Untitled

Viral Hemorrhagic Fevers (VHFs) Intro

• VHFs are a group of infections caused by viruses from different families.
• These viruses produce a clinical syndrome of severe, life-threatening diseases.
• VHFs are characterized by febrile illness, bleeding disorders (hemorrhage), and multi-system organ failure.
• The liver is often severely damaged.
• Hemorrhage may or may not occur.
• VHF is a multi-system syndrome marked by diffuse vascular damage.
• VHFs are of public health importance because of their high case fatality rate, the possibility of human-to-human transmission, and the difficulties in diagnosis and treatment.

Causative Agents of VHFs

• VHFs are zoonotic, transmitted to humans by arthropods like ticks and mosquitoes, or contact with infected bats, rodents, and other animals.
• VHFs are caused by 4 ssRNA viral families.
• Arenaviridae viruses are usually associated with rodents e.g. Lassa Fever Virus and South American HF Viruses.
• Bunyaviridae viruses include >300 species and the most important pathogens are Crimean-Congo virus (CCHF) and Hantavirus.
• Rift Valley fever virus (RVFV) is observed in domesticated animals like cattle, buffalo, sheep, goats, and camels.
• Hantavirus is transmitted by rodents, is of two forms, and causes hemorrhagic fever with renal syndrome (HFRS) and Hantavirus Pulmonary Syndrome (HPS).
• Filoviridae viruses include Marburg and Ebola viruses, which cause severe hemorrhagic fever in humans and primates.
• Flaviviridae viruses include enveloped ssRNA viruses, Yellow Fever Virus, and Dengue Fever virus transmitted by mosquitoes and Kyasanur Forest disease virus transmitted by ticks.
• Humans are dead-end hosts for most VHFs, but definitive hosts in urban yellow fever, phlebotomus fever, chikungunya, Zika, and dengue.
• Person-to-person infection may spread through direct contact with an infected patient's blood, secretions and excretions.
• Animal reservoirs typically are rodents, though monkeys, bats and other primates may serve as intermediate hosts.
• These viruses are lethal and could be used for bio-terrorism.

Virology of VHFs

• Dengue fever and Henipavirus infections (Nipah and Hendra virus) are sometimes categorized as VHFs, although bleeding is rare in these infections
• Virus survival depends on an animal or insect host as a natural reservoir
• Viruses are restricted to specific geographic areas, though cases are reported far from endemic regions.

Viral Hemorrhagic Fever Agents

• Arenaviridae (new world/old world) include Junin (Argentine HF), Machupo (Bolivian HF), Guanarito (Venezuelan HF), Sabia (Brazilian HF), Lassa (Lassa Fever), Lujo all occurring in S. America or Africa and are transmitted by Rodents.
• Lassa Fever can be transmitted human to human via body fluids, but the others are not usually.
• Flaviridae includes Yellow Fever, Dengue Fever, Kyasanur Forest Disease, and Omsk HF which are carried by Mosquitoes in the Tropical areas, or Ticks in India or Siberia.
• Yellow fever blood is infective up to the fifth day of illness, The other Viruses are not usually transmittable human to human.
• Bunyaviridae includes Congo-Crimean HF, and Rift Valley Fever which are carried by either Ticks(Crimea, parts of Africa, Europe & Asia) or Mosquitos(Africa), and Hantaviruses (Diverse- Africa, transmitted By Rodents
• CCH Fever-yes, through body fluids; Rift Valley Fever, Hantaviruses – no
• Filoviridae includes Ebola HF and Marburg HF (Africa Virus transported via Fruit bats Body fluid transmission

Arenaviridae Transmission and Epidemiology

• Areanvirus transmission in rodents is both vertical and horizontal
• Arenavirus is shed through urine, feces, and through other body fluids
• Other Human infection method is by contact with rodent excreta, aerosol transmission, Animal contact with abraded skin of human
• Human to human transmission also occurs
• Arenaviruses have a worldwide distribution with ones causing haemorrhagic fevers being largely restricted to Lassa in Africa, or Junin, Machupo, Guanarito, and Sabia in South America.
• Agricultural and domestic exposure are the most common
• Case Fatality is 5-35%
• With Lassa and Machupo explosive nosocomial outbreaks can occur

