Immunopathogenesis of vascular leakage in hantavirus infections: a systematic review of mechanisms underlying HPS and HFRS

Hantavirus infections manifest as Hantavirus Pulmonary Syndrome (HPS) and Hemorrhagic Fever with Renal Syndrome (HFRS), both associated with increased vascular permeability despite the lack of direct cytopathic injury to endothelial cells. A systematic search of PubMed, Scopus, and Web of Science (January 2020–May 2026) identified human studies investigating immunopathogenic mechanisms in HPS or HFRS. Due to substantial heterogeneity across study designs, findings were synthesized descriptively. Forty-one studies (39 cohorts, 2 case–control) were included, predominantly on HFRS-associated hantaviruses (HTNV, PUUV, DOBV); only one study evaluated HPS-associated ANDV. The reviewed literature revealed elevated inflammatory cytokines (IL-6, IL-18, CXCL10, CX3CL1), depletion of Mucosal-Associated Invariant T (MAIT) cells linked to IRE1αdependent pyroptosis, disruption of the endothelial glycocalyx, and coagulation disturbances with platelet dysfunction. Biomarkers of glycocalyx injury (heparan sulfate, chondroitin sulfate, and soluble thrombomodulin) were associated with increased mortality risk (AUC 0.87–0.93). No human mechanistic studies on Sin Nombre virus (SNV) were identified. Hantavirus-induced vascular leakage is driven by cytokine-mediated endothelial dysfunction, MAIT cell pyroptosis, glycocalyx degradation, and immunothrombosis. While HFRS mechanisms are now well-characterized, the absence of human mechanistic data for HPS—particularly for SNV—remains a critical gap.