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Background: Varicella-zoster virus (VZV) pretransplant immunization rates, exposures, and posttransplant disease are poorly characterized among pediatric solid organ transplant (SOT) recipients in the two-dose varicella vaccine era., Methods: A retrospective analysis of the electronic health records among children <18 years old who received SOT from January 1, 2011 through December 31, 2021, was performed at a single center to assess for missed pretransplant varicella vaccination opportunities, characterize VZV exposures, and describe posttransplant disease., Results: Among 525 children, 444 were ≥6 months old (m.o.) at SOT with a documented VZV vaccine status. Eighty-five (19%) did not receive VZV Dose One; 30 out of 85 (35%) could have been immunized. Infants 6-11 m.o. accounted for 14 out of 30 (47%) missed opportunities. Among children ≥12 m.o. with documented Dose Two status (n = 383), 72 had missed vaccination opportunities; 57 out of 72 (79%) were children 1-4 years old. Most children had unclassifiable pre-SOT serostatus as varicella serology was either not obtained/documented (n = 171) or the possibility of passive antibodies was not excluded (n = 137). Of those with classified serology (n = 188), 69 were seroimmune. Forty-seven of 525 (9%) children had recorded VZV exposures; two developed varicella-neither had documented pre-SOT seroimmunity nor had received post-exposure prophylaxis. Nine additional children had medically attended disease: four primary varicella and five zoster. Of the 11 cases, 10 had cutaneous lesions without invasive disease; one had multi-dermatomal zoster with transaminitis. Seven (64%) received treatment exclusively outpatient., Conclusions: VZV exposure and disease still occur. Optimizing immunization among eligible candidates and ensuring patients have a defined VZV serostatus pretransplantation remain goals of care., (© 2024 Wiley Periodicals LLC.)

Background: There have been over 51 000 pediatric solid organ transplants since 1988 in the United States alone, leading to a growing population of long-term survivors who face complications of childhood organ failure and long-term immunosuppression., Aims: This is an educational review of existing literature., Results: Pediatric solid organ transplant recipients are at increased risk for risk for cardiovascular and kidney disease, skin cancers, and growth problems, though the severity of impact may vary by organ type. Pediatric recipients often are able to complete schooling, maintain a job, and form family and social networks in adulthood, though at somewhat lower rates than the general population, but face additional challenges related to neurocognitive deficits, mental health disorders, and discrimination., Conclusions: Transplant centers and research programs should expand their focus to include long-term well-being. Increased collaboration between pediatric and adult transplant specialists will be necessary to better understand and manage long-term complications., (© 2024 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.)

Background: Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorders (PTLD) is the most common malignancy in children after transplant; however, difficulties for early detection may worsen the prognosis., Methods: The prospective, multicenter, study enrolled 944 children (≤21 years of age). Of these, 872 received liver, heart, kidney, intestinal, or multivisceral transplants in seven US centers between 2014 and 2019 (NCT02182986). In total, 34 pediatric EBV+ PTLD (3.9%) were identified by biopsy. Variables included sex, age, race, ethnicity, transplanted organ, EBV viral load, pre-transplant EBV serology, immunosuppression, response to chemotherapy and rituximab, and histopathological diagnosis., Results: The uni-/multivariable competing risk analyses revealed the combination of EBV-seropositive donor and EBV-naïve recipient (D+R-) was a significant risk factor for PTLD development (sub-hazard ratio: 2.79 [1.34-5.78], p = .006) and EBV DNAemia (2.65 [1.72-4.09], p < .001). Patients with D+R- were significantly more associated with monomorphic/polymorphic PTLD than those with the other combinations (p = .02). Patients with monomorphic/polymorphic PTLD (n = 21) had significantly more EBV DNAemia than non-PTLD patients (p < .001) and an earlier clinical presentation of PTLD than patients with hyperplasias (p < .001), within 6-month post-transplant. Among non-liver transplant recipients, monomorphic/polymorphic PTLD were significantly more frequent than hyperplasias in patients ≥5 years of age at transplant (p = .01)., Conclusions: D+R- is a risk factor for PTLD and EBV DNAemia and associated with the incidence of monomorphic/polymorphic PTLD. Intensive follow-up of EBV viral load within 6-month post-transplant, especially for patients with D+R- and/or non-liver transplant recipients ≥5 years of age at transplant, may help detect monomorphic/polymorphic PTLD early in pediatric transplant., (© 2024 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.)

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., (© 2022 Wiley Periodicals LLC.)

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., (© 2023 Wiley Periodicals LLC.)

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., (© 2022 Wiley Periodicals LLC.)

Background: Low-vaccination rates worldwide have led to the re-emergence of vaccine-preventable infections, including measles. Immunocompromised patients, including pediatric solid organ transplant (SOT) recipients, are at risk for measles because of suboptimal vaccination, reduced or waning vaccine immunity, lifelong immunosuppression, and global re-emergence of measles., Objectives: To review published cases of measles in pediatric SOT recipients to heighten awareness of its clinical manifestations, summarize diagnostic and treatment strategies, and identify opportunities to optimize prevention., Methods: We conducted a literature review of published natural measles infections in SOT recipients ≤21 years of age, summarizing management and outcomes. We describe measles epidemiology, recommended diagnostics, treatment, and highlight prevention strategies., Results: There are seven published reports of measles infection in 12 pediatric SOT recipients, the majority of whom were unvaccinated or incompletely vaccinated. Subjects had atypical or severe clinical presentations, including lack of rash and complications, most frequently with encephalitis and pneumonitis, resulting in 33% mortality. Updated recommendations on testing and vaccination are provided. Treatment options beyond supportive care and vitamin A are limited, with no approved antivirals., Conclusion: While measles is infrequently reported in pediatric SOT recipients, morbidity and mortality remain significant. A high index of suspicion is warranted in susceptible SOT recipients with clinically compatible illness or exposure. Providers must recognize this risk, educate families, and be aware of both classic and atypical presentations of measles to rapidly identify, isolate, and diagnose measles in pediatric SOT recipients. Continued efforts to optimize measles vaccination both pre- and post-SOT are warranted., (© 2023 Wiley Periodicals LLC.)

