viral hemorrhagic fevers (vhf) amber m. vasquez, md assistant professor, division of infectious...

Viral Hemorrhagic Fevers (VHF) Amber M. Vasquez, MD Assistant Professor, Division of Infectious Diseases Associate Program Director, Infectious Diseases Fellowship The Ohio State University Wexner Medical Center Office Phone: 614-366-2306 Email: [email protected]

Learning Objectives Describe the structure and microbial physiology of Hemorrhagic Fever viruses and integrate this information with the human pathophysiologic correlates Describe physical and chemical properties of Hemorrhagic Fever viruses Describe the replication of Hemorrhagic Fever viruses Describe the underlying genetic mechanisms of Hemorrhagic Fever viruses Describe the physiology of Hemorrhagic Fever viruses Identify the normal human immune response to infection with Hemorrhagic Fever viruses At the end of this module you will learn to:

Learning Objectives Recognize the epidemiology and ecology of infection due to Hemorrhagic Fever viruses Describe and differentiate the principles of laboratory diagnosis for Hemorrhagic Fever viral infections Describe the treatment, prevention and control of Hemorrhagic Fever viral infections

Hemorrhagic Fever viruses Filoviridae Marburg virus Ebola virus Flavivirdae Yellow Fever virus Dengue virus Bunyaviridae Rift Valley Fever virus Hantavirus Arenaviridae Lassa Fever virus - Japanese Encephalitis - St. Louis Encephalitis - West Nile Virus and more - Guanarito Virus: Venezuelan hemorrhagic fever - Machupo Virus: Bolivian hemorrhagic fever and more

Marburg and Ebola Filoviruses Filamentous, enveloped, negative-strand RNA viruses Severe or fatal hemorrhagic fevers www.utmb.edu php.med.unsw.edu.au Ebola virion

Structure and Replication viralzone.expasy.org

Lancet 2011;377:849-62 Pathogenesis

Epidemiology Mostly Sub-Saharan Africa Endemic in fruit bats, wild monkeys Contact with animal reservoir Human-to-human spread via contact with infected blood or secretions Monkey Handlers Healthcare exposures Accidental Injection Contaminated Syringes Healthcare workers in close contact www.who.int/csr/disease/ebola/Global_EbolaOutbreakRisk_20090510

2014 Ebola Outbreak West Africa Sierra Leone Guinea Liberia Nigeria, Senegal United States, Mali, Spain Contributing factors Sheer volume of cases Strained infrastructure Personal Protective Equipment Local burial customs http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/previous-updates.html

Clinical Syndromes Most severe causes of VHFs Incubation period typically 5 10 days (up to 21 days) Flu-like illness (fever, malaise) Nausea, vomiting, diarrhea; possible cough, pharyngitis May have photophobia, CNS symptoms (somnolence, delirium) Day 5: Maculo-papular rash may develop on trunk Subsequent hemorrhage from multiple sites (esp. GI tract) Week 2: Clinical improvement vs. Death from shock with multi- organ failure Case fatality rate of up to 90%

Laboratory Diagnosis Biosafety Level 4 Isolation Marburg virus rapid tissue culture growth Ebola virus may require animal inoculation Eosinophilic cytoplasmic inclusion bodies Viral antigen detection in tissue by direct immunoflourescence and in fluids by ELISA RT-PCR amplification in secretions IgM/IgG to filoviruses; false (+)s confirm testing jamanetwork.com Macrophage Journal of Infectious Diseases 1999;179 (Suppl 1):S54-9

Treatment and Infection Control No definitive management and no vaccine Supportive care Replacement of coagulation factors and platelets as needed Antibody-containing serum and interferon therapy Containment is key! Standard precautions Mask, gloves, gown, goggles Appropriate cleaning of medical supplies Proper burial techniques microbewiki.kenyon.edu

Yellow Fever and Dengue Flaviviruses Yellow Fever virions hardinmd.lib.uiowa.edu Dengue Fever virions www.stanford.edu

