Crimean-Congo Hemorrhagic Fever Virus and Fever

Crimean-Congo hemorrhagic fever virus (CCHFV) is a member of the Nairovirus genus. It was first isolated from

Biosafety Level 3 containment is currently recommended for laboratory usage of OROV (BMBL 5th Edition)

Epidemiology

Oropouche fever is currently a disease that occurs in South and Central America, but there are concerns that climate change may result in expansion of the range of this virus by changing the distribution of its insect vectors.

Since its original description in 1961, more than 30 significant outbreaks of Oropouche fever have occurred in Trinidad, Brazil, Peru, Ecuador and Panama. A number of these recorded outbreaks were very large, involving tens of thousands of human patients. Moreover, surveys have indicated the virus to be much more broadly distributed in adjacent countries, but not yet recognized.

Transmission Cycles and Arthropod Vectors

OROV is a vector-borne pathogen transmitted predominantly by biting midges and secondarily by mosquitoes, although additional work is needed to better define the roles of these vectors. Both urban and sylvatic transmission cycles have been described. The urban cycle appears to be maintained solely by vector transmission among infected humans, whereas the sylvatic cycle likely involves a number of amplifying hosts, including primates, other mammals such as sloths, and possibly birds.

The principle arthropod vector responsible for transmission of OROV among humans in the urban cycle appears to be the Culicoides paraensis midge. Mosquitoes of several species seem to also serve as vectors for the virus and may be important in the sylvatic cycle, including especially the southern house mosquito (Culex quinquefasciatus), which is highly abundant in endemic areas and appears capable of transmitting the virus.

Human Disease

The onset of CCHF is sudden, with initial signs and symptoms including headache, high fever, back pain, joint pain, stomach pain, and vomiting. Red eyes, a flushed face, a red throat, and petechiae (red spots) on the palate are common. Symptoms may also include jaundice, and in severe cases, changes in mood and sensory perception. As the illness progresses, 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. In documented outbreaks of CCHF, fatality rates in hospitalized patients have ranged from 9% to as high as 50%. The length of the incubation period depends on the mode of acquisition of the virus. Following infection by a tick bite, the incubation period is usually one to three days, with a maximum of nine days. The incubation period following contact with infected blood or tissues is usually five to six days, with a documented maximum of 13 days. Onset of symptoms is sudden, with fever, myalgia, (muscle ache), dizziness, neck pain and stiffness, backache, headache, sore eyes and photophobia (sensitivity to light). There may be nausea, vomiting, diarrhoea, abdominal pain and sore throat early on, followed by sharp mood swings and confusion. After two to four days, the agitation may be replaced by sleepiness, depression and lassitude, and the abdominal pain may localize to the upper right quadrant, with detectable hepatomegaly (liver enlargement). Other clinical signs include tachycardia (fast heart rate), lymphadenopathy (enlarged lymph nodes), and a petechial rash (a rash caused by bleeding into the skin) on internal mucosal surfaces, such as in 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, sudden liver failure or pulmonary failure after the fifth day of illness. The mortality rate from CCHF is approximately 30%, with death 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.

Human infection with OROV induces a febrile disease that is similar to that resulting from infection by several other pathogens that are endemic in South American, including dengue, Mayaro, chikungunya, and Zika viruses. The incubation period is between 3-8 days and clinical disease with fever typically lasts for 2-7 days. There are no apparent differences in development of disease based on age or gender.

The most common clinical complaints of patients infected with OROV include fever, headache, arthralgia, myalgia, and vomiting. Other common signs include chills, dizziness, photophobia and rash. Less commonly, but of clinical importance, the virus causes central nervous system disease (e.g. meningitis) and hemorrhagic manifestations. Some patients experience recurrent disease for several weeks, and it appears that a significant number of infections are subclinical in nature. Human mortality due to infection with OROV has not been observed.

A large fraction of patient tested during the first few days of clinical disease are viremic, with virus titers between 10³ and 10⁷ infectious doses per ml of serum, supporting the view that humans serve as the sole amplifying host during urban outbreaks.

There are no specific therapies for Oropouche fever, and treatment is symptomatic. Vaccines to prevent OROV infection have not yet been developed. The principle means of control for this pathogen is vector control and use of repellents.

Non-Human Animal Hosts

The original isolation of OROV was from a sloth in Brazil in 1960, followed shortly by isolation from a marmoset, also in Brazil. These events indicated that Oropouche fever is likely a zoonotic disease, although subsequent studies suggested that the urban cycle is driven by human-vector-human transmission only.

Experimental inoculation of OROV into diverse animals revealed that several species of South American monkeys, three-toed sloths, and cane mice developed viremia and may serve as virus amplifying hosts. Although chickens appear highly resistant to infection, antibodies to the virus were detected in a small number of wild birds, suggesting that they possibly participate in sylvatic transmission cycles. Antibodies were not detected in dogs, cats, marsupials, bats, pigs, or reptiles, but such data are far from definitive in delineating host range for this virus.

Diagnostic Testing and Laboratory Assay

Similarities in the disease induced by OROV versus a number of other arthropod-borne pathogens make diagnosis based on clinical signs and common laboratory parameters not feasible. Rather, diagnosis depends on specific testing for OROV, usually by PCR, or by assays for antibody specific to that pathogen. A number of serologic tests have been applied to diagnosis of OROV infection, including hemagglutination-inhibition, neutralization and IgM capture assays.

OROV replicates cytopathically in a broad range of vertebrate cells and plaque assay is commonly used to quantitate the virus in stocks or samples from infected animals.

References and Reviews

• U.S. Centers for Disease Control and Prevention. Crimean-Congo Hemorrhagic Fever (CCHF)
• World Health Organization. Crimean-Congo Hemorrhagic Fever (CCHF).

Updated July 2019. Send comments to Richard.Bowen@colostate.edu