Download Hantavirus Pulmonary Syndrome in Northern Alberta, Canada

Hantavirus Pulmonary Syndrome in Northern Alberta, Canada: Clinical and Laboratory
Findings for 19 Cases
Author(s): R. Verity, E. Prasad, K. Grimsrud, H. Artsob, M. Drebot, L. Miedzinski, J.
Preikasaitis
Source: Clinical Infectious Diseases, Vol. 31, No. 4 (Oct., 2000), pp. 942-946
Published by: The University of Chicago Press
Stable URL: http://www.jstor.org/stable/4461342
Accessed: 31/08/2009 15:37
Your use of the JSTOR archive indicates your acceptance of JSTOR's Terms and Conditions of Use, available at
http://www.jstor.org/page/info/about/policies/terms.jsp. JSTOR's Terms and Conditions of Use provides, in part, that unless
you have obtained prior permission, you may not download an entire issue of a journal or multiple copies of articles, and you
may use content in the JSTOR archive only for your personal, non-commercial use.
Please contact the publisher regarding any further use of this work. Publisher contact information may be obtained at
http://www.jstor.org/action/showPublisher?publisherCode=ucpress.
Each copy of any part of a JSTOR transmission must contain the same copyright notice that appears on the screen or printed
page of such transmission.
JSTOR is a not-for-profit organization founded in 1995 to build trusted digital archives for scholarship. We work with the
scholarly community to preserve their work and the materials they rely upon, and to build a common research platform that
promotes the discovery and use of these resources. For more information about JSTOR, please contact [email protected].
The University of Chicago Press is collaborating with JSTOR to digitize, preserve and extend access to
Clinical Infectious Diseases.
http://www.jstor.org
942
Hantavirus Pulmonary Syndromein Northern Alberta, Canada:
Clinical and Laboratory Findings for 19 Cases
R. Verity,1 E. Prasad,1 K. Grimsrud,2 H. Artsob,4
M. Drebot,4 L. Miedzinski,3 and J. Preiksaitist'3
'Provincial Laboratory of Public Health for Northern Alberta,
2AlbertaHealth, and 3Departmentof Medicine, University of Alberta,
Edmonton, Alberta, Canada; and 4CanadianScience Centrefor Human
and Animal Health, Winnipeg, Manitoba, Canada
We reviewed the clinical and laboratory findings for 19 cases of hantavirus pulmonary
syndrome (HPS) identified either serologically or by immunohistochemical testing of archival
tissue at our tertiary care center. Fever (95%), cough (89%), and dyspnea (89%)were the most
common presenting symptoms. The most prevalent presenting signs were respiratory abnormalities (95%) and tachycardia (84%). Common laboratory findings included thrombocytopenia (95%) and leukocytosis (79%). Elevated aspartate aminotransferase and lactate dehydrogenase levels were found in all patients tested. Intubation was required in 58% of the
patients, and inotropic support was required in 53%. Our study confirms that serological
responses appear early during clinical illness, making the enzyme immunoassay a useful tool
for the diagnosis of acute HPS. The mortality (26%)and severity of disease that we observed
among patients with HPS appear to be less than those reported elsewhere.
In fall of 1992, there was an exceptional amount of rainfall
in the Four Corners region of the United States; this led to the
growth of a massive deer mouse (Peromyscusmaniculatis) population during the following year [1]. In May 1993, an outbreak
of a mysterious disease occurred in rural New Mexico [1]. A
case definition was developed by the Centers for Disease Control and Prevention (CDC) [1]. The causative agent of this disease, a hantavirus identified by the CDC by means of serological testing, was designated as "Sin Nombre" ("No Name")
virus, and the syndrome became known as hantavirus pulmonary syndrome (HPS) [1-9]. Transmission of Sin Nombre
virus to humans in North America is believed to occur through
exposure to deer mice or deer mice excreta [10, 11]. The mortality associated with this syndrome has been reported to be as
high as 43% in the United States (as of May 1999) [12].
