Viral Hemorrhagic Fever

Viral Hemorrhagic Fever
Center for Food Security and Public Health Iowa State University

Viral Hemorrhagic Fever
Viruses of four distinct families Arenaviruses Filoviruses Bunyaviruses Flaviviruses RNA viruses Enveloped in lipid coating Survival dependent on an animal or insect host, for the natural reservoir VHF viruses are members of four distinct families: arenaviruses, filoviruses, bunyaviruses and flaviviruses. They are all RNA viruses that are enveloped in a lipid coating. The survival of these viruses is dependant on their natural reservoir, which in most cases is an animal or an insect host. Image: Ebola virus, from CDC. Center for Food Security and Public Health Iowa State University

Classification Arenaviridae Bunyaviridae Filoviridae Flaviviridae
Junin Crimean- Congo H.F. Ebola Kyasanur Forest Disease Machupo Hantavirus Marburg Omsk H.F. Sabia Rift Valley fever Yellow Fever Guanarito Dengue Lassa The Arenaviridae family contains the following viruses: Junin, Machupo, Sabia, Guanarito, and Lassa. The Bunyaviridae include: Crimean-Congo hemorrhagic fever, Hantavirus, and Rift Valley fever. Marburg and Ebola are the two viruses within the Filoviridae family. The Flaviridae family includes: Kyasanur Forest Disease, Omsk hemorrhagic fever, Yellow fever and Dengue. Several of these virus families contain many more viruses but for the purposes of this presentation, only the viruses causing hemorrhagic fever will be discussed. Center for Food Security and Public Health Iowa State University

Junin virus Machupo virus Guanarito virus Lassa virus Sabia virus
Arenaviridae Junin virus Machupo virus Guanarito virus Lassa virus Sabia virus

Arenaviridae History First isolated in 1933
1958: Junin virus - Argentina First to cause hemorrhagic fever Argentine hemorrhagic fever 1963: Machupo virus – Bolivia Bolivian hemorrhagic fever 1969: Lassa virus – Nigeria Lassa fever The first arenavirus was isolated in 1933 during an outbreak of St. Louis Encephalitis virus. In 1958, the Junin virus was isolated in the plains of Argentina in agricultural workers. It was the first arenavirus found to cause hemorrhagic fever. Others soon followed including Machupo virus in Bolivia in 1963 and Lassa virus in Nigeria in Since 1956, a new arenavirus has been discovered every one to three years, but not all cause hemorrhagic fever. Center for Food Security and Public Health Iowa State University

Arenaviridae Transmission
Virus transmission and amplification occurs in rodents Shed virus through urine, feces, and other excreta Human infection Contact with excreta Contaminated materials Aerosol transmission Person-to-person transmission New and Old World rats and mice are chronically infected with arenaviruses. The virus is vertically transmitted from host to offspring with most viruses in this family. Transmission among adult rodents may also occur through bites and other wounds. Rodents shed the viruses into the environment through urine, fecal droppings, and other excreta. Humans can become infected when coming into contact with rodent excreta or contaminated materials such as contact through abraded skin or ingestion of contaminated food. Inhalation of rodent excreta may also result in disease. Person to person transmission has also been documented in healthcare settings through close contact with infected individuals and contact with infected blood and medical equipment. Center for Food Security and Public Health Iowa State University

Arenaviridae Epidemiology
Africa Lassa South America Junin, Machupo, Guanarito, and Sabia Contact with rodent excreta Case fatality: 5 – 35% Explosive nosicomial outbreaks with Lassa and Machupo Arenaviruses are found worldwide; however the viruses responsible for causing hemorrhagic fever are restricted to two continents. Lassa virus is endemic to the region of West Africa while Junin, Machupo, Guanarito, and Sabia viruses are all found in South America. The later are grouped together as the Latin American hemorrhagic fevers. Humans who have frequent contact with rodent excreta have an increase risk of developing an infection with an arenavirus. Who is exposed depends on the type of rodent carrying the virus. Agricultural and domestic exposure are the most common. Case fatality for arenaviruses ranges from 5 -35%. Lassa and Machupo can cause explosive hospital-acquired outbreaks. Center for Food Security and Public Health Iowa State University

Arenaviridae in Humans
Incubation period 10–14 days Fever and malaise 2–4 days Hemorrhagic stage Hemorrhage, leukopenia, thrombocytopenia Neurologic signs The incubation period for arenaviruses is typically between 10 – 14 days. Disease onset begins with a fever and general malaise for days. Most patients with Lassa fever will recover following this stage; however, those infected with the Latin American hemorrhagic fevers typical progress to more severe symptoms. The hemorrhagic stage of the disease quickly follows and leads to hemorrhaging, neurologic signs, leukopenia and thrombocytopenia. Center for Food Security and Public Health Iowa State University

Bunyaviridae Rift Valley Fever virus
Crimean-Congo Hemorrhagic Fever virus Hantavirus

Bunyaviridae History 1930: Rift Valley Fever – Egypt
Epizootic in sheep 1940s: CCHF - Crimean peninsula Hemorrhagic fever in agricultural workers 1951: Hantavirus – Korea Hemorrhagic fever in UN troops 5 genera with over 350 viruses RVF virus was first isolated in 1930 from an infected newborn lamb, as part of investigation of a large epizootic of disease causing abortion and high mortality in sheep in Egypt. Crimean-Congo Hemorrhagic Fever virus was first recognized in the Crimean peninsula located in southeastern Europe on the northern coast of the Black Sea in the mid-1940s, when a large outbreak of severe hemorrhagic fever among agricultural workers was identified. The outbreak included more than 200 cases and a case fatality of about 10%. The discovery of hantaviruses traces back to 1951 to 1953 when United Nations troops were deployed during the border conflict between North and South Korea. More than 3,000 cases of an acute febrile illness were seen among the troops, about one third of which exhibited hemorrhagic manifestations, and an overall mortality of 5% to 10% was seen. The family now consists of five genera which contain 350 viruses that are significant human, animal, and plant pathogens. Center for Food Security and Public Health Iowa State University

