Outbreaks: West Nile Virus, Rift Valley Fever, and Ebola Virus Infection—What and Where Next?
Abstracts & Commentary
Synopsis: These three viral infections keep expanding their areas of activity.
Sources: CDC. Outbreak of Rift Valley fever—Saudi Arabia, August-October, 2000. MMWR Morb Mortal Wkly Rep 2000;49:905-908; Ebola hemorrhagic fever in Uganda—Update. http://www.who.int/disease-outbreak-news/; West Nile Virus, http://www.promedmail.org.
An outbreak of haemorrhagic fever in saudi arabia, which had affected more than 450 individuals by October 26th, has been demonstrated to be due to Rift Valley Fever (RVF) virus. The diagnosis was confirmed by the Centers for Disease Control (CDC) using multiple methodologies, including ELISA antigen detection and IgM antibody tests, PCR, and immunohistocytochemistry. Eighty-eight (20%) of those affected have died. Affected individuals had resided in or visited the floodplains of the wadis, or seasonal riverbeds, in the southwestern area of Saudi Arabia. The adjacent area of Yemen was also affected with a total of 706 cases and 97 deaths.
Outbreaks of RVF in ruminants and humans are associated with periodic heavy rainfalls in otherwise arid areas. Its transmission to humans is predominantly by the bite of infected Aedes and Culex mosquitoes, as well as by contact with infected animal body fluids.
This is the first report of acquisition of RVF outside of Africa, but its location is not surprising. The Rift Valley, from which the virus takes its name, is a geological feature that extends 6500 kilometers from the coast of Mozambique all the way to the Dead Sea. The most recent outbreak of this infection occurred in Kenya in 1997-1998 and was associated with more than 300 human fatalities.1
Symptomatic infection with this phlebovirus is associated, after an incubation period of 3-7 days, with fever, headache, arthralgias, myalgias, and photophobia. The vast majority of cases are uncomplicated and self-limited. Several percent of those affected develop macular and perimacular retinitis with vasculitis, a complication that may cause permanent blindness. Encephalitis may also occur. Approximately 1% develop fulminant hemorrhagic fever. Ribavirin therapy has been reported to be effective in animal models of infection, but its efficacy in human infection is unknown. An inactivated RVF vaccine has been reported to be safe and immunogenic in humans.2
Ebola Virus
As of October 29th, the Ministry of Health of Uganda had reported 211 cases of haemorrhagic fever, including 72 deaths from Gulu province. Laboratory testing carried out at the National Institute of Virology in South Africa indicates that the cause of the outbreak is the Ebola virus. These are the first cases of Ebola ever reported in Uganda.
The Associated Press reported that one of the first recognized victims of this outbreak was Esther Awate, who died on September 7. In keeping with custom, her body was kept in her hut for two days and ritually bathed by family and close friends before burial. Ms. Awate’s mother, 9-month-old child, and six other relatives have since also died. An 8-year-old son who did not take part in the funeral ritual has survived.
Laurie Garrett reported that another early victim was an infant in Kabede Opon whose family had fled the Lord’s Resistance Army, a terrorist group based in Sudan. Kabede Opon is just a few miles from Gulu (225 miles north of Kampala) and is only 200 kilometers from Maridi, Sudan, where Ebola outbreaks had occurred in 1976 and 1979.
Ebola is a filovirus that causes sporadic infections and periodic outbreaks of infection in Africa, as in the large 1998 outbreak in Kikwit, Zaire.3 The illness usually begins abruptly, after a usual incubation period of 4-10 days, with fever, headache, arthralgia, and myalgia. Bradycardia, pharyngitis, and conjunctivitis may also occur, as well as a measle-like skin eruption. With progression, hematemesis and other hemorrhagic manifestations occur. The reported usual fatality rate is as high as 90%, although it appears to be only 34% in the current outbreak.
The endemic reservoir of Ebola virus appears to be small rodents, but during outbreaks it is also transmitted between humans by direct contact with body fluids. The burial practices of affected populations, especially the ritual bathing, are believed to play an important role in many cases.
Recent experimental studies have improved our understanding of this infection. Interferon production is inhibited by Ebola infection by a mechanism involving viral VP35 protein.4 The Ebola secretory glycoprotein alters the physical linkage between neutrophil FcgRIIIB (CD16b) and CR3, inhibiting L-selectin shedding.5 Ebola glycoprotein is also associated with endothelial damage and, presumably, is critical to the pathogenicity of the virus, contributing to the haemorrhagic manifestations of infection.6 Thus, secreted glycoprotein inhibits early neutrophil activation, which likely affects the host response to infection, as does the effect of VP135 on interferon production. In addition, binding of the transmembrane glycoprotein to endothelial cells may contribute to the haemorrhagic symptoms of this disease.7
Studies in primates suggest that the lymphocytopenia seen in Ebola infection is associated with lymphocyte apoptosis.8 Fatal Ebola infection is associated with impaired antibody response and, in the last five days of life, with massive intravascular apoptosis with disappearance of T-cell mediated mRNA.9
Protective monoclonal antibodies against epitopes of the Ebola glycoprotein, including one epitope that is conserved among all known Ebola strains pathogenic for humans, have been generated.10 The detection of potentially protective epitopes raises hope for effective vaccine development.
