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Definition

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Crimean-Congo hemorrhagic fever (CCHF) is a life-threatening, tick-borne, viral, zoonotic disease (Bente et al, 2013). It was first designated Crimean hemorrhagic fever during an epidemic among Soviet soldiers with fever and bleeding in 1944 in the Crimea. Later, in 1956, a case with the same manifestations in what was then the Congo was designated Congo hemorrhagic fever. It was subsequently shown that the cause of both diseases was the same, and this entity has since been referred to as CCHF (Casals, 1969; Hoogstraal, 1979). While most hemorrhagic fevers occur in specific regions, CCHF poses a significant public health challenge over a wide geographic area (Fig. 1; Table 1) (Al-Abri et al, 2017; Leblebicioglu, 2010; Leblebicioglu et al, 2015a; Mertens et al, 2013; Papa et al, 2015). The global distribution of CCHF is similar to that of Hyalomma ticks, its primary vectors. The annual number of cases exceeds 1000 in southeastern Europe and Eurasia (Al-Abri et al, 2017; Leblebicioglu et al, 2015b; Leblebicioglu et al, 2017; Mertens et al, 2013; Ozaras et al, 2016).

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Figure 1

Geographic distribution of Crimean-Congo hemorrhagic fever.

UAE, United Arab Emirates. (Source: www.cdc.gov/vhf/crimean-congo/resources/distribution-map.html).

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Etiologic Agent

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CCHF virus is of the Nairovirus genus and a member of the Bunyaviridae, a family of negative-strand, enveloped RNA viruses. CCHF virions are spherical, with a diameter of ~90–100 nm. The CCHF viral genome has three segments: small (S), medium (M), and large (L) (Zehender et al, 2013). CCHF virus shows substantial genetic diversity. Phylogenetic analysis of the complete S segment revealed seven distinct clades (Table 1) (Chinikar et al, 2016; Deyde et al, 2006; Leblebicioglu, 2010; Hewson et al, 2004; Zehender et al, 2013). Sequence analyses showed that strains in different geographic regions differ significantly. Strains may be spread among countries via migrating birds (Leblebicioglu et al, 2014; Leblebicioglu et al, 2015c) and illegal transportation of animals (Mahzounieh et al, 2012; Alavi-Naini et al, 2006). More than one virus strain can be detected in the same country (Chinikar et al, 2016).

Geographic Distribution of CCHF Virus According to S-Segment Analysis +
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Table 1Geographic Distribution of CCHF Virus According to S-Segment Analysis

Transmission

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Hyalomma marginatum (a member of the family Ixodidae) is the primary vector for CCHF virus (Flick, Whitehouse, 2005). Other members of this tick family—Rhipicephalus (including subgenus Boophilus) and Dermacentor—also are associated with transmission of this virus (Hoogstraal, 1981). Immature ticks (larvae, nymphs) acquire virus by feeding on small animals such as guineafowl, hares, and hedgehogs. Mature ticks infect livestock such as cattle, sheep, and goats (Fig. 2). CCHF is spread to humans by tick bites or by holding/crushing of ticks bare-handed. CCHF virus can also be transmitted to humans through direct contact with blood, bodily fluids, and tissue of viremic livestock during and after slaughter. This infection is particularly common among persons in high-risk occupations, such as butchers, abattoir workers, and veterinarians. A history of tick bite or exposure may be absent in 30–40% of cases, either because the bite was unnoticed or because another mode of transmission was involved (Bakir et al, 2005; Yilmaz et al, 2009); its absence does not exclude CCHF in an endemic setting. Asymptomatic CCHF viremia has been detected in a wide range of animals, such as cattle, goats, sheep, hares, and hedgehogs (Al-Abri et al, 2017). In addition, birds can spread the infection without being affected (except ostriches, which can become ill from infection) (Swanepoel et al, 1998; Capua, 1998).

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Figure 2

Life cycle of Hyalomma ticks. (Adapted from Bente et al, 2013.)