Bunyaviridae Transmission
Arthropod vector Exception – Hantaviruses RVF – Aedes mosquito CCHF – Ixodid tick Hantavirus – Rodents Less common Aerosol Exposure to infected animal tissue Most Bunyaviruses except for Hantaviruses utilize an arthropod vector to transmit the virus from host to host. In some cases the virus may be transmitted from adult arthropods to their offspring. Humans are generally dead end hosts for the viruses and the cycle is maintained by wild or domestic animals. Crimean-Congo Hemorrhagic Fever virus is transmitted by ixodid ticks and domestic and wild animals such as hares, hedgehogs, sheep, etc. serve as amplifying and reservoir hosts. In contrast, Rift Valley Fever virus is transmitted by Aedes mosquitoes resulting in large epizootics in livestock. Humans are incidentally infected when bitten by infected mosquitoes or when coming into contact with infected animal tissues. The viruses is believed to be maintained by transovarial transmission between the mosquito and its offspring. Hantaviruses cycle in rodent hosts and humans become infected by coming into contact with rodent urine. Aerosolization of viruses and exposure to infected animal tissues are also two lesson common modes of transmission for some Bunyaviruses. Center for Food Security and Public Health Iowa State University

Bunyaviridae Epidemiology
RVF - Africa and Arabian Peninsula 1% case fatality rate CCHF - Africa, Eastern Europe, Asia 30% case fatality rate Hantavirus - North and South America, Eastern Europe, and Eastern Asia 1-50% case fatality rate Bunyaviruses are found worldwide but each virus is usually isolated to a local region. RVF is found primarily in sub-Saharan Africa and was recently isolated in Saudi Arabia and Yemen in The case fatality rate in humans is generally around 1%. CCHF is found in most of sub-Saharan Africa, eastern Europe and Asia. The case fatality rate is 30% and nosicomial outbreaks have been documented through exposure to infected blood products. Hantaviruses are divided into two groups based on location: Old World Viruses are found in eastern Europe and eastern Asia while New World viruses are found in North and South America. Depending on the virus, case fatality rate can vary between 1 and 50%. Center for Food Security and Public Health Iowa State University

Bunyaviridae Humans RVF CCHF Hantavirus Incubation period – 2-5 days
0.5% - Hemorrhagic Fever CCHF Incubation period – 3-7 days Hemorrhagic Fever - 3–6 days following clinical signs Hantavirus Incubation period – 7–21 days HPS and HFRS Most humans suffering from Rift Valley Fever will experience flu-like symptoms and recover with no complications after an incubation period of 2-5 days. In 0.5% of cases, hemorrhagic fever will develop following the initial febrile stage. Another 0.5% of cases will develop retinitis or encephalitis 1 to 4 weeks following infection. Most human infections will occur one to two weeks following the appearance of abortion or disease in livestock. In contrast to RVF, most humans infected with CCHF will develop hemorrhagic fever. The incubation for the disease is 3-7 days and most patients will develop hemorrhagic fever 3 to 6 days following the onset of flu-like symptoms. Hantaviruses generally cause one of two clinical presentations: HFRS, Hemorrhagic Fever with Renal Syndrome generally caused by Old World Hantaviruses or HPS, Hantavirus Pulmonary Syndrome generally caused by New World Hantaviruses. Incubation period is 7 to 21 days followed by a clinical phase of 3-5 days. Severity of illness is dependent on the virus. Center for Food Security and Public Health Iowa State University

Bunyaviridae Animals RVF CCHF Hantaviruses Abortion – 100%
Mortality rate >90% in young 5-60% in older animals CCHF Unapparent infection in livestock Hantaviruses Unapparent infection in rodents Rift Valley Fever causes severe disease in livestock animals. Abortion rates can reach 100%. Mortality rates in animals less than 2 weeks of age can be greater than 90% with most animals succumbing to disease within 24 – 36 hours from the onset of fever. Older animals also suffer from a less severe febrile illness with mortality rates ranging from 5 – 60%. In contrast, CCHF virus causes an unapparent or subclinical disease in most livestock species and is maintained in the herds through the bite of a tick. Rodents are persistently infected with Hantaviruses but show no clinical signs. The virus is transmitted from rodent to rodent through biting, scratching, and possible aersolization of rodent urine. Note: For more information of Hantaviruses and Rift Valley Fever, please see those disease specific PowerPoint presentations. Center for Food Security and Public Health Iowa State University

Marburg virus Ebola virus
Filoviridae Marburg virus Ebola virus

Filoviridae History 1967: Marburg virus 1976: Ebola virus
European laboratory workers 1976: Ebola virus Ebola Zaire Ebola Sudan 1989 and 1992: Ebola Reston USA and Italy Imported macaques from Philippines 1994: Ebola Côte d'Ivoire Marburg virus was first isolated in 1967 from several cases of hemorrhagic fever in European laboratory workers in Germany and former Yugoslavia working with tissues and blood from African green monkeys imported from Uganda. Ebola virus was first reported simultaneously in Zaire and Sudan in 1976 when two distinct subtypes were isolated in two hemorrhagic fever epidemics. Both subypes later named Zaire and Sudan caused severe disease and mortality rates greater than 50%. A third subtype of Ebola (Reston) was later found in macaques imported from the Philippines into the US in 1989 and Italy in Four humans were asymptomatically infected and recovered without any signs of hemorrhagic fever. In 1994, a fourth subtype of Ebola was isolated from a animal worker in Côte d'Ivoire who had preformed a necropsy on an infected chimpanzee. Scattered outbreaks have occurred periodically with latest being an outbreak of Ebola in the Republic of the Congo in 2003. Center for Food Security and Public Health Iowa State University

