Viral Hemorrhagic Fevers

The lecture gives concise review about the main four groups of viruses causing hemorrhagic fever i.e. Flavivirues, Filoviruses, Arenaviruses and Bunyaviruses.

1. Viral hemorrhagic fevers (vhf) Dr Mostafa Mahmoud, MD, Ph D, Consultant Microbiologist Labs & Blood Banks Admin, Riyadh. Head of IP&C Dept. Iman Hospital Assist. Prof. of Medical Microbiology & Immunology

2. What are VHFs? Initial nonspecific prodromal stage Fever Malaise Headache Myalgia/ arthralgia Abdominal pain Non-bloody diarrhea Clinical multi-system illness associated with fever & bleeding diathesis (tendencies) caused by several distinct families of viruses.

3. Then Progresses to more severe symptoms & death Hemorrhage (not all cases) Increased vascular permeability Hypotension and Shock Multiorgan failure Many cause rapidly progressive illness & high mortality rates

4. Causative Viral groups (4) Viral group Representative viruses 1- Filoviruses Ebola V and Marburg V 2- Flaviviruses (82 members) -Yellow fever V –West Nile V – Dengue Fever V 3- Bunyaviruses ( Rift Valley fever virus ( RVV ), Crimean-Congo hemorrhagic fever (CCHF) virus , and Hantavirus pulmonary syndrome (HPS) . 2- Arenavirus Lassa Fever V New World Arena Viruses

5. Flaviviruses

6. Virology of vhf (features of the viruses) All are single -stranded RNA. All are enveloped ( transmission by foods or drinks??? ). Infectious during viremia stage. Low infectivity dose ( 1-10 viruses can cause infections). Geographically restricted to areas where host lives. Humans are not the natural reservoir but accidentally infected when comes in contact with infected hosts. Human outbreaks are sporadic and irregular .

7. When human is infected can infect another human No established treatment (with few exceptions) The best treatment is control of infection. Role in bioterrorism (biological weapons due to high morbidity and mortality and due to aerosol transmission of most of them except dengue fever virus)

8. Epidemiology of HFV Disease Transmission - HFVs are zoonosis : Animal hosts (Rodents) and arthropod vectors are main reservoirs. A. Natural infection of humans (mode of transmission): 1. Bite of infected arthropod (ticks or mosquitos) 2. Aerosol from infected rodent excreta 3. Direct contact with infected animals/carcasses or fomites

9. B- Human to Human & Nosocomial Transmission Possible for most HFVs (except ??) - Most person-to-person spread due to direct contact with infected blood & body fluids (Hospital acquires infections , HAIs - Mucous membrane contact, - Aerosolized , (airborne in Ebola, Lassa, Junín, & may be yellow fever) - Semen , - vomitus - Sweat, Incubation period ranging from 2 to 21 days for all of them.

10. pathogenesis The target organ is the vascular bed (hemorrhage) The replication of virus is intracellularly Cytokine release leads to shock and hypotension. Affects platelet functions and numbers (thrombocytopenia) Affects bone marrow and clotting factors .

11. Case-fatality (mortality) rate Virus Mortality rate Filoviruses Around 90% for Ebola virus (the highest) Flaviviruses 0.5% Arenaviruses 15-30% Causes of death: 1- Hemorrhagic diathesis (several body sites & orifices) 2- Shock 3- Multi-organ failure

12. Differential Diagnosis Infectious conditions Non-infectious conditions Influenza Viral hepatitis Staphylococcal or gram – sepsis Meningococcemia Salmonellosis and shigellosis Leptospirosis Malaria* Rickettsial disease Measles Smallpox – hemorrhagic Toxic Shock Septicemic Plague Trypanosomiasis DIC ITP TTP / HUS Acute leukemia Vasculitis Collagen-vascular diseases

13. I- filoviruses A- ebola viral disease ( EVD ), B- Marburg virus 1- Category A bioweapon (bioterrorism) agents (CDC 1999). 2- Potential to cause widespread illness / death Ease of dissemination or person-to-person transmission . First appeared in Zaire and Sudan simultaneously in 1976. Outbreak in 2013 in guinea then to Liberia, Sierra Leone , and lately Nigeria .

