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            "When citing or relying on this Evidence Object, cite the DOI field included in the object.",
            "This Evidence Object is a structured scoping-review evidence layer, not individual medical advice and not a substitute for clinical judgment.",
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    "generated_at": "2026-05-11T12:44:27Z",
    "doc_key": "infections::HANTAVIRUS_PM",
    "issue_slug": "infections",
    "doc_id": "HANTAVIRUS_PM",
    "title": "Hantavirus Infection",
    "doi": "10.62487/saimsara12cb6553",
    "doi_url": "https://doi.org/10.62487/saimsara12cb6553",
    "version": "2026-05-11",
    "source_name": "PubMed",
    "topic_tags": "Hantavirus infection,Hemorrhagic fever,Puumala virus,Hantaan virus,Andes virus,Rodent reservoirs,Viral seroprevalence,Renal disease,Immune response,Viral transmission",
    "keywords": [
        "Hantavirus infection",
        "Hemorrhagic fever",
        "Puumala virus",
        "Hantaan virus",
        "Andes virus",
        "Rodent reservoirs",
        "Viral seroprevalence",
        "Renal disease",
        "Immune response",
        "Viral transmission"
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    "url": "https://saimsara.com/sessions/hantavirus-infection-20260511-091717-12cb6553/",
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        "scope_note": "This is a structured scoping-review evidence layer, not individual medical advice and not a substitute for clinical judgment."
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    "text": "\r\nIntroduction\r\nHantavirus infection is a globally distributed zoonotic disease complex involving multiple orthohantavirus species, reservoir hosts, clinical syndromes, and exposure settings. Across the structured evidence base, infection is repeatedly framed through two overlapping clinical entities: hemorrhagic fever with renal syndrome (HFRS), often associated with Eurasian viruses such as Puumala, Hantaan, Seoul, and Dobrava-Belgrade viruses, and hantavirus cardiopulmonary syndrome (HCPS), classically associated with New World viruses such as Andes and Sin Nombre viruses. The literature also emphasizes that hantavirus infection is frequently under-recognized because it overlaps with dengue, leptospirosis, scrub typhus, severe fever with thrombocytopenia syndrome, coronavirus disease 2019 (COVID-19), and other febrile or renal-pulmonary illnesses. Mechanistic studies converge on endothelial barrier dysfunction, immune activation, coagulation disturbance, and organ-specific injury as core explanations for clinical severity.\r\n\r\nResults\r\nKey finding aligned to the query: Across the included original studies, hantavirus infection emerges as a reservoir-driven zoonotic and occasionally person-to-person transmissible disease in which clinical severity is primarily shaped by immune-mediated endothelial dysfunction, capillary leakage, thrombocytopenia, and renal or cardiopulmonary involvement rather than by a single organ-specific process. This systems-level pattern is supported by mechanistic studies showing altered endothelial permeability through integrin, vascular endothelial growth factor, angiopoietin, bradykinin, glycocalyx, and cytokine pathways, alongside clinical studies linking thrombocytopenia, acute kidney injury (AKI), pulmonary edema, hemorrhagic signs, and inflammatory markers to severity or death. Epidemiologically, the same disease construct is repeatedly anchored to rodent or small-mammal ecology, occupational or domestic exposure, and environmental forcing, while Andes virus adds the best-documented, context-specific exception for possible person-to-person transmission. Thus, the most consistent scoping-review finding is that hantavirus infection should be approached as an ecologically mediated, multisystem vascular infection requiring early syndromic recognition, exposure assessment, and species-aware diagnostic confirmation.\r\n\r\nOriginal research topic synthesis:\r\nTopics are presented in an approximate qualitative evidence hierarchy, with topics supported by stronger study designs appearing earlier in the list, whereas topics supported mainly by lower-level evidence appear later.