Before the outbreak in New Mexico occurred in 1993, there
had been no reports of HPS in North America. Since the original outbreak of HPS occurred in the Four Corners region of
the United States in 1993, there have been numerous reports
of the disease throughout both North and South America
[12-19]. In Canada, 20 cases have been reported in Alberta, 6
in British Columbia, 5 in Saskatchewan, and 1 in Manitoba
(as of 1 September 1999).
We observed (a) that the cases of HPS seen in northern AlReceived 1 October 1999;revised9 March2000; electronicallypublished
25 October 2000.
Reprints or correspondence:Robert Verity, Microbiology and Public
Health, 2B3.01 Walter C. Mackenzie Health Sciences Centre, University
of Alberta Hospitals, 8440-112 St., Edmonton, Alberta T6G 2J2, Canada
([email protected]).
ClinicalInfectiousDiseases 2000;31:942-6
? 2000 by the InfectiousDiseasesSocietyof America.All rightsreserved.
1058-4838/2000/3104-0014$03.00
berta were associated with a mortality rate that was lower than
that previously reported in the United States and (b) that the
majority of cases in Canada have occurred in Alberta. This
report describes the exposure history, symptoms, signs, treatment, outcome, and laboratory diagnosis of 19 cases of HPS
that occurred in northern Alberta from 1989 through June 1998.
Patients and Methods
Patient population. During the period from September1994
through June 1998, 19 cases of HPS were identifiedat 3 tertiary
care centers in Edmonton, Alberta, Canada. Three of these cases
occurredin 1989, 1990, and 1992, respectively,and were identified
retrospectivelywith the use of archivalblood and tissue samples.
All cases of HPS were confirmedeither by positive serology or by
immunohistochemicalstaining of archivaltissues. All cases fit the
CDC case definition of HPS [1]. A chart review of the exposure
history, symptoms, signs, treatment,and outcome was performed
for all cases of HPS treated in Alberta, by use of a standardized
database form.
Diagnostic tests. Serum samples obtained from the patients
were tested against Sin Nombre nucleocapsidantigenand a normal
control antigen by use of an EIA, as describedelsewhere [8]. In
February 1998, all but 3 of the patients' specimenswere tested at
the Canadian Science Centre for Human and Animal Health, in
Winnipeg,Manitoba, by use of an EIA on 1 standardizedtest run.
Those patients whose serum specimenswere not included in this
test run had HPS diagnosed after December 1997. The dilutions
of human serum that were used were 1:100, 1:400, 1:1600, and 1:
6400. The cutoff point for a positive test was an optical density of
0.1 when comparedto background.The serumtiterwas determined
to be the highest dilution at which a positive result was obtained.
Formalin-fixedtissue specimensfrom 2 patients were tested by
means of immunohistochemicalstaining (testing was done by Dr.
S. Zaki, CDC, Atlanta) [8]. Blood clots and tissues from both a
CID 2000;31 (October)
HPS in Northern Alberta, Canada
representativeseropositivedeermouse and a patientwith HPS were
used for reverse transcriptase-PCRamplificationof a portion of
the hantavirusG1 gene, with use of primersdescribedby Johnson
et al. [20].
Statistical analysis. A 2-tailed nonparametric1-sample t test
(a = .05), done with the use of SPSS software,version 9.0 (SPSS,
Chicago), was performed to compare the number of days from
onset of symptoms to presentationin the patients who survived
and in those who died.
andr-~~~~~~~~0
943
9
11998
1,~~~1997
~~~~
87~
7
1
a 6-1
8~~~
~~51
r1996
?
0~1
~1
0
1111995
01994
11992
1989
Zell/L)
23
Results
The medical records of all 19 patients were available for this
study. The median age of the patients was 40 years (range, 15-65
years). Eleven (58%) of the patients were men. The median time
from onset of symptoms to presentation was 5 days (range,
2-19 days). The majority of cases of HPS occurred in the spring
(figure 1). Ten (53%) of the 19 cases presented between 1 June
1997 and 19 June 1998.
All of the patients were treated at our 3 tertiary care centers.
