Emerging Infectious Diseases: Recent Emergent Viruses

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Emerging Infectious DiseasesRecent Emergent
Viruses
David WangDept. of Molecular Microbiology
and PathologyImmunology davewang_at_borcim.wustl.edu

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Are Infectious Diseases Really Important?

• It is time to close the book on the problem of
  infectious diseases
• 1969 US Surgeon General
• The future of infectious diseases will be very
  dull
• 1972 Macfarlane Burnet
• (1960 Nobel prize winner in medicine)

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Infectious Disease Mortality-US
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Emerging Infectious Diseases

• Infections that newly appear in a population,
  or have existed but are rapidly increasing in
  incidence or geographic range
• Joshua Lederberg and Samuel Morse 1980s

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1994 Founding of the Journal Emerging Infectious
Disease
GOAL Recognition of new and re-emerging
infections and understanding of factors involved
in disease emergence, prevention, and
elimination.
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The challenge of emerging and re-emerging
infectious diseases Nature 2004
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A Brief History of Emerging and Re-Emerging
Viruses

• 1400-1500s Smallpox
• 1967 Marburg
• 1976 Ebola
• 1983 HIV
• 1993 Sin Nombre Hantavirus
• 1994 Hendra Virus
• 1997 H5N1 Avian Influenza
• 1998 Nipah virus
• 1999 West Nile
• 2003 SARS
• 2003 MonkeyPox

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National Academy/Institute of Medicine Reports

• 1992 Emerging Infections Microbial Threats to
  Health in the United States
• 2003 Microbial Threats to Health
  Emergence, Detection and Response

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Factors in Emergence

• Climate and weather
• Changing ecosystems
• Human demographics and behavior
• Economic development and land use
• International travel and commerce
• Technology and Industry
• Lack of public health measures
• Poverty and social inequality
• War and famine
• Lack of political will
• Microbial Threats to Health Emergence,
  Detection and Response (2003)

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Factors in Emergence

• Climate and Weather
• Altered vector range
• El Nino- Hantavirus
• Economic Development and Land Use
• Agriculture expansion
• Deforestation
• Human Demographics and Behavior
• Urbanization/crowding

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Factors in Emergence II

• Technology and Industry
• Transfusion/Transplantation/Immunosuppression
• Hepatitis, HIV, Kaposis Sarcoma
• Animal husbandry practices
• Influenza
• International Travel/Commerce
• Exotic pet trade
• MonkeyPox
• Travel
• (smallpox-gtAmericas)
• (SARS-gtglobal)
• Poor Public Health Infrastructure
• Marburg Angola 2004-2005

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Case Studies

• Hantavirus Pulmonary Syndrome 1993
• Nipah Virus- Malaysia, 1999
• Zoos Asian/African Elephant Herpes
• SARS 2003
• Marburg- Angola 2004-2005

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1993 Hantavirus outbreak

• May Unexplained acute respiratory failure
• New Mexico
• Initial cluster of 5 patients healthy adults
  20-40 yrs
• Overall case fatality rate 60
• June 4 -serological cross reaction with
  hantaviruses
• Prototype Hantaan virus identified in Korea
• Hantaan associated with field mice
• Degenerate PCR revealed a novel hantavirus

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What is the reservoir?
Deer Mouse, Peromyscus Maniculatus
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Rodent to Human Transmission
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Why Did Sin Nombre Virus emerge in 1993?