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CCHF virus can be transmitted from person to person by exposure to infected body fluids and tissues or by needlestick injury (Conger et al, 2015). Needlestick injuries are the most common mode of transmission in hospitals, accounting for 62.7% of cases (Leblebicioglu et al, 2016a). Aerosol transmission has been reported (Pshenichnaya et al, 2015), but data are insufficient to ascertain the risk of CCHF virus transmission through aerosol-generating procedures. In endemic areas with limited resources, most nosocomial cases result from failure to adhere to recommended infection-control practices, including the use of personal protective equipment such as gloves, eye-protective gear, medical masks, and gowns.

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Vertical transmission of CCHF can occur at any stage of pregnancy (Gozel et al, 2014a; Pshenichnaya et al, 2017). No cases of CCHF attributable to breast-feeding have been reported (Erbay et al, 2008). Possible sexual transmission during acute infection or convalescence has recently been reported (Ergonul et al, 2014; Pshenichnaya et al, 2016).

Epidemiology

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Dry regions and agricultural land (patches of woodland and farmland) are suitable habitats for H. marginatum (Leblebicioglu, 2010; Estrada-Pena et al, 2010). CCHF has a seasonal pattern related to the seasonal activity of ticks. The disease is often seen from May to September and shows a clear peak in June and July in the Northern Hemisphere and in the dry season in the Southern Hemisphere (Abbas et al, 2017; Hoogstraal, 1979; Lwande et al, 2012; Vorou, 2009; Yilmaz et al, 2009).

Risk Groups

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Most cases of CCHF occur in persons who live in rural areas where the disease is endemic and who are engaged in agriculture, animal husbandry, and backyard slaughter (Gunes et al, 2009; Koksal et al, 2014; Yagci-Caglayik et al, 2014). Elsewhere, CCHF is also common among those employed in animal industries—e.g., agricultural workers, slaughterhouse workers, and veterinarians (Leblebicioglu et al, 2015a). Seroprevalence rates have been shown to be 10–15% among high-risk individuals (Bodur et al, 2012; Gunes et al, 2009; Koksal et al, 2014). Because of the contribution of occupational risk, CCHF is less common among children than among adults (Aslani et al, 2017; Dilber et al, 2009).

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Health workers caring for patients with CCHF in endemic areas are likewise at risk of infection through needlestick injuries or unprotected contact with blood and body fluids of CCHF patients. Failure to recognize the disease early increases the risk of nosocomial transmission (Conger et al, 2015). Close contacts and relatives of patients are at low risk of infection (Izadi et al, 2008; Gozalan et al, 2007; Gozel et al, 2014b). CCHF is rare among travelers but may be encountered in those who undertake high-risk activities such as hunting, camping, picnicking, hiking, cycling, and slaughtering in endemic areas (Leblebicioglu et al, 2016b).

Pathogenesis

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The pathogenesis of CCHF in humans is still not well defined. The pathogenic hallmark of CCHF is a strong pro-inflammatory response with excessive release of cytokines and increased endothelial permeability resulting in leakage of plasma into tissues, with consequent edema, effusion, and shock. Apoptotic cellular damage and coagulation activation contribute to thrombocytopenia, with bleeding, disseminated intravascular coagulation (DIC), and end-organ damage occurring in severe cases (Akinci et al, 2013; Papa et al, 2006; Zivcec et al, 2016).

Incubation Period

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The incubation period varies from 1 to 13 days (mean, 1–3 days), depending on the route of infection and the size of the viral inoculum. Although the incubation period is reported to be longer for nosocomial infection (3–7 days) than after a tick bite (1–3 days), infection may develop sooner with nosocomial transmission, depending on the inoculum (Bente et al, 2013; Sunbul et al, 2015).

