Crimean-Congo Hemorrhagic Fever

Infectious MONDO:0020501 Pathograph 41 Show in embeddings browser Viral hemorrhagic fever

Crimean-Congo hemorrhagic fever (CCHF) is the most widely distributed tick-borne viral hemorrhagic fever of humans, caused by the Crimean-Congo hemorrhagic fever orthonairovirus (CCHFV), a tri-segmented negative-sense RNA virus of the family Nairoviridae, order Bunyavirales. It is endemic across Africa, the Balkans, the Middle East and much of Asia, following the range of its Hyalomma tick vector and reservoir. Humans acquire it by tick bite, by contact with the blood and tissues of viraemic livestock at slaughter, and nosocomially through blood and body-fluid exposure - the combination of all three routes being distinctive among the viral hemorrhagic fevers. After a short incubation the illness runs through pre-haemorrhagic, haemorrhagic and convalescent phases; severe disease converges on the shared vascular and hemostatic lesion of the viral hemorrhagic fevers - endothelial activation, increased vascular permeability, consumptive coagulopathy, hepatocellular injury and thrombocytopenia - producing disseminated intravascular coagulation, bleeding, shock and multi-organ failure, with case-fatality rates reported above 30%.

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9
Pathophys.
29
Phenotypes
2
Gaps
41
Pathograph
3
Medical Actions
2
Models
1
Deep Research
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Discussions and Knowledge Gaps

2
Does ribavirin reduce mortality in Crimean-Congo hemorrhagic fever, and if so in which patients and at what time from onset?
KNOWLEDGE GAP OPEN cchf_ribavirin_efficacy_uncertain
Attached to
treatments#Ribavirin
Ribavirin is widely used and widely assumed to help, but the pooled evidence does not show a survival benefit and is dominated by observational studies with biased control selection. An adequately powered randomised placebo-controlled trial has not been done.
Show evidence (1 reference)
PMID:21482564 SUPPORT REVIEW SYNTHESIS Human Clinical
"ribavirin did not improve survival in CCHF (relative risk 1.06, 95% confidence interval 0.97-1.16)"
The meta-analysis found no survival benefit, which is the open question this gap records.
How faithfully do type I interferon-deficient mouse models, in which innate immunity must be ablated to produce lethal disease, represent CCHF pathogenesis in immunocompetent humans?
HUMAN MODEL MISMATCH OPEN cchf_interferon_deficient_model_fidelity
Attached to
pathophysiology#OTU-mediated interferon antagonism and high viremia
Wild-type mice resist lethal CCHFV infection, so the standard small-animal models require genetic or antibody-mediated ablation of type I interferon signalling. This confounds study of how intact innate immunity controls the virus and of how the virus antagonises it, which is the human-relevant question, and biases the models toward immune-evasion mechanisms.
Show evidence (1 reference)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Model Organism
"disease is typically associated with uncontrolled viral replication, inflammatory immune responses, liver pathology and eventually death"
Describes the interferon-deficient lethal mouse model whose translational fidelity is the open question.
⚙

Pathophysiology

9
CCHFV inoculation and LDLR-mediated entry into monocytes, macrophages and endothelium
Inoculated CCHFV uses its surface glycoproteins Gn and Gc for receptor binding, with the low-density lipoprotein receptor (LDLR) acting as a critical entry receptor, and enters the mononuclear phagocytes, dendritic cells, endothelial cells and hepatocytes that are the main cellular targets of infection.
monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology. macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology. dendritic cell CL:0000451 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves dendritic cell (CL:0000451). CL:0000451 is a cell type from the Cell Ontology. vascular endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vascular endothelial cell, annotated with endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
viral entry into host cell GO:0046718 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased viral entry into host cell, annotated with symbiont entry into host cell (GO:0046718). GO:0046718 is a biological process from the Gene Ontology.
Downstream
OTU-mediated interferon antagonism and high viremia Productive infection of the first target cells seeds systemic viral replication.
Show evidence (3 references)
PMID:38548922 SUPPORT In Vitro
"the Low Density Lipoprotein Receptor (LDLR) is a critical receptor for CCHFV cell entry, playing a vital role in CCHFV infection in cell culture and blood vessel organoids"
Identifies LDLR as a critical entry receptor in cell culture and blood-vessel organoids.
PMID:36918725 SUPPORT REVIEW SYNTHESIS Other
"The viral glycoproteins Gn and Gc are found on the virion surface and are responsible for receptor binding and viral entry"
Supports Gn/Gc as the glycoproteins mediating receptor binding and entry.
PMID:27110812 SUPPORT REVIEW SYNTHESIS Other
"The main cellular targets of infection are mononuclear phagocytes, endothelial cells, and hepatocytes"
Establishes the mononuclear phagocyte, endothelial and hepatocyte targets of infection.
OTU-mediated interferon antagonism and high viremia
The OTU (ovarian tumour-like protease) domain of the CCHFV L protein blocks RIG-I-dependent initiation of the type I interferon response through its deubiquitylating activity. Early failure of antiviral immunity permits high-titre viraemia, and the severity of CCHF correlates with the magnitude of viral load and dissemination. This is the CCHF-specific substitution at the module's shared high-viremia node.
mononuclear phagocyte CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves mononuclear phagocyte, annotated with macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
negative regulation of type I interferon production GO:0032480 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased negative regulation of type I interferon production (GO:0032480). GO:0032480 is a biological process from the Gene Ontology. viral genome replication GO:0019079 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased viral genome replication (GO:0019079). GO:0019079 is a biological process from the Gene Ontology.
Animal models
Type I interferon-deficient mouse Mouse recapitulates Lethal infection in interferon-deficient mice reproduces the uncontrolled high-titre replication that type I interferon normally restricts.
Cynomolgus macaque Cynomolgus macaque partially recapitulates Macaques develop CCHFV viraemia and, in severe cases, the hallmarks of human disease, in an immunocompetent primate host.
Downstream
Dysregulated proinflammatory cytokine response High viral burden presented to myeloid cells drives an inflammatory cytokine response.
Hepatocyte infection and hepatocellular necrosis Disseminated high-titre virus reaches and injures the liver, a major target organ.
Endothelial activation and vascular damage High-titre virus is presented to the vascular endothelium, the vascular arm of the syndrome.
Leukopenia High viraemia is accompanied by an early fall in the circulating leukocyte count.
Splenomegaly Infection of the reticuloendothelial system during high viraemia produces splenic enlargement.
Show evidence (2 references)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Other
"The OTU domain of the CCHFV L protein blocks RIG-I-dependent initiation of the type I interferon response via its deubiquitylating function."
Supports the OTU-mediated antagonism of type I interferon signalling.
PMID:27110812 SUPPORT REVIEW SYNTHESIS Human Clinical
"Severity of CCHF correlates with increased viral load and dissemination, low anti-CCHFV antibody titers, severity of thrombocytopenia, increased clotting times, hemorrhage"
Links high viral load and dissemination to disease severity.
Dysregulated proinflammatory cytokine response
Infected myeloid cells release a dysregulated proinflammatory cytokine response. In fatal CCHF, serum interleukin-6 and tumour necrosis factor alpha are significantly higher than in nonfatal disease and correlate positively with disseminated intravascular coagulation scores, implicating the cytokine response in the constitutional illness and in the hemostatic failure of severe disease.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
inflammatory response GO:0006954 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology.
Downstream
Endothelial activation and vascular damage Circulating proinflammatory cytokines act on the vascular endothelium.
Consumptive coagulopathy and disseminated intravascular coagulation The proinflammatory cytokine response tracks with the consumptive coagulopathy of fatal disease.
Fever The systemic inflammatory response produces fever at the onset of illness.
Headache Constitutional symptom of the systemic inflammatory response.
Myalgia Constitutional symptom of the systemic inflammatory response.
Nausea Constitutional symptom of the pre-haemorrhagic illness.
Vomiting Constitutional gastrointestinal symptom of the pre-haemorrhagic illness.
Abdominal pain Constitutional gastrointestinal symptom of the pre-haemorrhagic illness.
Diarrhea Constitutional gastrointestinal symptom of the pre-haemorrhagic illness.
Show evidence (2 references)
PMID:16518755 SUPPORT Human Clinical
"were significantly higher in patients with fatal CCHF than in patients with nonfatal CCHF"
Shows IL-6 and TNF-alpha are elevated in fatal relative to nonfatal CCHF.
PMID:16518755 SUPPORT Human Clinical
"Levels of IL-6 and TNF-alpha were positively correlated with DIC scores"
Links the proinflammatory cytokine response to the consumptive coagulopathy of severe disease.
Hepatocyte infection and hepatocellular necrosis
The liver is a major target organ. In mouse models hepatocytes are targets of CCHFV infection, and liver pathology is associated with activation of the tumour necrosis factor superfamily and apoptosis in infected and bystander cells. Hepatocellular injury is reflected clinically in markedly elevated serum transaminases and other markers of cell damage, and contributes to the loss of hepatic synthetic function.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
hepatocyte apoptotic process GO:0097284 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased hepatocyte apoptotic process (GO:0097284). GO:0097284 is a biological process from the Gene Ontology.
Animal models
Type I interferon-deficient mouse Mouse recapitulates Infected interferon-deficient mice develop the liver pathology seen in fatal human disease, with hepatocytes as targets of infection.
Downstream
Decreased hepatic coagulation factor production Hepatocellular injury reduces synthesis of coagulation factors made in the liver.
Elevated hepatic transaminases Hepatocellular damage releases aspartate and alanine aminotransferases into the serum.
Increased lactate dehydrogenase Tissue and hepatocellular injury raises serum lactate dehydrogenase.
Elevated creatine kinase Tissue injury raises serum creatine kinase in fatal disease.
Hyperbilirubinemia Hepatocellular injury raises serum bilirubin.
Hepatic failure Severe hepatocellular necrosis can progress to liver failure.
Hepatomegaly Hepatic infection and injury produce liver enlargement.
Show evidence (3 references)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Model Organism
"In mice, hepatocytes and endothelial cells are targets of CCHFV infection"
Supports hepatocytes as direct targets of CCHFV infection in a model organism.
PMID:36918725 SUPPORT REVIEW SYNTHESIS Model Organism
"activation of the tumour necrosis factor (TNF) superfamily and extensive apoptosis in infected livers suggest that liver pathology may occur through induction of apoptosis in infected and uninfected bystander cells"
Supports TNF-superfamily-driven apoptosis as a mechanism of the hepatocellular injury.
PMID:2749111 SUPPORT Human Clinical
"Patients with fatal infections had thrombocytopenia and markedly elevated levels of serum aspartate and alanine aminotransaminases, gamma-glutamyltransferase, lactic dehydrogenase, creatine kinase, bilirubin, creatinine, and urea."
Documents the serum markers of hepatocellular and tissue injury in fatal human cases.
Endothelial activation and vascular damage
CCHFV reaches and acts on the vascular endothelium, both by direct infection (endothelial cells are targets of infection in mouse models) and through the circulating proinflammatory cytokines. The activated and damaged endothelium stops behaving as an intact barrier, which is the vascular arm of the hemorrhagic fever syndrome.
vascular endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vascular endothelial cell, annotated with endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
endothelial cell activation GO:0042118 ↑ INCREASED 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.
Downstream
Increased vascular permeability Endothelial activation and damage disrupt barrier integrity and raise vascular permeability.
Show evidence (2 references)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Model Organism
"In mice, hepatocytes and endothelial cells are targets of CCHFV infection"
Supports endothelial cells as direct targets of CCHFV infection in a model organism.
PMID:27110812 SUPPORT REVIEW SYNTHESIS Other
"The main cellular targets of infection are mononuclear phagocytes, endothelial cells, and hepatocytes"
Confirms the endothelium as a target compartment of CCHFV infection.
Increased vascular permeability
The damaged microvascular endothelium no longer restrains plasma and solute movement, producing increased vascular permeability. This is the rate-limiting vascular lesion of the hemorrhagic fever syndrome; in severe CCHF plasma loss and circulatory failure contribute to shock and multi-organ injury.
vascular endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vascular endothelial cell, annotated with endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
regulation of vascular permeability GO:0043114 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased regulation of vascular permeability (GO:0043114). GO:0043114 is a biological process from the Gene Ontology.
Downstream
Shock Severe plasma leakage and circulatory failure contribute to shock in fatal disease.
Acute kidney injury Microvascular leak and hypoperfusion contribute to acute kidney injury in severe disease.
Show evidence (2 references)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Human Clinical
"with rapid progression to disseminated intravascular coagulation, overt bleeding, kidney, liver or pulmonary failure, and shock"
Places shock and kidney failure among the severe outcomes of the vascular and hemostatic lesion.
PMID:27110812 SUPPORT REVIEW SYNTHESIS Human Clinical
"Fatal outcome is typically the result of disseminated intravascular coagulopathy, shock, and/or multi-organ failure"
Supports shock and multi-organ failure as the mode of fatal outcome.
Consumptive coagulopathy and disseminated intravascular coagulation
Widespread activation of coagulation consumes clotting factors and platelets, producing disseminated intravascular coagulation. In fatal CCHF the prothrombin ratio, activated partial thromboplastin time, thrombin time and fibrin degradation products are grossly elevated, the laboratory signature of DIC, which drives the bleeding of the haemorrhagic phase.
blood coagulation GO:0007596 ⚠ ABNORMAL 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.
Downstream
Disseminated intravascular coagulation Consumptive activation of coagulation is detected clinically as DIC.
Prolonged prothrombin time Consumption of coagulation factors prolongs the prothrombin time.
Prolonged partial thromboplastin time Consumption of coagulation factors prolongs the activated partial thromboplastin time.
Epistaxis Coagulation failure produces mucosal bleeding including epistaxis.
Hematemesis Coagulation failure produces upper gastrointestinal bleeding.
Melena Coagulation failure produces gastrointestinal bleeding manifest as melena.
Gastrointestinal hemorrhage Coagulation failure produces gastrointestinal hemorrhage.
Hematuria Coagulation failure produces urinary tract bleeding.
Show evidence (2 references)
PMID:2749111 SUPPORT Human Clinical
"Values for prothrombin ratio, activated partial thromboplastin time, thrombin time, and fibrin degradation products were grossly elevated, findings that indicate the occurrence of disseminated intravascular coagulopathy."
Documents the laboratory signature of DIC in fatal human CCHF.
PMID:2749111 SUPPORT Human Clinical
"Petechial rash and hemorrhagic signs such as epistaxis, hematemesis, and melena supervened on days 3-6 of illness."
Documents the mucosal and gastrointestinal bleeding of the haemorrhagic phase.
Decreased hepatic coagulation factor production
Hepatocellular injury reduces the liver's synthesis of coagulation factors, a second route to bleeding separable from consumption. In fatal CCHF serum fibrinogen, total protein and albumin are depressed, consistent with impaired hepatic synthetic function.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
Downstream
Hypofibrinogenemia Reduced hepatic synthesis lowers circulating fibrinogen.
Show evidence (1 reference)
PMID:2749111 SUPPORT Human Clinical
"Total protein, albumin, fibrinogen, and hemoglobin levels were depressed."
Documents depressed fibrinogen and other hepatically synthesised proteins in fatal disease.
Platelet consumption and reduced platelet number
Platelets are consumed and lost, producing the thrombocytopenia that is a hallmark of severe CCHF and a marker of fatal outcome. Loss of platelets, with the coagulopathy, converts vascular fragility into overt bleeding such as petechiae and ecchymoses.
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 ⚠ ABNORMAL 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.
Downstream
Thrombocytopenia Platelet consumption and loss are detected clinically as thrombocytopenia.
Petechiae Thrombocytopenia with vascular fragility produces a petechial rash.
Ecchymosis Thrombocytopenia with vascular fragility produces extended ecchymoses.
Show evidence (2 references)
PMID:2749111 SUPPORT Human Clinical
"Patients with fatal infections had thrombocytopenia and markedly elevated levels of serum aspartate and alanine aminotransaminases, gamma-glutamyltransferase, lactic dehydrogenase, creatine kinase, bilirubin, creatinine, and urea."
Documents thrombocytopenia as a feature of fatal human CCHF.
PMID:36918725 SUPPORT REVIEW SYNTHESIS Human Clinical
"Haemorrhagic manifestations range from petechia to extended ecchymoses on mucous membranes and skin, a finding particularly pronounced with CCHF compared with other viral haemorrhagic fevers"
Documents petechiae and ecchymoses as prominent bleeding manifestations of CCHF.
⬡

