The IPTA Nashville Consensus Conference on Post-Transplant lymphoproliferative disorders after solid organ transplantation in children: III - Consensus guidelines for Epstein-Barr virus load and other biomarker monitoring.

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders after solid organ transplantation in children. In this report from the Viral Load and Biomarker Monitoring Working Group, we reviewed the existing literature regarding the role of Epstein-Barr viral load and other biomarkers in peripheral blood for predicting the development of PTLD, for PTLD diagnosis, and for monitoring of response to treatment. Key recommendations from the group highlighted the strong recommendation for use of the term EBV DNAemia instead of "viremia" to describe EBV DNA levels in peripheral blood as well as concerns with comparison of EBV DNAemia measurement results performed at different institutions even when tests are calibrated using the WHO international standard. The working group concluded that either whole blood or plasma could be used as matrices for EBV DNA measurement; optimal specimen type may be clinical context dependent. Whole blood testing has some advantages for surveillance to inform pre-emptive interventions while plasma testing may be preferred in the setting of clinical symptoms and treatment monitoring. However, EBV DNAemia testing alone was not recommended for PTLD diagnosis. Quantitative EBV DNAemia surveillance to identify patients at risk for PTLD and to inform pre-emptive interventions in patients who are EBV seronegative pre-transplant was recommended. In contrast, with the exception of intestinal transplant recipients or those with recent primary EBV infection prior to SOT, surveillance was not recommended in pediatric SOT recipients EBV seropositive pre-transplant. Implications of viral load kinetic parameters including peak load and viral set point on pre-emptive PTLD prevention monitoring algorithms were discussed. Use of additional markers, including measurements of EBV specific cell mediated immunity was discussed but not recommended though the importance of obtaining additional data from prospective multicenter studies was highlighted as a key research priority.

The IPTA Nashville consensus conference on post-transplant lymphoproliferative disorders after solid organ transplantation in children: IV-consensus guidelines for the management of post-transplant lymphoproliferative disorders in children and adolescents.

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders (PTLD) after pediatric solid organ transplantation. This report addresses the outcomes of deliberations by the PTLD Management Working Group. A strong recommendation was made for reduction in immunosuppression as the first step in management. Similarly, strong recommendations were made for the use of the anti-CD20 monoclonal antibody (rituximab) as was the case for chemotherapy in selected scenarios. In some scenarios, there is uncoupling of the strength of the recommendations from the available evidence in situations where such evidence is lacking but collective clinical experiences drive decision-making. Of note, there are no large, randomized phase III trials of any treatment for PTLD in the pediatric age group. Current gaps and future research priorities are highlighted.

Safety and immunogenicity of the live-attenuated varicella vaccine in pediatric solid organ transplant recipients: A systematic review and meta-analysis.

This study aimed to synthesize the available evidence on the immunogenicity, safety, and effectiveness of live-attenuated varicella vaccine in solid organ transplant recipients. Medline and EMBASE were searched using predefined search terms to identify relevant studies. The included articles reported varicella vaccine administration in the posttransplant period in children and adults. A pooled proportion of transplant recipients who seroconverted and who developed vaccine-strain varicella and varicella disease was generated. Eighteen articles (14 observational studies and 4 case reports) were included, reporting on 711 transplant recipients who received the varicella vaccine. The pooled proportion was 88.2% (95% confidence interval 78.0%-96.0%, 13 studies) for vaccinees who seroconverted, 0% (0%-1.2%, 13 studies) for vaccine-strain varicella, and 0.8% (0%-4.9%, 9 studies) for varicella disease. Most studies followed clinical guidelines for administering live-attenuated vaccines, with criteria that could include being at least 1 year posttransplant, 2 months postrejection episode, and on low-dose immunosuppressive medications. Varicella vaccination in transplant recipients was overall safe in the included studies, with few cases of vaccine-strain-induced varicella or vaccine failure, and although it was immunogenic, the proportion of recipients who seroconverted was lower than that seen in the general population. Our data support varicella vaccination in select pediatric solid organ transplant recipients.

