1. Viral Hemorrhagic Fevers Or The Viruses that you Desperately want to Avoid Eric Gorgon Shaw, MD, FACEP, FAAEM, FAWM

2. Objectives Describe the relevance of Viral Hemorrhagic Fevers (VHF) to Wilderness Medicine Describe geographical distribution of VHFs Describe common clinical features of VHFs Describe preventative measures for travel with potential exposure List therapeutic options for patients with VHF List infection control precautions for healthcare providers caring for patients with VHF

3. Lecture Overview Pathophysiology & Common Clinical Findings Virus-specific information VHF from the perspective of the traveler VHF from the perspective of the clinician Case Presentation

4. Why Learn about Viral Hemorrhagic Fevers at a WMS Conference? Remote locations of outbreaks Worldwide distribution Relation to Travel Medicine Fever in a traveler

5. Viral Hemorrhagic Fever What is it? An acute viral infection causing: Diffuse vascular damage Hemorrhage Multisystem compromise Relatively high mortality

6. Quick Overview: Who are they? VHFs are: Lipid-encapsulated Single-strand RNA Zoonotic (animal-borne)* Geographically restricted by host Persistent in nature (rodents, bats, mosquitoes, ticks, livestock, monkeys, primates)

7. Quick Overview: Who are they? Arenaviridae Lassa Fever Argentine HF (Junin) Bolivian HF (Machupo) Brazilian HF (Sabia) Venezuelan HF (Guanarito) Bunyaviridae Rift Valley Fever (RVF) Crimean Congo HF (CCHF) Hantavirus (Hemorrhagic Fever with Renal Syndrome (HFRS)) Hantavirus Pulmonary Syndrome (HPS) Filoviridae Marburg Ebola Flaviviridae Yellow Fever Dengue Fever Omsk HF Kyasanur Forest Disease Not to be confused with…

8. Quick Overview: How do we get infected? Rodents & Arthropods, both reservoir & vector Bites of infected mosquito or tick Inhalation of rodent excreta Infected animal product exposure Person-to-Person Blood/body fluid exposure Airborne potential for some arenaviridae, filoviridae

9. Common Pathophysiology Small vessel involvement Increased vascular permeability Multiple cytokine activation Cellular damage Abnormal vascular regulation: Early -> mild hypotension Severe/Advanced -> Shock Viremia Macrophage involvement Inadequate/delayed immune response

10. Common Pathophysiology Multisystem Involvement Hematopoietic Neurologic Pulmonary Hepatic (Ebola, Marburg, RVF, CCHF, Yellow Fever) Renal (Hantavirus) Hemorrhagic complications Hepatic damage Consumptive coagulopathy Primary marrow injury to megakaryocytes

11. Common Clinical Features: Early/Prodromal Symptoms Fever Myalgia Malaise Fatigue/weakness Headache Dizziness Arthralgia Nausea Non-bloody diarrhea

12. Common Clinical Features: Progressive Signs Conjunctivitis Facial & thoracic flushing Pharyngitis Exanthems Periorbital edema Pulmonary edema Hemorrhage Subconjunctival hemorrhage Ecchymosis Petechiae But the hemorrhage itself is rarely life- threatening.

13. Common Clinical Features: Laboratory Findings Leukopenia Thrombocytopenia (not Lassa) Proteinuria Hepatic inflammation

14. Common Clinical Features: Severe/End-stage Multisystem compromise Profuse bleeding Consumptive coagulopathy/DIC Encephalopathy Shock Death BUT…

15. Symptoms/Signs vary with the type of VHF

16. Quick Overview: Mortality Case-Fatality <10%: Dengue HF, Rift Valley Fever 53% (225/425): Ebola-Sudan in Uganda (2000). 81% (257/317): Ebola-Zaire in Kikwit, Zaire (1995). (2/3 of patients were health care workers = 171 health care workers dead!) 90% (227/252): Marburg in Angola (2004-2005)

17. Arenaviridae Spread to humans by rodent contact (virus found in urine, feces, and other excreta) Lassa Fever (West Africa) New World HFs Machupo (Bolivia) Junin (Argentina) Guanarito (Venezuela) Sabia (Brazil) Explosive Nosocomial outbreaks with Lassa & Machupo

18. Arenaviridae: Lassa Fever First seen in Lassa, Nigeria in 1969. Now in all countries of West Africa 5-14% of all hospitalized febrile illness Rodent-borne (Mastomys natalensis) Interpersonal transmission Direct Contact Sex Breast Feeding

19. Lassa Fever Distinguishing Features Gradual onset Retro-sternal pain Exudative pharyngitis Hearing loss in 25% may be persistent Spontaneous abortion Mortality 1-3% overall (up to 50% in epidemics) Therapy: Ribavirin

20. Arenaviridae: South American HFs Rodent-borne Potential for person-to-person transmission Junin: uncommon Machupo: probable Guanarito: not-documented Distinguishing characteristics: Gradual onset Hyporeflexia, hyperesthesia High mortality (20-30%) 70% recovery in 7-8 days without sequelae Therapy: Ribavirin (?)