Pathograph

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

29
Blood 12
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."
Documents the petechial rash of the haemorrhagic phase.
Ecchymosis HP:0031364 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ecchymosis (HP:0031364). HP:0031364 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Human Clinical
"Haemorrhagic manifestations range from petechia to extended ecchymoses on mucous membranes and skin, a finding particularly pronounced with CCHF compared with other viral haemorrhagic fevers"
Documents extended ecchymoses, a feature particularly pronounced in CCHF.
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."
Documents epistaxis in the haemorrhagic phase.
Hematemesis HP:0002248 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hematemesis (HP:0002248). HP:0002248 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."
Documents hematemesis in the haemorrhagic phase.
Melena HP:0002249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Melena (HP:0002249). HP:0002249 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."
Documents melena in the haemorrhagic phase.
Gastrointestinal hemorrhage HP:0002239 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastrointestinal hemorrhage (HP:0002239). HP:0002239 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Human Clinical
"Epistaxis, melena, haematemesis, haematuria and haemoptysis are common as is bleeding from injection sites"
Documents gastrointestinal and other bleeding common in the haemorrhagic phase.
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:36918725 SUPPORT REVIEW SYNTHESIS Human Clinical
"Haematology and blood chemistry commonly show thrombocytopenia, leukopenia and elevated levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase and creatine phosphokinase"
Documents thrombocytopenia as a common laboratory finding.
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:36918725 SUPPORT REVIEW SYNTHESIS Human Clinical
"Haematology and blood chemistry commonly show thrombocytopenia, leukopenia and elevated levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase and creatine phosphokinase"
Documents leukopenia as a common laboratory finding.
Disseminated intravascular coagulation HP:0005521 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Disseminated intravascular coagulation (HP:0005521). HP:0005521 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2749111 SUPPORT Human Clinical
"Values for prothrombin ratio, activated partial thromboplastin time, thrombin time, and fibrin degradation products were grossly elevated, findings that indicate the occurrence of disseminated intravascular coagulopathy."
Documents disseminated intravascular coagulation in fatal human CCHF.
Prolonged prothrombin time HP:0008151 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prolonged prothrombin time (HP:0008151). HP:0008151 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2749111 SUPPORT Human Clinical
"Values for prothrombin ratio, activated partial thromboplastin time, thrombin time, and fibrin degradation products were grossly elevated, findings that indicate the occurrence of disseminated intravascular coagulopathy."
Documents prolonged prothrombin time in fatal human CCHF.
Prolonged partial thromboplastin time HP:0003645 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prolonged partial thromboplastin time (HP:0003645). HP:0003645 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2749111 SUPPORT Human Clinical
"Values for prothrombin ratio, activated partial thromboplastin time, thrombin time, and fibrin degradation products were grossly elevated, findings that indicate the occurrence of disseminated intravascular coagulopathy."
Documents prolonged activated partial thromboplastin time in fatal human CCHF.
Hypofibrinogenemia HP:0011900 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypofibrinogenemia (HP:0011900). HP:0011900 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2749111 SUPPORT Human Clinical
"Total protein, albumin, fibrinogen, and hemoglobin levels were depressed."
Documents depressed fibrinogen in fatal human CCHF.
Cardiovascular 2
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:27110812 SUPPORT REVIEW SYNTHESIS Human Clinical
"Fatal outcome is typically the result of disseminated intravascular coagulopathy, shock, and/or multi-organ failure"
Documents shock as a component of fatal outcome.
Splenomegaly HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Human Clinical
"Hepatomegaly and splenomegaly may also be present"
Documents splenomegaly as a clinical finding.
Digestive 5
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
"patients had a sudden onset of disease with fever, nausea, severe headache, and myalgia"
Documents nausea in the pre-haemorrhagic illness.
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:27110812 SUPPORT REVIEW SYNTHESIS Human Clinical
"Following a brief incubation period (usually <7 days), CCHFV infection initially causes non-specific symptoms, including a rapid onset high-grade fever, fatigue, and myalgia, frequently accompanied by vomiting and diarrhea."
Documents vomiting among the early nonspecific symptoms.
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:27110812 SUPPORT REVIEW SYNTHESIS Human Clinical
"Following a brief incubation period (usually <7 days), CCHFV infection initially causes non-specific symptoms, including a rapid onset high-grade fever, fatigue, and myalgia, frequently accompanied by vomiting and diarrhea."
Documents diarrhea among the early nonspecific symptoms.
Hepatic failure HP:0001399 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatic failure (HP:0001399). HP:0001399 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Human Clinical
"with rapid progression to disseminated intravascular coagulation, overt bleeding, kidney, liver or pulmonary failure, and shock"
Documents liver failure among the severe-stage outcomes.
Hepatomegaly HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Human Clinical
"Hepatomegaly and splenomegaly may also be present"
Documents hepatomegaly as a clinical finding.
Genitourinary 2
Hematuria HP:0000790 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hematuria (HP:0000790). HP:0000790 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Human Clinical
"Epistaxis, melena, haematemesis, haematuria and haemoptysis are common as is bleeding from injection sites"
Documents haematuria among the common bleeding manifestations.
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:36918725 SUPPORT REVIEW SYNTHESIS Human Clinical
"with rapid progression to disseminated intravascular coagulation, overt bleeding, kidney, liver or pulmonary failure, and shock"
Documents kidney failure among the severe-stage outcomes.
Metabolism 5
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:2749111 SUPPORT Human Clinical
"patients had a sudden onset of disease with fever, nausea, severe headache, and myalgia"
Documents sudden-onset fever at the start of illness.
Elevated hepatic transaminases Elevated circulating hepatic transaminase concentration HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated hepatic transaminases, annotated with Elevated circulating hepatic transaminase concentration (HP:0002910). HP:0002910 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Human Clinical
"Haematology and blood chemistry commonly show thrombocytopenia, leukopenia and elevated levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase and creatine phosphokinase"
Documents elevated AST and ALT as a common finding.
Increased lactate dehydrogenase Increased circulating lactate dehydrogenase concentration HP:0025435 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased lactate dehydrogenase, annotated with Increased circulating lactate dehydrogenase concentration (HP:0025435). HP:0025435 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2749111 SUPPORT Human Clinical
"Patients with fatal infections had thrombocytopenia and markedly elevated levels of serum aspartate and alanine aminotransaminases, gamma-glutamyltransferase, lactic dehydrogenase, creatine kinase, bilirubin, creatinine, and urea."
Documents elevated lactic dehydrogenase in fatal human cases.
Elevated creatine kinase Elevated circulating creatine kinase activity HP:0003236 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated creatine kinase, annotated with Elevated circulating creatine kinase activity (HP:0003236). HP:0003236 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2749111 SUPPORT Human Clinical
"Patients with fatal infections had thrombocytopenia and markedly elevated levels of serum aspartate and alanine aminotransaminases, gamma-glutamyltransferase, lactic dehydrogenase, creatine kinase, bilirubin, creatinine, and urea."
Documents elevated creatine kinase in fatal human cases.
Hyperbilirubinemia HP:0002904 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperbilirubinemia (HP:0002904). HP:0002904 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2749111 SUPPORT Human Clinical
"Patients with fatal infections had thrombocytopenia and markedly elevated levels of serum aspartate and alanine aminotransaminases, gamma-glutamyltransferase, lactic dehydrogenase, creatine kinase, bilirubin, creatinine, and urea."
Documents elevated bilirubin in fatal human cases.
Nervous System 1
Headache HP:0002315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe headache, annotated with Headache (HP:0002315). HP:0002315 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:2749111 SUPPORT Human Clinical
"patients had a sudden onset of disease with fever, nausea, severe headache, and myalgia"
Documents severe headache in the pre-haemorrhagic illness.
Constitutional 2
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:2749111 SUPPORT Human Clinical
"patients had a sudden onset of disease with fever, nausea, severe headache, and myalgia"
Documents myalgia in the pre-haemorrhagic illness.
Abdominal pain HP:0002027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abdominal pain (HP:0002027). HP:0002027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Human Clinical
"This may be accompanied by sore throat, abdominal pain, nausea, vomiting and diarrhoea"
Documents abdominal pain in the pre-haemorrhagic stage.
💊

Medical Actions

3
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
Platform: Other
Supportive care is the mainstay of management - fluid and electrolyte management, blood-product replacement for bleeding and DIC, and organ support - because there is no licensed vaccine or proven specific antiviral for CCHF.
Show evidence (1 reference)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Other
"There are currently no approved vaccines or therapeutics for CCHF."
Supports supportive care as the mainstay in the absence of approved specific therapy.
Ribavirin
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.
Platform: Small molecule
Ribavirin, an antiviral nucleoside analogue, is widely used for CCHF, but its efficacy is unproven: a systematic review and meta-analysis found no survival benefit and concluded that the available data are inadequate to support a claim of efficacy.
Show evidence (1 reference)
PMID:21482564 SUPPORT REVIEW SYNTHESIS Human Clinical
"the available data in the literature are inadequate to support a claim of efficacy of ribavirin in CCHF"
Supports the statement that ribavirin efficacy in CCHF is unproven.
Favipiravir
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: favipiravir CHEBI:134722 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses favipiravir (CHEBI:134722). CHEBI:134722 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Favipiravir, a nucleoside-analogue antiviral, is an experimental candidate: it protected immunocompetent mice from lethal CCHFV infection even when treatment was delayed, but it is not an approved CCHF therapy and has not been shown effective in humans.
Show evidence (1 reference)
PMID:37611878 SUPPORT Model Organism
"favipiravir and ribavirin protected animals from clinical disease and death even when treatment was delayed"
Demonstrates favipiravir protection in an immunocompetent mouse model of lethal CCHFV infection.
🌍

