The viral hemorrhagic fevers are febrile illnesses accompanied by abnormal vascular regulation and vascular damage caused by members of the Arenaviridae, Filoviridae, Bunyaviridae, and Flaviviridae families of viruses. Found in diverse areas of the world, hemorrhagic fever viruses are potentially present in anyone who steps off a plane from an endemic area. Although the high mortality and exceptional epidemics of viral hemorrhagic fevers have been well publicized, neurologic aspects of these diseases are less familiar. Neurologic complications occur in many of the viral hemorrhagic fevers, and the CNS diseases are not simple reflections of what has started in the periphery. Some viral hemorrhagic fevers present as pure neurologic illness.
In this article, the dark history, role in human experimentation, global ecology and epidemiology, clinical and neurologic aspects, and treatment and prevention of viral hemorrhagic fevers are presented. Travel-acquired viral hemorrhagic fever cases and the widening geographic home range, including the United States, of important human and veterinary viruses and vectors are updated. There was prolonged maintenance (across 2 years) of dengue infections in A aegypti mosquitoes in Florida in the absence of an index human case and the first detection in the United States of indigenous Asian tick vectors of severe fever with thrombocytopenia syndrome (bunya) virus (SFTSV). The largest Ebola epidemic, the West African epidemic, declared in December 2013 and over in June 2016, has been reported with attention to characterization of encephalitis cases, evidence of persistent infection that includes the CNS, transmission risk from men and women long after recovery, and descriptions of Ebola and post-Ebola syndromes with neurologic manifestations. Guinea’s newest Ebola epidemic, declared Feb 14, 2021 and believed to have started with sexual transmission by someone who was probably infected 5 to 7 years ago (179; 291), extends the meaning of viral persistence and recrudescence in immune privileged sanctuary sites. The clinical research agenda, drug and vaccine pipeline, and vaccine use carried forward into the current 2018 to 2021 Ebola epidemics in the Democratic Republic of Congo are presented. WHO and FDA approvals for Ebola vaccines and recommendations for use of the first universal (types 1 to 4) dengue vaccine are updated.
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• Most of the viral hemorrhagic fever agents cause severe, life-threatening disease, and most of these viruses are handled in Biosafety Level 4 (BSL4) containment facilities. Awareness and diagnosis of the viral hemorrhagic fevers is increasingly relevant for all countries.
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• Excepting agents requiring mosquito intermediates, all other agents have a degree of aerosol infectivity. Body fluids should be considered infectious.
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• There is no cure or established drug treatment for many of the viral hemorrhagic fevers. The exceptions are hyperimmune globulin for Argentinian hemorrhagic fever and ribavirin for Lassa fever, Crimean-Congo hemorrhagic fever, Argentinian hemorrhagic fever, and severe fever with thrombocytopenia syndrome.
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• Categories of investigational drugs include nucleoside and nucleotide analogues, nucleic acid-based drugs, and immunotherapeutics. Several investigational drugs (ZMapp, Brincidofovir, TKM-Ebola, Favipiravir, AVI-7537, BCX4430, GS-5734) and blood transfusion of convalescent plasma from recovered patients were used to treat Ebola patients during the 2013 to 2016 West African outbreak. In the Democratic Republic of Congo in 2019, antibody-based therapies MAb114 or REGN-EB3 were shown superior to ZMapp or remdesivir (the nucleotide analogue GS-5734) in reducing Ebola virus mortality.
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• Merck’s rVSV-ZEBOV vaccine (now Ervebo) has been licensed. Ad26.ZEBOV/MVA-BN-Filo is available under investigational protocols to be used outside of outbreak zones as preventive vaccine in lower-risk, not-yet-exposed groups.
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• The 2009 WHO case classification for severe dengue has been broadened to include CNS involvement, and dengue has been identified in 4% to 47% of hospitalized patients with encephalitis-like illness in endemic areas.
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• Within the next few years, dengue and Chikungunya may become the main causes of encephalitis worldwide due to increasing numbers of infected individuals. Coinfection of dengue with other agents may promote emergence of complicated cases, especially neurologic cases.
