Post-transplant lymphoproliferative disease in pediatric lung transplant recipients: Recent advances in monitoring

Abstract: To investigate the clinical validity of newer diagnostic tests such as monitoring of EBVqPCR and lymphocyte function assay ImmuKnow in helping to diagnose PTLD in pediatric lung transplant recipients. Single‐center, retrospective case–control study. CsA trough levels, EBVqPCR and ImmuKnow (Cyclex Inc., Columbia, MD, USA) levels were measured serially as part of routine care. Re‐transplant patients and patients who did not reach 12 months post‐transplant at the time of analysis were excluded. Twenty‐seven patients met the inclusion criteria. The study group consisted of seven patients who developed PTLD, five of which were EBV? recipients who received EBV+ lungs. The rest of the eligible patients served as controls. Median time to develop PTLD was 273 days (range: 166–343). One, two, three, six, and nine months after transplant, mean (±s.d.) CsA trough whole blood levels (ng/mL) were not different between the two groups: 378 ± 38, 390 ± 52, 402 ± 89, 359 ± 42, and 342 ± 115, vs. 416 ± 105, 347 ± 64, 337 ± 78, 333 ± 86, and 281 ± 54 [PTLD vs. no‐PTLD, respectively (p > 0.05 for all time points)]. Mean (±s.d.) EBVqPCR levels (copies/mL) measured at three, six, and nine months post‐transplant were significantly elevated in PTLD group compared to no‐PTLD group: 84 ± 99, 3384 ± 7428 and 839 ± 1444 vs. 9 ± 26, 8 ± 36 and 32 ± 136, respectively (p < 0.05 for all time points). Mean (±s.d.) ImmuKnow levels (ATP ng/mL) at three, six, and nine months post‐transplant were significantly lower in the PTLD group when compared with no‐PTLD group: 144 ± 67, 137 ± 110, and 120 ± 153 vs. 290 ± 161, 300 ± 162, and 293 ± 190, respectively (p < 0.05 for all time points). Close monitoring of EBV viral load by qPCR and the degree of immunosuppression via ImmuKnow may guide physicians to reach the diagnosis of PTLD early.     

Diagnosis and treatment of post-transplantation lymphoproliferative disorder in pediatric heart transplant patients

PTLD is a severe complication in transplant recipients. Detection of increased EBV load in the peripheral blood acts as a surrogate marker for increased risk of PTLD development. We analyzed the time course of the disease, its severity, the organs involved, and mortality rates in our institutional experience of pediatric heart transplantation. This paper identifies risk factors for PTLD and describes the different ways of diagnosing and treating the disease. PTLD was screened for in 146 pediatric heart transplant patients using a retrospective analysis in patients who received transplantation before 1998. Prospective determination was performed in 72/146 patients transplanted after 1998 within the post-transplant follow-up. The occurrence of PTLD with all interventions, including tapering of immunosuppression, surgery, viral monitoring, and antiviral interventions, was recorded. PTLD was diagnosed in 12/147 (8.2%) children at a mean age of 7.2 +/- 3.3 yr after a mean post-transplant period of 3.2 +/- 2.2 yr. PTLD manifested in: lymph nodes (n = 4), intestine (n = 3), tonsils and adenoids (n = 2), eye (n = 2), and lung (n = 1). It was diagnosed in 7/12 as a monomorphic B-cell lymphoma and in four patients as a monomorphic Burkitt lymphoma, a polymorphic B-cell lymphoma, a T-cell rich or angiocentric lymphoma (Liebow) and as reactive plasmacytic hyperplasia (early lesion), respectively. Histology was not possible in one patient with ocular manifestation. EBV association was 83%. Risk factors in the comparison with patients without PTLD were age at time of Tx, primary EBV infection after Tx, use of Azathioprine and >or=3 doses of ATG. CMV mismatch and CMV infection, rejection episodes and steroids were not risk factors. Despite reduction of immunosuppression, treatment consisted of surgical procedures to remove tumor masses (n = 6), Rituximab (n = 5), polychemotherapy (n = 3), antiviral (n = 1) and autologous T-cell therapy (n = 1). All patients demonstrated full remission without death related to PTLD or treatment at 3.9 (1.3-6.2) yr median follow-up time. The manifestation of PTLD in pediatric heart transplant recipients is associated with EBV infection and is predominantly in the form of a B-cell lymphoma. A tight and specific follow-up including early assessment of immunity status and specific therapeutic intervention to improve cellular immunity is warranted and may contribute to a significant reduction of PTLD-related morbidity and mortality.     