Eighteen of the 19 patients were from rural Alberta, and 1
patient, who was working in Fort St. John, British Columbia,
was from Saskatchewan (figure 2). All but one of the patients
had a known exposure to mice or mice excreta in the 6 weeks
prior to the onset of illness. The one patient who did not have
an identified history of exposure to mice had a pet gerbil at
home. A blood sample obtained from the gerbil was sent for
serological testing and was found to be negative for evidence
of hantavirus infection.
Symptoms and signs. In a retrospective study, it is difficult
to ascertain whether the physician who obtained the history
asked about specific symptoms, since negative findings are
sometimes not recorded. We assume that a search for the symptoms listed below was done for all critically ill patients. The
most common symptoms at the time of presentation were fever
(95%), cough (89%), and dyspnea (89%). In 7 (41%) of the 17
patients, the cough was nonproductive. Other frequently reported symptoms included nausea (74%), chills (63%), and
vomiting (58%). Headache was reported by 12 patients (63%),
of whom 4 had a lumbar puncture performed as part of their
initial workup. The occurrence of rhinorrhea and sore throat,
symptoms that may not have been consistently sought, was
documented in only 2 patients.
The most prevalent presenting signs were respiratory abnormalities (95%), tachypnea (84%), and tachycardia (84%). Hypotension at presentation, which was defined by a value of<100
mm Hg systolic pressure, was noted in only 32% of patients.
Abnormalities on chest radiography were seen in 18 (95%) of
19 patients at the time of presentation. All of these patients
had interstitial infiltrates, and 5 (28%) of 18 patients had pleural
effusions.
Laboratory values. Common hematological abnormalities
that were seen during the clinical course of HPS included
thrombocytopenia (95%) and leukocytosis (79%). The trough
Sprng
Summer
Fall
Winter
Figure 1. Seasonalityof cases of hantaviruspulmonarysyndrome
(HPS)in northernAlberta,Canada(as of December1998).Eachpatternrepresentsa yearin whichat leastone caseof HPSwas diagnosed.
medianplateletcount was 52 x 109cells/L(range,193-9 x 109
cells/L),and the peakmedianWBCcount was 18.5x 109cells/
L (range, 5.7-59.2 x 109cells/L). Increasedhemoglobinand
hemoconcentration were seen in 5 (26%) of the 19 patients. The
partial thromboplastin time was increased in 16 (89%) of 18
patients. Five (45%) of the 11 patients who had a peripheral
blood smear prepared, with or without bone marrow aspiration,
had atypical lymphocytes seen by a hematopathologist.
The other laboratory abnormalities included elevated levels
of aspartate aminotransferase in 17 patients and elevated levels
of lactate dehydrogenase in 15 patients. The peak median value
was 124 IU/L (range, 57-23,120 IU/L) for aspartate aminotransferase and 657 IU/L (range, 279-20,200 IU/L) for lactate
dehydrogenase. Thirteen (93%) of 14 patients had hypoalbuminemia. An increased creatinine kinase concentration was seen
in 6 (43%) of 14 patients. The creatinine level was elevated in
58% of patients. For 6 patients, the median arterial partial
pressure of 02 on room air at the time of admission was 46.5
mm Hg (range, 39-51 mm Hg). All of the patients required
supplemental oxygen at the time of admission.
The plasma lactate level was elevated in 5 (50%) of 10 patients, and the venous bicarbonate level was low in 15 (79%)
of 19 patients during the hospital days prior to and during the
first week in the intensive care unit. The peak median level of
plasma lactate was 2.7 mM/L (range, 1.0-20.4 mM/L), and the
trough median level for venous bicarbonate was 18 mM/L
(range, 8.2-25 mM/L) during this time.
Clinical outcome. Five (26%) of the 19 patients died. One
(33%) of the 3 patients who had HPS diagnosed retrospectively
before 1994 and 4 (25%) of the 16 patients who had HPS diagnosed after 1994 did not survive. For the 10 cases diagnosed
from 1997 through 1998, the mortality rate was 30%.