21. Bunyaviridae Rift Valley Fever (RVF) Crimean-Congo Hemorrhagic Fever (CCHF) Hantavirus Old World: Hemorrhagic fever with renal syndrome (HFRS) New World: Hantavirus pulmonary syndrome (HPS) Sin Nombre (1993 outbreak in SW US) 5 genera with over 350 viruses

22. Bunyaviridae Transmission to humans Arthropod vector (RVF, CCHF) Contact with animal blood or products of infected livestock Rodents (Hantavirus) Laboratory aerosol Person-to-person transmission with CCHF

23. Bunyaviridae: Rift Valley Fever Transmission to humans Aedes mosquito Contact with blood/products of infected livestock Found throughout Africa, not just around the Rift Valley

24. Rift Valley Fever Predominantly a disease of sheep and cattle 1930: First identified in an infected newborn lamb in Egypt In livestock: ~100% abortion 90% mortality in young 5-60% mortality in adults

25. Rift Valley Fever Asymptomatic or mild illness in humans Distinguishing Characteristics Hemorrhagic complications rare (<5%) Vision loss (retinal hemorrhage, vasculitis) in 1-10% Overall mortality 1% Therapy: Ribavirin?

26. Bunyaviridae: Crimean-Congo HF Transmission to humans: Ixodid, Hyalomma spp. ticks Contact with animal blood/products Person-to-person Laboratory aerosols Extensive geographical distribution

27. Crimean-Congo Hemorrhagic Fever 1940s: Crimean Peninsula Hemorrhagic Fever in agricultural workers >200 cases 10% case-fatality Maintained in livestock, but unapparent/subclinical disease

28. Crimean-Congo Hemorrhagic Fever Distinguishing features Abrupt onset Most humans infected will develop hemorrhagic fever Profuse hemorrhage Mortality 15-40% Therapy: Ribavirin

29. Bunyaviridae: Hantaviruses Transmission to humans: Exposure to rodent saliva and excreta Inhalation Bites Ingestion in contaminated food/water (?) Person-to-person (Andes virus in Argentina)

30. Hantavirus Worldwide distribution = Rodent distribution Old World: Hemorrhagic Fever with Renal Syndrome (HFRS) Hantaan virus: eastern Asia (China, Russia, Korea) Seoul virus: worldwide Dobrova-Belgrade virus: Balkans Puumala virus: Scandinavia, western Europe, Russia New World: Hantavirus Pulmonary Syndrome (HPS) (non-hemorrhagic) Sin Nombre virus of US New York virus of US Black Creek Canal virus of US Bayou virus of US Andes virus of Argentina, Chile

31. Hantavirus: Hemorrhagic Fever with Renal Syndrome (HFRS) 1951: Korea – Hemorrhagic Fever in UN Troops >3000 cases of acute febrile illness ~33% hemorrhagic manifestations 5-10% case-fatality One of 7 HFs researched by US for biological weapons

32. Hemorrhagic Fever with Renal Syndrome (HFRS) Distinguishing Features Insidious onset Intense headaches, Blurred vision kidney failure (causing severe fluid overload) Mortality: 1-15%

33. Filoviridae Ebola Ebola-Zaire Ebola-Sudan Ebola-Ivory Coast Ebola-Bundibugyo (Ebola-Reston) Marburg

34. Filoviridae: Ebola Rapidly fatal febrile hemorrhagic illness Transmission: bats implicated as reservoir Person-to-person Nosocomial Five subtypes Ebola-Zaire, Ebola-Sudan, Ebola-Ivory Coast, Ebola- Bundibugyo, Ebola-Reston Ebola-Reston imported to US, but only causes illness in non- human primates Human-infectious subtypes found only in Africa

35. Filoviridae: Ebola Sporadic Outbreaks (16 from 1976 – 2008) First described in 1976 along the Ebola River in Zaire (now Congo) and Sudan. Ebola River, Zaire, 1976 (Ebola-Zaire) 318 cases, 88% mortality Kikwit, Zaire, 1995 (Ebola-Zaire) 315 cases, 81% mortality Uganda, 2000 (Ebola-Sudan) 425 cases, 53% mortality Congo, 2007 (Ebola-Zaire) 264 cases, 71% mortality Uganda, 2007-8 (Ebola-Bundibugyo) 149 cases, 25% mortality

36. Filoviridae: Ebola Distinguishing features: Acute onset Weight loss/protration 25-89% case-fatality

37. Filoviridae: Marburg Transmission: Animal host unknown Person-to-person infected animal blood/fluid exposure Indigenous to Africa Uganda Western Kenya Zimbabwe Democratic Republic of Congo Angola

