Jpn. J. Infect. Dis., 54, 95‑102, 2001

Review

Epidemiology and Epizootiology of Hantavirus Infection in Japan
Jiro Arikawa*, Kumiko Yoshimatsu and Hiroaki Kariwal

lnstitutefor Animal Experimentation, Hokkaido UniversiO, Graduate School of Medicine,
Kita‑15, Nishi‑ 7, Sapporo 060‑8638 andJDepartment of Veterinary Public Health, Hokkaido UniversiO,

Graduate School of Veterinary Medicine,
Kita‑18, Nishi‑9, Sapporo 060‑0818, Japan(Received June 6, 2001･ Accepted August 3, 2001)
CONllENTS:
Summarylntroduction

Clinical manifestations of HFRS and HPS
Ⅵral agents ofHFRS and 出PS

Distribution of HFRS and HPSHistorical background of HFRS in Japan
Prevalence or anti‑hantavims antibodies in the Japanese population
EpizootiologlC Study of hantavirus infection among rodents in Japan

Conclusion

SUMMARY: Hantaviruses cause two severe human diseases: hemorrhagic fever with renal syndrome (HFRS)
and hantavirus pulmonary syndrome (HPS). Various rodent species act as animal reservoirs for hantaviruS. ln
Japan, urban rat‑ (Rattus norveFicus) and laboratory rat‑derived human infections were reported during the
1960s and 1970S‑1984, respectlVely. Although no human cases of infection have been reported since 1984,
infected urban rats have been found throughout Japan, and infected grey red‑backed voles (Clethrionomys

rufocanus) have been identified in Hokkaido･ These carrieTs can be considered to be potential sources of humaninfection･ This review examines the epidemiology and epIZOOtiology of this important zoonosis in Japan.

HPS was first reported in the Southwestem United States

Introd uction(US) in 1993 as an acute respiratory distresP syndrome with

Hantaviruses are members of the Hantavirus genus of thegreater than 40% mortality (20). The causatlVe Virus of HPS

Bunyaviridae family (1). Hantaviruses are associated withis transmitted from PeflOmySCuS maniculatus and several otherrodents and other small mammals and are the causative agentsrodent species, all of which are members of the sub familyof hemorrhagic fever with renal syndrome (HFRS) (2) andSigmodontinae (21). Since these rodent species inhabit the

hant?virus pulmonary syndrome (HPS) (3) in humansI Trans‑

American continent only, no HPS cases have been reported
outside the Americas. However, the introduction of infected

misslOn Ofthe vims to humans occurs either via the inhalationof infectious aerosols generated from hantaviruS‑containlng

rodents into other countries represents a potential public healthanimal secretions (4‑6) or via contaminated saliva.in animal

bites (7)･ Thus, HFRS and HPS are regarded as lmpOrtant

problem.
In 1 998, a new law aimed at controlling infectious diseases

rodent‑bome viral zoonoses (8).

was introduced in Japan. Under the new law, HFRS and HPS

Between 150,000 and 200,000 HFRS cases are reported

are graded as group 4 diseases, and afnicted patients must be

ammually throughout the world (9). The majorityofthese cases

reported to the govemmentJn splte Or these new regulations,occur in Asia and Europe, particularly in China, where 50,000

infbmation on these diseases is still qulte limited.

to 100,000 cases have been reglStered annually since 1985

ln this report, We review hantavims epidemiology and(10). In Japan, there have been two recent outbreaks ofHFRS,

epizootiology in Japan,and emphasize the necessity for caution

one in the 1960s and one in the 1970S‑1984. The fbmer

in dealing with unfamiliar diseases.

outbreak was traced to brown rats (Rattus non,egicus) in Osaka

City (1 1,12), and the latter to laboratory rats (13). Although

CIinical manifestations of HFRS (22,23) andHPS (23,24)

no human HFRS cases have been reported in Japan since 1984,
brown rats in several port areas (14‑17) and field grey

red‑backed voles (Clethrionomys rufocanus) in Hokkaido

The premonitory symptoms common to both HFRS and(1 8, 1 9) have been fわund to be hantavims‑positive. Therefわre,HPS, including fever, myalgia, and headache, are seen in more

the re‑emergence ofHFRS as a human infectious disease inthan 90% of infections. However, the later‑stage clinicalJapan remains possible.

symptoms differ between HFRS and HPS. In HFRS, severecases usually show four different phases: fTebrile, hypotensive,*Corresponding author: Tel: +81‑1 1170616905, Fax: +81‑1 1‑706‑

oliguriC,and diuretiC･ However, the severityof infection varie.S,

7879, E‑mail: j‑arika@med.hokudai.ac.jp

primarily according to thetype of infecting virus, but also ln95

cases involving viruses or the same type. Therefわre, disease

analysts Of the rodent‑associated hantaviruses has revealed

confirmation is based not only on clinical signs and laboratory

three prlmary lineages: the Murinae, Arvicolinae, andfindings, but also on the demonstration of specific lgM anti‑
bodies by EuSA or a fourfold or greaterrise in anti‑hantaviruS

