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ISSN 1021-366X Hantavirus Pulmonary Syndrome (HPS) Introduction An outbreak of an unexplained illness occurred in May 1993 in “Four Corners”, an area of the Southwest shared by New Mexico, Arizona, Colorado, and Utah. A number of previously healthy young adults developed acute respiratory symptoms; about half died soon thereafter. The New Mexico Department of Health, the Arizona Department of Health Services, the Colorado Department of Health, the Utah Department of Health, the Indian Health Service, and the US CDC, with the assistance of the Navajo Nation Division of Health, rapidly mounted an intensive investigation.(1,2) Researchers soon found that this unexplained illness was caused by a newly identified Sin Nombre virus (SNV)(3-5) As the lungs were the primary site of infection, the illness was different from the hemorrhagic fever with renal syndrome (HFRS) which affects primarily the kidneys (Table 1)(6); the disease was named hantavirus pulmonary syndrome (HPS). The principal carrier of the virus was deer mouse.(7) Chances of man being infected are rare, however once infected, the illness can be very serious. In the past about 50% of those infected died. Dr CJ Peter of the 24 Epidemiology Bulletin February 25, 2001 US Center for Disease Control and Prevention’s Special Pathogens Research Unit pointed out that HPS first appeared in the Southwest, but now it can be found all over the US.(8) The virus is not new, and in the late 1970’s, some Americans died of this then unrecognized pulmonary disease. HPS therefore is a re-emerging disease. Definition of Case(9) A suspected HPS case is defined by the US CDC as one who has a fever of 0 101 F (38.30C) and above, and pulmonary edema of both lungs. A previously healthy person will develop dyspnea about 72 hours after hospitalization and need respirator assisted oxygenation. Symptoms(10) Early symptoms include fever, headache and myalgia, especially of the large muscle groups such as thighs, hips, and back. There may also be abdominal symptoms such as nausea and vomiting, as well as dizziness, and chills. Four to five days after the initial phase of illness, the late symptoms of HPS, such as wet lungs, coughing, and dyspnea will appear. may even succumb to shock. significantly different (Table 2). Patients Clinical symptoms of HPS and HFRS are (11) Pathogenic Agent and Hosts(12) Hantavirus, of the Bunyaviridae family, is transmitted by animals to man. The virus is round, of about 100nm in diameter, and is composed of negative stranded RNA with tripartate genomes. The virus is lipid enveloped and can be inactivated by lipid solvents such as alcohol, common disinfectants, and bleach. Hantavirus linked definitely to human disease comes in two major groups (Table 3).(13) The first group of Hantaan, Puumula and Seoul is found more Vol. 17 No.2 Epidemiology Bulletin often in Asia and Europe. 25 They cause hantavirus hemorrhagic fever, or hemorrhagic fever with renal syndrome (HFRS). HFRS will induce renal failure, and in serious cases, circulatory impairment leading to shock, bleeding and pulmonary edema. Fatality is less than 10%. causes HPS is found only in the Americas. The other group that Host of the Sin Nombre virus in the US is the deer mouse, found in large numbers in the Four Corners area, and was the cause of the outbreak in 1993. Three newly identified viruses that also cause HPS, the Black Creek Canal virus, the Bayou virus, and the New York-1 virus, are found in Florida, Louisiana, and New York State. Their hosts are cotton rat, rice rat, and white-footed rat respectively. Mode of Transmission(14) Carrier rodents shed the virus in their urine, droppings and saliva. The virus is transmitted to healthy rodents. Rodents do not develop illness. The virus is transmitted to humans when they inhale air or are exposed to objects contaminated with the virus, or are bitten by infected rodents. The principal carrier of the virus is deer mice commonly found