Environmental Factors

1
Tick bite or contact with viraemic livestock blood
Tick bite or contact with viraemic livestock blood ECTO:3000001 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is Tick bite or contact with viraemic livestock blood, annotated with exposure to virus (ECTO:3000001). ECTO:3000001 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
ECTO was searched for a CCHFV- or tick-bite-specific exposure term: "l~tick" returns only ECTO:3000183 exposure to Tick-borne encephalitis virus, and "l~bite" returns no arthropod-bite exposure class. The broad class ECTO:3000001 "exposure to virus" is the bound term (the same class Ebola_Virus_Disease_EVD binds for its animal-reservoir exposure); the specific route is carried in preferred_term.
The environmental exposure that initiates infection: the bite of an infected Hyalomma tick, or direct contact with the blood and tissues of a viraemic animal at slaughter. It is bound to the broad ECTO class "exposure to virus" because ECTO has no CCHFV- or tick-bite-specific exposure term.
Show evidence (1 reference)
PMID:23906741 SUPPORT REVIEW SYNTHESIS Other
"Hyalomma ticks are the principal source of human infection"
Supports tick exposure as the principal source of human infection.
Mechanism Target:
TRIGGERS CCHFV inoculation and LDLR-mediated entry into monocytes, macrophages and endothelium — Tick bite or contact with viraemic livestock blood is the route by which CCHFV is inoculated into the host and the infection begins.
Show evidence (1 reference)
PMID:23906741 SUPPORT REVIEW SYNTHESIS Other
"CCHF occurs most frequently among agricultural workers following the bite of an infected tick"
Establishes the tick bite as the route by which the inoculating exposure occurs.
🔬

Diagnosis

2
Molecular detection of CCHFV RNA
Quantitative reverse transcription PCR is the method of choice for rapid detection of CCHFV during the acute, viraemic phase. Antigen detection and virus isolation are alternatives, the latter requiring high-containment (BSL-4) facilities.
Show evidence (1 reference)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Other
"The method of choice for rapid CCHFV detection is quantitative reverse transcription PCR"
Establishes qRT-PCR as the first-line acute-phase diagnostic.
Serological detection of anti-CCHFV antibody
IgM-capture and IgG enzyme-linked immunosorbent assays detect the antibody response and are used for diagnosis, particularly later in illness when viraemia is falling; an IgM-capture ELISA was one of the two assays used to confirm cases in a national reference laboratory.
Show evidence (1 reference)
PMID:39558265 SUPPORT Human Clinical
"tested for CCHF virus infection by the use of RT-PCR and IgM Capture Enzyme-Linked Immunosorbent Assay (MAC-ELISA)"
Documents IgM-capture ELISA serology as a confirmatory diagnostic assay alongside RT-PCR.
📈

Progression

4
Incubation
The incubation period is short and depends on the route of exposure: about 1-3 days after a tick bite and 5-6 days after exposure to blood, tissue and secretions, up to about 9 days overall.
Show evidence (2 references)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Human Clinical
"The incubation period is usually less than a week (range 1-9 days) and depends on the route of exposure and virus dose. It seems shortest following a tick bite (usually 1-3 days) and slightly longer following exposure to blood, tissue and secretions of infected livestock and humans (5-6 days)."
Supports the short incubation that is shortest after tick bite and longer after blood or tissue exposure.
PMID:2749111 SUPPORT Human Clinical
"Following an incubation period of 2-9 days after exposure to infection"
Gives the observed incubation range in a human clinical series.
Pre-hemorrhagic
An abrupt febrile illness lasting about 2-4 days with nonspecific fever, headache, myalgia and gastrointestinal symptoms before any bleeding.
Show evidence (1 reference)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Human Clinical
"The pre-haemorrhagic stage lasts about 2-4 days on average (range 1-7 days) and begins abruptly with rather nonspecific symptoms"
Establishes the duration and abrupt nonspecific onset of the pre-haemorrhagic stage.
Hemorrhagic
A usually short (about 2-3 days) but sometimes prolonged stage of bleeding, liver injury, coagulopathy and, in severe cases, disseminated intravascular coagulation, shock and multi-organ failure; death, when it occurs, is usually in the second week.
Show evidence (2 references)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Human Clinical
"The haemorrhagic stage is usually short (approximately 2-3 days) but can be prolonged up to 2 weeks"
Establishes the duration of the haemorrhagic stage.
PMID:2749111 SUPPORT Human Clinical
"Deaths occurred on days 5-14 of illness."
Gives the observed timing of death in a human clinical series.
Convalescence
In survivors, recovery begins around 9-10 days after onset (range about 9-20 days) with a return of laboratory parameters toward normal and the development of anti-CCHFV immunity.
Show evidence (1 reference)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Human Clinical
"In survivors, convalescence generally begins around 9-10 days post-onset of illness (range 9-20 days) and is associated with a return to normal for laboratory parameters"
Establishes the convalescent phase and its timing in survivors.
🦠

Infectious Agent

1
Crimean-Congo hemorrhagic fever orthonairovirus (CCHFV)
The etiological agent is Crimean-Congo hemorrhagic fever orthonairovirus (CCHFV), an enveloped, tri-segmented, negative-sense RNA virus of the genus Orthonairovirus, family Nairoviridae, order Bunyavirales. Its surface glycoproteins Gn and Gc mediate receptor binding and entry, and the OTU domain of its L protein antagonises the host type I interferon response.
Crimean-Congo hemorrhagic fever orthonairovirus NCBITaxon:3052518 NCBI Taxonomy (NCBITaxon)
Show evidence (2 references)
PMID:39558265 SUPPORT BACKGROUND Other
"a tick-borne RNA virus belonging to the genus Orthonairovirus, family Nairoviridae, in the Bunyavirales order"
Places CCHFV taxonomically in the genus Orthonairovirus, family Nairoviridae, order Bunyavirales.
PMID:36918725 SUPPORT REVIEW SYNTHESIS Other
"CCHFV is an enveloped negative-sense RNA virus belonging to the Orthonairovirus genus in the Nairoviridae family of the Bunyavirales order"
Confirms the virus genome type and taxonomic classification.
↔️

Transmission

3
Tick bite by Hyalomma ticks
The commonest route of human infection is the bite of an infected Hyalomma tick, with agricultural and outdoor workers at highest risk. Hyalomma ticks are the principal source of human infection.
Show evidence (2 references)
PMID:23906741 SUPPORT REVIEW SYNTHESIS Other
"Hyalomma ticks are the principal source of human infection"
Identifies the tick bite by Hyalomma as the principal route of human infection.
PMID:23906741 SUPPORT REVIEW SYNTHESIS Other
"CCHF occurs most frequently among agricultural workers following the bite of an infected tick"
Ties tick-bite transmission to the agricultural occupational setting where it occurs most often.
Contact with blood and tissues of viraemic livestock
Humans are also infected by direct contact with the blood and tissues of infected livestock, chiefly during slaughter and butchering; livestock are viraemic but show no apparent illness. Slaughterhouse workers, shepherds, butchers and veterinarians are at risk.
Show evidence (1 reference)
PMID:23906741 SUPPORT REVIEW SYNTHESIS Other
"slaughterhouse workers exposed to the blood and tissues of infected livestock"
Documents contact with viraemic livestock blood and tissue as a route of infection.
Nosocomial and person-to-person blood and body-fluid exposure
CCHFV spreads to medical personnel and family caregivers through contact with the blood and body fluids of infected patients. In a national series of confirmed healthcare-worker infections the predominant nosocomial routes were percutaneous needle-stick, mucosal blood splash, and skin contact with blood.
Show evidence (2 references)
PMID:23906741 SUPPORT REVIEW SYNTHESIS Other
"medical personnel through contact with the body fluids of infected patients"
Establishes person-to-person transmission to medical personnel via body fluids.
PMID:39558265 SUPPORT Human Clinical
"Percutaneous exposure (needle stick) (three cases), mucosal exposure (blood splash in to face) (three cases) and skin contact with blood (three cases) constituted the most prevalent routes of transmission."
Reconstructs the occupational blood-exposure routes from the national healthcare-worker series.
⚖️

Clinical Burden

High
CCHF is the most important tick-borne viral disease of humans and carries case-fatality rates reported above 30% in some regions, with no licensed vaccine or specific antiviral and a propensity for high-mortality nosocomial outbreaks.
Show evidence (2 references)
PMID:23906741 SUPPORT REVIEW SYNTHESIS Other
"is the most important tick-borne viral disease of humans, causing sporadic cases or outbreaks of severe illness across a huge geographic area"
Establishes CCHF as the leading tick-borne viral disease of humans with a wide range.
PMID:36918725 SUPPORT REVIEW SYNTHESIS Human Clinical
"Case fatality rates vary but can be higher than 30% in some regions."
Quantifies the high case-fatality rate underlying the burden level.
🐁

Animal Models

2
Type I interferon-deficient mouse
Wild-type adult mice are resistant to lethal CCHFV infection; mice deficient in the type I interferon receptor or in STAT1 develop lethal disease with uncontrolled viral replication, inflammatory immune responses and liver pathology, recapitulating correlates of fatal human disease.
Species
Mouse
Genotype
Type I interferon receptor (Ifnar) or STAT1 deficient
Publication
PMID:36918725
Pathograph links
OTU-mediated interferon antagonism and high viremia recapitulates fidelity: moderate observes: organism Lethal infection in interferon-deficient mice reproduces the uncontrolled high-titre replication that type I interferon normally restricts.
Limitations: Disease requires genetic or antibody-mediated ablation of type I interferon signalling; immunocompetent wild-type mice resist lethal infection, so the model cannot address how intact innate immunity controls CCHFV and biases toward immune-evasion questions.
Show evidence (1 reference)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Model Organism
"disease is typically associated with uncontrolled viral replication, inflammatory immune responses, liver pathology and eventually death"
Describes the lethal phenotype of interferon-deficient mice infected with CCHFV.
Hepatocyte infection and hepatocellular necrosis recapitulates fidelity: moderate observes: organism Infected interferon-deficient mice develop the liver pathology seen in fatal human disease, with hepatocytes as targets of infection.
Limitations: Liver pathology occurs on an interferon-ablated background rather than in an immunocompetent host, so its relationship to the human lesion is by correlation of outcome rather than by matched immune context.
Show evidence (1 reference)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Model Organism
"In mice, hepatocytes and endothelial cells are targets of CCHFV infection"
Supports hepatocyte infection and liver injury in the mouse model.
Cynomolgus macaque
Cynomolgus macaques infected with CCHFV recapitulate many aspects of human disease, including a varied outcome; severe disease shows liver pathology, inflammatory cytokines, high viral loads and coagulation disorders, but many animals develop only mild-to-moderate disease.
Species
Cynomolgus macaque
Publication
PMID:36918725
Pathograph links
OTU-mediated interferon antagonism and high viremia partially recapitulates fidelity: moderate observes: organism Macaques develop CCHFV viraemia and, in severe cases, the hallmarks of human disease, in an immunocompetent primate host.
Limitations: Disease outcome is variable and often only mild-to-moderate, with many animals not reaching severe disease, so the model reproduces the human severe course inconsistently.
Show evidence (2 references)
PMID:36918725 SUPPORT REVIEW SYNTHESIS Model Organism
"Cynomolgus macaques infected with CCHFV recapitulate many aspects of human CCHFV, including varied disease outcome."
Supports the macaque model and its variable disease outcome.
+ 1 more reference
{ }

