Marburg Hemorrhagic Fever — The Forgotten Cousin Strikes
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《新英格兰医药杂志》
More than 30 years after the discovery of Marburg virus as the causative agent of an outbreak of severe viral hemorrhagic fever in Germany and the former Yugoslavia in 1967, the long-forgotten pathogen has struck twice in the recent past, leaving no doubt about its survival in nature or its pathogenic potential. The first strike came in 1998 (and lasted until 2000), when Marburg virus hit a gold-mining community in the northeastern region of the Democratic Republic of the Congo, as discussed by Bausch and colleagues in this issue of the Journal (pages 909–919). A second outbreak followed in northern Angola in 2004 and 2005.1 Between 1967 and 1998, Marburg virus infections were rare events, with only three incidences reported, each involving either a single case (Kenya, 1987) or an index case plus the infection of a traveling companion, medical personnel, or both (Zimbabwe–South Africa, 1975, and Kenya, 1980) (see map).1
Marburg Hemorrhagic Fever in Africa.
Locations of Marburg hemorrhagic fever outbreaks and cases are indicated by red symbols. The green symbol indicates the source of the African green monkeys (inset) that were shipped to Europe in 1967, bringing Marburg virus with them.
The 1998 outbreak in the Democratic Republic of the Congo represented the first community-based Marburg virus outbreak in Africa. It occurred in an area that was geographically close to previously reported Marburg virus activity, but it was unique among reported filovirus outbreaks in that continuous infections occurred over a period of almost two years. Bausch et al. describe a seasonal pattern to that event, with transmission beginning in October and November and peaking in January and February. Cases occurred first in miners and then spread to their family members and other members of the community.
Unlike most filovirus outbreaks, this one included few nosocomial infections. The case fatality rate of 83 percent was much higher than that reported during the 1967 outbreak (23 percent). In this sense, it was more similar to outbreaks of the most virulent Zaire species of Ebola virus, the better-known cousin of Marburg within the family Filoviridae. Cases were associated with at least nine different genetic lineages of Marburg virus, representing the entire genetic repertoire of previously characterized East African isolates of the Lake Victoria Marburg virus species.1 A similar situation has been reported from the border region between Gabon and the Republic of the Congo, where multiple genetic lineages of the Zaire species of Ebola virus cocirculate, causing smaller outbreaks of viral hemorrhagic fever mainly in hunting communities.2 By contrast, filovirus sequences derived from patients involved in a distinct chain of epidemic transmission have generally been shown to be highly conserved within an outbreak.1
Marburg virus surprised everyone with its recent emergence in northern Angola, where most experts would have expected Ebola virus to be more likely to arise (see map).1 The Angolan outbreak represents the first appearance of Marburg virus in western Africa and is the largest outbreak to date. It was probably caused by a single introduction of the virus, just as the previously reported Ebola virus outbreaks have usually started with a single index patient, who transmitted the virus to family and community members, and have then been amplified in hospital settings. The Angolan outbreak, however, involved many cases in children, whereas such infections in children were previously considered extremely rare. In addition, there seemed to be a short incubation period in many cases, and the case fatality rate was even higher than that during the 1998–2000 outbreak in the Democratic Republic of the Congo.1
With the exception of the Reston species of Ebola virus found in the Philippines, the Marburg and Ebola viruses seem to be endemic in Central African countries (see map).1 Outbreaks remain unpredictable, in part because the reservoir of these presumed zoonotic pathogens remains mysterious. However, we may be one step closer to solving the mystery after a recent report described evidence of Ebola virus infection in three distinct species of fruit bats whose geographic distribution covers most of the areas where human outbreaks of Ebola and Marburg viruses have occurred.3 Bats had already been implicated as sources of infection in index cases in previous filovirus outbreaks, including the outbreak of Marburg hemorrhagic fever in the Democratic Republic of the Congo. It was further demonstrated that experimentally infected wild African fruit and insectivorous bats support replication and circulation of Ebola virus without becoming symptomatic. It remains unexplained, however, why researchers have not yet been able to isolate the virus from wild bats, given the relative ease of isolating filoviruses from human specimens. The definitive identification of the reservoir and determination of the route of transmission from the reservoir to humans or nonhuman primates (the other susceptible hosts) remain high priorities for public health professionals, who would like to respond with travel advisories or restrictions, education of residents of areas of endemic disease, measures to prevent exposure, and reservoir control.
