Crimean-Congo Hemorrhagic Fever

CCHF virus belongs to the genus Nairovirus, of the order Bunyaviridae. The genus Nairovirus includes 34 different viruses divided into 7 distinct serological subgroups, 3 of which can cause disease in humans. The nairovirus genome is structured into 3 single-stranded RNA segments, named L, M, and S according to their respective sizes. The virion consists of a lipid envelope and its diameter measures about 90 to 120 nm. Today the viral RNA (particularly the S segment) has been sequenced and eight genetic lines have been identified.

• A European strain that includes viruses found in Eastern Europe covering a region between the Balkan Peninsula and Russia via Turkey.
• The AP92 strain identified mainly in Greece forms an independent group and is probably less pathogenic.
• The strain found in Central Asia (Kazakhstan, Tajikistan, Uzbekistan and China).
• The Pakistan/Madagascar strain plus some identified in Iran.
• The strain consisting of the remaining strains found in Iran plus those from Senegal and Mauritania.
• The other three lineages are found only in Africa.

CCHF virus has been found in about 30 different tick species. The most efficient vector belongs to the genus Ixodes, the tick Hyalomma marginatum, which can acquire the virus by feeding on an infected host. The virus replicates in the tick's organism, particularly in the cells of the intestinal wall, and spreads to various tissue types, reaching the highest concentrations in salivary glands and reproductive organs. Vertebrates are the hosts that contribute most to the spread of CCHF. Surveys of seropositivity rates have shown that large herbivores are most frequently infected. Birds, on the other hand, do not develop the virus, with the exception of ostriches, although they help spread the disease by carrying CCHF-infected ticks for hundreds of kilometers.

Human infection usually occurs through contact with infected blood from a tick (by direct bite or by crushing an infected tick with hands without gloves).

An increase in the number of cases occurs in spring and summer, when adult ticks feed to complete their life cycle, especially if the previous winter was mild, aiding the survival of these arachnids.

The ability of ticks to transmit CCHF virus to humans also depends on the ecosystem in which they develop. In regions where there are large numbers of both small mammals such as hares and hedgehogs and large mammals such as cattle and sheep, the virus seems to circulate silently with only a few sporadic "incidental" human cases.

Conversely, as seemed to have been the case in Crimea in 1944, when wild hares had proliferated on farms abandoned during the German occupation and the number of farm animals had declined significantly, soldiers and laborers repopulating the area indirectly represented a new blood source for adult Hyalomma ticks, resulting in a high incidence of CCHF cases in humans.

Humans can also be infected by direct contact with animal blood or other infected tissues, although muscle acidification after the death of the animal inactivates the virus.

In a study describing a series of 1,820 cases recorded in Turkey between 2002 and 2007, 62 percent of patients reported close contact with animals. Nearly 90% of the reported cases occurred in farmers, slaughterhouse workers or butchers. It has also been shown that the seropositivity rate is higher in the categories just mentioned, as well as in elderly patients and those of lower socioeconomic status. Human cases are predominantly observed in male individuals, a fact strongly related to the distribution of occupations in countries at risk, where agricultural activities are mostly performed by men. Possible sexual transmission of CCHF should also be considered, although very few cases have been documented. Instead, several cases of mother-to-child transmission have been reported, with severe hemorrhagic syndromes in infants and subsequent death. Under these circumstances, however, not all infants are infected, suggesting that the virus is not transmitted vertically in all cases.

CCHF has the widest geographic distribution of all tick-borne viruses with human consequences and the second largest geographic distribution of all arboviruses after Dengue virus. During the 20th century, major outbreaks of CCHF occurred in the former Soviet Union (e.g., Crimea, Rostov, Astrakhan), Bulgaria with 1,105 cases reported between 1953 and 1974, and China where 260 farmers were infected between 1965 and 1994 in the Xinjiang region, with a reported mortality of 80 percent (probably skewed because only the most severe cases were recorded). Currently, the main outbreaks are in the Middle East (Turkey and Iran), with more than 10,000 cases documented in Turkey since 2002. Numerous studies have been conducted to determine the seropositivity rate and delimit the geographical area affected by the virus. A high number of seropositivity cases have been found in ruminants (sheep, cows, goats), amplifying hosts of CCHF that serve as reliable indicators of the presence of the virus in certain regions.