in North America. Thus far, no person to person transmission has been reported in the United States. Laboratory Testing(15) HPS is confirmed when serological testing is positive, or virus antigens are found through immunohistochemistry, or virus RNA is found in blood/tissue, and the patient has a history similar to that of HPS. 1.Serological Testing (1)Virus antigen testing of Sin Nombre virus specificity is a routine test. (2)The US CDC uses the ELISA method to test SNV-IgM antibody and other acute infections of hantavirus. (3)IgG antibody testing and MAC-ELISA (IgM antibody capture ELISA) are 26 Epidemiology Bulletin performed concurrently. February 25, 2001 Infection is confirmed when IgG antibody level in the acute phase and the convalescence phase has increased by four times and IgM antibody in the acute phase is positive. (4)By using reorganized antigens to differentiate IgM and IgG antibodies through the western blot method. (5)Testing the SNV immunodominant epitope antibody. The 43rd amino acid of the SNV nucleocapsid protein and the 31st amino acid of the G1 glycoprotein are the immunodominant epitope of the virus immunity, and are conserved among SNV strains. Testing of epitope antibody can verify the SNV specificity. (6)The conventional neutralizing plaque assays is used to serologically confirm hantavirus infection. 2.Isolation of Virus Isolation of hantavirus from humans is most difficult. virus strains like SNV have been isolated. Thus far, no Virus isolation, therefore, cannot be used as a tool for diagnosis. 3.Immunohistochemistry Method Specific monoclonal and polyclonal antibodies are used to test for hantavirus antigens of formalin-fixed tissues. This is a relatively sensitive method, and can be used for the confirmation diagnosis of hantavirus infection. 4.Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) RT-PCR can be used to test freshly frozen lung tissue, blood clot, or nucleated blood cells for hantaviral RNA. However, RT-PCR is prone to cross contamination, and care should be taken. test for hantavirus infection in the US. This is not yet a routine Vol. 17 No.2 Epidemiology Bulletin 27 Hantavirus Infections in the Americas(16) HPS occurs primarily in the Americas including the US, Canada, and Argentina, Brazil, Chile, Paraguay and Uruguay of Central and South America. HPS, therefore, is an important zoonotic (animal to human) transmitted disease in North and South America. USA(17) By December 13, 1999, there were 231 confirmed HPS cases (Table 4) (18) in the U.S. 60% of the patients were male, and 40% female. averaged 37 years of age, ranging from 10 to 71. were likely to be equally infected with HPS. throughout the year (Table 5), summer. (19) They Therefore all age groups Although there were cases more cases occurred during the spring and Localities affected included 30 states; almost all Western and some Eastern states had cases reported. Half of the confirmed cases occurred Corners in states outside the Four area (Table 6).(20) Three-quarters of cases lived in rural areas. Central and South America(21-22) By November 1998, there were 191 HPS cases in Argentina, 12 in Brazil, 70 in Chile, 34 in Paraguay, and 5 in Uruguay. Though rodents in Bolivia, Costa Rica and Mexico have been found to carry hantavirus similar to the Sin Nombre virus of the US, the virus has not been found to be associated with any diseases of man. Argentina(23) Between September 22 and December 5, 1996, 18 HPS cases occurred in the El Bolson region south of the Andes mountains in the Rio Negro province of Argentina. They all showed distinct characteristics of HPS. patients demonstrated hemorrhagic fever-like rash on their faces. Some Researchers 28 Epidemiology Bulletin February 25, 2001 collected lung and liver tissue from a patient who died of the same disease in the same region in March 1995, and tested them using the PCR method. A new hantavirus, later named Andes virus, was isolated. These patients were either residents of the El Bolson region, or had visited the region 2-5 weeks before the onset of infection. became infected. Three doctors who treated these patients also Of special interest was that most of the cases had had contact with patients 2-3 weeks before the onset of infection. What was unusual about the outbreak was that all available data indicated that it was probably a person-to-person transmission. A doctor from Buenos Aires (2,000 km away from El Bolson) treated a patient who had moved from El Bolson to Buenos Aires. 