Crimean-Congo haemorrhagic fever virus

Crimean-Congo haemorrhagic fever virus, abbreviated CCHFV, is a tick-borne member of the family Nairoviridae and the cause of a severe viral haemorrhagic fever with case-fatality that reaches 30% or more in some outbreaks. It is the most widely distributed tick-borne virus in the world, endemic across Africa, south-eastern Europe, the Middle East, Central Asia and the Indian subcontinent wherever its principal vector, ticks of the genus Hyalomma, is found. The virus circulates silently between ticks and wild and domestic animals, which show no illness; humans are incidental, dead-end hosts and the only species in which it causes disease.

Two features make it a persistent public-health concern beyond its endemic foci. It spreads efficiently from person to person through contact with blood and body fluids, so it causes nosocomial and abattoir-associated clusters, and it is carried by long-lived ticks whose range is expanding, which has brought autochthonous cases into western Europe. There is no widely licensed vaccine and no antiviral of proven benefit, so prevention rests on avoiding tick and livestock exposure and on rigorous infection control. The World Health Organization lists it as a priority pathogen for research and development.

Discovery and historical significance

The disease entered the medical record in 1944, when an outbreak of severe haemorrhagic fever struck Soviet troops and agricultural workers in the Crimean peninsula and was named Crimean haemorrhagic fever. The causative agent could not be isolated with the methods of the time, and formal isolation waited until 1967.

The modern name records a piece of viral taxonomy resolved by serology. In 1956 an apparently unrelated agent had been recovered from a febrile patient in the Belgian Congo and designated Congo virus. In 1969 Jordi Casals showed that the Crimean and Congo agents were one and the same, and the two names were joined to give Crimean-Congo haemorrhagic fever virus. The genus was later reorganised on genetic grounds, and the virus now sits as the species Orthonairovirus haemorrhagiae in the family Nairoviridae, the most medically important member of a family otherwise made up of animal viruses such as Nairobi sheep disease virus and Hazara virus.

Classification, structure, and genome

Classification

CCHFV is the species Orthonairovirus haemorrhagiae in the genus Orthonairovirus, family Nairoviridae, order Bunyavirales. It is the only nairovirus that causes serious human disease. The virus is genetically diverse, resolving into several geographically structured lineages spanning Africa, Asia and Europe, and the segmented genome allows reassortment between them, though this appears to be a rare event. One European lineage, represented by the Greek strain AP92, has been associated with little or no human disease, a reminder that virulence is not uniform across the species.

Virion structure

The virion is enveloped, roughly spherical and pleomorphic, about 80 to 120 nm in diameter. Two glycoproteins, Gn and Gc, project from a lipid envelope and mediate receptor binding and fusion. Unlike some enveloped viruses there is no matrix protein bridging the envelope and the core. Within, the three genome segments are each wrapped by nucleocapsid protein and associated with the large L polymerase to form ribonucleoprotein complexes, the functional units of transcription and replication.

Genome organisation

The genome is three segments of negative-sense single-stranded RNA, totalling about 19 kilobases. The small (S) segment encodes the nucleocapsid protein; the medium (M) segment encodes a glycoprotein precursor that is cleaved into the structural Gn and Gc, a secreted mucin-like protein called GP38, and a non-structural NSm; and the large (L) segment encodes the RNA-dependent RNA polymerase. A distinctive feature of the virus is that its L and M segments are considerably larger than those of other bunyavirals, and the oversized L protein carries, in addition to the polymerase and a cap-snatching endonuclease, an ovarian-tumour (OTU) domain that acts as a deubiquitinase and contributes to immune evasion. Sequence divergence between strains is high, of the order of 20% in the S segment and up to 30% in the M segment, yet the virus remains fit in both tick and vertebrate.

Replication cycle

CCHFV follows the general bunyaviral scheme, executed entirely in the cytoplasm. Attachment is mediated by the Gc and Gn glycoproteins, though the host cell receptor that determines its tropism is still not defined. The bound virion is taken up by receptor-mediated endocytosis.