14. Case fatality rate ( CFR ) approaches 90% . The virus was transmitted to humans from wild animals . Fruit Bats are considered as the natural host for the virus. Other reservoirs rodents and plant virus?

15. EBOLA VIRUS DISEASE TRANSMISSION 1- By direct human-to-human contact with the blood, or other body secretions (saliva, breast milk, tears, stool, skin, or semen) of infected persons or even Dead bodies . (N.B. Lab staff at risk) 2- Transmission through semen may occur up to 7 weeks after clinical recovery ( Sexual transmission) . 3- Indirect contact transmission via environment contaminated with such infected secretions. 4- By handling ill or dead infected chimpanzees or other infected animals.

16. 5- Health care workers ( HCWs ) have frequently been infected while attending patients (direct contact body fluids , Needle sticks , aerosols) .

17. Health care workers (HCWs) have critical situations

18. Filoviruses: Ebola & Marburg - Cause severe HF that similar to fulminant septic shock. - Mortality Rate: Ebola: 50-90% Marburg: 25-30% - Incubation period: 2-21 days for Ebola (Mean 8 -10). 3-10 days for Marburg 9.6 days (mean) from symptom onset to death

19. Virology Filovirus family includes Ebola and Marburg viruses. Single stranded-RNA ( ssRNA ), enveloped virus. Ebola virus contains 5 strains with different phylogenic tree ( Zaire, Sudan, Ivory Coast, Reston & New 5 th Guinea strain. High mutational potentials. Rapidly replicating within 8 Hs . U or 6-shape virus.

20. What is wrong here??

21. II- Flaviviruses A- Yellow Fever B- Dengue Fever C- Omsk HF D- Kyasanur Forest Disease N.B. Flavus in Latin means yellow.

22. Mode of transmission - Yellow Fever – Aedes mosquito ( A. aegypti , A. africanus , A. simpsoni , A. furcifer , A. luteocephalus , and A. albopictus (Asian tiger mosquito) - Dengue Fever – mosquito ( Aedes aegypti ) - Omsk HF/ Kyasanur FD: Tick bite No reported cases of person to-person transmission

23. Yellow Fever cycles 3 cycles for yellow fever: Jungle Urban intermediate

24. Flavivirus

25. A- Yellow Fever Incubation period: short - 3-6 days . C/P: 1- Initial symptoms Fever, chills, severe HA, back pain, muscle aches, nausea, fatigue. Most symptomatic patients develop only this stage however, in 15% of symptomatic patients severe form will develop after short period of symptom remission ( Toxic shock) . 2- Toxic phase - fever returns with initial symptoms PLUS Coagulopathy & hemorrhage - hematemesis (black vomit) Jaundice , Hypotension, shock, metabolic acidosis, arrhythmias Confusion, seizures, and coma can occur.

26. N.B. The majority of persons infected with yellow fever virus have no illness or only mild illness. - Faget’s sign – relative bradycardia with fever. - Mortality rate: 5-10% (20-50% in epidemics and hospitalized pts). N.B . 90% of cases occur in Africa , 10% in South America . Vaccine is available ( Atiqa PHC & Airport) and indicated to travels to endemic area in Africa or South America. live-attenuated vaccine, single dose, To > 9 months travelers or living in endemic areas Immunity in 1 week in 95% of people - Protection for 30-35 years. - No specific treatment available.

