INFECTION PAR LES VIRUS HANTAAN DESC de réanimation Mai 2005 Marie Simon

Rivière Hantaan 38° parallèle HISTORIQUE 1951-1954 : Guerre de Corée Korean Hemorrhagic Fever >3000 soldats atteints Nouveau virus isolé en 1977 HTN Rivière Hantaan 38° parallèle Lee HW J Kor Soc Vir 1977; 7: 1-9 HFRS was first recognized by western physicians from 1951 to 1954 when 3,200 cases of a debilitating, acute, febrile illness were reported among United Nations forces in Korea. The soldiers were living in foxholes while stabilizing the contested border between North and South Korea and had close contact with rodents. The mortality rate was 10-15% so the Hemorrhagic Fever Commission of the United States Army began an enormous investigation. H. Lee, P. Lee, and K. Johnson are credited with finding the antigen in the lungs of a Korean field mouse (Apodemus agrarius coreae). Isolation of the organism occurred in 1977 and named Hantaan for the river that runs near the 38th parallel separating North and South Korea. Much to the credit of the Hemorrhagic Fever Commission, over 600 serum samples from 245 soldiers were preserved until 1990. It resulted in 94% of the samples having antibodies to Hantaan, almost 40 years after the outbreak. In 1979, a virus similar to Hantaan was causing hemorrhagic fever in laboratory workers that had contact with rats in Japan and Europe. This virus was carried by Rattus norvegicus, R. rattus and named Seoul virus after the site of the initial studies. The ongoing risk of shipping these laboratory rats worldwide lead to the dissemination of the Seoul virus. 1990: 94% des échantillons de sérums des soldats en 1950 avaient des anticorps

Brummer-Korvenkontion J Infect Dis 1980;141:131-4 HISTORIQUE 1979 : Seoul virus SEO : forme plus modérée 1980 : virus Puumala PUU principal sérotype en Europe, responsable de : Nephropathia epidemica WW I : Néphrite des tranchées WW II : troupes allemandes en Laponie Lee J Infect Dis 1982;146:638-644 HFRS was first recognized by western physicians from 1951 to 1954 when 3,200 cases of a debilitating, acute, febrile illness were reported among United Nations forces in Korea. The soldiers were living in foxholes while stabilizing the contested border between North and South Korea and had close contact with rodents. The mortality rate was 10-15% so the Hemorrhagic Fever Commission of the United States Army began an enormous investigation. H. Lee, P. Lee, and K. Johnson are credited with finding the antigen in the lungs of a Korean field mouse (Apodemus agrarius coreae). Isolation of the organism occurred in 1977 and named Hantaan for the river that runs near the 38th parallel separating North and South Korea. Much to the credit of the Hemorrhagic Fever Commission, over 600 serum samples from 245 soldiers were preserved until 1990. It resulted in 94% of the samples having antibodies to Hantaan, almost 40 years after the outbreak. In 1979, a virus similar to Hantaan was causing hemorrhagic fever in laboratory workers that had contact with rats in Japan and Europe. This virus was carried by Rattus norvegicus, R. rattus and named Seoul virus after the site of the initial studies. The ongoing risk of shipping these laboratory rats worldwide lead to the dissemination of the Seoul virus. Brummer-Korvenkontion J Infect Dis 1980;141:131-4

Nichol Science 1993 ; 914-917 Kziazek Am J Trop Med Hyg 1995 HISTORIQUE USA : sérotype connu Prospect Hill PH non pathogène Mai 1993 : épidémie “The Four Corners” SDRA inexpliqué Mortalité >50% Sérologie croisée avec Hantaan, Seoul, Puumala Sin Nombre virus SN Several young and healthy members of the Navajo Nation in New Mexico presented to the Indian Health Service physicians with a sudden onset of respiratory failure in May 1993, and by June, twelve people had died. It was originally diagnosed as unexplained Adult Respiratory Distress Syndrome (ARDS). Clinical signs included an abrupt fever, myalgia, headache, and cough, followed by acute progressive pulmonary edema, leading to respiratory failure and hypotension and death 2-10 days after onset. The Department of Public Health for New Mexico along with the Centers for Disease Control and Prevention became involved and set up surveillance and testing. Initial results of acute and convalescent sera against Hantaan, Seoul, and Puumala virus antigens showed cross-reactive antibodies. It had taken a pulmonary form which was unlike any other clinical presentation of hantavirus. Nearly 1700 small mammals representing 31 species were subsequently captured and tested. Almost half of the mammals captured were deer mice (Peromyscus maniculatus) and 30% had antibody the now named Sin Nombre Virus. Nichol Science 1993 ; 914-917 Kziazek Am J Trop Med Hyg 1995