Acidification of the endosome drives a Gc-mediated fusion of the viral and endosomal membranes, releasing the three ribonucleoprotein segments into the cytoplasm. There the L polymerase transcribes each segment into messenger RNA, priming synthesis by cap-snatching, in which its endonuclease cleaves short capped fragments from host transcripts to serve as primers. The same polymerase later switches to full-length replication of the genome through a positive-sense intermediate.

Newly synthesised nucleocapsid protein encapsidates the progeny genomes, while Gn and Gc mature through the secretory pathway and concentrate at the Golgi. Assembly and budding occur into Golgi membranes, and mature virions are carried to the cell surface and released by exocytosis. Throughout, the virus works to stay ahead of the cell’s innate defences, the L protein’s OTU-domain deubiquitinase stripping the regulatory ubiquitin and ISG15 marks from signalling proteins and so damping the type I interferon response that would otherwise restrain replication.

Pathogenesis

Understanding of pathogenesis is limited by the sporadic nature of cases, the requirement for maximum containment and, until recently, the lack of a good animal model, and much of it is pieced together from patient biomarkers and a small number of autopsies. After a tick bite or contact with infected blood, the virus is thought to replicate first in resident dendritic cells and macrophages of the skin, then spread by way of the draining lymph nodes and the blood to the major organs. Initial targets are the mononuclear phagocytes and the endothelium, with the liver the principal site of secondary replication.

The liver bears the brunt of the injury. Autopsies show hepatocellular necrosis with Councilman bodies and Kupffer-cell hyperplasia, viral antigen is demonstrable in hepatocytes and Kupffer cells, and the steep rise in transaminases during the haemorrhagic phase mirrors this damage. Beyond the liver there is lymphoid depletion in the spleen and widespread congestion, oedema and focal haemorrhage.

The bleeding diathesis is driven more by the host response than by direct destruction of the vasculature. A dysregulated release of pro-inflammatory cytokines, with high levels of tumour necrosis factor alpha, interleukin-6 and interleukin-8, correlates with severe disease and disturbs endothelial function, while platelet aggregation and activation of the coagulation cascade proceed toward disseminated intravascular coagulation. Viral load is a powerful determinant of outcome: titres above about 10⁸ genome copies per millilitre of blood predict a fatal course, whereas lower loads accompany milder illness. Antibody responses are feeble or absent in those who die and develop briskly in those who survive, and host genetic factors such as certain interferon-pathway polymorphisms appear to influence severity.

Epidemiology

CCHFV is maintained in nature in a silent enzootic cycle between ixodid (hard) ticks and the wild and domestic animals on which they feed. The tick is both vector and reservoir: once infected it stays infected for life, passing the virus across the moults of its life cycle (transstadially) and to its offspring through the egg (transovarially). Ticks of the genus Hyalomma are the principal vectors, and the global map of human disease follows their distribution closely across Africa, the Balkans, the Middle East, southern Russia, Central Asia and the Indian subcontinent. Animals amplify the virus without falling ill, developing a transient viraemia that infects feeding ticks; livestock, hares and ground-feeding birds are important amplifying hosts.

Humans acquire the virus in three main ways: by the bite of an infected tick, by crushing an engorged tick against the skin, and by contact with the blood or tissues of a viraemic animal, above all during slaughter. Cases therefore cluster in shepherds, farmers, veterinarians and abattoir workers, with a seasonal peak in the warmer months when ticks are active. A fourth route, contact with the blood of an infected patient, produces nosocomial outbreaks when an unsuspected case undergoes surgery or intensive care without barrier precautions. Seroprevalence in endemic rural populations can reach striking levels, with many infections evidently subclinical, so that reported cases represent only the severe end of a broader spectrum.

