CRIMEAN-CONGO HEMORRHAGIC FEVER

India is fast becoming a hotspot for emerging illnesses. The last decade has seen infectious diseases and viral hemorrhagic fever of emerging and re-emerging forms in the country. Crimean-Congo hemorrhagic fever (CCHF) is a widespread disease caused by a tick-borne virus, Nairovirus of family Bunyaviridae. The disease was first characterized in Crimea in 1944 and then later in 1969 as the cause of illness in Congo, thus resulting in the current name of the disease. CCHFV has been isolated from domesticated and wild mammals including cattle, sheep, goats, water buffalo and hares. Nineteen samples of blood taken from cows and buffaloes were found positive for Crimean-Congo Hemorrhagic Fever (CCHF) antibodies in Jodhpur in September, 2019, where two people had already died of the disease. CCHF is a zoonotic disease and tick vectors are widespread, thus, numerous animals can be hosts. Major risk groups include farmers, veterinarians and abattoir workers in endemic areas and most of the affected cases deal with agriculture and/or domestic animal husbandry and slaughtering activities. Therefore, monitoring of virus circulation in zoonotic foci and education of high-risk groups are important. Animals become infected by the bite of infected ticks of the genus Hyalomma and play a crucial role in the life cycle of ticks as well as in the transmission and amplification of the virus and are, therefore in the focus of veterinary public health. The typical course of CCHF infection has four distinct phasesincubation period, pre-hemorrhagic phase, hemorrhagic phase and convalescent phase. The virus enters and gets released in endothelial cells causing endothelial damage, increased vascular permeability and impairment of the immune response. Infected mice revealed discolored liver and spleen, serosal petechia and intestinal hyperemia. The liver texture appeared brittle and white pulp in the spleen was diminished. There was massive hepatocyte necrosis and mild sinusoidal congestion. Human infection with CCHFV often results in severe hemorrhagic disease.


INTRODUCTION
India is fast becoming a hotspot for emerging illnesses. The last decade has seen infectious diseases such as Nipah, Avian influenza, pandemic influenza, Severe Acute Respiratory Syndrome (SARS) corona virus, chikungunya virus and viral hemorrhagic fever of emerging and reemerging forms in the country. Few diseases have the capacity to stimulate the interest and instill concern both in the general population and the health-care community as do viral hemorrhagic fevers (VHFs). Some of the major hemorrhagic fever viruses like Lassa, Marburg, Ebola, agents of South American VHF, Hanta and Crimean-Congo, share a distinct characteristic that has important clinical and public health consequences, namely the potential for person-to-person transmission (Mardani and Keshtkar-Jahromi, 2007). Crimean-Congo hemorrhagic fever (CCHF) is a widespread disease caused by a tickborne virus Nairovirus of the Bunyaviridae family which causes severe human hemorrhagic fever disease characterized by fever, weakness, myalgia and hemorrhagic signs (Center for Disease Control and Prevention, 2013).

HISTORICAL PERSPECTIVE
The virus was recognized from an outbreak of "Crimean hemorrhagic fever" in soldiers and peasants in the Crimean Peninsula in 1944 but was not isolated or characterized until 1967. "Congo hemorrhagic fever" virus, isolated from a patient in the former Zaire (now Democratic Republic of Congo) in 1956, was shown in 1969 to be the same virus. As a consequence, the names of both countries have been used in combination to describe the disease (Hoogstraal, 1979). Distribution of the virus reflects the broad distribution of Hyalomma ticks, the predominant vector of the virus (Swanepoel and Paweska, 2011).

DISCOVERY OF THE VIRUS
Crimean hemorrhagic fever (CHF) was first described as a clinical entity in 1944-1945 when about 200 Soviet military personnel were infected during an epidemic in war-torn Crimea (Chumakov,1947). After that, a viral etiology was suggested by reproducing a febrile syndrome in psychiatric patients undergoing pyrogenic therapy after inoculation with a filterable agent from the blood of CHF patients. In 1967, a breakthrough in CHF research came when Chumakov and his colleagues at the Institute of Poliomyelitis and Viral Encephalitides in Moscow first used newborn white mice for CHF virus isolation (Chumakov et al., 1968). The resulting Drosdov strain, isolated by this method from a patient (Drosdov) in Astrakhan, became the prototype strain for experimental work in Russia and elsewhere.

