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ŤƈƄŝƍŨƌũ"ô«õ?ŉōõĀŤƈƄŝƍŨƌũ"ô«ŤƈƄŝƍŨƌũ"ô«(A) #\(B) qÝą
【tick-animal cycles】"【tick-tick cycles】"egg"

Adult tick"Domesticanimals"(sheep)"Transovarial"
transmission"premature tick"õ?ōµ´Fď¾«nôS£T¾à

Shi-Wen Wang, Ph.D., Kang-Lin Wan, Ph.D., Huai-Qi Jing, M.D.,
Jin-Xin Lu, M.D., Wen-Wu Yin, M.Ph., Hang Zhou, M.S, Xu-Hua Guan, Ph.D.,
Jia-Fa Liu, M.D., Zhen-Qiang Bi, Ph.D., Guo-Hua Liu, M.D., Jun Ren, M.D.,
Hua Wang, M.D., Zhuo Zhao, M.D., Jing-Dong Song, M.Sc., Jin-Rong He, B.Sc.,
Tao Wan, Ph.D., Jing-Shan Zhang, M.S., Xiu-Ping Fu, M.S., Li-Na Sun, Ph.D.,
Xiao-Ping Dong, Ph.D., Zi-Jian Feng, M.D., Wei-Zhong Yang, M.D., Tao Hong, M.D.,
Yu Zhang, M.D., David H. Walker, M.D., Yu Wang, M.D., Ph.D., and De-Xin Li, M.D.

A bs t r ac t
Background

Heightened surveillance of acute febrile illness in China since 2009 has led to theidentification of a severe fever with thrombocytopenia syndrome (SFTS) with an unknown cause. Infection with Anaplasma phagocytophilum has been suggested as a cause,
but the pathogen has not been detected in most patients on laboratory testing.

The authors’ affiliations are listed in theAppendix. Address reprint requests toDr. Li at the National Institute for Viral
Disease Control and Prevention or Dr. Y.
Wang — both at the Chinese Center for
Disease Control and Prevention, Beijing
Methods
102206 China, or at lidx@chinacdc.cn orwangyu@chinacdc.cn.
Into the hot zone. Xue-jieWeYu (left,in blueshirt)
looks onfrom
as farmers
dogcasefor ticks;
forest-hugging
were hard hit by the emerging virus (inset).
obtainedblood
samplespatientscheckwithathedefinitionof SFTS infarms
six (right)

provinces in China. The blood samples were used to isolate the causal pathogen by *Deceased.
inoculation of cell culture and for detection of viral RNA on polymerase-chain1 OCTOBER
VOL 330SCIENCEwww.sciencemag.org
reaction assay. Thepathogen was2010
characterized
on electron
microscopy
and nucleic Drs. Yu, Liang, Zhang, Liu, Li, and Sun
Published by AAAS
acid sequencing. We used enzyme-linked immunosorbent
assay, indirect immuno- contributed equally to this article.
fluorescence assay, and neutralization testing to analyze the level of virus-specific This article (10.1056/NEJMoa1010095) was
published on March 16, 2011, at NEJM.org.
antibody in patients’ serum samples.

20Results

N Engl J Med 2011;364:1523-32.

We isolated a novel virus, designated SFTS bunyavirus, from patients who presented
with fever, thrombocytopenia, leukocytopenia, and multiorgan dysfunction. RNA
sequence analysis revealed that the virus was a newly identified member of thegenus phlebovirus in the Bunyaviridae family. Electron-microscopical examination
revealed virions with the morphologic characteristics of a bunyavirus. The presenceof the virus was confirmed in 171 patients with SFTS from six provinces by detectionof viral RNA, specific antibodies to the virus in blood, or both. Serologic assays
showed a virus-specific immune response in all 35 pairs of serum samples collected from patients during the acute and convalescent phases of the illness.

Copyright © 2011 Massachusetts Medical Society.

