[Emerging Infectious Diseases * Volume 4 * Number 1 * January - March 1998]
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Dispatches
Hantavirus Infection in Children in Argentina
Noem C. Pini,* Amanda Resa, Gladys del Jess Laime, Gustavo Lecot,
Thomas G. Ksiazek, Silvana Levis,* and Delia A. Enria*
*Instituto Nacional de Enfermedades Virales Humanas "Dr. Julio I
Maiztegui," Pergamino, Argentina; Hospital de El Bolsn, Ro Negro,
Argentina; Hospital de Orn, Salta, Argentina; Hospital de Olavarra,
Buenos Aires, Argentina; and Centers for Disease Control and Prevention,
Atlanta, Georgia, USA
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Text Version
      Clinical hantavirus infection was diagnosed in five Argentine
      children ages 5 to 11 years by immunoglobulin M (IgM)- capture
      enzyme-linked immunosorbent assay using Sin Nombre virus (SNV)
      antigens. Death in three of the children was associated with
      absence of detectable IgG to SNV antigens. An additional two
      cases in healthy children were studied: one, a breast-fed
      15-month-old whose mother died of suspected hantavirus
      pulmonary syndrome (HPS) 8 months previously, had hantavirus
      IgG(>/= 1:6400); a second, whose mother survived HPS during month
      three of pregnancy, apparently had maternal antibodies no
      longer detectable 1 year after birth.
In May 1993, a new hantaviral illness, hantavirus pulmonary syndrome (HPS),
was recognized in the southwestern region of the United States (1). HPS is
a viral zoonosis characterized by a febrile prodrome in young, healthy
adults; the disease progresses to respiratory failure with the clinical
picture of adult respiratory distress syndrome (ARDS). The striking
pulmonary involvement differentiates HPS from a previously described
hantaviral disease known as hemorrhagic fever with renal syndrome.
In the first 100 HPS cases in the United States, the average age was 34.9
years (range 11 to 69); eight cases were in children or adolescents under
16 years of age (2). In Argentina, from 1987 to July 1997, 114 cases were
diagnosed in three areas of the country where several strains of new world
hantaviruses are known to cause HPS diseases (3,4). Before 1995, no cases
were detected in Argentine children under 12 years of age. Ten cases were
reported among adolescents (13 to 19 years) with a case-fatality rate of
30% (Instituto Nacional de Enfermedades Virales Humanas, [INEVH], unpub.
data).
The initial case definition referred to ARDS and included adults and young
adults (5) as the affected population. The lack of HPS cases among children
in the original outbreaks led to a circulating hypothesis that children
were not at risk or were at a very low risk for HPS. Another hypothesis was
that children were protected from pulmonary involvement, perhaps by immune
system immaturity or a lack of other risk factors (such as cigarette
smoking) for lung injury.
In this report we describe five cases in children; in all of them the
etiologic diagnosis was established by the presence of immunoglobulin M
(IgM) antibody to Sin Nombre virus (SNV) antigens. Serologic results for
two of the children were also positive for SNV IgG antibody. Serum samples
were tested for IgM and IgG antibodies to SNV by enzyme-linked
immunosorbent assay (ELISA) (6). An ELISA titer greater than or equal to
1:400 was considered positive (Table 1)
Table 1. Hantavirus infection in children, Argentina, 1995-1997
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                                          Serology(supa)
                                             Date
                                Date of      IgM
   Case       Sex    Age (yrs)   onset       IgG       Area(supb) Outcome
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     1         M         9      4-19-95     5-3-95     South       Alive
                                            >6400
                                             1600
     2         F         5      3-21-97    3-23-97     North       Dead
                                            >6400
                                             Neg
     3         M         9      3-30-97    4-23-97     North       Alive
                                             1600
                                             400
     4         F        11      4-14-97    4-16-97     North       Dead
                                             1600
                                             Neg
     5         M         5      4-27-97    4-28-97    Central      Dead
                                             1600
                                             Neg
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(supa)Titer expressed as the reciprocal of the serum dilution reactive in
enzyme-linked  immunosorbent assay.
