Haemorrhagic Fever and Dengue Fever Notes
Haemorrhagic Fever
Definition:
Multi-system illness
Multiple organ dysfunction
Characterized by:
Fatigue
Generalized pain
Weakness and exhaustion
Fever (pyrexia)
Haemorrhage (bleeding)
Virus Classification
Baltimore Classification System:
Group I: dsDNA viruses
Group II: ssDNA viruses
Group III: dsRNA viruses
Group IV: Positive-sense, ssRNA viruses
Group V: Negative-sense, ssRNA viruses
Group VI: RNA reverse transcribing viruses
Group VII: DNA reverse transcribing viruses
Haemorrhagic Fever-Causing Viruses
Four main families:
Arenaviridae (Group V)
Filoviridae (Group V)
Flaviviridae (Group IV)
Bunyaviridae (Group V)
Arenaviridae
Characteristics:
Group V (- ssRNA)
Natural reservoir: rodents
Geographically restricted
Diagnosis: Clinical presentation, ELISA, RT-PCR, virus isolation
Prevention:
Isolation
Vaccine (Candid-1) for Argentina and Bolivian haemorrhagic fevers
Treatment:
Ribavirin
Supportive therapy
Specific Arenaviruses and Diseases
Lassa Fever
Causative agent: Lassa virus
Incubation period: 6-21 days
Symptoms: Cough, retrosternal pain, dyspnoea, pleuritis, unilateral or bilateral hearing deficit, seizures, tremors
Mortality rate: 1% overall, 15-20% in hospitalized patients, 50% during epidemics, 80% in 3rd trimester of pregnant women, 95% in foetus
Route of transmission: Inhalation of aerosols from excretions of rodents (Mastomys natalensis)
Other significant features: Endemic in West African countries, detection of rodents, complications (abortion, deafness, neurological disorders)
Argentine Haemorrhagic Fever
Causative agent: Junin virus
Incubation period: 7-14 days
Symptoms: Hypotension, infrequent urination, bradycardia, bleeding from all systems
Mortality rate: 3-30%
Transmission: Inhalation of aerosols from excretions of rodents (Calomys laucha and Calomys musculinus)
Restricted to the area of Junin, Argentina. Detection of rodents.
Bolivian Haemorrhagic Fever
Causative agent: Machupo virus
Incubation period: 7-16 days
Symptoms: Epistaxis, hematemesis (frequently present in the early stages), convulsions
Mortality rate: 3-30%
Transmission: Inhalation of aerosols, person-to-person, small abrasions and cuts in the skin.
Restricted to Bolivia. Detection of Calomys rodents aids diagnosis.
Venezuelan Haemorrhagic Fever
Causative agent: Guanarito virus
Incubation period: 7-16 days
Symptoms: Epistaxis, bleeding gums, hematemesis, melena, menorrhagia
Mortality rate: 30%
Transmission: Contact with excreta of two rodent species: Cane mouse (Zygodontomys brevicauda) and cotton rat (Sigmodon alstoni)
Confined area of central Venezuela. Detection of rodents.
