Effect of age on lipid profiles in pediatric heart transplant recipients

This study's objectives were to determine if pediatric orthotopic heart transplant (OHT) recipients over all ages develop hyperlipidemia and, secondarily, to identify the effects of immunosuppressive agents and statins on lipid profiles in these patients. Retrospective chart review was performed for pediatric patients transplanted between January 1987 and June 2002. Of the 100 OHTs performed, 50 patients satisfied the inclusion criteria and were grouped by age at OHT as follows: group 1 (n = 16): 0-4 yr; group 2 (n = 10): 5-9 yr; group 3 (n = 15): 10-14 yr; group 4 (n = 9): 15-18 yr. There were 2789 lipid levels recorded, and each patient had an average of 14 post-OHT lipoprotein panels measured. Post-OHT total cholesterol and low-density lipoprotein (LDL) levels were significantly greater than those of the general population for the entire follow-up period in all age groups, except for LDL levels in group 2. Cyclosporin level and prednisone dose were positively associated with total cholesterol and LDL levels (p < 0.03). Statins significantly decreased total cholesterol and LDL levels (p < 0.001). Hyperlipidemia affects OHT patients of all ages. Even the youngest patients may benefit from immunosuppression using an alternative to cyclosporin, such as tacrolimus, and steroid-free regimens, which may improve lipid profiles. Once safety and efficacy data are available, all age groups may benefit from statins.     

Post-transplant lymphoproliferative disease in pediatric lung transplant recipients: Recent advances in monitoring

Abstract: To investigate the clinical validity of newer diagnostic tests such as monitoring of EBVqPCR and lymphocyte function assay ImmuKnow in helping to diagnose PTLD in pediatric lung transplant recipients. Single‐center, retrospective case–control study. CsA trough levels, EBVqPCR and ImmuKnow (Cyclex Inc., Columbia, MD, USA) levels were measured serially as part of routine care. Re‐transplant patients and patients who did not reach 12 months post‐transplant at the time of analysis were excluded. Twenty‐seven patients met the inclusion criteria. The study group consisted of seven patients who developed PTLD, five of which were EBV? recipients who received EBV+ lungs. The rest of the eligible patients served as controls. Median time to develop PTLD was 273 days (range: 166–343). One, two, three, six, and nine months after transplant, mean (±s.d.) CsA trough whole blood levels (ng/mL) were not different between the two groups: 378 ± 38, 390 ± 52, 402 ± 89, 359 ± 42, and 342 ± 115, vs. 416 ± 105, 347 ± 64, 337 ± 78, 333 ± 86, and 281 ± 54 [PTLD vs. no‐PTLD, respectively (p > 0.05 for all time points)]. Mean (±s.d.) EBVqPCR levels (copies/mL) measured at three, six, and nine months post‐transplant were significantly elevated in PTLD group compared to no‐PTLD group: 84 ± 99, 3384 ± 7428 and 839 ± 1444 vs. 9 ± 26, 8 ± 36 and 32 ± 136, respectively (p < 0.05 for all time points). Mean (±s.d.) ImmuKnow levels (ATP ng/mL) at three, six, and nine months post‐transplant were significantly lower in the PTLD group when compared with no‐PTLD group: 144 ± 67, 137 ± 110, and 120 ± 153 vs. 290 ± 161, 300 ± 162, and 293 ± 190, respectively (p < 0.05 for all time points). Close monitoring of EBV viral load by qPCR and the degree of immunosuppression via ImmuKnow may guide physicians to reach the diagnosis of PTLD early.     

