|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 2 (January 15), 1999:
pp. 721-727
Persistence and Clinical Outcome of Hepatitis G Virus Infection
in Pediatric Bone Marrow Transplant Recipients and Children Treated
for Hematological Malignancy
By
Maki Yamada-Osaki,
Ryo Sumazaki,
Masahiro Tsuchida,
Kazutoshi Koike,
Takashi Fukushima, and
Akira Matsui
From the Department of Pediatrics, University of Tsukuba, Tsukuba,
Japan; and the Department of Pediatrics, Ibaraki Children's Hospital,
Ibaraki, Japan.
 |
ABSTRACT |
The natural course and the clinical significance of hepatitis G
virus (HGV) infection were investigated in 106 pediatric patients who
received chemotherapy for hematological malignancy or underwent bone
marrow transplantation (BMT) using HGV-RNA and antibodies to the HGV-E2
protein (anti-E2). HGV markers were detected in 21 patients (19.8%;
HGV-RNA in 19 and anti-E2 in 2). Longitudinal analysis of these
HGV-infected patients showed that 1 had anti-E2 before the initial
blood transfusion, 14 had persistent viremia, and 6 became clear of
circulating HGV-RNA after completion of therapy, although 5 of the 6 HGV-cleared patients never developed anti-E2. Reactivation of HGV
infection during chemotherapy was observed in two anti-E2-positive,
HGV-RNA-negative patients; the reappearance of the same HGV strain was
confirmed by phylogenetic analysis. Among BMT survivors without other
known causes of liver dysfunction, HGV-RNA-positive patients had a
higher peak serum alanine amino transferase (ALT) value
than negative patients. Contrary to previous reports, immunosuppressed
patients can apparently recover from HGV infection without detectable
anti-E2 and some patients who supposedly recovered from HGV infection
can nonetheless suffer exacerbation when subsequently immunosuppressed.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
PATIENTS WITH HEMATOLOGIC malignancies
and bone marrow transplant (BMT) recipients are at high risk for
acquiring blood-borne viruses because of a large number of blood
transfusions.1-3 Furthermore, a severe immunodeficiency in
these patients, caused by the underlying diseases and by intensive
chemotherapy or immunosuppressive therapy, often affects the course of
the viral infection.4,5
Two new blood-borne viruses were recently described, and the viral
isolates were named GB virus C6 and hepatitis G virus
(HGV).7 Sequence analyses of these viruses showed that they
are possibly different genotypes of the same virus8 and
belong to the Flaviviridae family, with a similar genomic
organization to hepatitis C virus (HCV).9 We refer to
this virus simply as HGV throughout this report. HGV is universally prevalent, and the viral RNA has been detected in 1.5% to 2.0% of
volunteer blood donors in the United States7,10 and also in
Japan.11 An increased prevalence of viremia has been
reported for persons with parenteral exposure: more than 40% of
leukemia patients and BMT recipients.3,12 Although HGV has
been associated with transfusion-related or other types of hepatitis,
its clinical relevance and the long-term course of infection remain
largely unresolved.
The recent availability of serologic tests for the detection of
antibodies to the recombinant HGV second envelope protein (anti-E2)
permits us to clarify new aspects of HGV
infection;13,14 longitudinal analysis of patients
with posttransfusion hepatitis showed that the development of anti-E2
was associated with loss of HGV viremia, indicating that serum anti-E2
serves as a marker of recovery from HGV infection.15
Studies detecting both HGV-RNA and anti-E2 should therefore bring
progress in our understanding of the natural course and clinical
significance of HGV infection.
In this report, we analyze HGV-RNA and anti-E2 sequentially in
pediatric BMT recipients and hematological malignancies to make the
following clear: first, the natural course and long-term clinical
outcome of HGV infection in these patients, and second, whether this
virus may contribute to liver dysfunction in survivors who have
undergone BMT and chemotherapy.
| |
MATERIALS AND METHODS |
Patients.
A total of 106 consecutive patients who were treated at two pediatric
hematological departments in Ibaraki prefecture in Japan were included
in the cross-sectional study to assess the prevalence of HGV infection.
They received BMT (42 patients) or were treated with conventional
combined chemotherapy for hematological malignancy (64 patients). There
were 54 boys and 52 girls. Mean age at diagnosis was 5.7 years (range,
6 months to 15 years). Anti-HCV antibody was detected in 14 patients.
