Download emerging and reemerging viral infectious diseases

Emerging and Reemerging Viral
Infectious Diseases
Joseph Becker, MD
Michele Barry, MD FACP
Yale University School of Medicine
January, 2009
Prepared as part of an education project of the
Global Health Education Consortium
and collaborating partners
Learning Objectives
1.
2.
3.
4.
5.
Ecology of Emerging & Re-emerging Diseases
Public Health Relevance
Relevant host-vector-pathogen interactions
Ecological, Epidemiological, and Clinical
Characteristics
Current Approaches to Surveillance
Page 2
Emerging Infectious Diseases:
Historical Context
• 1340: Bubonic Plague “Black
Death”: 75 million deaths
- 30-60% of European
population killed
• 1500s: Smallpox to the
Americas: 10-15 million deaths
- End of Aztec civilization
• 20th Century: HIV/AIDS:
>50 million deaths
Fig 1: Illustration from the Toggenburg
Bible of those afflicted by the Bubonic
Plague
Page 3
Why Emerging Infectious Disease?
1*
• Multiple explanations for the emergence and
reemergence of infectious diseases:
- Climate change
- Injudicious and widespread use of
antimicrobials
- Bioterrorism (‘weaponization’ of
pathogens)
- Mobile human populations
- Environmental modification (Legionnaires
disease)
*Superscript references can be found at the end of this module
Page 4
Why Emerging Infectious Disease?
Continued:
- Human population encroachment on
wilderness (vector populations)
- Concentration of human populations
- Dispersal of vectors (and pathogens)
through trade, transport, migration
- Immuno-compromised populations
Page 5
The State of Emerging
Infectious Diseases
• Analysis of 335 “EID Events”: 1940 to 2004
• Control for geographic and historical reporting bias
• EIDs dominated by zoonoses (60% of EIDs)
- 71.8% of zoonoses arise in wildlife
• Viral EIDs: 25% of all EIDs
• Vector borne EIDs: 23% of EIDs: significant recent rise
• Threat of EIDs is increasing
• Non-random geographic distribution of EIDs
Jones K, Patel G, Levy M, et al. Global trends in emerging infectious diseases.
Nature 2008. 451:21; 990-994.
Page 6
The State of Emerging Infectious
Diseases Continued
.
• Antimicrobial resistant EIDs: 20.9% of EIDs
- attributable to increase in antimicrobial use
• Zoonotic EID events correlate with geographic wildlife diversity
- No correlation with population growth
• Zoonotic non wildlife EIDs: predicted by human population
density/growth
• Vector borne EIDs: No correlation with rainfall, human
population or wildlife diversity
• Human population density independent predictor of EID events
Jones K, Patel G, Levy M, et al. Global trends in emerging infectious diseases.
Nature 2008. 451:21; 990-994.
Page 7
Geographic Distribution of Detection of EIDS (1940-2004)
Fig 2: Geographic Distribution of EIDs 1940-2006: Jones et al.
This graphic demonstrates the geographic distribution of detected EIDs portraying the trend that EIDs are
largely detected once they have reached Europe and the US, while their geographic origins are shown in the
following slide. The size of each circle is proportional to the number of EID events.
Page 8
Global EID Risk Distribution
Fig 3: Global EID Risk Distribution: a) zoonoses from wildlife, b) zoonoses from non-wildlife, c) drug resistant
pathogens, d) vector borne pathogens. Jones et al.
This slide demonstrates the regions at most risk for the development of EIDs based on the historical sample in this
study. The upper left box (a) shows zoonotic pathogens from wildlife. Box b (upper right) zoonotic pathogens from nonwildlife. Box c (lower left box) drug resistant pathogens, and lastly box d (lower right hand box) demonstrating vector
borne pathogens.