Brazilian Haemorrhagic Fever
Causative agent: Sabia virus
Incubation period: 2-14 days
Symptoms: Multisystem bleeding, purpuric skin lesions
Mortality rate: 33%
Transmission: Inhaling infected aerosols
Confined to the area of Sao Paulo, Brazil
Filoviridae
Characteristics:
Group V (- ssRNA)
Natural reservoir: Unknown (possibly fruit bats or humans)
Diagnosis: Clinical presentation, ELISA, RT-PCR, virus isolation
Prevention:
Isolation
Minimizing contact
Barrier protection
Treatment: Supportive
Balancing electrolytes and lost body fluid
Maintaining patients’ oxygen and blood pressure in optimal level
Vaccine: Under development
Specific Filoviruses and Diseases
Ebola Haemorrhagic Fever
Causative agent: Ebola virus
Incubation period: 2-21 days
Symptoms: Abrupt onset of fever, blinding headache, joint and muscle pain, red eyes, skin rash, internal and external bleedings, bleeding from all systems, hiccup, diarrhoea, abdominal pain, multiple organ failure, lethargy, shock, death
Mortality rate: >90%
Transmission: Person-to-person, infected objects
Endemic in the tropics. Natural reservoir possibly human
Marburg Haemorrhagic Fever
Causative agent: Marburg virus
Incubation period: 5-10 days
Symptoms: Early stages - Abrupt fever, chills, general pain; Later - Maculopapular rash, liver failure, jaundice, shock, massive haemorrhage, multi-organ dysfunction
Mortality rate: Mild cases (23-25%), Severe cases (80-90%)
Transmission: Person-to-person, infected objects
Endemic in the tropics. Natural reservoir possibly bat
Flaviviridae
Characteristics:
Group IV (+ ssRNA)
Natural reservoir: Arthropods (mosquitoes)
Diagnosis: Clinical presentation, ELISA, RT-PCR, virus isolation
Prevention:
Vaccines (in some cases)
Isolation
Protective clothing
Insect repellent
Eradication of mosquitoes
Treatment: Supportive
Rebalance of lost fluid and electrolyte
Combating hypotension
Dialysis in acute renal failure
Specific Flaviviruses and Diseases
Yellow Fever
Causative agent: Yellow fever virus
Incubation period: 3-6 days
Symptoms: Early stage (3-4 days) - Pains, fever, jaundice; Period of remission - Fever and other symptoms alleviate, but 15% of infected individuals move to the third or the most dangerous stage within 24 hours; Period of intoxication - Seizures, multi-organ dysfunction, bleeding disorders, liver failure, kidney failure, coma, shock, death
Mortality Rate: 15-50%
Transmission: Insect bite
Disease is geographically distributed to 90% of Africa. The elderly are more prone to severe infection. Detection of mosquito Aedes aegypti for diagnosis.
Dengue Haemorrhagic Fever
Causative agent: Dengue viruses
Incubation period: 3-5 days
Symptoms: Headache, general body pain, localized retro orbital pain, increased vascular leakage, haemorrhagic phenomena, nausea and vomiting, leucopoenia
Mortality rate: Non-treated (20%), Treated (1%)
Transmission: Insect bite
World-wide distribution, but mostly in the tropics. Detection of vector Aedes aegyptiand Aedes albopictus. for diagnosis
Bunyaviridae
Characteristics:
Group V (- ssRNA)
Vectors: Ticks, mosquitoes, sand flies
Diagnosis: Clinical presentation, ELISA, RT-PCR, virus isolation
Prevention:
Isolation
Barrier protection
Reduced contact with infected animals
Self hygiene
Eradication of carrier
Treatment:
Ribavirin
Supportive therapy
Specific Bunyaviruses and Diseases
Rift Valley Fever
Causative agent: Rift Valley fever virus
Incubation period: 2-6 days
Symptoms: Mild - Asymptomatic, flue-like symptoms, meningitis-like symptoms; Severe - Ocular (0.5-2%) OR Meingoencephalitis (<1%) OR Severe haemorrhagic fever (>1%)
Mortality rate: Mild (1%), Severe (50%)
Transmission: Body fluid, tissue of infected animal, unpasteurized milk, mosquito bite, exposure to infected blood
Confined to the cattle & sheep raising regions e.g. Eastern and Southern Africa. No human-to-human transmission (except vertically in Sudan).
Haemorrhagic Fever with Renal Syndrome (HFRS)
Causative agent: Hantavirus
Incubation period: 7-14 days
Symptoms: Sudden onset of fever, blurred vision, acute shock, vascular haemorrhage, kidney failure
Mortality rate: Almost confined to Korean sub-continent, 5-15%
Transmission: Aerosols from rodents excreta, direct transmission of above with broken skin, mucous membrane of eyes, mouth & nose, rodent bites.
Crimean-Congo Haemorrhagic Fever (CCHF)
Causative agent: Crimean-Congo Haemorrhagic Fever Virus
Incubation period: 1-9 days
Symptoms: Early stages - Generalized pain, photophobia, non-bloody diarrhoea; Late stages - Confused, aggressive, bleeding from all systems/orifices, hepatomegaly, tachycardia, hepatorenal & pulmonary failure
Mortality rate: 30-50% (2nd week)
Transmission: Tick bite (ixodid tick), direct contact with infected tissues of livestock, direct contact with live livestock, human-to-human (nosocomial – hospital acquired)
Endemic regions in Asia, Africa, and Europe. Involvement with livestock, their fluid, tissue, and slaughter.
