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“VIRAL INFECTIONS AND CHILDHOOD HEMATOLOGICAL
MALIGNACIES ”
Dr. Regkli Areti, Kalargyroy K.,
Mallis Panayiotis., Gerontara G.,Kyriazi V., Matsis K. and Panagoula Kollia
Abstract
Viral infections in
hematological malignancies play significant role in the pathogenesis of diseases and have been of continued interest. An important
number of molecular studies have tried
to establish a pathogenetic role for viral infections in lymphoid malignancies.
Also there is strong correlation between HHV-6, EBV and HCV infections in
childhood hematological malignancies but the results from molecular studies
remain controversial. In particular, HHV-6 is increasingly recognized as an
important opportunistic pathogen and its reactivation is common among
recipients of allogenic stem cell transplantation, linked to various clinical
manifestetions. Infections with EBV is widespread and affect at important grade
patients with primary immunodeficiency diseases. Also hepatitis C virus
infection plays a significant role in the etiology of liver disease in patients
treated for childhood leukemia. The recent availability of serologic tests for
detection of antibodies to HCV permits a reappraisal of the diagnosis of HCV
infection in these patients. In this review we try to demonstrate the links
between viral infections in development and during the treatment of childhood
hematological and lymphoprliferative diseases.
Key words:Viral infections,
childhood hematological malignancies, immunodefiency, EBV, HHV-6
Introduction
Epstein-Barr
Virus (EBV)
In 1958 Dennis Burkitt
described a lymphoma that represented the most common tumor affecting children
in certain parts of
Immunodificiency
patients and lymphomas
Patients with primary
immunodeficiency diseases such as X-linked lymphoproliferative syndrome (XLP)
and Wiscott-Aldrich syndrome are at increased risk of developing EBV-associated
B cell lymphomas1. Because these tumors are extremely rare little is
known of their association with EBV infection. Mortality from XLP is high with
around 50% of patients developing fatal IM after primary infection with EBV and
an additional 30% of patients developing malignant lymphoma. Allograft recipients
receiving immunosuppressive therapy and patients receiving immunosuppressive
therapy with AIDS are also at increased risk for development
lymphoproliferative-lymphomas. The incidence of B cell lymphomas in allograft
recipients varies with the type of organ transplanted and with the type of
immunosuppressive regimen used. Allogenic bone marrow transplantation into EBV
seronegative children is particular risk factor for the development of virus
associated B cells lymphomas1. The incidence of non-Hodgin lymphoma
in AIDS patients is increased approxiamately 60 fold compared to the normal
population. Around 60% of these tumors are large-cell lymphomas like those
found in allograft recipients, 20% are primary brain lymphomas and 20% are of
the BL type. Recent studies have demonstrated that 50% of AIDS lymphomas are
EBV-positive and that this association varies with the histological tumor type.
Thus, only 38% of the BL tumors are EBV-positive compared with 65% of the
large-cell lymphomas.
T
cell lymphomas
Recent studies have
demonstrated EBV infection in a considerable proportion of T cell non-Hodgkin’s
lymphomas. Nasal T cell lymphomas, a tumor which is more common in the
Hodgkin’s
disease
Epidemiological studies
originally suggested a possible role for EBV in the etiology of Hodgkin;s
disease (HD). Thus, elevated antibody titers with HD and these increased
antibody levels are present before the diagnosis of disease. Furthermore, there
is an increased risk of HD following IM. EBV has been demonstrated in around
50% of HD cases with both viral nucleic acid (DNA/RNA) and virus latent
antigens localized to the malignant component of HD, the Reed-Sternberg cells and their
variants2. The association of HD with EBV is age-related, pediatric
and older adult cases are usually EBV-associated whereas HD in young adults is less frequently virus-positive. The
proportion of EBV-positive HD in developing countries is high consistent with a
greater incidence of HD in children and more frequent prevalence of the mixed
cellularity histiotype. Although the incidence of HD is relatively low
(1-3/100000 per year) this tumor is not geographically restricted, making its
association with EBV significant in world health terms.