Filoviridae Transmission
Reservoir is UNKNOWN Bats implicated with Marburg Intimate contact Nosicomial transmission Reuse of needles and syringes Exposure to infectious tissues, excretions, and hospital wastes Aerosol transmission Primates The reservoir for filoviruses is still unknown. Bats have been implicated for Marburg virus, but no evidence of Ebola viruses have been found in over 3000 species of animals tested in the areas of human outbreaks. Intimate person-to-person contact is the main means of transmission of filoviruses for humans. Nosicomial transmission has been a major problem in outbreaks in Africa through the reuse of needles and syringes and exposure to infected tissues, fluids, and hospital materials. Aerosol transmission has been observed in primates but does not seem to be a major means in humans. Center for Food Security and Public Health Iowa State University

Filoviridae Epidemiology
Marburg – Africa Case fatality – 23-33% Ebola - Sudan, Zaire and Côte d'Ivoire – Africa Case fatality – 53-88% Ebola – Reston – Philippines Pattern of disease is UNKOWN Marburg and Ebola subtypes Sudan, Zaire, and Côte d'Ivoire appear to be found only in Africa and all three Ebola subtypes have only been isolated from human cases in Africa. The case fatality rate for Marburg ranges from 23-33% and 53-88% for Ebola with the highest rates found in Ebola Zaire. The presence of Ebola Reston in macaques from the Philippines marked the first time a filovirus was found in Asia. The pattern of disease of humans in nature is relatively unknown except for major epidemics. Center for Food Security and Public Health Iowa State University

Filoviridae Humans Most severe hemorrhagic fever
Incubation period: 4–10 days Abrupt onset Fever, chills, malaise, and myalgia Hemorrhage and DIC Death around day 7–11 Painful recovery Filoviruses cause the most severe hemorrhagic fever in humans. The incubation period for both Marburg and Ebola is generally 4 to 10 days followed by abrupt onset of fever, chills, malaise, and myalgia. The patient rapidly deteriorates and progresses to multisystem failure. Bleeding from mucosal membranes, venipucture sites and the gastrointestinal organs occurs followed by DIC. Death or clinical improvement usually occurs around day 7 to 11. Survivors of the hemorrhagic fever are often plagued with arthralgia, uveitis, psychosocial disturbances, and orchitis for weeks following the initial fever. Center for Food Security and Public Health Iowa State University

Filoviridae Animals Hemorrhagic fever Ebola Reston
Same clinical course as humans Ebola Reston High primate mortality - ~82% Filoviruses cause severe hemorrhagic fever in non-human primates. The signs and symptoms found are identical to humans. The only major difference is Ebola Reston has a high mortality in primates (~82%) while it does not seem to be pathogenic to humans. Center for Food Security and Public Health Iowa State University

Flaviviridae Dengue virus Yellow Fever virus
Omsk Hemorrhagic Fever virus Kyassnur Forest Disease virus Flaviviruses can cause an array of clinical manifestations. For the purposes of this presentation, we will concentrate on those causing hemorrhagic fever.

Flaviviridae History 1648 : Yellow Fever described 17th–20th century
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 Yellow Fever was first described in 1648 in Yucatan. It later caused huge outbreaks in tropical Americas in 17th, 18th, 19th, and 20th century. The French failed to complete the Panama Canal because their work force was decimated by Yellow Fever. Yellow Fever virus was first flavivirus isolated in 1927 and the first virus to be proved to be transmitted by an arthropod vector. Dengue virus which was also found to be transmitted by an arthropod was isolated in Major outbreaks of dengue with hemorrhagic fever have occurred in Australia in 1897, Greece in 1928, and Formosa Since the cessation of the use of DDT to control mosquito vectors, dengue has now spread to most of the tropical regions of the world. Omsk hemorrhagic fever virus was first isolated in 1947 from the blood of a patient with hemorrhagic fever during an epidemic in Omsk and Novosibirsk Oblasts of the former Soviet Union. Kyasanur Forest virus was isolated from a sick monkey in the Kyasanur Forest in India in Since its recognition 400 to 500 cases a year have been reported. Center for Food Security and Public Health Iowa State University

Flaviviridae Transmission
Arthropod vector Yellow Fever and Dengue viruses Aedes aegypti Sylvatic cycle Urban cycle Kasanur Forest Virus Ixodid tick Omsk Hemorrhagic Fever virus Muskrat urine, feces, or blood Flaviruses utilize an arthropod vector to transmit disease. Yellow Fever is a zoonotic diseases that is maintained in non-human primates. The virus is passed from primate to primate through the bite of the mosquito. This is known as the sylvatic cycle. Humans contract the disease when bitten by an infected mosquito usually Ae. aegypti and the disease can then be epidemically spread from human to human by these mosquitoes. This cycle is known as the urban cycle. Dengue virus is maintained in the human population and is primarily transmitted in this manor. Kyasanur Forest virus is transmitted by an ixodid tick. The tick can pass the virus from adult to eggs and from one stage of development to another. The basic transmission cycle involves ixodid ticks and wild vertebrates, principally rodents and insect-eating animals. Humans become infected when bitten by an infected tick. The basic transmission cycle of the Omsk Hemorrhagic Fever virus is unknown. An ixodid tick are believed to transmit the viruses from rodent to rodent. Muskrats are epizootic hosts, and human infections occur by direct contact with their urine, feces, or blood. Center for Food Security and Public Health Iowa State University

