Crimean-Congo hemorrhagic fever

INTRODUCTION — Crimean-Congo hemorrhagic fever (CCHF) is a zoonotic disease transmitted by ticks and characterized by fever and hemorrhage [1,2]. It was first described in Soviet soldiers in the Crimea in 1944 and was named Crimean fever. In 1956, the virus was isolated from a child in the Congo with similar symptoms and was named Congo virus [3]. The causative agent of both illnesses was shown to be the same virus, which was subsequently termed CCHF virus [4]. CCHF infects a range of animals; humans are the only known host that develops disease.

EPIDEMIOLOGY — CCHF is an emerging infectious disease given the expanding distribution of its main vector, ticks of the genus Hyalomma. Each year, more than 1000 human cases are reported from southeastern Europe and western Asia [5-7]. The primary means of transmission to humans is via tick bites.

Geography — CCHF is endemic in parts of Africa, the Middle East, Asia, and southeastern Europe, and has been observed in over 30 countries [5,6,8-15]. In 2022, Iraq reported a surge of over 200 infections during the first half of the year [12]. Outside of known endemic areas, a case acquired from a tick bite in Spain has been reported and was associated with a secondary case in a health care worker [8,14].

A recent map of cases can be seen in the figure (figure 1) [5,8-12].

Seasonal variation — In the Northern Hemisphere, transmission of CCHFV is common between May and September, with a peak incidence in June and July [16]. In Pakistan, CCHF has biannual peaks between March and May and between August and October [17]. In Turkey, there is peak transmission in early summer months and a strong association with living at altitude greater than 836.5 m [18]. Seasonal transmission at moderate altitudes, typically around 1000 m, has been reported in other studies, presumably reflecting optimum conditions for tick populations [19,20].

Tick vectors — CCHFV is primarily transmitted via hard-bodied Hyalomma ticks of the family Ixodes, particularly Hyalomma marginatum [21]. The geography of CCHF infection reflects the distribution of Hyalomma ticks, which have a northern geographic limit of 48° north latitude [22]. CCHFV has also been isolated from Rhipicephalus, Boophilus, and Dermacentor spp, which may also transmit the virus [23].

The most common viral reservoirs are domestic livestock (sheep, goat, cattle, and pig), which are infected by adult ticks. Larvae and nymphs tend to feed on rodents, hares, hedgehogs, and ground-dwelling birds, which serve as amplifying hosts for the virus [2]. Hyalomma ticks have a two-year life cycle (figure 2), and blood meals are required for development at each life cycle stage. Ticks can remain attached for 2 to 13 days; after completion of feeding, the ticks detach from the host and begin to search for new hosts. The virus begins to multiply within 36 hours of attachment [24]; it does not have the ability to survive outside the host but may persist in infected body fluids such as blood, stool, or vomit.

Ticks survive most readily in relatively warm, dry habitats. Tick density increases markedly following a preceding mild winter and in the setting of diminished rainfall; these conditions are associated with increased numbers of human CCHF cases [25,26].

Changing tick habitats and elimination of usual host animals may lead to an increase in the spread of tick-borne disease [27]. Environmental factors associated with CCHF infection include livestock grazing at the edge of forests and presence of scrub and herbaceous vegetation [28,29]. (See 'Disease emergence' below.)

Disease emergence — The incidence of CCHF appears to be increasing. Possible causes of CCHF outbreaks include changing agricultural practices, climate change [30-32], movement of domestic animals [32-34], migrating birds [35,36], increasing numbers of susceptible animals, and increasing tick populations [5,9]. Changing agriculture practices such as deforestation and irrigation projects may be associated with increased contact with vectors [23,33]. Conversely, reducing agricultural activities may be associated with increases in wildlife and numbers of ticks in a particular area; subsequent utilization of such areas for farming may be associated with CCHF outbreaks [3,37]. Increased diagnostic awareness may also play a role in the apparent increased incidence [13].

Transmission to humans — CCHF is transmitted via ticks, direct contact with blood or other bodily fluids of infected animals, nosocomial transmission, and vertical transmission.