Background: The SARS-CoV-2 pandemic and corresponding acute respiratory syndrome have affected all populations and led to millions of deaths worldwide. The pandemic disproportionately affected immunocompromised and immunosuppressed adult patients who had received solid organ transplants (SOTs). With the onset of the pandemic, transplant societies across the world recommended reducing SOT activities to avoid exposing immunosuppressed recipients. Due to the risk of COVID-19-related outcomes, SOT providers adapted the way they deliver care to their patients, leading to a reliance on telehealth. Telehealth has helped organ transplant programs continue treatment regimens while protecting patients and physicians from COVID-19 transmission. This review highlights the adverse effects of COVID-19 on transplant activities and summarizes the increased role of telehealth in the management of solid organ transplant recipients (SOTRs) in both pediatric and adult populations., Methods: A comprehensive systematic review and meta-analysis were conducted to accentuate the outcomes of COVID-19 and analyze the efficacy of telehealth on transplant activities. This in-depth examination summarizes extensive data on the clinical detriments of COVID-19 in transplant recipients, advantages, disadvantages, patient/physician perspectives, and effectiveness in transplant treatment plans via telehealth., Results: COVID-19 has caused an increase in mortality, morbidity, hospitalization, and ICU admission in SOTRs. Telehealth efficacy and benefits to both patients and physicians have increasingly been reported., Conclusions: Developing effective systems of telehealth delivery has become a top priority for healthcare providers during the COVID-19 pandemic. Further research is necessary to validate the effectiveness of telehealth in other settings., (© 2023 Wiley Periodicals LLC.)

Background: Gastrointestinal symptoms are common among solid organ transplant (SOT) recipients. Information about colonoscopy findings after pediatric SOT is limited. This retrospective study reports endoscopy findings in a nationwide pediatric transplant recipient cohort., Methods: All pediatric recipients (kidney, liver, or heart) transplanted between 2010 and 2020 at our institution (n = 193) who had undergone ileocolonoscopy and upper gastrointestinal endoscopy after SOT were enrolled. Sixteen patients were identified. A meticulous search on clinical data including transplantation, gastrointestinal symptoms, endoscopy findings, and follow-up data was performed., Results: Endoscopy was performed at a median of 2.6 years (0.4-13.3) after the first transplantation (median age at SOT 1.2 years). Gastrointestinal symptoms leading to endoscopy did not differ between the different transplant groups. The leading endoscopy indications were prolonged diarrhea and anemia. PTLD was found in 8 (50%) patients. Five were histologically early PTLD lesions and three were monomorphic large B-cell PTLDs (two EBV-positive and one EBV-negative), one having previously been diagnosed with autoimmune enteropathy. One patient had EBV enteritis. De novo inflammatory bowel disease was found in one patient, eosinophilic gastroenteritis in another, and in one patient with several episodes of watery diarrhea, the histological finding was mild non-specific colitis. In four patients, the endoscopy finding remained unclear and the symptoms were suspected to be caused by infectious agents or mycophenolate., Conclusions: PTDL with various stages is a common finding after pediatric SOT in patients with gastrointestinal symptoms. Endoscopy should be considered in transplant recipients with prolonged diarrhea, anemia, and/or abdominal pain., (© 2022 Wiley Periodicals LLC.)

Malignancies are among the top three causes of patient death in pediatric and adult kidney transplant (KT) recipients. Solid organ transplant (SOT) recipients, including KT individuals, experience more cancer compared with the general population, including human papillomavirus (HPV)-related anogenital and oropharyngeal cancers. This article describes the epidemiology, pathophysiology and natural history of the HPV infection in both the general population and in SOT recipients, as well as its role in the development of HPV-related pre-cancerous lesions and cancers. Emphasis is given to the primary prevention strategy, HPV vaccination in SOT recipients, and its particularities compared with the general population. Secondary prevention strategies in SOT recipients are discussed and compared with the general population, highlighting cervical cancer screening needs within SOT populations. The article emphasizes how these primary and secondary HPV prevention strategies applied during childhood and adolescence by the pediatric transplant professionals, can lower the burden of HPV-related cancers for SOT recipients in subsequent years, during their adult life., (© 2022 The Authors. Pediatric Transplantation published by Wiley Periodicals LLC.)

Background: Acute kidney disease (AKD) is defined as impaired kidney function present for <90 days with or without an acute kidney injury (AKI) event. Adults with AKD have an increased risk for progression to chronic kidney disease (CKD) and mortality. There are no data on the epidemiology of AKD in children after transplant. The aim of this study was to evaluate the incidence and risk factors for AKI, AKD, and CKD in children after transplantation., Methods: This is a retrospective cohort study of all children undergoing non-kidney solid organ transplant between 2011 and 2019 at UPMC Children's Hospital of Pittsburgh. AKI and AKD were defined using the Kidney Disease Improving Global Outcomes criteria. Patients with a new estimated glomerular filtration rate <60 ml/min/1.73m 2 persisting for >3 months met criteria for new CKD. Variables associated with AKI, AKD, and CKD were analyzed., Results: Among 338 patients, 37.9% met criteria for severe AKI, 13% for AKD, and 8% for a new diagnosis of CKD. Stage 3 AKI was independently associated with AKD (OR: 5.35; 95% CI: 2.23-12.86). Severe AKI was not associated with new-onset CKD, whereas AKD was associated with new-onset CKD (OR: 29.74; CI: 11.22-78.82)., Conclusion: AKD may be superior to AKI in predicting risk of CKD in children after non-kidney solid organ transplantation., (© 2021 Wiley Periodicals LLC.)