Reported case-fatality is wide, from a few percent to over 30%, reflecting real differences in virus strain, care and diagnostic completeness. Turkey, with the largest case numbers, reports a case-fatality just under 5%, whereas figures from some Balkan foci are far higher. Pregnancy carries a poor prognosis, with high maternal fatality and frequent fetal loss. The incidence and geographic range of the disease have grown over the past two decades, and the recent appearance of autochthonous cases in Spain, together with the northward spread of Hyalomma ticks, is widely attributed to changes in climate, land use and animal movement.

Natural history

The incubation period depends on the route of infection and the dose. After a tick bite it is short, usually 1 to 3 days and up to about 9; after contact with infected blood or tissue it is longer, around 5 to 7 days and up to 13. South African data put the interval at about 3 days after a tick bite, 5 days after exposure to livestock blood or tissue and just under 6 days after exposure to infected human blood.

Symptomatic illness then runs through a characteristic sequence. A prehaemorrhagic phase of sudden fever, severe myalgia, headache and malaise lasts on average about three days. In those who progress, a haemorrhagic phase develops rapidly, usually between the third and fifth day of illness and lasting only a few days, during which bleeding and multi-organ dysfunction dominate. Death, when it comes, falls typically between days 5 and 14 and is due to cardiovascular collapse and multi-organ failure. Survivors enter a prolonged convalescence, beginning about 10 to 20 days after onset and sometimes lasting a year, occasionally marked by weakness, transient hair loss, polyneuritis and impaired hearing or vision.

Clinical presentations and complications

The prehaemorrhagic phase begins abruptly with high fever, often 39 to 41°C, severe myalgia, headache, dizziness and, in many patients, nausea, vomiting and diarrhoea. Facial and truncal flushing, injected sclerae and conjunctivitis are common. This phase is clinically indistinguishable from many other febrile illnesses, which is precisely why exposure history matters so much.

The haemorrhagic phase, when it occurs, announces itself with petechiae and ecchymoses on the skin and mucous membranes. Bleeding follows from the nose, gums, gastrointestinal tract (haematemesis and melaena), genitourinary tract and, less often, the respiratory tract; large ecchymoses and bleeding from puncture sites reflect the underlying coagulopathy. Hepatomegaly and splenomegaly are found in about a third of patients, and the liver injury that underlies much of the disease is expressed in jaundice and grossly elevated transaminases. The characteristic laboratory picture is thrombocytopenia and leukopenia with raised aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase, and prolonged prothrombin and activated partial thromboplastin times; frank disseminated intravascular coagulation marks the most severe cases. Combinations of these values, particularly viral load, platelet count and clotting times, have been assembled into severity scores that help predict outcome.

Disease is generally milder in children, with lower fatality, and most severe in pregnancy, where it threatens both mother and fetus. The convalescent syndrome, when present, can include lasting fatigue, neuropsychiatric symptoms and sensory disturbance.

Diagnosis

Diagnosis rests on recognising the clinical syndrome in someone with a compatible exposure and then confirming it in a suitably contained laboratory. Because the virus requires maximum biocontainment, virus isolation is reserved for reference laboratories and is not a first-line test; the practical mainstay is nucleic acid detection.

Real-time reverse-transcription PCR on acute-phase blood is sensitive, rapid and, importantly, can be run on chemically inactivated samples, which reduces the biosafety hazard of testing. The virus, its genome and its antigen are usually detectable for the first one to two weeks of illness, and quantitative assays additionally give the viral load that carries prognostic weight. Antigen-capture ELISA on acute sera is a useful adjunct where available. Serology by IgM-capture and IgG ELISA or immunofluorescence completes the picture: specific IgM and IgG appear around days 5 to 7 in those destined to survive but are characteristically absent in fatal cases, so a negative serology never excludes the diagnosis in a severely ill patient, and molecular testing is decisive. The clinical differential spans the other viral haemorrhagic fevers, severe leptospirosis, rickettsial disease, malaria and the sandfly fevers, varying by region.

