Transcript Slide 1

Viral Haemorrhagic Fevers
Craig Corcoran
NHLS Virology, Groote Schuur Hospital
VHF- what is it all about?
• VHF’s attract the attention of
medical professionals and the
general public for a variety of
reasons
• They are high on the public mind
as they are thought of as highly
infectious, killing their victims in a
dramatic way
• Mysteries remain as to the source
of some of them
“Viral Haemorrhagic Fever”
An acute febrile illness characterized by
malaise, myalgia, and prostration
dominated by generalized abnormalities of
vascular permeability, and regulation.
Bleeding manifestations often occur,
particularly in severe cases; they are
usually diffuse and reflect widespread
vascular damage rather than lifethreatening volume loss.
Flaviviridae
(dengue, yellow fever,
TBE encephalitides)
Viral Haemorrhagic Fevers
Arenaviridae
(Lassa, Junin, Machupo, Guanarito)
Enveloped
RNA viruses
Filoviridae
(Ebola, Marburg)
Bunyaviridae
(CCHF, RVF,
Hantaviruses)
These viruses share a number of
features:
• They are all RNA viruses and are enveloped (i.e covered
in a fatty (lipid) coating
• Their survival is dependent on an animal or insect host
called the natural reservoir
• They are geographically restricted to areas where their
host species live
• Humans are not the natural reservoir for any of these
viruses. Humans are infected when they come into
contact with infected hosts, and with some viruses, can
transmit the virus to one another
• Human outbreaks occur sporadically and irregularly.
These outbreaks cannot be easily predicted
• With few exceptions, there is no cure or established drug
treatment for VHFs
• VHF and other
infectious diseases
travel quickly
nowadays
• Early clinical signs
and symptoms may
be very discrete and
cannot easily be
distinguished from
those of other
illnesses
• Clinical signs and
symptoms are easier
to interpret once the
disease has
progressed already
VHF-clinical picture
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Short incubation period
Non-specific onset of illness
Headache, myalgia, arthralgia
Pharyngitis, conjunctival injection/bleed
GIT discomfort/disturbances
Impaired consciousness
Haemorrhages
Proteinuria
Jaundice
Rash, exanthema
VHF-differential diagnosis
• VHF vs. VHF:
– clinical picture-unreliable, epidemiology-approximate, laboratoryproof
• VHF vs. bacterial infections
– Typhoid, leptospirosis, tick-bite fever, shigellosis, purulent
pharyngitis, sepsis (streptococcal, staphylococcal,
meningococcal), plague
• VHF vs. parasitic diseases
– Malaria, african trypanosomiasis, amoebiasis
• VHF vs. viral diseases
– Viral hepatitis, herpes simplex
Dengue fever
• Main hosts- non human
primates
• Human-to-human
transmission through
Aedes spp.
• 2.5 billion individuals at
risk
• 40-80 million infected
each year with thousands
of deaths
Dengue-clinical features
• Fever, headache, back pain , chills, musculoskeletal
pain, rash, leucopaenia, thrombocytopaenia
• Usually lasts 4-10 days
• Dengue haemorrhagic fever/Dengue shock syndrome
– Acute vascular hyperpermeability plus abnormal haemostasis
– Rapid deterioration after 2-5 days
– Scattered petechiae, ecchymoses, easy bruising/bleeding,
hepatomegaly, epigastric pain
• Pathogenesis: enhancing antibodies- maternal in infants,
second infection with a different serotype
• Supportive treatment, vaccine in development
dengue tourniquet test
DHF
Yellow Fever
• Historic illness stretching back
400 years
• yellow: jaundice affecting
certain patients
• Mosquitos (Aedes and
haemogogus) are the true
reservoir and vector
• Estimated 200 000 cases/year,
30 000 deaths
• Symptoms vary from mild to
severe with haemorrhagic
manifestations
Africa and South
America only
• ‘acute’ phase- fever,
headache, muscle pain,
GIT disturbance
• 15% enter a ‘toxic’ phase
and rapidly develop
jaundice with bleeding
manifestations and renal
failure. 50% die within 1014 days
• Supportive treatment
• Prevention: vaccine- 17D
live attenuated, safe and
highly effective
Filoviruses: Ebola HF
• 1976- Simultaneous large
outbreaks in Yambuku (Zaire, now
DRC) and Nzara/Maridi (Sudan)
• Originally thought to be one
outbreak
• Virology now recognises 2 distinct
viruses
• EBO-Z: 318 cases; 88% fatal
• EBO-S: 284 cases; 53% fatal
Ebola Outbreaks
1979, 2004
Ivory Coast
1994
Sudan
1976, 1979,
2004
Gabon
1994, 1996, 1996
Congo
2003 DRC
Uganda
2000
(formerly Zaire)
1976, 1995
0
2,000
kilometers
4,000
South Africa
1996*
*Doctor returning
from Gabon
Filoviruses: Marburg HF
• 1967: Marburg, Frankfurt & Belgrade