Famille Bunyaviridae 5 genres, 250 espèces Genre Pathologies chez l’homme Bunyavirus Encéphalite de La Crosse, autres Phlebovirus Fièvre de la vallée du Rift, fièvre des phlébotomes Nairovirus Fièvres hémorragiques de Crimée et du Congo Tospovirus Pas d’atteinte humaine connue Hantavirus Fièvre hémorragique avec syndrome rénal Syndrome pulmonaire à Hantavirus 2. Family Bunyaviridae: Hantaviruses are members of the family Bunyaviridae, which consists of 5 genera and 250 species. Hantaviruses can cause hantavirus pulmonary syndrome (HPS) or hemorrhagic fever with renal syndrome (HFRS). The 5 genera of Bunyaviridae include Bunyavirus, Phlebovirus, Nairovirus, Tospovirus, and Hantavirus.

Hantavirus Seul : vecteur non arthropode, hôte vertébré, en général rongeur Génome ARN Plus de 25 espèces Chaque espèce est spécifique d’un hôte

Particules virales sphériques : 80-120 nm Protéines structurales : Glycoprotéines : G1, G2 Nucléoprotéine : N ARN : trois segments Inactivé par chaleur, détergents, solvants organiques, solutions chlorées

Phylogeny of Hantaviruses: Based on Sequence of M Segment (Subfamily, Hantavirus, Location, Host) HTN Korea Apodemus agrarius M HTN China Apodemus agrarius SEO Japan Rattus norvegicus SEO Korea Rattus norvegicus SEO China Rattus norvegicus THAI Thailand Bandicotta indica DOB Slovenia Apodemus flavicollis MURINAE PUU Sweden Clethrionomys glareolus PUU Russia Clethrionomys glareolus ARVICOLINAE PUU Finland Clethrionomys glareolus PUU Belgium Clethrionomys glareolus TUL Czech Microtus arvalis PH Maryland Microtus pennsylvanicus SIGMODONTINAE BCC Florida Sigmodon hispidus BAY Southeastern US Oryzomys palustris Hu39694 Argentina unknown 6. Phylogeny of Hantaviruses, Based on the Sequence of the M Segment (one of three genomic RNA segments): This phylogenetic tree depicts the relationship among the viruses, the primary rodent reservoir of the virus, and the geographic origin of the characterized virus. 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 Indiana Peromyscus leucopus BR Oklahoma Peromyscus leucopus ELMC Western US & Mexico Reithrodontomys megalotis

Implique que les virus Hantaan soient des agents infectieux très anciens qui ont co-évolué avec leur hôte La phylogénie des virus reflète celle des rongeurs

INFECTION CHEZ L’ANIMAL Porteurs asymptomatiques : sans effet sur : La survie Les capacités reproductives Persistance de l’antigène à vie Transmission entre animaux adultes Virus isolé de nombreux organes, notamment : poumons, rate, reins ... Rodents are the reservoir for hantavirus but are asymptomatic carriers. They carry an abundance of viral antigens in their blood, kidneys, liver, fat, nervous tissue, and lungs which makes them infectious for life and can transmit to other rodent species and to man. Other mammals such as carnivores were tested and all were seronegative to SNV.

