BK polyomavirus DNAemia, allograft rejection, and de novo donor-specific antibodies after lowering target tacrolimus levels in pediatric kidney transplant recipients.

BACKGROUND: BK polyomavirus (BKV) DNAemia is a challenging infectious complication after kidney transplant (KT). Reduction of immunosuppression is the mainstay of management, and tacrolimus is often the first immunosuppressive medication adjusted upon the diagnosis of BKV DNAemia. This study aimed to evaluate the impact of a new institutional protocol with lower target tacrolimus levels on BKV DNAemia, allograft rejection, and de novo donor-specific antibodies (dnDSA) among pediatric KT recipients. METHODS: We conducted a retrospective chart review of all KT episodes between January 2013 and December 2018. The new protocol with lower target tacrolimus levels was implemented in March 2015. One hundred twenty-seven patients were included in primary analysis. All patients received induction with basiliximab and methylprednisolone and were maintained on a steroid-based immunosuppressive regimen. RESULTS: In the post-intervention cohort, cumulative incidence of BKV DNAemia at 100 days (13.4% vs. 17.8%, p = .605) and 18 months post-KT (34.1% vs. 26.7%, p = .504) was not significantly different from the pre-intervention cohort. Biopsy-proven rejection rate did not change. However, we observed a trend toward earlier development of dnDSA in the post-intervention cohort using the Kaplan-Meier survival analysis (log-rank p = .06). Younger recipient age at the time of transplant was found to slightly increase the risk of BKV DNAemia (OR: 1.09, 95% CI [1.01, 1.16], p = .024). There was an association between BKV DNAemia and biopsy-proven rejection of any type (adjustedOR: 2.77, 95% CI [1.26, 6.23], p = .012), especially acute T-cell-mediated rejection grade 1A and above (adjustedOR: 2.95, 95% CI [1.06, 8.30], p = .037), after adjusted for recipient age at the time of transplant. CONCLUSIONS: Targeting lower tacrolimus levels did not decrease the incidence of BKV DNAemia within 100 days or 18 months post-KT, nor did it increase the risk of biopsy-proven rejection among pediatric KT recipients in our center. However, there was a trend toward earlier development of dnDSA, which may portend worse long-term graft outcome post-KT. Our findings highlight the need for individualized immunosuppressive regimens based on immunologic and infectious risk factors and the importance of implementing innovative biomarkers to guide therapy and improve outcomes.

Incidence of cytomegalovirus DNAemia in pediatric kidney, liver, and heart transplant recipients: Efficacy and risk factors associated with failure of weight-based dosed valganciclovir prophylaxis.

BACKGROUND: Cytomegalovirus (CMV) is associated with morbidity and mortality in solid organ transplant recipients (SOTR). Valganciclovir (VGC) is extensively used for prophylaxis. Optimal dosing in children, risk factors for failure, and the impact of dose adjustments on CMV DNAemia is not well established. METHODS: This retrospective cohort study of pediatric SOTR transplanted between 2010-2018 evaluated the epidemiology of CMV DNAemia and used Cox-regression to assess the risk factors for CMV DNAemia within one-year following SOTR. RESULTS: In 393 pediatric SOTR (heart [96, 24.4%], kidney [180, 45.6%], liver [117, 29.8%]; median age 9.5 ± 0.3 years), overall CMV DNAemia incidence was 6.6/10 000 days (95%CI 5.1/10 000-7.9/10 000) and varied by organ groups: heart 8.2/10 000 days (95%CI 4.9/10 000-11.4/10 000), kidney 5.8/10 000 days (95%CI 3.9/10 000-7.8/10 000), liver 6.2/10 000 days (95%CI 3.7/10 000-8.7/10 000). CMV DNAemia was detected in 75 of 275 (27.2%) patients who received prophylaxis (40 cases occurred during prophylaxis and 35 occurred after completion of prophylaxis). The median VGC dose given according to institutional weight-based algorithm was approximately 1.5-fold lower than the manufacturer-recommended dose. This discordance was more prominent at younger age groups (3.2-fold lower in <2-year-old [100 mg versus 325 mg], 2.5-fold lower in <6-year-old [200 mg versus 447 mg]). Dose reduction due to adverse events was an independent risk factor for breakthrough CMV DNAemia (hazard ratio 2.2, 95%CI 1.2-3.8) among patients with similar age, CMV risk stratification, starting VGC dose, immunosuppressive therapy, and organ group. CONCLUSION: CMV events occurred while on VGC prophylaxis. Weight-based VGC may prevent supratherapeutic VGC exposure especially in younger children. Dose reduction of VGC prophylaxis for adverse event management places patients at an increased risk for CMV DNAemia suggesting other agents with fewer adverse effects should be considered and need to be studied in children.