– African green monkeys from Uganda
• 25 primary
• 6 secondary
– 1 sexual transmission from husband to wife
85 days after onset of illness, virus cultured
from semen
• 7 deaths
Marburg outbreaks
Routes of transmission: filoviruses
• Contact with body fluids of an ill patient
– HCW and relatives
• Infected carcasses (handling/cutting of dead
primates)
• Needle transfer
• Preparation of body for burial
• Sexual transmission
• Laboratory accident
• Aerosol infectivity potential demonstrated
experimentally in monkeys (Ebola)
Reservoir of infection
• Not identified in terrestrial animals or in
insects
• Non-human primates suffer but are not the
reservoir
• Association with caves and mines make
bats suspects for Marburg
• Fruit bats- ? reservoir for Ebola and
Marburg (antibodies and RNA found by
researchers in Gabon)
Filoviruses: clinical
presentation
• 1-2 week incubation
• Abrupt onset fever, headache, myalgia
• Non-pruritic papular erythematous
eruption becoming large coalescing
macules and papules
• Palatal petechiae and haemorrhages
• GI symptoms, chest pain, delirium
• Sever cases- haemorrhages from
venipuncture sites, mucous membranes
and venipuncture sites
• 53-88% case-fatality
• ~ 45% hemorrhage
• Supportive treatment
• Vaccines in development
Marburg blanching maculopapular rash, day 5,
Johannesburg 1975
Marburg 2005:
335 cases, 283
deaths
Arenaviridae
• Arenaviruses associated with human disease
Virus
Origin of Name
Year Distribution
Lassa
Town, Nigeria
1969 West Africa
Junin
Town, Argentina
1957 South America
Machupo River, Bolivia
1962 South America
Guanarito Area, Venezuela
1989 South America
Sabia
Town, Brazil
1990 South America
LCMV
Clinical disease
1933 Worldwide
Lassa: general facts
• Viral hemorrhagic fever caused by the
Arenavirus Lassa
• Transmitted from rodents to humans
• Discovered in Nigeria, 1969
• Endemic in portions of West Africa
• Seasonal clustering: Late rainy and early dry
season
• Affects all age groups and both sexes
Lassa virus
“arenosus”
(Latin “sandy”)
• Endemic in areas of West Africa,
including Nigeria, Liberia, Sierra
Leone, and Guinea
• Estimated 300,000-500,000
infections/year, with 5000 deaths
• Rodent-to-human transmission
(the “multimammate rat”,
Mastomys species-complex)
• Secondary human-to-human
transmission with the potential
for nosocomial outbreaks with
high case-fatality
Rodent reservoir
Mastomys species complex
Lassa: Transmission
• Rodent-to-human:
– Inhalation of aerosolized virus
– Ingestion of food or materials contaminated
by infected rodent excreta
– Catching and preparing Mastomys as a
food source
Lassa: Transmission
• Human-to-human:
– Direct contact with blood, tissues,
secretions or excretions of infected
humans
– Needlestick or cut
– Inhalation of aerosolized virus
– Sex
– Breast feeding
Lassa: Clinical Aspects
• 80% asymptomatic
• Incubation period of 5-21 days
• Gradual onset of fever, headache, malaise and
other non-specific signs and symptoms
• Pharyngitis, myalgias, retro-sternal pain, cough
and gastrointestinal symptoms typically seen
• A minority present with classic symptoms of
bleeding, neck/facial swelling and shock
• Case fatality of hospitalized cases: 15-20%
• Particularly severe in pregnant women and their
offspring
• Deafness a common sequela
Lassa: Treatment
• Supportive measures
• Ribavirin
– Guanosine nucleoside analog:
blocks viral replication by inhibiting IMP
dehydrogenase
– Licensed for treatment of RSV and HCV
– Potential adverse effects:
• Dose dependent reversible anemia
• Pancreatitis
• Teratogen in rodents
Crimean-Congo Haemorrhagic Fever
CCHF-some background
• 1944- Crimean peninsula- Crimean haemorrhagic fever
(about 200 cases)
• 1956- Belgian Congo- 1 child- Congo Fever
• Virus isolated in suckling mice in 1967
• 1-10 cases diagnosed annually in South Africa
• Case fatality rate 20-25%, 30-50% without proper
medical attention
• Mid 1980’s- nosocomial outbreak at TBH- 8 cases, 2
deaths
• 27 cases October 1996- Oudtshoorn ostrich abattoir
workers
Distribution of CCHF
virus
Distribution of the bont-legged
ticks in South Africa
•reservoir and vector
Hyalomma marginatum
rufipes
Hyalomma marginatum
turanicum
Hyalomma truncatum
Hyalommas are two host ticks
- Lavae and nymphs feed on
the first host
- Adults feed on the second
host
-Cattle
-Sheep
-Goats
-Ostriches
So when are humans at risk?
• Bitten by tick/s or crushed tick/s with bare hands
• Direct contact with fresh blood or other tissues of
livestock or game animals (ear tagging,
castration ect.)