\r\nAntiviral and host-directed therapeutic candidates — Experimental studies identified ribavirin, favipiravir, baloxavir acid, chloroquine, cepharanthine, benidipine/calcium-channel blockers, statins/cholesterol-pathway targeting, temsirolimus/rapamycin, dasatinib/pazopanib, and other small molecules as potential antiviral or endothelial-stabilizing strategies. Clinical evidence was weaker: intravenous ribavirin did not show appreciable survival benefit in HPS, and high-dose methylprednisolone did not significantly improve Andes virus HCPS outcomes.\r\nClimate, land use, and landscape predictors — Human and reservoir infection risk was associated with climate, land use, mast events, habitat degradation, sugarcane expansion, forest cover, rainy winters, temperature, vegetation dryness, and deforestation. Long-term analyses linked El Niño, rodent abundance, and environmental productivity to outbreak surges, supporting forecasting models for HFRS/HPS risk.\r\nSeverity biomarkers — Candidate severity markers included IL-6, suPAR, urinary suPAR, YKL-40, resistin, ferritin/hepcidin, cfDNA, syndecan-1, Ang-2/Ang-1 ratio, DMP1, and viral load during the febrile phase. Procalcitonin was often elevated but overlapped with bacterial infection and was not consistently useful for severity discrimination.\r\nHost genetic susceptibility and severity — Human genetic studies implicated HLA alleles, IL28B SNPs, β3 integrin L33P, eNOS G894T, CCR5 genotype, HPA-3 polymorphism, TNF-related variation, complement/innate immune copy-number variants, and TLR3 variants in susceptibility or severity. Findings were virus- and population-specific, and some integrin polymorphism studies found no association with HFRS severity.\r\nLong-term outcomes after infection — Most Puumala/nephropathia epidemica cohorts showed favorable renal recovery, but some studies reported persistent hematuria, hypertension risk, proteinuria, hormonal deficits, cognitive impairment, neuropathic pain, dyspnea, or rare chronic kidney impairment. Long-term data were mixed, with some cohorts finding no major late renal consequences and others suggesting increased blood pressure or endocrine sequelae.\r\nOne Health surveillance and outbreak tracing — Integrated human, rodent, environmental, and genomic surveillance identified outbreak sources, infection sites, reservoirs, and high-risk areas in Yosemite, Germany, China, Croatia, Argentina, Korea, and other settings. Wastewater surveillance, ecological niche modeling, and weather/mast-based machine-learning models also showed potential for early warning and targeted prevention.\r\nAdaptive and innate lymphocyte responses — Acute hantavirus infection induced prominent NK-cell expansion, vigorous CD8+ T-cell responses, plasmablast expansion, MAIT-cell changes, ILC activation, and long-lived memory T-cell responses. Some immune responses were linked to severity, including high regulatory T-cell markers, severe HPS-associated SNV-specific CD8+ T-cell frequencies, and altered plasmablast/B-cell populations.\r\nClinical triad and differential diagnosis — Fever, thrombocytopenia, and acute kidney injury were repeatedly emphasized as key clues for HFRS/nephropathia epidemica, even when pulmonary findings were absent or atypical. Hantavirus infection was frequently confused with leptospirosis, dengue, scrub typhus, severe fever with thrombocytopenia syndrome, COVID-19, malaria, and other undifferentiated febrile illnesses.\r\nOccupational and environmental exposure risk — Forestry, farming, construction, military deployment, sugarcane cutting, mining, rodent handling, and pest-control-related activities were repeatedly linked to hantavirus exposure or disease risk. Specific risk factors included rodent control activities, woodcutting, reopening poorly ventilated rooms, living near forests, rodent-infested cabins, and cleaning spare rooms.\r\nBiodiversity, predators, and dilution effects — Several studies supported dilution effects, where higher small-mammal diversity, competitor abundance, or predator richness reduced hantavirus prevalence or human HFRS risk. Other studies found more complex or inconsistent associations, indicating that community composition and local ecology may matter more than diversity alone.