Page 9
Selected Emerging Viruses of
Public Health Significance
• SIV/HIV
• Viral Hemorrhagic Fevers
- Filoviruses
- Arenaviruses
- Bunyaviridae
• Flaviviruses (Yellow Fever, Dengue, West Nile)
• Emerging Respiratory Pathogens
- SARS
- Avian Flu
Page 10
Lentiviruses: SIV and HIV 4
• SIV/HIV: retroviruses (RNA viral genome converted to DNA via enzyme
reverse transcriptase)
• Simian Immunodeficiency Viruses (SIVs) are the origin of Human
Immunodeficiency Viruses (HIV 1,2)
• Origin of HIV 1: SIVcpz (Chimpanzee: Pan troglodytes troglodytes)
• Origin of HIV 2: SIVsm (Sooty Mangabee: Cercocebus atys)
• SIVcpz/SIVsm cause no discernable disease in their hosts
• SIVcpz and SIVsm have existed for millennia
HIV-1 and HIV-2 are direct descendants from SIVcpz (Chimpanzee) (Cameroon, Gabon, DRC, central Africa)
and SIVsm (Sootey Mangabey) (Sierra Leone, Liberia). SIVcpz and SIVsm have existed for thousands of
years and no longer cause discernable disease in their hosts. However, these same viruses cause lethal
immunodeficiency in other primates, particularly Asian Macaques. It is likely that humans have had contact
with these viruses for an extensive period of time. However, HIV is likely a fairly new pathogen as HIV was
not carried to the New World with the estimated 10 million slaves that were forcibly transported to the
Americas. Evidence suggests that HIV developed within the past 100 years. It is unknown what behavioral,
societal or biological factors contributed to the emergence of these cross species transmission events in the
last century. It is as well unknown if these factors are still in existence and could therefore contribute to the
emergence of further epidemic or pandemic subtypes of HIV.
Page 11
Lentiviruses: SIV and HIV 4,5
• Human contact with SIVs is likely longstanding (> 1000 years) through
hunting and butchering of Non-Human Primates (NHPs) for food
• Despite longstanding human SIV exposure: epidemic HIV only emerges
only in last 60 years
• No HIV brought to the New World with >10 million African slaves
• Unclear mechanism of cross species transmission and origin of
epidemic HIVs
• 11 individual cross species transmission events documented (HIV-1
subgroups M,N,O and HIV-2 subgroups A-G) in mid twentieth century
Page 12
SIV and HIV :
•
•
•
•
•
•
•
Cross species transmission events may
be ongoing
33 species of Non-Human Primates
(NHPs) harbor their own SIV species
Hunting and butchering of NHPs for food
common in central Africa
SIVs isolated from bushmeat prepared for
human consumption
Ancestral strains of HIV-1 persist in wild
chimps
Precedent of laboratory worker acquired
SIV infection
12 of 16 SIVs capable of infecting human
lymphocytes in vitro
Fig 4: Bushmeat: Source:
www.bonoboincongo.com
Page 13
SIV and HIV: Human SIV Exposure
6
• Cameroonians (HIV 1 & 2 -) with reported history of high, medium and
low levels of exposure to NHPs and bushmeat tested for presence of
SIV antibodies
• Findings:
- 17.1% reactive in high exposure group
- 7.8% exposure in low exposure
- 2.3% in the general population
• Conclusion: Humans are exposed and possibly infected with SIVs
• Implications: blood supply safety, further emerging zoonotic lentiviral
epidemics/pandemics
Kalish M, Wolfe N, Ndongmo C, et al. Central African Hunters Exposed to Simian
Immunodeficiency Virus. Emerging Infectious Diseases 2005. 11(12) 1928-1931.
Although a significant portion of the general population is positive for SIV antibodies, no SIV viral nucleic
acid has been isolated from human blood. This may indicate that the SIVs that have produced antibody
responses in humans, are non productive or at least not capable of producing chronic infection.
