Special Pathogens Branch DVRD/NCID/CDC Hantavirus Pulmonary Syndrome (HPS)

Genus Human disease BunyavirusLaCrosse encephalitis, others PhlebovirusRift Valley fever, sandfly fever NairovirusCrimean-Congo hemorrhagic fever TospovirusPlant virus, no known human disease HantavirusHemorrhagic fever with renal syndrome Hantavirus pulmonary syndrome 5 genera, 250 species Family Bunyaviridae

No arthropod vector established Unique among genera of Bunyaviridae Rodent hosts Rodent hosts Genus and possibly species specific Genus and possibly species specific Transmission Transmission Aerosolization of rodent excreta Aerosolization of rodent excreta Characteristics of Hantaviruses

Chronically infected rodent Virus is present in aerosolized excreta, particularly urine Horizontal transmission of infection by intraspecific aggressive behavior Virus also present in throat swab and feces Secondary aerosols, mucous membrane contact, and skin breaches are also sources of infection Transmission of Hantaviruses

HTN Korea Apodemus agrarius DOB Slovenia Apodemus flavicollis SEO Japan Rattus norvegicus PUU Finland Clethrionomys glareolus PUU Russia Clethrionomys glareolus PUU Sweden Clethrionomys glareolus S PUU Belgium Clethrionomys glareolus TOP Russia Lemmus sibiricus KBR Russia Microtus fortis TUL Russia Microtus arvalis TUL Czech Microtus arvalis TUL Slovakia Microtus arvalis PH New York Microtus pennsylvanicus PH Maryland Microtus pennsylvanicus ISLA California Microtus californicus MULE Southern US Sigmodon hispidus (texianus) BCC Florida Sigmodon hispidus BAY Southeastern US Oryzomys palustris ANDES Argentina & Chile Oligoryzomys longicaudatus LEC Argentina Oligoryzomys flavescens RIOM Bolivia & Peru Oligoryzomys microtis LN Paraguay & Bolivia Calomys laucha SN New Mexico Peromyscus maniculatus SN California Peromyscus maniculatus NY New York Peromyscus leucopus NY Rhode Island Peromyscus leucopus MON West Virginia Peromyscus maniculatus ELMC Western US & Mexico Reithrodontomys megalotis RIOS Costa Rica Reithrodontomys mexicanus Phylogeny of Hantaviruses: Based on Sequence of S Segment (Subfamily, Hantavirus, Location, Host) MURINAE ARVICOLINAE SIGMODONTINAE

HTN Korea Apodemus agrarius HTN China Apodemus agrarius M Phylogeny of Hantaviruses: Based on Sequence of M Segment (Subfamily, Hantavirus, Location, Host) SEO Japan Rattus norvegicus SEO Korea Rattus norvegicus THAI Thailand Bandicotta indica DOB Slovenia Apodemus flavicollis PUU Sweden Clethrionomys glareolus PUU Russia Clethrionomys glareolus PUU Finland Clethrionomys glareolus PUU Belgium Clethrionomys glareolus TUL Czech Microtus arvalis PH Maryland Microtus pennsylvanicus BCC Florida Sigmodon hispidus BAY Southeastern US Oryzomys palustris Hu39694 Argentina unknown LEC Argentina Oligoryzomys flavescens ORN Argentina Oligoryzomys longicaudatus LN Paraguay & Bolivia Calomys laucha SN California Peromyscus maniculatus SN New Mexico Peromyscus maniculatus NY Rhode Island Peromyscus leucopus NY New York Peromyscus leucopus BR Oklahoma Peromyscus leucopus BR Indiana Peromyscus leucopus ELMC Western US & Mexico Reithrodontomys megalotis MURINAE ARVICOLINAE SIGMODONTINAE SEO China Rattus norvegicus

Subfamily Murinae associated viruses Virus HostLocation Disease Hantaan Apodemus agrarius Asia, Far East RussiaHFRS Dobrava Apodemus flavicollisBalkansHFRS Apodemus agrariusEurope Seoul Rattus norvegicusWorldwideHFRS Rattus rattus Subfamily Arvicolinae associated viruses Virus Host Location Disease Puumala Clethrionomys glareolus EuropeHFRS Numerous other hantaviruses have been identified but not linked to human disease Hantaviruses in the Old World

Subfamily Sigmodontinae associated viruses Virus HostLocation Disease Sin Nombre Peromyscus maniculatus West & Central HPS U.S. & Canada U.S. & Canada Monongahela Peromyscus maniculatus Eastern U.S. & HPS Monongahela Peromyscus maniculatus Eastern U.S. & HPSCanada New York Peromyscus leucopus Eastern U.S. HPS New York Peromyscus leucopus Eastern U.S. HPS Bayou Oryzomys palustris Southeastern U.S. HPS Black Creek Canal Sigmodon hispidusFlorida HPS Numerous other hantaviruses have been identified but not linked to human disease Numerous other hantaviruses have been identified but not linked to human disease Hantaviruses in the New World (1)