CREDITS: COURTESY OF XUE-JIE YU/ UNIVERSITY OF TEXAS MEDICAL BRANCH; (INSET) COURTESY OF LI DEXIN/CHINESE CDC

ď¾«nôS£T¾àƏSFTSƐDownloaded from www.sciencemag.org on October 30, 2011in China.
blood ofsamplesweretoProgram,isolate thedown with an illness characterized provincesby high complete
RNAThesequences
11 strains,
to usedTalents
whichcausal
brings pathogen
overseas sci-by * Deceased.
fever and gastrointestinal (GI) distress.
The Lancet.
charges andLi’s groupwith try- entists
to China.
inoculationof cellYuculture
for detectionof viralRNA on polymerase-chainMany victims bled profusely, and anreaction
alarm- assay.
ing to rob
himpathogenof the discovery;
Li says Yu’s
Thatsummer,microscopy
the pathogen surfacedinDrs. Yu, Liang, Zhang, Liu, Li, and Sun
The
was characterized
onelectron
and nucleic
ing number of the sick—rough estimates viral sequence is incomplete and that his team Henan and Hubei provinces. In June, Yu
contributed equally to this article.
acidBysequencing.
Wevirusused
enzyme-linked
immunosorbent
immunoare as high as 30% in some areas—died.
identified theas thekiller.
went to Hubei’sassay,
capital,indirect
Wuhan, tocollectassay,keyandneutralization
testing
to analyzeof virus-specificearly 2007, scientists at the ChinesefluorescenceCenterSeveralquestions
are disputedor bloodsamples thefromlevel
patients.
“They did notThis article (10.1056/NEJMoa1010095) was
published on March 16, 2011, at NEJM.org.
for Disease Control and Preventionantibody(CDC) unanswered.
Forserum
starters,samples.
researchers do not look like typical HGA cases,” he says. Afterin patients’
here fingered the killer as human granu- know how lethal the virus is. The mortality he failed to detect A. phagocytophilum, Yu
N Engl J Med 2011;364:1523-32.
locytic anaplasmosis (HGA), an Results
emerg- rate may be high in China in part because clin- says he urged Chinese CDC scientists toing bacterial infection from tick bites.
Buticsoftenprescribe
thesteroiddexa
methasoneconsideraviralpathogen—butresearchers
We isolated a novel virus, designated SFTS bunyavirus, from patients who presented Copyright © 2011 Massachusetts Medical Society.
to Yu, an expert on tick-borne diseases at to bring down high fevers; steroids suppress there flatly rejected the idea. Yu persistedwith fever, thrombocytopenia, leukocytopenia, and multiorgan dysfunction. RNA
the University of Texas Medical Branch in the immune system, which usually worsens and spotted virus particles that December
analysisScientists
revealedvirus wasin acellnewly
memberof theGalveston, things didn’t add up. sequenceinfections.
alsothatdiffertheon whether
cultureidentified
using electron
microscopy.
genus
in theBunyaviridae
family.Then
Electron-microscopicalexamination“The fatality rate was too high,” Yusays, phlebovirus
the virus should
be handled
in a biosafety
in February, he says, a memberof hisand in his experience it was “rare” forHGA virions
level 3 facility—reservedfor dangerous
Texas lab,ofYanLiu, “cracked thecodeof therevealedwith the morphologic
characteristics
a bunyavirus.
Thepresence
patients to have GI symptoms. Working at pathogens—or in less secure laboratories. viral genome.” Two days after he informedof the virus was confirmed in 171 patients with SFTS from six provinces by detection
the Chinese CDC’s National Institute of And although the infection shows a seasonal scientists at the Chinese CDC about hisviral RNA,
antibodies
the virusfindings,
in blood,or both.
Serologic
assaysCommunicable Disease Control and ofPrevenpattern specificassociated withtick-bornetodiseases—
he says,his 1000
Talents affi
liation (NICDC) here, Yu tested blood samples
begin in early springand peakin mid- intion
wasserumterminated.
showed acases
virus-specificimmuneresponse
allwith35 NICDC
pairs ofsamples colfor Anaplasma phagocytophilum, theHGA summer
before during
tapering off
autumn—theChinese phases
CDC Director
Yu waslectedpatients
theby
and convalescentof theWang
illness.
T h e n e wfrom
e ng l an d j o u r na
l o f m e dic
i nacutee
bacterium—and came up empty. Last Decem- vector is still a mystery.
intrigued by Xue-jie Yu’s findings and invitedber, his team identified a new kind ofConclusions
bunyaOne indisputable fact is that the emerging him to share them at a 15 April meeting at
virus, a family that includes infamous
disease has claimed
scores of lives—mostlyto plot strategy
for studyA novel phlebovirus
was identifiedin patients CDC
withheadquarters
a life-threatening
illness
associoriginal article
members such as hantavirus and Rift Valley of farmers—in China’s heartland. The first ing the disease. Among the attendees were Li
withdocumented
fever andoutbreakthrombocytopenia
China.
by theChina
Mega-Project
fever virus. The finding, in a paper atedsubmitwas in 2006, in inAnhuiand(FundedCDC virologist
Liang
Mifang;they foundfor Infectious
Diseasesanda teamothers.)
ted to The New England Journal of Medicine
Province.
At that time,
led by NICDC Yu’s presentation unconvincing. “He said heFeverwith Thrombocytopenia
Associated(NEJM), unmasks a dangerous
new emerging
Director Xu Jianguo, Chinese
CDC’s chief isolated a bunyavirus, but he had gotten justvirus—not a bacterial outbreak—andexplainsbacteriologist,rushed toin
Anhui.
Using PCR fragments,” says Liang. Yu confirms that thewitha Novel
Bunyavirus
China
why antibiotics failed to stop it.
they found A. phagocytophilum DNA in the virologists were dismissive: “Li tried to deny1523
n engl j med 364;16 nejm.org april 21, 2011
Xue-Jie
Ph.D.,blood
Mi-Fang
M.D., Shou-Yin
Zhang,
Behind the scenes, however,a fiYu,erceM.D.,
arguof Liang,
one patient
who diedandPh.D.,*in fam- the importance of my work,” Yu says. Yu and
Yan Liu,M.D., Jian-Dong
Li, members
Ph.D., Yu-Lan
M.D., LihongZhang
M.D.,Newhis
ment has broken out over who
discovered
the ilyandSun,
hospitalstaff who
becamecolleagues
have
named the virus Dabie
The
England
Journalof Medicine
Quan-Fu Zhang, B.Sc., Vsevolod L. Popov, Ph.D., Chuan Li, B.Sc., Jing Qu, B.Sc.,
Downloaded
fromnejm.orgat
NATIONAL
INSTITUTE
OF
INFECTIOUS
DISEASE
onMay26,2011.
For
personaluseonly.
Nootheruses
without
permission.
Qun Li, M.D., Yan-Ping Zhang, M.D., Rong Hai, M.D., Wei Wu, M.Sc.,
Copyright©Kan,
2011
Massachusetts Medical Society. All rights reserved.
Qin Wang, Ph.D., Fa-Xian Zhan, Ph.D., Xian-Jun Wang,M.D., Biao
Ph.D.,

