Crimean Congo Hemorrhagic Fever Analysis Biology Essay
Crimean Congo hemorrhagic fever (CCHF) is one of the deadly hemorrhagic fevers that are endemic in Africa, Asia, Eastern Europe and the Middle East. It is a tick borne zoonotic viral disease caused by CCHF virus in the genus Nairovirus under family Bunyaviridae. CCHF not only forms an important public health threat but has a significant effect on the health care personnel especially in resource poor countries. India was always a potentially endemic area until an outbreak hit parts of Gujarat taking four lives including the treating medical team. The current review is an attempt to summarize the updated knowledge on the disease particularly in modern era with a special emphasis on the nosocomial infections. The knowledge about the disease may help answer certain questions regarding entry of virus in India and future threat to community.
Key words: Crimean Congo Hemorrhagic fever, update, nosocomial.
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Crimean Congo hemorrhagic fever (CCHF) is one of the severe forms of hemorrhagic fevers that are endemic in Africa, Asia, Eastern Europe and the Middle East with a near fatal mortality rate. CCHF not only forms an important public health threat but has a significant effect on the health care personnel especially in resource poor countries. India was always under the potential threat of CCHF viral infection until an outbreak hit parts of Gujarat taking four lives including the treating medical team few weeks ago. When the questions regarding the acquisition of virus in the region, the index case and the viral status in this country are yet to be revealed, the endemic potentiality of this vast country poses a challenge to control the CCHF viral infection not only for India but also for all the neighboring countries. The current review is an attempt to summarize the updated knowledge on the disease.
CCHF fever is a zoonotic viral disease caused by tick borne virus in the genus Nairovirus under family Bunyaviridae. The disease has a wide distribution that correlates with the global distribution of Hyalloma tick, the vector responsible for viral transmission. The disease is generally asymptomatic in infected animals but is highly fatal in humans. In humans the disease begins as non specific febrile symptoms which progresses to hemorrhagic syndrome. Although tick is a major vector in transmission of the disease, further secondary cases are frequently seen due to human to human transmission via percutaneous or per mucosal exposure to blood and body fluids containing the virus . This type of uncommon transmission takes place most often among health care workers in hospital settings thus posing a significant nosocomial hazard. Adhering to universal precautions while caring for the patients, timely infection-control measures and administration of prophylactic therapy to health care workers after exposure can serve as important measures in limiting the spread of infection.[2, 3] However, additional community-based control measures like use of pesticides to control tick population are necessary to decrease disease transmission and prevent further spread in the community.
History of CCHF:
The first evidence of CCHF dates back to 12th century, where a description of a hemorrhagic syndrome in Tajikistan and the description of the arthropod that caused the disease appear to be similar to the modern day CCHF. In the modern era, CCHF was described for the first time among Soviet Union military personnel in Crimea during World War 2(1944-45) and was named Crimea hemorrhagic fever. The virus was isolated from blood and tissues of patients using intracerebral inoculation of suckling mice.  Subsequently it was shown that the virus responsible for Crimea hemorrhagic fever was indistinguishable from Congo virus that caused febrile illness in Belgian Congo. Hence linking the two names led to new nomenclature the Crimean Congo hemorrhagic fever virus.
The geographic range of CCHF virus is the most extensive among the tick borne viruses that affect human health, and the second most widespread of all medically important arboviruses, after dengue virus.[5, 7] Since its discovery in 1967, nearly 140 outbreaks involving more than 5000 cases have been reported all over the world. A total of 52 countries have been recognized as endemic or potentially endemic regions reporting substantial number of cases every year. The distribution of Hyalomma spp., the principal tick vectors also has wide distribution. CCHFV is mainly seen in, the Middle East and Asia and parts of Europe including southern portions of the former USSR.
In the initial years after the virus was first described in 1967 majority of the cases were reported from the former Soviet Union (Crimea, Astrakhan, Rostov, Uzbekistan, Kazakhstan, Tajikistan) and Bulgaria.[4, 5] In the following years outbreaks were reported from parts of Africa such as the Democratic Republic of the Congo, Uganda and Mauritania.[8, 9]. A substantial number of cases were also reported from middle eastern countries such as Iraq, the United Arab Emirates (UAE) and Saudi Arabia. In the previous decade most cases have been reported from Pakistan, Iran, Bulgaria, Turkey[16-18], and from the outbreak noted in Gujarat India. Majority of these outbreaks are seen in the community and contact with livestock animals infested with ticks is noted. However in some outbreaks nosocomial spread was documented where contact with blood and other body fluids from patient have been the main mode of transmission. Between 1953 and 2005 nearly eighty cases of CCHF infection has been described among health care personnel. The table 1 shows the nosocomial outbreaks of CCHF seen during the past few years. The persons who come in direct contact with the patient like clinicians, nurses and other hospital staff are at great risk. This happens more when the knowledge about the disease is lacking. Thus it becomes essential to train health care personnel in endemic and potentially endemic regions to handle such situations so as to minimize the nosocomial spread of infection. Emphasis on standard and universal precautions should be given especially in resource poor countries.
