Hantavirus Hemorrhagic Fever with Renal Syndrome

Infectious Disease MONDO:0005784 Pathograph 21 Show in embeddings browser Hantavirus infectious disease Viral hemorrhagic fever

Hemorrhagic fever with renal syndrome (HFRS) is the Old World arm of human orthohantavirus disease, endemic across Asia and Europe and caused chiefly by Hantaan, Seoul, Puumala, and Dobrava-Belgrade viruses acquired from aerosolised rodent excreta. Hantaviruses enter endothelial cells, platelets, and macrophages via beta3 integrins and replicate in the microvascular endothelium without a cytopathic effect; disease instead arises from increased vascular permeability and acute thrombocytopenia, producing a characteristic staged illness of fever, hypotension, oliguric acute kidney injury, polyuric diuresis, and convalescence. It is the counterpart of the New World hantavirus cardiopulmonary syndrome, sharing the same endothelial target and leak physiology but centred on the kidney rather than the lung.

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12
Pathophys.
23
Phenotypes
3
Hypotheses
3
Gaps
21
Pathograph
6
Medical Actions
4
Subtypes
1
Differentials
1
Datasets
◆

Subtypes

4
Hantaan virus HFRS (classic Korean/epidemic hemorrhagic fever)
The classic severe form of HFRS, endemic in Asia (notably China and Korea) and carried by the striped field mouse Apodemus agrarius.
Show evidence (1 reference)
PMID:35384417 SUPPORT Human Clinical
"The old world hantaviruses, primarily Hantaan virus (HTNV), responsible for causing HFRS occurs endemically in Asia and Europe."
Identifies HTNV as the primary Old World agent of HFRS.
Seoul virus HFRS (rat-borne, urban and pet-rat associated)
Moderate-severity HFRS caused by Seoul orthohantavirus, whose reservoir is the globally distributed brown rat. Unlike the other agents it has an urban and pet/feeder-rat exposure route, and its presentation is often mild or atypical with only transient proteinuria and microhaematuria.
Show evidence (1 reference)
PMID:31319534 SUPPORT Human Clinical
"Given the mostly milder and atypical clinical presentation, sometimes even with preserved normal kidney function, the importance of simple but repeated urine examination is stressed, since initial but transient proteinuria and microhematuria are rarely lacking."
Describes the distinctively mild and atypical SEOV presentation.
Puumala virus HFRS (nephropathia epidemica)
The mild European form, also called nephropathia epidemica, carried by the bank vole and associated with mortality below 1%. It nonetheless produces genuine acute kidney injury and can be complicated by pituitary haemorrhage.
Show evidence (1 reference)
PMID:24750436 SUPPORT Human Clinical
"whereas Seoul virus causes moderate and Puumala virus and Saaremaa virus cause mild forms of disease with mortality rates <1%"
Places PUUV at the mild end of the HFRS severity spectrum.
Dobrava-Belgrade virus HFRS
The most severe European form, carried by Apodemus mice, with a case-fatality rate in the same 5-15% range as Hantaan virus.
Show evidence (1 reference)
PMID:24750436 SUPPORT Human Clinical
"In general, HFRS caused by Hantaan virus, Amur virus and Dobrava virus are more severe with mortality rates from 5 to 15%"
Places DOBV with HTNV at the severe end of the spectrum.
◈

Mechanistic Hypotheses

3
VEGF hypersensitisation and VE-cadherin degradation open the barrier
vegf_ve_cadherin_model CANONICAL
Evidence balance 1 support
The most widely cited explanation of hantavirus vascular leak: infection raises secreted VEGF and hypersensitises the endothelium to it, VEGF-R2 engagement dissociates from and internalises VE-cadherin, and the adherens junction is dismantled without cell death. Blocking VEGF-R2 prevents the VE-cadherin loss. It is curated as CANONICAL because it is the dominant published model, not because it is unchallenged; the direct experimental challenge is recorded on the node and in the kallikrein-kinin alternative.
Pathograph links
Noncytopathic microvascular endothelial infection -> VEGF-driven VE-cadherin destabilisation of endothelial adherens junctions DIRECT Infection raises secreted VEGF and lowers junctional VE-cadherin.
VEGF-driven VE-cadherin destabilisation of endothelial adherens junctions -> Increased vascular permeability and capillary leak DIRECT Loss of junctional VE-cadherin opens the paracellular route.
Show evidence (1 reference)
PMID:20810734 SUPPORT In Vitro
"These data implicate virus induction of VEGF and reduction in VE-cadherin in the endothelial cell permeability seen in HPS and suggest potential immunotherapeutic targets for the treatment of the disease."
The authors' own statement of the model.
Factor XII-dependent kallikrein-kinin activation and bradykinin drive the leak
kallikrein_kinin_model ALTERNATIVE
Evidence balance 1 support
An alternative proximal mechanism proposed after the VEGF model failed to reproduce in a three-dimensional endothelial/smooth-muscle vessel model. FXII binds and autoactivates on the infected endothelial surface, generating kallikrein activity and liberating bradykinin, which increases permeability; the effect is abolished by blocking bradykinin binding, FXIIa, or kallikrein. Its clinical corollary is that a bradykinin B2 receptor antagonist should help, which a single severe Puumala case report supports.
Pathograph links
Noncytopathic microvascular endothelial infection -> Factor XII-dependent kallikrein-kinin activation and bradykinin release DIRECT The infected endothelial surface promotes FXII binding and autoactivation.
Factor XII-dependent kallikrein-kinin activation and bradykinin release -> Increased vascular permeability and capillary leak DIRECT Liberated bradykinin acts on the endothelium to open the barrier.
Show evidence (1 reference)
PMID:23874198 SUPPORT In Vitro
"Here, we present evidence for a novel mechanism of hantavirus-induced vascular leakage involving activation of the plasma kallikrein-kinin system (KKS)."
The authors' statement of the alternative model.
Hantavirus-specific cytotoxic T cells attacking infected endothelium cause the leak
t_cell_immunopathogenesis_model ALTERNATIVE
Evidence balance 1 support
An immunopathological model in which capillary permeability results from cytotoxic T cells attacking endothelial cells presenting viral antigen. Curated as ALTERNATIVE rather than EMERGING because it is long-standing, and not as CANONICAL because its supporting clinical correlation is direction-inconsistent between HFRS and HCPS.
Pathograph links
Noncytopathic microvascular endothelial infection -> Cytotoxic T cell attack on antigen-presenting endothelium DIRECT Infected endothelium presents viral antigen and becomes a target of the hantavirus-specific cytotoxic T cell response.
Cytotoxic T cell attack on antigen-presenting endothelium -> Increased vascular permeability and capillary leak INDIRECT UNKNOWN INTERMEDIATES Cytotoxic attack on infected endothelium compromises barrier integrity.
Show evidence (1 reference)
PMID:21994770 SUPPORT Human Clinical
"These seemingly contradictory findings may suggest delicate balance in T cell responses between protection and immunopathogenesis. Both too strong and too weak T cell responses may lead to severe disease."
The review's own summary of why the T cell model cannot currently be promoted above the endothelial-signalling models.
?

Discussions and Knowledge Gaps

3
Which proximal mechanism actually opens the endothelial barrier in HFRS - VEGF-driven VE-cadherin degradation, factor XII-dependent kallikrein-kinin activation with bradykinin release, or cytotoxic T cell attack on antigen-presenting endothelium - and are they sequential, parallel, or artefacts of different model systems?
CONTROVERSY OPEN hfrs_leak_mechanism_competing_models
Attached to
pathophysiology#VEGF-driven VE-cadherin destabilisation of endothelial adherens junctions pathophysiology#Factor XII-dependent kallikrein-kinin activation and bradykinin release pathophysiology#Cytotoxic T cell attack on antigen-presenting endothelium pathophysiology#Increased vascular permeability and capillary leak
The three models are not merely underdetermined, they are in direct experimental tension. The VEGF/VE-cadherin model rests on infected endothelial monolayers; in a co-cultured endothelial/smooth-muscle vessel model, infected vessels retained integrity and showed no VE-cadherin degradation despite viral replication and the presence of VEGF, which is what motivated the kallikrein-kinin proposal. The T cell model has clinical correlations that run in opposite directions in HFRS and HCPS. The choice matters therapeutically: the models nominate anti-VEGF/VEGF-R2 blockade, a bradykinin B2 antagonist, and immunosuppression respectively - three interventions that are not interchangeable, and one of which (immunosuppression) could be harmful if the T cell response is protective.
Proposed experiments
Head-to-head test of the VEGF and kallikrein-kinin leak models in a three-dimensional vessel using an HFRS agent
exp_hfrs_leak_model_head_to_head_3d_vessel
Run the VEGF/VE-cadherin and kallikrein-kinin readouts side by side in the same co-cultured endothelial/smooth-muscle vessel model, infected with an HFRS-causing agent (Hantaan or Puumala) rather than the HPS-associated Andes virus, so that virus identity and model dimensionality stop being confounded with each other. Measure secreted VEGF, junctional VE-cadherin, FXIIa/kallikrein activity, liberated bradykinin, and barrier impedance in the same wells.
Decision criterion
If VE-cadherin degrades in the three-dimensional vessel with an Old World agent, the earlier negative result was virus-specific rather than model-specific; if bradykinin liberation but not VE-cadherin loss tracks the impedance fall, the kallikrein-kinin model is the better account of HFRS leak.
Serial plasma leak-mediator profiling across the five clinical phases of HFRS
exp_hfrs_serial_leak_biomarkers_patient_cohort
Measure plasma bradykinin, cleaved high-molecular-weight kininogen, VEGF, and soluble VE-cadherin serially in the same HFRS patient cohort, sampled by clinical phase, and test which mediator's rise precedes the onset of measured capillary leak and haemoconcentration.
Decision criterion
The mediator whose rise consistently precedes rather than follows the leak onset is the candidate proximal driver in humans; a mediator that rises only after leak is established is downstream or epiphenomenal.
Randomised trial of a bradykinin B2 receptor antagonist in severe HFRS
exp_hfrs_bradykinin_antagonist_rct
Run an adequately powered randomised controlled trial of icatibant or an equivalent bradykinin B2 receptor antagonist in severe HFRS, with capillary leak and progression to the oliguric phase as primary endpoints. This is the interventional test that the existing single case report cannot provide.
Decision criterion
A reduction in leak and in oliguric-phase entry would confirm the kallikrein-kinin arm as causal and therapeutically actionable in humans; a null result would leave the mechanism as an in-vitro finding without clinical reach.
Show evidence (1 reference)
PMID:23874198 SUPPORT In Vitro
"In contrast to results obtained in monolayers of cultured EC, we found that despite viral replication in both cell types as well as the presence of VEGF, infected in vitro vessels neither lost integrity nor displayed evidence of VE-cadherin degradation."
The direct experimental statement of the tension between the two endothelial-signalling models.
Does the VEGF/VE-cadherin leak mechanism, demonstrated with the HPS-associated Andes virus in human lung endothelial cells, actually operate in the Old World HFRS agents and in the renal microvasculature they injure?
HUMAN MODEL MISMATCH OPEN hfrs_vegf_evidence_from_new_world_virus
Attached to
pathophysiology#VEGF-driven VE-cadherin destabilisation of endothelial adherens junctions
The canonical VEGF/VE-cadherin evidence in this entry is generated with Andes virus - a New World, HCPS-causing agent - in primary human lung endothelial cells. HFRS is caused by different viruses and its defining organ injury is renal, not pulmonary. Old and New World hantaviruses are known to differ in cell tropism, so importing the mechanism wholesale risks asserting a lung-derived, HPS-derived model as HFRS pathophysiology. This is a model-fidelity question rather than an absence of evidence: the experiments exist and are sound, but their translational reach to HFRS is the open question.
Proposed experiments
VEGF induction and VE-cadherin loss in human renal microvascular endothelium infected with Old World hantaviruses
exp_hfrs_vegf_in_renal_microvascular_endothelium
Repeat the VEGF induction and VE-cadherin degradation measurements in primary human renal microvascular endothelial cells infected with Hantaan and Puumala virus, and compare them head to head with Andes virus in the same system, so that virus origin and vascular bed are varied independently.
Decision criterion
Reproduction of VEGF induction and VE-cadherin loss with Old World agents in renal endothelium would license the mechanism for HFRS; failure would require the entry to demote this node to an HPS-specific model.
Show evidence (1 reference)
PMID:40857262 SUPPORT In Vitro
"SNV readily infected pulmonary endothelial cells, while HTNV robustly amplified in endothelial cells, cardiomyocytes, and astrocytes."
Demonstrates that Old and New World hantaviruses differ in cell tropism, which is why an Andes-virus-derived mechanism cannot simply be assumed to hold for the HFRS agents.
Is intravenous ribavirin genuinely effective in HFRS, and if so within what window - given that the single supporting randomised trial is from 1991 in China and that the same drug failed in cardiopulmonary-stage HCPS?
OPEN QUESTION OPEN hfrs_ribavirin_efficacy_and_treatment_window
Attached to
pathophysiology#Acute kidney injury with oliguric renal failure
HFRS is unusual among viral haemorrhagic fevers in having a positive placebo-controlled antiviral trial: intravenous ribavirin reduced mortality sevenfold after adjustment and reduced the risk of entering the oliguric phase. But that trial was conducted in 1991 in a single country, the effect estimate is adjusted rather than crude, and a later randomised trial of the same drug in the cardiopulmonary stage of the New World syndrome found no trend towards benefit. Contemporary reviews continue to state that no specific effective antiviral treatment is available, so the field has not absorbed the 1991 result as practice-changing. Whether the discrepancy is about the drug, the syndrome, or the timing of administration is unresolved and directly determines whether an HFRS patient should be offered ribavirin.
Proposed experiments
Modern phase-stratified randomised trial of intravenous ribavirin in HFRS
exp_hfrs_ribavirin_phase_stratified_rct
Conduct a multicentre randomised trial of intravenous ribavirin in HFRS stratified by clinical phase at enrolment (febrile versus hypotensive versus oliguric), against contemporary supportive care including renal replacement therapy, to test whether the 1991 benefit is real and whether it is confined to an early treatment window.
Decision criterion
Benefit confined to febrile-phase enrolment would reconcile the positive 1991 HFRS trial with the negative cardiopulmonary-stage HCPS trial as a treatment-window effect rather than a syndrome difference; a uniformly null result would retire ribavirin for HFRS.
Show evidence (2 references)
PMID:1683355 SUPPORT Human Clinical
"Mortality was significantly reduced (sevenfold decrease in risk) among ribavirin-treated patients, when comparisons were adjusted for baseline risk estimators of mortality (P = .01; two-tailed)."
The positive randomised result that sits in tension with current practice statements.
PMID:37105214 REFUTE Human Clinical
"No specific effective antiviral treatment is available."
A 2023 Lancet Infectious Diseases review still states that no specific effective antiviral exists, which is what makes the 1991 positive trial an open question rather than settled practice.
⚙

