Joyce K. Johnston

Association of Viral Genome with Graft Loss in Children after Cardiac Transplantation

BACKGROUND The survival of recipients of cardiac allografts is limited by rejection, lymphoproliferative disease, and coronary vasculopathy. The purpose of this study in children who had received heart transplants was to evaluate the cardiac allografts for myocardial viral infections and to determine whether the presence of viral genome in the myocardium correlates with rejection, coronary vasculopathy, or graft loss. METHODS We enrolled heart-transplant recipients 1 day to 18 years old who were undergoing evaluation for possible rejection and coronary vasculopathy. Endomyocardial-biopsy specimens were evaluated for evidence of rejection with the use of standard criteria and were analyzed for the presence of virus by the polymerase chain reaction (PCR). RESULTS PCR analyses were performed on 553 consecutive biopsy samples from 149 transplant recipients. Viral genome was amplified from 48 samples (8.7 percent) from 34 patients (23 percent); adenovirus was found in 30 samples, enterovirus in 9 samples, parvovirus in 5 samples, cytomegalovirus in 2 samples, herpes simplex virus in 1 sample, and Epstein-Barr virus in 1 sample. In 29 of the 34 patients with positive results on PCR (85 percent), an adverse cardiac event occurred within three months after the positive biopsy, and 9 of the 34 patients had graft loss due to coronary vasculopathy, chronic graft failure, or acute rejection. In 39 of the 115 patients with negative results on PCR (34 percent), an adverse cardiac event occurred within three months of the negative PCR finding; graft loss did not occur in any of the patients in this group. The odds of graft loss were 6.5 times as great among those with positive results on PCR (P=0.006). The detection of adenovirus was associated with considerably reduced graft survival (P=0.002). CONCLUSIONS Identification of viral genome, particularly adenovirus, in the myocardium of pediatric transplant recipients is predictive of adverse clinical events, including coronary vasculopathy and graft loss.

Transplantation as a primary treatment for hypoplastic left heart syndrome: intermediate-term results.

BACKGROUND Hypoplastic left heart syndrome is a lethal malformation. For the last 10 years, orthotopic cardiac transplantation has been our preferred treatment for infants with hypoplastic left heart syndrome. METHODS One hundred seventy-six infants with hypoplastic left heart syndrome were entered into a cardiac transplant protocol between November 1985 and November 1995. Interventional procedures to stent the ductus arteriosus or enlarge the interatrial communication were performed in 8 and 35 patients, respectively. Thirty-four patients (19%) died during the waiting period, and 142 infants underwent cardiac transplantation. Age at cardiac transplantation ranged from 1.5 hours to 6 months (median, 29 days). The majority of grafts were oversized, and the median graft ischemic time was 273 minutes (range, 60 to 576 minutes). The implantation procedure used a period of hypothermic circulatory arrest ranging from 23 to 110 minutes (median, 53 minutes). Repair of other significant defects included interrupted aortic arch and total or partial anomalous pulmonary venous connection. RESULTS There were 13 early and 22 late deaths. Patient actuarial survival at 1 month and at 1, 5 and 7 years was 91%, 84%, 76%, and 70% respectively. Half of the late deaths were due to rejection. Severe graft vasculopathy was confirmed in 8 patients. Retransplantation was performed in 5 patients for graft vasculopathy 4 and rejection 1. Lymphoblastic leukemia developed in 1 patient 3 years after cardiac transplantation. CONCLUSIONS Cardiac transplantation can be performed in infants with hypoplastic left heart syndrome with good operative and intermediate-term results. Improved survival can be achieved with increased donor availability, better management of rejection, and control of graft vasculopathy.

The Medium-Term Findings in Coronary Arteries by Intravascular Ultrasound in Infants and Children After Heart Transplantation

OBJECTIVES The study purposes were to determine 1) whether intravascular ultrasound (IVUS) was more sensitive than angiography for the detection of post-transplant coronary artery disease (PTCAD) in pediatric patients; and 2) whether those transplanted as neonates reacted differently than older patients. BACKGROUND Experience with IVUS for the diagnosis of PTCAD in children is limited. METHODS Patients were divided into two groups: those transplanted as neonates (early group) and those transplanted in infancy or childhood (late group). Morphometric analysis was performed, including maximal intimal thickness (MIT) and intimal index (II). Stanford classification was used to grade lesion severity. Acute rejection and cytomegalovirus (CMV) status were correlated with MIT and II. RESULTS Thirty children were studied (early group, n = 13; late group, n = 17). All segments studied were angiographically normal. Mean MIT and mean II were significantly greater in the late group (0.26 +/- 0.14 vs. 0.13 +/- 0.04 mm, p < 0.001 and 0.11 +/- 0.07 vs. 0.07 +/- 0.03 mm, p = 0.04, respectively). There was a significant correlation between MIT and II in those who had acute rejection in the late group. Patients in the late group who were CMV-positive had a significantly higher MIT compared with those in the late group with negative serology (p = 0.04). CONCLUSIONS Intravascular ultrasound was more sensitive than angiography in detecting PTCAD after pediatric heart transplantation. There is a possible role for acute rejection and CMV in the development of PTCAD.