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India: CCHF viral infection had not been reported in human beings from India before, though previous sero-prevalence studies have shown the viral antibodies both in animals and humans.. In 1973 Shanmugam et al in their study tested a total 643 human sera from all over India, where nine samples from Kerala and Pondicherry were positive for anti CCHF virus antibody. In the same study a total of 34 out of 655 serum samples collected from sheep, horse, goat and domestic animals from all over India showed evidence of CCHF virus. Subsequently in 1977, Kaul et al conducted a survey of ixodid ticks to determine the Crimean hemorrhagic fever (CHF) virus activity in Jammu & Kashmir state of India but CCHF virus was not isolated in any of 138 pools comprising eight species under six genera of ticks. However, a related species of the genus Nairovirus- Ganjam virus that belongs to the Nairobi Sheep group is transmitted locally by Hemaphysalis ticks. This virus has veterinary importance in India and has been demonstrated in mosquitoes, man and sheep. The recent 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.
Modes of transmission:
Humans get infection by the bite of or by crushing an infected tick of the Hyalloma spp., against bare skin. The infection can also be acquired by percutaneous and permucosal route by contact with animal blood or tissues and drinking unpasteurized milk. The possibility of aerosol transmission though suspected in few cases in Russia, but no definite evidence exist. Human-to-human transmission is possible and is an important route in a nosocomial set up when skin or mucous membranes are exposed to blood and body fluids of patients with hemorrhage. (Fig 1) In addition, possible horizontal transmission from a mother to her child has also been reported.
Reservoirs and Vectors
CCHF virus circulates in an enzootic tick-vertebrate-tick cycle. However, there is no evidence that the virus causes disease in animals. Wide range of domestic and wild animals may get CCHF virus infection. The virus infection has been commonly demonstrated among smaller wildlife species-e.g., hares and hedgehogs that act as hosts for the immature stages of the tick vectors.[4, 5] These small animals are believed to act as amplifying hosts and maintain the virus in nature. This virus has been found in at least 31 species of ticks, including seven genera of the family Ixodidae (hard ticks). Among the various genera of family Ixodidae the most efficient and common vectors for CCHF appear to be members of the Hyalomma genus. Other ixodid ticks including members of the genera Rhipicephalus, Boophilus, Dermacentor and Ixodes may also transmit the virus. These vectors have both trans-ovarial and trans-stadial transmission of virus, thus contributing to circulation of the virus in nature by remaining infected throughout their developmental stages and also by passing to the next generation. Immature ticks (nymphs) generally habitat smaller animals while the mature ticks transmit the infection to large vertebrates, such as livestock.
Taxonomy: CCHF virus is a member of the Nairovirus genus under family Bunyaviridae which has four other genera namely Hantavirus, Phlebovirus, Orthobunyavirus and Tospovirus. Genus Nairovirus has around 34 described tick borne viruses that are grouped into seven serogroups. Among these, only three members are known to cause disease in humans and they are CCHF, Nairobi sheep disease virus and Dugbe virus. CCHF virus is a spherical enveloped virus with approximately 100 nm diameter and has glycoprotein spikes 8-10 nm in length. Under electron microscopy the virion of CCHF can be distinguished from other members within the Bunyaviridae family, as they possess very small morphologic surface units with no central holes arranged in no obvious order 
Genetic diversity in CCHF: The genome of family Bunyaviridae has a tripartite and consists of 3 segments of negative-sense, single-stranded RNA, small (S), medium (M), and large (L), which encode the nucleocapsid protein, glycoproteins (Gn and Gc), and viral polymerase, respectively. Additionally, an M segment- encoded nonstructural protein, NSM, is recently identified in the Nairovirus-Crimean-Congo hemorrhagic fever virus (CCHFV). Initially the antigenic structures the CCHF viruses from various geographic regions were thought to be indistinguishable. With the availability of nucleotide and amino acid sequence information extensive genetic diversity has been shown in these viruses. Most nucleic acid sequence analyses are based on the S segment of the genome, and according to these studies, CCHF virus has eight genetically distinct clades. (Table 2). The knowledge of the various clades has great epidemiological implications. These can give clue regarding the source of infection in an outbreak in an endemic region and can also help in tracing the path of spread imported cases. The significant antigenic differences among various clades should be considered while choosing target for vaccine.