Flaviviridae Epidemiology
Yellow Fever Virus – Africa and Americas Case fatality rate – varies Dengue Virus – Asia, Africa, Australia, and Americas Case fatality rate – 1-10% Kyasanur Forest virus – India Case fatality rate – 3–5% Omsk Hemorrhagic Fever virus – Europe Case fatlity rate – 0.5–3% Yellow Fever virus is found throughout sub-Sahran Africa and tropical South America but activity is intermittent and localized. The annual incidence is believe to be about 200,000 cases per year globally. Case fatality rate ranges greatly depending on the epidemic but may reach up to 50% in severe yellow fever cases. Dengue virus is found throughout the tropical Americas, Africa, Australia, and Asia. Cases of Dengue Hemorrhagic Fever (DHF) have been increasing as the distribution of Ae. aegypti increases following the collapse of mosquito control efforts. Case fatality rates for DHF is generally low 1-10% depending on available treatment. Kyasanur Forest virus is confined to Mysore State of India but spreading. Case fatality rate is 3 -5%. Omsk Hemorrhagic Fever virus is still isolated to the Omsk and Novosibirsk regions of the former Soviet Union. Case fatality is 0.5 – 3%. Center for Food Security and Public Health Iowa State University

Flaviviridae Humans Yellow Fever Dengue Hemorrhagic Fever
Incubation period – 3–6 days Short remission Dengue Hemorrhagic Fever Incubation period – 2–5 days Infection with different serotype Kyasanur Forest Disease Omsk Hemorrhagic Fever Lasting sequela Yellow Fever can cause a severe hemorrhagic fever. The incubation period in humans is 3 to 6 days. The clinical manifestations can range from mild to severe signs. Severe Yellow Fever begins abruptly with fever, chills, severe headache, lumbosacral pain, generalized myalgia, anorexia, nausea and vomiting, and minor gingival hemorrhages. A period of remission may occur for 24 hours followed by an increase in the severity of symptoms. Death usually occurs on day 7 – 10. Dengue virus will cause a mild flu-like illness upon first exposure. If the person is then infected by a different sero-type, dengue hemorrhagic fever can occur. The disease will begin like a normal infection of dengue virus with an incubation period of 2-5 days but will quickly progress to a hemorrhagic syndrome. Rapid shock ensues but can be reversed with appropriate treatment. Kyasanur Forest virus in humans is characterized by fever, headache, myalgia, cough, bradycardia, dehydration, hypotension, gastrointestinal symptoms, and hemorrhages. Recovery is generally uncomplicated with no lasting sequelae. Omsk Hemorrhagic Fever virus has a similar presentation to Kyasanur Forest virus however hearing loss, hair loss, neuropsychiatric complaints are commonly reported following recovery. Center for Food Security and Public Health Iowa State University

Flaviviridae Animals Yellow Fever virus Dengue virus
Non-human primates – varying clinical signs Dengue virus Non-human primates – No symptoms Kyasanur Forest Disease Virus Livestock – No symptoms Omsk Hemorrhagic Fever Virus Rodents – No symptoms Yellow Fever is maintained in non-human primates. Depending on species, yellow fever may be an unapparent infection or a severe hemorrhagic illness. Dengue has been isolated from several non-human primates in Africa but does not cause clinical signs. Livestock may develop a viremia with Kyasanur Forest Disease Virus but generally do not show clinical signs. Omsk Hemorrhagic Fever Virus is maintained in rodents but does not cause clinical signs. Center for Food Security and Public Health Iowa State University

Disease in Humans

Clinical Symptoms Differ slightly depending on virus Initial symptoms
Marked fever Fatigue Dizziness Muscle aches Exhaustion Specific signs and symptoms vary by the type of VHF, but initial signs and symptoms often include marked fever, fatigue, dizziness, muscle aches, loss of strength, and exhaustion. Image: A Medical Officer at Lacor hospital in Gulu, Uganda examines a child suspected of being infected with the Ebola virus. (AP Photo/Sayyid Azim) Center for Food Security and Public Health Iowa State University

Clinical Symptoms More severe Bleeding under skin
Petechiae, echymoses, conjunctivitis Bleeding in internal organs Bleeding from orifices Blood loss rarely cause of death More severe clinical symptoms include bleeding under the skin causing petechia, echymoses and conjunctivitis. Bleeding may also occur in internal organs and from orifices (like the eye, nose or mouth). Despite widespread bleeding, blood loss is rarely the cause of the death. Center for Food Security and Public Health Iowa State University

Diagnosis Specimens must be sent to CDC
U.S. Army Medical Research Institute of Infectious Disease (USAMRIID) Serology PCR IHC Viral isolation Electron microscopy Clinical microbiology and public health laboratories are not currently equipped to make a rapid diagnosis of any of these viruses, and clinical specimens in an outbreak need to be sent to the CDC or the US Army Medical Research Institute of Infectious Diseases (USAMRIID) located in Frederick, Md. These are the only 2 level D laboratories in the Laboratory Response Network. These laboratories can conduct serology, PCR, immunohistochemistry, viral isolation and electron microscopy of VHFs. Center for Food Security and Public Health Iowa State University

