IL‐17E but not IL‐17A is associated with allergic sensitization: results from the LISA study

Herberth G, Daegelmann C, Röder S, Behrendt H, Krämer U, Borte M, Heinrich J, Herbarth O, Lehmann I for the LISAplus study group. IL‐17E but not IL‐17A is associated with allergic sensitization: results from the LISA study.
Pediatr Allergy Immunol 2010: 21: 1086–1090.
© 2010 John Wiley & Sons A/S Functional studies have provided evidence for the importance of IL‐17A and IL‐17E in the regulation of immune responses. IL‐17A is involved in inflammation and IL‐17E is able to induce Th2 cytokine production and eosinophilia. By now it is not clear whether these cytokines correlate with specific IgE levels. The aim of our investigation was to analyse the relationship of these two cytokines to allergic sensitization in context of an epidemiological study. Within the Life style Immune System Allergy study (LISA), we analysed phytohemagglutinin (PHA)‐stimulated blood samples of 6 yr old children for the concentration of IL‐17A and IL‐17E and sera for levels of specific IgE. In total, data from 293 children were available for blood analysis and for the analysis of confounding factors for the allergic sensitization. Among the investigated children, 29% reacted against inhalant and 13.6% against food allergens, whereas 33.1% of children were sensitized to any allergen. IL‐17E was associated with high levels of any specific IgE (adjusted odds ratio (OR) 1.45, 95% confidence interval (CI) 1.11–1.90). Furthermore, children with high IL‐17E responses (>208.8 pg/ml) were sensitized to food and inhalant allergens (OR 1.45, 95% CI 1.02–2.07 and OR 1.35, 95% CI 1.03–1.77, respectively) and to Der p 1 (OR 1.55, 95% CI 1.12–2.15). In contrast, IL‐17A, in trend, was negatively associated to sensitization to timothy (p for trend=0.013) and rye (p for trend=0.026). Concluding IL‐17E production is linked to the amount of specific IgE antibodies in blood samples of 6 yr old children.     

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.     

Chronic high Epstein–Barr viral load carriage in pediatric small bowel transplant recipients

Lau AH, Soltys K, Sindhi RK, Bond G, Mazariegos GV, Green M. Chronic high Epstein–Barr viral load carriage in pediatric small bowel transplant recipients.
Pediatr Transplantation 2010: 14:549–553. © 2010 John Wiley & Sons A/S. Abstract: The development of EBV infection and PTLD is normally associated with a high EBV load in peripheral blood. Often, children undergoing primary or reactivation of EBV infection subsequent to ITx will have chronically elevated EBV loads. To better understand this phenomenon and its consequences, we retrospectively reviewed the records of children who underwent ITx (either isolated or part of multivisceral transplantation) at our center from 1992 to 2007, to identify chronic high EBV load carriers in this population. CHL state was defined as the presence of high load for >50% of samples for greater than or equal to six months following either asymptomatic infection or complete clinical resolution of EBV disease/PTLD. Thirty‐five CHL carriers were identified from our patient population. Pretransplant serologies were available on 34 of these patients: 17 were EBV negative and 17 seropositive; one had unknown EBV serostatus prior to transplant. Seven of the 17 seronegative patients developed their CHL carrier state at the time of their primary EBV infection. Thirteen of the 35 (37%) HLC patients developed EBV disease after meeting the definition of high‐load carrier states. EBV‐related diseases developing in CHL carriers included EBV adenitis (n = 1), EBV enteritis (n = 7), PTLD (n = 4), and EBV+ spindle cell tumor (n = 1). Disease was seen in 7/17 of the seronegative (one PTLD) and 6/17 of the seropositive patients (three PTLD). Thirteen of 35 patients (37%) resolved their CHL state without apparent sequelae while nine remain asymptomatic CHL carriers. Three children have had more than one episode of CHL. These data provide important information about the outcome of chronic EBV high‐load carriage in pediatric intestinal transplant recipients.     