ETIOLOGY
The virus is now placed in genus Nairovirus, family Bunyaviridae, is an enveloped, negative sense trisegmented single stranded RNA virus. When viewed by negative stain electron microscopy, CCHF virions appear to be distinct from other viruses within the Bunyaviridae family, as they possess very small morphologic surface units with central holes arranged in no obvious order (Martin et al., 1985). Its genome is of three singlestranded RNA segments encapsidated by the nucleocapsid protein (CCHFV N) to form the ribonucleoprotein complex. This ribonucleoprotein complex is required during replication and transcription of the viral genomic RNA. Virions of members of the family Bunyaviridae contain three structural proteins: two envelope glycoproteins (G2 and G1 [more recently termed Gn and Gc, respectively] named in accordance with their relative proximity to the amino or carboxy terminus of the M segment encoded polyprotein) and a nucleocapsid protein (N), plus a large polypeptide (L) (approximately 200 kDa), which is the viron-associated RNA-dependent RNA polymerase. The viruses are approximately 80 to 120 nanometers in diameter and are enveloped viruses with negative sense, single stranded RNA genomes in three segments: L (large), M (medium) and S (small), each of which is contained in a separate nucleocapsid (N) within the virion, Gn and Gc glycoproteins, and the L polymerase respectively. The virus can be isolated from serum or plasma samples collected during the febrile or viraemic stage of infection or from liver of infected animals (OIE, 2018). The S segment codes for a nucleocapsid (N) protein, the M segment encodes a precursor for the 2 envelope glycoproteins Gn and Gc and the L segment codes for the RNA dependent RNA polymerase (Haferkamp et al., 2005). CCHFV can survive for a short time in the environment, especially in some organic material. Infectious virus was found for up to 10 days and occasionally longer, in blood kept at 4°C (39°F). CCHFV was also reported to remain infectious in serum for at least a few days at unspecified ambient temperatures and to be stable "under wet conditions" for 15 days at 4°C, 11 days at 20°C (68°F) and 7 hours at 37°C (99°F). Dried virus was found to remain infectious for less than 24 hours (Center for Food Security and Public Health, 2019).

SPECIES AFFECTED
CCHFV has been isolated from domesticated and wild mammals including cattle, sheep, goats, water buffalo, hares, African hedgehogs and multimammate mice. Serological evidence of exposure has been reported in many additional species, such as horses, donkeys, camels, water buffalo, dogs, red foxes, wild dogs, Pallas cats, genets, a number of African ungulates, various rodents and bats (Chinikar et al., 2012). Serological surveys in birds have mostly found no evidence for infection. However, ostriches are susceptible to CCHFV and are sometimes infected in nature. A low level of viremia was also reported in an experimentally infected guinea fowl and antibodies were found in one naturally infected magpie, although pooled sera from several groups of magpies were seronegative (Nalca and Whitehouse, 2007). A hornbill and a glossy starling developed antibodies to CCHFV and ticks fed on these birds apparently acquired the virus and transmitted it to rabbits (Turell, 2007). There is very little information about reptiles, but one tortoise from Tadzhikistan was seropositive (Spengler et al., 2016).

TRANSMISSION Reservoir
Crimean-Congo hemorrhagic fever virus circulates in a silent enzootic tick-vertebrate-tick cycle, and there is no evidence that the virus causes any disease in animals. Tick is not only a vector but can also be a reservoir of the virus via vertical transmission (OIE, 2018). Ticks from the Hyalomma genus are the principal vectors of CCHF virus (Ozdarendeli et al., 2008). Although the virus has also been isolated from other genera of Ixodid tick. Hyalomma marginatum is the main vector for CCHF in southern Europe; the virus has also been identified in Hyalomma lusitanicum in Spain (Estrada-Pena et al., 2012). Hares and hedgehogs act as amplifying hosts for the immature stages of the ticks. Hyalomma marginatum is usually activated by the increasing temperature in spring (beginning of April) and the immature stages are active in summer between May and September in the northern hemisphere (Ergonul and Whitehouse, 2007). Virus replicates in the host tick as it passes from the larva through adult stages (transstadial transmission) and it can also be transmitted from one generation to other (transovarial transmission).