Pathophysiology

12
Aerosol exposure and Old World hantavirus inoculation
Inhalation of aerosolised rodent excreta delivers Old World orthohantaviruses to the human host, initiating a systemic infection whose principal target is the vascular endothelium rather than any single organ parenchyma.
viral process GO:0016032 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal viral process (GO:0016032). GO:0016032 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Beta3 integrin-mediated viral entry into endothelium, platelets, and macrophages Inoculated virions engage beta3 integrins on the cells that determine leak physiology.
Show evidence (1 reference)
PMID:36851775 SUPPORT Human Clinical
"This zoonotic infection is the result of exposure to the virus-contaminated aerosols."
Supports aerosol exposure as the initiating event.
Beta3 integrin-mediated viral entry into endothelium, platelets, and macrophages
Cellular entry of the HFRS-causing hantaviruses Hantaan, Seoul, and Puumala is facilitated by alphavbeta3 and alphaIIbbeta3 integrins. Because beta3 integrins are displayed on endothelial cells, platelets, and macrophages, and because they themselves regulate vascular permeability and platelet function, receptor choice places the virus directly on the two cell types whose failure defines the syndrome.
endothelial cell of vascular tree CL:0002139 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell of vascular tree (CL:0002139). CL:0002139 is a cell type from the Cell Ontology. platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology. macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
receptor-mediated virion attachment to host cell GO:0046813 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased receptor-mediated virion attachment to host cell (GO:0046813). GO:0046813 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Noncytopathic microvascular endothelial infection Integrin engagement delivers virus into the microvascular endothelium.
Acute thrombocytopenia and platelet dysfunction Beta3 integrin usage places the virus on platelets, coupling receptor tropism to the platelet loss that accompanies vascular leak.
Show evidence (2 references)
PMID:10196290 SUPPORT In Vitro
"Infection of human umbilical vein endothelial cells and Vero E6 cells by the HFRS-causing hantaviruses Hantaan (HTN), Seoul (SEO), and Puumala (PUU) is inhibited by antibodies to alphavbeta3 integrins and by the integrin ligand vitronectin."
Directly demonstrates beta3 integrin dependence for the three main HFRS agents in human endothelial cells.
PMID:10196290 SUPPORT In Vitro
"Since beta3 integrins regulate vascular permeability and platelet function, these findings also correlate beta3 integrin usage with common elements of hantavirus pathogenesis."
Links the receptor to the two downstream nodes of this pathograph, vascular permeability and platelet dysfunction.
Noncytopathic microvascular endothelial infection
Hantaviruses replicate to high levels in microvascular endothelial cells without producing a cytopathic effect. This is the central mechanistic constraint on the disease: because the endothelium is not killed, the ensuing microvascular leak must be explained by dysregulated signalling rather than by structural destruction of the barrier.
Factor XII-dependent kallikrein-kinin activation and bradykinin drive the leak Hantavirus-specific cytotoxic T cells attacking infected endothelium cause the leak VEGF hypersensitisation and VE-cadherin degradation open the barrier
endothelial cell of vascular tree CL:0002139 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell of vascular tree (CL:0002139). CL:0002139 is a cell type from the Cell Ontology.
viral process GO:0016032 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased viral process (GO:0016032). GO:0016032 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Cytokine amplification and IL-6 trans-signaling Infected endothelium drives an amplifying inflammatory cytokine programme.
VEGF-driven VE-cadherin destabilisation of endothelial adherens junctions Infection raises secreted VEGF and lowers junctional VE-cadherin. VEGF hypersensitisation and VE-cadherin degradation open the barrier
Factor XII-dependent kallikrein-kinin activation and bradykinin release The infected endothelial surface promotes FXII binding and autoactivation. Factor XII-dependent kallikrein-kinin activation and bradykinin drive the leak
Cytotoxic T cell attack on antigen-presenting endothelium Infected endothelium presents viral antigen and becomes a target of the hantavirus-specific cytotoxic T cell response. Hantavirus-specific cytotoxic T cells attacking infected endothelium cause the leak
Show evidence (2 references)
PMID:20810734 SUPPORT In Vitro
"High levels of virus replication occur in microvascular endothelial cells but without a virus-induced cytopathic effect."
States the noncytopathic high-replication phenotype that constrains all downstream mechanistic models. The framing of this paper covers both HPS and HFRS, though its experiments used the HPS-associated Andes virus.
PMID:10196290 SUPPORT In Vitro
"Hantaviruses replicate primarily in the vascular endothelium and cause two human diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS)."
Establishes the vascular endothelium as the primary replication site in HFRS.
Cytokine amplification and IL-6 trans-signaling
Infected endothelium amplifies an inflammatory cytokine programme. In primary human endothelial cells, soluble IL-6 receptor (trans-signaling) treatment of infected cells increased IL-6 and CCL2 secretion, upregulated ICAM-1, and disrupted VE-cadherin and barrier integrity; Puumala-infected HFRS patients showed a shifted sIL-6R/sgp130 ratio consistent with enhanced trans-signaling potential, which tracked with clinical severity.
endothelial cell of vascular tree CL:0002139 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell of vascular tree (CL:0002139). CL:0002139 is a cell type from the Cell Ontology.
interleukin-6-mediated signaling pathway GO:0070102 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased interleukin-6-mediated signaling pathway (GO:0070102). GO:0070102 is a biological process from the Gene Ontology. ↑ INCREASED cytokine-mediated signaling pathway GO:0019221 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cytokine-mediated signaling pathway (GO:0019221). GO:0019221 is a biological process from the Gene Ontology. ↑ INCREASED inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Increased vascular permeability and capillary leak Cytokine-driven endothelial activation degrades barrier function.
Show evidence (3 references)
PMID:40203030 SUPPORT In Vitro
"In vitro, sIL-6R treatment of infected cells enhanced IL-6 and CCL2 secretion, upregulated ICAM-1, and affected VE-cadherin leading to a disrupted cell barrier integrity."
Demonstrates the cytokine-to-barrier-failure link in infected primary human endothelial cells.
PMID:40203030 SUPPORT Human Clinical
"HFRS patients showed altered plasma levels of sIL-6R and soluble gp130 (sgp130) resulting in an increased sIL-6R/sgp130 ratio suggesting enhanced IL-6 trans-signaling potential."
Confirms the trans-signaling shift in a cohort of Puumala-infected HFRS patients, not only in cell culture.
PMID:40203030 SUPPORT Human Clinical
"Patients receiving oxygen treatment displayed a higher sIL-6R/sgp130 ratio compared to patients that did not."
Ties the trans-signaling shift to clinical severity in HFRS.
VEGF-driven VE-cadherin destabilisation of endothelial adherens junctions
In the most widely cited model of hantavirus leak, infection raises secreted VEGF, and VEGF binding to VEGF-R2 dissociates the receptor from VE-cadherin and drives VE-cadherin internalisation and degradation, dismantling the adherens junction without killing the cell. Blocking VEGF-R2 activation prevents the infection-induced VE-cadherin loss.
VEGF hypersensitisation and VE-cadherin degradation open the barrier
endothelial cell of vascular tree CL:0002139 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell of vascular tree (CL:0002139). CL:0002139 is a cell type from the Cell Ontology.
vascular endothelial growth factor receptor signaling pathway GO:0048010 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased vascular endothelial growth factor receptor signaling pathway (GO:0048010). GO:0048010 is a biological process from the Gene Ontology. ↑ INCREASED adherens junction organization GO:0034332 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased adherens junction organization (GO:0034332). GO:0034332 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Increased vascular permeability and capillary leak Loss of junctional VE-cadherin opens the paracellular route. VEGF hypersensitisation and VE-cadherin degradation open the barrier
Show evidence (3 references)
PMID:20810734 SUPPORT In Vitro
"Here we report that increased secreted VEGF and concomitant decreased VE-cadherin are seen at early times postinfection of human primary lung endothelial cells with an HPS-associated hantavirus, Andes virus."
The primary experimental support for the VEGF/VE-cadherin model. Note the virus used was the HPS-associated Andes virus, so the extension to HFRS agents is by mechanistic analogy rather than direct demonstration.
PMID:20810734 SUPPORT In Vitro
"Consistent with this, we showed that an antibody which blocks VEGF-R2 activation resulted in inhibition of the Andes virus-induced VE-cadherin reduction."
Provides the pharmacological test that establishes VEGF-R2 as the mediator.
PMID:23874198 REFUTE In Vitro
"despite viral replication in both cell types as well as the presence of VEGF, infected in vitro vessels neither lost integrity nor displayed evidence of VE-cadherin degradation"
In a three-dimensional endothelial/smooth-muscle vessel model the VEGF/VE-cadherin mechanism did not reproduce, which is the direct experimental challenge to this node and the reason it is curated as one of several competing hypotheses rather than as settled mechanism.
Factor XII-dependent kallikrein-kinin activation and bradykinin release
A competing, non-mutually-exclusive model of the same leak. Factor XII binding and autoactivation are increased on the surface of hantavirus-infected endothelial cells; incubation with FXII, prekallikrein, and high-molecular-weight kininogen yields increased kininogen cleavage, higher FXIIa/kallikrein activity, and liberation of bradykinin, which dramatically increases endothelial permeability. Blocking bradykinin binding, FXIIa, or kallikrein prevents the permeability change.
Factor XII-dependent kallikrein-kinin activation and bradykinin drive the leak
endothelial cell of vascular tree CL:0002139 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell of vascular tree (CL:0002139). CL:0002139 is a cell type from the Cell Ontology.
kinin cascade GO:0002254 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased kinin cascade (GO:0002254). GO:0002254 is a biological process from the Gene Ontology. ↑ INCREASED blood coagulation, intrinsic pathway GO:0007597 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased blood coagulation, intrinsic pathway (GO:0007597). GO:0007597 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Increased vascular permeability and capillary leak Liberated bradykinin acts on the endothelium to open the barrier. Factor XII-dependent kallikrein-kinin activation and bradykinin drive the leak
Show evidence (2 references)
PMID:23874198 SUPPORT In Vitro
"We show that incubation of factor XII (FXII), prekallikrein (PK), and high molecular weight kininogen (HK) plasma proteins with hantavirus-infected EC results in increased cleavage of HK, higher enzymatic activities of FXIIa/kallikrein (KAL) and increased liberation of bradykinin (BK)."
Establishes kallikrein-kinin system activation on infected endothelium.
PMID:23874198 SUPPORT In Vitro
"Furthermore, the alterations in permeability could be prevented using inhibitors that directly block BK binding, the activity of FXIIa, or the activity of KAL."
Provides the interventional test linking bradykinin to permeability and the rationale for the icatibant treatment entry.
Cytotoxic T cell attack on antigen-presenting endothelium
A third, immunopathological model holds that hantavirus-specific cytotoxic T cells attack endothelial cells displaying viral antigen, and that this is what raises capillary permeability. The clinical correlation is direction-dependent and unresolved: T cell responses correlate positively with severity in HCPS but negatively with severity in HFRS in at least one report, so both too strong and too weak a T cell response may worsen disease.
Hantavirus-specific cytotoxic T cells attacking infected endothelium cause the leak
CD8-positive, alpha-beta T cell CL:0000625 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD8-positive, alpha-beta T cell (CL:0000625). CL:0000625 is a cell type from the Cell Ontology. endothelial cell of vascular tree CL:0002139 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell of vascular tree (CL:0002139). CL:0002139 is a cell type from the Cell Ontology.
T cell mediated cytotoxicity GO:0001913 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased T cell mediated cytotoxicity (GO:0001913). GO:0001913 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Increased vascular permeability and capillary leak Cytotoxic attack on infected endothelium compromises barrier integrity. Hantavirus-specific cytotoxic T cells attacking infected endothelium cause the leak
Show evidence (2 references)
PMID:21994770 SUPPORT Human Clinical
"We previously hypothesized that increased capillary permeability observed in both hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome (HFRS) may be caused by hantavirus-specific cytotoxic T cells attacking endothelial cells presenting viral antigens on their..."
States the immunopathological hypothesis. It is curated as PARTIAL because the same review reports that the supporting clinical correlation runs in opposite directions in HFRS and HCPS.
PMID:24750436 SUPPORT Human Clinical
"The pathogenesis is likely to be a complex multifactorial process that includes contributions from immune responses, platelet dysfunction and the deregulation of endothelial cell barrier functions."
Supports an immune contribution as one component of a multifactorial pathogenesis rather than as the sole mechanism.
Increased vascular permeability and capillary leak
The convergent hub of HFRS pathogenesis. Whatever the proximal signalling route, the endothelial barrier becomes permeable, plasma extravasates, haemoconcentration and hypotension follow, and every organ served by the affected microvasculature is exposed to leak. In HFRS the kidney bears the brunt.
endothelial cell of vascular tree CL:0002139 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell of vascular tree (CL:0002139). CL:0002139 is a cell type from the Cell Ontology.
regulation of vascular permeability GO:0043114 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased regulation of vascular permeability (GO:0043114). GO:0043114 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Acute kidney injury with oliguric renal failure Renal microvascular leak and interstitial oedema drive the defining organ injury.
Acute thrombocytopenia and platelet dysfunction Leak physiology is accompanied by consumptive platelet loss.
Show evidence (2 references)
PMID:37105214 SUPPORT Human Clinical
"As hantaviruses target endothelial cells, they can affect diverse organ systems; increased vascular permeability is central to pathogenesis."
Establishes increased vascular permeability as the central pathogenic event.
PMID:35384417 SUPPORT Human Clinical
"The major clinical manifestations includes increased vascular permeability causing vascular leakage, acute kidney injury and coagulation abnormalities."
Links the leak hub to the two downstream nodes, renal injury and coagulopathy.
Acute thrombocytopenia and platelet dysfunction
Acute thrombocytopenia is, with vascular permeability, one of the two central phenomena of hantavirus disease. Platelets display the same beta3 integrins the virus uses for entry, and platelet dysfunction is an independent contributor to pathogenesis alongside barrier failure.
platelet CL:0000233 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves platelet (CL:0000233). CL:0000233 is a cell type from the Cell Ontology.
platelet activation GO:0030168 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal platelet activation (GO:0030168). GO:0030168 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Haemorrhagic manifestations Platelet loss and dysfunction convert vascular fragility into overt bleeding.
Show evidence (2 references)
PMID:24750436 SUPPORT Human Clinical
"The central phenomena behind the pathogenesis of both HFRS and HCPS are increased vascular permeability and acute thrombocytopenia."
Establishes acute thrombocytopenia as a central pathogenic phenomenon.
PMID:10196290 SUPPORT In Vitro
"These findings indicate that pathogenic HPS- and HFRS-causing hantaviruses enter cells via beta3 integrins, which are present on the surfaces of platelets, endothelial cells, and macrophages."
Places the viral receptor on platelets, connecting tropism to thrombocytopenia.
Acute kidney injury with oliguric renal failure
The organ-defining lesion of HFRS. Renal microvascular leak produces interstitial oedema and tubular injury with proteinuria, haematuria, rising creatinine, and oliguria that may require renal replacement therapy, followed in survivors by a polyuric recovery phase.
kidney tubule cell CL:1000507 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves kidney tubule cell (CL:1000507). CL:1000507 is a cell type from the Cell Ontology. glomerular endothelial cell CL:0002188 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves glomerular endothelial cell (CL:0002188). CL:0002188 is a cell type from the Cell Ontology.
Downstream
Staged renal recovery and convalescence Surviving nephrons recover, producing the diuretic and convalescent phases.
Show evidence (2 references)
PMID:36851775 SUPPORT Human Clinical
"Orthohantavirus infection may cause Hemorrhagic Fever with Renal Syndrome (HRFS), a disease that is characterized by acute kidney injury and increased vascular permeability."
Defines HFRS by acute kidney injury plus increased vascular permeability. The acronym is mistyped as HRFS in the source abstract and the snippet is quoted verbatim so it validates against the cached text.
PMID:1683355 SUPPORT Human Clinical
"Only occurrence of oliguric phase and hemorrhage was associated with severity of clinical disease in the placebo group."
Ties the oliguric phase of renal failure to clinical severity.
Haemorrhagic manifestations
Coagulation abnormalities and thrombocytopenia produce the haemorrhagic component of the syndrome, ranging from petechiae and conjunctival haemorrhage to gastrointestinal and, in Puumala infection, pituitary bleeding. Haemorrhage was one of only two features associated with clinical severity in the placebo arm of the Chinese ribavirin trial.
Show evidence (2 references)
PMID:35384417 SUPPORT Human Clinical
"The major clinical manifestations includes increased vascular permeability causing vascular leakage, acute kidney injury and coagulation abnormalities."
Establishes coagulation abnormalities as a core manifestation.
PMID:26202013 SUPPORT Human Clinical
"Pituitary haemorrhage and hypopituitarism may complicate recovery from acute NE."
Documents pituitary haemorrhage as a site-specific bleeding complication of PUUV HFRS.
Staged renal recovery and convalescence
HFRS resolves through a diuretic phase of high urine output and then convalescence. The five-phase structure (febrile, hypotensive, oliguric, diuretic, convalescent) is the clinical signature of the disease and is the frame in which treatment timing is judged.
Show evidence (1 reference)
PMID:1683355 SUPPORT Human Clinical
"HFRS typically consists of five consecutive but frequently overlapping clinical phases."
Supports the staged course through to convalescence.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hantavirus Hemorrhagic Fever with Renal Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