Dengue Fever
General Information:
Infects more than 50 million people annually, killing about 24,000 each year.
Acute, fever-causing disease, found in the tropics and Africa (geographically similar range to malaria).
Caused by one of four closely related virus serotypes of the genus Flavivirus, family Flaviviridae.
Transmitted to humans via the Aedes aegypti mosquito (Aedes albopictus).
Viral Genome:
Characterized by a small, enveloped virion.
Positive-sense, single-stranded RNA genome.
Causative agent of Dengue fever and Dengue haemorrhagic fever in humans.
Dengue Virus Types:
Difficult to examine because there are no laboratory or animal models of the disease.
Four distinct antigenic types (DEN-1, DEN-2, DEN-3 and DEN-4).
Indirect evidence suggests important biological differences among the viral genotypes.
Epidemiology:
Dengue is the most important arthropod-borne disease of humans.
DENV group consists of four antigenically closely related viruses: DENV1-4
DEN-1 and DEN-2 first identified during WWII in the Pacific; DEN-3 and DEN-4 isolated in Philippines in 1956
Over 2.5 billion people live in risk areas for dengue infection
50-100 million cases annually, 20,000 deaths
Prevention and control: no vaccine yet available, vector control includes mosquito larvae source reduction and insecticide sprays
Clinical Features:
Most asymptomatic
Classical dengue fever: - Acute febrile illness, older children and adults, fever, rash, headache, muscle/joint pain, nausea, vomiting, rarely haemorrhage, convalescence of several weeks
Dengue haemorrhagic fever (DHF)/ Dengue shock syndrome (DSS): - severe form of the disease, fever, haemorrhage, vascular leakage, petechiae, hepatitis, risk factors: virus strain and previous infection with a different DEN serotype induced by Antibody Dependent Enhancement
No chemotherapy available, fluid replacement for DHF treatment
Antibody Dependent Enhancement
Mechanism:
First infection with a serotype of DEN
Mostly asymptomatic
May get DF, usually mild illness
Production of neutralizing antibodies to that serotype
Second infection with a different serotype
Antibodies to first serotype not neutralizing for second serotype
Antibodies attach with low affinity, enough to allow macrophages to take up virus (receptors for Fc)
Macrophages disseminate/spread virus though body
Transmission of Dengue
Cycles:
DENVs originated and are maintained in a forest (sylvan) transmission cycle involving canopy-dwelling Aedes spp. mosquitoes and primates
DENVs have fully adapted to humans and can also be maintained independently in an urban transmission cycle involving Ae. aegypti
Ae. aegypti is a highly domesticated (‘anthropophilic’) mosquito that has adapted to humans, preferring to feed on them and lay their eggs close to houses/ dwellings
Changing Epidemiology of Dengue
Global Emergence:
In the past 50 years, there has been a global emergence and re-emergence of epidemic dengue.
Reasons for Increased Dengue Activity
Factors:
Unplanned urbanization occurred in urban centres of SE Asia after WWII and in the Pacific and American tropics in the 1970s and 1980s
Lack of mosquito control in these newly populated centres
Advent of modern air travel increased movement of people, many of them infected and carrying DENV
Increased international commerce and trade has led to vector transport
Spread of vector due to changing environment (e.g., Europe)
Dengue in Australia
Historical Context:
Dengue occurred in Northern Territory, Queensland and New South Wales in the first part of the last century.
It disappeared following an epidemic in 1955 and reappeared in 1981 (DEN1)
Since then, regular epidemics in Northeast Qld
Current Status:
The distribution of the dengue vector Ae. aegypti is currently restricted to areas of Nthn Qld
Dengue is not considered endemic in Australia; epidemics arise from virus introduced by infected travellers.
Dengue Vaccine Development
Challenges:
DENV vaccine development has been underway for over 60 years.
The problems in development reflect the requirements of the vaccine to provide immunity to each the four serotypes (tetravalent).
Reasons for Tetravalent Requirement:
Infection with one serotype provides long-term protective immunity to this serotype, but not to others.
Severe DEN infection is associated with prior infection with a different serotype
Believed to be mediated by non-neutralising antibodies that remain from the first infection.
Mechanism of action is Antibody-Dependent-Enhancement (ADE), whereby pre-existing cross-reacting Abs facilitate entry of second infecting DENV into cells.
