Objectives: Central perivenulitis can occur in association with T-cell-mediated rejection and can sometimes require strong immunosuppressant therapy as refractory rejection. Furthermore, patients with central perivenulitis are more likely to have subsequent episodes of T-cell-mediated rejection and develop chronic rejection than those without central perivenulitis. We retrospectively analyzed clinical data of pediatric patients with episodes of T-cell-mediated rejection according to severity of central perivenulitis and monitored HLA-DR-positive CD8-positive T cells and recent thymic emigrants during treatment for T-cell-mediated rejection.

Materials and Methods: We identified biopsy-proven T-cell-mediated rejection in 50 liver transplant recipients (45 with living-related donors, 5 with deceased donors) between September 2014 and August 2018. Lymphocyte subsets in peripheral blood samples were analyzed.

Results: Of 50 pediatric patients, 30 were boys and 20 were girls (median age at transplant of 1.1 y; inter­quartile range, 0.6-6.2 y). Central perivenulitis was found in 46 patients (92%), which was mild in 13, moderate in 16, and severe in 17. Antithymocyte globulin was more frequently administered to patients with severe central perivenulitis than others (P < .05). Patients with antithymocyte globulin treatment were less likely to have subsequent episodes of T-cell-mediated rejection than those without this treatment (P < .05). The absolute number of CD8-positive HLA-DR-positive T cells in patients during treatment was significantly higher than in control patients (P < .05). The absolute number of recent thymic emigrants in patients with active infection was significantly lower than in patients without infection (P < .05).

Conclusions: Our results suggest the efficacy and safety of antithymocyte globulin for treating T-cell-mediated rejection with severe central perivenulitis in pediatric liver transplant recipients and suggest that anti­thymocyte globulin can prevent subsequent episodes of T-cell-mediated rejection. Analyzing lymphocyte subsets during treatment for rejection may help highlight viable therapeutic strategies for achieving a good outcome.

Key words : Central perivenulitis, Recent thymic emigrants, Rejection, T cells

Introduction

With the introduction of the currently available immunosuppressants, rejection rates after liver transplant (LT) range from 10% to 20% in adults, and over 90% of acute rejection episodes are in response to steroid bolus therapy.¹ However, rejection after LT occurs more frequently in children than in adults, with reported rates of 48% to 60%.^2,3 Furthermore, refractory rejection after LT in pediatric patients remains a challenging issue, occurring in 8.1% to 34% of cases.^2,4,5 Patients who do not receive appropriate treatment for refractory rejection can develop graft failure and patient mortality. Furthermore, centri­lobular changes, often termed central perivenulitis (CP), have been gradually recognized during episodes of T-cell-mediated rejection (TCMR), and patients with CP have a significantly high risk of developing recurrent episodes of TCMR and changes consistent with chronic rejection than those without CP.⁶

Antithymocyte globulin (ATG) is a polyclonal antibody that has been proven to be effective for depleting T cells in several immune-mediated conditions. It has been widely used in the field of LT to prevent or treat rejection. Although the effective use of ATG in patients with refractory rejection has been reported, the increased risk of infectious complications associated with T-cell depletion remains a significant issue.^7-9 Among these infectious complications, cytomegalovirus (CMV) infection occurs particularly frequently, especially when ATG is used to treat rejection.¹⁰ Therefore, evaluating the immune status during ATG treatment is important so that the immunosuppressant drug dose can be adjusted to achieve a good outcome.

Human leukocyte antigen DR (HLA-DR) is commonly used as a marker for T-cell activation.^11-13 Recent thymic emigrants (RTEs), indicators of thymus function, are the youngest subset of peripheral T cells; these differ functionally and phenotypically from others in the naïve T-cell pool.¹⁴ Monitoring the amount of RTEs can be a potential marker for infectious complications.

The main objective of our study was to analyze retrospectively the clinical data of pediatric patients with episodes of TCMR according to CP severity and to assess the efficacy and safety of ATG. Subsequently, we reviewed peripheral blood lymphocyte levels during treatment for rejection.