Given the past failures, future epidemiologic and ecologic studies will require alternative strategies and enhanced detection assays. Foremost, we need additional and more reliable serologic surveys in humans and animals to pinpoint the areas of Africa where these viruses are endemic. Closer surveillance of affected animal populations, such as the great apes, should be undertaken, as should experimental studies in potential reservoir species that can elucidate the transmission and persistence of these viruses. The testing of sentinel animals, which have been used successfully for surveillance of arbovirus infections, may prove to be superior to the random testing of a variety of African wildlife species. One challenge is that more than one reservoir, and perhaps even amplifying hosts, may be involved in transmission to humans and nonhuman primates. Another challenge will be the difficulty of implementing appropriate projects in the remote areas where the viruses seem to be endemic, especially given the understandable concerns of the local residents, biosafety considerations, and the lack of funding for such endeavors.
The two recent outbreaks of Marburg hemorrhagic fever have had much higher case fatality rates than the initial 1967 outbreak, reaching or even exceeding those associated with the Zaire species of Ebola virus.1 There are currently no convincing data to support the hypothesis that genetic variation among Marburg virus strains would explain the difference in virulence. Thus, survival rates may be more heavily influenced by other factors, including underlying malnutrition, coinfections, and the level of health care available. Intensive care measures were applied in all cases during the 1967 outbreak but not in the more recent outbreaks in the Democratic Republic of the Congo and Angola. Thus, future responses should include enhanced health care combined with early and rapid on-site biochemical and microbiologic laboratory capacities. On-site virologic laboratory support was successfully provided during the Ebola virus outbreak in Uganda and the Marburg virus outbreak in Angola.1
Although there is as yet no licensed treatment or vaccine available for either filovirus infection, discussions should be initiated regarding the potential application of candidate drugs and vaccines that show some efficacy in animal models. The most promising approaches include treatment with anticoagulants (e.g., recombinant nematode anticoagulant protein c2, or rNAPc2,4 though its efficacy has been demonstrated only for Ebola virus), down-regulation of viral replication through the inhibition of viral transcription, and therapeutic antibodies. Therapeutic vaccines also seem promising.5 Combined approaches seem more likely to be successful in slowing disease progression in order to mobilize innate and adaptive immune responses that may be sufficient to overcome infection. The timing of treatment will be critical, because disease progresses quickly and the consequences are severe once viremia reaches a certain threshold.
The fear of bioterrorism has greatly changed societal attitudes toward dangerous infectious pathogens such as Marburg virus. Developed countries have spent a great deal on research, emergency response, and infrastructure, and they will continue supporting efforts to develop countermeasures against biothreat agents. Soon, we should have sufficient infrastructure, in the form of biocontainment facilities, to perform the necessary in vitro and in vivo work with agents such as Marburg and Ebola viruses. Of course, a more even distribution and worldwide coverage of such facilities, especially in or close to areas where known pathogens are endemic and regions that are prone to the emergence or reemergence of infectious diseases, would probably be more effective. But such an expansion would be difficult, if not impossible, to achieve, given the tremendous costs of building, operating, and maintaining facilities with the requisite high level of technology. It is possible that national and international collaborations will help, though even developed countries may encounter problems with maintaining facilities, long-term research funding, and the establishment of a supply of well-trained personnel. Biosecurity and biosafety are acknowledged mandatory components of all current and future operations in high-containment facilities, but we must nevertheless ensure that intensified policies and regulations will not inhibit the essential scientific exchange and collaboration and block the transfer of reference material and diagnostic specimens at the national and international levels.
Source Information
Dr. Feldmann is chief of the Special Pathogens Program at the National Microbiology Laboratory, Public Health Agency of Canada, and an associate professor of medical microbiology at the University of Manitoba — both in Winnipeg, Canada.
References
Towner JS, Khristova ML, Sealy TK, et al. Marburgvirus genomics and association with a large hemorrhagic fever outbreak in Angola. J Virol 2006;80:6497-6516.
Leroy EM, Rouquet P, Formenty P, et al. Multiple Ebola virus transmission events and rapid decline of central African wildlife. Science 2004;303:387-390.
Leroy EM, Kumulungui B, Pourrut X, et al. Fruit bats as reservoirs of Ebola virus. Nature 2005;438:575-576.
