Treatment of hepatic veno‐occlusive disease in children with N‐acetylcysteine

In our institution, hepatic veno‐occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) has been treated with N‐acetylcysteine (NAC) since 2008—a loading dose of 150 mg/kg, followed by 12 doses of 70 mg/kg 6 hourly. Nine children were diagnosed with hepatic VOD/SOS. Hepatic VOD/SOS occurred in seven children after stem cell transplantation and two were receiving chemotherapy for Wilms tumor. Their clinical severity was classified as moderate in two and severe in seven by the European Society for Blood and Marrow Transplantation criteria. All children recovered and were discharged from 4 to 16 days after diagnosis. No side effects were observed. Intravenous NAC is an effective treatment for hepatic VOD/SOS.     

Autoimmune hemolytic anemia and immune thrombocytopenia following hematopoietic stem cell transplant: A critical review of the literature

Autoimmune cytopenias (AIC) post‐hematopoietic stem cell transplant (HSCT) are rare but exceptionally challenging complication. We conducted a comprehensive literature review and identified a pooled incidence of post‐HSCT autoimmune hemolytic anemia and/or immune thrombocytopenia of 2.66% (SE = 0.27) in pediatric patients. Nonmalignant disease, unrelated donor transplant, peripheral or cord blood stem cell source, conditioning regimen without total body irradiation, and presence of chronic graft‐versus‐host disease were prominent risk factors. Treatment was highly variable, and cytopenias were commonly refractory. AIC represent a significant post‐HSCT complication. We report here the incidence, risk factors, and possible biology behind the development of AIC in pediatric post‐HSCT patients.     

Effects of cryotherapy on high‐dose melphalan‐induced oral mucositis in pediatric patients undergoing autologous stem cell transplantation

Cryotherapy is a conventional method for preventing melphalan‐induced oral mucositis (OM) in adult patients. We retrospectively examined the clinical benefits of cryotherapy in 41 pediatric patients undergoing autologous stem cell transplantation using a melphalan‐etoposide‐carboplatin regimen. Twenty‐two patients received cryotherapy. The cumulative incidence of grade 3‐4 OM was significantly lower in the cryotherapy group (57.1%) than in the noncryotherapy group (89.5%; P = .041). Multivariate analyses identified cryotherapy and the melphalan dose as independent factors for the lower occurrence of OM. The present study demonstrates the clinically significant efficacy of cryotherapy for preventing melphalan‐induced OM in pediatric patients.     

Longitudinal evaluation of liver stiffness in three pediatric patients with veno‐occlusive disease

Liver stiffness measurement by transient elastography is a non‐invasive ultrasound‐based technique used mainly for the evaluation of liver fibrosis in patients with chronic liver diseases. Some authors have suggested that it could be useful in the assessment of hepatic complications during hematopoietic stem cell transplant (HSCT), especially veno‐occlusive disease (VOD) or sinusoidal obstructive syndrome (SOS). Here, we present the evaluation of liver stiffness in three patients who developed severe hepatic VOD/SOS after HSCT. Liver stiffness measurement values were normal before transplant and afterward until the diagnosis of VOD/SOS when a dramatic increase was observed. After the VOD/SOS specific treatment, the values of stiffness showed a similar pattern of progressive reduction in all the three patients, with normalization after two weeks. In this report, we discuss the role of LSM in the management of patients after the diagnosis of VOD/SOS.     

Ocular hemorrhage secondary to thioguanine‐associated veno‐occlusive disease in a child with acute lymphoblastic leukemia in delayed intensification

Hepatic VOD is a potentially fatal complication during stem cell transplantation and is rarely seen in the non‐transplant setting. We report the case of a five‐year‐old boy who presented with visual complaints during delayed intensification phase of treatment for ALL. He was found to have bilateral retinal hemorrhages associated with profound thrombocytopenia due to chemotherapy. VOD was diagnosed based on EBMT criteria and was managed with supportive care. Despite resolution of VOD, his vision progressively deteriorated and resulted in blindness. This case highlights the significance of close monitoring of ALL patients in delayed intensification when they are at risk for developing VOD, the importance of refractory thrombocytopenia as a diagnostic feature and the potential for VOD to manifest with intraocular bleeding.     

