Longitudinal stability of medication adherence among adolescent solid organ transplant recipients

Solid organ transplantation requires ongoing adherence to immunosuppressants and other medications. Although adolescence is a risk factor for poor medication‐taking, little is known about the patterns of adherence within individuals over time. This study aimed to examine the stability of adherence over time using three different assessment techniques. Sixty‐six AYA transplant recipients and/or their caregiver completed interviews of adherence at baseline and at least one yr later. Serum immunosuppressant assay levels were collected via medical chart review. Non‐adherence percentages based on AYA report, caregiver report, and bioassay did not differ from Time 1 to Time 2. However, correlations for these measures across time were non‐significant. Further, the majority of AYAs shifted to a different adherence category from Time 1 to Time 2. Overall, these results demonstrate individual variability in non‐adherence over the course of adolescence and young adulthood and highlight the importance of frequent assessment across time for solid organ transplant recipients.     

Cell phone support to improve medication adherence among solid organ transplant recipients

For many adolescent and young adult solid organ transplant recipients, medication non‐adherence is a mortal issue. This study investigated the feasibility, acceptability, and potential efficacy of a 12‐week cell phone support intervention to improve immunosuppressant medication adherence. A small sample (N = 8) of non‐adherent adolescent and young adult transplant recipients, aged 15‐20.5 years, was enrolled. Cell phone support consisted of short calls each weekday including medication reminders, discussion of needs, problem‐solving support, and promotion of clinic and community resources. Changes in adherence were measured by self‐report and laboratory values, and intervention acceptability, adherence barriers, social support, depression, and substance use were assessed by self‐report. Pre‐post effect sizes showed medium‐to‐large improvements in adherence, lasting through a 12‐week follow‐up assessment. There were also small‐to‐medium changes in adherence barriers, social support, and depression. However, acceptability and feasibility were limited, due to a low rate of enrollment by eligible male participants. Cell phone support interventions may promote medication adherence among adolescents and young adults. Cell phone support warrants further investigation, including a randomized controlled trial to evaluate efficacy.     

Perceived barriers to medication adherence in pediatric and adolescent solid organ transplantation

Comparisons of perceived barriers to adherence in pediatric and adolescent SOT have not been systematically conducted despite association between medication non‐adherence and poor outcome. Fifteen centers in CTOT‐C enrolled patients in a cross‐sectional study. Subjects' guardians completed the PMBS and subjects over eight completed the Adolescent Scale (AMBS). Association of three identified PMBS factors and subject age was assessed. Secondary analyses assessed associations between PMBS, AMBS, and patient demographics. Three hundred sixty‐eight subjects or their guardians completed PMBS or AMBS. A total of 107 subjects were 6–11 yr; 261 were ≥12. Unadjusted and propensity‐adjusted analyses indicated higher perceived barriers in guardians of adolescents as compared to guardians of pre‐adolescents medication scheduling and frustration domains regardless of organ (p < 0.05). PMBS and AMBS comparisons revealed that guardians reported fewer ingestion issues than patients (p = 0.018), and differences appeared more pronounced within younger responders for scheduling (p = 0.025) and frustration (p = 0.019). Screening revealed guardians of older patients report increased perceived barriers to adherence independent of socioeconomic status. Guardians of adolescents reported fewer perceived barriers to ingestion/side effects than patients themselves, particularly in pre‐adolescents (8–11 yr). Brief screening measures to assess perceived barriers should be further studied in adherence improvement programs.     

Medication adherence in the transition of adolescent kidney transplant recipients to the adult care

Non‐adherence is common in adolescent and young adult kidney transplant recipients, leading to adverse graft outcomes. The aim of this study was to determine whether adherence to immunosuppressant medications changes during transition from a pediatric to an adult program within the same transplant center. Adherence was assessed for a period of two yr before and two yr after the transfer. Subtherapeutic trough levels of serum tacrolimus and level variability were used as measures of adherence. Twenty‐five patients were transitioned between 1996 and 2011 at the median age of 22.3 [IQR 21.6–23.0] yr. Young adults 21–25 yr of age (n = 26) and non‐transitioned adolescents 17–21 yr of age (currently followed in the program, n = 24 and those that lost their grafts prior to the transfer, 22) formed the comparison groups. In the transitioned group, adherence prior to the transfer was not significantly different from the adherence after the transfer (p = 0.53). The rate of non‐adherence in the group of non‐transitioned adolescents who lost their grafts (68%) was significantly higher than in the transitioned group (32%, p = 0.01). In the group of young adults, adherence was not significantly different from the transitioned group (p = 0.27). Thus, transition was not associated with differences in medication adherence in this single‐center study. Large‐scale studies are needed to evaluate the national data on medication adherence after transfer.     

