Hemorrhagic Fever Viruses as Biological Weapons

Borio, Luciana; Inglesby, Thomas V.; Peters, C. J.; Schmaljohn, Alan L.; Hughes, James M.; Jahrling, Peter B.; Ksiazek, Thomas G.; Johnson, Karl M.; Meyerhoff, Andrea; O’Toole, Tara; Ascher, Michael S.; Bartlett, John G.; Breman, Joel G.; Eitzen, Edward M.; Hamburg, Margaret A.; Hauer, Jerry; Henderson, Donald A.; Johnson, Richard T.; Kwik, Gigi; Layton, Marci; Lillibridge, Scott R.; Nabel, Gary J.; Osterholm, Michael T.; Perl, Trish M.; Russell, Philip K.; Tonat, Kevin

doi:10.1001/jama.287.18.2391

Cited by 626 publications

(507 citation statements)

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“…The epidemic continued unabated for over 2 years, finally ending in January 2016 with 28,616 cases and 11,301 deaths 3 . In addition to concerns of natural outbreaks in regions of Central and West Africa, filoviruses are known to have been a focus of former biological weapons programmes and have the potential for deliberate misuse 4 . Currently, there are no preventive filovirus vaccines or post-exposure treatments approved for human use.…”

mentioning

confidence: 99%

Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

107

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| The filoviruses -Ebola virus and Marburg virus -cause lethal haemorrhagic fever in humans and non-human primates (NHPs). Filoviruses present a global health threat both as naturally acquired diseases and as potential agents of bioterrorism. In the recent 2013-2016 outbreak of Ebola virus, the most promising therapies for post-exposure use with demonstrated efficacy in the gold-standard NHP models of filovirus disease were unable to show statistically significant protection in patients infected with Ebola virus. This Review briefly discusses these failures and what has been learned from these experiences, and summarizes the current status of post-exposure medical countermeasures in development, including antibodies, small interfering RNA and small molecules. We outline how our current knowledge could be applied to the identification of novel interventions and ways to use interventions more effectively. R E V I E W SNATURE REVIEWS | DRUG DISCOVERY VOLUME 17 | JUNE 2018 | 413 © 2 0 1 8 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d . AstheniaMuscular weakness. MyalgiaMuscular pain. ArthralgiaJoint pain. LeukopeniaA condition of having a low number of circulating leukocytes, including neutrophils, eosinophils, basophils, lymphocytes and monocytes. LymphocytopeniaA condition of having a low number of circulating leukocytes, including natural killer cells, T cells and B cells. ThrombocytopeniaA condition of having a low number of circulating thrombocytes, also known as platelets.and Ebolavirus. The Marburgvirus genus contains a single species, Marburg marburgvirus, which contains two members, Marburg virus (MARV) and Ravn virus (RAVV). The Ebolavirus genus consists of five distinct species: Bundibugyo ebolavirus (BDBV), Reston ebolavirus (RESTV), Sudan ebolavirus (SUDV), Tai Forest ebolavirus (TAFV; previously termed 'Côte d'Ivoire ebolavirus' but more commonly known as 'Ivory Coast ebolavirus') and Zaire ebolavirus (EBOV). MARV, RAVV, BDBV, SUDV and EBOV are important human pathogens, with case fatality rates often up to 90% for MARV, RAVV and EBOV, and around 55% for SUDV 8,10 . On the basis of two small outbreaks in 2007 and 2012, BDBV seems to be the least pathogenic, with a case fatality rate of about 40-48% 11,12 . In 1994, TAFV was associated with a number of deaths in chimpanzees and a single symptomatic but non-lethal human infection in the Republic of Côte d'Ivoire 13,14 . RESTV is lethal for macaques but is not thought to cause disease in humans 15 . An outbreak of RESTV was reported in pigs in the Philippines in 2008; however, it remains uncertain whether the disease observed in the pigs was caused by RESTV or other agents reported to have co-infected the animals 16 . Clinical manifestationsClinical and laboratory signs of disease caused by filovirus infection are nonspecific and usually associated with an incubation period of 2-21 days (mean 4-10 days) 8,17 . Illness begins with an abrupt onset of fever, astheni...

