Viral Hemorrhagic Fever

Infectious Disease MONDO:0018087 Pathograph 11 Show in embeddings browser Viral infectious disease Hemorrhagic fever

Viral hemorrhagic fever is a heterogeneous group of severe infections caused by selected enveloped RNA viruses. The umbrella entry models recurring vascular, immune, and hemostatic patterns rather than one uniform disease: individual viruses differ in transmission, organ tropism, bleeding mechanism, clinical course, diagnostics, prevention, and treatment, and overt hemorrhage is not present in every infection. Severe disease can include acute febrile illness, impaired antiviral immunity, high viremia, endothelial dysfunction, capillary leak, coagulopathy, hemorrhagic manifestations, shock, and organ dysfunction.

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6
Pathophys.
16
Phenotypes
2
Gaps
11
Pathograph
5
Medical Actions
8
Subtypes
2
Datasets
1
Deep Research
🏷

Classifications

Harrison's Part
INFECTIOUS DISEASES
◆

Subtypes

8
Ebola virus disease
Filovirus hemorrhagic fever caused by ebolaviruses.
Marburg virus disease
Filovirus hemorrhagic fever caused by marburgviruses.
Lassa fever
Arenavirus hemorrhagic fever transmitted primarily from rodent reservoirs.
Crimean-Congo hemorrhagic fever
Nairovirus hemorrhagic fever transmitted mainly by ticks or infected blood and tissues.
Dengue hemorrhagic fever
Severe dengue phenotype with plasma leakage, bleeding, and shock.
Yellow fever
Mosquito-borne flavivirus infection that can progress to severe hemorrhagic disease.
Rift Valley fever
Phenuivirus infection transmitted by mosquitoes or animal exposure, with rare hemorrhagic manifestations.
Hantavirus hemorrhagic fever with renal syndrome
Rodent-borne hantavirus VHF subtype characterized by renal involvement.
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Discussions and Knowledge Gaps

2
Which endothelial, coagulation-factor, consumptive-coagulopathy, and platelet mechanisms are genuinely shared across VHFs, and which are specific to a virus, disease stage, or bleeding site?
KNOWLEDGE GAP OPEN vhf_shared_vs_agent_specific_bleeding_mechanisms
Attached to
pathophysiology#Endothelial activation and damage pathophysiology#Increased vascular permeability pathophysiology#Consumptive coagulopathy pathophysiology#Decreased coagulation factor production pathophysiology#Reduced platelet number pathophysiology#Platelet dysfunction
The umbrella entry represents recurring routes, not universal mechanisms. Comparative evidence remains insufficient to assign the same causal weight or sequence to each route across all VHF agents.
Show evidence (1 reference)
PMID:41410052 SUPPORT Other
"There are likely both common and distinct mechanisms underlying bleeding in different VHFs, as sites of bleeding differ between the viruses."
The review explicitly identifies the unresolved common-versus-agent-specific mechanism question.
How faithfully do animal, conventional two-dimensional culture, and emerging microphysiological models reproduce human VHF vascular dynamics across different agents?
HUMAN MODEL MISMATCH OPEN vhf_human_vascular_model_fidelity
Attached to
pathophysiology#Endothelial activation and damage pathophysiology#Increased vascular permeability
Existing animal and cell-culture systems have produced mechanistic insights, but a vascular-model review specifically questions their fidelity to human in-vivo dynamics and presents microphysiological systems as promising rather than validated replacements.
Show evidence (1 reference)
PMID:38749416 SUPPORT Other
"While animal models and traditional 2D cell cultures have contributed insight into the mechanisms by which these pathogens affect the vasculature, these models fall short in replicatingin vivohuman vascular dynamics."
The review directly states the translational limitation of existing model systems.
⚙

Pathophysiology

6
Endothelial activation and damage
Endothelial activation or damage is a recurring vascular mechanism in VHF, although its direct viral and host-mediated drivers vary among agents.
endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
endothelial cell activation GO:0042118 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased endothelial cell activation (GO:0042118). GO:0042118 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Increased vascular permeability Endothelial activation and damage can disrupt barrier integrity and increase vascular permeability.
Show evidence (2 references)
PMID:38749416 SUPPORT Other
"Named after their common symptom hemorrhage, these viruses induce significant vascular dysfunction by affecting endothelial cells, altering immunity, and disrupting the clotting system."
This supports endothelial involvement, immune alteration, clotting disruption, and vascular dysfunction as shared VHF mechanisms.
PMID:41410052 SUPPORT Other
"Herein, we discuss the potential mechanisms leading to bleeding during VHF, which include a consumptive coagulopathy, decreased coagulation factor production, thrombocytopenia and platelet dysfunction, and endothelial cell activation and damage, resulting in increased vascular permeability."
This supports endothelial activation/damage and increased vascular permeability as mechanisms linked to VHF bleeding.
Increased vascular permeability
Increased endothelial permeability permits plasma leakage and intravascular volume loss. Its prominence and clinical consequences differ by VHF agent.
endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 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 abnormal regulation of vascular permeability (GO:0043114). GO:0043114 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Capillary leak Increased vascular permeability is expressed clinically as capillary leak.
Shock Severe plasma leakage can contribute to shock through intravascular volume depletion and hypotension.
Show evidence (2 references)
PMID:41734218 SUPPORT Other
"Their pathogenesis is characterized by early failure of antiviral immunity, high viremia, endothelial dysfunction, capillary leak, and coagulopathy."
This supports capillary leak as a distinct recurring VHF pathogenesis feature.
PMID:41410052 SUPPORT Other
"Herein, we discuss the potential mechanisms leading to bleeding during VHF, which include a consumptive coagulopathy, decreased coagulation factor production, thrombocytopenia and platelet dysfunction, and endothelial cell activation and damage, resulting in increased vascular permeability."
The review directly links endothelial activation and damage to increased vascular permeability.
Consumptive coagulopathy
Consumptive coagulopathy is one potential VHF bleeding mechanism; it is not asserted to occur in every VHF infection or to have equal importance across agents.
blood coagulation GO:0007596 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal blood coagulation (GO:0007596). GO:0007596 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Hemorrhage Consumption of coagulation components can contribute to hemorrhagic manifestations.
Coagulopathy Consumptive hemostatic dysfunction is clinically detected as coagulopathy.
Show evidence (2 references)
PMID:41410052 SUPPORT Other
"Both direct effects from viral infection of host cells and indirect effects caused by the host response to the virus contribute to dysregulation of the hemostatic system."
This supports direct and host-response-mediated hemostatic dysregulation in VHF.
PMID:41410052 SUPPORT Other
"Herein, we discuss the potential mechanisms leading to bleeding during VHF, which include a consumptive coagulopathy, decreased coagulation factor production, thrombocytopenia and platelet dysfunction, and endothelial cell activation and damage, resulting in increased vascular permeability."
This directly identifies consumptive coagulopathy as a distinct VHF bleeding mechanism.
Decreased coagulation factor production
Reduced coagulation factor production is a distinct hemostatic mechanism that may contribute to bleeding in some VHFs.
blood coagulation GO:0007596 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased blood coagulation (GO:0007596). GO:0007596 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Hemorrhage Reduced coagulation-factor availability can increase bleeding risk.
Coagulopathy Reduced coagulation-factor availability contributes to an abnormal coagulation profile.
Show evidence (1 reference)
PMID:41410052 SUPPORT Other
"Herein, we discuss the potential mechanisms leading to bleeding during VHF, which include a consumptive coagulopathy, decreased coagulation factor production, thrombocytopenia and platelet dysfunction, and endothelial cell activation and damage, resulting in increased vascular permeability."
This directly identifies decreased coagulation factor production as a distinct VHF bleeding mechanism.
Reduced platelet number
Reduced platelet number is one potential VHF bleeding mechanism. Its occurrence and contribution to hemorrhage vary by agent, and the dengue-specific observation below is not generalized to every VHF.
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.
Downstream
Thrombocytopenia Reduced platelet number is clinically detected as thrombocytopenia.
Hemorrhage Reduced platelet number can contribute to hemorrhagic manifestations.
Show evidence (2 references)
PMID:41410052 SUPPORT Other
"In dengue virus infection, thrombocytopenia and platelet dysfunction occur."
This supports reduced platelet number in dengue as a representative, subtype-specific VHF example.
PMID:41410052 SUPPORT Other
"Herein, we discuss the potential mechanisms leading to bleeding during VHF, which include a consumptive coagulopathy, decreased coagulation factor production, thrombocytopenia and platelet dysfunction, and endothelial cell activation and damage, resulting in increased vascular permeability."
This directly identifies thrombocytopenia as one VHF bleeding mechanism.
Platelet dysfunction
Abnormal platelet function is a separate potential route to hemorrhagic manifestations. Its occurrence and importance differ by VHF agent, and the dengue-specific observation below is not generalized to every VHF.
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
Hemorrhage Platelet dysfunction can contribute to hemorrhagic manifestations.
Show evidence (2 references)
PMID:41410052 SUPPORT Other
"In dengue virus infection, thrombocytopenia and platelet dysfunction occur."
This supports platelet dysfunction in dengue as a representative, subtype-specific VHF example.
PMID:41410052 SUPPORT Other
"Herein, we discuss the potential mechanisms leading to bleeding during VHF, which include a consumptive coagulopathy, decreased coagulation factor production, thrombocytopenia and platelet dysfunction, and endothelial cell activation and damage, resulting in increased vascular permeability."
This directly identifies platelet dysfunction as one VHF bleeding mechanism.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Viral Hemorrhagic Fever 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

16
Blood 6
Hemorrhage Abnormal bleeding HP:0001892 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemorrhage, annotated with Abnormal bleeding (HP:0001892). HP:0001892 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31668201 SUPPORT Other
"Viral hemorrhagic fevers are severe febrile illnesses with hemorrhagic phenomena."
This supports hemorrhagic manifestations as a defining clinical feature.
Coagulopathy Abnormality of the coagulation cascade HP:0003256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coagulopathy, annotated with Abnormality of the coagulation cascade (HP:0003256). HP:0003256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41734218 SUPPORT Other
"Their pathogenesis is characterized by early failure of antiviral immunity, high viremia, endothelial dysfunction, capillary leak, and coagulopathy."
This directly supports coagulopathy as a recurring severe VHF feature.
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.
Show evidence (1 reference)
PMID:2749111 SUPPORT Human Clinical
"Petechial rash and hemorrhagic signs such as epistaxis, hematemesis, and melena supervened on days 3-6 of illness."
This clinical pathology series supports petechial rash in Crimean-Congo hemorrhagic fever specifically.
Epistaxis HP:0000421 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epistaxis (HP:0000421). HP:0000421 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2749111 SUPPORT Human Clinical
"Petechial rash and hemorrhagic signs such as epistaxis, hematemesis, and melena supervened on days 3-6 of illness."
This clinical pathology series supports epistaxis in Crimean-Congo hemorrhagic fever specifically.
Thrombocytopenia HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41734218 SUPPORT Other
"Laboratory findings commonly include early leukopenia, thrombocytopenia, and elevated liver enzymes."
This supports thrombocytopenia as a common laboratory abnormality.
Leukopenia Decreased total leukocyte count HP:0001882 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukopenia, annotated with Decreased total leukocyte count (HP:0001882). HP:0001882 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41734218 SUPPORT Other
"Laboratory findings commonly include early leukopenia, thrombocytopenia, and elevated liver enzymes."
This supports leukopenia as a common laboratory abnormality.
Cardiovascular 1
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.
Show evidence (1 reference)
PMID:41734218 SUPPORT Other
"Clinically, they initially present as non-specific febrile illnesses, but may progress to organ dysfunction, hemorrhagic manifestations, or shock."
This supports shock as a severe clinical manifestation.
Digestive 3
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.
Show evidence (1 reference)
PMID:2749111 SUPPORT Human Clinical
"Following an incubation period of 2-9 days after exposure to infection, patients had a sudden onset of disease with fever, nausea, severe headache, and myalgia."
This clinical series supports nausea in Crimean-Congo hemorrhagic fever specifically.
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.
Show evidence (1 reference)
PMID:25493109 SUPPORT Other
"Symptoms of EVD include abrupt onset of fever, myalgias, and headache in the early phase, followed by vomiting, diarrhea and possible progression to hemorrhagic rash, life-threatening bleeding, and multi-organ failure in the later phase."
This review identifies vomiting in Ebola virus disease specifically.
Diarrhea HP:0002014 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diarrhea (HP:0002014). HP:0002014 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25493109 SUPPORT Other
"Symptoms of EVD include abrupt onset of fever, myalgias, and headache in the early phase, followed by vomiting, diarrhea and possible progression to hemorrhagic rash, life-threatening bleeding, and multi-organ failure in the later phase."
This review identifies diarrhea in Ebola virus disease specifically.
Genitourinary 1
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:18620963 SUPPORT Other
"Acute kidney injury is an uncommon complication but renal dysfunction has been associated with various VHFs."
This narrative review supports acute kidney injury as an uncommon associated complication without establishing a universal causal route.
Metabolism 2
Fever HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41734218 SUPPORT Other
"Clinically, they initially present as non-specific febrile illnesses, but may progress to organ dysfunction, hemorrhagic manifestations, or shock."
This supports fever as an early clinical feature.
Elevated liver enzymes Elevated circulating hepatic transaminase concentration HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated liver enzymes, annotated with Elevated circulating hepatic transaminase concentration (HP:0002910). HP:0002910 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41734218 SUPPORT Other
"Laboratory findings commonly include early leukopenia, thrombocytopenia, and elevated liver enzymes."
This supports liver enzyme elevation as a common laboratory abnormality.
Nervous System 1
Headache 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 (2 references)
PMID:25493109 SUPPORT Other
"Symptoms of EVD include abrupt onset of fever, myalgias, and headache in the early phase, followed by vomiting, diarrhea and possible progression to hemorrhagic rash, life-threatening bleeding, and multi-organ failure in the later phase."
This Ebola VHF review identifies headache as an early clinical feature.
PMID:2749111 SUPPORT Human Clinical
"Following an incubation period of 2-9 days after exposure to infection, patients had a sudden onset of disease with fever, nausea, severe headache, and myalgia."
This CCHF clinical series supports severe headache in another VHF subtype.
Constitutional 1
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.
Show evidence (1 reference)
PMID:25493109 SUPPORT Other
"Symptoms of EVD include abrupt onset of fever, myalgias, and headache in the early phase, followed by vomiting, diarrhea and possible progression to hemorrhagic rash, life-threatening bleeding, and multi-organ failure in the later phase."
This Ebola VHF review identifies myalgias as part of the early clinical phase.
Other 1
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:41734218 SUPPORT Other
"Their pathogenesis is characterized by early failure of antiviral immunity, high viremia, endothelial dysfunction, capillary leak, and coagulopathy."
This directly supports capillary leak as a recurring severe VHF feature.
💊

