Pandemic Influenza: Interventions

1
Hantaviruses and Hantavirus Pulmonary Syndrome
(HPS)
Objectives

• Describe common hantaviruses in the United
• States and their reservoirs
• Know the clinical nature of hantavirus infection
• Understand the epidemiology of hantavirus in
• Washington State

2
Hantaviruses

• RNA viruses
• Asian, European, and American species
• Renal syndrome in Asia, Europe
• (Milder form in Europe)
• Respiratory syndrome in Americas
• Bunyavirus family with three subfamilies

3
Identification of Hantaviruses

• Syndrome reported from Asia as hemorrhagic
  fever with renal syndrome
• (HFRS) including in Korean War troops
• Virus isolated in 1976 from striped field
• mouse trapped near Hantaan River in Korea
• No arthropod vector established (... unique
  among genera of Bunyaviridae)

4
Hantaviruses in Asia and Europe

• Subfamily Murinae associated viruses (HFRS)
• Virus Host
  Location Disease
• Hantaan Apodemus agrarius Asia, Far
  East Russia HFRS
• Dobrava Apodemus flavicollis Balkans
  HFRS
• Apodemus agrarius
  Europe
• Seoul Rattus norvegicus
  Worldwide HFRS
• Rattus rattus
• Subfamily Arvicolinae associated viruses
• Virus Host
  Location Disease
• Puumala Clethrionomys glareolus Europe
  HFRS
• Numerous other hantaviruses have been
  identified
• but not linked to human disease

5
Hemorrhagic Fever with Renal Syndrome

• Incubation 5-35 days
• Prodrome malaise, loss of appetite, nausea,
  vomiting, conjunctivitis
• Decreased platelets, vascular permeability
• Hemorrhagic symptoms
• petechiae, conjunctival hemorrhage,
• renal failure, GI bleeding
• shock with 5-30 fatality rate

6
Hantaviruses in the Americas

• Subfamily Sigmodontinae associated viruses
  (HPS)
• Virus Host Location Disease
• Sin Nombre Peromyscus maniculatus West/Central
  HPS
• U.S. Canada
• Monongahela Peromyscus maniculatus Eastern
  U.S. HPS
• Canada
• New York Peromyscus leucopus Eastern U.S.
  HPS
• Bayou Oryzomys palustris Southeastern
  U.S. HPS
• Black Cr. Sigmodon hispidus Florida HPS
• Andes Oligoryzomys longicaudatus Argentina
  HPS Chile
• Oran Oligorozomys longicaudatus Northwestern
  HPS
• Argentina
• Lechiguanas Oligoryzomys flavescens Central
  Argentina HPS
• Hu39694 Unknown Central Argentina HPS
• Laguna Negra Calomys laucha Paraguay
  HPS Bolivia
• Juquitiba Unknown Brazil HPS
• Etc.

7
Sin Nombre Virus

• Circular single stranded RNA
• Total genome 10500-22700 nucleotides long
• 100 (80-120) nm in diameter
• Surface projections of envelope distinct spikes
  (of about 10 nm)
• www.virology.net/Big_ Virology/BVRNAbunya.html

8
Hantavirus (Cardio)Pulmonary Syndrome

• Agent Sin Nombre virus, others
• (e.g., Monongahela virus)
• Vector deer mouse (Peromyscus maniculatus)
• mouse exposure may not be recognized
• Regions western US, Mexico, Canada for SNV
• other viruses throughout Americas
• including South American
• Mild or asymptomatic disease rare

9
HPS Pathophysiology

• Replication primarily in pulmonary endothelial
  cells
• Found widely in capillary endothelial cells
• Interstitial pneumonitis and mononuclear
  infiltrates
• Vascular permability and capillary leakage
  result
• High neutralizing antibody with better outcome
• May be genetic predisposition HLA
• In some studies Sin Nombre virus associated with
  certain HLA types
• Puumala renal syndrome associated with
  HLA-B8-DR3

10
HPS Presentation

• Incubation 1-6 weeks
• Prodrome fever, chills, myalgias (aches in
  legs and back) lasting 1-7 days may be nausea,
  vomiting, diarrhea
• Cough, URI symptoms rapidly progress to
• pulmonary edema, hypoxia, ARDS
• cold/flu syndrome without nasal discharge,
• sore throat, sinusitis, ear infection
• Many causes of similar symptoms

11
HPS Clinical Course

• Shock with hypoxia, alveolar edema fluid
• poor oxygenation causes renal failure
• Normal-to-low pulmonary wedge pressure
• Decreased cardiac index
• Increased systemic vascular resistance
• Mortality 30

