University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln USGS Staff -- ubP lished Research US Geological Survey 2013 Crimean-Congo hemorrhagic fever: History, epidemiology, pathogenesis, clinical syndrome and genetic diversity Dennis A. Bente University of Texas Medical Branch, [email protected] Naomi L. Forrester University of Texas Medical Branch Douglas M. Watts University of Texas at El Paso Alexander J. McAuley University of Texas Medical Branch Chris A. Whitehouse US Geological Survey See next page for additional authors Follow this and additional works at: http://digitalcommons.unl.edu/usgsstaffpub Bente, Dennis A.; Forrester, Naomi L.; Watts, ouD glas M.; McAuley, Alexander J.; Whitehouse, Chris A.; and Bray, Mike, "Crimean- Congo hemorrhagic fever: History, epidemiology, pathogenesis, clinical syndrome and genetic diversity" (2013). USGS Staff -- Published Research. 761. http://digitalcommons.unl.edu/usgsstaffpub/761 This Article is brought to you for free and open access by the US Geological Survey at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in USGS Staff -- ubP lished Research by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. Authors Dennis A. Bente, Naomi L. Forrester, Douglas M. Watts, Alexander J. McAuley, Chris A. Whitehouse, and Mike Bray This article is available at DigitalCommons@University of Nebraska - Lincoln: http://digitalcommons.unl.edu/usgsstaffpub/761 Antiviral Research 100 (2013) 159–189 Contents lists available at ScienceDirect Antiviral Research journal homepage: www.elsevier.com/locate/antiviral Review Crimean-Congo hemorrhagic fever: History, epidemiology, pathogenesis, clinical syndrome and genetic diversity ⇑ Dennis A. Bente a, , Naomi L. Forrester b, Douglas M. Watts c, Alexander J. McAuley a, Chris A. Whitehouse d, Mike Bray e a Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, United States b Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555-0610, United States c Department of Veterinary Services, University of Texas at El Paso, El Paso, TX 79968, United States d National Wildlife Health Center, U.S. Geological Survey, Madison, WI 53711, United States e Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States article info abstract Article history: Crimean–Congo hemorrhagic fever (CCHF) is the most important tick-borne viral disease of humans, Received 15 May 2013 causing sporadic cases or outbreaks of severe illness across a huge geographic area, from western China Revised 5 July 2013 to the Middle East and southeastern Europe and throughout most of Africa. CCHFV is maintained in ver- Accepted 9 July 2013 tical and horizontal transmission cycles involving ixodid ticks and a variety of wild and domestic verte- Available online 29 July 2013 brates, which do not show signs of illness. The virus circulates in a number of tick genera, but Hyalomma ticks are the principal source of human infection, probably because both immature and adult forms Keywords: actively seek hosts for the blood meals required at each stage of maturation. CCHF occurs most frequently Crimean–Congo hemorrhagic fever virus among agricultural workers following the bite of an infected tick, and to a lesser extent among slaugh- Tick-borne virus Arbovirus terhouse workers exposed to the blood and tissues of infected livestock and medical personnel through Nairovirus contact with the body fluids of infected patients. CCHFV is the most genetically diverse of the arboviruses, Bunyavirus with nucleotide sequence differences among isolates ranging from 20% for the viral S segment to 31% for Viral hemorrhagic fever the M segment. Viruses with diverse sequences can be found within the same geographic area, while clo- sely related viruses have been isolated in far distant regions, suggesting that widespread dispersion of CCHFV has occurred at times in the past, possibly by ticks carried on migratory birds or through the inter- national livestock trade. Reassortment among genome segments during co-infection of ticks or verte- brates appears to have played an important role in generating diversity, and represents a potential future source of novel viruses. In this article, we first review current knowledge of CCHFV, summarizing its molecular biology, maintenance and transmission, epidemiology and geographic range. We also include an extensive discussion of CCHFV genetic diversity, including maps of the range of the virus with superimposed phylogenetic trees. We then review the features of CCHF, including the clinical syndrome, diagnosis, treatment, pathogenesis, vaccine development and laboratory animal models of CCHF. The paper ends with a discussion of the possible future geographic range of the virus. For the benefit of researchers, we include a Supplementary Table listing all published reports of CCHF cases and outbreaks in the English-language literature, plus some principal articles in other languages, with total case num- bers, case fatality rates and all CCHFV strains on GenBank. Ó 2013 Elsevier B.V. All rights reserved. Contents 1. Introduction . ...................................................................................................... 160 2. Discovery and naming of CCHF . ................................................................................... 161 3. The causative agent . ................................................................................... 163 3.1. Classification . ......................................................................................... 163 3.2. Virion structure, genome organization and encoded proteins . ...................................................... 164 3.2.1. The S segment. .............................................................................. 164 ⇑ Corresponding author. Tel.: +1 409 266 6935; fax: +1 409 266 6810. E-mail address: [email protected] (D.A. Bente). 0166-3542/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.antiviral.2013.07.006 160 D.A. Bente et al. / Antiviral Research 100 (2013) 159–189 3.2.2. The M segment . ................................................................................. 164 3.2.3. The L segment. ................................................................................. 165 3.3. Replication cycle . ............................................................................................... 165 4. Maintenance and transmission of CCHFV . ...................................................................... 167 4.1. Tick vectors of CCHFV . ............................................................................ 167 4.1.1. Ticks, nairoviruses and CCHFV. ................................................................. 168 4.1.2. Vertical transmission . ................................................................................. 168 4.1.3. Horizontal transmission . ................................................................................. 168 4.1.4. Competent tick vectors and their geographic distribution. .............................................. 169 4.2. Infection of wild and domestic mammals ............................................................................ 170 4.2.1. Identification of vertebrate hosts. ................................................................. 170 4.2.2. Experimental infections of wild and domestic animals . .............................................. 170 4.3. Features of an enzootic focus . ............................................................................ 170 4.4. Role of birds in the maintenance and spread of CCHFV . ............................................................ 171 4.5. Transmission to humans. ............................................................................ 171 5. Geographic range of CCHFV. ......................................................................................... 171 5.1. CCHF in western areas of the former Soviet Union and in southern Europe. ......................................... 171 5.1.1. The former Soviet Union . ................................................................................. 171 5.1.2. Southeastern Europe . ................................................................................. 171 5.1.3. Southwestern Europe . ................................................................................. 172 5.2. CCHF in eastern and central Asia . ............................................................................ 172 5.3. CCHF in the Middle East and Turkey . ............................................................................ 172 5.3.1. The Middle East . ................................................................................. 172 5.3.2. Turkey . ................................................................................. 172 5.4. CCHF in Africa . ............................................................................................... 173 6. Genetic diversity of CCHFV . ......................................................................................... 173 6.1. Genetic drift. ............................................................................................... 173 6.2. Formation of discrete genetic lineages. ............................................................................ 175 6.3. Evidence of long-distance