Cause of death in pediatric and infant heart transplant recipients: review of a 20-year, single-institution cohort.

BACKGROUND As infant and pediatric heart transplantation becomes more common, there is a growing need to better understand the causes of failure or death, if we are to continue to improve the outcome in these children. METHODS A multidisciplinary team reviewed all deaths occurring in the cohort of infants and children transplanted during the first 20 years of the Loma Linda Pediatric Heart Transplant program, with 2 additional years of follow-up beyond the 20-year accrual period, and classified them as to cause. RESULTS There were 169 deaths among 421 recipients, with a median follow-up of 9.7 years. Autopsy was performed in 128 cases. The causes of death, in decreasing order of frequency, included acute rejection (26.0%), infection (16.0%), cardiac allograft vasculopathy (CAV) (14.2%), technical issues (8.3%), acute graft dysfunction (6.5%), neoplasm (7.1%), chronic graft dysfunction (4.7%) and miscellaneous factors (10.1%), and in twelve deaths (7.1%) the cause was unclassified. Acute graft dysfunction and technical issues accounted for nearly two-thirds of the deaths in the first 30 days after transplant, while acute rejection resulted in the largest number of deaths after the first year (30.4%), with CAV a close second (23.5%). CONCLUSIONS Acute graft dysfunction and technical issues were the most frequent cause of early death. Late deaths were most often due to acute rejection and CAV, which differs somewhat from the experience reported in adults. Acute rejection was the single most important cause of late mortality, and resulted in a significant number of late sudden and unexpected deaths.

Post-transplant diabetes mellitus in pediatric liver transplantation

Abstract:  To determine the characteristics of pediatric liver transplant recipients who develop GI and/or PTDM, data on children undergoing their first liver transplant from the SPLIT database were analyzed (n = 1611). Recipient and donor characteristics that were evaluated included age at transplant, gender, race, primary disease, hospitalization status at transplant, BMI, recipient and donor CMV status, donor type, donor age, and primary immunosuppression. GI/PTDM was found in 214 individuals (13%) of whom 166 (78%) were diagnosed within 30 days of transplantation (early GI/PTDM). Multivariate analyses suggests that age >5 yr at transplant, hospitalization at transplant, a primary diagnosis other than BA, early steroid use, and tacrolimus use are associated with increased incidence of early GI. Routine monitoring for the development of GI and post‐transplant diabetes is indicated in the short‐ and long‐term care of children after liver transplantation.

ABO-incompatible heart transplantation in early childhood: An international multicenter study of clinical experiences and limits

BACKGROUND Intentional blood group (BG)-incompatible (ABOi) heart transplantation in childhood is emerging in many centers. Safety limits remain undetermined. In this multicenter study we have compiled experience on clinical and immunologic boundaries. METHODS Data from six centers in Europe and North America on ABOi transplantation were collected in a standardized survey. RESULTS Fifty-eight ABOi transplants were performed in 57 patients. Median age at transplant was 6.8 months (0.03 to 90 months); post-transplant follow-up was 37.7 months (0.46 to 117 months), accumulating 188 patient-years. Forty-seven percent of the patients received pretransplant mechanical circulatory support. Donors were either blood group A (n = 25), B (n = 18) or AB (n = 15). The median peak antibody titer to the donor BG pretransplant was 1:8 (0 to 1:64) for anti-A and 1:4 (0 to 1:32) for anti-B. Titers against the donor BG were lower post- than pretransplant in B recipients (p = 0.02), whereas third-party antibodies in BG O recipients developed normally post-transplant. Induction immunosuppression included anti-thymocyte globulin (61%), basiliximab (32%) or none (7%). All patients received calcineurin inhibitors, including 62% with mycophenolate mofetil, 10% with azathioprine, 2% with everolimus and 24% with steroids. There were 4 episodes of cellular rejection (Grade≥2R) and 7 antibody-mediated rejections. Five patients underwent antibody removal post-transplant. One patient developed severe graft vasculopathy. Freedom from death or retransplantation was 100%/96%/69% at 1/5/10 years. No graft loss was attributed to BG antibodies. CONCLUSIONS Successful ABOi heart transplantation can be performed at an older age and with higher isohemagglutinin titers than initially assumed and using similar immunosuppressive regimens as for ABO-compatible transplants. Rejection and graft vasculopathy are rare. Persistently low titers of antibodies to the donor BG post-transplant suggest elements of tolerance and/or accommodation.