The median time from the onset of symptoms to presentation
was 6.5 days (range, 2-19 days) for the patients who survived
944
Verityet al.
and 3 days (range, 2-6 days) for those who died. With regard
to the time from onset of symptoms to presentation, there was
no significant difference between the survivors and those who
died.
Intubation was required for 11 (58%) of 19 patients. For
those patients who survived, the median time from onset of
symptoms to intubation was 6.5 days (range, 4-21 days); for
those who died, it was 4 days (range, 2-6 days). The median
duration of intubation was 6 days (range, 2-70 days) for those
who survived and 1 day (range, 1-4 days) for those who died.
Ten (71%) of the 14 patients who survived had a mean arterial
pressure (MAP) of <70 mm Hg recorded during the clinical
course of HPS, and 5 (50%) of these 10 patients required inotropic support. All patients who died had a MAP of <70 mm
Hg during the clinical course of HPS and required inotropic
support.
The median duration of hospitalization was 9 days (range,
6-85 days) for those who survived, and for those who died, the
median interval from presentation to death was 2 days (range,
1-5 days). Two (14%) of the 14 surviving patients were treated
with ribavirin, and 5 patients (26%) were enrolled in a randomized clinical trial of ribavirin versus placebo.
Diagnostic testing. Blood samples for serological testing
were collected from all of the patients (table 1). A positive IgM
response was seen in 17 (89%) of 19 patients at the time of the
first serological testing, at a median of 7 days (range, 2-21 days)
after the onset of symptoms. One of the patients who was
initially seronegative had a positive IgM response when retested
14 days after the onset of symptoms, and the other (for whom
CID 2000;31 (October)
Table 1. Results of serological testing of blood samples obtained
from 19 patients with hantavirus pulmonary syndrome (HPS).
Reciprocal
titer for 1st
Reciprocal
titer for 2d
Reciprocal
titer for 3d
specimen
specimen
specimen
Patient
IgM
IgG
Daya
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1600
100
6400
400
100
400
<100
1600
1600
1600
100
400
<100
1600
6400
100
1600
400
1600
100
<100
100
400
<100
400
<100
<100
100
100
<100
<100
<100
100
100
<100
1600
400
<100
2
4
4
4
4
5
6
6
7
7
7
7
IgM
IgG
Daya
IgM
IgG
Daya
400
400
1600
100
8
16
<100
<100
1600
400
37
361
400
<100
14
400
400
31
1600
400
21
1600
400
22
<100
400
1600
400
149
27
<100
400
62
400
100
34
<100
400
1545
7b
8
9
10
18
21
21
a
Number of days from onset of symptoms to serology.
b
HPSwasdiagnosedin thispatientby meansof immunohistochemical
staining of archivaltissues.A blood samplehad been collectedfromthis patientin
1989, which may account for the lack of IgM reactivity.
no further serological results were available) had the diagnosis
confirmed by immunohistochemical staining of tissue. Blood
samples from this patient had been collected in 1989. The long
period of storage may account for the lack of IgM reactivity.
Alberta
? Edmonton
* Calgary
Figure 2. Geographic locations of cases of hantavirus pulmonary syndrome (HPS) in northern Alberta, Canada. One patient, who was referred
to our tertiary care center from Fort St. John, British Columbia, was a resident of Saskatchewan. Squares, cities; circles, cases of HPS.
CID 2000;31 (October)
The IgM responsewas positivein 14 (88%)of 16 patientswho
had theirblood collectedwithin 10 days of the onset of symptoms, and it lasted as long as 34 days in 1 patient.After this
point, the IgM responsebegins to decline.In 10 (53%)of 19
patients,an IgM and IgG responsewas seen duringthe first
serologicaltest. Duringsubsequenttesting,whichwas done at
a median of 25 days (range, 16-31 days) after the onset of
symptoms,a further4 (44%)of 9 patientshad a Sin Nombre-specificIgG responsedetected.Four years after development of acute HPS, 1 patienthad an IgG titer of 1:400to Sin
Nombrevirus.
