Crimean–Congo hemorrhagic fever (CCHF) is a viral disease. Symptoms of CCHF may include fever, muscle pains, headache, vomiting, diarrhea, and bleeding into the skin. Onset of symptoms is less than two weeks following exposure. Complications may include liver failure. Survivors generally recover around two weeks after onset. CCHF is a tick-borne disease.
The causative agent of CCHF is the CCHF virus, which belongs to the genus Orthonairovirus. This virus was initially detected in the 1940s, when Soviet troops and local civilians in Crimea experienced a severe hemorrhagic illness. Decades later, during the 1960s, a similar virus was identified in Kisangani, today in the Democratic Republic of Congo. The two viruses were found to share antigenic properties, leading to their classification under the unified name Crimean-Congo Hemorrhagic Fever Virus (CCHFV). The CCHFV is typically spread by tick bites or close contact with the blood, secretions, organs or other bodily fluids of infected persons or animals. Groups that are at high risk of infection are farmers and those who work in slaughterhouses. The virus can also spread between people via body fluids. Diagnosis can be made by detecting antibodies, the virus's RNA, or viral proteins (antigens). It is a type of viral hemorrhagic fever where both reduced platelet count and disruption of coagulation of pathway contribute to hemorrhage.
There are no FDA- or WHO-approved therapeutics for CCHF, and a vaccine is not commercially available. Prevention involves avoiding tick bites, following safe practices in meat processing plants, and observing universal healthcare precautions. Treatment is typically with supportive care, and while the medication ribavirin is often used, as of 2023, there is not sufficient, high-quality evidence of its efficacy.
CCHF is a geographically widespread viral hemorrhagic fever, found in Eastern and Southern Europe, the Mediterranean, northwestern China, central Asia, Africa, the Middle East, and the Indian subcontinent. It is typically found in regions south of the 50th parallel north. Typically small outbreaks are seen in areas where the virus is endemic. In 2013 Iran, Russia, Turkey, and Uzbekistan documented more than 50 cases. Unlike most viral hemorrhagic fever diseases which occur usually in Africa, Asia and South America, CCHF is prevalent also in parts of Europe, especially in the Balkans and former USSR states (hantavirus hemorrhagic fever with renal syndrome caused by Puumala virus and Dobrava-Belgrade virus also occurs in Europe). The fatality rate of CCHF is typically between 10 and 40% though fatalities as high as 60%-80% and as low as 0%-5% have been observed in some outbreaks. The virus was first observed in Crimea in the 1940s. The case fatality for the Kosovo outbreak that occurred in the period of 1995 to 2013 was 25.5%.
In the past 20 years, CCHF outbreaks have been reported in eastern Europe, particularly in the former Soviet Union, throughout the Mediterranean, in northwestern China, central Asia, southern Europe, Africa, the Middle East, and the Indian subcontinent. In recent years the disease has extended its geographical range, moving towards the western part of Mediterranean Europe; in 2024, Portugal recorded its first-ever laboratory-confirmed human death from CCHF. CCHF is on WHO's priority list for Research and Development and the US National Institute of Allergy and Infectious Diseases (NIH/NIAID) priority A list, as a disease posing the highest level of risk to national security and public health. CCHF is the most widely distributed tick-borne viral disease in the world. In addition to becoming indigenous to the Iberian peninsula in the 21st century (with the first autochthonous human cases in the region confirmed in Spain in 2016), antibodies in cattle and wildlife have been detected in Southern France (although no human cases).
In the 12th century, a hemorrhagic syndrome with symptoms similar to CCHF was described on the territory of present day Tajikistan, and was said to be caused by an arthropod which was tough, small, related to a louse or tick, and normally parasitising a black bird.
Signs and symptoms The clinical illness associated with CCHFV (the CCHF virus) is a severe form of hemorrhagic fever. Following infection by a tick bite, the incubation period is typically two to three days but can last as long as nine days, while the incubation period following contact with infected blood or tissues is usually five to six days with a documented maximum of 13 days. After entering the human body, the virus multiplies within specific target cells, including endothelial cells, macrophages, and epithelial cells. This process activates both the innate and adaptive branches of the immune system. The onset of symptoms ushering in the pre-hemorrhagic phase is sudden, with fever, myalgia (muscle ache), dizziness, neck pain and stiffness, backache, headache, sore eyes, and photophobia (sensitivity to light).
Typical symptoms include nausea, vomiting (which may progress to severe bleeding and can be fatal if not treated), diarrhea, abdominal pain and sore throat early in the acute infection phase, followed by sharp mood swings, agitations and confusion. After several days, agitation may be replaced by sleepiness, depression and lassitude, and the abdominal pain may localize to the upper right quadrant, with detectable liver enlargement.
