Factsheet about Crimean-Congo haemorrhagic fever - ISS-G20 Laboratorium Repository

Case definition

CCHF in humans is a notifiable disease at the EU/EEA level [1]. The case definition for viral haemorrhagic fevers is defined according to the Commission Implementing Decision (EU) 2018/945 of 22 June 2018 [3].

The pathogen 

CCHFV belongs to the genus Orthonairovirus (family Nairoviridae, order Bunyavirales). The disease was first identified in 1944 in Crimea (Crimean haemorrhagic fever), while the virus was first isolated in 1956 in Congo (Congo virus), resulting in the current name of the virus and the disease. The virion is spherical with an approximate diameter of 80–100 nm. The CCHFV genome consists of three segments of single-stranded negative sense RN — the small (S), medium (M) and large (L) segments — which encode the viral nucleocapsid, the glycoprotein precursor (which is cleaved into two envelope glycoproteins, GN and GC, and various non-structural proteins) and the polymerase, respectively. Based on the S segment sequences, the currently identified CCHFV strains can be classified into seven genotypes (genotypes I to VII), with genotype IV divided further into two subgenotypes (IVf and IVg). The CCHFV phylogeny differs in the three segments due to reassortment events among strains of different genotypes. In March 2021, the International Committee on Taxonomy of Viruses updated the taxonomy of the phylum Negarnaviricota (which includes the orders Bunyavirales and Mononegavirales) [4]. One of the changes included the assignment of CCHFV genogroup VI into a novel species of the Orthonairovirus genus named Congoid orthonairovirus, which includes the prototype strain AP-92 isolated in 1975 from Rhipicephalus bursa ticks sampled in Vergina (ancient Aigai) in northern Greece, and it has now been renamed Aigai virus [5]. 

Clinical features and sequelae

The incubation period of CCHF is three to seven days (range: 1–14 days); it is generally shorter after a tick bite or needle-stick injury than following contact with infected blood. Seroprevalence studies show that the majority of CCHF cases (>80%) are asymptomatic or mild. Children usually present a milder form of the disease. In severe cases, the main pathophysiology features are increased vascular permeability and cytokine storm. The disease is characterised by a sudden onset of flu-like symptoms (fever, headache, myalgia and malaise), photophobia, abdominal pain, diarrhea and vomiting. Haemorrhagic manifestations can be present in severe cases, ranging from petechiae, epistaxis and ecchymoses at venepuncture and injection sites to severe haemorrhages from various systems. Few patients may present mood swings, confusion and aggression. 

The virus enters the host through the epithelial cells and, after a local amplification, enters the lymphatic system and infects the organs — specifically the liver and spleen, but also other organs — leading to multiorgan failure. Severe cases follow a typical course with four distinct phases: incubation, pre-haemorrhagic, haemorrhagic and, if the patient survives, convalescence [6]. The case fatality rate in hospitalised patients is approximately 30%. In survivors, improvement is seen 9–10 days after symptom onset, at which time they are discharged from the hospital. Recovery may be slower in a small proportion of patients. Hematological and biochemical abnormalities include thrombocytopenia, leukopenia, transaminasemia, prolonged coagulation times, elevated D-dimers, decreased fibrinogen levels, and elevated levels of creatine phosphokinase and lactate dehydrogenase. High viral load, severe thrombocytopenia, elevated liver enzymes and prolonged bleeding times are predictors of severe disease and fatal outcome [7].

Wild and domestic animals are susceptible to CCHFV infection and serve as hosts of the virus. When infected, they become viraemic for approximately 2–15 days, but they do not present clinical symptoms.

Epidemiology

CCHF is the most widespread viral tick-transmitted haemorrhagic fever [6]. It is estimated that three billion people are at risk of infection globally, and 10 000 to 15 000 infections — 500 of them fatal — occur every year. Cases have been reported in over 30 countries in Africa, Asia and Europe, in regions where Hyalomma spp. ticks are established. CCHF nosocomial infections with considerable mortality rates have been observed in various countries [8]. Cases imported from endemic countries have been reported; therefore, awareness should be raised among health practitioners that a patient’s travel history needs to be recorded in detail.