Sequence analysis of hantavirusG1 ampliconsgenerated
from both a patientwith HPS (patient8; table 1) and a seropositivedeermousefromnorthernAlbertaseemsto show that
thesehantavirusesweregenotypicallyrelatedto eachother(figure 3). Althoughgenotypicallydistinctfrom Sin Nombreand
Convict Creek 107 strains,the northernAlbertahantaviruses
appearto be morecloselyrelatedto thesestrainsthanto eastern
North Americanhantaviruses,such as the New Yorkor Black
CreekCanalviruses(figure3).
Discussion
945
HPS in Northern Alberta, Canada
Ab-rodent
Ab-human
CC107
SN
-~-
NY
BCC
PH
TUL
PUU
HTN
SEO
Figure 3. Phylogenetic relationship of northern Alberta (Ab) Sin
Nombre-like viral strains to other hantaviruses, according to the nucleotide sequence from the G1 gene. This tree was generated with the
use of Clustal V (included in the Lasergene Megalign program;DNASTAR, Madison, WI) [21]. Definitions of strains and GenBank accession
numbers (given in parentheses) for the sequence are as follows: CC107,
Convict Creek 107 (L33474); SN, Sin Nombre virus strain (NMH10
and L25783); NY, New York-1 (U36802); BCC, Black Creek Canal
virus (L39950); PH, Prospect Hill (X55129); TUL, Tula/Moravia/5286/
94 strain (Z66538); PUU, Puumala, Sotkama strain (X61034); HTN,
Hantaan virus (M14627); and SEO, Seoul virus strain KI-83-262
(D17592).
which was noted in 32%of patients,comparedwith 50%of
patientsin an earlierstudy[4].Only 2 patientshad rhinorrhea
and a sorethroat,a findingdemonstratingthatthesesymptoms
are usefulin differentiatingHPS fromdiseasecausedby influenza [22]. In contrastto a previousstudy of symptomsseen
withHPS,manypatientsin our serieshadcoughas a presenting
symptom,suggestingthat lack of cough was not usefulin differentiatingHPS from other causesof pneumonia[23].
The laboratoryresultsseen in this seriesof cases are similar
During the period from June 1997 throughJune 1998, 10
cases of HPS were diagnosedat our centers;this is a greater
numberof casesthanwas reportedin the areaduringtheperiod
from 1989 through1996.As previouslydiscussedwith regard
to the Four Cornersoutbreak,El Nifio weathereffectsseemed
to boost the deer mouse population[1]. A similarpopulation
explosionmay have occurredamongdeermicein Albertadurto those reported elsewhere, with thrombocytopenia, leukocying the summerof 1997, resultingin increasedexposureof
humansto mice. In 1997,most of the cases of HPS occurred tosis with a left shift, and an increasein lactatedehydrogenase
duringthe fall, when the mice may have been seekingshelter level being common [1-9]. However,the patientsin our study
indoors.
did not have the same incidenceof hemoconcentration,
which
The age rangeof the patientsvariedwidelyin our study,with
is anothermarkerof severedisease.A recentstudyalso showed
the youngestpatientbeing 15 yearsold. This is similarto findthatthefindingby hematopathologists
of an increasein atypical
from
in
studies
the
United
4
States,where,as of February lymphocytesin peripheralblood smearsis useful for the diings
2000, there have been no confirmedcases involvingchildren agnosis of HPS; this observationwas made for 45% of our
level
aged <10 years age (www.cdc.gov/ncidod/diseases/hanta/hps/patients[1]. In this study,the aspartateaminotransferase
was elevatedin 100%of the patients,a findingthat suggests
noframes/caseinfo.htm).
Why childrendo not contractthe illthat a normalresultmakes a diagnosisof HPS far less likely.
ness, however,is not entirelyunderstood.One hypothesisis
that HPS is immunopathologicalin natureand that repeated
A study of the first 100 cases found in the United States
showed that 65 (84%)of 77 patients requiredintubation,a
exposureto Sin Nombrevirusis requiredto cause disease.