Sigmodontinae subfamilies (30,3 1 )･ Since the evolutionary
trees of the hantavirus and rodent genomes are superimposable

antibodytiter in paired sera, as measured by serologlCal testlng･(32), hantavirus‑rodent coevolution has been hypothesized･Moreover, renal failure, as evidenced by proteinuria, is observedin lOO% of cases (Table. 1). h addition, mild cases orHFRS

Among the known hantavimses, the Hantaan, (HTN), Seouloccasionally show hepatic dysfunction (25). lt is important

known to cause HFRS, and the Sin Nombre (SN), New Yorkto differentiate HFRS from other acute infectious diseases(NY), Black Creek Canal (BCC), Bayou (BAY), Lagna Negra(LN), and Andes (AND) vimses cause HPS (22, 29) (Table(SEO), Dobrava (DOB), and Puumala (PUU) Viruses are

such as influenza, tsutsugamushi disease, and leptosplrOSis･

HPS, on the other hand, is characterized by a resplratOry

2).

syndrome such as tachypnea caused by pulmonary edema

and a high mortality rate (30 to 40%) due to pulmonary edema

J)istribution of HFRS and ups

and the rapid onset of shock･
Diagnostic protocols f♭r HFRS and HPS have previously

Due to the close relationship between hantavirus type andbeen published (26,27) and released as an information leanet

rodent species, the distribution ofHFRS and 出PS cases hasby the Ministry of Health and Welfare of Japan in 1999 (28)･

been confined to areas inhabited by the specific rodent
reseⅣoir (Fig. 1 ). Since HPS‑reseⅣOir rodents live in North andViral agents of HFRS and HPSSouth America, HPS has only been reported in these reg10nS･
HFRS cases caused by HTN, PUU, and DOB viruses have

To date, at least 22 hantaviruses have been identified bybeen reported primarily in EastemAsia, Northem and Eastem

based on comparisons of nucleotide‑sequence similarity andEurope, and Central Europe, respectively. Since brown rats

evolutionary classifications of viral genomes (29). All

infected with SEO virus are distributed worldwide, infections

hantaviruses have specific rodent reservoirs. Phylogenetic

With this virus might be expected in many countries. However,Table L Clinical manifestations ofhcmorrhagic fbvcrwith rcnalsyndrome (HFRS) and hantavirus pulmonary
symdromc (HPS)
H

FRS

HPS

Incubation period (week)

2‑3

ト2

Prodromc

fcvcr, myalgia and headache

cough(Common to both HFRS and HPS patients)
Symptoms

lsevcre case; caused by HTN, DOB, SEO]

tachypnea, tachycardia, hypotension,1 ) febrile phase pulmonary cdcma, bilateral interstitia12) hypotension phase (hemorrhage)

pulmonary infiltrates, shock3) oliguria phase (proteinuria)
4) diuretic phase (rccovcry)[mild case; caused by PUU]
fever and protcinuria

lungTarget organkidneyHcmatology

clcvatcd white ICCll count,thrombocytopcnla,
hemoconcentration(common to both HFRS and H戸S)

1‑15% (HTN, SEO, DOB)
<1% (PUU)

Dcath rate

30‑40%

Table 2. Viruses ofthC causative agent ofHFRS and ups
Viruses(Abbreviation)

Princlpal species Origmal isolation in Distribution ofrcservoir Disease

Murinae subfamily‑associated viruses
Apodemus agrarius

Korea

Dobrava‑Bclgradc DOB

Apodem us flavLIco lltls

Slovcnia Europe, Middle East HFRS

Seoul

Rattus non,eglCuS, R. rattus

Korea Asia, Europe, the Americas HFRS

Clethrionomys glareolus

Finland Europe,Asia

Hantaan

HTN

S

EO

Asia,

Europe

HFRS

An,icolinae subfamily‑associated viruses
PuumalaPUU

St'gmodontE'nae subfamily‑associatcdviruscs
Sin

NombrcSN

PeflOmySCuS maniculatus

New Mexico North America

New

York

NY

Peromyscus leu copus

Ncw York North America

Black Crcck Canal BCC

SL'gmodon hispL‑dus

Florida The Americas

Bayou

OtyZO myS Pa lus IrisLouisiana Southcastcm US

Lagna

BAY

Ncgra

Andes

LN

AND

Calomys laucha

Paraguay South America

Olt'goyyzomys

Argentina South America96

H H H H H H H F Dt D▲ nr nr nr nr R s s s s s s S

Fig. 1. Distribution ofhantaviruses and hantaviraldiseases･

HFRS cases due to SEO virus have been confined, thus far,to Asian countries.

endemic countries.