CCHF is most commonly transmitted via tick bites or crushing ticks with bare fingers. Ticks can attach to all sites of the human body, including the trunk, extremities, and head and neck [38]; H. marginatum commonly attaches to the trunk [39].

Transmission can also occur via direct contact with blood or other bodily fluids of livestock; abattoir workers and farmers are at increased risk for infection [2,40-42]. In a large epidemiologic study including more than 1800 cases of CCHF, 69 percent of patients reported a history of tick bite or tick contact, 62 percent reported close contact with animals, and 10 percent had history of direct contact with animal body fluids or tissue [16].

The risk of community-based transmission to close contacts and relatives of patients with CCHF is low [43-45]. Relatives and caregivers should avoid direct contact with infected patients and their blood/bodily fluids, wear gloves and protective clothes, and wash hands regularly. Personal items such as razors or toothbrushes should not be shared.

Nosocomial transmission of CCHFV has been described [46-48]. The risk is highest during later stages of disease, which are associated with higher viral loads as well as diarrhea, vomiting, and hemorrhage [49]. Direct contact with blood and body fluids, needle-stick injuries, and splash exposures are common causes of nosocomial transmission [49-52]. Health care personnel are also at risk of infection during aerosol-generating procedures [53,54]. Transmission between patients sharing the same hospital room has occurred, likely due to contact with infected blood or body fluids [55]. (See 'Infection control' below.)

Vertical (mother-to-child) transmission of CCHFV has been described; in such cases, fetal prognosis may be guarded [56,57]. Thus far, breastfeeding has not been associated with CCHFV transmission [58]. The role of sexual transmission is uncertain [59,60]; CCHF with epididymoorchitis has been described [61] as has detection of CCHFV in urine [62,63].

The risk of laboratory exposure to CCHFV while processing blood samples is low if routine laboratory procedures are followed [49].

Risk factors and seroprevalence — Individuals at risk for CCHFV infection include agricultural workers, individuals in rural areas engaged in animal husbandry, abattoir workers, veterinarians, leather factory workers in areas with high tick density, campers and hikers, hunters, soldiers, health care workers, and travelers to endemic areas (particularly in the setting of exposure to farming and slaughtering) [2,12,40,54,64-70].

In high-risk populations, the seroprevalence of CCHFV infection is 10 to 14 percent [71-73]. Independent risk factors for seropositivity include history of tick bite, manually removing ticks from animals, animal husbandry or farming, age >60 years, and residence in a rural area [71-74]. Data are insufficient regarding the risk of CCHFV infection in immunocompromised hosts.

VIROLOGY — CCHF virus (CCHFV) is a member of the Nairovirus family within the Bunyavirus order, which contains negative-stranded, enveloped RNA viruses. The genome of CCHFV has three segments, which are small (S), medium (M), and large (L). Based on the CCHFV S-segment sequences, CCHFV strains have seven clades in different geographical locations [9,75-79]. All Balkan strains are clustered in the same branch [80], and they are closely related to Turkish and southwestern Russian strains [9]. Detection of several viral variants and differences in clade distribution have been demonstrated over time [81], and cross-border movements of livestock may have contributed to the insertion of new clades into countries and spread of the disease [82]. Wild birds have also been shown to have the capacity to carry ticks containing CCHFV to different geographic areas [35].

CLINICAL MANIFESTATIONS — The spectrum of clinical manifestations ranges from subclinical illness (88 percent) to acute infection with hemorrhage and multiorgan failure [16,71]. The incubation period ranges from 1 to 13 days; it correlates with viral load and the type of transmission. The incubation period following tick bite is typically one to three days; the incubation period following contact with blood and body fluids is typically three to seven days [83,84]. Relatively short incubation periods have been described in cases due to nosocomial infection during later stages of disease, which are associated with high viral loads as well as diarrhea, vomiting, and hemorrhage [49,85].

