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Crimean–Congo hemorrhagic fever virus: new outbreaks, new discoveries
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Crimean–Congo hemorrhagic fever virus: new outbreaks, new discoveries Onder Ergonul Crimean-Congo hemorrhagic fever (CCHF) is a fatal viral infection described in Asia, Africa and Europe. Humans become infected through the bites of ticks, by contact with a patient with CCHF during the acute phase of infection, or by contact with blood or tissues from viremic livestock. The occurrence of CCHF closely approximates the known world distribution of Hyalomma spp. ticks. The novel studies of phylogenetic analyses reveal the interesting relations between the strains from distant outbreaks. The clinical features show common dramatic progress characterized by hemorrhage, myalgia, and fever. Besides the direct infection of endothelium, indirect damage by viral or virus mediated host-derived soluble factors that cause endothelial activations and dysfunction occur. In diagnosis, enzyme linked immunoassay and real-time reverse transcription-polymerase chain reaction are used. Early diagnosis is critical for the patient and potential nosocomial infections. Supportive therapy is the essential part of the case management. Ribavirin was suggested as an effective drug in recent studies, and it was found to be beneficial. The health care workers are under serious risk of transmission of the infection, particularly during the follow-up of the patient, with hemorrhages from the nose, mouth, gums, vagina, and injection sites. Address Koc¸ University, School of Medicine, Infectious Diseases Department, Istanbul, Turkey Corresponding author: Ergonul, Onder ([email protected])
Current Opinion in Virology 2012, 2:215–220 This review comes from a themed issue on Emerging viruses Edited by Erica Ollmann Saphire and Heinz Feldmann
1879-6257/$ – see front matter Published by Elsevier B.V.
health, and the second most widespread, after dengue, of all medically important arboviruses [3]. Humans become infected through the bites of ticks, by contact with a patient with CCHF during the acute phase of infection, or by contact with blood or tissues from viremic livestock [1–3]. The widespread geographical distribution of CCHFV, its ability to produce severe human disease with high mortality rates, and fears about its intentional use as a bioterrorism agent [3] makes CCHFV an extremely important human pathogen and a worldwide public health concern. Ecological complexity of vector borne diseases, therapeutic approaches, and human-to-human transmission increase the interest on CCHFV infection.
Update on epidemiology of the CCHFV infection Crimean hemorrhagic fever (CHF) was firstly described as a clinical entity in 1944–1945, when about 200 Soviet military personnel were infected while assisting peasants in devastated Crimea after Nazi invasion [2]. By the year 2000, new outbreaks have been reported from Pakistan [4], Iran [5], Senegal [6], Albania [7], Kosovo [8], Bulgaria [9], Turkey [10], Greece [11], Kenya [12], Mauritania [13], and recently from India [14,15]. The serologic evidence for CCHFV was documented from Egypt, Portugal, Hungary, France, and Benin, although no human case was reported yet [16]. Cases were distributed among actively working age groups [2] that were eventually exposed to the tick population. The great majority of the affected cases deal with agriculture and/or husbandry. Almost 90% of cases in the recent outbreak in Turkey were farmers [16,17]. Health care workers (HCWs) are the second most affected groups in the literature. The gender distribution differs between countries, depending on the participation of the women in agricultural work.
Introduction
There are eight genetically distinct clades based on the S segment of the genome. Among these, clade AP92 was previously known to cause no symptomatic disease, although a recent study from Turkey reported a mild symptomatic child infected by a virus very closely related to the AP92 strain [18]. There are at least two different clades of CCHFV currently circulating in Turkey [19].
Crimean–Congo hemorrhagic fever (CCHF) is a fatal viral infection described in parts of Africa, Asia, Eastern Europe, and Middle East [1,2]. The virus belongs to the genus Nairovirus in the Bunyaviridae family and causes severe diseases in humans with a reported mortality rate of 3–30% [1,3]. The geographic range of CCHFV is the most extensive among tickborne viruses related to human
CCHFV circulates in nature in an enzootic tick– vertebrate–tick cycle. Although humans have been infected with CCHFV after contact with livestock and other animals, there is no evidence that the virus causes disease among animals [3]. Antibody surveys among livestock in endemic areas have shown high prevalence
DOI 10.1016/j.coviro.2012.03.001
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among both cattle and sheep. CCHF viral infection has been demonstrated more commonly among smaller wildlife species, such as hares and hedgehogs, that act as hosts for the immature stages of the tick vectors [2]. Birds may play a role in the transportation of CCHFV infected ticks between the countries. The spatial distribution of CCHF was well described in Turkey since the onset of the CCHF epidemic in 2003. Case notifications and spatial analysis of CCHF disease patterns were studied in detail, and climate data (temperature and normalized difference vegetation index) were used to develop a predictive model of the habitat suitability (HS) for Hyalomma marginatum in Turkey [20]. Approximately 62% of CCHF cases resided in areas of HS above 50, indicating a strong spatial correlation between favorable environmental features for tick populations and CCHF cases. Interestingly, positive HS was predicted to exist outside of the main foci of disease, underlining the existence of additional factors involved in the maintenance of disease foci.
Table 1 The laboratory characteristics of CCHFV infection Test Complete blood count White Blood cell count Platelet count Hemoglobin and/or hematocrit Liver enzymes Coagulation studies (INR, PT, PTT, fibrinogen, fibrin split products, platelets, D-dimer) Lactate dehydrogenase Creatinin phosphokinase
Blood urea nitrogen and creatinin
Findings and comments Moderate or severe leukopenia, sometimes leucosytosis Mild to severe decrease Could be decreased later in disease course Increased, usually AST > ALT Hemophagocytosis and DIC are common
A level greater than 4 mmol/L (36 mg/dL) may indicate persistent hypo-perfusion and sepsis elevated Renal failure may occur late in disease course, but proteinuria may occur.