27 days later, the doctor developed symptoms of infection. This demonstrated probably that the virus in Argentina was transmitted person-to-person.(24) Prior to this incident there had never been any reports of person-to-person transmission of HPS from North, Central, or South America, Europe or Asia. Chile(25,26) An outbreak of HPS occurred for the first time in Chile in October 1995. By July 1997, there were nine confirmed cases. An outbreak of HPS occurred in the Aysen region between August 1 and October 8, 1997, with 25 reported cases; of them, 12 were confirmed. household clustering were noticed. Two cases of Upon the request of the Chilean government, a group of epidemiologists from the US CDC Special Pathogens Research Unit visited the site on September 24 to investigate the scale of the outbreak, rodents and their infection with hantavirus, and major risk factors of infection. Of the 21 confirmed cases, 13 died (fatality 62%), four were children younger than 17, and 76% were male. Genetic sequencing analysis of a case confirmed that the pathogenic agent was Andes virus. Vol. 17 No.2 Epidemiology Bulletin 29 The two cases of household clustering occurred in the Aysen region. Case 1, the index case (onset of disease on July 15) was from the Lago Verde community. His wife (onset on August 2), their child of two years (onset on August 9), another 12 year old child (onset on August 18), a relative occasionally visiting the family(onset on September 5) were infected. Case 2 was in the Coyhaique community. Three out of four members of the family became ill between August 23 and 28. Investigation indicated that the outbreak was due to the high density of rodents. The number of rodents caught in the Aysen region was five times greater than the number caught in the non-infection areas 600 km to the north and 35 km to the south. 253 rats were caught in 569 rattraps; of the 253, 47% were Oligoryzomys longicaudatus, the same species as the rodents in Argentina that carried Andes virus. Treatment(27) At the present time, there is no specific treatment other than supportive therapy with presumptive antibiotics for hantavirus infection. Immediate action should be taken to restore the electrolyte balance in the lung and blood. If infected individuals are recognized early and referred to an intensive care unit for endotracheal intubation and oxygen therapy, they may better survive the period of severe respiratory distress. Prevention(28) HPS is transmitted by carrier rodents. Prevention of HPS can be accomplished by controlling the population of rodents. Sanitary conditions of public places including restaurants, hotels, food stands, markets, food factories etc. should be well maintained. 1.Indoor Prevention (1)Elimination of food sources for rodents --dish washing, cleaning of floors and corners 30 Epidemiology Bulletin February 25, 2001 --Food residues and wastes should be well sealed and disposed of promptly --Food and animal feed should be tightly covered. --Food and drinking water for pets should be stored properly. (2)Preventing rats from entering --Lawns and shrubs around the house should be well trimmed to avoid concealment of rats. --Cracks and openings of walls and windows should be closed. All likely entrances of rats should be sealed. (3)Use of mousetraps 2.Outdoor Prevention (1)Eliminate all possible sites of rat nesting --Hay and wood should be kept above ground and at least 100 feet away from the house. --Wastes should be properly disposed of to avoid rat nesting. (2)Elimination of food sources --Animal feed should be kept in containers and covered. --Dispose of food remnants every evening. --Water containers should be well covered every evening. (3)Natural rat predators --non-poisonous snakes --owls --eagles The Likelihood of HPS Outbreaks in Taiwan Thus far, no indigenous HFPS cases have been reported in Taiwan.