Source YAML

click to show 
name: Crimean-Congo Hemorrhagic Fever
creation_date: "2026-10-12T04:05:10Z"
category: Infectious
description: >-
  Crimean-Congo hemorrhagic fever (CCHF) is the most widely distributed
  tick-borne viral hemorrhagic fever of humans, caused by the Crimean-Congo
  hemorrhagic fever orthonairovirus (CCHFV), a tri-segmented negative-sense RNA
  virus of the family Nairoviridae, order Bunyavirales. It is endemic across
  Africa, the Balkans, the Middle East and much of Asia, following the range of
  its Hyalomma tick vector and reservoir. Humans acquire it by tick bite, by
  contact with the blood and tissues of viraemic livestock at slaughter, and
  nosocomially through blood and body-fluid exposure - the combination of all
  three routes being distinctive among the viral hemorrhagic fevers. After a
  short incubation the illness runs through pre-haemorrhagic, haemorrhagic and
  convalescent phases; severe disease converges on the shared vascular and
  hemostatic lesion of the viral hemorrhagic fevers - endothelial activation,
  increased vascular permeability, consumptive coagulopathy, hepatocellular
  injury and thrombocytopenia - producing disseminated intravascular
  coagulation, bleeding, shock and multi-organ failure, with case-fatality
  rates reported above 30%.
disease_term:
  preferred_term: Crimean-Congo hemorrhagic fever
  term:
    id: MONDO:0020501
    label: Crimean-Congo hemorrhagic fever
parents:
- Viral hemorrhagic fever
synonyms:
- CCHF
- Crimean-Congo haemorrhagic fever
- Congo fever
- Crimean hemorrhagic fever
clinical_burden:
  burden_level: HIGH
  rationale: >-
    CCHF is the most important tick-borne viral disease of humans and carries
    case-fatality rates reported above 30% in some regions, with no licensed
    vaccine or specific antiviral and a propensity for high-mortality
    nosocomial outbreaks.
  evidence:
  - reference: PMID:23906741
    reference_title: "Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      is the most important tick-borne viral disease of humans, causing sporadic cases or outbreaks of severe illness across a huge geographic area
    explanation: Establishes CCHF as the leading tick-borne viral disease of humans with a wide range.
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Case fatality rates vary but can be higher than 30% in some regions.
    explanation: Quantifies the high case-fatality rate underlying the burden level.
infectious_agent:
- name: Crimean-Congo hemorrhagic fever orthonairovirus (CCHFV)
  description: >-
    The etiological agent is Crimean-Congo hemorrhagic fever orthonairovirus
    (CCHFV), an enveloped, tri-segmented, negative-sense RNA virus of the genus
    Orthonairovirus, family Nairoviridae, order Bunyavirales. Its surface
    glycoproteins Gn and Gc mediate receptor binding and entry, and the OTU
    domain of its L protein antagonises the host type I interferon response.
  infectious_agent_term:
    preferred_term: Crimean-Congo hemorrhagic fever orthonairovirus
    term:
      id: NCBITaxon:3052518
      label: Orthonairovirus haemorrhagiae
  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: OTHER
    quote_role: BACKGROUND
    snippet: >-
      a tick-borne RNA virus belonging to the genus Orthonairovirus, family Nairoviridae, in the Bunyavirales order
    explanation: Places CCHFV taxonomically in the genus Orthonairovirus, family Nairoviridae, order Bunyavirales.
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      CCHFV is an enveloped negative-sense RNA virus belonging to the Orthonairovirus genus in the Nairoviridae family of the Bunyavirales order
    explanation: Confirms the virus genome type and taxonomic classification.
transmission:
- name: Tick bite by Hyalomma ticks
  description: >-
    The commonest route of human infection is the bite of an infected Hyalomma
    tick, with agricultural and outdoor workers at highest risk. Hyalomma ticks
    are the principal source of human infection.
  evidence:
  - reference: PMID:23906741
    reference_title: "Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Hyalomma ticks are the principal source of human infection
    explanation: Identifies the tick bite by Hyalomma as the principal route of human infection.
  - reference: PMID:23906741
    reference_title: "Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      CCHF occurs most frequently among agricultural workers following the bite of an infected tick
    explanation: Ties tick-bite transmission to the agricultural occupational setting where it occurs most often.
- name: Contact with blood and tissues of viraemic livestock
  description: >-
    Humans are also infected by direct contact with the blood and tissues of
    infected livestock, chiefly during slaughter and butchering; livestock are
    viraemic but show no apparent illness. Slaughterhouse workers, shepherds,
    butchers and veterinarians are at risk.
  evidence:
  - reference: PMID:23906741
    reference_title: "Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      slaughterhouse workers exposed to the blood and tissues of infected livestock
    explanation: Documents contact with viraemic livestock blood and tissue as a route of infection.
- name: Nosocomial and person-to-person blood and body-fluid exposure
  description: >-
    CCHFV spreads to medical personnel and family caregivers through contact
    with the blood and body fluids of infected patients. In a national series
    of confirmed healthcare-worker infections the predominant nosocomial routes
    were percutaneous needle-stick, mucosal blood splash, and skin contact with
    blood.
  evidence:
  - reference: PMID:23906741
    reference_title: "Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      medical personnel through contact with the body fluids of infected patients
    explanation: Establishes person-to-person transmission to medical personnel via body fluids.
  - 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: >-
      Percutaneous exposure (needle stick) (three cases), mucosal exposure (blood splash in to face) (three cases) and skin contact with blood (three cases) constituted the most prevalent routes of transmission.
    explanation: Reconstructs the occupational blood-exposure routes from the national healthcare-worker series.
agent_life_cycle:
  description: >-
    CCHFV is maintained in an enzootic cycle between Hyalomma ticks, the
    principal vector and reservoir, and a range of wild and domestic
    vertebrates that develop viraemia without apparent illness and serve as
    amplifying hosts (livestock such as cattle, sheep and goats, and wild hosts
    including hares, small rodents and ostriches). The virus is passed in both
    vertical and horizontal transmission cycles within the tick population, and
    amplifying hosts spread virus from infected to uninfected ticks by
    co-feeding or by supporting a viraemic blood meal. Humans are incidental,
    dead-end hosts that do not maintain the cycle.
  hosts:
  - preferred_term: Hyalomma tick (principal vector and reservoir)
    role: vector and reservoir host
    term:
      id: NCBITaxon:34625
      label: Hyalomma
  - preferred_term: Human (incidental dead-end host)
    role: incidental (dead-end) host
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  vectors:
  - Hyalomma spp. ticks (principal vector and reservoir)
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Studies have identified ticks of the Hyalomma genus to be the principal vector and reservoir of CCHFV
    explanation: Identifies Hyalomma ticks as the principal vector and reservoir of the virus.
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      These animal species serve as important amplifying hosts for CCHFV, enabling CCHFV to spread from infected ticks to uninfected ticks through either co-feeding or feeding on a viraemic animal
    explanation: Establishes vertebrate amplifying hosts and the tick-to-tick spread they enable.
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Given that humans are incidental hosts for CCHFV
    explanation: Supports humans as incidental, dead-end hosts.
  - reference: PMID:23906741
    reference_title: "Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      CCHFV is maintained in vertical and horizontal transmission cycles involving ixodid ticks and a variety of wild and domestic vertebrates, which do not show signs of illness.
    explanation: Supports the vertical and horizontal tick maintenance cycle and the asymptomatic vertebrate hosts.
environmental:
- name: Tick bite or contact with viraemic livestock blood
  description: >-
    The environmental exposure that initiates infection: the bite of an
    infected Hyalomma tick, or direct contact with the blood and tissues of a
    viraemic animal at slaughter. It is bound to the broad ECTO class
    "exposure to virus" because ECTO has no CCHFV- or tick-bite-specific
    exposure term.
  exposure_term:
    preferred_term: Tick bite or contact with viraemic livestock blood
    term:
      id: ECTO:3000001
      label: exposure to virus
  influences_mechanisms:
  - target: CCHFV inoculation and LDLR-mediated entry into monocytes, macrophages and endothelium
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Tick bite or contact with viraemic livestock blood is the route by which
      CCHFV is inoculated into the host and the infection begins.
    evidence:
    - reference: PMID:23906741
      reference_title: "Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        CCHF occurs most frequently among agricultural workers following the bite of an infected tick
      explanation: Establishes the tick bite as the route by which the inoculating exposure occurs.
  notes: >-
    ECTO was searched for a CCHFV- or tick-bite-specific exposure term: "l~tick"
    returns only ECTO:3000183 exposure to Tick-borne encephalitis virus, and
    "l~bite" returns no arthropod-bite exposure class. The broad class
    ECTO:3000001 "exposure to virus" is the bound term (the same class
    Ebola_Virus_Disease_EVD binds for its animal-reservoir exposure); the
    specific route is carried in preferred_term.
  evidence:
  - reference: PMID:23906741
    reference_title: "Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Hyalomma ticks are the principal source of human infection
    explanation: Supports tick exposure as the principal source of human infection.
pathophysiology:
- name: CCHFV inoculation and LDLR-mediated entry into monocytes, macrophages and endothelium
  biological_scale: MOLECULAR
  description: >-
    Inoculated CCHFV uses its surface glycoproteins Gn and Gc for receptor
    binding, with the low-density lipoprotein receptor (LDLR) acting as a
    critical entry receptor, and enters the mononuclear phagocytes, dendritic
    cells, endothelial cells and hepatocytes that are the main cellular targets
    of infection.
  downstream:
  - target: OTU-mediated interferon antagonism and high viremia
    description: Productive infection of the first target cells seeds systemic viral replication.
    causal_link_type: DIRECT
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  - preferred_term: vascular endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: viral entry into host cell
    modifier: INCREASED
    term:
      id: GO:0046718
      label: symbiont entry into host cell
  evidence:
  - reference: PMID:38548922
    reference_title: Crimean-Congo haemorrhagic fever virus uses LDLR to bind and enter host cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the Low Density Lipoprotein Receptor (LDLR) is a critical receptor for CCHFV cell entry, playing a vital role in CCHFV infection in cell culture and blood vessel organoids
    explanation: Identifies LDLR as a critical entry receptor in cell culture and blood-vessel organoids.
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The viral glycoproteins Gn and Gc are found on the virion surface and are responsible for receptor binding and viral entry
    explanation: Supports Gn/Gc as the glycoproteins mediating receptor binding and entry.
  - reference: PMID:27110812
    reference_title: Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The main cellular targets of infection are mononuclear phagocytes, endothelial cells, and hepatocytes
    explanation: Establishes the mononuclear phagocyte, endothelial and hepatocyte targets of infection.
- name: OTU-mediated interferon antagonism and high viremia
  conforms_to: "viral_hemorrhagic_fever_syndrome#High Viremia and Vascular Target Infection"
  biological_scale: ORGANISM
  description: >-
    The OTU (ovarian tumour-like protease) domain of the CCHFV L protein blocks
    RIG-I-dependent initiation of the type I interferon response through its
    deubiquitylating activity. Early failure of antiviral immunity permits
    high-titre viraemia, and the severity of CCHF correlates with the magnitude
    of viral load and dissemination. This is the CCHF-specific substitution at
    the module's shared high-viremia node.
  downstream:
  - target: Dysregulated proinflammatory cytokine response
    description: High viral burden presented to myeloid cells drives an inflammatory cytokine response.
    causal_link_type: DIRECT
  - target: Hepatocyte infection and hepatocellular necrosis
    description: Disseminated high-titre virus reaches and injures the liver, a major target organ.
    causal_link_type: DIRECT
  - target: Endothelial activation and vascular damage
    description: High-titre virus is presented to the vascular endothelium, the vascular arm of the syndrome.
    causal_link_type: DIRECT
  - target: Leukopenia
    description: High viraemia is accompanied by an early fall in the circulating leukocyte count.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Splenomegaly
    description: Infection of the reticuloendothelial system during high viraemia produces splenic enlargement.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  biological_processes:
  - preferred_term: negative regulation of type I interferon production
    modifier: INCREASED
    term:
      id: GO:0032480
      label: negative regulation of type I interferon production
  - preferred_term: viral genome replication
    modifier: INCREASED
    term:
      id: GO:0019079
      label: viral genome replication
  cell_types:
  - preferred_term: mononuclear phagocyte
    term:
      id: CL:0000235
      label: macrophage
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The OTU domain of the CCHFV L protein blocks RIG-I-dependent initiation of the type I interferon response via its deubiquitylating function.
    explanation: Supports the OTU-mediated antagonism of type I interferon signalling.
  - reference: PMID:27110812
    reference_title: Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Severity of CCHF correlates with increased viral load and dissemination, low anti-CCHFV antibody titers, severity of thrombocytopenia, increased clotting times, hemorrhage
    explanation: Links high viral load and dissemination to disease severity.
- name: Dysregulated proinflammatory cytokine response
  biological_scale: CELLULAR
  description: >-
    Infected myeloid cells release a dysregulated proinflammatory cytokine
    response. In fatal CCHF, serum interleukin-6 and tumour necrosis factor
    alpha are significantly higher than in nonfatal disease and correlate
    positively with disseminated intravascular coagulation scores, implicating
    the cytokine response in the constitutional illness and in the hemostatic
    failure of severe disease.
  downstream:
  - target: Endothelial activation and vascular damage
    description: Circulating proinflammatory cytokines act on the vascular endothelium.
    causal_link_type: DIRECT
  - target: Consumptive coagulopathy and disseminated intravascular coagulation
    description: The proinflammatory cytokine response tracks with the consumptive coagulopathy of fatal disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Fever
    description: The systemic inflammatory response produces fever at the onset of illness.
    causal_link_type: DIRECT
  - target: Headache
    description: Constitutional symptom of the systemic inflammatory response.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Myalgia
    description: Constitutional symptom of the systemic inflammatory response.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Nausea
    description: Constitutional symptom of the pre-haemorrhagic illness.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Vomiting
    description: Constitutional gastrointestinal symptom of the pre-haemorrhagic illness.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abdominal pain
    description: Constitutional gastrointestinal symptom of the pre-haemorrhagic illness.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Diarrhea
    description: Constitutional gastrointestinal symptom of the pre-haemorrhagic illness.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  evidence:
  - reference: PMID:16518755
    reference_title: "Evaluation of serum levels of interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha in patients with Crimean-Congo hemorrhagic fever."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      were significantly higher in patients with fatal CCHF than in patients with nonfatal CCHF
    explanation: Shows IL-6 and TNF-alpha are elevated in fatal relative to nonfatal CCHF.
  - reference: PMID:16518755
    reference_title: "Evaluation of serum levels of interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha in patients with Crimean-Congo hemorrhagic fever."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Levels of IL-6 and TNF-alpha were positively correlated with DIC scores
    explanation: Links the proinflammatory cytokine response to the consumptive coagulopathy of severe disease.
- name: Hepatocyte infection and hepatocellular necrosis
  biological_scale: CELLULAR
  description: >-
    The liver is a major target organ. In mouse models hepatocytes are targets
    of CCHFV infection, and liver pathology is associated with activation of the
