None for animals.
Commercial ELISA tests: For both IgG and IgM
– ELISA CCHF IgG (Vektor-Best, Russia)
– ELISA CCHF IgM (Vektor-Best, Russia)
Commercial IFA tests:
- CCHF IgG Sandwich ELISA (Biological Diagnostic Supplies Limited, BDSL®)
- IFA test based on recombinant antigens GPC and N / biochip technology, under evaluation (Euroimmun®)
PCR assay AmpliSens CCHF:
- Real Time RT-PCR assay by Altona (Germany)Altona Diagnostic PCR (Europe)
- Developed and manufactured by Central Institute of Epidemiology, Russia.
- Specific for CCHF virus RNA.
- Target: S segment RNA; internal control included.
Antibody detection detects evidence of exposure not necessarily current infection (unless an IgM test is used). Little information is available about how quickly antibody levels drop, nor whether the antibodies are protective.
Development of novel bio-safe neutralization assays.
Yes. Euroimmune (IFA) and Altona (IFA (as above)
ELISA (as above).PCR (as above).
None in animals. In humans, an inactivated vaccine derived from mouse brain has been used in the former Soviet Union and Bulgaria (not FDA approved).
GAP: Development of a safe and effective vaccine for human use has a high priority.
Approaches for diagnostic methods should be standardised and validated.Limited requirements for new diagnostics in animals.
Developing standards (serum and virus strain panels) for diagnostic validation.Establishing a European laboratory network with capacities to test performance of novel diagnostic developments.
It is considered that a major hindrance in developing vaccines against CCHF virus is the wide genetic variation noted in different strains. Nucleic acid sequence analysis has demonstrated extensive genetic diversity, particularly between viruses from different geographic regions. However genetic variation does not correlate with serotype variants, since currently there is only one serotype for CCHFV.Animal models for CCHF infection are currently available.GAP: More extensive preclinical trials to confirm whether/how genetic variation affects vaccine efficacy should be performed using currently available animal models.
CCHF is a zoonotic viral disease that is asymptomatic in infected animals, but a serious threat to humans. The virus which causes CCHF is an arbovirus which is a member of the Nairovirus genus, a group of related viruses forming one of the five genera in the Bunyaviridae family of viruses.
The general knowledge of migration, epidemiology, re-assortment, recombination and pathogenesis of the virus is very limited.
Knowledge about pathogenicity differences among strains is missing.
The CCHF virus may infect a wide range of domestic and wild animals but there is no evidence that the virus causes disease in animals. Many birds are resistant to infection, but ostriches are susceptible and may show a high prevalence of infection in endemic areas. CCHFV can be found in ostrich blood for 1 to 4 days and in visceral organs for up to five days after experimental infection.
GAP: Prevalence needs to be measured in animals in endemic areas.
Members of the Nairovirus genus are transmitted by argasid or ixodid ticks. Once infected, the tick remains infected through its developmental stages. The mature tick may transmit the infection to large vertebrates, such as livestock.
Population dynamics depends on climatic factors — ecologic changes — wildlife and human factors.
Some studies on CCHFV molecular detection in ticks have been published.
GAP: Tick competence studies in different species needs to be addressed to understand their role as virus reservoirs.
Trans-ovarial, transstadial and venereal transmission have been demonstrated amongst some vector species, in particular the Hyalomma ticks. Many species of mammals can transmit CCHFV to ticks when they are viraemic.
Tick attachement time for efficient virus transmission to the host (animal/human).
Knowledge about virus receptors in animals and humans is missing.
CCHFV usually circulates between asymptomatic animals and ticks in an enzootic cycle.
An understanding of the pathogenesis and cycle in animals would be of use. Especially the incubation time, length of the viraemic phase and the length of time after the initial infection and viraemic phase that infected animals would continue to be able to infect ticks. Once the viraemic phase is completed is there a low level of circulating virus in the blood which has the potential to infect feeding ticks or does the development of antibodies preclude any circulating virus?
There is no evidence that the virus causes disease in animals although a wide range of domestic and wild animals may become infected with CCHF virus. Sheep, goats and cattle develop high titers of virus in blood, but tend not to fall ill. Birds are generally resistant with the exception of ostriches.
Will the high titres developed reduce the levels of circulating virus resulting in the animals being less infectious to ticks?
Why animals do not develop any sign of disease?
Mammals become viraemic and can transmit CCHFV in their blood and tissues. Domesticated ruminants including cattle, sheep and goats are viraemic for one week after experimental infection.
Domestic ruminant animals, such as cattle, sheep and goats, are viraemic for around one week after becoming infected.
Studies to better understand and reveal the natural cycle of CCHF virus in animals, humans and vectors.
Virus transmission between animals can occur in the absence of vector? Is there evidence for vertical virus transmission?
Non-pathogenic in animals.
GAP: Research on CCHF pathogenesis and immune response in experimentally infected animals.
The incubation period in humans is 1-14 days depending on the route of transmission.
