Crimean-Congo hemorrhagic fever (CCHF) is a viral, tick borne, and zoonotic disease. Crimean-Congo hemorrhagic fever disease was 1st appeared in 1944 in Crimea, about 200 cases were reported. At that time its name was given as ‘Crimean hemorrhagic fever’ but the virus isolation and identification were not done.
Authors: Dr. Ameema Ayub, Dr. Muhammad Muneeb, Dr. Tahir Sarfaraz, Dr. Muhammad Ali Tahir
Introduction and History:
In 1956 the same virus was isolated from the Congo region, and its name was decided as Crimean-Congo Hemorrhagic fever. CCHF is an acute disease and has prevalence throughout the world such as in Africa, Europe, the Middle East, and Asia. New outbreaks had been reported from Pakistan, India, Afghanistan, Senegal, Iran, Kosovo, Albania, Kenya, turkey, Russia, Bulgaria, Greece, Spain, and Mauritania in 2000. Through serological testing, it has been confirmed that CCHFV occurred in different parts of France, Hungary, Greece, and Portugal in the 19’s. The incidence ratio of CCHF increased from 2008 to 2012. CCHF has zoonotic importance so its prevalence is a threat to global health because of the high mortality, epidemic potential, nosocomial infection, and difficulties in prevention and treatment.
Etiology:
CCHFV belongs to the genus Nairovirus and family Bunyaviridae. This family has 5 genera and 3 of them (Phlebovirus, Nairovirus, and Hantavirus) are a major cause of hemorrhagic fever. Nairovirus has 7 serogroups. CCHF virus is spherical and about 100nm in diameter and a host-derived lipid envelope. This virus is categorized as a negative-sense RNA virus. The virus has 3 main segments; small, medium and large, each contains separate nucleocapsid in virion. Negative-sense RNA has low rates of recombination. Two phylogenetic researches gave us authentication about the potential recombination only among the S segments but not among M and L. Different recombinants of CCHFV strains include Drosdov, Kashmanov, and STV/HU29223 from Russia, HY-13 and 66109 from China, TI10145 from Uzbekistan, and JD206 from Pakistan. This recombination occurred in specific and short genome regions.
Transmission:
CCHFV required a vector for the transmission. Ticks, genus Hyalomma, are the major source of the CCHFV transmission. About 28 Ixodid spp and 2 Argaisdae spp are the main reservoirs and vector source for CCHFV. Ticks have metamorphosis in their life cycle. They develop in egg, larvae, nymph, and adult. Larvae hatched from the eggs and climb to the fodder or vegetation then pass to the animals. Transstadial transmission occurs in some species of Rhipicephalus, Dermacentor, and Hyalomma. The virus passes from larva to nymph and then adult after feeding on an infected host. The virus spread throughout the world, endemic to nonendemic areas, via livestock transfer and migratory birds. Migratory birds carry infected ticks and play an important role in virus distribution on a large scale. Importing livestock also the source of transfer of the infected ticks into other regions. Transovarial transmission and venereal transmission also occur in some vector species. Also, the venereal transmission has been demonstrated among some vector species, which continue the flow of virus circulation in nature. Also, ticks itself infected by co-feeding with other infected ticks on uninfected hosts.
Humans are infected through the tick bite or by direct contact to the infected animals or anything in contact with the virus. CCHF is highly zoonotic and fatal. Veterinarians, owners, caretakers, slaughterhouse officers, workers, and farmers are at high risk during the outbreak. The virus can be transferred person to person by direct or indirect contact with body fluids, skin, and mucous membrane of the infected person. Hospital setting and fomites used to treat the patient can also be the source of the infection spreading. High temperature and carbon dioxide concentration contribute to virus proliferation. Spring and summer season may accelerate the tick’s life by interstadial development.
