Imported Crimean-Congo Hemorrhagic Fever
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微生物临床杂志 2005年第9期
Service de Maladies Infectieuses et Reanimation Medicale, Pontchaillou University Hospital, Rennes, France
Institut National de Veille Sanitaire, Paris, France
Institut Pasteur, Dakar, Senegal
Centre National de Reference des Fievres Hemorragiques, Institut Pasteur, Lyon, France
ABSTRACT
Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease that may also be transmitted through person-to-person transmission by exposure to infected body fluids. Despite its wide geographic distribution in animals, CCHF virus is rarely associated with recognized human diseases. We report the first case of imported CCHF in France.
CASE REPORT
On 4 November 2004, a 60-year-old French woman was hospitalized in Dakar, Senegal (western Africa), for a severe influenza-like illness of 3 days in duration. The patient had been in Senegal since 8 October, working as a volunteer technician for a private radiologist in Dakar. Since her arrival, she had spent two weekends at Saly Portudal, 80 km south of Dakar (Fig. 1). She didn't recall any tick bite, and there was no contact with livestock or people with hemorrhagic disease. She was correctly immunized against yellow fever and hepatitis B virus before her trip, but she didn't take any chemoprophylaxis against malaria. On admission, her body temperature was 40°C. Initial laboratory values were remarkable for thrombocytopenia and elevated liver enzymes. No Plasmodium species were seen on three consecutive blood smears. On 7 November, diffuse hemorrhagic signs appeared with purpuric lesions and gingival bleeding, while body temperature increased to 41°C. On 10 November, she was transferred to the intensive care unit of the Hpital Principal, Dakar, because of hematemesis and shock. Her platelet count was 5,000 per mm3 (normal range, 150,000 to 500,000/mm3), hemoglobin level was 5.2 g/dl (normal range, 12 to 16 g/dl), and white blood cell count was 2,770 per mm3 (normal range, 4,000 to 8,000/mm3). Coagulation testing revealed disseminated intravascular coagulation (DIC) with an international normalized ratio of 2 and a fibrinogen level of 0.9 g/liter (normal range, 1.5 to 4 g/liter). Aspartate aminotransferase was 632 IU/liter, and alanine aminotransferase was 360 IU/liter (normal range, 7 to 40 IU/liter). The serum creatinine level was 210 μmol/liter (normal range, 40 to 120 μmol/liter). She received packed red blood cells (platelet concentrates) and was transferred by plane without any isolation procedures to Rennes University Hospital, France, on 14 November. There was no international alert about any viral hemorrhagic fever (VHF) outbreak in Senegal at that time.
On admission to the intensive care unit, she was isolated in a single room with contact isolation procedures. Physical examination revealed cutaneous ecchymosis of both arms and legs. Her body temperature was 37°C and remained below 37.8°C until her discharge from the hospital 10 days later. No further hemorrhagic signs were noticed, and DIC gradually disappeared without further treatment. On 23 November, the formal diagnosis was obtained from a blood sample drawn on 15 November with (i) a positive test for anti-Crimean-Congo hemorrhagic fever (CCHF) immunoglobulin M (IgM) antibody by enzyme-linked immunosorbent assay in the absence of IgG and (ii) isolation of the CCHF genome by nested reverse transcriptase PCR (Pasteur Institute, Lyon, France) (5). Other hemorrhagic infectious diseases (malaria, leptospirosis, viral hepatitis, severe sepsis, dengue hemorrhagic fever, Lassa fever, Rift Valley fever, hantavirosis, and Wesselsbron virosis) were ruled out (enzyme-linked immunosorbent assay). All health care workers and community contacts of the patient were screened for potential exposure to infectious body fluid and followed up until 10 days after the last contact: There was no secondary case in Senegal and in France. All blood samples collected during the hospitalization were destroyed except for 14, which were sent to the National Reference Center of VHF for research purposes (Pasteur Institute, Lyon).
CCHF was first clinically described in 1944 in Crimea of the former Soviet Union during a large outbreak of over 200 cases. CCHF virus was identified in 1967, from a patient in Uzbekistan, and was found to be similar to a virus isolated in 1956 in Congo, hence the name Crimean-Congo (3, 14). CCHF virus, from the Nairovirus genus, Bunyaviridae family, is now known to have a wide geographic range, circulating in Africa, the Middle East, Asia, and central and eastern Europe. It may be transmitted by the bite of infected ticks, contact with infected animals, or through person-to-person transmission by percutaneous or permucosal exposure to blood or other infected body fluids (4, 7, 10, 14, 16). CCHF virus infects the reticuloendothelial system and frequently involves the hepatocytes, leading to icteric hepatitis (2). CCHF is a severe hemorrhagic fever with shock, DIC, and frequent extensive bleeding (1, 9, 11). Case fatality ratios from 20% to 35% have been reported, but the effects of supportive treatment on reducing the morbidity and the mortality from CCHF can be dramatic (12). Ribavirin has been used in CCHF, and its efficacy was estimated at 89% in patients with confirmed CCHF and 70% in patients with suspected CCHF in a large clinical study of 139 treated patients (6).