Defibrotide for the treatment of hepatic veno‐occlusive disease/sinusoidal obstruction syndrome following nontransplant‐associated chemotherapy: Final results from a post hoc analysis of data from an expanded‐access program

1 Background

Hepatic veno‐occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) but can occur after nontransplant‐associated chemotherapy. Following HSCT, VOD/SOS with multi‐organ dysfunction (MOD) may be associated with >80% mortality. Defibrotide is approved to treat severe hepatic VOD/SOS post‐HSCT in patients aged >1 month in the European Union and hepatic VOD/SOS with renal or pulmonary dysfunction post‐HSCT in the United States. Prior to US approval, defibrotide was available to treat VOD/SOS through an expanded‐access treatment (T‐IND) program. A post hoc analysis of nontransplant‐associated VOD/SOS patients treated with defibrotide initiated within 30 days of starting chemotherapy and followed for 70 days is presented.

2 Procedure

Patients were diagnosed by Baltimore or modified Seattle criteria or biopsy, and received defibrotide 25 mg/kg/day in four divided doses (≥21 days recommended).

3 Results

Of the 1,154 patients in the T‐IND, 137 had nontransplant‐associated VOD/SOS, 82 of whom developed VOD/SOS within 30 days of starting chemotherapy. Of them, 66 (80.5%) were aged ≤16 years. Across all the 82 patients, Kaplan–Meier estimated day +70 survival was 74.1%, 65.8% in patients with MOD (n = 38), and 81.3% in patients without MOD (n = 44). By age group, Kaplan–Meier estimated day +70 survival was 80.1% in pediatric patients (n = 66) and 50.0% in adults (n = 16). Treatment‐related adverse events occurred in 26.8%.

4 Conclusions

In this post hoc analysis of 82 patients initiating defibrotide within 30 days of starting chemotherapy, Kaplan–Meier estimated survival was 74.1% at 70 days after defibrotide initiation. Safety profile was consistent with prior defibrotide studies.     

The value of immunoprophylaxis for cytomegalovirus infection with intravenous immunoglobulin in pediatric liver transplant recipients receiving a low-dose immunosupressive regimen

Krampe K, Briem-Richter A, Fischer L, Nashan B, Ganschow R. The value of immunoprophylaxis for cytomegalovirus infection with intravenous immunoglobulin in pediatric liver transplant recipients receiving a low-dose immunosupressive regimen.
Pediatr Transplantation 2010: 14: 67–71. © 2009 Wiley Periodicals, Inc.
Abstract:  The incidence of CMV infection following pediatric Ltx is particularly high, which can be attributed to the increased number of patients at high risk for primary infection (donor CMV+, recipient CMV−). Current approaches to cope with this complication producing post-operative morbidity include prophylactic or preemptive ganciclovir therapy. As the risk for symptomatic CMV infection is directly correlated with the intensity of immunosuppression, the aim of our study was to assess the value of IVIG in order to protect children receiving low-dose immunosuppression from CMV disease. Twenty-eight consecutive children (median age 62.2 months) at high risk prospectively received three infusions of IVIG on days four, 14, and 28 post-transplant and were monitored for six months post-Ltx. Immunosuppression consisted of cyclosporine (initial trough levels 170–200 μg/L) and prednisolone (starting dose 15 mg/m²) as well as basiliximab induction therapy. Patient survival was 100% and graft survival was 92.9%. Two subjects developed laboratory findings of CMV infection (8%) and one child suffered from tissue invasive CMV disease (4%). Three patients were excluded from the study because of protocol violations. We conclude that there was a low incidence of CMV disease among a prospective cohort receiving low-dose immunosuppression and a standard IVIG product.     