Medical Actions

5
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. NCIT:C15747
Supportive care remains the cornerstone for most VHFs. Its components and intensity must be tailored to the responsible virus, manifestations, and severity; this umbrella record does not define a cross-agent care protocol.
Show evidence (2 references)
PMID:31668201 SUPPORT Other
"Treatment is essentially supportive."
This supports supportive care as the core management approach for many VHFs.
PMID:42076078 SUPPORT Other
"Supportive care continues to represent the cornerstone of clinical management for most infections, while pathogen-targeted therapies are available only for a restricted number of diseases."
This supports supportive care as the cross-VHF cornerstone while explicitly limiting targeted therapy to selected diseases.
Ribavirin antiviral pharmacotherapy
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: 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.
Ribavirin is included here only for Lassa fever, where guidelines recommend it but a systematic review found a weak and potentially severity-dependent evidence base. It is not asserted as an umbrella VHF treatment.
Show evidence (1 reference)
PMID:31357056 SUPPORT Human Clinical
"Ribavirin is recommended as standard treatment for LF in national and international guidelines but the evidence base for this recommendation has been questioned recently."
This supports ribavirin as a guideline-recommended targeted antiviral for Lassa fever while preserving uncertainty about the evidence base.
Ebola monoclonal antibody therapy
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: monoclonal antibody NCIT:C20401 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses monoclonal antibody (NCIT:C20401). NCIT:C20401 is a therapeutic agent from the NCI Thesaurus.
Monoclonal antibody therapy is the targeted pharmacotherapy class with the strongest regulatory success among VHFs. This record is restricted to Ebola virus disease and does not imply activity against other VHF agents.
Show evidence (1 reference)
PMID:42076078 SUPPORT Other
"Monoclonal antibody-based therapies have achieved the most significant regulatory success to date, particularly for Ebola virus disease."
This supports Ebola monoclonal antibody pharmacotherapy as an established targeted VHF treatment class.
Isolation, contact tracing, and PPE-based infection control
Category: Therapeutic 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
For VHFs capable of person-to-person or nosocomial transmission, rapid patient isolation, contact tracing, and appropriate healthcare-worker PPE and infection-control measures help prevent spread. Applicability and implementation are agent-, setting-, and jurisdiction-specific; this umbrella entry does not prescribe an operational protocol or apply unchanged to vector- or reservoir-borne transmission.
Show evidence (3 references)
PMID:41734218 SUPPORT Other
"Continuous surveillance of imported cases, together with access to high-quality laboratory testing, effective infection control including prevention of nosocomial spread, and vigilance in febrile patients with relevant epidemiological exposure, are essential."
This cross-VHF narrative review directly supports infection control and prevention of nosocomial spread as high-level preventive measures.
PMID:30047375 SUPPORT Human Clinical
"Early detection, rapid patient isolation, contact tracing, and the ongoing vaccination programme should sufficiently control the outbreak."
This human Ebola outbreak study supports isolation and contact tracing as subtype-specific components of the broader preventive intervention.
PMID:25493109 SUPPORT Other
"Emergency department personnel on the frontlines must be prepared to rapidly identify and isolate febrile travelers if indicated. All healthcare workers involved in care of EVD patients should wear personal protective equipment."
This Ebola-focused public-health review supports patient isolation and healthcare-worker PPE as subtype-specific components.
Selected VHF vaccination
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
Vaccination is preventive and agent-specific. Licensed vaccines exist for selected VHFs, including Ebola, yellow fever, and dengue; this does not imply a vaccine is available for the umbrella syndrome or every listed subtype.
Show evidence (1 reference)
PMID:42076078 SUPPORT Other
"Vaccine development has progressed further, with licensed vaccines available for selected VHFs, including Ebola, yellow fever, and dengue, and multiple candidates based on diverse technological platforms advancing through clinical evaluation."
This supports vaccination availability for selected VHFs and ongoing vaccine development.
🔬

Diagnosis

3
Exposure-informed recognition and reference-laboratory referral
Early clinical findings are nonspecific. Recognition therefore depends on compatible epidemiologic exposure, prompt isolation and infection-control action, and access to appropriate laboratory testing; exact public-health procedures are agent- and jurisdiction-specific.
Show evidence (1 reference)
PMID:41734218 SUPPORT Other
"Continuous surveillance of imported cases, together with access to high-quality laboratory testing, effective infection control including prevention of nosocomial spread, and vigilance in febrile patients with relevant epidemiological exposure, are essential."
This directly supports exposure-informed vigilance, laboratory access, and infection control as linked parts of recognition and response.
Agent-specific molecular and serological testing
Molecular and serological tests are established diagnostic categories, but assay choice, specimen timing, interpretation, and containment requirements differ by suspected virus and illness stage. This umbrella entry does not prescribe an interchangeable test algorithm across VHF agents.
Show evidence (2 references)
PMID:31668201 SUPPORT Other
"Laboratory diagnosis takes place in highly specialized reference laboratories."
This supports specialist laboratory involvement for VHF diagnosis.
PMID:41754561 SUPPORT Other
"Current molecular and serological diagnostic tests, while efficient and effective, lack the characteristics required of a POC test (POCT) to quickly and easily respond to a VHF outbreak while maintaining a low cost."
This directly distinguishes established molecular and serological testing from the unmet point-of-care need.
CRISPR-based point-of-care assays (investigational)
CRISPR-based assays are an investigational point-of-care direction rather than an established replacement for current agent-specific molecular and serological testing; published VHF development studies remain limited.
Show evidence (1 reference)
PMID:41754561 SUPPORT Other
"However, studies on the development of CRISPR-based POC diagnostic tests for VHFs are limited."
The review explicitly identifies the limited evidence base, supporting investigational rather than established status.
📈

Progression

2
Acute febrile illness
Illness usually begins as a nonspecific acute febrile syndrome, which makes early clinical recognition difficult without exposure context and laboratory testing.
Show evidence (1 reference)
PMID:41734218 SUPPORT Other
"Clinically, they initially present as non-specific febrile illnesses, but may progress to organ dysfunction, hemorrhagic manifestations, or shock."
This directly supports the early febrile presentation and possible progression to severe disease.
Severe vascular-hemostatic disease
Severe disease reflects vascular leak, coagulation disturbance, bleeding, and systemic organ dysfunction.
Show evidence (1 reference)
PMID:41734218 SUPPORT Other
"Their pathogenesis is characterized by early failure of antiviral immunity, high viremia, endothelial dysfunction, capillary leak, and coagulopathy."
This supports the vascular and hemostatic transition that defines severe VHF.
🦠

Infectious Agent

1
Viral hemorrhagic fever RNA viruses
Viral hemorrhagic fevers are caused by selected enveloped RNA viruses, including agents from Filoviridae, Arenaviridae, Flaviviridae, and the order Bunyavirales.
Show evidence (1 reference)
PMID:41734218 SUPPORT Other
"Viral hemorrhagic fevers are severe infections caused by selected enveloped RNA viruses from the families Filoviridae, Arenaviridae, Flaviviridae, and the order Bunyavirales."
This review identifies the major viral groups that cause the VHF syndrome.
↔️

Transmission

2
Vector, zoonotic, and nosocomial transmission
Transmission routes vary by virus and include arthropod vectors, zoonotic spread from infected animals or reservoirs, and healthcare-associated or household transmission through exposure to infectious blood or body fluids.
Show evidence (1 reference)
PMID:41734218 SUPPORT Other
"For many of these infections, transmission via vectors, zoonotic spread, or nosocomial transmission plays a significant role."
This supports the broad transmission categories across VHF agents.
Occupational blood exposure
Healthcare workers can acquire VHF through needlestick, mucosal, or skin exposure to infected blood, illustrated by Crimean-Congo hemorrhagic fever nosocomial infections.
Show evidence (1 reference)
PMID:39558265 SUPPORT Human Clinical
"The routes of transmission mainly include direct exposures via needle-stick, mucosal or direct contact with the skin to infected blood."
This healthcare-worker cohort supports blood exposure as an occupational transmission route for a representative VHF.
📊

Related Datasets

2
Gene expression associated with liver metabolism during viral hemorrhagic fever geo:GSE12254
Rhesus macaques (Macaca mulatta) infected with a lethal dose of lymphocytic choriomeningitis virus-strain WE (LCMV-WE) provide a model for Lassa fever virus infection of man. Like Lassa fever in human beings, disease begins with flu-like symptoms but can progress to morbidity fairly rapidly. Previously, we profiled the blood transcriptome of LCMV-infected monkeys (M. Djavani et al. J. Virol. 2007: PMID 17522210) showing distinct pre-viremic and viremic stages that discriminated between virulent and benign infections.
MICROARRAY n=20
PMID:19216742
Identified by GEO DataSets index search for Viral Hemorrhagic Fever (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Species-specific responses during Seoul orthohantavirus infection in human and rat lung microvascular endothelial cells geo:GSE245916
Orthohantaviruses are viruses generally carried by rodents in which they do not cause overt disease. Seoul orthohantavirus (SEOV) predominantly exists as a persistent infection in the omnipresent reservoir host, the Norway rat, Rattus norvegicus. Upon respiratory transmission via aerosolized infectious rodent excreta to humans, SEOV causes an acute disease named hemorrhagic fever with renal syndrome (HFRS). Lack of disease in rats is attributed to downregulation of pro-inflammatory and upregulation of regulatory host responses.
BULK RNA SEQ n=24
PMID:38536871
Identified by GEO DataSets index search for Viral Hemorrhagic Fever (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
{ }