Clinical manifestations of CCHF include sudden onset of fever, headache, malaise, myalgia, sore throat, dizziness, conjunctivitis, photophobia, abdominal pain, nausea, and vomiting [1,16,86,87]. One case series including more than 1600 patients with CCHF reported frequency of clinical manifestations as follows: fever (89 percent), headache (68 percent), myalgia (70 percent), fatigue (92 percent), nausea (65 percent), vomiting (43 percent), diarrhea (25 percent), and hemorrhage (23 percent) [16]. Rales are generally associated with pulmonary hemorrhage [88]. Ocular findings include subconjunctival and retinal hemorrhage, which may occur in the absence of visual complaints [89]. Other clinical findings include tachycardia, hepatomegaly, lymphadenopathy, and confusion.

The initial period of nonspecific symptoms generally lasts up to seven days and is followed by either recovery or progression to severe disease [90]. The convalescence period in recovering patients generally lasts up to four weeks with no long-term sequelae.

In severe cases, hemorrhagic manifestations are observed; these include petechiae (picture 1), ecchymoses (picture 2 and picture 3), epistaxis, and gum bleeding (picture 4). Pulmonary hemorrhage, intra-abdominal bleeding, hematuria, melena, and vaginal bleeding (heavy menstrual bleeding or early menstrual bleeding) can also occur. Severe disease is thought to be due to an exaggerated proinflammatory cytokine response ("cytokine storm"), causing endothelial cell activation and increased vascular permeability, resulting in hypotension, shock, multiple organ failure, and death [91-95].

Laboratory findings may include thrombocytopenia, leukopenia, hyperbilirubinemia with elevated transaminases, and prolongation of international normalized ratio, prothrombin time, and activated partial thromboplastin time [16,96]. Anemia is observed in some cases. In the setting of multiorgan failure, elevated blood urea nitrogen, creatinine, and creatine phosphokinase may be present. Patients with disseminated intravascular coagulation have decreased fibrinogen levels and increased fibrin-degradation products [47].

DIAGNOSIS — The diagnosis of CCHF should be suspected in patients presenting with fever and bleeding who have relevant geographic and epidemiologic risk factors (including exposure to an endemic region within the previous two weeks in addition to known tick bite and/or contact with animal tissue or body fluids). (See 'Epidemiology' above.)

Diagnostic tools include detection of CCHF virus (CCHFV) RNA by reverse-transcriptase polymerase chain reaction (RT-PCR) and specific immunoglobulin (Ig)M and IgG by enzyme-linked immunosorbent assay. In endemic areas, diagnostic testing may be limited to reference laboratories. If available, RT-PCR is preferred; this test allows rapid and accurate diagnosis of CCHFV with high sensitivity and specificity [97-99]. Specific IgM and IgG antibodies are detectable five days from the onset of symptoms [100], and IgG antibodies can remain detectable for at least five years [2]. Specific IgM positivity in a single sample indicates current infection, and seroconversion or fourfold rise of CCHFV IgG antibody levels in paired sera confirm recent or current infection [2].

CCHFV can be cultured in cell culture; this requires biosafety level 4 laboratories and is only used for research purposes.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis depends on the geographic region and includes:

●Other viral hemorrhagic fevers – Other viruses capable of causing hemorrhagic fever include dengue, Ebola, Marburg, Lassa, and yellow fever. These illnesses can all cause severe multiorgan system illness accompanied by hemorrhage. The diseases may be distinguished based on relevant epidemiologic exposure and polymerase chain reaction or serologic testing. (See "Dengue virus infection: Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of Ebola virus disease" and "Marburg virus" and "Yellow fever: Epidemiology, clinical manifestations, and diagnosis" and "Lassa fever".)

●Malaria – Clinical manifestations of malaria include fever, chills, malaise, fatigue, diaphoresis, headache, cough, anorexia, nausea, vomiting, abdominal pain, diarrhea, arthralgias, and myalgias. The diagnosis is established by microscopy or rapid diagnostic testing. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children" and "Laboratory tools for diagnosis of malaria".)

●Rickettsial infection – Certain rickettsial infections (such as scrub typhus, African tick bite fever) may begin insidiously or abruptly; most patients develop high fever, headache, and myalgias, and an eschar or rash may develop in a subset of patients. The diagnosis is confirmed via serology. (See "Other spotted fever group rickettsial infections" and "Scrub typhus".)