Wild and domestic animals serve as hosts of CCHFV, as they support tick populations by providing blood meals and they can transmit the virus to both ticks and humans when they are viraemic. They may also transport ticks across long distances. CCHFV-specific antibodies have been detected in a variety of wild and domestic animals (e.g. livestock, horses, dogs, chickens, camels, ostriches, swine, hares, deer, buffalo and rhinoceroses), while in birds, antibodies have only been detected in guinea fowl and ostriches. Seroprevalence studies in humans, wild animals and domestic animals, as well as screening of ticks for CCHFV infection, provide useful information about the circulation of the virus in a region and identify potential disease foci [9-12]. 
Several biotic and abiotic factors play a role in the emergence and spread of CCHFV in a region, such as climatic factors favouring tick abundance, land fragmentation, legal or illegal livestock trade, and activities in abandoned agricultural areas that increase human exposure to ticks. Climatic changes may also redirect the route of migratory birds, and if they are infested with infected ticks, CCHFV can be introduced into new areas. Predictive risk models have been constructed based on ecological determinants [13].

In the EU/EEA and its neighbouring countries, sporadic cases and/or outbreaks of CCHF have been reported in Albania, Bulgaria, Georgia, Greece, Kosovo , Russia, Spain, Ukraine and Turkey. Spain reported its first case in 2016, but a retrospective study revealed that another case had occurred in 2013 [14]. Since the first report, several sporadic cases have been reported in the western part of the country. The CCHFV strains detected in Spain belong to various genotypes, and a reassortant has also been identified [15]. In Greece, one single CCHF case has been reported, in 2008; since the CCHFV seroprevalence in humans in specific regions of the country is high (>5%), it has been suggested that it may be related with a non- or low-pathogenic strain causing asymptomatic infections [16]. Detailed information on CCHF cases that have occurred in the EU/EEA since 2013 is available [17].

Transmission

CCHFV circulates in nature between ixodid ticks and vertebrate hosts. It is transmitted to humans by bites from infected ticks or by direct contact with blood or tissues of infected ticks, viraemic patients or viraemic livestock. There have been a few reports of infection after drinking unpasteurised milk or after consumption of raw meat from freshly slaughtered livestock. CCHFV is usually inactivated in meat due to post-slaughter acidification.

Hyalomma ticks (mainly H. marginatum, H. anatolicum, H. rufipes and H. asiaticum) are competent CCHFV vectors and reservoirs. The principal tick vector in Europe is H. marginatum. Detailed information on H. marginatum is available [18]. In Spain, CCHFV was detected in H. lusitanicum ticks before the identification of the first human case, and it seems that this tick species plays an important role in virus circulation in the country [19,20]. Maps showing the geographical distribution of H. marginatum and H. lusitanicum in the EU/EEA and neighbouring countries are available [21].

CCHFV is transmitted among ticks transstadially, transovarially and venereally, while transmission by co-feeding may also occur. After infection, ticks remain infective for their whole life.

Hospital-acquired infections can occur due to direct contact with blood or tissues of viraemic patients or improperly sterilised medical devices. CCHF cases in pregnant women are rare, but the risk for maternal and foetal mortality is high, and nosocomial transmission in this group has been reported [22]. The epidemiological and behavioural factors contributing to acquisition of CCHFV infection differ among countries [23].

The incubation period of CCHF is three to seven days (range: 1–14 days), although longer periods have been reported. It can be shorter when the viral dose is high and in cases with bloodstream infections.