In Japan, both brown rat‑ and laboratory rat‑associated

HFRS cases Tere reported in the 1960S (1 I) and 1970S‑1984(13), respectlVely. SEO‑type hantavirus strain SR‑1 1 was

Historical background of HFRS in Japan (Table 3)

first isolated from infected rat‑lung tissues in 1982 (34)･

Russian and Japanese physiciansencountered severe febrile

Subsequently, SEO viruses closely related to strain SR‑ 1 1 weredisease among troops in Far Eastem Russia and North Eastem

isolated Bom both laboratory rats (35) and brown rats in Japan

China between 1 930 and 1940, respectively. The disease was(14, 36)･ Isolation of the vlruSeS allowed for the establish‑

referred to as "epidemic nephrosonephritis" in Russia andment of serological diagnostlC Pr?cedures (37) and facilitatedepidemiologlC and epizootiologlC lnVeStlgations ･ Due to exten‑"epidemic hemorrhagic fever" in Japan. These physicians

identified the agent of disease as a virus and Apodemus

sive surveillance of laboratory rat populations, no laboratory‑

agrarius as the rodent reservoir. They also identified theraトrelated HFRS cases have been reported since 1984.

However, infected brown rats have been detected throughout

gamasid mite (Laelaps jettmari) as an arthropod vector of
the hantavirus (33). Recent reports by Chinese researchers

Japan (38), and infected grey red‑backed voles have been

have demonstrated hantavirus multiplication in gamasid andidentified in Hokkaido (1 8,36). SEO and PUU viruses havechigger mites as well as transovarial and transstadial trans一been isolated from both brown rats and voles, respectively･

missiop of the virus (1 0)･ However, no reports of hantavirustransmlSSion via arthropods have been forthcomlngfrom other

Therefわre, these animals might be considered potential sourcesof human infection. The results of the epidemiologlC and

Table 3. Historical background ofhemorrhagic fcvcrwith renal syndrome in Japan
Year

place

Rcscrvoirrodent

1 940th China

No.

Apodemuspatient

agrarius

1

No.

0,000

died
3

,000

(Manchuria)
I 960th Umeda

RattusnoyveglCuS

1

1

9

2

(Osaka)I 970‑ 1 984

Laboratory fわr animal

cxpcrimentatioll

Laboratory

rat

1

26

1

(Rattus nowegicus)(2 1 Institutions throughout Japan)
1 984‑prcscnt

1 992‑present

Port areas

Rattus nan,eglCuS No patient has been rcportcd(more than 13 portareas)

Hokkaido(more than 10 areas)

Clethrionomys
rufoca n us

97

No patient has been rcportcd

human HFRS. Analysts Of the nucleotide sequences of the

eplZOOtiologlC S山dies are described in the fbllowlng SeCtion･

entire co°ing reglOn Of the enveloped glycoprotein of SEO

viruses isolated from brown rats from China (strain R22),

PrevaJence of anti‑hantavirus antibodies in the

Seoul (strain R22), Osaka (strainB‑ 1), Sapporo (strainSR‑1 1),
and Kamiiso‑Hokkaido (strains K‑83, 85, and 88) indicatedJapanese population
The sera of individuals not involved in animal experimenta‑

a close relationship between geographic orlgln and straintion were examined for hantavirus antibody (Table 4). Thus

phylogepy (45 )･ However, nucleotide‑sequence identities amoヮgfar, only five positive sera with low antibody titers (1 : 1 6, 32

the stralnS Were more than 93%. In addition, phylogenetlC

by IFA test) have been identified (39). In contrast, high‑risk

analysis based on the partial sequences or23 SEO viruses
from China, Korea, Japan, and the US revealed a slngle clustergroups, including workers at dumplng grounds inhabited by

infected rats (39) and members of the Japanese Self‑Defense
Forces who trained on lands where infected grey red‑backed(46) (Fig. 2). Therefore, the relatively low genetic variability
might be explained by a recent expansion, Via ships arrivlng atvoles have been detected (40), showed higher antibody titers

various countries, of infected rat populationsfrom a common

than the general public. However, no members of these two

Source.

high‑risk groups have shown any of the typlCal symptoms of

The results obtained in Japan for rodents other than brown

HFRS. During a laboratory rat‑associated outbreak of HFRS

rats are summarized in Table 5. These results were collectedin the 1970S‑1984, a total of 126 people were fわund to befrom published papers ( 1 8), abstracts (47), and unpublishedpositive for hantavirus antibody. Among these, at least 1 8 Werereported as cases of apparent infection ( 1 3)A Although only adata. The majorityof seropositives was obtainedfrOm grey red‑backed voles (C. rufocanus) in Hokkaido. Antibody‑positive

limited amount of sera was examined, these sero‑epidemiologlC

animals were captured at 1 0 different polntS around Hokkaido,

results indicate that human‑pathogenic hantavimses exist in

indicatlng that hantaviruses are widely distributed among C.

