A Clear and Present Danger: Tick-borne Diseases in Europe

Paul Heyman; Christel Cochez; Agnetha Hofhuis; Joke van der Giessen; Hein Sprong; Sarah Rebecca Porter; Bertrand Losson; Claude Saegerman; Oliver Donoso-Mantke; Matthias Niedrig; Anna Papa


Expert Rev Anti Infect Ther. 2010;8(1):33-50. 

In This Article

Crimean-congo Hemorrhagic Fever

Crimean-Congo hemorrhagic fever is a severe tick-borne viral disease with the most extensive geographic distribution of the medically important tick-borne viral diseases.[197] Endemic foci are present in Asia, Africa and Europe. The name of the virus comes from the combination of 'Crimean hemorrhagic fever', a disease initially recognized in 1944 in the former Soviet Union, and 'Congo virus', a virus isolated in 1956 from a febrile patient in Belgian Congo.[198–200]

Crimean-Congo hemorrhagic fever virus belongs to the Nairovirus genus in the Bunyaviridae family. Virions possess a negative-sense ssRNA genome comprising of three segments, small (S), medium (M) and large (L), encoding the nucleocapsid (N) protein, the glycoprotein precursor (giving rise to the two glycoproteins Gn and Gc), and the RNA-dependent RNA polymerase, respectively.[201]

The virus is transmitted to humans and animals by the bite of Ixodid ticks, mainly those of the Hyalomma genus, thus the geographic distribution of CCHF is closely related to the global distribution of Hyalomma spp. ticks, having a 50° North latitude limit. An additional route of virus transmission to humans is the direct contact of broken skin or mucus membranes with the blood or tissues of viremic livestock or CCHF patients. Risk groups include individuals who are exposed to ticks (mainly farmers, shepherds and veterinarians), and persons who come in close contact with CCHF patients, thus family or nosocomial outbreaks of the disease are observed.[202,203]

The first clinical signs and symptoms are observed 1–3 (maximum 9) days after a tick bite, or 5 to 6 (maximum 13) days following direct contact with viremic livestock or CCHF patients. They include abrupt high fever, severe headache, malaise, nausea, vomiting, diarrhea and sore throat. Typically, the disease follows a four-phase course: incubation, prehemorrhagic and hemorrhagic phases and convalescence.[197,204–206] Main laboratory abnormalities in CCHF include leucopenia or leucocytosis, thrombocytopenia, elevated liver enzymes and prolonged coagulation times. Criteria predicting a fatal outcome, during the first 5 days of the disease include: platelets 20 × 109/l or less, aspartate aminotransferase 700 U/l or more, or alanine transaminase 900 U/l or more, partial thromboplastin time 60 s or more, and fibrinogen 110 mg/dl or less.[207] High viral load is also associated with fatal outcome.[206,208–210] In severe cases, approximately 7 days after the onset of the disease, hemorrhagic manifestations are observed, mainly petechiae, epistaxis and hematomas. Death usually occurs on the tenth day of illness, while survivors show progressive improvement. The disease is milder in children and in secondary or tertiary cases.[208] Remarkable hemophagocytosis in the bone marrow is seen in several cases.[210–212] Hemophagocytosis is related to increased serum ferritin levels, which may be related to disease severity. NK cells are also increased in severe cases.[213]

Little is known about the pathogenesis of CCHF; however, it was shown that main targets of the virus are mononuclear phagocytes, endothelial cells and hepatocytes,[214] while proinflammatory cytokines, IL-6 and TNF-α (especially in severe cases), are elevated during CCHFV infection.[215–217] It was suggested that a virulence factor encoded by CCHFV delays the host defense and allows rapid viral spread in the host.[218] Recently, it was found that monocyte-derived dendritic cells are the most permissive to CCHFV infection.[219]

Laboratory diagnosis during the first days of the disease is set by molecular methods, while IgM and IgG antibodies become detectable by indirect immunofluorescence assay or ELISA after the fifth day.[220–222] However, in severe cases, no antibody response is observed. For rapid diagnosis of CCHFV infections, real-time RT-PCR, probe technology and macroarray techniques have been developed.[206,209,223,224] As isolation procedures of CCHFV require a high-containment Biosafety Level-4 laboratory, RNA detection combined with serology is the best protocol for laboratory diagnosis.

Diseases from which CCHF has to be differentiated in Europe are leptospirosis, rickettsiosis, hemorrhagic fever with renal syndrome, borreliosis, brucellosis and Q fever.[208,225] The initial nonspecific symptoms of CCHF can mimic other common infections, leading to misdiagnosis, with a delay of proper treatment resulting in a high risk for outbreaks, including nosocomial ones.[224,226] Patient history is very informative, especially when tick bite or travel to endemic areas is evident.