38. Filoviridae: Marburg Sporadic outbreaks (8 from 1967 – 2008) First seen in 1967, in simultaneous outbreaks of laboratories in Marburg, Frankfurt, and Belgrade Marburg, Frankfurt, Belgrade, 1967 32 cases, 21% mortality Durba, DRC, 1998-2000 154 cases, 83% mortality Angola, 2004-2005 252 cases, 90% mortality

39. Filoviridae: Marburg Distinguising features Sudden onset Chest pain Maculopapular rash on trunk Pancreatitis Jaundice 21-90% mortality

40. Flaviviridae Yellow Fever Dengue Omsk Hemorrhagic Fever (OHF) Kyanasur Forest

41. Yellow Fever 1649: First reported in Cuba Enormous toll of soldiers during Spanish- American War (1898) American 400 Combat deaths 2000 from Yellow Fever Spanish 16,000 deaths from YF between 1895-1898 (out of an original force of 230,000)

42. Flaviviridae: Yellow Fever Transmission: Aedes aegypti mosquito Sylvatic Cycle Infected monkeys Urban Cycle Human host

43. Yellow Fever Distinguishing features Biphasic infection Common hepatic involvement & jaundice (thus, its name) Mortality: 15-50%

44. Flaviviridae: Dengue Dengue Fever (DF) Dengue Hemorrhagic Fever (DHF) Dengue Shock Syndrome (DSS) Four distinct serotypes DEN-1, DEN-2, DEN-3, DEN-4 Infection with one does NOT confer immunity to the others  A person can become infected multiple times with Dengue  Counterintuitively increases the risk for DHF with subsequent infection Transmission Aedes aegypti, Aedes albopictus mosquito spp. Sylvatic & Urban Cycles

45. Dengue Fever: History & Distribution 1779-1780: First reported epidemic of DF Near simultaneous occurrence in Asia, Africa, North America After WWII: pandemic began in SE Asia 1950s: DHF emergence into the Pacific region & Americas Since discontinuation of Ae. aegypti eradication program, DF/DHF range has expanded

46. Dengue 50-100 million cases of DF/year ~300,000 cases of CHF/year Distinguishing Features Sudden onset Eye pain Rash Complications/sequelae uncommon Illness less severe in younger children 2000 Bangladesh epidemic: no deaths in pts < 5y/o 82% of hospitalized patients were adults Case-Fatality: DF: <1% DHF: 5-6% DSS: 12-44%

47. Flaviviridae: Omsk Hemorrhagic Fever Transmission Tick bite: Dermacentor, Ixodes Host: rodents (water vole, muskrat) Infected Animal Contact Milk from infected goats, sheep. 1945-1947: First described in Omsk, Russia Distribution: western Siberia regions of Omsk, Novosibirsk, Kurgan and Tyumen

48. Omsk Hemorrhagic Fever Distinguishing Features Acute Onset Biphasic infection Complications Hearing loss Hair loss Psycho-behavioral difficulties Mortality: 0.5 – 3%

49. Flaviviridae: Kyanasur Forest Transmission: Tick bite (Haemaphysalis spinigera nymphs, Ixodes petauristae) Contact with infected animal Host: small rodents, monkeys, shrews, bats, porcupines Distribution: limited to Karnataka State, India 1957: First identified from a sick monkey Distinguishing Features Acute onset Biphasic Case-fatality: 3-5% (400-500 cases annually)

50. VHFs Prevention for the World-traveller Vaccinations Yellow Fever Kyanasur Forest Disease? Investigational/non-FDA-approved Argentine HF Rift Valley Fever Hantavirus Ongoing research All the others Dengue Fever Filoviridae

51. VHFs Prevention for the World-traveller Rodent Exposure Precautions Don’t mess with live/dead rodents, or their burrows/nests Don’t use rodent-infested cabins/shelters Don’t pitch tents or sleep near rodent feces, burrows, or potential rodent shelters (garbage dumps, woodpiles) Avoid sleeping on the ground (cot >12 inches up, or tent w/ floor) Keep food rodent-proof Dispose of waste appropriately

52. VHF Prevention for the World-traveller Mosquito Exposure Precautions DEET (20-30%) on exposed skin Permethrine on clothing, bednets Headnets Bednets

53. VHF Prevention for the World-traveller Tick Exposure Precautions DEET (20-30%) on exposed skin Permethrine on clothing, bednets Light-colored clothing Routine tick-check

54. VHF Prevention for the World-traveller Livestock & Animal Exposure Precautions Know from where your food is coming Avoid participation in birthing or butchering of livestock or game Wild monkeys don’t make good pets!