Japan. A correlation between hepatitis and hantavirus infec‑

rufocanus in Hokkaido. Although attempts at virus isolationfrom C･ rufocanus wer.e unsuccessful, viral sequencestion has been reported in South Asia (41) and Belgium (42)･
Antibody‑positive cases among hepatitis patients withamplified from seroposltlVe rodent lung tlSSueS, designatedunknown etiology have also been reported in Japan (43). The

as Tobetsu and Kamiiso, indicated PUU virus infection (1 8).

anti‑hantavirus antibodies were con血med by several serologlC

Since all the PUU viruses identified thus far are harbored byprocedures, including IFA, ELISA, Westem blottlng, andeither Clethrionomys spp. or Eothenomys ylegulus (fomerly

neutralization tests. However, since all of the positive sera

classified as Clethrionomys regulus) (48), a close relationshipbetween hantavirus type and rodent reservoir was confirmed･
Phylogenetic analysts indicated that the Japanese PUU vinlSeS
form a lineage distinct from that of the EuropeanPUU viruses･

were obtained from patients with chronic rather than acutehepatic disease, no virus orviral genomic samples were isolated

from the patients. Therefore,further study is needed to elucidate
whether hantavirus causes hepatitis in Japan.

Therefわre, it is possible that the PUU vims was introduced

by infected Clethrionomys spp. brought from the Eurasiancontinent through Sakhalin during glacial era when Hokkaido
was connected with the continent. Two seropositives weredetected; one from an Apodemus speciosus in OkushiriIsland,
Hokkaido, and the other from an A. Speciosus in Hirosaki

Epizootiologic study of hantavirus infection
among rodents in Japan

HantaviruS‑infected brown rats have been reported, prlma‑

rily in the port areas of Otaru, Kamiiso, Tokyo, Yokohama,
Nagoya, Robe, Tbkuyama, Mqji, Hakata, Nagasaki, Niigata,
Osaka, and Shimizu, and at Kansai Airport (38). These results

City in Aomori Prefecture (unpublished observations)･
However, since no infbmation relating to the vims or viralsuggest that brownィat‑associated SEO vims can be readily

confirm the source of infection.

genomic sequences is available, fdher study is necessary to

distributed worldwide through transportation systems･ ln

Phylogenetic analysis based on 300 base palrS Ofa nucleotide

Nagoya City, SEO‑virus‑infected rats were captured in asequence from the M genome segments of 38 HTN viruses

residential area adjoining a pier in the port (44), indicating(34 from China, 4 from Korea) and 24 SEO viruses (19from
China, 2from Japan, 2 &om US, I from Korea) isolatedfrom

that the brown‑rat‑bone SEO virus is a possible source ofTable 4. ScrocpidcmiologlC Study ofhantavirus infection among humanPrcfccturc

Gcncral public

Year

of

collection

Numberofsera

Numberofpositivc

(%)

Tbkyo

5

(0.94)

Akita, Iwatc, Miyagi, Niigata,

0

(0.0)

Gunma, Nagano, Saitama, Fukuoka
Hokkaido

1993

1

Total

High risk group

Workers at dumplmg ground(Positive group)in Tokyo Bay

,000

0

(0.0)

2,080

5

(0.24)

33

(4.5)

2

(1.0)

Mcmbcrs ofJapancsc Self‑Diffbncc
Forces (Hokkaido)

Hepatitis paticntwith unhown etiology(Tokyo)I(Hokkaido)

1 990th

990th

Total

98

105
60

1 , 104

Table 5･ SeroepIZOOtiologlC Study ofhantavirus infection among rodents in Japanprefecbrc Rodent species NuemxbaeliOnfescra a,(e"aus:1ccryoefd, ,:suiTvbccrseorfa (Nu‑bcrofarea)
Hokkaido

Clethrionomys ntfbcanus

I 985‑2000

Clethrionomys ruEilustJ 2 2 O 7 2 4(13)

5 5 4 つJ O′‑U O 4 0 0

nHJ川u

1 ( ー ( (0 0 2 0 0

ー ー ヽ■/ ー ヽ′

(2)

Apodemus speciosus(13)

Apodemus argenleus(12)

Sorex sp.

Rest of the Eolhenomys smL'thii

つJ

(6)

ヽノ ､ー ー 1 1 ) 1ヽ′ ヽノ ヽ′ ヽ■/ ) ー ーっJ ∠U O 45 4 tJ 2 7 tJ つJ 4tー(ー ー ー ー ー

4 1 CXU 7 2 2 1一I

00100000(ー(ー ー(ー(00100000

parts of Japan Eothenomys andef‑71.
I 988‑2000

Apodemus speciosus
Apodemus arge17(eusUrotrichus talpoL‑desCrocidura dsinezumL‑

Microtus monteberi
Suncus murinus. Ou ーrl n P n矧汲Ei挑Fig･ 2･ Phylogcnctic trees for hantaviruses based on partialsequcnccs of(a) the M (nuclcotides 2001 ‑2301 ) and (b) S (nuclcotides

1 21 1‑terminus) scgmcnts, excluding the primer scquenccs. The numbers at the nodes arc bootstrap conrldence lcvcls for
100 rcplicates･ The numbers onthe right side of the figure indicate the subgroup numbers ofHTN and SEOviruses. The
refcrcnce viruses (Sin Nombrc, Thailand, and Dobrava/Belgrade) arc indicated in boldface type.