Pathogenesis Microvascular instability and impaired hemostasis are the hallmarks of CCHFV infection. Interpretation of data derived from animal studies may be confounded by a series of factors, such as the species of the animal, the route of inoculation, and the virus dose. Recently, Bente et al. described a new mouse model, which was reported as exhibiting key features of fatal human CCHF [21]. This model could be useful for the testing of therapeutic strategies, and can be used to study virus attenuation. After inoculation, virus first replicates in dendritic cells and other local tissues, with subsequent migration to regional lymph nodes and then dissemination through the lymph and blood monocytes to a broad range of tissues and organs, including the liver, spleen, and lymph nodes. Migration of tissue macrophages results in secondary infection of permissive parenchymal cells. Although lymphocytes remain free of infection, they may be destroyed in massive numbers over the course of illness through apoptosis, as seen in other forms of septic shock. The synthesis of cell surface tissue factor triggers the extrinsic coagulation pathway. Impaired hemostasis may entail endothelial cell, platelet, and/or coagulation factor dysfunction. Disseminated intravascular coagulopathy (DIC) is frequently noted in CCHF virus infections. Reduced levels of coagulation factors may be secondary to hepatic dysfunction and/or disseminated intravascular coagulation. In addition, CCHFV may lead to a hemorrhagic diathesis through direct damage of platelets and endothelial cells and/or indirectly through immunological and inflammatory pathways [22–24]. These changes appear to be largely the consequence of the release of cytokines, chemokines, and other proinflammatory mediators from virus-infected monocytes and macrophages [25,26]. Tissue damage may be mediated through direct necrosis of infected cells or indirectly Current Opinion in Virology 2012, 2:215–220
through apoptosis of immune cells. The hepatocytes were reported to be particularly effected in CCHFV infection [27]. On the footsteps of the findings reported by Rodrigues et al., further studies are needed.
Clinical manifestations The incubation period for CCHFV ranges from one to nine days. Patients initially exhibit a nonspecific prodrome, which typically lasts less than one week. Symptoms typically include high fever, headache, malaise, arthralgias, myalgias, nausea, abdominal pain, and rarely diarrhea [25]. Early signs typically include fever, hypotension, conjunctivitis, and cutaneous flushing or a skin rash. Later, patients may develop signs of progressive hemorrhagic diathesis, such as petechiae, mucous membrane and conjunctival hemorrhage; hematuria; hematemesis; and melena. Disseminated intravascular coagulation and circulatory shock may ensue. Death is typically preceded by hemorrhagic diathesis, shock, and multiorgan system failure one to two weeks following onset of symptoms. The disease was reported to be milder among the children [28]. Laboratory abnormalities include usually leukopenia, thrombocytopenia, and elevated liver enzymes. Anemia is not usually seen at the early phase of the disease, but may develop late in the disease course. Coagulation abnormalities may include prolonged bleeding time, prothrombin time, and activated partial thromboplastin time; elevated fibrin degradation products; and decreased fibrinogen (Table 1).
Diagnosis Case management of CCHFV infection, including diagnosis is summarized in Table 2. Diagnosis is performed by detection of the viral RNA genome and/or antigen and www.sciencedirect.com
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Table 2 Case management strategies for CCHFV infection Evaluation of the suspected case Clinical symptoms (fever, myalgia, bleeding from various sites) Patient history i. Referral from endemic area ii. Outdoor activities (picnic, tracking, among others) in endemic area iii History of tick bite iv. Dealing with husbandry in endemic area Laboratory tests (low thrombocyte and white blood cell count, elevated AST, ALT, LDH, and CPK) Preventive measures a. Isolate the patient b. Inform and educate colleagues and staff c. Use barrier precautions Investigative tests for confirmation Serum for PCR and ELISA a. IgM positivity or PCR positive confirms diagnosis, IgG positivity cannot. b. Sera for differential diagnosis Decision making for therapy 1. Start ribavirin for early cases 2. Do not neglect other causes of the clinical picture. Starting doxycycline or equivalent should be considered 3. Hematological support a. Fresh frozen plasma to improve the homeostasis b. Thrombocyte solutions 4. Respiratory support Follow-up No recurrence of cases has been reported. Therefore, there is no definition of follow-up Postexposure prophylaxis Health care workers, or other individuals who were exposed to the virus should be assessed for level of risk. Individuals at high risk should receive ribavirin, whereas individuals at low risk should be followed up with complete blood counts and biochemical tests for 14 days
the detection of specific IgM antibodies in human serum or blood. Methods of diagnosis at specialized laboratories include antigen detection by antigen-capture enzymelinked immunosorbent assay (ELISA), IgM antibody detection by antibody-capture ELISA, reverse transcriptase polymerase chain reaction (RT-PCR), and viral isolation. Antigen detection (by ELISA) and RT-PCR are the most useful diagnostic techniques in the acute clinical setting. Viral isolation is of limited value because it requires a biosafety level 4 (BSL-4) laboratory. Either the presence of IgM or a fourfold rise in titer of IgG antibody between acute phase and convalescent-phase serum samples is diagnostic of CCHFV infection [29,30]. Direct and indirect approaches are combined for the diagnosis of VHF virus infection: specifically, viral isolation, detection of viral genome or antigen, and detection of specific antibodies. Likewise, leukopenia, particularly neutropenia, thrombocytopenia, high levels of liver enzymes alanine aminotransferase (ASL) and aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) are regularly reported in patients with VHF. www.sciencedirect.com
Viral isolation
The most definitive test is viral culture. However, the time to diagnosis, which is 2–10 days for the virus to grow is too long for management of acute cases. Moreover, the need for high containment facilities renders this technique more of a confirmatory test and research tool. CCHFV has been isolated most frequently by intracranial inoculation of newborn suckling mice [30]. Molecular detection: RT-PCR
RT-PCR is a useful test, although careful attention must be paid to the potential for false-positive results owing to laboratory contamination. PCR is a very sensitive method for the identification of an agent and possible quantification of viral load in a sample within a few hours. Techniques usually combine the reverse transcription step with specific amplification, minimizing the risks of contaminations. As one of the examples of recent improvements in diagnosis, one-step real time RTPCR assays using primers to the same nucleoprotein gene have been developed but the development of these assays has been hampered by the high diversity of genome sequence [31,32]. Indirect serological diagnosis