A novel pattern of transaminase elevation associated with autologous transplant for neuroblastoma

To determine the pattern and degree of hepatic transaminitis experienced by children undergoing autologous transplantation for neuroblastoma. Sixty-four children with high-risk neuroblastoma received an autologous transplant with cyclophosphamide, etoposide, and carboplatin conditioning. Forty-eight went on to receive a second transplant with M and TBI conditioning. Charts were reviewed for evidence of hepatic regimen-related toxicity. A high rate of transaminitis was observed after both regimens. In each transplant, there was an early period of transaminitis during conditioning, from which patients recovered, followed by a second period of transaminase elevation. The degree of elevation was not associated with age, whether the administered dose was calculated based on a per kg or per M(2) basis or the presence of regimen-related severe mucositis. Elevated transaminases at admission were not associated with maximal hepatotoxicity during the first transplant although there was an association in the second transplant. However, the magnitude of transaminase elevation was less in the second transplant. VOD occurred in one and three patients in transplants 1 and 2, respectively. Both conditioning regimens were associated with an early and late elevation of transaminases without significant cholestasis. This biphasic pattern of transaminitis has not been reported previously. The high prevalence of transaminase elevation at time of both transplants was not associated with an increased incidence of VOD. We conclude that elevated transaminases should not preclude proceeding to a first or second autologous transplant with these regimens.     

Buying time: The use of extracorporeal membrane oxygenation as a bridge to lung transplantation in pediatric patients

To describe our experience to date of four children with end‐stage lung disease who have been bridged with ECMO to successful lung transplantation in our institution. Between March 2006 and June 2012, a total of 21 pediatric patients successfully underwent lung transplantation within The Alfred's lung transplantation program. This included four children who were bridged on ECMO prior to transplantation according to the “ECMO bridge to transplant” protocol and whose clinical notes and outcomes were reviewed. Lung transplantation is an established life‐saving treatment for patients with severe lung disease, but remains limited due to scarcity of suitable donor organs. This is a particular issue in the pediatric setting, where the smaller child waits disproportionately longer compared with adult patients for size‐matched donor lungs. As ECMO has become more widely accepted, its use as a bridge to lung transplantation in pediatric patients with severe acute lung injury or end‐stage chronic lung disease has been considered. The medical notes from the four pediatric patients were retrospectively reviewed. Our report describes excellent short‐ and medium‐term outcomes in a small number of children who have been bridged to transplant on ECMO.     

Variability in standard care for cytomegalovirus prevention and detection in pediatric lung transplantation: survey of eight pediatric lung transplant programs

Cytomegalovirus (CMV) infection after pediatric lung transplantation is a significant risk factor for morbidity and mortality in the first year after transplantation. Multiple strategies have been reported for CMV prevention among adult lung transplant programs. In contrast, little information has been reported regarding protocols for prevention and detection of CMV from pediatric programs. We conducted a survey to better understand the range of practice patterns for CMV prevention and detection at pediatric lung transplant centers. A self-administered questionnaire was distributed to 11 pediatric lung transplant centers identified through the International Pediatric Lung Transplant Collaborative in September 2002. A member of the lung transplant team from each institution was asked to provide the methods of CMV prevention and surveillance. Eight of 11 centers surveyed responded to the questionnaire accounting for 45.6% (26 of 57) and 100% (three of three) of the pediatric lung transplants performed in the US and UK in 2001, respectively. All centers used prophylactic therapy against CMV with either ganciclovir or valganciclovir with duration ranging from 3.5 wk to indefinitely. Most centers (six of eight) prescribed a prophylactic regimen based on donor and recipient CMV serostatus. Half (four of eight) of the centers report using CMV hyperimmune globulin in addition to an antiviral agent. Method for CMV detection varied widely, including use of conventional viral culture (n = 1), antigenemia (n = 7), and polymerase chain reaction (n = 2). A wide range of strategies is used to prevent and detect CMV in pediatric lung transplant recipients with little empiric evidence demonstrating the optimal approach. A retrospective analysis among these centers is being conducted to evaluate the efficacy of these approaches.     