Hospital readmission following pediatric heart transplantation

The frequency, indications, and outcomes for readmission following pediatric heart transplantation are poorly characterized. A better understanding of this phenomenon will help guide strategies to address the causes of readmission. Data from the Clinical Trials in Organ Transplantation for Children (CTOTC‐04) multi‐institutional collaborative study were utilized to determine incidence of, and risk factors for, hospital readmission within 30 days and 1 year from initial hospital discharge. Among 240 transplants at 8 centers, 227 subjects were discharged and had follow‐up. 129 subjects (56.8%) were readmitted within one year; 71 had two or more readmissions. The 30‐day and 1‐year freedom from readmission were 70.5% (CI: 64.1%, 76.0%) and 42.2% (CI: 35.7%, 48.7%), respectively. The most common indications for readmissions were infection followed by rejection and fever without confirmed infection, accounting for 25.0%, 10.6%, and 6.2% of readmissions, respectively. Factors independently associated with increased risk of first readmission within 1 year (Cox proportional hazard model) were as follows: transplant in infancy (P = .05), longer transplant hospitalization (P = .04), lower UNOS urgency status (2/IB vs 1A) at transplant (P = .04), and Hispanic ethnicity (P = .05). Hospital readmission occurs frequently in the first year following discharge after heart transplantation with highest risk in the first 30 days. Infection is more common than rejection as cause for readmission, with death during readmission being rare. A number of patient factors are associated with higher risk of readmission. A fuller understanding of these risk factors may help tailor strategies to reduce unnecessary hospital readmission.     

Severe cold agglutinin disease caused by recurrent monomorphic Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD), clonally related to an EBV-negative plasmacytic hyperplasia in a pediatric multivisceral organ transplant recipient

PTLD represent major post-transplant complications. The major etiologic factor is EBV. Association with cold agglutinin disease has not been described so far. We report a three-yr-old girl who developed oligoclonal EBV-negative plasmacytic hyperplasia as well as Coombs test-positive anemia one yr after multivisceral organ transplantation, performed after subtotal bowel resection for colointestinal aganglionosis and liver cirrhosis resulting from long-term parenteral nutrition. The patient was treated for plasmacytic hyperplasia with cyclophosphamide and prednisolone and achieved clinical remission. One yr later PTLD progressed possibly driven by EBV to DLBCL. The migration patterns of the amplified Ig heavy chain genes demonstrated a probable clonal relationship of the DLBCL to a clone almost present in the plasmacytic hyperplasia. This progression was accompanied by a rapid rise of cold agglutinin titers with symptoms of severe cold agglutinin disease, leading to right femoral and extern iliac vein thromboses requiring partial leg amputation. After four cycles of rituximab, cyclophosphamide, and prednisolone, the patient achieved complete PTLD remission and the cold agglutinins disappeared. Summarizing, PTLD may be accompanied by cold agglutinin disease, and both may be successfully treated by immuno-chemotherapy. The appearance of cold agglutinins in transplant patients may indicate PTLD development.     

Post-transplantation lymphoproliferative disorder in pediatric kidney-transplant recipients - A national study

