Elsevier

Antiviral Research

Volume 100, Issue 1, October 2013, Pages 159-189
Antiviral Research

Review
Crimean-Congo hemorrhagic fever: History, epidemiology, pathogenesis, clinical syndrome and genetic diversity

https://doi.org/10.1016/j.antiviral.2013.07.006Get rights and content

Highlights

  • Crimean–Congo hemorrhagic fever (CCHF) is the most widespread tick-borne viral disease of humans.

  • Its incidence in Turkey and Iran has markedly increased in the past decade.

  • The broad sequence diversity of the virus reflects prolonged genetic drift and reassortment between strains.

  • Until recently, vaccine and drug development have been hindered by the lack of animal models.

  • Research is needed to develop effective countermeasures against CCHF.

Abstract

Crimean–Congo hemorrhagic fever (CCHF) is the most important tick-borne viral disease of humans, causing sporadic cases or outbreaks of severe illness across a huge geographic area, from western China to the Middle East and southeastern Europe and throughout most of Africa. CCHFV is maintained in vertical and horizontal transmission cycles involving ixodid ticks and a variety of wild and domestic vertebrates, 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 actively seek hosts for the blood meals required at each stage of maturation. CCHF occurs most frequently among agricultural workers following the bite of an infected tick, and to a lesser extent among slaughterhouse workers exposed to the blood and tissues of infected livestock and medical personnel through contact with the body fluids of infected patients. CCHFV is the most genetically diverse of the arboviruses, with nucleotide sequence differences among isolates ranging from 20% for the viral S segment to 31% for the M segment. Viruses with diverse sequences can be found within the same geographic area, while closely 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 international livestock trade. Reassortment among genome segments during co-infection of ticks or vertebrates 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 numbers, case fatality rates and all CCHFV strains on GenBank.

Introduction

Crimean–Congo hemorrhagic fever (CCHF) is the most widespread tick-borne viral infection of humans, occurring across a vast area from western China through southern Asia and the Middle East to southeastern Europe and throughout most of Africa. The causative agent, CCHF virus, is maintained through vertical and horizontal transmission in several genera of ixodid (hard) ticks, which spread the virus to a variety of wild and domestic mammals, which develop a transient viremia without signs of illness. Human infections occur through tick bite or exposure to the blood or other body fluids of an infected animal or of a CCHF patient. Ticks of the genus Hyalomma are the principal source of human infection, probably because both the immature and the adult forms actively seek hosts for their obligate blood meals. As Hoogstraal noted in his definitive review (1979): “[CCHFV] is remarkable among arboviruses infecting humans for the number and variety of reservoir-vector species linked with it and the numerous ecological environments in which it circulates.”

CCHF was first recognized as a discrete human illness in the Crimean region of the former Soviet Union in 1944, and over subsequent decades was reported principally in a number of southern Soviet republics, Bulgaria and South Africa (Fig. 1, Fig. 2).

Since 2000, however, the incidence and geographic range of confirmed CCHF cases have markedly increased, with the disease being reported for the first time in Turkey, Iran, India, Greece, the Republic of Georgia, and some Balkan countries, and the detection of viral RNA in Hyalomma ticks recovered from deer in Spain (see below). Remarkably, even though the first cases of CCHF in Turkey were identified in 2002, more than 6300 cases have been diagnosed in the ensuing 10 years. A large increase has also occurred in Iran since the first human infection was recognized in 1999 (Chinikar et al., 2010).

CCHF shows a spectrum of severity, from a mild, nonspecific febrile syndrome through vascular leak, multi-organ failure, shock and hemorrhage (Fig. 3). Probably because clinicians are most likely to publish descriptions of patients with severe or fatal illness, the fatality rate in case reports has ranged from 20% to 30% or higher (Table 1, Table 2, Table 3, Table 4 and Supplementary Table 1). In contrast, for large case series the case fatality rate is generally lower, probably because they also include patients with milder disease; for the more than 6000 cases reported from Turkey, it has been 5% (Table 3, Supplementary Table 1).

Increasing scientific and clinical interest in CCHF has led to the recovery and sequencing of numerous virus isolates across its geographic range, which have revealed a degree of sequence diversity greater than that of any other arthropod-borne virus. As discussed below, this marked genetic diversity suggests a lengthy history of geographic dispersion of the virus in its tick vector, while the identification of CCHF viruses with diverse sequences within the same geographic area, and of similar viruses at widely distant locations, are consistent with the transport of virus by infected ticks on migratory birds or through the international livestock trade (Mild et al., 2010). Phylogenetic analysis has also revealed evidence of genome reassortment and recombination during co-infection of a single host, indicating the potential for the future emergence of novel variants (Chamberlain et al., 2005, Hewson et al., 2004b).