(ref. 46)

either humans or rodents indicates the existence of 9 HTN
and 5 SEO genetic subtypes (46) (Fig･ 2)･ Interestingly, o?ethe PUU virus(Fig. 3). h Korea, Muju virus was identified from

HTN virus isolated from Niviventer confucianus (straln

Eothenomys Tlegulus (47). Phylogenetic analysis of fullllength

NC 1 67) captured in the Anhui Province of China, and one SEO

S genome segments suggested that Muju virus was evolution‑arily distinct from other Clethrionomys‑ and Microtus‑bone

and Vladivostok ( 1 9) bore hantaviruses distinguishable丘omvirus isolated from Rattus rattus (strain Gou3) capturedinthe
Zhejiang Province of China showed the highest nucleotide

hantavimses (48). These results indicate that a variety ofdivergencyamong all the HTN or SEO viruses examined. More‑over, examples of Micy10tuSfortis captured in Khabarovsk (49)rodents carrylng different hantaviruses exist in Far‑East Asia
(Fig. 4).

99

Fig･ 3･ Phylogenetic analyses ofhantaviruses. Hantavirus sequcnccs were analyzed by neighbor‑joining methods using Phylip.
Bootstrap confidence limits were calculated斤om I 00 rcplicatcs and are shown in parentheses. (A) Phylogenetic dendrogram

ofthe S genome sequences from nuclcotidcs 1 to 1251 in the PUU sequence. (B) Phylogcnetic dcndrogram of the M
genomc sequences from nucleotideS 2673 to 3652 in the PUU sequence.

China

I HFRS patientcaused bySeou■viruヲ

i HFRS patientcaused by Hantaan v･rus
各

日FRS patientcaused byAmurvirus←1‑

F7attus norvegicus infected with Seoul virus

細L Apodemus agrarI'us infected with Hantaan virus

敏乱≠

C/ethn'onomys rurocanus infected with Puumala virus

拍L MI'crotus Fortjs infected with Khabarovsk virus

拍L Microtus fortl's infected with VIadivostok virus

敵Eo的enOmyS regulus infected with Muju virus

Fig. 4. Distribution orHFRS and hantavimses in Japan and Far‑East Asia.

100(ref. 19)

Geographical distribution of hemorrhagic fever withrenal syndrome and hantavimses. Arch. Virol., Suppl. 1 ,Conclusion

Although no recent cases of HFRS have been reported in

5‑18.

Japan, infected brown rats are distributed throughout Japan.

10. Song, G. (1999): Epidemiological progresses ofhemor‑

In addition, grey red‑backed voles in Hokkaido are heavily
infected with PUU virus. There may therefore be many casesof undiagnosed HFRS in Japan.
HFRS is still prevalent in Far‑East Asia, as are the several
rodent varieties carrying different hantaviruses (Fig. 4). There‑

rhagic fever with renal syndrome in China. Chin. Med.
J., 112, 472‑477.
日. Tamura, M. ( I 964): Occurrence of epidemic hemorrhagic

fever in Osaka City: first cases found in Japan withcharacteristic feature of marked proteinuria. Biken J., 7,

fore, steps must be taken to prevent the introduction of

79‑94.

infected rodents via increased international transport. In

12. Lee, H. W., Lee, P. W., Tamura, M., Tamura, T. andaddition, the eplZOOtiologlC investlgations among wild rodents,

Okuno, Y･ (1979): Etiological relation between Koreチnparticularly in Honshu, Shikoku and Kyushu, have been qulte
limited. A program of serological surveillance should thereR)rehemorrhagic fever and epidemic hemorrhagic fever lnJapan. Biken ∫., 22, 4ト45.

be carried out among wild rodents throughout the country.

13. Kawamata, ∫., Yamanouchi, T., Dohmae, 良., Miyamoto,

In addition to HFRS and HPS, various zoonotic diseases

H., Takahashi, M., Yamanishi, K., Kurata, T. and Lee, H.

have been registered as category 4 diseases, i.e., disease cases

W. ( 1 987): Control of laboratory acquired hemo血agicthat must be reported to the govemment by a physician infever with renal syndrome (HFRS) in Japan. Lab. Anim･

accordance with the new law on infectious disease control.

Sci., 37, 43ト436.