Mode of transmission
Humans become infected through bites of infected ticks or by contact with infected blood or other livestock tissue. Nosocomial transmission may occur through direct contact with infected blood or body fluids, or through contaminated medical equipment or supply (Gurbuz et al., 2009).

Risk groups
Major risk groups include farmers, veterinarians and abattoir workers in endemic areas and most of the affected cases deal with agriculture and/or domestic animal husbandry and slaughtering activities (Tekin et al., 2010). Meat itself is not the source of infection because the virus is inactivated by post-slaughter acidification of the tissue, and CCHF virus does not survive cooking. Healthcare workers are the second most affected group while treating CCHF patients with severe bleeding and hemorrhage in a hospital setting, without strict barrier nursing procedures. Outdoor activities in endemic areas are a risk factor for tick exposure. The natural cycle of CCHFV includes transovarial and trans-stadial transmission among ticks and a tickvertebrate-tick cycle involving a variety of wild and domestic animals. Infection can also be transferred between infected and uninfected ticks during co-feeding on a host; also called 'non-viraemic transmission' phenomenon. Hyalomma ticks feed on a variety of domestic ruminants (sheep, goats, and cattle) and wild herbivores, hares, hedgehogs, and certain rodents. Although animal infections are generally subclinical, the associated viraemia levels are sufficient to enable virus transmission to uninfected ticks (Swanepoel and Paweska, 2011). Although they do not appear to become viraemic, ground feeding birds may act as a vehicle for spread of CCHFV infected ticks. Results from serological surveys conducted in Africa and Eurasia indicate extensive circulation of the virus in livestock and wild vertebrates (Swanepoel and Burt, 2004).

EPIDEMIOLOGY
The CCHF virus causes severe viral hemorrhagic fever outbreaks with a case fatality rate of 10-40%. CCHF is endemic in Africa, the Balkans, the Middle East, Southern Europe, Eastern Europe (particularly in the former Soviet Union), throughout the Mediterranean, northwestern China, central Asia and the Indian subcontinent i.e. Asian countries and south of the 50th parallel north is the geographical limit of the principal tick vector (WHO, 2013). Seasonal variations have been described. In Iran, the high incidence was in August and September. In Pakistan, CCHF was more common between March and May and again, between August and October, depicting a biannual surge (Sheikh et al., 2005). Changes in climatic conditions have been suggested to be one of the factors that have facilitated reproduction of the tick population, and consequently the increased incidence of tick-borne infectious diseases (Gubler et al., 2001). Molecular epidemiology of African and Asian CCHF isolates by examining phylogenetic relationships were examined for 70 CCHFV isolates from southern, central, and western parts of Africa, the Middle East and Greece using sequence data determined for a region of the S segment of the genome. Analysis revealed up to 18% genetic differences (Burt and Swanepoel, 2005). Tree topology supports previous evidence for the existence of three groups of genetically related isolates; A, B, and C. Within group A, there are two clades: an African clade and a predominantly Asian clade comprising isolates from Pakistan, China, Iran, Russia, and Madagascar. Group B includes isolates from South and West Africa and Iran and group C includes a single isolate from Greece. Despite the potential of dispersal of the virus between Africa and Eurasia, it appears that circulation of the virus is largely compartmentalized within the two land masses, and the inference is that the geographic distribution of phylogenetic groups is related to the distribution and dispersal of tick vectors of the virus (Burt and Swanepoel, 2005).

