FDG‐PET in macrophage activation syndrome associated with systemic juvenile idiopathic arthritis

We herein describe a case of systemic juvenile idiopathic arthritis (s‐JIA)‐associated macrophage activation syndrome (MAS) in which the ^18Ffluorodeoxyglucose positron emission tomography (^18FFDG‐PET) findings were characteristic. The pattern of greater ^18FFDG accumulation into the spleen compared with the liver was more remarkable in this patient compared with s‐JIA. This pattern, however, was also observed in cases of acute leukemia. In the present patient, serum interleukin (IL)‐18 was extremely elevated (255 000 pg/mL), whereas in leukemia patients it is mildly elevated (360–1480 pg/mL). ^18FFDG‐PET might be a useful indicator of s‐JIA and MAS in patients with fever of unknown origin. The pattern of ^18FFDG accumulation, however, can also be observed in acute leukemia. The combination of ^18FFDG‐PET and serum IL‐18 might be useful for the diagnosis of s‐JIA and MAS.     

Mortality after pediatric kidney transplantation in England – a population‐based cohort study

The aim of this study was to explore mortality after pediatric kidney transplantation in England over the last decade. We used data from HES to select all kidney transplant procedures performed in England between April 2001 and March 2012. Data linkage analysis was performed with the ONS to identify all deaths occurring among this study cohort. Data for 1189 pediatric recipients were compared to 17 914 adult recipients (number of deaths, 33 vs. 2052, respectively, p < 0.001), with median follow‐up 4.4 yr (interquartile range 2.2–7.3 yr). There was no difference in mortality within the pediatric cohort; age 0–1 (n = 25, patient survival 100.0%), age 2–5 (n = 198, patient survival 96.0%), age 6–12 (n = 359, patient survival 97.5%), and age 13–18 (n = 607, patient survival 97.4%), respectively (p = 0.567). The most common causes of death were renal (n = 8, 24.2%), infection (n = 6, 18.2%), and malignancy (n = 5, 15.2%). All deaths from malignancy were secondary to PTLD. In a fully adjusted Cox regression model, only white ethnicity was significantly associated with risk of pediatric mortality post‐kidney transplantation (hazard ratio 2.7, 95% confidence interval [1.0–7.3], p = 0.047). To conclude, this population‐based cohort study confirms low mortality after pediatric kidney transplantation with short follow‐up.     

Eosinophilic esophagitis in children following cardiac transplantation: Association with post‐transplant lymphoproliferative disorder and other transplant outcomes

Although cardiac transplantation is life‐saving, morbidities from immunosuppression are significant. EoE is a complication of calcineurin inhibitors following liver transplant causing feeding intolerance, weight loss, vomiting, and dysphagia. There are limited reports of EoE following heart transplantation. We performed a retrospective single‐center review of pediatric cardiac transplant patients from 2000 to 2010. A case–control analysis of patients with and without EoE was performed evaluating heart transplantation outcomes such as rates of rejection, CAV, PTLD, and graft loss. Eighty‐six transplants were performed in 84 patients; 34 (40%) underwent diagnostic endoscopy, and 10 (12%) had EoE. Median time to diagnosis of EoE was 3.7 yr (IQR: 2.0–5.2). There were no differences in demographics or use of induction medications between patients with or without EoE. Patients with EoE had fewer episodes of treated rejection (1.0 vs. 2.5; p = 0.04). Four of 10 (40%) EoE patients had PTLD compared with only 2/24 (8%) of those without EoE (p = 0.048; OR 7.33 [95% CI: 1.1–50.2]). There were no differences in CAV or graft loss between groups. EoE should be considered as a cause of GI symptoms in children after cardiac transplantation and may be associated with fewer rejection episodes and increased rates of PTLD, thus representing a marker of over‐immunosuppression.     

Post‐transplant lymphoproliferative disorder: No relationship to recombinant human growth hormone use in Australian and New Zealand pediatric kidney transplant recipients

PTLD is a potentially life‐limiting complication of pediatric transplantation. Previous registry‐based studies in renal transplantation have suggested a link between rhGH use and PTLD. In this study, demographic and transplant data on those aged <18 yr and transplanted between 1991 and 2008 were collected from the ANZDATA Registry. Associations between gender, age at time of transplant, recipient CMV and EBV status, use of monoclonal antibody therapy, and use of rhGH were studied as potential predictors of PTLD. Among 650 transplants, there were 20 cases (3.1%) of PTLD, with half presenting within two yr post‐transplant. Eight patients exposed to rhGH at any time developed PTLD, and this association was not statistically significant (RR = 1.5[0.6–3.4], p = 0.36). On multivariate analysis, there were no significant predictors for PTLD. In this study, previously identified potential risk factors were not identified as significant predictors for the development of PTLD. Although limited sample size may affect our ability to infer safety, this large retrospective cohort study does not suggest an increased risk of PTLD in pediatric kidney transplant recipients who received rhGH treatment.     

