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CORRESPONDENCE Various infectious agents have been implicated in causing
aplastic anemia (AA), either by direct lytic infection or by inducing a
pathophysiologic host immune response.1 But little
attention has been given to cytomegalovirus (CMV), even though the
myelosuppressive potential of this virus, in vivo as well as in vitro,
is well established.2-6 Undoubtedly, the relatively high
prevalence of this virus has made it an unlikely agent for AA, which is
a very rare disease. But CMV has a broad spectrum of pathogenicities and sites of infection. Mechanisms responsible for this
heterogeneity are not defined but are hypothesized to include both host
and viral differences. Our past studies indicate that genetically distinct strains of CMV,
identified by variations in the gene encoding envelope glycoprotein B
(gB), occur at variable frequencies and can be associated with
different clinical outcomes.5-8 CMV gB types 1 and 2 were
shown to be more frequently associated with survival following marrow
transplantation than were types 3 and 4.7 In a second
study, types 3 and 4 were specifically associated with death due to
persistent neutropenia.5 Given the strong statistical association between CMV gB3/4 with
posttransplantation myelosuppression, we hypothesized that these
strains may also contribute to the pathogenesis of AA and, if so, that
the virus would be detected more frequently in AA marrow than in marrow
from patients with other hematologic diseases and, further, that gB
types 3 and/or 4 would be overrepresented. To test this hypothesis, we measured the incidence of
CMV-infected marrow and the distribution of gB types in AA
patients compared to patients with other hematologic diseases.
Experimental samples consisted of fresh-frozen marrow biopsies obtained
from 100 CMV-seropositive AA patients before transplantation.
Controls consisted of marrow aspirates from 151 CMV-seropositive non-AA patients harvested at day 28 after
allogeneic marrow transplantation. This control population was chosen
because it has an increased risk of CMV exposure, reactivation, and
disease, thereby raising the background of CMV in the control samples
and making our estimate of differences between AA patients and controls
more conservative. Patient groups were similar for gender and ethnic
background but differed in regard to age, with the AA patient group
being much younger. For this reason, the logistic regression
analysis was adjusted for age. CMV genotyping was based on sequence
variations in the gene encoding gB as detected by restriction analysis
of polymerase chain reaction (PCR)-amplified gB DNA.5
Table 1 shows that the frequency
distribution of CMV gB types differs between AA and control patients,
with the control group being comparable to previously reported results.
Results shown in Table 2 indicate that
the odds of possessing CMV in the marrow, particularly gB type 3, are
significantly increased among AA patients. This association, together
with previous reports, makes it reasonable to hypothesize a
role for CMV in the pathogenesis of aplastic anemia in some
patients.
Beverly Torok-Storb, Laura Bolles, Mineo Iwata, Kristine Doney, George E. Sale, Theodore
A. Gooley, and Rainer Storb
References
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