Diagnostics

Early and accurate diagnosis of CCHF is critical for the patient’s life and for timely response and control measures. Laboratory diagnosis in the acute phase of the disease is achieved mainly by detection of CCHFV RNA using molecular methods, but also by detection of CCHFV antigen and isolation of the virus (in high containment facilities). Prolonged detection of CCHFV RNA has been reported, but — in general — molecular methods are helpful during the first week of illness. The high genetic variability of CCHFV strains may diminish the efficacy of molecular tests, affecting their diagnostic potential [24]. Metagenomic next generation sequencing can support pathogen identification, especially in cases with complicated symptomatology. CCHFV-specific IgM and IgG antibodies are detectable after the fifth day of the disease using serological methods (ELISA or indirect immunofluorescence). CCHFV infection is confirmed by detection of IgM antibodies or seroconversion, or four-fold increase in IgG antibody titres in serial serum samples. It should be noted that antibody response is often absent or delayed in severe or fatal cases. A combination of molecular and serological methods is the best diagnostic approach. Obtaining a detailed medical history from a potential CCHF case, as well as understanding the virus kinetics in the blood and antibody responses, will support health practitioners to make an accurate diagnosis.

Case management and treatment

No specific antiviral drug is currently available for CCHF treatment. Therefore, medical management consists of monitoring a patient’s fluid and electrolytes balance and organ functions, including their coagulation system [25]. Ribavirin, a broad-spectrum antiviral drug, can be given early after symptom onset to prevent severe infection or as post-exposure prophylaxis. The antiviral Favipiravir has been studied in vitro and in animal models and results are encouraging [26]. Administration of human anti-CCHFV immunoglobulins from convalescent patients has been reported for prevention and treatment in some countries [27]. Early clinical suspicion and laboratory confirmation are essential for successful treatment of patients and for prompt implementation of appropriate infection control measures to mitigate disease spread. Strict barrier nursing procedures should be applied for suspected and confirmed CCHF cases.

Public health control measures

At the population level, the most effective control measure is the dissemination of information to residents and visitors in endemic areas. Such information should highlight personal protective measures to reduce the risk of tick bites (use of tick repellents such as DEET, wearing clothes that minimise skin exposure), how to perform a self-check for ticks and how to properly remove an attached tick. Special attention should be paid to abandoned agricultural areas, which serve as habitats for large populations of virus hosts (e.g. hares).

Application of acaricides on livestock is useful to protect workers in slaughterhouses and to avoid transporting CCHFV-infected ticks to other regions through transport of animals. Residents are also advised to store meat at 4–8oC, to cook meat thoroughly and to follow good hygiene practices during meat preparation [28].

Contact tracing and active surveillance of people who have been exposed to CCHFV is necessary. Those who have been exposed to the virus should be advised to seek medical advice if they experience any symptoms of the disease within 14 days after last contact with the case [29]. No specific safety measures with regard to substances of human origin are recommended.

Infection control, personal protection and prevention

Groups at risk in endemic areas include people doing outdoor activities, farmers, animal breeders, veterinarians, people engaged in informal slaughtering, hunters and healthcare workers. People in risk groups should apply personal protective measures to avoid tick bites, including wearing protective clothing and using chemical tick repellent such as permethrin or deltamethrin.

There is no vaccine against CCHF licensed by the European Medicines Agency for the EU/EEA market. However, a vaccine derived from inactivated CCHFV, propagated in mouse brain, is used in Bulgaria [30]. Several studies on vaccine development are in progress [31,32].

For infection control, education of personnel in healthcare settings is needed. This includes training in barrier nursing procedures and the use of personal protective equipment (e.g. gloves, respiratory masks, waterproof gowns, goggles). Contact tracing is critical to prevent further spread of the virus. In general, it is necessary to follow the guidelines recommended for the management and control of viral haemorrhagic fevers [33]. The collection and processing of specimens from suspected and confirmed CCHF cases should be done following the biosafety laboratory guidelines, while work with infectious CCHFV particles requires a maximum biocontainment laboratory.

CCHF outbreak response relies on early pathogen identification and application of infection control measures that integrate laboratory, clinical and public health personnel [34]. CCHF is an excellent example of a disease that is well-suited to the One Health approach and, as such, collaboration and networking play an essential role in strengthening the preparedness, capacity and capability to respond to an outbreak.

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