Background: This study aimed to characterize features present at the time of diagnosis and describe outcomes in patients with post-transplant lymphoproliferative disorder (PTLD) following pediatric solid organ transplantation., Methods: We performed a retrospective review of solid organ transplant patients who developed pathologically confirmed PTLD at our center from 2006 to 2016., Results: Of 594 patients included in this study, 41(6.9%) were diagnosed with PTLD. Median age at transplant was 5.6(IQR 1.7-16.1) years. Proportion of PTLD cases by organ transplanted and median time (IQR) to disease onset were: heart 11/144(7.6%) at 13.6(8.5-55.6) months, lung 7/52(13.5%) at 9.1(4.9-35) months, kidney 8/255(3.1%) at 39.5(13.9-57.1) months, liver 12/125(9.6%) at 7.7(5.5-22) months, intestine 0/4(0%), and multi-visceral 3/14(21.4%) at 5.4(5.4-5.6) months. No significant correlation was seen between recipient EBV status at transplant and timing of development of PTLD. There were six early lesions, 15 polymorphic, 19 monomorphic, and one uncharacterizable PTLD. Following immunosuppression reduction, 30 patients received rituximab, and 14 required chemotherapy. At median 25(IQR 12-53) months follow-up from the onset of PTLD, eight patients died secondary to transplant related complications, three are alive with active disease, and 30 have no evidence of disease., Conclusion: PTLD is a significant complication following pediatric solid organ transplantation. EBV levels in conjunction with symptomatic presentation following transplant may assist in detection of PTLD. Most patients can achieve long-term disease-free survival through immunosuppression reduction, anti-CD20 treatment, and chemotherapy in refractory cases., (© 2022 Wiley Periodicals LLC.)

Background: Cytomegalovirus (CMV) is an important cause of morbidity and mortality in pediatric solid organ transplant (SOT) recipients. However, the impact of asymptomatic CMV infections (ie, DNAemia) on clinical outcomes is not well established., Methods: We performed a retrospective cohort study of children undergoing first SOT at our institution from January 2012 to June 2018. We evaluated the epidemiology of CMV infections and performed multivariable Cox regression to assess the association between CMV DNAemia without disease or CMV disease (syndrome or end-organ disease) on negative outcomes (death, re-transplantation, or moderate/severe rejection) within the first year after SOT., Results: Among 271 individuals, 43 (15.9%) developed ≥1 CMV infection during the first year after SOT. There were 56 unique CMV infections including 14 episodes of CMV disease. In 167 patients offered CMV prophylaxis, only 8 (4.8%) developed their first CMV DNAemia episode while on prophylaxis 32 developed CMV DNAemia after prophylaxis completion; only 1 episode of CMV disease occurred while on antiviral prophylaxis. When accounting for receipt of ATG, oral steroids, and number of immunosuppressives on a given day, CMV disease was more strongly associated with negative outcomes (Hazard Ratio (HR): 3.28, 95% CI: 0.73-14.64; p = .12) than CMV DNAemia without disease (HR 1.42, 95% CI: 0.19- 10.79; p = .74), although not to a statistically significant degree., Conclusions: Most CMV infections occurred after completion of antiviral prophylaxis. CMV disease was more strongly associated with negative outcomes than asymptomatic CMV DNAemia and should be the focus of CMV prevention practices., (© 2022 Wiley Periodicals LLC.)

Living with end-stage organ failure is associated with an accumulation of traumatic medical events, and despite recovery after solid-organ transplantation (SOT), many children continue to exhibit lower quality of life (QOL). Few studies have examined the relationship between post-traumatic stress disorder (PTSD) and QOL among pediatric SOT recipients. We conducted a retrospective, cross-sectional review of 61 pediatric SOT recipients (12 heart, 30 kidney, and 19 liver) to evaluate the association of PTSD with self-reported QOL. PTSD was measured by the Child Trauma Screening Questionnaire (CTSQ), and QOL was measured using the PedsQL and PedsQL Transplant Module (PedsQL-TM) surveys. Demographics, baseline, and contemporaneous factors were tested for independent association. SOT recipients were 15.2 (12.1-17.6) years old at survey completion. Median CTSQ score was 2 (1-3), highest in kidney recipients, and 13% were identified as high risk for PTSD. Median PedsQL score was 83 (70-91) and significantly associated with the CTSQ score (r = -.68, p < .001). Median PedsQL Transplant Module score was 89 (83-95) and similarly associated with the CTSQ score (r = -.64, p < .001). Age at time of surveys and presence of any disability were also independently associated with PedsQL and PedsQL-TM, respectively. When adjusted for Emotional Functioning, CTSQ remained associated with PedsQL subscores (r = -.65, p < .001). Trauma symptoms are a major modifiable risk factor for lower self-perceived QOL and represent a potentially important target for post-transplant rehabilitation. Additional research is needed to understand the root contributors to PTSD and potential treatments in this population., (© 2021 Wiley Periodicals LLC.)

