Myocyte growth, repair, and oxidative stress following pediatric heart transplantation.

Cardiac remodeling is associated with plasma biomarkers of fibrinogenesis, inflammation, and oxidative stress, and upregulation of mitogenic, pro-fibrotic, and apoptotic signaling pathways. Our primary objective was to evaluate biomarker and subcellular myocardial changes in pediatric heart transplant recipients. Fifty-two-week prospective, randomized (tacrolimus, Tac, vs. cyclosporine, CsA), open-label, parallel group study. Serial myocardial biopsies were probed for mitogenic and pro-inflammatory proteins. Plasma biomarkers of oxidative stress (F2α isoprostanes, nitrotyrosine), and inflammation and oxidation (hsCRP and cystatin-C) were measured. Nine of 11 randomized patients completed the study (four Tac, five CsA). Mean levels of F2α isoprostanes, hsCRP, and cystatin-C were maximal at Week 2. Peak activation of all MAP kinases in myocardial tissue was maximal at Week 10; no association was seen with rejection. Cardiac Bax/Bcl-2 levels (index of apoptosis) correlated negatively with F2α isoprostanes at Week 2 (r = -0.88) and with hsCRP at Week 52 (r = -0.67). At Week 52, hsCRP levels correlated positively with molecular indices of cardiac cell growth. We found evidence of systemic and myocardial oxidative damage and inflammation early posttransplant, which may be related to the remodeling process. Further study is needed to better understand the cardiac and systemic repair processes following pediatric heart transplantation.

Effect of acute graft-versus-host disease on the outcome of second allogeneic hematopoietic stem cell transplant in children.

Studies have shown second allogeneic hematopoietic stem cell transplant (HSCT) to have a potential role in treating relapse after HSCT. We sought to evaluate the outcome of second allogeneic HSCT for children with relapsed leukemia with focus on factors that potentially improve outcome. Thirty-eight children were identified. The median time between transplants was 18.6 months (range 6.7-50.1 months). With median follow-up of 44 months the 2-year overall survival (OS) was 59.1 ± 8.2%. The leukemia-free survival was 51.8 ± 8.2% and the non-relapse mortality 30.8 ± 7.9%. Eleven patients (30%) died of non-relapse mortality at a median of 37 days (range 16-260 days) from second HSCT. Twenty-one patients developed acute graft-versus-host disease (aGVHD) after second HSCT. Patients who developed aGVHD had lower risk for mortality compared to patients who did not have aGVHD, with a hazard ratio (HR) of 0.27 (95% confidence interval [CI] 0.095-0.788, p-value 0.0163). Similarly, patients who developed aGVHD following second HSCT had lower risk for relapse (HR = 0.21, 95% CI 0.051-0.857, p-value 0.0297). Patients who developed aGVHD after first HSCT were less likely to benefit from second HSCT compared to patients without aGVHD after first HSCT. Our experience suggests that second HSCT for pediatric relapsed leukemia can result in acceptable survival and aGVHD is associated with improved outcome.

Body image and eating attitudes and behaviors among adolescent heart and lung transplant recipients: a brief report.

BACKGROUND: Adolescents with chronic illnesses are at increased risk for body image and eating disorders; however, this has not been investigated in solid organ transplant recipients. Adolescent transplant recipients are a vulnerable cohort because of the sustained follow-up and immune-suppressing therapies, which often include steroids and may lead to weight gain and cosmetic changes. Consequences of body dissatisfaction such as disordered behaviors have not been well studied in transplant recipients. PURPOSE: To examine body image, eating attitudes, and behaviors among 28 adolescent thoracic transplant recipients. METHODS: Adolescent (11-18 years old) heart and lung transplant recipients a minimum of 3 months after transplant provided informed written consent and completed a standardized questionnaire package about eating attitudes and behaviors; body image and drive for thinness; actual, perceived, and desired weight; and medical and anthropometric information (eg, body mass index) during regular transplant clinics. RESULTS: Of 25 heart and 3 lung transplant recipients (54% female; median age, 14.5 years; median, 1.6 years after transplant), 37% perceived their current weight as too high or low. Moreover, 81% were dissatisfied with their current weight (38% wanted to lose and 44% wanted to gain weight), yet few engaged in disordered behaviors. CONCLUSIONS: Despite high levels of self-reported body dissatisfaction, low rates of disordered behaviors were observed. Weight dissatisfaction was high (81%) but bidirectional (to lose or to gain weight). Future assessment of disordered eating behaviors should include insidious activities such as medication nonadherence, in addition to traditional weight-control behaviors such as binge eating, strict dieting, or assiduous exercise. Further research will delineate the impact of body dissatisfaction and eating behaviors and outcomes on long-term transplant survivors, older adolescent cohorts, and other recipients of solid organ transplants.

