Hantaviruses and Hantavirus Pulmonary Syndrome HPS Objectives Describe

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

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

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)

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 Apodemus agrarius Seoul Rattus norvegicus Rattus rattus Balkans Europe Worldwide HFRS Subfamily Arvicolinae associated viruses Virus Host Location Puumala Clethrionomys glareolus Europe *Numerous other hantaviruses have been identified but not linked to human disease Disease HFRS

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

Hantaviruses in the Americas Subfamily Sigmodontinae associated viruses (HPS) Virus Host Location. Disease Sin Nombre Peromyscus maniculatus West/Central U. S. & Canada Monongahela Peromyscus maniculatus Eastern U. S. & Canada New York Peromyscus leucopus Eastern U. S. Bayou Oryzomys palustris Southeastern U. S. Black Cr. Sigmodon hispidus Florida Andes Oligoryzomys longicaudatus Argentina & HPS Chile Oran Oligorozomys longicaudatus Northwestern HPS Argentina Lechiguanas Oligoryzomys flavescens Central Argentina Hu 39694 Unknown Central Argentina HPS Laguna Negra Calomys laucha Paraguay & HPS Bolivia Juquitiba Unknown Brazil HPS Etc. HPS HPS HPS * Numerous other hantaviruses have been identified but not linked to human disease

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

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

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-B 8 DR 3

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

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%

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 Ig. M and Ig. G antibody testing • Immunohistochemistry, PCR serum, frozen tissue, tissue blocks, BAL • Culture

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

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

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

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

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

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

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

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

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 Ig. G 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

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

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

Hantavirus Outbreak, 1993 • Impact on local community – Loss of tourism and associated income – Prejudice – Media intrusion – Disregard for religious observances