[Emerging Infectious Diseases * Volume 3 * Number 2 * April-June 1997]

Dispatches

   An Unusual Hantavirus Outbreak in Southern Argentina: Person-to-Person
                               Transmission?

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      Hantavirus pulmonary syndrome is a rodent-borne zoonosis first
      recognized in the United States in 1993. Person-to-person
      transmission has not been reported; however, in the outbreak of
      20 cases reported here, epidemiologic evidence strongly
      suggests this route of transmission.

In 1995, a novel hantavirus (Andes virus) was identified in samples from
patients in southern Argentina (1). The patients had hantavirus pulmonary
syndrome (HPS), a disease first described 2 years earlier in the United
States, in association with Sin Nombre virus (a new world hantavirus)
(2,3). Old World hantaviruses (Puumala, Seoul, Hantaan, and Dobrava) have
been recognized causes of hemorrhagic fever with renal syndrome (HFRS) for
at least 40 years and are responsible for more than 100,000 cases each year
in Eurasia (4). Hantaviruses (family Bunyaviridae, genus Hantavirus) are
rodent-borne viral zoonotic agents believed to be transmitted to humans
primarily by inhalation of aerosols of infected rodent excretions (4).
Person-to-person transmission of hantaviruses has not been reported despite
extensive epidemiologic studies. Between September 22 and December 5, 1996,
18 cases of HPS occurred in residents of, or visitors to, the towns of El
Bolsn, Bariloche, and Esquel in southern Argentina. Two additional persons
who had contact with El Bolsn patients but had not visited the area,
contracted HPS during this period (5). Five of the patients were
physicians; three were directly responsible for the clinical care of an HPS
patient. Epidemiologic links between all but four of the cases and evidence
of low rodent population density in the area strongly suggest
person-to-person transmission of HPS during this outbreak.

Sporadic cases of HPS and possible cases of HFRS from as early as 1987,
have been retrospectively identified in Argentina (6). In 1995, genetic
material from Andes virus, a unique hantavirus, was identified in the lungs
of a patient from El Bolsn (population ~15,000) in southern Argentina (1).
The outbreak of HPS reported in this dispatch began on September 22, 1996,
when the 41-year-old index patient (patient I) (also from El Bolsn) became
ill with HPS (Figure 1). El Bolsn, a rural town in Rio Negro Province, is
approximately 350 meters above sea level in the foothills of the Andes.
Patients requiring intensive care are transferred to Bariloche (population
80,000), 150 kilometers to the north (Figure 2).

                 [Figure 1] [Figures not available in ASCII version]
                 Figure 1. Transmission tree for HPS cases
                 in southern Argentina, September-December
                 1996, indicating dates of onset of
                 symptoms, survivor status, and proposed
                 lines of transmission. Lines of
                 transmission are hypothetical since many
                 of the patients had contact with multiple
                 HPS patients. Bold lines denote husband
                 and wife. The two sporadic cases, U and
                 R, are not shown.

                   [Figure 2] [Figures not available in ASCII version]
                   Figure 2. Towns involved in the 1996
                   HPS outbreak in southern Argentina.

Potential cases were identified by local physicians familiar with the
clinical features of HPS (3) and were accepted as cases when enzyme-linked
immunosorbent assay detected IgM antibodies reacting with Sin Nombre virus
and/or when reverse transcriptase and polymerase chain reaction detected
hantaviral RNA (1,2,6,7). Viral sequences indicated a sigmodontine-derived
hantavirus related to, but clearly distinct from, Sin Nombre virus;
additional sequencing and phylogenetic studies are under way.