Clinical features in Humans:
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Human beings are the only host of CCHFV in whom the disease manifestations are seen. The typical course of CCHF infection has four distinct phases- Incubation period, prehemorrhagic phase, hemorrhagic phase and convalescent phase. The incubation period for CCHF virus ranges from 3-7 days. The mean duration is largely influenced by the route of infection, viral load and source of infection-blood or tissue from live stock. The minimum viral load required for transmission of disease is 1 to 10 organisms. The disease begins with the pre-hemorrhagic phase characterized by non specific prodromal symptoms during which period 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, tachypnoea, conjunctivitis, pharyngitis and cutaneous flushing or rash. The prehemorrhagic phase lasts for around 4-5 days and in majority of the patients it progresses to hemorrhagic phase. The hemorrhagic phase is generally short and has rapid course with signs of progressive hemorrhage and diathesis. These include petichiae, conjuctival hemorrhage, epistaxis, hematemesis, hemoptysis and melena. Some patients may also have hepatosplenomegaly.[16, 18, 36]The disease is fatal in 40-60% of the cases. In severe cases multiorgan failure, disseminated intravascular coagulation and circulatory shock leads to death. Acute respiratory distress syndrome (ARDS) and diffuse alveolar hemorrhage, accompanied by systemic inflammatory reaction, have also been reported during hemorrhagic manifestations.[37, 38] 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, loss of memory and loss of hair. However these after effects have been reported only in few outbreaks.[4, 11, 16, 17]
The pathogenesis of CCHF is not well understood. A common pathogenic feature of hemorrhagic fever viruses is their ability to disable the host immune response by attacking and manipulating the cells that initiate the antiviral response. This damage is characterized by rapid replication of the virus along with dysregulation of the vascular system and lymphoid organs. As seen in other viral hemorrhagic fevers, damage to the endothelium plays an important role in CCHF pathogenesis. Endothelial damage contributes to hemostatic failure by stimulating platelet aggregation and degranulation, with consequent activation of the intrinsic coagulation cascade. (Fig 2) Marked pro-inflammatory response disproportional to the extent of lesion is a striking feature seen in these patients. The proinflammatory cytokines are the key regulators in the pathogenesis and mortality of patients with CCHF. Levels of IL6 and TNF Î± are shown to be significantly higher in patients with fatal CCHF as compared to non fatal infection.
Early diagnosis is very essential, not only for patient management but also to prevent further transmission of disease as it has the potential for nosocomial spread. High index of suspicion is very essential in the early phase because the clinical presentations are non specific. History of travel to endemic areas, tick bite and exposure to blood or tissues of livestock or human patients are the key pointers to suspect CCHF viral infection. The important differential diagnoses for CCHF viral infection are bacterial infections like rickettsiosis (tick-borne typhus and African tick bite fever), leptospirosis, and borreliosis (relapsing fever) and other infections, which present as hemorrhagic disease such as meningococcal infections, Hantavirus hemorrhagic fever, malaria, yellow fever, dengue, Omsk hemorrhagic fever, and Kyasanur Forest disease. Knowledge of endemicity of these infections should be kept in mind to proceed with further diagnostic modalities.
Viral isolation: The most definitive way of diagnosis is the demonstration of virus or viral genome. Isolation by cell culture is simpler and rapid as compared with traditional methods of intracranial inoculation of a sample in newborn mice one can proceed with viral isolation. Virus can be isolated using cell lines including 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 immunofluorescence assay tests with specific monoclonal antibodies. However, viral isolation is useful only in the early phase of infection when the viral load is very high but suffers from poor sensitivity and 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 is the method of choice for rapid laboratory diagnosis of CCHF virus infection. Another benefit to molecular diagnostic assays is their rapidity compared to virus culture, and a presumptive diagnosis can be made within 8 hour. Further improvisation of this technique is automated real time assay. The real-time PCR assay has many advantages over conventional RT-PCR methods, including lower contamination rate, higher sensitivity and specificity, and they are rapid, providing results in minutes instead of hours. Drosten et al. developed a one-step real-time RT-PCR assay for detecting CCHFV using primers to the nucleoprotein gene; using DNA-intercalating dye, SybrGreen I.. Later a real-time RT-PCR assay using TaqMan-minor groove binding protein (MGB) probe, which had higher specificity with a shorter probe length was developed.
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, haemagglutination-inhibition and reversed passive haemagglutination 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.[41-43]ELISAs to detect specific I M 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. Recently, a recombinant nucleoprotein(rNP)-based IgG ELISA for serological diagnosis of CCHF virus infections was developed and was shown to be a valuable tool for diagnosis and epidemiological investigations of CCHFV infections.Similarly CCHFV rNP-based IgM-capture ELISA has shown to be useful method for the diagnosis of CCHFV infections.
