Heinrich Netz

CNS or Bone Marrow Involvement As Risk Factors for Poor Survival in Post-Transplantation Lymphoproliferative Disorders in Children After Solid Organ Transplantation

PURPOSE To identify prognostic factors of survival in pediatric post-transplantation lymphoproliferative disorder (PTLD) after solid organ transplantation. PATIENTS AND METHODS A multicenter, retrospective case analysis of 55 pediatric solid organ graft recipients (kidney, liver, heart/lung) developing PTLD were reported to the German Pediatric-PTLD registry. Patient charts were analyzed for tumor characteristics (histology, immunophenotypes, cytogenetics, Epstein-Barr virus [EBV] detection), stage, treatment, and outcome. Probability of overall and event-free survival was analyzed in defined subgroups using univariate and Cox regression analyses. RESULTS PTLD was diagnosed at a median time of 29 months after organ transplantation, with a significantly shorter lag time in liver (0.83 years) versus heart or renal graft recipients (3.33 and 3.10 years, respectively; P = .001). The 5-year overall and event-free survival was 68% and 59%, respectively, with 59% of patients surviving 10 years. Stage IV disease with bone marrow and/or CNS involvement was associated independently with poor survival (P = .0005). No differences in outcome were observed between early- and late-onset PTLD, monomorphic or polymorphic PTLD, and EBV-positive or EBV-negative PTLD, respectively. Patients with Burkitt or Burkitt-like PTLD and c-myc translocations had short survival (< 1 year). CONCLUSION Stage IV disease is an independent risk factor for poor survival in pediatric PTLD patients. Prospective multicenter trials are needed to delineate additional risk factors and to assess treatment approaches for pediatric PTLD.

Relation of Increased Short-Term Variability of QT Interval to Congenital Long-QT Syndrome

Apart from clinical symptoms the diagnosis and risk stratification in long-QT syndrome (LQTS) is usually based on the surface electrocardiogram. Studies have indicated that not only prolongation of the QT interval but also an increased short-term variability of QT interval (STV(QT)) is a marker for a decreased repolarization reserve in patients with drug-induced LQTS. The aims of this study were to determine if STV(QT) (1) is higher in patients with LQTS compared with controls, (2) if this effect is more pronounced in a high-risk LQTS population, and (3) could increase the diagnostic power of the surface electrocardiogram in identifying mutation carriers. Forty mutation carriers were compared with age- and gender-matched control subjects in the absence of beta-receptor-blocking agents. Lead II or V(5) RR and QT intervals from 30 consecutive beats were manually measured. STV(QT) was determined from Poincaré plots of QT intervals (STV(QT) = Sigma|QTn + 1 - QTn|/[30 x radical2]). Compared with controls, patients with LQTS had a prolonged QTc interval (449 +/- 41 vs 411 +/- 32 ms, p = 0.00049) and increased STV(QT) (6.4 +/- 3.2 vs 4.1 +/- 1.6 ms, p = 0.005). In patients with the highest risk of clinical events, defined as a QTc interval >500 ms or symptoms before beta-blocker therapy, STV(QT) was 9 +/- 4 ms. QTc interval had a sensitivity of 43% and a specificity of 97% in identifying mutation carriers (thresholds 450 ms for men and 460 ms for women). Receiver operator characteristic analysis showed that an STV(QT) of 4.9 ms was the optimal cut-off value to predict mutation carriers. When incorporating an STV(QT) >4.9 ms for those whose QTc interval was within the normal limits, sensitivity to distinguish mutation carriers increased to 83% with a specificity of 68%, so that another 15 mutation carriers could be identified. In conclusion, these are the first results in humans showing that STV(QT) is increased in congenital LQTS, this effect is increased in patients with symptoms before therapy, and, hence, STV(QT) could prove to be a useful noninvasive additive marker for diagnostic screening to bridge the gap before results of genetic testing are available.