Materials and Methods

The use of ATG for LT patients has been covered by the universal health insurance system in Japan since September 2014. From September 2014 to August 2018, 228 pediatric LT procedures were performed at the National Center for Child Health and Development (NCCHD), Tokyo, Japan. Most pediatric LT procedures involve living donors, with all grafts from living donors being related. Included patients had at least 1 rejection episode and had been followed for more than 1 year after treatment.

We obtained written informed consent from all guardians of patients involved in this study. This study was conducted with the approval of the ethics committee of the NCCHD (No. 152).

Basic immunosuppression protocol
The maintenance immunosuppressive regimens included a double regimen (tacrolimus and steroids) or triple regimen (tacrolimus, steroids, and myco­phenolate mofetil [MMF]). The trough level of tacrolimus was maintained between 10 and 12 ng/mL for the first month and between 8 and 10 ng/mL for the subsequent 3 months. Methylprednisolone was administered at a dose of 1 mg/kg from posto­perative day (POD) 1 to POD3, at 0.5 mg/kg from POD4 to POD6, and at 0.3 mg/kg on POD7. Prednisolone was given orally at a dose of 0.3 mg/kg from POD8 to POD28, at 0.1 mg/kg after POD29 for 2 months, and then basically withdrawn after 3 months.

Diagnosis of rejection
Rejection was suspected in patients with clinical manifestations (a continuous fever or massive ascites) and/or elevated liver function test findings, such as elevated levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltrans­ferase, and total bilirubin. The diagnosis and grading of rejection were made on the bases of pathologic evidence from a liver biopsy according to the Banff schematic diagram by 2 pathologists (R.I. and T.Y.).¹⁵ The diagnosis of CP related to TCMR was confirmed with an algorithm proposed by the Banff Working Group.¹⁶ Central perivenulitis was graded as mild when there was isolated central vein endothelitis, moderate when hemorrhaging was present with endothelitis, and severe when necrosis involved perivenular regions. Doppler ultrasonography and blood tests were performed to exclude the possible causes of CP rather than TCMR, including vascular issues, viral hepatitis, and autoimmune hepatitis. Fibrosis in centrilobular lesions was assessed and scored according to the fibrosis scoring system proposed by Venturi and associates.¹⁷

Treatment for patients with T-cell-mediated rejection
Pediatric patients with TCMR were initially treated with 10 mg/kg intravenous methylprednisolone for a few consecutive days once rejection was pathologically diagnosed. Antithymocyte globulin was introduced to patients suspected to have a refractory rejection episode with persistent clinical manifestations and/or significantly elevated liver function test findings that did not respond to 10 mg/kg steroid bolus therapy for 3 to 5 days. Patients received a daily dose of ATG of 1 to 1.5 mg/kg over 5 to 7 days via central venous line. Pretreatment consisted of 1 mg/kg methylpredni­solone and 0.5 mg/kg acetaminophen to prevent cytokine release syndrome. During treatment with ATG, the serum concentration of tacrolimus was maintained at half of the target range, and MMF treatment was stopped to avoid overimmunosup­pression. Intra­venous antibiotics were not routinely applied as prophylactic treatment. Prophylactic ganciclovir was not routinely used in our institution, even when the serologic status of the donor and recipient indicated a high risk, such as a donor-positive/recipient-negative status.

Lymphocyte subset analyses
CD8-positive HLA-DR-positive T-cells and RTEs in peripheral blood samples were analyzed by flow cytometry. Peripheral blood samples were collected from enrolled patients and from those without any episodes of rejection as control samples (n = 4). Blood samples were obtained during treatment with steroid bolus therapy or ATG and/or within 1 week after those treatments had been completed. According to CD8 analyses, patients with active infection were excluded. In the RTE analysis, the patients were divided into 2 groups: active infection and nonactive infection. Data were described in absolute numbers.

Treatment of infection
Infection after treatment for rejection was defined as the detection of CMV and Epstein-Barr virus (EBV) from the peripheral blood or a fever with positive bacteriologic cultures less than 1 month after the completion of rejection therapy. Active CMV antigenemia was defined by the presence of more than 1 pp65 antigen-positive cell/50 000 leukocytes. Active EBV was defined by the detection of more than 102 copies/μg DNA.¹⁷

Statistical analyses
Quantitative variables are expressed as medians and interquartile range (IQR). Qualitative variables were reported as percentages. The chi-square or Fisher exact tests were used for comparisons of categorical variables. Differences between continuous variables were analyzed with the Mann-Whitney U test or a 1-way analysis of variance. Statistical analyses were performed using SPSS software version 22.0 (SPSS Inc., Chicago, IL, USA). P < .05 was considered to be statistically significant in this study.