Source YAML

click to show 
name: Viral Hemorrhagic Fever
creation_date: "2026-05-09T13:23:18Z"
description: >-
  Viral hemorrhagic fever is a heterogeneous group of severe infections caused
  by selected enveloped RNA viruses. The umbrella entry models recurring
  vascular, immune, and hemostatic patterns rather than one uniform disease:
  individual viruses differ in transmission, organ tropism, bleeding mechanism,
  clinical course, diagnostics, prevention, and treatment, and overt hemorrhage
  is not present in every infection. Severe disease can include acute febrile
  illness, impaired antiviral immunity, high viremia, endothelial dysfunction,
  capillary leak, coagulopathy, hemorrhagic manifestations, shock, and organ
  dysfunction.
category: Infectious Disease
classifications:
  harrisons_chapter:
  - classification_value: INFECTIOUS_DISEASES
    evidence:
    - reference: PMID:41734218
      reference_title: "[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations]."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Viral hemorrhagic fevers are severe infections caused by selected enveloped RNA viruses from the families Filoviridae, Arenaviridae, Flaviviridae, and the order Bunyavirales.
      explanation: The review explicitly characterizes VHFs as severe viral infections, supporting infectious-disease classification.
disease_term:
  preferred_term: viral hemorrhagic fever
  term:
    id: MONDO:0018087
    label: viral hemorrhagic fever
synonyms:
- VHF
- Viral hemorrhagic fevers
- Hemorrhagic fever viruses
parents:
- Viral infectious disease
- Hemorrhagic fever
has_subtypes:
- name: Ebola virus disease
  description: Filovirus hemorrhagic fever caused by ebolaviruses.
- name: Marburg virus disease
  description: Filovirus hemorrhagic fever caused by marburgviruses.
- name: Lassa fever
  description: Arenavirus hemorrhagic fever transmitted primarily from rodent reservoirs.
- name: Crimean-Congo hemorrhagic fever
  description: Nairovirus hemorrhagic fever transmitted mainly by ticks or infected blood and tissues.
- name: Dengue hemorrhagic fever
  description: Severe dengue phenotype with plasma leakage, bleeding, and shock.
- name: Yellow fever
  description: Mosquito-borne flavivirus infection that can progress to severe hemorrhagic disease.
- name: Rift Valley fever
  description: Phenuivirus infection transmitted by mosquitoes or animal exposure, with rare hemorrhagic manifestations.
- name: Hantavirus hemorrhagic fever with renal syndrome
  description: Rodent-borne hantavirus VHF subtype characterized by renal involvement.
infectious_agent:
- name: Viral hemorrhagic fever RNA viruses
  description: >-
    Viral hemorrhagic fevers are caused by selected enveloped RNA viruses,
    including agents from Filoviridae, Arenaviridae, Flaviviridae, and the order
    Bunyavirales.
  evidence:
  - reference: PMID:41734218
    reference_title: "[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Viral hemorrhagic fevers are severe infections caused by selected enveloped RNA viruses from the families Filoviridae, Arenaviridae, Flaviviridae, and the order Bunyavirales.
    explanation: This review identifies the major viral groups that cause the VHF syndrome.
progression:
- phase: Acute febrile illness
  notes: >-
    Illness usually begins as a nonspecific acute febrile syndrome, which makes
    early clinical recognition difficult without exposure context and laboratory
    testing.
  evidence:
  - reference: PMID:41734218
    reference_title: "[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinically, they initially present as non-specific febrile illnesses, but may progress to organ dysfunction, hemorrhagic manifestations, or shock.
    explanation: This directly supports the early febrile presentation and possible progression to severe disease.
- phase: Severe vascular-hemostatic disease
  notes: >-
    Severe disease reflects vascular leak, coagulation disturbance, bleeding,
    and systemic organ dysfunction.
  evidence:
  - reference: PMID:41734218
    reference_title: "[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Their pathogenesis is characterized by early failure of antiviral immunity, high viremia, endothelial dysfunction, capillary leak, and coagulopathy.
    explanation: This supports the vascular and hemostatic transition that defines severe VHF.
transmission:
- name: Vector, zoonotic, and nosocomial transmission
  description: >-
    Transmission routes vary by virus and include arthropod vectors, zoonotic
    spread from infected animals or reservoirs, and healthcare-associated or
    household transmission through exposure to infectious blood or body fluids.
  evidence:
  - reference: PMID:41734218
    reference_title: "[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For many of these infections, transmission via vectors, zoonotic spread, or nosocomial transmission plays a significant role.
    explanation: This supports the broad transmission categories across VHF agents.
- name: Occupational blood exposure
  description: >-
    Healthcare workers can acquire VHF through needlestick, mucosal, or skin
    exposure to infected blood, illustrated by Crimean-Congo hemorrhagic fever
    nosocomial infections.
  evidence:
  - reference: PMID:39558265
    reference_title: "Crimean-Congo haemorrhagic fever among healthcare workers in Iran 2000-2023, a report of National Reference Laboratory."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The routes of transmission mainly include direct exposures via needle-stick, mucosal or direct contact with the skin to infected blood.
    explanation: This healthcare-worker cohort supports blood exposure as an occupational transmission route for a representative VHF.
pathophysiology:
- name: Endothelial activation and damage
  description: >-
    Endothelial activation or damage is a recurring vascular mechanism in VHF,
    although its direct viral and host-mediated drivers vary among agents.
  downstream:
  - target: Increased vascular permeability
    description: Endothelial activation and damage can disrupt barrier integrity and increase vascular permeability.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41410052
      reference_title: Potential Mechanisms Underlying Bleeding During Infection With Hemorrhagic Fever Viruses.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Herein, we discuss the potential mechanisms leading to bleeding during VHF, which include a consumptive coagulopathy, decreased coagulation factor production, thrombocytopenia and platelet dysfunction, and endothelial cell activation and damage, resulting in increased vascular permeability.
      explanation: The review directly states that endothelial activation and damage result in increased vascular permeability.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: endothelial cell activation
    modifier: INCREASED
    term:
      id: GO:0042118
      label: endothelial cell activation
  evidence:
  - reference: PMID:38749416
    reference_title: "Vascular dysfunction in hemorrhagic viral fevers: opportunities for organotypic modeling."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Named after their common symptom hemorrhage, these viruses induce significant vascular dysfunction by affecting endothelial cells, altering immunity, and disrupting the clotting system.
    explanation: This supports endothelial involvement, immune alteration, clotting disruption, and vascular dysfunction as shared VHF mechanisms.
  - reference: PMID:41410052
    reference_title: Potential Mechanisms Underlying Bleeding During Infection With Hemorrhagic Fever Viruses.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Herein, we discuss the potential mechanisms leading to bleeding during VHF, which include a consumptive coagulopathy, decreased coagulation factor production, thrombocytopenia and platelet dysfunction, and endothelial cell activation and damage, resulting in increased vascular permeability.
    explanation: This supports endothelial activation/damage and increased vascular permeability as mechanisms linked to VHF bleeding.
- name: Increased vascular permeability
  description: >-
    Increased endothelial permeability permits plasma leakage and intravascular
    volume loss. Its prominence and clinical consequences differ by VHF agent.
  downstream:
  - target: Capillary leak
    description: Increased vascular permeability is expressed clinically as capillary leak.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41734218
      reference_title: "[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations]."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Their pathogenesis is characterized by early failure of antiviral immunity, high viremia, endothelial dysfunction, capillary leak, and coagulopathy.
      explanation: This supports capillary leak as the clinical manifestation of the permeability abnormality represented by this node.
  - target: Shock
    description: Severe plasma leakage can contribute to shock through intravascular volume depletion and hypotension.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - intravascular volume depletion and hypotension
    evidence:
    - reference: PMID:30507366
      reference_title: "Beyond thrombocytopaenia, haemorrhage and shock: the expanded dengue syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Dengue infection classically presents with fever, thrombocytopaenia, and varying degrees of plasma leakage, giving rise to shock.
      explanation: >-
        This directly supports the leakage-to-shock route in dengue, but is
        graded PARTIAL for the heterogeneous VHF umbrella because the route is
        not equally prominent across agents.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: regulation of vascular permeability
    modifier: ABNORMAL
    term:
      id: GO:0043114
      label: regulation of vascular permeability
  evidence:
  - reference: PMID:41734218
    reference_title: "[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Their pathogenesis is characterized by early failure of antiviral immunity, high viremia, endothelial dysfunction, capillary leak, and coagulopathy.
    explanation: This supports capillary leak as a distinct recurring VHF pathogenesis feature.
  - reference: PMID:41410052
    reference_title: Potential Mechanisms Underlying Bleeding During Infection With Hemorrhagic Fever Viruses.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Herein, we discuss the potential mechanisms leading to bleeding during VHF, which include a consumptive coagulopathy, decreased coagulation factor production, thrombocytopenia and platelet dysfunction, and endothelial cell activation and damage, resulting in increased vascular permeability.
    explanation: The review directly links endothelial activation and damage to increased vascular permeability.
- name: Consumptive coagulopathy
  description: >-
    Consumptive coagulopathy is one potential VHF bleeding mechanism; it is not
    asserted to occur in every VHF infection or to have equal importance across
    agents.
  downstream:
  - target: Hemorrhage
    description: Consumption of coagulation components can contribute to hemorrhagic manifestations.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence: &vhf_hemostatic_to_bleeding_evidence
    - reference: PMID:41410052
      reference_title: Potential Mechanisms Underlying Bleeding During Infection With Hemorrhagic Fever Viruses.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Herein, we discuss the potential mechanisms leading to bleeding during VHF, which include a consumptive coagulopathy, decreased coagulation factor production, thrombocytopenia and platelet dysfunction, and endothelial cell activation and damage, resulting in increased vascular permeability.
      explanation: >-
        The review identifies consumptive coagulopathy, reduced factor
        production, and platelet abnormalities as mechanisms leading to VHF
        bleeding, without assigning equal importance across agents.
  - target: Coagulopathy
    description: Consumptive hemostatic dysfunction is clinically detected as coagulopathy.
    causal_link_type: DIRECT
    evidence: *vhf_hemostatic_to_bleeding_evidence
  biological_processes:
  - preferred_term: blood coagulation
    modifier: ABNORMAL
    term:
      id: GO:0007596
      label: blood coagulation
  evidence:
  - reference: PMID:41410052
    reference_title: Potential Mechanisms Underlying Bleeding During Infection With Hemorrhagic Fever Viruses.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Both direct effects from viral infection of host cells and indirect effects caused by the host response to the virus contribute to dysregulation of the hemostatic system.
    explanation: This supports direct and host-response-mediated hemostatic dysregulation in VHF.
  - reference: PMID:41410052
    reference_title: Potential Mechanisms Underlying Bleeding During Infection With Hemorrhagic Fever Viruses.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Herein, we discuss the potential mechanisms leading to bleeding during VHF, which include a consumptive coagulopathy, decreased coagulation factor production, thrombocytopenia and platelet dysfunction, and endothelial cell activation and damage, resulting in increased vascular permeability.
    explanation: This directly identifies consumptive coagulopathy as a distinct VHF bleeding mechanism.
- name: Decreased coagulation factor production
  description: >-
    Reduced coagulation factor production is a distinct hemostatic mechanism
    that may contribute to bleeding in some VHFs.
  downstream:
  - target: Hemorrhage
    description: Reduced coagulation-factor availability can increase bleeding risk.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence: *vhf_hemostatic_to_bleeding_evidence
  - target: Coagulopathy
    description: Reduced coagulation-factor availability contributes to an abnormal coagulation profile.
    causal_link_type: DIRECT
    evidence: *vhf_hemostatic_to_bleeding_evidence
  biological_processes:
  - preferred_term: blood coagulation
    modifier: DECREASED
    term:
      id: GO:0007596
      label: blood coagulation
  evidence:
  - reference: PMID:41410052
    reference_title: Potential Mechanisms Underlying Bleeding During Infection With Hemorrhagic Fever Viruses.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Herein, we discuss the potential mechanisms leading to bleeding during VHF, which include a consumptive coagulopathy, decreased coagulation factor production, thrombocytopenia and platelet dysfunction, and endothelial cell activation and damage, resulting in increased vascular permeability.
    explanation: This directly identifies decreased coagulation factor production as a distinct VHF bleeding mechanism.
- name: Reduced platelet number
  description: >-
    Reduced platelet number is one potential VHF bleeding mechanism. Its
    occurrence and contribution to hemorrhage vary by agent, and the
    dengue-specific observation below is not generalized to every VHF.
  downstream:
  - target: Thrombocytopenia
    description: Reduced platelet number is clinically detected as thrombocytopenia.
    causal_link_type: DIRECT
    evidence: &vhf_platelet_to_bleeding_evidence
    - reference: PMID:41410052
      reference_title: Potential Mechanisms Underlying Bleeding During Infection With Hemorrhagic Fever Viruses.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Herein, we discuss the potential mechanisms leading to bleeding during VHF, which include a consumptive coagulopathy, decreased coagulation factor production, thrombocytopenia and platelet dysfunction, and endothelial cell activation and damage, resulting in increased vascular permeability.
      explanation: >-
        The review identifies thrombocytopenia and platelet dysfunction as
        distinct mechanisms leading to VHF bleeding without establishing a
        universal frequency or sequence.
  - target: Hemorrhage
    description: Reduced platelet number can contribute to hemorrhagic manifestations.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence: *vhf_platelet_to_bleeding_evidence
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  evidence:
  - reference: PMID:41410052
    reference_title: Potential Mechanisms Underlying Bleeding During Infection With Hemorrhagic Fever Viruses.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In dengue virus infection, thrombocytopenia and platelet dysfunction occur.
    explanation: This supports reduced platelet number in dengue as a representative, subtype-specific VHF example.
  - reference: PMID:41410052
    reference_title: Potential Mechanisms Underlying Bleeding During Infection With Hemorrhagic Fever Viruses.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Herein, we discuss the potential mechanisms leading to bleeding during VHF, which include a consumptive coagulopathy, decreased coagulation factor production, thrombocytopenia and platelet dysfunction, and endothelial cell activation and damage, resulting in increased vascular permeability.
    explanation: This directly identifies thrombocytopenia as one VHF bleeding mechanism.
- name: Platelet dysfunction
  description: >-
    Abnormal platelet function is a separate potential route to hemorrhagic
    manifestations. Its occurrence and importance differ by VHF agent, and the
    dengue-specific observation below is not generalized to every VHF.
  downstream:
  - target: Hemorrhage
    description: Platelet dysfunction can contribute to hemorrhagic manifestations.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence: *vhf_platelet_to_bleeding_evidence
  biological_processes:
  - preferred_term: platelet activation
    modifier: ABNORMAL
    term:
      id: GO:0030168
      label: platelet activation
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  evidence:
  - reference: PMID:41410052
    reference_title: Potential Mechanisms Underlying Bleeding During Infection With Hemorrhagic Fever Viruses.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In dengue virus infection, thrombocytopenia and platelet dysfunction occur.
    explanation: This supports platelet dysfunction in dengue as a representative, subtype-specific VHF example.
  - reference: PMID:41410052
    reference_title: Potential Mechanisms Underlying Bleeding During Infection With Hemorrhagic Fever Viruses.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Herein, we discuss the potential mechanisms leading to bleeding during VHF, which include a consumptive coagulopathy, decreased coagulation factor production, thrombocytopenia and platelet dysfunction, and endothelial cell activation and damage, resulting in increased vascular permeability.
    explanation: This directly identifies platelet dysfunction as one VHF bleeding mechanism.
phenotypes:
- name: Fever
  category: Systemic
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:41734218
    reference_title: "[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinically, they initially present as non-specific febrile illnesses, but may progress to organ dysfunction, hemorrhagic manifestations, or shock.
    explanation: This supports fever as an early clinical feature.
- name: Myalgia
  category: Systemic
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:25493109
    reference_title: "Ebola Virus Disease: essential public health principles for clinicians."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Symptoms of EVD include abrupt onset of fever, myalgias, and headache in the early phase, followed by vomiting, diarrhea and possible progression to hemorrhagic rash, life-threatening bleeding, and multi-organ failure in the later phase.
    explanation: This Ebola VHF review identifies myalgias as part of the early clinical phase.
- name: Headache
  category: Neurologic
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:25493109
    reference_title: "Ebola Virus Disease: essential public health principles for clinicians."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Symptoms of EVD include abrupt onset of fever, myalgias, and headache in the early phase, followed by vomiting, diarrhea and possible progression to hemorrhagic rash, life-threatening bleeding, and multi-organ failure in the later phase.
    explanation: This Ebola VHF review identifies headache as an early clinical feature.
  - reference: PMID:2749111
    reference_title: The clinical pathology of Crimean-Congo hemorrhagic fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Following an incubation period of 2-9 days after exposure to infection, patients had a sudden onset of disease with fever, nausea, severe headache, and myalgia.
    explanation: This CCHF clinical series supports severe headache in another VHF subtype.
- name: Nausea
  category: Gastrointestinal
  description: >-
    This assertion is supported here by a Crimean-Congo hemorrhagic fever
    clinical series and is not assigned a cross-VHF frequency.
  phenotype_term:
    preferred_term: Nausea
    term:
      id: HP:0002018
      label: Nausea
  evidence:
  - reference: PMID:2749111
    reference_title: The clinical pathology of Crimean-Congo hemorrhagic fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Following an incubation period of 2-9 days after exposure to infection, patients had a sudden onset of disease with fever, nausea, severe headache, and myalgia.