Human infections begin with nonspecific febrile symptoms, but progress to a serious hemorrhagic syndrome with a high case fatality rate. After a short incubation period (1-14 days), the onset of symptoms is sudden, with fever, chills, myalgia (aching muscles), dizziness, neck pain and stiffness, backache, severe headache, sore eyes and photophobia and back and abdominal pains. There may be nausea, vomiting and sore throat early on, which may be accompanied by diarrhoea and generalised abdominal pain. Over the next few days, the patient may experience sharp mood swings, and may become confused and aggressive. After two to four days, the agitation may be replaced by sleepiness, depression and lassitude, and the abdominal pain may localize to the right upper quadrant, with detectable hepatomegaly (liver enlargement).
Additional symptoms can include neuropsychiatric, and cardiovascular changes. In severe cases, hemorrhagic manifestations, ranging from petechiae to large areas of ecchymosis, develop. (2)
Few studies on immune response in CCHF have been published.
GAP: The knowledge is limited and further research on CCHF pathogenesis and immune response is necessary.
CCHF virus is distributed through large areas of Sub-Saharan Africa, South-Eastern Europe, Middle-East, Central Asia, India and North- West of China. It has been found in parts of Europe including southern regions of the former USSR (Crimea, Astrakhan, Rostov, Uzbekistan, Kazakhstan, Tajikistan), Turkey, Bulgaria, Greece (1 case), Albania and Kosovo province of the former Yugoslavia. The geographical distribution of the virus mirrors that of its principal tick vector Hyalomma spp. Presence of CCHFV genome detected in ticks from deers in southwest Spain. Recent human cases derived from tick bite and nosocomial infection appeared Spain in September 2016 as the first cases in Western Europe.
GAP: Further evaluation and classification of environmental conditions that can influence the spatiotemporal distribution and dynamics of CCHF.
Climatic factors can influence the numbers of ticks in the environment and the incidence of disease.In some countries, CCHF tends to be seasonal. This disease is most common in Iran during August and September, and in Pakistan from March to May and August to October. In Turkey disease appears earlier and ends in October.
Potential for transboundary movement especially with the movement of potentially asymptomatic carriers which have the potential to infect ticks at their new destination.
GAP: Do long term asymptomatic carriers exist or is it only the incubating and viraemic animals which pose a problem?
Some studies on immune response have been published. A cytokine storm is observed.
Animal models are available.
Today, there is an animal model for developing vaccine and antivirals, however, still we need to identify an animal model for studying host response to infection.
Further research is needed to study the immune response in animal models and in patients for evaluation of intervention and control strategies.
Persons living in endemic areas should use personal protective measures that include avoidance of areas where tick vectors are abundant and when they are active (Spring to Fall); regular examination of clothing and skin for ticks, and their removal; and use of repellents.
Persons who work with livestock or other animals in the endemic areas can take practical measures to protect themselves. These include the use of repellents on the skin (e.g. DEET) and clothing (e.g. permethrin) and wearing gloves or other protective clothing to prevent skin contact with infected tissue or blood (1).
CCHF can be diagnosed by isolating the virus from blood, plasma or tissues. Cell cultures can only detect high concentrations of the virus, and this technique is most useful during the first five days of illness. Animal inoculation into newborn mice is more sensitive than culture, and can detect the virus for a longer period. CCHFV is identified by indirect immunofluorescence or reverse transcription-polymerase chain reaction (RT-PCR) assays. Virus isolation must be carried out in maximum biocontainment laboratories (BSL-4).
The use of real-time reverse transcription-polymerase chain reaction (RT-PCR), in clinical and tick samples has allowed for both rapid diagnosis of disease and molecular epidemiology studies. Whilst this technique is highly sensitive the genetic variability in CCHFV strains, means that single set of primers cannot detect all virus variants, and most RT-PCR assays are either designed to detect local variants or lack sensitivity. Viral antigens can be identified with enzyme-linked immunoassay (ELISA) or immunofluorescence, but this test is less sensitive than PCR.
Tests detect CCHFV-specific IgM, or a rise in IgG titers in paired acute and convalescent sera. IgG and IgM can usually be found with indirect immunofluorescence or ELISA after 7-9 days of illness. Other serologic tests such as complement fixation and hemagglutination inhibition have been used but lacked sensitivity.
Serology can identify animals that have been infected or exposed to CCHFV. An IgG ELISA can detect antibodies for the remainder of the animal’s life; other tests, including complement fixation and indirect fluorescent antibody, usually detect antibodies for shorter periods. Viraemia can be recognized by virus isolation and other techniques but these tests are not used diagnostically.
GAP: Commercial kits for serology in animals are missing.
A mouse-brain derived vaccine is used in specific groups in Bulgaria (not FDA approved).Few reports on vaccine potential have been published.
To date, a few several candidates available (tested in IFNAR -/- mice), however, the research program needs to further investigate these candidates.An FDA approved vaccine for humans is needed.
The CCHF virus is also a potential bioterrorist agent; it has been listed in the U.S. as a CDC/NIAID Category C priority pathogen.