TRANSMISSION Rongeur infecté Transmission horizontale au sein de la même espèce par contact Virus present dans excrétions aérosolisées : Urine Salive Sécrétions respiratoires selles Transmission occurs through inhalation of aerosolized virus particles from rodent excrement. Transmission of hantavirus infection starts with the reservoir host, a chronically infected rodent. Rodents shed the viral particles in their urine, feces, and saliva. Humans become infected when they disturb the microenvironment of rodents and breathe the tiny droplets in the air of these infected particles, a process called aerosolization. Direct contact with rodent excreta on human mucous membranes or through skin abrasions may also result in transmission. The virus particles can contaminate food consumed by humans and cause infection, and in very rare cases, a bite from an infected rodent can precipitate the disease. Horizontal transmission occurs between rodents of the same species and to man. Vertical transmission is negligible or absent and infection is asymptomatic and not deleterious to the rodent reservoir.

Wells RM Emerg Infect Dis 1996 TRANSMISSION Jusqu’en 1996 : pas de preuve de transmission inter-humaine 1996 : en Argentine : Épidémie de 18 cas d’HPS Dont 5 médecins ayant traité cas index ou autres cas Épidémies humaines liées à  de la population des hôtes rongeurs résultant de changements climatiques et environnementaux Wells RM Emerg Infect Dis 1996 Seroprevalence in non-rodent animals is often low. A total of 164 species of mammals and birds have shown evidence of hantavirus infection. In 200 samples from cats in Austria, 5% were positive and cat ownership has been described as a risk factor for hantavirus disease in China. Research has failed to demonstrate the excretion of infectious particles from these species. Some species, such as the dog and cat, remain a bigger risk factor for bringing infected rodents into a domestic setting. A study involving 396 health care workers in the southwest United States demonstrated nosocomial transmission was not a factor in disease spread. Exposure to bodily fluids of an infected person could result in secondary transmission as was the suspected case in Southern Argentina. An outbreak of Andes virus Hantavirus Pulmonary Syndrome occurred in 1995 in the towns of El Bolson and Bariloche when a Buenos Aires physician apparently contracted the infection after minimal exposure to an infected patient. Person-to-person transmission of HFRS in Asia and HPS in the United States have not been reported. Therefore, CDC guidelines for management of HPS patients in the U.S. recommend standard precautions. There have been several lab-associated outbreaks of HFRS.

PUU TUL SEO DOB

HTN SN

CLINIQUE : HFRS Phase fébrile : Phase hypotensive : Brutale, pas de prodrome, dure 3-7 jours Associée à céphalées, myalgies Phase hypotensive : Hémorragies pétéchiales, thrombopénie Caractéristique : hémorragie conjonctivale et myopie aiguë avec ou sans douleur oculaire Protéinurie Durée : quelques heures à quelques jours There are five phases of Hemorrhagic Fever with Renal Syndrome characterized as febrile, hypotensive, oliguric, diuretic, and convalescent. In the febrile phase, onset is sudden and follows with chills despite a sustained high fever, lethargy, headache, myalgia, vomiting and diarrhea. Thrombocytopenia is often a clue to diagnosis, while the conjunctiva and skin show petechiae. The hypotensive phase often results in an increased hematocrit with sinus bradycardia even with the fever.

CLINIQUE : HFRS Phase oligurique : Phase polyurique : Début avec le retour à normotension Insuffisance rénale Durée : 3-7 jours Phase polyurique : Durée : jusqu’à plusieurs semaines Plusieurs litres de diurèse par jour Convalescence : souvent prolongée There are five phases of the disease characterized as febrile, hypotensive, oliguric, diuretic, and convalescent. In the oliguric phase, urine output decreases leading to higher serum concentrations of urea and creatinine. Metabolic acidosis occurs due to the electrolyte imbalance. Death occurs 75% of the time in the first 10 days, generally during the oliguric phase of the disease due to circulatory or renal failure. The diuretic phase occurs spontaneously and as a result renal function can return to normal. The convalescent phase can last weeks to months with the patient unable to concentrate urine.

HFRS : selon virus Hantaan, Dobrava Seoul : intermédiaire Puumala complications hémorragiques sévères Mortalité > 10 % Seoul : intermédiaire Puumala Mortalité < 0,2 % Hantaan, Seoul, Dobrava viruses have severe hemorrhagic complications during the oliguric phase. Puumala virus causes a condition known as nephropathia epidemica that causes an acute febrile disease with renal involvement and a transient thrombocytopenia.