Invasive fungal infections in pediatric heart transplant recipients: incidence, risk factors, and outcomes

There are limited data on the incidence or risk factors for IFI in pediatric heart transplant recipients. The purpose of this study was to describe the incidence and types of IFI, to determine risk factors for outcomes of IFI, and to assist in decision-making concerning the need for prophylactic strategies in pediatric heart transplant recipients. Data from a multi-institutional registry of 1854 patients transplanted between 01/93 and 12/04 were analyzed to determine risk factors and outcomes of children with IFI post-heart transplantation. One hundred and thirty-nine episodes of IFI occurred in 123 patients and made up 6.8% of the total number of post-transplant infections. IFI was most commonly attributed to yeast (66.2%), followed by mold (15.8%) and Pneumocystis jiroveci (13%). Ninety percent of the yeast infections were caused by Candida spp., and Aspergillus spp. was causative in 82% of the mold infections. There was a significantly increased risk of fungal infection associated with pretransplant invasive procedures (e.g., ECMO, prior surgery, VAD, mechanical ventilation) with an incremental risk with increasing numbers of invasive procedures (early phase 0 vs. 1, RR 1.3; 0 vs. 3, RR 2.3; p<0.001). In multivariate analysis, previous surgery (p=0.05) and mechanical support at transplantation (p=0.01) remained significant. Forty-nine percent of recipients with IFI died, all within six months post-transplant. Invasive fungal infections are uncommon in pediatric heart transplant recipients. Risk and mortality are highest in the first six months post-transplant especially in patients with previous surgery and those requiring mechanical support. Prophylactic strategies for high-risk patients should be considered and warrants further study.     

New approaches to the autosomal recessive polycystic kidney disease patient with dual kidney–liver complications

Improved neonatal medical care and renal replacement technology have improved the long‐term survival of patients with ARPKD. Ten‐yr survival of those surviving the first year of life is reported to be 82% and is continuing to improve further. However, despite increases in overall survival and improved treatment of systemic hypertension and other complications of their renal disease, nearly 50% of survivors will develop ESRD within the first decade of life. In addition to renal pathology, patients with ARPKD develop ductal plate malformations with cystic dilation of intra‐ and extrahepatic bile ducts resulting in CHF and Caroli syndrome. Many patients with CHF will develop portal hypertension with resulting esophageal varices, splenomegaly, hypersplenism, protein losing enteropathy, and gastrointestinal bleeding. Management of portal hypertension may require EBL of esophageal varices or porto‐systemic shunting. Complications of hepatic involvement can include ascending cholangitis, cholestasis with malabsorption of fat‐soluble vitamins, and rarely benign or malignant liver tumors. Patients with ARPKD who eventually reach ESRD, and ultimately require kidney transplantation, present a unique set of complications related to their underlying hepato‐biliary disease. In this review, we focus on new approaches to these challenging patients, including the indications for liver transplantation in ARPKD patients with severe chronic kidney disease awaiting kidney transplant. While survival in patients with ARPKD and isolated kidney transplant is comparable to that of age‐matched pediatric patients who have received kidney transplants due to other primary renal diseases, 64–80% of the mortality occurring in ARPKD kidney transplant patients is attributed to cholangitis/sepsis, which is related to their hepato‐biliary disease. Recent data demonstrate that surgical mortality among pediatric liver transplant recipients is decreased to <10% at one yr. The immunosuppressive regimen used for kidney transplant recipients is adequate for most liver transplant recipients. We therefore suggest that in a select group of ARPKD patients with recurrent cholangitis or complications of portal hypertension, combined liver–kidney transplant is a viable option. Although further study is necessary to confirm our approach, we believe that combined liver–kidney transplantation can potentially decrease overall mortality and morbidity in carefully selected ARPKD patients with ESRD and clinically significant CHF.     

Clinical predictors of autoimmune and severe atopic disease in pediatric heart transplant recipients

Autoimmune and allergic diseases cause morbidity and diminished quality of life in pediatric organ transplant recipients. We hypothesize that younger age at transplantation and immunosuppression regimen play a role in the development of immune‐mediated disease following heart transplant. A single institution retrospective review identified all patients undergoing heart transplant at ≤18 yr of age from 1987 to 2010 who survived ≥1 yr. Using medical record and database review, patients were evaluated for development of autoimmune or severe allergic disease. Of 129 patients who met criteria, seven patients (5.4%) with autoimmune or severe atopic disease were identified. Immune‐mediated diseases included inflammatory bowel disease (n = 3), eosinophilic esophagitis/colitis (n = 4), and chronic bullous disease of childhood (n = 1). Patients <1 yr of age at transplant were at greater risk of developing autoimmune disease than patients 1–18 yr at transplant (OR = 9.3, 95% CI 1.1–79.2, p = 0.02). All affected patients underwent thymectomy at <1 yr of age (7/71 vs. 0/58, p = 0.02). In our experience, heart transplantation in infancy is associated with the development of immune‐mediated gastrointestinal and dermatologic diseases. Further study is needed to determine risk factors for the development of immune‐mediated disease to identify best practices to decrease incidence.     