Passive immunoprophylaxis and therapy is also under investigation, as are potential antivirals. A caprine hyperimmune globulin preparation was effective when given 48 hours after infection of guinea pigs.11 Carbocyclic 3-deazaadenosine, an inhibitor of S-adenosylhomocysteine hydrolase, is effective in a murine model of Ebola infection.12
West Nile Virus
West Nile virus (WNV), after making its first U.S. appearance last year, reared its ugly head once again this summer. As of October 28, 18 human cases with one death had been detected, all having occurred within six different counties of New York, New Jersey, and Connecticut.
This flavivirus also affects other mammals and the extent of this involvement has become apparent through active surveillance programs. Almost 3000 birds have been documented as infected with WNV in 2000. The total number of WNV-positive specimens from New York state alone for this year as of October 13th was 1080 birds, 317 mosquito pools, two sentinel chickens, seven live wild birds, 14 bats, eight horses, two cats, two raccoons, three domestic rabbits, three squirrels, one chipmunk, and 13 human cases.
Infected birds were recently detected for the first time in Vermont, Virginia, and North Carolina, having previously been found in Pennsylvania, New York, Rhode Island, District of Columbia, Maryland, Massachusetts, Connecticut, and New Jersey. Infected horses have been detected in New York, Rhode Island, Massachusetts, New Jersey, Connecticut, and Pennsylvania. (Equine infection with WNV has recently occurred for the first time in 40 years in the Camargue region of southern France). Infected mosquitoes have been detected in New York, Pennsylvania, New Jersey, and Massachusetts.
Active surveillance and mosquito abatement measures have kept the number of human cases low. It is anticipated, however, that the virus will be spread to other areas of North America, as well as to areas of South America that are visited by infected birds during their annual migrations.
Treatment of WNV infection is supportive, but recent evidence indicates that ribavirin has inhibitory activity against this virus in human neural cells in vitro.14
References
1. Deresinski SC. Outbreak: Rift valley fever in Kenya. Infectious Disease Alert 1998;17:68-70.
2. Pittman PR, et al. Immunogenicity of an inactivated Rift Valley fever vaccine in humans: a 12-year experience. Vaccine 1999;18:181-189.
3. Deresinski SC. Ebola fever: Where next? Infectious Disease Alert 1995;14:134-136.
4. Basler CF, et al. The Ebola virus VP35 protein functions as a type I IFN antagonist. Proc Natl Acad Sci U S A 2000;97(22):12289-12294.
5. Kindzelskii AL, et al. Ebola virus secretory glycoprotein (sGP) diminishes Fc gamma RIIIB-to-CR3 proximity on neutrophils. J Immunol 2000;164:953-958.
6. Yang ZY, et al. Identification of the Ebola virus glycoprotein as the main viral determinant of vascular cell cytotoxicity and injury. Nat Med 2000;6:886-889.
7. Yang Z, et al. Distinct interactions of secreted and transmembrane Ebola virus glycoproteins. Science 1998;286:1034-1037.
8. Geisbert TW, et al. Apoptosis induced in vitro and in vivo during infection by Ebola and Marburg viruses. Lab Invest 2000;80:171-186.
9. Baize S, et al. Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients. Nat Med 1999;5:423-426.
10. Wilson JA, et al. Epitopes involved in antibody-mediated protection from Ebola virus. Science 2000;287: 1664-1666.
11. Kudoyarova-Zubavichene NM, et al. Preparation and use of hyperimmune serum for prophylaxis and therapy of Ebola virus infections. J Infect Dis 1999; 179(Suppl 1):S218-S223.
12. Huggins J, Zhang ZX, Bray M. Antiviral drug therapy of filovirus infections: S-adenosylhomocysteine hydrolase inhibitors inhibit Ebola virus in vitro and in a lethal mouse model. J Infect Dis 1999;179(Suppl 1): S240-S247.
13. Rappole JH, Derrickson SR, Hubalek Z. Migratory birds and spread of West Nile virus in the Western Hemisphere. Emerg Infect Dis 2000;6:19-28.
14. Jordan I, et al. Ribavirin inhibits West Nile virus replication and cytopathic effect in neural cells. J Infect Dis 2000;182:1214-1217.
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