23
Blood 5
Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873), qualified as temporality acute. HP:0001873 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:24750436 SUPPORT Human Clinical
"The central phenomena behind the pathogenesis of both HFRS and HCPS are increased vascular permeability and acute thrombocytopenia."
Directly supports acute thrombocytopenia as a defining feature.
Hemoconcentration Increased hematocrit HP:0001899 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased hematocrit (HP:0001899). HP:0001899 is a phenotype from the Human Phenotype Ontology.
Leukocytosis Increased total leukocyte count HP:0001974 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukocytosis, annotated with Increased total leukocyte count (HP:0001974). HP:0001974 is a phenotype from the Human Phenotype Ontology.
Petechiae HP:0000967 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Petechiae (HP:0000967). HP:0000967 is a phenotype from the Human Phenotype Ontology.
Gastrointestinal hemorrhage HP:0002239 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastrointestinal hemorrhage (HP:0002239). HP:0002239 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:1683355 SUPPORT Human Clinical
"Only occurrence of oliguric phase and hemorrhage was associated with severity of clinical disease in the placebo group."
Supports haemorrhage as a severity-defining manifestation.
Cardiovascular 3
Capillary leak HP:0030005 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Capillary leak (HP:0030005). HP:0030005 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37105214 SUPPORT Human Clinical
"As hantaviruses target endothelial cells, they can affect diverse organ systems; increased vascular permeability is central to pathogenesis."
Supports capillary leak as the central clinical-pathological feature.
Hypotension HP:0002615 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotension (HP:0002615). HP:0002615 is a phenotype from the Human Phenotype Ontology.
Shock HP:0031273 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Shock (HP:0031273). HP:0031273 is a phenotype from the Human Phenotype Ontology.
Digestive 2
Nausea HP:0002018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nausea (HP:0002018). HP:0002018 is a phenotype from the Human Phenotype Ontology.
Vomiting HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013). HP:0002013 is a phenotype from the Human Phenotype Ontology.
Endocrine 1
Hypopituitarism VERY_RARE HP:0040075 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypopituitarism (HP:0040075). HP:0040075 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26202013 SUPPORT Human Clinical
"Pituitary haemorrhage and hypopituitarism may complicate recovery from acute NE."
Supports hypopituitarism as a complication of acute PUUV HFRS.
PMID:26202013 SUPPORT Human Clinical
"Two patients had suffered from pituitary haemorrhage, but many others exhibited pituitary oedema during their acute infection."
Two of 47 followed patients had pituitary haemorrhage, supporting the VERY_RARE frequency band assigned here.
Eye 1
Blurred vision HP:0000622 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Blurred vision (HP:0000622), qualified as temporality transient. HP:0000622 is a phenotype from the Human Phenotype Ontology.
Temporal: TRANSIENT
Genitourinary 5
Acute kidney injury HP:0001919 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acute kidney injury (HP:0001919). HP:0001919 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36851775 SUPPORT Human Clinical
"Orthohantavirus infection may cause Hemorrhagic Fever with Renal Syndrome (HRFS), a disease that is characterized by acute kidney injury and increased vascular permeability."
Defines HFRS by acute kidney injury. The acronym is mistyped in the source abstract and the snippet is quoted verbatim.
Oliguria HP:0100520 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oliguria (HP:0100520). HP:0100520 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:1683355 SUPPORT Human Clinical
"Only occurrence of oliguric phase and hemorrhage was associated with severity of clinical disease in the placebo group."
Supports oliguria as a severity-defining phase of HFRS.
Polyuria HP:0000103 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polyuria (HP:0000103). HP:0000103 is a phenotype from the Human Phenotype Ontology.
Proteinuria HP:0000093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31319534 SUPPORT Human Clinical
"initial but transient proteinuria and microhematuria are rarely lacking"
Supports proteinuria as an essentially constant finding even in mild Seoul virus disease.
Hematuria HP:0000790 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hematuria (HP:0000790). HP:0000790 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31319534 SUPPORT Human Clinical
"initial but transient proteinuria and microhematuria are rarely lacking"
Supports microhaematuria as an essentially constant acute finding.
Metabolism 2
Fever VERY_FREQUENT HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945), qualified as temporality acute. HP:0001945 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:35384417 SUPPORT Human Clinical
"In Korea, fever (94.0%), abdominal discomfort (64.0%) and headache (50.7%) are the most common early clinical symptoms."
Reported frequency of 94.0% in a Korean series falls in the VERY_FREQUENT band (80-99%).
Elevated serum creatinine Elevated circulating creatinine concentration HP:0003259 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating creatinine concentration (HP:0003259). HP:0003259 is a phenotype from the Human Phenotype Ontology.
Nervous System 1
Headache FREQUENT HP:0002315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Headache (HP:0002315). HP:0002315 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35384417 SUPPORT Human Clinical
"In Korea, fever (94.0%), abdominal discomfort (64.0%) and headache (50.7%) are the most common early clinical symptoms."
Reported frequency of 50.7% in a Korean series falls in the FREQUENT band (30-79%).
Constitutional 3
Myalgia HP:0003326 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myalgia (HP:0003326). HP:0003326 is a phenotype from the Human Phenotype Ontology.
Abdominal pain FREQUENT HP:0002027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abdominal pain (HP:0002027). HP:0002027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35384417 SUPPORT Human Clinical
"In Korea, fever (94.0%), abdominal discomfort (64.0%) and headache (50.7%) are the most common early clinical symptoms."
Reported frequency of 64.0% in a Korean series falls in the FREQUENT band (30-79%). The source terms this "abdominal discomfort", curated here against the closest HPO term, Abdominal pain.
Flank pain HP:0030157 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Flank pain (HP:0030157). HP:0030157 is a phenotype from the Human Phenotype Ontology.
💊

Medical Actions

6
Intensive supportive care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
Management is primarily supportive: careful fluid and haemodynamic management through the capillary leak and hypotensive phases, and renal replacement therapy for the oliguric phase when needed. No specific effective antiviral is established in contemporary practice.
Target Phenotypes: Acute kidney injury HP:0001919 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Acute kidney injury (HP:0001919). HP:0001919 is a phenotype from the Human Phenotype Ontology. Shock HP:0031273 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Shock (HP:0031273). HP:0031273 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37105214 SUPPORT Human Clinical
"No specific effective antiviral treatment is available."
Establishes that management is supportive because no specific antiviral is established.
Haemodialysis
Action: hemodialysisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hemodialysis (NCIT:C15248). NCIT:C15248 is a clinical intervention from the NCI Thesaurus. Ontology label: Hemodialysis NCIT:C15248
Platform: Device
Renal replacement therapy supports patients through the oliguric phase until the diuretic phase of recovery begins.
Target Phenotypes: Oliguria HP:0100520 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Oliguria (HP:0100520). HP:0100520 is a phenotype from the Human Phenotype Ontology. Acute kidney injury HP:0001919 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Acute kidney injury (HP:0001919). HP:0001919 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:1683355 SUPPORT Human Clinical
"Only occurrence of oliguric phase and hemorrhage was associated with severity of clinical disease in the placebo group."
Supports the oliguric phase as the severity-driving stage that renal replacement therapy is deployed to survive. It does not itself evaluate dialysis, which is standard of care rather than a trialled intervention in HFRS.
Intravenous ribavirin
Action: antiviral therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antiviral therapy (NCIT:C16119). NCIT:C16119 is a clinical intervention from the NCI Thesaurus. Ontology label: Antiviral Therapy NCIT:C16119
Agent: ribavirin CHEBI:63580 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ribavirin (CHEBI:63580). CHEBI:63580 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
In a 1991 placebo-controlled randomised trial of 242 patients in China, intravenous ribavirin reduced adjusted mortality sevenfold and reduced the risk of entering the oliguric phase and of haemorrhage, at the cost of a reversible anaemia. Contemporary reviews nevertheless still state that no specific effective antiviral treatment is available, and the same drug failed in cardiopulmonary-stage HCPS, so its place in current practice is unsettled.
Mechanism Target:
INHIBITS Noncytopathic microvascular endothelial infection — Ribavirin is a nucleoside analogue acting on viral replication, so its mechanistic join point is the infected endothelium rather than the downstream renal lesion. Consistent with acting upstream, it reduced the risk of entering the oliguric phase in the 1991 randomised trial; that clinical outcome is captured in target_phenotypes (Oliguria).
Target Phenotypes: Oliguria HP:0100520 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Oliguria (HP:0100520). HP:0100520 is a phenotype from the Human Phenotype Ontology. Gastrointestinal hemorrhage HP:0002239 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Gastrointestinal hemorrhage (HP:0002239). HP:0002239 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:1683355 SUPPORT Human Clinical
"Ribavirin therapy also resulted in a significant reduction in the risk of entering the oliguric phase and experiencing hemorrhage."
The randomised evidence that ribavirin reduces progression to the oliguric phase and to haemorrhage.
PMID:1683355 SUPPORT Human Clinical
"The only ribavirin-related side effect was a well-recognized, fully reversible anemia after completion of therapy."
Documents the toxicity profile observed in the trial.
PMID:37105214 REFUTE Human Clinical
"No specific effective antiviral treatment is available."
A 2023 review contradicts the practical adoption of ribavirin, which is why this treatment is curated alongside an open discussion rather than as established therapy.
Icatibant (bradykinin B2 receptor antagonist)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: icatibant CHEBI:68556 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses icatibant (CHEBI:68556). CHEBI:68556 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Peptide
The therapeutic corollary of the kallikrein-kinin model of vascular leak. A single severe Puumala virus case responded dramatically to one dose of the bradykinin receptor antagonist icatibant. This is a single case report; the authors themselves call for testing in larger numbers of patients, and it is curated here as a mechanism-matched hypothesis rather than as established therapy.
Mechanism Target:
INHIBITS Factor XII-dependent kallikrein-kinin activation and bradykinin release — Icatibant blocks the bradykinin B2 receptor, the terminal step of the kallikrein-kinin arm of this pathograph.
Target Phenotypes: Capillary leak HP:0030005 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Capillary leak (HP:0030005). HP:0030005 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23294035 SUPPORT Human Clinical
"A patient with severe capillary leakage syndrome caused by a Puumala hantavirus infection was treated with a single dose of icatibant, a bradykinin receptor antagonist, with a dramatic positive response."
Single-patient evidence of benefit, curated as PARTIAL because n=1 cannot establish efficacy.
PMID:23294035 SUPPORT Human Clinical
"We suggest that this drug should be tested in a larger number of patients with severe hantavirus infection."
The authors' own statement that the evidence is not yet sufficient.
Hantavax (formalin-inactivated Hantaan virus vaccine)
Action: vaccinationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is vaccination (NCIT:C15346). NCIT:C15346 is a clinical intervention from the NCI Thesaurus. Ontology label: Vaccination NCIT:C15346
Platform: Vaccine
A formalin-inactivated, rodent-brain-derived Hantaan virus vaccine (Hantavax, Korea Green Cross) is licensed and commercially available in Korea. It is not available worldwide and the protective antibody response it elicits has been reported to be short-lived, so it supplements rather than replaces rodent-exposure reduction.
Show evidence (1 reference)
PMID:35384417 SUPPORT Human Clinical
"Hantavax (Korea Green Cross, Seoul, Korea), a formalin-inactivated HTNV vaccine made from rodent brain–derived virus, is commercially accessible in Korea, however, the protective response has been reported to be short-lived"
Establishes that a licensed HFRS vaccine exists in Korea, and is curated as PARTIAL because the same sentence reports the protective response to be short-lived.
Rodent exposure reduction and One Health prevention
Action: preventive interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is preventive intervention (NCIT:C15843). NCIT:C15843 is a clinical intervention from the NCI Thesaurus. Ontology label: Preventive Intervention NCIT:C15843
Platform: Behavioral / lifestyle
With no globally available vaccine — Hantavax is licensed only in Korea and its protection is short-lived — and no established antiviral, prevention turns on reducing contact with rodent reservoirs and their aerosolised excreta, on surveillance, and on integrated One Health strategies spanning the rodent, environmental, and human compartments.
Show evidence (2 references)
PMID:42430118 SUPPORT Other
"In addition, it explores emerging challenges related to vaccine development, surveillance, and the integration of One Health strategies in the prevention and control of hantavirus infections."
The lit-scan source review frames prevention around vaccine development, surveillance, and One Health integration.
PMID:42430118 SUPPORT Other
"Strengthening multidisciplinary approaches and improving early detection remain critical to mitigating the global impact of these infections."
Supports early detection and multidisciplinary prevention as the current control strategy.
🔬

Diagnosis

2
Hantavirus serology and viral RNA detection
Diagnosis rests on recognising a compatible febrile illness with thrombocytopenia and acute kidney injury in someone with rodent exposure, then confirming orthohantavirus infection serologically or molecularly.
laboratory procedure NCIT:C25294 NCI Thesaurus (NCIT)
Results: Hantavirus-specific IgM or viral RNA in a patient with the clinical triad of fever, thrombocytopenia, and acute kidney injury.
Show evidence (2 references)
PMID:35384417 SUPPORT Human Clinical
"The laboratory diagnosis of hantavirus infection is mostly dependent on four types of tests: serology, molecular techniques, viral isolation and immunochemistry"
Names the four laboratory modalities on which confirmation of hantavirus infection rests, of which serology and molecular testing are the two curated here.
PMID:35384417 SUPPORT Human Clinical
"serological assays that detect IgM and/or IgG antibodies to hantaviral antigens in serum are the most often used techniques for diagnostic testing of HFRS"
Establishes IgM/IgG serology as the first-line confirmatory test in HFRS, which is the primary claim of this diagnosis entry.
Serial urinalysis in suspected Seoul virus exposure
Because Seoul virus disease is often mild and atypical, sometimes with preserved kidney function, repeated simple urine examination is the recommended way to avoid missing cases in people exposed to pet, feeder, or wild rats.
urinalysis NCIT:C17241 NCI Thesaurus (NCIT)
Results: Transient proteinuria and microhaematuria, which are rarely absent even in mild disease.
Show evidence (1 reference)
PMID:31319534 SUPPORT Human Clinical
"the importance of simple but repeated urine examination is stressed, since initial but transient proteinuria and microhematuria are rarely lacking"
Directly supports serial urinalysis as the recommended detection strategy in SEOV disease.
📈

Progression

5
Febrile phase
Age: Any age after exposure
HFRS classically runs through five consecutive but frequently overlapping clinical phases. The first is an abrupt febrile illness with headache, myalgia, abdominal or flank pain, and gastrointestinal symptoms.
Show evidence (1 reference)
PMID:1683355 SUPPORT Human Clinical
"HFRS typically consists of five consecutive but frequently overlapping clinical phases."
Establishes the canonical five-phase clinical course of HFRS.
Hypotensive phase
Age: Acute illness, typically days 4-7
Capillary leak causes plasma extravasation, haemoconcentration, and hypotension that may progress to shock, coinciding with the nadir of the platelet count.
Show evidence (1 reference)
PMID:24750436 SUPPORT Human Clinical
"The central phenomena behind the pathogenesis of both HFRS and HCPS are increased vascular permeability and acute thrombocytopenia."
Supports the leak-and-thrombocytopenia physiology underlying the hypotensive phase.
Oliguric phase
Age: Acute illness, typically days 6-12
Acute kidney injury with falling urine output is the defining stage of HFRS. Entry into the oliguric phase, along with haemorrhage, is one of the two features that tracked with clinical severity in the placebo arm of the Chinese ribavirin trial.
Show evidence (1 reference)
PMID:1683355 SUPPORT Human Clinical
"Only occurrence of oliguric phase and hemorrhage was associated with severity of clinical disease in the placebo group."
Identifies the oliguric phase as a severity marker in a placebo-controlled HFRS cohort.
Polyuric (diuretic) phase
Age: Recovery, typically after day 10
Renal recovery is heralded by a diuretic phase with large urine volumes and a risk of dehydration and electrolyte loss.
Show evidence (1 reference)
PMID:15011467 SUPPORT Human Clinical
"The oliguric stage is followed by the polyuric stage which can last for up to two weeks, and is characterized by excretion of a large quantity of urine of low specific gravity (up to 15 liters during 24 hours)."
Directly supports the timing, duration, and high urine output of the polyuric recovery phase.
Convalescent phase
Age: Weeks to months after acute illness
Most patients recover renal function. Pituitary involvement can complicate recovery from Puumala virus HFRS, although late-onset hypopituitarism was not observed in long-term follow-up of a Finnish cohort.
Show evidence (1 reference)
PMID:26202013 SUPPORT Human Clinical
"None of our patients had developed obvious late-onset hypopituitarism despite of the fact that pituitary gland can be affected during acute NE."
Supports pituitary involvement during acute disease while explicitly not supporting late-onset hypopituitarism as a routine sequela.
📊

