Elsevier

Journal of Clinical Virology

Volume 64, March 2015, Pages 137-143
Journal of Clinical Virology

Recent advances in research on Crimean-Congo hemorrhagic fever

https://doi.org/10.1016/j.jcv.2014.08.029Get rights and content

Abstract

Crimean-Congo hemorrhagic fever (CCHF) is an expanding tick-borne hemorrhagic disease with increasing human and animal health impact. Immense knowledge was gained over the past 10 years mainly due to advances in molecular biology, but also driven by an increased global interest in CCHFV as an emerging/re-emerging zoonotic pathogen. In the present article, we discuss the advances in research with focus on CCHF ecology, epidemiology, pathogenesis, diagnostics, prophylaxis and treatment. Despite tremendous achievements, future activities have to concentrate on the development of vaccines and antivirals/therapeutics to combat CCHF. Vector studies need to continue for better public and animal health preparedness and response. We conclude with a roadmap for future research priorities.

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.

References (91)

  • H. Karlberg et al.

    Induction of caspase activation and cleavage of the viral nucleocapsid protein in different cell types during Crimean-Congo hemorrhagic fever virus infection

    J Biol Chem

    (2011)
  • P.J. Hertzog et al.

    The interferon in TLR signaling: more than just antiviral

    Trends Immunol

    (2003)
  • A. Le Bon et al.

    Links between innate and adaptive immunity via type I interferon

    Curr Opin Immunol

    (2002)
  • N. Frias-Staheli et al.

    Ovarian tumor domain-containing viral proteases evade ubiquitin- and ISG15-dependent innate immune responses

    Cell Host Microbe

    (2007)
  • K. Kondiah et al.

    A simple-probe real-time PCR assay for genotyping reassorted and non-reassorted isolates of Crimean-Congo hemorrhagic fever virus in southern Africa

    J Virol Methods

    (2010)
  • C. Filippone et al.

    Molecular diagnostic and genetic characterization of highly pathogenic viruses: application during Crimean-Congo haemorrhagic fever virus outbreaks in Eastern Europe and the Middle East

    Clin Microbiol Infect

    (2013)
  • H.A. Osman et al.

    Development and evaluation of loop-mediated isothermal amplification assay for detection of Crimean Congo hemorrhagic fever virus in Sudan

    J Virol Methods

    (2013)
  • C. Andersson et al.

    In situ rolling circle amplification detection of Crimean Congo hemorrhagic fever virus (CCHFV) complementary and viral RNA

    Virology

    (2012)
  • P. Emmerich et al.

    Early serodiagnosis of acute human Crimean-Congo hemorrhagic fever virus infections by novel capture assays

    J Clin Virol

    (2010)
  • S.D. Dowall et al.

    Development of an indirect ELISA method for the parallel measurement of IgG and IgM antibodies against Crimean-Congo haemorrhagic fever (CCHF) virus using recombinant nucleoprotein as antigen

    J Virol Methods

    (2012)
  • M. Keshtkar-Jahromi et al.

    Crimean-Congo hemorrhagic fever: current and future prospects of vaccines and therapies

    Antiviral Res

    (2011)
  • O. Ergonul

    Treatment of Crimean-Congo hemorrhagic fever

    Antiviral Res

    (2008)
  • I. Koksal et al.

    The efficacy of ribavirin in the treatment of Crimean-Congo hemorrhagic fever in Eastern Black Sea region in Turkey

    J Clin Virol: Off Publ Pan Am Soc Clin Virol

    (2010)
  • G.H. Tignor et al.

    Ribavirin efficacy in an in vivo model of Crimean-Congo hemorrhagic fever virus (CCHF) infection

    Antiviral Res

    (1993)
  • G.R. Yilmaz et al.

    The epidemiology of Crimean-Congo hemorrhagic fever in Turkey, 2002–2007

    Int J Infect Dis

    (2009)
  • I. Koksal et al.

    The efficacy of ribavirin in the treatment of Crimean-Congo hemorrhagic fever in Eastern Black Sea region in Turkey

    J Clin Virol

    (2010)
  • O. Ergonul

    Crimean-Congo hemorrhagic fever virus: new outbreaks, new discoveries

    Curr Opin Virol

    (2012)
  • M. Mertens et al.

    The impact of Crimean-Congo hemorrhagic fever virus on public health

    Antiviral Res

    (2013)
  • A. Papa

    Crimean-Congo hemorrhagic fever and hantavirus infections

  • I.E. Aradaib et al.

    Nosocomial outbreak of Crimean-Congo hemorrhagic fever, Sudan

    Emerg Infect Dis

    (2010)
  • H.R. Naderi et al.

    Nosocomial outbreak of Crimean-Congo haemorrhagic fever

    Epidemiol Infect

    (2011)
  • M. Sargianou et al.

    Epidemiological and behavioural factors associated with CCHFV infections in humans

    Expert Rev Anti Infect Ther

    (2013)
  • O. Ergonul

    Clinical and pathological features of Crimean-Congo haemorrhagic fever

  • ProMED-mail post. Crimean-Congo hem. fever – Uganda (03): (KM, AG) fatal;...
  • S.S. Karti et al.

    Crimean-Congo hemorrhagic fever in Turkey

    Emerg Infect Dis

    (2004)
  • H. Hoogstraal

    The epidemiology of tick-borne Crimean-Congo hemorrhagic fever in Asia, Europe, and Africa

    J Med Entomol

    (1979)
  • A. Estrada-Pena et al.

    Unraveling the ecological complexities of tick-associated Crimean-Congo hemorrhagic Fever virus transmission: a gap analysis for the Western palearctic

    Vector Borne Zoonotic Dis

    (2012)
  • D.M. Watts et al.

    Crimean-Congo hemorrhagic fever

  • A.J. Shepherd et al.

    Experimental studies on the replication and transmission of Crimean-Congo hemorrhagic fever virus in some African tick species

    Am J Trop Med Hyg

    (1989)
  • H. Albayrak et al.

    Molecular detection of Crimean-Congo Haemorrhagic Fever Virus (CCHFV) but not West Nile Virus (WNV) in hard ticks from provinces in Northern Turkey

    Zoonoses Public Health

    (2010)
  • S. Tekin et al.

    Crimean-Congo hemorrhagic fever virus in various ixodid tick species from a highly endemic area

    Vet Parasitol

    (2011)
  • Z. Telmadarraiy et al.

    A survey of Crimean-Congo haemorrhagic fever in livestock and ticks in Ardabil Province, Iran during 2004–2005

    Scand J Infect Dis

    (2010)
  • N.A. Hartemink et al.

    The basic reproduction number for complex disease systems: defining R(0) for tick-borne infections

    Am Nat

    (2008)
  • S.E. Randolph

    The shifting landscape of tick-borne zoonoses: tick-borne encephalitis and Lyme borreliosis in Europe

    Philos Trans R Soc Lond B Biol Sci

    (2001)
  • D. Sumilo et al.

    Climate change cannot explain the upsurge of tick-borne encephalitis in the Baltics

    PLoS ONE

    (2007)
  • Cited by (0)

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