Geisbert TW, Hensley LE, Jahrling PB, et al. Treatment of Ebola virus infection with recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys. Lancet 2003;362:1953-1958.
Daddario-DiCaprio KM, Geisbert TW, Stroher U, et al. Postexposure protection against Marburg haemorrhagic fever with recombinant vesicular stomatitis virus vectors in non-human primates: an efficacy assessment. Lancet 2006;367:1399-1404.(Heinz Feldmann, M.D.)
Marburg Hemorrhagic Fever in Africa.
Locations of Marburg hemorrhagic fever outbreaks and cases are indicated by red symbols. The green symbol indicates the source of the African green monkeys (inset) that were shipped to Europe in 1967, bringing Marburg virus with them.
The 1998 outbreak in the Democratic Republic of the Congo represented the first community-based Marburg virus outbreak in Africa. It occurred in an area that was geographically close to previously reported Marburg virus activity, but it was unique among reported filovirus outbreaks in that continuous infections occurred over a period of almost two years. Bausch et al. describe a seasonal pattern to that event, with transmission beginning in October and November and peaking in January and February. Cases occurred first in miners and then spread to their family members and other members of the community.
Unlike most filovirus outbreaks, this one included few nosocomial infections. The case fatality rate of 83 percent was much higher than that reported during the 1967 outbreak (23 percent). In this sense, it was more similar to outbreaks of the most virulent Zaire species of Ebola virus, the better-known cousin of Marburg within the family Filoviridae. Cases were associated with at least nine different genetic lineages of Marburg virus, representing the entire genetic repertoire of previously characterized East African isolates of the Lake Victoria Marburg virus species.1 A similar situation has been reported from the border region between Gabon and the Republic of the Congo, where multiple genetic lineages of the Zaire species of Ebola virus cocirculate, causing smaller outbreaks of viral hemorrhagic fever mainly in hunting communities.2 By contrast, filovirus sequences derived from patients involved in a distinct chain of epidemic transmission have generally been shown to be highly conserved within an outbreak.1
Marburg virus surprised everyone with its recent emergence in northern Angola, where most experts would have expected Ebola virus to be more likely to arise (see map).1 The Angolan outbreak represents the first appearance of Marburg virus in western Africa and is the largest outbreak to date. It was probably caused by a single introduction of the virus, just as the previously reported Ebola virus outbreaks have usually started with a single index patient, who transmitted the virus to family and community members, and have then been amplified in hospital settings. The Angolan outbreak, however, involved many cases in children, whereas such infections in children were previously considered extremely rare. In addition, there seemed to be a short incubation period in many cases, and the case fatality rate was even higher than that during the 1998–2000 outbreak in the Democratic Republic of the Congo.1
With the exception of the Reston species of Ebola virus found in the Philippines, the Marburg and Ebola viruses seem to be endemic in Central African countries (see map).1 Outbreaks remain unpredictable, in part because the reservoir of these presumed zoonotic pathogens remains mysterious. However, we may be one step closer to solving the mystery after a recent report described evidence of Ebola virus infection in three distinct species of fruit bats whose geographic distribution covers most of the areas where human outbreaks of Ebola and Marburg viruses have occurred.3 Bats had already been implicated as sources of infection in index cases in previous filovirus outbreaks, including the outbreak of Marburg hemorrhagic fever in the Democratic Republic of the Congo. It was further demonstrated that experimentally infected wild African fruit and insectivorous bats support replication and circulation of Ebola virus without becoming symptomatic. It remains unexplained, however, why researchers have not yet been able to isolate the virus from wild bats, given the relative ease of isolating filoviruses from human specimens. The definitive identification of the reservoir and determination of the route of transmission from the reservoir to humans or nonhuman primates (the other susceptible hosts) remain high priorities for public health professionals, who would like to respond with travel advisories or restrictions, education of residents of areas of endemic disease, measures to prevent exposure, and reservoir control.