27. 90% of yellow fever cases occur in Africa

28. 10% of yellow fever cases occur in S. America

29. - Described as “ breakbone fever” by Benjamin Rush in 1789. - Endemic throughout Americas, Asia & Africa - Vector - Aedes aegypti & Aedes albopictus . - Virus replicates in mosquitos. - Very Rare by blood transfusion, organs transplant. & Vertical transmission). - Incubation period: 3-14 days. The Most prevalent mosquito-borne viral disease in the world. - 1/3 of world populations are exposed ( 400 million cases yearly ) B- Dengue Fever

30. - > 100 countries have endemic dengue transmission. - In USA: Dengue - 10.4% of post-travel systemic febrile illness for travelers returning from endemic areas. No vaccine available (in 2015 new one is used successfully by Sanofi Pasteur for people in endemic areas). No specific treatment . - In KSA it is present in Mecca and Jeddah .

31. Four Dengue Virus Serotypes (DEN 1,2,3, and 4) - All can cause severe & fatal infection Infection by one serotype gives No cross immunity to other types but life long immunity to the same type, however, more predisposition to DHF / DSS if infected by another serotype. 2o immunopathological mechanism triggered by sequential infections with different dengue viral serotypes. Complicated pathogenesis – partially attributable to Ab-dependent enhancement. - Humans are the main reservoir but monkeys may be.

32. 4 Clinical Manifestations of disease 1- Undifferentiated fever 2- Classic Dengue Fever 3- Dengue Hemorrhagic Fever 4- Dengue Shock Syndrome

33. 2- Classic Dengue Fever - Acute febrile illness - Severe Hemorrhage mainly retro-ocular ; - Myalgia & arthralgia – often severe ( breakbone fever); - Nausea & vomiting > 50%; diarrhea (30%) - Rash (50%) (of variable appearances; maculopapular, petechial, or erythematous.

34. 3- Dengue Hemorrhagic Fever ( DHF ): - Most serious form of dengue infection - WHO estimates 500,000 cases /year - Mortality ≈ 10%; high as 50% - WHO 4 diagnostic criteria ( Fever (2-7 days) – Hemorrhagic manifestations – Low platelet counts (< 100000 /ml) – evidence of leaky capillaries )

35. 4- Dengue Shock Syndrome ( DSS ): 4 WHO criteria for DHF AND Evidence of circulatory failure or shock : - Rapid, weak pulse, narrow pulse pressure (< 20 mm Hg) - Hypotension for age - Cold, clammy skin, AMS (Altered Mental Status).

36. Epidemic year Total cases DHF DSS Deaths 1993 1 st case in Jeddah 1994 (DEN-2)* 469 23 2 2 2006 (DEN-1)* 1269 27 2 6 2008 (DEN-3)* 775 9 4 4 2011 ** 2376 2013 ** 4411 * http://apps.who.int/iris/bitstream/10665/44188/1/9789241547871_eng.pdf ** http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057576/ Dengue Fever in KSA 3 serotypes present (1, 2, & 3), Jeddah & Makkah are affected due to pilgrims, Aedes aegypti was detected also in Al- Maddinah **

37. III- Bunyaviruses : A- Rift Valley Fever B- Hantavirus C- Crimean Congo HF Viral hosts : arthropod vectors & rodents. Mosquitoes – Rift Valley Fever Ticks – Crimean Congo Fever Rodents – Hantaan Virus All can be acquired by: - Exposure to infected animals or their carcasses - Contact with blood & bodily secretions of infected persons - By aerosol

38. A- Rift Valley Fever - Mosquito-borne disease affects primarily sheep & goats also cattle, buffalos and camels . - Most human infections are unapparent Self limited febrile illness first reported in Kenya’s Rift Valley in the early 1910s . Rare severe forms ( Ocular ; retina, Meningoencephalitis , or Hemorrhagic fever form) - 1% develops typical VHF. - Short incubation: 3-6 days. - Mortality (variable) but less than 1%.

