Crimean-Congo Hemorrhagic Fever

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.

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

• Bente et al. 2013, Antiviral Research 100(1):159–189, PMID 23906741 (bibliographic details only)
• Zivcec et al. 2016, Viruses, PMID 27110812 (identified in the search; I did not confirm the PMC link maps to this paper)
• CCHFV for Clinicians: Virology, Pathogenesis, and Pathology
• CCHFV: Current Advances and Future Prospects of Antiviral Strategies
• Systematic review of treatment strategies in CCHF, Int J Infect
• Favipiravir and ribavirin protect immunocompetent mice from lethal CCHFV infection
• CDC CCHF fact sheet
• ECDC CCHF factsheet for healthcare professionals

Reference Validation

Checked with linkml-reference-validator 0.3.0.

All extracted references resolved successfully.

Term Validation

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

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