    tumour necrosis factor superfamily and apoptosis in infected and bystander
    cells. Hepatocellular injury is reflected clinically in markedly elevated
    serum transaminases and other markers of cell damage, and contributes to
    the loss of hepatic synthetic function.
  downstream:
  - target: Decreased hepatic coagulation factor production
    description: Hepatocellular injury reduces synthesis of coagulation factors made in the liver.
    causal_link_type: DIRECT
  - target: Elevated hepatic transaminases
    description: Hepatocellular damage releases aspartate and alanine aminotransferases into the serum.
    causal_link_type: DIRECT
  - target: Increased lactate dehydrogenase
    description: Tissue and hepatocellular injury raises serum lactate dehydrogenase.
    causal_link_type: DIRECT
  - target: Elevated creatine kinase
    description: Tissue injury raises serum creatine kinase in fatal disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hyperbilirubinemia
    description: Hepatocellular injury raises serum bilirubin.
    causal_link_type: DIRECT
  - target: Hepatic failure
    description: Severe hepatocellular necrosis can progress to liver failure.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Hepatomegaly
    description: Hepatic infection and injury produce liver enlargement.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: hepatocyte apoptotic process
    modifier: INCREASED
    term:
      id: GO:0097284
      label: hepatocyte apoptotic process
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In mice, hepatocytes and endothelial cells are targets of CCHFV infection
    explanation: Supports hepatocytes as direct targets of CCHFV infection in a model organism.
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      activation of the tumour necrosis factor (TNF) superfamily and extensive apoptosis in infected livers suggest that liver pathology may occur through induction of apoptosis in infected and uninfected bystander cells
    explanation: Supports TNF-superfamily-driven apoptosis as a mechanism of the hepatocellular injury.
  - reference: PMID:2749111
    reference_title: The clinical pathology of Crimean-Congo hemorrhagic fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with fatal infections had thrombocytopenia and markedly elevated levels of serum aspartate and alanine aminotransaminases, gamma-glutamyltransferase, lactic dehydrogenase, creatine kinase, bilirubin, creatinine, and urea.
    explanation: Documents the serum markers of hepatocellular and tissue injury in fatal human cases.
- name: Endothelial activation and vascular damage
  conforms_to: "viral_hemorrhagic_fever_syndrome#Endothelial Activation and Damage"
  biological_scale: CELLULAR
  description: >-
    CCHFV reaches and acts on the vascular endothelium, both by direct infection
    (endothelial cells are targets of infection in mouse models) and through the
    circulating proinflammatory cytokines. The activated and damaged endothelium
    stops behaving as an intact barrier, which is the vascular arm of the
    hemorrhagic fever syndrome.
  downstream:
  - target: Increased vascular permeability
    description: Endothelial activation and damage disrupt barrier integrity and raise vascular permeability.
    causal_link_type: DIRECT
  cell_types:
  - preferred_term: vascular 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:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In mice, hepatocytes and endothelial cells are targets of CCHFV infection
    explanation: Supports endothelial cells as direct targets of CCHFV infection in a model organism.
  - reference: PMID:27110812
    reference_title: Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The main cellular targets of infection are mononuclear phagocytes, endothelial cells, and hepatocytes
    explanation: Confirms the endothelium as a target compartment of CCHFV infection.
- name: Increased vascular permeability
  conforms_to: "viral_hemorrhagic_fever_syndrome#Increased Vascular Permeability"
  biological_scale: TISSUE
  description: >-
    The damaged microvascular endothelium no longer restrains plasma and solute
    movement, producing increased vascular permeability. This is the
    rate-limiting vascular lesion of the hemorrhagic fever syndrome; in severe
    CCHF plasma loss and circulatory failure contribute to shock and
    multi-organ injury.
  downstream:
  - target: Shock
    description: Severe plasma leakage and circulatory failure contribute to shock in fatal disease.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - intravascular volume depletion and hypotension
  - target: Acute kidney injury
    description: Microvascular leak and hypoperfusion contribute to acute kidney injury in severe disease.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  cell_types:
  - preferred_term: vascular endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: regulation of vascular permeability
    modifier: INCREASED
    term:
      id: GO:0043114
      label: regulation of vascular permeability
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      with rapid progression to disseminated intravascular coagulation, overt bleeding, kidney, liver or pulmonary failure, and shock
    explanation: Places shock and kidney failure among the severe outcomes of the vascular and hemostatic lesion.
  - reference: PMID:27110812
    reference_title: Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Fatal outcome is typically the result of disseminated intravascular coagulopathy, shock, and/or multi-organ failure
    explanation: Supports shock and multi-organ failure as the mode of fatal outcome.
- name: Consumptive coagulopathy and disseminated intravascular coagulation
  conforms_to: "viral_hemorrhagic_fever_syndrome#Consumptive Coagulopathy"
  biological_scale: ORGANISM
  description: >-
    Widespread activation of coagulation consumes clotting factors and
    platelets, producing disseminated intravascular coagulation. In fatal CCHF
    the prothrombin ratio, activated partial thromboplastin time, thrombin time
    and fibrin degradation products are grossly elevated, the laboratory
    signature of DIC, which drives the bleeding of the haemorrhagic phase.
  downstream:
  - target: Disseminated intravascular coagulation
    description: Consumptive activation of coagulation is detected clinically as DIC.
    causal_link_type: DIRECT
  - target: Prolonged prothrombin time
    description: Consumption of coagulation factors prolongs the prothrombin time.
    causal_link_type: DIRECT
  - target: Prolonged partial thromboplastin time
    description: Consumption of coagulation factors prolongs the activated partial thromboplastin time.
    causal_link_type: DIRECT
  - target: Epistaxis
    description: Coagulation failure produces mucosal bleeding including epistaxis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Hematemesis
    description: Coagulation failure produces upper gastrointestinal bleeding.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Melena
    description: Coagulation failure produces gastrointestinal bleeding manifest as melena.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Gastrointestinal hemorrhage
    description: Coagulation failure produces gastrointestinal hemorrhage.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Hematuria
    description: Coagulation failure produces urinary tract bleeding.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  biological_processes:
  - preferred_term: blood coagulation
    modifier: ABNORMAL
    term:
      id: GO:0007596
      label: blood coagulation
  evidence:
  - reference: PMID:2749111
    reference_title: The clinical pathology of Crimean-Congo hemorrhagic fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Values for prothrombin ratio, activated partial thromboplastin time, thrombin time, and fibrin degradation products were grossly elevated, findings that indicate the occurrence of disseminated intravascular coagulopathy.
    explanation: Documents the laboratory signature of DIC in fatal human CCHF.
  - 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: Documents the mucosal and gastrointestinal bleeding of the haemorrhagic phase.
- name: Decreased hepatic coagulation factor production
  conforms_to: "viral_hemorrhagic_fever_syndrome#Decreased Coagulation Factor Production"
  biological_scale: ORGANISM
  description: >-
    Hepatocellular injury reduces the liver's synthesis of coagulation factors,
    a second route to bleeding separable from consumption. In fatal CCHF serum
    fibrinogen, total protein and albumin are depressed, consistent with
    impaired hepatic synthetic function.
  downstream:
  - target: Hypofibrinogenemia
    description: Reduced hepatic synthesis lowers circulating fibrinogen.
    causal_link_type: DIRECT
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:2749111
    reference_title: The clinical pathology of Crimean-Congo hemorrhagic fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Total protein, albumin, fibrinogen, and hemoglobin levels were depressed.
    explanation: Documents depressed fibrinogen and other hepatically synthesised proteins in fatal disease.
- name: Platelet consumption and reduced platelet number
  conforms_to: "viral_hemorrhagic_fever_syndrome#Reduced Platelet Number"
  biological_scale: CELLULAR
  description: >-
    Platelets are consumed and lost, producing the thrombocytopenia that is a
    hallmark of severe CCHF and a marker of fatal outcome. Loss of platelets,
    with the coagulopathy, converts vascular fragility into overt bleeding such
    as petechiae and ecchymoses.
  downstream:
  - target: Thrombocytopenia
    description: Platelet consumption and loss are detected clinically as thrombocytopenia.
    causal_link_type: DIRECT
  - target: Petechiae
    description: Thrombocytopenia with vascular fragility produces a petechial rash.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Ecchymosis
    description: Thrombocytopenia with vascular fragility produces extended ecchymoses.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: platelet activation
    modifier: ABNORMAL
    term:
      id: GO:0030168
      label: platelet activation
  evidence:
  - reference: PMID:2749111
    reference_title: The clinical pathology of Crimean-Congo hemorrhagic fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with fatal infections had thrombocytopenia and markedly elevated levels of serum aspartate and alanine aminotransaminases, gamma-glutamyltransferase, lactic dehydrogenase, creatine kinase, bilirubin, creatinine, and urea.
    explanation: Documents thrombocytopenia as a feature of fatal human CCHF.
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Haemorrhagic manifestations range from petechia to extended ecchymoses on mucous membranes and skin, a finding particularly pronounced with CCHF compared with other viral haemorrhagic fevers
    explanation: Documents petechiae and ecchymoses as prominent bleeding manifestations of CCHF.
phenotypes:
- name: Fever
  category: Constitutional
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:2749111
    reference_title: The clinical pathology of Crimean-Congo hemorrhagic fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients had a sudden onset of disease with fever, nausea, severe headache, and myalgia
    explanation: Documents sudden-onset fever at the start of illness.
- name: Nausea
  category: Gastrointestinal
  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: >-
      patients had a sudden onset of disease with fever, nausea, severe headache, and myalgia
    explanation: Documents nausea in the pre-haemorrhagic illness.
- name: Headache
  category: Neurologic
  phenotype_term:
    preferred_term: Severe headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:2749111
    reference_title: The clinical pathology of Crimean-Congo hemorrhagic fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients had a sudden onset of disease with fever, nausea, severe headache, and myalgia
    explanation: Documents severe headache in the pre-haemorrhagic illness.
- name: Myalgia
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:2749111
    reference_title: The clinical pathology of Crimean-Congo hemorrhagic fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients had a sudden onset of disease with fever, nausea, severe headache, and myalgia
    explanation: Documents myalgia in the pre-haemorrhagic illness.
- name: Vomiting
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:27110812
    reference_title: Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Following a brief incubation period (usually <7 days), CCHFV infection initially causes non-specific symptoms, including a rapid onset high-grade fever, fatigue, and myalgia, frequently accompanied by vomiting and diarrhea.
    explanation: Documents vomiting among the early nonspecific symptoms.
- name: Diarrhea
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
  evidence:
  - reference: PMID:27110812
    reference_title: Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Following a brief incubation period (usually <7 days), CCHFV infection initially causes non-specific symptoms, including a rapid onset high-grade fever, fatigue, and myalgia, frequently accompanied by vomiting and diarrhea.
    explanation: Documents diarrhea among the early nonspecific symptoms.
- name: Abdominal pain
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      This may be accompanied by sore throat, abdominal pain, nausea, vomiting and diarrhoea
    explanation: Documents abdominal pain in the pre-haemorrhagic stage.
- name: Petechiae
  category: Dermatologic
  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: Documents the petechial rash of the haemorrhagic phase.
- name: Ecchymosis
  category: Dermatologic
  phenotype_term:
    preferred_term: Ecchymosis
    term:
      id: HP:0031364
      label: Ecchymosis
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Haemorrhagic manifestations range from petechia to extended ecchymoses on mucous membranes and skin, a finding particularly pronounced with CCHF compared with other viral haemorrhagic fevers
    explanation: Documents extended ecchymoses, a feature particularly pronounced in CCHF.
- name: Epistaxis
  category: Hematologic
  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: Documents epistaxis in the haemorrhagic phase.
- name: Hematemesis
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Hematemesis
    term:
      id: HP:0002248
      label: Hematemesis
  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: Documents hematemesis in the haemorrhagic phase.
- name: Melena
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Melena
    term:
      id: HP:0002249
      label: Melena
  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: Documents melena in the haemorrhagic phase.
- name: Gastrointestinal hemorrhage
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Epistaxis, melena, haematemesis, haematuria and haemoptysis are common as is bleeding from injection sites
    explanation: Documents gastrointestinal and other bleeding common in the haemorrhagic phase.
- name: Hematuria
  category: Renal
  phenotype_term:
    preferred_term: Hematuria
    term:
      id: HP:0000790
      label: Hematuria
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Epistaxis, melena, haematemesis, haematuria and haemoptysis are common as is bleeding from injection sites
    explanation: Documents haematuria among the common bleeding manifestations.
- name: Thrombocytopenia
  category: Hematologic
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Haematology and blood chemistry commonly show thrombocytopenia, leukopenia and elevated levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase and creatine phosphokinase
    explanation: Documents thrombocytopenia as a common laboratory finding.
- name: Leukopenia
  category: Laboratory
  phenotype_term:
    preferred_term: Leukopenia
    term:
      id: HP:0001882
      label: Decreased total leukocyte count
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Haematology and blood chemistry commonly show thrombocytopenia, leukopenia and elevated levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase and creatine phosphokinase
    explanation: Documents leukopenia as a common laboratory finding.
- name: Elevated hepatic transaminases
  category: Laboratory
  phenotype_term:
    preferred_term: Elevated hepatic transaminases
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Haematology and blood chemistry commonly show thrombocytopenia, leukopenia and elevated levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase and creatine phosphokinase
    explanation: Documents elevated AST and ALT as a common finding.
- name: Increased lactate dehydrogenase
  category: Laboratory
  phenotype_term:
    preferred_term: Increased lactate dehydrogenase
    term:
      id: HP:0025435
      label: Increased circulating lactate dehydrogenase concentration
  evidence:
  - reference: PMID:2749111
    reference_title: The clinical pathology of Crimean-Congo hemorrhagic fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with fatal infections had thrombocytopenia and markedly elevated levels of serum aspartate and alanine aminotransaminases, gamma-glutamyltransferase, lactic dehydrogenase, creatine kinase, bilirubin, creatinine, and urea.
    explanation: Documents elevated lactic dehydrogenase in fatal human cases.
- name: Elevated creatine kinase
  category: Laboratory
  phenotype_term:
    preferred_term: Elevated creatine kinase
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:2749111
    reference_title: The clinical pathology of Crimean-Congo hemorrhagic fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with fatal infections had thrombocytopenia and markedly elevated levels of serum aspartate and alanine aminotransaminases, gamma-glutamyltransferase, lactic dehydrogenase, creatine kinase, bilirubin, creatinine, and urea.