Those who had an increased serum alanine amino transferase
(ALT) value for longer than 3 months were also tested with
HCV-RNA, and 11 were positive for HCV-RNA. None was positive for
hepatitis B virus surface (HBs) antigen or human immunodeficiency virus
(HIV) antibody. The study population included 57 cases of acute
lymphoblastic leukemia, 17 of acute myeloid leukemia, 11 of
non-Hodgkin's lymphoma, 6 of severe aplastic anemia, 5 of
neuroblastoma, 3 of other solid tumors, 3 of chronic myeloid leukemia,
2 of Kostman's hereditary neutropenia, and 1 of severe combined
immunodeficiency. Seventeen of these patients were treated with related
allogeneic BMT, 16 with unrelated allogeneic BMT, and 9 with autologous
BMT.
In the longitudinal study to analyze the natural course of HGV
infection, serial serum samples from patients with positive HGV-RNA
and/or anti-E2 antibody in the cross-sectional study were retrospectively collected from frozen samples stored between 1987 and
1997. These stored samples included sera taken from each patient before
treatment, at least twice while on therapy and about once yearly during
the follow-up period. Samples for detection of anti-E2 were obtained at
least 6 months apart from receiving transfusion or Ig preparations to
avoid detection of passively transferred antibodies. The blood obtained
was centrifuged within 4 hours, a part of the serum was examined for
liver function, and another part was frozen and stored at
 80°C until HGV testing. Patients gave consent for samples to
be taken for investigational use.
The ALT value was measured at least twice a week during inpatient stay
and on every hospital visit. Mean ALT values in individual patients
were calculated by averaging the mean of ALT values measured during
each month so as to exclude the influence of frequent measurement of
ALT in those with abnormal liver function tests. To analyze the
participation of HGV infection in liver dysfunction, we reviewed the
medical records to determine the ALT value and other factors such as
ferritin, transfused red blood cell units, and episodes of acute and
chronic graft-versus-host disease (GVHD) and veno-occlusive disease
(VOD). Donor exposures were counted using the total number of
individual units of red blood cells, platelets, and fresh frozen plasma. Patients who had any hepatopathic factor, such as a positive hepatitis virus marker, including HCV antibodies, HCV-RNA, or chronic
GVHD, were excluded from the analysis of liver function studies.
Detection of HGV-RNA.
Methods that detected HGV-RNA were reported elsewhere.16
Briefly, RNA extracted from 125 µL of serum was reverse transcribed and served for nested polymerase chain reaction (PCR) with two sets of
primers corresponding to 5 -noncoding (5NC) and helicase (NS3)
regions of HGV. Primers specific for the 5NC region have been described
by Orito et al17 and those for NS3 by Simons et
al.6 The second-round PCR products were run on 3% SYNERGEL (Diversified Biotech, Boston, MA) and examined for size. The presence of HGV RNA in the tested sample was defined by the positive finding of
PCR products of either the 5NC or NS3 region. The correspondence of the
results by primer sets of 5NC and of NS3 was 98% of all samples.
Phylogenetic analysis.
The E2 region containing 312 bp was amplified from cDNA with primers,
as described by Kao et al.18 Both first and second PCR
included 35 cycles consisting of denaturation for 30 seconds at
94.0°C, annealing for 60 seconds at 53.0°C and 55.0°C for
the first and second cycle, respectively, extension for 90 seconds at
72°C, and final extension for 7 minutes at 72°C. Three of the 50 µL of the first-round PCR product served as the template in the
second-round PCR. PCR products were confirmed for size with SYNERGEL.
PCR products of 5NC, NS3, and E2 regions were directly sequenced using
cycle sequence protocol, with reagents supplied with the Taq Dye
Terminator Cycle Sequencing Kit (ABI, Foster City, CA) and automated
sequencer (ABI PRISM 377 DNA Sequencer; ABI). Phylogenetic
analysis of the E2 region was performed by the neighbor-joining
method,19 which is as efficient as other available methods,
or more, for constructing the correct phylogenetic tree.20
Measurement of anti-E2 antibodies to HGV.
Anti-E2 antibody was measured with an immunoassay kit (Enzymun-Test
Anti-HGenv; Boehringer Mannheim, Mannheim, Germany)
developed by Tacke et al.13 The principle of assay is the
enzyme-linked immunosorbent assay (ELISA)/3-step sandwich assay using
Streptavidin technology. Briefly, recombinant HGV envelope protein from
CHO cells binding to biotinylated monoclonal anti-E2 antibodies and a
serum sample were incubated in a Streptavidin-coated ELISA plate and,
after washing, again incubated with peroxidase-labeled antihuman-Fc antibodies. After adding a substrate of ABTS
[2,2-Azino-bis-(3-ethylbenzothiazoline-6-sulfonate)] and
H2O2 and development of color, an absorbance of
422 nm was measured. Positive results were assured by the confirmatory
test according to the instruction manual. That is, each serum sample was measured in parallel with either lysates of HGV-E2
region-transfected and untransfected CHO cells, and sera were defined
as positive for anti-E2 if the absorbance of anti-E2/anti-CHO ratio was
greater than 1.5.