Prolonged intestinal cold storage causes considerable mucosal breakdown, which could bolster bacterial translocation and cause life-threatening infection for the transplant recipient. The intestine has an intraluminal compartment, which could be a target for intervention, but has not yet been fully investigated. Hydrogen gas exerts organ protection and has used been recently in several clinical and basic research studies on topics including intestinal transplantation. In this study, we aimed to investigate the cytoprotective efficacy of intraluminally administered hydrogen-rich saline on cold IR injury in intestinal transplantation. Isogeneic intestinal transplantation with 6 hours of cold ischemia was performed on Lewis rats. Hydrogen-rich saline (H 2 concentration at 5 ppm) or normal saline was intraluminally introduced immediately before preservation. Graft intestine was excised 3 hours after reperfusion and analyzed. Histopathological analysis of control grafts revealed blunting of the villi and erosion. These mucosal changes were notably attenuated by intraluminal hydrogen. Intestinal mucosa damage caused by IR injury led to considerable deterioration of gut barrier function 3 h post-reperfusion. However, this decline in permeability was critically prevented by hydrogen treatment. IR-induced upregulation of proinflammatory cytokine mRNAs such as IL-6 was mitigated by hydrogen treatment. Western blot revealed that hydrogen treatment regulated loss of the transmembrane protein ZO-1. Hydrogen-rich saline intraluminally administered in the graft intestine modulated IR injury to transplanted intestine in rats. Successful abrogation of intestinal IR injury with a novel strategy using intraluminal hydrogen may be easily clinically applicable and will compellingly improve patient care after transplantation., (© 2020 Wiley Periodicals LLC.)

Discrimination based on disability is prohibited in organ transplantation, yet studies suggest it continues in listing practices for intellectual disability and genetic diseases. It is not known if this differs between adult and pediatric programs, or by organ type. We performed an online, forced-choice survey of psychosocial listing criteria for adult and pediatric heart, kidney, liver, and lung transplant programs in the United States. Of 650 programs contacted, 343 (52.8%) submitted complete. A minority of programs had formal listing guidelines for any condition considered (Down Syndrome, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, DiGeorge Syndrome, and Wolf Hirschhorn Syndrome; and mild [IQ < 70] and severe [IQ < 35] intellectual disability), although a majority had encountered most. Pediatric programs were significantly (P < .02) more lenient in the level of contraindication to listing for all genetic conditions considered except Duchenne Muscular Dystrophy, and for mild and severe intellectual disability. Level of contraindication differed significantly by organ type (heart, lung, liver, and kidney) for Duchenne Muscular dystrophy (P = <.001), Becker Muscular Dystrophy (P < .001), DiGeorge Syndrome (P < .001), Wolf-Hirschhorn syndrome (P = .0012), and severe intellectual disability (P < .001). There is significant variation among transplant programs in availability of guidelines for as well as listing practices regarding genetic diseases and intellectual disability, differing by both adult vs pediatric program, and organ type. Programs with absolute contraindications to listing for specific genetic diseases or intellectual disability should reframe their approach, ensuring individualized assessments and avoiding elimination of patients based on membership in a particular group., (© 2020 Wiley Periodicals LLC.)

Background: SOT is the treatment of choice for end-stage organ disease. Improved long-term survival after NKSOT has uncovered chronic morbidity including CKD. AKI is common after NKSOT and may be associated with long-term CKD., Methods: We performed a retrospective cohort study looking at AKI and CKD after pediatric heart (n = 109) or liver (n = 112) transplant. AKI was defined using KDIGO creatinine-based criteria. pAKI was AKI ≤ 7 days post-transplant; CKD 3-5 was eGFR < 60 mL/min/1.73 m 2 by modified Schwartz formula for > 3 months. We looked at the incidence of CKD 3-5 and the effect of perioperative pAKI on the slope of eGFR post-transplant., Results: pAKI was seen in 63% (n = 69) after heart and 38% (n = 43) after liver transplant. pAKI was associated with longer ICU and hospital stays. Cumulative incidence (95% CI) of CKD 3-5 at 60 months post-heart transplant was 40.9% (27.9%-57.1%) in patients with AKI vs 35.8% (17.1%-64.8%) in those without (P = NS). Post-liver transplant, the cumulative incidence of CKD 3-5 at 60 months was 0% in those without pAKI vs 10% (3.2%-29.3%) in those with (P = .01). Patients with pAKI had lower eGFR at last follow-up., Conclusion: pAKI and CKD are common after NKSOT. Incidence of CKD is higher in those with pAKI. AKI episodes are associated with a drop in eGFR during follow-up. Identifying patients who have had AKI is an important first step in identifying those at risk of repeated AKI episodes. These patients would benefit from closer monitoring for CKD, lower nephrotoxic drug use, and follow-up with nephrology., (© 2020 Wiley Periodicals LLC.)

Background: Diarrhea is a common problem in the pediatric post-solid organ transplant and post-hematopoietic stem cell transplant populations. Infectious etiology incidences are poorly defined, and the possibility of multi-organism positivity is often uninvestigated. The aim of this study is to utilize stool multiplex GIP assays to compare the PTP and NTP regarding the incidence and profiles of single-organism and multi-organism infectious diarrhea., Methods: A single-center retrospective review was conducted, investigating stool multiplex GIP panel results over a more than 3-year period, for pediatric patients. Assays test for 23 viral, bacterial, and protozoal organisms., Results: Positive assays in the PTP and NTP were 70/101 (69.3%) and 962/1716 (56.1%), respectively (P = .009). Thirty-two percent (32/101) of assays within the PTP were multi-organism positive, significantly more than 14.8% (254/1716) in the NTP (P < .00001). There was no significant difference in the incidence of single-organism positives, 37.6% (38/101) in PTP and 41.3% (708/1716) in the NTP. The PTP demonstrated a statistically significantly higher incidence of the following organisms within multi-agent positive GIPs (P < .05 for each): Clostridioides difficile, Cryptosporidium, EPEC, norovirus, and sapovirus., Conclusions: The pediatric PTP demonstrates higher incidence of positive GIPs, higher rate of multi-organism positivity, and unique infectious organism incidence profiles. These data can provide a framework for understanding organism-specific pathogenicity factors, assessing the clinical impact of enteric co-infection, and understanding the utility of this testing modality in this unique population., (© 2020 Wiley Periodicals LLC.)