Food allergy after liver transplantation in children: a prospective study

Food allergy has been increasingly reported in children who had orthotopic liver transplantation (OLT). We aimed to conduct a prospective study to investigate the prevalence of sensitizations and food allergy in pediatric OLT recipients. We also aimed to identify potential risk factors. The study group consisted of 28 children (14 male, 14 female, mean age 4.96 ± 0.76 yrs) who had OLT. Total eosinophil count (TEC), total IgE, and specific IgEs were studied before and 3, 6, 12 months after OLT. Six patients (21%) developed multiple food allergies. Mean age of six patients at OLT who developed food allergy was younger compared to the non‐food allergy group (10.2 months vs. 68.9 months, p < 0.05). Food allergy has been developed within 1 yr in 5, and in 20 months in one patient after OLT. All six patients had cow’s milk and egg allergy after OLT. Five children developed wheat, one children developed lentil and another one developed peach allergy in addition to cow’s milk and egg allergy. Out of six food‐allergic patients after OLT, four children developed Epstein–Barr virus (EBV) infection prior to food allergy. Before OLT, TECs and total IgE levels were not differed among food allergic and non‐food allergic patients (p > 0.05). Mean of TECs were significantly higher in food allergic group compared to non‐food allergic group at each time point after OLT (p < 0.05). Though statistically insignificant, mean of total IgE levels were also higher in the food allergic group (p > 0.05). These findings suggest that food allergy should be considered after OLT in patients who are younger than 1 yr of age, who developed hypereosinophilia, high total IgE levels or EBV viremia.     

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.     

Cytotoxic T‐lymphocyte therapy for post‐transplant lymphoproliferative disorder after solid organ transplantation in children

EBV‐CTL immunotherapy targets EBV antigens expressed by tumor cells in PTLD. Data on outcome of EBV‐CTL in pSOT patients are limited. The aim of the study is to describe our experience with allogeneic, third‐party EBV‐CTL for the treatment of PTLD in pSOT patients in a single tertiary center. Retrospective review was performed of all pSOT patients who received EBV‐CTL for PTLD. PTLD was diagnosed using World Health Organization histologic criteria. EBV‐CTLs were derived from human leukocyte antigen‐typed, EBV‐seropositive third‐party donors, and cryopreserved and maintained by an accredited national blood transfusion service. Ten patients received EBV‐CTL for histologically proven PTLD from 1999 to 2016 following liver (n=5), combined intestinal/liver (n=4), and liver/kidney (n=1) transplantation. PTLD occurred at median age of 40 months (range: 12‐144) and median post‐transplant interval of 8 months (range: 2‐107). Seven had monomorphic, two had polymorphic, and one had Hodgkin‐type PTLD. All were of B‐cell origin and EBV‐positive on histology. EBV‐CTL achieved an overall remission rate of 80% (8 of 10). Transient adverse effects included fever, tachycardia, and vomiting. None developed graft‐versus‐host disease or opportunistic infections. EBV‐CTL is an effective treatment for PTLD in pSOT patients, with good remission rate and minimal toxicity.     

Gene expression using microarrays in transplant recipients at risk of EBV lymphoproliferation after organ transplantation: Preliminary proof‐of‐concept

Abstract: We hypothesized that aspects of the virus–host interaction could be measured to help predict progression to EBV–PTLD. We examined the spectrum of host genes differentially expressed and any relevant clustering in children at risk of EBV lymphoproliferation after organ transplantation. We compared the genes expressed among patients with different levels of viral loads. Gene expression was measured by microarray analysis of RNA from CD19+ B lymphocytes using the Human Genome U133 Plus 2.0 GeneChip. Among 27 samples from 26 transplant recipients, the viral load categories were: low or undetectable loads (LU), n = 14; high or intermediate loads (HI), n = 13. There were seven healthy EBV‐seropositive (P) and ‐seronegative controls (N). Median time of post‐transplantation was 0.5 yr (range 0.1–3.8). We identified 24–54 differentially expressed genes in each of four comparisons of HI vs. P, LU vs. P, HI vs. LU, and P vs. N. We identified patterns of 563 gene expressions, creating five clusters aligned with levels of viral load. PTLD occurred in four of five clusters. In summary, we demonstrated varying degrees of alignment between levels of VL and gene clusters. Analyses for differential expression of genes showed genes that could be implicated in the pathogenesis of EBV–PTLD.     

