Discussion
Many studies have confirmed that EBV infection is directly related to
the incidence of PTLD 12,13. This fact was confirmed
by the findings of this study. The EBV infection rate of the 24 PTLD
patients included in the analysis was 95.8%. The analysis suggested
that EBV infection was an important risk factor for PTLD. In the PTLD
group, the time of peak EBV copying was closely related to the time of
PTLD onset, which indicates that PTLD is likely to occur when the EBV
infection replicates rapidly and reaches its peak. Therefore, monitoring
changes in the EBV copy number in transplant patients will allow
clinicians to monitor PTLD and appropriately adjust the level of
immunosuppressants administered to patients. Furthermore, changes in the
EBV copy number may prompt the use of rituximab
therapy14. Recent research observed that the
first-time application of rituximab could be performed in patients whose
EBV-DNA load is >40000 U/mL after transplantation if they
similarly exhibited at least one symptom of PTLD or demonstrated
evidence of PTLD upon imaging 15.
CMV infection is common after liver transplantation in children and is
associated with the following symptoms: fever of unknown origin
(38.3°C), fatigue or systemic myalgia, and leukopenia or
thrombocytopenia. The relationship between CMV and PTLD remains unclear.
Some studies believe that CMV infection is a risk factor of PTLD,
although the mechanism of action is currently unknown. Most studies
believe that CMV infections are not related to the occurrence of PTLD.
JM, Kim 16 analyzed 119 liver transplant patients.
Among them, 66 (55.5%) patients had a CMV infection, and 15 of 119
patients eventually developed PTLD. Among them, 10 patients with PTLD
had a CMV infection, whereas 5 patients had no CMV infection.
Statistical analysis showed that the occurrence of PTLD was not related
to CMV infection (P=0.258). In this study, the CMV infection rate was
22.2%, and the final incidence of PTLD in CMV-infected patients was
31.2%. No statistically significant relationship was observed between
CMV infection and PTLD (P=1.000).
Studies have shown that donor EBV+/recipient
EBV- is an important risk factor for PTLD as a high
EBV infection rate can cause PTLD in younger patients. Previous research
has found that in donor EBV+/recipient
EBV- patients, 67% of patients develop a
postoperative EBV infection. A higher postoperative EBV infection rate
increases the risk of PTLD in patients. EBV-negative patients receiving
EBV-positive organs are at high risk of developing
PTLD17. This study assessed the viral infection status
of the donors. Seven of the study patients received cadaveric liver
transplants; thus, in these cases, the infection status of the donor
could not be obtained. Only 65 patients who underwent liver transplants
were analyzed, and the virus infection rate of the donor was not high.
Subsequently, no statistical significance was identified; this may be
due to the sample size.
Some studies have suggested that a high serum concentration of
tacrolimus is a risk factor for the onset of PTLD18.
Daizo Fukushima 19 analyzed the changes in tacrolimus
concentrations when the EBV load continued to increase and observed that
the tacrolimus concentrations in the PTLD group were significantly
higher than those in the control group. Other research has focused on
the correlation between tacrolimus and EBV infection. By monitoring
serum tacrolimus concentrations within 2 weeks of liver transplantation,
Lu 20 found that the EBV infection rate increased
within 2-4 weeks post-operatively in patients with a high serum
concentration of tacrolimus.
Bakker21 observed that when the immunosuppressant dosages
were reduced in patients suffering from uncontrolled, post-operative EBV
infections, the EBV load significantly reduced.
This study evaluated the relationship between serum tacrolimus
concentrations, PTLD, and EBV. Univariate analysis of the PTLD group and
the control group showed a statistical difference in the serum
concentrations of tacrolimus (P=0.021); however, multivariate analysis
demonstrated that serum tacrolimus concentration levels were not a risk
factor for PTLD, although the serum tacrolimus concentrations of
patients in the PTLD group were higher than those of the control group.
However, when analyzing the relationship between the peak time of EBV
infection and the serum tacrolimus concentrations of patients in the
PTLD group, it was observed that at a higher level of immunosuppression,
EBV is prone to uncontrolled proliferation. This is because tacrolimus
acts upon both B lymphocytes and T lymphocytes while suppressing humoral
and cellular immunity. This subsequently leaves patients prone to EBV
infections after surgery and makes it difficult to control EBV
proliferation after infection 22,23. In view of the
fact that EBV infection is a risk factor for PTLD, it is suggested that
when an uncontrolled proliferation of EBV occurs after organ
transplantation, the amount of immunosuppressive agents should be
appropriately reduced to prevent PTLD.
In this study, no association was observed between baseline
characteristics, laboratory indicators, and transplantation-related
indicators and the occurrence of PTLD. The current controversy is the
relationship between the patient’s age at the time of transplantation
and PTLD. A study observed that younger patients undergoing organ
transplantation are at a greater risk of PTLD, especially children (1-10
years old)24; Other research concluded that the risk
of postoperative PTLD reduces by 15% with a yearly increase in age25 and found that younger patients (at the time of
transplantation) is a risk factor for EBV and CMV after surgery26. No association was observed between age at
transplantation and the occurrence of PTLD; the possible reason could be
that the primary disease of the patients included in this study was
mostly biliary atresia, and the transplantation age of patients is
generally within 2 years. Young patients are probably more susceptible
to PTLD because they have a higher viral infection rate than adults at
the time of transplantation.