To our knowledge, imported CCHF has never been reported in northern Europe or in America. Two important lessons deserve to be outlined from this report. First, recent data showed that CCHF virus can use different means to infect humans. In this observation, the only risk factor was the patient's occupation. Indeed, nosocomial transmissions to health care workers have been reported in Europe, Asia, and Africa, including transmissions to laboratory personnel (13). CCHF virus is thus classified as a biosafety level 4 pathogen. However, the patient didn't recall any occupational exposure to blood during the previous weeks. Apart from her occupation, the patient didn't recall any other classical exposure to CCHF virus (tick bite or contact with livestock animals or people with hemorrhagic signs) (4), but she may have been contaminated during her stay in Saly Portudal, close to the Popenguine district, where a study conducted in the human population between 1986 and 1988 showed a prevalence of anti-CCHF IgG of 3.2% (15) and where previous ecological studies have shown a large CCHF virus circulation (17). In the same district, a shepherd who became ill in 2003 was the only clinical case who was ever reported in Senegal. The mode of infection could not be clearly identified, but he was living in close proximity to goats and cattle (4, 8).
Second, this observation illustrates that even in the absence of any international alert about an ongoing epidemic of VHF, every febrile hemorrhagic syndrome coming from an area where VHF has been reported must be considered as a VHF until proven otherwise. This requires respiratory and contact isolation procedures in a single room with a secure process for obtaining any blood samples. In the observation reported herein, as the physicians in charge of the patient estimated that the probability of VHF was very low, isolation procedures recommended for any suspicion of VHF were not implemented initially. Consequently, more than 100 patient contacts had to be followed up to ensure that there were no secondary cases. Fortunately, CCHF virus is only rarely associated with outbreaks of recognized human diseases, despite (i) its wide geographic distribution, (ii) its important circulation in numerous vertebrate species in areas of disease endemicity, and (iii) its multiple modes of transmission to humans. However, with the constant rise in the number of people traveling abroad and the large spread of CCHF vector and reservoir, an increasing number of such cases can unfortunately occur.
REFERENCES
Burney, M. I., A. Ghafoor, M. Saleen, P. A. Webb, and J. Casals. 1980. Nosocomial outbreak of viral hemorrhagic fever caused by Crimean hemorrhagic fever-Congo virus in Pakistan, January 1976. Am. J. Trop. Med. Hyg. 29:941-947.
Burt, F. J., R. Swanepoel, W. J. Shieh et al. 1997. Immunohistochemical and in situ localization of Crimean-Congo hemorrhagic fever (CCHF) virus in human tissues and implications for CCHF pathogenesis. Arch. Pathol. Lab. Med. 121:839-846.
Casals, J. 1969. Antigenic similarity between the virus causing Crimean hemorrhagic fever and Congo virus. Proc. Soc. Exp. Biol. Med. 131:233-236.
Chapman, L. E., M. L. Wilson, D. B. Hall et al. 1991. Risk factors for Crimean-Congo hemorrhagic fever in rural northern Senegal. J. Infect. Dis. 164:686-692.
Drosten, C., B. M. Kummerer, H. Schmitz, and S. Gunther. 2003. Molecular diagnostics of viral hemorrhagic fevers. Antivir. Res. 57:61-87.
Mardani, M., M. K. Jahromi, K. H. Naieni, and M. Zeinali. 2003. The efficacy of oral ribavirin in the treatment of Crimean-Congo hemorrhagic fever in Iran. Clin. Infect. Dis. 36:1613-1618.
Nabeth, P., D. Cheikh, B. Lo, O. Faye, I. Vall, and M. Niang. 2004. Crimean-Congo hemorrhagic fever, Mauritania. Emerg. Infect. Dis. 10:2143-2149.
Nabeth, P., M. Thior, O. Faye, and F. Simon. 2004. Human Crimean-Congo hemorrhagic fever, Senegal. Emerg. Infect. Dis. 10:1881-1882.