The serological diagnosis of VHF infection is based on the detection of specific IgM and IgG antibodies induced by the immune response principally to the nucleoprotein, which is recognized as the predominant antigen [36]. Seroconversion with detection of CCHFV IgM antibodies or a 4-fold increase in antibody titer between two successive blood samples is evidence of a recent infection [51,52]. The serological diagnosis is valid after several days post onset of the disease; nevertheless the antibody response rarely is observed in fatal cases [46]. The ELISA is the most common technique for CCHFV antibody detection with the sensitivity of more than 90%. The ELISA was reported to be more sensitive than IFA [33]. All native antigens have to be produced in a BSL-4 laboratory and irradiated before use. Usually IgM and IgG antibodies are detected four to five days post onset of symptoms. The IgM titer is maximal two to three weeks after onset of the disease, and the IgM antibodies generally disappear within four months. The IgG antibodies remain detectable for several years [30]. Rapid detection
Rapid diagnosis of the CCHFV can provide significant advantages including therapy and infection control. Some broad-range approaches for the rapid detection of VHF agents have been designed by the use of unique multiplex assays, such as MassTag-PCR [34]. One of these assays represents a first-generation rapid field test for the detection of Ebola virus antigen that can be performed in 30 min without electrical power or expensive or sensitive equipment [35]. Current Opinion in Virology 2012, 2:215–220
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Table 3 Differential diagnosis list for viral hemorrhagic fevers. Disease categories
Differentials
Infections Brucellosis Q fever Rickettsia Ehrlichiosis Hanta
Pancytopenia, Wright agglutination Serology (ELISA or IFAT) Weil-felix test Serology (ELISA) Pulmonary or renal involvement, Serology, PCR Other viral hemorrhagic infections Ebola Geographic location Marburg Geographic location Leptospira Agglutination Salmonella Widal test Non-infectious reasons Vitamin B12 deficiency Pancytopenia, and B12 level in serum Febrile neutropenia Underlying disease HELLP syndrome Geographic location Drug side effects Metamizole History
Differential diagnosis
The combined approach of viral genome detection and IgM detection is recommended for diagnosis of CCHF in humans. CCHFV has an extended geographical distribution including Africa, southern Europe, Middle East, Russia, India, and China. Other viral etiologies have to be considered according to the origin of the patient and the risks of potential exposure. These would include Alkhurma and Rift Valley fever in the Middle East; Omsk hemorrhagic fever in Russia; Kyasanur Forest disease in India; hantaviruses in Europe and Asia; Lassa, Ebola, Marburg, Rift Valley fever, yellow fever in Africa; and dengue in various locations [36]. In tropical and subtropical countries, malaria is the most important alternative diagnosis to be excluded in cases of suspected VHF. The differential diagnosis list should include, hepatitis viruses, influenza, Neisseria meningitidis, leptospirosis, borreliosis, typhoid, rickettsiosis, and Q fever (Coxiella burnetii) staphylococcal or gram-negative sepsis, toxic shock syndrome, salmonellosis and shigellosis, psittacosis, trypanosomiasis, septicemic plague, rubella, measles, and hemorrhagic smallpox [3,29,30] (Table 3). Noninfectious processes associated with bleeding diathesis that should be included in the differential diagnosis include idiopathic or thrombotic thrombocytopenic purpura, HELP syndrome among pregnant women, hemolytic uremic syndrome, acute leukemia, vitamin B12 deficiency, and collagen-vascular diseases [3,37]. Ribavirin is the antiviral of choice
Ribavirin is the only antiviral drug that has been used to treat viral hemorrhagic fever syndromes, including CCHF and Lassa fever [38–40]. Viruses in the Bunyaviridae family are generally sensitive to ribavirin [41]. Ribavirin Current Opinion in Virology 2012, 2:215–220
was shown, early on, to be effective against CCHFV in vitro [42–44]. In suckling mice, ribavirin treatment reduced CCHF virus growth in the liver; significantly decreased, but did not prevent viremia; and significantly reduced mortality and extended the geometric mean time to death [42]. In clinical practice, ribavirin was found to be beneficial, especially at the earlier phase of the infection [45–48]. Ribavirin is placed on the WHO essential medicines list (15th Model List of Essential Medicines, March 2007) to be used against CCHFV infection. In a recent review, ethical concerns about conducting a randomized controlled trial of ribavirin in the treatment of Crimean– Congo hemorrhagic fever were detailed [49]. Despite the need for more evidence about the impact of ribavirin in treatment, the authors described why it was not ethical to conduct a RCT in such a fatal disease with only one antiviral alternative [49]. Bulgarian investigators suggested that immunotherapeutic treatment of seven patients with severe CCHF via passive simultaneous transfer of two different specific immunoglobulin preparations, CCHF-bulin (for intramuscular use) and CCHF-venin (for intravenous use), prepared from the plasma of CCHF survivor donors, boosted with one dose of CCHF vaccine, resulted in quick recovery of all patients [50]. Further, they suggested that the intravenous preparation be used for treatment of all cases of CCHF [51]. In a recent study that included 22 severe patients from Turkey, prompt administration of CCHFV hyperimmunoglobulin was suggested as an alternative treatment approach, especially for highrisk individuals [52]. Further studies with larger sample size and more detailed design are necessary.
Infection control measures Bunyaviruses are highly infectious after direct contact with infected blood and bodily secretions. A suspected case of CCHF must be immediately reported to the hospital epidemiologist (or infection control professional) and to the local or state health department. The epidemiologist (or infection control professional) should, in turn, notify the clinical laboratory (so that additional precautions are put in place) as well as other clinicians and public health authorities.
Isolation precautions Direct contact with infected blood and bodily fluids has accounted for the majority of person-to-person transmission. Therefore, it was recommended that in the case of any patient with suspected or documented CCHFV infection, specific barrier precautions should be implemented immediately. Airborne transmission was suspected in one Lassa Fever outbreak in 1969 [53], but there has never been any documented case of airborne transmission of that virus to humans. A prospective serological study from Sierra Leone suggested that the hospital staff who cared for Lassa fever patients using www.sciencedirect.com
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simple barrier nursing methods have no higher risk of infection than the local population [54]. A similar study from Turkey reported the lack of airborne transmission of CCHF to the HCWs after CCHF epidemic [55]. Usually the standard precautions including health hygiene, using gloves, gowns, face shields and masks are sufficient to be protected. However, when procedures to be performed could generate an aerosol, HCW should consider wearing an N95 or FFP2 respirator (European Norm (EN) 61010-1) [56]. An integrated strategy for the control of accidental exposure to blood and body fluids is critical to provide protection among HCWs [56]. Sharps containers are the foremost piece of safety equipment, which should be available at all times to all units. The use of safetyengineered devices should also be considered in order to decrease the risk of needlestick injuries [56].