Page 14
Viral Hemorrhagic Fevers (VHFs)
• Enveloped RNA viruses of diverse families
• May be arthropod borne with multiple, different animal
reservoirs
• Symptoms and disease severity vary widely
• Precedent of international travel transporting viruses
into non-endemic countries
• Precedent for nosocomial outbreaks involving
healthcare workers and laboratory personnel
Page 15
Distinct VHF Families
• Filoviridae
- Ebola
- Marburg
• Arenaviridae
- Lassa Hemorrhagic Fever
- South American Hemorrhagic Fevers
• Bunyaviridae
- Rift Valley Fever
- Crimean Congo Fever
Page 16
VHFs: Clinical Factors
• Initial symptoms nonspecific - incubation period of 2-14 days
• Severe sore throat, abdominal pain, progressive fever, vomiting
and diarrhea (bloody), easy bruising and bleeding
• Conjunctival injection and non-pruritic torso rash
• Multi-organ hemorrhage and failure with widespread necrosis
and microvascular thrombosis
• Uncontrolled activation of systemic inflammatory and
coagulation pathways
• Ebola and Marburg: most severe with mortality 25-100%
Page 17
VHFs: Filoviridae: Ebola 7,8
• Ebola (5 species)
- Sudan
- Zaire
- Ivory Coast
- Reston Agent
- Uganda
• First appearance in 1976
• Sporadic outbreaks
Fig 5: Electron micrograph of Ebola virus:
Photo Source: Dr. F.A. Murphy
Page 18
VHFs: Ebola: Documented Outbreaks 9
•
•
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Zaire sp.: 9 outbreaks
- Mortality: 57-88%
Sudan virus: 4 outbreaks
- 50% case fatality rate
Ivory Coast: two individuals (one survived)
Uganda: 1 outbreak (2005)
- different symptom profile: 31% case fatality rate
Reston Agent: No documented epidemics in humans
(epidemic in captive laboratory primates)
Page 19
VHFs: Filoviridae: Marburg 9,10
• All isolates considered single
species
• Varying pathogenicity (mortality
ranging from 21-80%)
• Responsible for 1967 outbreak
in Europe
• Outbreaks in 2000 in
Democratic Republic of the
Congo and 2005 in Angola
Figure 2: Electron micrograph of Marburg Virus.
Photo Source: Centers for Disease Control and Prevention
Page 20
VHFs: Ebola and Marburg: Epidemiology
9-11-12
•
•
•
•
Disease burden in comparison to HIV/Malaria/Tb is small
Total number of identified cases <3000
Increasing frequency of outbreaks in sub-Saharan Africa
Significant ongoing outbreaks in wild (endangered) non human primate
species (chimpanzees)
• Unknown natural reservoir: primates likely secondarily infected (bats
suspected to be reservoir)
• Diagnosis: Currently ELISA viral antigen or PCR based field techniques
(antibody response can be muted)
Viral hemorrhagic fevers, including Ebola and Marburg have been implicated in several epidemics amongst endangered nonhuman primate species including gorillas and chimpanzees. Surveillance for primate illness has been suggested as a method
for detecting emerging VHF epidemics prior to significant human infections.
ELISA: Enzyme Linked Immunosorbency Assay is a method for detecting antigens and antibodies specific to particular
pathogens in blood or other body fluids. PCR: Polymerase Chain Reaction is a laboratory method for amplifying potentially
minute amounts of viral nucleic acid from body fluids.
Page 21
VHFs: Ebola and Marburg:
Transmission 9,13,14
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Person-person spread: contact with infected fluids
Corpse preparation a risk factor for exposure
Sexual transmission: documented but likely rare
Droplet infection via mouth or eyes
Aerosol spread documented in animals (likely minimal
role of respiratory spread in epidemics)
• No evidence for mosquito or arthropod spread
• Animal to human transmission: dead primates butchered
and eaten
Page 22
VHFs: Ebola and Marburg:
Transmission
• Nosocomial Transmission:
- Syringe reuse/contaminated blood products
- Explosive and exponential outbreaks
- Exposure during procedures and care giving
- Exposure during preparation of bodies for burial
- Extremely variable rates of health care worker infection
• Epidemic “burnout”:
- Short incubation period
- Precipitous progression of disease and death
- Extreme clinical manifestation and symptoms
- Limited means of transmission
Page 23
VHFs: Ebola and Marburg: The
13,14
Reservoir Hunt
• Traditionally infectious disease causes mild or no disease in reservoir
species
• Primates succumb to HF after infection
• No definite reservoir or vector identified
• Epidemic and vector control hampered by lack of clear reservoir animal
• Evidence for fruit bats as possible reservoirs (asymptomatic hosts)
- Experimentally infectable
- Bats strongly present in epidemic environments
- ~5% of 3 species of fruit bat have Ebola IgG in epidemic and
non-epidemic areas
Page 24
VHFs: Ebola and Marburg:
Infection Control
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•
•
•
CDC Documents: 2005: Interim guidance for managing patients with
suspected viral hemorrhagic fever in US hospitals/Infection Control for
viral hemorrhagic fevers in the African Healthcare Setting
www.cdc.gov/ncidod/dhqp/bp_vhf_interimGuidance.html
