Recent advances in research on Crimean-Congo hemorrhagic fever
Introduction
Crimean-Congo hemorrhagic fever (CCHF) is characterized by fever and hemorrhagic manifestations with fatality up to 30% [1]. It is endemic in focal areas in Asia, Europe and Africa, with geographic distribution following that of Hyalomma ticks, the main vectors of CCHF virus (CCHFV). Apart from the bite of an infected tick (Fig. 1), the virus can be transmitted to humans by direct contact with blood or tissues of viremic patients or animals. Nosocomial and intra-family transmission have been reported [2], [3], [4].
The disease typically presents with an incubation phase (1–9 days), prehemorrhagic and hemorrhagic phases (in severe cases), and convalescence [5]. The hemorrhagic manifestations range from petechiae and epistaxis to extended ecchymosis and bleeding from various systems (Fig. 2).
CCHFV (genus Nairovirus, family Bunyaviridae) is an enveloped single-stranded negative sense RNA virus with a tri-segmented genome consisting of a small, medium and large RNA segments, encoding for the nucleocapsid protein (N), the glycoproteins Gn and Gc and the RNA-dependent RNA polymerase, respectively. CCHFV is characterized by a great genetic variability with complex evolutionary patterns [6]. Due to its high pathogenicity and the lack of approved vaccines and specific intervention strategies, CCHFV must be handled under biosafety level 4 (BSL-4) containment. The recent emergence of CCHFV causing either sporadic human infections [7], [8] or epidemics in previously unaffected areas [9], [10], has raised animal and public health concerns. As a result, great progress has been made in CCHF pathogenesis, diagnostics and epidemiology/ecology, while efforts are underway to design effective vaccines and treatment strategies including antiviral and immunotherapeutic compounds. This article summarizes and discusses the progress in the field over the past decade and identifies knowledge gaps and future research perspectives.
Section snippets
Advances in eco-epidemiology
CCHFV is maintained in nature by ixodid ticks mainly of the genus Hyalomma [11], [12]. Additional tick species from the genera Dermacentor, Boophilus, Amblyomma, Rhipicephalus, and Haemaphysalis, have been implicated in harboring CCHFV in the field or were shown to be experimentally infected, but there is little evidence for a role of these species in natural transmission or maintenance of CCHFV [13]. Thus, it appears that Hyalomma ticks are necessary for the maintenance of active CCHFV foci
Advances in basic virology
Humans are the only known host that develops disease after CCHFV infection. The major pathological abnormalities of CCHF are related to vascular dysfunction resulting in hemorrhagic manifestations largely driven by erythrocyte and plasma leakage into the tissues [28]. Endothelial damage can contribute to coagulopathy by deregulated stimulation of platelet aggregation, which in turn activates the intrinsic coagulation cascade, ultimately leading to clotting factor deficiency and hemorrhages.
Advances in clinical virology
A prompt and accurate laboratory diagnosis during the first days of the disease is critical for both patient management and prevention of transmission. Virus isolation is seldom tried for CCHF diagnosis, due to the time-consuming procedure and the biocontainment needed for handling specimens. Molecular methods are increasingly used for the detection of CCHFV in acute clinical samples. Furthermore, in combination with genetic characterization an immediate insight into the molecular epidemiology
Advances in prophylaxis and therapy
A number of studies regarding treatment and prevention have been recently performed. No specific therapy has been confirmed as effective enough for the treatment of CCHF patients. Differential diagnosis is very important. The initial nonspecific symptoms of CCHF can mimic other infections, leading to misdiagnosis and delay of proper treatment. CCHF patients must be closely monitored for effective supportive treatment [69], [70].
Ten-year research roadmap
CCHFV is the most widely distributed tick-borne hemorrhagic fever virus with endemic areas in more than 30 countries. Recent emergence and re-emergence of CCHFV underline the importance of this pathogen for global human and animal health. The tick vector of CCHFV is widely distributed in the Old World; its movement and expansion will define known and new endemic regions for this pathogen and CCHF disease. Despite improving knowledge on the biology of the virus, a better understanding of the
Funding
Anna Papa and Ali Mirazimi are partners of the CCH Fever Network (Collaborative Project) supported by the European Commission under the Health Cooperation Work Program of the 7th Framework Program (Grant agreement no. 260427). Ali Mirazimi is also supported by the Swedish Research Council. Heinz Feldmann is supported by the Intramural Research Program of the NIAID, NIH.
Competing interests
None.
Ethical approval
Not required.
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