PD-L1 and PD-1 expression in pediatric post-transplant Burkitt lymphoma and other monomorphic post-transplant lymphoproliferative disorders.

BACKGROUND: Post-transplant lymphoproliferative disorders (PTLD) develop as a consequence of immune suppression. Programmed death protein 1 (PD-1), a regulator of host immune activation, binds to programmed death-ligand 1 (PD-L1) to suppress the T-cell immune response. PD-1/PD-L1 pathway may play a role in PTLD. The objective was to describe intratumoral expression of PD-L1 and PD-1 in pediatric monomorphic PTLD, and assess if density of these cells is associated with progression-free survival (PFS) and overall survival (OS). PROCEDURE: Clinical variables and outcome data were collected on B-cell monomorphic PTLD treated in Toronto, Canada between 2000 and 2017. Diagnostic area from tumor tissue was identified to count CD3-positive or PD-1-positive cells and CD3-negative lymphoma B cells or PD-L1-positive cells. CD3+ , PD-1+ , and PD-L1+ cell densities were compared between cases of PTLD. OS and PFS were analyzed. RESULTS: We identified 25 cases of B-cell monomorphic PTLD; majority Burkitt lymphoma (32%) and diffuse large B-cell lymphoma (56%). All cases had CD3+ cells infiltrating the tumor, and median percentage of CD3+ cells was 14% (interquartile range: 6.2%-25%). Twelve cases (48%) had PD-1+ cell infiltrating (range: 1%-83%) and 13 cases (52%) had no PD-1+ cells infiltrating. Sixteen cases (64%) had PD-L1+ cells present; however, there was no PD-L1 expression on any Burkitt lymphoma tissue. When comparing PD-1 and PD-L1 expression, there was no difference in OS or PFS. CONCLUSION: Intratumoral presence of PD-1+ and PD-L1+ cells varied in pediatric patients with monomorphic PTLD; however, no relationship to OS and PFS was identified.

Immunogenicity of a quadrivalent human papillomavirus vaccine in pediatric kidney and liver transplant recipients.

BACKGROUND: Solid-organ transplant recipients are at increased risk of developing human papillomavirus-related diseases. METHODS: To evaluate the immunogenicity of a quadrivalent vaccine, a prospective observational study included females aged 12-19 years who had received kidney or liver transplants, or were otherwise healthy volunteers. With the three-dose vaccination, serum antibodies were measured. RESULTS: The study included 17 transplant recipients (seven kidney and 10 liver) and 16 healthy participants. Six of seven kidney transplant recipients were on three immunosuppressive medications, whereas 9 of the 10 liver transplant recipients were on one. For the serology within 6 months from the last vaccine dose, the geometric mean titers of human papillomavirus types 6, 11, 16, and 18 were 26.7, 8.6, 35.7, and 42.4 (kidney transplant); 579.2, 569.3, 3097.3, and 835.7 (liver transplant); and 860.5, 638.8, 4391.6, and 902.6 milli-Merck Units/ml (healthy). The seropositivity rates of kidney transplant recipients for the four serotypes ranged from 50% to 75%, while all liver transplant recipients and healthy participants had 100% seropositivity rates for all four types. While there were no statistical differences of titers between liver transplant recipients and healthy participants, the titers of kidney transplant recipients were lower than those of healthy participants for type 6 (p = .034), type 11 (p = .032), and type 16 (p = .032). CONCLUSIONS: The results support the recommendation of human papillomavirus vaccination in pediatric transplant recipients given the significant risk of human papillomavirus-related diseases in this population, though immunogenicity was lower in kidney transplant recipients on multiple immunosuppressive medications.

Differences in medication adherence by sex and organ type among adolescent and young adult solid organ transplant recipients.

