Post‐transplant malignancies in pediatric organ transplant recipients

The majority of cancer diagnoses in pediatric solid organ transplant recipients (SOTRs) are post‐transplantation lymphoproliferative disorders (PTLD) or skin cancers. However, pediatric SOTRs are also at significantly elevated risk for multiple other solid and hematological cancers. The risks of specific cancers vary by transplanted organ, underlying disease, and immunosuppression factors. More than one‐quarter of pediatric SOTRs develop cancer within 30 years of transplantation and their risk of solid cancer is 14 times greater than the general population. Pediatric SOTRs are at significantly higher risk of cancer‐associated death. Improving patient survival among pediatric SOTRs puts them at risk of adult epithelial cancers associated with environmental carcinogenic exposures. Vaccination against oncogenic viruses and avoidance of excessive immunosuppression may reduce the risk of solid cancers following transplantation. Patient and family education regarding photoprotection is an essential component of skin cancer prevention. There is significant variability in cancer screening recommendations for SOTRs and general population approaches are typically not validated for transplant populations. An individualized approach to cancer screening should be developed based on estimated cancer risk, patient life expectancy, and screening test performance.     

Epstein‐Barr viral load monitoring for diagnosing post‐transplant lymphoproliferative disorder in pediatric liver transplant recipients

This study aimed to investigate the incidence of PTLD in pediatric liver transplant recipients and the risk factors for the development of PTLD. We also determined clinically useful quantitative EBV PCR parameters for aiding in the diagnosis of EBV‐associated PTLD in the pediatric liver transplant recipients at our institute. We reviewed children < 18 years old who had undergone liver transplantations and quantitative analysis of whole blood EBV load at our institute from January 2006 to March 2015. A total of 142 liver transplant recipients were included, and their median age was 1.5 years. Clinically significant high‐level EBV DNAemia ≥ 10 000 copies/mL at least twice was observed in 53.5% and PTLD occurred in 9.9%. Among PTLD group, graft failure and mortality rate were as high as 21.4% and 14.3%, respectively. Deceased donor, presence of high‐level EBV DNAemia, and primary CMV infection following transplant were associated with an increased risk for PTLD in the multivariate analysis. The peak titer at 10 875 copies/mL could be used as a cutoff value with a sensitivity of 92.9% and a specificity of 37.9%; the rate of increase in EBV load suggested a sensitivity of 64.3% and a specificity of 70.9% at the cutoff value of 44 000 copies/mL/week. In conclusion, the incidence of PTLD following liver transplant in children was as high as 10%. PTLD is associated with significant morbidity and mortality. Close monitoring of EBV DNAemia is crucial for the early diagnosis and proper treatment of PTLD in pediatric liver transplant recipients.     

School and sports participation post‐transplant

Pediatric recipients of life‐saving organ transplants are living longer, with improved graft and overall survivals. After successful transplant, children are encouraged to return to “normal life,” with school attendance and participation in age‐appropriate physical activities. This transition may cause stress to the recipients, parents, teachers, and other participating caregivers and staff. Planning for school reentry and assuring education for and open lines of communication with the school staff can help alleviate some of this discomfort and ease the process for the patient and the family. Cardiovascular disease has emerged as the leading cause of death in survivors of pediatric transplantation and is contributed to by modifiable risk factors such as obesity, hypertension, and the MS. Physical activity is a proven tool in decreasing surrogate markers of this risk. Sports participation is an important way to promote an enjoyment of physical activity that can ideally persist into adulthood, but conflicting advice and opinions exist regarding type and participation in physical activity. Moreover, specific recommendations are likely not applicable to all recipients, as certain degrees of rehabilitation may be needed depending on degree and length of illness. In general, a program of rehabilitation and increased physical activity has been shown to be safe and effective for most pediatric transplant recipients. Focusing on optimizing the “normal” childhood activities of going to school and participating in sports can improve the physical, social, cognitive, and mental health outcomes of this population after transplant and should be prioritized.     