Treatment is mainly supportive, with careful fluid and electrolyte balance monitoring and replacement with platelets, fresh frozen plasma and erythrocyte preparations.[227] The effect of ribavirin is controversial,[227,228] and although the drug has not been approved for the treatment of CCHF by the US FDA, it is, at present, the only antiviral agent with promising effect, if administered before the fifth day of the disease.[203,227,228] CCHF-venin, an immunoglobulin preparation, is being used intravenously for the treatment of CCHF patients in Bulgaria.[229] As more data on immune response are becoming available, new drugs affecting the cytokine cascade may be much more effective. A formalin-inactivated suckling mouse brain-based vaccine (not approved by the FDA) has been used in Bulgaria and the former Soviet Union.[230,205]

As in other vector-borne diseases, the main means of CCHF outbreak control is breaking the transmission chains. Avoiding or minimizing exposure to the virus achieves prevention. Barrier nursing techniques have to be subjected to all confirmed and suspected cases of CCHF, while persons who have had contact with them should be followed up with daily temperature and symptom monitoring for at least 14 days after the putative exposure. Healthcare workers should take all necessary precaution measures to prevent occupational exposure.[231]

Crimean-Congo hemorrhagic fever virus follows an enzootic tick–vertebrate–tick cycle. Although the virus has been detected in more than 30 tick species, Hyalomma ticks are the main vectors, while a variety of animals are involved as hosts of the virus, although the time of viremia in animals is short (1–2 weeks).

The wide distribution, the ability to cause disease in humans with a high mortality rate, the potential to cause nosocomial cases and even outbreaks, and its inclusion in the list of bioterrorism agents, characterize CCHFV as a challenging virus. In Europe, as in most parts of the Palaearctic region, the main vector of CCHFV seems to be Hyalomma marginatum marginatum (Mediterranean Hyalomma), a two-host tick.[204] Following the lifecycle of Hyalomma ticks, CCHF cases occur mainly from spring to early autumn, as during this period immature ticks are active. High tick activity is associated with warm winters and dry, hot summers.

Crimean-Congo hemorrhagic fever is of high importance for EU public health, as cases are observed almost every year in former Soviet Union countries, Balkan countries and in Turkey. The Rostov and Stavropol regions in European Russia are highly affected, with an increasing number of cases since 2004. In Bulgaria, cases were observed soon after the first recognition of the disease in Crimea in 1944. Main endemic foci are in central and eastern parts of Bulgaria, while a new focus, in southwest Bulgaria, was observed in 2008.[232] In Kosovo, CCHF was first registered in 1957; since then, cases are observed almost every year. A large outbreak took place in 2001.[233] In the same year, an outbreak took place in the neighboring two Kosovo regions, Kukes and Has, in Albania, which are known endemic areas.[225] In 2002, CCHF emerged in Turkey, and since then the annual number of cases is increasing.[234] In 2008, 1315 CCHF cases were confirmed in Turkey, 63 of them fatal. The provinces under high risk were on the Middle Black Sea and the north of Central Anatolia.[235] Cases of the disease were also recently reported in western Anatolia.[236] The conditions during 2008 were extremely favorable for CCHFV, as an increased number of cases were observed in Russia and Turkey, and new foci of the disease emerged: in southwest Bulgaria and in Greece, where the first CCHF case was reported.[237]

A great genetic variability is seen among strains isolated or detected in different regions, while co-circulation of different strains in one region is also seen.[238,239] The most divergent is the Greek strain AP92, which was isolated from Rhipicephalus bursa ticks collected in May 1975 from goats in Vergina village, 80 km west from Thessaloniki. A recent study has shown that the evolution rates of the M and L RNA segments are high (1.22 × 10−4 and 1.01 × 10−4, respectively) compared with that of the S RNA segment (0.34 × 10−4), suggesting that the virus tries to adapt to a variety of vectors and hosts, while keeping its nucleoprotein gene conserved.[240] The pathogenicity of strains has not been studied thus far; however, it was suggested that Asian strains are more pathogenic, while the less pathogenic seems to be the Greek strain AP92. Recently, one mild human case caused by an AP92-like strain was observed in the Balkan region of Turkey.[241]

Climate change is considered one of the main factors that plays a role in tick abundance and, hence, in virus distribution. Additional factors such as habitat fragmentations, demographic modifications and other environmental changes may also be involved.[242] The emergence of CCHF in Turkey in 2002 and in Greece in 2008 suggests that there is also a risk for emergence in other European countries with similar geographic characteristics. Although knowledge regarding the virus and its epidemiology has greatly improved during the last decade, further studies are needed to elucidate the lifecycle of CCHFV, the antigenic differences, the neutralizing epitopes, and the human immune response for effective treatment and vaccine development. In the meantime, the best way for prevention of the disease is the education of risk groups and awareness in healthcare workers.