Preoperative assessment and management of pediatric heart transplantation

The period of preoperative management of the pediatric cardiac transplant patient can be divided into three phases: determination of transplant feasibility, listing, and medical management. Chronic infection, irreversible elevation of pulmonary vascular resistance, and intractable disease in other organ systems may all be contraindications for transplantation. The United Network for Organ Sharing has recently changed its listing guidelines. Adolescent donors are now preferentially, to some extent, allocated to adolescent recipients. Management of pediatric patients awaiting cardiac transplantation encompasses optimization of cardiac output through the use of vasodilators and oral and intravenous inotropic agents. For those patients listed for transplantation who have single ventricle lesions, such as hypoplastic left heart syndrome, management of heart failure also includes balancing systemic and pulmonary blood flows. Mechanical support of the circulation with extracorporeal membrane oxygenation or ventricular assist devices can be used as a bridge to transplant in pediatric patients.     

Marijuana in pediatric and adult congenital heart disease heart transplant listing: A survey of provider practices and attitudes

Despite increasing legalization and use of marijuana, there is no consensus among pediatric heart transplant institutions or providers regarding users' eligibility for cardiac transplant. We sent a survey to pediatric and ACHD transplant providers (physicians, surgeons, transplant coordinators, and pharmacists) assessing their current institution's policies and their personal opinions about marijuana use in patients being considered for heart transplantation. Of the respondents, 84% practice in the United States and Canada. Most providers (80%) care for both pediatric and ACHD patients. Respondents included cardiologists (77%) and surgeons (11%), with the remaining being coordinators and pharmacists. Most providers (73%) reported their institution had no policy regarding marijuana use in heart transplant candidates. Only 20% of respondents' institutions consider mode of consumption, with 87% and 53% approving of oral and transdermal routes, respectively, and only 7% approving of vaporized or smoked routes. While 73% of providers would consider illegal marijuana use an absolute/relative contraindication to heart transplant listing, the number decreases to 57% for legal recreational users and 21% for legal medical users. Most providers personally believe marijuana to be physically and mentally/emotionally harmful to pediatric patients (67% and 72%, respectively). Many institutions lack a policy regarding marijuana use in pediatric and ACHD heart transplant candidates, and there is considerable disagreement among providers on the best practice. With increasing legalization and use of marijuana, each institution will have to address this issue thoughtfully to continue to provide high‐quality, consistent, and equitable care for pediatric and ACHD heart transplant candidates.     

New insights into family functioning and quality of life after pediatric liver transplantation

Denny B, Beyerle K, Kienhuis M, Cora A, Gavidia‐Payne S, Hardikar W. New insights into family functioning and quality of life after pediatric liver transplantation. Abstract: Thorough research of the medical aspects of pediatric liver transplantation has given way to recent interest in the impact of the transplantation process on the QOL of recipients and their families. In this cross‐sectional study, we compared the family functioning and QOL of children (n = 30) aged between three and 16 yr (M = 10.10, s.d. = 3.62) who had received a liver transplant in the previous 1–12 yr (M = 5.31, s.d. = 3.44) with non‐transplant children (n = 33), as reported via parent proxy. Results showed that parents of pediatric liver transplant recipients made significantly more adjustments to family routines to accommodate their children, particularly in relation to childcare. Impaired family functioning was also found to be associated with decreased QOL. These preliminary findings of relative deficits in family functioning may inform psychosocial interventions to assist pediatric liver transplant patients and their families. Further investigation beyond a single‐center study incorporating subjective information from pediatric patients and their parents is recommended.     