Human
Herpesvirus 6 (HHV-6)
Human herpesvirus 6 was
isolated in 1986 from the peripheral blood mononuclear cells of 6 patients
affected with various lymphoproliferative disorders. This enveloped virion
contains about 160 kb of linear
double-stranded DNA3, and is now classified as a member of the
Roseolovirus genus in the Betaherpesvirinae subfamily of human herpesviruses.
Type A and type B variants of HHV-6 have been identified, exhibiting different
epidemiological and biological characteristics and disease associations4.
HHV-6 is highly prevalent in the human population, infecting virtually all
children with in the first few years of life5,6. Like the other
herpesviruses HHV-6 is capable of persisting in the host after primary
infection. Under conditions of immunosuppression, HHV-6 can reactive from
latency. Both HHV-6A and HHV-6B replicate most efficiency in vitro in CD4+
T cells7. The host tissue range of HHV-
HHV-6
and Acute Leukemia
Various hypotheses have been
proposed concerning the involvement of infectious mechanism in the development
of acute leukemia. The role of HHV-
HHV-6
and Chromosomal Integration
The unique form of HHV-6
persistence is characterized by integration of the viral DNA sequences into
chromosomes. The incidence of chromosomal integration (CI) for HHV-6 is about
2% in the population of the
Hepatitis
C Virus
Hepatitis C Virus
(HCV) infection plays a significant
role in the etiology of liver disease in patients treated for childhood
leukemia24.The recent availability of serologic tests for the
detection of antibodies to HCV (anti- HCV) permits a reappraisal of the
diagnosis of HCV infection in these patients. However, only limited
information, usually obtained by first-generation enzyme immunoassay (EIA l),
is available on the overall prevalence of anti-HCV among patients cured of
their leukemia25. Retrospective analysis of sera collected from
on-therapy patients recently demonstrated a 19% prevalence of anti-HCV
reactivity26. However, anti-HCV is not an indicator of active
infection. Furthermore, patients receiving immunosuppressive therapy may
develop anti-HCV reactivity only after treatment withdrawal Thus, studies of
HCV prevalence among patients who undergo immunosuppressive therapy should
include those with long-term follow-up, and study methods should be used that
allow direct virus detection.
Maurizio Arico et al 27reported in their
study that over 40% of patients who completed leukemia-directed treatment had
evidence of exposure to HCV, and the majority of these showed ongoing HCV
infection, as assessed by the presence of circulating HCV-RNA. This is in
keeping with a recent study reporting anti-HCV prevalence of 35% in a similar
population tested by EIA 1 at least 2 years after
initiation of treatment28.Approximately one half of these patients
were simultaneously seropositive for anti-HCV and HCV-RNA with evidence of
liver enzyme elevation in 50% of the cases. This group showed biochemical and
virologic features typically observed in children with transfusion-associated
hepatitis C29.
About 10% of the
patients were anti-HCV+ and HCVRNA- and had normal liver enzyme activity. These
patients might have had recovered from HCV infection or might have had low
fluctuating levels of viremia below the limits of detection of the RT-PCR
assay. Approximately one third of HCV-infected patients did not have serologic
evidence of infection. Specificity and reproducibility of the PCR results were
confirmed by follow-up evaluation of nine patients, of whom four were
repeatedly HCV-RNA+. It must be emphasized that HCV-RNA levels may fluctuate
considerably30 as a function of time, thus providing an explanation
for the five patients who were found to be PCR- upon follow-up evaluation.