Postexposure management Postexposure management systems are an integral part of an effort to enhance HCW safety. In CCHF [45] and Lassa Fever [40], use of oral ribavirin as postexposure prophylaxis was well described as effective and beneficial drug. Ribavirin prophylaxis is generally well tolerated, potentially useful and should therefore be recommended for HCWs who are at high risk of exposures such as percutaneous injuries or splash of contaminated blood or body fluid to the face or mucosal surfaces of the HCWs [56]. In a similar approach with other agents of viral hemorrhagic fever such as filoviruses and arenaviruses, it might be recommended that the patients convalescing from CCHF infection should refrain from sexual activity for three months after clinical recovery [29]. In conclusion, many recent developments were noted in epidemiology, pathogenesis and early detection; however, there is neither alternative antiviral therapy nor vaccine on the pipeline yet.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest
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25. Bray M: Comparative pathogenesis of Crimean Congo hemorrhagic fever and Ebola hemorrhagic fever. In Crimean Congo Hemorrhagic Fever: A Global Perspective. Edited by Ergonul O, Whitehouse CA. Dordrecht, NL: Springer; 2007:221-231. 26. Ergonul O, Tuncbilek S, Baykam N, Celikbas A, Dokuzoguz B: Evaluation of serum levels of interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha in patients with Crimean–Congo hemorrhagic fever. J Infect Dis 2006, 193:941-944. This is the first study for demonstration of the role of the pro-inflammatory cytokines in fatality of CCHF cases. 27. Rodrigues R, Paranhos-Baccala G, Vernet G, Peyrefitte CN: Crimean–Congo hemorrhagic fever virus-infected hepatocytes induce ER-stress and apoptosis crosstalk. PLoS One 2012, 7:e29712. The results this study suggest that CCHFV is able to induce ER-stress, activate inflammatory mediators and modulate both mitochondrial and death receptor pathways of apoptosis in hepatocyte cells, which may, in part, explain the role of the liver in the pathogenesis of CCHFV. 28. Tezer H, Sucakli IA, Sayli TR et al.: Crimean–Congo hemorrhagic fever in children. J Clin Virol 2010, 48:184-186. The results of this study suggests that the clinical course of CCHF among children seems to be milder than in adults. 29. Borio L, Inglesby T, Peters CJ et al.: Hemorrhagic fever viruses as biological weapons: medical and public health management. JAMA 2002, 287:2391-2405. 30. Zeller H: Laboratory diagnosis of crimean congo hemorrhagic fever. In Crimean Congo Hemorrhagic Fever: A Global Perspective. Edited by Ergonul O, Whitehouse CA. Dordrecht, NL: Springer; 2007:233-243. 31. Drosten C, Kummerer BM, Schmitz H, Gunther S: Molecular diagnostics of viral hemorrhagic fevers. Antiviral Res 2003, 57:61-87. 32. Drosten C, Gottig S, Schilling S et al.: Rapid detection and quantification of RNA of Ebola and Marburg viruses, Lassa virus, Crimean–Congo hemorrhagic fever virus, Rift Valley fever virus, dengue virus, and yellow fever virus by real-time reverse transcription-PCR. J Clin Microbiol 2002, 40:2323-2330. 33. Burt FJ, Swanepoel R, Braack LE: Enzyme-linked immunosorbent assays for the detection of antibody to Crimean–Congo haemorrhagic fever virus in the sera of livestock and wild vertebrates. Epidemiol Infect 1993, 111:547-557. 34. Palacios G, Briese T, Kapoor V et al.: MassTag polymerase chain reaction for differential diagnosis of viral hemorrhagic fever. Emerg Infect Dis 2006, 12:692-695. 35. Lucht A, Formenty P, Feldmann H et al.: Development of an immunofiltration-based antigen-detection assay for rapid diagnosis of Ebola virus infection. J Infect Dis 2007, 196:S184-S192. 36. Ergonul O: Clinical and pathologic features of Crimean Congo hemorrhagic fever. In Crimean Congo Hemorrhagic Fever: A Global Perspective. Edited by Ergonul O, Whitehouse CA. Dordrecht, NL: Springer; 2007:207-220. 37. Ergonul O, Celikbas A, Yildirim U et al.: Pregnancy and Crimean–Congo haemorrhagic fever. Clin Microbiol Infect 2010, 16:647-650. Transmission of the CCHF infection could be either intrauterine or perinatal. In endemic regions, CCHF infection should be considered in the differential diagnosis of HELLP syndrome (haemolytic anaemia, elevated liver enzymes, low platelet count), and obstetricians should be familiar with the characteristics of CCHF infection. In the aetiology of necrotising enterocolitis, CCHF should be considered. 38. Ergonul O: Treatment of Crimean Congo hemorrhagic fever. In Crimean Congo Hemorrhagic Fever: A Global Perspective. Edited by Ergonul O, Whitehouse CA. Dordrecht, NL: Springer; 2007:245-260. 39. McCormick JB, King IJ, Webb PA et al.: Lassa fever. Effective therapy with ribavirin. N Engl J Med 1986, 314:20-26.