    explanation: This clinical series supports nausea in Crimean-Congo hemorrhagic fever specifically.
- name: Vomiting
  category: Gastrointestinal
  description: >-
    This assertion is supported here by Ebola virus disease evidence as a
    subtype example and is not asserted for every VHF agent.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:25493109
    reference_title: "Ebola Virus Disease: essential public health principles for clinicians."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Symptoms of EVD include abrupt onset of fever, myalgias, and headache in the early phase, followed by vomiting, diarrhea and possible progression to hemorrhagic rash, life-threatening bleeding, and multi-organ failure in the later phase.
    explanation: This review identifies vomiting in Ebola virus disease specifically.
- name: Diarrhea
  category: Gastrointestinal
  description: >-
    This assertion is supported here by Ebola virus disease evidence as a
    subtype example and is not asserted for every VHF agent.
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:25493109
    reference_title: "Ebola Virus Disease: essential public health principles for clinicians."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Symptoms of EVD include abrupt onset of fever, myalgias, and headache in the early phase, followed by vomiting, diarrhea and possible progression to hemorrhagic rash, life-threatening bleeding, and multi-organ failure in the later phase.
    explanation: This review identifies diarrhea in Ebola virus disease specifically.
- name: Capillary leak
  category: Cardiovascular
  phenotype_term:
    preferred_term: Capillary leak
    term:
      id: HP:0030005
      label: Capillary leak
  evidence:
  - reference: PMID:41734218
    reference_title: "[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Their pathogenesis is characterized by early failure of antiviral immunity, high viremia, endothelial dysfunction, capillary leak, and coagulopathy.
    explanation: This directly supports capillary leak as a recurring severe VHF feature.
- name: Hemorrhage
  category: Hematologic
  description: >-
    Hemorrhagic manifestations define the syndrome historically but vary greatly
    by virus and case severity and are not asserted to occur in every infection.
  phenotype_term:
    preferred_term: Hemorrhage
    term:
      id: HP:0001892
      label: Abnormal bleeding
  evidence:
  - reference: PMID:31668201
    reference_title: Viral Hemorrhagic Fevers Other than Ebola and Lassa.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Viral hemorrhagic fevers are severe febrile illnesses with hemorrhagic phenomena.
    explanation: This supports hemorrhagic manifestations as a defining clinical feature.
- name: Coagulopathy
  category: Hematologic
  phenotype_term:
    preferred_term: Coagulopathy
    term:
      id: HP:0003256
      label: Abnormality of the coagulation cascade
  evidence:
  - reference: PMID:41734218
    reference_title: "[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Their pathogenesis is characterized by early failure of antiviral immunity, high viremia, endothelial dysfunction, capillary leak, and coagulopathy.
    explanation: This directly supports coagulopathy as a recurring severe VHF feature.
- name: Petechiae
  category: Hematologic
  description: >-
    This assertion is supported here by a Crimean-Congo hemorrhagic fever
    clinical series and is not assigned a cross-VHF frequency.
  phenotype_term:
    preferred_term: Petechiae
    term:
      id: HP:0000967
      label: Petechiae
  evidence:
  - reference: PMID:2749111
    reference_title: The clinical pathology of Crimean-Congo hemorrhagic fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Petechial rash and hemorrhagic signs such as epistaxis, hematemesis, and melena supervened on days 3-6 of illness.
    explanation: This clinical pathology series supports petechial rash in Crimean-Congo hemorrhagic fever specifically.
- name: Epistaxis
  category: Hematologic
  description: >-
    This assertion is supported here by a Crimean-Congo hemorrhagic fever
    clinical series and is not assigned a cross-VHF frequency.
  phenotype_term:
    preferred_term: Epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
  evidence:
  - reference: PMID:2749111
    reference_title: The clinical pathology of Crimean-Congo hemorrhagic fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Petechial rash and hemorrhagic signs such as epistaxis, hematemesis, and melena supervened on days 3-6 of illness.
    explanation: This clinical pathology series supports epistaxis in Crimean-Congo hemorrhagic fever specifically.
- name: Thrombocytopenia
  category: Hematologic
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:41734218
    reference_title: "[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Laboratory findings commonly include early leukopenia, thrombocytopenia, and elevated liver enzymes.
    explanation: This supports thrombocytopenia as a common laboratory abnormality.
- name: Leukopenia
  category: Hematologic
  phenotype_term:
    preferred_term: Leukopenia
    term:
      id: HP:0001882
      label: Decreased total leukocyte count
  evidence:
  - reference: PMID:41734218
    reference_title: "[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Laboratory findings commonly include early leukopenia, thrombocytopenia, and elevated liver enzymes.
    explanation: This supports leukopenia as a common laboratory abnormality.
- name: Elevated liver enzymes
  category: Hepatic
  phenotype_term:
    preferred_term: Elevated liver enzymes
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:41734218
    reference_title: "[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Laboratory findings commonly include early leukopenia, thrombocytopenia, and elevated liver enzymes.
    explanation: This supports liver enzyme elevation as a common laboratory abnormality.
- name: Shock
  category: Cardiovascular
  phenotype_term:
    preferred_term: Shock
    term:
      id: HP:0031273
      label: Shock
  evidence:
  - reference: PMID:41734218
    reference_title: "[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinically, they initially present as non-specific febrile illnesses, but may progress to organ dysfunction, hemorrhagic manifestations, or shock.
    explanation: This supports shock as a severe clinical manifestation.
- name: Acute kidney injury
  category: Renal
  description: >-
    Acute kidney injury is retained as an uncommon, agent-variable VHF
    complication. The reviewed evidence supports an association but not a
    universal causal route from shock or a generic organ-dysfunction state.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: PMID:18620963
    reference_title: Viral hemorrhagic fever-induced acute kidney injury.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute kidney injury is an uncommon complication but renal dysfunction has been associated with various VHFs.
    explanation: This narrative review supports acute kidney injury as an uncommon associated complication without establishing a universal causal route.
diagnosis:
- name: Exposure-informed recognition and reference-laboratory referral
  description: >-
    Early clinical findings are nonspecific. Recognition therefore depends on
    compatible epidemiologic exposure, prompt isolation and infection-control
    action, and access to appropriate laboratory testing; exact public-health
    procedures are agent- and jurisdiction-specific.
  evidence:
  - reference: PMID:41734218
    reference_title: "[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Continuous surveillance of imported cases, together with access to high-quality laboratory testing, effective infection control including prevention of nosocomial spread, and vigilance in febrile patients with relevant epidemiological exposure, are essential.
    explanation: This directly supports exposure-informed vigilance, laboratory access, and infection control as linked parts of recognition and response.
- name: Agent-specific molecular and serological testing
  description: >-
    Molecular and serological tests are established diagnostic categories, but
    assay choice, specimen timing, interpretation, and containment requirements
    differ by suspected virus and illness stage. This umbrella entry does not
    prescribe an interchangeable test algorithm across VHF agents.
  evidence:
  - reference: PMID:31668201
    reference_title: Viral Hemorrhagic Fevers Other than Ebola and Lassa.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Laboratory diagnosis takes place in highly specialized reference laboratories.
    explanation: This supports specialist laboratory involvement for VHF diagnosis.
  - reference: PMID:41754561
    reference_title: CRISPR-Based Detection of Viral Hemorrhagic Fevers at the Point of Care.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Current molecular and serological diagnostic tests, while efficient and effective, lack the characteristics required of a POC test (POCT) to quickly and easily respond to a VHF outbreak while maintaining a low cost.
    explanation: This directly distinguishes established molecular and serological testing from the unmet point-of-care need.
- name: CRISPR-based point-of-care assays (investigational)
  description: >-
    CRISPR-based assays are an investigational point-of-care direction rather
    than an established replacement for current agent-specific molecular and
    serological testing; published VHF development studies remain limited.
  evidence:
  - reference: PMID:41754561
    reference_title: CRISPR-Based Detection of Viral Hemorrhagic Fevers at the Point of Care.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, studies on the development of CRISPR-based POC diagnostic tests for VHFs are limited.
    explanation: The review explicitly identifies the limited evidence base, supporting investigational rather than established status.
treatments:
- name: Supportive care
  description: >-
    Supportive care remains the cornerstone for most VHFs. Its components and
    intensity must be tailored to the responsible virus, manifestations, and
    severity; this umbrella record does not define a cross-agent care protocol.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:31668201
    reference_title: Viral Hemorrhagic Fevers Other than Ebola and Lassa.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Treatment is essentially supportive.
    explanation: This supports supportive care as the core management approach for many VHFs.
  - reference: PMID:42076078
    reference_title: "Achievements and Challenges in Therapy and Vaccines Development of Viral Hemorrhagic Fevers: An Up-to-Date Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Supportive care continues to represent the cornerstone of clinical management for most infections, while pathogen-targeted therapies are available only for a restricted number of diseases.
    explanation: This supports supportive care as the cross-VHF cornerstone while explicitly limiting targeted therapy to selected diseases.
- name: Ribavirin antiviral pharmacotherapy
  description: >-
    Ribavirin is included here only for Lassa fever, where guidelines recommend
    it but a systematic review found a weak and potentially severity-dependent
    evidence base. It is not asserted as an umbrella VHF treatment.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ribavirin
      term:
        id: CHEBI:63580
        label: ribavirin
  evidence:
  - reference: PMID:31357056
    reference_title: "Ribavirin for the treatment of Lassa fever: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ribavirin is recommended as standard treatment for LF in national and international guidelines but the evidence base for this recommendation has been questioned recently.
    explanation: >
      This supports ribavirin as a guideline-recommended targeted antiviral for
      Lassa fever while preserving uncertainty about the evidence base.
- name: Ebola monoclonal antibody therapy
  description: >-
    Monoclonal antibody therapy is the targeted pharmacotherapy class with the
    strongest regulatory success among VHFs. This record is restricted to Ebola
    virus disease and does not imply activity against other VHF agents.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: monoclonal antibody
      term:
        id: NCIT:C20401
        label: Monoclonal Antibody
  evidence:
  - reference: PMID:42076078
    reference_title: "Achievements and Challenges in Therapy and Vaccines Development of Viral Hemorrhagic Fevers: An Up-to-Date Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Monoclonal antibody-based therapies have achieved the most significant regulatory success to date, particularly for Ebola virus disease.
    explanation: This supports Ebola monoclonal antibody pharmacotherapy as an established targeted VHF treatment class.
- name: Isolation, contact tracing, and PPE-based infection control
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  description: >-
    For VHFs capable of person-to-person or nosocomial transmission, rapid
    patient isolation, contact tracing, and appropriate healthcare-worker PPE
    and infection-control measures help prevent spread. Applicability and
    implementation are agent-, setting-, and jurisdiction-specific; this
    umbrella entry does not prescribe an operational protocol or apply
    unchanged to vector- or reservoir-borne transmission.
  treatment_term:
    preferred_term: preventive intervention
    term:
      id: NCIT:C15843
      label: Preventive Intervention
  evidence:
  - reference: PMID:41734218
    reference_title: "[Viral hemorrhagic fevers: Pathogenesis, epidemiology and clinical manifestations]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Continuous surveillance of imported cases, together with access to high-quality laboratory testing, effective infection control including prevention of nosocomial spread, and vigilance in febrile patients with relevant epidemiological exposure, are essential.
    explanation: This cross-VHF narrative review directly supports infection control and prevention of nosocomial spread as high-level preventive measures.
  - reference: PMID:30047375
    reference_title: "Outbreak of Ebola virus disease in the Democratic Republic of the Congo, April-May, 2018: an epidemiological study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early detection, rapid patient isolation, contact tracing, and the ongoing vaccination programme should sufficiently control the outbreak.
    explanation: This human Ebola outbreak study supports isolation and contact tracing as subtype-specific components of the broader preventive intervention.
  - reference: PMID:25493109
    reference_title: "Ebola Virus Disease: essential public health principles for clinicians."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Emergency department personnel on the frontlines must be prepared to rapidly identify and isolate febrile travelers if indicated. All healthcare workers involved in care of EVD patients should wear personal protective equipment.
    explanation: This Ebola-focused public-health review supports patient isolation and healthcare-worker PPE as subtype-specific components.
- name: Selected VHF vaccination
  description: >-
    Vaccination is preventive and agent-specific. Licensed vaccines exist for
    selected VHFs, including Ebola, yellow fever, and dengue; this does not imply
    a vaccine is available for the umbrella syndrome or every listed subtype.
  therapeutic_modality: VACCINE
  treatment_term:
    preferred_term: vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
  evidence:
  - reference: PMID:42076078
    reference_title: "Achievements and Challenges in Therapy and Vaccines Development of Viral Hemorrhagic Fevers: An Up-to-Date Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Vaccine development has progressed further, with licensed vaccines available for selected VHFs, including Ebola, yellow fever, and dengue, and multiple candidates based on diverse technological platforms advancing through clinical evaluation.
    explanation: This supports vaccination availability for selected VHFs and ongoing vaccine development.
datasets:
- accession: geo:GSE12254
  title: Gene expression associated with liver metabolism during viral hemorrhagic fever
  description: 'Rhesus macaques (Macaca mulatta) infected with a lethal dose of lymphocytic choriomeningitis virus-strain WE (LCMV-WE) provide a model for Lassa fever virus infection of man. Like Lassa fever in human beings, disease begins with flu-like symptoms but can progress to morbidity fairly rapidly. Previously, we profiled the blood transcriptome of LCMV-infected monkeys (M. Djavani et al. J. Virol. 2007: PMID 17522210) showing distinct pre-viremic and viremic stages that discriminated between virulent and benign infections.'
  data_type: MICROARRAY
  sample_count: 20
  publication: PMID:19216742
  notes: Identified by GEO DataSets index search for Viral Hemorrhagic Fever (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE245916
  title: Species-specific responses during Seoul orthohantavirus infection in human and rat lung microvascular endothelial cells
  description: Orthohantaviruses are viruses generally carried by rodents in which they do not cause overt disease. Seoul orthohantavirus (SEOV) predominantly exists as a persistent infection in the omnipresent reservoir host, the Norway rat, Rattus norvegicus. Upon respiratory transmission via aerosolized infectious rodent excreta to humans, SEOV causes an acute disease named hemorrhagic fever with renal syndrome (HFRS). Lack of disease in rats is attributed to downregulation of pro-inflammatory and upregulation of regulatory host responses.
  data_type: BULK_RNA_SEQ
  sample_count: 24
  publication: PMID:38536871
  notes: Identified by GEO DataSets index search for Viral Hemorrhagic Fever (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
discussions:
- discussion_id: vhf_shared_vs_agent_specific_bleeding_mechanisms
  prompt: >-
    Which endothelial, coagulation-factor, consumptive-coagulopathy, and platelet
    mechanisms are genuinely shared across VHFs, and which are specific to a
    virus, disease stage, or bleeding site?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Endothelial activation and damage
  - pathophysiology#Increased vascular permeability
  - pathophysiology#Consumptive coagulopathy
  - pathophysiology#Decreased coagulation factor production
  - pathophysiology#Reduced platelet number
  - pathophysiology#Platelet dysfunction
  rationale: >-
    The umbrella entry represents recurring routes, not universal mechanisms.
    Comparative evidence remains insufficient to assign the same causal weight
    or sequence to each route across all VHF agents.
  evidence:
  - reference: PMID:41410052
    reference_title: Potential Mechanisms Underlying Bleeding During Infection With Hemorrhagic Fever Viruses.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      There are likely both common and distinct mechanisms underlying bleeding in different VHFs, as sites of bleeding differ between the viruses.
    explanation: The review explicitly identifies the unresolved common-versus-agent-specific mechanism question.
- discussion_id: vhf_human_vascular_model_fidelity
  prompt: >-
    How faithfully do animal, conventional two-dimensional culture, and emerging
    microphysiological models reproduce human VHF vascular dynamics across
    different agents?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Endothelial activation and damage
  - pathophysiology#Increased vascular permeability
  rationale: >-
    Existing animal and cell-culture systems have produced mechanistic insights,
    but a vascular-model review specifically questions their fidelity to human
    in-vivo dynamics and presents microphysiological systems as promising rather
    than validated replacements.
  evidence:
  - reference: PMID:38749416
    reference_title: "Vascular dysfunction in hemorrhagic viral fevers: opportunities for organotypic modeling."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      While animal models and traditional 2D cell cultures have contributed insight into the mechanisms by which these pathogens affect the vasculature, these models fall short in replicatingin vivohuman vascular dynamics.
    explanation: The review directly states the translational limitation of existing model systems.
review_notes: >-
  This review intentionally keeps the entry at the cross-VHF syndrome level.
  Virus-specific incubation periods, case-fatality estimates, organ tropism,
  approved products, assay algorithms, and detailed management belong on the
  corresponding agent-specific disorder entries unless a cross-VHF source
  supports an umbrella claim. No single prevalence or incidence estimate was
  added because outbreak ecology and population burden differ fundamentally by
  virus and setting. The matching Falcon deep-research artifact was treated as a
  lead; retained claims were checked against tool-generated reference caches.
📚