Post-transplant lymphoproliferative disorder in pediatric heart transplant recipients.

BACKGROUND: Post-transplantation lymphoproliferative disorder (PTLD) is a major cause of morbidity and mortality after pediatric heart transplantation. METHODS: Heart transplant recipients at The Hospital for Sick Children, Toronto, from 1990 to May 2008, were reviewed. Competing risk hazard analysis was used to model the natural history of the disease. Patients were matched for gender and duration of follow-up to identify potential covariates associated with increased risk of PTLD. RESULTS: A total of 173 heart transplant recipients (42% <1 year old) were reviewed. Twenty-three developed PTLD at a median of 4 years post-transplantation. After transplantation, PTLD affected 9%, 15% and 28% at 3, 5 and 10 years, respectively. Freedom from death or PTLD recurrence was 72%, 58% and 50% at 1, 3 and 5 years, respectively, after PTLD diagnosis. Higher maximum Epstein-Barr viral (EBV) load (hazard ratio [HR]: 2.6, p = 0.004) and longer duration of induction therapy (HR: 1.7, p = 0.02) were associated with increased risks of PTLD. Higher cumulative cyclosporine doses over the first year post-transplantation were associated with increased risks of PTLD (HR: 1.2 per 1 mg/kg/day equivalent, p = 0.03), but higher tacrolimus doses were not (p = 0.38). Patients on cyclosporine at 6 months post-transplantation were at higher risk of PTLD than those on tacrolimus (HR: 5.2, p = 0.003). The use of anti-viral prophylaxis in patients with high EBV load may provide some protection (HR: 7.6 vs 15.4 with no anti-viral, p = 0.02). CONCLUSIONS: PTLD is a major concern in pediatric heart transplant recipients and is associated with high morbidity/mortality. Exposure to EBV and higher intensity of immunosuppression seems to be associated with increased risk.

Pediatric heart transplantation in human leukocyte antigen sensitized patients: evolving management and assessment of intermediate-term outcomes in a high-risk population.

BACKGROUND: There is an elevated risk for poor outcomes after heart transplant (HTx) in patients sensitized to human leukocyte antigens including graft dysfunction, acute cellular and antibody-mediated (AMR) rejection, and cardiac allograft vasculopathy. We report our experience with human leukocyte antigens-sensitized pediatric HTx recipients. METHODS AND RESULTS: We identified pediatric HTx patients with elevated pre-HTx Panel Reactive Antibody (Class I/II; > 10%), or a positive T- or B-cell crossmatch. Thirteen patients met criteria (5 female, 39%). The median age at HTx was 7 months (3.5 months to 15.5 years). Nine were infants who had prior palliation for congenital heart disease. Four were older patients (median 7.3 years; 4.8 to 15.5 years): 2 had congenital heart disease (Fontan), 2 were re-HTx. B-cell therapies were used in all patients, guided by assessment of CD19+ and CD20+ cells. Immunosuppression included thymoglobulin induction, and tacrolimus, mycophenolate mofetil, and steroids. Daily plasmapheresis +/- intravenous immunoglobulin G was used if there was a positive crossmatch on day 1, with a gradual, biopsy-guided weaning schedule. Rituximab was used when AMR was detected on biopsy: more recently (n=3), used empirically perioperatively. AMR was confirmed in 9 patients within median 0.9 months post-HTx. Seven had early acute cellular rejection (> or = ISHLT Grade 2 R) with no hemodynamic compromise or graft dysfunction. There were 4 deaths post-HTx (range, 11 days to 9 months). The median follow-up of 9 survivors was 1.7 years (0.3 to 3.7 years). Of 7 patients > 6 months post-HTx, no AMR or cardiac allograft vasculopathy was observed at a mean of 1.9+1.1 years post-HTx and no cardiac allograft vasculopathy. CONCLUSIONS: Despite aggressive management, acute cellular rejection and AMR occurred frequently early post-HTx. An algorithm of B cell-directed strategies can be effective in managing these patients with reasonable intermediate-term outcomes.

