viral hemorrhagic fevers

1. Viral Hemorrhagic Fevers Paige Jordan RN, BSN Region II Epidemiologist January 9, 2004

3. What are Viral Hemorrhagic Fevers (VHFs)? A group of illnesses that are caused by several distinct families of viruses. A severe multisystem syndrome (multiple organ systems in the body are affected). Vascular system damaged Body’s ability to regulate itself is impaired. Many cause severe and life-threatening disease.

4. What are Viral Hemorrhagic Fevers (VHF)? Cont. Classified as biosafety level four (BSL4) pathogens. Classified as Category A Agent

5. How are VHF grouped? 4 distinct families Arenaviridae Filoviridae Bunyaviridae Flaviviridae

9. HFVs as potential biological weapons HFVs – weaponized by the Russia and US Yellow fever may have been weaponized by North Korea Source: JAMA, 2002; 287:2393

10. Epidemiology of HFVs All RNA viruses, and all are covered, or enveloped, in a fatty (lipid) coating Survival depend on an animal or insect host (the natural reservoir) Geographically restricted to areas where their host species live Humans - not the natural reservoir but are infected via contact with infected hosts or arthropod vectors

11. Epidemiology of HFVs cont. Naturally reside in an animal reservoir host or arthropod vector Rodents and arthropods – main reservoirs for viruses causing VHFs. Ticks and mosquitoes – vectors for some VHFs Ebola and Marburg – unknown host factors

12. Epidemiology of HFVs cont. Incubation Typical 5-10 days Range 2-16 days (except Hantavirus: 9-35 days)

13. Transmission to Humans Aerosols Desiccated rodent excreta: Arenaviruses, hantaviruses Generated by field mice caught in agricultural machinery: New World arenaviruses Generated during slaughter of infected livestock: CCHF, RVF Contaminated food/water Arenavirus (Lassa)

14. Transmission to Humans Arthropod vectors: Mosquitoes Bunyavirus: RVF Flaviviruses: Dengue, Yellow fever Ticks Bunyavirus: CCHF Flaviviruses: Kyanasur Forest Disease, Omsk HF Hematophagous flies: Bunyaviruses: RVF

15. Transmission to Humans:BW Implications With exception of dengue, all VHF agents transmitted by aerosol in laboratory (animal models) Stabilization in aerosols

16. Infectious Period Viruses have been found in seminal fluid of patients or sexually transmitted as follows: Ebola – 82-101 days after symptom onset Marburg – 83 days Lassa – 90 days Junin – 7-22 days Lassa fever virus – in urine of patients 32 days after symptom onset

17. VHF Evolution Prostration Pharyngeal, chest or abdominal pain Mucous membrane bleeding, ecchymosis Shock Usually improving or moribund within a week (except HFRS, arenaviruses) Bleeding, CNS involvement, marked elevation SGOT portend poor prognosis Mortality agent dependent (<10-90%)

18. VHF Sequelae Prolonged Convalescence Hair Loss, Furrowed Nails Deafness (Lassa, EBO) Retinitis (RVF, KFD) Uveitis (RVF, MBG) Encephalitis (AHF, BHF, RVF, KFD, OHF) Pericarditis (Lassa) Renal insufficiency (HFRS)

19. VHF Clinical Lab Leukopenia is suggestive, but WBC may be normal, elevated, or leukemoid Thrombocytopenia is typical, but sometimes mild or absent Hematocrit normal or increased early AST (SGOT) typically elevated; prognostic value BUN/Cr related to circulatory status (except in HFRS)

21. VHF: Differential Diagnosis Bacterial typhoid fever, meningoccemia, rickettsioses, leptospirosis Protozoal falciparum malaria Other vasculitis, TTP, HUS, heat stroke

22. How are HFVs transmitted? Exposure of urine, fecal matter, saliva, or other body excretions from infected reservoir hosts or vectors, e.g. rodents Vector From animals to humans Person to person: e.g. Ebola, Marburg, Lassa and Crimean-Congo hemorrhagic fever

23. Arenaviridae Classification: Old World and New World groups Life-long association with a rodent reservoir Found in 1956 as Tacaribe virus (New World virus) and discovered new arenaviruses have been discovered every one to three years

25. The Arenaviridae (Source: Chapter 29, VHFs by Peter B Jahrling)

26. Arenaviridae Zoonotic Rodents located in Europe, Asia, Africa, and the Americas Some Old World arenaviruses - rodent population generation after generation Some New World arenaviruses – transmitted among adult rodents Exception Tacaribe virus found in Trinidad – isolated from a bat

27. Arenaviridae The viruses - shed into the environment in the urine or droppings of the infected hosts Human infection – incidental – contact with excretions materials contaminated with the excretions of an infected rodent ingestion of contaminated food, or by direct contact with broken skin with rodent excrement Aerosol transmission (inhalation of tiny particles soiled with rodent urine or saliva Agricultural work Human homes or other buildings – domestic settings