Prevalence

5
Worldwide
Annual Incidence
About 100,000 cases of HFRS are reported globally each year, most of them in China, Korea, and Russia. No rate_per_100000 is recorded because the source reports absolute annual case counts and no denominator population; deriving a rate would require an external denominator the source does not supply.
Show evidence (1 reference)
PMID:35384417 SUPPORT Human Clinical
"Every year, about 100,000 instances of HFRS are reported, the majority of which occur in China, Korea, and Russia"
The global annual case count and its geographic concentration.
China
Annual Incidence
China accounts for more than 90% of HFRS cases worldwide over recent decades.
Show evidence (1 reference)
PMID:35384417 SUPPORT Human Clinical
"China is the most severely impacted country and accounting for around more than 90% of all HFRS cases worldwide in the last few decades"
Establishes China as the dominant contributor to global HFRS burden.
China
Annual Incidence HTNV HFRS
Over 10,000-20,000 HTNV-related HFRS cases reported per year in China.
Show evidence (1 reference)
PMID:35384417 SUPPORT Human Clinical
"Every year, over 10,000 - 20,000 cases of HTNV-related HFRS are reported in China, whereas about 300 - 900 cases are reported in Korea"
Country-level annual case counts for the Hantaan virus subtype.
Korea
Annual Incidence HTNV HFRS
About 300-900 HTNV-related HFRS cases reported per year in Korea.
Show evidence (1 reference)
PMID:35384417 SUPPORT Human Clinical
"Every year, over 10,000 - 20,000 cases of HTNV-related HFRS are reported in China, whereas about 300 - 900 cases are reported in Korea"
The Korean arm of the same country-level comparison.
Europe
Annual Incidence
Over 9,000 HFRS cases recorded per year in Europe, where Puumala virus infection is the most prevalent form and Dobrava-Belgrade virus causes the severe cases.
Show evidence (1 reference)
PMID:35384417 SUPPORT Human Clinical
"In Europe, over than 9,000 HFRS are recorded each year, with PUUV infections being the most prevalent."
European annual case count and the predominance of Puumala virus there. The snippet quotes the published wording verbatim, including its grammatical slip ("over than").
🦠

Infectious Agent

5
Old World orthohantaviruses
HFRS is caused by a set of rodent-borne Old World orthohantaviruses, of which Hantaan, Puumala, and Seoul viruses are the most commonly implicated; Dobrava-Belgrade virus accounts for the most severe European disease.
Orthohantavirus NCBITaxon:1980442 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:36851775 SUPPORT Human Clinical
"Several species of orthohantaviruses were identified as causing infection, where Hantaan, Puumala, and Seoul viruses are most common."
Names the orthohantavirus species most commonly causing HFRS.
Orthohantavirus hantanense (Hantaan virus)
The prototype HFRS agent, endemic in Asia and Europe, whose principal reservoir is the striped field mouse Apodemus agrarius.
Hantaan virus NCBITaxon:3052480 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:35384417 SUPPORT Human Clinical
"Apodernus agraricus, a striped field mouse, is being considered as main host reservoir for HTNV."
Identifies the reservoir rodent for Hantaan virus. The rodent binomial is misspelled in the source abstract; the snippet is quoted verbatim as published so it validates against the cached text.
Orthohantavirus seoulense (Seoul virus)
A rat-borne orthohantavirus with a worldwide distribution following its reservoir, the brown rat, and an emerging urban and pet/feeder-rat exposure route in Europe and North America.
Seoul virus NCBITaxon:3052498 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:33801789 SUPPORT Other
"Seoul virus (SEOV) is a zoonotic orthohantavirus carried by rats. In humans, SEOV can cause hemorrhagic fever with renal syndrome."
Establishes SEOV as a rat-borne cause of HFRS.
Orthohantavirus puumalaense (Puumala virus)
The agent of nephropathia epidemica, the mild European form of HFRS, carried by the bank vole.
Puumala virus NCBITaxon:3052493 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:26202013 SUPPORT Human Clinical
"Nephropathia epidemica (NE) is a haemorrhagic fever with renal syndrome (HFRS) caused by Puumala hantavirus (PUUV)."
Equates nephropathia epidemica with PUUV-caused HFRS.
Orthohantavirus dobravaense (Dobrava-Belgrade virus)
The most severe European HFRS agent, carried by Apodemus mice, with mortality comparable to Hantaan virus.
Dobrava-Belgrade virus NCBITaxon:3052477 NCBI Taxonomy (NCBITaxon)
Show evidence (1 reference)
PMID:24750436 SUPPORT Human Clinical
"In general, HFRS caused by Hantaan virus, Amur virus and Dobrava virus are more severe with mortality rates from 5 to 15%"
Identifies Dobrava virus as a severe HFRS agent.
↔️

Transmission

2
Aerosolised rodent excreta exposure
Human infection is accidental and follows inhalation of aerosols generated from virus-contaminated rodent urine, faeces, or saliva. Unlike Andes virus in the Americas, the Old World HFRS agents are not known to spread person to person.
Show evidence (2 references)
PMID:35384417 SUPPORT Human Clinical
"Infection in humans is typically accidental and occurs when virus-containing rodent excretions such as urine, feces, or saliva are aerosolized."
Describes the aerosol route of acquisition.
PMID:37105214 SUPPORT Human Clinical
"Transmission to humans occurs by exposure to infected rodents in endemic areas; however, Andes hantavirus is unique in that it can be transmitted from person to person."
Confirms rodent exposure as the transmission route and marks person-to-person spread as unique to Andes virus, i.e. not an HFRS agent.
Urban and pet/feeder-rat exposure to Seoul virus
Seoul virus circulates in domesticated rat populations and has produced human HFRS cases in the USA, United Kingdom, France, and the Netherlands linked to pet or feeder rats, extending the exposure setting from rural fieldwork to urban households and the rodent trade.
Show evidence (3 references)
PMID:33801789 SUPPORT Human Clinical
"Recent human SEOV cases described in the USA, United Kingdom, France and the Netherlands were associated with contact with pet or feeder rats."
Documents the pet/feeder-rat exposure route for human SEOV disease.
PMID:33801789 SUPPORT Other
"In all three investigated groups, RT-qPCR-positive rats were found: in 1/29 rats from private owners (3.6%), 2/56 rats from ratteries (3.4%) and 11/90 rats from commercial breeders (12.2%)."
Quantifies SEOV carriage across domesticated rat populations.
PMID:42430118 SUPPORT Other
"Particular attention is given to the emerging global epidemiology of Seoul virus (SEOV), an urban-associated hantavirus linked to brown rats and pet rodents."
The 2026 review that triggered this entry frames SEOV as an urban-associated, pet-rodent-linked emerging exposure pattern.
⚖️

Clinical Burden

High
HFRS is the most frequently diagnosed zoonosis in Asia and carries a case-fatality rate of roughly 5-10% depending on the causative orthohantavirus, with severe cases requiring intensive care and renal replacement therapy.
Show evidence (2 references)
PMID:36851775 SUPPORT Human Clinical
"Hemorrhagic Fever with Renal Syndrome (HFRS) is the most frequently diagnosed zoonosis in Asia."
Establishes the regional disease burden of HFRS.
PMID:35384417 SUPPORT Human Clinical
"The case fatality rate of HFRS varies around 5.0 - 10.0% depending on the causative viral agent."
Quantifies mortality and supports a high burden level.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Hantavirus Hemorrhagic Fever with Renal Syndrome:

Hantavirus pulmonary syndrome MONDO:0017879
Overlapping Features The New World counterpart, caused by Sin Nombre, Andes, and related viruses in the Americas. It shares the endothelial target and the leak-plus-thrombocytopenia physiology but centres on noncardiogenic pulmonary oedema and cardiogenic shock rather than acute kidney injury, and Andes virus is additionally capable of person-to-person transmission.
Distinguishing Features
  • Geography - Americas rather than Asia and Europe
  • Organ of failure - noncardiogenic pulmonary oedema rather than oliguric acute kidney injury
  • Person-to-person transmissibility of Andes virus, which has no HFRS counterpart
Show evidence (2 references)
PMID:37105214 SUPPORT Human Clinical
"The main clinical syndromes associated with hantaviruses are haemorrhagic fever with renal syndrome (HFRS), which is endemic in Europe and Asia, and hantavirus cardiopulmonary syndrome (HCPS), which is endemic in the Americas."
Establishes the geographic and syndromic split between the two entities.
PMID:37105214 SUPPORT Human Clinical
"HCPS and HFRS are separate clinical entities, but they share several features and have many overlapping symptoms, signs, and pathogenic alterations."
Confirms that the two are separate clinical entities, which is why dismech models them as distinct disease entries rather than one blended graph.
📊

Related Datasets

1
Species-specific responses during Seoul orthohantavirus infection in human and rat lung microvascular endothelial cells geo:GSE245916
Paired transcriptional profiling of primary human and rat lung microvascular endothelial cells infected with Seoul orthohantavirus, the agent of a milder form of HFRS. The comparison is the point: the same infection is acute disease in humans and a persistent, asymptomatic infection in the reservoir rat, so the divergent endothelial host response bears directly on why the microvascular barrier fails only in the human host.
BULK RNA SEQ n=24
PMID:38536871
Relocated from the retired Viral_Hemorrhagic_Fever umbrella entry (issue dismech#10115), where it had been indexed under the umbrella by scripts/discover_datasets.py; it is a Seoul-orthohantavirus HFRS dataset and belongs on this entry. Accession and metadata were verified against NCBI E-utilities on 2026-08-01 when first added. Title, sample count, and organism are GEO's own values.
{ }