The effect of cardiovascular risk factors on the longitudinal evolution of the carotid intima medial thickness in children with type 1 diabetes mellitus

BackgroundType 1 diabetes mellitus is a generally accepted atherogenic risk factor. The aim of this prospective longitudinal study was to evaluate changes in carotid intima media thickness (cIMT) in children and adolescents with type 1 diabetes mellitus (T1DM) using standardized methods.MethodsWe re-evaluated cIMT in 70 (38 f) of initial 150 (80 f) patients with T1DM after 4 years. At re-evaluation, mean (± SD) age was 16.45 ± 2.59 y, mean diabetes duration was 9.2 ± 3.24 y and patients had a mean HbA1c of 8.14 ± 1.06%.ResultsMean cIMT z-scores increased significantly during 4 years (0.58 ± 0.75, p < 0.001) as well as BMI-z-score (0.41 ± 0.81, p < 0.01), systolic blood pressure (0.77 ± 1.15, p < 0.01) and HbA1c (0.90 ± 1.07, < 0.001). In a linear regression model systolic blood pressure z-score at first measurement (0.02, CI: 0.01, 0.04) was a significant predictor for the mean effect on cIMT z-score. In a logistic regression model significant risk factors for an increase in IMT of ≥1.5 z-scores were BMI z-scores (OR: 3.02, CI:1.11, 10.14), diabetes duration (OR:1.32, CI:1.04, 1.77) and systolic blood pressure (OR: 1.14, CI: 1.04, 1.27) at first measurement each.ConclusionsLongitudinal cIMT measurements revealed progression in subclinical atherosclerosis during a four year period in diabetic children and adolescents. Systolic blood pressure and BMI were related to cIMT increment. Control of these risk factors by lifestyle and medical intervention may prevent progression of cIMT in diabetic children.

A post-receptor defect of adenylyl cyclase in severely failing myocardium from children with congenital heart disease.

The aim of this study was to determine whether a defect at the post-receptor level of adenylyl cyclase may also contribute to the decreased effectiveness of cAMP-increasing agents in severely failing patients with congenital heart disease. The severity of congestive heart failure in 31 patients with congenital heart disease was graded by a scoring system which included a description of historical and clinical variables. Patients were divided into a group with no or mild heart failure (score < or = 6) and a group with severe heart failure (score > 6). beta-Adrenoceptor-stimulated adenylyl cyclase activity was significantly decreased by 65% in patients with severe heart failure in comparison to the group of patients with no or mild heart failure. In addition, receptor-independent adenylyl cyclase stimulation by forskolin was reduced by 52% in patients with score > 6 compared to patients with score < or = 6. This post-receptor defect of adenylyl cyclase was apparently due to a decrease in the activity of catalytic subunit of adenylyl cyclase as adenylyl cyclase stimulation by forskolin in the presence of Mn2+ which uncouples catalytic subunit from the G proteins, G(s) and G(i), was also significantly diminished in the patients with severe heart failure. In contrast, the level of inhibitory G protein alpha-subunits was apparently not different in the two groups. In summary, the data indicate that a defect at the catalytic subunit of adenylyl cyclase apparently contributes to the decreased effectiveness of cAMP-increasing agents in severely failing patients with congenital heart disease.

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.

Distribution of Myocardial β‐Adrenoceptor Subtypes and Coupling to the Adenylate Cyclase in Children With Congenital Heart Disease and Implications for Treatment

In congestive heart failure, down‐regulation of myocardial β‐adrenoceptors (β‐AR) due to an elevated sympathetic tone is well known. In infancy and childhood, heart failure is usually related to congenital heart disease (CHD). Therefore, 71 samples of right atrial tissue of infants and children with CHD undergoing cardiac surgery were studied for β‐adrenoceptor density and distribution of the β1‐/β2‐AR subtypes. In 49 cases, the coupling of the β‐AR to the adenylate cyclase (AC) was examined. In a further study of 19 myocardial samples, AC was selectively stimulated with β1‐ or β2‐AR whereas the other subtype was blocked by an antagonist. The following results were obtained: (1) Infants and children with severe acyanotic or cyanotic CHD had severely reduced β‐AR densities. (2) In most of the cases, the β‐AR down regulation is β1‐subtype selective, but in critically ill newborns with congenital aortic valve stenosis or transposition of the great arteries, there is additional significant β2‐AR down‐regulation. In Fallot patients treated with the β‐antagonist propranolol, a significant increased β‐AR number compared with untreated Fallot patients was found. (3) β‐Adrenoceptor reduction in CHD is correlated with elevated noradrenaline plasma levels, thus proving a sympathetic dysregulation. (4) In CHD with moderate hemodynamic load, β2‐AR coupling to AC was markedly more efficient than β1‐AR coupling. The small number of myocardial β2‐AR produced most of the cyclic adenosine monophosphate. (5) In severe acyanotic and cyanotic CHD, a partial decoupling of the β2‐AR to the AC occurred. This may be a first step before β2‐AR are reduced in number in severe cardiac failure. These results explain why catecholamine therapy in in/ants and children with CHD sometime fails. Because the contractile force can be increased by β2‐AR, partial β2‐agonists may improve cardiac performance in acute heart failure. The most appropriate drugs are those that modulate or bypass the neurohumoral pathomechanisms in chronic heart failure like angiotensin‐converting enzyme‐inhibitors, β‐AR antagonists, dopamine2‐agonists, and phosphodiesterase‐inhibitors. Further studies are needed to validate the actions of these therapeutics in infants and children with CHD.