Vaccination in pediatric solid organ transplant: A primer for the immunizing clinician.

Pediatric solid organ transplant (SOT) recipients are at a uniquely elevated risk for vaccine preventable illness (VPI) secondary to a multitude of factors including incomplete immunization at the time of transplant, inadequate response to vaccines with immunosuppression, waning antibody titers observed post-SOT, and uncertainty among providers on the correct immunization schedule to utilize post-SOT. Multiple guidelines are in existence from the Infectious Diseases Society of America and the American Society of Transplantation, which require use in adjunct with additional published references. We summarize the present state of SOT vaccine recommendations from relevant resources in tandem with the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices guidance utilizing both routine and rapid catch-up schedules. The purpose of this all-inclusive review is to provide improved clarity on the most optimal pre- and post-transplant vaccine management within a one-stop-shop for the immunizing clinician.

Vaccine-induced protection against hepatitis B in pediatric solid organ transplant patients.

BACKGROUND: Vaccination against hepatitis B virus (HBV) has led to a worldwide reduction in disease burden and mortality. Vaccine immunogenicity data in transplanted children are limited, and vaccine-induced protection may be reduced. We evaluated HBV vaccination coverage, seroprotection rates, and factors influencing vaccine immunity among pediatric solid organ transplant (SOT) patients. METHODS: We retrospectively identified patients ≤21 years of age evaluated for SOT and/or transplanted at our center between January 1, 2015, and December 31, 2018. A detailed chart review was conducted using a standard questionnaire to gather information on demographic, clinical, and laboratory features of patients' HBV vaccination, and hepatitis B surface antibody (HBsAb) titers. RESULTS: A total of 381 patients undergoing evaluation and/or transplantation were included: 139 (36.5%) liver, 138 (36.2%) kidney, and 104 (27.3%) heart. Overall, HBsAb at evaluation was reactive in 216 (56.7%), indeterminate in 17 (4.5%), non-reactive in 138 (36.2%), and not available in 10 (2.6%). Of those that completed a primary HBV vaccine series (n = 304), HBsAb was reactive in 164 (53.9%), indeterminate in 13 (4.3%), non-reactive in 119 (39.1%), and not available in 8 (2.6%). For those up to date for age on HBV vaccinations with non-reactive/indeterminate titers at evaluation, revaccination and a follow-up HBsAb were available in 45 patients of which 33 (73.3%) seroconverted to a reactive HBsAb titer. CONCLUSION: Vaccine-induced protection against HBV infection among high-risk pediatric SOT recipients can be improved by serology-based intervention. Though the absence of HBsAb does not always indicate loss of protection, boosting or completing primary series is recommended.

Considerations and controversies of pharmacologic management of the pediatric kidney transplant recipient.

Pediatric kidney transplantation has experienced considerable growth and improvement in patient and allograft outcomes over the past 20 years, in part due to advancements in immunosuppressive regimens and management. Despite this progress, care for this unique population can be challenging due to limited pediatric transplant data and trials, intricacies related to differences in children and adolescents compared with their adult counterparts, and limitations to long-term survival facing all solid organ transplant populations. Immunosuppression and infection prevention practices vary from one pediatric transplant center to another and clinical controversies exist surrounding treatment and dosing. This review aims to summarize key aspects of pharmacologic management in this population and present pertinent data that describe the influence of practice to serve as a resource for practitioners caring for this unique specialty patient population. Additionally, this review highlights select controversies that exist within pediatric kidney transplantation.