Prevalence:
CCHF is more prevent in the stress and hot environment, most probably in July and august months. In these months the tick infestation is more as compared to the other months of the year. In specific occasions like Eid-ul-Azha and Mandi season when animals have to face humid and stress conditions in gathering, the disease transmission and tick infestation increase at its peak.
Clinical Signs:
CCHF has 4 progressive distinct phases; incubation, pre-hemorrhagic, hemorrhagic, and recovery regarding diseased conditions. The incubation period is variable and depends on the route of virus exposure. When the infection is occurred by a tick bite, the incubation period is 1 to 3 days normally and maximum for 9 days. This period increases 5 to 6 days and a maximum for 13 days if the infection is through infected blood or tissues. Once the incubation period has been completed the pre-hemorrhagic stage starts with chills, fever, myalgia, photophobia, severe headache, and nauseatic symptoms. After 3 to 6 days of onset of disease, the hemorrhagic stage rapidly takes its place. Here is petechial to ecchymotic hemorrhages on nose, gums, mucosal membranes, internal organs, and GIT.
The fatality rate in CCHF is 9% to 50%. The mortality rate is much higher due to nosocomial infections than the tick bite. It has been seen that in dead animals, there is little antibody response against the heavy viral load. The patients with high immunity will enter in the recovery period and takes 15 to 20 days at least. Full recovery can also take about 1 year. In this period, general weakness, dizziness, headache, poor appetite, loss of hair, loss of memory and loss of vision can be observed.
Pathogenesis:
As we know that CCHF is a tick-borne disease. Due to its highly zoonotic properties, its pathogenesis is being clarify day by day. The main thing about the pathogenesis is virus interaction to the animal or human. Two theories are there about the pathogenesis. One is virus interact through the endothelial cells directly and the other is virus interact indirectly to the immune cells with subsequent release of the soluble mediators. Endothelial cells activated on the infection by upregulation of the soluble molecules proinflammatory cytokines. Deregulation and excessively release of the cytokines accompanied by endothelial activation produces toxic effects that cause increased vasodilatation, vascular permeability, and subsequently hypotension, shock, multiple organ failure, and death. CCHF virus is also related to the innate immune system and delayed the adaptive immune response that is a critical condition for the clearance of CCHFV. The virus has so many different processes to stop the immune response, leading to uncontrolled viral replication and spread towards all the systems of the body. Macrophages and dendritic cells activation delayed the induction of the interferons so, weaken the antibody response, and cause apoptosis of the lymphocytes.
Laboratory Findings:
Blood and Liver function tests indicate leukopenia and thrombocytopenia in CCHF patients and reveal increased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and creatine kinase (CK). CCHF patients suffer from increased prothrombin time (PT) and activated partial thromboplastin time (aPTT). Major targets in CCHF are hepatic endothelial cells, Kupffer cells, and hepatocytes. An increase in liver enzymes is basically due to the necrosis of hepatocytes. Leukocyte lysis increased due to the increased myeloperoxidase in the cells. The leakage and damage of the vasculature occur in CCHF due to infection by virus or destruction by secreted cytokines.
As CCHFV is highly zoonotic, it must be approached in biosafety level (BSL)–4 laboratories. The virus can be isolated in a different variety of cell lines e.g. SW-13, Vero, BHK-21, LLC-MK2, and CER1. The cell culture technique is useful when virus concentration is high especially in the first 5 days of the onset of disease. CCHFV produces very poor cytopathic effects (CPEs), so immunofluorescence assay (IFA) using monoclonal antibodies, is the best method to confirm it.
Diagnosis & Treatment:
The best option for the diagnosis of CCHFV is the reverse transcription-polymerase chain reaction (RT-PCR), as this technique is specific, sensitive, and rapid. Blood, Serum, and tissue autopsy are the best samples for RT-PCR. Viral DNA and RNA can also be detected through RT-PCR at 16 days of illness. Nowadays real-time RT-PCR has been introduced for quantification of CCHFV. ELISA is also in practice for antibody (IgG and IgM) detection. CCHF is a viral disease so supportive treatment is recommended. The serum is prepared from recovered patients, is somehow effective treatment. The antiviral drug ‘ribavirin’ is normally used because of its inhibitory effect on virus replication. Fluid therapy, electrolyte balance, hemodynamic support, and oxygenation must be considered during the diseased condition. Other testings that can be used are Antigen Detection, Serum Neutralization, and virus isolation by Cell Culture.