Management

Treatment is largely supportive: careful fluid and electrolyte management, and replacement of blood, platelets and clotting factors guided by the coagulopathy. Because most cases occur in rural settings with limited infrastructure, access to intensive support is itself an important determinant of survival.

Specific antiviral therapy is unsettled. Ribavirin, a nucleoside analogue with in vitro and animal activity against the virus, has been used to treat CCHF for decades and is generally considered beneficial when started early in the illness. Recent meta-analyses have, however, questioned whether ribavirin changes outcome, and several investigators have called for randomised trials to settle the matter; in practice it is still given in many endemic countries, and its early use is recommended when CCHF cannot be distinguished from other haemorrhagic fevers. Favipiravir, another polymerase inhibitor, has outperformed ribavirin in animal studies and is an interesting candidate for evaluation. Immune plasma and other experimental approaches have been tried without clear benefit. There is no licensed monoclonal-antibody therapy, although the GP38 and glycoprotein targets are under active investigation.

Prevention and public health

Vector control

Because there is no vaccine and no reliable treatment, preventing exposure is the core of control. In endemic areas this means avoiding tick bites and handling of potentially infected livestock. Treating clothing with pyrethroid acaricides, which repel and kill ticks, is recommended for shepherds, shearers, veterinarians and abattoir workers, alongside the use of gloves and the avoidance of crushing ticks with bare fingers. Acaricidal treatment of livestock reduces the tick burden, but no anti-Hyalomma vaccine is available, and the wide host range and hardiness of the ticks make eradication impractical.

Vaccination

There is no widely licensed human or veterinary CCHF vaccine. An inactivated vaccine derived from suckling-mouse brain has been used in Bulgaria since the 1970s and is offered to high-risk personnel; a reported fall in national incidence has been attributed to it, but its efficacy has never been rigorously characterised, and the mouse-brain substrate and multi-dose schedule limit wider use. A range of modern candidates, including inactivated whole-virus, virus-like-particle, viral-vectored, DNA and subunit vaccines, are in preclinical and early clinical development, several targeting the glycoproteins and GP38.

Infection prevention and control

CCHFV is readily transmitted from patients to carers through blood and body fluids, and nosocomial outbreaks are a recurrent feature, often seeded when an unsuspected case is operated on or nursed without precautions. Suspected and confirmed cases require strict barrier nursing: gloves, gowns, eye protection and respiratory protection, safe handling and disposal of sharps and body fluids, and careful management of the laboratory samples that carry a real risk to staff. Prompt clinical suspicion is the single most important safeguard, since precautions taken late are precautions taken too late.

Post-exposure prophylaxis

Health workers and others with a defined high-risk exposure, such as a needlestick from a case or unprotected contact with blood, are monitored for fever for the length of the incubation period. Oral ribavirin is frequently offered as post-exposure prophylaxis in this situation, and although the evidence for it is limited and largely observational, its use is widespread in endemic settings and endorsed by several national protocols.

Surveillance and notification

CCHF is a notifiable condition in most endemic countries and is subject to outbreak investigation, contact tracing and monitoring of exposed health workers. Surveillance links human, animal and vector data, in keeping with the One Health character of a zoonosis maintained in ticks and livestock, and underpins the risk maps used to warn clinicians and travellers.

South African context

CCHF is an indigenous but uncommon disease of South Africa’s drier interior, with sporadic cases most years and small case totals rather than large outbreaks. The first recognised South African case was diagnosed in 1981, and cases have since been reported chiefly from the Northern Cape, Free State and the Karoo, the rangeland where the vector and livestock farming overlap. The principal vector is Hyalomma marginatum rufipes, a two-host tick of cattle, sheep and game, and the same ticks feed on hares and ground-feeding birds that help maintain the virus.

