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Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2485-2490
TT Virus in Bone Marrow Transplant Recipients
By
Yoshinobu Kanda,
Yuji Tanaka,
Masahiro Kami,
Toshiki Saito,
Takashi Asai,
Koji Izutsu,
Koichiro Yuji,
Seishi Ogawa,
Hiroaki Honda,
Kinuko Mitani,
Shigeru Chiba,
Yoshio Yazaki, and
Hisamaru Hirai
From the Department of Cell Therapy and Transplantation Medicine and
the Third Department of Internal Medicine, Faculty of Medicine,
University of Tokyo, Tokyo, Japan.
 |
ABSTRACT |
TT virus (TTV) is a newly discovered transfusion-transmissible
DNA virus, which may cause posttransfusion hepatitis. The virus was
detected in 12% of Japanese blood donors. The aim of the study is to
investigate the prevalence and clinical influence of TTV in bone marrow
transplant (BMT) recipients. Sera from 25 BMT recipients obtained 6 to
12 weeks after the transplant were examined for TTV-DNA by the
seminested polymerase chain reaction. Serial samples were additionally
analyzed in patients with TTV-DNA. Fifteen of 25 recipients (60%) were
positive for TTV-DNA after transplant, whereas it was detected in only
two of 20 BMT donors (10%). In patients positive for TTV-DNA before
BMT, the amount of TTV-DNA decreased to an undetectable level during
the myelosuppressed period after BMT. We also found that there was a
novel group of TTV, G3, classified by the nucleotide sequences. The
median peak alanine aminotransferase (ALT) levels were 135.0 IU/L and
116.5 IU/L (normal range, 4 to 36 IU/L) in TTV-positive and
TTV-negative recipients, respectively. In one of the seven TTV-positive
patients who developed hepatic injury (ALT > 150 IU/L), a serial
change in the serum TTV titer showed a good correlation with the ALT level. We concluded that (1) the prevalence of TTV is high in BMT
recipients, (2) TTV might be replicated mainly in hematopoietic cells,
(3) transfusion-transmitted TTV may cause persistent infection, (4) a
novel genetic group of TTV, G3, was discovered, and (5) TTV does not
seem to frequently cause hepatic injury, although one patient was
strongly suggested to have TTV-induced hepatitis.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
HEPATIC DYSFUNCTION IS one of the
frequent complications after bone marrow transplantation (BMT). Some of
them are caused by drug toxicity or tumor infiltration. Hepatic
venoocclusive disease (VOD), which is characterized by painful
hepatomegaly, ascites, and jaundice, is considered to be a toxicity of
preparative regimen before BMT. Graft-versus-host disease (GVHD) also
causes severe hepatic injury, which is difficult to treat. We, however, sometimes meet with hepatic dysfunction of unknown etiology.
Posttransfusion hepatitis, which has been reduced by screening for
hepatitis B virus (HBV) and hepatitis C virus (HCV), is still
responsible for a part of hepatic problems. Hepatitis G virus (HGV),
also called GB virus C, is a recently discovered
transfusion-transmissible flavivirus and had been expected to be a
responsible agent for posttransfusion hepatitis.1 However,
accumulating data showed that this virus rarely causes
hepatitis.2 Studies in bone marrow transplant recipients
also failed to show the relationship between HGV infection and liver
injury, although immunosuppression associated with BMT might increase
the risk of HGV infection after transfusion-related exposure.3-6 Nishizawa et al7 cloned a novel
DNA virus from serum of a patient with posttransfusion hepatitis. The
virus was designated TT virus (TTV) after the patient from whom it was
derived. The name also stands for a "transfusion-transmitted
virus". TTV-DNA was detected in sera from three of five patients
with posttransfusion non-A to G hepatitis, and the increase in serum
TTV-DNA coincided with the elevation of serum alanine aminotransferase
(ALT).7 Now, it is highlighted as a candidate for the
causative agent for such hepatitis. TTV is an unenveloped
single-stranded DNA virus of at lease 3,700 bases and resembles
parvovirus in some features.8 However, little is known
about the clinical characteristics of the virus except for the 12%
prevalence in Japanese blood donors.8 Whether TTV is
replicated in the liver is also unknown. In this study, we
retrospectively investigated the prevalence and clinical impact of TTV
in 25 BMT recipients at our institute.
| |
MATERIALS AND METHODS |
Patients.