Cleper R, Ben Shalom E, Landau D, Weissman I, Krause I, Konen O, Rahamimov R, Mor E, Bar‐Nathan N, Frishberg Y, Davidovits M. Post‐transplantation lymphoproliferative disorder in pediatric kidney‐transplant recipients – A national study. Abstract: PTLD is the most common malignancy in pediatric kidney‐transplant recipients. We examined the prevalence, clinical features, and outcome of PTLD in Israel. Twelve (4.4%) of 272 pediatric (<19 yr) kidney‐transplant recipients retrieved from a search of the NIKTR for 1991–2008 had acquired PTLD at a median of 3.2 yr post‐transplantation. PTLD‐affected patients were younger at transplantation (4.2 vs. 12.5 yr, p = 0.02), had a higher rate of OKT3 therapy for acute rejection (25% vs. 4%, p = 0.015), and 5/12 were EBV‐seropositive at transplantation. Graft dysfunction was the presenting sign in six (50%). PTLD was predominantly abdominal (83%) and B‐cell type (67%); T‐cell PTLD occurred exclusively in EBV‐seropositive patients. Treatment consisted of immunosuppression cessation (6/12, 50%), antiviral agents (7/12, 58%), anti‐CD20 monoclonal antibodies (4/12, 33%), and chemotherapy (6/12, 50%). Survival was 100% in the EBV‐naïve patients and 40% in the EBV‐seropositive patients. Graft loss occurred in three of eight survivors (37.5%). PTLD‐associated mortality risk was older age: 11.2 vs. 3.4 yr, longer dialysis: 15 vs. 6.5 months, T‐cell type disease (75%), later PTLD onset: 6.35 vs. 1.9 yr post‐transplantation and era of transplantation (43% mortality before vs. 20% after 2001). Pretransplantation EBV‐seronegative status might confer a survival benefit with early detected PTLD. EBV‐seropositive patients are at risk for aggressive late‐onset lethal PTLD.     

Complete immunosuppressive withdrawal as a uniform approach to post-transplant lymphoproliferative disease in pediatric liver transplantation

Epstein–Barr virus (EBV)‐associated post‐transplant lymphoproliferative disease (PTLD) in pediatric liver transplant recipients is associated with a high mortality (up to 60%) and the younger age groups, who are predominantly EBV‐naïve, are at highest risk for development of this disease. The aim of this study is to assess, in this high‐risk group, patient outcome and graft loss to rejection when complete withdrawal of immunosuppressive agents (IMS) is instituted as the mainstay of treatment in addition to the use of standard therapy. A retrospective analysis of 335 pediatric patients whose liver transplants were performed by our team between September 1988 and September 2002, was carried out through review of computer records, database and patient charts. Fifty patients developed either EBV or PTLD; 80% were ≤2 yr of age. Of these 50 patients, 19 had a positive tissue diagnosis for PTLD and 31 were diagnosed with EBV infection, 14 of whom had positive tissue for EBV. Fifty‐eight percent of patients who developed PTLD and 51.6% of patients with EBV received antibody for induction or treatment of rejection prior to onset of disease. Forty‐six patients (92%) received post‐transplant antiviral prophylaxis with ganciclovir or acyclovir. Antiviral treatment included ganciclovir in 76%, acyclovir in 20% and Cytogam (in addition to one of the former agents) in 44%. In those with PTLD, treatment included chemotherapy (n = 1), Rituximab (n = 2), and ocular radiation (n = 1). IMS was stopped in all patients with PTLD and in 19 with EBV infection and was held as long as there was no allograft rejection. Eight patients have remained off IMS for a mean of 1535.5 ± 623 days. Of the 21 patients who were restarted on IMS for acute rejection, 18 responded to steroids and/or reinstitution of low‐dose calcineurin inhibitors. The mean time to rejection while off IMS in this group was 107.43 ± 140 days (range: 7–476). Two patients were re‐transplanted for chronic rejection; one had chronic rejection that existed prior to discontinuing IMS. The mortality rate in our series was 31.6% in those with PTLD and 6% in those with EBV disease. The cause of death was related to PTLD or sepsis in all cases; no deaths were due to graft loss from acute or chronic rejection. PTLD is associated with high mortality in the pediatric population. Based on this report, we advocate aggressive management of PTLD that is composed of early cessation of IMS, the use of antiviral therapy, and chemotherapy when indicated. Episodes of rejection that occur after stopping IMS can be successfully treated with standard therapy without graft loss to acute rejection.     