Structure and Replication Flavivirus cross-section www.niaid.nih.gov

Pathogenesis Arthropod-borne viruses (arboviruses) Aedes aegypti mosquito Human and Nonhuman primate reservoir Smaller mammals maintain viremia Humans are dead-end hosts

Immunity Humoral and cellular immunity Viral replication Interferon Stimulates innate and immune responses Rapid onset flu-like illness IgM blocks viremic spread Inflammation from cell-mediated response Weakens vasculature; causes rupture/hemorrhage Non-neutralizing antibody can enhance viral uptake Worsens symptoms on repeat infection

Epidemiology Yellow Fever Sub-Saharan Africa Tropical S. America Summer months Rainy season Standing water, drainage ditches, open sewers Winter vector not present; virus dormant in arthropod larvae/eggs; migrating birds www.who.int

Epidemiology Dengue www.yalescientific.org

Clinical Syndrome Yellow Fever Most benign, self-limiting Incubation 3-6 days Fever, chills, myalgia, back pain, severe headache Most resolve after this ~15% progress to severe disease High fever, jaundice, hepatitis, hyperbilirubinemia, hemorrhage Shock, multi-organ failure

Clinical Syndrome Dengue Most benign, self-limiting 50-80% are asymptomatic or have undifferentiated fever 4 7 day incubation period Classic Dengue Fever Breakbone Fever Dengue Hemorrhagic Fever Bruises, epistaxis, gum and GI bleed Dengue Shock Syndrome Hypotension

Laboratory Diagnosis IgM/IgG ELISA Primary method of diagnosis in acute illness from Dengue IgM (+) after 5 days from symptom onset (follow seroconversion) IgG titers for recent or past infection (4-fold increase) False positive risk crossreactivity with other flaviviruses or vaccinations RT-PCR from serum, CSF, autopsy tissue in first 7 days Serum PCR to detect viremia is test of choice for Yellow Fever Viral culture not routinely done

Treatment and Prevention Supportive care only Yellow Fever Vaccine Live vaccine Confers lifelong immunity Fever, myalgias, headache, nausea/emesis 2 5 days after administration Only for those going to an endemic region Mosquito vector control profiles.nlm.nih.gov Biosafety Level 3 or 4

Rift Valley Fever and Hantavirus Bunyaviruses Supergroup of 200 enveloped, segmented, negative- strand RNA viruses web.uct.ac.za/depts/mmi/stannard/emimages.html virology-online.com/viruses/Hantaviruses Rift Valley Fever Hantavirus particle

Structure and Replication Nucleocapsid L RNA large M RNA medium S RNA small RNA Polymerase Replicate similar to other enveloped, negative- strand RNA viruses

Pathogenesis Rift Valley Fever arbovirus Reservoir: Livestock (cattle, buffalo, sheep, goats) Vector: mosquito (Aedes genus) Humans infected by bite of mosquito or exposure to infected tissue of the animal (more common) Hantavirus NOT an arbovirus Certain species of rodents Deer mouse, cotton rat, rice rat, white-footed mouse Other rodents worldwide Hantaan, Sin Nombre, and many more! Aerosolized urine Deer mouse www.cdc.gov

Epidemiology Rift Valley Fever Sub-Saharan and North Africa Kenya Somalia Tanzania Saudi Arabia and Yemen cdc.gov

Epidemiology Hantavirus Worldwide Old World Hantaan, Dobrava Europe, Asia, Africa Hemorrhagic fever with renal syndrome New World Sin Nombre N. and S. America Hantavirus pulmonary syndrome www.cdc.gov Curry Village tent cabins

Clinical Syndromes Rift Valley Fever Incubation period of 48 hours Flu-like illness from viremia; fever lasts about 3 days Can be mild or progress to severe illness with hemorrhage Petechial hemorrhages, ecchymosis, epistaxis, GI and gum bleeding Hantavirus Hemorrhagic Fever with Renal Syndrome Similar to Rift Valley Fever but with acute renal failure Hantavirus Pulmonary Syndrome Flu-like illness (fever, headache, myalgias, nausea/vomiting, diarrhea) Rapid progression to cough, short of breath, pulmonary edema, respiratory failure, and death within days Mortality as high as 50% with hemorrhagic disease

Laboratory Diagnosis RT-PCR to detect viral RNA Most common diagnostic tool IgM antibodies by ELISA in acute illness IgG with four-fold increase in titers recent infection ELISA may be able to detect antigen in very viremic patients, such as those infected early with Rift Valley Fever

Treatment, Prevention, and Control Biosafety Level 3 or 4 Supportive management Rift Valley vaccine not licensed or commercially available Has been used for veterinary and laboratory personnel at high risk of exposure Vector control!!