Section snippets

Discovery and naming of CCHF

Although some accounts of CCHF describe it as a disease that has only recently “emerged,” the wide distribution of the virus in ticks and vertebrates across southern Asia, southeastern Europe and Africa suggests that human infections have occurred for millennia. A severe hemorrhagic illness attributed to the bite of a tick or louse was described in Tadjikistan in the 12th century, and similar diseases were known in other parts of Central Asia (Hoogstraal, 1979). Recognition of CCHF as a

Classification

CCHFV is a member of the genus Nairovirus in the family Bunyaviridae, which also includes the genera Orthobunyavirus, Hantavirus, Phlebovirus and Tospovirus. The nairoviruses are tick-borne viruses, which are distinguished from other bunyaviruses by their large L segments (see below). They are divided into seven serogroups; CCHFV and Hazara virus (HAZV) make up the CCHF serogroup. HAZV was isolated from ticks recovered from wild rodents in Pakistan (Begum et al., 1970; Dowall et al., 2012a). It

Maintenance and transmission of CCHFV

In the nearly 70 years since CCHF was recognized as a human disease, researchers have characterized the general features of the circulation of its causative agent among ticks and various species of small and large mammals. The role of ticks in the maintenance of the virus has been established both through studies of field-collected ticks and in experimental assessments of vector competence in the laboratory. In contrast, because most vertebrates infected with CCHFV apparently develop only a

Geographic range of CCHFV

Since CCHF was first recognized in 1944, the known geographic distribution of its causative agent has expanded from the Crimea in the southern Soviet Union to cover a huge area, from western China across southern Asia to the Middle East, Bulgaria and the Balkans, and throughout most of Africa (Fig. 1, Fig. 2). Most nations within this region have reported cases of CCHF in humans. In some countries where the disease has never been diagnosed, evidence of virus circulation is based on the recovery

Genetic diversity of CCHFV

As a means of studying the evolutionary history of CCHFV and the mechanisms responsible for its marked degree of sequence diversity, a number of research groups have generated phylogenetic trees of the S-, M- and L-segments of the viral genome. Such trees have often been based on partial or complete sequences of the S-segment, because the largest number of sequences have been archived. However, the most informative phylogenetic analyses have made use of the more limited number of complete S-,

Clinical features

Although many infections with CCHFV result in a mild, nonspecific febrile illness, some patients develop severe hemorrhagic disease. In the 1944 Crimean outbreak, hospitalized patients showed a sudden onset of fever, accompanied by weakness, headache and muscular pains, vomiting, marked hyperemia of the face and oropharynx, a hemorrhagic rash with development of ecchymoses and bleeding from the nasopharynx, gastrointestinal tract and other sites (Grashchenkov, 1945). Similar findings were

Diagnosis

CCHF should be suspected when a person with an appropriate exposure history becomes acutely ill with fever, malaise and other nonspecific signs and symptoms, together with physical findings suggestive of vascular leak and coagulation defects. Suspicion is strengthened if the initial laboratory evaluation shows leukopenia, thrombocytopenia and elevated serum AST and ALT levels. A specific diagnosis may be made by testing a serum specimen for viral RNA by RT-PCR and for virus-specific IgM and/or

General supportive measures

Most CCHFV infections are either asymptomatic or result in a nonspecific febrile illness that does not require hospitalization or specific therapy. In the small percentage of patients who develop hypotension and hemorrhage, current medical management is largely supportive. The fall in blood pressure and diminished organ perfusion that result from increased vascular permeability call for volume replacement, usually with intravenous fluids, with careful monitoring to prevent the development of

Pathogenesis of CCHF

When CCHF was first identified in 1944, it was clear that its major pathologic abnormality was vascular dysfunction, resulting in hemorrhage and loss of fluid from the plasma into the interstitial space. Soviet clinicians referred to the disease as “infectious capillary toxicosis,” based on autopsy findings that “the main pathologic process in the organs is caused by blood circulatory disturbances, chiefly in capillaries and small vessels…” (Grashchenkov, 1945). Since that time, it has been

Laboratory animal models of CCHF

Although Soviet scientists claimed the successful transmission of CCHFV to a variety of laboratory animals soon after the 1944 Crimea outbreak, these infections were subsequently recognized to be the result of microbial contamination (Grashchenkov, 1945). Since that time, many researchers have tried unsuccessfully to reproduce the features of human CCHF in mice, rats, hamsters, guinea pigs, rabbits and other laboratory animals (Nalca and Whitehouse, 2007), but only newborn mice were found to be

Vaccines

A formalin-inactivated mouse-brain CCHF vaccine was developed in the Soviet Union and approved for use in 1970 (Tkachenko et al., 1970). Testing of serum samples from several thousand recipients demonstrated that repeated vaccination induced a low-level neutralizing antibody response; however, its protective efficacy was not evaluated (Tkachenko et al., 1971). A similar vaccine continues to be used in Bulgaria, where it is given to soldiers, medical personnel and other high-risk groups in

Future geographic range and incidence of CCHF

A number of investigators have expressed concern that the trend toward warmer climates in central and northern Europe might permit CCHFV to expand outside its current geographic range, through the introduction of infected Hyalomma or other reservoir ticks by migratory birds or the international livestock trade (Gray et al., 2009, Estrada-Pena et al., 2012e, Heyman et al., 2010, Maltezou and Papa, 2010, Mild et al., 2010). It has long been known that larvae and nymphs of ticks indigenous to the

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