Clinical Manifestations

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CCHF is characterized by an abrupt onset of fever and fatigue (Fig. 3) (Yilmaz et al, 2009), often accompanied by nonspecific symptoms such as headache, sore throat, chills, muscle pain, abdominal pain, nausea, vomiting, and nonbloody diarrhea. The early febrile nonhemorrhagic phase lasts for 1–7 days. Hemorrhage and progressively worsening multiple-organ failure (hepatic, renal, pulmonary) characterize the next stage. The hemorrhagic period is not seen in all cases (Mardani, Keshtkar-Jahromi, 2007). Only 23% of patients present with bleeding (Yilmaz et al, 2009). The most common hemorrhagic manifestations are petechiae, epistaxis, and ecchymosis at injection sites (Fig. 4). Hemorrhage includes epistaxis, gum bleeding, hematemesis, melena, hemoptysis, hematuria, vaginal bleeding, and intracranial bleeding (Swanepoel et al, 1989; Whitehouse, 2004). Jaundice indicates liver damage. DIC, shock, and multiple-organ failure can result in death (Whitehouse, 2004; Vorou et al, 2007).

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Figure 3

The clinical course of Crimean-Congo hemorrhagic fever (CCHF).

ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; CCHFv, CCHF virus; CK, creatine kinase; DIC, disseminated intravascular coagulation; INR, international normalized ratio; PCR, polymerase chain reaction; PT, prothrombin time.

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Figure 4

Ecchymosis at the site of injection of Crimean-Congo hemorrhagic fever virus.

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Subclinical infections are common (88% of all infections) in endemic areas (Bodur et al, 2012). Children with CCHF may present with clinical features similar to those in adults, and the majority of cases in children are thought to be mild (Tezer et al, 2010; Tezer, Polat, 2015). Patients with mild cases of CCHF recover fully in 7–10 days. The period of convalescence may extend to 2–4 months, with fatigue, nausea, polyneuritis, sweating, headache, vertigo, poor appetite, poor vision, loss of hearing, and loss of memory (Bente et al, 2013; Hoogstraal, 1979). Relapse has not been reported (Leblebicioglu et al, 2016c).

Diagnosis

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Early diagnosis is necessary for treatment and for prevention of transmission. Presentation with fever and thrombocytopenia, combined with a history of tick bite or contact with blood or body fluids of livestock in an endemic setting, is highly suggestive of CCHF. However, there are no pathognomonic clinical signs for CCHF. The differential diagnosis must include other viral hemorrhagic fevers and other diseases listed in the differential diagnosis section (see below), and laboratory confirmation is essential.

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CCHF virus can be isolated from blood, body fluids, and tissues. Virus should be cultured in a BSL-4 laboratory, which is available only for research purposes, not in routine practice. The most commonly used diagnostic method is reverse transcription polymerase chain reaction (RT-PCR). However, RT-PCR is mostly limited to reference laboratories, and the results may not be available for 3–5 days or longer (Al-Abri et al, 2017). Viral RNA can be detected as early as the first day of clinical presentation (Bente et al, 2013). The mean duration of viremia is 3 days (range, 1–6 days) (Ergunay et al, 2014).

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IgM and IgG responses can be detected 5–7 days after disease onset (Bente et al, 2013; Uyar et al, 2010). The presence of IgM antibody or a fourfold or greater rise in titer of IgG antibodies in paired sera suggests acute infection. The IgG response appears to be inversely proportional to viral load (Duh et al, 2007). Patients with a fatal outcome usually do not develop a measurable IgG response but have detectable viral RNA (Bente et al, 2013; Aradaib et al, 2010).

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Thrombocytopenia is one of the most common abnormal findings in CCHF (Bente et al, 2013; Mostafavi et al, 2014). Other typical laboratory findings include leukopenia; elevated levels of aminotransferases, creatine kinase, and creatine phosphokinase; and prolongation of the international normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT) (Fig. 3) (Joubert et al, 1985; Kilinc et al, 2016; Swanepoel et al, 1989; Yilmaz et al, 2009).

Differential Diagnosis

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Patients without a history of tick exposure often have significant delays in diagnosis, particularly during the early stage of CCHF, when symptoms are nonspecific. The diagnosis is commonly overlooked (i.e., in 68% of cases) (Fisgin et al, 2010), and CCHF cannot be distinguished clinically from a range of other infectious and noninfectious diseases (Beeching et al, 2010; Leblebicioglu et al, 2015b). The differential diagnosis of CCHF includes Q fever, spotted fever–group rickettsiosis, relapsing fever, leptospirosis, brucellosis, viral hepatitis, other viral hemorrhagic fevers (Table 2), malaria, tularemia endocarditis, and meningococcemia. Noninfectious disorders such as idiopathic thrombocytopenic purpura (ITP), acute leukemia, and drug reactions may mimic CCHF (Beeching et al, 2010; Gozalan et al, 2005; Karabay et al, 2011; Leblebicioglu, 2016; Tanyel et al, 2017).