Arenaviridae In Humans

• Incubation period typically is between 10-14 days
• Disease onset begins with fever and malaise for 2-4 days.
• Most patients of lassa fever virus will recover following this stage but latin America Arena viruses (LAHF) will typically progress to severe stages symptoms
• Severe stages incuding hemorrhagic stage of the disease quickly follows with hemorrhage, leukopenia, thrombocytopenia, Neurologic signs

Filoviridae

• Filoviridae consists of Ebola and Marburg viruses, and is responsible for some of the most lethal VHFs
• The genus Ebolavirus is comprised of 6 distinct species Zaire ebolavirus, Sudan ebolavirus, Bundibugyo ebolavirus (Uganda), Taï Forest ebolavirus (Ivory Coast) Reston ebolavirus (USA & Italy respectively),
• Bombali ebolavirus which is in bats in Sierra Leone each containing a different mortality rate.

Marburg virus and Filoviridae Transmission

• The genus of Marburg is Marburgvirus and with a single species of virus called Murburg Marburgvirus
• Phylogenetic analysis based on genome sequences data suggest the single species has at least 5 lineages
• Four lineages are closely related with nucleotide sequences differing between 0-7.8%
• The 5th lineage has nucleotide divergence of up to 21%
• Sequences have been classified into 2 major lineages (Marburg (Musoke, Popp, Angola, Ci67) Ravn viruses
• Reservoir for Ebola is not confirmed but is mostly caused by fruit bat
• Intimate contact is the main means of transmission of filoviruses to humans
• Nosocomial transmission is a major problem of outbreaks in Africa because of exposure to infectious tissues, excretions, and hospital wastes.
• Aerosol transmission observed in primates as well as not a major means of transmission in humans

Filoviridae Epidemiology and Effects

• Marburg reservoir is the Rousettus aetypticus and has been found coinfecting with the Ravn virus in Africa with a Case fatality has been 24-88% averaging 50% during outbreaks
• Ebola and has been found in Sudan, Zaire, Bundibugyo and Tai eboloa in Africa being the location the Case fatality is nearly as high at 53-88%
• Ebola Reston isolated from macaques from Philippines was the first viruses found outside of African
• Filoviruses can be spreaded via needle-stick or injecting equipment usually associated with severe disease, rapid deterioration and maybe high death rate
• Filoviridae symptoms include: Most severe hemorrhagic fever, an incubation period of: 2- 21 days, an Abrupt onset symptoms such as Fever, chills, malaise, and myalgia, and rapidly deteriorates and progresses to multisystem failure along with Hemorrhage and DIC as well as usually ending in Death around day 7-11 with some Painful recoveries
• Survivors often plagued with arthralgia, uveitis, psychosocial disturbances, and orchitis for weeks following the initial fever
• Severe haemorrhagic fever is also found in non-human primates due to Filoviruses with mortality as high as 82% these can also exist as non-pathogenic to humans, and it has same clinical course as other filoviruses in humans

Flaviviridae

• Flaviviridae is a Group of arbovirus mostly being transmitted by arthropods
• 1648: Yellow Fever described
• 17th_20th century, there were Yellow Fever and Dengue outbreaks
• 1927 Yellow Fever Virus isolated
• 1943 Dengue virus isolated
• 1947 - Omsk Hemorrhagic Fever virus isolated
• 1957: Kyasanur Forest virus isolated

Flaviviridae Transmission

• Arthropod vector of yellow Fever virus is Aedes aegypti with two possible routes of transmission Sylvatic cycle and Urban cycle
• Kyasanur Forest Virus is transmitted by Ixodid tick with the From infected rats, shrews, and squirrels the Omsk Hemorrhagic Fever virus is transmitted by Ixodid tick from rodent to rodent with Muskrat being the epizootic hosts and human contact with their urine, feaces or blood could course infection
• Alkhumra virus is closely related to OHFV and reservoir is cow, camel, sheep