Initial posaconazole dosing to achieve therapeutic serum posaconazole concentrations among children, adolescents, and young adults receiving delayed-release tablet and intravenous posaconazole.

Posaconazole is a broad-spectrum antifungal used for prophylaxis and treatment of invasive fungal diseases. There are limited data on the optimal dosing, safety, and efficacy of the DRT and IV formulations in immunocompromised pediatric and adolescent patients. We describe our experience including dosing, plasma trough concentrations, safety, and tolerability. Plasma concentrations ≥.7 µg/mL were considered therapeutic for prophylaxis and ≥1.0 µg/mL for treatment. Fifty-four patients (median age of 16 years) received DRT or IV formulations of posaconazole. Thirty-one (57%) patients received posaconazole for treatment and 23 (43%) for prophylaxis. Overall, 36 (67%) patients achieved targeted initial plasma trough concentrations (median 1.3 µg/mL) (Figure 1). The median daily dose among patients <13 years of age who achieved the targeted initial concentrations was 7.3 mg/kg/day for the DRT formulation and 9.8 mg/kg/day for the IV formulation. The median daily dose among patients ≥13 years of age who achieved the targeted initial concentrations was 4.9 mg/kg/day for the DRT formulation and 5.6 mg/kg/day for the IV formulation. Thirty-six patients (67%) developed transaminitis, mostly grade 1. Our observations show that DRT and IV formulations are safe and effective in immunocompromised children, adolescents, and young adults. Higher dosing per body weight of DRT and IV posaconazole may be required in patients <13 years of age compared with patients 13 years of age and older to achieve therapeutic plasma concentrations. [Figure: see text].

Brincidofovir for the treatment of human adenovirus infection in pediatric solid organ transplant recipients: A case series.

HAdV viremia can cause significant morbidity among pediatric recipients of SOT with variability in incidence and severity of disease based on the type of allograft. Currently, there are no US FDA-approved treatments for HAdV infections, and historically, the mainstay of treatment has been decreasing immunosuppression, with antiviral therapies reserved for those with severe disease. We describe the treatment of four pediatric SOT recipients (two kidney, one combined kidney-liver, and one liver) presenting with HAdV disease at our institution using brincidofovir. Our case series highlights the variability in presentation and the potential for severe disease in pediatric SOT recipients as we review disease presentation, disease course, complications, and treatment with brincidofovir.

Cryptosporidiosis among solid organ transplant recipient attendees at a summer camp.

We report a cluster of pediatric cryptosporidiosis infections among solid organ transplant recipients at a summer camp in Georgia, USA. A retrospective cohort study was conducted to investigate the risk factors for infection. A total of 118 campers attended the camp during July 23-28, 2017. The overall attack rate among campers during the outbreak was 11% (13/118). Sanger-based amplicon sequencing of stool specimens from 7 (80%) campers identified Cryptosporidium hominis as the suspected etiologic agent. All infected campers were heart or kidney transplant recipients receiving immunosuppressive therapy. The median reported symptom duration was 12 days (range 6-18 days) and 9 (69.2%) were hospitalized for at least one night (median length of stay 5 days, range 2-16 days). There were no deaths or acute rejection events attributed to infection. The results of the epidemiologic and environmental investigation suggest a recreational pool as the presumed source, although there was no direct evidence to support this. Many long-term interventions were implemented, and there have been no further outbreaks at the camp in the following two years. This outbreak demonstrates that cryptosporidiosis may be associated with notable burden in pediatric transplant recipients, and illustrates the challenges associated with source identification and containment.

Impact of Pharmacy-Initiated Interventions on Influenza Vaccination Rates in Pediatric Solid Organ Transplant Recipients.