References & Deep Research

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 29 citations 2026-05-09T09:41:57.662998

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Viral Hemorrhagic Fever
  • MONDO ID: (if available)
  • Category: Infectious

Research Objectives

Please provide a comprehensive research report on Viral Hemorrhagic Fever covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Viral Hemorrhagic Fever (VHF): Comprehensive Disease Characteristics Report (Infectious)

Target disease

Disease name: Viral Hemorrhagic Fever (VHF) — a clinical syndrome/group of diseases, not a single etiologic entity. (srivastav2024compendiummanagementof pages 1-3, perkins2026potentialmechanismsunderlying pages 1-3)

Evidence base note

The report below is derived from aggregated disease-level resources and the scientific literature (mostly narrative reviews plus selected cohort/epidemiology studies), rather than EHR-derived single-patient datasets. (srivastav2024compendiummanagementof pages 1-3, alageedi2025viralhemorrhagicfever pages 9-11, fazlalipour2024crimeancongohaemorrhagicfever pages 1-2)

1. Disease information

1.1 Concise overview (definition)

VHF refers to a group of severe febrile illnesses characterized by vascular dysregulation/damage with variable hemorrhagic manifestations. One recent definition describes VHF as “a severe febrile illness characterized by aberrant vascular control, vascular damage, and hemorrhagic symptoms.” (srivastav2024compendiummanagementof pages 1-3)

A contemporary mechanistic framing emphasizes that bleeding is not solely due to direct viral cytopathic effects, but often results from combined direct and host-response–mediated dysregulation of hemostasis (coagulation factors, platelets, and endothelium). (perkins2026potentialmechanismsunderlying pages 1-3, perkins2026potentialmechanismsunderlying pages 6-8)

1.2 Causative virus families (current understanding)

Multiple virus families contain agents capable of producing VHF syndromes. Perkins & Mackman (2026) explicitly list six families: Filoviridae, Nairoviridae, Phenuiviridae, Hantaviridae, Arenaviridae, Flaviviridae. (perkins2026potentialmechanismsunderlying pages 1-3)

A separate 2024 review includes additional families in the broader “VHF” grouping (e.g., Paramyxoviridae) depending on taxonomy/classification usage. (srivastav2024compendiummanagementof pages 1-3)

1.3 Common synonyms / alternative names

  • “Viral hemorrhagic fevers (VHFs)” (plural), “hemorrhagic fever viruses (HFVs)” (zaratesanchez2024vasculardysfunctionin pages 1-3)
  • Historically for Ebola: “Ebola hemorrhagic fever” is cited as a synonym for “Ebola virus disease (EVD)”. (nicastri2019ebolavirusdisease pages 1-4)

1.4 Key identifiers (ontologies/codes)

Limitations of retrieved evidence: In the collected sources, explicit MeSH identifiers, MONDO IDs, ICD-10 codes, and a VHF-wide ICD-11 code were not explicitly provided for the umbrella syndrome “viral hemorrhagic fever.” (nicastri2019ebolavirusdisease pages 1-4)

However, ICD-11 is discussed in the context of filoviruses: a 2019 EVD review states that substantial changes were proposed in ICD-11, including an “innovative EVD case definition that links epidemiologic and clinical perspectives” to improve sensitivity relative to older hemorrhagic-fever–centric case definitions. (nicastri2019ebolavirusdisease pages 1-4)

Ontology suggestions (for knowledge-base integration; not directly evidenced as exact codes in retrieved texts): - MONDO: likely exists as a grouped term (umbrella syndrome); not confirmed from evidence in this run. - MeSH: “Hemorrhagic Fever, Viral” (commonly used); not confirmed with identifier string from evidence.