Subfamily Sigmodontinae associated viruses (cont.) Virus Host Location Disease AndesOligoryzomys longicaudatusArgentina & ChileHPS OranOligorozomys longicaudatus Northwestern Argentina OranOligorozomys longicaudatus Northwestern Argentina LechiguanasOligoryzomys flavescensCentral Argentina LechiguanasOligoryzomys flavescensCentral Argentina Hu39694UnknownCentral Argentina Hu39694UnknownCentral Argentina Laguna NegraCalomys lauchaParaguay &HPS Bolivia BermejoOligoryzomys chacoensisNorthwesternHPS Argentina JuquitibaUnknownBrazilHPS ChocloOligoryzomys fulvescensPanamaHPS Numerous other hantaviruses have been identified but not linked to human disease Numerous other hantaviruses have been identified but not linked to human disease Hantaviruses in the New World (2)

Sin Nombre Peromyscus maniculatus Rio Segundo Reithrodontomys mexicanus El Moro Canyon Reithrodontomys megalotis Andes Oligoryzomys longicaudatus Bayou Oryzomys palustris Black Creek Canal Sigmodon hispidus Rio Mamore Oligoryzomys microtis Laguna Negra Calomys laucha Muleshoe Sigmodon hispidus New York Peromyscus leucopus Juquitiba Unknown Host Maciel Necromys benefactus Hu39694 Unknown Host Lechiguanas Oligoryzomys flavescens Pergamino Akodon azarae Orán Oligoryzomys longicaudatus Caño Delgadito Sigmodon alstoni Isla Vista Microtus californicus Bloodland Lake Microtus ochrogaster Prospect Hill Microtus pennsylvanicus New World Hantaviruses Bermejo Oligoryzomys chacoensis Calabazo Zygodontomys brevicauda Choclo Oligoryzomys fulvescens

Hantavirus Pulmonary Syndrome Chile (273) 5 Argentina (404) 4 Brazil (168) 2 Uruguay (23) 1 Paraguay (74) 1 Panama (31) 6 Bolivia (20) 4 United States (335) 7 Canada (36) 3 Number of cases by date 1 PAHO 01 2 January 02 3 May 02 4 August 02 5 September 02 6 October 02 7 November 02 Countries with reported cases of HPS (no of cases) Countries with no reported cases of HPS

Peromyscus maniculatus Deer mouse Sigmodon hispidus Cotton rat

FamilyTransmission Viral particles Structural proteins GenomeBunyaviridae vertebrate hosts, no arthropod vectors spherical, nm Glycoproteins: G1, G2 nucleoprotein: N ss-RNA, trisegmented, negative polarity Sin Nombre Virus Characteristics

Most Frequent OtherRare FeverDizzinessRhinorrhea MyalgiaArthralgia Sore Throat Nausea/VomitingCough Shortness of Breath (late in the course of disease) Hantavirus Pulmonary Syndrome Clinical Presentation

Tachypnea Tachypnea Tachycardia Tachycardia Hypotension Hypotension Crackles or rales on lung examination Crackles or rales on lung examination Hantavirus Pulmonary Syndrome Physical Examination

Bilateral interstitial infiltrates - moderate to rapid progression Bilateral interstitial infiltrates - moderate to rapid progression Bilateral alveolar infiltrates Bilateral alveolar infiltrates Pleural effusion Pleural effusion Hantavirus Pulmonary Syndrome Radiographic Findings

May 27, 1993 May 30, 1993 May 31, 1993 Source: Dr. L. Ketai Radiographic Progression of HPS in the Lungs

Chemistry Low albumin Elevated LDH Elevated AST (SGOT) Elevated ALT (SGPT) Hematology Low platelet count Atypical lymphocytes (immunoblasts) Left shift on WBC differential Elevated hematocrit Elevated WBC Hantavirus Pulmonary Syndrome Common Laboratory Findings

+ + + Fever Pulmonary edema Shock Diuresis ProdromeCardiorespiratory Convalescence Immunoblasts HCT AST LDH 3-6 days 7-10 days Platelets Clinical Progression of HPS

Early aggressive intensive careEarly aggressive intensive care Early use of inotropic agents (Dobutamine)Early use of inotropic agents (Dobutamine) Early ventilationEarly ventilation Careful monitoringCareful monitoring – Oxygenation – Fluid balance – Blood pressure HPS Management

Early use of inotropic agentsEarly use of inotropic agents Mechanical ventilationMechanical ventilation Judicious volume resuscitationJudicious volume resuscitation Early PA catheterEarly PA catheter SQS 6/95 ICU Monitoring and Therapy

Serology SerologyIgMIgG Immunohistochemistry Immunohistochemistry Reverse transcription and polymerase chain reaction (RT-PCR) Reverse transcription and polymerase chain reaction (RT-PCR) Hantavirus Pulmonary Syndrome Laboratory-confirmed Diagnosis

Interstitial Pneumonitis – Congestion – Interstitial infiltrate of enlarged mononuclear cells (immunoblasts) – Intra-alveolar and septal edema – Focal hyaline membranes Histopathology Lung (1)