Indian Scenario
With the presence of CCHF virus confirmed in adjoining Pakistan, China and Afghanistan -countries that India has had trade ties with for years -scientists have long suspected the presence of the virus here. CCHF viral infection had not been reported in humans from India before, though previous seroprevalence studies have shown viral antibodies both in animals and humans. A total of 643 human sera were tested from all over India, out of which, nine samples from Kerala and Pondicherry were positive for anti-CCHF virus antibody. In the same study, 34 of 655 serum samples collected from sheep, horse, goat and domestic animals from all over India showed evidence of CCHF virus (Shanmugam et al., 1976). In 1977, a survey of Ixodid ticks was conducted to determine the Crimean hemorrhagic fever (CHF) virus activity in Jammu and Kashmir but CCHF virus was not isolated in any of the 138 pools comprising eight species under six genera of ticks (Kaul et al., 1990). However, a related species of the genus Nairovirus -Ganjam virus, that belongs to the Nairobi Sheep group transmitted locally by Hemaphysalis ticks was identified. This virus has veterinary importance in India and has been demonstrated in mosquitoes, man and sheep (Sudeep et al., 2009). The nosocomial outbreak of CCHF viral infection in Gujarat is the first notable report from India. The striking feature of this outbreak was high fatality and rapid spread among treating medical team, taking four lives including the treating medical team (Appannanavar and Mishra, 2011). In Ahemdabad, Gujarat, a patient and her attending nurse were admitted to the hospital with history of high fever for last 3 days and vomiting. Haemoptysis, bleeding from the lips, haematuria, palatal petechiae, haematemesis and difficulty in breathing were observed and death due to multi-organ failure and disseminated intravascular coagulation.
The patient was the first laboratoryconfirmed case of CCHF from India . Studies conducted at the National Institute of Virology (NIV), Pune, had reported the presence of anti-CCHF IgG antibodies in domestic animals (Yadav et al., 2014) and in shepherds (Makwana et al., 2015) from Sirohi district, Rajasthan State. A 30-year-old male was hospitalized in a private hospital in Jodhpur, Rajasthan State, who subsequently had developed thrombocytopenia and showed hemorrhagic manifestations and died in the hospital. Later on, four nursing staff from the same hospital also developed the similar symptoms (Yadav et al., 2016). Nineteen samples of blood taken from cows and buffaloes were found positive for Crimean-Congo Hemorrhagic Fever (CCHF) antibodies in Jodhpur in September, 2019, where two person had already died of the disease. However, one tick out of 26 also tested positive for CCHF. Department of Animal Husbandry (DAH) had sent 30 samples of cattle (cows and buffaloes) and 10 samples of goat. From the test reports received from National Institute of Virology (NIV), Pune, it has been found that goats were not infected with CCHFV but it is cattle which have CCHF antibodies (Times News Network, 2019).

PATHOGENESIS
The interaction of the virus with host cells is most likely responsible for the pathogenesis of CCHF. The main contributors are endothelial cells (ECs) and immune cells. There are two theories underlying the CCHF pathogenesis: One is that the virus interacts with the ECs directly and the other that it interacts indirectly via immune cells with subsequent release of soluble mediators. Following steps are associated with the pathogenesis of the disease (Akinci et al., 2013).

VIRUS ENTRY AND RELEASE IN ENDOTHELIAL CELLS:
The virus probably overcomes its first barrier i.e. epithelium with the help of the tick bite. Viral attachment proteins are localized in the basolateral membrane. As the basolateral compartment of endothelial cells (ECs) is directed toward the blood vessels, viral release from the basolateral membrane into the bloodstream causes systemic dissemination.

DISSEMINATION OF THE VIRUS:
The tick bite promotes viral release into the vascular system and the virus then amplifies in tissue resident macrophages and dendritic cells (DCs) which may facilitate transmission of the virus to the local lymph nodes, spleen and finally to systemic circulation of the host. Primary replication occurs in blood which is subsequently followed by liver and spleen (Bente et al., 2010).