Given the past failures, future epidemiologic and ecologic studies will require alternative strategies and enhanced detection assays. Foremost, we need additional and more reliable serologic surveys in humans and animals to pinpoint the areas of Africa where these viruses are endemic. Closer surveillance of affected animal populations, such as the great apes, should be undertaken, as should experimental studies in potential reservoir species that can elucidate the transmission and persistence of these viruses. The testing of sentinel animals, which have been used successfully for surveillance of arbovirus infections, may prove to be superior to the random testing of a variety of African wildlife species. One challenge is that more than one reservoir, and perhaps even amplifying hosts, may be involved in transmission to humans and nonhuman primates. Another challenge will be the difficulty of implementing appropriate projects in the remote areas where the viruses seem to be endemic, especially given the understandable concerns of the local residents, biosafety considerations, and the lack of funding for such endeavors.
The two recent outbreaks of Marburg hemorrhagic fever have had much higher case fatality rates than the initial 1967 outbreak, reaching or even exceeding those associated with the Zaire species of Ebola virus.1 There are currently no convincing data to support the hypothesis that genetic variation among Marburg virus strains would explain the difference in virulence. Thus, survival rates may be more heavily influenced by other factors, including underlying malnutrition, coinfections, and the level of health care available. Intensive care measures were applied in all cases during the 1967 outbreak but not in the more recent outbreaks in the Democratic Republic of the Congo and Angola. Thus, future responses should include enhanced health care combined with early and rapid on-site biochemical and microbiologic laboratory capacities. On-site virologic laboratory support was successfully provided during the Ebola virus outbreak in Uganda and the Marburg virus outbreak in Angola.1
Although there is as yet no licensed treatment or vaccine available for either filovirus infection, discussions should be initiated regarding the potential application of candidate drugs and vaccines that show some efficacy in animal models. The most promising approaches include treatment with anticoagulants (e.g., recombinant nematode anticoagulant protein c2, or rNAPc2,4 though its efficacy has been demonstrated only for Ebola virus), down-regulation of viral replication through the inhibition of viral transcription, and therapeutic antibodies. Therapeutic vaccines also seem promising.5 Combined approaches seem more likely to be successful in slowing disease progression in order to mobilize innate and adaptive immune responses that may be sufficient to overcome infection. The timing of treatment will be critical, because disease progresses quickly and the consequences are severe once viremia reaches a certain threshold.
The fear of bioterrorism has greatly changed societal attitudes toward dangerous infectious pathogens such as Marburg virus. Developed countries have spent a great deal on research, emergency response, and infrastructure, and they will continue supporting efforts to develop countermeasures against biothreat agents. Soon, we should have sufficient infrastructure, in the form of biocontainment facilities, to perform the necessary in vitro and in vivo work with agents such as Marburg and Ebola viruses. Of course, a more even distribution and worldwide coverage of such facilities, especially in or close to areas where known pathogens are endemic and regions that are prone to the emergence or reemergence of infectious diseases, would probably be more effective. But such an expansion would be difficult, if not impossible, to achieve, given the tremendous costs of building, operating, and maintaining facilities with the requisite high level of technology. It is possible that national and international collaborations will help, though even developed countries may encounter problems with maintaining facilities, long-term research funding, and the establishment of a supply of well-trained personnel. Biosecurity and biosafety are acknowledged mandatory components of all current and future operations in high-containment facilities, but we must nevertheless ensure that intensified policies and regulations will not inhibit the essential scientific exchange and collaboration and block the transfer of reference material and diagnostic specimens at the national and international levels.
Source Information
Dr. Feldmann is chief of the Special Pathogens Program at the National Microbiology Laboratory, Public Health Agency of Canada, and an associate professor of medical microbiology at the University of Manitoba — both in Winnipeg, Canada.
References
Towner JS, Khristova ML, Sealy TK, et al. Marburgvirus genomics and association with a large hemorrhagic fever outbreak in Angola. J Virol 2006;80:6497-6516.
Leroy EM, Rouquet P, Formenty P, et al. Multiple Ebola virus transmission events and rapid decline of central African wildlife. Science 2004;303:387-390.
Leroy EM, Kumulungui B, Pourrut X, et al. Fruit bats as reservoirs of Ebola virus. Nature 2005;438:575-576.
Geisbert TW, Hensley LE, Jahrling PB, et al. Treatment of Ebola virus infection with recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys. Lancet 2003;362:1953-1958.
Daddario-DiCaprio KM, Geisbert TW, Stroher U, et al. Postexposure protection against Marburg haemorrhagic fever with recombinant vesicular stomatitis virus vectors in non-human primates: an efficacy assessment. Lancet 2006;367:1399-1404.(Heinz Feldmann, M.D.)