As the illness progresses into the hemorrhagic phase, large areas of severe bruising, severe nosebleeds, and uncontrolled bleeding at injection sites can be seen, beginning on about the fourth day of illness and lasting for about two weeks. Other clinical signs include tachycardia (fast heart rate), lymphadenopathy (enlarged lymph nodes), and petechiae (a rash caused by bleeding into the skin) on internal mucosal surfaces, such as the mouth and throat, and on the skin. The petechiae may give way to larger rashes called ecchymoses, and other haemorrhagic phenomena. There is usually evidence of hepatitis, and severely ill patients may experience rapid kidney deterioration, liver failure, or pulmonary failure after the fifth day of illness.
In documented outbreaks of CCHF, fatality rates in hospitalized patients have ranged from 9% to as high as 70%, though the WHO notes a typical range of 10–40%, with death often occurring in the second week of illness. In patients who recover, improvement generally begins on the ninth or tenth day after the onset of illness. The long-term effects of CCHF infection have not been studied adequately in survivors to determine whether or not specific complications exist. However, recovery is slow.
Cause Virology
Crimean–Congo hemorrhagic fever virus (CCHFV) is a member of the genus Orthonairovirus, family Nairoviridae of RNA viruses.Virus Taxonomy: 2018 Release, EC 50, Washington, DC, July 2018, Email ratification October 2018 (MSL #33) https://ictv.global/taxonomy
The virions are 80–120 nanometers (nm) in diameter and are pleomorphic. There are no host ribosomes within the virion. Each virion contains three distinct RNA sequences, which together make up the viral genome. The envelope is single-layered and consists of a lipid bilayer 5 nm thick. It has no external protrusions. The envelope proteins form small projections ~5–10 nm long. The nucleocapsids are filamentous and circular with a length of 200–3000 nm. Viral entry is thought to be clathrin-mediated, with the cell surface protein nucleolin playing a role.
Molecular biology The genome is circular, negative-sense RNA in three parts – Small (S), Medium (M), and Large (L). The L segment is 11–14.4 kilobases in length, while the M and S segments are 4.4–6.3 and 1.7–2.1 kilobases long, respectively. The L segment encodes the RNA polymerase, the M segment encodes the envelope glycoproteins (Gc and Gn), and the S segment encodes the nucleocapsid protein. The mutation rates for the three parts of the genome were estimated to be: 1.09, 1.52 and 0.58 substitutions/site/year for the S, M, and L segments, respectively.
Population genetics CCHFV is the most genetically diverse of the arboviruses: its nucleotide sequences frequently differ between different strains, ranging from a 20% variability for the viral S segment to 31% for the M segment. Viruses with diverse sequences can be found within the same geographic area; closely related viruses have been isolated from widely separated regions, suggesting that viral dispersion has occurred, possibly by ticks carried on migratory birds or through international livestock trade. Reassortment among genome segments during coinfection of ticks or vertebrates seems likely to have played a role in generating diversity in this virus.
Based on the sequence data, seven genotypes of CCHFV have been recognised: Africa 1 (Senegal), Africa 2 (Democratic Republic of the Congo and South Africa), Africa 3 (southern and western Africa), Europe 1 (Albania, Bulgaria, Kosovo, Russia and Turkey), Europe 2 (Greece), Asia 1 (the Middle East, Iran and Pakistan) and Asia 2 (China, Kazakhstan, Tajikistan and Uzbekistan).
Transmission
Ticks are both "environmental reservoir" and vector for the virus, carrying it from wild animals to domestic animals and humans. Tick species identified as infected with the virus include Argas reflexus, Hyalomma anatolicum, Hyalomma detritum, Hyalomma marginatum marginatum and Rhipicephalus sanguineus. At least 31 different species of ticks from the genera Haemaphysalis and Hyalomma in southeastern Iran have been found to carry the virus.
Wild animals and small mammals, particularly European hare, Middle-African hedgehogs, and multimammate rats are the "amplifying hosts" of the virus. Birds are generally resistant to CCHF, except ostriches. Domestic animals like sheep, goats and cattle can develop high titers of virus in their blood, but tend not to fall ill.
The "sporadic infection" of humans is usually caused by a Hyalomma tick bite. Animals can transmit the virus to humans, but this would usually be as part of a disease cluster. When clusters of illness occur, it is typically after people treat, butcher, or eat infected livestock, particularly ruminants and ostriches. Outbreaks have occurred in abattoirs and other places where workers have been exposed to infected human or animal blood and fomites Humans can infect humans, and outbreaks also occur in clinical facilities through infected blood and unclean medical instruments.
Prevention
Where mammalian tick infection is common, agricultural regulations require deticking farm animals before transportation or delivery for slaughter. Personal tick avoidance measures are recommended, such as the use of insect repellents, adequate clothing, and body inspection for adherent ticks.
When feverish patients with evidence of bleeding require resuscitation or intensive care, body substance isolation precautions should be taken.
Vaccine Since the 1970s, several vaccine trials around the world against CCHF have been terminated due to high toxicity.
, the only available and probably somewhat efficacious CCHF vaccine has been an inactivated antigen preparation then used in Bulgaria. No publication in the scientific literature related to this vaccine exists, which a Turkish virologist called suspicious both because antiquated technology and mouse brain were used to manufacture it.