Results

Biopsy-proven TCMR was identified in 50 patients (21.9%) within 3 months after LT (45 with living-donor LT, 5 with deceased-donor LT), which was initially treated with steroid bolus injection therapy (Table 1). Median age and body weight at LT were 1.1 years (IQR, 0.6-6.2 y) and 9.0 kg (IQR, 7.3-16.4 kg), respectively. There were 30 male and 20 female pediatric patients. Underlying liver diseases for LT included biliary atresia (n = 26), metabolic disorder (n = 5), graft failure (n = 5), acute liver failure (n = 4), idiopathic liver cirrhosis (n = 3), Alagille syndrome (n = 2), congenital hepatic fibrosis (n = 2), liver tumor (n = 2), and congenital portosystemic shunt (n = 1). Central perivenulitis was found in 46 patients (92%), including 13 with mild, 16 with moderate, and 17 with severe. Patient characteristics based on severity of CP are summarized in Table 2.

Comparisons of clinical course and outcomes of patients according to central perivenulitis
As shown in Table 3, there were no significant differences in median time from LT to TCMR episodes, the median total dose of methylprednisolone, the median duration of methylprednisolone therapy, and immunosuppression at the time of the biopsy in the 4 groups (no CP and mild, moderate, and severe CP). Antithymocyte globulin was introduced more frequently in patients with severe CP than in others (P < .05). The rejection activity index differed significantly among the 4 groups (P < .05) (Table 4). With increased severity of CP, the incidence of fibrosis in pathologic findings became increased; in particular, the incidence rate of perivenular fibrosis was significantly higher (P < .05).

The incidence rate of infectious complications, including CMV, EBV, and sepsis, was higher in patients with severe CP than in others, albeit not to a significant degree. With regard to CMV antigenemia, no patient had infectious disease symptoms, and all patients responded to oral valganciclovir or intravenous ganciclovir therapy.

One patient with severe CP died of graft dysfunction due to recurrent rejection, and 2 patients with moderate CP died due to sepsis and respiratory failure secondary to pulmonary fibrosis. One patient with severe CP underwent retransplant because of graft dysfunction due to antibody-mediated rejection (Table 5). There were no significant differences in patient and graft survival among the 4 groups. Thirty-nine patients are currently alive with normal liver function (normal serum transaminases, normal serum gamma-glutamyltransferase, and normal serum bilirubin); however, patients with severe CP were more likely to have deranged liver function test findings than others (P < .05). Most patients (3 without CP, 8 with mild CP, 8 with moderate CP, and 5 with severe CP) are currently being treated with calcineurin inhibitor monotherapy as maintenance immunosup­pressive therapy. Dual therapy com­bining calcineurin inhibitor with either steroid or MMF was administered to 4 patients with mild CP, 2 with moderate CP, and 5 with severe CP. A combination of more than 2 different immunosup­pressants was taken in 1 patient without CP, 1 with mild CP, 4 with moderate CP, and 6 with severe CP. There was no significant difference in the current immunosup­pressant status among these patients. Patients with greater CP severity were more likely to have subsequent episodes of TCMR, chronic rejection, and progression of fibrosis than others, although not significantly.