• In a nutshell
• More Nuts More Mice Increased Exposure
• 1992 El Nino, heavy rainfall, increase in pinon
  nuts, foliage
• 10-fold deer mouse population increase
• May 1992 2 mice/hectare
• May 1993 30 mice/hectare
• July 1993 20 mice/hectare
• Aug 1993 4 mice/hectare
• Univ. New Mexico population survey of
  deer mouse
• 30-50 of all deer mice seropositive

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Hantavirus Pulmonary Syndrome Coincides with Deer
Mouse Range
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Hantavirus Summary

• Novel hantavirus emerged
• Deer Mice and other rodents are carriers
• Key factor increased proximity between rodents
  and humans
• Recognized in 1993 because of case cluster
• Previously healthy young adults
• Retrospectively identified sporadic cases
• Problem 50-150,000 unexplained respiratory
  deaths in US/year
• Emerging diseases at low levels can go
  unrecognized for some time

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Nipah Outbreak Timeline

• Sep 1998 Outbreak of encephalitis in Malaysia
• Mainly pig farmers
• Also, respiratory illness and encephalitis in
  pigs
• 28 patients
• Initially presumed to be Japanese Encephalitis
• 50 cases per year
• 4/28 patients seropositive for Japanese
  Encephalitis
• Government increased mosquito control,
  immunizations for JEV
• Spread to other villages and farms
• March 1999, reached Singapore
• 11 patients, all abattoir workers

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Nipah Outbreak Timeline

• Probably not Japanese Encephalitis
• Unusual epidemiology
• Mostly adult male pig workers, few children
  affected
• No effect of control measures (vaccination,
  mosquito spraying)
• March 1999- Novel Virus cultured from patient
  CSF in Vero cells
• Cross reaction with Hendra virus antibodies
• A Novel paramyxovirus
• Nipah and Hendra form genus henipavirus
• 18 kb genome
• Pigs are key link
• Pig-human transmission

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Stopping Pig Human Transmission

• Outbreak controlled by
• Singapore Import ban on pigs from Malaysia No
  further transmission/cases
• Malaysia gt 1,000,000 pigs culled
• Last Case, May 1999

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Nipah Statistics

• Overall Human Stats
• 265 cases
• 40 fatality rate
• 93 of patients had direct contact with pigs
• Very rare person to person transmission
• Pig statistics
• Highly transmissible from pig to pig
• 5-15 mortality

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Where did it come from?

• Search for Reservoir
• Dogs, cats, goats, horses all seropositive
• Fruit Bats?
• Virus isolated from
• bat urine
• partially eaten fruit (bats)
• Antibodies to Nipah in
• Island flying fox
• Malayan flying fox

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Possible Transmission of Nipah
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Why did Nipah Emerge in 1998-99?

• A hypothesis
• Fruit bat habitat reduced by deforestation
• El nino 1997-1998 induced drought led to fires,
  further decrease in fruit availability
• Expanded foraging range including fruit orchards
• Juxtaposition of orchards/pig farms
• Bat urine and eaten fruit dropped onto pigs
• Infected pigs magnify transmit virus to humans
• Pigs transported to other regions/Singapore
  expanded epidemic

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Factors in Nipah Emergence

• Deforestation
• Agricultural Practices
• Travel/Commerce

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Nipah Returns Bangladesh

• April, May 2001
• Cluster of 9 case, febrile neurologic illness
• January 2003
• 8 deaths
• January-April 2004
• 17 deaths, 23 cases 74 mortality
• 2nd outbreak 18 deaths/30 cases
• Mostly young boys
• Jan 2005
• 11/12 fatalities
• Feb-May 2007 (India-Bangladesh border region)
• 100 cases

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Differences between Recent Nipah Events and
Original Malaysian outbreak

• No pigs involved!
• Possible person-person transmission?
• Fruit bats seropositive for Nipah detected
• Bangladesh strain 95 identity to Malaysian
  strain
• Suspected Date Palm Juice link

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Palm Juice Collection
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2002-2003 SARS Outbreak Chronology

• 16 Nov 1st case of atypical pneumonia,
  Guangdong
• 21 Feb Dr. A from Guangdong checks into
  Metropole Hotel, Hong Kong
• 22 Feb Dr. A suffers respiratory failure,
  enters hospital in HK
• Feb-Mar Spread to Vietnam, Canada, Singapore
• 15 Mar WHO global alert
• 24 Mar Novel coronavirus identified
• Overall gt8000 cases, 774 deaths
• Quarantine effective at breaking transmission
• Hospitals were epicenters of transmission

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Where did SARS come from?