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• A universal vaccine that includes all 4 serotypes of dengue, Dengvaxia (Sanofi-Pasteur CYD-TDV), is licensed with an indication for use in individuals aged 9 years and older, the (9-16 years) age group that would benefit most from the vaccine.
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•Coinfection of dengue with other agents may promote emergence of complicated cases, especially neurologic cases.
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• In areas of dengue and Zika virus cocirculation, a complex relation between dengue and Zika virus antibodies is recognized and studied. Cross-reacting antibodies to dengue can yield false-positive serology for Zika and cross-reactivity has the potential to be either immune-protective or be associated with aggravated forms of disease.
Historical note and terminology
Viral hemorrhagic fevers are febrile illnesses with abnormal vascular regulation and vascular damage. The combination of fever and hemorrhage can be caused by a number of human pathogens: viruses, rickettsiae, bacteria, protozoa, and fungi. However, the term hemorrhagic fever usually refers to a group of illnesses that are caused by 4 different families of viruses: Arenaviridae, Filoviridae, Bunyaviridae, and Flaviviridae. All viral hemorrhagic fever viruses are lipid-enveloped RNA viruses that persist in nature in an animal or insect host. Except for some viruses in the Flaviviridae family, humans are not normally the natural reservoirs but become infected after contact with infected vectors or natural hosts, usually arthropods or rodents. For some viruses, accidental infection of humans may be followed by human-to-human transmission. The viruses are geographically restricted to areas where the natural hosts live, usually rural areas but occasionally urban cities. Modern transportation can export viremic individuals, infectious host species, or vectors to any location.
Except for the dengue viruses, yellow fever virus, and Chikungunya (Togaviridae family, genus Alphavirus) that require a mosquito intermediate, all of the other agents have a degree of aerosol infectivity. Because of the manner of infection, high virulence, and associated high mortality, these viruses are handled in biocontainment level 4 laboratories and facilities.
Epidemic hemorrhagic fever, a possible manifestation of hantavirus infection, may have existed in China as early as 960 CE (Common Era) (133). In early China, there were also descriptions of a dengue-like disease called “water poison,” because of its linkage with water-associated flying insects and fever, rash, arthralgia, myalgia, and hemorrhage, in Chinese literature from the Chin (CE 265-420), Tang (CE 610), and Northern Sung (CE 992) dynasties (122). Other diseases known before modern understanding of pathogens and transmission were named after appearances of the afflicted or sites of epidemics. For example, “yellow fever” applied to jaundiced individuals. “Dengue” was a Spanish attempt at the Swahili phrase “ki denga pepo,” translated as “cramp-like seizure caused by an evil spirit” during a Caribbean outbreak in 1827 (12). The naming of diseases after the location of first encounter yielded the geographic eponyms of Ebola (Ebola River, Zaire 1976), Marburg (Marburg, Germany 1967), Lassa fever (Lassa, Nigeria 1969), as well as Argentine, Bolivian, Rift Valley, Crimean-Congo, Kyasanur Forest, Omsk, Hantaan, Seoul, or Korean hemorrhagic fever.
Hantaviruses have an interesting and dark history. Records of outbreaks of fever, hemorrhage, and severe renal disease occurring in spring and early summer and again in fall starting in 1913 were retrieved from the archives of a hospital in Vladivostok (52). The Russian and Japanese medical workers who encountered these sporadic epidemic hemorrhagic fever cases in the early 1900s went on to develop a practical working knowledge of the disease. Russian workers produced the Far Eastern disease in humans by parenteral injection of bacteria-filtered serum and urine from patients with natural disease. Experimental subjects were hospitalized, and psychiatric patients required pyrogenic therapy (107). A Japanese group working in Manchuria between 1938 and 1945 also isolated a filterable agent from field rodents and reproduced the disease. The sudden close of World War II interrupted the group’s work and their transmissible agent was lost at the time of surrender (144). In Scandinavia in the 1930s, an acute renal disease was seen, similar to hemorrhagic fever described in the Far East. Sixty Finnish and 1000 German frontline troops in Lapland had nephropathia epidemica (Puumala virus) in 1942 (181). Over 3000 United Nations soldiers serving in Korea between 1950 and 1953 contracted Korean hemorrhagic fever (189). Today, hantaviruses, agents well adapted in nature to a number of common rodents, are becoming a worldwide problem. Actual human cases or seropositive rodents have been found on every continent except Antarctica, so that the potential for Hantaan human disease exists in any area of the world where rodent-human contact is common (188; 187).