Everolimus‐associated perianal ulcers in an eight‐month‐old heart transplant recipient

mTOR inhibitors have a wide spectrum of therapeutic applications in adults and children. Little is known, however, about serious adverse effects in children undergoing mTOR inhibitor therapy. Oral ulcers are common and sometimes severe, but no other gastrointestinal involvement has been reported so far. Here we present a case of everolimus‐associated perianal ulcers in an eight‐month‐old infant, 3 months after heart transplantation, which necessitated the drug's discontinuation. In a thorough series of diagnostic tests, we identified no other cause for the progressive perianal ulceration. The recognition and appropriate management of mTOR inhibitors' adverse effects in pediatric patients are essential and remain challenging.     

Invasive pneumococcal infections in pediatric liver‐small bowel‐pancreas transplant recipients

Children undergoing LSBPTx are at increased risk of IPI due to splenectomy. We aimed to describe the clinical features and outcomes of IPI in pediatric LSBPTx recipients. Between 2008 and 2016, 122 LSBPTx children at our center were retrospectively reviewed. Nine patients had 12 episodes of IPI; the median age at first infection was 3.5 years (range: 1.5‐7.1 years). The median time from transplant to first infection was 3 years (range: 0.8‐5.8 years). Clinical presentation included as follows: pneumonia (n = 1), bacteremia/sepsis (n = 7), pneumonia with sepsis (n = 1), meningitis with sepsis (n = 2), pneumonia and meningitis with sepsis (n = 1). The overall risk for IPI was 7.4% or 0.9% per year. The mortality rate was 22%. Seven (78%) children had received at least one dose of PCV13, four (44%) patients had received 23‐valent pneumococcal polysaccharide vaccine prior to IPI. All patients were on oral penicillin prophylaxis. In conclusion, despite partial or complete pneumococcal immunization and reported antimicrobial prophylaxis, IPI in LSBPTx children can have a fatal outcome. Routine monitoring of pneumococcal serotype antibodies to determine the timing for revaccination might be warranted to ensure protective immunity in these transplant recipients.     

Clinicopathologic features of post‐transplant lymphoproliferative disorders arising after pediatric small bowel transplant

Few studies examined the clinicopathologic features of PTLD arising in pediatric SBT patients. Particularly, the association between ATG and PTLD in this population has not been described. Retrospective review of 81 pediatric patient charts with SBT – isolated or in combination with other organs – showed a PTLD incidence of 11%, occurring more frequently in females (median age of four yr) and with clinically advanced disease. Monomorphic PTLD was the most common histological subtype. There was a significant difference in the use of ATG between patients who developed PTLD and those who did not (p < 0.01); a similar difference was seen with the use of sirolimus (p < 0.001). These results suggested a link between the combination of ATG and sirolimus and development of more clinically and histologically advanced PTLD; however, the risk of ATG by itself was not clear. EBV viral loads were higher in patients with PTLD, and median time between detection of EBV to PTLD diagnosis was three months. However, viral loads at the time of PTLD diagnosis were most often lower than at EBV detection, thereby raising questions on the correlation between decreasing viral genomes and risk of PTLD.     

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‐renal transplant erythrocytosis: A case report

PTE is defined as hematocrit >51% or hemoglobin >17 g/dL after renal transplantation. Risk factors include native kidneys with adequate erythropoiesis pretransplant, smoking, renal artery stenosis, and cyclosporine treatment. We report the case of a 14‐yr‐old female kidney transplant patient, with triple therapy immunosuppression and stable graft function who developed PTE at 12 months post‐transplant with hemoglobin 17.3 g/dL, hematocrit 54.2%, stable graft function, and normotensive with normal cardiac echocardiogram and erythropoietin levels. The only risk factor found was tobacco use. As she had no spontaneous improvement, enalapril treatment was started at 19 months post‐transplant with a hemoglobin level of 17.5 g/dL and hematocrit 53%; by 23 months post‐transplant, hemoglobin lowered to 15 g/dL and hematocrit to 44.5% and continued to be in normal range thereafter. PTE is a rare condition in childhood and can be successfully treated with enalapril.     