(29) One imported case in 1995, another one in 1996, and two more in 1997 were brought in by people visiting mainland China. China is a high HFPS epidemic area. The southeastern part of The short distance between Taiwan Vol. 17 No.2 Epidemiology Bulletin 31 and mainland China and the similar species of rodent population in both areas make it relatively likely that HFPS can be brought into Taiwan. Epidemiological studies, surveillance of rodents, virological and molecular biological studies in the Americas have found that, geographically, specific rodents are responsible for the transmission of HPS. Epidemiological, virological, and molecular biological studies and understanding of rodents and ecology in Taiwan should help understand the circumstances surrounding hantavirus infection in Taiwan. The fact that hantavirus is widely distributed and that there are as many as 11 species of rodents in Taiwan suggest that chances of HPS outbreaks in Taiwan are high. More should be done in the area of disease control. As hantavirus is transmitted between rodents and from rodents to man, rodent control at ports of entry should not be relaxed. Rodent control is the key to the prevention of hantavirus. The public should be made aware of the control measures for both HFRS and HPS. Conclusion Rodent-transmitted hantavirus hemorrhagic fever occurs almost in the whole Eastern Hemisphere. HPS, identified in the US in 1993, is an important rodent-transmitted disease in the Americas. hantaviruses have since epidemiological studies. been identified through Even further ecological and They are found everywhere and may soon present a major threat to human health.. Studies of hantavirus have now become an important public health issue worldwide. Acknowledgements This article including context and Tables, except other specified, was reproduced, cited, and summarized from the information, statistical data and charts provided by the web page at http://webdev.cdc.gov/ncidod/dvrd/spb 32 Epidemiology Bulletin February 25, 2001 /spbwebpage/, Special Pathogens Branch, Division of Viral and Rickettsial Diseases, National Center for infectious Disease, CDC. We would like to express our sincere thanks to all the above mentioned web page and Center for Disease Control and Prevention, USA for their kindly permission for us to use web page information.. Prepared by: L Chow, TH Lin Division of Vector-borne Infectious Diseases, Center for Disease Control, Department of Health References 1. http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/outbreak.htm. 2. http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/history.htm. 3. S Nichol, CF Spiropoulou, S Morzunov, PE Rollin, TG Ksiazek, H Feldmann, A Sanchez, J Childs, S Zaki, CJ Peters. Genetic Identification of Hantavirus Associated with an Outbreak of Acute Respiratory Illness. Science 1993; 262:914-917. 4. TG Ksiazek, CJ Peters, PE Rollin, S Zaki, S Nichol, C Spiropoulou, S Morzunov, H Feldmann, A Sanchez, AS Khan, BWJ Mahy, K Wachsmuth, JC Butler. Identification of a new North American Hantavirus that causes acute pulmonary insufficiency. Am.J. Trop Med. Hyg 1995; 52(2): 117-123. 5. AL Schmaliohn, D Li, DL Negley, DS Bressler, MJ Turell, GW Korch, MS Ascher, CS Schmaliohn. Isolation and initial characterization of a newfound hantavirus from California. Virology 1995; 206: 963-972. 6. http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/phys/virology.htm 7. JE Childs, TG Ksiazek, CF Spiropoulou, JW Krebs, S Morzunov, GO Maupin, KL Gage, PE Rollin, J Sarisky, RE Enscore, JK Frey, CJ Peters, ST Nichol. Serologic and genetic identification of Peromyscus maniculatus as the primary rodent reservoir for a new hantavirus in the Southwestern United States. J Infect Vol. 17 No.2 Epidemiology Bulletin 33 Dis 1994; 169:1271-80. 