www.cdc.gov/ncidod/dvrd/spb/mnpages/vhfmanual.htm
Universal precautions are sufficient to prevent transmission –
- N-95 masks or respirators
- Gowns, face shield, rubber boots, double glove
- Triton X decontamination of all medical, laboratory
equipment and surfaces
Private rooms with negative pressure for patients (if available)
Restrict access to infected or exposed patients
Page 25
VHFs: Ebola and Marburg:
Infection Control
• Low Resource Isolation:
- limit access to suspected cases
- separate from
general patient population
- isolate early
- limit staff in isolation area
- isolated toilet
- changing room
- adequate ventilation
- screened windows
• Low Resource Waste Disposal
- 1/10 and 1/100 bleach solutions
after cleaning with soap solution for
reusable equipment
- liquid waste, laboratory samples,
and used disinfectants: discard in
isolated latrine
- solid waste, disposable medical
equipment: burned (diesel fuel)
- cleaning and waste disposal staff:
personal protective equipment
Page 26
VHFs: Vaccine Development
15
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Pan-filovirus vaccine under development
Live attenuated viruses risk possibility of reversion to pathogenicity
Adenovirus vector expressing multiple filoviral antigens
Inoculation of nonhuman primates at 1,000 times lethal dose
100% protection against infection by 2 species of Ebola virus and 3
Marburg virus subtypes
• Utility for biodefense and epidemic preparation: early epidemics
typically undifferentiated
Dana L. Swenson, Danher Wang, Min Luo, Kelly L. et al. Vaccine To Confer to Nonhuman Primates
Complete Protection against Multistrain Ebola and Marburg Virus Infections. Clin Vaccine Immunol.
2008 March; 15(3): 460–467.
Page 27
VHFs: Ebola and Marburg: Treatment
12
• Treatment:
- Supportive care
- Respiratory support
- Reversal of coagulopathy
- Limited role for convalescent sera
- No role for ribavirin
- Post-exposure prophylaxis for exposed patients:
Research underway
- Interferons: Research underway
Ribavirin is an anti-viral medication useful in treating some viral infections (Lassa) it has not
been shown to be useful in Ebola Marburg or HIV infections. Interferon is a man-made
molecule (cytokine) that plays a central role in the immune response to viral infection.
Page 28
VHFs: Reston Agent 16
• Considered an Ebola species
• Possible animal reservoirPhilippine Islands
• Outbreak amongst non-human
primates in quarantine facilities in
US leading to widely fatal
hemorrhagic fever in captive
primates
• Unclear human pathogenicity
• Unclear role of airborne or droplet
spread in primate outbreaks
Page 29
VHFs: Filoviridae: Marburg and
Ebola-Summary Points
• Potential for global spread via transportation networks
• Limited large scale epidemic potential given short incubation
period, severity of illness and limited transmission patterns
• Likely bat reservoir species
• Potential for impact on non-human primate populations
• Concerning for severe illness in returned travelers from central
Africa (and the Philippine Islands?)
• Limited treatment options
• Concern for development as bioterrorism agents
Page 30
VHFs: Arenaviruses
•
•
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•
Enveloped RNA viruses
Hemorrhagic disease is typical
Generally rodent transmitted disease
Rodents have no apparent illness
Incidental human infection via contact with infected
rodent urine or feces
• Contact with infected material typically from agricultural
work or rodent infestation of homes or other buildings
• Documented nosocomial and person to person spread
Page 31
VHFs: Arenaviruses
• Hemorrhagic febrile syndrome
• Variable case infection and
mortality rates
• Old World Arenavirus:
- Lassa Fever (West
Africa)
• New World Arenaviruses:
- South American
Hemorrhagic Fevers
Fig. 5: New World Arenavirus particles
budding out of an infected cell: Source CDC
Page 32
Arenaviruses: Lassa Fever 17-18-19
• Localized to West Africa although travel has resulted in cases in
Europe and North America
• Discovered in 1969
• Likely asymptomatic/mild disease in ~80% of infected
• Can manifest outbreaks with case fatality rates of 50%
• Estimated 100-300,000 cases/year in West Africa
• Significant contribution to population mortality in selected communities
in Nigeria, Sierra Leone
• Diagnosis: ELISA for Lassa IgM or Lassa Antigen, PCR
- substantial population with prior exposure (IgG)
IgM and IgG are two types of antibodies produced by B cells to combat infection. IgM (Immunoglobulin M) is typically
produced early in infection and as the infection progresses the antibody response shifts and IgG (Immunoglobulin G)
antibodies become prominent. IgG responses are typically more specific to the pathogen antigens than IgM responses. The
IgG response may be lifelong and as such IgG positivity may reflect prior exposure, rather than acute infection, which is
typically suggested by the presence of IgM. Acute and convalescent sera is another means for detecting acute infection.