Papa, A., S. Bino, A. Llagami et al. 2002. Crimean-Congo hemorrhagic fever in Albania, 2001. Eur. J. Clin. Microbiol. Infect. Dis. 21:603-606.
Smego, R. A., A. R. Sarwari, and A. R. Siddiqui. 2004. Crimean-Congo hemorrhagic fever: prevention and control limitations in a resource-poor country. Clin. Infect. Dis. 38:1731-1735.
van Eeden, P. J., J. R. Joubert, B. W. van de Wal, J. B. King, A. de Kock, and J. H. Groenewald. 1985. A nosocomial outbreak of Crimean-Congo haemorrhagic fever at Tygerberg Hospital. Part I. Clinical features. S. Afr. Med. J. 68:711-717.
van Eeden, P. J., S. F. van Eeden, J. R. Joubert, J. B. King, B. W. van de Wal, and W. L. Michell. 1985. A nosocomial outbreak of Crimean-Congo haemorrhagic fever at Tygerberg Hospital. Part II. Management of patients. S. Afr. Med. J. 68:718-721.
Weber, D. J., and W. A. Rutala. 2001. Risks and prevention of nosocomial transmission of rare zoonotic diseases. Clin. Infect. Dis. 32:446-456.
Whitehouse, C. A. 2004. Crimean-Congo hemorrhagic fever. Antivir. Res. 64:145-160.
Wilson, M. L, J. P. Gonzales, B. LeGuenno, J. P. Cornet, M. Guillaud, and M. A. Calvo.1990. Epidemiology of Crimean-Congo hemorrhagic fever in Senegal: temporal and spatial patterns. Arch. Virol. Suppl. 1:323-340.
Wilson, M. L., B. LeGuenno, M. Guillaud, D. Desoutter, J. P. Gonzalez, and J. L. Camicas. 1990. Distribution of Crimean-Congo hemorrhagic fever viral antibody in Senegal: environmental and vectorial correlates. Am. J. Trop. Med. Hyg. 43:557-566.
Zeller, H. G., J. P. Cornet, A. Diop, and J. L. Camicas. 1997. Crimean-Congo hemorrhagic fever in ticks (Acari: Ixodidae) and ruminants: field observations of an epizootic in Bandia, Senegal (1989-1992). J. Med. Entomol. 34:511-516.(Stephane Jaureguiberry, P)
Institut National de Veille Sanitaire, Paris, France
Institut Pasteur, Dakar, Senegal
Centre National de Reference des Fievres Hemorragiques, Institut Pasteur, Lyon, France
ABSTRACT
Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease that may also be transmitted through person-to-person transmission by exposure to infected body fluids. Despite its wide geographic distribution in animals, CCHF virus is rarely associated with recognized human diseases. We report the first case of imported CCHF in France.
CASE REPORT
On 4 November 2004, a 60-year-old French woman was hospitalized in Dakar, Senegal (western Africa), for a severe influenza-like illness of 3 days in duration. The patient had been in Senegal since 8 October, working as a volunteer technician for a private radiologist in Dakar. Since her arrival, she had spent two weekends at Saly Portudal, 80 km south of Dakar (Fig. 1). She didn't recall any tick bite, and there was no contact with livestock or people with hemorrhagic disease. She was correctly immunized against yellow fever and hepatitis B virus before her trip, but she didn't take any chemoprophylaxis against malaria. On admission, her body temperature was 40°C. Initial laboratory values were remarkable for thrombocytopenia and elevated liver enzymes. No Plasmodium species were seen on three consecutive blood smears. On 7 November, diffuse hemorrhagic signs appeared with purpuric lesions and gingival bleeding, while body temperature increased to 41°C. On 10 November, she was transferred to the intensive care unit of the Hpital Principal, Dakar, because of hematemesis and shock. Her platelet count was 5,000 per mm3 (normal range, 150,000 to 500,000/mm3), hemoglobin level was 5.2 g/dl (normal range, 12 to 16 g/dl), and white blood cell count was 2,770 per mm3 (normal range, 4,000 to 8,000/mm3). Coagulation testing revealed disseminated intravascular coagulation (DIC) with an international normalized ratio of 2 and a fibrinogen level of 0.9 g/liter (normal range, 1.5 to 4 g/liter). Aspartate aminotransferase was 632 IU/liter, and alanine aminotransferase was 360 IU/liter (normal range, 7 to 40 IU/liter). The serum creatinine level was 210 μmol/liter (normal range, 40 to 120 μmol/liter). She received packed red blood cells (platelet concentrates) and was transferred by plane without any isolation procedures to Rennes University Hospital, France, on 14 November. There was no international alert about any viral hemorrhagic fever (VHF) outbreak in Senegal at that time.