Induction regimens and post‐transplantation lymphoproliferative disorder after pediatric intestinal transplantation: Single‐center experience

Pediatric recipients of intestinal transplants have a high incidence of PTLD, but the impact of specific induction immunosuppression agents is unclear. In this single‐center retrospective review from 2000 to 2017, we describe the incidence, characteristics, and outcomes of PTLD after primary intestinal transplantation in 173 children with or without liver, after induction with rATG, alemtuzumab, or anti‐IL‐2R agents. Thirty cases of PTLD occurred among 28 children, 28 EBV+ and 2 EBV?. Although not statistically significant, the PTLD incidence was higher after isolated intestinal transplant compared with liver‐inclusive allograft (19.3% vs 13.3%, P = .393) and after induction with anti‐IL‐2R antibody and alemtuzumab compared with rATG (28.6% and 27.3% vs 13.3%, P = .076). The 30 PTLD cases included 13 monomorphic PTLD, 13 polymorphic PTLD, one spindle cell, one Burkitt lymphoma, and two cases too necrotic to classify. After reduction of immunosuppression, management was based on disease histology and extent. Resection with or without rituximab was used for polymorphic tumors and limited disease extent, whereas chemotherapy was used for diffuse disease. Of the 28 patients, 11 recovered with functioning allografts (39.3%), 10 recovered after enterectomy (35.7%), and seven patients died (25%), three due to PTLD and four due to other causes. All who died of progressive PTLD had received chemotherapy, highlighting the mortality of PTLD, toxicity of treatment and need for novel agents. Alemtuzumab is no longer used for induction at our center.     

The changing face of post‐transplant lymphoproliferative disease in the era of molecular EBV monitoring

Kerkar N, Morotti RA, Madan RP, Shneider B, Herold BC, Dugan C, Miloh T, Karabicak I, Strauchen JA, Emre S. The changing face of post‐transplant lymphoproliferative disease in the era of molecular EBV monitoring.
Pediatr Transplantation 2010: 14:504–511. © 2010 John Wiley & Sons A/S. Abstract: Pediatric PTLD is often associated with primary EBV infection and immunosuppression. The aim was to retrospectively review the spectrum of histologically documented PTLD for two time intervals differentiated by changes in use of molecular EBV monitoring. Eleven of 146 patients (7.5%) in 2001–2005 (Era A) and 10 of 92 (10.9%) in 1993–1997 (Era B) were diagnosed with PTLD. The median age at liver transplantation (0.8 and 0.9 yr, respectively) and the median duration between liver transplant and diagnosis of PTLD (0.6 and 0.7 yr, respectively) were similar in both eras. However, patients in Era A presented with significantly less advanced histological disease compared to patients in Era B (p = 0.03). Specifically, nine patients (82%) in Era A had Pl hyperplasia/polymorphic PTLD, whereas in Era B, six had advanced histological disease (five monomorphic and one unclassified). Three transplant recipients in Era B died secondary to PTLD, whereas there were no PTLD‐related deaths in Era A (p = 0.03). Heightened awareness of risk for PTLD, alterations in baseline immunosuppression regimens, implementation of molecular EBV monitoring, pre‐emptive reduction in immunosuppression and improved therapeutic options may have all contributed to a milder PTLD phenotype and improved clinical outcomes.     

IL13 variants are associated with total serum IgE and early sensitization to food allergens in children with atopic dermatitis

Increased total and specific serum immunoglobulin E (IgE) levels are common characteristics of atopic diseases and their basal production is proposed to be under strong genetic control. Interleukin 13 (IL13) variants have been consistently associated with total serum IgE levels in white populations with a strongest association in non‐atopics. The aim of this study was to test the IL13 p.R130Q and c.1‐1111C>T variants in children with atopic dermatitis (AD) for associations with total serum IgE and early sensitization to common food and inhalant allergens and with asthma. We included 453 children with AD [participants of the Early Treatment of the Atopic Child (ETAC) study] that were followed from the age of 12–24 months for 3 yr. Total and specific IgE were determined at four time points. We genotyped the IL13 p.R130Q and c.1‐1111C>T variants by melting curve analysis. In children up to 4 yr of age, the 130Q allele was related to slightly higher total IgE levels compared to heterozygotes and 130R homozygotes. More importantly, both IL13 variants were significantly associated with sensitization to food allergens, with most significant results for sensitization to egg (p = 0.0001). Although early sensitization to hen’s egg represents a strong risk factor for subsequent sensitization to inhalant allergens and asthma, the investigated IL13 variants were not associated with these phenotypes at the age of 48–60 months. In summary IL13 variants contribute to elevated levels of total serum IgE in young atopic children and are strongly associated with sensitization to food allergens, particularly to hen’s egg. These findings suggest that IL13 variants play a major role not only in non‐cognate but also in allergen specific IgE synthesis.     