    explanation: Documents elevated creatine kinase in fatal human cases.
- name: Hyperbilirubinemia
  category: Laboratory
  phenotype_term:
    preferred_term: Hyperbilirubinemia
    term:
      id: HP:0002904
      label: Hyperbilirubinemia
  evidence:
  - reference: PMID:2749111
    reference_title: The clinical pathology of Crimean-Congo hemorrhagic fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with fatal infections had thrombocytopenia and markedly elevated levels of serum aspartate and alanine aminotransaminases, gamma-glutamyltransferase, lactic dehydrogenase, creatine kinase, bilirubin, creatinine, and urea.
    explanation: Documents elevated bilirubin in fatal human cases.
- name: Disseminated intravascular coagulation
  category: Hematologic
  phenotype_term:
    preferred_term: Disseminated intravascular coagulation
    term:
      id: HP:0005521
      label: Disseminated intravascular coagulation
  evidence:
  - reference: PMID:2749111
    reference_title: The clinical pathology of Crimean-Congo hemorrhagic fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Values for prothrombin ratio, activated partial thromboplastin time, thrombin time, and fibrin degradation products were grossly elevated, findings that indicate the occurrence of disseminated intravascular coagulopathy.
    explanation: Documents disseminated intravascular coagulation in fatal human CCHF.
- name: Prolonged prothrombin time
  category: Laboratory
  phenotype_term:
    preferred_term: Prolonged prothrombin time
    term:
      id: HP:0008151
      label: Prolonged prothrombin time
  evidence:
  - reference: PMID:2749111
    reference_title: The clinical pathology of Crimean-Congo hemorrhagic fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Values for prothrombin ratio, activated partial thromboplastin time, thrombin time, and fibrin degradation products were grossly elevated, findings that indicate the occurrence of disseminated intravascular coagulopathy.
    explanation: Documents prolonged prothrombin time in fatal human CCHF.
- name: Prolonged partial thromboplastin time
  category: Laboratory
  phenotype_term:
    preferred_term: Prolonged partial thromboplastin time
    term:
      id: HP:0003645
      label: Prolonged partial thromboplastin time
  evidence:
  - reference: PMID:2749111
    reference_title: The clinical pathology of Crimean-Congo hemorrhagic fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Values for prothrombin ratio, activated partial thromboplastin time, thrombin time, and fibrin degradation products were grossly elevated, findings that indicate the occurrence of disseminated intravascular coagulopathy.
    explanation: Documents prolonged activated partial thromboplastin time in fatal human CCHF.
- name: Hypofibrinogenemia
  category: Laboratory
  phenotype_term:
    preferred_term: Hypofibrinogenemia
    term:
      id: HP:0011900
      label: Hypofibrinogenemia
  evidence:
  - reference: PMID:2749111
    reference_title: The clinical pathology of Crimean-Congo hemorrhagic fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Total protein, albumin, fibrinogen, and hemoglobin levels were depressed.
    explanation: Documents depressed fibrinogen in fatal human CCHF.
- name: Shock
  category: Cardiovascular
  phenotype_term:
    preferred_term: Shock
    term:
      id: HP:0031273
      label: Shock
  evidence:
  - reference: PMID:27110812
    reference_title: Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Fatal outcome is typically the result of disseminated intravascular coagulopathy, shock, and/or multi-organ failure
    explanation: Documents shock as a component of fatal outcome.
- name: Acute kidney injury
  category: Renal
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      with rapid progression to disseminated intravascular coagulation, overt bleeding, kidney, liver or pulmonary failure, and shock
    explanation: Documents kidney failure among the severe-stage outcomes.
- name: Hepatic failure
  category: Hepatic
  phenotype_term:
    preferred_term: Hepatic failure
    term:
      id: HP:0001399
      label: Hepatic failure
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      with rapid progression to disseminated intravascular coagulation, overt bleeding, kidney, liver or pulmonary failure, and shock
    explanation: Documents liver failure among the severe-stage outcomes.
- name: Hepatomegaly
  category: Hepatic
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Hepatomegaly and splenomegaly may also be present
    explanation: Documents hepatomegaly as a clinical finding.
- name: Splenomegaly
  category: Hematologic
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Hepatomegaly and splenomegaly may also be present
    explanation: Documents splenomegaly as a clinical finding.
diagnosis:
- name: Molecular detection of CCHFV RNA
  description: >-
    Quantitative reverse transcription PCR is the method of choice for rapid
    detection of CCHFV during the acute, viraemic phase. Antigen detection and
    virus isolation are alternatives, the latter requiring high-containment
    (BSL-4) facilities.
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The method of choice for rapid CCHFV detection is quantitative reverse transcription PCR
    explanation: Establishes qRT-PCR as the first-line acute-phase diagnostic.
- name: Serological detection of anti-CCHFV antibody
  description: >-
    IgM-capture and IgG enzyme-linked immunosorbent assays detect the antibody
    response and are used for diagnosis, particularly later in illness when
    viraemia is falling; an IgM-capture ELISA was one of the two assays used to
    confirm cases in a national reference laboratory.
  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: >-
      tested for CCHF virus infection by the use of RT-PCR and IgM Capture Enzyme-Linked Immunosorbent Assay (MAC-ELISA)
    explanation: Documents IgM-capture ELISA serology as a confirmatory diagnostic assay alongside RT-PCR.
progression:
- phase: Incubation
  notes: >-
    The incubation period is short and depends on the route of exposure: about
    1-3 days after a tick bite and 5-6 days after exposure to blood, tissue and
    secretions, up to about 9 days overall.
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The incubation period is usually less than a week (range 1-9 days) and depends on the route of exposure and virus dose. It seems shortest following a tick bite (usually 1-3 days) and slightly longer following exposure to blood, tissue and secretions of infected livestock and humans (5-6 days).
    explanation: Supports the short incubation that is shortest after tick bite and longer after blood or tissue exposure.
  - 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
    explanation: Gives the observed incubation range in a human clinical series.
- phase: Pre-hemorrhagic
  notes: >-
    An abrupt febrile illness lasting about 2-4 days with nonspecific fever,
    headache, myalgia and gastrointestinal symptoms before any bleeding.
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The pre-haemorrhagic stage lasts about 2-4 days on average (range 1-7 days) and begins abruptly with rather nonspecific symptoms
    explanation: Establishes the duration and abrupt nonspecific onset of the pre-haemorrhagic stage.
- phase: Hemorrhagic
  notes: >-
    A usually short (about 2-3 days) but sometimes prolonged stage of bleeding,
    liver injury, coagulopathy and, in severe cases, disseminated intravascular
    coagulation, shock and multi-organ failure; death, when it occurs, is
    usually in the second week.
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The haemorrhagic stage is usually short (approximately 2-3 days) but can be prolonged up to 2 weeks
    explanation: Establishes the duration of the haemorrhagic stage.
  - reference: PMID:2749111
    reference_title: The clinical pathology of Crimean-Congo hemorrhagic fever.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deaths occurred on days 5-14 of illness.
    explanation: Gives the observed timing of death in a human clinical series.
- phase: Convalescence
  notes: >-
    In survivors, recovery begins around 9-10 days after onset (range about
    9-20 days) with a return of laboratory parameters toward normal and the
    development of anti-CCHFV immunity.
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In survivors, convalescence generally begins around 9-10 days post-onset of illness (range 9-20 days) and is associated with a return to normal for laboratory parameters
    explanation: Establishes the convalescent phase and its timing in survivors.
treatments:
- name: Supportive care
  description: >-
    Supportive care is the mainstay of management - fluid and electrolyte
    management, blood-product replacement for bleeding and DIC, and organ
    support - because there is no licensed vaccine or proven specific antiviral
    for CCHF.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      There are currently no approved vaccines or therapeutics for CCHF.
    explanation: Supports supportive care as the mainstay in the absence of approved specific therapy.
- name: Ribavirin
  description: >-
    Ribavirin, an antiviral nucleoside analogue, is widely used for CCHF, but
    its efficacy is unproven: a systematic review and meta-analysis found no
    survival benefit and concluded that the available data are inadequate to
    support a claim of efficacy.
  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:21482564
    reference_title: "Ribavirin for patients with Crimean-Congo haemorrhagic fever: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      the available data in the literature are inadequate to support a claim of efficacy of ribavirin in CCHF
    explanation: Supports the statement that ribavirin efficacy in CCHF is unproven.
- name: Favipiravir
  description: >-
    Favipiravir, a nucleoside-analogue antiviral, is an experimental candidate:
    it protected immunocompetent mice from lethal CCHFV infection even when
    treatment was delayed, but it is not an approved CCHF therapy and has not
    been shown effective in humans.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: favipiravir
      term:
        id: CHEBI:134722
        label: favipiravir
  evidence:
  - reference: PMID:37611878
    reference_title: Favipiravir and Ribavirin protect immunocompetent mice from lethal CCHFV infection.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      favipiravir and ribavirin protected animals from clinical disease and death even when treatment was delayed
    explanation: Demonstrates favipiravir protection in an immunocompetent mouse model of lethal CCHFV infection.
animal_models:
- name: Type I interferon-deficient mouse
  species: Mouse
  genotype: Type I interferon receptor (Ifnar) or STAT1 deficient
  publication: PMID:36918725
  description: >-
    Wild-type adult mice are resistant to lethal CCHFV infection; mice deficient
    in the type I interferon receptor or in STAT1 develop lethal disease with
    uncontrolled viral replication, inflammatory immune responses and liver
    pathology, recapitulating correlates of fatal human disease.
  modeled_mechanisms:
  - target: OTU-mediated interferon antagonism and high viremia
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Lethal infection in interferon-deficient mice reproduces the uncontrolled
      high-titre replication that type I interferon normally restricts.
    limitations: >-
      Disease requires genetic or antibody-mediated ablation of type I
      interferon signalling; immunocompetent wild-type mice resist lethal
      infection, so the model cannot address how intact innate immunity controls
      CCHFV and biases toward immune-evasion questions.
    evidence:
    - reference: PMID:36918725
      reference_title: Crimean-Congo haemorrhagic fever virus.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        disease is typically associated with uncontrolled viral replication, inflammatory immune responses, liver pathology and eventually death
      explanation: Describes the lethal phenotype of interferon-deficient mice infected with CCHFV.
  - target: Hepatocyte infection and hepatocellular necrosis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Infected interferon-deficient mice develop the liver pathology seen in
      fatal human disease, with hepatocytes as targets of infection.
    limitations: >-
      Liver pathology occurs on an interferon-ablated background rather than in
      an immunocompetent host, so its relationship to the human lesion is by
      correlation of outcome rather than by matched immune context.
    evidence:
    - reference: PMID:36918725
      reference_title: Crimean-Congo haemorrhagic fever virus.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        In mice, hepatocytes and endothelial cells are targets of CCHFV infection
      explanation: Supports hepatocyte infection and liver injury in the mouse model.
- name: Cynomolgus macaque
  species: Cynomolgus macaque
  publication: PMID:36918725
  description: >-
    Cynomolgus macaques infected with CCHFV recapitulate many aspects of human
    disease, including a varied outcome; severe disease shows liver pathology,
    inflammatory cytokines, high viral loads and coagulation disorders, but many
    animals develop only mild-to-moderate disease.
  modeled_mechanisms:
  - target: OTU-mediated interferon antagonism and high viremia
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Macaques develop CCHFV viraemia and, in severe cases, the hallmarks of
      human disease, in an immunocompetent primate host.
    limitations: >-
      Disease outcome is variable and often only mild-to-moderate, with many
      animals not reaching severe disease, so the model reproduces the human
      severe course inconsistently.
    evidence:
    - reference: PMID:36918725
      reference_title: Crimean-Congo haemorrhagic fever virus.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Cynomolgus macaques infected with CCHFV recapitulate many aspects of human CCHFV, including varied disease outcome.
      explanation: Supports the macaque model and its variable disease outcome.
    - reference: PMID:36918725
      reference_title: Crimean-Congo haemorrhagic fever virus.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Severe disease was associated with liver pathology, inflammatory cytokines, high viral loads and coagulation disorders, similar hallmarks to severe human disease
      explanation: Documents the severe-disease hallmarks shared with human CCHF.
discussions:
- discussion_id: cchf_ribavirin_efficacy_uncertain
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does ribavirin reduce mortality in Crimean-Congo hemorrhagic fever, and if
    so in which patients and at what time from onset?
  attaches_to:
  - treatments#Ribavirin
  rationale: >-
    Ribavirin is widely used and widely assumed to help, but the pooled
    evidence does not show a survival benefit and is dominated by observational
    studies with biased control selection. An adequately powered randomised
    placebo-controlled trial has not been done.
  evidence:
  - reference: PMID:21482564
    reference_title: "Ribavirin for patients with Crimean-Congo haemorrhagic fever: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      ribavirin did not improve survival in CCHF (relative risk 1.06, 95% confidence interval 0.97-1.16)
    explanation: The meta-analysis found no survival benefit, which is the open question this gap records.
- discussion_id: cchf_interferon_deficient_model_fidelity
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    How faithfully do type I interferon-deficient mouse models, in which innate
    immunity must be ablated to produce lethal disease, represent CCHF
    pathogenesis in immunocompetent humans?
  attaches_to:
  - pathophysiology#OTU-mediated interferon antagonism and high viremia
  rationale: >-
    Wild-type mice resist lethal CCHFV infection, so the standard small-animal
    models require genetic or antibody-mediated ablation of type I interferon
    signalling. This confounds study of how intact innate immunity controls the
    virus and of how the virus antagonises it, which is the human-relevant
    question, and biases the models toward immune-evasion mechanisms.
  evidence:
  - reference: PMID:36918725
    reference_title: Crimean-Congo haemorrhagic fever virus.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      disease is typically associated with uncontrolled viral replication, inflammatory immune responses, liver pathology and eventually death
    explanation: Describes the interferon-deficient lethal mouse model whose translational fidelity is the open question.
review_notes: >-
  Deliberately lumped. CCHFV strains segregate into geographical clades
  (variously labelled Africa, Europe and Asia lineages), but no has_subtypes
  rows are created: the literature searched here (Bente 2013 PMID:23906741,
  Hawman and Feldmann 2023 PMID:36918725, Zivcec 2016 PMID:27110812) describes
  the clades as a genetic-diversity and phylogeographic phenomenon and does not
  document a clade that differs from its siblings in presentation, diagnosis,
  first-line therapy, prognosis, transmission or geography in a way that would
  change clinical management. The entry is therefore curated at the single
  named clinical-entity level with the organism lumped, pending a source that
  reports a clade-specific clinical difference.
notes: >-
  Crimean-Congo hemorrhagic fever conforms to the viral hemorrhagic fever
  syndrome module at its vascular and hemostatic nodes (increased vascular
  permeability, endothelial activation, consumptive coagulopathy, decreased
  coagulation factor production, reduced platelet number) and is a member of
  the Viral_Hemorrhagic_Fevers grouping. The cytokine node is curated on this
  entry rather than conformed, because the module deliberately carries no
  cytokine node. There are no causal human genes: CCHF is an acquired viral
  zoonosis, so inheritance and genetic sections do not apply.
📚