Zoonotic Importance:
The persons dealing with the infected animals are highly susceptible to the CCHFV and suffered from CCHF with early exposure to the virus. The clinical signs in the humans can be high fever, abdominal pain, nausea, diarrhea, purpuric lesion, and hematoma formation, in starting days. After 1-week bleeding may starts from natural orifices e.g. nose and Vigina, because of thrombocytopenia. Sometimes hematological malignancy and ecchymosis at the time of venipuncture can be observed. Hematological malignancy indicates the hem-phagocytosis of neutrophils, erythrocytes, and thrombocytes by histocytes. The fate of the CCHF is the death of the patient. The handler and the doctors must be careful during the treatment of the patient because of viral disease it spread very easily.
The following are some measures that must be used to avoid the zoonotic effects:
- Reduce the risk of tick-to-human transmission:
- Wear long sleeves and long trousers clothing, least area to be exposed to the environment during treating with the animals.
- Wear light-colored clothing that makes easy detection of ticks on the person.
- Use recommended acaricides on clothes to avoid the ticks.
- use recommended repellent on the skin.
- Regularly examine skin and clothes for ticks for our safety.
- Reduce the risk of animal-to-human transmission:
- Wear protective clothes and gloves during handling the animals or treated them in endemic areas.
- Special precautionary measures should be adopted during the slaughtering or culling of the animals.
- Must quarantine the animals before entered in the slaughterhouse and check them thoroughly.
- Reduce the risk of human-to-human transmission:
- Avoid physical contact with the CCHF-infected person,
- Wear protective equipment during taking care of an infected person.
- Personal hygiene is very very important during the outbreak season.
Control and Prevention:
Two vaccines have been prepared by scientists against CCHFV. One of them is a formalin-inactivated vaccine, prepared in Bulgaria from an infected sucking mouse brain. The other one is a DNA vaccine was tested in mice. But these vaccines are not recommended for use publically. Farmers, workers, and every person who deals with the animals must have to use insect repellents on skin and clothing. DEET (N, N-diethyl-m-toluamide), an insect repellent, is most effective against ticks. Gloves and protective clothing must be used during dealing with the animals. Nobody should be allowed to be in contact with an infected animal’s blood or any other body secretions. CCHFV is susceptible to 2% glutaraldehyde and 1% hypochlorite and destroyed by heating at 56°C for 30 minutes. Illegal transportation of animals may help to reduce the spread of CCHFV.
Crimean-Congo Hemorrhagic Fever is the big growing public health threat in the Eastern Mediterranean. It occurs in outbreaks with high fatalities. The representatives of Public health from affected countries arranged the meeting with a group of WHO experts in disciplines of epidemiology, virology, entomology and laboratory science, communication, social mobilization, clinical management, infection control, and veterinary epidemiology. WHO experts in each domain discussed the matter in the plenary session and then start to work on the plan until the eradication of the diseased problem. At the end of the complete group work with specific recommendations on public health measures related to the functional domain were compiled and formulated in the plenary through an informed debate that facilitates the best control measures.
WHO response:
World Health Organization (WHO) is collaborated with the partners to support CCHF surveillance, outbreak response, diagnostic capacity, and activities in Asia, the Middle East, Europe, and Africa.WHO also arranged the data documentation to speed up disease investigation, diagnosis, and control.
Authors: Dr. Ameema Ayub, Dr. Muhammad Muneeb, Dr. Tahir Sarfaraz, Dr. Muhammad Ali Tahir