ENDOTHELIAL DAMAGE:
Activation of endothelial cells is critical for starting the inflammatory reactions involving leukocyte rolling, adhesion and transmigration into inflamed areas as well as organization of the immune response to infection and increase of vascular permeability (Connolly-Andersen et al., 2011). Release of proinflammatory cytokines like IL-1, IL-6, IL-8, IL-10 and tumor necrosis factor-α (TNF-α) also contribute to the progression of the disease which have toxic effects on the endothelium leading to increased vascular permeability, vasodilatation, multiorgan failure and shock. Thus, the pathogenesis of CCHF and sepsis is similar.

INCREASED VASCULAR PERMEABILITY:
The release of vasoactive mediators by activated ECs is likely to be responsible for increased vascular permeability. TNF-α possibly causes vascular leakage in CCHF. When ECs are exposed to TNF-α, vascular permeability due to destabilization of microtubules is observed with disruption of tight junctions followed by increased permeability and leakage (Petrache et al., 2003).

IMPAIRMENT IN THE IMMUNE RESPONSE:
CCHFV can impair the innate immune system and cause a delay in the adaptive immune response, which is critical for clearance of CCHFV (Saksida et al., 2010). The virus has many different ways to block the immune response like partial activation of macrophages and dendritic cells, leading to uncontrolled viral replication and the systemic spread of the virus throughout the body, hemophagocytosis, delayed induction of interferons, undetectable antibody response and depletion in the numbers of natural killer cells and lymphocytes. The systemic spread of virus to macrophages and dendritic cells leads to the release of mediators that modify vascular function and have procoagulant activity (Bray, 2005).

CLINICAL SIGNS:
CCHFV is thought to infect animals with few or no clinical signs (Nalca and Whitehouse, 2007). No illnesses have been attributed to this virus in naturally infected animals. Most experimentally infected livestock (cattle, sheep, goats, horses, donkeys) and wild species (e.g., hares, hedgehogs) also remained asymptomatic, although a transient mild fever was seen in some individuals and two calves were lethargic, with a reduced appetite, for a few days. One virus was isolated from a febrile cow during an outbreak of abortions, but whether other agents also occurred in the herd is unclear. Viremia levels and duration are relatively low and short and antibodies are detectable shortly after cessation of viremia. Human beings are the only host of CCHFV in whom the disease manifestations are visible. In contrast to the inapparent infection in most other vertebrate hosts, human infection with CCHFV often results in severe hemorrhagic disease. The typical course of CCHF infection has four distinct phases -incubation period, pre-hemorrhagic phase, hemorrhagic phase and convalescent phase (WHO, 2018). The incubation period for CCHF virus is in the range of 3-7 days. The mean duration is largely influenced by the route of infection, viral load and source of infection-blood or tissue from livestock. The minimum viral load required for transmission of disease is 1-10 organisms (Franz et al., 1997). The disease begins with the pre-hemorrhagic phase, characterized by non-specific prodromal symptoms, during which it mimics other viral diseases. The major symptoms include high fever, myalgia, headache, nausea, abdominal pain and non-bloody diarrhea. This is accompanied by hypotension, relative bradycardia, tachypnea, conjunctivitis, pharyngitis and cutaneous flushing or rash (Swanepoel, 1994). The pre-hemorrhagic phase lasts for 4-5 days and in a majority of the patients, it progresses to hemorrhagic phase. The hemorrhagic phase is generally short and has a rapid course with signs of progressive hemorrhage and diathesis. These include petechiae, conjunctival hemorrhage, epistaxis, hematemesis, hemoptysis and melena. Certain patients may also have hepatosplenomegaly (Ozkurt et al., 2006). The disease is fatal in 40-60% of the cases. In severe cases, death occurs as a result of multiorgan failure, disseminated intravascular coagulation and circulatory shock. Acute respiratory distress syndrome (ARDS) and diffuse alveolar hemorrhage, accompanied by systemic inflammatory reaction, have also been reported during hemorrhagic manifestations (Doganci et al., 2008). In the survivors, the convalescent period begins 10-20 days after the onset of illness. During this phase, patients may have feeble pulse, tachycardia, loss of hearing, memory loss and alopecia. Clinical studies have demonstrated that thrombocytopenia, leucopenia and raised levels of liver transaminases are hallmarks of CCHFV infection and can be used to predict fatal outcome in 90% of patients (Joubert et al., 1985).