Source YAML

click to show 
name: Hantavirus Hemorrhagic Fever with Renal Syndrome
creation_date: '2026-08-04T16:00:00Z'
description: >-
  Hemorrhagic fever with renal syndrome (HFRS) is the Old World arm of human
  orthohantavirus disease, endemic across Asia and Europe and caused chiefly by
  Hantaan, Seoul, Puumala, and Dobrava-Belgrade viruses acquired from
  aerosolised rodent excreta. Hantaviruses enter endothelial cells, platelets,
  and macrophages via beta3 integrins and replicate in the microvascular
  endothelium without a cytopathic effect; disease instead arises from
  increased vascular permeability and acute thrombocytopenia, producing a
  characteristic staged illness of fever, hypotension, oliguric acute kidney
  injury, polyuric diuresis, and convalescence. It is the counterpart of the
  New World hantavirus cardiopulmonary syndrome, sharing the same endothelial
  target and leak physiology but centred on the kidney rather than the lung.
category: Infectious Disease
disease_term:
  preferred_term: hantavirus hemorrhagic fever with renal syndrome
  term:
    id: MONDO:0005784
    label: hantavirus hemorrhagic fever with renal syndrome
parents:
- Hantavirus infectious disease
- Viral hemorrhagic fever
synonyms:
- HFRS
- Korean hemorrhagic fever
- epidemic hemorrhagic fever
- nephropathia epidemica
clinical_burden:
  burden_level: HIGH
  rationale: >-
    HFRS is the most frequently diagnosed zoonosis in Asia and carries a
    case-fatality rate of roughly 5-10% depending on the causative
    orthohantavirus, with severe cases requiring intensive care and renal
    replacement therapy.
  evidence:
  - reference: PMID:36851775
    reference_title: "Hemorrhagic Fever with Renal Syndrome in Asia: History, Pathogenesis, Diagnosis, Treatment, and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hemorrhagic Fever with Renal Syndrome (HFRS) is the most frequently
      diagnosed zoonosis in Asia.
    explanation: Establishes the regional disease burden of HFRS.
  - reference: PMID:35384417
    reference_title: "Hemorrhagic Fever with Renal Syndrome: Literature Review, Epidemiology, Clinical Picture and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The case fatality rate of HFRS varies around 5.0 - 10.0% depending on the
      causative viral agent.
    explanation: Quantifies mortality and supports a high burden level.
has_subtypes:
- name: HTNV HFRS
  display_name: Hantaan virus HFRS (classic Korean/epidemic hemorrhagic fever)
  description: >-
    The classic severe form of HFRS, endemic in Asia (notably China and Korea)
    and carried by the striped field mouse Apodemus agrarius.
  geography:
  - Asia
  evidence:
  - reference: PMID:35384417
    reference_title: "Hemorrhagic Fever with Renal Syndrome: Literature Review, Epidemiology, Clinical Picture and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The old world hantaviruses, primarily Hantaan virus (HTNV), responsible
      for causing HFRS occurs endemically in Asia and Europe.
    explanation: Identifies HTNV as the primary Old World agent of HFRS.
- name: SEOV HFRS
  display_name: Seoul virus HFRS (rat-borne, urban and pet-rat associated)
  description: >-
    Moderate-severity HFRS caused by Seoul orthohantavirus, whose reservoir is
    the globally distributed brown rat. Unlike the other agents it has an urban
    and pet/feeder-rat exposure route, and its presentation is often mild or
    atypical with only transient proteinuria and microhaematuria.
  evidence:
  - reference: PMID:31319534
    reference_title: "Wild Rats, Laboratory Rats, Pet Rats: Global Seoul Hantavirus Disease Revisited."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given the mostly milder and atypical clinical presentation, sometimes even
      with preserved normal kidney function, the importance of simple but
      repeated urine examination is stressed, since initial but transient
      proteinuria and microhematuria are rarely lacking.
    explanation: Describes the distinctively mild and atypical SEOV presentation.
- name: PUUV HFRS
  display_name: Puumala virus HFRS (nephropathia epidemica)
  description: >-
    The mild European form, also called nephropathia epidemica, carried by the
    bank vole and associated with mortality below 1%. It nonetheless produces
    genuine acute kidney injury and can be complicated by pituitary
    haemorrhage.
  geography:
  - Europe
  evidence:
  - reference: PMID:24750436
    reference_title: Hantavirus infections.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      whereas Seoul virus causes moderate and Puumala virus and Saaremaa virus
      cause mild forms of disease with mortality rates <1%
    explanation: Places PUUV at the mild end of the HFRS severity spectrum.
- name: DOBV HFRS
  display_name: Dobrava-Belgrade virus HFRS
  description: >-
    The most severe European form, carried by Apodemus mice, with a
    case-fatality rate in the same 5-15% range as Hantaan virus.
  geography:
  - Europe
  evidence:
  - reference: PMID:24750436
    reference_title: Hantavirus infections.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In general, HFRS caused by Hantaan virus, Amur virus and Dobrava virus are
      more severe with mortality rates from 5 to 15%
    explanation: Places DOBV with HTNV at the severe end of the spectrum.
infectious_agent:
- name: Old World orthohantaviruses
  description: >-
    HFRS is caused by a set of rodent-borne Old World orthohantaviruses, of
    which Hantaan, Puumala, and Seoul viruses are the most commonly implicated;
    Dobrava-Belgrade virus accounts for the most severe European disease.
  infectious_agent_term:
    preferred_term: Orthohantavirus
    term:
      id: NCBITaxon:1980442
      label: Orthohantavirus
  evidence:
  - reference: PMID:36851775
    reference_title: "Hemorrhagic Fever with Renal Syndrome in Asia: History, Pathogenesis, Diagnosis, Treatment, and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Several species of orthohantaviruses were identified as causing infection,
      where Hantaan, Puumala, and Seoul viruses are most common.
    explanation: Names the orthohantavirus species most commonly causing HFRS.
- name: Orthohantavirus hantanense (Hantaan virus)
  description: >-
    The prototype HFRS agent, endemic in Asia and Europe, whose principal
    reservoir is the striped field mouse Apodemus agrarius.
  infectious_agent_term:
    preferred_term: Hantaan virus
    term:
      id: NCBITaxon:3052480
      label: Orthohantavirus hantanense
  evidence:
  - reference: PMID:35384417
    reference_title: "Hemorrhagic Fever with Renal Syndrome: Literature Review, Epidemiology, Clinical Picture and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Apodernus agraricus, a striped field mouse, is being considered as main
      host reservoir for HTNV.
    explanation: >-
      Identifies the reservoir rodent for Hantaan virus. The rodent binomial is
      misspelled in the source abstract; the snippet is quoted verbatim as
      published so it validates against the cached text.
- name: Orthohantavirus seoulense (Seoul virus)
  description: >-
    A rat-borne orthohantavirus with a worldwide distribution following its
    reservoir, the brown rat, and an emerging urban and pet/feeder-rat exposure
    route in Europe and North America.
  infectious_agent_term:
    preferred_term: Seoul virus
    term:
      id: NCBITaxon:3052498
      label: Orthohantavirus seoulense
  evidence:
  - reference: PMID:33801789
    reference_title: Seoul Virus in Pet and Feeder Rats in The Netherlands.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Seoul virus (SEOV) is a zoonotic orthohantavirus carried by rats. In
      humans, SEOV can cause hemorrhagic fever with renal syndrome.
    explanation: Establishes SEOV as a rat-borne cause of HFRS.
- name: Orthohantavirus puumalaense (Puumala virus)
  description: >-
    The agent of nephropathia epidemica, the mild European form of HFRS,
    carried by the bank vole.
  infectious_agent_term:
    preferred_term: Puumala virus
    term:
      id: NCBITaxon:3052493
      label: Orthohantavirus puumalaense
  evidence:
  - reference: PMID:26202013
    reference_title: Long-term hormonal follow-up after human Puumala hantavirus infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nephropathia epidemica (NE) is a haemorrhagic fever with renal syndrome
      (HFRS) caused by Puumala hantavirus (PUUV).
    explanation: Equates nephropathia epidemica with PUUV-caused HFRS.
- name: Orthohantavirus dobravaense (Dobrava-Belgrade virus)
  description: >-
    The most severe European HFRS agent, carried by Apodemus mice, with
    mortality comparable to Hantaan virus.
  infectious_agent_term:
    preferred_term: Dobrava-Belgrade virus
    term:
      id: NCBITaxon:3052477
      label: Orthohantavirus dobravaense
  evidence:
  - reference: PMID:24750436
    reference_title: Hantavirus infections.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In general, HFRS caused by Hantaan virus, Amur virus and Dobrava virus are
      more severe with mortality rates from 5 to 15%
    explanation: Identifies Dobrava virus as a severe HFRS agent.
transmission:
- name: Aerosolised rodent excreta exposure
  description: >-
    Human infection is accidental and follows inhalation of aerosols generated
    from virus-contaminated rodent urine, faeces, or saliva. Unlike Andes
    virus in the Americas, the Old World HFRS agents are not known to spread
    person to person.
  evidence:
  - reference: PMID:35384417
    reference_title: "Hemorrhagic Fever with Renal Syndrome: Literature Review, Epidemiology, Clinical Picture and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infection in humans is typically accidental and occurs when
      virus-containing rodent excretions such as urine, feces, or saliva are
      aerosolized.
    explanation: Describes the aerosol route of acquisition.
  - reference: PMID:37105214
    reference_title: "Hantavirus in humans: a review of clinical aspects and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transmission to humans occurs by exposure to infected rodents in endemic
      areas; however, Andes hantavirus is unique in that it can be transmitted
      from person to person.
    explanation: >-
      Confirms rodent exposure as the transmission route and marks
      person-to-person spread as unique to Andes virus, i.e. not an HFRS agent.
- name: Urban and pet/feeder-rat exposure to Seoul virus
  description: >-
    Seoul virus circulates in domesticated rat populations and has produced
    human HFRS cases in the USA, United Kingdom, France, and the Netherlands
    linked to pet or feeder rats, extending the exposure setting from rural
    fieldwork to urban households and the rodent trade.
  evidence:
  - reference: PMID:33801789
    reference_title: Seoul Virus in Pet and Feeder Rats in The Netherlands.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recent human SEOV cases described in the USA, United Kingdom, France and
      the Netherlands were associated with contact with pet or feeder rats.
    explanation: Documents the pet/feeder-rat exposure route for human SEOV disease.
  - reference: PMID:33801789
    reference_title: Seoul Virus in Pet and Feeder Rats in The Netherlands.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In all three investigated groups, RT-qPCR-positive rats were found: in
      1/29 rats from private owners (3.6%), 2/56 rats from ratteries (3.4%) and
      11/90 rats from commercial breeders (12.2%).
    explanation: Quantifies SEOV carriage across domesticated rat populations.
  - reference: PMID:42430118
    reference_title: "Hantavirus infections in a changing world: epidemiology, pathogenesis, and one health challenges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Particular attention is given to the emerging global epidemiology of Seoul
      virus (SEOV), an urban-associated hantavirus linked to brown rats and pet
      rodents.
    explanation: >-
      The 2026 review that triggered this entry frames SEOV as an
      urban-associated, pet-rodent-linked emerging exposure pattern.
progression:
- phase: Febrile phase
  age_range: Any age after exposure
  notes: >-
    HFRS classically runs through five consecutive but frequently overlapping
    clinical phases. The first is an abrupt febrile illness with headache,
    myalgia, abdominal or flank pain, and gastrointestinal symptoms.
  evidence:
  - reference: PMID:1683355
    reference_title: Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HFRS typically consists of five consecutive but frequently overlapping
      clinical phases.
    explanation: Establishes the canonical five-phase clinical course of HFRS.
- phase: Hypotensive phase
  age_range: Acute illness, typically days 4-7
  notes: >-
    Capillary leak causes plasma extravasation, haemoconcentration, and
    hypotension that may progress to shock, coinciding with the nadir of the
    platelet count.
  evidence:
  - reference: PMID:24750436
    reference_title: Hantavirus infections.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The central phenomena behind the pathogenesis of both HFRS and HCPS are
      increased vascular permeability and acute thrombocytopenia.
    explanation: >-
      Supports the leak-and-thrombocytopenia physiology underlying the
      hypotensive phase.
- phase: Oliguric phase
  age_range: Acute illness, typically days 6-12
  notes: >-
    Acute kidney injury with falling urine output is the defining stage of
    HFRS. Entry into the oliguric phase, along with haemorrhage, is one of the
    two features that tracked with clinical severity in the placebo arm of the
    Chinese ribavirin trial.
  evidence:
  - reference: PMID:1683355
    reference_title: Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only occurrence of oliguric phase and hemorrhage was associated with
      severity of clinical disease in the placebo group.
    explanation: >-
      Identifies the oliguric phase as a severity marker in a placebo-controlled
      HFRS cohort.
- phase: Polyuric (diuretic) phase
  age_range: Recovery, typically after day 10
  notes: >-
    Renal recovery is heralded by a diuretic phase with large urine volumes and
    a risk of dehydration and electrolyte loss.
  evidence:
  - reference: PMID:15011467
    reference_title: '[Clinical picture of hemorrhagic fever with renal syndrome in Croatia].'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The oliguric stage is followed by the polyuric stage which can last for
      up to two weeks, and is characterized by excretion of a large quantity of
      urine of low specific gravity (up to 15 liters during 24 hours).
    explanation: >-
      Directly supports the timing, duration, and high urine output of the
      polyuric recovery phase.
- phase: Convalescent phase
  age_range: Weeks to months after acute illness
  notes: >-
    Most patients recover renal function. Pituitary involvement can complicate
    recovery from Puumala virus HFRS, although late-onset hypopituitarism was
    not observed in long-term follow-up of a Finnish cohort.
  evidence:
  - reference: PMID:26202013
    reference_title: Long-term hormonal follow-up after human Puumala hantavirus infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None of our patients had developed obvious late-onset hypopituitarism
      despite of the fact that pituitary gland can be affected during acute NE.
    explanation: >-
      Supports pituitary involvement during acute disease while explicitly not
      supporting late-onset hypopituitarism as a routine sequela.
prevalence:
- population: Worldwide
  measure_type: ANNUAL_INCIDENCE
  notes: >-
    About 100,000 cases of HFRS are reported globally each year, most of them in
    China, Korea, and Russia. No rate_per_100000 is recorded because the source
    reports absolute annual case counts and no denominator population; deriving
    a rate would require an external denominator the source does not supply.
  evidence:
  - reference: PMID:35384417
    reference_title: "Hemorrhagic Fever with Renal Syndrome: Literature Review, Epidemiology, Clinical Picture and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Every year, about 100,000 instances of HFRS are reported, the majority of
      which occur in China, Korea, and Russia
    explanation: The global annual case count and its geographic concentration.
- population: China
  measure_type: ANNUAL_INCIDENCE
  notes: >-
    China accounts for more than 90% of HFRS cases worldwide over recent
    decades.
  evidence:
  - reference: PMID:35384417
    reference_title: "Hemorrhagic Fever with Renal Syndrome: Literature Review, Epidemiology, Clinical Picture and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      China is the most severely impacted country and accounting for around more
      than 90% of all HFRS cases worldwide in the last few decades
    explanation: Establishes China as the dominant contributor to global HFRS burden.
- subtype: HTNV HFRS
  population: China
  measure_type: ANNUAL_INCIDENCE
  notes: Over 10,000-20,000 HTNV-related HFRS cases reported per year in China.
  evidence:
  - reference: PMID:35384417
    reference_title: "Hemorrhagic Fever with Renal Syndrome: Literature Review, Epidemiology, Clinical Picture and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Every year, over 10,000 - 20,000 cases of HTNV-related HFRS are reported in
      China, whereas about 300 - 900 cases are reported in Korea
    explanation: Country-level annual case counts for the Hantaan virus subtype.
- subtype: HTNV HFRS
  population: Korea
  measure_type: ANNUAL_INCIDENCE
  notes: About 300-900 HTNV-related HFRS cases reported per year in Korea.
  evidence:
  - reference: PMID:35384417
    reference_title: "Hemorrhagic Fever with Renal Syndrome: Literature Review, Epidemiology, Clinical Picture and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Every year, over 10,000 - 20,000 cases of HTNV-related HFRS are reported in
      China, whereas about 300 - 900 cases are reported in Korea
    explanation: The Korean arm of the same country-level comparison.
- population: Europe
  measure_type: ANNUAL_INCIDENCE
  notes: >-
    Over 9,000 HFRS cases recorded per year in Europe, where Puumala virus
    infection is the most prevalent form and Dobrava-Belgrade virus causes the
    severe cases.
  evidence:
  - reference: PMID:35384417
    reference_title: "Hemorrhagic Fever with Renal Syndrome: Literature Review, Epidemiology, Clinical Picture and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In Europe, over than 9,000 HFRS are recorded each year, with PUUV
      infections being the most prevalent.
    explanation: >-
      European annual case count and the predominance of Puumala virus there.
      The snippet quotes the published wording verbatim, including its
      grammatical slip ("over than").
pathophysiology:
- name: Aerosol exposure and Old World hantavirus inoculation
  biological_scale: ORGANISM
  description: >-
    Inhalation of aerosolised rodent excreta delivers Old World
    orthohantaviruses to the human host, initiating a systemic infection whose
    principal target is the vascular endothelium rather than any single organ
    parenchyma.
  downstream:
  - target: Beta3 integrin-mediated viral entry into endothelium, platelets, and macrophages
    description: Inoculated virions engage beta3 integrins on the cells that determine leak physiology.
    causal_link_type: DIRECT
  biological_processes:
  - preferred_term: viral process
    modifier: ABNORMAL
    term:
      id: GO:0016032
      label: viral process
  evidence:
  - reference: PMID:36851775
    reference_title: "Hemorrhagic Fever with Renal Syndrome in Asia: History, Pathogenesis, Diagnosis, Treatment, and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This zoonotic infection is the result of exposure to the
      virus-contaminated aerosols.
    explanation: Supports aerosol exposure as the initiating event.
- name: Beta3 integrin-mediated viral entry into endothelium, platelets, and macrophages
  biological_scale: MOLECULAR
  description: >-
    Cellular entry of the HFRS-causing hantaviruses Hantaan, Seoul, and Puumala
    is facilitated by alphavbeta3 and alphaIIbbeta3 integrins. Because beta3
    integrins are displayed on endothelial cells, platelets, and macrophages,
    and because they themselves regulate vascular permeability and platelet
    function, receptor choice places the virus directly on the two cell types
    whose failure defines the syndrome.
  downstream:
  - target: Noncytopathic microvascular endothelial infection
    description: Integrin engagement delivers virus into the microvascular endothelium.
    causal_link_type: DIRECT
  - target: Acute thrombocytopenia and platelet dysfunction
    description: >-
      Beta3 integrin usage places the virus on platelets, coupling receptor
      tropism to the platelet loss that accompanies vascular leak.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  cell_types:
  - preferred_term: endothelial cell of vascular tree
    term:
      id: CL:0002139
      label: endothelial cell of vascular tree
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: receptor-mediated virion attachment to host cell
    modifier: INCREASED
    term:
      id: GO:0046813
      label: receptor-mediated virion attachment to host cell
  evidence:
  - reference: PMID:10196290
    reference_title: Cellular entry of hantaviruses which cause hemorrhagic fever with renal syndrome is mediated by beta3 integrins.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Infection of human umbilical vein endothelial cells and Vero E6 cells by
      the HFRS-causing hantaviruses Hantaan (HTN), Seoul (SEO), and Puumala
      (PUU) is inhibited by antibodies to alphavbeta3 integrins and by the
      integrin ligand vitronectin.
    explanation: >-
      Directly demonstrates beta3 integrin dependence for the three main HFRS
      agents in human endothelial cells.
  - reference: PMID:10196290
    reference_title: Cellular entry of hantaviruses which cause hemorrhagic fever with renal syndrome is mediated by beta3 integrins.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Since beta3 integrins regulate vascular permeability and platelet
      function, these findings also correlate beta3 integrin usage with common
      elements of hantavirus pathogenesis.
    explanation: >-
      Links the receptor to the two downstream nodes of this pathograph, vascular
      permeability and platelet dysfunction.
- name: Noncytopathic microvascular endothelial infection
  biological_scale: CELLULAR
  description: >-
    Hantaviruses replicate to high levels in microvascular endothelial cells
    without producing a cytopathic effect. This is the central mechanistic
    constraint on the disease: because the endothelium is not killed, the
    ensuing microvascular leak must be explained by dysregulated signalling
    rather than by structural destruction of the barrier.
  downstream:
  - target: Cytokine amplification and IL-6 trans-signaling
    description: Infected endothelium drives an amplifying inflammatory cytokine programme.
    causal_link_type: DIRECT
  - target: VEGF-driven VE-cadherin destabilisation of endothelial adherens junctions
    description: Infection raises secreted VEGF and lowers junctional VE-cadherin.
    causal_link_type: DIRECT
    hypothesis_groups:
    - vegf_ve_cadherin_model
  - target: Factor XII-dependent kallikrein-kinin activation and bradykinin release
    description: The infected endothelial surface promotes FXII binding and autoactivation.
    causal_link_type: DIRECT
    hypothesis_groups:
    - kallikrein_kinin_model
  - target: Cytotoxic T cell attack on antigen-presenting endothelium
    description: >-
      Infected endothelium presents viral antigen and becomes a target of the
      hantavirus-specific cytotoxic T cell response.
    causal_link_type: DIRECT
    hypothesis_groups:
    - t_cell_immunopathogenesis_model
  cell_types:
  - preferred_term: endothelial cell of vascular tree
    term:
      id: CL:0002139
      label: endothelial cell of vascular tree
  biological_processes:
  - preferred_term: viral process
    modifier: INCREASED
    term:
      id: GO:0016032
      label: viral process
  evidence:
  - reference: PMID:20810734
    reference_title: Andes virus disrupts the endothelial cell barrier by induction of vascular endothelial growth factor and downregulation of VE-cadherin.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      High levels of virus replication occur in microvascular endothelial cells
      but without a virus-induced cytopathic effect.
    explanation: >-
      States the noncytopathic high-replication phenotype that constrains all
      downstream mechanistic models. The framing of this paper covers both HPS
      and HFRS, though its experiments used the HPS-associated Andes virus.
  - reference: PMID:10196290
    reference_title: Cellular entry of hantaviruses which cause hemorrhagic fever with renal syndrome is mediated by beta3 integrins.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Hantaviruses replicate primarily in the vascular endothelium and cause two
      human diseases, hemorrhagic fever with renal syndrome (HFRS) and
      hantavirus pulmonary syndrome (HPS).
    explanation: Establishes the vascular endothelium as the primary replication site in HFRS.
- name: Cytokine amplification and IL-6 trans-signaling
  biological_scale: CELLULAR
  description: >-
    Infected endothelium amplifies an inflammatory cytokine programme. In
    primary human endothelial cells, soluble IL-6 receptor (trans-signaling)
    treatment of infected cells increased IL-6 and CCL2 secretion, upregulated
    ICAM-1, and disrupted VE-cadherin and barrier integrity; Puumala-infected
    HFRS patients showed a shifted sIL-6R/sgp130 ratio consistent with enhanced
    trans-signaling potential, which tracked with clinical severity.
  downstream:
  - target: Increased vascular permeability and capillary leak
    description: Cytokine-driven endothelial activation degrades barrier function.
    causal_link_type: DIRECT
  cell_types:
  - preferred_term: endothelial cell of vascular tree
    term:
      id: CL:0002139
      label: endothelial cell of vascular tree
  biological_processes:
  - preferred_term: interleukin-6-mediated signaling pathway
    modifier: INCREASED
    term:
      id: GO:0070102
      label: interleukin-6-mediated signaling pathway
  - preferred_term: cytokine-mediated signaling pathway
    modifier: INCREASED
    term:
      id: GO:0019221
      label: cytokine-mediated signaling pathway
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:40203030
    reference_title: IL-6 trans-signaling mediates cytokine secretion and barrier dysfunction in hantavirus-infected cells and correlates to severity in HFRS.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro, sIL-6R treatment of infected cells enhanced IL-6 and CCL2
      secretion, upregulated ICAM-1, and affected VE-cadherin leading to a
      disrupted cell barrier integrity.
    explanation: >-
      Demonstrates the cytokine-to-barrier-failure link in infected primary human
      endothelial cells.
  - reference: PMID:40203030
    reference_title: IL-6 trans-signaling mediates cytokine secretion and barrier dysfunction in hantavirus-infected cells and correlates to severity in HFRS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HFRS patients showed altered plasma levels of sIL-6R and soluble gp130
      (sgp130) resulting in an increased sIL-6R/sgp130 ratio suggesting enhanced
      IL-6 trans-signaling potential.
    explanation: >-
      Confirms the trans-signaling shift in a cohort of Puumala-infected HFRS