Lassa Fever Arenavirus Pleomorphic, enveloped viruses Greek word arenosa = sandy Lassa fever virion

Structure and Replication Vhfc.org/lassa fever/virology Two single-stranded RNA - L segment: encodes polymerase - S segment: nucleoprotein and glycoproteins

Epidemiology Endemic to West Africa African rodent population Mastomys natalensis Rodent urine, droppings Colonize human homes Inhalation of aerosols Contaminated food Contact with open cuts, sores Person-to-person spread Infected secretions, bodily fluids www.travelapproved.nl

Clinical Syndrome Incubation: 1 3 weeks Fever, sore throat, retrosternal pain, abdominal pain, vomiting, diarrhea Facial swelling, proteinuria, conjunctivitis Coagulopathy, petechiae, occasional visceral hemorrhage Hemorrhage and Shock Highest rates of death in 3 rd trimester pregnancy Varying degrees of deafness in approximately 1/3 www.standford.edu; www.g-influencemagazine.com

Laboratory Diagnosis Biosafety Level 3 or 4 Precautions Throat and urine specimens for isolation Takes 7-10 days to grow ELISA: IgM/IgG or Lassa antigen RT-PCR

Treatment, Prevention, and Control Supportive care Fluids, electrolytes, oxygen and blood pressure support Limited Ribavirin activity Has successfully decreased mortality in prior studies Most effective if given in the first 6 days of treatment Prevention Rodent control; trapping Proper food storage Contact precautions and equipment sterilization N Engl J Med. 1986 Jan 2:314:20-6

Summary Marburg and Ebola Filoviruses Sub-Saharan Africa; fruit bats, wild monkeys Human-to-human spread via infected blood/tissue Severe hemorrhagic fever syndrome Yellow Fever and Dengue Fever Flaviviruses YF: Sub-Saharan Africa; Tropical S. America (less) DF: Similar to YF, plus Asia, Caribbean, the Pacific Mosquito vector transmission (arboviruses) Aedes aegypti YF: Flu-like; progress to jaundice, hemorrhage DF: Breakbone fever, Hemorrhagic fever, Shock Syndrome

Summary Rift Valley Fever and Hantavirus Bunyaviruses Rift Valley: mosquito vector; livestock reservoir; sub-Saharan and North Africa Hanta: infected urine from rodents; U.S. (pulmonary syndrome); worldwide (hemorrhagic fever + renal failure) Lassa Fever Arenavirus West Africa Rodents; aerosolized urine, contaminated food Person to person spread infected blood/tissue Fever, sore throat, retrosternal pain, proteinuria Hemorrhage and Shock

Summary All require Biosafety Level 3 or 4 Most common means of diagnosis: ELISA antibody testing (IgM/IgG) RT-PCR All are primarily managed by supportive care Prevention: vector control (insect or rodent); isolation precautions; sterile medical equipment Vaccines available for: Yellow Fever (commonly used) Rift Valley Fever (not commonly used)

Thank you for completing this module I hope that I was able to teach the subject clearly. If you have any questions, please email me at [email protected]

References Medical Microbiology, 7 th Ed. Murray, Rosenthal & Pfaller; Chapter 58, pages 537 538; Chapter 60, pages 549 556; Chapter 61, pages 561 566. Principles and Practice of Infectious Diseases, 7 th Ed. Mandell, Douglas, and Bennett; Chapters 153, 164, 166, 167.

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viral hemorrhagic fevers (vhf) amber m. vasquez, md assistant professor, division of infectious...

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