LESIONS: Gross lesions: -
In study conducted by Negredo et al. (2017), gross examination of organs from CCHFV-infected STAT129 mice revealed discolored liver and spleen, serosal petechia and intestinal hyperemia. The liver texture appeared brittle and white pulp in the spleen was diminished (Bente et al., 2010). In humans, gross examination revealed generalized visceral edema with substantial amounts of serohematic ascitic fluid and disseminated cutaneous and visceral hemorrhages. The liver was normal in both weight and size, with a brownish appearance and softened consistency (Negredo et al., 2017).

Histopathological lesions
Prominent histopathologic changes were observed in liver and spleen tissues in CCHFV-infected STAT129 mice in a study conducted by Bente et al., 2010. There was massive hepatocyte necrosis, with sparing of narrow periportal and pericentral rims and mild sinusoidal congestion. No Kupffer-cell hyperplasia or inflammatory infiltrates were observed. The hepatocytes had a swollen appearance and widespread necrosis. In general, the hepatocytes contained cytoplasmic macro and microvesiculation. Although most mucosae were preserved, the appearance of the colon was striking owing to its complete epithelial denudation. The crypts were filled with basophilic mucoid material and walled by sloughed apoptotic cells, again without inflammatory infiltrates. Occasional microthrombi were observed. The bone marrow showed hemorrhages and a preserved megakaryocyte population with a normal morphologic appearance. The spleen showed slight lymphoid depletion and hemorrhage but no necrotic areas were observed by the workers.

LABORATORY DIAGNOSIS
Common laboratory findings reveal leucopenia and thrombocytopenia in patients with CCHF and indicate elevated levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK) and lactate dehydrogenase (LDH) along with prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT) (Shayan et al., 2015). Also, increased myeloperoxidase expression in leukocytes leads to increased leukocyte lysis. Therefore, leucopenia in patients with CCHF may be attributed to lysis (Guven et al., 2013). Clinical studies have demonstrated that thrombocytopenia, leucopenia and raised levels of liver transaminases are hallmarks of CCHFV infection and can be used to predict fatal outcome in 90% of patients (Joubert et al., 1985). As CCHF mimics a wide range of common illnesses caused by different etiological agents which are endemic in India, differential diagnosis should be done based on clinical, biochemical, haematological, bacteriological and virological findings. These include Kyasanur forest disease, hepatitis, Neisseria meningitidis infection, leptospirosis, borreliosis, typhoid, rickettsiosis, dengue and malaria. However, malaria diagnosis can be excluded in cases of suspected viral haemorrhagic fever (Zeller, 2007). Following methods can be used for identification of the causal agent:

Viral isolation
The most definitive way of diagnosis is the demonstration of virus or viral genome. The virus may be isolated from blood or tissue specimens in the first five days of illness and grown in cell culture (Shephered et al., 1986). Viral isolation is done by using cell lines such as LLC-MK2, Vero, BHK-21, and SW-13.4 and can be achieved in 2-5 days. CCHF virus generally produces no or little cytopathic effect and can be identified by immune fluorescence assay with specific monoclonal antibodies. However, viral isolation is useful only in the early phase of infection when the viral load is high but suffers from poor sensitivity. Moreover, this can be done only if the Biosafety Level 4 containment facilities are available.

Molecular methods
Demonstration of viral genome is by far the most definitive form of diagnosis. Reverse-transcriptase PCR (RT PCR) is the method of choice for rapid laboratory diagnosis of CCHF virus infection. Another benefit to molecular diagnostic assays is their rapidity as compared to virus culture and a presumptive diagnosis can be made within 8 hours. The real-time PCR assay has various advantages like lower contamination rate, higher sensitivity and specificity and provides result in a few minutes. A one-step real-time RT-PCR assay for detecting CCHFV using primers to the nucleoprotein gene, using DNA-intercalating dye, SybrGreen I was used (Drosten et al., 2003). Later, a real-time RT-PCR assay was developed using TaqMan-Minor Groove Binding Protein (MGB) probe, which had higher specificity and a shorter probe length (Whitehouse, 2004).