Twenty-one and 20 days, respectively, after the index patient became
symptomatic, his 70-year-old mother (patient B) and one of his doctors
(patient A) contracted HPS. The doctor's spouse, also a doctor (patient C),
became ill with HPS 27 days after her husband's first symptoms (19 days
after his death). She traveled to Buenos Aires for medical care. In a
Buenos Aires hospital, an admitting doctor (patient D) spent 1 hour taking
a clinical history and examining her. The doctor (patient D) applied
pressure to a venipuncture site on patient C's arm with multiple layers of
gauze; no obvious blood contact occurred. The only other contact between
this doctor and patient C occurred 2 days later, when the doctor briefly
visited the hospital's intensive care unit to attend to another patient.
Twenty-four days after attending patient C, the doctor became ill with HPS.
The doctor, patient D, had not traveled outside Buenos Aires, and she
reported no contact with rodents during the 2 months preceding her illness
(5).

A 40-year-old doctor (patient E) from Buenos Aires contracted HPS 17 days
after patient C was admitted to the hospital. This doctor was a friend of
patients A and C and spent 3 days in El Bolsn after the death of patient
A. She visited patient C often in the hospital but was not directly
involved in the clinical management of any HPS patients. A fifth doctor
with HPS (patient F) reported having close contact with several HPS
patients. He intubated patient B and examined patients I and G. He also had
daily contact with his colleague, (patient A), and spoke briefly with
patient I's sister (patient H), brother-in-law (patient J), and friend
(patient K).

At the funeral of patient B, patient I's housekeeper (patient L) was
already symptomatic. She returned to Buenos Aires by car with patients H,
J, and their daughter (patient M). Symptoms developed in the latter three
occupants of the car 11, 15, and 29 days, respectively, after the drive
back to Buenos Aires. No evidence of rodent infestation was found when the
car was examined 3 weeks later. Although patients H and J had stayed at the
home of patient I for several nights, patient M had not been to El Bolsn
in the preceding months, traveling only as far as Jacobacci (~250 miles
from El Bolsn) for patient B's funeral.

A second group of HPS cases occurred in Bariloche. Four people who had
visited or worked in the hospital to which many of the El Bolsn patients
were transferred (a modern 40-bed facility with a three-bed intensive care
unit) contracted HPS: the hospital's night receptionist (patient N), a
40-year-old woman (patient O) who visited an unrelated patient, a
27-year-old man (patient P), and his wife (patient Q). Patients P and Q
developed a close relationship with patient N during their many visits to
the hospital between September 20 (when their 27-week-gestation baby was
born) and October 27 (when the baby died). The three shared mate (a local
tea drunk through a communal metal straw), and patient P occasionally
rested on patient N's camp bed. The baby got abdominal distention and shock
37 days after birth. The clinical signs suggested necrotizing
enterocolitis, but no serum or tissue specimens from the infant were
available for definitive diagnosis.

The remaining three HPS patients in El Bolsn during this period were men
aged 44 (patient G), 29 (patient R), and 14 (patient T) years. Patients G
and T were friends or acquaintances of one or more of the HPS patients, but
did not recall contact with an HPS patient in the 6 weeks before the onset
of their symptoms.

Both patients R and U likely had coincidental sporadic cases of HPS.
Patient R lived in the Chilean mountains and had prodromal symptoms of HPS
on arrival in El Bolsn. Patient U, a 33-year-old man living and working in
Futalaufqun National Park, Chubut Province (150 km south of El Bolsn),
also contracted HPS during this period but is unlikely to have had contact
with HPS patients in El Bolsn.

Overall, 11 (55%) of the 20 patients were male, the mean age was 38 years
(range 13-70 years), and the case-fatality rate was 50%. The death rate
among cases for which epidemiologic links were identified (Figure 1) was
lower during the latter stage of the outbreak (three of nine patients with
onset of symptoms in November-December died compared with six of seven
patients with onset of symptoms in October). The clinical picture was
similar to that of HPS in the United States, although several atypical
features, such as conjunctival injection and head and neck suffusion, were
noted. Coughing did not occur earlier or more frequently in Argentinean HPS
patients than in U.S. patients, which suggests that coughing was not the
critical factor in person-to-person transmission.