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40. Bausch DG, Hadi CM, Khan SH, Lertora JJ: Review of the literature and proposed guidelines for the use of oral ribavirin as postexposure prophylaxis for Lassa fever. Clin Infect Dis 2010, 51:1435-1441. The authors review the pertinent issues and propose guidelines based on extensive review of the literature, as well as their experience in this field. The authors recommend oral ribavirin postexposure prophylaxis for Lassa fever exclusively for definitive high-risk exposures. These guidelines may also serve for exposure to other hemorrhagic fever viruses susceptible to ribavirin. 41. Sidwell RW, Smee DF: Viruses of the Bunya- and Togaviridae families: potential as bioterrorism agents and means of control. Antiviral Res 2003, 57:101-111. 42. Tignor GH, Hanham CA: Ribavirin efficacy in an in vivo model of Crimean–Congo hemorrhagic fever virus (CCHF) infection. Antiviral Res 1993, 22:309-325. 43. Watts DM, Ussery MA, Nash D, Peters CJ: Inhibition of Crimean– Congo hemorrhagic fever viral infectivity yields in vitro by ribavirin. Am J Trop Med Hyg 1989, 41:581-585. 44. Paragas J, Whitehouse CA, Endy TP, Bray M: A simple assay for determining antiviral activity against Crimean–Congo hemorrhagic fever virus. Antiviral Res 2004, 62:21-25. 45. Ergonul O: Treatment of Crimean–Congo hemorrhagic fever. Antiviral Res 2008, 78:125-131. 46. Tasdelen Fisgin N, Ergonul O, Doganci L, Tulek N: The role of ribavirin in the therapy of Crimean–Congo hemorrhagic fever: early use is promising. Eur J Clin Microbiol Infect Dis 2009, 28:929-933. 47. Izadi S, Salehi M: Evaluation of the efficacy of ribavirin therapy on survival of Crimean–Congo hemorrhagic fever patients: a case-control study. Jpn J Infect Dis 2009, 62:11-15. 48. Ozbey SB: Impact of early ribavirin use on fatality of CCHF. Klimik J 2010, 23:6-10. 49. Arda B, Aciduman A, Johnston JC: A randomised controlled trial of ribavirin in Crimean Congo haemorrhagic fever: ethical considerations. J Med Ethics 2012, 38:117-120. This paper addresses the need for an RCT of ribavirin in the treatment of Crimean Congo haemorrhagic fever, and highlights underlying ethical concerns in light of the current medical, virological and ethical literature. The authors reported that conduction of a RCT for ribavirin use in CCHF was not likely according to Helsinki declaration. 50. Vassilenko SM, Vassilev TL, Bozadjiev LG, Bineva IL, Kazarov GZ: Specific intravenous immunoglobulin for Crimean–Congo haemorrhagic fever. Lancet 1990, 335:791-792. 51. Dimitrov DS: Antibodies to CCHFV for prophylaxis and treatment. In Crimean–Congo Hemorrhagic Fever: A Global Perspective. Edited by Ergonul O, Whitehouse CA. Dordrecht, NL: Springer; 2007:261-269. 52. Kubar A, Haciomeroglu M, Ozkul A et al.: Prompt administration of Crimean–Congo hemorrhagic fever (CCHF) virus hyperimmunoglobulin in patients diagnosed with CCHF and viral load monitorization by reverse transcriptase-PCR. Jpn J Infect Dis 2011, 64:439-443. 53. Carey DE, Kemp GE, White HA et al.: Lassa fever. Epidemiological aspects of the 1970 epidemic, Jos, Nigeria. Trans R Soc Trop Med Hyg 1972, 66:402-408. 54. Helmick CG, Webb PA, Scribner CL, Krebs JW, McCormick JB: No evidence for increased risk of Lassa fever infection in hospital staff. Lancet 1986, 2:1202-1205. 55. Ergonul O, Zeller HG, Celikbas A, Dokuzoguz B: The lack of Crimean–Congo hemorrhagic fever virus antibodies in healthcare workers in an endemic region. Int J Infect Dis 2007, 11:48-51. 56. Tarantola A, Ergonul O, Tattevin P: Estimates and prevention of Crimean Congo hemorrhagic fever risks for health care workers. In Crimean–Congo Hemorrhagic Fever: A Global Perspective. Edited by Ergonul O, Whitehouse CA. Dordrecht, NL: Springer; 2007:281-294.
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Crimean–Congo hemorrhagic fever virus: new outbreaks, new discoveries Onder Ergonul Crimean-Congo hemorrhagic fever (CCHF) is a fatal viral infection described in Asia, Africa and Europe. Humans become infected through the bites of ticks, by contact with a patient with CCHF during the acute phase of infection, or by contact with blood or tissues from viremic livestock. The occurrence of CCHF closely approximates the known world distribution of Hyalomma spp. ticks. The novel studies of phylogenetic analyses reveal the interesting relations between the strains from distant outbreaks. The clinical features show common dramatic progress characterized by hemorrhage, myalgia, and fever. Besides the direct infection of endothelium, indirect damage by viral or virus mediated host-derived soluble factors that cause endothelial activations and dysfunction occur. In diagnosis, enzyme linked immunoassay and real-time reverse transcription-polymerase chain reaction are used. Early diagnosis is critical for the patient and potential nosocomial infections. Supportive therapy is the essential part of the case management. Ribavirin was suggested as an effective drug in recent studies, and it was found to be beneficial. The health care workers are under serious risk of transmission of the infection, particularly during the follow-up of the patient, with hemorrhages from the nose, mouth, gums, vagina, and injection sites. Address Koc¸ University, School of Medicine, Infectious Diseases Department, Istanbul, Turkey Corresponding author: Ergonul, Onder ([email protected])
Current Opinion in Virology 2012, 2:215–220 This review comes from a themed issue on Emerging viruses Edited by Erica Ollmann Saphire and Heinz Feldmann
1879-6257/$ – see front matter Published by Elsevier B.V.
health, and the second most widespread, after dengue, of all medically important arboviruses [3]. Humans become infected through the bites of ticks, by contact with a patient with CCHF during the acute phase of infection, or by contact with blood or tissues from viremic livestock [1–3]. The widespread geographical distribution of CCHFV, its ability to produce severe human disease with high mortality rates, and fears about its intentional use as a bioterrorism agent [3] makes CCHFV an extremely important human pathogen and a worldwide public health concern. Ecological complexity of vector borne diseases, therapeutic approaches, and human-to-human transmission increase the interest on CCHFV infection.
Update on epidemiology of the CCHFV infection Crimean hemorrhagic fever (CHF) was firstly described as a clinical entity in 1944–1945, when about 200 Soviet military personnel were infected while assisting peasants in devastated Crimea after Nazi invasion [2]. By the year 2000, new outbreaks have been reported from Pakistan [4], Iran [5], Senegal [6], Albania [7], Kosovo [8], Bulgaria [9], Turkey [10], Greece [11], Kenya [12], Mauritania [13], and recently from India [14,15]. The serologic evidence for CCHFV was documented from Egypt, Portugal, Hungary, France, and Benin, although no human case was reported yet [16]. Cases were distributed among actively working age groups [2] that were eventually exposed to the tick population. The great majority of the affected cases deal with agriculture and/or husbandry. Almost 90% of cases in the recent outbreak in Turkey were farmers [16,17]. Health care workers (HCWs) are the second most affected groups in the literature. The gender distribution differs between countries, depending on the participation of the women in agricultural work.
Introduction
There are eight genetically distinct clades based on the S segment of the genome. Among these, clade AP92 was previously known to cause no symptomatic disease, although a recent study from Turkey reported a mild symptomatic child infected by a virus very closely related to the AP92 strain [18]. There are at least two different clades of CCHFV currently circulating in Turkey [19].