Long-term outcome of intensive initial immunosuppression protocol in pediatric deceased donor renal transplantation

Olaitan OK, Zimmermann JA, Shields WP, Rodriguez-Navas G, Awan A, Mohan P, Little DM, Hickey DP. Long-term outcome of intensive initial immunosuppression protocol in pediatric deceased donor renal transplantation.
Pediatr Transplantation 2010: 14: 87–92. © 2009 John Wiley & Sons A/S.
Abstract:  To report the long-term outcome of deceased donor kidney transplantation in children with emphasis on the use of an intensive initial immunosuppression protocol using R-ATG as antibody induction. Between January 1991 and December 1997, 82 deceased donor kidney transplantations were performed in 75 pediatric recipients. Mean recipient age at transplantation was 12.9 yr and the mean follow-up period was 12.6 yr. All patients received quadruple immunosuppression with steroid, cyclosporine, azathioprine, and antibody induction using R-ATG-Fresenius^®. Actual one, five, and 10 yr patient survival rates were 99%, 97%, and 94%, respectively; only one patient (1.2%) developed PTLD. Actual one, five, and 10 yr overall graft survival rates were 84%, 71%, and 50%, respectively; there were five cases (6%) of graft thrombosis and the actual immunological graft survival rates were 91%, 78%, and 63% at one, five, and 10 yr, respectively. The use of an intensive initial immunosuppression protocol with R-ATG as antibody induction is safe and effective in pediatric recipients of deceased donor kidneys with excellent immunological graft survival without an increase in PTLD or other neoplasms over a minimum 10-yr follow up.     

Post-transplant lymphoproliferative disease in children

Epstein-Barr virus (EBV)-driven post-transplant lymphoproliferative disease (PTLD) is an important cause of morbidity and mortality following transplantation, and it occurs more frequently in children than in adults. Of 22 (5%) children at our institution who developed tissue-proven PTLD 1-60 months (mean 16.5 months) following organ transplant, 11 died: nine of these 22 patients developed PTLD between 1989 and 1993, and seven (78%) died; the remaining 13 developed PTLD between 1994 and 1998, and four (31%) died (p = 0.08). All nine patients who developed PTLD < 6 months after transplant died, but 11 of 13 patients who manifested disease > or = 6 months after transplant survived (p = 0.0002). Ten of 11 (91%) survivors, but only two of eight (25%) children who died, had serologic evidence of EBV infection at the time of PTLD diagnosis (p = 0.04). EBV seroconversion identified patients at risk for developing PTLD, but also characterized patients with sufficient immune function to survive EBV-related lymphoid proliferation. In situ hybridization for EBER1 mRNA was diagnostically helpful because it detected EBV in tissue sections of all 20 patients with B-cell PTLD, including those with negative serology.     

Central nervous system lymphoproliferative disorder in pediatric kidney transplant recipients

Post-transplant lymphoproliferative disorder (PTLD) is a complication of transplantation resulting from impaired immune surveillance because of pharmacologic immunosuppression. We present two cases of central nervous system (CNS) PTLD in children on calcineurin-inhibitor free immunosuppression with dramatically different presentations and outcomes. One patient had brain and spinal cord lymphoma with a rapid and fatal course. The other patient had brain and ocular PTLD that responded to multimodal therapy with reduction of immunosuppression, high-dose steroids, and rituximab given in a dose-escalation protocol. This protocol may have enhanced the penetration of rituximab into the CNS. We review the literature on CNS and ocular PTLD and elaborate on the treatments available for both diseases.     

Late airway complications following pediatric liver transplantation: A case series

Background

Late airway complications, as consequence of immunosuppression following pediatric liver transplantation are uncommonly reported.

Methods

In this retrospective case series, we describe two young children presenting with symptoms of airway obstruction, secondary to differing pathologies in the supraglottic airway, as a result of immunosuppression following liver transplantation.

Results

Case 1, a 2-year-old girl who presented with stridor 12-months following liver transplantation, was found to have a proliferative soft tissue mass involving the supraglottic larynx. Biopsies were consistent with infiltrative eosinophilic laryngitis and associated eosinophilic esophagitis. Case 2, a 12-month-old female who presented with stridor 5-months following liver transplantation, was found to have an exophytic soft tissue mass involving the supraglottis and hypopharynx. Biopsies revealed polymorphic Epstein–Barr virus (EBV) driven post-transplant lymphoproliferative disease (PTLD). Case 1 was managed with local resection and high dose oral corticosteroids. Case 2 responded to debulking of the necrotic supraglottic mass, reduction of immunosuppression and rituximab.

Conclusion

A high index of suspicion needs to be maintained for complications of immunosuppression for appropriate diagnosis of airway presentations following pediatric liver transplantation. Further research is necessary to improve early detection and consolidate management strategies for these airway lesions.     