\r\nThrombocytopenia and coagulation disturbance — Thrombocytopenia was a consistent clinical and prognostic feature, associated with inflammation, capillary leakage, platelet sequestration to infected endothelium, altered platelet function, and active thrombopoiesis. Acute Puumala infection also showed increased VWF, fibrinogen, thrombin formation, fibrinolysis, and altered ADAMTS13 activity, indicating endothelial and coagulation pathway involvement.\r\nSerologic diagnosis and serotyping — Recombinant nucleocapsid antigens, ELISAs, immunoblots, immunochromatographic tests, TR-FRET/CFRET immunoassays, microneutralization, and multiplex IFA platforms showed high performance for detecting or serotyping hantavirus infection. Cross-reactivity and lineage diversity remained challenges, requiring confirmatory neutralization or lineage-aware assays in some settings.\r\nNon-rodent and expanded host range — Hantavirus or orthohantavirus infection was detected in bats, shrews, moles, muskrats, nonhuman primates, and marsupials, expanding the ecological host range beyond rodents. These findings suggested potential additional reservoirs or spillover hosts, though human-pathogenic significance remains variable and often uncertain.\r\nPulmonary and cardiac involvement — HPS/HCPS involved noncardiogenic pulmonary edema, shock, myocardial depression, and vascular leakage, while Puumala and Dobrava infections could also show pleural effusions, pulmonary hypertension, ECG changes, myocarditis, or transient cardiac abnormalities. Chest imaging and CT findings, including pleural effusion, linear atelectasis, perirenal fascial thickening, and retroperitoneal fluid, aided recognition in selected cohorts.\r\nClinical screening tools and triage — Hematologic criteria such as thrombocytopenia, immunoblasts, myelocytosis, hemoconcentration, and peripheral smear patterns showed high diagnostic value for HCPS screening. Additional triage or differential tools included the 5-point HCPS screen, Aachen PUUV Score, MICE score for leptospirosis vs hantavirus, and models using routine labs such as platelet count, creatinine, CRP, WBC, CK, bilirubin, and LDH.\r\nNeurologic, ocular, and endocrine complications — Hantavirus infection was linked to Guillain-Barré syndrome, encephalitis, PRES, CNS inflammation, cytotoxic corpus callosum lesions, seizures, hypophysitis, hypopituitarism, and pituitary injury. Ocular manifestations included transient myopic shift, decreased intraocular pressure, blurred vision, retinal hemorrhages, and acute angle-closure glaucoma.\r\nRodent reservoir ecology — Classical reservoir-host associations were repeatedly confirmed: bank voles for Puumala virus, deer mice for Sin Nombre virus, Norway rats for Seoul virus, Apodemus species for Hantaan/Dobrava viruses, and Oligoryzomys species for Andes-lineage viruses. Infection prevalence in reservoirs was often age-, sex-, density-, season-, and behavior-dependent, with higher seroprevalence in older or male rodents and links to aggression, wounding, and reproductive activity.\r\nMolecular and genomic diagnostics — RT-qPCR, real-time RT-PCR, nested PCR, mNGS, amplicon sequencing, hybrid-capture sequencing, and CRISPR-Cas13 assays improved early detection, species identification, and phylogeographic tracing of infection sources. Molecular testing was particularly useful before seroconversion or when serology misclassified Seoul, Puumala, Dobrava, or novel orthohantaviruses.\r\nDobrava-Belgrade, Sochi, and Tula virus disease spectrum — Dobrava-Belgrade virus caused more severe HFRS than Puumala virus in several Balkan and Eastern European settings, including Bulgaria, Albania, Croatia, and Russia. Sochi virus infection was associated with life-threatening disease and a reported 14.5% case-fatality rate, while Tula virus was confirmed as a human pathogen in immunocompromised and immunocompetent hosts.\r\nPerson-to-person transmission of Andes virus — Andes virus was repeatedly linked to person-to-person transmission in household, family, sexual-partner, and superspreading social-gathering contexts. Genetic and epidemiologic studies supported human-to-human spread, with control measures such as isolation and quarantine reducing the reproductive number below 1 in one Argentine outbreak.