Air travel in women with lymphangioleiomyomatosis.

BACKGROUND AND OBJECTIVE: The safety of air travel in patients with pneumothorax-prone pulmonary diseases, such as lymphangioleiomyomatosis (LAM), has not been studied to any great extent. A questionnaire-based evaluation of air travel in patients with LAM was conducted to determine experiences aboard commercial aircraft. METHODS: A survey was sent to women listed in the US LAM Foundation registry (n = 389) and the UK LAM Action registry (n = 59) to assess air travel, including problems occurring during flight. Women reporting a pneumothorax in flight were followed up to ascertain further details about the incident. RESULTS: 327 (73%) women completed the survey. 308 women answered the travel section, of whom 276 (90%) had "ever" travelled by aeroplane for a total of 454 flights. 95 (35%) women had been advised by their doctor to avoid air travel. Adverse events reported included shortness of breath (14%), pneumothorax (2%, 8/10 confirmed by chest radiograph), nausea or dizziness (8%), chest pain (12%), unusual fatigue (11%), oxygen desaturation (8%), headache (9%), blue hands (2%), haemoptysis (0.4%) and anxiety (22%). 5 of 10 patients with pneumothorax had symptoms that began before the flight: 2 occurred during cruising altitude, 2 soon after landing and 1 not known. The main symptoms were severe chest pain and shortness of breath. DISCUSSION AND CONCLUSION: Adverse effects occurred during air travel in patients with LAM, particularly dyspnoea and chest pain. Hypoxaemia and pneumothorax were reported. The decision to travel should be individualised; patients with unexplained shortness of breath or chest pain before scheduled flights should not board. Patients with borderline oxygen saturations on the ground should be evaluated for supplemental oxygen therapy during flight. Although many women had been advised not to travel by air, most travelled without the occurrence of serious adverse effects.

Patient perspectives on management of pneumothorax in lymphangioleiomyomatosis.

STUDY OBJECTIVES: The American College of Chest Physicians Delphi Consensus Statement on management of spontaneous pneumothorax recommended pleurodesis after the first secondary spontaneous pneumothorax to prevent recurrence, and evaluation of patients' perspectives regarding pneumothorax treatment was identified as a future research priority. Patients with lymphangioleiomyomatosis (LAM) are an ideal population for performing these studies, since pneumothorax occurs and recurs more commonly in LAM than in any other chronic pulmonary disorder. STUDY DESIGN AND PARTICIPANTS: A 23-item questionnaire evaluating opinions of pneumothorax treatment was distributed to 615 patients in the LAM Foundation patient database, with a response rate of 52%. RESULTS: Of respondents, 69% (216 of 314 patients) reported a history of radiographically documented pneumothorax, and 181 patients (84%) reported at least one pleurodesis procedure. Neither a history of pneumothorax nor surgical management of pneumothorax affected reported oxygen use or perception of overall lung function, yet 41% thought that their pneumothorax had contributed to a decline in lung function. Few patients (12%) worried frequently about a pneumothorax developing, but one third made lifestyle modifications due to fear of pneumothorax. Extensive pain associated with chest tube placement and inadequate pain management throughout treatment for pneumothorax were frequent concerns. Only 25% of respondents thought that pleurodesis was appropriate for a first pneumothorax, while 60% favored pleurodesis for a second pneumothorax. Despite the apparent reluctance to undergo pleurodesis, most patients agreed that pleurodesis helps prevent pneumothorax recurrence. One third of patients believed that their physicians did not consider their preferences regarding pneumothorax management. CONCLUSIONS: LAM patients and physicians may have different views about the significance of pneumothorax, in that most patients appear to favor a conservative initial approach to pneumothorax management. In conjunction with appropriate pain management, a better understanding of patients' perspectives will facilitate cooperative decision making and may ultimately improve clinical outcomes in LAM related to pneumothorax.