Serum is drawn at the onset of illness and antibody response and then is measured again after several days. An interval
increase in the IgM or IgG response during this time is suggestive of acute infection.
Page 33
Arenaviruses: Lassa Fever:
Transmission
• Vector: Rodents: Mastomys
genus
• Transmission occurs with
human contact or inhalation of
infected rodent urine and feces
• Mastomys sometimes
consumed as food source
• Nosocomial transmission via
contact with infected medical
equipment
Fig 6.: Lassa virions (arenavirus).
Source : CDC
Page 34
Arenaviruses: Lassa Fever:
Clinical Notes
• Incubation period lasts 1-3 weeks
• Symptoms:
- High Fever
- Conjunctivitis
- Retrosternal Pain
- Vomiting
- Neurologic Deficits
- Hemorrhage
- Liver inflammation
- Sore throat
• Complications: Deafness (may occur with mild or serious
infection)
• Prognosis: Mortality: 15-20% of symptomatic cases but only
~1% of overall cases
Page 35
Lassa Fever: Prevention and
Treatment
Prevention:
• Safe food storage
• Rodent control
• Wet down surfaces prior to
sweeping
• Lassa vaccine (?)
Treatment:
• Ribavirin (early treatment
improves survival)
• Supportive care
• Correction of coagulation
abnormalities, resuscitation
Fig.: 7 African Countries endemic
for Lassa Fever
Page 36
Ribavirin for Lassa Fever
20
• Sierra Leone, 1986
• Study of therapy/prognostic factors in Lassa Fever
• Findings:
- Elevated aspartate aminotransferase (AST) > 150 IU/L
at admission associated with 55% mortality rate
- Viremia > 10(3.6) TCID50 per milliliter on admission
associated with a case-fatality rate of 76%
• Intravenous ribavirin within first 6-7 days of fever associated with
reduced mortality (5-9% vs 55-76%)
Lassa Fever: Effective therapy with ribavirin. McCormick JB, King IJ, Webb PA.
N Engl J Med. 1986 Jan 2;314(1):20-6.
Page 37
Arenaviruses: South American Hemorrhagic
Fevers (HFs)
•
•
Viruses:
- Machupo (Bolivia HF)
- Junin (Argentine HF)
- Guanarito (Venezuelan HF)
- Sabia (Brazilian HF)
As with other arenaviruses:
- rodents serve as vector
- significant hemorrhage
- rural populations and
farmers frequently infected
- documented nosocomial &
occupational spread
(Machupo/Sabia)
Fig 6: Victim of Bolivian Hemorrhagic Fever.