Emergency department utilization in pediatric heart transplant recipients

We used the NEDS database (2010) to evaluate ED utilization in PED HT recipients compared to other patient populations with focus on characteristics of ED visits, risk factors for admission, and charges. We analyzed 433 ED visits by PED HT recipients (median age 8 [range: 0‐18] years). The most common primary diagnosis category was infectious (n=163, 37.6%), with pneumonia being the most common infectious etiology. When compared to all PED visits, HT visits were more likely to result in hospital admission (32.6% versus 3.9%, P<.001), had greater hospital LOS (median of 3 days [IQR 2‐4] versus 2 days [IQR 1‐4], P=.001), and accumulated greater total hospital charges (median $26 317 [IQR $11 438‐$46 407] versus $12 332 [IQR $7092‐$22 583], P<.001). When compared to visits by other SOT recipients, results varied with similar rates of hospital admission for HT, LUNGT, and KT visits and similar LOS for HT and KT visits but differing total hospital charges. Although PED HT recipients account for a small percentage of overall ED visits, they are more likely to be hospitalized and require greater resource utilization compared to the general PED population, but not when compared to other SOT recipients.     

Basiliximab treatment for autoimmune bowel disease in a pediatric heart transplant patient

Autoimmune‐mediated bowel disease has been reported after pediatric heart transplantation. Recognition and treatment of these patients has been difficult. We describe a patient who responded to steroids and basiliximab therapy after an inflammatory process secondary to abnormal T‐cell activation. Our patient is a 28‐month‐old female who received a heart transplant at five wk of age. At 24 months post‐transplant, she developed fever and bloody stools. Initial investigations were significant for an elevated ESR (>120) and CRP (15.2). Symptoms persisted despite bowel rest and mycophenolate discontinuation. Endoscopic evaluation revealed discontinuous ulcerative disease involving esophagus, terminal ileum, right and left colon, necessitating extensive bowel resection. She had additional airway inflammation leading to a TEF at the site of esophageal ulceration, requiring tracheostomy. Immune evaluation revealed autoimmune dysregulation that responded to parenteral methylprednisolone. Chronic basiliximab therapy allowed for successful weaning of steroids with sustained remission. She has been transitioned to sirolimus and tacrolimus maintenance immunosuppression with plans to discontinue basiliximab once off steroids. In conclusion, bowel disease in the setting of pediatric heart transplantation can be severe and refractory to traditional treatment methods. Tailoring immune therapy to activated T cells can result in remission. Basiliximab therapy was used in our patient to maintain steroid‐induced remission, but long‐term complications of this disease process are unknown.     

Autoimmune enteropathy and hepatitis in pediatric heart transplant recipient

AIE is a rare disorder in children that presents with severe diarrhea and malabsorption, caused by immune‐mediated damage to intestinal mucosa. AIE is often associated with various syndromes of immunodeficiency including IPEX syndrome (immune dysregulation, polyendocrinopathy and enteropathy, X‐linked). Dysfunctional T regulatory cells are the source of pathology in both IPEX syndrome and AIE as they are essential in maintaining tolerance to self‐antigens and eliminating autoreactive B cells. This case report describes a 10‐year‐old cardiac transplant and total thymectomy patient on chronic immunosuppression with tacrolimus that presented with AIE and extraintestinal manifestations of cyclical hepatitis. Transition from tacrolimus to sirolimus successfully increased T regulatory cells and resolved enteritis and hepatitis symptoms. Data support that thymectomy at <1 year of age increases risk of autoimmune disease due to abnormal immune maturation. Studies suggest that the sirolimus promotes the upregulation of the FoxP3 protein that is classically associated with Tregs. In turn, Tregs prevent the maturation of autoreactive B cells that lead to autoimmune reactions.     

Presentation of atopic disease in a large cohort of pediatric liver transplant recipients