BACKGROUND: Identification of differences in medication adherence by sex or organ type may help in planning interventions to optimize outcomes. We compared immunosuppressive medication adherence between males and females, and between kidney, liver and heart transplant recipients. METHODS: This multicenter study of prevalent kidney, liver and heart transplant recipients 14-25 years assessed adherence 3 times (0, 3, 6 months post-enrollment) with the BAASIS self-report tool. At each visit, participants were classified as adherent if they missed no doses in the prior 4 weeks and non-adherent otherwise. Adherence was also assessed using the coefficient of variation (CV) of tacrolimus trough levels; CV < 30% was classified as adherent. We used multivariable mixed effects logistic regression models adjusted for potential confounders to compare adherence by sex and by organ. RESULTS: Across all visits, males (n = 150, median age 20.4 years, IQR 17.2-23.3) had lower odds of self-reported adherence than females (n = 120, median age 19.8 years, IQR 17.1-22.7) (OR 0.41, 95% CI 0.21-0.80) but higher odds of adherence by tacrolimus CV (OR 2.50, 95% CI 1.30-4.82). No significant differences in adherence (by self-report or tacrolimus CV) were noted between the 184 kidney, 58 liver, and 28 heart recipients. CONCLUSION: Females show better self-reported adherence than males but greater variability in tacrolimus levels. Social desirability bias, more common in females than males, may contribute to better self-reported adherence among females. Higher tacrolimus variability among females may reflect biologic differences in tacrolimus metabolism between males and females rather than sex differences in adherence. There were no significant differences in adherence by organ type.

Antimicrobial stewardship in pediatric solid organ transplantation: Is it possible?

BACKGROUND: Solid organ transplant (SOT) recipients are at increased risk of severe outcomes associated with antimicrobial resistance (AMR). Antimicrobial stewardship programs (ASPs) play a vital role in mitigating the negative impacts of AMR. Pediatric evidence regarding ASP for SOT recipients is scarce, although many pediatric SOT centers have implemented different forms of ASP. METHODS: This article summarized the available evidence relating to AMR among pediatric SOT recipients and discussed key strategies for the successful implementation of ASP among this population. The focus is primarily on antibacterial and secondarily on antifungal management. RESULTS: The development of multidisciplinary antimicrobial stewardship teams for pediatric SOT recipients is essential for successful stewardship implementation. Key stakeholders may include but are not limited to SOT recipients and their caregivers, primary SOT teams (transplant physicians, transplant pharmacists, transplant unit nurses, and transplant outpatient care team), transplant surgery teams, transplant infectious diseases teams, hospital AST, microbiology teams, infection prevention teams, quality improvement teams, and information technology teams. CONCLUSION: As the evidence for optimal ASP in pediatric SOT is still evolving, it is important to measure the impact of implemented interventions.

The IPTA Nashville consensus conference on post-transplant lymphoproliferative disorders after solid organ transplantation in children: I-Methodology for the development of consensus practice guidelines.

The International Pediatric Transplant Association (IPTA) Consensus Conference on Practice Guidelines for the Diagnosis, Prevention, and Management of Post-Transplant Lymphoproliferative Disorders after Solid Organ Transplantation in Children took place on March 12-13, 2019, and the work of conference members continued until the end of December 2021. The goal was to produce evidence-based consensus guidelines on the definitions, diagnosis, prevention, and management of PTLD and related disorders based on the critical review of the literature and consensus of experts. This report describes the goals, organization, and methodology of the consensus conference and follow-up activities. The results of each working group (Definitions, Prevention, Management, and Epstein-Barr viral [EBV] load/Biomarker Monitoring) are presented in separate manuscripts within this volume of Pediatric Transplantation.

The IPTA Nashville consensus conference on Post-Transplant lymphoproliferative disorders after solid organ transplantation in children: II-consensus guidelines for prevention.

The International Pediatric Transplant Association (IPTA) convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorder after solid organ transplantation in children. In this report from the Prevention Working Group, we reviewed the existing literature regarding immunoprophylaxis and chemoprophylaxis, and pre-emptive strategies. While the group made a strong recommendation for pre-emptive reduction of immunosuppression at the time of EBV DNAemia (low to moderate evidence), no recommendations for use could be made for any prophylactic strategy or alternate pre-emptive strategy, largely due to insufficient or conflicting evidence. Current gaps and future research priorities are highlighted.

Population pharmacokinetics of vancomycin in paediatric patients with febrile neutropenia and augmented renal clearance: development of new dosing recommendations.