Absence or minimal evidence of: – Cellular debris – Neutrophils – Epithelial injury – Viral inclusions – Fungi or bacteria by specific stains Histopathology Lung (2)

Enlarged mononuclear cells (immunoblasts) Enlarged mononuclear cells (immunoblasts) – Lymph nodes (sinuses and paracortex) – Spleen (red pulp and periarteriolar sheaths) – Liver (triaditis) – Vessels (different organs) Other changes (minor) Other changes (minor) Spleen Histopathology Other Organs

Peridomestic exposure Peridomestic & occupationalexposure Peridomestic & recreational exposure Occupational exposure Entering/cleaning rodent-infested structures Armstrong, L.R. et al., JID 1995; 172 (October) Armstrong, L.R. et al., JID 1995; 172 (October) 69% (48/70) 19% (13/70) 9% (6/70) 9% (6/70) 4% (3/70) 4% (3/70) 9% (6/70) 9% (6/70) Rodent Exposure 70 confirmed HPS cases

Risk group Forest workers 1 Health care workers 2 Prodromal HPS 3 Contacts 4 Rural OCC 5 Rodent workers 6 TotalLocation/time SW US, 1993 SW US, 1994 US, 1994 Postive/tested (%) 0/1430/396 3/299 (1.0%) 3/239 (1.3%) 1/522 (0.2%) 8/932 (0.9%) 15/2531 (0.6%) 1. Vitek et al, Vitek et al, Simonsen et al, Zeitz et al, Zeitz et al, Armstrong et al, 1995 Prevalence of SNV IgG Antibodies in Select U.S. Populations

CountryPositive/tested (%)Time Paraguay 1 44/345 (12.8%)1995 Western Paraguay 2 78/193 (40.4%) (Indian Population) Argentina 3 <1%1996 Salta Province 2 38/222 (17.1%) (Indian Population) Salta Province 2 38/222 (17.1%) (Indian Population) Chile % Williams, Ferrer, Peters, 1998; Weissenbacher, 1996 Prevalence of SNV IgG Antibodies in Select South American Populations

Control Mice Inside Control Mice Outside Use Safety Precautions HPS Prevention

Eliminate food sources Eliminate food sources – Wash dishes and clean the floor and counters – Put pet food and water away at night – Store food / garbage in containers with tight lids Control Mice Inside

Prevent mice from entering – Clear brush and grass from around foundation – Seal holes or use flashing around the base of the house Use continuous trapping efforts Use continuous trapping efforts Control Mice Inside

Eliminate possible nesting sites – Elevate hay, woodpiles, and garbage cans – Locate them at least 100 feet from house – Eliminate junk or things that provide shelter to rodents Control Mice Outside

Eliminate food sources Eliminate food sources – Store all animal feed in containers with lids – Discard excess food in the evening into containers with lids – Take up water bowls in the evening Control Mice Outside

Natural predators are beneficial Natural predators are beneficial – Non-poisonous snakes – Owls – Hawks Control Mice Outside

When cleaning in areas infested with rodents When cleaning in areas infested with rodents – Wear rubber gloves – Don't stir up and breathe dust – Wet contaminated areas with disinfectant – Dispose of dead animals properly – Disinfect used gloves Use Safety Precautions

When enjoying outdoor activities When enjoying outdoor activities – Avoid contact with rodents – Stay away from rodent burrows or nests – Keep campsite clean and food tightly sealed – Open unused cabins and air out before entering or cleaning – Avoid sleeping on bare ground Use Safety Precautions

Hantavirus Infection HPS Hantavirus Illness Spectrum of Illness

MMWR 1993; 42: Febrile illness (T > 38.3°C) Unexplained ARDS or bilateral infiltrates following hospitalization Unexplained ARDS or bilateral infiltrates following hospitalization Supplemental oxygen Supplemental oxygenor Noncardiogenic pulmonary edema at autopsy Noncardiogenic pulmonary edema at autopsy No identifiable specific cause of death No identifiable specific cause of death HPS National Surveillance HPS Case Definition

Febrile illness (T > 38.0º C) Febrile illness (T > 38.0º C) No bilateral diffuse interstitial or alveolar infiltrates No bilateral diffuse interstitial or alveolar infiltrates HPS National Surveillance Mild Hantaviral Illness Case Definition

Full clinical spectrum of HPS is undefined Full clinical spectrum of HPS is undefined – Cases with mild pulmonary disease – Cases with accompanying renal disease Depending on resources, screening criteria could include : Depending on resources, screening criteria could include : – Mild pulmonary disease – Unexplained acute febrile renal disease – Other febrile syndromes HPS National Surveillance Comments

Safety Safety – Label as infectious substance and/or human blood precautions – Double container with absorbent material sufficient for volume being sent – Plastic tubes preferable over glass Conditions Conditions – Sera -- room temperature or cold pack – Clot or buffy coat -- dry ice – Fresh tissues (1-cm cubes) -- dry ice – Formalin-fixed tissue and blocks -- room temperature (don't freeze) Shipping

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