Viral Haemorrhagic Fevers

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Viral Haemorrhagic Fevers
Craig Corcoran NHLS Virology, Groote Schuur
Hospital
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VHF- what is it all about?

• VHFs 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

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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
  life-threatening volume loss.

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Viral Haemorrhagic Fevers
Arenaviridae (Lassa, Junin, Machupo, Guanarito)
Enveloped RNA viruses
Bunyaviridae (CCHF, RVF, Hantaviruses)
Filoviridae (Ebola, Marburg)
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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

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• VHF and other infectious diseases travel quickly
  nowadays

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• Early clinical signs and symptoms may be very
  discrete and cannot easily be distinguished from
  those of other illnesses

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• Clinical signs and symptoms are easier to
  interpret once the disease has progressed already

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VHF-clinical picture

• 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

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VHF-differential diagnosis

• VHF vs. VHF
• clinical picture-unreliable, epidemiology-approxim
  ate, laboratory-proof
• 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

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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

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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

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dengue tourniquet test
DHF
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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
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• 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 10-14 days
• Supportive treatment
• Prevention vaccine- 17D live attenuated, safe
  and highly effective

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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

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Ebola Outbreaks

• 1979, 2004

1994
1976, 1979, 2004
1994, 1996, 1996
2000
Congo 2003
1976, 1995
Doctor returning from Gabon
1996
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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

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Marburg outbreaks
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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)

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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)

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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

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Marburg blanching maculopapular rash, day 5,
Johannesburg 1975
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Marburg 2005 335 cases, 283 deaths
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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

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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

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Lassa virus
arenosus (Latin sandy)
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• 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

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Rodent reservoir
Mastomys species complex
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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

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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

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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

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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

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Crimean-Congo Haemorrhagic Fever
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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 1980s- nosocomial outbreak at TBH- 8 cases,
  2 deaths
• 27 cases October 1996- Oudtshoorn ostrich
  abattoir workers

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Distribution of CCHF virus
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• Distribution of the bont-legged ticks in South
  Africa
• reservoir and vector

Hyalomma marginatum rufipes
Hyalomma marginatum turanicum
Hyalomma truncatum
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• Hyalommas are two host ticks
• Lavae and nymphs feed on the first host
• Adults feed on the second host
• Cattle
• Sheep
• Goats
• Ostriches

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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 lt 7days

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What are the clinical features?

• 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

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Skin petechiae
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Petechial haemorrhages on the palate
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Large ecchymoses
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CCHF- laboratory findings

• Leukopaenia or leukocytosis
• WCClt 3 x 109/l or 9 x 109/l
• Thrombocytopaenia
• Platelet lt 150 x 109/l
• Usually lt 100 x 109/l
• Abnormal INR and APTT
• Transaminitis
• AST 100iu/l
• ALT 100iu/l

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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

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CCHF viral/antibody kinetics
IgM
IgG
viremia
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0
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RT-PCR
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Viral isolation
ELISA IgM IgG
IFA
IgM duration 2-3 months up to 6 months
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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

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Specific management
Isolation and barrier nursing
Supportive monitoring of vital functions blood,
fluid replacement treatment of DIC Specific Rib
avirin ?? Immune plasma
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PREVENTION OF CCHF

• Ticks most active during Dec, Jan, Feb, March-
  avoid 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.

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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)

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Infection Control
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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

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• 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

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• 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

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BSL-2 cabinet ?

• provide personnel, environmental and product
  protection
• Approx 30 air exhausted, 70 re-circulated

A. front openingB. sashC. exhaust HEPA
filterD. rear plenumE. supply HEPA filterF.
blower
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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.

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Laboratory safety BSL-4

• In contrast to patient-care,
• high-level protection required for
• Laboratory manipulation
• Mechanical generation of aerosols
• Concentrated infectious material
• Viral culture

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