Crimean-Congo hemorrhagic fever (CCHF) is a potentially fatal viral disease. The CCHF virus is a member of the Nairovirus genus of the Bunyaviridae family. This genus includes other species which are pathogens in humans such as the Dugbe virus and the Nairobi sheep disease virus [1
]. It possesses 3 segments of negative-sense RNA [3
] and an RNA dependant RNA polymerase packed within a lipid envelope which contains 2 viral glycoproteins [Gn and Gc]. This structure is characteristic of other members of the Bunyaviridae family.
The virus is transmitted to humans through tick bites or exposure to blood and tissues of infected animals. Different domestic and wild animals have been identified as a reservoir for this virus, including cattle, sheep, goats, hedgehogs and hares [5
]. Numerous species of ticks can carry the virus, however very few of them have been implicated as vectors. The most important tick vector is the Hyalomma spp
., as the virus was isolated from it and its geographic distribution coincides with that of the disease [9
]. Another transmission route of the virus in humans is through contact with the blood of an infected person during the acute phase of the disease [10
]. This is especially significant among healthcare workers who may be infected while treating CCHF patients during an outbreak [11
One of the most important features of the virus is its diverse geographic distribution including Africa, Asia, Eastern Europe and the Middle East [12
], making it the most widespread tick-borne virus infecting humans. Outbreaks have been documented in all these areas since the 1960 s, with the most recent cases coming from Iran [13
] and Turkey [14
]. In addition, climatic, environmental and agricultural changes may affect the distribution of the tick vector and influence the location and timing of outbreaks.
The pathogenesis of CCHF remains elusive, mainly due to lack of adequate animal models and laboratories with the proper bio-safety containment level. Studies in human patients reveal endothelial damage resulting from either direct infection of the cells or indirect effect of viral and host factors [15
]. The clinical features of CCHF are divided into four periods - incubation, pre-hemorrhagic, hemorrhagic, and convalescence [9
]. The incubation period may vary between 2-9 days according to the transmission route [10
]. This may be followed by a sudden onset of signs such as fever, headache, myalgia, arthralgia, abdominal pain and vomiting. Additional signs may also appear including sore throat, conjunctivitis, jaundice, photophobia and various sensory and mood alterations. In severe cases, hemorrhagic manifestations may appear as early as 3-6 days following disease onset. Petechiae and ecchymosis of the skin and mucous membranes, as well as gastrointestinal bleeding are the most common signs at this stage, while cerebral hemorrhage and liver necrosis reveal a more severe manifestation with poorer prognosis [14
]. Mortality rates usually range between 5-50% [9
], although numbers as high as 80% have been reported sporadically [6
Early diagnosis is essential in CCHF cases and is currently possible using first line molecular methods for rapid diagnosis such as reverse transcription PCR (RT-PCR) and real-time PCR. Serological methods such as ELISA and immunofluorescent assays may also provide a sensitive and specific diagnosis approximately 7 days following disease onset. Different cell line cultures and inoculation of the virus into mice may be used for virus isolation [14
Prompt supportive treatment including blood products administration is the major current therapeutic option, although several attempts have been made in the past to treat patients with immunoglobulins produced from vaccinated horses [9
] and with serum taken from convalescing CCHF patients [17
]. To date, however, no clinical trials have been reported testing the latter interventions. More recently, the antiviral drug ribavirin - a synthetic purine nucleoside analogue synthesized in 1972 [18
] - has revealed promising activity against the CCHF virus in vitro [19
] and in an animal model of mice [20
]. Several observational studies suggest efficacy of ribavirin in human patients [21
], while evidence from randomised controlled clinical studies is lacking.
As CCHF activity appears to be increasing, particularly in European regions [24
], it becomes essential to assess the effectiveness of ribavirin treatment. If results indicate that treatment with ribavirin is promising, efforts will need to be made to ensure its availability in areas of the world where CCHF is present. On the other hand, if the evidence is of poor quality and results remain inconclusive, focus will need to be targeted on securing better data as well as diminishing harm experienced by the patient. At the moment, there appears to be a gap between strongly held clinical beliefs and actual provision of ribavirin.
Our goal was to appraise and summarise the evidence about benefits and harms of ribavirin for treating CCHF in humans. Secondary objectives were to evaluate the effects of ribavirin, according to severity of disease and number of days from onset of illness that the drug was started, duration of ribavirin treatment, via of administration; and to evaluate whether prophylactic use following exposure to CCHF virus should be recommended.