39. Humans acquire infection by: - Bite of infected mosquito (several species- vertical trans for yrs ) - Contact with infected animal tissues - Aerosolization of virus from infected animal carcasses ( Lab Staff) - Ingestio n of contaminated raw animal milk ??? (No reported cases of human-to-human transmission- still theoretical risk to HCWs ). Standard precautions are enough. Vaccination of animals but not during epidemics. Inactivated human vaccine is not licensed for use.

40. KSA Outbreak * - Saudi Arabia, Jizan & Asir ( from 26 August 2000 through 22 September 2001 ) 886 infected / 87 dead ( 13.7% ). - The first time infection to be reported out of Africa. Vision loss 10/683. Hemorrhagic manifestations were in 35/494. CNS and liver affection occurs. * http://www.kau.edu.sa/Files/140/Researches/50678_20846.pdf

41. Rift Valley fever Distribution

42. IV- Arenavirus A- Lassa Fever B- New World Arena Viruses

43. - Arenaviruses - rodent borne HFVs mainly rats and mice - Severe VHF in Africa & S. America - One case in North America - Incubation period: 3-19 days 2 Types : Old World & New World i - Old World – Africa & Europe - Lassa Fever - Lymphocytic Choriomeningitis (LCM) ii- New World - Americas - South American HFVs - Junin (Argentine HF) - Machupo (Bolivian HF) - Whitewater Arroyho (North America) - Sabia virus (Brazilian HF)

44. Mode of transmission : - Inhaled aerosols of rodent urine/feces - Ingestion of food or water contaminated with rodent excreta - Direct contact of rodent excreta with abraded skin / mucous membranes - Contact with contaminated fomites - Contact with rodent blood Sexual transmission is likely in Lassa virus (3 months in semen).

45. Person to person transmission does occur however; - Direct contact with blood, urine, pharyngeal secretions & other body fluids of patients ( HCWs ) - Airborne transmission possible ( HCWs ) - Sexual transmission likely (Lassa fever virus detected in semen up to 3 months after acute infection).

46. Diagnosis, management and control of vhf

47. Diagnosis of VHF & HFVs Case Definition , VHFs – Ebola, Marburg, New World Arenaviruses, Old World Arenaviruses, and CCHF (CDC 2011). Patient must have: One or more of the following Fever ≥ 40 o C. - No predisposing factors for hemorrhagic manifestations -AND no established alternative diagnosis -Severe headache -Muscle pain -Erythematous maculopapular rash on the trunk with fine desquamation 3–4 days after rash onset - Vomiting -Diarrhea - Abdominal pain -Thrombocytopenia - Bleeding not related to injury - Pharyngitis (arenavirus only) - Retrosternal chest pain (arenavirus only) - Proteinuria (arenavirus only).

48. Important History within 21 days of: 1. Patient from or travel to endemic areas 􀂄 Even if nonspecific S+S 􀂄 Comprehensive travel history critical 2. History of tick, mosquito bites. 3. Contact with mice or their excreta 4. History of contact with patient with above risk factors & VHF symptoms 5. Contact with sick animals or carcasses in endemic areas. 6- In the event of Bioterrorist attack event

49. 1- Non-specific Lab Abnormalities - Leukopenia -Anemia - Hemoconcentration - Thrombocytopenia - Elevated LFTs Azotemia 2- Coagulation abnormalities - Prolonged bleeding time, PT, PTT Increased FDP ( fibrin degradation products) - Decreased Fibrinogen - DIC 3-Urine analysis Hematuria, proteinuria, oliguria A- Non specific Lab Abnormalities in HFV Infection

50. Test Notes Lab level Antigen detection by PCR - The Early rapid diagnostic test 2 nd or 3 rd BSL Antigen detection by ELISA test Rapid diagnostic test. 2 nd or 3 rd BSL IgM detection by ELISA Late diagnosis after 10 days of onset of infection 2 nd or 3 rd BSL Viral isolation Takes 3-days to complete. Mostly in research less in clinical diagnosis 4 th BSL B- Specific Lab diagnostic test in HFV Infection