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mentioning

confidence: 99%

Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

107

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“…In addition to cytokine effects on vascular permeability, causes of excessive bleeding can include plummets in platelet numbers, severe liver damage and the activation of tissue factor in monocytes and macrophages 92 . The time from infection to death is generally 1-2 weeks, with some variability depending on the virus and host species, as well as on initial dose 93 . For survivors, recovery is a lengthy process.…”

Section: Box 1 | Filovirus-disease Basicsmentioning

confidence: 99%

“…Currently, no effective therapies are available for human use, not even treatments useful shortly after exposure (and before disease symptoms develop), nor prophylactic measures. However, prospects for such therapies are encouraging, based on various preliminary successes in animal models (reviewed in detail elsewhere 17,66,77,93 ). In brief, these include the possibility of therapy with virus-specific antibodies; mitigation of virus-induced coagulation deficits using recombinant nematode anticoagulant protein c2; antisense compounds or small interfering RNAs to inhibit viral genes; inhibitors of putative specific or nonspecific viral receptors on susceptible cells; interferons; and the possibility of using specific peptides to mitigate adverse consequences of interactions between filoviruses and neutrophils.…”

Section: Box 2 | Therapies For Filovirus Infectionmentioning

confidence: 99%

How Ebola and Marburg viruses battle the immune system

2007

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PantropicTending towards the capacity to infect a wide range of cells and organs. CoagulopathyRefers to a group of conditions of the blood-clotting system in which bleeding is prolonged and excessive. Cell tropismA virus's affinity for or tendency towards preferential infection of certain cells. How Ebola and Marburg viruses battle the immune systemMansour Mohamadzadeh* ‡ , Lieping Chen ‡ , and Alan L. Schmaljohn* Abstract | The filoviruses Ebola and Marburg have emerged in the past decade from relative obscurity to serve now as archetypes for some of the more intriguing and daunting challenges posed by such agents. Public imagination is captured by deadly outbreaks of these viruses and reinforced by the specter of bioterrorism. As research on these agents has accelerated, it has been found increasingly that filoviruses use a combination of familiar and apparently new ways to baffle and battle the immune system. Filoviruses have provided thereby a new lens through which to examine the immune system itself. R E V I E W S Report Documentation PageForm Public reporting burden for the collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden, to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to a penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number.

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“…The incubation period is shorter, and the characteristic rash presents as a dark, dusky erythema followed by petechiae and frank hemorrhage into the skin and GI tract. This form is almost uniformly fatal [64]; death occurs 5 to 6 days after the onset of the rash [62]. This illness could be confused with meningococcemia or acute leukemia.…”

Section: Smallpox (Category A)mentioning

confidence: 99%

“…Within hours or days after initial presentation, the clinical condition rapidly deteriorates, which results from the affinity for the vascular system of the virus. Increased vascular permeability leads to flushing, petechial hemorrhages, mucus membrane hemorrhage, and shock, often with neurological, pulmonary, or hepatic involvement [64].…”

Section: Viral Hemorrhagic Feversmentioning

confidence: 99%

Treatment of Neuroterrorism

Busl

Bleck

2012

Neurotherapeutics

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Bioterrorism is defined as the intentional use of biological, chemical, nuclear, or radiological agents to cause disease, death, or environmental damage. Early recognition of a bioterrorist attack is of utmost importance to minimize casualties and initiate appropriate therapy. The range of agents that could potentially be used as weapons is wide, however, only a few of these agents have all the characteristics making them ideal for that purpose. Many of the chemical and biological weapons can cause neurological symptoms and damage the nervous system in varying degrees. Therefore, preparedness among neurologists is important. The main challenge is to be cognizant of the clinical syndromes and to be able to differentiate diseases caused by bioterrorism from naturally occurring disorders. This review provides an overview of the biological and chemical warfare agents, with a focus on neurological manifestation and an approach to treatment from a perspective of neurological critical care.

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Hemorrhagic Fever Viruses as Biological Weapons

Cited by 626 publications

References 105 publications

Post-exposure treatments for Ebola and Marburg virus infections

Post-exposure treatments for Ebola and Marburg virus infections

How Ebola and Marburg viruses battle the immune system

Treatment of Neuroterrorism

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