OBJECTIVES: The purpose of this study was to evaluate the influence of augmented renal clearance (ARC) on vancomycin clearance and provide dosage recommendations for paediatric patients with febrile neutropenia following HSCT. METHODS: A population pharmacokinetic analysis was performed based on a two-compartment model structure using a non-linear mixed-effect modelling approach. Monte Carlo simulations were conducted as a target attainment analysis of AUC between 400 mg·h/L and 650 mg·h/L for MRSA at an MIC of 1 mg/L. RESULTS: A total of 165 paediatric patients and 276 vancomycin serum concentrations were analysed in this study. Age, body weight, estimated glomerular filtration rate (eGFR) and fever (≥38.0°C) were identified as factors that significantly influenced vancomycin clearance. The median eGFR of the population was 143 mL/min/1.73 m2 and 34% of patients showed an eGFR ≥160 mL/min/1.73 m2, which may be classified as ARC. Our simulations showed that current dosing recommendations result in poor target attainment. In particular, children aged 6 months old to 6 years old with ARC require an initial vancomycin dose up to 35%-65% higher than the current dosing guidelines. CONCLUSIONS: ARC is frequently observed in paediatric patients with post-HSCT febrile neutropenia, resulting in a significant increase in vancomycin clearance. We propose a vancomycin dosing strategy for children with febrile neutropenia following HSCT based on eGFR, age, weight and body temperature.

Solid organ transplant-specific antibiogram in a tertiary pediatric hospital in Canada.

SOT recipients are more vulnerable to infections with antimicrobial-resistant organisms, and therefore, it may be useful for transplant centers to create transplant-specific antibiograms to direct empirical antimicrobial regimens and monitor trends in antimicrobial resistance. SOT-specific antibiograms were created using antimicrobial susceptibility data on isolates from 2012 to 2018 at The Hospital for Sick Children, Toronto, Ontario, Canada. The CLSI guidelines were followed to generate the antibiograms except that results from 2 years of data were pooled on a rolling basis to achieve larger sample sizes. The 3 most frequent organisms in one analysis period of the SOT antibiogram were Escherichia coli (average sample size ±standard deviation; n = 28.7 ± 3.8), Staphylococcus aureus (n = 27.8 ± 5.0), and Pseudomonas aeruginosa (non-CF) (n = 19.8 ± 8.8). For E.coli, susceptibilities in the SOT antibiogram were significantly lower than those in the hospital-wide antibiogram in 2017-2018 for ampicillin (27% vs 47%; p = .014), piperacillin/tazobactam (55% vs 88%; p < .001), cefotaxime (59% vs 89%; p < .001), ciprofloxacin (71% vs 88%; p = .007), and trimethoprim-sulfamethoxazole (41% vs 69%; p = .001), but not significantly different for aminoglycosides and meropenem. In the SOT antibiogram of E. coli, decreased susceptibility trend was confirmed in some antibiotics, including piperacillin/tazobactam (83% in 2012-2013 vs 55% in 2017-2018). At our center, the solid organ transplant-specific antibiogram revealed important differences in E. coli susceptibilities and trends in antimicrobial resistance. Developing a SOT antibiogram will assist in revising and improving empiric treatment guidelines as well as monitoring antimicrobial resistance in this population.

Care processes and structures associated with higher medication adherence in adolescent and young adult transplant recipients.