Atopic disease occurs in solid organ transplant recipients with an increasingly recognized frequency. The time course for the development of these atopic diseases in liver transplantation has not been described. The objective was to characterize the atopic manifestations of children receiving chronic immunosuppression after orthotopic liver transplantation (OLT). Chart review and follow-up questionnaire were utilized for 176 OLT pediatric recipients at a single institution for manifestations of allergic disease. Atopic disease was present in 25 (14.2%) patients. Median age at transplant was 16 months with a median follow-up of 63 months. Food allergy and non-food related atopic symptoms presented at a median of 11.5 (IQR, 6-28) and 19 (IQR, 5-41) months post-transplantation, respectively. The median age at transplant of the non-atopic children was 72 months, higher than patients with atopy (p < 0.001). Food allergy and atopic skin disease symptoms were present in 40% and 56% of cases, respectively. Asthma, allergic rhinitis, or both were found in 66% of cases. The onset of symptoms of food allergy and eczema (median, 12 months post-transplantation) preceded symptoms of allergic rhinitis and asthma. (median of 27 and 30 months post-transplantation, respectively). Atopy occurs in ～14% of pediatric liver transplant recipients, with manifestations including food allergy, eczema, allergic rhinitis, and asthma.     

Empiric switch from calcineurin inhibitor to sirolimus‐based immunosuppression in pediatric heart transplantation recipients

Sirolimus is used in heart transplant patients with CAV and CNI‐induced nephropathy. However, little is known regarding the tolerability, rejection rate, and effect on renal function when used empirically in children. We describe our experience with the empiric use of a sirolimus‐based immunosuppressive regimen in pediatric heart transplantation recipients. We reviewed records of patients in whom conversion was attempted to a CNI‐free sirolimus‐based regimen. Rejection episodes and measures of renal function were recorded. We attempted to convert 20 patients, of which 16 were successful. In total, six of 20 patients (30%) experienced adverse effects. Of the 16 converted, four patients converted to sirolimus due to CNI‐induced disease (three nephropathy, one CAV), while 12 patients (mean age 5.5 yr, range 0.1–21 yr; 33% female; 33% with a history of congenital heart disease) were empirically switched to sirolimus at a mean of 2.3 yr after transplant. Follow‐up was available for a mean of 2.5 yr after conversion (range 0.5–8.3 yr). The rate of rejection while taking CNIs was 0.18 rejection episodes per patient‐year (total of five episodes), compared with 0.03 rejection episodes per patient‐year (total of one episode) while on sirolimus. Renal function, in terms of GFR, significantly improved after sirolimus conversion at latest follow‐up (from 86 ± 37 mL/min to 130 ± 49 mL/min, p = 0.02). Here, we demonstrate the potential benefit of empiric use of sirolimus in pediatric heart transplant patients in a CNI‐free regimen. Larger and longer studies are needed to further clarify risks of rejection and adverse effect profiles.     

Outcomes of Pneumocystis jiroveci pneumonia infections in pediatric heart transplant recipients

PJP is known to cause significant morbidity and rarely death in immunosuppressed patients. The prevalence and outcomes of PJP in pediatric solid-organ transplant patients are not well established. This study utilizes data from the PHTS to establish the prevalence and outcome of PJP in pediatric heart transplant recipients. We conducted a retrospective cohort study using data from the PHTS, including data from 24 institutions between January 1, 1993, and December 31, 2004. Infections that occur in PHTS subjects are recorded in a standardized data collection form. The prevalence and outcomes of PJP in pediatric heart transplant recipients were determined. There were a total of 18 patients (1%) with PJP out of the 1854 pediatric heart transplant recipients in the PHTS database. A majority of PJP occurred two months to two yr post-transplant, and patients with PJP had a significantly decreased mortality compared with other fungal infections. PJP is an infrequent complication experienced by pediatric heart transplant recipients. Patients that have experienced PJP have an increased survival compared to patients with other fungal infections, and most PJP occurred within two yr of transplant.     