Statistics.
Both the  2 test and the Fisher exact test were used for
qualitative variables, and the Student's t-test was used for
quantitative variables. A P value less than .05 was considered
as being significant. All statistical analysis was performed using
StatView for Macintosh (Abacus Concepts, Inc, Berkeley, CA).
| |
RESULTS |
Cross-sectional study in 1993.
To assess the prevalence of HGV infection, serum samples collected in
1993 were tested for HGV-RNA and anti-E2. Among 106 patients, HGV-RNA
and anti-E2 were detected in 19 (17.9%) and 2 patients (1.9%),
respectively. The two HGV markers did not coexist in any patient. At
the time of sample collection, 74 patients were still under treatment
with immunosuppressive agents or antileukemic drugs and the other 32 had completed treatment. The prevalence of HGV-RNA and anti-E2
according to the stage of treatment is indicated in
Table 1. There was no significant
difference in HGV positivity rate between those undergoing chemotherapy
or immunosuppressive therapy and those having completed therapy. In
total, the frequency of HGV infection in our cohort, calculated as the
positivity rate of HGV-RNA and anti-E2, was 21 of 106 (19.8%).
Longitudinal study of HGV markers.
To clarify the natural course of HGV infection in hematological
malignancy, the 21 patients who showed either HGV-RNA or anti-E2 positivity in cross-sectional study were precisely examined by analysis
using serially collected sera. The results are shown in
Table 2. Among the 21 patients with HGV
infection, 6 (patients no. 1 through 6) had become clear of HGV-RNA
during their off-therapy period. None became HGV-RNA-negative under
chemotherapy or immunosuppressive therapy. Of the 6 who became clear of
HGV-RNA, only 1 patient (patient no. 1) developed anti-E2 concomitantly
with clearance of HGV-RNA; however, the anti-E2 had disappeared after 3 years and he presented no HGV marker thereafter. The other 9 survivors (patients no. 7 through 15) remained HGV-RNA-positive at the last sample collection. The HGV-RNA viremia persisted over a follow-up period of 3 to 10 years. Five patients (patients no. 16 through 20) had
died with HGV viremia while undergoing chemotherapy. One other patient
(patient no. 21) had been positive for anti-E2 before initial blood
transfusion. The long-term outcome of HGV infection in the survivors
was as follows: HGV viremia was cleared in 3 of 6 (50%) of BMT
recipients, 3 of 9 (33%) of children treated with conventional
chemotherapy, and 6 of 15 (40%) of all survivors. There was no
significant difference in the clearance rate according to the treatment
modality.
In 2 patients who were persistently HGV-RNA-positive in 1997, retrospective evaluation disclosed relapsing of HGV viremia during
execution of chemotherapy for acute lymphoblastic leukemia (ALL).
Patient no. 12 was infected with HGV during the first remission induction therapy. During the off-therapy period, which lasted for 1 year, while the immunocompetence seemed to be restored, HGV-RNA became
undetectable simultaneously with the development of anti-E2. However,
during the second remission induction against relapsing ALL, anti-E2
had disappeared concurrently with the reappearance of HGV-RNA
(Fig 1A). To investigate
whether this HGV-RNA was due to reactivation of the former strain or
reinfection by other strains, phylogenetic analysis of HGV sequences
from different isolates was performed (Fig 1B). In each of the 5NC, NS3
(data not shown), and E2 regions, the reappearing HGV consistently
showed the nearest homology with the formerly infecting isolate.
Patient no. 13 (Fig 1C) had been transfused with red blood cells at the
time of operation for spontaneous occlusion of the circle of Willis
(Moyamoya disease),21 5 years before the development of
ALL. He had been anti-E2-positive and HGV-RNA-negative at the start
of remission induction therapy for ALL, before the initial transfusion
of blood products. After chemotherapy was initiated, anti-E2
disappeared and, concurrently, HGV-RNA became positive.
View larger version (11K):
[in this window]
[in a new window]
View larger version (23K):
[in this window]
[in a new window]
View larger version (9K):
[in this window]
[in a new window]
| Fig 1.