Frozen sera from 25 BMT recipients transplanted between June 1995 and
January 1998 were retrospectively analyzed for TTV-DNA. There were 20 men and five women with a median age of 35.0 years (range, 18 to 48 years). Nine patients with chronic myelocytic leukemia, six with acute
lymphoblastic leukemia, six with acute myeloblastic leukemia, three
with myelodysplastic syndrome, and one with severe aplastic anemia were
included. Eighteen patients had a history of transfusion before BMT.
Seventeen patients were transplanted from HLA-identical siblings, three
from one-locus-mismatched related donors, and five from HLA-matched
unrelated donors. Preparative regimens among the cases were various
including 18 irradiating regimens (mainly, 120 mg/kg cyclophosphamide
and 12 Gy total body irradiation) and seven nonirradiating regimens
(mainly, 16 mg/kg busulfan and 120 mg/kg cyclophosphamide). Prophylaxis
for GVHD was performed with cyclosporin A and short-course
methotrexate. Fluconazole, tosufloxacin, sulfamethoxazole-trimethoprim,
and aciclovir were administered prophylactically.
First, sera obtained between 6 and 12 weeks after BMT were subjected to
the analyses. Next, sera just before BMT, during the myelosuppressed
period after BMT, and more than 6 months after BMT were additionally
examined, if available, for patients with TTV-DNA. Sera from bone
marrow donors were also examined.
Detection of TTV-DNA by seminested polymerase chain reaction.
DNA was extracted from sera by a modified method originally described
by Okamoto et al.9 Serum (50 µL) was mixed with 150 µL
of 1.3x lysis buffer (13.3 mmol/L Tris-HCl pH 8.0, 6.7 mmol/L EDTA,
0.67% sodium dodecyl sulfate, and 133 µg/mL proteinase K) and
incubated at 70°C for 3 hours. After thorough mixing by Vortex with
200 µL of phenol-chloroform, the aliquots were centrifuged at 15,000 rpm for 10 minutes. The supernatants were collected and incubated with
20 µL of 3 mol/L NaOAc, 500 µL of ethanol, and 7.5 µg of carrier
tRNA (final, 10 µg/mL) in dry ice for 5 minutes. After a
centrifugation at 15,000 rpm for 15 minutes at 4°C, the
supernatants were discarded. The pellet was washed with 70% ethanol,
dried up, and dissolved with 20 µL of TE (10 mmol/L Tris-HCl pH 8.0, 1 mmol/L EDTA). A half portion of the extracts was subjected to
seminested polymerase chain reaction (PCR) for TTV-DNA. The first-round
PCR was performed with NG059 primer (5'-ACA GAC AGA GGA GAA GGC
AAC ATG-3') and NG063 primer (5'-CTG GCA TTT TAC CAT TTC
CAA AGT T-3') for 35 cycles (94°C, 30 seconds; 60°C, 45 seconds; 72°C, 45 seconds).8 The second-round PCR was
performed with NG061 primer (5'-GGC AAC ATG YTR TGG ATA GAC
TGG-3' [Y = T or C; R = A or G]) and NG063 primer for 25 cycles
at the same condition for the amplification of a 271-bp
product.8 One third of the products was electrophoresed on
2% agarose gel and stained with ethidium bromide. For the positive
samples, amplified products were cloned into pBluescript plasmid, and
the nucleotide sequence of several clones from each PCR product was
determined by the dideoxy chain termination method. Amplified products
were also digested with an endonuclease, ScaI, or EcoRI,
electrophoresed on 3% agarose gel, and stained with ethidium bromide.
The digestion patterns were helpful to confirm the genetic
classification. TTV titer was estimated by PCR using the serially
10-fold diluted template DNA. The titer was described as the highest
dilution giving a positive result.
Screening for HBV, HCV, and HGV.
HBV and HCV were screened by the conventional serological methods.
Detection of HGV-RNA was performed by the method described previously.10
Statistical analyses.
Results are described as median values with the ranges of distribution.
Statistical comparison between groups was performed using the Fisher's
exact test or the Mann-Whitney U test.
| |
RESULTS |
Prevalence of TTV.