Serological assays
Serological tests are useful in the second week of illness. Serological tests formerly used for the detection of antibody to the virus, such as complement fixation, hemagglutination inhibition and reverse passive hemagglutination inhibition, lacked sensitivity and reproducibility, but indirect Immunofluorescence (IF) could detect IgG and IgM antibody responses by days 7-9 of illness in all survivors of the infection. Enzyme-Linked Immunosorbent Assay (ELISA) to detect specific IgM and IgG have largely replaced these conventional serodiagnostic tests. Specific IgM persists for up to 4 months post-infection while IgG remains detectable for at least 5 years. Recent or current infection is confirmed by demonstrating IgM, using IgM antibody capture (MAC)-ELISA in a single sample or a fourfold or greater increase in antibody titer in paired serum samples (Charrel et al., 2004). A recombinant nucleoprotein (rNP)-based IgG ELISA was developed for serological diagnosis of CCHF virus infections. This was shown to be a valuable tool for diagnosis and epidemiological investigations of CCHFV infections (Saijo et al., 2002).

TREATMENT
Lack of significant clinical disease in livestock warrants no treatment considerations. Supportive therapy is the most essential part of case management in humans and includes the administration of thrombocytes, fresh frozen plasma and erythrocyte preparations. Replacement therapy with these blood products should be done after checking the patient's complete blood count, which should be done once or twice a day Fluid and electrolyte balance should also be monitored meticulously. Ribavirin is the recommended antiviral agent for infected patients, although its mechanism of action is not clear. In one invitro study, ribavirin was shown to inhibit viral activity and some CCHF viral strains appeared more sensitive than others (Watts et al., 1989). In an experimental study done in mice, ribavirin treatment substantially reduced infant mouse mortality and extended the mean time to death (Tignor and Hanham, 1993).

CONTROL AND PREVENTION
Currently, 2 vaccines against CCHFV have been developed for use in humans. The first one is a formalininactivated vaccine, which was developed in Bulgaria from infected suckling mouse brain. The second is a DNA vaccine tested in mice. Neither vaccine has undergone official randomized clinical trials (Papa et al., 2011). Efficient ways to protect against CCHFV infection are tick control and limited exposure to infected livestock or humans. To minimize tick exposure, protective clothing and application of repellent is recommended (WHO, 2013). Insect repellants containing DEET (N, N-diethylm-toluamide) are most effective in warding off ticks. Clothing should be chosen to prevent tick attachment, especially covering legs and arms. Healthcare workers in endemic areas may be exposed to infected blood or tissue from patients with CCHF. Therefore, such workers should wear gloves, gowns and face masks to reduce the risk of exposure. Also, they must follow proper infection-control precautions to prevent occupational exposure (Bajpai and Nadkar, 2011). Illegal transportation of animals among countries may result in expansion of CCHFV; therefore, prevention of illegal transportation of animals may reduce the spread of CCHFV (Vorou, 2009).

CONCLUSION
Crimean Congo hemorrhagic fever is a considerable public health threat which can have significant effect on abattoir workers and healthcare personnel, especially in resourcepoor countries. The fact that a huge population of the livestock is in close contact with the human beings indicates the possibility of spread of this virus in different parts of India. In a developing country like India, only a few Biosafety level-4 laboratories are available and out of those only a few are capable to carry out viral diagnosis. This is one of the main limitations to deal with this infectious disease. It is also necessary to develop a network of health officials at root level to report the cases and co-ordinate with samples sharing, diagnosis and implementation of necessary actions in coordination with state governments for appropriate control of this disease. There is a need for active surveillance not only for existing pathogens in any geographic location but also for those that pose future threat. National inter-sectoral surveillance and response system and cross-border sharing of information and establishing special community-based laboratory surveillance programs for at risk population groups needs to be developed.