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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1502-1505
RAPID COMMUNICATION
A Prospective Study on TT Virus Infection in Transfusion-Dependent
Patients With  -Thalassemia
By
Daniele Prati,
Yu-Huei Lin,
Claudia De Mattei,
Jen-Kuei Liu,
Elena Farma,
Latha Ramaswamy,
Alberto Zanella,
Helen Lee,
Paolo Rebulla,
Jean-Pierre Allain,
Girolamo Sirchia, and
Benjamin Chen for the
Cooleycare Cooperative Group
From the Centro Trasfusionale e di Immunologia dei Trapianti and
Divisione di Ematologia, IRCCS Ospedale Maggiore, Milano, Italy;
Sentinel Biosciences, Inc, Palo Alto, CA; and University of Cambridge,
Cambridge, UK.
 |
ABSTRACT |
A novel DNA virus designated TT virus (TTV) has been reported to be
involved in the development of posttransfusion non-A-C hepatitis. We
evaluated the frequency and natural course of TTV infection in a cohort
of transfusion-dependent thalassemic patients in a 3-year follow-up
study. Ninety-three serum hepatitis C virus (HCV) antibody-negative
patients (median age of 8 years; range, 0 to 25) from eight centers
were studied. Of them, 34 (37%) had an abnormal
alanine-aminotransferase (ALT) baseline pattern, and the other 12 (13%) showed ALT flare-ups during the follow-up. TTV DNA in patient
sera collected at the time of enrollment and at the end of follow-up
was determined by polymerase chain reaction (PCR). In parallel, serum
samples from 100 healthy blood donors were also tested. At baseline, 87 patient sera (93.5%) tested positive for the TTV DNA. Of these TTV
DNA-positive patients, 84 (96.5%) remained viremic at the end of the
study period. Of the 6 TTV DNA-negative patients, 3 acquired TTV
infection during follow-up. However, no definite relation was observed
between the results of TTV DNA determination and ALT patterns. TTV
viremia was also detectable in 22% of blood donors. In conclusion, TTV infection is frequent and persistent among Italian
transfusion-dependent patients. The high rate of viremia observed in
healthy donors indicates that the parenteral route is not the only mode
of TTV spread.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
THE INCIDENCE of transfusion-associated
hepatitis has been substantially reduced after the implementation of
screening for antibodies to hepatitis C virus (HCV) in blood
donors.1-6 Nevertheless, chronic transfusion recipients,
such as patients affected with homozygous  -thalassemia, still have a
high frequency of liver disease due to transfusion-related iron
overload and infection with bloodborne agents, either known or
undiscovered.6 Hepatitis G virus (HGV), a member of the
Flaviviridae family, was initially suggested as a causative
agent of transfusion-associated non-A-C hepatitis,7,8 but
this was not confirmed in further studies.9-12 Hence, the
existence of other agent(s) capable of inducing non-A-C hepatitis has
been hypothesized. A novel DNA virus designated TT virus (TTV) has been
recently identified by representational difference analysis of sera
from a patient with transfusion-associated hepatitis of unknown
etiology.13,14 Preliminary data from the United Kingdom and
Japan indicate that TTV sequences are detectable in 25% to 45% of
patients with fulminant or chronic hepatitis of unknown origin, in 27%
to 68% of hemophiliacs, and in 1.9% to 12% of apparently healthy
blood donors.14-16 However, more epidemiological and
clinical information from both blood donors and recipients is required
to establish if TTV is transfusion-transmissible and to clarify its
role in the pathogenesis of non-A-C hepatitis. This study provides
data on the prevalence of TTV in Italian thalassemic patients. These
patients were enrolled in the multicenter Cooleycare program for
improving the quality of treatment for -thalassemia.17 As part of the Cooleycare effort, a survey program has been
specifically designed for estimating the transfusion risk and
describing the natural history of bloodborne infections among chronic
transfusion recipients.6,12,18-20 This cohort of
transfusion-dependent patients was free of known hepatotropic
infections and they were followed for 3 years for clinical signs of
liver diseases. The primary aims of this study were (1) to assess the
frequency of TTV infection, (2) to investigate the possible relation of
viremia with hepatic dysfunction, and (3) to describe the natural
course of TTV infection.
| |
SUBJECTS AND METHODS |
Thalassemic patients.