Prompt diagnosis and management of Epstein–Barr virus‐associated post‐transplant lymphoproliferative disorder and hemophagocytosis: A dreaded complication in a post‐liver transplant child

EBV‐associated PTLD is increasingly recognized as an important cause of morbidity and mortality in both solid organ and hematopoietic stem cell transplant recipients. Mortality rates due to PTLD and virus‐induced HLH are reported to be quite high. We report a case of EBV‐associated PTLD and HLH in a child after liver transplantation who was successfully managed due to timely intervention. This case highlights that measurement of EBV load by quantitative polymerase chain reaction assays is an important aid in the surveillance and diagnosis of PTLD and early detection of EBV‐induced PTLD, and aggressive treatment with rituximab is a key to survival in patients who have undergone liver transplantation.     

Roux‐en‐Y intussusception after pediatric liver transplant – A case report

Small bowel obstruction in a pediatric patient following liver transplant often results from adhesions, hernias, or post‐transplant lymphoproliferative disease. Here, we present an unusual and previously unreported entity – Roux‐en‐Y intussusception in an eight‐yr‐old female several years after liver transplantation. Although a rare complication, Roux‐en‐Y intussusception should be considered as a potential etiology in the patient presenting with bowel obstruction, with specific attention to acute presentation accompanying jaundice.     

Hyponatremia,hypo‐osmolality,and seizures in children early post‐kidney transplant

Post‐transplant seizures are uncommon in young kidney transplant recipients but can be harbingers of devastating outcomes such as cerebral edema and death. We reviewed all transplants performed at our institution from January 2013 to January 2014 and compared three patients who seized within 24 h post‐transplant (cases) with the remaining 33 transplant recipients (controls). Records were reviewed for hyponatremia, hypocalcemia, hypomagnesemia, BUN clearance, osmolality shifts, and blood pressure control in the first 24 h post‐transplant. All cases had more pronounced (p < 0.001) shifts in serum sodium and calculated serum osmolality, with their sodium decreasing by >15 mmol/L to nadir values of 124, 131, and 131 mmol/L, respectively. There were no differences in serum calcium corrected for hypoalbuminemia, serum magnesium, urine output, or blood pressure control between the groups. Our study suggests that mild hyponatremia and an acute decrease in serum osmolality are risk factors for potentially severe postoperative neurologic complications following kidney transplantation. Thus, peri‐transplant management should be optimized to anticipate and prevent these abnormalities.     

Pediatric post‐transplant hepatic kaposi sarcoma due to donor‐derived human herpesvirus 8

In areas of the world where human herpesvirus 8 (HHV‐8) is endemic, Kaposi sarcoma (KS) is a common SOT‐associated cancer. In the United States, where the virus is not prevalent, PTKS is rare, and there is little literature on pediatric PTKS. We present a North American female who underwent deceased donor, left lateral segment liver transplant for biliary atresia at age 11 months. The donor was a male with no known history of KS, originally from an HHV‐8‐endemic country. Three months after transplantation, the patient developed liver nodules and portal vein thrombosis. Analysis of needle biopsy established the diagnosis of KS and confirmed that the transformed cells were donor‐derived. HHV‐8 viremia was detected, and ganciclovir dosing (which had been started prophylactically) was increased. Immunosuppression was changed from tacrolimus to sirolimus. After further disease progression, 8 cycles of paclitaxel were administered. Under this treatment, her nodules regressed, HHV‐8 viremia resolved, and she had marked clinic improvement. Notably, the adult recipient of the right liver lobe from the same donor also developed PTKS. This is one of few pediatric PTKS cases described in the literature. It contributes to the mechanistic understanding of PTKS development, illustrating the risk posed by donors from HHV‐8‐endemic countries, as well as the potential for strong PTKS correlation between multiple recipients of organs from a single shared donor.