Treatment Supportive treatment Ribavirin Convalescent-phase plasma
Not approved by FDA Effective in some individuals Arenaviridae and Bunyaviridae only Convalescent-phase plasma Argentine HF, Bolivian HF and Ebola Strict isolation of affected patients is required Report to health authorities Patients infected with a VHF receive supportive therapy, with special attention paid to maintaining fluid and electrolyte balance, circulatory volume, blood pressure and treating for any complicating infections. There is no other established treatment. While there are no antiviral drugs approved by the U.S. Drug Administration (FDA) for treatment of VHF’s. Ribavirin, has been effective in treating some individuals with Arenaviridae and Bunyaviridae but has not shown success against Filoviridae or Flaviviridae infections. Treatment with convalescent-phase plasma has been used with success in some patients with Junin, Machupo, and Ebola. If infection with a VHF is suspected it should be reported to health authorities immediately. Strict isolation of a patient is also required. Center for Food Security and Public Health Iowa State University

Prevention and Control

Avoid contact with host species Rodents Control rodent populations Discourage rodents from entering or living in human populations Safe clean up of rodent nests and droppings Insects Use insect repellents Proper clothing and bed nets Window screens and other barriers to insects Prevention of VHFs is done by avoiding contact with the host species. Because many of the hosts that carry VHFs are rodents, prevention should involve rodent control methods. Steps for rodent prevention include the control of rodent populations, discouraging their entry into homes and safe clean up of nesting areas and droppings. For VHFs that are spread by arthropod vectors, prevention efforts should focus on community-wide insect and arthropod control. In addition, people are encouraged to use insect repellant, proper clothing, bed nets, window screens, and other insect barriers to avoid being bitten. Center for Food Security and Public Health Iowa State University

Vaccine available for Yellow fever Experimental vaccines under study Argentine HF, Rift Valley Fever, Hantavirus and Dengue HF If human case occurs Decrease person-to-person transmission Isolation of infected individuals The only established and licensed vaccine is for yellow fever. This live vaccine is safe and effective and gives immunity lasting 10 or more years. An experimental vaccine is under study for Junin virus which provides some cross protection to Machupo virus. Investigational vaccines are in the development phase for Rift Valley Fever, Hantavirus and Dengue. For VHF’s that can be transmitted person-to-person including: the Arenaviridae, the Bunyaviridae (excluding Rift Valley Fever) and the Filoviridae, close physical contact with infected people and their body fluids should be avoided. One infection control technique is to isolate infected individuals to decrease person to person transmission. Center for Food Security and Public Health Iowa State University

Protective clothing Disposable gowns, gloves, masks and shoe covers, protective eyewear when splashing might occur, or if patient is disoriented or uncooperative WHO and CDC developed manual “Infection Control for Viral Hemorrhagic Fevers In the African Health Care Setting” Wearing protective clothing is also needed to reduce transmission between people. The World Health Organization (WHO), and CDC have developed practical, hospital-based guidelines, entitled “Infection Control for Viral Hemorrhagic Fevers In the African Health Care Setting.” The manual can help health-care facilities recognize cases and prevent further hospital-based disease transmission using locally available materials and few financial resources. Center for Food Security and Public Health Iowa State University

Zairian nurse in full protective clothing prepares to enter the isolation ward during the Ebola VHF outbreak in Kikwit, Zaire, 1995. Image from CDC. Protective equipment worn by a nurse during Ebola outbreak in Zaire, 1995 Center for Food Security and Public Health Iowa State University

Anyone suspected of having a VHF must use a chemical toilet Disinfect and dispose of instruments Use a 0.5% solution of sodium hypochlorite (1:10 dilution of bleach) Other infection control recommendations include proper use, disinfection, and disposal of instruments and equipment used in treating or caring for patients with VHF, such as needles and thermometers. Place any disposable items, including linens, in a double plastic bag and saturate with 0.5% sodium hypo chlorite (1:10 dilution of bleach). Place sharps in the sharps container saturated with the 0.5% solution, wipe the containers with the 0.5% solution and send them to be incinerated. Center for Food Security and Public Health Iowa State University

Crimean-Congo Hemorrhagic Fever

Overview Organism History Epidemiology Transmission Disease in Humans
Disease in Animals Prevention and Control In today’s presentation we will cover information regarding the organism that causes Crimean-Congo hemorrhagic fever and its epidemiology. We will also talk about the history of the disease, how it is transmitted, species that it affects (including humans), and clinical and necropsy signs observed. Finally, we will address prevention and control measures, as well as actions to take if Crimean-Congo hemorrhagic fever is suspected. Center for Food Security and Public Health, Iowa State University, 2013

The Organism

The Organism Crimean-Congo hemorrhagic fever virus (CCHFV)
Genus Nairovirus CCHF serogroup Extensive genetic diversity Viruses from different geographic regions Crimean-Congo hemorrhagic fever is caused by Crimean-Congo hemorrhagic fever virus (CCHFV). This virus is a member of the genus Nairovirus in the family Bunyaviridae. It belongs to the CCHF serogroup. Although early serological studies revealed very few differences between strains of CCHFV, nucleic acid sequence analysis has demonstrated extensive genetic diversity, particularly between viruses from different geographic regions. Center for Food Security and Public Health, Iowa State University, 2013

History

History 1944 1969 Outbreaks continue to occur
First described in Crimea Soviet military personnel 1969 Also detected in Congo Outbreaks continue to occur Potential bioterrorist agent CDC/NIAID Category C pathogen The disease was first characterized in the Crimea in 1944 and given the name Crimean hemorrhagic fever. Illness was detected in about 200 Soviet military personnel assisting peasants in the area following the Nazi invasion. It was then later recognized in 1969 as the cause of illness in the Congo, thus resulting in the current name of the disease. New outbreaks have occurred in recent years. The CCHF virus is also a potential bioterrorist agent; it has been listed in the U.S. as a CDC/NIAID Category C priority pathogen. Sources: CDC and Curr Opin Virol Apr;2(2): doi: /j.coviro [Photo: Crimea (depicted in dark green) shown in relation to Ukraine (light green). Source: Wikimedia Commons] Center for Food Security and Public Health, Iowa State University, 2013