51. Supportive (Main treatment) Specific antiviral treatment Contraindicated Isolation (Airborne in Lassa, Ebola Marburg ) No FDA approved antiviral agents. Aspirin & NSAIDs Fluid & electrolyte balance Ribavirin used in Arenaviruses and in Bunyaviruses . Anticoagulant therapies Supplemental O2 , & Mechanical Ventilation Ribavirin not active against (F) Filoviruses of Flaviviruses Steroids are of no benefit Treatment of HFVs Infection

52. Supportive (Main treatment) Specific antiviral treatment Contraindicated Circulatory & BP support Early vasopressors Blood products: (Platelets Clotting factor, & FFP Pain control Secondary infections common -aggressive treatment with antimicrobials Treatment of HFV Infection (Continue)

53. Immunization and infection control in HFVs 1- Passive immunization Immune plasma in Arenavirusis ( Junin and Machupo ) Whole blood from Ebloa survivors

54. 2- Active Immunization for HFVs 1- Live-attenuated vaccine available and effective for yellow fever virus. 2- Inactivated virus for dengue fever is under trial with good success 3- Vaccines for Junin ( Argentine ) virus under trial. 4- Also Rift Valley virus vaccine is under trial.

55. Infection Control & HFVs Infection-control Guidelines: - Stick to the standard precautions is the gold standard. - Report suspected cases immediately to Infection control officer, MOH , which notify the CDC, - Isolation of all suspected cases (Negative pressure Room or single room) - Strict hand washing ( HH ) - Double gloving - Use of impermeable gowns

56. - N-95 masks or powered air-purifying respirators ( PAPR ). - Negative pressure isolation with 6-12 air exchanges / hour - Leg & shoe covering - Face shields & goggles - All contacts of patients diagnosed with VHF including hospital personnel & lab workers should be placed under medical surveillance for signs of VHF infection for 21 days.

57. Notification Process in VHF ( MOH-KSA ) The following notifications are mandatory if suspected cases of VHF are admitted: 1. The Admitting Consultant notifies the: a. Infectious Diseases Consultant. b. Nurse in charge of Emergency Department and Ward where patient is to be admitted. 2. The Infectious Diseases Consultant notifies the: a. Chairman of the Infection Control Committee who will then notify the: i . Medical Director ii. Executive on Duty iii. Infection Control Practitioner

58. 3 . The Nurse in charge of ER notifies the: a. Nursing Supervisor or Duty Administrator b. ICU Head Nurse if the patient is to be admitted to the ICU 4. The Chairman of Infection Control Committee notifies the: a. Hospital Director b. Laboratory and Radiology Departments c. Employee Health Department

59. 5. The Infection Control Practitioner notifies the: a. Housekeeping Manager b. CSSD Manager c. Ministry of Health d. Utilities and Maintenance for ventilation modification in patient rooms. 6. The Nursing Supervisor notifies the: a. Director of Nursing b. Nurse manager to consult on staffing. c. Materials department for equipment for strict isolation.

60. Infection Control and Lab Testing All HFVs are highly infectious in lab setting May be transmitted to lab personnel by small particle aerosols Notify lab immediately if VHF suspected All specimens should be:: - Clearly identified - Double bagged - Hand carried to lab - Do NOT transport specimens in pneumatic tube

61. CDC Recommendations for personal protection during specimen collection : Full face shield or goggles, masks to cover all of nose and mouth, gloves , fluid resistant or impermeable gowns . Additional PPE may be required in certain situations.

62. Specimen Handling for Routine Laboratory Testing (suspected Ebola case but not for Ebola Diagnosis ) (CDC) Routine laboratory testing includes traditional chemistry, hematology, and other laboratory testing used to support and treat patients. The following precautions are required to deal with specimens suspected to contain Ebola virus for routine laboratory: Full face shield or goggles , masks to cover all of nose and mouth , gloves , fluid resistant or impermeable gowns AND use of a certified class II Biosafety cabinet or plexiglass splash guard, as well as manufacturer-installed safety features for instruments.