(A) HGV markers and serum ALT levels of a
patient (patient no. 12) with relapse of HGV viremia during
chemotherapy. The patient was 14 years old at development of ALL. The
horizontal line and solid bar mean years from diagnosis and periods
under immunosuppressive therapy or chemotherapy, respectively. The
inverted triangle indicates the timing of BMT. In the clinical course
of ALT, the normal range for ALT is indicated as a horizontal line.
Phylogenetic analysis was performed with the strains obtained at the
timing of figures in the circle. (B) Phylogenetic analysis of different
HGV isolates from the patient with reactivation of HGV infection.
Figures in the circles show the strains from patient no. 12. Homology
of nucleotide sequence of 312-bp E2 cDNA between reappearing and former
isolates from patient no. 12 were 98% to 99%, although the homology
among the other sequences was 79.8% to 88.3%. In the phylogenetic
tree, HGV R10291 and PNF2164 are in the same E2 regions of the original
HGV strain, and GBV-C is also in the original. We sequenced two strains
derived from another patient (patient no. 15), and the strain first
appearing showed just the same nucleotide sequence as the other that
was obtained 2 years later. D90600, 90601, 87262, 87263, and U63715 are
the accession numbers of previously reported HGV or GBV-C sequences in
GenBank. Numbers 1 through 10 are strains derived from Taiwanese
patients reported by Kao et al.18 (C) HGV markers and serum
ALT levels of another patient (patient no. 15) with reactivation of HGV
viremia during chemotherapy. Clinical courses are represented by
similar notations as in (A).
|
|
Liver dysfunction in HGV infection.
There seemed to be many causes of liver damage in the subjects studied.
To determine the possible role of HGV in liver dysfunction, patients
without any known cause of hepatotoxicity, including HCV-antibodies,
HCV-RNA, HBs-antigen, HBV-DNA, antinuclear antibodies, anti-smooth
muscle antibody, acute and chronic GVHD, VOD, and iron overload, were
analyzed. To exclude drug influence, we examined the liver function
only after completion of chemotherapy or immunosuppressive therapy.
Among this subgroup, liver function was compared between the
HGV-infected and uninfected patients in each treatment modality (Table 3). In the BMT recipients,
HGV-infected subjects showed higher maximum ALT values than
HGV-uninfected (P = .0064), although there was no such
difference in the patients who received conventional chemotherapy
alone. The clinical characteristics of these BMT recipients were
evaluated according to their HGV status
(Table 4), but there was no significant
difference in respect of BMT modalities, conditioning regimen, donor
exposure, or ferritin within 1 year after completion of
immunosuppressive therapy. Transfused red blood cell units of
HGV-infected BMT recipients were more than those of the uninfected, but
the serum ferritin was elevated equally in both groups. Among these
HGV-infected BMT recipients, 3 (patients no. 3, 5, and 6) later became
cleared of HGV viremia. All three had transient peak ALT levels (77 to
91 IU/L) only during the viremic period. The maximum ALT values during
the viremic period in these 3 patients were higher than those after
clearance of HGV-RNA (P = .0366).
View this table:
[in this window]
[in a new window]
|
Table 3.
Liver Function in 31 Evaluable Patients According to HGV
Status and Treatment Modalities After Completion of Drug Therapy
|
|
Among the 9 survivors with persistent HGV infection, only 1 (patient
no. 11) suffered from chronic liver dysfunction, with ALT values at 100 to 180 IU/L, for more than 5 years after cessation of drug therapy. He
did not have any autoantibodies, HCV antibodies, or HCV-RNA. Anti-HBs
and anti-HBc antibody were positive, but HBs antigen was negative and
HBV-DNA was never detected by nested PCR in either serum or liver
tissue. No marker of other hepatitis virus, EB virus, cytomegalovirus,
or herpesvirus indicated any other etiologic factor for the liver
dysfunction.
| |
DISCUSSION |
The natural course of HGV infection is poorly understood.15
This is the first study investigating the natural history and clinical
outcome of HGV infection in patients with hematological malignancy and
BMT recipients. Our findings clearly show that these patients are
frequently exposed to HGV due to multiple blood transfusions and that
they suffer from severe immunosuppression, which has a significant
influence on the clearance of HGV viremia and the production of anti-E2
immune response.
