Introduction

Viral hemorrhagic fevers (VHF) present as nonspecific febrile illnesses in those who have visited or are from endemic areas. Viral hemorrhagic fevers are characterized by fever, rash, and sore throat. Patients can also present with headaches, nausea, vomiting, diarrhea, cough, and myalgia. Patients may then in severe cases develop hepatitis, encephalopathy, and hemorrhage. This febrile illness can progress to severe hemorrhagic manifestations secondary to endothelial damage, coagulopathy, platelet loss, platelet dysfunction, and potentially death [7, 8]. Several of the viral hemorrhagic fevers are capable of human to human transmission. Due to the nonspecific generalized initial presentation it is essential that as medical practitioners we remain vigilant to VHF as a public health threat and potential differential diagnosis in those with epidemiological risk factors and suggestive clinical presentations.

Transmission of VHF is via infected blood or bodily fluid coming into contact with mucous membranes or broken skin. Transmission can also be vector borne via mosquitoes (Rift Valley fever) or via ticks (Congo – Crimean hemorrhagic fever/Omsk hemorrhagic fever, Kyasanur forest disease, and Alkhurma viruses) [9]. Transmission can also be via zoonotic spread including contact with infected animal carcasses or ingestion of infected meat or unpasteurized milk. Infection can occur after contact with infected animal reservoirs or their excreta (rats). VHFs are largely zoonotic with accidental human transmission, this limits their transmission in humans to those who are endemic to high risk areas or who have visited the area. This can then be specified further to epidemiological risk within the last 21 days because of their limited incubation periods.

VHFs are caused by enveloped RNA viruses and fall within several families; Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae (Table 1)

Table 1 Viral hemorrhagic fever viruses
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Filoviruses

There are 2 viruses in this family which cause VHF, Ebola virus, and Marburg virus. Filoviruses are elongated filament like structures. They are nonsegmented negative stranded RNA enveloped viruses that have a genome length of 19 kb [10]. This morphology make them stable and highly infectious [7]. There is no proven animal reservoir, however, great apes and a variety of species of fruit bats have been shown to harbor the virus. It is postulated that fruit bat migration may contribute to disease propogation [11].

Marburg virus was first identified in 1967 in African green monkeys that subsequently transmitted the infection to close human contacts. Since then Marburg infection has occurred in Kenya and Zimbabwe. Marburg infection has a mortality rate of approximately 25 % [7].

Ebola virus was identified in 1976. Fatality rates differ between the different subtypes of Ebola infection. There are 5 sub-types Zaire, Sudan, Cote d’Ivoire, and most recently Bundibugyo. Zaire Ebola virus has a significant mortality rate of 90 % [12]. Sudan VHF has a case fatality rate of 50 % [1•], and Bugdibugyo has a case fatality rate of 40 % [12].

Travel to endemic regions, contact with infected monkeys or known human cases, and presentation with macular-papular rash may be suggestive of filovirus related VHF [7].

Filovirus is usually diagnosed clinically. Confirmation can be sought in the form of reverse transcriptase polymerase chain reaction (PCR) or serology. Antigen detection via indirect immune-fluorescence is a first-line test. These tests can be performed on radiation/ chemically inactivated samples. Specimens are sent to National or International reference laboratories for processing. Electron microscopy is rarely used, as it is insensitive and expensive. Virus culture is rarely used in practice as it is slow and requires significant levels of viremia, and required viable highly infectious virus [8, 10].

Treatment

Specific treatment against Filovirus VHF is not available. Treatment is largely supportive. Supportive care delivered by MSF and the minister of Health in affected areas includes oral rehydration solution, nutritional support, psycho-social support, anti-emetics, dyspeptics, anti-anxiolytics, analgesia, and consideration of appropriate anti-biotic or anti-malarial regimes [13•]. With increasing confidence with personal protective equipment there is also scope to increase supportive care to include intra-venous goal directed therapies, and provide higher level care monitoring.

Emerging therapies

A large volume of research in Ebola viral hemorrhagic fever suggests promising developments in more specific directed therapy in nonhuman primates, particularly in the field of viral replication inhibition. Studies have found significant protective benefits in rhesus macaques treated with pooled anti-Ebola virus small interference RNAs within 30 min of exposure and then at day 1, 2, 3, 4, 5, and 6 [14]. This protective effect was also witnessed in a further study examining MB003 Monoclonal Antibody cocktail following Ebola virus challenge [15]. Positively charged phosphorodiamidate morpholino poligomers (PMO plus) given within 30–60 min of Filo virus exposure was also found to be protective [16]. Although promising research, this is likely to be of limited value in clinical practice as the majority of patients are unaware at the time of exposure and may not have immediate access to this level of health care.