One or several serotypes can circulate simultaneously and serotypes can also change from one season to the next.
Vaccine Choices - Inactivated vs. Live-Attenuated
Inactivated Vaccine:
Require multiple inoculations for full protection
Elicit short-term immunity, requiring booster immunisation
Do not induce full range of immune responses observed during natural infection
Expensive to produce
Live-Attenuated (LAV) Vaccine:
Require 1-2 inoculations
Induce strong and long-lasting protective immunity
Immune response mimics natural infection
Relatively inexpensive to produce
Live-Attenuated Tetravalent Dengue Vaccine
Development:
The introduction of infectious cDNA technology has led to the development of LAVs for dengue and other flaviviruses.
For DENV, the most promising LAV is a chimeric virus which utilises an infectious clone of the Yellow Fever (17D) vaccine strain
YF17D is attenuated virus developed in the 1930s by serial infections of mouse embryos
Is one of the oldest vaccines and considered one of the safest and effective vaccines
~400 million doses administered worldwide
In the chimeric vaccine (ChimeriVax-DEN), the genes encoding the YFV prM-Env have been replaced by those of DENV
Env protein is the dominant viral antigen, neutralizing antibodies
prM (pre-M protein, M is an envelope protein of unknown function) also induces neutralizing antibodies
Strategy for Constructing Chimeric Vaccine
Method
prM-Env genes of YF-17D removed by restriction digest
prM-Env genes of DENV amplified by RT-PCR
prM-Env genes of DENV ligated into YF-17D backbone
ChimeriVax-DEN Performance Evaluation/Trial Results
Preclinical Results
Cell culture: Replicated to high titres
Neurovirulence in mice: Non-neurovirulent
Rhesus monkeys: Immunogenic (full seroconversion), Low level viraemia
Replication in Ae. Aegypti: Reduced growth, loss of virus dissemination
Clinical Phase I Results
Safety and immunogenicity: Consistent with YF17D vaccine, pre-immunity to DENV does not affect response, pre-immunity to YFV enhanced DENV antibody response, 100% seroconversion
Haemorrhagic Fever Outbreak in Herat, Afghanistan - Case Study
Location:
Gulran, Herat, Afghanistan
Shoor Ab Village
Population: 500 people
Occupation: animal husbandry, farming
Epidemiology:
Number of infected individuals: 26
Symptoms: Fever, haemorrhagic manifestations from all systems/orifices, dizziness, lethargy, headache, petechial rash, hepatomegaly and liver failure, renal failure, pulmonary failure
Age: 22-70, mainly in 40s
Index cases:
Two shepherds
One butcher
One farmer
Other cases:
13 - family members of the index cases
1 - Mullah of the community
8 - shepherds, farmers, teachers in the village
Timeline:
May 2000: initiation of outbreak
DoH initiated investigation 2 weeks after 1st cases
June 2000: WHO was called for their assistance
A group of experts from WHO arrived in the region <10 days after DoH commenced investigation
An isolation room setup within Herat Hospital, equipped
Samples from all patients were sent to NIV
Treatment and control measures were established 10 days post DoH investigation
Training seminars for health care staff
July 2000: NIV reported causative agent not identified
July 2000: Another group of experts arrived in Herat
Post Outbreak Summary:
The causative agent: not identified
Control measures: appropriate BUT delayed commencement
Treatment: Ribavirin, supportive BUT delayed commencement
The year 2000 drought in the country killed all livestock and this contributed to eradication
Mortality: n=15/26 (58%)
Factors Contributing to High Mortality Rate
Reasons:
Lack of awareness of healthcare workers of haemorrhagic fever
Taliban Government: underdeveloped health system
No reporting of suspected cases following the first cases
DoH only initiated investigation two weeks late
Control measures and treatment: 25 days late
Public lack of awareness
Why Causative Agent was Not Identified?
Possible Errors:
Error in sample collection?
Error in transporting?
Inappropriate transport media?
Time elapsed between sample collection and laboratory examination
Virus Family, Viruses, Epidemiology, Human-to-Human Transmission, Clinical Features
Arenaviridae
Lassa virus: Endemic in West African Countries, NO Human Transmission Rodents
Junnin virus: Argentina, NO Human Transmission
Machupo virus: Bolivia, YES Human Transmission
Guanarito virus: Venezuela, NO Human Transmission
Sabia virus: Brazil, NO Human Transmission
Filoviridae
Ebola virus: Tropics, YES Human Transmission Fruit bat?, Human?