The prevalence of HGV-RNA in these pediatric patients with
hematological malignancy or BMT recipients was 17.9%. This percentage is lower than that reported in a group of adult patients (30% to
48%).3,12 The discrepancy may be related to the age,
therapeutic stage, or geographic area of the study populations. The
study of serial samples showed that all the patients with HGV viremia became positive for HGV-RNA after the beginning of the therapy, indicating that the HGV was transmitted almost solely by blood transfusion. It is noteworthy that the prevalence of anti-E2 was much
lower than that of HGV-RNA in this cohort. In contrast, all previous
reports, including our own data,16 from various
immunocompetent subjects showed that the prevalence of anti-E2 was
higher than or at least equal to that of HGV-RNA. This difference
implies an immunodeficiency status in our study population that induces the persistence of HGV viremia and suppression of the anti-E2 immune
response. It is theoretically possible that the pediatric age of the
study population may play some role in lowering the prevalence of
anti-E2, because in HBV infection, infants hardly acquire any anti-HBs
antibody.22 Up to now, there has been no report concerning
anti-E2 production in children, but we observed that 4 of 6 immunocompetent children who were infected with HGV by transfusion
developed a persistent anti-E2 response (unpublished data). Further study will clarify this point.
The results of the longitudinal study of HGV markers in this cohort,
which demonstrated the natural course of HGV infection in the
immunodeficient status, differ in several points from those in
immunocompetent subjects, which have been previously reported. In
studies of posttransfusion hepatitis and intravenous drug users, more
than half of the acute HGV infections were transient and HGV-RNA
cleared spontaneously within a rather short period.23,24 Among the 19 cases of acute HGV infection in this study, none had
eliminated HGV viremia in the immunosuppression status under chemotherapy or BMT, indicating that this immunosuppression interfered with HGV clearance. This may account for the higher prevalence of
HGV-RNA in BMT and renal transplant recipients.25,26
Anti-E2 has been interpreted as the marker of clearance of HGV
infection, because the antibody appears after or just before the
clearance of HGV-RNA.13 In previous reports, almost all of
the patients who became clear of HGV-RNA developed
anti-E2.13-15 In contrast, among the 6 patients with
self-limiting HGV infections in our series, 5 became clear of HGV
viremia without any anti-E2 immune response. These findings evidently
show that the immune response to anti-E2 does not play an essential
role in the recovery from HGV viremia. We previously reported
hemophiliacs who became clear of HGV-RNA several years before the
appearance of anti-E2. Tacke et al15 also reported one case
who became HGV-RNA-negative before any anti-E2 response and another
who had coexistent anti-E2 and HGV-RNA for at least 75 weeks and
suggested that the cytotoxic T cell may play an important role in the
elimination of HGV. This plausible hypothesis is further supported by
the present study.
In addition, anti-E2 has been used as a marker of recovery from HGV
infection in calculating the HGV-exposure rate in epidemiological studies. Anti-E2 was detected in 3% to 14% of volunteer blood donors,13,15,27 41% to 85.2% of drug
users,13,14,27 and 32% of hemophiliacs.16 In
this series, the first study of immunocompromised patients, about half
of the survivors of BMT and hematological malignancy were clear of
HGV-RNA; however, anti-E2 was prevalent in only 3% or less in the
cross-sectional and longitudinal studies. The lower prevalence of
antiviral antibodies holds true also for HBV and HCV infections under
the same immunosuppressed condition. Among patients seronegative for
HBV and HCV after treatment of acute leukemia, 10.5% were revealed to
be HBV antigen positive by histology.28 Only 70% of
HCV-infected pediatric patients with acute lymphoblastic leukemia were
positive for the HCV antibody in various serological assays, and the
remaining 30% were seronegative despite positive
HCV-RNA.29 These findings imply that the use of serological
assay of anti-E2 is of limited value and that determination of HGV-RNA
by PCR should be recommended in these patients.
Reactivation of HGV after anti-E2 immune response has never before been
observed. It is important that these 2 patients became anti-E2-negative and HGV-RNA-positive simultaneously. These
observations suggest the following two possibilities: ongoing
replication of HGV at undetectable levels, or latent HGV, may occur
after loss of detectable HGV viremia in concurrence with the
development of anti-E2 response; and there may be neutralizing or
protective activity in at least some anti-E2 antibodies, which usually
suppress large-scale replication of HGV. In some cases of impaired
immunocompetence, the loss of these antibodies may induce the
reactivation of HGV. Future studies will clarify the mechanisms of
persistent infection with HGV, a unique member of the
Flaviviridae family.
