Available at www.veterinaryworld.org/Vol.6/Oct-2013/24.pdf REVIEW ARTICLE Open Access Crimean-Congo hemorrhagic fever: a comprehensive review

Crimean-Congo Hemorrhagic Fever (CCHF) is an emerging tick-born zoonotic disease in India which is caused by Nairovirus of Bunyaviridae family. CCHF is reported from about 30 countries of the world. An outbreak of CCHF has been reported two years back in Gujarat which killed four people including two physicians, one nurse and a rural housewife. Tick bite, contact with infected material and nosocomial routes are the main routes of infection. This disease is not much important in animals as animals are asymptomatic but domestic livestock play a vital role in the transmission of disease to humans. So the persons associated with animals like veterinarians, farmers and slaughter house workers are also at the high risk of getting the infection. The disease has a great public health importance. Rapid diagnosis of disease is very important. The advent of molecular techniques including real-time PCR allow the rapid diagnosis of CCHF. There are limited treatment options for CCHF. Ribavirin is the only known drug which is effective against CCHF.


Introduction
to-human transmission also reported in some cases in various countries [2].Infectious diseases are the leading contributors of mortality and morbidity in humans and animals across History the globe.Many emerging diseases, even epidemics CCHF was first described in the Crimea, Russia are a direct consequence of zoonosis.Some infectious in 1944 by soviet scientists during an outbreak which diseases like viral hemorrhagic fevers (VHFs)are a involved 200 cases of CCHF in soviet military matter of great concern due to their zoonotic nature and personnel.They called it Crimean hemorrhagic fever associated fatality.VHFs are now becoming a severe (CHF) [3].Later in 1956 it was found that the causative threat to animals and humans.Crimean-Congo agent was identical to a virus isolated from a patient in hemorrhagic fever (CCHF) is one of the most widely Congo and the name CCHF was adopted after that [5].distributed viral hemorrhagic fevers among these [1].It Epidemiology and geographical distribution is an emerging zoonotic disease which has drawn attention of international community .Although, it is CCHFV has a mostextensive geographic new to India, outbreaks have been recorded from distribution among all tick viruses and it is widespread various countries in Africa, Asia, South-East Europe, in Eurasia and Africa [6,7].The geographic and Middle East [2].
distribution pattern of disease coincides with the CCHF is a tick born viral zoonotic disease caused distribution of Hyalomma tick vector.The virus is by virus of genus Nairovirus of Bunyaviridae family reported from about 30 countries which include Africa [3].The disease is distributed globally which can be (Uganda, Sudan, Democratic Republic of Congo, correlated by the global distribution of the tick vector Nigeria, Mauritania, Senegal and South Africa etc), (Hyalomma tick) which is responsible for viral Southeast Europe (Kosovo, Russia, Bulgaria, Greece transmission [2].The disease has been recognized by and Turkey etc.), Middle East (Iraq, Iran, Saudi Arabia different names as Asian Ebola, Hungribta (blood and Oman) and Asia (Kazakhstan, Tajikistan, taking), Khunymuny (nose bleeding) or Karakhalak Uzbekistan, Pakistan, China and India) [8,9,10].(Black Death) in the different parts of world [4].In the In Africa, due to limited sanitary facilities, virus last 2 years, in India, CCHF is emerging as an surveillance is difficult.In the last decade lesser than important zoonotic disease and a potential threat for the 100 cases were reported in Africa and most of the cases persons associated with animals as farmers, animal occurred in South Africa [11].In 2003, outbreak handlers and veterinarians due to its potential occurred in Mauritania [12] and in 2008, a nosocomial transmission from animal to human.However, humanoutbreak was reported in Sudan [11,13].
In Europe, Bulgaria is the only country where CCHF is endemic but outbreaks have been recorded with increased number of cases in other countries like Kosovo, Turkey, Albania, Ukraine and South-west of the Russian Federation [14].[17].So, India is always at potential risk of acquiring CCHFV is a member of Nairovirus genus of the CCHFV from its neighbors.
Bunyaviridae family [3].It is enveloped spherical virus Glycoprotein precursor (GPC) and Nucleocapsid (N) respectively [36].A schematic representation of CCHFV genome is given in the Figure -1.The latter two Seasonal variations have been reported in the form the structural proteins.The Glycoprotein occurrence of CCHF.In Iran, higher number of cases precursor undergoes proteolytic processing to form reported in August and September [25].In Pakistan structural proteins Gn (37kDa) and Gc (75kDa) and high incidence is common between March and May, possible non structural proteins (mucin,GP160, GP85, and again between August and October, showing GP38 and NSm).In case of Indian isolate L, M and S biannual surge [26].Climatic change is always a segments are 12166 bp, 5396 bp and 1667 bp long and contributing factor for the occurrence of disease that encode proteins of 444.6 kDa, 186.9 kDa and 53.97 affects the reproduction of tick population resulting in kDa respectively [36].increased incidence of tick born infections [27,28].
The first documented outbreak of CCHF in India was reported from Ahmedabad, Gujarat province of western India in December 2010 cases.