Disease modifying agents including recombinant activated Protein C as postexposure prophylaxis in filovirus VHF has had very limited success. Despite an exaggerated inflammatory response and disseminated intra-vascular coagulopathy, disease-modifying agents have not been shown to be effective in non-human primate models [13•].

Vaccination

Live attenuated recombinant vesicular stomatitis virus vaccine vector was also found to have good levels of protection against Marburg hemorrhagic fever in nonhuman primates when given up to 24 h after exposure and protection levels of 33 % if given 48 h after exposure [17].

Arenaviruses

Arenaviruses are grouped into old world and new world. Lassa hemorrhagic fever is an old world virus detected in Nigeria in 1963. New World hemorrhagic fevers include Junín from Argentina isolated in 1958, Machupo from Bolivia isolated in 1963, and more recently Guanarito, Sabia, Chaparo, and Liyo as part of the Tacaribe complex of South American hemorrhagic fevers [7]. Arenaviruses are positive single stranded cubic RNA viruses. They have a genome length of 11–12 kb [8]. They are zoonotic. The natural reservoir of this infection is largely rodents and can also include voles and gerbils. Mastomys natalensis is associated with Lassa VHF. Lassa causes hundreds of thousands of infections per year with high mortality rates amongst those hospitalized [18], and approximately 5000 deaths per year in West Africa [1•].

Transmission of arenavirus requires contact with contaminated material or excreta from chronically infected animal reservoir. This can happen via ingestion, mucosal exposure, or broken skin. Lassa VF, Machupo, and Liyo are also capable of person to person transmission and hence nosocomial transmission [19].

Lassa VHF may also present as a non-specific febrile illness, however, certain clinical signs are of significance. One-third of patients presenting will have clinical evidence of conjunctivitis. Two-thirds of patients may have evidence of pharyngitis and 15 %–20 % will have hemorrhage at presentation [1•].

Arenaviruses can be isolated from blood, throat swabs, breast milk, cerebrospinal fluid (CSF), urine, or tissue. Due to the infectivity of this virus, culture is rarely performed, as it required viable virus and high security laboratory facilities [8]. Enzyme linked immuno-fluorescence assays are very useful in diagnosis. PCR also has a high sensitivity [8].

Treatment

Ribavirin is the only anti-viral therapy that has been used successfully to treat Lassa fever. As a guanosine analogue it directly inhibits RNA dependent RNA polymerases, host inosine monophosphate dehydrogenase, and viral capping enzymes. It also modulates host immune response [1•]. Increased Aspartate aminotransferase (>150 iu/L at Lassa VHF presentation) is associated with an increased case fatality rate of approximately 55 %, this is reduced to 5 % if treated with Ribavirin and continues to have a protective effect to a lesser extent if commenced up to 6 days after exposure [2]. Viraemia >103.6/mL is also associated with increased mortality in Lassa fever (76 %), this is reduced to 6 % with Ribavirin therapy [2]. As a postexposure prophylaxis, Ribavirin is only efficacious via intravenous or intramuscular routes in animal models. This limitation and the significant side effect profile of ribavirin means that published research would only recommend its use in definitive high-risk exposures [1•] (Table 2).

Table 2 Ribavirin side effects
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Supportive care is also very important in Arenavirus VHF, this should include close observation, review of electrolyte disturbances, fluid balance, and respiratory support. Caution is needed with fluid replacement, necessitating careful fluid balance assessment [1•].

Emerging therapies

Newer data looking at cell models in Lassa fever has also suggested combination of site 1 protease inhibitor and Ribavirin may have a greater than additive effect in successful treatment of Lassa fever, as it aids specific blocking of viral spread and production [20]. Site-1 protease inhibitor and protease subtilisin kexin isozyme-1 inhibitor prevent glycoprotein precursor production, therefore, preventing viral envelope formation and subsequent viral replication [21].

Administration of Lassa convalescent plasma has not been shown to be effective in reducing mortality in Lassa VHF [2].

Bunyaviridae

Bunyaviruses are icosahedral enveloped negative single stranded RNA viruses [8]. They have a genome length of between 10 and 22.7 kb. Within the Bunyavirus family Nairovirus, Crimean Congo hemorrhagic fever and Hantavirus cause hemorrhagic fevers.