Liver dysfunction frequently develops in patients with hematologic
malignancy. Especially in BMT recipients, liver disease sometimes has a
major impact on the prognosis. Besides the hepatotoxic effects of
drugs, viral hepatitis (HBV or HCV), chronic GVHD, and iron overload
are possible causes of such liver damage in long-term
survivors.30 The pathogen remained undefined in 30% of
hepatitis in survivors of pediatric malignancies.28 To
clarify the influence of HGV infection alone on liver damage, we
compared ALT levels, hepatitis markers, conditioning regimen, dose of
transfusion, and serum ferritin between HGV-viremic and uninfected
patients during off-therapy periods, according to the treatment
modality. HGV infection seemed likely to have some relation to liver
dysfunction in long-term survivors of BMT recipients, because, after
exclusion of other known kinds of viral hepatitis and chronic GVHD,
maximum ALT values of HGV-infected patients were statistically higher than those of uninfected patients, whereas mean values of ALT showed no
difference. This finding would imply that the effect of HGV on ALT is
transient and self-limiting, whereas the viral infection persists in
almost all cases even after abnormal liver function is resolved. We
also found a patient who was infected solely with HGV and presented
persistent liver dysfunction over 5 years after therapy withdrawal. The
clinical significance of the HGV infection remains unclear. Recent
studies have suggested that transfusion-associated HGV infection rarely
results in liver disease,31 although there are some reports
indicating the pathogenic role of acute HGV infection in
posttransfusion liver dysfunction.13,14 Up to now,
HGV-related hepatotoxicity has been discussed in terms of viral factors
such as specific viral strains in fulminant hepatitis32,33; however, our study implies that alteration of the host's
immunocompetence may influence the hepatotoxicity of HGV. A parallel
can be drawn with HCV infection in immunodeficient patients; rapidly
progressive HCV infection sometimes occurs in HIV-infected
hemophiliacs34,35 and in congenital
hypogammaglobulinemia.36,37 Further studies of large
numbers of HGV-infected patients combined with pathological studies
will be needed to establish the clinical significance of HGV infection
in an immunosuppressed population.
| |
FOOTNOTES |
Submitted March 17, 1998;
accepted September 21, 1998.
Supported in part by a grant from the Mother and Child Health
Foundation (No.10-6) and the Ministry of Health and Welfare of Japan.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Ryo Sumazaki, MD, Department of Pediatrics,
Institute of Clinical Medicine, University of Tsukuba, Tsukuba,
Ibaraki, 305 Japan.
| |
REFERENCES |
1.
Vyas GN:
Inactivation and removal of blood-borne viruses.
Transfusion
35:367, 1995[Medline]
[Order article via Infotrieve]
2.
Ljungman P, Johansson N, Aschan J, Glaumann H, Lonnqvist B, Ringden O, Sparrelid E, Sonnerborg A, Winiarski J, Gahrton G:
Long-term effects of hepatitis C virus infection in allogeneic bone marrow transplant recipients.
Blood
86:1614, 1995[Abstract/Free Full Text]
3.
Skidmore SJ, Collingham KE, Harrison P, Neilson JR, Pillay D, Milligan DW:
High prevalence of hepatitis G virus in bone marrow transplant recipients and patients treated for acute leukemia.
Blood
89:3853, 1997[Abstract/Free Full Text]
4.
Locasciulli A, Cavalletto D, Pontisso P, Cavalletto L, Scovena E, Uderzo C, Masera G, Alberti A:
Hepatitis C virus serum markers and liver disease in children with leukemia during and after chemotherapy.
Blood
82:2564, 1993[Abstract/Free Full Text]
5.
Vento S, Cainelli F, Mirandola F, Cosco L, Perri GD, Solbiati M, Ferraro T, Concia E:
Fulminant hepatitis on withdrawal of chemotherapy in carriers of hepatitis C virus.
Lancet
347:92, 1996[Medline]
[Order article via Infotrieve]
6.
Simons JN, Leary TP, Dawson GJ, Pilot MT, Muerhoff AS, Schlauder GG, Desai SM, Mushahwar IK:
Isolation of novel virus-like sequences associated with human hepatitis.
Nat Med
1:564, 1995[Medline]
[Order article via Infotrieve]
7.
Linnen J, Wages JJ, Zhang KZ, Fry KE, Krawczynski KZ, Alter H, Koonin E, Gallagher M, Alter M, Hadziyannis S, Karayiannis P, Fung K, Nakatsuji Y, Shih JW, Young L, Piatak MJ, Hoover C, Fernandez J, Chen S, Zou JC, Morris T, Hyams KC, Ismay S, Lifson JD, Kim JP:
Molecular cloning and disease association of hepatitis G virus: A transfusion-transmissible agent.
Science
271:505, 1996[Abstract]
8.