Analysisof the geographiclocationsof the cases of HPS on
proportionthat is higherthan the 11 (58%)of 19 patientswho
a map of Albertarevealsthat they fit into a belt-likepattern requiredintubationin our study [5]. When hypotensionwas
in the midregionof the province(figure2). Recentstudieshave
recordedduring the clinicalcourse of HPS, 79%of patients
had a MAP of u70 mm Hg, and 53% required inotropic supsuggestedthat multipleenvironmentalfactorsmay play a part
in the increasein the numberof deer mice and in subsequent port. Data on hypotensionduringthe clinicalcourse of HPS
increasesin the numberof cases of HPS [22]. Most of the
have not been given in previousstudy reports.
in
our
involved
the
inhalation
of
aerosols
from
Our study confirmsthat serologicalresponsesappearearly
exposures
study
areascontaminatedwith mouse excreta.
duringclinical illness, making the EIA a useful tool for the
The symptomsand signs observedat presentationin this
diagnosisof acuteHPS. The IgM serologyfor 1 of the patients
are
similar
to
those
for
a
lower
was
study
reportedpreviously,except
negativeon day 6 of the illness but becamepositive on
incidenceof markersof severe disease, such as hypotension, day 14; this findingemphasizesthat if there is a clinicalsus-
946
Verityet al.
picion of HPS, serological testing should be repeated. The IgG
antibodies to Sin Nombre virus seem to persist for a long time,
as was illustrated by the patient who had an IgG titer of 1:400
4 years after acute HPS developed.
A recent study indicated that the Sin Nombre-like viruses
found in Alberta deer mice were genotypically distinct from the
Sin Nombre virus strains in the southwestern United States
[24]. However, this study also showed that western North American Sin Nombre-like viruses seemed, at the genotypic level,
to be more related to each other than to strains found in eastern
regions of the continent. Our findings are consistent with this
observation. Northern Alberta viral strains both from a patient
with HPS and a seropositive deer mouse also showed a closer
genetic relationship to western Sin Nombre viruses than to such
viruses as the New York or Black Creek Canal viruses.
In our series, we observed a lower incidence of signs of severe
disease at admission, a lower incidence of intubation, and a
lower mortality (26%) than those observed by other investigators. The case-fatality rate of 25% seen since 1994 in our
series of patients can be compared with the case-fatality rate
of 34% reported from the United States since 1994 (as of 4
February 2000); however, because of the small number of patients in our study, this difference may not be significant (www
.cdc.gov/ncidod/diseases/hanta/hps/noframes/caseinfo.htm).
The low case-fatality rate observed may be the result of earlier
detection of infection, aggressive intensive care unit management, the viral inoculum to which the patients were exposed,
the genetic predisposition of the patients, or the presence of a
variant of the virus in northern Alberta. Further genetic analyses of Sin Nombre isolates from our region and from other
regions would be useful for differentiating between these possibilities.
Acknowledgments
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
We thank the staffs of the IntensiveCare Unit and the Infectious
DiseasesDivision and the attendingphysicians,for the clinicalmanagementof thesecases;RichardSherbure and Rae Roulston,for help
in preparationof themanuscript;
andAnjaliChudasama,forproviding
the statisticalanalysis.
References
1. Mertz GJ, Hjelle BL, Bryan RT. Hantavirusinfection.Adv InternMed
1997;42:369-421.
2. MoolenarRL, BreimanRF, PetersCJ. Hantaviruspulmonarysyndrome.
SeminRespirInfect1997;12:31-9.
3. ButlerJC,PetersCJ.Hantaviruses
andhantaviruspulmonarysyndrome.Clin
InfectDis 1994;19:387-95.
4. DuchinJS, KosterFT, PetersCJ, et al. Hantaviruspulmonarysyndrome:a
20.
21.
22.
23.
24.
CID 2000;31 (October)
clinical description of 17 patients with a newly recognized disease. N Engl
J Med 1994; 330:949-55.