Crimean–Congo hemorrhagic fever (CCHF) is a fatal viral infection described in parts of Africa, Asia, Eastern Europe, and Middle East [1,2]. The virus belongs to the genus Nairovirus in the Bunyaviridae family and causes severe diseases in humans with a reported mortality rate of 3–30% [1,3]. The geographic range of CCHFV is the most extensive among tickborne viruses related to human
CCHFV circulates in nature in an enzootic tick– vertebrate–tick cycle. Although humans have been infected with CCHFV after contact with livestock and other animals, there is no evidence that the virus causes disease among animals [3]. Antibody surveys among livestock in endemic areas have shown high prevalence
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among both cattle and sheep. CCHF viral infection has been demonstrated more commonly among smaller wildlife species, such as hares and hedgehogs, that act as hosts for the immature stages of the tick vectors [2]. Birds may play a role in the transportation of CCHFV infected ticks between the countries. The spatial distribution of CCHF was well described in Turkey since the onset of the CCHF epidemic in 2003. Case notifications and spatial analysis of CCHF disease patterns were studied in detail, and climate data (temperature and normalized difference vegetation index) were used to develop a predictive model of the habitat suitability (HS) for Hyalomma marginatum in Turkey [20]. Approximately 62% of CCHF cases resided in areas of HS above 50, indicating a strong spatial correlation between favorable environmental features for tick populations and CCHF cases. Interestingly, positive HS was predicted to exist outside of the main foci of disease, underlining the existence of additional factors involved in the maintenance of disease foci.
Table 1 The laboratory characteristics of CCHFV infection Test Complete blood count White Blood cell count Platelet count Hemoglobin and/or hematocrit Liver enzymes Coagulation studies (INR, PT, PTT, fibrinogen, fibrin split products, platelets, D-dimer) Lactate dehydrogenase Creatinin phosphokinase
Blood urea nitrogen and creatinin
Findings and comments Moderate or severe leukopenia, sometimes leucosytosis Mild to severe decrease Could be decreased later in disease course Increased, usually AST > ALT Hemophagocytosis and DIC are common
A level greater than 4 mmol/L (36 mg/dL) may indicate persistent hypo-perfusion and sepsis elevated Renal failure may occur late in disease course, but proteinuria may occur.
Pathogenesis Microvascular instability and impaired hemostasis are the hallmarks of CCHFV infection. Interpretation of data derived from animal studies may be confounded by a series of factors, such as the species of the animal, the route of inoculation, and the virus dose. Recently, Bente et al. described a new mouse model, which was reported as exhibiting key features of fatal human CCHF [21]. This model could be useful for the testing of therapeutic strategies, and can be used to study virus attenuation. After inoculation, virus first replicates in dendritic cells and other local tissues, with subsequent migration to regional lymph nodes and then dissemination through the lymph and blood monocytes to a broad range of tissues and organs, including the liver, spleen, and lymph nodes. Migration of tissue macrophages results in secondary infection of permissive parenchymal cells. Although lymphocytes remain free of infection, they may be destroyed in massive numbers over the course of illness through apoptosis, as seen in other forms of septic shock. The synthesis of cell surface tissue factor triggers the extrinsic coagulation pathway. Impaired hemostasis may entail endothelial cell, platelet, and/or coagulation factor dysfunction. Disseminated intravascular coagulopathy (DIC) is frequently noted in CCHF virus infections. Reduced levels of coagulation factors may be secondary to hepatic dysfunction and/or disseminated intravascular coagulation. In addition, CCHFV may lead to a hemorrhagic diathesis through direct damage of platelets and endothelial cells and/or indirectly through immunological and inflammatory pathways [22–24]. These changes appear to be largely the consequence of the release of cytokines, chemokines, and other proinflammatory mediators from virus-infected monocytes and macrophages [25,26]. Tissue damage may be mediated through direct necrosis of infected cells or indirectly Current Opinion in Virology 2012, 2:215–220
through apoptosis of immune cells. The hepatocytes were reported to be particularly effected in CCHFV infection [27]. On the footsteps of the findings reported by Rodrigues et al., further studies are needed.
Clinical manifestations The incubation period for CCHFV ranges from one to nine days. Patients initially exhibit a nonspecific prodrome, which typically lasts less than one week. Symptoms typically include high fever, headache, malaise, arthralgias, myalgias, nausea, abdominal pain, and rarely diarrhea [25]. Early signs typically include fever, hypotension, conjunctivitis, and cutaneous flushing or a skin rash. Later, patients may develop signs of progressive hemorrhagic diathesis, such as petechiae, mucous membrane and conjunctival hemorrhage; hematuria; hematemesis; and melena. Disseminated intravascular coagulation and circulatory shock may ensue. Death is typically preceded by hemorrhagic diathesis, shock, and multiorgan system failure one to two weeks following onset of symptoms. The disease was reported to be milder among the children [28]. Laboratory abnormalities include usually leukopenia, thrombocytopenia, and elevated liver enzymes. Anemia is not usually seen at the early phase of the disease, but may develop late in the disease course. Coagulation abnormalities may include prolonged bleeding time, prothrombin time, and activated partial thromboplastin time; elevated fibrin degradation products; and decreased fibrinogen (Table 1).