      patients, not only in cell culture.
  - reference: PMID:40203030
    reference_title: IL-6 trans-signaling mediates cytokine secretion and barrier dysfunction in hantavirus-infected cells and correlates to severity in HFRS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients receiving oxygen treatment displayed a higher sIL-6R/sgp130 ratio
      compared to patients that did not.
    explanation: Ties the trans-signaling shift to clinical severity in HFRS.
- name: VEGF-driven VE-cadherin destabilisation of endothelial adherens junctions
  biological_scale: MOLECULAR
  description: >-
    In the most widely cited model of hantavirus leak, infection raises secreted
    VEGF, and VEGF binding to VEGF-R2 dissociates the receptor from VE-cadherin
    and drives VE-cadherin internalisation and degradation, dismantling the
    adherens junction without killing the cell. Blocking VEGF-R2 activation
    prevents the infection-induced VE-cadherin loss.
  downstream:
  - target: Increased vascular permeability and capillary leak
    description: Loss of junctional VE-cadherin opens the paracellular route.
    causal_link_type: DIRECT
    hypothesis_groups:
    - vegf_ve_cadherin_model
  cell_types:
  - preferred_term: endothelial cell of vascular tree
    term:
      id: CL:0002139
      label: endothelial cell of vascular tree
  biological_processes:
  - preferred_term: vascular endothelial growth factor receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0048010
      label: vascular endothelial growth factor receptor signaling pathway
  - preferred_term: adherens junction organization
    modifier: DECREASED
    term:
      id: GO:0034332
      label: adherens junction organization
  evidence:
  - reference: PMID:20810734
    reference_title: Andes virus disrupts the endothelial cell barrier by induction of vascular endothelial growth factor and downregulation of VE-cadherin.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here we report that increased secreted VEGF and concomitant decreased
      VE-cadherin are seen at early times postinfection of human primary lung
      endothelial cells with an HPS-associated hantavirus, Andes virus.
    explanation: >-
      The primary experimental support for the VEGF/VE-cadherin model. Note the
      virus used was the HPS-associated Andes virus, so the extension to HFRS
      agents is by mechanistic analogy rather than direct demonstration.
  - reference: PMID:20810734
    reference_title: Andes virus disrupts the endothelial cell barrier by induction of vascular endothelial growth factor and downregulation of VE-cadherin.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consistent with this, we showed that an antibody which blocks VEGF-R2
      activation resulted in inhibition of the Andes virus-induced VE-cadherin
      reduction.
    explanation: Provides the pharmacological test that establishes VEGF-R2 as the mediator.
  - reference: PMID:23874198
    reference_title: Endothelial cell permeability during hantavirus infection involves factor XII-dependent increased activation of the kallikrein-kinin system.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      despite viral replication in both cell types as well as the presence of
      VEGF, infected in vitro vessels neither lost integrity nor displayed
      evidence of VE-cadherin degradation
    explanation: >-
      In a three-dimensional endothelial/smooth-muscle vessel model the
      VEGF/VE-cadherin mechanism did not reproduce, which is the direct
      experimental challenge to this node and the reason it is curated as one of
      several competing hypotheses rather than as settled mechanism.
- name: Factor XII-dependent kallikrein-kinin activation and bradykinin release
  biological_scale: MOLECULAR
  description: >-
    A competing, non-mutually-exclusive model of the same leak. Factor XII
    binding and autoactivation are increased on the surface of
    hantavirus-infected endothelial cells; incubation with FXII, prekallikrein,
    and high-molecular-weight kininogen yields increased kininogen cleavage,
    higher FXIIa/kallikrein activity, and liberation of bradykinin, which
    dramatically increases endothelial permeability. Blocking bradykinin
    binding, FXIIa, or kallikrein prevents the permeability change.
  downstream:
  - target: Increased vascular permeability and capillary leak
    description: Liberated bradykinin acts on the endothelium to open the barrier.
    causal_link_type: DIRECT
    hypothesis_groups:
    - kallikrein_kinin_model
  cell_types:
  - preferred_term: endothelial cell of vascular tree
    term:
      id: CL:0002139
      label: endothelial cell of vascular tree
  biological_processes:
  - preferred_term: kinin cascade
    modifier: INCREASED
    term:
      id: GO:0002254
      label: kinin cascade
  - preferred_term: blood coagulation, intrinsic pathway
    modifier: INCREASED
    term:
      id: GO:0007597
      label: blood coagulation, intrinsic pathway
  evidence:
  - reference: PMID:23874198
    reference_title: Endothelial cell permeability during hantavirus infection involves factor XII-dependent increased activation of the kallikrein-kinin system.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that incubation of factor XII (FXII), prekallikrein (PK), and high
      molecular weight kininogen (HK) plasma proteins with hantavirus-infected EC
      results in increased cleavage of HK, higher enzymatic activities of
      FXIIa/kallikrein (KAL) and increased liberation of bradykinin (BK).
    explanation: Establishes kallikrein-kinin system activation on infected endothelium.
  - reference: PMID:23874198
    reference_title: Endothelial cell permeability during hantavirus infection involves factor XII-dependent increased activation of the kallikrein-kinin system.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, the alterations in permeability could be prevented using
      inhibitors that directly block BK binding, the activity of FXIIa, or the
      activity of KAL.
    explanation: >-
      Provides the interventional test linking bradykinin to permeability and the
      rationale for the icatibant treatment entry.
- name: Cytotoxic T cell attack on antigen-presenting endothelium
  biological_scale: CELLULAR
  description: >-
    A third, immunopathological model holds that hantavirus-specific cytotoxic T
    cells attack endothelial cells displaying viral antigen, and that this is
    what raises capillary permeability. The clinical correlation is
    direction-dependent and unresolved: T cell responses correlate positively
    with severity in HCPS but negatively with severity in HFRS in at least one
    report, so both too strong and too weak a T cell response may worsen disease.
  downstream:
  - target: Increased vascular permeability and capillary leak
    description: Cytotoxic attack on infected endothelium compromises barrier integrity.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - t_cell_immunopathogenesis_model
  cell_types:
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  - preferred_term: endothelial cell of vascular tree
    term:
      id: CL:0002139
      label: endothelial cell of vascular tree
  biological_processes:
  - preferred_term: T cell mediated cytotoxicity
    modifier: INCREASED
    term:
      id: GO:0001913
      label: T cell mediated cytotoxicity
  evidence:
  - reference: PMID:21994770
    reference_title: T cells and pathogenesis of hantavirus cardiopulmonary syndrome and hemorrhagic fever with renal syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We previously hypothesized that increased capillary permeability observed
      in both hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever
      with renal syndrome (HFRS) may be caused by hantavirus-specific cytotoxic T
      cells attacking endothelial cells presenting viral antigens on their
      surface based on clinical observations and in vitro experiments.
    explanation: >-
      States the immunopathological hypothesis. It is curated as PARTIAL because
      the same review reports that the supporting clinical correlation runs in
      opposite directions in HFRS and HCPS.
  - reference: PMID:24750436
    reference_title: Hantavirus infections.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pathogenesis is likely to be a complex multifactorial process that
      includes contributions from immune responses, platelet dysfunction and the
      deregulation of endothelial cell barrier functions.
    explanation: >-
      Supports an immune contribution as one component of a multifactorial
      pathogenesis rather than as the sole mechanism.
- name: Increased vascular permeability and capillary leak
  conforms_to: viral_hemorrhagic_fever_syndrome#Increased Vascular Permeability
  biological_scale: TISSUE
  description: >-
    The convergent hub of HFRS pathogenesis. Whatever the proximal signalling
    route, the endothelial barrier becomes permeable, plasma extravasates,
    haemoconcentration and hypotension follow, and every organ served by the
    affected microvasculature is exposed to leak. In HFRS the kidney bears the
    brunt.
  downstream:
  - target: Acute kidney injury with oliguric renal failure
    description: Renal microvascular leak and interstitial oedema drive the defining organ injury.
    causal_link_type: DIRECT
  - target: Acute thrombocytopenia and platelet dysfunction
    description: Leak physiology is accompanied by consumptive platelet loss.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  cell_types:
  - preferred_term: endothelial cell of vascular tree
    term:
      id: CL:0002139
      label: endothelial cell of vascular tree
  biological_processes:
  - preferred_term: regulation of vascular permeability
    modifier: INCREASED
    term:
      id: GO:0043114
      label: regulation of vascular permeability
  evidence:
  - reference: PMID:37105214
    reference_title: "Hantavirus in humans: a review of clinical aspects and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As hantaviruses target endothelial cells, they can affect diverse organ
      systems; increased vascular permeability is central to pathogenesis.
    explanation: Establishes increased vascular permeability as the central pathogenic event.
  - reference: PMID:35384417
    reference_title: "Hemorrhagic Fever with Renal Syndrome: Literature Review, Epidemiology, Clinical Picture and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The major clinical manifestations includes increased vascular permeability
      causing vascular leakage, acute kidney injury and coagulation
      abnormalities.
    explanation: Links the leak hub to the two downstream nodes, renal injury and coagulopathy.
- name: Acute thrombocytopenia and platelet dysfunction
  biological_scale: CELLULAR
  description: >-
    Acute thrombocytopenia is, with vascular permeability, one of the two
    central phenomena of hantavirus disease. Platelets display the same beta3
    integrins the virus uses for entry, and platelet dysfunction is an
    independent contributor to pathogenesis alongside barrier failure.
  downstream:
  - target: Haemorrhagic manifestations
    description: Platelet loss and dysfunction convert vascular fragility into overt bleeding.
    causal_link_type: DIRECT
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: platelet activation
    modifier: ABNORMAL
    term:
      id: GO:0030168
      label: platelet activation
  evidence:
  - reference: PMID:24750436
    reference_title: Hantavirus infections.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The central phenomena behind the pathogenesis of both HFRS and HCPS are
      increased vascular permeability and acute thrombocytopenia.
    explanation: Establishes acute thrombocytopenia as a central pathogenic phenomenon.
  - reference: PMID:10196290
    reference_title: Cellular entry of hantaviruses which cause hemorrhagic fever with renal syndrome is mediated by beta3 integrins.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These findings indicate that pathogenic HPS- and HFRS-causing hantaviruses
      enter cells via beta3 integrins, which are present on the surfaces of
      platelets, endothelial cells, and macrophages.
    explanation: Places the viral receptor on platelets, connecting tropism to thrombocytopenia.
- name: Acute kidney injury with oliguric renal failure
  biological_scale: TISSUE
  description: >-
    The organ-defining lesion of HFRS. Renal microvascular leak produces
    interstitial oedema and tubular injury with proteinuria, haematuria, rising
    creatinine, and oliguria that may require renal replacement therapy, followed
    in survivors by a polyuric recovery phase.
  downstream:
  - target: Staged renal recovery and convalescence
    description: Surviving nephrons recover, producing the diuretic and convalescent phases.
    causal_link_type: DIRECT
  cell_types:
  - preferred_term: kidney tubule cell
    term:
      id: CL:1000507
      label: kidney tubule cell
  - preferred_term: glomerular endothelial cell
    term:
      id: CL:0002188
      label: glomerular endothelial cell
  evidence:
  - reference: PMID:36851775
    reference_title: "Hemorrhagic Fever with Renal Syndrome in Asia: History, Pathogenesis, Diagnosis, Treatment, and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Orthohantavirus infection may cause Hemorrhagic Fever with Renal Syndrome
      (HRFS), a disease that is characterized by acute kidney injury and
      increased vascular permeability.
    explanation: >-
      Defines HFRS by acute kidney injury plus increased vascular permeability.
      The acronym is mistyped as HRFS in the source abstract and the snippet is
      quoted verbatim so it validates against the cached text.
  - reference: PMID:1683355
    reference_title: Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only occurrence of oliguric phase and hemorrhage was associated with
      severity of clinical disease in the placebo group.
    explanation: Ties the oliguric phase of renal failure to clinical severity.
- name: Haemorrhagic manifestations
  biological_scale: ORGANISM
  description: >-
    Coagulation abnormalities and thrombocytopenia produce the haemorrhagic
    component of the syndrome, ranging from petechiae and conjunctival
    haemorrhage to gastrointestinal and, in Puumala infection, pituitary
    bleeding. Haemorrhage was one of only two features associated with clinical
    severity in the placebo arm of the Chinese ribavirin trial.
  evidence:
  - reference: PMID:35384417
    reference_title: "Hemorrhagic Fever with Renal Syndrome: Literature Review, Epidemiology, Clinical Picture and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The major clinical manifestations includes increased vascular permeability
      causing vascular leakage, acute kidney injury and coagulation
      abnormalities.
    explanation: Establishes coagulation abnormalities as a core manifestation.
  - reference: PMID:26202013
    reference_title: Long-term hormonal follow-up after human Puumala hantavirus infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pituitary haemorrhage and hypopituitarism may complicate recovery from
      acute NE.
    explanation: Documents pituitary haemorrhage as a site-specific bleeding complication of PUUV HFRS.
- name: Staged renal recovery and convalescence
  biological_scale: ORGANISM
  description: >-
    HFRS resolves through a diuretic phase of high urine output and then
    convalescence. The five-phase structure (febrile, hypotensive, oliguric,
    diuretic, convalescent) is the clinical signature of the disease and is the
    frame in which treatment timing is judged.
  evidence:
  - reference: PMID:1683355
    reference_title: Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HFRS typically consists of five consecutive but frequently overlapping
      clinical phases.
    explanation: Supports the staged course through to convalescence.
mechanistic_hypotheses:
- hypothesis_group_id: vegf_ve_cadherin_model
  hypothesis_label: VEGF hypersensitisation and VE-cadherin degradation open the barrier
  status: CANONICAL
  description: >-
    The most widely cited explanation of hantavirus vascular leak: infection
    raises secreted VEGF and hypersensitises the endothelium to it, VEGF-R2
    engagement dissociates from and internalises VE-cadherin, and the adherens
    junction is dismantled without cell death. Blocking VEGF-R2 prevents the
    VE-cadherin loss. It is curated as CANONICAL because it is the dominant
    published model, not because it is unchallenged; the direct experimental
    challenge is recorded on the node and in the kallikrein-kinin alternative.
  evidence:
  - reference: PMID:20810734
    reference_title: Andes virus disrupts the endothelial cell barrier by induction of vascular endothelial growth factor and downregulation of VE-cadherin.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These data implicate virus induction of VEGF and reduction in VE-cadherin
      in the endothelial cell permeability seen in HPS and suggest potential
      immunotherapeutic targets for the treatment of the disease.
    explanation: The authors' own statement of the model.
- hypothesis_group_id: kallikrein_kinin_model
  hypothesis_label: Factor XII-dependent kallikrein-kinin activation and bradykinin drive the leak
  status: ALTERNATIVE
  description: >-
    An alternative proximal mechanism proposed after the VEGF model failed to
    reproduce in a three-dimensional endothelial/smooth-muscle vessel model.
    FXII binds and autoactivates on the infected endothelial surface, generating
    kallikrein activity and liberating bradykinin, which increases permeability;
    the effect is abolished by blocking bradykinin binding, FXIIa, or
    kallikrein. Its clinical corollary is that a bradykinin B2 receptor
    antagonist should help, which a single severe Puumala case report supports.
  evidence:
  - reference: PMID:23874198
    reference_title: Endothelial cell permeability during hantavirus infection involves factor XII-dependent increased activation of the kallikrein-kinin system.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we present evidence for a novel mechanism of hantavirus-induced
      vascular leakage involving activation of the plasma kallikrein-kinin system
      (KKS).
    explanation: The authors' statement of the alternative model.
- hypothesis_group_id: t_cell_immunopathogenesis_model
  hypothesis_label: Hantavirus-specific cytotoxic T cells attacking infected endothelium cause the leak
  status: ALTERNATIVE
  description: >-
    An immunopathological model in which capillary permeability results from
    cytotoxic T cells attacking endothelial cells presenting viral antigen.
    Curated as ALTERNATIVE rather than EMERGING because it is long-standing, and
    not as CANONICAL because its supporting clinical correlation is
    direction-inconsistent between HFRS and HCPS.
  evidence:
  - reference: PMID:21994770
    reference_title: T cells and pathogenesis of hantavirus cardiopulmonary syndrome and hemorrhagic fever with renal syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These seemingly contradictory findings may suggest delicate balance in T
      cell responses between protection and immunopathogenesis. Both too strong
      and too weak T cell responses may lead to severe disease.
    explanation: >-
      The review's own summary of why the T cell model cannot currently be
      promoted above the endothelial-signalling models.
datasets:
- accession: geo:GSE245916
  title: Species-specific responses during Seoul orthohantavirus infection in human and rat lung microvascular endothelial cells
  description: >-
    Paired transcriptional profiling of primary human and rat lung
    microvascular endothelial cells infected with Seoul orthohantavirus, the
    agent of a milder form of HFRS. The comparison is the point: the same
    infection is acute disease in humans and a persistent, asymptomatic
    infection in the reservoir rat, so the divergent endothelial host response
    bears directly on why the microvascular barrier fails only in the human
    host.
  data_type: BULK_RNA_SEQ
  sample_count: 24
  publication: PMID:38536871
  notes: >-
    Relocated from the retired Viral_Hemorrhagic_Fever umbrella entry
    (issue dismech#10115), where it had been indexed under the umbrella by
    scripts/discover_datasets.py; it is a Seoul-orthohantavirus HFRS dataset
    and belongs on this entry. Accession and metadata were verified against
    NCBI E-utilities on 2026-08-01 when first added. Title, sample count, and
    organism are GEO's own values.
discussions:
- discussion_id: hfrs_leak_mechanism_competing_models
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Which proximal mechanism actually opens the endothelial barrier in HFRS -
    VEGF-driven VE-cadherin degradation, factor XII-dependent kallikrein-kinin
    activation with bradykinin release, or cytotoxic T cell attack on
    antigen-presenting endothelium - and are they sequential, parallel, or
    artefacts of different model systems?
  attaches_to:
  - pathophysiology#VEGF-driven VE-cadherin destabilisation of endothelial adherens junctions
  - pathophysiology#Factor XII-dependent kallikrein-kinin activation and bradykinin release
  - pathophysiology#Cytotoxic T cell attack on antigen-presenting endothelium
  - pathophysiology#Increased vascular permeability and capillary leak
  rationale: >-
    The three models are not merely underdetermined, they are in direct
    experimental tension. The VEGF/VE-cadherin model rests on infected
    endothelial monolayers; in a co-cultured endothelial/smooth-muscle vessel
    model, infected vessels retained integrity and showed no VE-cadherin
    degradation despite viral replication and the presence of VEGF, which is
    what motivated the kallikrein-kinin proposal. The T cell model has clinical
    correlations that run in opposite directions in HFRS and HCPS. The choice
    matters therapeutically: the models nominate anti-VEGF/VEGF-R2 blockade, a
    bradykinin B2 antagonist, and immunosuppression respectively - three
    interventions that are not interchangeable, and one of which
    (immunosuppression) could be harmful if the T cell response is protective.
  proposed_experiments:
  - experiment_id: exp_hfrs_leak_model_head_to_head_3d_vessel
    name: Head-to-head test of the VEGF and kallikrein-kinin leak models in a three-dimensional vessel using an HFRS agent
    description: >-
      Run the VEGF/VE-cadherin and kallikrein-kinin readouts side by side in the
      same co-cultured endothelial/smooth-muscle vessel model, infected with an
      HFRS-causing agent (Hantaan or Puumala) rather than the HPS-associated
      Andes virus, so that virus identity and model dimensionality stop being
      confounded with each other. Measure secreted VEGF, junctional VE-cadherin,
      FXIIa/kallikrein activity, liberated bradykinin, and barrier impedance in
      the same wells.
    decision_criterion: >-
      If VE-cadherin degrades in the three-dimensional vessel with an Old World
      agent, the earlier negative result was virus-specific rather than
      model-specific; if bradykinin liberation but not VE-cadherin loss tracks
      the impedance fall, the kallikrein-kinin model is the better account of
      HFRS leak.
  - experiment_id: exp_hfrs_serial_leak_biomarkers_patient_cohort
    name: Serial plasma leak-mediator profiling across the five clinical phases of HFRS
    description: >-
      Measure plasma bradykinin, cleaved high-molecular-weight kininogen, VEGF,
      and soluble VE-cadherin serially in the same HFRS patient cohort, sampled
      by clinical phase, and test which mediator's rise precedes the onset of
      measured capillary leak and haemoconcentration.
    decision_criterion: >-
      The mediator whose rise consistently precedes rather than follows the leak
      onset is the candidate proximal driver in humans; a mediator that rises
      only after leak is established is downstream or epiphenomenal.
  - experiment_id: exp_hfrs_bradykinin_antagonist_rct
    name: Randomised trial of a bradykinin B2 receptor antagonist in severe HFRS
    description: >-
      Run an adequately powered randomised controlled trial of icatibant or an
      equivalent bradykinin B2 receptor antagonist in severe HFRS, with capillary
      leak and progression to the oliguric phase as primary endpoints. This is
      the interventional test that the existing single case report cannot
      provide.
    decision_criterion: >-
      A reduction in leak and in oliguric-phase entry would confirm the
      kallikrein-kinin arm as causal and therapeutically actionable in humans; a
      null result would leave the mechanism as an in-vitro finding without
      clinical reach.
  evidence:
  - reference: PMID:23874198
    reference_title: Endothelial cell permeability during hantavirus infection involves factor XII-dependent increased activation of the kallikrein-kinin system.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In contrast to results obtained in monolayers of cultured EC, we found that
      despite viral replication in both cell types as well as the presence of
      VEGF, infected in vitro vessels neither lost integrity nor displayed
      evidence of VE-cadherin degradation.
    explanation: The direct experimental statement of the tension between the two endothelial-signalling models.
- discussion_id: hfrs_vegf_evidence_from_new_world_virus
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does the VEGF/VE-cadherin leak mechanism, demonstrated with the
    HPS-associated Andes virus in human lung endothelial cells, actually operate
    in the Old World HFRS agents and in the renal microvasculature they injure?
  attaches_to:
  - pathophysiology#VEGF-driven VE-cadherin destabilisation of endothelial adherens junctions
  rationale: >-
    The canonical VEGF/VE-cadherin evidence in this entry is generated with
    Andes virus - a New World, HCPS-causing agent - in primary human lung
    endothelial cells. HFRS is caused by different viruses and its defining organ
    injury is renal, not pulmonary. Old and New World hantaviruses are known to
    differ in cell tropism, so importing the mechanism wholesale risks asserting
    a lung-derived, HPS-derived model as HFRS pathophysiology. This is a
    model-fidelity question rather than an absence of evidence: the experiments
    exist and are sound, but their translational reach to HFRS is the open
    question.
  proposed_experiments:
  - experiment_id: exp_hfrs_vegf_in_renal_microvascular_endothelium
    name: VEGF induction and VE-cadherin loss in human renal microvascular endothelium infected with Old World hantaviruses
    description: >-
      Repeat the VEGF induction and VE-cadherin degradation measurements in
      primary human renal microvascular endothelial cells infected with Hantaan
      and Puumala virus, and compare them head to head with Andes virus in the
      same system, so that virus origin and vascular bed are varied
      independently.
    decision_criterion: >-
      Reproduction of VEGF induction and VE-cadherin loss with Old World agents
      in renal endothelium would license the mechanism for HFRS; failure would
      require the entry to demote this node to an HPS-specific model.
  evidence:
  - reference: PMID:40857262
    reference_title: Differential tropisms of old and new world hantaviruses influence virulence and developing host-directed antiviral candidates.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      SNV readily infected pulmonary endothelial cells, while HTNV robustly