Comparison of clinical course between patients with and without antithymocyte globulin treatment
Twenty-one patients received ATG treatment for biopsy-proven TCMR after LT. Central perivenulitis was detected in all TCMR episodes with ATG treatment, including 3 with mild, 7 with moderate, and 11 with severe status, with mild-type TCMR episodes seen in 10 patients, moderate-type TCMR episodes seen in 9 patients, and severe-type TCMR episodes seen in 6 patients without ATG treatment. In patients with TCMR who did not have ATG treatment, the severity of CP had a significantly negative impact on the duration (in days) of methylprednisolone bolus (P < .05) (Figure 1a). The total dose of methylprednisolone in patients with TCMR without ATG treatment was higher in cases of rejection with severe CP than in those cases without severe CP; however, the difference did not reach statistical significance (Figure 1b). Infectious disease occurred in 11 patients (61.1%) with ATG treatment and in 14 patients (48.3%) without ATG treatment. Patients with ATG treatment were less likely to have subsequent episodes than those without ATG treatment, with subsequent episodes shown in 2 patients (9.5%) with ATG treatment and in 8 patients (28%) without ATG treatment (P < .05).

Lymphocyte subset analyses
Figure 2 shows the clinical course of 1 patient in the ATG group who had serial monitoring of the lymphocyte subset and liver biopsy. A large population of T cells was identified, with a substantial number of CD8-positive HLA-DR-positive T cells also detected in the peripheral blood at the time that ATG treatment was introduced. In addition, the number of T cells dramatically decreased after completion of ATG treatment.

Of 26 lymphocyte subset samples (n = 18 patients) that were analyzed, 21 were assessed for CD8-positive HLA-DR-positive T cells and all 26 were assessed for RTEs. Eleven samples for CD8-positive HLA-DR-positive T-cell analyses were obtained during treatment for rejection. The absolute number of CD8-positive HLA-DR-positive T cells was significantly higher in patients during treatment than in patients after treatment and control patients (P < .05) (Figure 3a).

In the RTE analysis, 5 of 26 samples were obtained from patients with active infection, including CMV in 5 samples and both CMV and EBV in 1 sample. The absolute number of RTEs in patients who had an active infection was significantly lower than in patients without infection (P < .05) (Figure 3b). There were no significant correlations between the absolute number of RTEs and the time interval to infection.

Discussion

Although the rate of incidence of refractory rejection is low, some patients have graft loss and even death unless appropriate treatment is applied. Central perivenulitis has been gradually recognized during episodes of TCMR and is attributed to a variety of causes, including not only rejection but also ischemic reperfusion injury, compromised blood flow to the graft, viral infections, recurrent disease, and autoimmune hepatitis.^6,19,20 Previous reports have proposed that CP was likely a component of the rejection process when accompanied by TCMR.^19,21-24 Furthermore, some episodes of CP have proven resistant to standard therapy and require additional immunosuppressant therapy. Indeed, in the present study, TCMR episodes with severe CP were prone to requiring ATG treatment. In patients without CP, ATG was never administered for TCMR episodes.

Causes of the original liver disease should be considered when determining the cause of CP. Previous studies have reported that TCMR after LT for acute liver failure often shows pathologic findings of CP that are refractory to methylprednisolone bolus therapy.^25,26 Although there were no marked dif­ferences in causes in our patient group as shown by CP severity, ATG treatment was needed in all patients with acute liver failure. Special attention should be given when TCMR episodes are encountered after LT for acute liver failure, as the incidence of refractory rejection in such patients may be high.

With respect to the clinical course of patients with CP, Lovell and colleagues reported a high incidence of subsequent episodes of TCMR and the deve­lopment of chronic rejection.⁶ Although some patients in our study had subsequent episodes of TCMR and chronic rejection, the incidence rate was lower than that described by Lovell and colleagues. We also reported that patients with severe CP had a significantly higher rejection activity index and were likely to have a finding of fibrosis in zone 1 to 3. Despite no significant differences being noted in the rate of subsequent episodes of progressive fibrosis among the patients with CP, rigorous clinical follow-up should be practiced in patients with severe CP, as these patients are more likely to show deranged liver function test findings at follow-up versus those without severe CP.