2. Etiology

2.1 Disease causal factors

Primary cause: infection with specific RNA viruses whose pathogenesis includes vascular/endothelial dysfunction, immune dysregulation, and/or coagulation abnormalities. (srivastav2024compendiummanagementof pages 1-3, perkins2026potentialmechanismsunderlying pages 1-3, zaratesanchez2024vasculardysfunctionin pages 1-3)

2.2 Risk factors

VHF risk is heavily driven by ecologic exposure pathways: - Zoonotic exposure to reservoirs (e.g., rodent contact or aerosolized excreta for arenaviruses/hantaviruses). (srivastav2024compendiummanagementof pages 1-3, perkins2026potentialmechanismsunderlying pages 3-5) - Arthropod vectors (mosquito- or tick-borne VHFs). (srivastav2024compendiummanagementof pages 1-3, perkins2026potentialmechanismsunderlying pages 3-5) - Nosocomial/occupational exposure to blood/body fluids (particularly for CCHF and filoviruses). (srivastav2024compendiummanagementof pages 3-4, fazlalipour2024crimeancongohaemorrhagicfever pages 1-2)

Healthcare worker exposure (quantitative, CCHF): In an Iranian national reference-lab series (2000–2023), 12 confirmed HCW CCHF cases were linked to blood exposures; the most prevalent routes were needle-stick (3), mucosal blood splash (3), and skin contact with blood (3); median incubation 6.8 days (range 1–22). (fazlalipour2024crimeancongohaemorrhagicfever pages 1-2)

2.3 Protective factors

Protective factors are primarily exposure and transmission control measures and (for selected VHFs) vaccination. - For Ebola (Zaire ebolavirus), vaccination with rVSV-ZEBOV (Ervebo) is a major protective intervention, with evidence from ring vaccination trials and outbreak deployment. (ayoubi2024recentadvancesin pages 5-6)

2.4 Gene–environment interactions

No robust, VHF-wide human gene–environment interaction loci were identified in the retrieved evidence for this run. The available sources emphasize exposure ecology and immune-pathogenesis rather than host genomic susceptibility. (perkins2026potentialmechanismsunderlying pages 1-3, zaratesanchez2024vasculardysfunctionin pages 1-3)

3. Phenotypes

3.1 Core clinical phenotype set (cross-VHF)

A typical VHF syndrome begins with non-specific influenza-like illness and can progress to shock and multi-organ failure. - Early symptoms reported: fever, myalgia, headache, nausea/vomiting, diarrhea. (alageedi2025viralhemorrhagicfever pages 9-11, perkins2026potentialmechanismsunderlying pages 1-3) - Hemorrhagic manifestations reported: petechiae, mucosal bleeding, GI bleeding, epistaxis, bruising, conjunctival injection. (alageedi2025viralhemorrhagicfever pages 9-11, perkins2026potentialmechanismsunderlying pages 1-3) - Severe outcomes: shock, acute renal failure, neurological decline, multi-organ failure. (alageedi2025viralhemorrhagicfever pages 9-11)

Abstract-quotable support (HFV vascular triad): Zarate-Sanchez et al. (2024) describe HFVs as inducing “significant vascular dysfunction by affecting endothelial cells, altering immunity, and disrupting the clotting system.” (zaratesanchez2024vasculardysfunctionin pages 1-3)

3.2 Laboratory abnormalities (examples)

Across VHF agents, common abnormalities include thrombocytopenia, coagulopathy, transaminase elevations, and leukopenia. - Perkins & Mackman emphasize thrombocytopenia/platelet dysfunction and coagulopathy in the bleeding phenotype across VHFs. (perkins2026potentialmechanismsunderlying pages 1-3, perkins2026potentialmechanismsunderlying pages 6-8) - A 2024 review provides practical lab patterns: for EBOV/Sudan/CCHFV: leukopenia, thrombocytopenia, elevated ALT/AST; for dengue: platelet <100×10^9/L, prolonged aPTT with often normal PT, elevated ALT/AST. (srivastav2024compendiummanagementof pages 4-6)

Quantitative HCW CCHF lab findings: thrombocytopenia (100%), elevated aminotransferases (75%), leukopenia (66.7%); epistaxis was the most frequent hemorrhagic sign (41.7%). (fazlalipour2024crimeancongohaemorrhagicfever pages 2-3)

3.3 Age of onset / progression / frequency

Onset is typically acute (days to weeks after exposure) and severity varies by agent. - Incubation examples: Ebola/Marburg 2–21 days; Lassa 1–3 weeks; CCHF 3–9 days after tick bite (5–13 after contact); yellow fever 3–6 days. (alageedi2025viralhemorrhagicfever pages 9-11)

3.4 Suggested HPO terms (examples; not exhaustive)

  • Fever: HP:0001945
  • Myalgia: HP:0003326
  • Diarrhea: HP:0002014
  • Vomiting: HP:0002013
  • Petechiae: HP:0000967
  • Epistaxis: HP:0000421
  • Hematemesis: HP:0002107
  • Melena/GI hemorrhage: HP:0002249
  • Shock: HP:0030149
  • Acute kidney injury: HP:0001919
  • Thrombocytopenia: HP:0001873
  • Leukopenia: HP:0001882
  • Elevated hepatic transaminases: HP:0002910

(These HPO mappings are standard ontology suggestions; the supporting clinical findings are evidenced in the cited sources.) (alageedi2025viralhemorrhagicfever pages 9-11, perkins2026potentialmechanismsunderlying pages 1-3, srivastav2024compendiummanagementof pages 4-6, fazlalipour2024crimeancongohaemorrhagicfever pages 2-3)

4. Genetic / molecular information

4.1 Causal genes / variants

Not applicable in the Mendelian sense: VHF is infectious and not caused by germline pathogenic variants. The causal “genetic material” is viral genomes.

4.2 Viral proteins/mechanisms with host interaction (examples)

A 2024 review notes that VHF viruses target monocytes/macrophages/dendritic cells and endothelial cells, and that viral factors (example given: VP35) suppress type I interferon responses, contributing to cytokine activation and endothelial damage. (srivastav2024compendiummanagementof pages 4-6)

4.3 Host molecular biomarkers (examples)

  • Tissue factor (TF) induction in PBMCs and extracellular vesicles is described for Ebola infection in nonhuman primate models. (perkins2026potentialmechanismsunderlying pages 1-3)

5. Environmental information

5.1 Environmental and exposure factors

  • Rodent infestation in domiciles and food storage settings (rodent-borne transmission) (srivastav2024compendiummanagementof pages 1-3)
  • Tick exposure in pastoral/rural settings (CCHF vectors such as Hyalomma ticks) (perkins2026potentialmechanismsunderlying pages 3-5)
  • Mosquito exposure and livestock-associated ecology (RVF) (perkins2026potentialmechanismsunderlying pages 3-5)

5.2 Lifestyle / occupational factors

  • Health-care work without adequate infection prevention and control (IPC) is a clear occupational risk (CCHF HCW series). (fazlalipour2024crimeancongohaemorrhagicfever pages 1-2)

6. Mechanism / pathophysiology

6.1 Unifying mechanistic framework (current understanding)

Across hemorrhagic fever viruses, a unifying framework is the vascular triad: 1) Endothelial barrier disruption / vascular permeability 2) Derangement of blood clotting / hemostasis 3) Immune dysregulation

This is explicitly stated in the 2024 Biofabrication review: “common features of the pathology include the triad of (1) disruption of the vascular endothelial barrier; (2) derangement of blood clotting; and (3) immune dysregulation.” (zaratesanchez2024vasculardysfunctionin pages 1-3)

6.2 Hemostasis/bleeding mechanisms (expert synthesis)

Perkins & Mackman (2026) summarize bleeding mechanisms in VHF as including: - Consumptive coagulopathy (DIC-like) - Decreased coagulation factor production - Thrombocytopenia and platelet dysfunction - Endothelial activation/damage leading to increased vascular permeability They emphasize that both direct viral infection effects and host responses drive hemostatic dysregulation. (perkins2026potentialmechanismsunderlying pages 1-3)

6.3 Upstream-to-downstream causal chain (generalized)

Exposure → infection of innate immune cells (dendritic cells/monocytes/macrophages) → impaired type I IFN signaling and immune evasion → cytokine amplification and tissue factor release → endothelial activation/damage + coagulation activation → microvascular instability and vascular leak → shock/multi-organ dysfunction; plus thrombocytopenia/consumptive coagulopathy → bleeding manifestations. (srivastav2024compendiummanagementof pages 4-6, perkins2026potentialmechanismsunderlying pages 1-3, perkins2026potentialmechanismsunderlying pages 6-8)

6.4 Molecular pathways and ontology term suggestions

GO Biological Process (suggested): - type I interferon signaling pathway (GO:0060337) (supported conceptually by IFN antagonism discussed in VHF pathogenesis) (srivastav2024compendiummanagementof pages 4-6) - inflammatory response (GO:0006954) (srivastav2024compendiummanagementof pages 4-6) - coagulation (GO:0050817) / hemostasis (GO:0007599) (perkins2026potentialmechanismsunderlying pages 6-8) - platelet activation (GO:0030168) (perkins2026potentialmechanismsunderlying pages 6-8) - regulation of vascular permeability (GO:0043114) / endothelial cell activation (GO:0042118) (perkins2026potentialmechanismsunderlying pages 1-3, zaratesanchez2024vasculardysfunctionin pages 1-3)

Cell Ontology (CL) (suggested): - endothelial cell (CL:0000115) (zaratesanchez2024vasculardysfunctionin pages 1-3) - monocyte (CL:0000576), macrophage (CL:0000235), dendritic cell (CL:0000451) (srivastav2024compendiummanagementof pages 4-6) - platelet (CL:0000233) (perkins2026potentialmechanismsunderlying pages 6-8)

6.5 Recent development: organotypic modeling (2024)

The 2024 Biofabrication review argues that animal models and 2D cultures “fall short in replicating in vivo human vascular dynamics,” and highlights the emergence of microphysiological systems (MPS)/organ-on-chip to model HFV-induced vascular dysfunction and aid treatment development. (zaratesanchez2024vasculardysfunctionin pages 1-3)

7. Anatomical structures affected

7.1 Organ/system level

VHF is systemic and commonly involves multi-organ injury with prominent vascular/endothelial involvement. - Commonly referenced organ involvement: liver, kidneys, heart, lungs in severe VHF presentations. (alageedi2025viralhemorrhagicfever pages 9-11)

UBERON suggestions: - blood vessel (UBERON:0001981) - endothelium (UBERON:0001986) - liver (UBERON:0002107) - kidney (UBERON:0002113) - lung (UBERON:0002048)

7.2 Tissue/cellular targets

Endothelial cells and innate immune cells are repeatedly emphasized as key cellular compartments in pathogenesis. (srivastav2024compendiummanagementof pages 4-6, zaratesanchez2024vasculardysfunctionin pages 1-3)

8. Temporal development

8.1 Onset pattern

Typically acute with an incubation period of days to weeks depending on agent (see incubation examples above). (alageedi2025viralhemorrhagicfever pages 9-11)

8.2 Staging (example)

Marburg virus disease is described as having early/peak/resolution phases; several VHFs have characteristic stage-based clinical progression (e.g., HFRS phases). (perkins2026potentialmechanismsunderlying pages 3-5)

9. Inheritance and population

9.1 Epidemiology and burden (selected quantitative statistics)

VHF burden is outbreak-driven and varies greatly by virus and setting.

Agent-level quantitative examples (from a mechanistic review table/summary): - Marburg virus disease: hemorrhagic manifestations 34–83%; average CFR ~50%. (perkins2026potentialmechanismsunderlying pages 3-5, perkins2026potentialmechanismsunderlying media b84e671f) - Lassa: ~80% asymptomatic; ~20% progress to severe disease; overt bleeding up to 40% of cases (perkins2026potentialmechanismsunderlying pages 3-5); overall CFR values are context-dependent (quantitative summary appears in Table 2). (perkins2026potentialmechanismsunderlying media b84e671f) - Rift Valley fever: <1% develop hemorrhagic manifestations; estimate of ~500,000 infections between 1997 and 2010. (perkins2026potentialmechanismsunderlying pages 3-5) - Hantaan virus (HFRS): overall CFR ~1%. (perkins2026potentialmechanismsunderlying pages 3-5)

Syndrome-level trend: VHF incidence may increase with expanding vector ranges and increased contact with animal reservoirs/hosts. (perkins2026potentialmechanismsunderlying pages 1-3)

9.2 Demographics / high-risk groups

  • Healthcare workers and caregivers have elevated risk during outbreaks (e.g., nosocomial CCHF exposures). (fazlalipour2024crimeancongohaemorrhagicfever pages 1-2)
  • Populations in endemic rural settings with rodent or tick exposure and limited IPC resources are at high risk. (srivastav2024compendiummanagementof pages 1-3, perkins2026potentialmechanismsunderlying pages 3-5)

10. Diagnostics

10.1 Standard clinical and laboratory testing approach

VHF diagnosis is challenging early because symptoms overlap with many febrile illnesses. (alageedi2025viralhemorrhagicfever pages 9-11, wupori2026crisprbaseddetectionof pages 1-2)

Preferred acute diagnostic modality: RT-PCR on blood and other fluids is described as highly sensitive/specific in acute illness in a 2024 VHF management review; viral culture is restricted to high-containment laboratories. (srivastav2024compendiummanagementof pages 4-6)

Serology limitations: A 2025 VHF review notes that serology may be less helpful acutely and that ELISA can lack specificity due to cross-reactivity (notably within flaviviruses and bunyaviruses). (alageedi2025viralhemorrhagicfever pages 9-11)

Real-world diagnostic yield (CCHF HCWs): RT-PCR positive in 11/12 (91.7%); IgM ELISA positive in 3/12 (25%). (fazlalipour2024crimeancongohaemorrhagicfever pages 1-2)

10.2 Emerging diagnostics (point-of-care direction)

A 2026 review highlights that current molecular/serological tests “lack the characteristics required of a POC test” for rapid outbreak response, and argues that CRISPR-based diagnostics have attractive POCT features (sensitivity/specificity, adaptability, low cost, quick turnaround). (wupori2026crisprbaseddetectionof pages 1-2)

