Viral Hemorrhagic Fevers

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

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.

• 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

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

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.

• 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)

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

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.

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.

CASE-FATALITY (MORTALITY) RATE
Virus Mortality rate
Filoviruses Around 90% for Ebola virus (the
highest)
Flaviviruse
s
0.5%
Arenavirus
es
15-30%
Causes of death:
1- Hemorrhagic diathesis
(several body sites & orifices)
2- Shock
3- Multi-organ failure

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
DIC
ITP
TTP / HUS
Acute leukemia
Vasculitis
Collagen-vascular diseases

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.

• 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?

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.

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

• Health care workers (HCWs) have critical

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

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 5th Guinea strain.
• High mutational potentials.
• Rapidly replicating within 8 Hs.
• U or 6-shape virus.

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

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

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

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.

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.

90% of
yellow
fever cases
occur in
Africa

10% of yellow
fever cases
occur in S.
America

- 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

- > 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 .

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.

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

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.

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)

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).

Epidemic
year
Total cases DHF DSS Deaths
1993 1st 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** http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057576/
Dengue Fever in KSA
3 serotypes present (1, 2, & 3), Jeddah & Makkah are affected
pilgrims, Aedes aegypti was detected also in Al-Maddinah **

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

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%.

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)
- Ingestion 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.

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

Rift Valley fever Distribution

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

- 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)

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).

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).

DIAGNOSIS,
MANAGEMENT AND
CONTROL OF VHF

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 oC.
- 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)

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

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
A- Non specific Lab Abnormalities in HFV Infection

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

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

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

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

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.

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

- 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.

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

3. The Nurse in charge of ERnotifies 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

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.

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

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.

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.

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 oC.
-Report any S/S of VHF
- Initiate Ribavirin if S/S of VHF develop (Arenavirus or
Bunyavirus only).

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

Postmortem Practices in VHF
- PPE for mortuary staffs during contact 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

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.

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

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 biolog

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 2-21 days 7-16 days Overall, 53%-88%

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

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

REFERENCES
• HTTP://HEALTH.MO.GOV/LIVING/HEALTHCONDISEASES/COMMUNICABLE/C
OMMUNICABLEDISEASE/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, 2ND EDITION. 2013.
© 2013 NATIONAL GUARD HEALTH AFFAIRS GULF COOPERATION COUNCIL –
CENTRE FOR INFECTION CONTROL. RIYADH 22490, KINGDOM OF SAUDI

Viral Hemorrhagic Fevers

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