12
HPS Laboratory Testing

• Hematology low platelets, myelocytes, left
• shift, elevated hematocrit, elevated WBC
• Chemistry low albumin, elevated LDH,
• elevated AST (SGOT), elevated ALT (SGPT)
• Serology specific test for Sin Nombre virus
• Asian viruses cross-react
• paired IgM and IgG antibody testing
• Immunohistochemistry, PCR
• serum, frozen tissue, tissue blocks, BAL
• Culture

13
Supportive Treatment

• Broad spectrum antibiotics until HPS proven
• Intensive care management monitor
• electrolytes, pulmonary, and hemodynamics
• Fluids (eg crystalloid) to get PAOP 12-15 mm
• Inotropic agents for myocardial contractility
• Dobutamine 5 - 20 micrograms/kg/min
• ? adult ECMO

14
Hantavirus Reservoirs

• Rodent hosts genus (possibly species) specific
• Rodents shed but are not symptomatic
• Disease distribution follows rodent distribution
• No person to person transmission in N. America
• Virus in aerosolized urine, also feces, saliva
• Horizontal transmission among mice by
• intraspecific aggressive behavior

15
Hantavirus and Deer Mice

• Sin Nombre virus throughout range of deer mice
• Difference in prevalence of mouse infection
• Transmission horizontally including aggressive
  encounters and bites
• Recently infected most likely to be infectious

16
Hantavirus Hypotheses

• Seasonal trends
• Virus overwinters in older adult mice with high
  prevalence
• Young mice dilute prevalence
• Young mice progressively infected through summer
• Temporal trends
• Increased rainfall can increase food and mouse
  populations
• Mild winter could increase winter survival and
  prevalence
• Mills Emerg Inf Dis Jan-Mar 1999

17
Hantavirus Infection of Deer Mice

• Trapping in Colorado 1994-1997
• Prevalence 9.5
• Range 0-43 for trapping periods
• Males more likely to be infected
• Wounds were associated with infection at only one
  of two trapping sites
• Calisher Emerg Inf Dis Jan-Mar 1999

18
Hantavirus Infection of Deer Mice

• Trapping in Montana 1994-2004
• 244,600 trap nights of effort
• Multiple captures for 2,747 deer mice
• Found 99 seroconversions between consecutive
  trapping sessions
• More likely to be older male, in breeding
  condition
• Not related to wounds or scars
• Infected mice with less weight gain than
  seronegative
• Douglass J Wildlife Dis 2007 4512-22

19
Hantavirus Infection of Deer Mice

• Trapping and fluorescent tagging in Utah 2005
• Study 15 days in Spring and 15 days in Autumn
• Five mice a night tagged and released
• Trapped following night, checked for fluorescence
  
• Infection prevalence 25-30
• Mice with more contacts averaged 11 percent
  heavier
• No effect of gender or breeding condition
• May be higher prevalence of hantavirus in
  populations where mice are older
• May reflect better food or cover
• Clay Proc. R. Soc. B April 7, 2009

20
HPS Epidemiology

• Greater number of cases in spring-summer
• Varies by elevation, location, biome
• Rainfall preceding year increases food supply
  prompting rodent population growth
• Risks exposure through rodent excreta
• MMWR June 9, 2006

21
Hantavirus Clusters in Argentina

• Hantavirus endemic in southern Argentina
• Clustering for 39 of cases (vs. 7.5 SNV)
• Eight clusters with gt 2 weeks between cases
• Breast fed infant IgG positive, mother died with
  ARDS
• Wife symptomatic 20 days after husband who
  handled mice
• Breast fed child with mild illness and
  seroconversion 19 days after mother
• Wife symptomatic 40 days after husband who
  cleared plants in wilderness
• Lazaro Emerg Inf Dis Jan 2007

22
Washington HPS Cases

• 28 cases reported as of Jan 2005
• 1-5 cases reported annually 1994-2005
• 9/28 (32) fatal
• Age range 20-75 years, 21 (75) male
• 14 exposed in eastern Washington counties, 11 in
  western Washington counties, 3 in multiple
  counties a/o out of state

23
Washington HPS Cases

• Exposures
• 21/24 cases lived in rural locations or settings
• 19/24 cases rodent exposure/signs reported
  or found on inspection in/around home or
  workplace
• 11/24 cases lived or worked in agricultural
  setting

24
Hantavirus Outbreak, 1993

• Impact on local community
• Loss of tourism and associated income
• Prejudice
• Media intrusion
• Disregard for religious observances