There is a logical relationship between a high rate of seropositivity in animals in a given region and the incidence of the disease in humans. In fact, in a study of 1,165 ruminants in Bulgaria and Turkey, seropositivity rates of 26 percent and 57 percent, respectively, were reported, with important divergences from region to region. In Africa, although fewer human cases of CCHF are reported than in the Middle East, seropositivity rates are sometimes high in cattle with 1.6% in the Democratic Republic of Congo, 66% in Mali, 67% in Mauritania, and 21% in dromedaries in Sudan.

In Europe, infection is at a lower level than in the African regions mentioned above; however, it has been identified in cattle found in Bulgaria, Hungary, Albania, Kosovo and Greece, and even in two bats in southern France.

In 2002, the virus was also detected for the first time in ticks taken from deer in Spain. The strain was the African strain, phylogenetically related to the strain found in ticks infesting migratory birds in Morocco. To date, however, very few ticks in Spain have been found to carry the virus, between 0 and 3.2 percent.

The very high seropositivity rates found in some endemic areas (as high as 27 percent in some regions of Romania and Greece), suggest that a great many CCHF cases are asymptomatic or cause such limited symptoms that patients do not seek medical treatment. In fact, an estimated 88 percent of HIV-positive patients in Turkey have experienced only limited symptoms. In symptomatic cases, the average incubation time is between 2 and 7 days. The onset is sudden, with fever, muscle pain, dizziness, neck pain and stiffness, back pain, headache, burning eyes, and photophobia (sensitivity to light). Nausea, vomiting, diarrhea, abdominal pain, and sore throat may also occur in the initial stage, followed by mood swings and confusion. After about 4 to 5 days, the hemorrhagic phase begins, characterized by bleeding in the mucous membranes: epistaxis, hematemesis, more rarely melena (presence of blood in the stool), hemoptysis (expulsion of blood with coughing), and hematuria (presence of blood in the urine), but bleeding is also often seen in the skin (ecchymosis/purple). The convalescence phase begins 10-20 days after the onset of the first clinical symptoms and lasts about 10 days. Patients experience marked fatigue, tachycardia with labile blood pressure, temporary alopecia, and memory disturbances.

Early diagnosis is difficult given the nonspecificity of symptomatology, as hemorrhagic manifestations are also characteristic of other infectious diseases in the same geographical areas. Some determinants must inevitably be taken into account such as:

• Tick bite;
• Contact with livestock;
• membership in particular occupational groups in endemic area;
• interhuman contact, including occupational contact with CCHF cases, particularly during established or suspected epidemics. Virological diagnosis of CCHF makes use of serology and virus detection. Antibodies (detected by ELISA, immunofluorescence, and neutralization methods) appear 5-7 days after disease onset, and in the early stage molecular techniques are most useful in diagnosis. However, specific IgG is detected for at least 5 years.An acute-phase infection can therefore be documented by detecting IgM (but not IgG) in an initial serum sample, then IgM and IgG simultaneously, or seroconversion with a fourfold increase in antibody titer between two subsequent serum samples. The specificity of the serological tests is excellent, with no reports of false positives or cross-reactivity with other viruses.

There is no specific drug therapy for CCHF. Treatment of patients with CCHF is based on symptomatic treatment, going to manage electrolyte imbalance caused by gastrointestinal disorders, correcting hemostasis in case of bleeding ( with fresh frozen plasma or platelet transfusion), transfusion of concentrated cells.
Based on encouraging data, some authors recommend treatment with ribavirin, which appears to be able to reduce the mortality rate, but only if administered at an early stage of the disease. Post-exposure prophylactic treatment also appears to reduce the risk of infection.

It is important that people traveling to endemic areas be adequately informed about vector control measures against tick-borne diseases (repellents, wearing long clothing), the need to wear gloves to remove ticks, and the risks of contamination through contact with livestock or in meat processing. In any case, the risk of contracting the disease while traveling to an endemic area, and then reimporting it back to one's home countries, is considered very low.
As for a vaccine, animal studies have led to divergent results. One team succeeded in triggering both a cell-mediated and humoral immune response in mice using a vaccine strain, a reaction that did not, however, reduce mortality rates.
Phase 1 vaccine trials are currently underway in humans, but the antibodies produced appear to have only limited ability to neutralize the virus.