Hemorrhagic Fever Viruses

Viruses causing hemorrhagic fever are broadly classified into five families as Arenaviridae, Bunyaviridae, Filoviridae, Flaviviridae & Rhabdoviridae. Some of them like Ebola virus can spread through aerosols and are considered aspotentialbioweapons. Most of them have reservoirs or amplifying hosts like rodents. Some of them are tick-borne and maintain tick-mammaltick cycle while others like dengue & yellow fever are mosquito borne. Human to human transmission has also been reported for some viruses.Those infected manifest with viral prodorme initially & have characteristic hemorrhagic manifestations during the first or second week of illness. They present with leukopenia, deranged coagulation profile and altered liver enzymes. Vaccines are available for a few viruses & ribavirin shows promising results in some cases. Extensive research is being carried for newer therapies for these hemorrhagic fevers which present with periodic epidemics. Prevention of the disease is possible through arthropod control, mosquito nets, barrier nursing & avoidance of close contact with infected people.


Introduction
Hemorrhagic fever (HF) viruses are simple RNA viruses with lipid envelopes. Five families have been recognised. 1

Arena Virus
Arenavirusesare spherical / pleomorphic virions, generally 110-130 nm in diameter. Itsgenome contains single-stranded RNA with 2 segments (both ambisense) measuring 11 kbp. Viral particles contain host ribosomes, which appear as dense granules 20-25 nm in diameter & give viruses "sandy" appearance {Latin word for sand-Arenosos} [3]. About 20 known species are taxonomically divided into Old World & New World (Tacaribe complex) groups [4]. They have associations with rodent hosts & humans become infected when exposed to these rodents or their excreta [5]. Frequent nosocomial transmission has been reported for Lassa fever & Ribavirin has been used for treatment / prophylaxis [6]. An attenuated recombinant vaccine produced protective immune responses in nonhuman primates [7]. Heparin, Vitamin K, coagulation factor replacement & blood transfusions have been effective in lessening / stopping hemorrhage in some cases.

Bunyaviridae
Bunyaviridae contains about 41 different tropical viruses.They areSpherical, lipid membrane-enclosed RNA viruses with glycosylated envelope proteins.Theymeasure between 80 -120 nm [8]. They contain a single negative strand of RNA organized into 3 segments; large, medium & small segments, which code for the virus nucleocapsid, glycoproteins& polymerase proteins, respectively [9]. The glycoproteins determine cell tropism, host pathogenicity & are sites for viral neutralization by antibody [10]. Factors associated with human disease are medium segmentencoded polyproteins that contain a mucin-like domain & a furin cleavage site [11], which have been implicated in causing endothelial damage, cellular cytotoxicity& interferon antagonism [12]. They exert a direct effect on host gene regulation during infection, as evidenced by the hantaviruses' ability to suppress cellular interferon responses [13].

Hantavirus
More than 20 genotypes of genus Hantavirus are maintained in the environment by specific rodent species [14]. Specific viruses include Hantaan, Puumala, Seoul, Dobrava Belgrade & Saarema viruses [11]. Theycauses Hemorrhagic fever with renal syndrome. Rodent is the reservoir & human infection occurs through aerosolized rodent urine.

Nairovirus
Nairovirus is enveloped& possesses a tripartite, negative sense, single-stranded RNA genome [8].All 32 members of Nairovirus genus are transmitted by Argasid/Ixodid ticks, but only 3 causehuman disease: Dugbe, Nairobi sheep viruses & Crimean-Congo Haemorrhagic Fever (CCHF). CCHF virus has Tickmammal-tick cycle & humans are infected from tick bite or contact with slaughtered ruminants.A suckling mouse brain, formalin-inactivated vaccine has been used [15]. High-dose corticosteroids, immune globulin intravenous &fresh frozen plasma have been reported to be successful in CCHF [16]. Ribavirin given for postexposure prophylaxis prevents death in CCHF [17].  [24]. In early epidemics, the re-use of non-sterile injections was responsible for many healthcare associated transmissions. The most infectious body fluids are blood, feces & vomitus. Infectious virus has also been detected in urine, semen, saliva, aqueous humor, vaginal fluid & breast milk [25,26,27]. The main confirmatory test for Ebola virus infection is a positive Ebola RT-PCR. ELISA though has high specificityis not universally available. Ebola specific IgM&IgG antibodies are useful in later stages of infection [28].