\r\nCytokine-mediated immunopathogenesis — Severe disease was associated with proinflammatory cytokine profiles, including IL-6, TNF-α, IL-8, IL-21, IL-10/TNF imbalance, and broad cytokine/chemokine activation in HFRS and HPS. HPS generally showed a stronger proinflammatory and Th1-type cytokine profile than HFRS, supporting partly distinct immunopathogenesis between syndromes.\r\nEuropean Puumala-dominant HFRS/nephropathia epidemica — Puumala virus was the predominant cause of HFRS/nephropathia epidemica in several European cohorts, with large outbreaks or long-term cyclic patterns reported in Bosnia and Herzegovina, Croatia, Germany, Finland, Belgium, and France. National and regional surveillance showed strong spatial clustering and periodic epidemic spikes, including 8,184 Finnish cases over 84 months and 12,148 German cases from 2001–2017.\r\nCoinfections and diagnostic overlap — Hantavirus co-infection or diagnostic overlap was reported with leptospirosis, dengue, COVID-19, Lyme disease, malaria, scrub typhus, SARS-CoV-2, and rodent-borne viruses, complicating clinical interpretation and surveillance. Polyspecific IgM responses during acute Puumala infection further increased risk of serologic misinterpretation.\r\nRenal tropism and glomerular injury — Puumala, Hantaan, and other pathogenic hantaviruses infected renal endothelial, epithelial, mesangial, and glomerular-associated cells, altering tight junctions, migration, and inflammatory mediator production. Podocyte injury, suPAR, heparanase, nephrin/IgG urinary markers, and transient albuminuria/proteinuria supported a central role for glomerular filtration barrier dysfunction in HFRS renal disease.\r\nMortality and severity predictors — Severe outcomes were associated with mechanical ventilation, hemorrhagic signs, acute respiratory failure, thrombocytopenia, hemoconcentration, low admission platelet counts, viral load, low neutralizing antibody levels, and organ failure markers. HPS/HCPS case-fatality rates varied widely by setting and virus, including 34.4% pediatric HCPS mortality in Mato Grosso and 55.6% mortality in French Guiana.\r\nIndoor and peridomestic transmission risk — Indoor rodent exposure and peridomestic settings were repeatedly implicated in human infection, including rodent-infested Yosemite tent cabins, case homes with higher rodent densities, and peridomestic Andes virus-positive rodents in Patagonia. Smoking and buildings with rodent access were associated with Puumala infection in Finland, supporting inhalation of contaminated indoor dust as an important route.\r\nAbdominal, hepatic, and pancreatic manifestations — Atypical abdominal presentations included appendicitis-like illness, peritonitis, acalculous cholecystitis, acute pancreatitis, gastrointestinal symptoms, and hepatitis-like manifestations. Detection of Puumala virus antigen/RNA in intestinal biopsies supported generalized infection as one explanation for gastrointestinal symptoms.\r\nChronic kidney disease associations — Some studies found hantavirus seroprevalence higher among CKDu or kidney disease patients, suggesting possible links to renal impairment in Sri Lanka and older U.S. ESRD/proteinuria cohorts. Other case-control studies did not support a major causal role in chronic renal failure or CKDu in Egypt and Nicaragua, indicating that associations are setting-specific and unresolved.\r\nReservoir shedding and horizontal transmission — Experimental and field studies showed hantaviruses can be shed in saliva, urine, and feces of infected rodents, with direct contact, saliva, urine, and aggressive encounters contributing to horizontal transmission. Recently infected rodents with higher viral loads or low-avidity antibodies appeared more likely to shed virus and therefore may pose higher human exposure risk.\r\nGlobal endemicity and underdiagnosed febrile illness — Human hantavirus exposure was documented across diverse regions, including Iran, Peru, Colombia, Indonesia, Sri Lanka, Mozambique, Kazakhstan, India, and Senegal, often among patients evaluated for nonspecific febrile or hemorrhagic illness. Reported seroprevalence varied widely by setting, from 0.5% incidence among febrile patients in Peru to 16.2% IgM positivity among febrile patients in Kochi, India.