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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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
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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
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Dis 1994; 169:1271-80.
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C Schmaljohn, B Hjelle. Hantaviruses : A Global Disease Problem.
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C Schmaljohn, B Hjelle. Hantaviruses : A Global Disease Problem. Emerging
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RM Wells, SS Estani, ZE Yadon, D Enria, P Padula, N pini, JN Mills, CJ
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Epidemiology Bulletin
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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).
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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
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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