Epidemiology

Geographic Distribution
Africa Middle East Asia Parts of Europe Southern parts of former USSR Turkey Bulgaria Greece Albania CCHFV is widespread in Africa, the Middle East and Asia. It has also been found in parts of Europe including southern portions of the former USSR (Crimea, Astrakhan, Rostov, Uzbekistan, Kazakhstan, Tajikistan), Turkey, Bulgaria, Greece, Albania and Kosovo province of the former Yugoslavia. Limited serological evidence suggests that CCHFV might also occur in parts of Hungary, France and Portugal. The occurrence of this virus is correlated with the distribution of Hyalomma spp., the principal tick vectors. Center for Food Security and Public Health, Iowa State University, 2013

Geographic Distribution
[Photo: Map showing the geographic distribution of Crimean-Congo Hemorrhagic Fever. Pale yellow indicates areas with Hyalomma tick vector presence; dark yellow indicates areas with CCHF virological or serological evidence and vector presence; orange indicates areas where 5-49 cases of CCHF are reported per year; and red indicates areas where 50 or more cases of CCHF are reported each year. Source: World Health Organization at Center for Food Security and Public Health, Iowa State University, 2013

Morbidity and Mortality: Humans
Seasonal trends Occupational exposures Farmers, shepherds, veterinarians, abattoir workers, laboratory workers Healthcare workers Recreational exposures Hiking Camping Climatic factors can influence the numbers of ticks in the environment and the incidence of disease. In some countries, Crimean-Congo hemorrhagic fever tends to be seasonal. This disease is most common in Iran during August and September, and in Pakistan from March to May and August to October. Most cases are the result of occupational exposure. CCHF is particularly common in farmers, shepherds, veterinarians, abattoir workers and laboratory workers. Healthcare workers are also at high risk, particularly after exposure to patients’ blood. In the general public, activities that increase tick exposure such as hiking and camping increase the risk of infection. Center for Food Security and Public Health, Iowa State University, 2013

Morbidity and Mortality: Humans
Case fatality rate: 30-50% Mortality rate: 10-80% Highest after tick bites Higher in some geographic areas Geographic differences in viral virulence suggested but unproven Also affected by availability of supportive treatment in hospitals The average case fatality rate is 30-50%, but mortality rates from 10% to 80% have been reported in various outbreaks. The mortality rate is usually higher for nosocomial infections than after tick bites; this may be related to the virus dose. Geographic location also seems to influence the death rate. Particularly high mortality rates have been reported in some outbreaks from the United Arab Emirates (73%) and China (80%). Geographic differences in viral virulence have been suggested, but are unproven. The mortality rate may also be influenced by the availability of rigorous supportive treatment in area hospitals. Center for Food Security and Public Health, Iowa State University, 2013

Morbidity and Mortality: Animals
Large herbivores Highest seroprevalence Seroprevalence rates 13-36% More than 50% Animals asymptomatic Large herbivores have the highest seroprevalence to CCHFV. Seroprevalence rates of 13–36% have been reported in some studies, while others suggest that more than 50% of adult livestock in endemic regions have antibodies. Animals carry CCHFV asymptomatically. Center for Food Security and Public Health, Iowa State University, 2013

Transmission

Vectors Transmitted by ticks Hyalomma spp. are principal vectors
Transovarial Transstadial Venereal Other ixodid ticks Biting midges? Soft ticks? CCHFV usually circulates between asymptomatic animals and ticks in an enzootic cycle. Members of the genus Hyalomma seem to be the principal vectors. Transovarial, transstadial and venereal transmission occur in this genus. Hyalomma marginatum marginatum is particularly important as a vector in Europe, but CCHFV is also found in Hyalomma anatolicum anatolicum and other Hyalomma spp. Other ixodid ticks including members of the genera Rhipicephalus, Boophilus, Dermacentor and Ixodes may also transmit the virus locally. Although CCHFV has been reported in other families of invertebrates, these species may not be biological vectors; the virus may have been ingested in a recent blood meal. In one study, CCHFV was reported from a biting midge (Culicoides spp.). It has also been found in two species of Argasidae (soft ticks); however, experimental infections suggest that CCHFV does not replicate in this family of ticks. [Photo: Hyalomma marginatum tick. Source: Adam Cuerden/Wikimedia Commons] Center for Food Security and Public Health, Iowa State University, 2013

Transmission in Humans
Tick bites Contact with infected, crushed ticks Contact with infected animal tissues Ingestion of unpasteurized milk Contact with infected people Blood, tissues Horizontal transmission? Aerosol? Humans become infected through the skin and by ingestion. Sources of exposure include being bitten by a tick, crushing an infected tick with bare skin, contacting animal blood or tissues and drinking unpasteurized milk. Human-to-human transmission occurs, particularly when skin or mucous membranes are exposed to blood during hemorrhages or tissues during surgery. CCHFV is stable for up to 10 days in blood kept at 40°C (104°F). Possible horizontal transmission has been reported from a mother to her child. Aerosol transmission was suspected in a few cases in Russia. Center for Food Security and Public Health, Iowa State University, 2013