BACKGROUND: We aimed to identify care processes and structures that were independently associated with higher medication adherence among young transplant recipients. METHODS: We conducted a prospective, observational cohort study of 270 prevalent kidney, liver, and heart transplant recipients 14-25 years old. Patients were ≥3 months post-transplant, ≥2 months post-discharge, and followed in one of 14 pediatric or 14 adult transplant programs in Canada. Patients were enrolled between June 2015 and March 2018 and followed for 6 months. Adherence was assessed at baseline, 3, and 6 months using the BAASIS© self-report tool. Patients were classified as adherent if no doses were missed in the prior 4 weeks. Transplant program directors and nurses completed questionnaires regarding care organization and processes. RESULTS: Of the 270 participants, 99 were followed in pediatric programs and 171 in adult programs. Median age was 20.3 years, and median time since transplant was 5 years. At baseline, 71.5% were adherent. Multivariable mixed effects logistic regression models with program as a random effect identified two program-level factors as independently associated with better adherence: minimum number of prescribed blood draws per year for those >3 years post-transplant (per 1 additional) (OR 1.12 [95% CI 1.00, 1.26]; p = .047), and average time nurses spend with patients in clinic (per 5 additional minutes) (OR 1.15 [1.03, 1.29]; p = .017). CONCLUSION: Program-level factors including protocols with a greater frequency of routine blood testing and more nurse time with patients were associated with better medication adherence. This suggests that interventions at the program level may support better adherence.

Burden of cytomegalovirus DNAemia among pediatric renal transplant patients on antiviral prophylaxis: A hospital-based analysis.

INTRODUCTION: We examined the burden of CMV DNAemia and time to such events among renal transplant patients receiving CMV prophylaxis. We targeted the first year after transplantation, with the primary focus being on the first 3 months. METHODS: We conducted a retrospective review of renal transplant patients (<18 years) who were transplanted and followed at our center between January 2007, and December 2017. Clinical and laboratory data were obtained from the medical records and laboratory databases. RESULTS: Among 141 patients, the median age at transplant was 12.7 years (range 0.87-17.83 years). CMV DNAemia was detected in 33 of 77 patients eligible for prophylaxis (42.9%; 95% CI 31.6-54.6) during the first post-transplant year. Proportionately more D+R- patients were present among patients with DNAemia compared with those without DNAemia (15/38, 39.5% vs 16/103, 15.5%, P = .005). Median time to first positivity was 134 days (range 0-304 days). Eight patients had a positive PCR during the first 3 months (5.7% of all patients). Among those eligible for prophylaxis, 6.5% had DNAemia during the first 3 months while on prophylaxis. Among patients whose first positive PCR was after 3 months post-transplant, the median time to positivity was 52 days (range 13-214 days) after the end of prophylaxis. CONCLUSIONS: Breakthrough CMV DNAemia was documented among children receiving antiviral prophylaxis. While routine monitoring while on prophylaxis might not be warranted for the majority of patients, studies are needed to determine the optimal indications for CMV PCR testing while on prophylaxis.

Management and prevention of varicella and measles infections in pediatric solid organ transplant candidates and recipients: An IPTA survey of current practice.

BACKGROUND: Varicella and measles infections can be life-threatening after solid organ transplantation (SOT) but may be preventable with live-attenuated vaccines (LAV). METHODS: This survey conducted in January 2019 among subscribers of the International Pediatric Transplantation Association listserv aimed to explore the current strategies to prevent and manage both infections in the pediatric SOT population, including recommending LAV after SOT. RESULTS: The answers given by 95 pediatric SOT healthcare workers show that these strategies are not yet optimal and call for further education. In particular, 59% of respondents are unnecessarily waiting for a SOT candidate to be >1 year of age to start administrating LAV before SOT. Interestingly, most respondents are willing to administer LAV after SOT (57%), and a fifth (21%) are already doing so, off-label. The survey queried the precautions taken to improve safety evaluations after LAV, and identified knowledge gaps and practitioners' concerns. CONCLUSION: The results of this survey could be used as a starting point for education and promotion of the safe administration of LAV in carefully selected SOT recipients; in turn, this would increase available data that would contribute to the development of evidence-based guidelines by the transplant societies and ultimately prevent these infections after SOT.

Charting the Path Forward: Development, Goals and Initiatives of the 2019 Infectious Diseases Society of America Strategic Plan.

