum markers correlated with severe thrombocytopenia in PUUV patients. Patients were considered to display significant thrombocytopenia when platelet counts were <100 × 10⁹/L. Statistical significance was calculated by the Mann–Whitney U test; *, indicating a p-value < 0.05, and **, indicating a p-value < 0.01, were considered statistically significant. Abbreviations: IL-18, interleukin-18.

Figure 2

Serum markers correlated with severe kidney dysfunction in PUUV patients. Patients with severe kidney dysfunction were identified by eGFR-values <30 m/min/1.73 m². Statistical significance was determined by the Mann–Whitney U test; *, indicating a p-value <0.05, and **, indicating a p-value < 0.01, were considered statistically significant. Abbreviations: IGFBP-7, insulin-like growth factor-binding protein 7; IP-10, interferon gamma-induced protein 10; TFF3, trefoil factor 3.