Muerhoff AS, Simons JN, Leary TP, Erker JC, Chalmers ML, Pilot-Matias TJ, Dawson GJ, Desai SM, Mushahwar IK:
Sequence heterogeneity within the 5-terminal region of the hepatitis GB virus C genome and evidence for genotypes.
J Hepatol
25:379, 1996[Medline]
[Order article via Infotrieve]
9.
Leary TP, Muerhoff AS, Simons JN, Pilot MT, Erker JC, Chalmers ML, Schlauder GG, Dawson GJ, Desai SM, Mushahwar IK:
Sequence and genomic organization of GBV-C: A novel member of the flaviviridae associated with human non-A-E hepatitis.
J Med Virol
48:60, 1996[Medline]
[Order article via Infotrieve]
10.
Dawson GJ, Schlauder GG, Pilot MT, Thiele D, Leary TP, Murphy P, Rosenblatt JE, Simons JN, Martinson FE, Gutierrez RA, Lentino JR, Pachucki C, Muerhoff AS, Widell A, Tegtmeier G, Desai S, Mushahwar IK:
Prevalence studies of GB virus-C infection using reverse transcriptase-polymerase chain reaction.
J Med Virol
50:97, 1996[Medline]
[Order article via Infotrieve]
11.
Yoshikawa A, Fukuda S, Itoh K, Kosaki N, Suzuki T, Hirakawa K, Nakao H, Inoue T, Fukuda M, Okamoto H:
Infection with hepatitis G virus and its strain variant, the GB agent (GBV-C), among blood donors in Japan.
Transfusion
37:657, 1997[Medline]
[Order article via Infotrieve]
12.
Rodriguez IE, Tomas JF, Gomez Gd SV, Bartolome J, Pinilla I, Amaro MJ, Carreno V, Fernandez RJ:
Hepatitis C and G virus infection and liver dysfunction after allogeneic bone marrow transplantation: Results from a prospective study.
Blood
90:1326, 1997[Abstract/Free Full Text]
13.
Tacke M, Kiyosawa K, Stark K, Schlueter V, Ofenloch HB, Hess G, Engel AM:
Detection of antibodies to a putative hepatitis G virus envelope protein.
Lancet
349:318, 1997[Medline]
[Order article via Infotrieve]
14.
Dille B, Surowy T, Gutierrez R, Coleman P, Knigge M, Carrick R, Aach R, Hollinger F, Stevens C, Barbosa L, Nemo G, Mosley J, Dauson G, Mushahwar I:
An ELISA for detection of antibodies to the E2 protein of GB virus C.
J Infect Dis
175:458, 1997[Medline]
[Order article via Infotrieve]
15.
Tacke M, Schmolke S, Schlueter V, Sauleda S, Esteban JI, Tanaka E, Kiyosawa K, Alter HJ, Snemitt U, Hess G, Ofenloch-Haehnle B, Engel AM:
Humoral immune response to the E2 protein of hepatitis G virus is associated with long-term recovery from infection and reveals a high frequency of hepatitis G virus exposure among healthy blood donors.
Hepatology
26:1626, 1997[Medline]
[Order article via Infotrieve]
16.
Yamada-Osaki M, Sumazaki R, Kajiwara Y, Miyakawa T, Shirahata A, Matsui A:
Natural course of GBV-C/HGV infection in haemophiliacs.
Br J Haematol
102:616, 1998[Medline]
[Order article via Infotrieve]
17.
Orito E, Mizokami M, Nakano T, Wu RR, Cao K, Ohba K, Ueda R, Mukaide M, Hikiji K, Matsumoto Y, Iino S:
GB virus C/hepatitis G virus infection among Japanese patients with chronic liver diseases and blood donors.
Virus Res
46:89, 1996[Medline]
[Order article via Infotrieve]
18.
Kao JH, Chen PJ, Chen W, Hsiang SC, Lai MY, Chen DS:
Amplification of GB virus-C/hepatitis G virus RNA with primers from different regions of the viral genome.
J Med Virol
51:284, 1997[Medline]
[Order article via Infotrieve]
19.
Saitou N, Nei M:
The neighbor-joining method: A new method for reconstructing phylogenetic trees.
Mol Biol Evol
4:406, 1987[Abstract]
20.
Saitou N, Imanishi T:
Relative efficiencies of the Fitch-Margoliash, maximum parsimony, maximum-likelihood, minimum-evolution, and neighbor-joining methods of phylogenetic tree construction in obtaining the correct tree.
Mol Biol Evol
6:514, 1989
21.
Ueki K, Neyer EB, Mellinger JF:
Moyamoya disease: The disorder and surgical treatment.
Mayo Clin Proc
69:749, 1994[Medline]
[Order article via Infotrieve]
22.