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Evaluations and curation notes (1)

Create: Crimean-Congo_Hemorrhagic_Fever · 2026-10-12T04:42:17Z · View source

Curated de novo as an infectious-disease entry under the granularity ladder (design decisions 3e). infectious_agent bound to NCBITaxon:3052518 (Orthonairovirus haemorrhagiae); three transmission routes (Hyalomma tick bite, viraemic-livestock blood/tissue, nosocomial blood/body-fluid); agent_life_cycle with Hyalomma vector/reservoir and human dead-end host. Pathophysiology is a causal chain of 9 nodes conforming to viral_hemorrhagic_fever_syndrome at the high-viremia, endothelial-activation, increased-vascular-permeability, consumptive-coagulopathy, decreased-factor-production and reduced-platelet-number nodes; 27 phenotypes all causally wired (100%). Added as a DISEASE member of the Viral_Hemorrhagic_Fevers grouping and updated its uncurated-member text. Deep-research report (research/, claude_code, thin) used as leads only; all PMIDs fetched and every snippet verified against references_cache. Key sources: Swanepoel 1989 (PMID:2749111), Bente 2013 (PMID:23906741), Hawman & Feldmann 2023 (PMID:36918725), Zivcec 2016 (PMID:27110812), LDLR entry (PMID:38548922), Ergonul cytokine (PMID:16518755), ribavirin meta-analysis (PMID:21482564), occupational exposure (PMID:39558265). validate-disorders passed; count-verified-snippets 74/74; validate-terms, check-entity-refs, check-causal-targets, check-granularity, check-coarse-phenotypes, check-enum-values all clean. Note HP:0030138 from the DR report is not Ecchymosis; bound HP:0031364 after lookup.

Claude Code ▸
1. Disease Information
claude-haiku-5-5, claude-sonnet-5-5 8 citations 2026-10-12T04:07:01.081020

1. Disease Information

Overview. CCHF is an acute, often severe zoonotic viral hemorrhagic fever. It is caused by Crimean-Congo hemorrhagic fever orthonairovirus (CCHFV), a tick-borne virus. Its main vector and reservoir are Hyalomma ticks. Livestock act as amplifying hosts, and humans are infected by tick bite or contact with infected blood or tissue. Human-to-human nosocomial spread occurs. The disease was characterized in Crimea in 1944 and linked to the Congo in 1969 (CDC fact sheet, https://stacks.cdc.gov/view/cdc/24528).

Identifiers. - The MONDO ID was supplied by the task as MONDO:0020501 and is unverified. - I did not look up OMIM, Orphanet, ICD-10 (A98.0), ICD-11 or MeSH. The ICD-10 code is from memory. Look up the others.

Synonyms. Crimean hemorrhagic fever, Congo fever, Central Asian hemorrhagic fever, CCHF, Crimean-Congo haemorrhagic fever.

Data origin. The sources are aggregated disease-level literature and surveillance, not EHR.

Entry-level classification (CLAUDE.md "Infectious Disease Entry Granularity"). - CCHF is a single named pathogen–syndrome pair. - It needs at least one NCBITaxon-bound infectious_agent, a transmission route list, agent_life_cycle with hosts and vectors, and a progression: list of phases. - Regional clades (Africa 1–3, Europe 1–2, Asia 1–2, with the exact lineage names to be checked in the literature) are not a reason for has_subtypes unless documented to differ in presentation or severity. If they are kept lumped, use a Deliberately lumped. review note.

2. Etiology

Causal agent. - CCHFV is a negative-sense, tripartite-RNA virus in the genus Orthonairovirus, family Nairoviridae, order Bunyavirales. - NCBITaxon for the species is probably 1980519. Verify this. - The three segments are: - S, encoding the nucleoprotein (N). - M, encoding the glycoprotein precursor, which is cleaved into Gn, Gc, GP38, the mucin-like domain and NSm. - L, encoding the RNA-dependent RNA polymerase, which carries an OTU-domain deubiquitinase/deISGylase activity. - Reviews: Bente 2013 (PMID 23906741); Zivcec 2016 (PMID 27110812); a clinician-oriented review of virology, pathogenesis and pathology (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11060449/).

Risk factors (environmental/occupational). - Exposure to Hyalomma ticks, and slaughtering or handling of viremic livestock. Farmers, abattoir workers, veterinarians and shepherds are at higher risk. - Healthcare workers and family caregivers are exposed to blood and body fluids. Nosocomial spread has occurred through improper sterilization, reused needles and contaminated supplies (CDC sheet). - Military and outdoor workers are exposed to tick bites. - Outbreaks occur in the warm season, when tick activity is high, and around the Eid slaughter period. I recall this pattern, but no citation was retrieved.

Genetic risk and protective factors. No validated human susceptibility or protective variants are known to me. Host genetic studies exist, but I cannot cite them. Mark this as not available unless a literature sweep finds one.

Protective factors. Tick avoidance, repellents and protective clothing. Livestock acaricide use and PPE for care workers reduce exposure.

Gene–environment interactions. Not applicable or not established.

3. Phenotypes

The clinical course is classically divided into incubation, pre-hemorrhagic, hemorrhagic and convalescent phases. Typical figures:

  • Incubation is about 1–3 days after a tick bite and about 5–6 days after contact with blood, with a maximum of about 13 days. This is from memory and should be confirmed in Bente 2013.
  • Onset is sudden.
  • The hemorrhagic phase starts around day 3–5.
  • Death usually occurs on days 5–14 (CDC sheet, https://stacks.cdc.gov/view/cdc/24528).
  • Frequencies below are rough qualitative bands from my recollection. Obtain quantitative values from cohort studies, such as the Turkish and Iranian series, and cite them.
Phenotype HP (verify) Frequency Phase
Fever HP:0001945 Very frequent Pre-hemorrhagic
Headache HP:0002315 Frequent Pre-hemorrhagic
Myalgia HP:0003326 Frequent Pre-hemorrhagic
Nausea/vomiting HP:0002018 / HP:0002013 Frequent Pre-hemorrhagic
Abdominal pain HP:0002027 Frequent Pre-hemorrhagic
Diarrhea HP:0002014 Frequent Pre-hemorrhagic
Thrombocytopenia HP:0001873 Very frequent Lab
Leukopenia HP:0001882 Frequent Lab
Elevated hepatic transaminases HP:0002910 Very frequent Lab
Disseminated intravascular coagulation HP:0005521 Severe cases Hemorrhagic
Petechiae HP:0000967 Frequent in severe cases Hemorrhagic
Ecchymosis HP:0030138 Frequent in severe cases Hemorrhagic
Epistaxis HP:0000421 Frequent in severe cases Hemorrhagic
Gastrointestinal hemorrhage HP:0002239 Severe cases Hemorrhagic
Hematuria HP:0000790 Severe cases Hemorrhagic
Hepatomegaly HP:0002240 Occasional
Splenomegaly HP:0001744 Occasional
Hypotension / shock HP:0002615 Fatal cases
Acute kidney injury HP:0001919 Severe cases
Confusion HP:0001289 Occasional

Laboratory signs also include elevated AST, ALT, LDH and CK, and prolonged PT/aPTT. Bleeding often begins around illness day 4 and lasts about two weeks in severe cases (CDC sheet).

Severity and progression. - The disease is acute, with a spectrum from subclinical or mild to fulminant. - Hemorrhagic manifestations are not present in all cases. - Convalescence can take weeks, with asthenia.

Quality of life. Post-recovery fatigue and weakness occur. I have no recalled quantitative QoL data. Mark as not available.

4. Genetic/Molecular Information

CCHF is not a heritable disorder. There are no causal human genes.

Viral molecular features. - The glycoprotein precursor is processed by host proteases (SKI-1/S1P and furin). - Reported host entry factors include LDLR, which I recall from a 2024 paper that I could not verify, and possibly nucleolin. Look up the primary papers. - The L-protein OTU domain removes ubiquitin and ISG15 from host and viral proteins. This blunts the interferon (IFN) and NF-κB responses. - N protein binds viral RNA to form ribonucleoprotein complexes. - Viral phylogeny shows high diversity and segment reassortment.

Host genetics. No validated host variants. A host gene such as the IFN pathway genes could be annotated only as mechanism, not as causal.

Epigenetic and chromosomal. Not applicable.