Diagnosis Case management of CCHFV infection, including diagnosis is summarized in Table 2. Diagnosis is performed by detection of the viral RNA genome and/or antigen and www.sciencedirect.com
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Table 2 Case management strategies for CCHFV infection Evaluation of the suspected case Clinical symptoms (fever, myalgia, bleeding from various sites) Patient history i. Referral from endemic area ii. Outdoor activities (picnic, tracking, among others) in endemic area iii History of tick bite iv. Dealing with husbandry in endemic area Laboratory tests (low thrombocyte and white blood cell count, elevated AST, ALT, LDH, and CPK) Preventive measures a. Isolate the patient b. Inform and educate colleagues and staff c. Use barrier precautions Investigative tests for confirmation Serum for PCR and ELISA a. IgM positivity or PCR positive confirms diagnosis, IgG positivity cannot. b. Sera for differential diagnosis Decision making for therapy 1. Start ribavirin for early cases 2. Do not neglect other causes of the clinical picture. Starting doxycycline or equivalent should be considered 3. Hematological support a. Fresh frozen plasma to improve the homeostasis b. Thrombocyte solutions 4. Respiratory support Follow-up No recurrence of cases has been reported. Therefore, there is no definition of follow-up Postexposure prophylaxis Health care workers, or other individuals who were exposed to the virus should be assessed for level of risk. Individuals at high risk should receive ribavirin, whereas individuals at low risk should be followed up with complete blood counts and biochemical tests for 14 days
the detection of specific IgM antibodies in human serum or blood. Methods of diagnosis at specialized laboratories include antigen detection by antigen-capture enzymelinked immunosorbent assay (ELISA), IgM antibody detection by antibody-capture ELISA, reverse transcriptase polymerase chain reaction (RT-PCR), and viral isolation. Antigen detection (by ELISA) and RT-PCR are the most useful diagnostic techniques in the acute clinical setting. Viral isolation is of limited value because it requires a biosafety level 4 (BSL-4) laboratory. Either the presence of IgM or a fourfold rise in titer of IgG antibody between acute phase and convalescent-phase serum samples is diagnostic of CCHFV infection [29,30]. Direct and indirect approaches are combined for the diagnosis of VHF virus infection: specifically, viral isolation, detection of viral genome or antigen, and detection of specific antibodies. Likewise, leukopenia, particularly neutropenia, thrombocytopenia, high levels of liver enzymes alanine aminotransferase (ASL) and aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) are regularly reported in patients with VHF. www.sciencedirect.com
Viral isolation
The most definitive test is viral culture. However, the time to diagnosis, which is 2–10 days for the virus to grow is too long for management of acute cases. Moreover, the need for high containment facilities renders this technique more of a confirmatory test and research tool. CCHFV has been isolated most frequently by intracranial inoculation of newborn suckling mice [30]. Molecular detection: RT-PCR
RT-PCR is a useful test, although careful attention must be paid to the potential for false-positive results owing to laboratory contamination. PCR is a very sensitive method for the identification of an agent and possible quantification of viral load in a sample within a few hours. Techniques usually combine the reverse transcription step with specific amplification, minimizing the risks of contaminations. As one of the examples of recent improvements in diagnosis, one-step real time RTPCR assays using primers to the same nucleoprotein gene have been developed but the development of these assays has been hampered by the high diversity of genome sequence [31,32]. Indirect serological diagnosis
The serological diagnosis of VHF infection is based on the detection of specific IgM and IgG antibodies induced by the immune response principally to the nucleoprotein, which is recognized as the predominant antigen [36]. Seroconversion with detection of CCHFV IgM antibodies or a 4-fold increase in antibody titer between two successive blood samples is evidence of a recent infection [51,52]. The serological diagnosis is valid after several days post onset of the disease; nevertheless the antibody response rarely is observed in fatal cases [46]. The ELISA is the most common technique for CCHFV antibody detection with the sensitivity of more than 90%. The ELISA was reported to be more sensitive than IFA [33]. All native antigens have to be produced in a BSL-4 laboratory and irradiated before use. Usually IgM and IgG antibodies are detected four to five days post onset of symptoms. The IgM titer is maximal two to three weeks after onset of the disease, and the IgM antibodies generally disappear within four months. The IgG antibodies remain detectable for several years [30]. Rapid detection
Rapid diagnosis of the CCHFV can provide significant advantages including therapy and infection control. Some broad-range approaches for the rapid detection of VHF agents have been designed by the use of unique multiplex assays, such as MassTag-PCR [34]. One of these assays represents a first-generation rapid field test for the detection of Ebola virus antigen that can be performed in 30 min without electrical power or expensive or sensitive equipment [35]. Current Opinion in Virology 2012, 2:215–220
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Table 3 Differential diagnosis list for viral hemorrhagic fevers. Disease categories
Differentials
Infections Brucellosis Q fever Rickettsia Ehrlichiosis Hanta
Pancytopenia, Wright agglutination Serology (ELISA or IFAT) Weil-felix test Serology (ELISA) Pulmonary or renal involvement, Serology, PCR Other viral hemorrhagic infections Ebola Geographic location Marburg Geographic location Leptospira Agglutination Salmonella Widal test Non-infectious reasons Vitamin B12 deficiency Pancytopenia, and B12 level in serum Febrile neutropenia Underlying disease HELLP syndrome Geographic location Drug side effects Metamizole History
Differential diagnosis
The combined approach of viral genome detection and IgM detection is recommended for diagnosis of CCHF in humans. CCHFV has an extended geographical distribution including Africa, southern Europe, Middle East, Russia, India, and China. Other viral etiologies have to be considered according to the origin of the patient and the risks of potential exposure. These would include Alkhurma and Rift Valley fever in the Middle East; Omsk hemorrhagic fever in Russia; Kyasanur Forest disease in India; hantaviruses in Europe and Asia; Lassa, Ebola, Marburg, Rift Valley fever, yellow fever in Africa; and dengue in various locations [36]. In tropical and subtropical countries, malaria is the most important alternative diagnosis to be excluded in cases of suspected VHF. The differential diagnosis list should include, hepatitis viruses, influenza, Neisseria meningitidis, leptospirosis, borreliosis, typhoid, rickettsiosis, and Q fever (Coxiella burnetii) staphylococcal or gram-negative sepsis, toxic shock syndrome, salmonellosis and shigellosis, psittacosis, trypanosomiasis, septicemic plague, rubella, measles, and hemorrhagic smallpox [3,29,30] (Table 3). Noninfectious processes associated with bleeding diathesis that should be included in the differential diagnosis include idiopathic or thrombotic thrombocytopenic purpura, HELP syndrome among pregnant women, hemolytic uremic syndrome, acute leukemia, vitamin B12 deficiency, and collagen-vascular diseases [3,37]. Ribavirin is the antiviral of choice
Ribavirin is the only antiviral drug that has been used to treat viral hemorrhagic fever syndromes, including CCHF and Lassa fever [38–40]. Viruses in the Bunyaviridae family are generally sensitive to ribavirin [41]. Ribavirin Current Opinion in Virology 2012, 2:215–220
was shown, early on, to be effective against CCHFV in vitro [42–44]. In suckling mice, ribavirin treatment reduced CCHF virus growth in the liver; significantly decreased, but did not prevent viremia; and significantly reduced mortality and extended the geometric mean time to death [42]. In clinical practice, ribavirin was found to be beneficial, especially at the earlier phase of the infection [45–48]. Ribavirin is placed on the WHO essential medicines list (15th Model List of Essential Medicines, March 2007) to be used against CCHFV infection. In a recent review, ethical concerns about conducting a randomized controlled trial of ribavirin in the treatment of Crimean– Congo hemorrhagic fever were detailed [49]. Despite the need for more evidence about the impact of ribavirin in treatment, the authors described why it was not ethical to conduct a RCT in such a fatal disease with only one antiviral alternative [49]. Bulgarian investigators suggested that immunotherapeutic treatment of seven patients with severe CCHF via passive simultaneous transfer of two different specific immunoglobulin preparations, CCHF-bulin (for intramuscular use) and CCHF-venin (for intravenous use), prepared from the plasma of CCHF survivor donors, boosted with one dose of CCHF vaccine, resulted in quick recovery of all patients [50]. Further, they suggested that the intravenous preparation be used for treatment of all cases of CCHF [51]. In a recent study that included 22 severe patients from Turkey, prompt administration of CCHFV hyperimmunoglobulin was suggested as an alternative treatment approach, especially for highrisk individuals [52]. Further studies with larger sample size and more detailed design are necessary.