CLINIQUE : HPS Incubation : 14-17 jours Phase prodromale : Fatigue, fièvre, myalgies, céphalées Durée : 3-5 jours 50% : diarrhées, vomissements, douleurs abdominales Incubation time is mostly between 14 to 17 days. Initial signs include fatigue, fever, myalgia of the large muscle groups (thighs, hips, back, shoulders), and headache lasting 3 to 5 days. About half of the patients will experience headaches, dizziness, chills, and various gastrointestinal symptoms such as nausea, vomiting, diarrhea and abdominal pain. CDC Infectious Disease Pathology Activity www.cdc.gov/ncidod/diseases/hanta/hps/noframes/printgenlsection.htm

CLINIQUE : HPS Phase cardio-pulmonaire : 4-10 jours après le début des symptômes Oedème aigu du poumon non cardiogénique rapidement progressif Hypotension sévère Le plus souvent : hospitalisation and ventilation mécanique Rhabdomyolyse fréquente Four to ten days after initial clinical signs, coughing and shortness of breath due to a rapidly progressive, non-cardiogenic pulmonary edema and severe hypotension. As the disease progresses rapidly, hospitalization and ventilation are necessary within 24 hours. Even with today’s technology, approximately 40% of patients die within the first 48 hours due to uncorrected hypoxia and shock. CDC All About Hantavirus www.cdc.gov/ncidod/diseases/hanta/hps/noframes/phys/clinical.htm

CLINIQUE : HPS Pas ou peu de signes hémorragiques Formes rénales en Amérique du Sud Additional signs of HPS include increased respiratory and heart rates, lowered blood pressure. Lung auscultation often reveals crackles or rales, and radiographs are warranted. CBC and blood chemistry should be run every 8 to 12 hours to monitor WBC count and platelet count. As pulmonary edema increases, the serum albumin values are lowered with a rise in hematocrit. The WBC count is often elevated while the platelet count falls below 150,000 units.

DIAGNOSTIC Indirect : sérologies : Direct : isolement du virus : ELISA : IgG et IgM Direct : isolement du virus : Immunohistochimie : détecte les antigènes viraux dans les tissues PCR Culture virale difficile The CDC uses ELISA to detect the presence of IgM in acute-phase serum or a four-fold rise in IgG antibody titer from acute- and convalescent-phase sera. Acute-phase serum as an initial diagnostic specimen may not yet have IgG but it is long lasting, and has been used in serologic investigations of the epidemiology of the disease. Immunohistochemistry can be used on formalin fixed tissues to detect hantavirus antigen when serum is unavailable. Virus isolation was accomplished using a serum sample from a seronegative child 2 days before clinical onset of signs of HPS. Other tests include the polymerase chain reaction for hantavirus RNA, currently experimental, a Western blot assay using recombinant antigens and isotype-specific conjugates for IgM-IgG differentiation and rapid immunoblot strip assay (RIBA) which is an investigational prototype assay used to identify serum antibody to recombinant proteins and peptides specific for SNV and other hantaviruses.

TRAITEMENT Symptomatique HPS : réanimation précoce, intensive Ribavirine : Semble efficace dans HFRS : études randomisées efficacité potentielle non démontrée dans HPS Utilisation précoce Treatment of patients with HPS requires early and aggressive intensive care, focusing on electrolyte balance, oxygenation of the blood, and maintaining blood pressure. Antiviral drugs, such as ribavirin, have questionable efficacy, possibly due to the late introduction after disease onset.