Indeed, two of them seroconverted to HCV by third generation ELISA. Locasciulli
et al31have reported
delayed appearance of anti-HCV in a population of viremic children who have
been infected early in the course of antileukemic chemotherapy. All patients except
one seroconverted after a median observation period of 10 months after
treatment withdrawal. Indeed, the median follow-up period was not significantly
different from that of our study population. However, in that study, patients were
retrospectively selected for the presence of anti-HCV, and search for HCV-RNA was
not systematically performed. The high number of seronegative infections observed
in our patients is similar to
that reported for HCV-infected
organ transplant recipient or vertically infected newborns.I6 Although this
phenomenon may be related to some extent to a long-term immunosuppressive effect
of antileukemic therapy, it is not easily explainable because immunocompetence should
have been fully restored after treatment withdrawal in the vast majority of our
patients. Chronic hepatitis with defective serologic expression of HBV has been
previously reported in leukemic children24, 32. Moreover, a pattern
of seronegative HCV viremia has been occasionally found in immunocompetent blood donors,I
as well as in nonleukemic children with chronic hepatitis, even though
evaluated with first-generation assay33. All the viremic patients.
except one who lacked anti-HCV, had normal transaminase activity, suggesting
mild or absent liver damage. However, this does not exclude the presence of
chronic liver disease in our patients, because it has been reported that
viremic patients with normal transaminase levels may occasionally have chronic
liver lesions." Our findings
confirm that transaminase determination is inadequate to predict HCV infection,
as has been previously reported in other risk categories. Analysis of HCV
genotypes in our patients showed a relatively low prevalence of type I, whereas
types I and II were equally represented. The proportion of the various genotypes was not significantly different from
other anti-HCV patient groups. However, genotype 11 was more frequently associated
with the absence of biochemical indicators of liver damage, as shown for other
patient categories. The era of treatment was related to the risk of HCV infection in our series. Sixty percent of
the patients treated up to 1984 were HCV+, and the infection rate decreased to
about 29% after the introduction of donor screening for anti-HCV in 1990.
However, two new HCV infections were found after blood transfusion since the
introduction of EIA 2 as a donorscreening test. In view of the recently
reported decline of the transfusion-associated risk of HCV infection,34
it is possible that the very high rate of HCV infection in these patients may
not only depend on clearly documented parenteral exposure but also on other
still unrecognized routes of transmission, possibly favored by associated
conditions such as immunosuppressive therapy.
Conclusion
Viral infections
play significant role in the pathogenesis of disease and especially affect
patients with hematological diseases. HHV-6 is increasingly been recognized as
an opportunistic pathogen rather than a casual pathogen among clinical
hematologists. Particularly in the field of stem cell transplantation, HHV-6 is
now considered as an important pathogen linked to life-threating encephalitis.
On the other hand, the clinical syndrome of HHV-6 reactivation in patients with
hematological malignancies who do not receive allogenic stem cell transplantation
is not well defined. Hepatitis C Virus (HCV) infection plays a significant role in the etiology of liver
disease in patients treated for childhood leukemia. Normal ALT levels did not
exclude the presence of HCV infection in more than half of viremic patients.
Thus, long term prospective studies of HCV infection in children, particularly
in those cured of their leukemia, are mandatory to depict the current incidence
and the natural history of liver disease in these subjects. The indications to
perform liver biopsy in patients with subclinical HCV infection must be
carefully considered, in accordance with current therapeutic options. Also EBV
is a crusial pathogen for limphoproliferative diseases. Recent studies have
demonstrated EBV infection in a considerable proportion of T cell non-Hodgkin’s
lymphomas. Nasal T cell lymphomas, Hodgkin’s disease is inavariably EBV-positive
whereas around 20% of T cell lymphomas arising at other sites
(gastrointestinal, lung, lymph nodes) are associated with EBV. Between
the lines, pathogenetic roles of viral infections in hematological malignancies
have been of continued interest. Many molecular studies have tried to establish
a pathogenetic role of virus in development and during treatment of
hematological malignancies. However whether viruses play role in these
pathologies remains unclear, a positive polymerase chain reaction results may
reflect latent infection or reactivation rather than presence of these viruses.
In this way more studies need to be done for the extraction of sure
conclusions.
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