Infection control measures Bunyaviruses are highly infectious after direct contact with infected blood and bodily secretions. A suspected case of CCHF must be immediately reported to the hospital epidemiologist (or infection control professional) and to the local or state health department. The epidemiologist (or infection control professional) should, in turn, notify the clinical laboratory (so that additional precautions are put in place) as well as other clinicians and public health authorities.
Isolation precautions Direct contact with infected blood and bodily fluids has accounted for the majority of person-to-person transmission. Therefore, it was recommended that in the case of any patient with suspected or documented CCHFV infection, specific barrier precautions should be implemented immediately. Airborne transmission was suspected in one Lassa Fever outbreak in 1969 [53], but there has never been any documented case of airborne transmission of that virus to humans. A prospective serological study from Sierra Leone suggested that the hospital staff who cared for Lassa fever patients using www.sciencedirect.com
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simple barrier nursing methods have no higher risk of infection than the local population [54]. A similar study from Turkey reported the lack of airborne transmission of CCHF to the HCWs after CCHF epidemic [55]. Usually the standard precautions including health hygiene, using gloves, gowns, face shields and masks are sufficient to be protected. However, when procedures to be performed could generate an aerosol, HCW should consider wearing an N95 or FFP2 respirator (European Norm (EN) 61010-1) [56]. An integrated strategy for the control of accidental exposure to blood and body fluids is critical to provide protection among HCWs [56]. Sharps containers are the foremost piece of safety equipment, which should be available at all times to all units. The use of safetyengineered devices should also be considered in order to decrease the risk of needlestick injuries [56].
Postexposure management Postexposure management systems are an integral part of an effort to enhance HCW safety. In CCHF [45] and Lassa Fever [40], use of oral ribavirin as postexposure prophylaxis was well described as effective and beneficial drug. Ribavirin prophylaxis is generally well tolerated, potentially useful and should therefore be recommended for HCWs who are at high risk of exposures such as percutaneous injuries or splash of contaminated blood or body fluid to the face or mucosal surfaces of the HCWs [56]. In a similar approach with other agents of viral hemorrhagic fever such as filoviruses and arenaviruses, it might be recommended that the patients convalescing from CCHF infection should refrain from sexual activity for three months after clinical recovery [29]. In conclusion, many recent developments were noted in epidemiology, pathogenesis and early detection; however, there is neither alternative antiviral therapy nor vaccine on the pipeline yet.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest
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10. Ergonul O, Celikbas A, Dokuzoguz B, Eren S, Baykam N, Esener H: Characteristics of patients with Crimean–Congo hemorrhagic fever in a recent outbreak in Turkey and impact of oral ribavirin therapy. Clin Infect Dis 2004, 39:284-287. 11. Maltezou HC, Papa A, Tsiodras S, Dalla V, Maltezos E, Antoniadis A: Crimean–Congo hemorrhagic fever in Greece: a public health perspective. Int J Infect Dis 2009, 13:713-716. 12. Dunster L, Dunster M, Ofula V et al.: First documentation of human Crimean–Congo hemorrhagic fever, Kenya. Emerg Infect Dis 2002, 8:1005-1006. 13. Nabeth P, Cheikh DO, Lo B et al.: Crimean–Congo hemorrhagic fever, Mauritania. Emerg Infect Dis 2004, 10:2143-2149. 14. Patel AK, Patel KK, Mehta M, Parikh TM, Toshniwal H, Patel K: First Crimean–Congo hemorrhagic fever outbreak in India. J Assoc Physicians India 2011, 59:585-589. 15. Mishra AC, Mehta M, Mourya DT, Gandhi S: Crimean–Congo haemorrhagic fever in India. Lancet 2011, 378:372. This is the first report of CCHF cases from India. 16. Ergonul O, Whitehouse CA: Introduction. In Crimean Congo Hemorrhagic Fever: A Global Perspective. Edited by Ergonul O, Whitehouse CA. Dordrecht, NL: Springer; 2007:3-11. 17. Yilmaz GR, Buzgan T, Irmak H et al.: The epidemiology of Crimean–Congo hemorrhagic fever in Turkey, 2002–2007. Int J Infect Dis 2008, 13:380-386. 18. Midilli K, Gargili A, Ergonul O et al.: The first clinical case due to AP92 like strain of Crimean–Congo hemorrhagic fever virus and a field survey. BMC Infect Dis 2009, 9:90. This is the first human case with AP92 like CCHFV infection. Furthermore, this is the first report of AP92 like strain in Turkey. 19. Gargili A, Midilli K, Ergonul O et al.: Crimean–Congo hemorrhagic fever in European part of Turkey: genetic analysis of the virus strains from ticks and a seroepidemiological study in humans. Vector Borne Zoonotic Dis 2011, 11:747-752. 20. Vatansever Z, Uzun R, Estrada-Pena A, Ergonul O: Crimean Congo hemorrhagic fever in Turkey. In Crimean Congo Hemorrhagic Fever: A Global Perspective. Edited by Ergonul O, Whitehouse CA. Dordrecht, NL: Springer; 2007:59-74.
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