Note: This is later than the requested 2023–2024 window but provides a current synthesis of the POC diagnostics direction. (wupori2026crisprbaseddetectionof pages 1-2)

10.3 Suggested LOINC-style lab concepts (examples)

  • Platelet count (thrombocytopenia)
  • PT/INR and aPTT (coagulopathy)
  • ALT/AST (transaminase elevation)
  • Creatinine/BUN (renal impairment) These test categories are explicitly referenced as part of clinical evaluation in VHF management reviews. (srivastav2024compendiummanagementof pages 4-6)

11. Outcome / prognosis

11.1 Mortality and CFR variability

Case fatality varies widely by virus and outbreak context. - The mechanistic VHF review reports Ebola pooled CFR ~60% with hemorrhagic symptoms up to ~50% (summary). (perkins2026potentialmechanismsunderlying pages 1-3) - In Ebola, delayed therapy is associated with worse outcomes; one review reports “increased the odds of death by 11% for each day of delayed…therapy.” (ayoubi2024recentadvancesin pages 1-2)

11.2 Complications and sequelae

  • Severe disease may culminate in shock and multi-organ failure (liver, kidneys, heart, lungs). (alageedi2025viralhemorrhagicfever pages 9-11)
  • Viral persistence in immune-privileged sites is noted as a post-acute concern in VHF clinical literature (general concept discussed in management reviews). (srivastav2024compendiummanagementof pages 3-4)

12. Treatment

12.1 General management

For most VHFs, supportive care is the cornerstone (fluids/electrolytes, monitoring, organ support), plus strict isolation and PPE. (alageedi2025viralhemorrhagicfever pages 9-11, srivastav2024compendiummanagementof pages 6-7)

12.2 Pathogen-targeted therapies (Ebola as the main approved example)

FDA-approved Ebola therapeutics (Zaire ebolavirus): - Inmazeb (atoltivimab/maftivimab/odesivimab; REGN-EB3) — FDA approval 2020 (review summary). (ayoubi2024recentadvancesin pages 1-2) - Ebanga (ansuvimab; mAb114) — FDA approval 2020 (review summary). (ayoubi2024recentadvancesin pages 1-2)

12.3 Vaccines and real-world implementation

Ervebo (rVSV-ZEBOV) vaccine - Regulatory milestone: first FDA-approved vaccine for EBOV in 2019; expanded FDA approval for children ≥1 year in 2023 (reviewed). (ayoubi2024recentadvancesin pages 1-2, ayoubi2024recentadvancesin pages 5-6) - Ring vaccination effectiveness: in Guinea 2015 trial, “none of 2,119 immediately vaccinated contacts developed EVD at 10 days versus 16 cases in delayed vaccination,” and outbreak deployments reported high effectiveness estimates (review summary). (ayoubi2024recentadvancesin pages 5-6) - Implementation constraints: stringent cold chain (e.g., <−60°C long-term), limited stability after thaw. (ayoubi2024recentadvancesin pages 5-6)

12.4 Antivirals used/considered across VHFs

  • Ribavirin is repeatedly cited as potentially helpful for Lassa fever and possibly CCHF, with variable evidence quality. (srivastav2024compendiummanagementof pages 4-6, alageedi2025viralhemorrhagicfever pages 9-11)
  • Favipiravir and other candidates appear as investigational in VHF management discussions. (srivastav2024compendiummanagementof pages 4-6)

12.5 MAXO term suggestions (examples)

  • Supportive care: MAXO:0000058 (supportive therapy; generic)
  • Intravenous fluid administration
  • Administration of monoclonal antibody therapy
  • Vaccination
  • Infection control / isolation (These are suggested mapping targets; intervention concepts are evidenced in cited sources.) (srivastav2024compendiummanagementof pages 6-7, ayoubi2024recentadvancesin pages 5-6)

12.6 Clinical trials (selected examples from ClinicalTrials.gov search results)

VHF-related vaccine trials present in the retrieved trial set include: - Rift Valley fever vaccine studies: e.g., NCT03609398 (Phase 2, recruiting), NCT04672824, NCT04754776, NCT06799234. (srivastav2024compendiummanagementof pages 3-4) - Ebola/Marburg vaccine trials: e.g., NCT00605514, NCT00997607, NCT04723602. (srivastav2024compendiummanagementof pages 3-4)

13. Prevention

13.1 Primary prevention

  • Vaccination where available (e.g., EBOV with Ervebo; yellow fever vaccine referenced as available in VHF reviews). (ayoubi2024recentadvancesin pages 5-6, alageedi2025viralhemorrhagicfever pages 9-11)
  • Vector control (mosquito/tick) and rodent control in endemic settings to reduce spillover. (srivastav2024compendiummanagementof pages 1-3)

13.2 Secondary/tertiary prevention

  • Early detection, isolation, contact tracing, and PPE/IPC to prevent transmission amplification and nosocomial spread. (srivastav2024compendiummanagementof pages 6-7, fazlalipour2024crimeancongohaemorrhagicfever pages 1-2)

14. Other species / natural disease

VHF ecology is frequently zoonotic with distinct reservoirs/vectors by agent: - EBOV: fruit bats are thought reservoirs (srivastav2024compendiummanagementof pages 1-3) - Lassa: multimammate rats (Mastomys) (perkins2026potentialmechanismsunderlying pages 3-5) - CCHF: Hyalomma ticks (perkins2026potentialmechanismsunderlying pages 3-5) - RVF: mosquitoes and livestock (perkins2026potentialmechanismsunderlying pages 3-5)

15. Model organisms

15.1 In vivo models

Nonhuman primate models are repeatedly emphasized for studying VHF-associated hemostatic dysregulation and biomarker dynamics (e.g., tissue factor induction in Ebola NHP models). (perkins2026potentialmechanismsunderlying pages 1-3)

15.2 Organotypic / in vitro advanced models (2024 development)

Microphysiological systems (“organ-on-chip”) are highlighted as a key emerging platform to capture human vascular dynamics not well represented in animals or 2D culture. (zaratesanchez2024vasculardysfunctionin pages 1-3, zaratesanchez2024vasculardysfunctionin pages 29-30)

Cross-agent quantitative summary (evidence table)

The following table summarizes the major VHF families and representative agents, including reservoirs/vectors, transmission routes, diagnostic notes, and severity metrics.

Virus family (ICTV) Representative virus / disease Typical reservoir / vector Key transmission routes Approx. CFR / hemorrhage frequency Incubation period Key diagnostic notes
Filoviridae Ebola virus / Ebola virus disease Fruit bats thought to be reservoir; humans accidental hosts Person-to-person and nosocomial spread via body fluids; zoonotic spillover (srivastav2024compendiummanagementof pages 1-3, srivastav2024compendiummanagementof pages 6-7) Pooled CFR ~60%; hemorrhagic symptoms in up to ~50% of cases (quantitative summary from Table 2) (perkins2026potentialmechanismsunderlying pages 1-3, perkins2026potentialmechanismsunderlying media b84e671f) 2–21 days (alageedi2025viralhemorrhagicfever pages 9-11) RT-PCR on blood/urine/saliva is highly sensitive/specific in acute illness; IgM/IgG usually appear around days 3 and 7; serology less sensitive acutely (srivastav2024compendiummanagementof pages 4-6)
Filoviridae Marburg virus / Marburg virus disease Not specified in gathered evidence Person-to-person and nosocomial spread recognized within VHF syndrome (srivastav2024compendiummanagementof pages 1-3) Average CFR ~50%; hemorrhagic manifestations 34–83% (quantitative summary from Table 2) (perkins2026potentialmechanismsunderlying pages 3-5, perkins2026potentialmechanismsunderlying media b84e671f) 2–21 days (alageedi2025viralhemorrhagicfever pages 9-11) Acute diagnosis prioritizes RT-PCR; serology supportive later, but acute serology is less useful (srivastav2024compendiummanagementof pages 4-6, alageedi2025viralhemorrhagicfever pages 9-11)
Arenaviridae Lassa virus / Lassa fever Multimammate rat (Mastomys); rodent-borne (perkins2026potentialmechanismsunderlying pages 3-5) Contact with rodents or aerosolized excreta; secondary interhuman spread also occurs within VHF syndrome (srivastav2024compendiummanagementof pages 1-3, srivastav2024compendiummanagementof pages 3-4) ~80% asymptomatic; ~20% progress to severe disease; overt bleeding up to 40% of cases; overall CFR ~1% in quantitative summary, but outbreak CFR can be much higher in some reports (perkins2026potentialmechanismsunderlying pages 3-5, perkins2026potentialmechanismsunderlying media b84e671f, srivastav2024compendiummanagementof pages 3-4) 1–3 weeks (alageedi2025viralhemorrhagicfever pages 9-11) RT-PCR preferred in acute phase; ribavirin noted as used clinically; serology less sensitive early (srivastav2024compendiummanagementof pages 4-6, srivastav2024compendiummanagementof pages 6-7)
Nairoviridae Crimean-Congo hemorrhagic fever virus / CCHF Hyalomma ticks (vector) (perkins2026potentialmechanismsunderlying pages 3-5) Tick bite; contact with infected animal blood/tissues; human-to-human and occupational/nosocomial exposure via blood/body fluids (perkins2026potentialmechanismsunderlying pages 3-5, alageedi2025viralhemorrhagicfever pages 9-11) Severe cases: hemorrhagic symptoms up to 50% of symptomatic individuals (<6% of all infections); severe cases may develop DIC; reported CFR ranges 5–50% or 10–40% across sources (perkins2026potentialmechanismsunderlying pages 3-5, alageedi2025viralhemorrhagicfever pages 9-11) Typically 3–9 days after tick bite; 5–13 days after contact exposure (alageedi2025viralhemorrhagicfever pages 9-11) RT-PCR is preferred acutely; IgM capture ELISA used, but serology may lack specificity/cross-react; ribavirin may be helpful (srivastav2024compendiummanagementof pages 4-6, alageedi2025viralhemorrhagicfever pages 9-11)
Phenuiviridae Rift Valley fever virus / Rift Valley fever Aedes mosquitoes and infected livestock (perkins2026potentialmechanismsunderlying pages 3-5) Vector-borne and animal exposure (perkins2026potentialmechanismsunderlying pages 3-5, srivastav2024compendiummanagementof pages 1-3) Most infections mild/subclinical; <1% develop hemorrhagic manifestations; estimates suggest ~500,000 infections during 1997–2010 (perkins2026potentialmechanismsunderlying pages 3-5) Not specified in gathered evidence Acute diagnosis generally favors RT-PCR; serology useful later but less reliable early in VHF settings (srivastav2024compendiummanagementof pages 4-6, alageedi2025viralhemorrhagicfever pages 9-11)
Hantaviridae Hantaan virus / hemorrhagic fever with renal syndrome (HFRS) Rodent hosts (Old World and New World rodent reservoirs noted) (perkins2026potentialmechanismsunderlying pages 3-5) Rodent-associated exposure, including aerosolized excreta within VHF syndrome (srivastav2024compendiummanagementof pages 1-3, perkins2026potentialmechanismsunderlying pages 3-5) Overall CFR for Hantaan infection ~1% (perkins2026potentialmechanismsunderlying pages 3-5) Not specified in gathered evidence RT-PCR preferred acutely; characteristic labs can include elevated BUN/creatinine in Hantaan/Seoul infections (srivastav2024compendiummanagementof pages 4-6)
Flaviviridae Dengue virus / dengue hemorrhagic fever Arthropod-borne; mosquito vector implied within VHF group (srivastav2024compendiummanagementof pages 1-3, srivastav2024compendiummanagementof pages 3-4) Mosquito-borne transmission (srivastav2024compendiummanagementof pages 1-3) CFR ~0.8–2.5%; thrombocytopenia/platelet dysfunction emphasized (srivastav2024compendiummanagementof pages 3-4, srivastav2024compendiummanagementof pages 1-3, srivastav2024compendiummanagementof pages 4-6) Not specified in gathered evidence Dengue often shows elevated ALT/AST, normal PT, prolonged aPTT, platelets <100 × 10^9/L; RT-PCR preferred acutely, serology may cross-react (srivastav2024compendiummanagementof pages 4-6, alageedi2025viralhemorrhagicfever pages 9-11)
Flaviviridae Yellow fever / yellow fever hemorrhagic disease Arthropod-borne; mosquito vector implied within VHF group (srivastav2024compendiummanagementof pages 1-3) Mosquito-borne transmission (srivastav2024compendiummanagementof pages 1-3) Quantitative CFR/hemorrhage frequency not specified in gathered evidence 3–6 days (alageedi2025viralhemorrhagicfever pages 9-11) Vaccine exists; acute VHF diagnosis still relies on molecular testing when available, while serology may cross-react in flaviviruses (alageedi2025viralhemorrhagicfever pages 9-11, srivastav2024compendiummanagementof pages 4-6)
VHF syndrome (cross-pathogen summary) Viral hemorrhagic fever as a syndrome Rodents, bats, ticks, mosquitoes, and infected animals are recurrent reservoirs/vectors depending on virus (srivastav2024compendiummanagementof pages 1-3, perkins2026potentialmechanismsunderlying pages 3-5) Zoonotic spillover, arthropod-borne spread, and person-to-person/nosocomial transmission depending on agent (srivastav2024compendiummanagementof pages 3-4, srivastav2024compendiummanagementof pages 1-3) Hallmarks include high-fatality potential, coagulopathy, thrombocytopenia, endothelial dysfunction, and DIC in severe disease (perkins2026potentialmechanismsunderlying pages 1-3, srivastav2024compendiummanagementof pages 4-6, perkins2026potentialmechanismsunderlying pages 6-8) Variable by virus General approach: RT-PCR is the main acute diagnostic test; serology (IgM/IgG ELISA) is more supportive later and may be less useful or less specific early in disease (srivastav2024compendiummanagementof pages 4-6, alageedi2025viralhemorrhagicfever pages 9-11)

Table: This table summarizes Viral Hemorrhagic Fever as a syndrome and the major causative virus families with representative agents, transmission ecology, approximate severity metrics, incubation periods, and diagnostic notes. It is useful as a compact disease-knowledge-base overview grounded in the gathered evidence, including quantitative values extracted from the Table 2 image in Perkins & Mackman 2026.