Perceived barriers to medication adherence remain stable following solid organ transplantation

Perceived barriers to adherence have previously been investigated in SOT to identify plausible intervention targets to improve adherence and transplant outcomes. Fifteen centers in CTOTC enrolled patients longitudinally. Patients >8 years completed Adolescent Scale(AMBS) at two visits at least 6 months apart in the first 17 months post‐transplant while their guardians completed PMBS. Differences over time for pre‐identified AMBS/PMBS factors were analyzed. Perceived barrier reporting impact on subsequent TAC levels was assessed. A total of 123 patients or their guardians completed PMBS or AMBS. Twenty‐six were 6‐11 years and 97 were ≥12. The final cohort consisted of kidney (66%), lung (19%), liver (8%), and heart (7%) recipients. Unadjusted analysis showed no statistically significant change in reported barriers from visit 1 (median 2.6 months, range 1.2‐3.7 post‐transplant) to visit 2 (median 12, range 8.9‐16.5). Of 102 patients with TAC levels, 74 had a single level reported at both visits. The factor of “Disease frustration” was identified through the PMBS/AMBS questions about fatigue around medication and disease. Each point increase in “disease frustration” at visit 1 on the AMBS/PMBS doubled the odds of a lower‐than‐threshold TAC level at visit 2. No clear change in overall level of perceived barriers to medication adherence in the first year post‐transplant was seen in pediatric SOT. However, disease frustration early post‐transplant was associated with a single subtherapeutic TAC levels at 12 months. A brief screening measure may allow for early self‐identification of risk.     

Development and field testing of Teen Pocket PATH®, a mobile health application to improve medication adherence in adolescent solid organ recipients

Applying principles of user‐centered design, we iteratively developed and tested the prototype of TPP, an mHealth application to promote medication adherence and enhance communication about medication management between adolescents and primary caregivers. A purposive sample of seven adolescent solid organ transplant recipients who were ≥one yr post‐transplant and their primary caregivers participated. Participants completed up to three face‐to‐face laboratory usability sessions, a 6‐week field test, and a debriefing session. Primary caregivers participated in an additional usability telephone session. Participants completed usability and satisfaction measures. Sample included liver (n = 4), heart (n = 2), and lung (n = 1) recipients aged 11–18 yr (57% were female, 86% were Caucasian), and nine primary caregivers aged 42–61 yr (88.9% were parents, 88% were female, 88% were Caucasian). Ninety percent of the adolescents endorsed the graphs or logs of missed/late medication dosing as useful and 100% endorsed the remaining features (e.g., medication list, dose time reminders/warnings) as useful. All adolescents expressed interest in using TPP for monitoring medications and satisfaction with the automatic messaging between adolescent and caregiver versions of the application. Adolescents unanimously found TPP easy to use. TPP shows promise as an mHealth adherence tool.     

Promoting medication adherence from the perspective of adolescent and young adult kidney transplant recipients,parents, and health care professionals: A TAKE‐IT TOO study

Medication non‐adherence is an important factor limiting allograft survival after kidney transplantation in AYA. Some interventions, including the TAKE‐IT, showed some success in promoting adherence but the potential for scalability and use in routine clinical practice is limited. We applied user‐centered design to gather the perspectives of recipients, parents, and health professionals concerning their needs, challenges, and potential intervention strategies to design an optimal, multi‐component medication adherence intervention. The qualitative study was conducted at four Canadian and three American kidney transplant programs. Separate focus groups for recipients, parents, and health professionals were convened to explore these stakeholders' perspectives. Directed content analysis was employed to identify themes that were shared vs distinct across stakeholders. All stakeholder groups reported challenges related to taking medications on time in the midst of their busy schedules and the demands of transitioning toward independence during adolescence. The stakeholders also made suggestions for the multi‐component behavioral intervention, including an expanded electronic pillbox and companion website, education materials, and customized digitized features to support shared responsibility and communication among recipients, parents, and health professionals. Several suggestions regarding the functionality and features of the potential intervention reported in this early stage will be explored in more depth as the iterative process unfolds. Our approach to actively involve all stakeholders in the process increases the likelihood of designing an adherence intervention that is truly user‐informed and fit for the clinical setting.     

Adenoviral disease in pediatric solid organ transplant recipients

Adenoviral disease in pediatric SOT recipients is emerging as an important viral pathogen, with serious consequences impacting morbidity, mortality and graft survival. The optimal diagnostic techniques, as well as therapy have yet to be established. This article reviews the current epidemiology of AdV in orthotopic liver, intestinal, cardiothoracic and renal transplant recipients. Issues related to diagnosis, notably the use of newer non-culture based viral detection methods and therapy, including anti-adenoviral agents and adoptive immunotherapy are discussed.     