Phylogenetic diversity in CCHFV Transmission from tick or animal-to-human: Animals
Previous studies based on serological testing do not show clinical signs but may act as a source of suggested very few significant differences among infection for humans [31].The virus is transmitted CCHFV strains [5].However studies based on nucleic from animals to humans either by direct contact with acid sequencing analysis revealed extensive global blood or tissue of infected animal.The tick biting or genetic diversity [37,38].The phylogenetic study of crushing of tick on skin or mucous membrane may be various CCHFV S, M and L segment sequences potential routes for transmission of CCHFV from tick available revealed the formation of distinct groups to human [32].[38].The virus isolates circulating in our neighboring country Pakistan is having considerable variation in S Human-to-human transmission: Human-to-human segment sequence from the Indian isolates [36].So the transmission occurs by direct contact of virus possibility of introduction of CCHFV from the tissues results in longer incubation period.In Indian neighboring country cannot be ruled out.The cases, the incubation period ranged from 7-12 days phylogenetic study of Indian isolates performed by through the later mode [4,24,29].Yadav P. D. et al (2012) revealed that the S segment was Pre-hemorrhagic symptoms are non specific and closest to a Tajikistan strain TADJ/ HU8966 of Southinclude fever, chills, severe headache, dizziness, Asia 2 type while the M segment was found to be of photophobia, myalgia and arthralagia.This phase may type M2 [36] .Both M and L segments were closest to last for 1-7 days [44].The hemorrhagic phase develops an Afghanistan strain Afg09-2990.Thus the Indian suddenly lasting for 2-3 days [44].A petechial rash may isolates were found as a South-Asia 2/M2 far-east virus be the first symptom both on the internal mucosal combination and it may be an intra-genotypic surfaces such as mouth and throat and on the skin.They reassortant [36].
are followed by ecchymoses and other hemorrhagic phenomenon such as hematemesis, melena, epistaxis, Endothelial damage is a common feature leading to thought to be resistant to CCHF infection; however capillary fragility and accounts for the characteristic some reports are available in ostriches where rash and contributes to hemostatic failure by experimentally infection was produced [39,40].In stimulating platelet aggregation and degranulation [4].South Africa, cases have been reported where the Thrombocytopenia occurs and dysregulation of the persons working in commercial ostrich slaughter house coagulation cascade leads to DIC.Proinflammatory suffered from disease [41].Birds may transfer the virus cytokines are important in pathogenesis and the ILinfected ticks even though they themselves remain 6and TNF-α level are significantly higher in fatal non-viremic.In a study recently CCHF was detected in CCHF [46].A study shows that viral genome can be the ticks from migratory birds in Morocco [42].So the detected from saliva and urine of infected patient [47].migratory birds may be a reason of transport of virus In CCHF there is increased serum ferritin level which from one place to other distinct places [42,43].Apart can be used as a marker for disease activity and from migratory birds, international trade and transport prognosis [48].

of livestock carrying ticks may transport virus from
Public health importance one country to other [43].
Tick act as both reservoir as well as vector for Humans readily succumb to CCHFV infection.CCHFV.CCHFV can infect a number of ticks of However domestic animals are either refractory or Ixodidae family but particularly ticks of genus undergo mild infection with transient viremia Hyalomma are the most common and efficient vectors sometimes, but they act as a main source of infection of CCHFV [32,40].Transovarial, transtadial and for humans [49].Persons living in close contact with venereal mode of transmission of virus is found in animals are at the high risk of getting CCHF.vector [32].So the tick remains infected throughout its Veterinarians and farmers may castrate, dehorn, attach life and transfer virus from one generation to next ear tags and immunize young animals and thus expose generation.Immature ticks feed on the blood of small themselves to the virus infected blood.They may have animals while the mature tick transfer infection to large broken skin or scratch on the skin through which they may get infected.Consumption of unboiled or animals including domestic livestock [1,3].
uncooked meat and milk of infected animal may be a