Nevertheless, since many category 4 diseases are nonexistent

14. Arikawa, ∫., Takashima, I., Hashimoto, N., Morita, C.,or occur rarely in Japan, many physiciansare unfamiliarwith

Sugiyama, K., Matsuura, Y, Shiga, S. and Kitamura, T.

them. As such zoonotic disease infわrmation, including( I 985): Epidemiological study ofhemorrhagic fever withgeographical distribution of enzootic fociand reservoir animals,
may assist physicians and personnel in related fields inrenal syndrome related virus infection among urban ratsin two islands in Tokyo Bay, Japan. Acta Viro1., 29, 66‑

diagnosis and control of these unfamiliar infections.

72.

15. Arikawa, J., lto, M., Yao, J. S" Kariwa, H., Takashima,
Ⅰ. and Hashimoto, N. (1994): Epizootiological studies of

REFERENCE S

hantavirus infection among urban rats in Hokkaido,l･ Schmaljolm, C. S., Hasty, S. E., Dalrymple, J. M., LeDuc,
J. W., Lee, H. W., von Bonsdorff, C. H., Brummer‑

Japan: evidences for the persistent infection from theKorvenkontio, M･, Vaheri, A., Tsai, T. F. and Regnery,tions ofhantavirus isolates. J. Vet. Med. Sci., 56, 27‑32.

H. L. (1985):Antigenic and genetic properties of viruses

16. Suglyama, K., Morita, C., Matsuura, Y., Shiga, S.,

linked to hemorrhagic fever with renal syndrome. Science,

Komatsu, T., Morikawa, S. and Kitamura, T. (1984):

227, 1041‑1044.

Isolation of a virus related to hemorrhagic fever with

sero‑eplZOOtiologlCal suⅣeys and antlgenic characteriza‑

2･ Working Group on Hemorrhagic Fever with Renal
Syndrome, WHO (1 983): Hemorrhagic fever with renal
syndrome: Memorandum from a WHO meetlng. Bull.

renal syndrome from urban rats in a nonendemic area. J.

Infect. Dis., 149, 473.
17. Suzuki, S., Shimamura, H., Nagasawa, R., Takigiku, I.,
Tamura, T., Shoji, K., Hotta, S., Shinka, S., Kurata, T.,

WH0., 61, 269‑275.
3･ Nichol, S. T., Spiropoulou, C. F., Morzunov, S., Rollin,

Aoyama, Y., Yoshida, T. H. and Lee, H. W. (1984):

P. E., Ksiazek, T. G., Feldmann, H., Sanchez, A., Childs,
J., Zaki, S. and Peters, C. J. (1993): Genetic identifica‑

Measurement of anti‑Hantaan vims antibody, detectionof endoparasaites, and karyotype analysis of wild rodents

tion ofa hantavims associated with an outbreak of acutecaptured in harbor area and in vessels at Port Shimizu,

Japan, 1981‑1984. 1CMRAnn., 4, 125‑141.

resplratOry illness. Science, 262, 914‑9 1 7.

4. Xu,Z.Y, Guo, C. S.,Wu,Y L,Zhang, X. W andLiu,K.

18. Kariwa, H., Yoshizumi, S., Arikawa, J., Yoshimatsu, K.,
Takahashi, K., Takashima, Ⅰ. and Hashimoto, N. ( I 995):( 1 985): Epidemiological studies of hemorrhagic feverwith renal syndrome: analysts Of risk factors and mode

Evidence fわr the existence or Puumula‑related virus

K血an, A. S., K血abbaz, R. F., Ksiazek, T. G. and Peters, C.

among Clethrionomys rufocanus in Hokkaido, Japan.
Am. J. Trop. Med. Hyg., 53, 222‑227.
19. Kariwa, H., Yoshimatsu, K., Sawabe, J., Yokota, E.,

oftransmission. J. Infect. Dis., 152, 1371144.

5.Amstrong, L. R., Zaki, S. R., GoldoR, M. J., Todd, R. L.,
J. (1995): Hantavims pulmonary syn血ome associatedArikawa, J., Takashima, I., Fukushima, H., Lundkvist,

with enterlng Or Cleanlng rarely used, rodent‑infested

A., Shubin, F. N., lsachkova, L M., Slonova, 良. A.,

structures. J. Infect. Dis., 172, 1 166.
6. Tsai, T. F. (1987): Hemorrhagic fever with renal syndrome:

Leono.V.a, G･ N･ and Hashimoto, N･ (1999): Genetic
diversltleS Of hantaviruses among rodents in Hokkaido,mode of transmission to humans. Lab. Anim. S°i., 37,

Japan and Far East Russia. Ⅵms Res., 59, 219‑228.

428‑430.

20. Hughes, ∫. M., Peters, C. ∫., Cohen, M･ L andMahy, B.

7. Douron, E., Moriniere, B., Matheron, S., Girard, P. M"
Gonzalez, J. P., Hirsch, F. and McCormick, J. B. (1984):

W. J. (1993): Hantavirus pulmonary syndrome: an emerg‑

HFRS after a wild rodent bite in the Haute‑Savoie‑andrisk of exposure to Hantaan‑like virus in a Paris laboratory.