Maturity and adherence in adolescent and young adult heart recipients

BACKGROUND: Pediatric transplant (txp) teams note high rates of non-adherence and risky behaviors linked to morbidity and mortality among adolescent and young adult recipients. Clinicians and parents alike report symptoms of social immaturity and failure to appreciate consequences of risky behavior; relationships between the two have not been studied in this population. METHOD: This two-phase mixed method study examined adherence, high-risk behaviors, and maturity in a sample of 27 heart recipients, aged 15-31, who underwent transplantation in childhood or adolescence at Children's Hospital of Pittsburgh. All subjects completed a projective ego development measure and a questionnaire about adherence to the post-txp regimen. Nine recipients, purposely selected for good or poor adherence according to criteria determined by the transplant team and matched on age, participated in phase 2 qualitative interviews and mood assessments. RESULTS: Sixty-three percent of the phase 1 sample missed medications, 67% missed appointments, 11% smoked, 37% had difficulty with diet, 89% exercised infrequently, 33% had tattoos, 26% had more than two body piercings, and 11% used street drugs. Six themes and a core construct of maturity were identified with qualitative methodology. Poor adherers were less mature on every theme and consistently scored at a less mature level on the projective measure of ego development. Chronological age was not related to the level of maturity in qualitative or projective data. Most interview subjects reported high levels of anxiety, and two reported clinically significant levels of depression and anger; mood was not related to adherence. CONCLUSIONS: Non-adherence and high-risk behaviors are prevalent among adolescent and young adult heart recipients. Level of maturity appears to be associated with ability to adhere to the treatment regimen and avoid high-risk behaviors.     

New algorithm for valganciclovir dosing in pediatric solid organ transplant recipients

CMV infections are common after SOT. v‐GCV is increasingly used in children. The aim of this study was to evaluate presently used dosing algorithms. Data from 104 pediatric SOT recipients (kidney, liver, and heart) aged 0.3–16.9 yr and receiving v‐GCV once a day were used for model development and validation with the Pmetrics package for R. Monte Carlo simulations were performed to compare the probability of a GCV AUC 40–60 mg*h/L with the different algorithms across a range of ages, weights, and GFRs. GCV pharmacokinetics was well described by the non‐parametric model. Clearance was dependent on GFR and Cockcroft‐Gault estimates improved the model fit over Schwartz. Simulations showed that our new algorithm, where v‐GCV dose is: Weight [kg]*(0.07*GFR [mL/min]+k), where k = 5 for GFR ≤ 30 mL/min, k = 10 for GFR > 30 mL/min and weight > 30 kg and k = 15 for GFR > 30 mL/min and weight ≤ 30 kg, outperformed the other algorithms. Thirty‐three percent of all patients achieve an exposure above and 21% within the therapeutic window. We propose a simple algorithm for initial v‐GCV dosing that standardizes plasma drug exposure better than current algorithms. Subsequent TDM is strongly suggested to achieve individual drug levels within the therapeutic window.     

Human herpesvirus type 8 infections among solid organ transplant recipients

Human herpes virus 8 (HHV-8) is known to be associated with Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and a form of Castleman's disease. Recently, it has also been shown to be associated with acute bone marrow failure in transplant patients. While, the full spectrum of clinical manifestations due to HHV-8 is yet to be defined in transplant recipients, it is known to cause post-transplant KS as a result of primary as well as secondary infection. This review will discuss the possible role of HHV-8 as a cause of disease in solid organ transplant recipients by focussing on important issues, including the biology of the virus, epidemiology, clinical manifestations, laboratory diagnosis and treatment, followed by a discussion of issues of relevance to the pediatric transplant recipient.     

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.     

Quantitation of peripheral blood cytomegalovirus DNA for monitoring recurrent cytomegalovirus retinitis in pediatric solid organ transplant recipients

Cytomegalovirus (CMV) infection is a major concern following solid organ transplantation, especially in the pediatric population who remain at high risk of primary infection. CMV disease leads not only to increased patient and graft morbidity, but also to increased health care costs. This study describes the usefulness of a quantitative CMV polymerase chain reaction (PCR) technique for monitoring peripheral blood CMV DNA in pediatric recipients of kidney and liver allografts who had recurrent CMV retinitis. The incidence of CMV disease in 28 pediatric transplant recipients was 28.6%, one-half of whom developed retinitis. Two of these patients had recurrent retinitis on cessation of anti-viral treatment. A peripheral blood CMV DNA copy number of > or =500/microg of DNA was associated with recrudescence of the retinitis in these patients. We conclude that the measurement of peripheral blood CMV DNA by PCR is a useful tool for the surveillance of disease resolution and recurrence. This is particularly important in patients with CMV retinitis, who may remain asymptomatic for a period of time, despite recurrences.     