Lymphocyte subset at time of Epstein‐Barr viremia post‐allogeneic hematopoietic stem cell transplantation in children may predict development of post‐transplant lymphoproliferative disease: CD8:CD20 ratio as a sensitive predictor

EBV–associated PTLD following allogeneic HSCT is a serious complication associated with significant mortality. In this retrospective study, we evaluated whether lymphocyte subset numbers and CD8:CD20 ratio at time of EBV viremia in children undergoing allogeneic HSCT could predict development of PTLD. Absolute lymphocyte count, lymphocyte subsets, and CD8:CD20 ratio at the time of EBV viremia were analyzed. Patients who were treated preemptively with rituximab for high blood EBV viral load were excluded. Out of 266 patients transplanted during the study period, 26 patients were included in the analysis. Patients were divided into two cohorts; cohort 1 included patients with EBV‐associated PTLD (n = 5; four with proven, one with probable PTLD). Cohort 2 included patients with EBV viremia without PTLD (n = 21). Lymphocyte recovery was slower in the PTLD group. CD8:CD20 ratio was significantly lower in the PTLD group (median 0.15) compared to the non‐PTLD group (median 2.4, P = .012). Using the ROC curve and 1 as the cutoff value, CD8:CD20 ratios were analyzed. In the PTLD group, 4/5 patients (80%) had a ratio <1 whereas in the non‐PTLD group, all 21 patients had a ratio >1. Sensitivity and specificity were 80% and 100%, respectively. Negative and PPVs were 95% and 100%, respectively. Profoundly low T‐cell count and CD8:CD20 ratio may be used to predict development of PTLD in the context of EBV viremia in children post‐allogeneic HSCT. Further studies are needed to validate this finding.     

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.     

Vitamin D Status of term exclusively breastfed infants and their mothers from India

Objectives: (i) To measure 25‐OH vitamin D levels in term infants at 10 weeks and 6 months and to correlate with maternal vitamin D levels at 10‐week postpartum (ii) To evaluate infants at 6 months for rickets. Patients and methods: A total of 179 exclusively breastfed infant–mother pairs 96 appropriate‐for‐gestational age (Group 1) and 83 small‐ for‐ gestational age infants (Group 2) recruited at 10 weeks. At 6 months, 52 in group 1 and 45 in group 2 were evaluated. Venous blood sample were collected at 10 weeks and 6 months in infants and at 10 weeks in mothers for calcium, phosphorus, alkaline phosphatase and 25‐OH vitamin D estimation. Results: Mean 25‐OH vitamin D levels of infants (n = 97) were 11.55 ± 7.17 ng/mL at 10 weeks and 16.96 ± 13.33 ng/mL at 6 months (p < 0.001). Mean vitamin D levels of infants in group 1 and group 2 did not differ at recruitment and 6 months (p > 0.05)). Maternal vitamin D levels in group 1 and group 2 were 8.89 ± 5.97 and 9.87 ± 6.44 ng/mL, respectively (p = 0.44). Significant correlation was observed between 25‐OH vitamin D of infants and mothers (p < 0.05). At 10 weeks, 55.67% infants, 70% mothers and at 6 months, 44.33% infants had vitamin D < 11 ng/mL. At 6 months, 16.49% infants developed rickets. Conclusions: Exclusively breastfed infants and their mothers are Vitamin D deficient, hence the need to improve vitamin D status.     

Epidemiology and outcome of chronic high Epstein‐Barr viral load carriage in pediatric kidney transplant recipients