• Outer Space?
• With respect to the SARS outbreak, a prima facie
  case for a possible space incidence can already
  be made Lancet (2003) 1832

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Where did SARS come from?

• Early hypotheses
• Civet cats, racoon dogs
• Higher disease incidence, seropositivity among
  exotic animal handlers in Guangdong

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Bats are the Likely Reservoir
Science (2005)
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Dr. A Stayed at Metropole Hotel
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Transmission to Guests on 9th Floor
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SARS Spread Impact of Jet Travel
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2004-2005 Angola Outbreak
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2004-2005 Outbreak Timeline

• Oct 2004- sporadic cases of hemorrhagic fever
  deaths
• March 21, 2005- identified as Marburg virus
• 102 cases, 95 fatalities

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Filovirus EM
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Marburg Emergence

• 1967 Marburg, Germany
• Lab workers dealing with African green monkeys
  from Uganda
• Hemorrhagic fever
• 25 mortality rate

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Marburg/Ebola History

• 2000 Congo
• largest previous Marburg outbreak
• 149 cases, 123 fatalities

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Locations of Ebola/Marburg Outbreaks
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Marburg in Northern Angola
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1st Marburg outbreak in Urban Setting

• Majority of cases in Uige
• population 500,000
• Few cases in Luanda
• Population 3,000,000

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Filo Hemorrhagic Fevers

• High mortality
• No vaccines or drug therapies
• No known reservoir!
• Human-human transmission requires close contact
• Isolation and contact tracing critical to
  stopping the outbreak

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Challenges for Stopping the Outbreak

• Surveillance and identification of cases impeded
  by
• Poor Infrastructure
• Poor access to remote communities
• Lack of basic supplies in hospitals--disinfectants
  
• Lack of training of health care workers
• Spread in hospitals
• Cultural factors
• Local beliefs about diseases
• Funeral rituals
• Fear- stoning/physical threats to WHO workers
• Fear- avoidance of hospitals, isolation ward

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Angola Facts

• Angola Civil War 1975-2002
• Life expectancy 46.6 years
• Infant mortality rate 154/1000
• 5 year mortality rate 260/1000
• 20 GDP spent on military
• 5 GDP spent on all social programs
• Average professional salary US15/month

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Why did Marburg emerge in Angola?

• Unknown at this time
• Possibilities
• Increased migration from Congo (via Uige)
• Refugees returning at end of Civil War
• Expanded range of unknown reservoir?
• Persistence of outbreak exacerbated by
• Poor infrastructure
• Poverty
• War

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Largest Marburg Outbreak

• As of 24 August, 374 cases of Marburg, 329 deaths
  (88 mortality).

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Conclusions

• Proximity of two or more species enables new
  transmission events
• Not just biology, but social, political,
  ecological factors contribute to emergence
• Biological, cultural, political, technological
  factors are critical to stop outbreaks

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Factors in Emergence

• Climate and weather
• Changing ecosystems
• Human demographics and behavior
• Economic development and land use
• International travel and commerce
• Technology and Industry
• Lack of public health measures
• Poverty and social inequality
• War and famine
• Lack of political will

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Selected Readings

• Microbial Threats to Health Emergence,
  Detection and Response Institute of Medicine
  2003
• Morens et al. The challenge of emerging and
  re-emerging infectious diseases Nature (2004)
  430.
• Nichol et al. Genetic Identification of a
  hantavirus Associated with an outbreak of Acute
  Respiratory Illness Science (1993) 914.
• Chua et al. Nipah Virus A Recently Emergent
  Deadly Paramyxovirus Science (2000) 1432
• Richman et al. Novel Endotheliotropic
  Herpeviruses Fatal for Asian and African
  Elephants Science (1999) 1171.