ď¾«nôS£T¾à• 2009`=¥*ÈŊ,ÈōXY?A#• ŹŴěÙ²ŝŵŽƇŮƃ¾ŌĜ#• Ã«İôS£Tİåè¾®İÄô²£T#• 21/171Ə12%Ɛ#• zÑōżŶƆşŞƉŭƏSFTSşŞƉŭƐ#• ŹŴĹŗŹŴőōq#• oâô¢į103-109ŨźƎ/ml#• õ?AōŻŰŴŧŲƃűŶ#5.4%Ėn##Conclusions

A novel phlebovirus was identified in patients with a life-threatening illness associated with fever and thrombocytopenia in China. (Funded by the China Mega-Projectfor Infectious Diseases and others.)n engl j med 364;16

nejm.org

1523

april 21, 2011

The New England Journal of Medicine
Downloaded from nejm.org at NATIONAL INSTITUTE OF INFECTIOUS DISEASE on May 26, 2011. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.

Febrile Thrombocytopenia and a Novel Virus in ChinaŻŰŴŧŲƃűŶ#Haemaphysalis+longicornis

Heilongjiang

Jilin
Liaoning

Xinjiang
Beijing

Neimenggu

Gansu

Hebei
Ningxia

Tianjin

ShanxiShandong

QinghaiJiangsu

Henan

Shaanxi

Anhui

XizangChongqing

Jiangxi

Shanghai

Hubei
SichuanZhejiang

Hunan
FujianGuizhou
YunnanGuangxi

Guangdong

HainanFigure 1. Geographic Distribution of SFTS in Mainland China.
Areas where SFTS surveillance was carried out and SFTS bunyavirus was isolated from patients are shown in red.

restriction-fragment–length-polymorphism assay
with amplified complementary DNA, as described
previously.6 For the remaining 11 strains of thevirus, the whole genomes were sequenced with theuse of the sequence-independent, single-primer
amplification (SISPA) method.7 The 5' and 3' terminals of viral RNA segments were determinedwith a RACE Kit (Invitrogen). Phylogenetic analyses were performed with the neighbor-joining
method with the use of the Poisson correction andcomplete deletion of gaps.

• } =Ō#\!
• ŷſūŝ¾/ò!
• } Ûx«ƈŦųŲŝ!
for 1.5 hours. The mixture was then added to a96-well plate containing Vero cells in quadruplicate. The plates were incubated at 37°C in a 5%
carbon dioxide atmosphere for 12 days. Viral infection was detected on specific immunofluorescence assays in serum samples from patients withlaboratory-confirmed infection. The end-point titer was expressed as the reciprocal of the highest
dilution of serum that prevented infection.

żŶƆşŞƉŭÐ#ŻƊƁşŞƉŭW} ŌĸĽřűŶŊSFTSşŞƉŭōđĉŌŇĵňŎƒ hōĀśgńŋļňŎŋŗŋĵƔPolymerase Chain Reaction

RNA that was extracted from serum, whole blood,or homogenized arthropods was amplified withFor microneutralization testing, serial dilutions the use of a one-step, multiplex real-time reverseof serum samples were mixed with an equal vol- transcriptase polymerase chain reaction (RT-PCR)
ume of 100 median tissue-culture infectious dos- with primers for SFTSV (Qiagen). The cutoff cyclees of SFTSV (strain HB29) and incubated at 37°C threshold value for a positive sample was set atNeutralization Assayn engl j med 364;16

nejm.org

1525

april 21, 2011

The New England Journal of Medicine
Downloaded from nejm.org at NATIONAL INSTITUTE OF INFECTIOUS DISEASE on May 26, 2011. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.

} ŉ%ŔňSFTSŊüyĿŚńoâĩĨĪĩīōqÝą
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