The development of EBV infection and PTLD is normally associated with a high EBV viral load in peripheral blood. Observations have previously identified existence of a CHL carrier state that demonstrated variable outcomes based upon the organ which was transplanted. Data defining the incidence and outcome of CHL in pediatric KTx are not well described. The charts of children undergoing isolated KTx at Children's Hospital of Pittsburgh between January 2000 and December 2014 were retrospectively reviewed. EBV loads in the peripheral blood were routinely measured as part of surveillance protocols at our center. CHL was defined as the presence of high load for >50% of samples for ≥6 months. PTLD was defined histologically using WHO definitions. Of 188 isolated KTx recipients, we identified a total of 16 (8%) children who developed CHL carrier state. No patient developed EBV‐driven late‐onset PTLD. Age at the time of KTx was significantly lower in the CHL group (median 3.9 years, interquartile range: IQR 2.9‐6.6, P = .0004). Children in the CHL group were more likely to be EBV‐seronegative prior to KTx (94%, 15/16), compared to the UVL and LVL groups (55% and 50%, respectively, P < .002). The median duration of CHL carrier state was 20 months (IQR 10.7‐35.8). Fifteen of the 16 CHL carriers experienced spontaneous resolution of CHL carrier state. Children in the CHL group were younger at the time of primary EBV infection (P = .023). Finally, antiviral medication was not effective in either preventing or decreasing the EBV viral load in blood (P = .84). Overall incidence of late‐onset PTLD is very low compared to heart and intestinal transplant, even though KTx recipients can develop CHL carrier state. The CHL carriers in KTx recipients were EBV‐seronegative prior to transplant and were younger both at the time of KTx and at the time of primary EBV infection compared to those in the UVL and HVL groups. Antivirals did not prevent EBV infection or decrease EBV viral loads.     

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.     

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.     

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.     

Increased serum‐soluble interleukin‐5 receptor alpha level precedes the development of eczema in children

Semic‐Jusufagic A, Gevaert P, Bachert C, Murray C, Simpson A, Custovic A. Increased serum‐soluble interleukin‐5 receptor alpha level precedes the development of eczema in children.
Pediatr Allergy Immunol 2010: 21: 1052–1058.
© 2010 John Wiley & Sons A/S Interleukin‐5 receptor α‐subunit expression may be implicated in the development of allergic diseases. In a population‐based birth cohort, we investigated the relationship between IL‐5Rα and the development of allergic phenotypes in childhood, using soluble IL‐5Rα (s‐IL‐5Rα) as a marker. Children (n = 510) were followed from birth and assessed at age 3, 5 and 8. Based on the onset and resolution of symptoms, we assigned children into the following wheeze and eczema phenotypes: never, transient, persistent, intermittent and late‐onset. Specific IgE to common allergens, s‐IL‐5Rα (ELISA) and urinary eosinophilic protein X (U‐EPX) levels was measured at age 5. s‐IL‐5Rα was significantly higher among atopic compared to non‐atopic children (pg/ml, geometric means [95% CI], 152.4 [126.0–184.5] vs. 103.4 [94.0–113.9], p < 0.0001). While we found no association between s‐IL‐5Rα and current eczema at age 5, there was a significant association between eczema phenotypes and s‐IL‐5Rα (multiple anova model adjusted for gender and atopy, F = 2.56, p = 0.04). After adjustment for multiple comparisons, we found that children with late‐onset eczema had significantly higher s‐IL‐5Rα compared to those who have never had eczema (mean difference [95% CI], 2.41 [1.03–5.62], p = 0.04) and those with intermittent eczema (2.63 [1.08–6.41], p = 0.02), with no difference between children who have never had eczema and other eczema phenotypes. We found no such association for wheeze phenotypes. There was a weak correlation between s‐IL‐5Rα and U‐EPX (r = 0.16, p < 0.0001). Increased serum s‐IL‐5Rα level at age 5 was associated with contemporaneous atopic sensitization and with subsequent development of eczema by age 8.     

The development of eosinophilic colitis after liver transplantation in children

Tacrolimus-based immunosuppression in pediatric liver transplant recipients is known to be associated with EGID. Our goal was to determine the incidence, risk factors, and characteristics of EGID in our pediatric liver transplantation program. This study was a retrospective analysis of 38 pediatric liver transplant recipients. Rectal mucosal biopsy was performed to evaluate for gastrointestinal PTLD and eosinophilic colitis. There were 14 patients (37%) who were diagnosed with eosinophilic colitis. The mean age at transplantation was 10.8 +/- 1.8 months. Those with eosinophilic colitis had a higher incidence of peripheral eosinophilia (p = 0.003) during the first two months following transplantation and had a higher EBV infection rate. Symptoms, such as diarrhea, hematochezia, and abdominal pain, became apparent after an average of three months; diagnoses were made at 6.9 +/- 2.0 months after transplantation. There were eight patients (57%) with elevated food-specific IgE levels. With food restriction treatment, the symptoms of patients improved. EGID should be considered when clinical symptoms are present, because symptoms of this disorder are similar to those of gastrointestinal PTLD. It should also be considered when peripheral eosinophila is detected or when EBV seroconversion develops during the first two months following transplantation.