Absence of Donor-Specific Anti-HLA Antibodies after ABO-Incompatible Heart Transplantation in Infancy – Altered Immunity or Age?

Specific B‐cell tolerance toward donor blood group antigens develops in infants after ABO‐incompatible heart transplantation, whereas their immune response toward protein antigens such as HLA has not been investigated. We assessed de novo HLA‐antibodies in 122 patients after pediatric thoracic transplantation (28 ABO‐incompatible) and 36 controls. Median age at transplantation was 1.7 years (1 day to 17.8 year) and samples were collected at median 3.48 years after transplantation. Antibodies were detected against HLA‐class I in 21 patients (17.2%), class II in 18 (14.8%) and against both classes in 10 (8.2%). Using single‐antigen beads, donor‐specific antibodies (DSAs) were identified in six patients (all class II, one additional class I). Patients with DSAs were significantly older at time of transplantation. In patients who had undergone pretransplant cardiac surgeries, class II antibodies were more frequent, although use of homografts or mechanical heart support had no influence. DSAs were absent in ABO‐incompatible recipients and class II antibodies were significantly less frequent than in children with ABO‐compatible transplants. This difference was present also when comparing only children transplanted below 2 years of age. Therefore, tolerance toward the donor blood group appears to be associated with an altered response to HLA beyond age‐related effects.

Successful ABO-incompatible heart transplantation in two infants

In the pediatric age group shortage of donor hearts leads to mortality rates of 30–50% on the waiting list. Because of the immaturity of the immune system of infants, ABO‐incompatible heart transplantation may be an option to increase donor availability. We transplanted two infants with blood type O at the age of 7 and 5 months, respectively, with complex congenital heart disease. Intraoperative plasma exchange was performed during cardiopulmonary bypass followed by standard immunosuppression. Both recipients received a blood type A donor organ. Plasma was exchanged up to six times until anti‐A antibodies were eliminated. No hyperacute rejection occurred, ventricular function is excellent and there have been no acute rejection episodes up to 4 months after transplantation. Anti‐A antibody titers remained low and eventually disappeared. ABO‐incompatible cardiac transplantation shows good short‐term results in young infants and appears to be a safe procedure to reduce mortality on the waiting list.

Subclinical atherosclerosis in diabetic children: results of a longitudinal study.

Dalla Pozza R, Netz H, Schwarz HP, Bechtold S. Subclinical atherosclerosis in diabetic children: results of a longitudinal study.

Interleukin-6 and procalcitonin in serum of children undergoing cardiac surgery with cardiopulmonary bypass.

Objective — The aim of our study was to investigate the systemic inflammatory response in children with congenital heart disease undergoing surgical correction with cardiopulmonary bypass. We wanted to discuss interleukin 6 and procalcitonin as components of the systemic inflammatory response syndrome to cardiopulmonary bypass and evaluate postoperative kinetics of these parameters in case of an uncomplicated course. Methods — Procalcitonin and interleukin 6 were determined before and after cardiopulmonary bypass surgery in 37 children on the day of surgery, the first and fourth postoperative day. The increased procalcitonin and interleukin 6 levels were evaluated in relationship to intraoperative variables such as duration of aortic cross clamping, incisional trauma and cardiac bypass temperature. Results — Peak levels of procalcitonin were detected on the first postoperative day, while interleukin 6 reached its highest values on the day of surgery. In contrast to interleukin 6 the median values of procalcitonin differed significantly between short versus long aortic clamping time and atriotomy versus ventriculotomy. Interleukin 6 reached normal levels on the fourth postoperative day, while procalcitonin was still clearly above normal. Conclusions — Serum concentrations of procalcitonin and interleukin 6 were influenced by systemic inflammatory response syndrome following cardiac surgery with cardiopulmonary bypass. Even in case of an uncomplicated course both parameters were elevated for at least four days.While procalcitonin serum concentrations were dependent on aortic clamping time or incisional trauma, interleukin 6 showed no significant relation with these intraoperative variables.