21. Khan, A. S., Ksiazek, T. G. andPeters, C. J. (1996):

Lancet, 1, 676‑677.

22. Schmaljohn, C. and Hjelle, B. (1997): Hantaviruses ‑ a

1ng infectious disease. Science, 262, 850‑85 1.

HantavinlS pulmonary syn血ome･ Lancet, 347, 739‑74 1 ･8･ quimby, F･ W･ (1 987): Zoonotic implications ofHantaan‑

global disease problem. Emerg. Infect. Dis., 3, 951104.

like viruses: an introduction. Lab. Anim. S°i., 37, 411‑

23. Lee, ∫. S., Lahdevirta, ∫., 比oster, F. and Levy, H. (1998):

412.

Chapter 5. Clinical manifestations and treatment ofHFRS

andHPS. p. 17138. In H. W. Lee, C. Calisherand C. S.

9. Lee, H. W., Lee, P. W.,Baek, L J. andChu,Y. K. (1990):

101

Schmaljohn (eds.), Manual of Hemorrhagic Fever with

Hashimoto, N･ and Suzuki, N･ (1996)‥ Westem blottiTg

Renal Syndrome and Hantavirus Pulmonary Syndrome･

uslng reCOmbinant Hantaan virus nucleocapsid proteln
expressed in silkwormas a serologlCal confirmation of
hantavirus infection in human seraJ. Vet. Med. Sci., 58,

WHO collaboratlng Center for virus reference andresearch (hantaviruses),Asan Institute for Life Sciences,

7ト74.

Seoul.

38. Yoshikawa, H. (1998): S山dies on control and prevention

24. Khan, A. S., Khabbaz, 良. ど., Amstrong,し. 良., Holman,

R. C., Bauer, S. P., Graber, J., Strine, T., Miller, G., Reef,of zoonosis. Report from the grant in aid kom JapaneseS., Tappero, J., Rollin, P. E., Nichol, S･ T･, Zaki, S･ R･,

Ministry of Health and Welfare, 42‑47 (in Japanese).

T. G. (1996): Hantavirus pulmonary syndrome: the丘rst

39. Ahkawa, J. and Hashimoto, N. (1986): Hemorrhagic feverwith a renal syndrome. Virus, 36, 233‑25 1. (in Japanese).

lOO US cases. J. Infect. Dis., 173, 1297‑1303.

40. Arikawa, ∫., Yoshimatsu, K., Kariwa, H., Araki, K.,

Bryan, 良. T., Chapman, L E., Peters, C. J. and Ksiazek,

25. Lee, H. W. and van der Groen, G. (1989): Hemorrhagic

Ogino, M., Ebihara, H., Lee, B. H･, Takashima, l･,

feverwith renal syndrome. Prog. Med. Viro1., 36, 621

Okumura, A., Fukuzawa, A. and Rokutanda, 良. (2000):

102.

SeroepidemiologlC investlgation to hantavirus infectionin Japan. p.186. Abstr. Annu. Meet･ Jpn･ Soc･ Virol･ (in26. Arikawa, J. (1999): Hemorrhagic fever with renal
syndrome. p. 128‑129. 1n Reserch Group on Diagnosis
and Treatment of Infectious Diseases (ed.), Diagnosis
and Treatment of Infectious Diseases. lgaku‑shoin,

Japanese).

41. Meng, G., Lan, Y., Nakagawa, M., Maehara, T･, Mitani, K･,Tbmiyama, T., Che, X. G. and Ohkubo, A. (1997): HighTbkyo (in Japanese).

prevalence ofhantavirus infection in a group of Chinese

27･ Arikawa, J･ (1999)‥ Hantavirus pulmoヮary syndrome･

patients with acute hepatitis of unknown aetiology. ∫.

p. 162‑ 163. 1n Reserch Group on DiagnosIS and Treatmentof lnfectiousDiseases (ed.), Diagnosis and Treatment oflnfectious Diseases. lgaku‑shoin, Tokyo (in Japanese).

42. Colson, P., Damoiseaux, P., Brisbois, J., Duvivier, E.,

28. Ministry ofHealth, Labour and We脆re (1999): Notice

and Clement, ∫. (1995): Epidemic orhantavims disease

from Ministry of Health, Labour and Welfare, March 30,

in Entre‑Sambre‑et‑Meuse: year 1 992‑ 1 993. Clinical andbiological aspects. Acta Clin. Belg., 50, 197‑206 (inⅥral Hepat., 4, 23ト234.

Levecque, P., Roger, J. M., Bouilliez, D. J., McKenna, P.

number 46.

29. Pan American Health Organization, WHO (1999): 2. The

French).