• Direct contact with blood, secretions or
excretions of a confirmed or suspected CCHF
patient including needlestick injuries
• Resided in or visited a rural environment where
contact with livestock or ticks was possible but a
specific incident constituting exposure cannot be
identified
• NB- incubation period usually 2-7 days hence
exposure usually < 7days
What are the clinical features?
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Sudden onset
Fever ≥ 38ºC on at least one occasion
Severe headache
Myalgia
Nausea and/or vomiting
Pharyngitis, conjunctivitis
Bleeding tendency: petechial rash, ecchymoses,
epistaxis, haematemesis, haematuria or
melaena
Skin petechiae
Petechial haemorrhages on the palate
Large ecchymoses
CCHF- laboratory findings
• Leukopaenia or leukocytosis
– WCC< 3 x 109/l or ≥ 9 x 109/l
• Thrombocytopaenia
– Platelet < 150 x 109/l
– Usually < 100 x 109/l
• Abnormal INR and APTT
• Transaminitis
– AST ≥ 100iu/l
– ALT ≥ 100iu/l
CCHF-differential diagnosis
• Malaria, tick bite fever, disseminated HSV,
viral hepatitis, typhoid, rift valley fever,
anthrax, brucellosis, Q fever…
• History of exposure, incubation period
following exposure, signs and symptoms,
laboratory findings
CCHF : viral/antibody kinetics
IgM
IgG
viremia
0
5
10
RT-PCR
16
Viral isolation
ELISA IgM IgG
IgM duration: 2-3 months up to 6 months…
IFA
CCHF : laboratory diagnosis
NICD, Johannesburg, BSL-4 (3)
Viral detection: (blood specimen)
– RT-PCR (nested)
– Cell culture (Vero E6 cells)
– Innoculation of newborn mice
Antibody detection : (serum sample)
- IFA
- ELISA
- NT
Specific management
Isolation and barrier nursing
Supportive:
monitoring of vital functions
blood, fluid replacement
treatment of DIC
Specific:
Ribavirin
?? Immune plasma
PREVENTION OF CCHF
• Ticks most active during Dec, Jan, Feb, Marchavoid hiking/camping
• DEET repellents for skin
• Permethrin repellents for clothing –
(0.5% permethrin should be applied to clothing ONLY)
• Check for and remove ticks at least twice daily.
• If a tick attaches, do not injure or rupture the tick.
Remove ticks by grasping mouthparts at the skin surface
using forceps and apply steady traction.
PREVENTION OF CCHF
• Persons working with livestock- wear gloves and
other protective clothing to prevent skin contact
with infected tissue or blood
• Quarantine and treatment with an ascaricide
prior to slaughter (ostriches)
Infection Control
Handling laboratory specimens from patients
with suspected or confirmed VHF-non viral
diagnostic specimens
• Common sense- know the risks
• Blood and other specimens are highly infectious
• Risk of transmission through skin/mucous membrane
contact and needle stick injuries. ?? Respiratory
transmission but avoid aerosolisation of specimens
• Limit laboratory testing to what is strictly necessary and
where possible run specimens at a time when there is
minimal disruption to routine work
• Useful to for two techs to work together- one to process
the specimen, other to operate the instrument
• Protective clothing: disposable gown, 2 pairs of gloves,
mask and eye protection
• Centrifuge with closed buckets and decontaminate after
use
• Open buckets, specimens and load instrument racks in a
BSL-2 cabinet
• Discard residual sample and sampling containers into
2% glutaraldehyde or sodium hypochlorite
• Decontaminate instruments according to manufacturers
instructions
• Clean BSL-2 cabinet with glutaraldehyde or sodium
hypochlorite
• Discard protective clothing, gloves, specimens, ect. Into
a biohazard labelled autoclave bag. Double bag and
send for autoclaving
• Haematology:
– prepare slides in a BSL-2 cabinet, once fixed regard
as non-infectious
– Regard air dried slides as infectious, decontaminate
microscope after use
• Microbiology:
– protective clothing, process specimens in BSL-2
cabinet, discard residual specimen into 2%
glutaraldehyde or sodium hypochlorite
– Process positive blood cultures in a BSL-2 cabinet
– Referral of specimens- appropriate packaging, inform
receiving laboratory
• Virology:
– Routine specimens- as above
– VHF diagnosis- requires BSL 3-4 laboratory
BSL-2 cabinet ?
• provide personnel,
environmental and
product protection
• Approx 30% air
exhausted, 70% recirculated
A. front opening
B. sash
C. exhaust HEPA filter
D. rear plenum
E. supply HEPA filter
BSL-4 laboratory?
• dangerous and exotic agents that
pose a high individual risk of
aerosol-transmitted laboratory
infections and life-threatening
disease
• special engineering and design
features to prevent
microorganisms from being
disseminated into the
environment.
• Activities are confined to Class III
biological safety cabinets, or
Class II biological safety cabinets
used with one-piece positive
pressure personnel suits
ventilated by a life support system.
Laboratory safety: BSL4
In contrast to patient-care,
high-level protection required for:
• Laboratory manipulation
• Mechanical generation of aerosols
• Concentrated infectious material
• Viral culture
THANK YOU…