●Q fever – Acute Q fever most commonly presents as a flu-like illness, pneumonia, or hepatitis, typically in association with animal exposure. The diagnosis is established via serology.

●Brucellosis – Acute brucellosis usually consists of fever, night sweats, arthralgias, myalgias, low back pain, and weight loss as well as weakness, fatigue, malaise, headache, dizziness, depression, and anorexia; it is transmitted via unpasteurized dairy products from infected animals. The diagnosis is established via culture or serology. (See "Brucellosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

●Leptospirosis – Leptospirosis presents with the abrupt onset of fever, rigors, myalgias, and headache; conjunctival suffusion is an important sign. The diagnosis is established by serologic testing. (See "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

●Relapsing fever – Clinical manifestations of relapsing fever include acute febrile episodes punctuated by an intervening afebrile period; headache, neck stiffness, arthralgia, myalgia, and nausea may accompany the fever. The diagnosis is established by blood smear. (See "Clinical features, diagnosis, and management of relapsing fever".)

●Viral hepatitis – Clinical manifestations of viral hepatitis include jaundice, hepatomegaly, and elevated aminotransferases; the diagnosis is established via serology. (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis" and "Hepatitis B virus: Clinical manifestations and natural history" and "Hepatitis B virus: Screening and diagnosis in adults" and "Screening and diagnosis of chronic hepatitis C virus infection".)

●Meningococcemia – Clinical manifestations of meningococcemia include fever, nausea, vomiting, headache, myalgias, and petechial rash. The diagnosis consists of isolation of Neisseria meningitidis by culture from a usually sterile body fluid, such as blood or cerebrospinal fluid. (See "Clinical manifestations of meningococcal infection" and "Diagnosis of meningococcal infection".)

In addition, noninfectious entities in the differential diagnosis include:

●Idiopathic thrombocytopenic purpura (ITP) – Clinical manifestations of ITP include bleeding (petechiae, epistaxis, purpura, and/or severe hemorrhage) and thrombocytopenia. The diagnosis is made following elimination of other potential causes of thrombocytopenia. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis".)

●Acute leukemia – Clinical manifestations of acute leukemia may include signs and symptoms of anemia (eg, shortness of breath, dyspnea on exertion, pallor), excess bleeding or bruising, and infection. The diagnosis is established via bone marrow biopsy. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

TREATMENT — There is no proven antiviral treatment for CCHF infection. Ribavirin has been studied in vitro, in animal models, and in some patients [101-105]; it has not been shown to reduce viral load or mortality in humans [86,106-111], and its clinical efficacy is controversial [86,108,112-115]. In addition, most of the studies evaluating the effectiveness of ribavirin are limited by methodology flaws [116]; further study is needed [115].

Management of CCHF consists of supportive care; in severe cases, blood product replacement is warranted [117]. Patients with CCHF should be managed in a health care center with appropriate facilities for diagnosis, treatment, and prevention of disease, including isolation precautions. (See 'Infection control' below.)

Data are insufficient to support routine use of steroids, intravenous immunoglobulin, or plasma exchange [117-120]. Use of hyperimmunoglobulin (which is prepared from the plasma of donors with antibody against CCHF) requires further study. Hyperimmunoglobulin can decrease viral load via direct neutralization, although viral strain variability may be an important determination in the use of this therapy [121].

Supportive care — Supportive treatment is essential for management of CCHF [117]. Careful attention should be paid to fluid balance and electrolytes. Mechanical ventilation, hemodialysis, vasopressor, and inotropic agents may be needed. Acetaminophen may be used for fever and pain management; nonsteroidal antiinflammatory drugs should be avoided as these agents can adversely affect normal clotting.

Platelet transfusion is warranted to maintain platelet count >50,000/mm³ in the setting of bleeding and for patients with platelet count <20,000/mm³ in the absence of bleeding [122]. The need for blood transfusion should be assessed based on the hemoglobin level as well as the general clinical status. Unnecessary interventional procedures should be avoided to minimize risk of bleeding.

