1. 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 Objectives Hantaviruses and Hantavirus Pulmonary Syndrome (HPS)

2. 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 Hantaviruses

3. 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) Identification of Hantaviruses

4. 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 Hantaviruses in Asia and Europe

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. Subfamily Sigmodontinae associated viruses (HPS) Virus HostLocationDisease Sin NombrePeromyscus maniculatusWest/Central HPS U.S. & Canada Monongahela Peromyscus maniculatusEastern U.S. &HPS Canada New YorkPeromyscus leucopus Eastern U.S. HPS BayouOryzomys palustris Southeastern U.S.HPS Black Cr.Sigmodon hispidusFloridaHPS AndesOligoryzomys longicaudatusArgentina & HPS Chile OranOligorozomys longicaudatusNorthwestern HPS Argentina LechiguanasOligoryzomys flavescensCentral Argentina HPS Hu39694UnknownCentral Argentina HPS Laguna NegraCalomys lauchaParaguay & HPS Bolivia JuquitibaUnknownBrazil HPS Etc. * Numerous other hantaviruses have been identified but not linked to human disease Hantaviruses in the Americas

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 includingSouth 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. 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% HPS Clinical Course

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. 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 Supportive Treatment

14. 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 Hantavirus Reservoirs

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 45:12-22

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. 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 HPS Epidemiology

21. Hantavirus Clusters in Argentina Hantavirus endemic in southern Argentina Clustering for 39% of cases (vs. 7.5% SNV) Eight clusters with > 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