Perceived barriers to adherence among adolescent renal transplant candidates

Non-adherence to medical regimens is a ubiquitous hindrance to quality health care among adolescent transplant recipients. Identification of potentially modifiable barriers to adherence when patients are listed for organ transplant would help with early intervention efforts to prepare adolescents for the stringent medication regimen post-transplant. Fifty-six adolescents listed for a kidney transplant, mean age 14.27 (s.d. = 2.2; range 11-18 yr), 73.2% male, 62.5% Caucasian participated in a semi-structured interview, the Medical Adherence Measure, to assesses the patient's knowledge of the prescribed regimen, reported adherence (missed and late doses), the system used to organized medications, and who holds the primary responsibility over medication management. Better knowledge of the medication regimen was associated with fewer missed doses (r = -0.48, p < 0.001). Patients who perceived more barriers had more missed (r = 0.38, p = 0.004) and late (r = 0.47, p < 0.001) doses. Patients who endorsed "just forget," the most common barrier (56.4%), reported significantly more missed (z = -4.25, p < 0.001) and late (z = -2.2, p = 0.02) doses. Only one-third of the transplant candidates used a pillbox to organize medications but these patients had significantly better adherence, z = -2.2, p = 0.03. With regard to responsibility over managing the regimens, adolescents missed fewer doses when their parents were in charge than when they were solely responsible, z = -2.1, p = 0.04. Interventions developed to prepare transplant candidates for a stringent post-transplant regimen need to focus on ensuring accurate knowledge of as simple a regimen as possible. Use of an organized system such as a pillbox to establish a routine and facilitate tracking of medications is recommended with integration of reminders that may be appealing for this age group. Although individuation is developmentally normative at this age, parent involvement seems critical until the adolescent is able to manage the responsibility more independently.     

Providers' assessment of transition readiness among adolescent and young adult kidney transplant recipients

The Readiness for Transition Questionnaire‐ provider version (RTQ‐Provider) was developed to evaluate adolescent patients' transition readiness and healthcare behaviors from the perspective of the healthcare provider. The RTQ‐Provider is a parallel version of the RTQ‐Teen and RTQ‐Parent completed by patients and parents. This study seeks to evaluate the psychometric properties of the RTQ‐Provider and its utility as a clinical transition planning tool. Participants consisted of 49 kidney transplant recipients between the ages of 15 and 21. The RTQ‐Provider was completed by the pediatric nephrologist and psychologist from the multidisciplinary healthcare team and compared to RTQ data from teens and parents. The RTQ‐Provider demonstrated good‐to‐excellent internal consistency and interrater reliability. Construct validity was supported through significant predictive relationships between providers' perceptions of transition readiness and older patient age, increased patient healthcare responsibility, and decreased parent involvement in health care. By providing parallel teen, parent, and provider forms, the RTQ has the potential to foster open communication between patients, families, and healthcare team members regarding transition readiness. The study provides initial support for the RTQ‐Provider as a clinical tool to assess providers' perceptions of transition readiness; however, future longitudinal research is needed to evaluate predictive validity following patients' transfer to adult care.     

Prediction of medication non‐adherence and associated outcomes in pediatric kidney transplant recipients

Studies have continued to evaluate risk factors associated with post‐transplant non‐adherence in pediatric patients. However, many of these studies fail to evaluate how risk factors can be utilized to predict MNA. The aims of this study were to (i) determine salient risk factors associated with MNA to develop an adequate predictive risk model and (ii) assess transplant outcomes based on the presence of MNA in a large, diverse cohort of pediatric KTX recipients. One hundred and seventy‐five solitary pediatric KTX recipients transplanted from 1999 to 2013 were included. AA, males, older patients, those who lived in urban environments, had legal issues, and lived shorter distances from the transplant center were more likely to have MNA. Using logistic regression, a parsimonious model applying nine risk factors together was developed for predicting MNA, demonstrating a PPV of 69% and a NPV of 81%. Patients with MNA had more than twice the risk of biopsy proven acute rejection, 1.6 times the risk of hospitalization, and 1.8 times the risk of graft loss. Utilization of a predictive model to determine risk of MNA after pediatric KTX may offer clinicians the ability to efficiently and effectively monitor MNA following transplant.