Photo Source: www.medicineworld.org
Page 38
Arenaviruses: South American HFs 21,22
• Case infection rate of 50% of exposed (overall)
• Mortality: 15-30% of those infected (overall)
• Symptoms similar to Lassa Fever with significant
neurologic manifestations
• Live, attenuated Junin virus vaccination in Argentina:
reduced incidence to less than 100 cases per year
• Significant success with vector control efforts
Page 39
VHFs: Bunyaviruses
• Enveloped RNA viruses
• Largest family of viruses with >200 species
• Diagnosis: Antigen detection and serological tests
available although virus isolation and PCR useful
• Most bunyaviruses require an arthropod vector
(exception: Hanta)
• Humans are usually dead end hosts
Page 40
VHFs: Bunyaviruses
23
• Crimean Congo Hemorrhagic Fever
- Bulgaria, Yugoslavia, former Soviet Union, China,
Middle East, Pakistan, and sub Saharan Africa
- Infection rate: 20-100% with case fatality rate: 15-30%
- Most severe bleeding and ecchymoses of VHFs
- Transmitted via tick bite (Hyalomma genus) or
exposure to aerosols or fomites of slaughtered livestock
- Nosocomial outbreaks documented
- Human vaccine available
- Vector control efforts of primary importance
Page 41
VHFs: Bunyaviruses 24
• Rift Valley Fever
- South Africa, Kenya, Uganda, Sudan, Egypt, Mauritania
- Appears as epizootics in sheep, cattle, camels, goats
-1% infection rate of exposed with mortality rate of 50%
- Retinal vasculitis that may cause blindness
- Transmission: mosquito or contact with infected
livestock blood
- No interhuman transmission documented
- Animal (sheep and cattle) vaccine available to break
transmission cycle
Page 42
Flaviviridae
• Wide range of clinical symptoms (including
hemorrhagic fever)
• RNA viruses
• Insect borne (arthropod borne)
• Main human pathogens:
- Yellow Fever
- Dengue
- West Nile Virus
- Encephalitic Viruses (Japanese, St Louis, Tick
Borne Encephalitis)
Page 43
Flaviviridae - Transmission
• Human to human
transmission noted for
Dengue, Yellow Fever, and
West Nile
• Humans are typically dead
end hosts
• Animal infection as well,
but likely dead end (NHP)
• Tick and mosquito vectors
Fig 6: Aedes sp mosquito taking a
blood meal. Photo Source:
www.aedesmosquito.com
Page 44
Flaviviruses: Yellow Fever
25,26,27
• Single serotype RNA virus
• Yearly incidence: 200,000 cases (90% in Africa) with
30,000 deaths
• Distribution: Sub-Saharan Africa, South America,
Central America, Caribbean
• Possible differences in mortality and epidemic incidence
between African and South American Yellow Fever
• Aedes sp. mosquitoes infect primates & humans
Page 45
Yellow Fever: Distribution
Fig 7: Yellow Fever distribution in South America and Africa (red areas).
Photo Source: www.geo.arc.nasa.gov
Page 46
Yellow Fever Transmission Cycles
• African Yellow Fever (Old
• South American Yellow Fever
World)
(New World)
- Jungle -virus circulation
- Introduction of virus from
between NHPs (no effect) and
Africa within 500 years
humans (dead end hosts)
- Haemagogus and Sabethes
- Intermediate- Small
species of mosquito
simultaneous epidemics
- S. American monkeys
in many small villages
die following infection
- Urban Yellow Fever: Human- Similar jungle and urban
human transmission can occur
transmission cycles to that of
in populated / urban areas
African YF (no intermediate
cycle)
(mosquito transmission)
Page 47
Yellow Fever: Clinical Points
• Symptoms range from asymptomatic to life threatening
shock, liver/kidney failure and hemorrhage
• Highest disease severity in elderly
• 3 distinct clinical phases:
- Period of Infection: viremia, fever, acute illness (3-4
days), relative neutropenia
- Period of Remission: potential recovery and clinical
improvement (2 days)
- Period of Intoxication: 15% progress to intoxication
with hemorrhage, multi-organ failure (20% mortality)
Page 48
Yellow Fever: Diagnosis and Treatment
• Diagnosis:
- Can be confused clinically with Dengue, other
VHFs, viral hepatitis, severe malaria
- ELISA for IgM (acute and convalescent sera) cross
reactivity with other flaviviruses confuses diagnosis
- Viral isolation: PCR, viral culture (special cases only)
• Treatment:
- Supportive and symptomatic care
- Unclear role for hyperimmune globulin
- Animal evidence: ribavirin or interleukins
Page 49
Yellow Fever Vaccination
• Effective attenuated vaccine
available since 1936
• 95% vaccine seroconversion
rate
• Recommended for travelers
or residents of endemic
areas (required for entry to
some nations)
• Few adverse effects (two
serious clinical syndromes)
Fig 7: Yellow Fever vaccination.