On admission to the intensive care unit, she was isolated in a single room with contact isolation procedures. Physical examination revealed cutaneous ecchymosis of both arms and legs. Her body temperature was 37°C and remained below 37.8°C until her discharge from the hospital 10 days later. No further hemorrhagic signs were noticed, and DIC gradually disappeared without further treatment. On 23 November, the formal diagnosis was obtained from a blood sample drawn on 15 November with (i) a positive test for anti-Crimean-Congo hemorrhagic fever (CCHF) immunoglobulin M (IgM) antibody by enzyme-linked immunosorbent assay in the absence of IgG and (ii) isolation of the CCHF genome by nested reverse transcriptase PCR (Pasteur Institute, Lyon, France) (5). Other hemorrhagic infectious diseases (malaria, leptospirosis, viral hepatitis, severe sepsis, dengue hemorrhagic fever, Lassa fever, Rift Valley fever, hantavirosis, and Wesselsbron virosis) were ruled out (enzyme-linked immunosorbent assay). All health care workers and community contacts of the patient were screened for potential exposure to infectious body fluid and followed up until 10 days after the last contact: There was no secondary case in Senegal and in France. All blood samples collected during the hospitalization were destroyed except for 14, which were sent to the National Reference Center of VHF for research purposes (Pasteur Institute, Lyon).
CCHF was first clinically described in 1944 in Crimea of the former Soviet Union during a large outbreak of over 200 cases. CCHF virus was identified in 1967, from a patient in Uzbekistan, and was found to be similar to a virus isolated in 1956 in Congo, hence the name Crimean-Congo (3, 14). CCHF virus, from the Nairovirus genus, Bunyaviridae family, is now known to have a wide geographic range, circulating in Africa, the Middle East, Asia, and central and eastern Europe. It may be transmitted by the bite of infected ticks, contact with infected animals, or through person-to-person transmission by percutaneous or permucosal exposure to blood or other infected body fluids (4, 7, 10, 14, 16). CCHF virus infects the reticuloendothelial system and frequently involves the hepatocytes, leading to icteric hepatitis (2). CCHF is a severe hemorrhagic fever with shock, DIC, and frequent extensive bleeding (1, 9, 11). Case fatality ratios from 20% to 35% have been reported, but the effects of supportive treatment on reducing the morbidity and the mortality from CCHF can be dramatic (12). Ribavirin has been used in CCHF, and its efficacy was estimated at 89% in patients with confirmed CCHF and 70% in patients with suspected CCHF in a large clinical study of 139 treated patients (6).
To our knowledge, imported CCHF has never been reported in northern Europe or in America. Two important lessons deserve to be outlined from this report. First, recent data showed that CCHF virus can use different means to infect humans. In this observation, the only risk factor was the patient's occupation. Indeed, nosocomial transmissions to health care workers have been reported in Europe, Asia, and Africa, including transmissions to laboratory personnel (13). CCHF virus is thus classified as a biosafety level 4 pathogen. However, the patient didn't recall any occupational exposure to blood during the previous weeks. Apart from her occupation, the patient didn't recall any other classical exposure to CCHF virus (tick bite or contact with livestock animals or people with hemorrhagic signs) (4), but she may have been contaminated during her stay in Saly Portudal, close to the Popenguine district, where a study conducted in the human population between 1986 and 1988 showed a prevalence of anti-CCHF IgG of 3.2% (15) and where previous ecological studies have shown a large CCHF virus circulation (17). In the same district, a shepherd who became ill in 2003 was the only clinical case who was ever reported in Senegal. The mode of infection could not be clearly identified, but he was living in close proximity to goats and cattle (4, 8).
Second, this observation illustrates that even in the absence of any international alert about an ongoing epidemic of VHF, every febrile hemorrhagic syndrome coming from an area where VHF has been reported must be considered as a VHF until proven otherwise. This requires respiratory and contact isolation procedures in a single room with a secure process for obtaining any blood samples. In the observation reported herein, as the physicians in charge of the patient estimated that the probability of VHF was very low, isolation procedures recommended for any suspicion of VHF were not implemented initially. Consequently, more than 100 patient contacts had to be followed up to ensure that there were no secondary cases. Fortunately, CCHF virus is only rarely associated with outbreaks of recognized human diseases, despite (i) its wide geographic distribution, (ii) its important circulation in numerous vertebrate species in areas of disease endemicity, and (iii) its multiple modes of transmission to humans. However, with the constant rise in the number of people traveling abroad and the large spread of CCHF vector and reservoir, an increasing number of such cases can unfortunately occur.