(supb)Area of origin in Argentina.
Patient 1 was identified during the study of the first outbreak in southern
Argentina in 1995 (5). Four patients in this outbreak were from the same
family. During interviews of the family members, we found that a 9-year-old
boy had a febrile disease without respiratory involvement, beginning on
April 19. Serology performed on May 3, 14 days after the onset of symptoms,
demonstrated IgM and IgG antibodies to SNV antigens.
The other four cases in children were identified during routine
surveillance. From 1995 to 1997, samples from 25 children (ages 3 months to
12 years; mean = 5.8 years) were sent to INEVH for diagnosis. Table 2
summarizes the main clinical and laboratory findings. None of the children
had renal failure; patient 2 had uremia of 0.30 g/l, and patient 4 had a
serum creatinine level of 1.40 g/l. All patients who later died received
supplemental oxygen as part of their treatment.
Two special situations involving children arose during the study of the
first cases of HPS in El Bolsn in 1995. 1) A woman belonging to the family
of patient 1 contracted HPS during the first quarter of pregnancy. She had
a febrile syndrome, without respiratory failure; chest X-rays showed
bilateral interstitial infiltrates. Serologic tests showed both SNV IgM
(>/=1:6400) and IgG (>/=:6400) on April 22, 1995, 8 days after the onset of
symptoms. She delivered a healthy infant in October 1995. A sample of the
newborn's cord blood was positive for SNV IgG (>/=1:6400) and negative for
SNV IgM. A serum sample drawn from the mother at the same time had a SNV
IgG titer >/=1:6400 and was negative for SNV IgM. A second serum sample,
taken from the baby a year later during November 1996, had no detectable
SNV IgG or IgM. 2) During a retrospective search for cases fulfilling the
HPS case definition, a woman who died of ARDS in September 1994 was
considered to have a possible case. No serum samples or autopsy tissues
were available to make an etiologic diagnosis. Before dying, this woman
breast-fed a 7-month-old baby; when tested for antibodies 8 months later in
May 1995 at 15 months of age, the baby had SNV IgG >/=1:6400) and no
detectable SNV IgM antibodies. A second serologic sample, collected 18
months later in November 1996, still had SNV IgG antibodies, with a similar
titer. Both babies have continued to develop normally as of October 1997.
Table 2. Laboratory results and clinical features of children with
hantavirus infection, Argentina, 1995-1997
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                                         Case
Tests and    --------------------------------------------------------------
features          1        2         3             4               5
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Leukocytes     9,200    27,000     12,800        10,600          69,200
[/mm(sup3)]
Hematocrit       44      66          43            55              53
(%)
Thrombocytes    ND(supa)266,000    200,000       97,000            ND
[/mm(sup3)]
Sedimentation   ND        4         28             8               1
rate (mm/hr)
GOT/GPT(supb)   ND    Increased   Increased     Increased      Increased
                                                                (mild)
Chest X-ray   HI(supc) DII(supd)    DII           DII            DII
Respiratory    None    Distress    Slight      Tachypnea,        Acute
symptoms                          dyspnea     clinical and    respiratory
                                                 X-ray       insufficiency
                                             disassociation,
                                             hypoventilation
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(supa)ND: Not done.
(supb)GOT/GPT: Glutamic oxalacetic transaminase/Glutamic pyruvic transaminase.
(supc)HI: Hilar indistinctness.
(supd)DII: Diffuse interstitial infiltrate.
A case similar to that of patient 1 was detected in New Mexico in June 1993
(7) in the course of the investigation of a fatal HPS case. In this case,
the patient also had a mild clinical course that did not meet the
surveillance case definition for HPS. This case definition (revised 9/96)
is as follows: "a febrile illness characterized by bilateral diffuse
interstitial edema that may radiographically resemble ARDS, with
respiratory compromise requiring supplemental oxygen, developing within 72
hours of hospitalization, and occurring in a previously healthy person; or
an unexplained respiratory illness resulting in death, with an autopsy
examination demonstrating noncardiogenic pulmonary edema without an
identifiable cause" (8).