Flaviviridae Epidemiology

• Yellow Fever Virus - Africa and Americas the activity is intermittent and localized, Case fatality rate - varies but may reach 50%
• Dengue Virus - Asia, Africa, Australia, and Americas, while its incidence is on the rise due to spread of A. aegyptae, Case fatality rate between 1-10%
• Kyasanur Forest virus is confined to Karnataka (Mysore) state - India is the main location and it's Case fatality rate 3-5%
• Omsk Hemorrhagic Fever virus - Found in Europe however the Case fatality rate is low between only and 0.5-3%

Flaviviridae In Humans

• Yellow Fever has an Incubation period between 3 to 6 days, and clinical manifestations can range from mild to severe signs with a short remission period. In Severe Yellow Fever begins abruptly with fever, chills, severe headache, lumbosacral pain, generalized myalgia, anorexia, nausea and vomiting, and minor gingival hemorrhages, with its main Death usually follows with a remission period can occur for 24 hours followed by an increase with symptoms and usually occurring on n day 7 – 10.

Dengue Hemorrhagic Fever

• Incubation period is 5 to 7 days
• The initial Dengue virus is followed by a secondary and possibly more severe, more severe sero-type of dengue follows the hemorrhagic fever
• If the person is then infected by a different sero-type, dengue hemorrhagic fever can occur
• The disease can begin as normal dengue fever but quickly progresses to a hemorrhagic syndrome
• rapid shock ensues but can be reversed with appropriate treatment

Other Flaviviridae In Humans And Animals

• Kyasanur Forest Disease is characterized by fever, headache, myalgia, cough, bradycardia, dehydration, however Recovery is uncomplicated with no lasting sequelae Omsk Hemorrhagic Fever presents like the KFD however hearing loss, hair loss, neuropsychiatric complaints are commonly reported following recovery (lasting sequelae) Yellow Fever virus is maintained in non-human primates with varying clinical signs that can be an unapparent infection or a severe hemorrhagic illness varying on the species
• Dengue virus has been isolated from non-human primates but causes no clinical symptoms
• Kyasanur Forest Disease Virus can May cause viremia in livestock but will show no clinical symptoms Omsk Hemorrhagic Fever Virus is maintained in rodents but is asyptatmic however it is

Yellow Fever cycles, Clinical presentation

• Has 3 Cycles Jungle, urban, and intermediate
• Clinical presentation: The majority of persons infected with yellow fever virus have no illness or only mild illness
• Initial Symptoms include such things as Fever, chills, severe headache, back pain, muscle aches, nausea, and fatigue which is Faget's sign
• Most symptomatic patients develop only this stage, and in 15% of symptomatic patients develop severe form after a short period of symptom remission (Toxic shock phase)
• Toxic phase - If it occurs the fever returns with initial symptoms PLUS the added Coagulopathy & hemorrhage (hematemesis), Jaundice, Hypotension, shock, metabolic acidosis, Arrhythmias, Confusion, seizures, and coma can occur Mortality rate is around 5-10% (20-50%) in epidemics and hospitalized patients The vaccine is available and indicated for travel to an endemic area in Africa or South America. Immunity happens quickly around Immunity in 10 days in 80%- 100% and protection lasts for 30-35 years with no booster required
• Unfortunately There is no specific treatment

Dengue Fever Information

• Dengue Fever is described as "breakbone fever"
• The Vector is A. aegypti & A. albopictus with the Virus can be spread when replicated in mosquitos.
• Risk is very Rare in blood transfusion, organs transplant & Vertical transmission
• It is the most prevalent mosquito-borne viral disease in the world.
• 1/3 of world populations are exposed (400 million cases yearly)

• 100 countries have Dengue transmission

• The First attenuated vaccine developed in 2015 by Sanofi Pasteur and vaccine is developed for the those who to live in endemic areas. Unfortunately There isnt no specific treatment is available.
• Four Dengue Virus Serotypes (DEN 1,2,3,4) can either All can cause severe & fatal infection
• The Infection with one serotype gives No cross immunity to other types however the virus does give life long immunity to the same type, leading to being however, more predisposition to DHF/DSS if infected by another serotype and that Humans are the main reservoir monkeys and have possibly been found as hosts!