REFERENCES
Burney, M. I., A. Ghafoor, M. Saleen, P. A. Webb, and J. Casals. 1980. Nosocomial outbreak of viral hemorrhagic fever caused by Crimean hemorrhagic fever-Congo virus in Pakistan, January 1976. Am. J. Trop. Med. Hyg. 29:941-947.
Burt, F. J., R. Swanepoel, W. J. Shieh et al. 1997. Immunohistochemical and in situ localization of Crimean-Congo hemorrhagic fever (CCHF) virus in human tissues and implications for CCHF pathogenesis. Arch. Pathol. Lab. Med. 121:839-846.
Casals, J. 1969. Antigenic similarity between the virus causing Crimean hemorrhagic fever and Congo virus. Proc. Soc. Exp. Biol. Med. 131:233-236.
Chapman, L. E., M. L. Wilson, D. B. Hall et al. 1991. Risk factors for Crimean-Congo hemorrhagic fever in rural northern Senegal. J. Infect. Dis. 164:686-692.
Drosten, C., B. M. Kummerer, H. Schmitz, and S. Gunther. 2003. Molecular diagnostics of viral hemorrhagic fevers. Antivir. Res. 57:61-87.
Mardani, M., M. K. Jahromi, K. H. Naieni, and M. Zeinali. 2003. The efficacy of oral ribavirin in the treatment of Crimean-Congo hemorrhagic fever in Iran. Clin. Infect. Dis. 36:1613-1618.
Nabeth, P., D. Cheikh, B. Lo, O. Faye, I. Vall, and M. Niang. 2004. Crimean-Congo hemorrhagic fever, Mauritania. Emerg. Infect. Dis. 10:2143-2149.
Nabeth, P., M. Thior, O. Faye, and F. Simon. 2004. Human Crimean-Congo hemorrhagic fever, Senegal. Emerg. Infect. Dis. 10:1881-1882.
Papa, A., S. Bino, A. Llagami et al. 2002. Crimean-Congo hemorrhagic fever in Albania, 2001. Eur. J. Clin. Microbiol. Infect. Dis. 21:603-606.
Smego, R. A., A. R. Sarwari, and A. R. Siddiqui. 2004. Crimean-Congo hemorrhagic fever: prevention and control limitations in a resource-poor country. Clin. Infect. Dis. 38:1731-1735.
van Eeden, P. J., J. R. Joubert, B. W. van de Wal, J. B. King, A. de Kock, and J. H. Groenewald. 1985. A nosocomial outbreak of Crimean-Congo haemorrhagic fever at Tygerberg Hospital. Part I. Clinical features. S. Afr. Med. J. 68:711-717.
van Eeden, P. J., S. F. van Eeden, J. R. Joubert, J. B. King, B. W. van de Wal, and W. L. Michell. 1985. A nosocomial outbreak of Crimean-Congo haemorrhagic fever at Tygerberg Hospital. Part II. Management of patients. S. Afr. Med. J. 68:718-721.
Weber, D. J., and W. A. Rutala. 2001. Risks and prevention of nosocomial transmission of rare zoonotic diseases. Clin. Infect. Dis. 32:446-456.
Whitehouse, C. A. 2004. Crimean-Congo hemorrhagic fever. Antivir. Res. 64:145-160.
Wilson, M. L, J. P. Gonzales, B. LeGuenno, J. P. Cornet, M. Guillaud, and M. A. Calvo.1990. Epidemiology of Crimean-Congo hemorrhagic fever in Senegal: temporal and spatial patterns. Arch. Virol. Suppl. 1:323-340.
Wilson, M. L., B. LeGuenno, M. Guillaud, D. Desoutter, J. P. Gonzalez, and J. L. Camicas. 1990. Distribution of Crimean-Congo hemorrhagic fever viral antibody in Senegal: environmental and vectorial correlates. Am. J. Trop. Med. Hyg. 43:557-566.
Zeller, H. G., J. P. Cornet, A. Diop, and J. L. Camicas. 1997. Crimean-Congo hemorrhagic fever in ticks (Acari: Ixodidae) and ruminants: field observations of an epizootic in Bandia, Senegal (1989-1992). J. Med. Entomol. 34:511-516.(Stephane Jaureguiberry, P)