8. http://www.cdc.gov/ncidod/diseases/hanta/html/hv94003.htm 9. http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/phys/casedefn.htm 10. 11. http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/symptoms.htm C Schmaljohn, B Hjelle. Hantaviruses : A Global Disease Problem. Emerging Infectious Diseases.1997;3(2). 12. http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/hanta.htm 13. C Schmaljohn, B Hjelle. Hantaviruses : A Global Disease Problem. Emerging Infectious Diseases.1997;3(2). 14. http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/transmit.htm 15. http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/phys/diag.htm 16. http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/whatsnew.htm 17. http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/whatsnew.htm 18. http://www.cdc.gov/ncidod/disease/hanta/hps/noframes/epislides/epis14.htm 19. http://www.cdc.gov/ncidod/disease/hanta/hps/noframes/epislides/epis12.htm 20. http://www.cdc.gov/ncidod/disease/hanta/hps/noframes/epislides/epis13.htm 21. http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/argtina.htm 22. http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/argmap.htm 23. http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/argtina.htm 24. RM Wells, SS Estani, ZE Yadon, D Enria, P Padula, N pini, JN Mills, CJ Peters, EL Segura, and the Hantavirus Pulmonary Syndrome Study Group for Patagonia. Emerging Infectious Diseases.1997;3(2). 25. http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/argtina.htm 26. R Murua, B Barra, JL Vera Mora, H Villalon, C Mansilla, M Tapia, JJ Chaparro, F Torres, J Barria, G Aguila, P Escobar, N Gallegos, R Valderrama, J Montecinos, K Mardoff, R Mansilla, JA Vergara. Hantavirus Pulmonary Syndrome-Chile,1997.MMWR 1997; 46(40):949-951 27. http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/treating.htm 28. http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/phys/prevent.htm 34 Epidemiology Bulletin 29. February 25, 2001 HL Chen, JY Yang, HY Chen, TH Lin, GR Wang, CB Horng. Surveillance of anti-Hantavirus antibodies among certain high-risk groups in Taiwan. J Formos Med Assoc 1998; 97:69-72 Table 1 HFRS and HPS Infection HFRS# HPS## Major site Kidneys Lungs Initial phase Fever Pre-symptoms of fever Intermediate phase Shock Shock, pulmonary edema Disease process Less urine, more urine, More urine, recovery recovery Fatality 1-15 % 50 % #Hantavirus hemorrhagic fever attacks primarily kidneys to induce failure of renal functions, and in severe cases, obstacles of circulation, including shock, bleeding and pulmonary edema. Fatality is lower than 10%. ##Hantavirus pulmonary symdrome attacks primarily the lungs. Early symptoms include fever, headache, and serious muscle aches such as thighs, hips and back. There may also be abdominal problems, nausea, vomiting, dizziness and chills. Four to five days later, more symptoms including wet lungs, coughing, shortness of breath may appear. shock. Patients may even die of Fatality is as high as 50%. Source: http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/phys/virology.htm Vol. 17 No.2 Epidemiology Bulletin 35 Table 2 Clinical Symptoms of HFRS and HPS Infection Seriousness HFRS HFRS HPS HPS moderate to moderate primary type renal type serious Fatality 1-15% <1% >40% >40% Pathogens* HTN PUU SN BAY (hantavirus) SEO NY BCC Distinct characteristics** DOB Andes Bleeding +++ + + + Azotemia / / / / Albuminuria +++/++++ +/++++ + ++/+++ Pulmonary +/++ -/+ ++++ +++/++++ Myositis +/+++ + - ++/++++ Conjunctival ++/++++ + -/+ -/++ capillary leak injection Eye pain/myopia ++/++++ ++/++++ * HTN:Hantaan; SEO:Seoul; DOB:Dobrava; PUU:Puumala; SN: Sin Nombre;NY:New York; BAY:Bayou; BCC:Black Creek Canal ** least/ most reported; -:rarely reported; + rarely seen or mild; ++、+++、++++ often seen or serious Source: C Schmaljohn, B Hjelle. Hantaviruses : A Global Disease Problem. Emerging Infectious Diseases.1997;3(2). 