Crimean Congo hemorrhagic fever occurs in a large geographical area. Its distribution corresponds to the Hyalomma tick [8]. Transmission is via tick bite, inoculation from crushed infected ticks, or contact with infected animals (cattle or sheep) [7]. Human to human transmission can also occur. Clinical infection causes coagulopathy, thrombocytopenia, bleeding, and shock. Mortality can range from 20 % to 50 % [7].

Hantaviruses are zoonotic viruses. Transmission occurs due to contact with, or aerosolization of rodent urine. Hanta virus can cause hemorrhagic fever in association with renal syndrome.

Rift valley fever virus is a phlebovirus of the Bunyavirus family. The virus infects sheep, cattle, buffalo, and rodents, amplifying infection. The Aedes mosquito acts as a capable vector [7, 8].

Bunyaviruses are Arboviruses. These viruses can be isolated from blood, cerebrospinal fluid (CSF), and tissue. Polymerase chain reaction (PCR) and indirect immune-fluorescence serology testing methods are the primary testing modalities [8].

Treatment

Crimean Congo hemorrhagic fever

At present there is no FDA approved anti-viral treatment for the treatment of Crimean Congo Hemorrhagic Fever. Ribavirin has demonstrated efficacy in-vitro, however, its use in clinical settings has not been fully evaluated [22]. Some observational studies have suggested that Ribavirin is useful in reducing mortality, and the use of corticosteroids has also been found to be beneficial in patients with severe disease [3]. Further case control studies have not consolidated this data, and have suggested that there is no protective effect with Ribavirin [23, 24].

WHO recommendations include the use of Ribavirin in CCHF, although WHO and CDC recommendations acknowledge this evidence basis is in-vitro rather than in clinical settings [25, 26].

Hanta virus

Ribavirin has been shown to be effective in the treatment of Hanta virus in in-vitro data and animal models [4•]. A double blinded randomized control trial study has also demonstrated a significant effect on morbidity and mortality associated with Hanta virus [5]. No data currently exists on the use of Ribavirin as postexposure prophylaxis.

Aggressive advanced life support has been shown to be beneficial in VHF. The need for strict isolation and infection control has in part prevented the implementation of this particularly in resource poor settings. The use of corticosteroids, hemodialysis, mechanical ventilation, inotropic support, and extracorporeal membrane oxygenation has been shown to reduce morbidity and improve survival in Hanta virus [27].

Favipiravir has been shown to reduce Hanta viremia postexposure in animal models [28].

The use of corticosteroids as part of aggressive advanced life support measures in the treatment of Hanta virus has been shown to reduce morbidity and improve survival [27].

Rift Valley fever

Ribavirin has also been shown to reduce viremia and mortality postexposure to Rift valley fever virus in in-vitro and animal models [6].

Favipiravir has been shown in vitro and in animal models to reduce viremia and reduce mortality postexposure to rift valley fever virus. This benefit appears to be intensified by the combination of Favipiravir with Ribavirin [6].

Vaccination

At present no vaccine is widely available for Crimean-Congo hemorrhagic fever animal or human disease prevention.

Deoxyribonucleic acid (DNA) based vaccines have been developed against Hanta virus strains. Although this vaccine is not currently available, preclinical experimental studies suggest it is a promising development [8].

Experimental live and killed vaccines are in development for Rift Valley Fever. Livestock vaccination has shown good levels of immunity and safety data, but no vaccine is currently widely available for human disease prevention [8].

Flaviviruses

Flaviviruses are positive single stranded cubic RNA viruses comprising of 3 structural proteins; a small core protein, a membrane protein, and an envelope protein [8]. They have a genome length of 10–11 kb. Flaviviruses are known to cause viral hemorrhagic fevers include Yellow fever, Dengue hemorrhagic fever, Omsk hemorrhagic fever and Kyasanur forest disease.

The Aedes mosquito transmits yellow fever. Transmission via infected mosquito can occur from human to human (urban cycle) or from infected monkey to human. (sylvatic cycle) [7]. Mortality can be as high as 50 % in some affected areas. Treatment is largely supportive, and strict infection control measures are required in areas with Aedes mosquitoes to prevent onward transmission

Dengue hemorrhagic fever (DHF) is also transmitted via the Aedes mosquito. Dengue hemorrhagic fever also used to display a sylvatic cycle however over time it has evolved to involve humans as reservoir and host [8]. Four distinct serotypes of Dengue virus exist. Infection with a second serotype at a later date is associated with increased risk of hemorrhagic complications and, therefore, occurs more commonly in people living in endemic areas rather than visitors. Mortality in untreated DHF can reach 50 %, however, this is reduced to <1 % with aggressive goal directed supportive treatment [7].