Children treated for epileptic encephalopathies show improved glucose metabolism

Epileptic neurological disorders in infants are often difficult to distinguish, and call for disparate treatments. Positron emission tomography (PET) using an [¹⁸F] fluoro‐2‐deoxyglucose (¹⁸FDG) tracer, is a powerful non‐invasive technique successful in improving the diagnosis of a number of conditions. Interestingly, this technique has shown that cerebral glucose hypometabolism is present in children with epileptic encephalopathies (EE). Ten children with age‐dependent EE were recruited and routine ¹⁸FDG PET images were evaluated for their ability to indicate cerebral glucose metabolism both before and after anti‐epileptic treatment. We found that there is diffuse glucose hypometabolism in both hemispheres before treatment, indicating EE. Following treatment, the number of epileptic episodes significantly decreased (P < 0.05), while cerebral glucose metabolism improved. Our findings suggest that ¹⁸FDG PET can be utilized to monitor cerebral glucose metabolism as a measure of treatment progress in EE.     

Hemophagocytic lymphohistiocytosis is a sign of poor outcome in pediatric Epstein‐Barr virus‐associated post‐transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation

EBV‐related PTLD developing after HSCT is a potentially life‐threatening disease. HLH is uncommon after allogeneic HSCT. Data on outcome of patients with PTLD and concomitant HLH after allogeneic HSCT are limited. In this retrospective study, we collected demographic, clinical, laboratory, and outcome data for 408 patients who underwent allogeneic HSCT from 2006 to 2015. Graft source included CB (n = 135; 33.1%), PBSCs (n = 34; 8.3%), and BM (n = 239; 58.6%). Eight out of 408 patients (2%) developed EBV‐PTLD with a median age at HSCT of 5.9 years (range: 2.3‐17.3). All eight patients received ATG as part of the conditioning regimen. Graft source was PBSC in three patients (37.5%), BM in four patients (50%), and CB in one patient (12.5%). Donors were matched unrelated in five patients (62.5%) and matched sibling in three patients (37.5%). Seven out of eight patients developed EBV‐PTLD within the first 100‐day post‐HSCT. Lymph node biopsy revealed early lesions in three patients, polymorphic in three patients, and monomorphic PTLD in two patients. Three patients (37.5%) died within 1 month of EBV‐PTLD diagnosis. All deceased patients developed HLH manifestations with two of them meeting HLH diagnostic criteria and one having an incomplete workup. PTLD after allogeneic HSCT with manifestations of HLH is associated with high mortality. Early identification and treatment of EBV‐PTLD seems imperative to control the disease, especially if signs of HLH are evolving.     

Post‐transplant lymphoproliferative disorders and other malignancies after pediatric intestinal transplantation: Incidence,clinical features and outcome

PTLDs are a well‐recognized and potentially fatal complication after intestinal transplantation. We analyzed the incidence, clinical features, and outcome in a 63 intestinal transplantation series performed in our unit between October 1999 and July 2011. Types of graft included ISB (n = 23), LSB (n = 20), and MV (n = 20). Patients were categorized into three groups of immunosuppression: I (n = 43) received basiliximab, tacrolimus, and steroids; II (n = 11) thymoglobulin and tacrolimus, and III (n = 9) alemtuzumab and tacrolimus. EBV status was serially assessed. All PTLD cases were biopsied to establish histopathological diagnosis. The incidence of PTLD was 14.2% (9/63). Median onset of PTLD after transplant was four months (range: 0.5–28), within first postoperative year in 6 (66.6%) patients. Fever was the most common symptom. Graft removal was needed in four patients (44%). The patient survival rate was 66.6% (6/9). We have not found any association between PTLD and immunosuppression regimen or transplant type. However, there was a statistical association with EBV active infection.     

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.     

FDG uptake in cervical lymph nodes in children without head and neck cancer

Background

Reactive cervical lymphadenopathy is common in children and may demonstrate increased ¹⁸F–fluoro-deoxyglucose (¹⁸F–FDG) uptake on positron emission tomography/computed tomography (PET/CT).