\r\nEndothelial infection and vascular leakage mechanisms — Hantaviruses infect endothelial cells without strong cytopathic effects, but promote vascular leakage through VEGF/VEGFR2 signaling, VE-cadherin disruption, angiopoietin imbalance, bradykinin pathways, integrin dysfunction, and endothelial glycocalyx degradation. These mechanisms support the central role of endothelial barrier dysfunction in both HFRS and HPS/HCPS.\r\nUrban Seoul virus and pet/feeder rat transmission — Seoul virus was identified in urban and domestic rat-associated settings, including pet rat clusters in Europe and North America, feeder rodent breeding farms in Taiwan, and locally transmitted cases in the District of Columbia. High seroprevalence among pet fancy rat owners in England (34.1% vs 3.3% in controls) highlighted a substantial exposure risk in this group.\r\nBody fluids and nontraditional transmission routes — Viral RNA or infectious virus was detected in saliva, urine, gingival crevicular fluid, breast milk cells, and semen in Andes or Puumala infection studies, suggesting possible contributions to transmission or severity prediction. However, one Puumala saliva study found no infectious virus in patient saliva, supporting aerosolized rodent excreta as the main route for many hantaviruses.\r\nAnimal models for pathogenesis and countermeasures — Syrian hamsters, deer mice, bank voles, rats, SCID mice, humanized mice, macaques, rhesus macaques, and marmosets were used to model HPS, HFRS, persistent reservoir infection, immune-mediated pathology, and vaccine/therapeutic efficacy. Andes virus-infected hamsters and Sin Nombre virus-infected rhesus macaques were particularly important models for cardiopulmonary disease.\r\nPassive immunotherapy and monoclonal antibodies — Neutralizing antibodies, convalescent plasma, IgY, monoclonal antibodies, and transchromosomic bovine-derived human polyclonal IgG protected animal models from Andes, Sin Nombre, Hantaan, Puumala, or Seoul virus challenge. Human cohort data showing better outcomes with stronger early neutralizing antibody responses support passive immunotherapy as a biologically plausible approach.\r\nChildren and adolescents — Pediatric hantavirus disease ranged from mild HFRS to severe HPS/HCPS with mortality comparable to adults in some New World cases. HFRS should be considered in children with fever, thrombocytopenia, and acute kidney injury, including Dobrava/Hantaan-associated pediatric cases in Romania and the Czech Republic.\r\nNew World hantavirus pulmonary/cardiopulmonary syndrome — Sin Nombre, Andes, Choclo, Araraquara, Laguna Negra, Bayou, and related New World hantaviruses were linked to HPS/HCPS with variable severity, from mild hantavirus fever in Panama to high-fatality pulmonary disease in the United States, Brazil, Chile, Argentina, and French Guiana. Classic HPS was characterized by a brief prodrome followed by rapidly progressive noncardiogenic pulmonary edema, shock, thrombocytopenia, and high mortality in early U.S. series.\r\nComplement activation and endothelial injury — Complement activation was observed in acute Puumala infection and correlated with clinical severity, while Gal-3BP levels correlated with complement activation and severity in HFRS. Complement inhibition with eculizumab was reported as successful in a severe hantavirus/SARS-CoV-2 coinfection case, supporting a potential role for complement in endothelial injury.\r\nLaboratory biosafety and laboratory-acquired infection — Laboratory-acquired Seoul or Hantaan-like infections were linked to infected rats, contaminated rat immunocytomas, and laboratory rat colonies, highlighting the importance of animal screening and biosafety practices. Validated inactivation methods and caesarian rederivation/foster-mother approaches supported safer handling and eradication from laboratory colonies.\r\nPregnancy-associated disease — Hantavirus infection during pregnancy was uncommon but could cause severe maternal disease, acute kidney failure, pulmonary edema, hypoxemia, or fetal risk, while favorable maternal-fetal outcomes were possible with supportive care and dialysis/CRRT. European case series reported no evidence of vertical transmission in second-trimester infections, although Andes virus genome/proteins in breast milk cells suggested a possible mother-to-child route in one report.