63. Post-Exposure Prophylaxis & Management No vaccine or antiviral agents Percutaneous or mucocutaneous exposures: Immediately wash affected skin with soap and water ; flush eyes . High Risk Exposures & Close Contacts: - Place under medical surveillance - Record temps. 2 times /day. Report any temp. ≥ 38 o C. -Report any S/S of VHF - Initiate Ribavirin if S/S of VHF develop (Arenavirus or Bunyavirus only).

64. Prophylactic antiviral therapy (including Ribaviran ) NOT recommended for persons exposed to HFVs in the absence of clinical illness .

65. Postmortem Practices in VHF - PPE for mortuary staffs during c ontact with cadavers as they are implicated in Ebola transmission - Recommendations in a VHF outbreak - Prompt burial or cremation - Minimal handling of corpses (washing only in hospital) - NO embalming - Surgery or post-mortem exams (Autopsy) only when absolutely necessary

66. Environmental Decontamination and housekeeping for HFVs Wear PPE when entering patient room (mask, gown & Gloves). Designated cleaning equipment (mops, paints, wet vacuum). - Double bag all linens and wash in bleach - Disinfect surfaces with 1:100 bleach solution ( Cholorox ). HFVs are not environmentally stable. Use of only yellow bag for garbage in isolation rooms.

67. Mosquitos control: Insecticides, meshes, mosquito-eating fishes, etc.

68. HFVs as Bioweapons

69. Character Availability - High Morbidity +Mortality. - Low infective dose. - Potential for person-person transmission. - Highly infectious by aerosol dissemination. - Vaccine unavailable or limited supply. - Potential to cause public & HCWs anxiety, fear. √ √ √ +/- √ √ √ - Availability of pathogen or toxin. - Feasibility of large scale production. - Environmental stability. - Prior research & development as weapon. +/- √ +/- √ √ √ Character of microorganism for being biological

70. Selected epidemiologic characteristics of illness caused by Category A biologic agents: Disease Incubation period Duration of illness Case fatality rates (CFR) Inhalational anthrax 1-6 days 3 - 5 days Untreated, 100% Treated, 45% Botulism 6 hrs-10 days 24 -72 hrs Outbreak-associated, first patient, 25% Subsequent patients, 4% Tularemia 1 - 21 days 2 weeks Untreated, 33% Treated <4% Pneumonic plague 2-3 days 1- 6 days Untreated, 40%-70% Treated, 5% Smallpox 7-17 days 4 weeks Overall, 20%-50% Viral hemorrhagic fevers 2-21 days 7-16 days Overall, 53%-88%

71. Weaponized HFv Virus Country of weaponization Ebola Virus Russia and former Soviet Union Japan (attempted) Marburg virus Russia and former Soviet Union Lassa virus Russia and former Soviet New World Arenaviridae ( Junin and Machupo ) Russia and former Soviet Rift Valley Fever Yellow Fever North Korea (reportedly) Omsk hemorrhagic fever Kyasanur Forest Disease

72. As HCWs , Everyone is responsible for infection control, he must break this chain at his point(s) of concern

73. References http://health.mo.gov/living/healthcondiseases/communicable/communicabledisease/cdmanual/pdf/Hemorrhagic.pdf . CDC’s National Notifiable Diseases Surveillance System ( NNDSS ) and Case Definitions. http://wwwn.cdc.gov/nndss/. http://www.cdc.gov/yellowfever/symptoms/index.html http://apps.who.int/iris/bitstream/10665/44188/1/9789241547871_eng.pdf http://www.who.int/mediacentre/factsheets/fs207/en/ GCC Infection Prevention and control Manual, 2 nd Edition. 2013. © 2013 National Guard Health Affairs Gulf Cooperation Council – Centre for Infection Control. Riyadh 22490, Kingdom of Saudi Arabia

74. Thank you