Objective

We sought to evaluate the frequency and significance of ¹⁸F–FDG uptake by neck lymph nodes in children with no history of head and neck cancer.

Materials and methods

The charts of 244 patients (114 female, mean age: 10.4 years) with a variety of tumors such as lymphoma and post-transplant lymphoproliferative diseases (PTLD), but no head and neck cancers, who had undergone ¹⁸F–FDG PET/CT were reviewed retrospectively. Using the maximum standardized uptake value (SUVmax), increased ¹⁸F–FDG uptake by neck lymph nodes was recorded and compared with the final diagnosis based on follow-up studies or biopsy results.

Results

Neck lymph node uptake was identified in 70/244 (28.6%) of the patients. In 38 patients, the lymph nodes were benign. In eight patients, the lymph nodes were malignant (seven PTLD and one lymphoma). In 24 patients, we were not able to confirm the final diagnosis. Seven out of the eight malignant lymph nodes were positive for PTLD. The mean SUVmax was significantly higher in malignant lesions (4.2) compared with benign lesions (2.1) (P = 0.00049).

Conclusion

¹⁸F–FDG uptake in neck lymph nodes is common in children and is frequently due to reactive lymph nodes, especially when the SUVmax is <3.2. The frequency of malignant cervical lymph nodes is higher in PTLD patients compared with other groups.

     

Safety and feasibility of granulocyte colony‐stimulating factor (G‐CSF) primed bone marrow (BM) using three days of G‐CSF priming as stem cell source for pediatric allogeneic BM transplantation

There are limited data on the optimal dosing and schedule of G‐CSF priming prior to BM harvest. We evaluated the safety and efficacy of three days of G‐CSF of primed BM from related pediatric donors. Forty‐five children were treated. All donors received 5 μg/kg per day of G‐CSF as a single subcutaneous injection for three consecutive days prior to the BM harvest. The median age of the donors was seven yr (range, 0.8–18) and no donor experienced major adverse events related to G‐CSF administration. The median age for the recipients was five yr (0.3–16 yr). Thirty‐five patients had non‐malignant disorders. The median dose of nucleated (TNC) and CD34+, CD3 cells infused per recipient weight was 5.4 × 10⁸/kg (range, 0.61–17), 4.7 × 10⁶/kg (range, 1.6–19), and 43.8 × 10⁶/kg (range, 1.8–95), respectively. All patients achieved neutrophil and platelets engraftment, at a median of 15 (range, 10–22) and 23 days (range, 13–111), respectively. At a median follow up of 60 months (range 12–100), the estimated five yr overall and EFS was 91% and 80%, respectively. Collection of BM following three days of G‐CSF priming from pediatric donors is safe and results in high TNC and CD34+ cell yield.     

Spectrum of pathogens in native liver,bile, and blood during pediatric liver transplantation

During LTX, there may be a risk that pathogens of the native liver are released into the systemic circulation. No investigations on incidence/spectrum of pathogens in native livers have been published. We hypothesized that pathogens are found in the native liver of a large proportion of pediatric patients during LTX and investigated the microbiology of native livers. These data may help optimize antibiotic therapy. Twenty‐two consecutive pediatric patients (median age 14 months, range, 5 months–15 yr) receiving LTX in our department from October 2010 to October 2011 were included in this prospective study. Tissue and bile were collected from the explanted liver and were cultivated on different media. All liver tissues were investigated using a broad‐range PCR (SepsiTest^®). In 16 patients, blood cultures were collected post‐transplantation. Eleven patients (50%) had at least one pathogen detected; nine of these patients had an underlying diagnosis of biliary atresia. SepsiTest^® was positive in seven patients. In four patients it was the only test detecting any pathogen. In detail, the positivity rate for liver tissue in all patients was 41% (n = 9); for bile 25% (n = 3); and for blood 25% (n = 4). Thirteen different pathogens (69% bacterial, 31% fungal) were isolated. A highly‐sensitive broad‐range PCR appears to be an effective method to detect pathogens in native livers of patients undergoing LTX. A high number and variety of microbes, including a high proportion of fungal pathogens, were detected.     

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.     

Is there an optimal organ acceptance rate for pediatric heart transplantation: “A sweet spot”?

