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Dispatch
Respiratory Tract Reinfections
by the New Human Metapneumovirus in an Immunocompromised Child
Gilles Pelletier,* Pierre Déry,* Yacine Abed,* and Guy Boivin*
*Centre Hospitalier Universitaire de Québec and Laval University,
Québec City, Québec, Canada
Suggested citation for this article: Pelletier G, Déry
P, Abed Y, Boivin G. Respiratory tract reinfections by the new human
Metapneumovirus in an immunocompromised child. Emerg Infect Dis
[serial online] 2002 Sep [date cited];8. Available from: URL:
http://www.cdc.gov/ncidod/EID/vol8no9/02-0238.htm
The human Metapneumovirus
(HMPV), a new member of the Paramyxoviridae family, has been
recently associated with respiratory tract infections in young children.
We report the case of a young, immunocompromised child who had severe
lower respiratory tract infections during two consecutive winter seasons
caused by genetically distinct HMPV strains.
A variety of viruses—such as the influenza viruses A and B, the Human
respiratory syncytial virus (HRSV), the parainfluenza viruses, and
the adenoviruses—cause seasonal respiratory tract infections in young
children. Symptoms range from influenzalike illnesses to lower respiratory
tract syndromes, such as bronchiolitis, croup, and pneumonitis (1–4).
These viruses may also cause severe respiratory infections in immunocompromised
patients (1,4). However, the cause of many cases of bronchiolitis
and pneumonitis remains unknown despite the extensive use of sensitive
diagnostic techniques.
The human metapneumovirus (HMPV) has been recently classified as a new
member of the Paramyxoviridae family based on nucleic acid sequence,
gene organization, and electron microscopy findings (5–7).
This virus has been reported to cause respiratory tract infections in
children <5 years of age from the Netherlands (5),
as well as in elderly patients from North America (7).
We describe a case of recurrent HMPV respiratory tract infections, associated
with genetically distinct viral strains, in an immunocompromised child.
Case Report
A 7-month-old girl, who had acute lymphoblastic leukemia with meningeal
involvement (treated with intravenous vincristine and doxorubicin, as
well as intrathecal methotrexate), was brought to the hospital on March
23, 1998, for recent onset of nasal congestion and nonproductive cough.
Her medical history showed that she had recent contact with family members
who had a common cold. On initial physical examination, her temperature
was 38.9°C with a respiratory rate of 40 per min, with no rales at lung
auscultation. Initial laboratory tests showed a leukocyte count of 1,800
X 109 cells/L with 25% neutrophils and 3% band forms. The child
was hospitalized and treated empirically with intravenous ceftazidime.
Urine and blood cultures were negative for bacterial pathogens. The patient
rapidly improved and was discharged from the hospital on day 3 after admission;
no antibiotics were given, and the presumptive diagnosis was viral upper
respiratory tract infection. The next day, the patient was brought to
the same hospital for an exacerbation of coughing and sneezing. On physical
examination, she had a temperature of 38.5°C, with bilateral wheezing
at lung auscultation. The respiratory rate was 36 per min, and a clear
nasal discharge was noted. The leukocyte count was 1,600 x 109
cells/L, with 33% neutrophils and 0% band forms. Blood was drawn for cultures,
and a nasopharyngeal aspirate (NPA) sample was obtained for HRSV antigenic
testing (Test Pack, Abbott Laboratories, Abbott Park, IL) and viral culture
on Madin Darby Kidney cells (MDKC), tertiary monkey kidney cells (LLC-MK2),
Hep-2, human foreskin fibroblast, Vero, Mink lung, human lung adenocarcinoma
(A-549), human rhabdomyosarcoma (RD), transformed human kidney 293, and
human colon adenocarcinoma (HT-29) cells. The patient was again treated
empirically with intravenous ceftazidime. Three days after admission her
condition had improved, and she was discharged from the hospital. The
final diagnosis was bronchiolitis, and antibiotics were not given. Bacterial
blood cultures and the rapid antigenic test for HRSV were negative. However,
after 17 days of incubation, the viral culture from the NPA showed a nonhemagglutinating
virus (isolate 1) growing in LLC-MK2 cells. Immunofluorescence assays
with antibodies against common respiratory pathogens (influenza viruses
A and B, HRSV, adenoviruses, and parainfluenza viruses 1–4) were all negative.
The next year, on January 18, 1999, during a scheduled medical appointment
for administration of intravenous (daunorubicin and vincristine) and intrathecal
(methotrexate, cytarabine, and hydroxyurea) chemotherapy in addition to
oral dexamethasone, the now 17-month-old girl again had nasal congestion
and nonproductive cough. Her father mentioned that he had an upper respiratory
tract infection 2 weeks earlier. An NPA sample was obtained for viral
culture and HRSV antigenic detection. The patient did not appear ill and
was allowed to go home the same day after chemotherapy. The HRSV antigenic
test came back negative, but the viral culture showed an unidentified
cytopathic effect only apparent in LLC-MK2 cells after 14 days of incubation
(isolate 2). Immunofluorescence assays were again negative for all common
respiratory viruses. The patient received another course of intravenous
chemotherapy (daunorubicin and vincristine) on January 25 at the outpatient
clinic, and her upper respiratory tract symptoms were then treated with
an oral antibiotic (axetil cefuroxime).
Five days later, on January 30, 1999, the child was admitted to the hospital
with a fever (39.9°C), persistent dry cough, and clear nasal discharge
while on oral antibiotic. On physical examination, her respiratory rate
was 28 per min with fine bilateral crackles at lung auscultation. An otoscopic
exam showed bilateral otitis. The leukocyte count showed neutropenia (0.400
x 109 cells/L), and ceftazidime plus vancomycin were initiated.