End-organ disease caused by CMV is a significant cause of morbidity and mortality in pediatric SOT recipients. Pediatric transplant centers have adopted various approaches for CMV disease prevention in this patient population. We observed significant practice variation in CMV testing, prophylaxis, and surveillance across SOT groups in our center. To address this, we implemented evidence-based standardized protocols and measured outcomes pre- and post-implementation of these protocols. We performed retrospective chart review for SOT recipients from 2009 to 2014 at Boston Children's Hospital. Using descriptive statistics, we measured practice improvement in provision of appropriate prophylaxis, occurrence of neutropenia and associated complications, and occurrence of CMV DNAemia and CMV disease pre- and post-intervention. The pre- and post-intervention periods included 141 and 109 patients, respectively. With the exception of kidney transplant recipients, provision of appropriate valganciclovir prophylaxis improved across SOT groups post-intervention (P < .01). Occurrence of >1 episode of neutropenia was greater in the preintervention period (30% vs 10%, P < .001). In both periods, neutropenia was associated with few episodes of invasive infections. The occurrence of CMV disease did not differ and was overall low. However, due to routine surveillance a significantly greater number of asymptomatic CMV DNAemia episodes were identified and treated in the post-intervention period. Implementation of standardized prevention protocols helped to improve the provision of appropriate prophylaxis to patients at risk for CMV acquisition, increased the diagnosis and treatment of asymptomatic CMV DNAemia, and decreased episodes of recurrent neutropenia in patients receiving prophylaxis., (© 2019 Wiley Periodicals, Inc.)

Subjective evaluation of medical care and disease outcomes from patients' perspectives has become increasingly important. Patient-reported outcome measures (PROMs) play a prominent role in engaging patients, capturing their experiences and improving patient care. This systematic review sought to identify PROMs that are used in the field of pediatric solid organ transplantation, with the aim to inform the implementation of PROMs into clinical practice for this population. A systematic review of English language, peer-reviewed articles was performed on key health science databases to identify publications using PROMs in pediatric solid organ transplantation. The search yielded 3670 articles, with a final data set of 62 articles that included 47 different PROMs. The three most frequently used PROMs included the following: (a) PedsQL™ Generic Core Scales (n = 25); (b) Children's Depression Inventory (n = 6); and (c) Child Health Questionnaire (n = 6). Of the 47 PROMs, 42 were generic and five were disease-specific; only six PROMS had a documented psychometric evaluation within a pediatric solid organ transplant population. This review outlines the attributes of the instruments (eg, domains captured), as well as the psychometric properties of those evaluated. PROMs are increasingly used in the field of pediatric transplantation; however, there are limited details in the current literature about their conceptual underpinnings and psychometric properties. This review highlights the need for additional psychometric evaluation of identified measures to establish the necessary foundation to inform the implementation of PROMs into clinical care for pediatric solid organ transplant patients., (© 2019 Wiley Periodicals, Inc.)

Introduction: Treatment of PTLD using immune-depleting agents such as RTX may be associated with increased risk of infections. The aim of this report was to describe the incidence of hypogammaglobulinemia and bacterial infections in children with PTLD after SOT at a single center since the introduction of RTX., Methods: A retrospective review was conducted over a study period of 2000-2016 in pediatric patients diagnosed with biopsy-proven PTLD based on the WHO histologic criteria. Hypogammaglobulinemia was defined by serum IgG <4 g/L; CPBI was defined by clinically significant infection by an identified pathogenic bacteria isolated from a normally sterile body site., Results: Twenty-eight patients were included, comprising 16 LTx and 12 ITx patients, and 17 patients received RTX therapy. Total of 31 episodes of CPBI occurred in 16 patients. Incidence of CPBI was 31.4 infections per 100 patient-years in RTX-treated patients, as compared to 8.4 infections per 100 patient-years in non-RTX-treated patients (P < 0.001). Hypogammaglobulinemia was significantly more prevalent after 6 months (P = 0.001) and 2 years (P = 0.005) in RTX-treated patients, as compared to none in the group that did not receive RTX. Hypogammaglobulinemia (P = 0.047), ITx (P = 0.027), and monomorphic PTLD (P = 0.024) were significantly associated with recurrent (≥2) CPBI and/or CPBI-related deaths within the first year post-PTLD., Conclusion: While RTX is an effective treatment for PTLD, hypogammaglobulinemia can persist for up to 2 years following RTX therapy, which may be associated with the higher cumulative rates of CPBI observed in RTX-treated patients., (© 2019 Wiley Periodicals, Inc.)

Information about HAdV infection in SOT recipients is limited. We aimed to describe HAdV infection epidemiology and outcomes in a single-center retrospective cohort during the era of PCR availability. SOT recipients transplanted at the CHOP 2004-2013 were followed up for 180 days post-transplant. HAdV infection was defined as a positive HAdV PCR from a clinical specimen. HAdV disease was defined by organ-specific radiologic and/or laboratory abnormalities. No HAdV surveillance protocols were employed during the study period; testing was solely per clinician discretion. Progression of HAdV infection was defined as HAdV disease or ≥1-log viral load increase since a corresponding site's first positive specimen. Of the assembled 425 SOT recipients, 227 (52.6%) had ≥1 HAdV PCR. Twenty-four (10.6%) had ≥1 HAdV-positive PCR. HAdV-positive subjects were younger than uninfected subjects (2.0 years vs 6.5, P = 0.001). Infection incidence rates were highest in liver recipients (15.3%), followed by heart (8.6%), kidney (8.3%), and lung (4.2%). Four subjects (16.7%) met HAdV disease criteria at virus detection. Five subjects (20.8%) had progression of HAdV infection. All-cause mortality rates in positive and negative subjects were 0% and 3.9%, respectively. HAdV infection was infrequently detected in SOT recipients. Over one-third of HAdV-positive patients met disease criteria at detection or had infection progression, but none died. This low all-cause mortality raises questions about benefits of HAdV surveillance. Larger multicenter studies are needed to assess incidence variance by center and comparative effectiveness of therapeutic interventions., (© 2019 Wiley Periodicals, Inc.)