Antithrombotic management and thrombosis rates in children post–liver transplantation: A case series and literature review

Thrombosis is a major postoperative complication in pediatric liver transplantation. There is marked heterogeneity in prophylactic antithrombotic therapies used, without established guidelines. This review summarizes current worldwide incidence of thrombotic events and compares antithrombotic therapies in children post–liver transplant, with comparison to our institution's experience. Of the twenty‐three articles with sufficient detail to compare antithrombotic regimens, the overall incidence of thrombosis ranged from 2.4% to 17.3%. Incidence of HAT ranged from 0% to 28.1%, of HVT from 0% to 4.7%, of PVT from 1.5% to 11.2%, and of IVC thrombosis from 0% to 2.8%. Re‐transplantation due to thrombosis ranged from 0% to 4.8%. Prophylactic antithrombotic therapies varied between studies, and bleeding complications were infrequently reported. Since 2010, 96 children underwent 100 liver transplants at our institution with thrombosis incidence comparable to international literature (HAT 6%, PVT 5%, IVC 1%, and HVT 0%). Re‐transplantation due to thrombosis occurred in 2% and major bleeding occurred in 10%. The prophylactic antithrombotic therapies used post–liver transplantation in children remain varied. Low rates of thrombosis have been reported with antiplatelet use both with and without anticoagulation. Standard definitions and consistent reporting of bleeding complications are required, in addition to thrombosis rates, so that true risk‐benefit assessment of reported regimes can be understood.     

Acute lower limb ischemia following pediatric renal transplantation

Goldsmith PJ, Fraser SM, Fitzpatrick M, Scott DJ, Ahmad N. Acute lower limb ischemia following pediatric renal transplantation.
Pediatr Transplantation 2010: 14:E93–E95. © 2009 John Wiley & Sons A/S. Abstract: Live donor renal transplantation remains the best treatment option for end stage renal failure in pediatric patients ( 1 - 3 ). Better understanding of the hemodynamics of donor–recipient size discrepancy and advances in interventional techniques with improved surgical techniques have decreased the incidence and severity of surgical complications and enhanced graft survival ( 1 , 2 ). We describe a rare complication occurring intra‐operatively in a pediatric renal transplant resulting in acute limb ischemia and the surgical option taken.     

Outcome after kidney transplantation in children with thrombotic risk factors

BACKGROUND: According to the data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS), vascular thrombosis accounts for 11.6% of graft losses in pediatric renal transplantation. In adults, inherited and acquired thrombophilic risk factors, e.g. factor V Leiden mutation, have been associated with early graft loss and increased rejection episodes. Data on the impact of these factors on the outcome of children after renal transplantation are rare. METHODS/PATIENTS: Sixty-six pediatric patients awaiting renal transplantation (mean age 10.1 yr) were screened for inherited and acquired risk factors for hypercoagulable disorders (protein C, S, and antithrombin III deficiency, antiphospholipid antibodies, factor V Leiden, prothrombin, and MTHFR mutation) in order to intensify anticoagulation in those with an increased risk for thrombophilia: intravenous heparin was administered with a partial prothrombin time (PTT) prolongation of 50 s for 14 days and switched to low-molecular-weight heparin for another 8 wk before aspirin was introduced for the first year. Patients without hypercoagulable risk factors were treated with heparin without PTT prolongation for 14 days and switched to aspirin immediately afterwards. The results on graft survival, incidence of acute rejection episodes, and long-term renal graft function were analyzed between recipients with and without hypercoagulable risk factors. RESULTS: Thrombophilic risk factors were identified in 27.3% of our patients. No thrombosis occurred. One serious bleeding complication led to a second surgical intervention. The rate of acute rejection episodes was not increased in patients with and without thrombotic risk factors after 90 days (16.7 vs. 25%), 1 yr (22.2 vs. 33.3%), and 3 yr (38.9 vs. 41.7%) of follow-up, respectively (p = n.s.). After a mean follow-up of 3 yr the kidney function was comparable in both groups, with 63.1 in recipients with and 69.8 mL/min/1.73 m(2) in recipients without hypercoagulable risk (p = n.s.). At latest follow-up, three graft losses were found not to be attributed to thrombotic risk factors. INTERPRETATION: Children with thrombophilic risk factors were identified and treated with an intensified anticoagulation regimen after renal transplantation. An increased risk for graft failure, acute rejection episodes, or impaired renal function for pediatric renal transplant recipients with hypercoagulable status was not found.