Clinical features and pathogenesis
potential source of infection [2].There is lack of CCHFV infections are asymptomatic in animals evidence of disease in urban consumers of meat but the and birds are thought to be resistant.Humans are the infected animal may reach to abattoir to pose a main victims to this disease.The course of the disease potential threat for workers and meat consumers.can be divided into four phases-incubation, pre-Exposure to aerosols while working with infected hemorrhagic, hemorrhagic and convalescence [3].The animals and in the hospital setting are the potential incubation period depends on the mode of infection.
hazards.The population in the infected or infection Infections acquired via tick bites usually become prone area should be aware of the potential routes of apparent after 1-3 days [4].Exposure to blood or infection and the safety measures to be taken to avoid the infection [40].CCHFV may be used for done without the need to culture the virus which bioterrorism or as a biowarfare agent [2].Due to this it requires BSL-4 facility [4].Molecular epidemiology is included in CDC/NIAID Category C Pathogen [32].
can also be performed by this technique.A further improvement on the conventional RT-PCR assay has Currently there is no specific antiviral therapy for and tissue of infected patient for the diagnosis.Virus CCHF approved by United States Food and Drug isolation should be performed in a high bio-Administration (FDA) for human use [30].Ribavarin, containment laboratory [31].A variety of cell lines a guanosine analogue is found effective against including vero, BHK-21, LLC-MK2 and SW-13 can be CCHFV [57][58][59].CCHFV is susceptible to ribavirin in used for virus culture [51].Cell culture can detect only vitro [58].According to some reports oral and high virus concentration and only useful during first intravenous ribavirin is effective for treating CCHFV five days of disease.Generally the virus produces no or infections [18].In India one case recovered by the oral little cytopathic effects so it can be identified by administration of ribavirin and discharged after ten immunofluorescence assay using specific monoclonal days [50].Passive immunotherapy using specific antibodies [4].The traditional method of animal immunoglobulin CCHF-Venin is also found beneficial inoculation of newborn mice is more sensitive than cell in CCHFV treatment [30].culture and also detects the virus for longer period [52].

Prevention and control
The virus isolation by cell culture is of limited value because it needs a biosafety level-4 laboratory (BSL-4) The prevention and control should be both at which is unavailable in most of the endemic areas [31].
community level as well as in nosocomial set up.In the first few days of illness usually the patients do Minimizing human contact with suspected livestock not develop a measurable antibody response so the and reducing the tick burden in the animals are the serological tests are useful in the second week of illness primary and most important preventive measures recommended to prevent tick attachment on the body inhibition and immunodiffusion suffered lack of surface.The unpasteurized milk and uncooked meat sensitivity and reproducibility [3].This problem was should not be taken.Human-to-human infection solved by IndirectImmunofluorescence assay (IFA) mainly occurs in the nosocomial setup by the contact of and Enzyme-linked immunosorbent assay (ELISA) for infected blood or tissue.So use of protective clothing, the detection of IgM and IgG antibodies.Both IgM and gloves, goggles and face-masks reduces the chances of IgG can be detected up to 7-9 days of illness by indirect exposure [59].Safe burial practices with proper use of FIA [4,53].ELISA has replaced the conventional disinfectants should be followed.Veterinarians, research methods for antibody detection.IgM can be detected workers, slaughter house workers and medical up to 4 months and IgG persist for 5 years postprofessionals should take utmost care to reduce the infection but its level decrease [4].
contact with suspected material.They should take the Molecular diagnostic assays such as reverse prophylactic treatment after high risk exposure.transcriptase polymerase chain reaction now serve as Laboratory and research workers are advised to follow the front-line tool in the diagnosis of CCHF [54].PCR stringent biosafety precautions during handling the based methods are sensitive, specific, rapid and can be pathogen and the work should be carried out under

Figure- 1 .
Figure-1.Schematic representation of CCHFV genome.(A).S segment encodes for nucleocapsid, (B).M segment encodes Diagnosis been the advent of automated real-time PCR basedTo save the patient and to prevent the further assays.The real-time PCR is more advantageousover transmission of disease, early diagnosis is essential.
[40].[1].There are various serological tests available for Animals should be carefully monitored for tick detection of CCHFV but these tests are of limited use in infestation and treated by appropriate acaricidal agents fatal cases as patients generally die without developing particularly before slaughter or export.Wearing fully antibodies.The conventional serological test for covered clothes and use of tick repellent is CCHFV like Complement fixation, heamagglutination