Omsk hemorrhagic fever

Omsk hemorrhagic fever is transmitted via ticks (Dermacentor reticulates) or by contact with infected muskrats. Infected muskrats have been responsible for outbreaks in Russia.

Kyasanur Forest disease

Kyasanur forest disease is also transmitted via ticks and is limited to Karnataka regions in India. Case fatality rates can be 5 %–10 % [7].

Flaviviruses can be isolated from blood, CSF, and tissue. PCR, and indirect immune-fluorescence serology testing methods are the primary testing modalities.

Treatment

There is no specific anti-viral treatment for yellow fever. Treatment is supportive.

Case series studies have suggested that cortico-steroids reduce morbidity and mortality associated with severe Dengue hemorrhagic fever multi-organ failure [29].

Case series studies state that the use of human intravenous immunoglobulin reduced morbidity and mortality associated with severe Dengue hemorrhagic fever when in association with multi-organ failure [29].

No specific anti-viral is currently licensed for the treatment of Omsk hemorrhagic fever therefore treatment is largely supportive.

No specific anti-viral regime is currently recommended in Kyasanur forest disease. This means treatment is again supportive.

Emerging therapies

Currently, there is no recommended anti-viral therapy available in Yellow fever. Animal models suggest using alpha interferon with adenovirus vector may be protective as prophylaxis and as postexposure prophylaxis but has been trialed only in animal models and in a limited time frame of 48 h postexposure [30]. Humanized monoclonal antibody has also been shown in mouse studies to reduce mortality when given hours postexposure [31]. In the clinical setting, this is likely to be of limited value as very few patients will be aware of their exposure and good vaccine protection is available. This may be more relevant to research laboratory exposure.

Vaccines

The 17D Yellow fever vaccine is highly effective and can offer 95 % protection [7].

Formalin inactivated tissue culture vaccine against Kayasanur Forest disease is available in the affected region. Uptake, however, is low (less than 50 %) and efficacy of the vaccine is 82.9 % only after 2 scheduled doses and a booster dose [32]. No vaccine is currently available against DHF.

Although no specific vaccine against Omsk hemorrhagic fever exists animal model studies suggest 100 % protection from the commercial Tick borne encephalitis vaccine [33].

Prevention

Medcin sans frontiers (MSF) and World Health Organization experience would suggest addressing the issue of filovirus VHF as a public health threat in endemic areas, we requires highly sensitive surveillance in parallel with specific rapid diagnostic equipment to enable prompt isolation and contact tracing, and prevent further transmission [12]. In this situation, prevention is a key priority.

WHO recommendations suggest that avoiding tick contact and increasing precautions to reduce risk of transmission from infected animals or humans is imperative in using prevention as means of control in Crimean- Congo hemorrhagic fever [25]. Vector and animal reservoir control is also imperative in other VHFs. However, the lifecycle and breeding environment of some of these vectors, notably the Aedes mosquito provide a constant challenge in this regard.

The nature of VHF and the route of transmission pose a risk of transmission within the Hospital environment. In the UK there have been no ward based documented cases of VHF transmission and only 1 case of transmission in a laboratory worker following a needle stick injury [34•]. Compliance with infection control procedures and isolation are paramount for staff protection and transmission reduction.

In 1981, The Advisory Committee on Dangerous Pathogens in the UK was established. Their role was to provide independent advice on safety measures and health protection protocols for staff members involved in the treatment of VHF. This documentation has been progressively developed to include advice about patient risk stratification, management, personal protective equipment, isolation, and laboratory procedures [34•]. Prompt diagnosis is essential to ensure isolation and follow-up of case contacts [12].

Efforts to implement isolation and infection control strategies in high-risk rural areas of Sub Saharan Africa has been reported to be hampered by lack of communication and, therefore, understanding from local population groups. Lack of adequate isolation facilities and staff protection measures have also in part limited the implementation of aggressive goal directed supportive care. Communication with affected population groups, inclusion of local leaders, and respected community figures and more intensive supportive therapy is needed to improve mortality associated with this severe and rapidly fatal disease. More research and greater evidence base is required to address further treatment options. At a time where tropical travel is increasing and there is greater communication with human and animal eco-systems, viral hemorrhagic fever poses an ever-increasing public health threat. It is imperative that viral hemorrhagic fever is not neglected at this time