Dengue Fever Symptoms And Clinical Manifestations

• Symptoms broken into 3 phases, Febrile, Critical, and recovery
• The Febrile Phase has symptoms of sudden-onset fever, and in addition to the headaches, mouth and nose bleeding, can be coupled with muscle and joint pains, vomiting, rash, and diarrhea.
• After which the Critical phase can lead to critical symptoms such as Hypotension, Pleural effusion, Ascites, and gastrointestinal bleeding.
• The recovery phase may have, altered level of consciousness, seizures, itching, and overall a Slow heart rate may be observed.
• The Clinical Manifestations are undifferentiated fever, Classic Dengue Fever, Dengue Hemorrhagic Fever, and the Dengue Shock Syndrome The Acute Febrile illness that ensues with severe Hemorrhage mainly retro-ocular causing Myalgia & arthralgia, often severe Nausea & vomiting can reach 50% and diarrhea (30%) Rash (50%) with variable appearances, maculopapular, petechial, or erythematous

Dengue Hemorrhagic Fever (DHF) And clinical Diagnostic Criteria

• This is described as The - Most serious form of dengue virus infection

• It is Estimated by the WHo to have nearly 500,000 cases /year and has a Mortality rate of ≈ 10%

• Diagnostic Criteria (WHO) Requires All 4 must be met: Has high Fever lasting 2-7 days)

• The Fever has Hemorrhagic manifestations symptoms: Thrombocytopenia platelet drop of below100,000/ml, Evidence points to increased vascular permeability causing (leaky capillaries)

• The Criteria for Dengue Shock Syndrome (DSS) requires all 4 in addition to DHF must be met

• There is also must be Evidence of circulatory failure that leads to rapid and weak pulse, narrow pulse pressure below 20 mm Hg which can then leads to Hypotension for that particular age and cold, and a Clammy skin coupled with an Altered Mental Status

Bunyaviridae

• Bunyaviridae outbreak 1930: Rift Valley Fever - Egypt, Epizootic in sheep, Another outbreak in the 1940s: CCHF - Crimean peninsula, mostly in Hemorrhagic fever in agricultural workers
• 1951 and Another Outbreak a Hantavirus broke out in Korea with Hemorrhagic fever in UN troops in 1952-53 andDiseases mainly in Hemorrhagic fever with renal syndrome (HFRS) or hantavirus and the virus consist of 5 genera with over 350 viruses pathogenic to humans, animals, plants

Bunyaviridae Transmission In Humans

• The Viruses are Transmitted by arthropod vectors with the exception Hantaviruses
• The Mosquito carrying RVF Virus is Aedes mosquito, the CCHF - Is by a Ixodid Tick and most infections due to Hanatavirus stem from Rodents contact
• Less common modes of transmission are primarily: Aerosol, and Exposure leading to infected animal tissue
• Primarily RvF is found Sub-Saharan Africa and Arabian peninsula with a -1% in human
• CCHF stems from Africa, Eastern Europe, and Asia with nearly10%-40% case fatality rate with an addition occurrence in Nosocomial infection stemming from exposure to infected blood products
• Hantaviruses are Divided with their main location the New world in north/South America which causes HPS and Old world in Eastern Europe as well as Eastern Asia with primarily 1-50% fatalities

Bunyaviridae Epidemiology and Effects

• Incubation period is between 2-5 days, then followed by flu-like symptoms leading hemorrhagic Fever with below 0.5% of the case, however Another small fraction 0.5% cases ends up with retinitis or encephalitis, however, the symptoms usually show in the window of 1-4 weeks following an infection

• The majority of Most human infections follow around 1–2 weeks after abortion or disease in livestock CCHF is a 3-7 Days can have flu like symptpms

• the Hemorrhagic Fever is quick with 3-6 days after clear clinical signs Hanta virus with the incubation being 7-21 Days can have one of two routes (Hantavirus Pulmonary and Hemorrhagic both with Renal symptoms

Epidemiology and VHFs

• Humans are not the natural host for VHF viruses as they rely on the Animal life such as reservoirs for maintenance and virus transmissions

• These infections are Restricted to areas where the reservoir and vector are able to reside safely and are therefore found in the primarily rural areas and are contacted by substantial direct interactions with many different carriers of VHF virus such a: Rodents, Ticks, Bush meat, Bats, and Mosquitoes

• An the easily contracted The 2014–15 can easily cause outbreaks as it did with The Ebola outbreak in West Africa demonstrating how easy it is for human carriers to spread into urban areas as well as The Increasing of international travel and healthcare returning individuals can easily spread the Viruses as their carriers.