Photo Source: Author
Page 50
Yellow Fever Vaccine Adverse Effects 27
• YEL-AND: YF Vaccine Associated Neurotropic Disease
- Viral presence in CSF after vaccination
- Historically in children < 9 months but can affect adults
- Symptoms consistent with viral encephalitis
- Incidence: 1.8-5.1/million
• YEL-AVD: YF Vaccine Associated Viscerotropic Disease
- Symptoms consistent with wild type Yellow Fever
Infection with identical mortality
- 2.2/million but higher in elderly
- No viral mutations identified, likely determined by host
susceptibility factors, immunodeficiency, thymus
removal (primary vaccination, >65 years old)
Page 51
Flaviviridae: Dengue Fever 25,28
•
•
•
•
•
Most prevalent mosquito (Aedes sp.) borne viral disease
Greater than 100 million dengue infections yearly
Wide range of clinical symptoms (mild to severe)
4 separate viruses (DEN 1-4)
Weak cross reactivity between subtype antibodies allows
multiple infections with different subtypes
• Range of symptoms from mild to severe
Page 52
Dengue Fever: Clinical Points #1 28,29,30
• Symptoms: Asymptomatic to life threatening shock and
hemorrhage
• Severity may be inversely proportional to age
• Incubation period of 4-7 days
• Laboratory: transaminitis (elevations in liver function tests),
leucopenia, thrombocytopenia
• Symptoms:
- Fever
- Retro-orbital pain
- Headache
- Muscle and join pain (“Break Bone Fever”)
- Rash - may be late
Page 53
Dengue Fever: Clinical Points #2
• Diagnosis: clinical diagnosis or IgM ELISA with paired
acute and convalescent sera
• Treatment: Supportive care, avoid NSAIDs (Reyes
Syndrome), fluid replacement
• Prevention: Mosquito control, tetravalent Dengue vaccine
(in development)
• Dengue Hemorrhagic Fever (DHF)
- Severe manifestation of Dengue infection
- Secondary exposure to different Dengue subtypes
- Circulatory failure, hemorrhage and shock
Page 54
Dengue Fever: 2 Transmission Patterns
Epidemic Dengue
• Introduction of single viral
subtype as isolated event
• Large susceptible populations:
explosive transmission (25-50%
incidence during epidemic)
• Predominant in small islands
• Low infection risk for travelers,
except in epidemics
• DHF frequency low
Hyperendemic Dengue
• Continuous transmission of
multiple subtypes in same area
• Year round presence of
susceptibles and mosquitoes
• Majority of Dengue infections
• 5-10% of the susceptibles are
afflicted annually
• Seasonal variation
• DHF frequency higher
Page 55
Flaviviridae: West Nile Virus 31,32,33
• First isolated in West Nile Province of Uganda in 1937
• 1999: 62 cases of encephalitis and 7 deaths
• WN Virus now detected across North America, Caribbean and
South America
• Nearly all human infections due to mosquitoes (Culex)
• Virus maintained/amplified in bird-mosquito-bird cycle
• Birds usually asymptomatic, with exceptions of native bird
deaths in North America (crows) and elsewhere
• Transmission documented from infected blood products and
organ transplantation (screening now in place)
Page 56
West Nile Virus: Clinical Points
32,34,35
• Symptoms
- 80% infections asymptomatic
- Immunity after infection thought to be life long
- Peak in late summer/early fall (mosquito cycles)
• West Nile Fever
- Self-limited febrile illness (fatigue, fever, headache, rash)
- Indistinguishable clinically from other viral illnesses
- Symptoms can last up to 30 days
• Neuroinvasive Disease
- Only 1 in 150 infections (2-12% case fatality rate)
- Encephalitis, meningitis, flaccid paralysis, cranial nerve palsies
- Associated with old age, diabetes and alcohol abuse
Page 57
West Nile Virus: Diagnosis & Treatment
• Diagnosis
- ELISA for IgM antibody (plasma or CSF)
- IgM may appear after 8 days of infection and may
persist for 6 months
- Viral isolation: Viral culture, PCR (not routine)
• Treatment
- Supportive care
- In vitro and animal evidence for interferon alfa efficacy
- Ribavirin: not proven and possibly detrimental in
animal models
- Possible role for IV immunoglobulin (unstudied)
Page 58
Emerging Respiratory Pathogens:
SARS 36,37,38