Post-transplant lymphoproliferative disorder after solid-organ transplant in children

The post-transplant lymphoproliferative disorders (PTLD) are a diverse group of potentially life-threatening conditions affecting organ transplant recipients. PTLD arises in the setting of an attenuated host immunologic system that is manipulated to allow a foreign graft but then fails to provide adequate immune surveillance of transformed malignant or premalignant lymphocytes. The diversity of biological behavior and clinical presentation makes for a challenging clinical situation for those involved in the care of children with PTLD occurring after solid-organ transplantation. This review details a large transplant center’s multidisciplinary approach to monitoring for PTLD and systematic approach to intervention, which has been essential for early recognition and successful treatment.     

Epstein-Barr viremia levels after pediatric liver transplantation as measured by real-time polymerase chain reaction

Abstract: Effective immunosuppression has improved the results following liver transplantation, but also increased the risk for opportunistic infections. Epstein–Barr virus (EBV) infection in transplant patients can cause various symptoms including the life‐threatening premalignant condition, post‐transplantation lymphoproliferative disorder (PTLD). Serum specimens from 24 consecutive children (mean 7.6 specimens/patient), who had undergone liver transplantation in Göteborg from January 1995 to May 2002, were analyzed retrospectively for EBV DNA by real‐time TaqMan^® polymerase chain reaction (PCR). The results were related to clinical picture, immunosuppression, graft rejection and infections with other agents. Eleven patients (46%) developed primary EBV infection at a mean time of 4.8 months after transplantation, and six (25%) reactivated EBV infection at a mean of 4.0 months after transplantation. Four of the 11 patients with primary infection had symptomatic EBV infection: two had PTLD and two hepatitis. One patient in the group with reactivated infection developed PTLD. EBV DNA levels were significantly higher in the group with primary symptomatic infection compared with the patients with primary asymptomatic infection (mean 65 500 copies/mL; range 14 200–194 300 vs. 3700 copies/mL; range 100–9780). In patients with symptomatic infection EBV DNA levels did not differ between PTLD and hepatitis patients. The data suggest that quantitative analysis of EBV DNA in serum by real‐time PCR is useful for identification of EBV‐related disease.     

Post‐transplant lymphoproliferative disorder in pediatric intestinal transplant recipients: A literature review

Intestinal transplantation is a successful treatment for children with intestinal failure, but has many potential complications. PTLD, a clinically and histologically diverse malignancy, occurs frequently after intestinal transplantation and can be fatal. The management of this disease is particularly challenging. The rejection‐prone intestinal allograft requires high levels of immunosuppression, a precondition for PTLD. While EBV infection clearly plays a role in disease pathogenesis, the relatively naïve immune system of children is another likely contributor. As a result, pediatric intestine recipients have a higher risk of developing PTLD than other solid organ recipients. Other risk factors for disease development such as molecular and genomic changes that precipitate malignant transformation are not fully understood, especially among children. Studies on adults have started to describe the molecular pathogenesis of PTLD, but the genomic landscape of the malignancy remains largely undefined in pediatric intestinal transplant patients. In this review, we describe what is known about PTLD in pediatric patients after intestinal transplant and highlight current knowledge gaps to better direct future investigations in the pediatric population.     

Post-transplantation lymphoproliferative disorders localizing to the gastrointestinal tract after liver transplantation: report of five pediatric cases

Post-transplantation lymphoproliferative disorder (PTLD) is a life-threatening complication of organ transplantation. PTLD can occur in every kind of organ transplantation. From July 1992 to July 2004, five patients were diagnosed at our transplantation center with PTLD after pediatric liver transplantation. During this period, there were 52 pediatric patients (<18 yr) receiving an orthotopic liver transplantation (OLT) at our center. All five patients had transmural gastrointestinal (GI) PTLD, which occurred mostly in the stomach and duodenum. Epstein-Barr virus (EBV) in situ was demonstrated in each case. EBV viral load was noted to be an important risk factor. Treatment included dose reduction of immunosuppressants and anti-CD20 antibody infusion. Chemotherapy, including cyclophosphamide, doxorubicin, vincristine, and prednisolone, was given to three patients. Four patients have survived more than 10 months until now after treatment. The one who was unresponsive to chemotherapy and anti-CD20 antibody had diffuse metastasis and died of systemic candidiasis. In our series, each PTLD involved the GI tract. The mechanism of this phenomenon is unclear, but these five cases indicate the high incidence of PTLD in pediatric solid organ transplantation.     