43. Kariwa, H., Yoshimatsu, K., Araki, K., Murphy, M. E.,
Ebihara, H., Ogino, M" Mizutani, T., Arikawa, J.,

viruses. p.2‑3. Hantaviruses in the Americas. Guidlines
for Diagnosis, Treatment, Prevention, and Control.,WHO, Washington, D.C.

Chayapa, K･, Kumada, H･ and Takashima, 1･ (2000)‥

30. Plyusnin, A., Vapalahti, 0. and Lundkvist, A. (1996):
Hantaviruses: genome structure, expression and evolution.
J. Gen. Viro1., 77, 2677‑2687.

DetectlOn Of hantaviral antibodies among patients with

hepatitis of unknown etiology in Japan. Microbiol.
lmmuno1., 44, 357‑362.

31･ Hughes, A･ L and Friedman, R･ (2000)‥ Evolutionary

44. Sugiyama, K., Takagi, K., Kinjo, T., Nakata, Y., Komatsu,

diversification of protein‑coding genes of hantavlruSeS.

T. and Kitamura, T. ( 1 995): Isolation and characterization

Mol. Biol. Evo1., 17, 1558‑1568.

of a hantavirus from Rattus norveglCuS in a residential

area ofNagoya City, Japan. J. Vet. Med. Sci., 57, 5 I‑54.

32. Ⅵlpalahti, 0., Lundkvist, A., Fedorov, V, Conroy, C. ∫.,45. Kariwa, H., Isegawa, Y.,Ankawa, J., Takashima, I., Ueda,

Hirvonen, S., Plyusnina, A., Nemirov, K., Fredga, K.,
Cook, J. A., Niemimaa, J., Kaikusalo, A., Henttonen,
H., Vaheri, A. and Plyusnin, A. (1999): Isolation andS., Yamanishi, K. and Hashimoto, N. (1994): Comparisonof nucleotide sequences of M genome segments among

characterization of a hantavirus from Lemmus sibiricus:

Seoul vinュs Strains isolated丘om eastem Asia. Vims Res.,

Evidence for host switch during hantavirus evolution. J.

33, 27‑38.

46. Wang, H., Yoshimatsu, K., Ebihara, H., Ogino, M., Araki,
K., Kariwa, H., Wang, Z., Luo, Z., Li, D., Hang, C. andViro1., 73, 5586‑5592.
33･ Gajdusek, C. D. (1962): Virus hemorrhagic fevers. J.

Arikawa, J･ (2000): Genetic diversity of hantavi.ruses

Pediat., 60, 841‑857.

34･ Kitamura, T., Morita, C., Komatsu, T., Sugiyama, K.,

isolated in China and characterization ofnovel hantavlruSeS

Arikawa, J., Shiga, S" Takeda, H., Akao, Y.,lmaizumi,

isolated from Niviventer confucianus and Rattus rattus.

K., Oya, A., Hashimoto, N. and Urasawa, S. (1983):

Ⅵrology, 278, 332‑345.

Isolation of virus causlng hemorrhagic fever with renal

47. Chua, P. K., Song, ∫. W., Masuzawa, T., Kadosaka, T.,

syndrome (HFRS) through a cell culture system. Jpn. J.

Takada, N., Morita, C. and Yanagihara, 良. (2001):

Med. S°i. 丘iol., 36, 17‑25.

Epizootiology ofhantavirus infection in Japan. Abstr. 5th

35. Yamanishi, K., Dantas, J. R., Takahashi, M., Yamanouchi,

lnt. Conf. HFRS, HPS, hantaviruses.

T., Domae, K., Kawamata, ∫. and Kurata, T. (1983):

48. Song, ∫. W, Back, L ∫., Kin, S. H., Lee, Y ∫.,Yanagihara,

Isolation of hemorrhagic fever with renal syndrome

R. and Song, K.∫. (1999): Puumala‑related hantavirus(HFRS) virus from a tumor specimen in a rat. Biken J.,

harboured by Eothenomys regulus in Korea. p.290. Abstr.

26, 155‑160.

l lth lnt. Cong. Ⅵrol.

49. Horling, J., Chizhikov, V., Lundkvist, A･, Jonsson, M"

36. Arikawa, J., Takashima, I., Hashimoto, N., Takahashi, K.,

Yagi, K. and Hattori, K. (1986): Epidemiological studiesof hemorrhagic fever with renal syndrome (HFRS)

lvanov,し., Dekonenko, A., Niklasson, a., Dzagurova,

related virus infection among urban rats in Hokkaido,T., Peters, C. J., Tkachenko, E. and Nichol, S. (1996):
Khabarovsk virus: a phylogenetically and serologlCally

Japan. Arch. Viro1., 88, 23ト240.

distinct hantavirus isolated from Microtusfortis trappedin far‑east Russia. J. Gen. Viro1., 77, 687‑694.

37. Yoshimatsu, K., Arikawa, ∫., Li, H., Kariwa, H.,

102