Despite a limited supply of donors, potential donor hearts are often declined for subjective concerns regarding organ quality. This analysis will investigate the relationship between donor heart AR and patient outcome at pediatric transplant centers. The UNOS database was used to identify all match runs for pediatric candidates (age < 18 years) from 2008 through March 2015 in which a heart offer was ultimately placed. Centers which received ≥10 offers/y were included (10 634 offers, 38 centers). Transplant centers were stratified based on their AR: low (<20%, n = 13), medium (20%‐40%, n = 16), or high (>40%, n = 9). Low AR centers experienced worse negative WL outcome compared with medium (P = .022) and high (P = .004) AR centers. Low AR centers had similar post‐transplant graft survival to medium (P = .311) or high (P = .393) AR centers; however, medium AR centers had better post‐transplant graft survival than high AR centers (P = .037). E‐F survival from listing regardless of transplant was worse for low AR centers compared with medium (P < .001) or high (P = .001) AR centers. Low AR centers experience worse WL outcomes without improvement in post‐transplant outcomes. High AR centers experience higher post‐transplant graft failure than medium AR centers. AR of 20%‐40% appears to have optimal WL and post‐transplant outcomes.     

Liver abnormalities and post‐transplant survival in pediatric Fontan patients

The impact of liver parenchymal abnormalities on survival post‐heart transplant remains unknown in pediatric Fontan patients. We assessed pediatric Fontan patients who underwent heart transplant and had documented pretransplant hepatic ultrasound (U/S) studies. Liver U/S findings were classified as normal (Group 1), mildly abnormal (Group 2, hepatomegaly/vascular congestion), or severely abnormal (Group 3, heterogeneous echotexture/nodularity). Among 30 study patients, 8 were classified as Group 1, 14 as Group 2, while 8 met Group 3 criteria. Pretransplant liver biochemistry and synthetic function were similar in all groups. Six Group 3 patients underwent liver biopsy; 4 demonstrated perisinusoidal or centrilobular fibrosis, and 2 had cirrhosis. Overall mortality was 30% (n = 9). Median follow‐up was 5 years (range, 0.25‐13 years). One‐year survival was similar among all 3 groups (P = .37), with a trend toward higher cumulative 5‐year survival in Group 1 (100%). The majority of pediatric Fontan patients who underwent heart transplant demonstrated abnormal preoperative liver ultrasound findings. Heterogeneous echotexture or nodularity detected on U/S frequently indicates underlying liver parenchymal abnormalities. The presence of severe liver abnormalities was not associated with higher early mortality post‐heart transplant in pediatric Fontan patients; however, late outcomes must be further elucidated.     

Comparison of outcomes of hand‐assisted laparoscopic to open donor nephrectomy for pediatric recipients

The purpose of this study is to compare the outcome of pediatric recipients of kidneys procured using a hand‐assisted laparoscopic (HALDN group) to an open technique (ODN group). Twenty‐eight patients ≤18 yr old (HALDN group) were compared with 17 patients (ODN group). The serum creatinine for HALDN and ODN groups at discharge were 0.93 ± 0.48 and 0.94 ± 0.54 mg/dL (p = 0.917), respectively. The serum creatinine for HALDN and ODN groups at six and 12 months was 1.01 ± 0.44 and 1.11 ± 0.55, and 1.04 ± 0.52 and 1.14 ± 0.46 mg/dL (p = 0.516, p = 0.554), respectively. The eGFR for HALDN and ODN groups at discharge was 108.66 ± 37.23 and 106.1 ± 50.55 mL/min/1.73 m² (p = 0.845), respectively. The eGFR for HALDN and ODN groups at six and 12 months was 97.77 ± 28.25 and 81.73 ± 27.46, and 94.56 ± 28.3 and 85.74 ± 30.1 mL/min/1.73 m2 (p = 0.085, p = 0.344), respectively. The patient and graft survival for both groups were 100% at 12 months post‐transplant. In conclusion, the short‐term outcome of recipients of kidneys procured via HALDN is comparable to that of kidneys procured via ODN in pediatric patients.     

Results after the adoption of a MELD/PELD‐based liver allocation policy in Argentina

In July 2005, Argentina switched from a categorical liver allocation system to a MELD/PELD‐based policy for patients with CLD. To analyze WL outcomes and survival after LT in children. From January 2000 to December 2010, 923 children were registered. Two consecutive five‐yr periods were analyzed and compared: Era I (January 2000–July 2005) (n = 379) and Era II (July 2005–December 31, 2010) (n = 544). All data were prospectively collected and analyzed using the Kaplan–Meier method. After adopting the MELD/PELD system, WL registrations increased by 44% (from 379 to 544) and the number of LT increased by only 24% (from 278 to 365). However, three‐month WL mortality rate (32% to 18%, p < 0.0001, HR 2.002 CI 95% 1.5–2.8) decreased significantly. No significant differences were observed between Era 1 and II in one‐yr post‐LT survival (77.5% vs. 84.1%, p = 0.3053) and in acute re‐LT rate (9% vs. 5%, p = 0.1746). Under the MELD/PELD‐based allocation system in Argentina, mortality on the WL significantly decreased in children with CLD without affecting post‐LT survival, although reduced access to LT was observed.     