Our remaining four cases were sporadic, in persons without previous contact
with other HPS patients, and were suspected because their clinical symptoms
were typical of HPS. Results of serologic testing with SNV antigens of the
household contacts in cases 2 and 5 (five persons each) were negative. The
clinical, radiologic, and laboratory findings were similar in children and
in adults; severely ill patients had greater variation in laboratory values
than mild cases, and in fatal cases, only SNV IgM was present.
The case-fatality rate in this series was 60%, but the small number of
cases does not permit conclusions. In previously reported cases in
adolescents 13 to 19 years of age, the case-fatality rate was 30%.
These cases originated in the three areas where the illness is endemic in
Argentina. This is an important point because an unusual case of HPS in
southern Argentina, with the possibility of person-to-person transmission,
had been reported (9,10). Patient 1 and the baby that was breast-feeding
when the mother died of suspected HPS could be further instances of
person-to-person transmission.
A case of hemorrhagic fever with renal syndrome and pregnancy was reported
in 1992 (11); the dynamics of serum antibody persistence were similar to
those found in the one instance where we believe antibody was passively
transferred from mother to baby. These results indicate that HPS should be
considered in the differential diagnosis of respiratory distress or
atypical bilateral pneumonia in children, at least in areas where these
diseases have been confirmed. Mild disease should be considered too,
especially in contacts of HPS patients and in younger age groups.
Our findings also suggest the transfer of passive antibodies from mother to
fetus (without fetal infection) and the possibility of transmission of
infection by maternal breast feeding.
References
  1. Centers for Disease Control and Prevention. Outbreak of acute illness:
     southwestern United States, 1993. MMWR Morb Mortal Wkly Rep
     1993;42:421-4.
  2. Khan AS, Khabbaz RF, Armstrong LR, Holman RC, Bauer SP, Graber J, et
     al. Hantavirus pulmonary syndrome: the first 100 US Cases. J Infect
     Dis 1996;173:1297-303.
  3. Parisi MN, Enria DA, Pini NC, Sabattini M. Deteccin retrospectiva de
     infecciones clnicas por hantavirus en la Argentina. Medicina (B
     Aires) 1996;56:1-13.
  4. Levis SC, Briggiler AM, Cacase M, Peters CJ, Ksiazek TG, Corts J, et
     al. Emergence of hantavirus pulmonary syndrome in Argentina
     [abstract]. Am J Trop Med Hyg 1995;53:233.
  5. Hughes JM, Peters CJ, Cohen ML, Mahy BWJ. Hantavirus pulmonary
     syndrome: an emerging infectious disease. Science 1993;262:850-1.
  6. 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;52:117-23.
  7. Armstrong LR, Bryan RT, Sarisky J, Khan AS, Rowe T, Ettestad PJ, et
     al. Mild hantavirus disease caused by Sin Nombre virus in a
     four-year-old-child. Pediatr Infect Dis J 1995;12:1108-10.
  8. Centers for Disease Control and Prevention. Case definitions for
     infectious conditions under public health surveillance. MMWR Morb
     Mortal Wkly Rep 1997;46:16.
  9. Enria D, Padula P, Segura EL, Pini N, Edelstein A, Riva Posse C,
     Weissenbacher MC. Hantavirus pulmonary syndrome in Argentina.
     Possibility of person-to-person transmission. Medicina (B Aires)
     1996;56:709-11.
 10. Wells RM, Sosa Estani S, Yadon ZE, Enria DA, Padula P, Pini N, et al.
     An unusual hantavirus outbreak in southern Argentina: person-to-person
     transmission? Emerg Infect Dis 1997;2:171-4.
 11. Silberberg L, Rollin PE, Keourani G, Courdrier D. Haemorrhagic fever
     with renal syndrome and pregnancy: a case report. Trans R Soc Trop Med
     Hyg 1993;87:65.
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