The blood cultures taken on the first day of hospitalization indicated
a coagulase-negative staphylococcus (1 of 2 bottles were positive). On
the fourth day of hospitalization, the patient’s clinical condition deteriorated
with desaturation (pO2, 0.88) and tachypnea (respiratory rate,
60–70 per min). A chest x-ray showed bilateral infiltrates compatible
with pneumonitis. The next day, an NPA sample was obtained for a viral
culture and direct immunofluorescent assays against typical respiratory
viruses. The results were negative. Intravenous erythromycin was administered
for empirical coverage of atypical pathogens. On day 10 of hospitalization,
the patient was transferred to the pediatric intensive-care unit and was
intubated. A bronchoscopy was performed, and a bronchoalveolar lavage
(BAL) sample was obtained for cultures of fungal, mycobacterial, viral,
and bacterial pathogens, as well as for specific staining procedures for
Pneumocystis carinii, fungi, bacteria, and mycobacteria. At that
point, ceftazidime was replaced by trimethoprim/sulfamethoxazole, and
an amphotericin B lipidic complex formulation (Abelcet, Liposome, Canada)
was added. All cultures and specific staining procedures performed with
the BAL sample were negative. Direct immunofluorescence assays on the
BAL sample also were negative for influenza A and B, parainfluenza 1–4,
and HRSV. On day 13 of hospitalization, the patient’s respiratory signs
deteriorated markedly, with bilateral pulmonary infiltrates compatible
with acute respiratory distress syndrome. Four days later, because of
free air in the pericardium and peritoneum (the patient was on high ventilatory
pressure), drainage tubes were placed, resulting in a temporary improvement
of pulmonary gas exchange. New blood cultures drawn on day 27 were negative.
The next day, shock developed, and vasopressive drugs were started. Because
of her irreversible condition, all treatment was stopped on day 30, and
the patient died shortly thereafter. No autopsy was performed.
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Click to view
enlarged image
Figure.
Comparison of the partial amino acid sequences of Human Metapneumovirus
(HMPV) isolates 1 (recovered in 1998) and 2 (recovered in 1999)
for the fusion protein (residues 1 to 253)....
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Two years after the child’s death, reverse transcription-polymerase chain
reaction assays for HMPV with infected LLC-MK2 cell culture supernatants
of the two unidentified isolates were performed and found to be positive.
On the basis of partial published sequences, a set of primers was designed
for amplification of the F gene of HMPV (5,7). The forward
primer sequence was 5´-ATGTCTTGGAAAGTGGTG-3´, and the reverse primer sequence
was 5´-TCTTCTTACCATTGCAC-3´. Amplified products were sequenced by an automated
DNA sequencer (ABI 377A [Perkin-Elmer Applied Biosystems, Foster City,
CA]) and the 759-bp nucleotide sequences of the two viral isolates from
consecutive seasons were aligned with the Clustal W software (8).
The two viral isolates differed by 114 nt in the F gene sequence, which
resulted in a change of 10 amino acids (Figure).
Conclusions
We describe the case of a young immunocompromised child who had respiratory
tract infections during two consecutive seasons, probably due to HMPV,
a newly discovered paramyxovirus. On the basis of sequence analysis of
the viral F gene, we found that the child was infected by two genetically
distinct HMPV strains.
In the first clinical episode (occurring at the age of 7 months), the
initial symptoms resembled a common cold and progressed to bronchiolitis,
followed by a complete resolution of symptoms within a few days. HMPV
was the only organism isolated in culture from an NPA sample, and the
HRSV rapid antigenic test was negative. Ten months later, the child had
a second respiratory tract infection, again with common cold symptoms.
HMPV was again the sole pathogen isolated in an NPA sample. In the next
weeks, however, the patient’s clinical condition deteriorated, with development
of bilateral pneumonitis and respiratory failure and ultimately death.
The BAL sample obtained showed no bacterial, viral, or fungal pathogens
by culture, antigenic testing, or special staining procedures. The exact
cause of respiratory failure in this immunocompromised child remains uncertain,
because autopsy was not performed. An opportunistic infection or a neoplastic
infiltrate was the most probable cause. HMPV could have led to the acute
respiratory distress syndrome in this immunocompromised patient. We suggest
that the initial upper respiratory tract infection may have progressed
to pneumonitis after the patient received intensive chemotherapy. The
fact that HMPV was not recovered in the last BAL sample does not rule
out such viral infection since paramyxoviruses are very labile (1),
and the culture may not have been incubated long enough for a cytopathic
effect to be observed.
The two HMPV isolates from this study had many differences at the nucleotide
level (similarity 85.0%) but much less at the amino acid level (similarity
96.0%) in the gene coding for the fusion (F) protein. Isolate 2, recovered
in 1999, had greater amino acid similarity with the prototype sequence
from the Netherlands (5) compared with isolate 1 (98.0%
vs. 96.0% similarity). Furthermore, the two strains seem to belong to
the two different HMPV lineages previously reported by Dutch and North
American groups (5,7). We suggest that many HMPV strains
may cocirculate in a specific population, and such viral diversity, coupled
with waning immunity, as found in elderly and immunocompromised patients,
may lead to multiple reinfections similar to HRSV (2,9–12).
Future studies are needed to evaluate the full clinical spectrum associated
with HMPV infection, the groups at risk for severe complications, and
the potential therapeutic options. Our data suggest that HMPV should be
added to the list of pathogens associated with severe respiratory tract
infections in immunocompromised patients.
Dr. Pelletier is a postdoctoral fellow in infectious diseases at Laval
University. His research interests include the molecular detection and
epidemiology of respiratory viruses.
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