Marburg virus: Tropics, YES Human Transmission
Flaviviridae
Yellow fever virus: 90% of Africa, NO Human Transmission Mosquito
Dengue virus: Worldwide, but mostly tropics, NO Human Transmission
Bunyaviridae
RVF virus: South African countries, Saudi Arabia, NO Human Transmission Mosquito
CCHF virus: Asia, Africa, Europe, YES Human Transmission Tick, Livestock
Hantavirus: Korea, South America, RARELY Human Transmission Rodents
Causative Agent of Herat Outbreak
Epidemiological Studies:
Livestock involvement
Crimean-Congo Haemorrhagic Fever (CCHF) is endemic in Iran and Pakistan
Refugees coming from endemic area
Livestock imported from endemic area
Clinical Features:
Dizziness
Lethargy
Hepatomegaly
Pulmonary failure
Haemorrhagic manifestations from all systems/orifices
CCHF Identified in Herat 2008
Second Outbreak:
August 2008
Same area, same clinical features
CCHFV isolated from patients’ samples
10 cases leading to 3 deaths
Treatment, control measures established within two days
No new cases and no further deaths
Eradication:
The disease eradicated in less than two weeks
Summary of Haemorrhagic Fevers
HF is a multi-system illness with bleeding and fever
Four families of viruses can cause HF
Severity, mortality rate and intervention differ according to the causative agent
Likely that the original outbreak in 2000 was caused by CCHF
Early diagnosis, treatment and prevention are essential in controlling the outbreak and preventing the spread of the disease
Here are the answers to your questions based on the provided notes:
Which 4 virus families are involved with causing haemorrhagic fever?
Arenaviridae
Filoviridae
Flaviviridae
Bunyaviridae
List the viruses in each family causing haemorrhagic fever
Arenaviridae: Lassa virus, Junin virus, Machupo virus, Guanarito virus, Sabia virus
Filoviridae: Ebola virus, Marburg virus
Flaviviridae: Yellow fever virus, Dengue viruses
Bunyaviridae: Rift Valley fever virus, Hantavirus, Crimean-Congo Hemorrhagic Fever Virus
List the types of clinical features caused by dengue.
Headache
General body pain
Localized retro orbital pain
Increased vascular leakage
Hemorrhagic phenomena
Nausea and vomiting
Leucopoenia
What is “antibody dependant enhancement”?
ADE occurs when a second infection with a different serotype of dengue virus happens.
Antibodies from the first infection are not neutralizing for the second serotype.
These antibodies attach with low affinity, allowing macrophages to take up the virus.
Macrophages then disseminate the virus throughout the body.
Give reasons for the increase in spread of dengue.
Unplanned urbanization in urban centers of Southeast Asia after WWII and in the Pacific and American tropics in the 1970s and 1980s.
Lack of mosquito control in these newly populated centers.
Increased modern air travel, increasing movement of infected people.
Increased international commerce and trade, leading to vector transport.
Spread of the vector due to changing environment.
What is the major issue with dengue vaccines?
The dengue vaccine must provide immunity to each of the four serotypes (tetravalent), as severe dengue infection is associated with prior infection with a different serotype.
How is the ChimeriVax-DEN vaccine made?
The ChimeriVax-DEN vaccine is a chimeric virus that utilizes an infectious clone of the Yellow Fever (17D) vaccine strain.
The genes encoding the Yellow Fever virus prM-Env proteins are replaced by those of the Dengue virus.
What were the contributing factors causing the mortality rate in the 2000 Gulran outbreak
Lack of awareness of healthcare workers of hemorrhagic fever.
Underdeveloped health system due to the Taliban government.
No reporting of suspected cases following the first cases.
Delayed investigation by the Department of Health.
Delayed control measures and treatment.
How was dengue and yellow fever excluded as possible causes of the 2000 Gulran outbreak?
The causative agent was not identified in the initial investigation by NIV (National Institute of Virology). Samples were sent from patients in the outbreak but came back without any determination of the cause. This would also include testing to see if it was Dengue or Yellow Fever.