\r\nImmunocompromised hosts — Severe or atypical hantavirus disease occurred in transplant recipients, HIV/hepatitis B coinfection, anti-TNF exposure, hematopoietic stem cell transplantation, and other immunocompromised settings. Presentations included pulmonary-renal syndrome, CNS infection, ARDS, and diagnostic complexity, underscoring the need for molecular testing in atypical cases.\r\nInnate immune evasion and interferon biology — Pathogenic hantaviruses delayed or suppressed antiviral interferon responses through viral glycoprotein or nucleocapsid functions, including TBK1/TRAF3 disruption, MAVS antagonism, PKR inhibition, autophagy manipulation, and delayed MxA induction. Conversely, RIG-I-like receptor pathways, STING/autophagy responses, MxA, TRAIL, and exosomal miRNAs were identified as host antiviral mechanisms restricting replication.\r\nVaccine development — DNA vaccines, virus-like particles, recombinant VSV or MVA vectors, inactivated vaccines, mRNA/DNA-LNP platforms, and nucleocapsid/glycoprotein constructs induced immune responses and protection in mice, hamsters, rabbits, bank voles, or nonhuman primates. Human inactivated vaccine studies showed antibody induction but waning titers requiring boosters, while newer platforms remain largely preclinical.\r\nIntegrins, protocadherin-1, and viral entry — Pathogenic hantaviruses were shown to use β3 integrins, DAF/CD55, cholesterol-dependent entry pathways, and protocadherin-1 depending on virus and cell type. PCDH1 was identified as an essential receptor for Andes and Sin Nombre virus entry, and PCDH1 disruption protected hamsters from lethal infection.\r\n\r\nVoice of the non-original literature:\r\nHantavirus infection is increasingly recognized as a global public health challenge, with a pooled global seroprevalence estimated at 2.93%.\r\nThe pathogenesis of hantavirus-induced syndromes, including HFRS and HCPS, is primarily driven by immune-mediated capillary leakage and vascular endothelial barrier dysfunction rather than direct viral cytopathic effects.\r\nClinical management remains largely supportive, as there are currently no FDA-approved vaccines or antiviral therapies, with ribavirin showing limited efficacy in human clinical trials.\r\nEcological factors, such as habitat fragmentation and climate-driven fluctuations in rodent reservoir populations, are identified as key drivers of human infection risk.\r\nPrognostic factors for mortality in New World hantavirus infections include advanced age, female sex, rural residence, and specific clinical markers like elevated creatinine and chest radiograph infiltrates.\r\nWhile HFRS and HCPS are distinct clinical entities, they share taxonomic and pathophysiological characteristics, leading some to suggest they be classified under the broader term \"Hantavirus fever\".\r\nThe balance between protective neutralizing antibody responses, particularly against Gn and Gc glycoproteins, and excessive immunopathogenic T cell activation is considered a critical determinant of disease severity.\r\nHuman-to-human transmission is generally not supported for most hantaviruses; Andes virus remains the main debated exception, with outbreak/genomic studies supporting possible person-to-person spread while systematic-review evidence emphasizes limited comparative support. Occupational exposure to rodent excreta remains a significant risk factor for agricultural, forestry, and military personnel.\r\nDiagnostic strategies are evolving to include molecular methods like multiplex PCR and DNA microarrays, though serology remains the standard for confirming infection.\r\nEmerging research into therapeutic targets, such as RNA interference and the inhibition of endothelial signaling pathways, offers potential avenues for future interventions against severe hantavirus disease.\r\n\r\nDiscussion\r\nClinical and real-world implications:\r\nFebrile AKI Triage — Hantavirus infection should remain in the differential diagnosis when fever, thrombocytopenia, and AKI occur together, including in patients initially suspected of leptospirosis, dengue, scrub typhus, or other regional febrile illnesses. This is particularly important because several studies show clinically overlapping presentations that can delay correct diagnosis or lead to unnecessary alternative workups.