Indications, results, and complications of tacrolimus conversion in pediatric renal transplantation

It is the practice of many pediatric renal transplant programs to 'convert' children taking cyclosporin A (CsA) to tacrolimus, although the indications for, outcome, and complications of this practice remain obscure. To better understand these aspects of tacrolimus 'conversion', a fax survey was sent to 119 North American pediatric renal transplant centers. Analyzable responses were received from 52 centers (44%), and included data from approximately 1,815 pediatric renal transplants performed between 1991 and 98. Strong indications for tacrolimus conversion were: antibody-resistant rejection, CsA-resistant rejection, and CsA intolerance (strong indication in 72%, 65%, and 52% of centers, respectively). Steroid-resistant rejection and cosmetic side-effects were considered strong indications less often. Initial anti-rejection therapy was usually increased corticosteroid dose (47/52 centers). Antibody therapy was most commonly used for steroid-resistant rejection (44 centers). For steroid- and antibody-resistant rejection, tacrolimus conversion was most common (33 centers). Tacrolimus conversion for antibody-resistant rejection led to improvement of serum creatinine (SCr) in 27% of patients, stabilization of SCr in 46%, worsening of SCr in 11%, and graft loss in 16%. Reported complications after tacrolimus conversion included hyperglycemia, hyperkalemia, lymphoproliferative disorder, infection, and neurologic problems. We conclude that the major indication for tacrolimus conversion in pediatric transplant programs appears to be rejection. Outcome after tacrolimus conversion appears good, with the majority of patients experiencing stable or improved allograft function. These data provide direction for further study, including timing of tacrolimus conversion and interaction with other therapies.     

儿童异基因造血干细胞移植后中枢神经系统淋巴增殖性疾病1例报告并文献复习

目的 探讨儿童异基因造血干细胞移植术(allo-HSCT)后中枢神经系统淋巴增殖性疾病(CNS-PTLD)的临床特点.方法 回顾分析1例行allo-HSCT患儿的临床资料,并复习相关文献.结果 患儿,13岁,男性,确诊为急性髓系白血病M 5型(TLS-ERG融合基因阳性),缓解化疗达完全缓解,TLS-ERG转为阴性,之...     

Risk factors for post-transplant lymphoproliferative disorder in pediatric patients: a case-control study

Post-transplant Lymphoproliferative Disorder (PTLD) because of the Epstein-Barr Virus (EBV) is a major concern after pediatric transplantation. The group at greatest risk is EBV-seronegative recipients who receive EBV-seropositive organs. Additional risk factors remain to be determined, including those among EBV-seropositive recipients. In this case-control study, PTLD cases were biopsy-proven over a period of 4 yr (1997-2000, inclusive). Each case was matched with 2 controls, based on the type of organ transplanted and the period of transplantation (+/-1 yr). Variables compared between cases and controls included those relating to the clinical and virologic profiles and immunosuppressive therapy. Twenty-two cases of PTLD were diagnosed during the study period. PTLD cases occurred at a median of 22.8 months post-transplantation (range 1-131). The median age of cases was 26.2 months (range 6.1-194) compared with 47.4 months (range 0.8-202.2) for controls (p = 0.93). Cases had a higher mean baseline EBV load compared with controls (3.1 log(10) (s.d. +/- 1.0) vs. 1.6 log(10)/10(6) PBMCs (s.d. +/- 1.4), with every 1 log increase in viral load resulting in a three times increase in the likelihood of PTLD (p < 0.007). Close to one in four cases of PTLD were EBV-seropositive pretransplantation. These seropositive recipients tended to be older patients with a trend to a worse outcome compared with their seronegative counterparts. The occurrence of PTLD was not associated with the use of any specific immunosuppressants. A significant proportion of PTLD cases occurred among EBV-seropositive transplant recipients, with a tendency towards an unfavorable outcome. Besides EBV-seronegative recipients who receive seropositive organs, some EBV-seropositive pediatric patients are at risk of PTLD. Additional studies are warranted to further define the factors associated with PTLD in EBV-seropositive transplant recipients.