VACCINATION Depuis 1990 Efficacité encore débattue HFRS chez militaires coréens malgré vaccination Mais  des cas d’HFRS depuis les campagnes de vaccination en Corée

HFRS Dans le monde : En Asie du Sud-Est : 150 000–200 000 cas par an Corée du sud : 300-700 cas par an Chine de l’est : ~100 000 cas par an There is a worldwide distribution of people afflicted with hemorrhagic fever with renal syndrome and approximately 150,000 to 200,000 hospitalizations are reported each year. More than half of these are in China where hantavirus has been recognized since 1931. Korean Hemorrhagic Fever reportedly causes 300-700 cases of HFRS annually in South Korea. Eastern China reports about 100,000 cases annually. HFRS outbreaks in Asia and Europe are linked to contact with field rodents through the planting and harvesting of crops.

New World Hantaviruses New York Peromyscus leucopus Sin Nombre Peromyscus maniculatus Prospect Hill Microtus pennsylvanicus Muleshoe Sigmodon hispidus Bloodland Lake Microtus ochrogaster Isla Vista Microtus californicus Bayou Oryzomys palustris Black Creek Canal Sigmodon hispidus El Moro Canyon Reithrodontomys megalotis Rio Segundo Reithrodontomys mexicanus Calabazo Zygodontomys brevicauda Juquitiba Unknown Host Caño Delgadito Sigmodon alstoni Laguna Negra Calomys laucha Choclo Oligoryzomys fulvescens Rio Mamore Oligoryzomys microtis Maciel Necromys benefactus 10. A map of Western Hemisphere shows the distribution of New World hantaviruses and their associated rodent hosts. The viruses in bold print cause disease in humans including: Sin Nombre, Choclo, Orán, Andes, New York, Bayou, Black Creek Canal, Juquitiba, Laguna Negra, Hu39694, and Lechiguanas. Virus (Rodent Host) Sin Nombre (Peromyscus maniculatus) Muleshoe (Sigmodon hispidus) Isla Vista (Microtus californicus) El Moro Canyon (Reithrodontomys megalotis) Calabazo (Zygodontomys brevicauda) Choclo (Oligoryzomys fulvescens) Caño Delgadito (Sigmodon alstoni) Rio Mamore (Oligoryzomys microtis) Orán (Oligoryzomys longicaudatus) Bermejo (Oligoryzomys chacoensis) Andes (Oligoryzomys longicaudatus) New York (Peromyscus leupous) Prospect Hill (Microtus pennsylcanicus) Bloodland Lake (Microtus ochrogaster) Bayou (Oryzomys palustris) Black Creek Canal (Sigmodon hispidus) Rio Segundo (Reithrodontomys mexicanus) Juquitiba (Unknown host) Laguna Negra (Calomys laucha) Maciel (Necromys benefactus) Hu39694 (Unknown host) Lechiguanas (Oligoryzomys flavescens) Pergamino (Akodon azarae) Orán Oligoryzomys longicaudatus Hu39694 Unknown Host Lechiguanas Oligoryzomys flavescens Bermejo Oligoryzomys chacoensis Pergamino Akodon azarae Andes Oligoryzomys longicaudatus

EN FRANCE Hantavirus le plus fréquent : Puumala PUU Zone endémique : quart nord-est Hantavirus le plus fréquent : Puumala PUU

EN FRANCE

PREVENTION Contrôle des facteurs à l’origine d’ de la densité de population des rongeurs Précautions lors du contact avec des rongeurs : Professionnel Domestique

PREVENTION Contrôle des rongeurs à l’intérieur et à l’extérieur The most effective way to prevent the risk of HPS is to limit exposure to rodents and their excreta, both inside the home and out. Utilizing proper precautions when in situations where mouse excreta exists will also decrease the risk of exposure. It is important to remember to minimize your exposure when enjoying outdoor activities. 1

Bibliographie McCaughey J Med Microbiol 2000;49:587-599 www.cdc.gov/ncidod/diseases/hanta/hps/noframes/phys/clinical.htm Mailles Médecine et maladies infectieuses 2005;35:68–72 Bugert Nephrol Dial Transplant 1999;14:1843-44 Sauvage Emerg Infect Dis 2002;8:1509-10 Crowcroft BMJ 1999;318:1737-38 Faulde Nephrol Dial Transplant 2000;15:751-53 www.invs.sante.fr/publications/2003/fhsr/rapport_fhsr.pdf Khan Lancet 1996;347:739-741