Donor‐specific antibodies in a pediatric kidney transplant population—Prevalence and association with antiproliferative drug dosing

Prevalence and implications of anti‐HLA class I and class II antibodies are beginning to be better characterized in pediatric kidney transplant recipients. dnDSA formation is predictive of AMR and downstream diminished graft function and survival. However, risk factors for the development of dnDSA are not well defined in this patient population. After introducing DSA surveillance into our pediatric kidney transplant program, we are reporting the prevalence of class I and class II DSA in 67 otherwise stable recipients. Secondary end‐points included risk factors for DSA development and assessment of graft function. Significantly, lower median daily MMF doses were observed in patients with DSAs compared to patients without DSAs (371 vs 617 mg/m²/d, respectively; P = 0.035). Class II DSA formation was more common, with a prevalence of 17.9%, as compared to 10.4% for class I DSA. Estimated glomerular filtration rate was also decreased in patients with positive DSA vs those with negative titers (71, SD 25 vs 78, SD 29 mL/min/1.73 m², respectively; P = 0.034). We conclude that reduced‐dose MMF is associated with dnDSA and DSA is associated with diminished graft function in stable pediatric kidney transplant recipients.     

Health‐related quality of life in pediatric intestinal transplantation

To determine HRQOL after pediatric intestinal transplantation. Thirty‐four IT survivors from 1999 to 2012 were asked to complete age‐specific HRQOL non‐disease‐specific questionnaires: TAPQOL (0–4 yr), KINDL‐R (5–7 yr; 8–12 yr; 13–17 yr), and SF‐36v2 (>18 yr), all validated with Spanish population. Primary caregiver completed a SF‐36 questionnaire and CBI. Thirty‐one participants were included. Median age was 10.2 yr (1–29) and time after transplant 4.4 yr (0–13). Overall patient scores were 78.2 ± 10.6 (n = 8), 83.3 ± 9.7 (n = 6), 72.2 ± 9.21 (n = 6), 80.5 ± 12.4 (n = 7), and 82.2 ± 12.4 (n = 4) for each age group. Highest scores were obtained for vitality (group I), self‐esteem (group IV), and physical and social functioning and emotions (group V). Lowest scores were obtained in appetite and behavior (I), family and school (III), and chronic disease perception (III, IV). No significant differences were found between caregivers and their children. CBI showed stress in 52%. SF‐36 for caregivers was lower than general population. No significant differences were found depending on relevant clinical and sociodemographic data. HRQOL was acceptable and improved with age and time since transplantation. Parents had a slighter own QOL and worse perception of health than their children. When successful, intestinal transplantation allows a normal life in most patients and can be offered as an attractive option.     

The successful use of alemtuzumab for treatment of steroid‐refractory acute graft‐versus‐host disease in pediatric patients

SR‐aGVHD remains a significant cause of morbidity and mortality in allogeneic HCT recipients. Alemtuzumab has been used with success in adult patients but has not been studied in the pediatric setting. To estimate the effectiveness of alemtuzumab for the treatment of SR‐aGVHD in pediatric patients, we retrospectively reviewed the charts of 19 patients (median age 4 yr, range 0.5–28 years) with grades II (n = 3), III (n = 10), or IV (n = 6) SR‐aGVHD who received alemtuzumab treatment. Patients received a median dose of 0.9 mg/kg alemtuzumab (range 0.3–2 mg/kg) divided over 2–6 days. Eighty‐nine percent of patients received additional courses. A complete response, defined as GVHD of grade 0 at four wk following the first alemtuzumab course, was observed in nine patients (47%). A partial response, defined as an improvement in grade after four wk, was observed in five patients (26%). There was no response in five patients (26%). The overall response rate at four wk was 73%. Infectious complications included bacteremia (47%), presumed or documented fungal infections (21%), adenovirus viremia (52%), EBV viremia (36%), and CMV viremia (36%). We conclude that alemtuzumab is effective for SR‐aGVHD in pediatric patients with a tolerable spectrum of complications.