In October 2018, the Infectious Diseases Society of America (IDSA) Board of Directors (BOD) decided to develop a 2019 IDSA Strategic Plan. The IDSA BOD has invested in strategic planning at regular intervals as part of an ongoing process to review and to renew the vision and direction of IDSA. Herein, the 2018-2019 strategic planning process and outcomes are described. The 2019 IDSA Strategic Plan presents 4 key initiatives: (1) optimize the development, dissemination, and adoption of timely and relevant ID guidance and guidelines that improve the outcomes of clinical care; (2) quantify, communicate, and advocate for the value of ID physicians to increase professional fulfillment and compensation; (3) facilitate the growth and development of the ID workforce to meet emerging scientific, clinical, and leadership needs; and (4) develop and position a new tool to serve as the leading US benchmark to measure and drive national progress on antimicrobial resistance. The BOD looks forward to developing, implementing, assessing, and advancing the 2019 IDSA Strategic Plan working with member volunteers, Society partners, and IDSA staff.

Pediatric Investigators Collaborative Network on Infections in Canada Study of Respiratory Syncytial Virus-associated Deaths in Pediatric Patients in Canada, 2003-2013.

Background: Respiratory syncytial virus (RSV) is a major cause of pneumonia and bronchiolitis in children. Mortality rates in previously healthy children hospitalized with RSV are <0.5%, but up to 37% in patients with underlying medical conditions. The objective of this study was to characterize factors associated with deaths among children hospitalized with RSV infection in Canadian pediatric centers. Methods: A retrospective case series of children aged ≤18 years with RSV-associated deaths at centers affiliated with the Pediatric Investigators Collaborative Network on Infections in Canada from 2003­2013, inclusive, was performed [corrected]. Cases were identified using RSV-specific International Classification of Diseases codes to capture deaths where a diagnosis of RSV infection was present. Results: Eleven centers reported 79 RSV-associated deaths. RSV was regarded as primarily responsible for death in 32 cases (40.5%). Median age at death was 11 months (range, <1 month to 16 years). Thirty-nine patients (49.4%) were male. Fourteen patients (17.7%) had no known risk factors for severe RSV infection. Healthcare-associated RSV infections (HAIs) accounted for 29 deaths (36.7%), with RSV judged to be the primary cause of death in 9 of these cases. Conclusions: RSV-associated deaths were predominantly associated with chronic medical conditions and immunocompromised states among infants; however, 1 in 5 deaths occurred among patients with no known risk factors for severe RSV. Mortality associated with HAI accounted for over a third of cases. These findings highlight patient groups that should be targeted for RSV prevention strategies such as infection control practices, immunoprophylaxis, and future vaccination programs.

Posttransplant lymphoproliferative disorder in pediatric patients: Survival rates according to primary sites of occurrence and a proposed clinical categorization.

Posttransplant lymphoproliferative disorder (PTLD) is a devastating complication of organ transplant. In a hospital-based registry, we identified biopsy-proven cases of PTLD among children during a 15-year period and reviewed trends in PTLD rates, the sites of involvement, and the associated survival rates. Cases that were included had at least 1 year of follow-up after the diagnosis of PTLD. We studied 82 patients with first-episode PTLD. Median age at diagnosis was 6.4 years (IQR 3.2-12.3 years). The most frequent PTLD sites were tonsillar/adenoidal (T/A [34%]) and gastrointestinal (32%), followed by miscellaneous (defined as less common sites including central nervous system, kidney, lung, and soft tissue [12%]), lymph node (11%), and multisite (11%). Kaplan-Meier survival curves showed that T/A PTLD was associated with decreased all-cause mortality compared with PTLD at other sites (log-rank 0.004), even after adjustment for histological subtype (P = .047). PTLD-related mortality was also decreased among T/A PTLD (log-rank 0.012) but showed a trend toward significance only after adjustment for histological subtype (P = .09). Among first episodes of PTLD, T/A PTLD was associated with a survival advantage compared with PTLD at other sites, even after adjustment for potential confounders. Based on our observations, we propose a clinical categorization of PTLD according to anatomical site of occurrence.

Post-transplant lymphoproliferative disorders, Epstein-Barr virus infection, and disease in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice.