Sera from only two of 20 bone marrow donors were positive for TTV-DNA
(10%). The prevalence is almost equivalent with the data in normal
blood donors in a previous report (12%).8 In contrast, 15 of 25 patients were positive for TTV-DNA after BMT (60%)
(Table 1). The mean numbers of blood
transfusion donors, including concentrated red blood cells and platelet
rich plasma, were 43.4 and 27.0 in the TTV-positive and TTV-negative
patients, respectively, the difference of which was not statistically
significant. None of the recipients enrolled were positive for HBV and
HCV, but six patients were positive for HGV-RNA. The prevalence of HGV-RNA was 33% and 10% in TTV-positive and TTV-negative patients, respectively (not significant). Serial samples from TTV-positive BMT
recipients were further analyzed, if available. TTV was detected in
seven of 12 (67%) available samples obtained before BMT
(Fig 1). It was also detected in three of
six (50%) samples obtained several months (280 to 568 days) after BMT
(Fig 1). In contrast, only one of six patients (17%) with positive TTV
before BMT was shown to have TTV during the myelosuppressed period
after BMT (Fig 1). This finding suggested that the amount of TTV might
decrease to an undetectable level in the myelosuppressed period after
BMT.
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| Fig 1.
Serial changes in the results of PCR for TTV-DNA. Open
and closed boxes indicate TTV-DNA negative and positive samples,
respectively. The area surrounded by the dashed line represents the
myelosuppressed period after transplant.
|
|
Nucleotide sequence of the amplified TTV-DNA.
Amplified products were cloned into the pBluescript plasmid, and
nucleotide sequences of several clones per each product were determined
by the dideoxy chain termination method. Okamoto et al8
classified the nucleotide sequences of TTV into four genetic subgroups;
G1a, G1b, G2a, and G2b. All of the sequences in our series belonged to
subgroups of G1a and G1b, except for 3, designated G3-group, which
belonged to none of the known four subgroups. The sequences of G3-group
differed by 0% to 3.6% in sequence to each other and by 36% to 42%
to G1a (Fig 2). It was also found that
UPN19, UPN35, and the donor of UPN21 simultaneously had two distinct
subgroups of TTV in their sera. To confirm these findings, amplified
products were digested with an endonuclease, ScaI, or EcoRI. The
G1b-subgroup and the G3-group have an internal digestion site for EcoRI
and ScaI, respectively, whereas the
G1a-subgroup has neither of the digestion sites. Thus, the genotype can
be distinguished by the pattern of digestion (Fig
3). From the nucleotide sequence and the digestion
patterns, TTV in each individual was classified as shown in
Table 2.
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| Fig 2.
Comparison of nucleotide sequences in genetic groups of
TTV. Nucleotide sequences of 222 bp spanning 1959-2180 are shown.
Primer sequences at both ends are excluded. Conserved nucleotides
between the groups are boxed.
|
|
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| Fig 3.
Genetic classification of TTV by digesting the amplified
products with endonucleases. Three lanes on the left side schematically
represents digestion patterns of the amplified products of G1a, G1b,
and G3 subtypes. Three lanes on the right side are photographs of the
gel stained with ethidium bromide on which amplified products from UPN
17, 19, and 31 were electrophoresed after digestion with an
endonuclease, ScaI, or EcoRI.
|
|
Relationship between TTV infection and liver dysfunction.
First, we investigated the relationship between pretransplant TTV
infection and liver dysfunction in the early period (0 to 5 weeks)
after BMT. The diagnosis of VOD was established according to
McDonald's criteria.11 Patients who satisfied at lease two of the following three criteria were diagnosed with VOD: jaundice (total bilirubin > 2.0 mg/dL), hepatomegaly and upper abdominal pain,
ascites and/or body weight gain (at least 5% gain from the baseline
body weight).11 As shown in
Table 3, the incidence of VOD was almost
equivalent in TTV-positive and TTV-negative patients. The median values
of peak total bilirubin levels and peak ALT (normal range, 4 to 36 IU/L) levels during the period were 1.0 mg/dL and 117 IU/L in the
TTV-positive patients and 1.4 mg/dL and 103 IU/L in the TTV-negative
patients, respectively. The differences were not statistically
significant. Thus, there seemed to be no relationship between the
regimen-related toxicity of the liver and pretransplant TTV infection.