During World War II, many countries on both sides examined various pathogens for their potential as biological weapons. These included anti-crop and anti-animal pathogens such as Rift Valley fever virus, in addition to human pathogens. In the United States, research on Rift Valley fever virus continued during the Cold War, and ended when the U.S. signed the Biological Weapons Convention agreement in 1972 (218).
Viral hemorrhagic fevers can cause neurologic disease. Neurologic complications independent of (ie, not directly linked to) metabolic or hemorrhagic complications have been recognized and reported for members of every viral hemorrhagic fever family. Lassa, Argentine hemorrhagic fever, Marburg, hantavirus, Puumala virus, Rift Valley fever, and dengue virus infections have neurologic manifestations or sequelae. Although the neurologic illness may be overshadowed by systemic or hemorrhagic illness, CNS disease is not a simple reflection of what has started in the periphery. Notably, South American hemorrhagic fever and Rift Valley fever may cause encephalitic disease without the hemorrhagic fever (399). Similarly, dengue virus CNS disease may occur without hematologic or hemorrhagic findings (178; 193), or encephalitic disease may occur even without signs of systemic disease (292).
Importantly, the viral hemorrhagic fevers are prime examples of viral emergence in recent history. Work on viral hemorrhagic fevers represents much of the pioneering work identifying factors that shape viral emergence: factors such as human behavior, dimensions of human-animal and human-wildlife interface, demographics, economic development, land use, technology and industry, international trade and travel, microbial adaptation and change, and global warming (185; 229; 132; 21).
Today, some of the most innovative work in structure-based antiviral drug design is in viral hemorrhagic fever laboratories. As with ribavirin, a promising agent against 1 or more viral hemorrhagic fevers may become a successful broad-spectrum antiviral of the future against multiple classes of viruses. However, a caveat is that fever is 1 of the critical clinical features in viral hemorrhagic fevers. Thus, antiviral drugs developed for treatment and based on the crystal structure of a protein prepared from normal body temperature may not fit perfectly in the target space of a protein at fever temperature. This may potentially induce a more virulent virus through viral gene mutation.
Work on the viral hemorrhagic fevers has also yielded critical recommendations for medical staff safety when implementing and maintaining viral containment measures (58). Looking back on the outbreaks, we find the effective use of nonpharmaceutical barrier nursing measures mitigated the impact of epidemics. Because epidemics may begin in resource-limited settings, lessons from the early Marburg, Ebola, and Lassa fever outbreaks can be as relevant today as in the 1960s and 1970s.
Currently, an estimated 49% of emerging viruses are characterized by encephalitis or serious neurologic clinical symptoms (256). The world is a small place, with constant reminders of the need for greater international monitoring of new viruses, increased investigating of virus ecology and policing of points of potential spillover to humans, and a broader understanding of basic viral and host factors. The viral hemorrhagic fevers outbreak experience helped crystallize these ideas and initiatives. When the viral hemorrhagic fevers emerged, they were brand new or new to man. What was learned from the viral hemorrhagic fevers can prepare us for future outbreaks, particularly management of the explosive outbreaks with high fatality rates, provided we pay attention. The viral hemorrhagic fevers: Crimean-Congo hemorrhagic fever, Ebola, Marburg, Lassa fever, and Rift Valley fever have been placed on World Health Organization’s 2018 blueprint list of priority diseases.