Improved exercise performance in pediatric heart transplant recipients after home exercise training

Abstract:  Pediatric heart transplant recipients have been shown to have reduced exercise performance. Studies of adult heart transplant recipients demonstrate improved endurance from regular aerobic exercise; however, this strategy has not been studied in children. We hypothesized that regular aerobic/strength training would improve exercise performance in children post-heart transplant. After an initial training session, an exercise protocol was performed at home for 12 wk, three days/wk. Aerobic exercise consisted of either running or use of an exercise bicycle to an established target HR for ≥20 min of a 30-min session for three days/wk. Subjects wore a HR monitor and kept a diary to monitor compliance. Two days/wk, strength training was performed with elastic bands to specifically exercise biceps and triceps groups for 15–20 min/session. Aerobic exercise capacity was assessed at baseline and post-training using the standard Bruce treadmill protocol. Strength was measured at baseline and post-intervention by dynamometer. Exercise and strength parameters at baseline and post-intervention were compared using paired student t- tests. Eleven subjects completed the 12-wk program, eight females and three males. The mean age at enrollment was 14.7 ± 5.3 yr (8–25) and mean time from transplant was 5.26 ± 5.34 yr (0.58–14.71). Endurance time and peak oxygen consumption improved significantly post-exercise; there was no difference in peak HR or systolic blood pressure. Strength improved in the triceps, quadriceps, and biceps groups. After a 12-wk inhome exercise intervention, pediatric heart recipients had improved exercise endurance and strength. The protocol was safe and implemented at relatively low cost. Further study is warranted to determine if the intervention can be extended to more children and whether benefits after such a short-term intervention can be sustained.     

Mycophenolate mofetil in pediatric heart transplant recipients: a single-center experience

Mycophenolate mofetil (MMF) is emerging as an effective agent for the treatment of both established rejection and primary rejection prophylaxis in solid-organ transplantation (Tx). However, little data is available on the use of MMF in the pediatric population. We therefore report on our experience with MMF in 21 pediatric heart transplant recipients. Data were obtained by retrospective chart review. Median age at time of review was 12.3 yr (range 11 months to 16.9 yr). Median age at Tx was 10.7 yr (range 55 days to 16.7 yr). MMF was started at a median of 4.3 months after Tx (range 1 day to 4.5 yr). At the time of MMF institution, all patients were concurrently on prednisone and azathioprine; 20 of these patients were also undergoing treatment with tacrolimus (median dose 0.18 mg/kg, range 0.03-0.64 mg/kg) and one with cyclo-sporin A (10 mg/kg). Azathioprine was discontinued at the time of commencing MMF. The average MMF dose was 40 +/- 14 mg/kg. The rationale for switching to MMF included rejection (International Society for Heart and Lung Transplantation [ISHLT] 3A/B), 66%; inability to wean steroids, 14%; ABO blood group donor-recipient mismatch, 10%; coronary artery disease (CAD), 5%; and side-effects of immuno-suppression, 5%. Of the patients switched for rejection, 93% demonstrated resolved or improving rejection. Both ABO donor-recipient mismatch patients were started on tacrolimus/MMF as primary therapy and had no significant episodes of rejection. Two patients had rejection classified as unchanged (one with CAD, one treated with addition of sirolimus prior to improvement). Corticosteroids were successfully discontinued in 28% of patients, and 20% are currently on a reduced dose. Fourteen per cent developed significant rejection while attempting to reduce the steroid dose. Steroid reduction has not yet been attempted in 38% of patients. The following side-effects were reported in 38% of the patients: diarrhea, 10%; gastrointestinal discomfort, 20%; and leukopenia, 20%. Dose reduction or temporary discontinuation was required in 63% of the patients who experienced side-effects (24% of the total number of patients). Opportunistic infections developed in 10% (cryptococcus, cytomegalovirus). Hence, MMF appears to be effective for treatment of rejection in the pediatric heart transplant population and has an acceptable side-effect profile. In addition, it may have a role in primary rejection prophylaxis and may facilitate a reduced steroid dosage or a steroid-free immunosuppression regimen.     