Next, we analyzed the relationship between posttransplant TTV infection
and liver dysfunction between 6 and 12 weeks after BMT. The median peak
serum ALT levels were 135.0 IU/L (range, 42 to 685 IU/L) and 116.5 IU/L
(range, 33 to 241 IU/L) in TTV-positive and TTV-negative patients,
respectively, the difference of which was not statistically significant
(Table 3). The incidence of grade II-IV GVHD was not different between
the groups. The serum ALT exceeded 150 IU/L in seven of the 15 TTV-positive recipients and in three of the 10 TTV-negative recipients
(not significant). Considering the clinical course, graft-versus-host
reaction was considered to be responsible for the liver injury in most
of the patients, although some of them did not fulfill the criteria of the diagnosis of GVHD. However, laboratory data suggested that the bile
duct damage in UPN21 was moderate compared with the hepatocyte injury,
which is atypical in hepatic GVHD. This patient had received liver
biopsy and the pathological findings of the specimen showed that there
was severe hepatocyte injury despite mild bile duct damage, which also
conflicted with the diagnosis of GVHD. Drug adverse reaction was denied
from the clinical course. We considered the hepatic injury of the
patient a result of TTV-associated hepatitis and conducted further analyses.
Serial semiquantitation of TTV-DNA in sera of UPN21.
DNA extracted from sera of UPN21 obtained before BMT and 18, 50, 67, 89, 106, and 158 days after BMT were serially 10-fold diluted and
subjected to PCR. TTV titers were estimated according to the highest
dilution giving a positive result. As shown in Fig
4, the serum TTV titer closely correlated
with the serum ALT level. The TTV titer decreased just after BMT and
increased in the ensuing period as the bone marrow recovered along with
the elevation of the serum ALT level. After day 150, both returned to
the level before BMT without treatment. The trough blood concentration of cyclosporine A was maintained between 150 and 250 ng/mL throughout the period. These findings strengthened the diagnosis of TTV-associated hepatitis.
Detection of TTV-DNA in the liver specimen from UPN21.
DNA was extracted from the formalin-fixed liver specimens from
UPN21 and subjected to PCR for TTV-DNA. The liver sample from UPN1, who
had suffered from chronic GVHD of the liver, was used as a negative
control. TTV-DNA was detected in the liver specimen from UPN21, but not
in the sample from UPN1. We performed in situ hybridization of the
TTV-DNA using the specimen, because PCR might detect TTV-DNA from
contaminated blood. However, we could not detect TTV-DNA by in situ
hybridization, probably due to its low sensitivity by use of
formalin-fixed tissue.
| |
DISCUSSION |
In the present study, we investigated the relationship between TTV and
the clinical course in BMT recipients. TTV-DNA was detected in 60% of
the BMT recipients. The prevalence is far higher than that (12%) in
normal blood donors in the previous report,8 as well as
that (10%) in the bone marrow donors in our series (P < .001). The TTV-negative recipients had received transfusion from 27.0 donors on average, suggesting that the infused TTV did not always cause
infection. Seven of the 12 TTV-positive patients were positive for TTV
before BMT and two (UPN20 and UPN21) of seven patients had no history
of transfusion before BMT. The bone marrow donor of UPN21, who is a
sister of UPN21, was also positive for TTV without a history of
transfusion. Therefore, there are routes of transmission other than
blood transfusion. Nucleotide sequencing showed that UPN21 had TTV of
G1a-subgroup before BMT and the donor of UPN21 had two types of TTV,
G1a and G1b. The sequences of G1a-subgroup TTV from the two individuals
were completely identical, suggesting that the TTV was acquired
vertically or environmentally (household contact, oral intake of
infected foods, and so on). The infection route of G1b-TTV in the donor
was unknown, because her sexual activity was normal, she was not a drug
abuser, and she did not have acupuncture or tattoos. TTV seemed to be transmissible other than vertically or by transfusion. UPN21 had received administration of interferon- (IFN-) as a treatment for
chronic myelocytic leukemia for 2 years before BMT, first at 3 million
units three times weekly and then at 6 million units daily. This
implies that IFN- did not eliminate TTV in the patient. The effect
of IFN- on eliminating TTV needs further investigation in a large
scale study.
We also found that TTV decreased to an undetectable level in the
myelosuppressed period after BMT in five of the six patients who were
positive for TTV before BMT. The same nucleotide sequences of TTV
present before BMT were not detected after BMT in two (UPN 21 and UPN
31) of the seven patients who were TTV-positive before BMT (Table 2).