55. VHF for the Clinician: Identification of Suspected Cases Temperature > 101 F (38.3 C) for < 3 weeks No predisposing factors for hemorrhagic manifestations 2 or more of the following: Hemorrhagic rash Epistaxis Hematemesis Hemoptysis Hematochezia/melena Other hemorrhagic signs No established alternative diagnosis

56. VHF for the Clinician Exposure Precautions Body Fluid Exposure Gloves (double) Face & Eye shields Gowns (impermeable) w/ leg & shoe coverings Masks (surgical v. N95) Sharp Instrument Precautions Hand-washing & disinfectants Cadaver-exposure Avoid Prompt burial by trained teams

57. VHF for the Clinician: Infection Control CDC Publication: "Infection Control for Viral Haemorrhagic Fevers in the African Health Care Setting“ Dedicated medical equipment Stethoscopes BP cuffs Etc. Point-of-care analysis of routine labs, if available

58. VHF in the lab: BSL-4 High-level protection required for: Laboratory manipulation Mechanical generation of aerosols Concentrated infectious material Viral culture

59. VHF for the Clinician: Differential Diagnosis Meningococcemia Acute Leukemia Hepatitis Rickettsial Infection Leptospirosis Thrombocytopenia Purpura (ITP or TTP) Fever in a traveller Malaria Typhoid fever VHF Others

60. VHF for the Clinician: Distinguishing Characteristics Signs: Eye pain: Dengue Exudative Pharyngitis: Lassa Fever Jaundice: Yellow Fever Anuria: RVF Severe ecchymosis: CCHF Marked wt. loss/prostration: Filoviridae Vision Loss: RVF Hearing Loss: Omsk Hair Loss: Omsk Onset: Insidious: Arenaviridae Acute: Filoviridae, Flaviviridae, RVF Course Incubation period: 2-21 days (varies by virus) Biphasic: Flaviviridae Laboratory Absence of/minor thrombocytopenia: Lassa Convalescence Deafness (20% Lassa)

61. VHF for the Clinician: Diagnostics Isolation of virus from tissue, cell culture Serum antigen detection ELISA RT-PCR Immunohistochemical staining of infected tissue

62. VHF for the Clinician: Treatment Specific Therapy Ribavirin (not FDA-licensed): Lassa Fever New World Arenaviruses Crimean-Congo Hemorrhagic Fever Convalescent-phase plasma Argentine Hemorrhagic Fever (Junin) Non-specific Therapy: Supportive Care Fluid & electrolyte management Oxygenation Blood pressure support Correct coagulopathies as needed No antiplatelet/anticoagulant drugs, IM therapy

63. VHF for the Clinician: Management of Exposures Medical surveillance x 21 days Potential exposures Close contacts High-risk exposures (percutaneous/mucocutaneous exposure) Percutaneous/mucocutaneous exposure to infected individual Percutaneous: wash thoroughly with soap & water Mucocutaneous: flush/irrigate with saline or water Prophylaxis Ribavirin for close contacts Lassa fever Crimean-Congo HF Convalescent abstinence from sex x 3 months (!) Arenaviridae Filoviridae

64. VHF for the Clinician: Infection Control Risk CategoryDescriptionSurveillance Casual Contacts Remote contact with index case (eg, stayed in same hotel) VHF not spread by casual contact, no special surveillance Close Contacts More than casual (eg, living with contact, caretaker, shook hands with contact) Place under surveillance once index case confirmed High-Risk Contacts Mucous membrane contact (egg, kissing, or penetrating injury involving contact with index case’s blood such as needlestick) Place under surveillance as soon as VHF diagnosis considered in index case

65. Case Presentation 38 y/o male complains of fever, chills, diarrhea, back pain, sore throat (Easy! Viral syndrome. Who’s next!) PE: Temp 103.6 F, BP 90/60 Skin w/ diffuse ecchymosis, maculopapular rash on extremities (Aw…Crap!) Travel History: just got back from a 4 month stay on his farms in Liberia and Sierra Leone (Oh…Frick!)

66. Case Presentation: Hospital Course Day #4: Patient developed ARDS Despite empiric antibiotics (incl. antimalarials) Intubated Day #5: Local & State Health Depts. notified. Investigational New Drug (IND) protocol to administer ribavirin Patient died before ribavirin administered

67. Case Presentation: Post-mortem Samples sent to CDC Lassa Fever confirmed Serum antigen detection Virus isolation in cell culture RT-PCR sequencing of virus Immunohistochemical staining of liver samples

68. Case Presentation: Exposure Management/Infection Control 5 High risk contacts 5 (wife, kids, visitor) 183 Low risk contacts 9 other family members 139 HCW at hospital: 42 labworkers, 32 RN, 11 MD 16 labworkers in Virginia and California 19 passengers on flight from London to Newark No additional cases

69. Summary You probably won’t be carrying Biohazard Level 4 gear. If you don’t have religion, this might be a good time… Don’t breathe rat poop!