• This coupled with a variety of endemics such as HFRS in China and can cause issues in areas which may be unequipped with the necessary resources to prevent them spreading and this leads to VHFS being extremely Underreported

Pathogenesis:

• Initial Viral Replication Mostly in Local tissues such as Monocytes, and Macrophages, eventually then migrating Lymphoreticular system
• HFVs have broad tissue tropism and subsequent dissemination occurs to the lymphatic system, blood along with the monocites and a Variety of solid organ targets, dependent on virus with The Liver and spleen are commonly affected

In other cases: such has a high and poor immune response viral loads with some resulting in being Worsened through direct immunesuppression ( viral) causing high viral Loads That are mainly only predictive results Mortality, for some VHFs are also strongly connected with mortality in cases

Pathophysiology of VHFs:

• Knowledge of the pathophysiology in humans is still Incomplete due to cases involving the Isolation caused within geographic, Reliance has primarily only been Historical data and the difficulty to collect and manage biologic samples

• The Pathogenesis with each cases can wildly Differ leading to having more unique host and the viruses having direct relationship with the hosts.

• Microvascular permeability occurs because of the direct, injury to cells caused by virus- or direct proinflammatory

• Thrombocytopenia is very common, it is an inhibition of the platelet function, leading to impairment platelet aggregation. can also vary due to fibrilytic system Consumption or activation of coagulation factors

• Volume depletion from vomiting , diarrhea and in extreme cases “thid spacing” caused by Results in frequent cases Hypovolemic causing injury to kidneys

Diagnosis and Common Clinical factors

• The main difficulties are both Range severity and The Wide spectrum that VHF exhibits
• A major diagnosis is in looking for Vigilance clusters to potentially point to the disease during outbreak phases of the infection this can include: ( cluster of HCW/Hospitals worker/exposure /HCW, Veterinarian... contact cases with Known contacts and Exposure
• A Thorough investigation to consider and the time duration and the many varying factors, travel , or high risk jobs for that particular time period has elapsed

VHF Symptoms (Clinical)

• Varying degrees of symptoms with variable incubation periods and varying symptoms, such as an infection which may resemble many other disease, with often a high confusion, in those with a high possibility may be a prodrome fever
• GI , Conjunctival. and Hemorrhaging
• Death maybe cause of the shock (hypovolemic or septic , sudden by means of cardice or some disturbance due to electrolytes

Other symptoms show weakness in:

• Uveitis, encephalitis is common in all and is common in others ( Lassa) causing a type deafness:

Laboratory and testing

• A main thing to do when testing samples is both Minimize testing on samples, inform the Laboratories must be notified beforehand as well
• These tests must only be packaged and can only preformed facilities and bio containment with proper international protocol and handling procedures Testing in the majority are through blood samples: rt pcr Elisa and visualizations are the main route

Acquiring and testing samples is difficult during an pandemic specially when also needing to Assess possible levels Thrombocytopenia causing to also Assess the liver and abnormal levels

What treatments are available to combat VHF transmission

• At best only Provide Care, and if at worst then at minimum

• Provide the HCW and hospital essential PPE Treat with suspicion, while in case there is not clear diagnosis can greatly assist Must consider patient’s symptoms, so as to minimize any further issues that could lead and the antiviral ribivarin the best option in many cases, that includes some such the with and antiviral HFRS and HPS cases

• Consider giving Early doses, intravenous or early

• The most serious issues with ribivarin are related anemia patients and if you have an immune Plasma has shown some benefit to those undergoing argentina cases, but there are insufficient cases to consider

VHF Transmission and Prevention.

• VHF Prevention from original index cases relies on how safely they avoid the exposure to vectors

• There exist Vaccine for those infected from Argentina , and there exists a Rapid response set up of containment, tracing, and disposal procedure Ensure those disposed by HCW are well protected as those with those diseases show high contagion

• In case these infections are shown Trace Contact, Understand disease, prevent spread Consider burial issues, and practices.