Early in the investigation of this outbreak, attention was focused on the
index patient's brick house, one of several dwellings located on a
semirural property on the outskirts of El Bolsn. Several weeks before
patient I became sick, he and patients B and L moved from a wooden cabin
into the brick house. Two doctors (patients A and F) made visits to this
house, and patients H and J stayed there at least one night during November
1996. The 13 other HPS patients in the outbreak did not visit the house.
One month after the onset of patient I's symptoms, an examination of the
brick house and other nearby structures found the buildings to be well
constructed with no obvious sites for rodent entry and no evidence of
rodent infestation (as confirmed by trapping studies). Trapping in and
around the homesites of the El Bolsn and Bariloche patients yielded few
rodents. Trap success (i.e., the number of rodents captured per 100 trap
nights) in neighboring areas of disturbed or natural vegetation indicated a
low rodent population density. Identification and serologic testing of
captured rodents are under way. The low trap success rate contrasted with
that of the 1993 HPS outbreak in the southwestern United States, when
rodents were plentiful overall and significantly more numerous in and
around homes of patients than in and around homes of controls (8).

The probable transmission of hantavirus from patient C to her doctor
(Patient D) is the best epidemiologic evidence available to support the
hypothesis that person-to-person transmission of hantavirus occurred during
this outbreak. When considered separately, links between other Argentinean
HPS patients are less convincing. However, when the contacts between
patients are viewed collectively, the probability that person-to-person
transmission played a major role in this outbreak strengthens. A comparison
of the relative success of rodent trapping efforts over the last 20 years
indicated that rodent population densities in the general area of the
outbreak during the spring of 1996 were lower than average (Pearson O,
pers. comm. 1996), adding further support for the hypothesis of
person-to-person transmission. It is highly unlikely that the low rodent
population density observed was the result of a precipitous decline in
rodent populations in late spring. Rodent populations in northwest
Patagonia are at minimal levels in the early spring and represent only
animals that have survived the winter. Renewed reproduction increases
population density throughout the spring (Guthmann N, pers. comm. 1997), as
was corroborated by the high percentage of immature animals captured during
trapping. Thus the rodent population density during our trapping in late
spring is likely to have been higher than density when the outbreak began.

The unique pattern of person-to-person transmission in this outbreak has
not been a feature of hantavirus epidemiology; in fact, a study performed
in New Mexico in 1993 found no disease or hantavirus antibodies in serum
specimens taken from 396 health care workers, including 266 who had been
exposed to patients with HPS or their body fluids 2 to 6 weeks earlier (9).
The high case-fatality ratio has precluded a detailed description of the
exact nature of contact between cases. Consequently, the likely mode of
transmissionwhether through direct contact, droplets, infectious aerosols,
or contaminated fomitesis not known. Because hantaviruses are difficult to
isolate and cultivate, few attempts have been made to study virus excretion
from patients or to assess viral stability under different environmental
conditions. Efforts to define the infectious stage of the disease and the
type and duration of contact that may have led to transmission are
continuing. Genetic sequences of viruses from patients and rodents are
being determined to define more clearly the pattern of transmission. In the
absence of any clear-cut evidence for nosocomial transmission of Sin Nombre
or related viruses in the United States, it is premature to suggest
changing the existing guidelines for care of HPS patients. The level of
suspicion should be raised to investigate any suspected person-to-person
spread of this rodent-borne zoonosis, however. Further epidemiologic and
laboratory studies are needed to clarify the requirements for protecting
both healthcare workers and others from hantaviral infections in Patagonia.

Rachel M. Wells,* Sergio Sosa Estani, Zaida E. Yadon, Delia Enria, Paula
Padula, Noemi Pini, James N. Mills,* Clarence J. Peters,* Elsa L.
Segura, and the Hantavirus Pulmonary Syndrome Study Group for Patagonia
*Centers For Disease Control and Prevention, Atlanta, Georgia, USA;
Instituto Nacional de Chagas "Dr. Mario Fatala Chaben," Buenos Aires,
Argentina; Administracin Nacional de Laboratorios e Institutos de Salud,
Buenos Aires, Argentina; Instituto Nacional de Enfermedades Virales
Humanas "Dr. Julio I. Maiztegui," Buenos Aires, Argentina