Khan AS, Khabbaz RF, Armstrong LR. Hantavirus pulmonary syndrome:
the first 100 cases. J Infect Dis 1996; 173:1297-1303.
Hjelle B, Jenison SA, Goade DE, Green WB, Feddersen RM, Scott AA.
Hantaviruses: clinical, microbiologic, and epidemiologic aspects. Crit Rev
Clin Lab Sci 1995;32:469-508.
Nolte KB, Feddersen RM, Foucar K, et al. Hantavirus pulmonary syndrome
in the United States: a pathological description of a disease caused by a
new agent. Hum Pathol 1995;26:110-20.
Zaki SR, Greer PW, Coffield LM, et al. Hantavirus pulmonary syndrome
pathogenesis of an emerging infectious disease. Am J Pathol 1995; 146:
552-79.
Foucar K, Nolte KB, Feddersen RM, et al. Outbreak of hantavirus pulmonary syndrome in the Southwestern United States: response of pathologists and other laboratorians. Am J Clin Pathol 1994; 101(Suppl 1):
S1-5.
Childs JE, Ksiazek TG, Spiropoulou CF Serologic and genetic identification
of Peronmyscusmaniculatus as the primary rodent reservoir for a new
hantavirus in the Southwestern United States. J Infect Dis 1994:169:
1271-80.
Fink TM. Rodents, human remains, and North American hantaviruses: risk
factors and prevention measures for forensic science personnel-a review.
J Forensic Sci 1996;41:1052-6.
Leslie M, Fritz C, Calisher C, et al. Update: hantavirus pulmonary syndrome:
United States. MMWR Morb Mortal Wkly Rep 1999;48:521-5.
Wells RM, Estani SS, Yadon ZE, et al. An unusual hantavirus outbreak in
southern Argentina: person-to-person transmission? Emerg Infect Dis
1997;3:171-4.
Padula PJ, Edelstein A, Miguel SD, L6pez NM, Rossi CM, Rabinovich RD.
Hantavirus pulmonary syndrome outbreak in Argentina: molecular evidence for person-to-person transmission of Andes virus. Virology 1998;
241:323-30.
Toro J, Vega JD, Khan AS, et al. An outbreak of hantavirus pulmonary
syndrome, Chile, 1997. Emerg Infect Dis 1998;4:687-94.
Young JC, Mills JN, Enria DA, Dolan NE, Khan AS, Ksiazek TG. New
World hantaviruses. Br Med Bull 1998;54:659-73.
Levis S, Morzunov SP, Rowe JE, et al. Genetic diversity and epidemiology
of hantaviruses in Argentina. J Infect Dis 1998:177:529-38.
Werker DH, Artsob H. Of mice and mostly men: hantavirus pulmonary
syndrome. CMAJ 1998;158:912-3.
Singh AE, WerkerDH, Boychuk LR, Miedzinski LJ. Hantavirus pulmonary
syndrome: report of four Alberta cases. Can J Infect Dis 1995;6:184-90.
Johnson AM, Bowen MD, Ksiazek TG, et al. Laguna Negra virus associated
with HPS in western Paraguay and Bolivia. Virology 1997;238:115-27.
Higgins DG. Clustal V: multiple alignment of DNA and protein sequences.
In: Griffin AM, Griffin HG, eds. Methods in moelcular biology: computer
analysis of sequence data, part II. Vol. 25. Totowa, NJ: Humana, 1994:
307-18.
Engelthaler DM, Mosley DG, Cheek JE, et al. Climatic and environmental
patterns associated with hantavirus pulmonary syndrome, Four Corners
region, United States. Emerg Infect Dis 1999;5:87-94.
Moolenaar RL, Dalton C, Lipman HB, et al. Clinical features that differentiate hantavirus pulmonary syndrome from three other acute respiratory
illnesses. Clin Infect Dis 1995;21:643-9.
Monroe MC, Morzunov SP, Johnson AM, et al. Genetic diversity and distribution of Peromyscus-borne hantaviruses in North America. Emerg
Infect Dis 1999; 5:75-86.