Transmission in Animals
Viremic mammals can transmit CCHFV to ticks Hares Hedgehogs Birds resistant to infection May act as mechanical vectors, transporting infected ticks Might spread virus between regions Many species of mammals can transmit CCHFV to ticks when they are viremic. Small vertebrates such as hares and hedgehogs, which are infested by immature ticks, may be particularly important as amplifying hosts. With a few exceptions, birds seem to be refractory to infection; however, they may act as mechanical vectors by transporting infected ticks. Migratory birds might spread the virus between distant geographic areas. Center for Food Security and Public Health, Iowa State University, 2013

Disease in Humans

Incubation in Humans Varies by route of exposure Tick bites
1-3 days (up to 9 days) Blood or tissues 5-6 days (up to 13 days) The incubation period is influenced by the route of exposure. Infections acquired via tick bites usually become apparent after 1 to 3 days; the longest incubation period reported by this route is nine days. Exposure to blood or tissues usually results in a longer incubation period. Current estimates suggest that these infections become apparent, on average, after 5 to 6 days, but incubation periods up to 13 days are known. Center for Food Security and Public Health, Iowa State University, 2013

Disease in Humans Pre-hemorrhagic phase Sudden onset fever
Chills, headache, dizziness Dizziness, photophobia, neck pain Myalgia, arthralgia Nausea, vomiting Non-bloody diarrhea Bradycardia Low blood pressure The first sign of Crimean-Congo hemorrhagic fever is a sudden onset of fever and other nonspecific symptoms including chills, severe headache, dizziness, photophobia, neck pain, myalgia and arthralgia. The fever may be very high. Gastrointestinal symptoms including nausea, vomiting, non-bloody diarrhea and abdominal pain are also common. Sharp mood changes, confusion and aggression have been reported in some cases. Cardiovascular changes such as bradycardia and low blood pressure can also occur. This early stage of disease is called the pre-hemorrhagic phase. It is followed, after several days, by the hemorrhagic phase. Center for Food Security and Public Health, Iowa State University, 2013

Disease in Humans Hemorrhagic phase Petechial rash
Ecchymoses and large bruises Hematemesis Melena Epistaxis Hematuria Hemoptysis Bleeding from other sites The hemorrhagic phase develops suddenly. It is usually short, lasting on average 2 to 3 days. A petechial rash may be the first symptom. The rash is followed by petechiae, ecchymoses and large bruises on the skin and mucous membranes. Hematemesis, melena, epistaxis, hematuria, hemoptysis and bleeding from venipuncture sites are also common. Bleeding can occur in other locations, including the brain. In one case, internal bleeding mimicked acute appendicitis. Hepatitis occurs in some patients, and may result in jaundice and hepatomegaly. Splenomegaly can also be seen. Some patients die from hemorrhages, hemorrhagic pneumonia or cardiovascular disturbances. [Photo: Male patient with Crimean-Congo hemorrhagic fever. Source: BE Henderson/CDC Public Health Image Library] Center for Food Security and Public Health, Iowa State University, 2013

Disease in Humans Convalescent phase
10-20 days after illness onset Generalized weakness Tachycardia Other nonspecific symptoms Recovery usually complete but slow May take up to one year Subclinical infections uncommon In patients who survive, recovery begins 10 to20 days after the onset of illness. The convalescent phase is characterized by generalized weakness, a weak pulse and tachycardia. Other symptoms including sweating, dryness of the mouth, headache, dizziness, nausea, poor appetite, labored breathing, polyneuritis, poor vision, loss of hearing, and memory loss have also be seen. Some patients temporarily lose all of their hair. Hepatorenal insufficiency has been reported in some countries but not others. Recovery is usually complete but slow, and can take up to a year. Subclinical infections can occur, but are thought to be uncommon. Mild febrile cases without hemorrhages are also seen. Center for Food Security and Public Health, Iowa State University, 2013

Diagnosis in Humans Virus isolation and identification RT-PCR
Blood, plasma, tissues Cell culture or animal inoculation BSL-4 required RT-PCR Blood Highly sensitive Used for local variants Crimean-Congo hemorrhagic fever can be diagnosed by isolating CCHFV from blood, plasma or tissues. At autopsy, the virus is most likely to be found in the lung, liver, spleen, bone marrow, kidney and brain. CCHFV can be isolated in a variety of cell lines. Cell cultures can only detect high concentrations of the virus, and this technique is most useful during the first five days of illness. Animal inoculation into newborn mice is more sensitive than culture, and can detect the virus for a longer period. CCHFV is identified by indirect immunofluorescence or reverse transcription-polymerase chain reaction (RT-PCR) assays. Virus isolation must be carried out in maximum biocontainment laboratories (BSL-4). Crimean-Congo hemorrhagic fever is often diagnosed by RT-PCR on blood samples. This technique is highly sensitive. However, due to the genetic variability in CCHFV strains, a single set of primers cannot detect all virus variants, and most RT-PCR assays are either designed to detect local variants or lack sensitivity. A real-time RT-PCR assay that can detect numerous variants has recently been published. Viral antigens can be identified with enzyme-linked immunoassay (ELISA) or immunofluorescence, but this test is less sensitive than PCR. [Photo: Under a high magnification of 400X, this Wilder’s reticulin-stained photomicrograph depicts the cytoarchitectural changes found in a liver tissue specimen extracted from a Congo/Crimean hemorrhagic fever patient. This particular view reveals a “thickening and a disassociation between the fibers of the reticular network.“ Source: CDC Public Health Image Library] Center for Food Security and Public Health, Iowa State University, 2013