BACKGROUND: In solid organ transplant (SOT) recipients, influenza infection can lead to subsequent graft dysfunction and death. Vaccination is the most effective approach to preventing influenza infection; however, vaccination rates are low, and interventions to optimize vaccine coverage are needed. The purpose of this study was to evaluate if pharmacy-initiated screening and recommendations for influenza immunization improve the rate of vaccination in pediatric SOT recipients. METHODS: We performed a retrospective pre-post chart review of all kidney, liver, and heart transplant recipients followed by Children's Healthcare of Atlanta/Emory University transplant services between September 1, 2011, and February 16, 2017. Influenza vaccination coverage and influenza rates before (2011-2013) and after (2014-2016) the implementation of pharmacy-driven vaccination in SOT recipients were assessed. RESULTS: A total of 822 patients were included; 101 (13%) of these patients were diagnosed with influenza, and 40 (5%) were hospitalized secondarily during the study period. Vaccination coverage increased over time (144 [36%] patients vaccinated in 2011 vs 430 [74%] in 2016; P < .001). Influenza diagnosis rates decreased between the 2 eras (P = .006). The median time in which 50% of the population was vaccinated decreased over time from 163 days in 2012 to 94 days in 2016 (P < .001). CONCLUSION: Within the constraints of the pre-post study design, we observed a significant increase in influenza vaccination rates after implementation of a transplant pharmacy-initiated screening and vaccination program. The number of patients diagnosed with influenza and the time to vaccination decreased after our pharmacy intervention. All efforts should be made to increase compliance with influenza vaccination; pharmacy-initiated interventions can improve protection against influenza infection in pediatric SOT recipients.

Acute cellular rejection treatment outcomes stratified by Banff grade in pediatric kidney transplant.

INTRODUCTION: There are limited data to guide optimal treatment strategies for acute cellular rejection (ACR) based on Banff grade for pediatric kidney transplant recipients. This report reviews a large pediatric transplant center's experience with ACR. MATERIALS AND METHODS: A retrospective analysis of pediatric kidney transplant recipients at our center from 2007 to 2014 was performed. Primary outcomes were incidence of graft failure and graft function one year following ACR based on Banff grade and treatment received. RESULTS: A total of 204 patients were reviewed, of which 65 received rejection treatment with either an oral steroid cycle (n = 16), intravenous steroid pulse (n = 28), or anti-thymocyte globulin (rATG, n = 21). Overall, patients received rATG for treatment of more severe rejection associated with impaired graft function and as a group experienced statistically significant improvements in eGFR over the year following treatment, though most did not regain baseline graft function. DISCUSSION: Our data suggest that rATG is partially effective in treating ACR, but our study was underpowered to determine the effect of different treatments based on Banff grade. Since there is limited literature to guide clinical treatment of ACR in children, large transplant centers should collaborate to evaluate outcomes and establish evidence-based practice.

Multimethod Assessment of Medication Nonadherence and Barriers in Adolescents and Young Adults With Solid Organ Transplants.

Objective: To (a) examine levels of medication nonadherence in adolescent and young adult (AYA) solid organ transplant recipients based on AYA- and caregiver proxy-reported nonadherence to different medication types and the medication-level variability index (MLVI) for tacrolimus, and (b) examine associations of adherence barriers and AYA and caregiver emotional distress symptoms with reported nonadherence and the MLVI. Method: The sample included 47 AYAs (M age = 16.67 years, SD = 1.74; transplant types: 25% kidney, 47% liver, 28% heart) and their caregivers (94 total participants). AYAs and caregivers reported on AYAs' adherence barriers and their own emotional functioning. Nonadherence was measured with AYA self- and caregiver proxy-report and the MLVI for tacrolimus. Results: The majority of AYAs and caregivers denied nonadherence, with lower rates of nonadherence reported for antirejection medications. In contrast, 40% of AYAs' MLVI values indicated nonadherence to tacrolimus. AYAs and caregivers who verbally acknowledged nonadherence had more AYA barriers and greater caregiver emotional distress symptoms compared with those who denied nonadherence. AYAs with MLVIs indicating nonadherence had more barriers than AYAs with MLVIs indicating adherence. Conclusions: Multimethod nonadherence evaluations for AYA transplant recipients should assess objective nonadherence using the MLVI, particularly in light of low reported nonadherence rates for antirejection medications. Assessments should include adherence barriers measures, given associations with the MLVI, and potentially prioritize assessing barriers over gauging nonadherence via self- or proxy-reports. Caregiver emotional distress symptoms may also be considered to provide insight into family or environmental barriers to adherence.