Pediatric cardiac retransplantation: Intermediate-term results

BACKGROUND Cardiac retransplantation (re-CTx) in children is a controversial therapy, yet it remains the best treatment option to recipients with failing grafts. Our objective was to determine the incidence of re-CTx in a large pediatric population of recipients and evaluate the outcome of such therapy. METHODS Between November 1985 and November 1999, 347 children underwent cardiac transplantation at the Loma Linda University Medical Center. Of these, 32 children were listed for re-CTx. Ten patients died while waiting, and 22 recipients underwent re-CTx. Median age at re-CTx was 7.1 years (range, 52 days to 20.1 years). RESULTS Indications for re-CTx were allograft vasculopathy (n = 16), primary graft failure (n = 5), and acute rejection (n = 1). Two patients with primary graft failure underwent retransplantation within 24 hours of the first transplantation procedure while on extracorporeal membrane oxygenation support. Median time interval to re-CTx for the others was 7.2 years (range, 32 days to 9.4 years). Operative mortality for all cardiac re-CTx procedures was 13.6%. Causes of hospital mortality were pulmonary hypertension with graft failure (n = 2) and multiorgan failure (n = 1). Median hospital stay after re-CTx was 14.1 days (range, 6 to 45 days). There was one late death from severe rejection. Actuarial survival at 3 years for re-CTx was 81.9% +/- 8.9% compared with 77.3% +/- 2.6% for primary cardiac transplantation recipients (p = 0.70). CONCLUSIONS Elective re-CTx can be performed with acceptable mortality. Although the number of patients undergoing retransplantation in this report is small and their long-term outcome is unknown, the intermediate-term survival after re-CTx is similar to that of children undergoing primary cardiac transplantation.

Pediatric Post-Transplant Diabetes: Data From a Large Cohort of Pediatric Heart-Transplant Recipients

A retrospective analysis of 381 pediatric heart‐transplant recipients was performed to determine the frequency, characteristics, and risk factors for post‐transplant diabetes. The rate of post‐transplant diabetes was 1.8% with antithymocyte globulin, cyclosporine and azathioprine as primary immunosuppressive therapy. Time from transplant to diabetes was 0.25–13 years. Diabetes was characterized by reversibility, and lack of insulinopenia and autoimmunity. The post‐transplant diabetes rate in tacrolimus‐converted children (n = 45) was 8.8%. In tacrolimus‐converted children, age at transplant, mean and maximum tacrolimus blood levels, and first‐year rejection episodes were higher in the post‐transplant diabetes group, which also consistently had DR‐mismatched transplants and HLA DR3/DR4 haplotypes. Body mass index was not different between diabetic and control tacrolimus‐converted children. In conclusion, pediatric post‐transplant diabetes may be related to reversible insulin resistance. Tacrolimus levels, HLA DR mismatch, and older age at transplant may predispose to post‐transplant diabetes.

Usefulness of cardiac transplantation in children with visceral heterotaxy (asplenic and polysplenic syndromes and single right-sided spleen with levocardia) and comparison of results with cardiac transplantation in children with dilated cardiomyopathy

Surgical mortality is high in children with visceral heterotaxy (VH), particularly if atrioventricular valve insufficiency, ventricular dysfunction, or aortic atresia is present. This study reviews the outcome of cardiac transplantation (CT) in infants and children with VH and congenital heart disease who are at high risk for standard palliative or corrective surgery. We reviewed CT outcomes in 29 children with VH, congenital heart disease, atrioventricular valve insufficiency, ventricular dysfunction, and/or aortic atresia. Median age at CT was 3.1 years. Cardiac surgery had been performed in 20 patients (69%) before CT. Follow-up since CT has been 8.5 ± 2.2 years. Outcomes were compared with 45 children who underwent transplantation for dilated cardiomyopathy. Actuarial graft survival in the VH group at 30 days and 1, 5, and 10 years was 100%, 86%, 68%, and 50%, respectively, compared with 100%, 96%, 83%, and 68% in children who underwent transplantation for dilated cardiomyopathy (p = 0.12). Splenic status, cardiac position, age at CT, number of prior cardiac surgeries, or systemic venous anomalies were not predictors of mortality after CT. Cardiopulmonary bypass and graft ischemic times were longer in the VH group; time on the ventilator after CT, length of hospitalization, and rejection, infection, post-transplant lymphoproliferative disease, and transplant coronary artery disease rates were equal. Thus, CT is a viable alternative therapy for high-risk patients with VH, possibly offering improved survival over standard surgical management.

Association of Race and Socioeconomic Position with Outcomes in Pediatric Heart Transplant Recipients

We assessed the association of socioeconomic (SE) position with graft loss in a multicenter cohort of pediatric heart transplant (HT) recipients. We extracted six SE variables from the US Census 2000 database for the neighborhood of residence of 490 children who underwent their primary HT at participating transplant centers. A composite SE score was derived for each child and four groups (quartiles) compared for graft loss (death or retransplant). Graft loss occurred in 152 children (122 deaths, 30 retransplant). In adjusted analysis, graft loss during the first posttransplant year had a borderline association with the highest SE quartile (HR 1.94, p = 0.05) but not with race. Among 1‐year survivors, both black race (HR 1.81, p = 0.02) and the lowest SE quartile (HR 1.77, p = 0.01) predicted subsequent graft loss in adjusted analysis. Among subgroups, the lowest SE quartile was associated with graft loss in white but not in black children. Thus, we found a complex relationship between SE position and graft loss in pediatric HT recipients. The finding of increased risk in the highest SE quartile children during the first year requires further confirmation. Black children and low SE position white children are at increased risk of graft loss after the first year.