In nonsevere cases, symptoms usually resolve in 7 to 10 days. In the absence of bleeding, transaminases and platelet counts tend to return to normal levels after 5 to 10 days.

Infection control

Precautions — Infection control precautions (including standard, contact, and droplet precautions) should be implemented to prevent nosocomial transmission of CCHF [9,123]. Patients with suspected or confirmed CCHF should be treated in isolation rooms [124]; if this is not possible, cohorting of patients is appropriate. The number of health care personnel entering patient rooms should be minimized. (See "Infection prevention: Precautions for preventing transmission of infection".)

Health care worker training about CCHF transmission, exposure prevention, hand hygiene, and use of personal protective equipment is essential [123,125]. Contact precautions include appropriate personal protective equipment (an impervious gown, gloves, mask, and eye/face protection) [123]. Respiratory protection (N95 mask or FFP3 respirator) is required during aerosol-generating procedures. Shoe covers are warranted when there is significant environmental contamination. It is essential to remove and dispose of personal protective equipment safely when leaving patient rooms [54,124,126].

Using "safe-sharps" systems help prevent needle-stick injuries. Principles of safe phlebotomy should be adhered to, and needles must not be recapped. All sharps and needles should be disposed of in hard containers and at the point of use.

Precautions may be discontinued for patients with no signs and symptoms of disease for at least three days, with a platelet count >50,000/mm³ and normal coagulation tests (international normalized ratio, prothrombin time, and activated partial thromboplastin time). If possible, a negative blood polymerase chain reaction for viral hemorrhagic fever should also be documented [127,128].

Postexposure management — The exposed individual should undergo a two-week period of monitoring for symptoms or signs of CCHF, including daily temperature measurement and weekly assessment of complete blood count measurement; no quarantine is required [83,129]. Development of a febrile illness during the monitoring period should prompt diagnostic testing. (See 'Diagnosis' above.)

The role of ribavirin for prevention of clinical illness when given as postexposure prophylaxis is uncertain [50,52,54,130,131]; further study is needed.

Environmental cleaning — CCHF virus (CCHFV) can be inactivated by disinfectants including 1% sodium hypochlorite (household bleach), 70% alcohol, 2% glutaraldehyde, hydrogen peroxide, and peracetic acid, and the virus is susceptible to high temperature at 56°C (133°F) for 30 minutes or 60°C (140°F) for 15 minutes. Areas contaminated with CCHFV can be disinfected with an approved hospital disinfectant or bleach [129]. Housekeeping staff should use personal protective equipment when cleaning.

PROGNOSIS — The mortality rate varies among countries and ranges from 2 to 80 percent [9,132-134]. Mortality rates in endemic countries are approximately 4 to 20 percent [7,135-139]. Most patients with CCHF live in rural areas and may have limited or delayed access to health care facilities, which may be associated with adverse outcomes.

CCHF is a notifiable disease in Turkey and Iran, and both countries have active surveillance and detection systems. Between 2002 and 2015, 9787 cases were reported to the Ministry of Health in Turkey, with a mortality rate of 4.8 percent [137]. The case-fatality rate is higher in nosocomial cases, probably due to high viral inoculum [126,140,141].

Independent predictors of mortality include presence of hemorrhage (particularly gastrointestinal bleeding and hematuria) [142], impaired consciousness [40,142], central nervous system involvement, diarrhea [143], splenomegaly [40], thrombocytopenia [142], leukocytosis, increased alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase [143,144], and decreased fibrinogen levels with a prolonged activated partial thromboplastin time [142-144]. In addition, CCHFV RNA level >10⁷ copies/mL is an important indicator for mortality (positive predictive value 80 percent, sensitivity 89 percent, specificity 93 percent) [145,146].

Severity scoring systems have been developed based on these factors [144,147-149]; further prospective studies are needed.

PREVENTION — Prevention consists of avoiding tick exposure and avoiding contact with animal bodily fluids. Issues related to prevention of nosocomial transmission are discussed above. (See 'Infection control' above.)