In 1992, the centers of the Cooleycare program were invited to
participate in a longitudinal study on the incidence of liver disease
in patients with -thalassemia, as a part of an ongoing survey on
transfusion transmitted infections.6,12,18-20 Thirty-one centers agreed to participate, and the 1,481 homozygous -thalassemia patients enrolled (760 male and 721 female patients with a median age
of 17 years; range, 0 to 45 years) received regular blood transfusions
at these centers. For each patient, a baseline serum sample collected
in December 1992 to March 1993 was sent to the reference laboratory of
the Cooleycare group in Milan for anti-HCV determination. Two hundred
nineteen patients (14.8%) were found to be anti-HCV and
1,262 (85.2%) were anti-HCV+. Additional serum samples of
the anti-HCV patients were requested from the
participating centers after 3 years, together with a record reporting
the results of alanine-aminotransferase (ALT) measurements determined
at each transfusion event and the number of red blood cell units
transfused. Informative records on 181 subjects (82.6%, 95 males and
86 females with a median age at enrollment of 7 years; range, 0 to 28 years) were obtained from 30 centers. The biochemical, clinical, and
virological features of this cohort of patients during the 3 years of
follow-up have been very recently described by the Cooleycare
group.6 For the purpose of this investigation, we decided
to study the 93 anti-HCV patients (48 males and 45 females, median age at enrollment of 8 years; range, 0 to 25 years)
attending 8 of the 30 centers which have completed the program (Fig
1). The participating centers were chosen
according to the following criteria: (1) being in charge of at least
seven anti-HCV patients each; (2) being representative
of the different regions of the country (at least one center from
Northern, Central-Insular, and Southern Italy). All the patients
received deferoxamine therapy according to current protocols. Hepatitis
B surface antigen (HBsAg) determination was negative in all cases.
Median levels of serum ferritin were 1,790 ng/mL (range, 330 to 7,110 ng/mL) at baseline, and 1,840 ng/mL (range, 340 to 6,480) at the end of
the follow-up. Analysis of the follow-up samples showed that 2 of the
93 patients seroconverted to HCV during the study period. In regard to
liver function, 34 patients (37%) had an abnormal ALT pattern at the baseline. ALT elevation was moderate in 27 subjects (79%), mild in 5 (15%), and minimal in 2 (6%). Another 12 anti-HCV patients (13%) showed biochemical signs of
liver dysfunction during the subsequent follow-up period. Of them, 3 (25%) had a moderate ALT increase, and were negative for HCV RNA, HGV
RNA, and antibodies to hepatitis B core antigen (anti-HBc)
determinations. During follow-up, 1 of the 3 patients developed chronic
liver dysfunction, while the ALT levels of the remaining 2 patients returned to baseline levels.
Blood donors.
The presence of TTV DNA was also determined in 100 Italian blood
donors. This group included 73 men and 27 women with a median age of 36 years (range, 21 to 64 years) and a median number of five blood
donations. No abnormality was detected in these donors at physical
examination and no sign or symptom of liver disease was reported in the
medical history, collected at each blood donation. HBsAg, anti-HCV, and
anti-HIV determinations were negative and serum ALT levels were normal.
Virological and biochemical laboratory tests.
The following assays, except for ALT determination in thalassemic
patients, were performed at the reference laboratory of the Cooleycare
group. The anti-HCV status was determined using second- and
third-generation assays (Ortho Diagnostic Systems, Raritan, NJ).
Qualitative serum HCV RNA determination was performed using the
Amplicor HCV kit (Roche Molecular Systems, Basel, Switzerland). HBsAg
and anti-HBc were determined by enzyme immunoassays (EIAs) (Murex, Dartford, UK; and Abbott Laboratories, Chicago, IL). HGV RNA
was performed by reverse transcriptase-polymerase chain reaction (RT-PCR), as previously described.12
Serum ferritin was determined on baseline and follow-up samples by IMx
Ferritina (Abbott Divisione Diagnostici, Roma, Italy). ALT measurements
were determined at each transfusion event in the Cooleycare centers
using standard methods. The upper reference limit (URL) for ALT was 40 U/L in males and 30 U/L in females. The ALT pattern was classified as
normal if the enzyme levels were persistently below the URL and as
abnormal if ALT values were persistently or intermittently above the
URL. As previously described elsewhere,6 a baseline ALT
pattern (based on the values observed during the first 6 months of the
study) and a follow-up pattern (based on the values reported during the
remaining study period) were defined for each patient. Liver
dysfunction was classified as minimal (for peak value of ALT less than
twice the URL), mild (between 2 and 3 times the URL), or moderate
(above 3 times the URL).
Determination of TTV DNA by PCR.