The risk of TB among pediatric SOT recipients increases as the globalization of medical care continues to broaden. Unlike adults, children and especially infants are more susceptible to TB as a complication after transplantation. Little data exist regarding the true incidence of TB and the optimal risk-based management of this very vulnerable population. Here, we highlight the theoretical and practical issues that complicate the management of these patients and pose some questions that should be addressed when managing these patients. More data are needed to provide optimal guidance of the best diagnostic and management practices to this unique population., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Optimal strategies to prevent cytomegalovirus (CMV) disease following pediatric solid organ transplantation remain controversial. The purpose of this study was to review the outcomes of a risk-stratified strategy that uses a hybrid or prophylactic strategy for donor (D)+ recipient (R)- patients, a preemptive strategy for D+R+/D-R+, and clinical follow-up alone for D-R+ patients. A retrospective chart review was undertaken at the Stollery Children's Hospital in Edmonton, Alberta for pediatric solid organ transplants 2004 through 2010. Transplants were risk-stratified according to D/R CMV serostatus, organ group, and type of induction or rejection immunosuppression. The incidence of DNAemia and CMV disease and adverse effects from prophylaxis were analyzed. The study included 197 recipients. CMV DNAemia was detected in 49 of 197 recipients (24.8%), and CMV disease occurred in eight of 197 (4%) of which all but one were D+R-. All recovered. Seventeen of 142 recipients who received prophylaxis (12%) had hematologic toxicity. No other toxicities were identified. In conclusion, A risk-stratified approach resulted in very low rates of CMV disease with minimal adverse effects. Lowering the dosage rather than stopping antivirals in the face of neutropenia has the potential to further lower the rate of CMV disease., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We present a 12-yr-old boy who received a combined liver-pancreas small bowel transplantation at the age of two. The post-operative period was complicated by wound closure problems resulting in a large asymptomatic abdominal wall defect. Further follow-up was uneventful, with the exception of new onset growth failure not explained by extensive routine investigations. An indirect calorimetry was performed. The resting energy expenditure (REE) was significantly increased (126% of predicted), demanding a daily caloric intake of 123 kcal/kg body weight (normal for age: 80 kcal/kg). In the absence of classic reasons for increased REE, a thermal camera revealed increased dermal heat loss at the abdominal wall defect (estimated surplus in energy loss of at least 29 kcal/day: 10.4% of the elevated REE). In addition, we found lower total lung capacity due to impaired abdominal breathing. In the exploration of growth failure in children after (ITx), increased REE must be taken into account. Indirect calorimetry can serve as a valuable diagnostic tool for evaluating individual energy requirements and nutritional support. In this child, exaggerated heat loss through an aberrant abdominal wall could be a potential important contributor to the patient's increased energy requirements., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This study examines EBV strains from transplant patients and patients with IM by sequencing major EBV genes. We also used NGS to detect EBV DNA within total genomic DNA, and to evaluate its genetic variation. Sanger sequencing of major EBV genes was used to compare SNVs from samples taken from transplant patients vs. patients with IM. We sequenced EBV DNA from a healthy EBV-seropositive individual on a HiSeq 2000 instrument. Data were mapped to the EBV reference genomes (AG876 and B95-8). The number of EBNA2 SNVs was higher than for EBNA1 and the other genes sequenced within comparable reference coordinates. For EBNA2, there was a median of 15 SNV among transplant samples compared with 10 among IM samples (p = 0.036). EBNA1 showed little variation between samples. For NGS, we identified 640 and 892 variants at an unadjusted p value of 5 × 10(-8) for AG876 and B95-8 genomes, respectively. We used complementary sequence strategies to examine EBV genetic diversity and its application to transplantation. The results provide the framework for further characterization of EBV strains and related outcomes after organ transplantation., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

EBV-SMT are a rare entity following organ transplantation. Given the rarity of the tumor, there is no standard approach to diagnosis and treatment. A literature search identified 28 reported cases of EBV-SMT in addition to our own experience with one case. The aim of this review is to summarize the existing data regarding pathogenesis, diagnosis, and treatment., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Transplantation is the accepted mode of treatment for patients with end-stage organ disease affecting the heart, lungs, kidney, pancreas, liver and intestine. Long-term outcomes have significantly improved and the aim of management is no longer only long-term survival, but also focuses on quality of life especially in children. Transplantation in Africa faces a number of challenges including wide socioeconomic disparity, lack of legislation around brain death and organ donation in many countries, shortage of skilled medical personnel and facilities, infectious disease burden and insecure access to and monitoring of immunosuppression. Whilst there is a need for transplantation, the establishment and sustainability of transplant programmes require careful planning with national government and institutional support. Legislation regarding brain death diagnosis and organ retrieval/donation; appropriate training of the transplant team; and transparent and equitable criteria for organ allocation are important to establish before embarking on a transplant programme. Establishing sustainable, self-sufficient transplant programmes in Africa with equal access to all citizens is an important step towards curtailing transplant tourism and organ trafficking and has a further beneficial effect in raising the level of medical and surgical care in these countries., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