Exposure is overwhelmingly occupational. Cases occur in farm workers, herders, veterinarians and abattoir workers, and South Africa has the particular feature of an ostrich industry: handling of ostriches and work in ostrich abattoirs, notably around Oudtshoorn, has been linked to infection, because these birds can carry infected ticks even though they do not become ill. Tick bite and the crushing of ticks during dipping or shearing, together with contact with fresh livestock blood at slaughter, are the usual routes, and nosocomial transmission to health workers has occurred when the diagnosis was not suspected early.

CCHF is a notifiable medical condition, and suspected cases are managed under the national viral haemorrhagic fever framework, which brings in barrier nursing, dedicated national guidance on viral haemorrhagic fevers, and referral of diagnostic testing to the specialised reference laboratory. Confirmatory testing is performed by the National Institute for Communicable Diseases, whose Special Viral Pathogens and arbovirus reference laboratories provide the molecular and serological diagnosis under the appropriate biosafety conditions, along with clinical and public-health advice through a national hotline. Because CCHF and the other haemorrhagic fevers cannot be told apart clinically at presentation, a patient with a compatible illness and exposure is managed as a possible viral haemorrhagic fever, with early ribavirin and full infection-control precautions, until the laboratory result is known.

The comparison below sets CCHF against Rift Valley fever, the other viral haemorrhagic fever endemic to South Africa, to highlight where the two diverge in vector, transmission and risk.

Feature	Crimean-Congo haemorrhagic fever	Rift Valley fever
Family, genus	Nairoviridae, Orthonairovirus	Phenuiviridae, Phlebovirus
Vector and reservoir	Hyalomma ticks (vector and reservoir)	Floodwater Aedes (maintenance), Culex (amplification) mosquitoes
Main route to humans	Tick bite, crushing ticks, livestock blood, nosocomial	Contact with infected animal tissue and blood; mosquito bite
Incubation	1 to 3 days after tick bite; 5 to 7 after blood contact	2 to 6 days
Hallmark severe disease	Haemorrhagic fever with hepatic necrosis and DIC	Hepatic and haemorrhagic disease, retinitis, encephalitis
Person-to-person spread	Yes (blood and body fluids)	Not documented
Biosafety level	BSL-4	BSL-3
Specific therapy	Ribavirin (contested)	None; supportive
Vaccine	None widely licensed (inactivated, Bulgaria only)	Veterinary vaccines; human candidates in trials

References and recommended reading

• Spiropoulou CF, Bente DA. Orthohantavirus, Orthonairovirus, Orthobunyavirus, and Phlebovirus. In: Fields Virology, 7th edition. Philadelphia: Wolters Kluwer; 2023. The principal source for the epidemiology, tick ecology, clinical course, pathogenesis, diagnosis and prevention set out here.
• Barr JN, Weber F, Schmaljohn CS. Bunyavirales: The Viruses and Their Replication. In: Fields Virology, 7th edition. Philadelphia: Wolters Kluwer; 2023. The reference for the segmented genome, cap-snatching transcription, glycoprotein processing and the OTU-domain deubiquitinase.
• Mertz GJ, Ahlm C, Jonsson CB. Bunyaviridae. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition. Washington: ASM Press; 2016. Background on the clinical virology and diagnosis of the bunyaviral haemorrhagic fevers.
• Burrell CJ, Howard CR, Murphy FA. Bunyaviruses. In: Fenner and White’s Medical Virology, 5th edition. London: Academic Press; 2017. A concise account of nairovirus classification, structure and replication.
• Hewson R. Understanding Viral Haemorrhagic Fevers: virus diversity, vector ecology, and public health strategies. Pathogens 2024;13(10):909. A current review of viral haemorrhagic fever ecology and control.
• National Institute for Communicable Diseases. Viral Haemorrhagic Fever Guidelines and Arboviral Disease resources. Johannesburg: NICD; 2015 onward. The source for the South African notification, biosafety and reference-laboratory pathway.