Diagnosis in Humans Serology Past serologic tests
Tests detect IgM or IgG (paired titers) Indirect immunofluorescence ELISA Past serologic tests Complement fixation Hemagglutination Crimean-Congo hemorrhagic fever can also be diagnosed by serology. Tests detect CCHFV-specific IgM, or a rise in IgG titers in paired acute and convalescent sera. IgG and IgM can usually be found with indirect immunofluorescence or ELISA after 7-9 days of illness. Other serologic tests such as complement fixation and hemagglutination inhibition were used to diagnose Crimean-Congo hemorrhagic fever in the past, but lacked sensitivity. In fatal cases, patients generally die without developing antibodies Center for Food Security and Public Health, Iowa State University, 2013

Treatment in Humans Supportive Ribavirin Passive immunotherapy
No randomized human clinical trials to support this therapy Passive immunotherapy Hyperimmune serum Value of treatment controversial Treatment is mainly supportive. Ribavirin is used in some cases. Observational studies in humans and studies in experimentally infected mice support the use of this drug; however, no randomized human clinical trials have been published. Passive immunotherapy with hyperimmune serum has been tested in a few cases, but the value of this treatment is controversial. Center for Food Security and Public Health, Iowa State University, 2013

Disease in Animals

Species Affected Many species of wild and domesticated mammals
Hosts for immature ticks Small mammals Hosts for mature ticks Large herbivores Other potential hosts Birds mostly seronegative Reptiles rarely affected CCHFV can be found in many species of wild and domesticated mammals including small animals that serve as hosts for immature ticks, and large herbivores that act as hosts for mature ticks. CCHFV has been isolated from a number of species including cattle, sheep, goats, hares, hedgehogs, dogs and mice (Mastomys spp.). Most species of birds are seronegative and are thought to be resistant to infection. Although immature Hyalomma anatolicum ticks sometimes feed on reptiles, antibodies to CCHFV have only been reported from one reptile, a tortoise from Tadzhikistan. [Photo: Large herbivores, such as cattle, can serve as hosts for mature ticks. Source: USDA ARS] Center for Food Security and Public Health, Iowa State University, 2013

Disease in Animals CCHFV infections usually asymptomatic in animals
Mild clinical signs possible in experimentally infected animals Newborn rodents Sheep and cattle CCHFV infections are asymptomatic in animals other than experimentally inoculated newborn rodents (laboratory mice, rats and Syrian hamsters). The only symptom in experimentally infected sheep and cattle was a transient, mild elevation in body temperature. No lesions have been reported except in newborn rodents. Center for Food Security and Public Health, Iowa State University, 2013

Diagnosis Serology Virus isolation and other techniques IgG ELISA
Complement fixation Indirect fluorescent antibody Virus isolation and other techniques Can detect viremia Not used diagnostically Serology can identify animals that have been infected or exposed to CCHFV. An IgG ELISA can detect antibodies for the remainder of the animal’s life; other tests, including complement fixation and indirect fluorescent antibody, usually detect antibodies for shorter periods. Viremia can be recognized by virus isolation and other techniques (see ‘Diagnostic Tests’ section under Human Infections), but these tests are not used diagnostically. Center for Food Security and Public Health, Iowa State University, 2013

Avoid tick bites Tick repellents Environmental modification Avoidance of tick habitat Examination of skin and clothing for ticks Clothing to prevent tick attachment Acaricides (animals) In endemic regions, prevention depends on avoiding bites from infected ticks. Measures to avoid tick bites include tick repellents, environmental modification (brush removal, insecticides), avoidance of tick habitat and regular examination of clothing and skin for ticks. Clothing should be chosen to prevent tick attachment; long pants tucked into boots and long-sleeved shirts are recommended. Acaricides can be used on livestock and other domesticated animals to control ticks, particularly before slaughter or export. Center for Food Security and Public Health, Iowa State University, 2013

Avoid contact with infected blood or tissues Wear protective clothing and gloves Food safety Do not consume unpasteurized milk Virus usually inactivated in meat by post-slaughter acidification Virus also killed by cooking Contact with infected blood or tissues should also be avoided. Protective clothing and gloves should be worn whenever skin or mucous membranes could be exposed to viremic animals, particularly when blood and tissues are handled. Unpasteurized milk should not be drunk. In meat, CCHFV is usually inactivated by post-slaughter acidification. It is also killed by cooking. Center for Food Security and Public Health, Iowa State University, 2013

Strict universal precautions Use when caring for human patients Barrier nursing Isolation Use of gloves, face-shields and goggles Prophylactic treatment Ribavirin Stringent biosafety precautions Strict universal precautions are necessary when caring for human patients. These recommendations include barrier nursing, isolation and the use of gloves, gowns, face-shields and goggles with side shields. Prophylactic treatment with ribavirin has occasionally been used after high-risk exposures. Safe burial practices, including the use of 1:10 liquid bleach solution as a disinfectant, have been published. Laboratory workers must follow stringent biosafety precautions. An inactivated vaccine from mouse brains has been used in the former Soviet Union and Bulgaria. In most countries, no vaccine is available. [Photo: Depicted here in this 2007 photograph, was a Centers for Disease Control microbiologist, and Special Pathogens Branch (SPB) staff member in the process of inserting a rack of boxes containing biological stocks into a liquid nitrogen freezer where they would be stored. Source: CDC Public Health Image Library] Center for Food Security and Public Health, Iowa State University, 2013

Disinfection 1% hypochlorite 2% glutaraldehyde Heat
56°C (133°F) for 30 min CCHFV can be inactivated by disinfectants including 1% hypochlorite and 2% glutaraldehyde. It is also destroyed by heating at 56°C (133°F) for 30 min. [Photo: Disinfectants. Source: Danelle Bickett-Weddle/CFSPH] Center for Food Security and Public Health, Iowa State University, 2013

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