Other Viral Hemorrhagic Fevers to Be Considered in the Differential Diagnosis of Crimean-Congo Hemorrhagic Fever +
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Table 2Other Viral Hemorrhagic Fevers to Be Considered in the Differential Diagnosis of Crimean-Congo Hemorrhagic Fever

Treatment

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Care and treatment of patients should be performed at experienced centers. Critically ill patients who require intensive care support as well as thrombocyte and fresh-frozen plasma transfusion must be referred to reference CCHF centers (Leblebicioglu et al, 2016d).

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Timely recognition and supportive treatment of CCHF are critical and may prevent a fatal outcome. Treatment consists primarily of supportive care with fluid replacement and the correction of coagulation abnormalities, including administration of platelets and coagulation factors. Monitoring of coagulation parameters such as thrombocyte count, PT, aPTT, and INR is recommended to assess the risk of bleeding. Patients with platelet counts <20,000/µL or with bleeding and platelet counts <50,000/µL should receive platelet transfusions. Fresh-frozen plasma may be transfused to maintain the INR and PTT values at <1.5 times the normal values (Leblebicioglu et al, 2012). Dialysis and mechanical ventilation are required for renal and respiratory failure, respectively. Unnecessary invasive procedures and intramuscular injections should be avoided because of the risk of bleeding. Nonsteroidal anti-inflammatory drugs also should be avoided, as they may increase the risk of hemorrhage. Progesterone can be used to control or delay menstrual bleeding; the usual regimen is 800 mg every 8 h for 10 days (Leblebicioglu et al, 2014).

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Currently, no antiviral drugs are approved for treatment of CCHF. Ribavirin has been used; it inhibits viral replication in vivo and reduces death in animal models. However, in humans, ribavirin has not been shown to reduce mortality rates or viral load—the major independent risk factor for a fatal outcome (Bodur et al, 2011; Cevik et al, 2007). The only randomized trial failed to show that ribavirin reduces mortality rates and alleviates laboratory abnormalities (Koksal et al, 2010). No effect of ribavirin on survival was found in two published meta-analyses (Ascioglu et al, 2011; Soares-Weiser et al, 2010). Some experts believe that treatment may be beneficial in early-stage disease; however, retrospective reports on the efficacy of early use of ribavirin in mild cases are controversial (Ertem et al, 2016; Ozbey et al, 2014). Favipiravir has been shown to be more effective than ribavirin in an experimental mouse model (Oestereich et al, 2014). Prospective, randomized, controlled studies are needed to evaluate the efficacy of both drugs.

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Passive immunotherapy, administration of hyperimmune serum, plasma exchange transfusion, double plasmapheresis, and glucocorticoid therapy have been used in some cases, but the results are controversial (Kubar et al, 2011; Kurnaz et al, 2011; Meco et al, 2013; Sharifi-Mood et al, 2013; Sunbul et al, 2015). Monoclonal antibodies may be useful in future treatment (Spengler, Bente, 2015).

Discharge Criteria

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The World Health Organization recommends the discharge of patients with viral hemorrhagic fevers that can be transmitted from person to person (e.g., Ebola, Lassa fever, CCHF) only when the patients have been asymptomatic for at least 3 days and have negative PCR results (World Health Organization, 2016). However, because of bed shortages, it is not feasible in most endemic settings to wait for PCR results, which may not be available for up to 5 days. Patients who have no fever, no bleeding, thrombocyte counts >100,000/µL (or >50,000/µL with an increasing trend), and normal coagulation parameters can be discharged safely (Leblebicioglu et al, 2016c).