DSS is a rare acquired abnormality of the LV outflow tract in children and adults. DSS can be seen with or without associated congenital heart disease, but the mechanism of its emergence has been poorly understood. Here, we report two cases of DSS that developed after solid organ transplant in childhood. One patient underwent liver and kidney transplant at three yr of age for hereditary polycystic disease, and the other had liver transplant at three months of age due to uncontrollable high-output failure secondary to a large hepatic hemangioma. Both patients developed mild dynamic LV outflow tract obstruction and systemic hypertension soon after transplant, both of which resolved by the time of discharge. Transient LV hypertrophy was observed in both cases. Corticosteroids, cyclosporine A, and tacrolimus were used as initial immunosuppressants. Both patients developed DSS long after the regression of the initial dynamic LV outflow tract obstruction. Herein, we report DSS as an atypical late cardiovascular complication after solid organ transplant and postulate that transient post-transplant hyperdynamic LV outflow tract obstruction and chronic immunosuppressive treatment may lead to subendocardial remodeling resulting in a fibromuscular membranous ridge in susceptible subjects., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

One of the ultimate goals of successful transplantation in pediatric solid organ transplant recipients is the attainment of optimal final adult height. This manuscript will discuss the attainment of height following solid organ transplantation in pediatric recipients of kidney, liver, heart, lung, and small bowel transplantation. Age is a primary factor with younger recipients exhibiting the greatest immediate catch up growth. Graft function is a significant contributory factor with a reduction in glomerular filtration rate correlating with poor growth in kidney recipients and the need for re-transplantation with impaired growth in liver recipients. The known adverse impact of steroids on growth has led to modification of steroid dosage and even to steroid withdrawal and steroid avoidance. In kidney and liver recipients, this has been associated with the development on occasion of acute rejection episodes. In infant heart transplantation, avoidance of maintenance corticosteroid immunosuppression is associated with normal growth velocity in the majority of patients. With marked improvement in patient and graft survival rates in pediatric organ graft recipients, it is timely that the quality of life issues, such as normal adult height, receive paramount attention. In general, normal growth post-transplantation should be an achievable goal that results in normal adult height for many solid organ transplantation recipients., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

CMV is the most common opportunistic infection affecting SOT recipients. Although current strategies to prevent both CMV infection and disease have been effective, CMV related complications continue to occur, particularly late-onset CMV disease. This literature review article examines the benefits and disadvantages of different prevention modalities, and presents emerging strategies to better prevent CMV in organ transplant recipients., (© 2013 John Wiley & Sons A/S.)

Respiratory viral infections are a major cause of morbidity and mortality in solid organ transplant recipients. Early detection of a viral etiology of a LRTI in a febrile transplant recipient can theoretically reduce the use of antibiotics, trigger modification of immunosuppression and prompt appropriate isolation procedures to reduce nosocomial infections. We retrospectively evaluated pediatric abdominal organ transplant recipients hospitalized with respiratory illnesses to determine the viral pathogens identified by various methods including multiplex RT-PCR performed on nasopharyngeal or endotracheal aspirates. Among 30 symptomatic subjects (median age, 2.5 yr) evaluated using this methodology, 25 (83%) were positive for at least one virus. Rhinovirus was the most frequently identified virus (14 subjects). RSV was identified in five subjects with associated mortality of 40%. Parainfluenza, influenza, metapneumovirus, and adenovirus were also identified. This study indicates that rhinovirus is a significant cause of morbidity in this single center cohort of pediatric abdominal organ transplant recipients., (© 2013 John Wiley & Sons A/S.)

ERCP is a diagnostic and therapeutic imaging modality widely used in adult pancreaticobiliary disease, including the treatment of anastomotic strictures following liver and small bowel transplant. We have previously reported a large series of ERCP in children and demonstrated its safety and utility in pediatric disease. The aim of this study was to evaluate the safety of and indications for ERCP following abdominal organ transplant among pediatric patients by performing a subgroup analysis of our large cohort. Forty-eight ERCPs were performed on 25 children ages 62 days to 20 yr following isolated liver, isolated small bowel, or composite graft transplant. Mean time from transplantation at the time of ERCP was 18 months. The most common indication for ERCP was the evaluation of non-specific hepatobiliary complaints, including abdominal pain and elevated liver enzymes. ERCP was also commonly performed for the evaluation or treatment of known or suspected biliary tree strictures. Seventy-seven percent of cases included therapeutic intervention, including sphincterotomy in 40%, stent placement in 29%, and stone extraction in 19%. The overall complication rate among post-transplant patients was low (2.9%) and not significantly different than the complication rate reported in our previous study. A history of abdominal organ transplant was not associated with an increased risk of complication following ERCP (OR = 0.41, 95% CI = 0.05-3.33). In our experience, ERCP can be safely performed in children following liver, small bowel, and composite graft transplant with outcomes similar to those seen in a general pediatric population and may be especially useful for the diagnosis and treatment for biliary strictures following transplant. Further investigation of the relationship between the timing of ERCP relative to transplant and the safety of the procedure is needed., (© 2012 John Wiley & Sons A/S.)

De novo malignancies represent an increasing concern in the transplant population, particularly as long-term graft and patient survival improves. EBV-associated B-cell lymphoma in the setting of PTLD is the leading malignancy in children following solid organ transplantation. Therapeutic strategies can be categorized as pharmacologic, biologic, and cell-based but the variable efficacy of these approaches and the complexity of PTLD suggest that new treatment options are warranted. Here, we review current therapeutic strategies for treatment of PTLD. We also describe the life cycle of EBV, addressing the viral mechanisms that contribute to the genesis and persistence of EBV+ B-cell lymphomas. Specifically, we focus on the oncogenic signaling pathways activated by the EBV LMP1 and LMP2a to understand the underlying mechanisms and mediators of lymphomagenesis with the goal of identifying novel, rational therapeutic targets for the treatment of EBV-associated malignancies., (© 2012 John Wiley & Sons A/S.)