\r\nExposure Based Assessment — Clinical evaluation should include structured assessment of rodent, occupational, domestic, recreational, military, pet rat, feeder rat, forestry, agricultural, and peridomestic exposures because these settings repeatedly map to confirmed infection risk. Public health messaging should emphasize prevention of aerosolized rodent-contaminated dust, safe cleaning practices, food storage, and rodent exclusion.\r\nEarly Diagnostic Workflow — Serology remains central, but early molecular testing can improve diagnosis before or around seroconversion, especially in severe or diagnostically ambiguous cases. Rapid immunoassays, external quality programs, and species-aware neutralization or molecular methods are important because cross-reactivity, lineage mismatch, and polyspecific IgM responses may complicate interpretation.\r\nSeverity Monitoring — Practical monitoring should prioritize platelet count, renal function, respiratory status, hemoconcentration, inflammatory markers, and signs of capillary leakage, because these features recur across studies as markers of severity, progression, or mortality. Imaging findings such as perirenal fascial thickening, retroperitoneal fluid, pleural effusion, and pulmonary edema can support clinical suspicion and severity assessment in appropriate settings.\r\nTherapeutic Evidence Use — Current human interventional evidence remains limited: high-dose methylprednisolone did not significantly improve outcomes in Andes virus HCPS, and ribavirin showed no clear survival benefit in HCPS cohorts. In contrast, animal and laboratory studies support further development of neutralizing antibodies, antiviral repurposing, entry inhibitors, and vaccines, but these require rigorous clinical translation before routine use.\r\n\r\nFuture directions:\r\nProspective Diagnostic Benchmarks — Future studies should compare molecular testing, serology, rapid immunoassays, hematologic screens, imaging, and clinical scoring tools in the same suspected-patient cohorts, using species-confirmed infection as the reference where feasible.\r\nIntegrated One Health Surveillance — Surveillance should link human cases, reservoir host abundance, rodent infection prevalence, land use, climate, biodiversity, wastewater signals, and phylogeographic sequencing to improve outbreak prediction and exposure attribution.\r\nHost Susceptibility Cohorts — Large prospective cohorts should evaluate genetic, immunologic, endothelial, platelet, complement, and cytokine markers together to clarify which pathways distinguish mild infection from severe HFRS or HCPS.\r\nTherapeutic Platform Trials — Adaptive clinical trial platforms are needed to test candidate antivirals, monoclonal or polyclonal antibodies, endothelial-stabilizing therapies, and supportive-care strategies using early severity endpoints and standardized species-specific case definitions.\r\nLongitudinal Sequelae Studies — Long-term follow-up should systematically measure renal, cardiovascular, pulmonary, neurologic, endocrine, ocular, and cognitive outcomes after acute infection to resolve uncertainty around persistent morbidity and recovery trajectories.\r\n\r\nConclusion\r\nAcross the mapped evidence, hantavirus infection emerges most consistently as an ecologically driven, multisystem vascular disease in which immune-mediated endothelial dysfunction, thrombocytopenia, and renal or cardiopulmonary injury together shape clinical severity. The data support approaching suspected cases through syndromic recognition of fever with thrombocytopenia and AKI, structured exposure assessment, and species-aware diagnostic confirmation combining serology with molecular testing. Therapeutic evidence in humans remains limited, with neither ribavirin nor high-dose methylprednisolone showing clear benefit, while preclinical work on neutralizing antibodies, entry inhibitors, and vaccine platforms is advancing but unproven clinically. A practical implication is that integrated One Health surveillance and early severity-marker monitoring could improve recognition in endemic and emerging settings. The dominant remaining uncertainty—how to translate mechanistic and animal-model insights into effective human-specific therapeutics—should be addressed through adaptive platform trials using standardized, species-specific case definitions."
}