Prognosis

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Recent data document mortality rates of 4–20% in endemic countries (Leblebicioglu et al, 2017). Outbreaks of CCHF with mortality rates as high as 80% have been reported (Hoogstraal, 1979; Schwarz et al, 1997). Several factors are associated with mortality risk, such as route of transmission, stage of disease, viral load, and availability of diagnostic and treatment facilities. Bleeding, diarrhea, somnolence, splenomegaly, high viral load, thrombocytopenia, leukocytosis, prolonged aPTT, low fibrinogen levels, and high levels of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase are independent risk factors for death (Akinci et al, 2016). A heavy viral load is the most prominent parameter predicting death (Cevik et al, 2007; Duh et al, 2007; Hasanoglu et al, 2016; Saksida et al, 2010). Because of large inocula, nosocomial transmission is also likely to be associated with a higher mortality risk.

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The mortality rate among pregnant women with CCHF is 34%, and the fetal/neonatal mortality rate is 58.5% (Pshenichnaya et al, 2017). Death from CCHF is rare among children (Tezer et al, 2010) in Turkey. The mortality rate ranges from 11.8% to 26.5% among children in Iran (Aslani et al, 2017; Sharifi-Mood et al, 2008). Differences in timing of the diagnosis, ease of access to treatment, the study population (e.g., in the Iranian studies, most children are adolescents), and levels of immunity may explain the discrepant mortality figures (Leblebicioglu et al, 2015b).

Prevention

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Because no proven therapy for or vaccine against CCHF exists and because the control of ticks in the environment is unlikely to occur in endemic areas, prevention of infection through the use of personal protective measures is critically important. Individuals living in endemic areas should protect themselves from tick bites. Ticks should not be handled with bare hands and, if attached to the body, should be removed gently with tweezers. Light-colored clothing facilitates the detection of ticks. Wearing long sleeves and long pants and tucking pants into socks can prevent tick bites. Application of repellents such as permethrin on clothes and DEET-based products on skin kills ticks. Upon return from tick-infested areas, the body and clothes should be checked for ticks. Taking a shower flushes away unattached ticks and offers a good opportunity to check for ticks on the body. Suitable protective clothing should be worn during animal slaughter, with care taken to avoid self-injury. Educational programs aimed at reducing the risk of transmission should target high-risk populations and rural communities in endemic areas. Acaricides can kill ixodid tick larvae, nymphs, and adults in livestock herds. Acaricide treatment of livestock before they enter the slaughterhouse and during CCHF season is an effective control measure in CCHF virus–endemic areas (Leblebicioglu et al, 2015a; Leblebicioglu et al, 2016d).

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Universal (barrier) precautions should be implemented in health care settings for patients with suspected or confirmed CCHF (Gozel et al, 2013). In a large series of patients with confirmed infection, CCHF was not the initial diagnosis in 25% of cases (Leblebicioglu et al, 2016a). In hospitalized patients, CCHF diagnosis is often delayed because of the nonspecific symptoms in the first days of infection, and this delay increases the risk of nosocomial transmission in the absence of proper barrier precautions (Sunbul et al, 2015). Patients with suspected or confirmed CCHF should be isolated promptly (Fletcher et al, 2014); in endemic settings, patients with confirmed CCHF may be cohorted together (Leblebicioglu et al, 2016c). Health care workers should use personal protective equipment such as gloves, gowns, medical masks, and eye protection/face shields (Leblebicioglu et al, 2017). All staff caring for these patients should be educated regularly about appropriate precautions, and adherence to preventive measures should be monitored by a trained observer (Leblebicioglu et al, 2016d). Laboratory staff must be notified of the possibility of CCHF virus in clinical samples and must comply with biosafety procedures (Weidmann et al, 2016).

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A potential benefit of ribavirin for postexposure prophylaxis (Leblebicioglu et al, 2016a) has been demonstrated. However, the dosage, duration, and timing of prophylaxis have not been defined.

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Travelers should avoid direct contact with ticks and should not participate in animal slaughtering procedures unless preventive and protective measures are taken (Ozaras, Leblebicioglu, 2016). The nosocomial transmission of CCHF virus to health care workers who manage cases in returning travelers highlights the need for a high index of suspicion (Conger et al, 2015; Leblebicioglu et al, 2016b).

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