Control of ticks.
Acaricides can be used on livestock and other domesticated animals to control ticks, particularly before slaughter or export,
In humans in endemic regions, prevention depends on avoiding bites from infected ticks and contact with infected blood or tissues. Measures to avoid tick bites include tick repellents, environmental modification (brush removal, insecticides), avoidance of tick habitat and regular examination of clothing and skin for ticks.
Protective clothing and gloves should be worn whenever skin or mucous membranes could be exposed to viremic animals, particularly when blood and tissues are handled. Unpasteurized milk should not be drunk. In meat, CCHFV is usually inactivated by post-slaughter acidification. It is also killed by cooking.
Human outbreaks have occurred after exposure to infected ostriches during slaughter; these infections seem to be preventable by keeping the birds free of ticks for 14 days before slaughter. In some countries, ostriches are subjected to a 30-day pre-slaughter quarantine period at export facilities.
GAP: The shedding and presence of the virus in meat should be investigated. To date there is possibility to investigate these issues in research facilities with capacities to perform animal experimentation with large animals (bovines, ovines) in BSL-4 conditions.
Serosurveillance of animals.
Seroprevalence studies in humans available.
GAP: The seroprevalence in wildlife is not sufficiently studied.
Limited impact at present although if the disease becomes a major problem could have an impact on tourism, however, the presence of CCHFV, in endemic areas have a big impact for farmers, which in turn may affect the production.
Effective methods to control the Hyalomma ticks
– Ectoparasitic: acaricidal control
– Develop genetically resistant animals
– Control movement of infected animals
– Anti-tick vaccines
– Pheromone-based tick control
– Integrated control of ticks
– Animal vaccines
It has been shown that where wild animals run with domestic animals (cattle) tick control on cattle will also reduce tick burden on the wild animals.
Information drawn from vector and animal surveillance is crucial for predicting human risk for CCHF infection but
also for other tick-borne diseases.
– The standardisation of protocols for tick collection from animals, their identification and screening for possible human pathogens would be helpful;
– Diagnostic capacity would need to be developed accordingly
– Vaccine development for domestic animals
A better understanding of the epidemiology of CCHF in ticks, domestic livestock and wild animal populations, will support the identification of human risk factors for infection and the development of better diagnostics, antiviral drugs and vaccines for humans.
Based on the distribution of the vector.
Population dynamics depends on climatic factors — ecologic changes — wildlife and human factors.
GAP: The role of environmental change, including climate change, needs further assessment.
Changes in climatic conditions could expand the range of the tick vectors, and increase the incidence of disease.
GAP: Tools to monitor and predict virus migration along with potential movement of the associate ticks as a result of climate change.
Over the last years, CCHF outbreaks have become more frequent in several European countries and neighbouring areas, and an increase of large outbreaks caused by CCHF virus (CCHFV) has been observed. Climate changes and recent detection of the CCHF Virus vector in southern Europe and Germany are a cause for concern in Europe. The first Western European human CCHF cases reported appeared in August 2016 in Spain.
The knowledge on CCHF pathogenesis and immune response is limited.
The research activities concerning CCHF disease have been restricted to very few institutes/laboratories, for several reasons:
1. Better understanding of the clinical aspects of the disease and the immune response to the virus.
2. Establishment of rapid and more sensitive diagnostics.
3. Future research on the virus-vector interaction, the CCHFV dynamics in reservoirs and vectors, the role of birds and wildlife.
4. Studies on the role of climate change in the distribution of ticks and the establishment of new CCHFV endemic areas.5. The development of vaccines and treatment strategies for humans and animals.
Expert group members are included where permission has been given.
Alejandro Brun Torres, INIA, Spain - [Leader]
Ali Mirazimi, Karolinska Institute, Sweden
Anna Papa, University of Thessaloniki, Greece
1. WHO Fact sheet N°208. Revised November 2001
http://www.who.int/mediacentre/factsheets/fs208/en/ accessed 29 May 2012
2. An Update on Crimean Congo Hemorrhagic Fever Suma B Appannanavar and Baijayantimala Mishra Glob Infect Dis. 2011 Jul-Sep; 3(3): 285–292.
3. Consultation on Crimean-Congo haemorragic fever prevention and control: Stockholm, September 2008; http://www.ecdc.europa.eu/en/publications/Publications/0809_MER_Crimean_Congo_Haemorragic_Fever_Prevention_and_Control.pdf
4. CCH fever: European research network (Collaborative Project) supported by the European Commission under the Health Cooperation Work Programme of the 7th Framework Programme.
5. Papa A, Mirazimi A, Köksal I, Estrada-Pena A, Feldmann H. Recent advances in research on Crimean-Congo haemorrhagic Fever. J Clin Virol 2015;64:137-43.
6. Papa A, Weber F, Hewson R, Weidmann M, Koksal I, Korukluoglu G, Mirazimi A. Meeting report: First International Conference on Crimean-Congo hemorrhagic fever. Antiviral Res. 2015;120:57-65.