A key quantitative source used for several CFR/hemorrhage frequency entries is Table 2 from Perkins & Mackman (2026), retrieved as an image. (perkins2026potentialmechanismsunderlying media b84e671f)

Expert opinion / analysis (authoritative synthesis)

  1. VHF is best treated as a syndrome defined by shared vascular/hemostatic failure pathways rather than by hemorrhage alone. Hemorrhage can be absent or variable across agents and outbreaks; pathogenesis commonly involves coagulation and endothelial activation/dysfunction. (perkins2026potentialmechanismsunderlying pages 1-3, zaratesanchez2024vasculardysfunctionin pages 1-3)
  2. The main translational bottleneck is that broad disease-modifying therapies remain elusive, while supportive care still dominates for most VHFs; Ebola is the major exception with approved mAbs and vaccines. (zaratesanchez2024vasculardysfunctionin pages 1-3, ayoubi2024recentadvancesin pages 1-2)
  3. Next-generation modeling and diagnostics are increasingly central to preparedness: microphysiological vascular systems to improve mechanistic inference and therapy screening (2024) (zaratesanchez2024vasculardysfunctionin pages 1-3) and point-of-care molecular diagnostics (e.g., CRISPR-based) to reduce delays and improve biosafety during outbreaks (2026 synthesis). (wupori2026crisprbaseddetectionof pages 1-2)

URLs and publication dates (selected high-priority sources used)

  • Zarate-Sanchez E. et al. Biofabrication (Published 2024-06-05). https://doi.org/10.1088/1758-5090/ad4c0b (zaratesanchez2024vasculardysfunctionin pages 1-3)
  • El Ayoubi L. W. E. et al. PLOS Pathogens (Published 2024-03). https://doi.org/10.1371/journal.ppat.1012038 (ayoubi2024recentadvancesin pages 1-2)
  • Fazlalipour M. et al. BMC Infectious Diseases (Published 2024-11). https://doi.org/10.1186/s12879-024-10199-1 (fazlalipour2024crimeancongohaemorrhagicfever pages 1-2)
  • Srivastav Y. et al. Asian J Res Infect Dis (Published 2024-03). https://doi.org/10.9734/ajrid/2024/v15i3334 (srivastav2024compendiummanagementof pages 1-3)
  • Perkins M. V., Mackman N. ATVB (Published 2026-02). https://doi.org/10.1161/atvbaha.125.323625 (perkins2026potentialmechanismsunderlying pages 1-3)

Gaps / items not fully resolved from retrieved evidence in this run

  • Explicit MONDO ID, MeSH IDs, and ICD-10/ICD-11 codes for the umbrella “viral hemorrhagic fever” entry were not directly extractable from the gathered sources; ICD-11 changes were discussed mainly for EVD case definitions rather than VHF as a single ICD entity. (nicastri2019ebolavirusdisease pages 1-4)
  • Population-level global prevalence/incidence for the VHF umbrella entity was not available in the retrieved evidence; agent-level outbreak statistics were available for some viruses. (perkins2026potentialmechanismsunderlying pages 3-5, ayoubi2024recentadvancesin pages 5-6)

References

  1. (srivastav2024compendiummanagementof pages 1-3): Yash Srivastav, Aniket Kumar, Jaya Singh, Aditya Srivastav, and Mohd. Imtiyaz Ahmad. Compendium: management of viral hemorrhagic fever (viral fever), involving its pathogenesis. Asian Journal of Research in Infectious Diseases, 15:17-25, Mar 2024. URL: https://doi.org/10.9734/ajrid/2024/v15i3334, doi:10.9734/ajrid/2024/v15i3334. This article has 4 citations.

  2. (perkins2026potentialmechanismsunderlying pages 1-3): Megan V. Perkins and Nigel Mackman. Potential mechanisms underlying bleeding during infection with hemorrhagic fever viruses. Arteriosclerosis, Thrombosis, and Vascular Biology, Feb 2026. URL: https://doi.org/10.1161/atvbaha.125.323625, doi:10.1161/atvbaha.125.323625. This article has 2 citations and is from a domain leading peer-reviewed journal.

  3. (alageedi2025viralhemorrhagicfever pages 9-11): Neyaf Majid Alageedi, Samar Abdulwahab Abdulla Mutar, Huda Abdul Hameed, Ragda Ayad Taha, and Shahrazad Ahmed khalah. Viral hemorrhagic fever: a literature review. Osol Journal for Medical Sciences, 3:36-49, Jun 2025. URL: https://doi.org/10.69946/ojms/2025.03.004, doi:10.69946/ojms/2025.03.004. This article has 0 citations.

  4. (fazlalipour2024crimeancongohaemorrhagicfever pages 1-2): Mehdi Fazlalipour, Tahmineh Jalali, Roger Hewson, Mohammad Hassan Pouriayevali, and Mostafa Salehi-Vaziri. Crimean-congo haemorrhagic fever among healthcare workers in iran 2000–2023, a report of national reference laboratory. BMC Infectious Diseases, Nov 2024. URL: https://doi.org/10.1186/s12879-024-10199-1, doi:10.1186/s12879-024-10199-1. This article has 10 citations and is from a peer-reviewed journal.

  5. (perkins2026potentialmechanismsunderlying pages 6-8): Megan V. Perkins and Nigel Mackman. Potential mechanisms underlying bleeding during infection with hemorrhagic fever viruses. Arteriosclerosis, Thrombosis, and Vascular Biology, Feb 2026. URL: https://doi.org/10.1161/atvbaha.125.323625, doi:10.1161/atvbaha.125.323625. This article has 2 citations and is from a domain leading peer-reviewed journal.

  6. (zaratesanchez2024vasculardysfunctionin pages 1-3): Evelyn Zarate-Sanchez, Steven C George, Monica L Moya, and Claire Robertson. Vascular dysfunction in hemorrhagic viral fevers: opportunities for organotypic modeling. Biofabrication, 16:032008, Jun 2024. URL: https://doi.org/10.1088/1758-5090/ad4c0b, doi:10.1088/1758-5090/ad4c0b. This article has 11 citations and is from a peer-reviewed journal.

  7. (nicastri2019ebolavirusdisease pages 1-4): Emanuele Nicastri, Gary Kobinger, Francesco Vairo, Chiara Montaldo, Leonard E.G. Mboera, Rashid Ansunama, Alimuddin Zumla, and Giuseppe Ippolito. Ebola virus disease: epidemiology, clinical features, management, and prevention. Infectious disease clinics of North America, 33 4:953-976, Dec 2019. URL: https://doi.org/10.1016/j.idc.2019.08.005, doi:10.1016/j.idc.2019.08.005. This article has 96 citations and is from a peer-reviewed journal.

  8. (perkins2026potentialmechanismsunderlying pages 3-5): Megan V. Perkins and Nigel Mackman. Potential mechanisms underlying bleeding during infection with hemorrhagic fever viruses. Arteriosclerosis, Thrombosis, and Vascular Biology, Feb 2026. URL: https://doi.org/10.1161/atvbaha.125.323625, doi:10.1161/atvbaha.125.323625. This article has 2 citations and is from a domain leading peer-reviewed journal.

  9. (srivastav2024compendiummanagementof pages 3-4): Yash Srivastav, Aniket Kumar, Jaya Singh, Aditya Srivastav, and Mohd. Imtiyaz Ahmad. Compendium: management of viral hemorrhagic fever (viral fever), involving its pathogenesis. Asian Journal of Research in Infectious Diseases, 15:17-25, Mar 2024. URL: https://doi.org/10.9734/ajrid/2024/v15i3334, doi:10.9734/ajrid/2024/v15i3334. This article has 4 citations.

  10. (ayoubi2024recentadvancesin pages 5-6): L’Emir Wassim El Ayoubi, Omar Mahmoud, Johnny Zakhour, and Souha S. Kanj. Recent advances in the treatment of ebola disease: a brief overview. PLOS Pathogens, 20:e1012038, Mar 2024. URL: https://doi.org/10.1371/journal.ppat.1012038, doi:10.1371/journal.ppat.1012038. This article has 49 citations and is from a highest quality peer-reviewed journal.

  11. (srivastav2024compendiummanagementof pages 4-6): Yash Srivastav, Aniket Kumar, Jaya Singh, Aditya Srivastav, and Mohd. Imtiyaz Ahmad. Compendium: management of viral hemorrhagic fever (viral fever), involving its pathogenesis. Asian Journal of Research in Infectious Diseases, 15:17-25, Mar 2024. URL: https://doi.org/10.9734/ajrid/2024/v15i3334, doi:10.9734/ajrid/2024/v15i3334. This article has 4 citations.

  12. (fazlalipour2024crimeancongohaemorrhagicfever pages 2-3): Mehdi Fazlalipour, Tahmineh Jalali, Roger Hewson, Mohammad Hassan Pouriayevali, and Mostafa Salehi-Vaziri. Crimean-congo haemorrhagic fever among healthcare workers in iran 2000–2023, a report of national reference laboratory. BMC Infectious Diseases, Nov 2024. URL: https://doi.org/10.1186/s12879-024-10199-1, doi:10.1186/s12879-024-10199-1. This article has 10 citations and is from a peer-reviewed journal.

  13. (perkins2026potentialmechanismsunderlying media b84e671f): Megan V. Perkins and Nigel Mackman. Potential mechanisms underlying bleeding during infection with hemorrhagic fever viruses. Arteriosclerosis, Thrombosis, and Vascular Biology, Feb 2026. URL: https://doi.org/10.1161/atvbaha.125.323625, doi:10.1161/atvbaha.125.323625. This article has 2 citations and is from a domain leading peer-reviewed journal.

  14. (wupori2026crisprbaseddetectionof pages 1-2): Kylene Wupori, Lauren Garnett, Alexander Bello, and James E. Strong. Crispr-based detection of viral hemorrhagic fevers at the point of care. Viruses, 18:218, Feb 2026. URL: https://doi.org/10.3390/v18020218, doi:10.3390/v18020218. This article has 0 citations.

  15. (ayoubi2024recentadvancesin pages 1-2): L’Emir Wassim El Ayoubi, Omar Mahmoud, Johnny Zakhour, and Souha S. Kanj. Recent advances in the treatment of ebola disease: a brief overview. PLOS Pathogens, 20:e1012038, Mar 2024. URL: https://doi.org/10.1371/journal.ppat.1012038, doi:10.1371/journal.ppat.1012038. This article has 49 citations and is from a highest quality peer-reviewed journal.

  16. (srivastav2024compendiummanagementof pages 6-7): Yash Srivastav, Aniket Kumar, Jaya Singh, Aditya Srivastav, and Mohd. Imtiyaz Ahmad. Compendium: management of viral hemorrhagic fever (viral fever), involving its pathogenesis. Asian Journal of Research in Infectious Diseases, 15:17-25, Mar 2024. URL: https://doi.org/10.9734/ajrid/2024/v15i3334, doi:10.9734/ajrid/2024/v15i3334. This article has 4 citations.

  17. (zaratesanchez2024vasculardysfunctionin pages 29-30): Evelyn Zarate-Sanchez, Steven C George, Monica L Moya, and Claire Robertson. Vascular dysfunction in hemorrhagic viral fevers: opportunities for organotypic modeling. Biofabrication, 16:032008, Jun 2024. URL: https://doi.org/10.1088/1758-5090/ad4c0b, doi:10.1088/1758-5090/ad4c0b. This article has 11 citations and is from a peer-reviewed journal.