      amplified in endothelial cells, cardiomyocytes, and astrocytes.
    explanation: >-
      Demonstrates that Old and New World hantaviruses differ in cell tropism,
      which is why an Andes-virus-derived mechanism cannot simply be assumed to
      hold for the HFRS agents.
- discussion_id: hfrs_ribavirin_efficacy_and_treatment_window
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Is intravenous ribavirin genuinely effective in HFRS, and if so within what
    window - given that the single supporting randomised trial is from 1991 in
    China and that the same drug failed in cardiopulmonary-stage HCPS?
  attaches_to:
  - pathophysiology#Acute kidney injury with oliguric renal failure
  rationale: >-
    HFRS is unusual among viral haemorrhagic fevers in having a positive
    placebo-controlled antiviral trial: intravenous ribavirin reduced mortality
    sevenfold after adjustment and reduced the risk of entering the oliguric
    phase. But that trial was conducted in 1991 in a single country, the effect
    estimate is adjusted rather than crude, and a later randomised trial of the
    same drug in the cardiopulmonary stage of the New World syndrome found no
    trend towards benefit. Contemporary reviews continue to state that no
    specific effective antiviral treatment is available, so the field has not
    absorbed the 1991 result as practice-changing. Whether the discrepancy is
    about the drug, the syndrome, or the timing of administration is unresolved
    and directly determines whether an HFRS patient should be offered ribavirin.
  proposed_experiments:
  - experiment_id: exp_hfrs_ribavirin_phase_stratified_rct
    name: Modern phase-stratified randomised trial of intravenous ribavirin in HFRS
    description: >-
      Conduct a multicentre randomised trial of intravenous ribavirin in HFRS
      stratified by clinical phase at enrolment (febrile versus hypotensive
      versus oliguric), against contemporary supportive care including renal
      replacement therapy, to test whether the 1991 benefit is real and whether
      it is confined to an early treatment window.
    decision_criterion: >-
      Benefit confined to febrile-phase enrolment would reconcile the positive
      1991 HFRS trial with the negative cardiopulmonary-stage HCPS trial as a
      treatment-window effect rather than a syndrome difference; a uniformly null
      result would retire ribavirin for HFRS.
  evidence:
  - reference: PMID:1683355
    reference_title: Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mortality was significantly reduced (sevenfold decrease in risk) among
      ribavirin-treated patients, when comparisons were adjusted for baseline
      risk estimators of mortality (P = .01; two-tailed).
    explanation: The positive randomised result that sits in tension with current practice statements.
  - reference: PMID:37105214
    reference_title: "Hantavirus in humans: a review of clinical aspects and management."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No specific effective antiviral treatment is available.
    explanation: >-
      A 2023 Lancet Infectious Diseases review still states that no specific
      effective antiviral exists, which is what makes the 1991 positive trial an
      open question rather than settled practice.
phenotypes:
- category: Constitutional
  name: Fever
  description: Abrupt fever opens the first of the five clinical phases.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
    temporality: ACUTE
  evidence:
  - reference: PMID:35384417
    reference_title: "Hemorrhagic Fever with Renal Syndrome: Literature Review, Epidemiology, Clinical Picture and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In Korea, fever (94.0%), abdominal discomfort (64.0%) and headache (50.7%)
      are the most common early clinical symptoms.
    explanation: >-
      Reported frequency of 94.0% in a Korean series falls in the VERY_FREQUENT
      band (80-99%).
- category: Constitutional
  name: Myalgia
  description: Myalgia accompanies the febrile prodrome.
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
- category: Neurological
  name: Headache
  description: Headache is a prominent early symptom.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:35384417
    reference_title: "Hemorrhagic Fever with Renal Syndrome: Literature Review, Epidemiology, Clinical Picture and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In Korea, fever (94.0%), abdominal discomfort (64.0%) and headache (50.7%)
      are the most common early clinical symptoms.
    explanation: >-
      Reported frequency of 50.7% in a Korean series falls in the FREQUENT band
      (30-79%).
- category: Gastrointestinal
  name: Abdominal pain
  description: Abdominal pain is common during the febrile and hypotensive phases.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:35384417
    reference_title: "Hemorrhagic Fever with Renal Syndrome: Literature Review, Epidemiology, Clinical Picture and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In Korea, fever (94.0%), abdominal discomfort (64.0%) and headache (50.7%)
      are the most common early clinical symptoms.
    explanation: >-
      Reported frequency of 64.0% in a Korean series falls in the FREQUENT band
      (30-79%). The source terms this "abdominal discomfort", curated here
      against the closest HPO term, Abdominal pain.
- category: Renal
  name: Flank pain
  description: Flank or lumbar pain reflects renal involvement and capsular distension.
  phenotype_term:
    preferred_term: Flank pain
    term:
      id: HP:0030157
      label: Flank pain
- category: Gastrointestinal
  name: Nausea
  description: Nausea forms part of the nonspecific early illness.
  phenotype_term:
    preferred_term: Nausea
    term:
      id: HP:0002018
      label: Nausea
- category: Gastrointestinal
  name: Vomiting
  description: Vomiting forms part of the nonspecific early illness.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
- category: Ophthalmological
  name: Blurred vision
  description: >-
    Transient visual blurring, often from an acute myopic shift and ocular
    involvement, is a recognised feature of nephropathia epidemica.
  phenotype_term:
    preferred_term: Blurred vision
    term:
      id: HP:0000622
      label: Blurred vision
    temporality: TRANSIENT
- category: Cardiovascular
  name: Capillary leak
  description: >-
    Increased vascular permeability with plasma extravasation is the central
    pathogenic event and is clinically evident as capillary leak.
  phenotype_term:
    preferred_term: Capillary leak
    term:
      id: HP:0030005
      label: Capillary leak
  evidence:
  - reference: PMID:37105214
    reference_title: "Hantavirus in humans: a review of clinical aspects and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As hantaviruses target endothelial cells, they can affect diverse organ
      systems; increased vascular permeability is central to pathogenesis.
    explanation: Supports capillary leak as the central clinical-pathological feature.
- category: Cardiovascular
  name: Hypotension
  description: Hypotension defines the second clinical phase and reflects plasma loss into the interstitium.
  phenotype_term:
    preferred_term: Hypotension
    term:
      id: HP:0002615
      label: Hypotension
- category: Cardiovascular
  name: Shock
  description: Severe capillary leak can progress to circulatory shock.
  phenotype_term:
    preferred_term: Shock
    term:
      id: HP:0031273
      label: Shock
- category: Hematologic
  name: Thrombocytopenia
  description: >-
    Acute thrombocytopenia is one of the two central phenomena of hantavirus
    disease, alongside increased vascular permeability.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
    temporality: ACUTE
  evidence:
  - reference: PMID:24750436
    reference_title: Hantavirus infections.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The central phenomena behind the pathogenesis of both HFRS and HCPS are
      increased vascular permeability and acute thrombocytopenia.
    explanation: Directly supports acute thrombocytopenia as a defining feature.
- category: Hematologic
  name: Hemoconcentration
  description: Plasma extravasation raises the haematocrit during the leak phase.
  phenotype_term:
    preferred_term: Increased hematocrit
    term:
      id: HP:0001899
      label: Increased hematocrit
- category: Hematologic
  name: Leukocytosis
  description: Leukocytosis accompanies the acute inflammatory response.
  phenotype_term:
    preferred_term: Leukocytosis
    term:
      id: HP:0001974
      label: Increased total leukocyte count
- category: Hematologic
  name: Petechiae
  description: Petechial haemorrhages reflect thrombocytopenia and vascular fragility.
  phenotype_term:
    preferred_term: Petechiae
    term:
      id: HP:0000967
      label: Petechiae
- category: Hematologic
  name: Gastrointestinal hemorrhage
  description: Overt bleeding, including gastrointestinal haemorrhage, marks severe disease.
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  evidence:
  - reference: PMID:1683355
    reference_title: Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only occurrence of oliguric phase and hemorrhage was associated with
      severity of clinical disease in the placebo group.
    explanation: Supports haemorrhage as a severity-defining manifestation.
- category: Renal
  name: Acute kidney injury
  description: >-
    Acute kidney injury is the organ-defining feature that distinguishes HFRS
    from the cardiopulmonary syndrome.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: PMID:36851775
    reference_title: "Hemorrhagic Fever with Renal Syndrome in Asia: History, Pathogenesis, Diagnosis, Treatment, and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Orthohantavirus infection may cause Hemorrhagic Fever with Renal Syndrome
      (HRFS), a disease that is characterized by acute kidney injury and
      increased vascular permeability.
    explanation: >-
      Defines HFRS by acute kidney injury. The acronym is mistyped in the source
      abstract and the snippet is quoted verbatim.
- category: Renal
  name: Oliguria
  description: The oliguric phase is the defining and most dangerous stage of the illness.
  phenotype_term:
    preferred_term: Oliguria
    term:
      id: HP:0100520
      label: Oliguria
  evidence:
  - reference: PMID:1683355
    reference_title: Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only occurrence of oliguric phase and hemorrhage was associated with
      severity of clinical disease in the placebo group.
    explanation: Supports oliguria as a severity-defining phase of HFRS.
- category: Renal
  name: Polyuria
  description: A diuretic phase with high urine output marks the onset of renal recovery.
  phenotype_term:
    preferred_term: Polyuria
    term:
      id: HP:0000103
      label: Polyuria
- category: Renal
  name: Proteinuria
  description: >-
    Proteinuria is near-universal in HFRS and may be the only renal finding in
    the milder Seoul virus form.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:31319534
    reference_title: "Wild Rats, Laboratory Rats, Pet Rats: Global Seoul Hantavirus Disease Revisited."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      initial but transient proteinuria and microhematuria are rarely lacking
    explanation: >-
      Supports proteinuria as an essentially constant finding even in mild
      Seoul virus disease.
- category: Renal
  name: Hematuria
  description: Microscopic haematuria accompanies proteinuria in the acute renal phase.
  phenotype_term:
    preferred_term: Hematuria
    term:
      id: HP:0000790
      label: Hematuria
  evidence:
  - reference: PMID:31319534
    reference_title: "Wild Rats, Laboratory Rats, Pet Rats: Global Seoul Hantavirus Disease Revisited."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      initial but transient proteinuria and microhematuria are rarely lacking
    explanation: Supports microhaematuria as an essentially constant acute finding.
- category: Renal
  name: Elevated serum creatinine
  description: Rising creatinine quantifies the acute loss of glomerular filtration.
  phenotype_term:
    preferred_term: Elevated circulating creatinine concentration
    term:
      id: HP:0003259
      label: Elevated circulating creatinine concentration
- category: Endocrine
  name: Hypopituitarism
  description: >-
    Pituitary haemorrhage during acute Puumala infection can cause
    hypopituitarism complicating recovery. Long-term follow-up did not find
    late-onset pituitary insufficiency, so this is an acute-phase complication
    rather than an expected chronic sequela.
  frequency: VERY_RARE
  subtype: PUUV HFRS
  phenotype_term:
    preferred_term: Hypopituitarism
    term:
      id: HP:0040075
      label: Hypopituitarism
  evidence:
  - reference: PMID:26202013
    reference_title: Long-term hormonal follow-up after human Puumala hantavirus infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pituitary haemorrhage and hypopituitarism may complicate recovery from
      acute NE.
    explanation: Supports hypopituitarism as a complication of acute PUUV HFRS.
  - reference: PMID:26202013
    reference_title: Long-term hormonal follow-up after human Puumala hantavirus infection.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two patients had suffered from pituitary haemorrhage, but many others
      exhibited pituitary oedema during their acute infection.
    explanation: >-
      Two of 47 followed patients had pituitary haemorrhage, supporting the
      VERY_RARE frequency band assigned here.
diagnosis:
- name: Hantavirus serology and viral RNA detection
  description: >-
    Diagnosis rests on recognising a compatible febrile illness with
    thrombocytopenia and acute kidney injury in someone with rodent exposure,
    then confirming orthohantavirus infection serologically or molecularly.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  results: >-
    Hantavirus-specific IgM or viral RNA in a patient with the clinical triad of
    fever, thrombocytopenia, and acute kidney injury.
  evidence:
  - reference: PMID:35384417
    reference_title: "Hemorrhagic Fever with Renal Syndrome: Literature Review, Epidemiology, Clinical Picture and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The laboratory diagnosis of hantavirus infection is mostly dependent on
      four types of tests: serology, molecular techniques, viral isolation and
      immunochemistry
    explanation: >-
      Names the four laboratory modalities on which confirmation of hantavirus
      infection rests, of which serology and molecular testing are the two
      curated here.
  - reference: PMID:35384417
    reference_title: "Hemorrhagic Fever with Renal Syndrome: Literature Review, Epidemiology, Clinical Picture and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      serological assays that detect IgM and/or IgG antibodies to hantaviral
      antigens in serum are the most often used techniques for diagnostic
      testing of HFRS
    explanation: >-
      Establishes IgM/IgG serology as the first-line confirmatory test in HFRS,
      which is the primary claim of this diagnosis entry.
- name: Serial urinalysis in suspected Seoul virus exposure
  description: >-
    Because Seoul virus disease is often mild and atypical, sometimes with
    preserved kidney function, repeated simple urine examination is the
    recommended way to avoid missing cases in people exposed to pet, feeder, or
    wild rats.
  diagnosis_term:
    preferred_term: urinalysis
    term:
      id: NCIT:C17241
      label: Urinalysis
  results: Transient proteinuria and microhaematuria, which are rarely absent even in mild disease.
  evidence:
  - reference: PMID:31319534
    reference_title: "Wild Rats, Laboratory Rats, Pet Rats: Global Seoul Hantavirus Disease Revisited."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the importance of simple but repeated urine examination is stressed, since
      initial but transient proteinuria and microhematuria are rarely lacking
    explanation: Directly supports serial urinalysis as the recommended detection strategy in SEOV disease.
treatments:
- name: Intensive supportive care
  description: >-
    Management is primarily supportive: careful fluid and haemodynamic
    management through the capillary leak and hypotensive phases, and renal
    replacement therapy for the oliguric phase when needed. No specific
    effective antiviral is established in contemporary practice.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: OTHER
  target_phenotypes:
  - preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  - preferred_term: Shock
    term:
      id: HP:0031273
      label: Shock
  evidence:
  - reference: PMID:37105214
    reference_title: "Hantavirus in humans: a review of clinical aspects and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No specific effective antiviral treatment is available.
    explanation: >-
      Establishes that management is supportive because no specific antiviral is
      established.
- name: Haemodialysis
  description: >-
    Renal replacement therapy supports patients through the oliguric phase until
    the diuretic phase of recovery begins.
  treatment_term:
    preferred_term: hemodialysis
    term:
      id: NCIT:C15248
      label: Hemodialysis
  therapeutic_modality: DEVICE
  target_phenotypes:
  - preferred_term: Oliguria
    term:
      id: HP:0100520
      label: Oliguria
  - preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: PMID:1683355
    reference_title: Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only occurrence of oliguric phase and hemorrhage was associated with
      severity of clinical disease in the placebo group.
    explanation: >-
      Supports the oliguric phase as the severity-driving stage that renal
      replacement therapy is deployed to survive. It does not itself evaluate
      dialysis, which is standard of care rather than a trialled intervention in
      HFRS.
- name: Intravenous ribavirin
  description: >-
    In a 1991 placebo-controlled randomised trial of 242 patients in China,
    intravenous ribavirin reduced adjusted mortality sevenfold and reduced the
    risk of entering the oliguric phase and of haemorrhage, at the cost of a
    reversible anaemia. Contemporary reviews nevertheless still state that no
    specific effective antiviral treatment is available, and the same drug
    failed in cardiopulmonary-stage HCPS, so its place in current practice is
    unsettled.
  treatment_term:
    preferred_term: antiviral therapy
    term:
      id: NCIT:C16119
      label: Antiviral Therapy
    therapeutic_agent:
    - preferred_term: ribavirin
      term:
        id: CHEBI:63580
        label: ribavirin
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Noncytopathic microvascular endothelial infection
    treatment_effect: INHIBITS
    description: >-
      Ribavirin is a nucleoside analogue acting on viral replication, so its
      mechanistic join point is the infected endothelium rather than the
      downstream renal lesion. Consistent with acting upstream, it reduced the
      risk of entering the oliguric phase in the 1991 randomised trial; that
      clinical outcome is captured in target_phenotypes (Oliguria).
  target_phenotypes:
  - preferred_term: Oliguria
    term:
      id: HP:0100520
      label: Oliguria
  - preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  evidence:
  - reference: PMID:1683355
    reference_title: Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ribavirin therapy also resulted in a significant reduction in the risk of
      entering the oliguric phase and experiencing hemorrhage.
    explanation: >-
      The randomised evidence that ribavirin reduces progression to the oliguric
      phase and to haemorrhage.
  - reference: PMID:1683355
    reference_title: Prospective, double-blind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The only ribavirin-related side effect was a well-recognized, fully
      reversible anemia after completion of therapy.
    explanation: Documents the toxicity profile observed in the trial.
  - reference: PMID:37105214
    reference_title: "Hantavirus in humans: a review of clinical aspects and management."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No specific effective antiviral treatment is available.
    explanation: >-
      A 2023 review contradicts the practical adoption of ribavirin, which is why
      this treatment is curated alongside an open discussion rather than as
      established therapy.
- name: Icatibant (bradykinin B2 receptor antagonist)
  description: >-
    The therapeutic corollary of the kallikrein-kinin model of vascular leak. A
    single severe Puumala virus case responded dramatically to one dose of the
    bradykinin receptor antagonist icatibant. This is a single case report; the
    authors themselves call for testing in larger numbers of patients, and it is
    curated here as a mechanism-matched hypothesis rather than as established
    therapy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: icatibant
      term:
        id: CHEBI:68556
        label: icatibant
  therapeutic_modality: PEPTIDE
  target_mechanisms:
  - target: Factor XII-dependent kallikrein-kinin activation and bradykinin release
    treatment_effect: INHIBITS
    description: >-
      Icatibant blocks the bradykinin B2 receptor, the terminal step of the
      kallikrein-kinin arm of this pathograph.
  target_phenotypes:
  - preferred_term: Capillary leak
    term:
      id: HP:0030005
      label: Capillary leak
  evidence:
  - reference: PMID:23294035
    reference_title: A severe case of Puumala hantavirus infection successfully treated with bradykinin receptor antagonist icatibant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A patient with severe capillary leakage syndrome caused by a Puumala
      hantavirus infection was treated with a single dose of icatibant, a
      bradykinin receptor antagonist, with a dramatic positive response.
    explanation: >-
      Single-patient evidence of benefit, curated as PARTIAL because n=1 cannot
      establish efficacy.
  - reference: PMID:23294035
    reference_title: A severe case of Puumala hantavirus infection successfully treated with bradykinin receptor antagonist icatibant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We suggest that this drug should be tested in a larger number of patients
      with severe hantavirus infection.
    explanation: The authors' own statement that the evidence is not yet sufficient.
- name: Hantavax (formalin-inactivated Hantaan virus vaccine)
  description: >-
    A formalin-inactivated, rodent-brain-derived Hantaan virus vaccine
    (Hantavax, Korea Green Cross) is licensed and commercially available in
    Korea. It is not available worldwide and the protective antibody response it
    elicits has been reported to be short-lived, so it supplements rather than
    replaces rodent-exposure reduction.
  treatment_term:
    preferred_term: vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
  therapeutic_modality: VACCINE
  evidence:
  - reference: PMID:35384417
    reference_title: "Hemorrhagic Fever with Renal Syndrome: Literature Review, Epidemiology, Clinical Picture and Pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hantavax (Korea Green Cross, Seoul, Korea), a formalin-inactivated HTNV
      vaccine made from rodent brain–derived virus, is commercially accessible
      in Korea, however, the protective response has been reported to be
      short-lived
    explanation: >-
      Establishes that a licensed HFRS vaccine exists in Korea, and is curated as
      PARTIAL because the same sentence reports the protective response to be
      short-lived.
- name: Rodent exposure reduction and One Health prevention
  description: >-
    With no globally available vaccine — Hantavax is licensed only in Korea and
    its protection is short-lived — and no established antiviral, prevention
    turns on reducing contact with rodent reservoirs and their aerosolised
    excreta, on surveillance, and on integrated One Health strategies spanning
    the rodent, environmental, and human compartments.
  treatment_term:
    preferred_term: preventive intervention
    term:
      id: NCIT:C15843
      label: Preventive Intervention
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:42430118
    reference_title: "Hantavirus infections in a changing world: epidemiology, pathogenesis, and one health challenges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In addition, it explores emerging challenges related to vaccine
      development, surveillance, and the integration of One Health strategies in
      the prevention and control of hantavirus infections.
    explanation: >-
      The lit-scan source review frames prevention around vaccine development,
      surveillance, and One Health integration.
  - reference: PMID:42430118
    reference_title: "Hantavirus infections in a changing world: epidemiology, pathogenesis, and one health challenges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Strengthening multidisciplinary approaches and improving early detection
      remain critical to mitigating the global impact of these infections.
    explanation: Supports early detection and multidisciplinary prevention as the current control strategy.
differential_diagnoses:
- name: Hantavirus pulmonary syndrome
  description: >-
    The New World counterpart, caused by Sin Nombre, Andes, and related viruses
    in the Americas. It shares the endothelial target and the
    leak-plus-thrombocytopenia physiology but centres on noncardiogenic
    pulmonary oedema and cardiogenic shock rather than acute kidney injury, and
    Andes virus is additionally capable of person-to-person transmission.
  disease_term:
    preferred_term: hantavirus pulmonary syndrome
    term:
      id: MONDO:0017879
      label: hantavirus pulmonary syndrome
  distinguishing_features:
  - Geography - Americas rather than Asia and Europe
  - Organ of failure - noncardiogenic pulmonary oedema rather than oliguric acute kidney injury
  - Person-to-person transmissibility of Andes virus, which has no HFRS counterpart
  evidence:
  - reference: PMID:37105214
    reference_title: "Hantavirus in humans: a review of clinical aspects and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main clinical syndromes associated with hantaviruses are haemorrhagic
      fever with renal syndrome (HFRS), which is endemic in Europe and Asia, and
      hantavirus cardiopulmonary syndrome (HCPS), which is endemic in the
      Americas.
    explanation: Establishes the geographic and syndromic split between the two entities.
  - reference: PMID:37105214
    reference_title: "Hantavirus in humans: a review of clinical aspects and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HCPS and HFRS are separate clinical entities, but they share several
      features and have many overlapping symptoms, signs, and pathogenic
      alterations.
    explanation: >-
      Confirms that the two are separate clinical entities, which is why dismech
      models them as distinct disease entries rather than one blended graph.
notes: >-
  Scope. This entry covers the Old World, renal arm of human orthohantavirus
  disease (MONDO:0005784) and is the deliberate sibling of the existing
  Hantavirus Pulmonary Syndrome entry (MONDO:0017879). The two are curated as
  separate entries because the source literature treats them as separate
  clinical entities with different agents, geography, and organ of failure,
  while acknowledging extensive mechanistic overlap at the endothelium.