Serum TTV DNA was detected by a seminested PCR. Specifically, serum DNA
purified from an equivalent of 7 µL of serum was amplified by PCR in
a 9600 thermal cycler (Perkin-Elmer, Emeryville, CA), using the
following protocol: 1 cycle at 95°C for 9 minutes; 35 cycles at
94°C for 30 seconds, 58°C for 30 seconds, 72°C for 45 seconds; 1 cycle at 72°C for 7 minutes. The reaction conditions were: 30 pmol of each primer (sense NG059 5'-ACA GAC AGA GGA GAA GGC AAC ATG-3',
antisense NG063 5'-CTG GCA TTT TAC CAT TTC CAA AGT-3'14) and 2.5 U of AmpliTaq Gold (Perkin-Elmer) in 50 µL reaction volume. Five microliters of the product of amplification was submitted to a second round of PCR using a semi-nested primer set
(sense NG061 5' GGC AAC ATG TTA TGG ATA GAC TGG 3', antisense NG063)
under the same conditions described above. Multiple positive and
negative controls were included in each PCR assay. PCR products were
analyzed in a 2% agarose gel electrophoresis with ethidium bromide
staining. Results of all samples testing positive for TTV DNA in the
PCR were confirmed in separate assays and sequences of PCR products
confirmed by automated sequencing on an ABI 373 sequencer
(Perkin-Elmer, Foster City, CA).
| |
RESULTS |
Thalassemic patients.
The results on PCR detection of TTV DNA in patient sera collected at
time of enrollment into the Cooleycare program (1992-1993) and at the
end of the 3-year follow-up period (1995-1996) are reported in Table
1. Of the 93 patient sera collected in
1992-1993, 87 (93.5%) tested positive for TTV DNA. Of these patients
with TTV viremia at baseline, 84 (96.5%) were still positive for TTV DNA at the end of the study period, while viremia became undetectable in the remaining 3 (3.5%) patients. Of the 6 patients with baseline negative TTV DNA, 3 (ages at enrollment were 1, 3, and 8 years) acquired TTV infection during the 3-year follow-up, as documented by
conversion to viremia in the sample collected in 1995-1996. Two of the
three patients had normal ALT levels throughout the follow-up period
while the remaining patient had biochemical evidence of hepatitis (ALT
peak, 196 U/L) (Fig 2). There was no
relation between the presence of TTV viremia and patients' age,
gender, serum ferritin levels, and pattern of ALT levels.
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| Fig 2.
Serum ALT profiles of a patient who acquired TTV
infection. Biochemical evidence of liver disease in this patient during
the study period was reflected by changes in the ALT level. The ALT
levels (U/L, dotted line) were plotted against the date of
determination; the upper reference limit for ALT was 40 U/L. Serum from
this patient collected at the time of enrollment tested negative for
TTV DNA by PCR. The serum samples collected at the
conclusion of the 3-year follow-up tested positive for TTV DNA.
|
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Blood donors.
Of the sera from 100 healthy blood donors, 22 were found to be
TTV+, representing a prevalence rate of 22%. TTV infection
was more frequent in male (20 of 73, 27.4%) than in female donors (2 of 27, 7.4%), representing a difference of 20% (95% confidence
interval [CI], 5.7 to 34.2). The age distribution was not
statistically different in TTV DNA+ and DNA
donors (40 years ± 11 v 38 years ± 11).
| |
DISCUSSION |
Specific TTV sequences were detected in a vast majority of
transfusion-dependent thalassemic patients in Italy, supporting the
hypothesis that TTV is a transfusion-transmissible agent. For the
patients evaluated in this study, the rate of TTV infection at the
baseline evaluation (93.5%) was higher than that previously found for
HCV and HGV in the same population of -thalassemic patients (85%
and 33% respectively).6,12 In addition, we found that 3 of
the 6 patients who were TTV DNA at the baseline
evaluation acquired the infection during the following 3 years of
observation. Although it seems reasonable to assume that these cases of
primary TTV infections resulted from the blood transfusion therapy, a
community-acquired origin could not be excluded. In this regard, a
longitudinal study comparing the incidence of TTV infection in
transfused versus nontransfused young patients would be informative.
TTV DNA was found in more than one fifth of Italian repeat blood
donors, which are selected on the basis of being at low risk for
bloodborne infections. By comparison, in the same population of donors,
the prevalences of HCV and HGV infections were 1.1% and 6.5%,
respectively.21-23 On the basis of these observations, it
is likely that the parenteral route may not be the only mode of spread
of TTV in Italy. In this regard, recent data showed that TTV DNA is
present in feces, which would suggest that the fecal-oral route of
viral transmission is possible.24 Some of the
epidemiological features identified in the present investigation, ie,
the higher frequency of TTV infection in Italian donors (22%) compared
with those in Japan and the United Kingdom (12% and
1.9%),14,15 and the higher prevalence of viremia in males
than in females (27.4% v 7.4%), may be helpful to clarify the
routes of infection, and will be the subject of future studies.