Ofatumumab for the treatment of childhood nephrotic syndrome.

BACKGROUND: Ofatumumab is a humanized anti-CD20 monoclonal antibody that has recently garnered interest as a potential therapeutic agent for nephrotic syndrome. We report our center's experience in administering ofatumumab to five pediatric patients with idiopathic nephrotic syndrome. METHODS: Between March 2015 and November 2016, five patients were treated with ofatumumab. One patient had post-transplant recurrent focal segmental glomerulosclerosis (FSGS) which had been resistant to plasmapheresis and numerous immunosuppressive agents. Four patients had nephrotic syndrome in their native kidneys, one with initial steroid-resistant disease and the others with subsequent development of steroid resistance. Two of the patients were treated with a desensitization protocol after experiencing hypersensitivity reactions to ofatumumab. RESULTS: One patient did not complete ofatumumab treatment due to infusion reactions. Of the four remaining patients, three achieved complete remission after treatment, and one achieved partial remission. One of the patients achieving complete remission represents the first reported case of successful treatment of post-transplant recurrent FSGS using ofatumumab. Two patients who received ofatumumab with our desensitization protocol were able to complete their treatments after initially experiencing hypersensitivity reactions. CONCLUSIONS: Ofatumumab may be an effective treatment for refractory childhood nephrotic syndrome and post-transplant recurrent FSGS. A desensitization protocol may be helpful to address hypersensitivity reactions.

The interactive effect of parent personality and medication knowledge on adherence in children awaiting solid organ transplantation.

OBJECTIVE: The study aimed to examine parent personality factors as predictors of parent medication knowledge and parent-report of child medication adherence. METHOD: Seventy-eight parents (Mage = 37.68, 87.2% female) of children (Mage = 8.89, range: 0-20 years) undergoing evaluation for a solid organ transplant were recruited. Parents completed questionnaires about their personality, knowledge of their child's medications, and their child's level of medication adherence. RESULTS: Greater time since the child's diagnosis predicted lower levels of medication knowledge, while higher levels of Neuroticism and Extraversion predicted greater levels of medication knowledge. Greater medication knowledge predicted greater levels of medication adherence, with this effect being moderated by conscientiousness. Children of parents with low knowledge and low conscientiousness had the lowest levels of adherence. CONCLUSIONS: Parent personality is significantly related to medication knowledge and children's adherence prior to transplant. As parent personality is theoretically stable, Neuroticism (N), Extraversion (E), and Conscientiousness (C) serve as risk and protective factors that may influence medication knowledge and adherence even after transplantation. Parent medication knowledge and adherence are modifiable factors that would be appropriate targets for intervention during the pretransplant period. (PsycINFO Database Record

Executive Functioning, Barriers to Adherence, and Nonadherence in Adolescent and Young Adult Transplant Recipients.

OBJECTIVE : To evaluate levels of executive functioning in a sample of adolescent and young adult (AYA) transplant recipients, and to examine executive functioning in association with barriers to adherence and medication nonadherence. METHOD : In all, 41 caregivers and 39 AYAs were administered self- and proxy-report measures. RESULTS : AYA transplant recipients have significant impairments in executive functioning abilities. Greater dysfunction in specific domains of executive functioning was significantly associated with more barriers to adherence and greater medication nonadherence. CONCLUSION : AYA transplant recipients are at increased risk for executive dysfunction. The assessment of executive functioning abilities may guide intervention efforts designed to decrease barriers to adherence and promote developmentally appropriate levels of treatment responsibility.