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.