Anthropometric growth and utilization of enteral feeding support in pediatric heart transplant recipients

Bannister L, Manlhiot C, Pollock‐BarZiv S, Stone T, McCrindle BW, Dipchand AI. Anthropometric growth and utilization of enteral feeding support in pediatric heart transplant recipients.
Pediatr Transplantation 2010: 14:879–886. © 2010 John Wiley & Sons A/S. Abstract: We sought to outline trends in anthropometric growth before and after cardiac transplantation and to document our experience with the use of EFS in this population. A total of 130 patients (59% male) were enrolled and followed for a median of 4.4 yr after transplantation. Negative changes over time in weight z‐score (EST: −0.256 [0.160] z/yr, p = 0.01), height z‐score (EST: −0.214 [0.096] z/yr, p = 0.03), and BMI z‐score (EST: −0.287 [0.161] z/yr, p = 0.07) were observed prior to transplantation. Significant increases in weight z‐score (EST: +0.342 [0.143] z/yr, p < 0.001) and BMI z‐score (EST: +0.396 [0.140] z/yr, p = 0.005) were seen in the first 18 months following transplantation. No further increases in height, weight, or BMI z‐score were seen beyond this. Forty‐two (32%) patients received EFS. Prior to transplantation, it was not found to be associated with change in anthropomorphic growth. Post‐transplantation exposure to EFS was associated with a faster increase in weight z‐score (EST: +0.480 [0.231] z/yr, p = 0.04) and height z‐score over time (EST: +0.366 [0.141] z/yr, p = 0.01). Normalization of weight and height z‐scores was not achieved during the study follow‐up period. This study suggests that further investigation into the role of EFS is warranted to identify strategies to improve growth in pediatric heart transplant recipients.     

Predictors of neuropsychological functioning and medication adherence in pediatric heart transplant recipients referred for neuropsychological evaluation

Children who undergo heart transplantation are at risk for long‐term neurodevelopmental sequelae secondary to heart disease and its treatment. Detailed neuropsychological profiles in clinical sample status post‐pediatric heart transplantation are sparse in the literature, and there is little information regarding predictors of neuropsychological functioning or how it relates to medication adherence in this population. The present study examined these questions in a retrospective analysis of 27 pediatric heart transplantation recipients referred for clinical neuropsychological evaluation. The sample demonstrated mild‐to‐moderate decrements across domains of neuropsychological functioning. Children with premorbid congenital heart disease performed more poorly in working memory, word reading, and parent‐rated conceptual adaptive skills compared to children with premorbid cardiomyopathy. Additionally, a higher number of rejection episodes were related to poorer verbal memory. Children with parent‐reported attention problems had better adherence to immunosuppressant medication, which may have represented greater caregiver involvement in medication management. Taken together, clinically referred children with history of heart transplantation showed broad‐based difficulties across neuropsychological domains according to formal testing and parent rating scales. This population requires routine neuropsychological monitoring and intervention.     

Neutropenia in pediatric heart transplant recipients

Neutropenia has been reported in pediatric heart transplant recipients, but its association with infectious morbidity and mortality is unknown. We sought to determine neutropenia's prevalence and impact on infection, rejection, and survival. A retrospective analysis of pediatric heart transplant recipients from March 2005 to August 2015 was performed. Demographics, medications, infection, and rejection data were collected. Of 142 pediatric heart transplant recipients, 77 (54.2%) developed neutropenia within 4.7 months [3.3‐12.1 months] of transplant. In all patients, the adjusted 5‐year cumulative incidence of neutropenia was 30.2%. Fifty‐one patients (66.2%) had recurrent neutropenia. Six of 14 tested had positive antineutrophil antibodies. Medications associated with neutropenia were decreased in 15 (19.5%) and discontinued in 42 (54.4%) patients with no change in 1‐year rejection rates compared to published data. Fifteen patients developed infection within 30 days of neutropenia and two from 30 days to 1 year, with an infection rate similar to the non‐neutropenic group. There was no significant difference in survival, ANC, rate of rejection or PTLD in neutropenic patients with and without infection at median follow‐up (5.5 years). Neutropenia is common in pediatric heart transplant recipients. Neutropenia had <20% risk of associated infection, similar to non‐neutropenic patients. Infection in neutropenic patients did not increase mortality.     