These findings suggested a possibility that TTV is replicated mainly in
the hematopoietic cells. Three of the six patients analyzed remained
positive for TTV more than 6 months after BMT, when the
immunosuppressants were discontinued. Two of the three had acquired TTV
after BMT, because the sequence of TTV after BMT was not detected
before BMT, suggesting that transfusion-transmitted TTV may cause
persistent infection.
Most of the nucleotide sequences of the amplified products belonged to
G1a or G1b-subgroups according to the classification by Okamoto et
al,8 although three sequences, designated G3-group, belonged to none of the known subgroups. They had 96.4% to 100% homology to each other and 58% to 62% homology to the G1a sequence. There were no published sequences with a high homology to the G3
sequence. The relationship between these subtypes and the
characteristics of the virus should be evaluated in further studies. We
have found persons who have two distinct strains simultaneously. In
such cases, direct sequencing of the amplified products may result in
detecting only one of the strains or in reading incorrect sequence. Thus, subcloning of the amplified products into a vector and sequencing several clones is necessary for the correct genetic classification. Digesting the amplified products with an endonuclease, ScaI, or EcoRI
and distinguishing the digestion pattern is also helpful to confirm the
genetic subtype. By this method, we can estimate the proportion of the
coexisting clones. Nucleotide sequencing, however, cannot be avoided
because there may be a mutation in the internal digestion site for
these endonucleases.
In the BMT recipients, TTV infection neither before nor after BMT
significantly affected the clinical course after BMT because the median
peak ALT levels were almost equivalent in TTV-positive and TTV-negative
BMT recipients. The incidence of VOD or GVHD was not influenced by the
TTV infection. Most of the hepatic injury (ALT > 150 IU/L) in
TTV-positive recipients was considered to be due to graft-versus-host
reaction. One patient, however, developed hepatic injury 55 days after
BMT and the serum ALT level showed significant correlation with the
serum TTV titer. The pathological findings of the liver specimen agreed
with the diagnosis of viral hepatitis. TTV was detected in the specimen
by PCR, but not by in situ hybridization, probably due to its low
sensitivity by use of formalin-fixed tissue. The sequence of TTV at the
time of hepatitis was different from that before BMT, suggesting that the hepatitis was induced by the infused TTV from the bone marrow donor
or the blood donors. Because the nucleotide sequence of G1b in UPN 21 after BMT was identical to that of the BMT donor of UPN 21, it was
likely that the TTV was derived from the BMT donor. The hepatitis
spontaneously regressed in several weeks, whereas TTV-DNA had remained
positive thereafter at low titers for more than 6 months. Cyclosporin A
did not affect the course of hepatitis. While it has been suggested
that HBV carriers have a risk of fulminant hepatitis after
BMT,12 HCV and HGV are relatively safe in
BMT.13,14 Although TTV does not seem to frequently cause
hepatitis in BMT recipients, a larger study is required to determine
the safety of the virus in BMT because we cannot deny the possibility
that TTV might be synergistically implicated in the hepatic injury of
the patients with GVHD. In addition, why TTV causes hepatitis in some
patients and does not in others remains to be resolved. There were some
patients whose TTV titer was higher than UPN 21, but who did not
develop liver injury. To determine whether TTV is replicated in the
liver is important to show that TTV is really a "hepatitis virus"
because our findings suggested that TTV might be replicated mainly in
the hematopoietic cells.
We concluded from these findings that (1) the prevalence of TTV is
extremely higher in BMT recipients than in the normal population, (2)
TTV decreased to an undetectable level during the myelosuppressed period after BMT, suggesting a possibility that TTV might be replicated mainly in hematopoietic cells, (3) transfusion-transmitted TTV may
cause persistent infection, (4) a novel genetic group, G3, was
discovered by the nucleotide sequencing, and (5) there was one patient
who was strongly suspected to have TTV-induced hepatitis.
| |
ACKNOWLEDGMENT |
We thank Dr Makoto Mayumi for his instructive advise and for providing
us the primers and control samples for PCR.
| |
FOOTNOTES |
Submitted April 21, 1998; accepted December 3, 1998.
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 Hisamaru Hirai, MD, Department of Cell
Therapy and Transplantation Medicine, Faculty of Medicine, University
of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan; e-mail:
hhirai-tky{at}umin.ac.jp.
| |
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TOP
ABSTRACT
INTRODUCTION