N. Guthmann, Centro Regional Universitario Bariloche; E. Argelo, F.
Klein, R. Levy, C. Nagel, Fundacin Favorolo; R. Calfin, F. de Rosas, M.
Lazaro, M. Rosales, P. Sandoval, Hospital Bariloche; L.A. Albornoz, R. L.
Antonia, J. C. Becerra, W.H. Benitez, A. Broide, C. Flandes, A. Honik, J.
Meza, L. Paganini, A. Resa, G. Roberts, P. Rodriguez, I.E. Rojo, G. Suppo,
A. Werenicz, S. Wisky, Hospital El Bolson; H. Quiroga, Hospital El Hoyo;
C.A. Cohen Arazi, L. Bogni, R. Lombardelli, B. Salvagno, C. Simeone,
Hospital Esquel; L. Clara, Hospital Italiano de la Ciudad de Buenos Aires;
M. del Castillo, Hospital Nacional de Clnicas "Jos de San Martn"; J.L.
Becker, H. Lopez, M. Palmigiani, Instituto Nacional de Enfermedades Virales
Humanas "Dr. Julio I. Maiztegui"; M. Ameztoy, A. Lawrynowicz, Instituto
Nacional de Epidemiologa "Dr. Juan H. Lara"; A. Edelstein, Instituto
Nacional de Microbiologa "Dr. Carlos Malbran"; A. Aguilera, V.O. Vigil,
Instituto Nacional de Parasitologa "Dr. Mario Fatala Chaben"; R. Chuit, C.
Riva Posse, Ministerio de Salud y Accin Social; C. Barclay, L. Caride, E.
De Orta, M. Furque, A. Picone, L. Samengo, Sanatorio San Carlos; R.
Fernandez, R. Gonzales, Sistema Provincial de Salud, Esquel; O. Arellano,
G. Cantoni, E. Larrieu, J. Vilosio, Sistema Provincial de Salud, PCIA de
Ro Negro; K. Busico, A. Khan, T.G. Ksiazek, W. Terry, J. Young, S. Zaki,
Centers for Disease Control and Prevention

References

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     identification of a new hantavirus causing severe pulmonary syndrome
     in Argentina. Virology 1996;220:223-6.
  2. Nichol ST, Spiropoulou CF, Morzunov S, Rollin P, Ksiazek TG, Feldmann
     H, et al. Genetic identification of a hantavirus associated with an
     outbreak of acute respiratory illness. Science 1993;262:914-7
  3. Khan A, Khabbaz RF, Armstrong L, Holman RC, Bauer SP, Graber J, et al.
     Hantavirus pulmonary syndrome: the first 100 cases. J Infect Dis
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  4. McKee KT, LeDuc JW, Peters CJ. Hantaviruses. In: Belshe R, editor.
     Textbook of human virology, 2nd edition. St. Louis: Mosby Year Book,
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  5. Enria D, Padula P, Segura EL, Pini N, Edelstein A, Riva Posse C, et
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  6. Parisi M, Enria D, Pini NC, Sabatini MS. Deteccin retrospectiva de
     infecciones clnicas por hantavirus en la Argentina. Medicina (B
     Aires) 1995;56:1-13.
  7. Ksiazek TG, Peters CJ, Rollin PE, Zaki S, Nichol S, Spiropoulou C, et
     al. Identification of a new North American hantavirus that causes
     acute pulmonary insufficiency. Am J Trop Med Hyg 1995;52:1017-23.
  8. Childs JE, Krebs JW, Ksiazek TG, Maupin GO, Gage KL, Rollin PE , et
     al. A household-based, case-control study of environmental factors
     associated with hantavirus pulmonary syndrome in the southwestern
     United States. Am J Trop Med Hyg 1995;52:393-7.
  9. Vitek CR, Breiman RF, Ksiazek TG, Rollin PE, McLaughin JC, Umland ET,
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Emerging Infectious Diseases
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Atlanta, GA

URL: ftp://ftp.cdc.gov/pub/EID/vol3no2/ascii/vol3no2/wells.txt