Educational and learning morbidity in pediatric heart transplant recipients: A pediatric heart transplant society study

Educational development is an important component of quality of life for children with heart transplant. Aims include determining prevalence of and risk factors for modified education placement in a large representative sample of pediatric heart transplant recipients. Participants included 1495 patients (age 6‐18 years) from the PHTS database. Data on education placement and clinical predictors were collected at listing and at 1 and 3 years post‐transplant. At listing, 88% of patients were in typical education placement, while 12% were in modified education. Males (P = .02), those with CHD (P < .0001), those with non‐private insurance (P < .0001), and those with longer hospital stay (P = .001) were more likely to be in a modified education placement at time of listing. Age, race, listing status, mechanical support, and waitlist time were not significantly associated with placement. The prevalence of typical education placement was similar (87% at 1‐year and 86% at 3‐year) post‐transplant. Predictors of modified education placement at 3‐year follow‐up included placement at listing (OR = 12.9 [95% CI 7.6‐21.9], P < .0001), non‐private insurance (OR = 2.0 [95% CI 1.3‐3.2], P = .001), CHD (OR = 1.8 [95% CI 1.1‐2.7, P = .01), history of post‐transplant infection (OR = 1.9 [95% CI 1.2‐2.9, P = .007), and number of post‐transplant infections (OR = 1.3 [95% CI 1.1‐1.5, P = .002). Among pediatric heart transplant recipients, males, those with non‐private insurance, those with CHD, and those who experience post‐transplant infections are at greatest risk for modified academic placement, which persists for several years post‐transplant and deserves targeted intervention.     

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.     

Value of soluble adhesion molecules and plasma coagulation markers in assessing transplant coronary artery disease in pediatric heart transplant recipients

BACKGROUND: With an increasing number of heart transplantations (HTx) performed in children and an extended long-term survival of these patients, the importance of transplant coronary artery disease (TCAD) rises in this group of transplant recipients. Reliable serum markers for diagnosis or non-invasive monitoring of this disease in pediatric transplant recipients are still missing. We studied the systemic expression of adhesion molecules as well as plasma coagulation markers and the occurrence of TCAD and/or rejection in pediatric heart transplant recipients. METHODS AND RESULTS: The systemic plasma levels of soluble forms of sVCAM-1 and sICAM-1, d-dimer, tissue factor (TF), prothombin fragments F(1+2), and tissue factor pathway inhibitor (TFPI) were assessed in serial venous blood samples (2-4 per patient) in 50 pediatric transplant recipients children and 63 age- and sex-matched non-transplanted controls. TCAD and rejection were diagnosed angiographically or by combined histological, echocardiographic, or clinical signs, respectively. Plasma levels of sICAM-1 and sVCAM-1, d-dimers and prothrombin fragment F(1+2) but not TF and TFPI were significantly increased in children following HTx compared with non-transplanted controls (p<0.001). Among the transplanted patients, sICAM-1 levels were significantly higher in patients with angiographically detectable TCAD than in patients without evidence of TCAD (p<0.005). Plasma sICAM-1 levels above a cutoff value of 1500 ng/mL (95.5 percentile of control values) were indicative of the presence of TCAD (odds ratio 2.7; 95% confidence interval, 1.34-5.56, p = 0.022; Fisher's exact test). Only d-dimers were found to be significantly elevated in children with signs of myocardial rejection compared with those without rejection. CONCLUSIONS: Our results suggest that plasma sICAM-1 and d-dimer levels may be potentially useful to non-invasively assess TCAD and rejection, respectively, in pediatric heart transplant recipients.     

Impaired exercise parameters in pediatric heart transplant recipients: comparison of biatrial and bicaval techniques

The exercise performance of pediatric heart transplant recipients and the effects of bicaval anastomosis were studied in 19 children using a Bruce protocol. Although all children had decreased exercise capacity and heart rates when compared with normals, the bicaval anastomosis patients had similar endurance and peak heart rates as the standard biatrial group.