36 Epidemiology Bulletin February 25, 2001 Table 3 Infection Sources of Hantavirus and Geographic Distribution Virus* Infection Source Distribution Distribution of Infection of Virus Sources Hantaan HFRS** Apodemus agrarius China, Southern Europe to the (HTN) (striped field mouse) Russia, Balkans, Caucasus, Tienshan, Korea Amot River to Korea, Tibet, Yunnan, Sichuan, Fukien, Taiwan The Balkans England and Wales, Dobrava HFRS Apodemus northwestern Spain, southern flavicollis (DOB) Scandinavia, southern Italy, (yellow neck mouse) the Balkans, Syria, Lebanon, Israel Seoul HFRS Rattus norvegicus Worldwide Worldwide (SEO) (Norway rat) Puumala HFRS Clethrionomys Europe, France, Scandinavia, northern (PUU) glareolus Russia, Spain, northern Italy, the (bank vole) Scandinavia Balkans, western Turkey, northern Kazakhstan, England, and southwestern Ireland US, Canada All states of the US except Sin Nombre HPS*** Peromyscus eastern and southeast coastal maniculatus (SN) states, Canada, Mexico (deer mouse) New York HPS Peromyscus leucopus US Middle and eastern states of the (NY) (white- footed mouse) US, Canada, the Caribbean, Mexico Black Creek HPS Sigmodon hispidus US Southeastern states of the US, Canal Mexico, Central and South (cotton rat) America, Panama, northern (BCC) Colombia, northern Venezuela Bayou HPS Oryzomys palustris US Southeastern part of Kansa to eastern part of Texas, (BAY) (rice rat) southern New Jersey and Florida Andes HPS Oligoryzomys Argentina Chile and Argentina in the central and southern parts of (AND) longicaudatus the Andes (long- tailed pygmy rice rat) * Hantaviruses of the Bunyaviridae family. **HFRS: hemorrhagic fever with renal syndrome *** HPS: hantavirus pulmonary syndrome Source: C Schmaljohn, B Hjelle. Hantaviruses : A Global Disease Problem. Emerging Infectious Diseases.1997;3(2). Vol. 17 No.2 Epidemiology Bulletin Table 4 Characteristics of 231 HPS Cases in the US# Age Sex Race 37 average 37 years, ranging 10 to 71 139(60%) males 176(76%) White 49(21%) American Indian 5(2%) Black 1(4%) Asian 23(10%) Hispanic 42% Ethnicity Case fatality #:by December 13, 1999. Of the 231 HPS cases in the US, the male to female sex ratio was 3:2; the average age, 37 years (10-70). Anyone could have been infected with HPS. Source: http://www.cdc.gov/ncidod/disease/hanta/hps/noframes/epislides/epis14.htm Table 5 Cases of HPS in US by Month (1993 to December 13, 1999)* Year Cases Jan 1993 0 1994 1995 1996 1997 1998 1999 Total Feb Mar Apr May Jun 0 4 2 0 2 1 2 1 2 2 1 1 3 9 12 2 4 1 2 2 0 3 14 5 2 3 2 2 3 2 19 6 6 2 1 5 1 4 25 10 4 3 3 1 3 4 28 Total Jul Aug Sep Oct Nov Dec 12 4 4 2 4 7 2 35 3 3 2 2 1 5 0 16 6 0 0 4 2 0 0 12 2 1 2 3 1 2 1 12 1 1 3 0 1 1 2 0 1 1 6 0 0 0 12 5 Result Recovered Died 48 21 32 20 24 14 22 15 23 18 30 21 20 12 199 121 *32 cases prior to 1993 not included. Source: http://www.cdc.gov/ncidod/disease/hanta/hps/noframes/epislides/epis12.htm 27 12 10 7 5 9 8 78 38 Epidemiology Bulletin Table 6 February 25, 2001 HPS Cases in US by Locality (by December 13, 1999) No. of Cases by Month Year Jan Feb Mar Apr May Jun Jul Aug Sept Oct Nov Total Dec # ! # ! # ! # ! # ! # ! # ! # ! # ! # ! # ! # ! # ! 1993 0 0 0 0 1 1 0 5 0 6 3 7 4 8 1 2 1 1 4 2 0 1 1 0 33 15 1994 3 1 0 2 2 2 0 2 2 4 2 2 2 2 2 1 0 1 0 0 0 1 1 0 18 14 1995 0 0 1 1 1 0 3 0 2 0 3 0 3 1 2 0 2 0 0 0 3 0 1 1 3 21 1996 1 0 1 1 2 0 2 0 1 0 2 1 2 0 2 0 2 1 2 2 0 0 0 0 5 17 1997 1 0 1 1 2 0 2 0 3 2 1 0 3 1 1 0 1 0 2 0 1 0 1 0 4 19 1998 1 1 1 0 0 0 0 3 1 0 1 2 4 3 2 3 1 1 0 0 4 2 0 0 15 15 1999 1 0 1 2 1 2 1 1 3 1 3 1 1 1 0 0 1 0 0 0 0 0 0 0 8 12 Subtotal 7 2 5 7 9 5 8 11 12 13 15 13 19 16 10 6 8 4 8 4 8 4 4 1 86 113 Total 9 12 14 19 25 28 35 16 12 12 12 5 199 32 cases prior to 1993 not included. #: cases in the Four Corners of Arizona, New Mexico, Colorado and Utah !: cases in states other than the Four Corners Source: http://www.cdc.gov/ncidod/disease/hanta/hps/noframes/epislides/epis13.htm