28. Arenaviridae Lassa and Machupo viruses Associated with secondary person-to-person and nosocomial (health-care setting) transmission Contact with contaminated objects – medical equipment

29. Filoviridae Filovirus Marburg – 1967 in Marburg, Germany and Yugoslavia Ebola – 1976 in Zaire and Sudan 4 species identified – Ivory Coast, Sudan, Zaire, & Reston 18 reports of human outbreak due to Ebola or Marburg viruses – approximately 1500 cases to date Most in Africa Source of Human infection: Unknown Incubation Period – 3-16 days

30. Filoviridae

31. Filoviridae High mortality rate especially percutaneous transmission Transmission due to needle stick injuries or use of contaminated syringes Require low inocula for infection

32. Transmission by mucosal exposure in experimental animals Human infections – through contact of contaminated fingers with oral mucosa or conjunctiva Person to person by small droplet airborne nuclei Filoviridae

33. Bunyaviridae

34. Flaviridae

35. Epidemiology of HFVs cont.

36. Clinical Manifestations of VHFs Nonspecific May not be possible to differentiate by clinical grounds alone Overall incubation period: 2 –21 days Initially – nonspecific prodrome lasts less than a week High fever, malaise, headache, arthralgias, myalgias, nausea, abdominal pain, and nonbloody diarrhea

37. Clinical Manifestations of VHFs Filoviruses, Rift Valley fever, and flaviviruses : characterized by an abrupt onset Arenaviruses – more insidious onset Early signs typically include Fever, hypotension, relative bradycardia, tachypnea, conjunctivitis, and pharyngitis Cutaneous flushing or a skin rash Petechiae, mucous membrane and conjunctival hemorrhage Hematuria, hematemesis, and melena DIC and circulatory shock CNS dysfunction

38. Maculopapular RashMarburg Disease 

39. Erythematous RashBolivian Hemorrhagic Fever

40. Ocular Manifestation Bolivian Hemorrhagic Fever

41. Clinical Characteristics of Hemorrhagic Fever Viruses

42. Clinical Characteristics of Hemorrhagic Fever Viruses

43. Clinical Characteristics of Hemorrhagic Fever Viruses (Source: JAMA, 2002; 287:2396)

44. Clinical Characteristics of Hemorrhagic Fever Viruses

46. Differential Diagnosis of VHFs Influenza Viral hepatitis Staphylococcal or gram-negative sepsis Toxic shock syndrome Meningococcemia Salmonellosis Shigellosis Rickettsial diseases (e.g. Rocky Mountain Spotted Fever) Leptospirosis Borreliosis Psittacosis Dengue Hantavirus pulmonary syndrome Malaria Trypanosomiasis Septicemic plague Rubella Mealses Hemorrhagic smallpox

47. Differential Diagnosis of VHFs cont. Noninfectious bleeding diathesis Idiopathic or thrombotic thrombocytopenic purpura Hemolytic uremic syndrome Acute leukemia Collagen-vascular diseases

48. Lab Abnormalities Leukopenia (except in some cases of Lassa fever – leukocytosis) Anemia or hemoconcentration Thrombocytopenia Elevated liver enzymes

49. Lab Abnormalities…cont.

50. Lab Testing for VHFs Blood and serum specimens Environmental samples should be taken when possible and appropriate for exposure assessment Specimens should be sent to OLS which will coordinate to submit to CDC IgM ELISA, PCR, Viral Isolation, IgG ELISA (recovered), Immunohistopathology testing for deceased

51. Public Health Action Protect employee health Identify high risk employees Educate high risk employees Personal Protective Equipment (PPE) Educate health care providers and the public in the recognition and diagnosis of VHF Educate providers and laboratories to report VHF to the LHD immediately

52. Public Health Action cont. When a VHF case is reported Isolation of case Confirm cases Obtain a complete clinical and lab history by using VHF case investigation form Assure to obtain appropriate lab specimens on each suspected case and send it to OLS Confirmation of an intentional or unintentional exposure and notification procedure Checking for natural exposures to HFV, contact of a case or travel to an endemic area within last 21 days If no clear source is identified, begin active surveillance

53. Public Health Action cont. Case Finding Develop a working case definition for the outbreak investigation Begin enhanced passive surveillance Issue a news release and provide alert to increase health care providers and the public recognition and diagnosis of VHF Educate providers and lab to immediately report possible VHF infections

54. Public Health Action cont. Identify contact Contact Definition Direct Contacts – any person who has had face-to-face contact (within 6 feet) with a suspected, probable, or confirmed case of VHFs during the infectious period (onset of symptoms until time of interview, recovery, or death and burial of case).