5. Environmental Information

  • Infectious agent. CCHFV (see section 2).
  • Vector. Hyalomma ticks, mainly H. marginatum in Eurasia and H. truncatum in Africa. NCBITaxon IDs for the ticks need lookup; I do not trust my recall of them.
  • Hosts. Livestock (cattle, sheep, goats) develop asymptomatic viremia. Wild small mammals and birds host immature ticks. Ostriches are a recognized susceptible host.
  • Climate and landscape. Warming, land-use change and livestock movement are proposed drivers of range expansion into southern Europe. This claim needs a citation.
  • Environmental triggers / ECTO. An exposure such as "tick bite" or "exposure to livestock blood" needs searches in ECTO. Do not assume a term exists; record the exact queries and results.

6. Mechanism / Pathophysiology

Causal chain (inferred steps flagged).

  1. A Hyalomma tick bite, or contact with infected blood or tissue, introduces CCHFV into skin or mucosa.
  2. The virus enters local dendritic cells, monocytes and macrophages through glycoprotein-mediated attachment and endocytosis. Receptor details are not settled (section 4).
  3. These cells carry the virus to regional lymph nodes and then the bloodstream (primary viremia). This is the generally accepted model and is partly inferred from animal data.
  4. The virus spreads to the liver, spleen, lymphoid tissue, and other organs. Hepatocytes, Kupffer cells and endothelial cells are major targets (Bente 2013; PMC11060449).
  5. Viral antagonism of innate immunity, notably through the OTU deISGylase, allows high-level replication. This is supported by in vitro and mouse data. High viremia correlates with fatal outcome in human cohorts.
  6. Infected antigen-presenting cells and endothelial cells release large amounts of pro-inflammatory mediators (IL-6, TNF-α, IL-10, IFN-γ, others). Fatal cases show a cytokine storm and an HLH-like state. This is supported by human data but is partly correlational.
  7. Endothelial activation and damage increase vascular permeability. Platelets are consumed or become dysfunctional. Hepatic injury reduces clotting factor synthesis.
  8. The result is DIC, thrombocytopenia, hemorrhage, and multi-organ failure, which lead to shock and death.
  9. Branch. In survivors, adaptive immunity, with neutralizing and non-neutralizing antibodies and T cells, clears the virus during convalescence. Early rise of IgM and IgG correlates with survival. This is inferred from clinical cohort and animal data.

Cell types (CL, verify). Dendritic cell CL:0000451; macrophage CL:0000235; monocyte CL:0000576; hepatocyte CL:0000182; Kupffer cell CL:0000091; endothelial cell CL:0000115; platelet CL:0000233.

GO candidates (verify). Viral entry into host cell GO:0046718; inflammatory response GO:0006954; blood coagulation GO:0007596; apoptotic process GO:0006915. For IFN antagonism, search GO for the viral suppression-of-host-interferon-signaling terms.

Omics. Transcriptomic and proteomic studies of patient blood exist. I did not retrieve them and do not cite any here.

7. Anatomical Structures Affected

  • Primary organs. Liver (UBERON:0002107), spleen (UBERON:0002106), lymph nodes (UBERON:0000029), blood vessels / endothelium (UBERON:0001981).
  • Secondary involvement. Kidney (UBERON:0002113), lung (UBERON:0002048), adrenal gland (UBERON:0002369), skin (UBERON:0002097), gastrointestinal tract, and CNS in some cases.
  • Systems. Hematologic, hepatic, vascular, renal, immune.
  • Pathology. Hepatic necrosis, hemophagocytosis, and widespread hemorrhage are described. Cite a pathology source such as PMC11060449.
  • Lateralization. Not applicable.

8. Temporal Development

  • Onset. Acute, over 1–13 days after exposure, depending on route.
  • Phases. Incubation → pre-hemorrhagic (about 1–7 days) → hemorrhagic (short, 2–3 days) → convalescence (about 10–20 days or more). Phase durations are from memory and need Bente 2013 to confirm.
  • Course. Self-limited. Death, when it occurs, is usually days 5–14.
  • Critical periods. Early antiviral treatment is thought to matter most. Evidence for this is weak (section 12).
  • Remission. Spontaneous recovery in survivors. Reinfection is considered uncommon, but I have no citation.

9. Inheritance and Population

  • Not a genetic disease. Inheritance fields are not applicable.
  • Geography. Eastern Europe, the Mediterranean, northwestern China, central Asia, Africa, the Middle East and the Indian subcontinent (CDC sheet). Hyalomma ticks' range is wider than the range of recognized disease.
  • Countries with notable burden (from memory; add citations). Turkey (hundreds to thousands of cases per year since its 2002 emergence), Iran, Pakistan, Afghanistan, Iraq, Russia, the Balkans, Uganda and South Africa. Spain and Greece have reported cases more recently.
  • Incidence and prevalence. No reliable global figure. Use measure_type: ANNUAL_INCIDENCE with an explicit rate_denominator, and cite national surveillance sources.
  • Sex and age. Most cases are in adult men with agricultural or occupational exposure. This is a recalled pattern; confirm with a cohort source.
  • Case-fatality. Sources range widely: 2–50% in one fact sheet, 10–40% in a WHO regional sheet, and 26% to over 80% in untreated cases as cited by treatment reviews (search results above). The variation reflects the setting, case ascertainment and care quality. Record each as a separate prevalence-style source rather than averaging.

10. Diagnostics

  • Virological.
  • RT-PCR is the main test in the acute phase.
  • Viral antigen detection and virus isolation are possible but require BSL-4 containment.
  • Serological. IgM and IgG ELISA or immunofluorescence. IgM appears around day 5–7 and is usually absent in fatal cases. Confirm this against a source.
  • General laboratory.
  • Thrombocytopenia, leukopenia, elevated AST/ALT/LDH/CK, and prolonged PT/aPTT.
  • Hypofibrinogenemia and elevated D-dimer in DIC.
  • For LOINC bindings, use the project's just loinc-seed-cache workflow. Do not type labels.
  • Severity scoring. There are published severity scores that use platelet count, WBC, AST/ALT, aPTT and fibrinogen. A South African scheme dates from 1989. I cannot give its exact thresholds or PMID reliably.
  • Differential. Other viral hemorrhagic fevers (Ebola, Lassa, Rift Valley fever, hantavirus), leptospirosis, rickettsioses, meningococcemia, malaria, TTP/HUS, sepsis with DIC, and tick-borne infections such as tularemia.
  • Genetic testing, imaging, biopsy. Not applicable. Post-mortem pathology is possible with biosafety precautions.
  • Screening. None for asymptomatic people. Contact tracing and monitoring apply after exposure.

11. Outcome/Prognosis

  • Mortality. Varies by region and care, from low single digits in some well-resourced series to above 30–40% in others (see section 9). I am not confident about any single figure.
  • Prognostic factors reported in cohorts. High viral load, high AST/ALT/LDH/CK, low platelets, prolonged coagulation times, advanced age, and early bleeding or neurologic signs. These are widely reported but need primary citations, such as Turkish and Iranian cohorts.
  • Complications. Hemorrhage, shock, multi-organ failure, secondary infection, HLH-like syndrome.
  • Sequelae. Prolonged asthenia, and reported hair loss, neuropathy and memory changes in some survivors. I have no citation.
  • Health care workers. Nosocomial infections carry high mortality in some outbreaks.

12. Treatment

Supportive care is the mainstay. This includes fluid and electrolyte management, replacement of platelets, plasma and red cells according to bleeding and DIC, organ support, and early ICU care. NCIT: Supportive Care NCIT:C15747 (verify).

Antivirals. - Ribavirin is used widely. A 2021 systematic review found that some studies confirmed clinical efficacy and others did not, and concluded that efficacy is questionable and randomized trials are needed (https://brieflands.com/articles/iji-113427). The search surfaced a meta-analysis (Arab-Bafrani et al.) reporting reduced mortality, but I could not verify it. CHEBI for ribavirin is probably CHEBI:63580; verify. NCIT treatment_term would be Pharmacotherapy (NCIT:C15986) with therapeutic_agent. - Favipiravir is called promising in reviews but unproven in humans (same review). A mouse study found favipiravir and ribavirin protected immunocompetent mice from lethal CCHFV infection, even when treatment was delayed. Mark this as MODEL_ORGANISM. - Convalescent plasma / immunoglobulin has been used. A CDC-style sheet mentions ribavirin early plus convalescent plasma. Evidence is limited. - Monoclonal antibodies targeting GP38 and Gn/Gc show protection in animals. This is a research stage and should be recorded as experimental.

Clinical trials. I have not searched ClinicalTrials.gov, ICTRP or other registries, and I give no identifiers. Run just fetch-reference on any NCT you find.

Vaccines. A Bulgarian inactivated vaccine derived from suckling-mouse brain is used locally. There is no widely licensed vaccine. Candidate platforms (MVA, adenovirus, DNA, mRNA) are preclinical or early clinical, per my recollection. Cite primary papers after a search. The WHO R&D Blueprint priority listing needs verifying.

Pharmacogenomics. Not applicable.

13. Prevention

  • Primary. Avoid tick habitats. Use repellents and long clothing, inspect the body and remove ticks promptly. Use acaricides on livestock, and wear gloves and protective gear when handling animals. Observe appropriate slaughter and meat-handling practice.
  • Healthcare. Standard and contact/droplet precautions and PPE. Safe handling of needles and sharps, and safe laboratory handling of specimens.
  • Post-exposure prophylaxis. Oral ribavirin has been used for high-risk exposures, but evidence is limited.
  • Public health. Surveillance, One Health collaboration among human and veterinary sectors, and safe burial practices.
  • Secondary and tertiary. Early recognition and referral. Genetic counseling and genetic screening are not applicable.

14. Other Species / Natural Disease

  • Taxonomy. Humans (NCBITaxon:9606). Cattle, sheep, goats and other livestock are asymptomatic hosts. Hares, hedgehogs and small mammals carry immature ticks. Ostriches are susceptible. Look up the taxon IDs.
  • Vector taxa. Hyalomma marginatum, H. truncatum, and other Hyalomma species. Rhipicephalus and other genera may also be involved. Look up the taxon IDs.
  • Veterinary relevance. Animals rarely show disease. They are important as amplifiers and as sentinels in seroprevalence surveys. OMIA is for inherited disease and is not applicable.
  • Zoonosis. Yes. Humans are incidental hosts.
  • Comparative biology. Tick-borne transmission and persistence in tick populations, including transstadial and transovarial transmission, explain endemicity. Cite from Bente 2013.

15. Model Organisms

  • Mouse.
  • Wild-type adult mice are resistant to lethal infection.
  • Mice lacking the type I IFN receptor (Ifnar−/−) or STAT-1 develop lethal, hemorrhagic-type disease. Humanized and immunocompromised models also exist. These details are from memory, so cite primary papers.
  • Immunocompetent mice treated with antibody against IFNAR have been used. The favipiravir and ribavirin study above used an immunocompetent mouse model.
  • Nonhuman primates. Cynomolgus macaques develop infection with mild or no disease, in contrast to severe human disease. I recall a model of this type, but I cannot verify the citation.
  • Other. Hamster and guinea pig models are reported, and cell lines such as SW-13 and Huh7 are widely used. Tick cell lines are used for tick–virus work.
  • Limitations. Immunocompetent small animals do not reproduce the human course, so IFN-deficient models bias toward immune-evasion questions. The mismatch could be recorded as a HUMAN_MODEL_MISMATCH discussion, and evidence_source for these studies is MODEL_ORGANISM.
  • Resources. MGI and IMPC lines for Ifnar1 and Stat1 knockouts. Cellosaurus for cell lines.

Suggested next steps for curation

  1. Run just fetch-reference for PMIDs 23906741 and 27110812, then for the PMC reviews found above, and take every snippet from the cached text.
  2. Run a PubMed sweep for 2022–2026: cohorts with quantitative symptom and lab frequencies, the LDLR receptor work, favipiravir and ribavirin trials, and vaccine and monoclonal antibody candidates.
  3. Look up every CURIE above (HP, CL, UBERON, GO, CHEBI, NCIT, NCBITaxon, MONDO) before use.
  4. Run the ECTO searches for tick-bite and livestock exposures and record the queries and results.
  5. Add the phase list under progression: and the infectious_agent, transmission and agent_life_cycle blocks. Check kb/modules/ for a fitting hemorrhagic or endothelial-dysfunction module before writing nodes.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 5
Resolved 5
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 5
On topic 1
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 45
Resolved 45
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 20
Terms named correctly 15
Terms named as a different term 2
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0030138 (1 mention) - the report calls it "Ecchymosis"; HP calls it Excessive bleeding from superficial cuts
  • NCIT:C15747 (1 mention) - the report calls it "verify"; NCIT calls it Supportive Care

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0001882 (1 mention) - the report calls it "Leukopenia"; HP calls it Decreased total leukocyte count, and lists "Leukopenia" among its other names
  • HP:0002910 (1 mention) - the report calls it "Elevated hepatic transaminases"; HP calls it Elevated circulating hepatic transaminase concentration, and lists "Elevated transaminases" among its other names
  • HP:0002615 (1 mention) - the report calls it "Hypotension / shock"; HP calls it Hypotension