Phlebovirus
Treatment options under trial include 1) ZMapp-a combination of three humanised monoclonal antibodies targeted at three Ebola virus glycoprotein epitopes [29]; 2) TKM-Ebola -interfering RNAs that target Ebola virus RNA polymerase L [29]; 3) Brincidofovir [30];4)Favipiravir-inhibits viral RNA dependent RNA polymerase [30];5)BCX-4430 -an adenosine inhibits viral RNA dependent RNA polymerase [31];6) AVI-7537 -antisense phosphorodiamidatemorpholino oligomers -targets the Ebola virus VP24 gene [32]. Amiodarone, clomiphene, and chloroquine shown to inhibit Ebola virus interactions with human cells in models [33]. Two experimental vaccines are currently undergoing trials [34]. cAd3-ZEBOV is a chimpanzee derived adenovirus vector with an Ebola virus gene inserted [35]. rVSV-ZEBOV is an attenuated vesicular stomatitis virus with one of its genes replaced by an Ebola virus gene. A Phase I clinical trial for an Ebola DNA vaccine was safe and produced an immune response in humans. Treatment with small interfering RNAs (siRNAs) produced protective immune response in an animal model (guinea pigs) [36]. Novel treatment studies using positively-charged phosphorodiamidatemorpholino oligomers demonstrate protection of monkeys infected with Ebola and Marburg viruses [37]. Studies of high-dose mannose-binding lectin therapy in mice suggest a promising future therapeutic modality for Ebola infection. [38,39].

Flaviviridae
Flaviviridaefamily{Latin word for yellow-flavus} contains more than 70 species [40] out of which 30 are known to cause human disease. They are small (40-50 mm), spherical with a lipid envelope studded with glycoproteins. The flavivirus genome is approximately 11,000 bases long & is made up of 3 structural & 7nonstructural proteins. There are 3 major complexes within this family namely tick-borne encephalitis virus, Japanese encephalitis virus&dengue virus. All flaviviruses have common group epitopes on their envelope protein which result in extensive crossreactions in serologic tests.

Yellow Fever Virus
Yellow fever (YF) is a mosquito-borne (Aedesaegypti) infection. Up to 50% of hemorrhagic-fever-related mortality worldwide can be attributed to YF [44]. Laboratory infections occur through parenteral exposure or aerosols. Vertical transmission from mother to infant & through breastfeeding occurs. A combination of DEET insect repellant (at least 30%) applied to the skin &permethrin insecticide applied to the clothing, both worn during the day, is an important means of preventing bites from mosquitoes carrying DF or YF. Vaccine-Rockefeller Foundation laboratories (New York) developed the 17D live, attenuated, YF vaccine in the 1930s [45], a single dose of which provides nearly complete protection for at least 10 years. A two-dose regimen of XRX-001 induced neutralizing antibodies in a high percentage of subjects [44].

Omsk Hemorrhagic Fever
This viral spread occurs through an unidentified cycle involving ticks, muskrats & voles. Omsk hemorrhagic fever virus can be transmitted through the milk of infected goats or sheep and has been isolated from aquatic animals and water, suggesting that the virus is relatively stable in the environment.

Kyasanur Forest Disease Virus
The virus spreads through Tick-mammal-tick cycle. Rodents, bats& monkeys appear to be amplifying hosts. A formalin inactivated vaccine is licensed for use in endemic areas [46]. Alkhurma HF virus is a variant of Kyasanur Forest disease virus found in Saudi Arabia [47]. Nanjianyin virus was identified in China is again considered a variant of Kyasanur Forest disease virus.

Ribavirin Therapy
Ribavirin is recommended for: (1) suspect or probable cases of VHF ofunknown viral type (2) suspect, probable, or confirmed cases caused by an Arenavirus orBunyavirus. Ribavirin has shown in vitro &in vivo activity against Arenaviruses (Lassa fever, New World hemorrhagic fevers) &Bunyaviruses (Rift Valley fever). It hasshown no activity against &is not recommended for Filoviruses (Ebola & Marburg hemorrhagicfever) or Flaviviruses (Yellow fever, Kyasanur Forest disease, Omsk hemorrhagic fever). Passive immunotherapy with convalescent human plasma has been used& was effective in Argentine HF (Junin) [2].

Disease Prevention
Because many of the hosts that carry HF viruses are rodents, disease prevention efforts include controlling rodent populations,discouraging rodents from entry into homes or workplaces & encouraging safe cleanup of rodent nests &droppings.For HF viruses spread by arthropod vectors, prevention is by community-wide insect &arthropod control. People should use insect repellant, proper clothing, bednets, window screens& other insect barriers to avoid being bitten. For those HF viruses transmitted from one person to another, avoiding close physical contact with infected people & their body fluids is mandatory. Barrier