The use of ATG for refractory rejection in adult patients after LT has resulted in excellent patient survival rates of 64% to 89%.^8,27 However, few data concerning the effectiveness of ATG after pediatric LT have been reported.⁷ In addition to the excellent outcomes obtained due to the introduction of ATG for pediatric patients after LT, our results could suggest that the use of ATG is a feasible treatment strategy for patients with severe CP. In our study, with regard to patients who did not receive ATG treatment, patients with severe CP took significantly longer to be weaned from methylprednisolone bolus therapy and the total amount of methylprednisolone administered was much greater than in those with mild or moderate CP. Long-term use of methyl­prednisolone could result from low responsiveness to methylprednisolone bolus therapy for TCMR. However, patients with ATG treatment had less frequent episodes of TCMR recurrence than those without ATG treatment. These results suggest that TCMR episodes with more severe CP should be treated with ATG at an earlier timepoint instead of the long-term use of methylprednisolone to avoid adverse effects of steroid and subsequent episodes of TCMR, even if TCMR responds to methylprednisolone.

However, complications, including severe infec­tions, are issues associated with ATG treatment. Although the severity of CP showed no association with the incidence of infection after treatment for rejection, patients with severe CP were more likely to present with infections than others. The rate of CMV antigenemia after TCMR episodes with ATG treatment was higher than without ATG treatment (data not shown), which was also more frequent than that described in previous reports.^28,29 Prophylaxis treatment for CMV during ATG administration was recommended, and CMV prophylaxis was reported to effectively decrease rates of CMV antigenemia.^9,10 Although no cases of CMV disease developed in this study and it is still unclear whether prophylaxis CMV during ATG treatment is needed, a novel treatment regimen for CMV during ATG therapy should still be considered in light of our results.^30,31

The present study also investigated the effects
of immunosuppressant therapy on CD8-positive HLA-DR-positive T cells and RTEs during TCMR episodes, which could be a significant biomarker for refractory rejection. The flow cytometric analysis of T-lymphocyte subsets showed a significant dif­ference in the absolute number of CD8-positive HLA-DR-positive T cells between patients without rejection and those being treated for rejection. The absolute number of CD8-positive HLA-DR-positive T cells during treatment was significantly larger than the number shown after treatment. Our results suggest that CD8-positive HLA-DR-positive T cells can be a marker of the effects of treatment for TCMR, and monitoring the changes in these cells may suggest a suitable timing for converting the immunosuppressant regimen from steroid bolus therapy to ATG, which can significantly reduce the absolute number of these cells. Patients with refractory rejection should therefore receive T-cell depletion therapy, including for CD8-positive HLA-DR-positive T cells in the liver, as in our case in Figure 2. In addition, our analyses also suggested the potential utility of monitoring of RTEs during TCMR therapy. Our data showed that the absolute number of RTEs was significantly decreased in patients with infectious complications. In some patients with severe human immunodeficiency virus infection, also described as compromised hosts, recovery of CD4-positive T-cell counts was poor, with notably reduced RTEs compared with healthy patients.¹⁴ Patients who receive TCMR therapy achieve T-cell circulation to a degree similar to that shown in patients with human immunodeficiency virus.

Several limitations associated with the present study warrant mention. First, the study is limited by its retrospective design and single-center patient cohort. In our center, we are hesitant to introduce ATG therapy for earlier patients with TCMR episodes who had received longer periods of methylprednisolone bolus therapy. Therefore, ATG was only occasionally administered to patients who had received short-term or long-term methylprednisolone bolus therapy. We suggest that a rigorous protocol for TCMR treatment should be established to assess the accuracy and efficacy of ATG treatment. Second, the feasibility of monitoring lymphocyte subsets in patients with TCMR was evaluated in only a small sample of patients, with sampling occurring at different times and in different patient types. Ideally, samples should be taken from the same patients in series. Third, we were not able to compare our limited sample with control patients (that is, totally healthy nontransplant patients) with respect to the utility of lymphocyte subset analyses. However, our study suggested the utility of ATG for pediatric patients with TCMR and the versatility of monitoring lymphocyte subsets during treatment for TCMR.

Conclusions

We observed excellent outcomes in patients with TCMR accompanied by CP who received ATG treatment. Our results suggest the efficacy and safety of ATG in treating pediatric patients with refractory rejection after LT and that patients who have TCMR episodes with severe CP should be considered for early administration of ATG. Use of ATG could help prevent subsequent episodes of TCMR. In addition, analyses of lymphocyte subsets during treatment for rejection may be useful for evaluating the effects of treatment and predicting the risk of infection, which may lead to the consideration of suitable therapeutic options for recurrent rejection.

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