Romero R, Lavine J:
Viral hepatitis in children.
Semin Liver Dis
14:289, 1994[Medline]
[Order article via Infotrieve]
23.
Wang JT, Tsai FC, Lee CZ, Chen PJ, Sheu JC, Wang TH, Chen DS:
A prospective study of transfusion-transmitted GB virus C infection: Similar frequency but different clinical presentation compared with hepatitis C virus.
Blood
88:1881, 1996[Abstract/Free Full Text]
24.
Thomas DL, Nakatsuji Y, Shih JW, Alter HJ, Nelson KE, Astemborski JA, Lyles CM, Vlahov D:
Persistence and clinical significance of hepatitis G virus infections in injecting drug users.
J Infect Dis
176:586, 1997[Medline]
[Order article via Infotrieve]
25.
Neilson J, Harrison P, Milligan DW, Skidmore SJ, Collingham KE:
Hepatitis G virus in long-term survivors of haematological malignancy.
Lancet
347:1632, 1996[Medline]
[Order article via Infotrieve]
26.
Kudo T, Morishima T, Tsuzuki K, Orito E, Mizokami M:
Hepatitis G virus in immunosuppressed paediatric allograft recipients.
Lancet
348:751, 1996[Medline]
[Order article via Infotrieve]
27.
Karayiannis P, Pickering J, Chiaramonte M, Thomas HC:
Hepatitis G virus infection.
Lancet
349:954, 1997[Medline]
[Order article via Infotrieve]
28.
Rossetti F, Cesaro S, Pizzocchero P, Cadrobbi P, Guido M, Zanesco L:
Chronic hepatitis B surface antigen-negative hepatitis after treatment of malignancy.
J Pediatr
121:39, 1992[Medline]
[Order article via Infotrieve]
29.
Arico M, Maggiore G, Silini E, Bono F, Vigano C, Cerino A, Mondelli MU:
Hepatitis C virus infection in children treated for acute lymphoblastic leukemia.
Blood
84:2919, 1994[Abstract/Free Full Text]
30.
Harrison P, Neilson JR, Marwah SS, Madden L, Bareford D, Milligan DW:
Role of non-transferrin bound iron in iron overload and liver dysfunction in long term survivors of acute leukaemia and bone marrow transplantation.
J Clin Pathol
49:853, 1996[Abstract/Free Full Text]
31.
Alter HJ, Nakatsuji Y, Melpolder J, Wages J, Wesley R, Shih JW, Kim JP:
The incidence of transfusion-associated hepatitis G virus infection and its relation to liver disease.
N Engl J Med
336:747, 1997[Abstract/Free Full Text]
32.
Heringlake S, Osterkamp S, Trautwein C, Tillmann HL, Boker K, Muerhoff S, Mushahwar IK, Hunsmann G, Manns MP:
Association between fulminant hepatic failure and a strain of GBV virus C.
Lancet
348:1626, 1996[Medline]
[Order article via Infotrieve]
33.
Tameda Y, Kosaka Y, Tagawa S, Takase K, Sawada N, Nakao H, Tsuda F, Tanaka T, Okamoto H, Miyakawa Y, Mayumi M:
Infection with GB virus C (GBV-C) in patients with fulminant hepatitis.
J Hepatol
25:842, 1996[Medline]
[Order article via Infotrieve]
34.
Telfer P, Sabin C, Devereux H, Scott F, Dusheiko G, Lee C:
The progression of HCV-associated liver disease in a cohort of haemophilic patients.
Br J Haematol
87:555, 1994[Medline]
[Order article via Infotrieve]
35.
Hanley JP, Jarvis LM, Andrews J, Dennis R, Lee R, Simmonds P, Piris J, Hayes P, Ludlam C:
Investigation of chronic hepatitis C infection in individuals with haemophilia: Assessment of invasive and non-invasive methods.
Br J Haematol
94:159, 1996[Medline]
[Order article via Infotrieve]
36.
Sumazaki R, Matsubara T, Aoki T, Nagai Y, Shibasaki M, Takita H:
Rapidly progressive hepatitis C in a patient with common variable immunodeficiency.
Eur J Pediatr
155:532, 1996[Medline]
[Order article via Infotrieve]
37.
Bjoro K, Froland SS, Yun Z, Samdal HH, Haaland T:
Hepatitis C infection in patients with primary hypogammaglobulinemia after treatment with contaminated immune globulin.
N Engl J Med
331:1607, 1994[Abstract/Free Full Text]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
|
|
Top
Abstract
Introduction