55. Public Health Action cont. Surveillance of case-contacts and exposed population: Interview case-contacts and exposed individuals: assure that all case-contacts and exposed are contacted within 24 hours and interview daily for 21 days after last exposure. Determine if fever>101•F or VHF symptoms Refer symptomatic persons to a clinical center for isolation and treatment

56. Public Health Action cont. Surveillance of exposed: If exposed does not have fever of 101? F or higher or signs/symptoms of VHF by end of 21 days – discontinue surveillance Interview all exposed individuals to verify they have no symptoms – indicate status of exposed individual as “closed” on Exposed Individual Line Listing Form

57. Public Health Action cont. If exposed have fever 101•F or higher, or signs/symptoms of VHF, then assure referral to a MD for diagnostic work-up Implement appropriate infection control and preventive interventions Enter status of exposed individual as a case and move to Case Line List Form Begin contact tracing for this new case

60. Infection Control(Arenavirus, Filovirus, CCHF) Single room w/ adjoining anteroom as only entrance Handwashing facility with decontamination solution 0.5% sodium hypochlorite, 2% glutaraldehyde, phenolic detergent, soap Changing area/protective equipment Negative air pressure; air not recirculated Prominent hemorrhage, cough, vomiting, diarrhea Consider negative air flow room, if available, in absense of these sxs/sxs to avoid having to transfer pt later

61. Infection Control(Arenavirus, Filovirus, CCHF)(Cont’d) Strict barrier precautions gloves, gown, mask, shoe covers, protective eyewear/faceshield HEPA-filtered mask or respirator Prominent hemorrhage, cough, vomiting, diarrhea

62. Infection ControlArenavirus, Filovirus, CCHF (cont.) Chemical toilet All body fluids disinfected Disposable equipment & sharps into rigid containers containing disinfectant -> autoclaved or incinerated Double-bag refuse outside bag disinfected then autoclaved or incinerated

63. Clinical Laboratory Procedures Strict barrier precautions gloves, gown, mask, shoe covers, protective eye/faceshield consider respirator with HEPA filter handle specimens in biosafety cabinet when possible Spills/splashes immediately cover with disinfectant, allow to soak for 30’ wipe with absorbent towel soaked in disinfectant Waste disposal same as for patient isolation practices

64. ExposuresFirst Aid Wash/irrigate wound/site immediately within 5 minutes of exposure Mucous membrane (eye, mouth, nose) continuous irrigation with rapidly flowing water or sterile saline for > 15 minutes Skin scrub for at least 15’ minutes while copiously soaking the wound with soap or detergent solution fresh Dakin's solution (0.5% hypochlorite): dilute 1 part standard laundry bleach (5% hypochlorite) with 9 parts tap water

66. VHF Vaccines YELLOW FEVER licensed 17D vaccine safe and efficacious cannot be used in persons with egg allergy ARGENTINE HEMORRHAGIC FEVER live, attenuated safe and efficacious; used in 150,000 protects monkeys against Bolivian HF

67. VHF Vaccines RIFT VALLEY FEVER formalin-inactivated safe but requires 3 shots, intermittent booster limited supply live, attenuated MP-12 Phase II testing HFRS (HANTAAN) vaccinia vectored recombinant vaccine

68. Treatment Recommendation The mainstay of treatment – supportive Fluid maintenance of fluid and electrolyte balance, circulatory volume, and blood pressure No approved antiviral drugs or vaccines If a case is suspected, probable or confirmed the following drug therapy is recommended: Initial supportive and ribavirin therapy immediately while diagnostic confirmation is pending If infection with Arenaviruses or Bunyaviruses is confirmed, continue 10-day course of ribavirin If infection with Filovirus or Flavirus is confirmed, or is the diagnosis of VHF is excluded or an alternative diagnosis is established, discontinue ribavirin.

69. VHF Management:Cardiovascular Hemodynamic resuscitation & monitoring invasive (S-G catheter) as warranted and feasible Careful fluid management use of colloid hemodialysis or hemofiltration as needed esp. HFRS patients Vasopressors and cardiotonic drugs Cautious sedation and analgesia

70. VHF ManagementHematologic Coagulation studies and clinical judgement as guide replacement of clotting factors platelet transfusions No antiplatelet drugs or IM injections DIC may be important in some VHFs (RVF, CCHF, Filoviruses)

71. VHF ManagementAnti-viral Therapy Ribavirin Arenaviridae (Lassa, AHF, BHF) Bunyaviridae (HFRS, RVF, CCHF) Immune (convalescent) plasma Arenaviridae (AHF, BHF, ?Lassa) Passive immunoprophylaxis post-exposure?

72. VHF ManagementOther R/O or treat empirically for malaria, typhoid fever, rickettsioses, etc. vigilance against secondary bacterial infections nosocomial pneumonia, UTI, bacteremia ONLY INTENSIVE CARE WILL SALVAGE THE SICKEST PATIENTS