Only a small proportion (3.5%) of the patients who had baseline
infection have undergone spontaneous clearance of serum TTV DNA during
the 3-year study period. The disappearance of detectable TTV DNA in
these cases, however, does not necessarily indicate a complete recovery
from infection, and may merely represent a latent phase of ongoing
infection. By comparison, we recently showed that more than 25% of the
thalassemic patients with transfusion-associated HGV recovered from
infection within a few years.12 It remains to be elucidated
if the persistence of TTV is due to chronic infection or to frequent
reinfection of the patients with different strains of TTV.
Based on the data reported here, some considerations on the clinical
significance of TTV infection may be appropriate. The high prevalence
of TTV in thalassemic patients, who frequently have hepatic dysfunction
despite the absence of known hepatotropic infections,6
together with the observation that one of the three patients who
acquired TTV infection during the study period had a clinical course
suggestive of posttransfusion hepatitis, would support the original
hypothesis that this agent might cause liver disease. On the other
hand, it should be taken into consideration that transfusion-dependent
patients can theoretically be infected by a number of unidentified
bloodborne pathogens other than TTV, and are also at risk of developing
iron-induced hepatic damage.6,25 Taken together, the
observations that approximately one half of the patients with
persistent viral replication had normal liver enzymes throughout the
period of follow-up and that TTV viremia is also very common in
apparently healthy individuals, would suggest that the course of TTV
infection is indolent in most cases. Our hypothesis is also supported
by the data of Naoumov et al,16 who found that the
prevalence of TTV infection is not any higher in patients with chronic
liver disease than in controls. However, a role of this agent in
inducing clinical disease in some individuals cannot be excluded.
Preliminary data seem to indicate that TTV has structural similarities
to parvoviruses,14 which may sometimes induce
life-threatening complications in blood recipients.26,27 In
addition, the DNA sequencing studies performed so far indicate that a
certain degree of genetic diversity exists between different isolates
of TTV. Thus, particular viral strains may have different pathogenetic
effects in inducing transfusion-associated disease.
In conclusion, this prospective survey on transfusion-associated TTV
infection adds new data to the growing literature indicating that
hitherto unidentified bloodborne agents continue to cause chronic
infections among transfusion recipients. Future efforts on the
identification and characterization of these viruses, as well as the
description of their effects in infected individuals, may be useful in
the management of patients and to further reduce the risk of blood transfusion.
| |
APPENDIX |
Cooleycare members who have provided samples and data for this study:
M. Alessi (Catania); C. Artaz (Aosta); M.G. Batzella (S. Gavino
Monreale); P. Bellavita (Bergamo); G. Bertrand (Sassari); F. Betto
(Rho); A. Biolchini (Iglesias); C. Borgna (Verona); S. Calò
(Magenta); A. Cambosu, A. Carta (Oristano); E. Cichella (Rovigo); V. Cilla (Matera); E. Corvaglia (Casarano); D. Costantino (Locri); C. De
Rosa (Napoli); F. Di Gregorio (Catania); P. Di Paola (Palermo); D. Gallisai (Sassari); G. Girelli (Roma); M. Lendini (Olbia); R. Longhi
(Como); C. Magnano (Catania); L. Luongo (Agrigento); A. Mangiagli
(Siracusa); A. Meo (Messina); S. Strada (Monza); S. Montin (Monselice);
G. Forni (Genova); P. Rizzone Favacchio (Ragusa); F. Schettini (Bari);
G. Sciorelli (Monza).
| |
ACKNOWLEDGMENT |
The authors thank Dr R. Bohenzky and the sequencing-informatics team at
Sentinel Biosciences, Inc for their expert technical support.
| |
FOOTNOTES |
Submitted October 5, 1998; accepted November 30, 1998.
Cooleycare members providing samples and data for this study are
reported in the Appendix.
Supported in part by a grant from the Italian National Institute of
Health ("Progetto Sangue," Istituto Superiore di Sanità).
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 Daniele Prati, MD, Centro Trasfusionale e
di Immunologia dei Trapianti, IRCCS Ospedale Maggiore, Via Francesco
Sforza, 35, 20122 Milano, Italy.
| |
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Abstract
Introduction