These updated guidelines from the American Society of Transplantation Infectious Diseases Community of Practice review the diagnosis, management, and prevention of post-transplant lymphoproliferative disorders (PTLD) and other Epstein-Barr virus (EBV) syndromes after solid organ transplantation. PTLD are a heterogeneous spectrum of predominantly B-cell disorders, often extra-nodal, with complex distinct pathogeneses and variable clinical presentations determined by pathologic subtype. Recent epidemiologic studies report a decrease in early EBV-positive (+) PTLD and an increase in late EBV-negative (-) PTLD. Pre-transplant EBV-seronegativity and primary EBV infection, often from donor-transmitted infection, are an important risk factors for EBV syndromes and early EBV + PTLD. Low-quality evidence supports preemptive prevention strategies for early EBV + PTLD in EBV-seronegative recipients that involve EBV DNA measurement in peripheral blood using assays requiring further result harmonization, combined with interventions to lower viral load. Reduction in immunosuppression (RIS) is the best validated intervention. WHO pathology classification of a tissue biopsy remains the gold standard for PTLD diagnosis; optimal staging procedures are uncertain. Treatment of CD20+ PTLD with the response-dependent sequential use of RIS, rituximab, and cytotoxic chemotherapy is recommended. Evidence gaps requiring future research and alternate treatment strategies including immunotherapy are highlighted.

Epstein-Barr virus latent gene EBNA-1 genetic diversity among transplant patients compared with patients with infectious mononucleosis.

INTRODUCTION: As a step toward evaluating the association between Epstein-Barr virus genetic diversity and post-transplant lymphoproliferative disorder (PTLD), we conducted a preliminary study to compare the genetic diversity of the EBNA-1 gene among transplant patients and patients with infectious mononucleosis (IM). METHODS: We sequenced the EBNA-1 gene in blood samples from study subjects using Sanger methodology. The sequences were aligned with a reference strain and compared with publicly available sequences. RESULTS: We analyzed 33 study samples and 25 publicly available sequences along with the reference strain B95-8. The evaluable samples were from sixteen patients with IM (median age 14.0 years, range 2-24) and 17 transplant patients. There were six children without PTLD (median age 1.93 years, range 0.79-7.46) and 11 who developed PTLD (median age 5.67 years, range 0.96-17.45). A predominant EBNA-1 variant (P-thr) was identified across the study groups. Differences were observed between the samples from the IM patients compared with the transplant samples. CONCLUSION: The predominant EBNA-1 strain is in contrast to reports of the predominant strain in North America. The results suggest differences between the EBNA-1 strains among the study groups. Further studies will examine the relationship between EBNA-1 strains and PTLD occurrence and outcomes.

Risk stratification of immunocompromised children, including pediatric transplant recipients at risk of severe respiratory syncytial virus disease.

BACKGROUND: Respiratory syncytial virus (RSV) infection is associated with increased morbidity and mortality in immunocompromised patients. Our goal was to develop a framework for risk stratifying immunocompromised patients, including transplant patients, for RSV prophylaxis. METHODS: Risk factors for severe RSV disease in immunocompromised patients were identified in the literature and by an expert panel via survey. Experts assigned a probability of developing severe disease (0 to 100 scale) to the risk factors for each immunocompromised population. The results were validated using a clinical dataset. Linear mixed models adjusted for within-expert clustering of ranks were used to estimate average scores, and differences were tested using paired t tests. Logistic regression was utilized to identify important determinants of severe RSV disease. RESULTS: The survey was emailed to twenty-seven experts and thirteen responded (48%). Across all transplant groups, age <2 years (mean 77.1, 95% CI 71.7, 82.5) and day care attendance (mean 72.8, 95% CI 67.3, 78.3) were assigned the highest risk of severe disease. The highest risk groups were lung transplant recipients (mean 73.2, 95% CI 67.6, 78.8), combined lung and heart transplant recipients (mean 75.2, 95% CI 69.6, 80.7), allogeneic stem cell transplant (mean 76.0, 95% CI 70.4, 81.6), and severe combined immunodeficiency (mean 74.7, 95% CI 69.1, 80.3). CONCLUSION: The results provide a logical validity to current practice and provide guidance for prioritizing patients to receive prophylactic agents to prevent severe RSV disease. The results will facilitate the development of a risk stratification tool for RSV prophylaxis for immunocompromised patients.