Cytopenias are common among pediatric SOT; however, autoimmune cytopenias are infrequently reported. We report five cases of autoimmune cytopenias in pediatric LT patients: two with isolated IgG-mediated AIHA, two with ITP, and one with Evans syndrome (ITP and AIHA). All patients were maintained on tacrolimus as immunosuppression. Viral illness commonly preceded the autoimmune cytopenias. All patients responded well to medical therapy (steroids, intravenous immunoglobulin, and rituximab) and lowering tacrolimus serum level. Prognosis appears to be worse when more than one cell line (e.g., Evans syndrome) is affected, and/or there is no preceding viral illness. A critical literature review of autoimmune cytopenias in children following SOT is conducted. Autoimmune cytopenias are a rarely reported complication of pediatric SOT, but clinicians taking care of pediatric transplant recipients need to be aware of this complication., (© 2011 John Wiley & Sons A/S.)

LaR Pediatric solid-organ transplantation is an increasingly successful treatment for organ failure. Five- and 10-yr patient survival rates have dramatically improved over the last couple of decades, and currently, over 80% of pediatric patients survive into adolescence and young adulthood. Waiting list mortality has been a concern for liver, heart, and intestinal transplantation, illustrating the importance of transplant as a life-saving therapy. Unfortunately, the success of pediatric transplantation comes at the cost of long-term or late complications that arise as a result of allograft rejection or injury, immunosuppression-related morbidity, or both. As transplant recipients enter adolescence treatment, non-adherence becomes a significant issue, and the medical and psychosocial impacts transition to adulthood not only with regard to healthcare but also in terms of functional outcomes, economic potential, and overall QoL. This review addresses the clinical and psychosocial challenges encountered by pediatric transplant recipients in the current era. A better understanding of pediatric transplant outcomes and adult morbidity and mortality requires further ongoing assessment., (© 2010 John Wiley & Sons A/S.)

PTLD is a major complication after transplantation. Treatment options for PTLD are not standardized, usually sequential, starting with reduction in immunosuppression. Recently, we have used a dual combination of rituximab and reduced dose chemotherapy (R/C) directly after failed RI. We retrospectively identified 30 pediatric PTLD cases across four organ systems at our center from 1995 to 2008. We assessed recent outcomes of PTLD in children, comparing the responses to different regimens. Two-yr failure-free survival was best in renal and heart recipients (80-88%), followed by liver (57%) and lung (0%). Of note, two patients were Epstein-Barr peripheral blood viral load low positive but tumor EBER negative. Three patients had no detectable viral load but were EBER positive. The R/C regimen (n = 8) had the highest CR rate (100%), low recurrence (12%) and lowest mortality (12%). Interferon (n = 4) had 75% CR, 33% recurrence and 25% mortality. Rituximab/prednisone (n = 5) had 80% CR, 50% recurrence and 20% mortality. Other chemotherapy (n = 7, including all 4 T-cell PTLDs) had 57% CR, 0% recurrence and 14% mortality. Direct dual R/C combination therapy after failed RI is effective and offers another treatment option for B-cell PTLD., (© 2010 John Wiley & Sons A/S.)

To review our experience with SRL as a second-line therapy in our series of 45 SBTx recipients (1997-2009). Retrospective review of five children converted to SRL: 3 M/2 F; median of three yr old (range 20 months-18 yr); rescue indications, adverse events with SRL, resolution of tacrolimus-related side effects, incidence of rejection, PTLD, or GVHD were summarized. Tacrolimus was discontinued (average 13 months after transplant) because of refractory hemolytic anemia in four patients with decreased renal function and because of advanced renal failure and unclear neutropenia in one. PTLD and GVHD had been previously diagnosed in two. Tacrolimus-related side effects disappeared in all five although other immunosuppressants and splenectomy were used simultaneously or later in most of them. Adverse events reported after the conversion were infections (tuberculosis and Pneumocystis carinii in two) and mild hypertriglyceridemia. No rejection, GVHD, or PTLD episode was observed. Four patients are alive with excellent quality of life (median follow-up 18 months). Sirolimus is a safe rescue therapy in SBTx children when tacrolimus is not well tolerated. Renal function and hematologic disorders seem to improve, although other simultaneous strategies could be also involved. Further studies could demonstrate its efficacy as a first-line treatment., (© 2010 John Wiley & Sons A/S.)

PTLD are the most frequent neoplasms in children postorgan transplantation. We describe our experience in the treatment of 14 children (three with early and 11 with late-onset disease) treated with a step-wise protocol developed at our institution. Treatment consisted of reducing immunosuppressants, followed by rituximab and chemotherapy if required. Rituximab, incorporated into the protocol in 2001, has been determinant for the total chemotherapy burden patients need to achieve remission. In seven patients who did not receive rituximab, anthracycline total dose ranged from 160 to 240 mg/m(2), while only one of the patients receiving rituximab required DOXO (range: 0-120 mg/m(2)) (p = 0.003). The use of alkylating agents was also notably lower in patients receiving rituximab (median dose = 1200 mg/m(2)) compared with those who did not receive rituximab (median dose = 5800 mg/m(2)) (p = 0.006). Twelve patients are in remission and two died, one from refractory disease and the other from septic shock. Two-year OS and EFS were 85.7% and 57%, respectively. In conclusion, our experience with the use of rituximab in children with PTLD after solid organ transplantation appeared to be associated with a lesser requirement for alkylating agents and anthracyclines compared with historical subjects, suggesting a reduction in the side effects of these agents., ((c) 2009 John Wiley & Sons A/S.)