• Severe Acute Respiratory Syndrome
• 2003: Severe, progressive respiratory infection in Hong
Kong, China, Viet Nam, Singapore, Taiwan, Canada
• First ever WHO travel advisories: Guangdong Province
China, Hong Kong, Taiwan, Hanoi, Singapore
• Contagion identified as a new Coronavirus
• Significant number of health care worker infections
• 9 cases due to viral research: National Institute of Virology,
Beijing
Page 59
SARS: WHO Case Definitions
• Suspected Case
- Fever >38 deg C plus
- Cough or respiratory distress plus
- Contact with a SARS patient, travel/residence in
affected area
• Probable Case
- Suspected Case + x-ray evidence: pneumonia, or ARDS
- Suspected Case with positive SARS diagnostic testing
- Fatal respiratory illness with evidence of ARDS
without other etiology
Page 60
SARS - Epidemiology
• First cases in Guangdong Province China
• Most cases in adults with higher mortality in elderly (43% case
fatality > 60 years old)
• Likely milder disease in children with no fatal pediatric cases
documented
• 2003 outbreak: 8422 cases with 916 deaths (case fatality rate
of 11%)
• Reservoir: Horseshoe bats harbor viruses with identical
sequence to SARS/Molecular similarity to civets (cat-like
animal) coronavirus
• Transmission likely via droplet (high rate of nosocomial
spread) and possibly airborne
Page 61
SARS: Clinical Points
•
•
•
•
•
Prodromal Phase: fever, myalgias, malaise
Respiratory Phase: 3-7 days: non productive cough, respiratory failure
Poor Prognostic Factors
- Diabetes
- Older age
- Acute Renal failure
- Comorbid conditions
- Elevated serum LDH
Diagnosis:
- Serology: ELISA (acute and convalescent sera)
- Viral isolation: PCR
Treatment: Supportive care (critical care and ventilatory support)
- No proven anti-viral therapy
- Interferon alfa may decrease symptom length (animal model)
Page 62
SARS: Prevention
• Avoidance of exposure and infection control for suspected
cases and contacts
• Infection control difficult as not all patients require
hospitalization
• Voluntary measures to avoid exposing others
• Closing of facilities (e.g., schools, hospitals, clubs) and
quarantines, travel advisories
• Strict adherence to infection control practices in hospitals
(droplet and airborne precautions)
• Avoid respiratory procedures
Page 63
Emerging Respiratory Pathogens:
Avian Flu
• Avian Influenza H5N1 endemic among bird and poultry in
Asia
• Spread via migratory birds
• Sporadic transmission to humans
• Concern for exchange of genetic material with co-infecting
human influenza viruses-new epidemics
• For further information please see the GHEC Module
entitled: Emerging Infectious Disease: Focus on
Avian Influenza
Page 64
Summary: Emerging and Reemerging
Viral Infectious Diseases
• Multiple biological, behavioral, ecological factors contributing
to the emergence and reemergence of viral infectious
diseases
• Multiple EID hotspots exist globally
• SIV/HIV
• Viral Hemorrhagic Fevers
- Filoviruses
- Arenaviruses
- Bunyaviridae
Page 65
Summary
• Flaviviruses
- Yellow Fever
- Dengue
- West Nile
• Emerging Respiratory Pathogens
- SARS
- Avian Flu H5N1
• Other viral pathogens not covered in this module:
- Hanta virus
- Viral Encephalitidies
- Hepatitis C
- Resistant pathogens (HIV)
Page 66
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Page 71
Credits
• Joseph U. Becker, MD:
– Chief Resident Yale University, Division of Emergency
Medicine, Department of Surgery
• Michele Barry, MD FACP:
– In 2009: Professor of Medicine and Global Health.
Director, Office of International Health, Yale University
– In 2013: Professor of Medicine, Senior Associate Dean
for Global Health, Director of Global Health Programs in
Medicine, Stanford University
Page 72
Sponsors
The Global Health Education Consortium gratefully acknowledges the support
provided for developing these teaching modules from:
Margaret Kendrick Blodgett Foundation
The Josiah Macy, Jr. Foundation
Arnold P. Gold Foundation
This work is licensed under a
Creative Commons Attribution-Noncommercial-No Derivative Works 3.0
United States License.