Residents of and travelers to endemic areas should be educated regarding personal protection measures to avoid tick bites [70,83]. Wearing light-colored clothing allows easy detection of ticks, and tucking shirts into pants and pants into socks is helpful to minimize exposure. The use of a 20 to 30% N,N-diethyl-m-toluamide (DEET) repellant for skin provides some protection, and permethrin-treated clothes also help to prevent tick bites. Grassy areas should be avoided in warm seasons when ticks are most active. Ticks should not be handled with bare hands and should not be crushed or squeezed. Skin and clothes should be examined regularly for presence of ticks, and attached ticks should be removed with tweezers. Following tick removal, the skin should be cleaned with antiseptic. (See "Prevention of arthropod and insect bites: Repellents and other measures".)

Control of CCHF in animals is difficult. Restricted areas should be established for slaughtering. To reduce the risk of human infection during slaughtering, animals should be quarantined for 14 days before slaughtering [12,150]. Quarantine could also be applied to imported cattle [151].

Acaricides are effective against ticks in livestock and should be applied to animals prior to entering slaughterhouses [12]. All butchers and slaughters should be educated for preventive measures [150]. Impervious protective clothes and gloves should be worn during slaughtering, butchering, and handling of animals [2].

There is no approved vaccine for use in humans or animals. An inactivated suckling mouse brain–derived vaccine developed for CCHF is used in Bulgaria; it is given in three doses with a booster dose after five years and affords variable protection [152]. Virus-neutralizing activity of this vaccine is low, and repeated doses are necessary to achieve adequate neutralizing antibody levels [153]. Another vaccine based on CCHF virus glycoproteins is under development [154,155]; further study is needed.

SUMMARY

●Crimean-Congo hemorrhagic fever (CCHF) is a zoonotic disease transmitted by ticks and characterized by fever and hemorrhage. CCHF is endemic in parts of Africa, the Middle East, Asia, and southeastern Europe (figure 1). In the Northern hemisphere, transmission of CCHF virus (CCHFV) is common between May and September; ticks survive most readily in relatively warm, dry habitats. (See 'Introduction' above and 'Epidemiology' above.)

●CCHFV is most commonly transmitted via ticks or direct contact with bodily fluids of infected animals; nosocomial transmission can also occur. Individuals in rural endemic areas working in animal husbandry are at highest risk for infection. The incubation period following tick bite is typically one to three days; the incubation period following contact with blood and body fluids is typically three to seven days. (See 'Transmission to humans' above and 'Clinical manifestations' above.)

●Clinical manifestations of CCHF include sudden onset of fever, headache, malaise, myalgia, sore throat, dizziness, conjunctivitis, photophobia, abdominal pain, nausea, and vomiting. In severe cases, hemorrhagic manifestations (petechiae, ecchymoses, epistaxis, and gum bleeding) are observed. Laboratory findings include thrombocytopenia, leukopenia, hyperbilirubinemia with elevated transaminases, and prolongation of prothrombin time and partial thromboplastin time. (See 'Clinical manifestations' above.)

●The diagnosis of CCHF should be suspected in patients presenting with fever and bleeding who have relevant geographic and epidemiologic risk factors. Diagnostic tools include detection of CCHFV RNA by reverse-transcriptase polymerase chain reaction (RT-PCR) and serology. If available, RT-PCR is preferred. Specific immunoglobulin (Ig)M and IgG antibodies are detectable five days from the onset of symptoms. (See 'Diagnosis' above.)

●Management of CCHF consists of supportive care; in severe cases, blood product replacement is warranted. Careful attention should be paid to fluid balance and electrolytes. Mechanical ventilation, hemodialysis, vasopressor, and inotropic agents may be needed. Acetaminophen may be used for fever and pain management; ibuprofen and aspirin should be avoided as these agents can adversely affect normal clotting. (See 'Treatment' above.)

●Patients with CCHF should be managed in a health care center with appropriate facilities for management and prevention of infection. Infection control precautions (including standard, contact, and droplet precautions) must be implemented to prevent nosocomial transmission. (See 'Infection control' above.)

●Prevention of CCHF consists of avoiding tick exposure and avoiding contact with animal bodily fluids. (See 'Prevention' above.)