  Evidence provenance. Several mechanistic nodes rest on experiments performed
  with the HPS-associated Andes virus (notably the VEGF/VE-cadherin work) or in
  cell systems rather than in HFRS patients. Those items carry IN_VITRO
  evidence_source and the model-fidelity concern is recorded explicitly as a
  HUMAN_MODEL_MISMATCH discussion rather than being smoothed over in prose.

  Two snippets quote typographical errors present in the published abstracts
  (HRFS for HFRS in PMID:36851775, Apodernus agraricus for Apodemus agrarius in
  PMID:35384417). They are quoted verbatim so that reference validation succeeds
  against the cached text; the corrected forms appear in the surrounding
  descriptions.

  Prevalence records report absolute annual case counts because that is what the
  source states; no rate_per_100000 or prevalence_class is asserted, since
  converting counts to a population rate would require a denominator the source
  does not supply.

  Not yet curated. Histopathology (acute tubulointerstitial nephritis with
  medullary haemorrhage) and HLA-linked genetic susceptibility are documented in
  the literature and are natural next additions. Differential diagnoses beyond
  hantavirus pulmonary syndrome (leptospirosis, dengue, other viral haemorrhagic
  fevers) are clinically standard but are not stated in any reference cached in
  this entry, so they are deferred rather than asserted without a quotable
  source.