The general approach in treatment of patients with CCHF viral infection depends on the severity of the clinical manifestation and is done by managing fluid and electrolyte imbalances. The early diagnosis and supportive care in the form of blood, platelet, and plasma replacement has proven to be life saving especially patients with hemorrhagic manifestation. There is no consensus on the role of specific antiviral therapy in the management of these patients. Tasdelen et al have shown the beneficial effect of ribavirin if given at an early phase of the CCHF.However, in a systematic meta analysis it was shown that there was no change in mortality rate with the use of ribavirin in the randomized control studies. While the pooled observational studies showed reduction in mortality by 44%. In addition no difference in length of hospital stay was reported. Thus no clear message of benefit is available from the current data on ribavirin as observational data are heavily confounded, These results clearly indicate the need for randomized control studies in a setting with optimal supportive care. According to WHO ribavirin is the anti-viral medication of choice for CCHF and the recommended dose is an initial dose of 30mg/kg followed by 15mg/kg for four days and then 7.5mg/kg for six days for a total of 10 days.
Apart from the specific antiviral therapy role of immunotherapy in the form of immunoglobulin has also been tried. A new specific immunoglobulin CCHF-Venin that contains antibodies to CCHF virus was prepared from the plasma pool of boosted donors, by a combined ethanol-polyethylene glycol fractionation method with an ion-exchange purification step. Unlike Ebola virus limited studies are available which show the beneficial effect of immunotherapy in CCHF.[30, 50]
In case of known direct contact with the blood or secretions of a probable or confirmed case such as needle stick injury or contact with mucous membranes such as eye or mouth, the recommended procedure is to do baseline blood studies and start the person on oral ribavirin. Household or other contacts of the case who may have had the same exposure to infected ticks or animals, or who recall indirect contact with case body fluids should be monitored for 14 days from the date of last contact with the patient or other source of infection by taking the temperature twice daily. If the patient develops a temperature of 38.5Â° C or greater, headache and muscle pains, he/she would be considered a probable case and should be admitted to hospital and started on ribavirin treatment. Experience with ribavirin in the prevention of CCHF is substantially limited as compared to other viral hemorrhagic fever like Lassa fever. The CDC states that use of ribavirin to treat the disease and to prevent infection in high-risk contacts seems reasonable based on in-vitro susceptibility data for this and other Bunyaviridae. The CDC recommends that similar procedures for care, including isolation and body fluid precautions and therapy, recommended for Lassa fever be followed for patients with CCHF and their contacts; however, additional study and experience is necessary.
Prevention and control measures:
The main stay of prevention and control of CCHF viral infection should target both the community level and at the level of noscomial set up. In the community level, care should be taken to prevent the human contact with live stock and minimizing the tick burden in these vertebrate hosts. 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. Fully covered clothing is recommended to prevent tick attachment; to body parts. Acaricides can be used on livestock and other domesticated animals to control ticks, particularly before slaughter or export. While handling live stocks, protective clothing and gloves should be used whenever there is chance of contact with skin or mucous membranes of viremic animals, particularly when blood and tissues are handled. Consumption of unpasteurized milk and uncooked meat should be avoided. Human-to-human transmission of CCHF virus is primarily associated with direct contact with blood and body fluids, and CCHF virus transmission to healthcare workers has been reported when appropriate infection control measures have not been observed. Strict universal precautions are necessary when caring for patients. These recommendations include barrier nursing, isolation and the use of gloves, gowns, face-shields and goggles with side shields. Safe burial practices, including the use of liquid bleach solution as a disinfectant, and covering the body in polythene bags have been published. Laboratory workers must follow stringent biosafety precautions and viral isolation techniques should be carried out in only those laboratories where biosafety level 4 is available. CCHFV can be inactivated by disinfectants including 1% hypochlorite and 2% glutaraldehyde and is also destroyed by heating at 56Â°C (133Â°F) for 30 min. Prophylactic treatment with ribavirin has occasionally been used after high-risk exposures but the role is also controversial.
Vaccine: The major hindrance in developing vaccine against CCHF virus is the great genetic variation noted in different strains. Despite this genetic variability, Ahmed et al have shown that some epitopes are conserved, and CCHFV vaccines may have to either immunogens derived from several CCHFV strains, or can target the immune response on conserved neutralizing epitopes. An inactivated vaccine from mouse brains has been used in the former Soviet Union and Bulgaria.. However, in most countries, no vaccine is available.
CCHF was always an impending threat to India that has become a reality now with the current outbreak in Gujarat. The vector and reservoir animals were already present. The related species of the genus Nairovirus like Ganjam virus of Nairobi sheep disease are also transmitted by same vector as CCHF virus and have been reported previously. The emergence of such a deadly viral infection in a large country like India possessing all ecological suitability for the virus is a challenge for the entire medical fraternity. This again emphasizes the need of active surveillance not only for the pathogens that already exist in any geographic location but also for those pathogens that posses the threat. The use of molecular techniques even for surveillance is of paramount importance to prevent further check on this highly pathogenic virus.
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