Impact on outcomes after listing and transplantation, of a strategy to accept ABO blood group-incompatible donor hearts for neonates and infants.

BACKGROUND: Recent data suggest that ABO blood group-incompatible donor hearts are immunologically well tolerated in infants undergoing transplantation. METHODS: Competing-risks methodology was used to assess outcomes after listing and the impact of a strategy to accept heart grafts from any blood group donor for infants less than 18 months of age. RESULTS: From 1992 to 2002, there were 91 listing episodes in 84 patients (including 20 fetuses; 50% were male and 63% had congenital heart disease). Beginning in 1995, a strategy to accept ABO-incompatible organs was adopted. Competing-risks analysis showed that after 20 months 60% underwent transplantation, 18% died, and less than 1% were still listed; the remaining 21% were de-listed because of a change of surgical strategy (9%), improved clinical condition (8%), and deterioration to ineligibility (4%). Risk factors for transplantation included only a strategy to accept ABO-incompatible organs (P <.001). Risk factors for death included failure to accept ABO-incompatible organs (P =.002) and Canadian listing status 3 (P =.085) or 4 (P <.001). Multivariable parametric models were used to create competing risk predictions for outcomes specific to status and ABO-incompatible strategy. Higher status resulted in greater mortality regardless of strategy, although for any status, more patients underwent transplantation and fewer died using a strategy to accept ABO-incompatible organs. Parametric modeling of time-related freedom from death or retransplantation demonstrated no significant difference at 4 years posttransplantation (P =.78) for ABO-incompatible (74%) versus ABO-compatible transplants (72%). CONCLUSIONS: A strategy to accept ABO-incompatible donor hearts for infant transplantation significantly improves the likelihood of transplantation and reduces waiting list mortality while not adversely altering outcomes after transplantation.

Patients' perceptions versus medical testing of function in women with lymphangioleiomyomatosis (LAM).

Lymphangioleiomyomatosis (LAM), a rare pulmonary disease that occurs primarily in women is characterized by progressive cystic lung lesions causing respiratory failure, which may require lung transplantation. It has been observed that in diseases of the lungs, objective medical tests frequently do not translate to subjective functional status. However, patient's perceptions of functional status directly impact quality of life. In order to evaluate this relationship in LAM, a cross sectional study of 31 lung transplant candidates and 43 lung transplant recipients with LAM was conducted to evaluate functional status. Objective tests (Pulmonary function tests, PFTs, 6 min walk) were obtained in 19 candidates and 23 recipients, and subjective function was assessed in all women using the Functional Performance Inventory. For both groups statistically significant relationships emerged between forced vital capacity with subjective measures of function including total, social and recreational function (P < 0.05). As well diffusing capacity related significantly to total function, ability to maintain household chores, body care, and social function (P < 0.05), where higher scores were associated with better subjective function. Forced expiratory volume in one second was not found to significantly relate to subjective function in these groups, except the physical exercise domain in transplant recipients. However, despite better PFT results in double lung transplant recipients, no differences were found in subjective measures of function between single and double lung recipients. Results suggest that clinicians need to better recognize that certain aspects of spirometry/6 min walk tests do not necessarily correlate well with patient's perceptions of their function. This has implications for the assessment and follow-up of women living with LAM; considering subjective aspects of function may help focus interventions and improve quality of life.

Canadian respirologists' experience with lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare pulmonary disease occurring primarily in women. A literature review of LAM in Canada found sporadic mention of LAM in case reports or within lung transplant studies. The LAM Foundation, a patient support and research funding organization, lists 23 Canadian patients in its database. The present study was designed to assess the scope of LAM across Canada and to identify potential patients for further evaluation. OBJECTIVES: To ascertain Canadian respirologists' experience with patients with LAM (current and historical), lung transplantation (single or bilateral) and deaths due to LAM, and awareness of the LAM Foundation. METHODS: Four hundred twelve brief surveys were sent anonymously to members of the Canadian Lung Association (inserted in their newsletters) to ascertain the experience of Canadian respirologists with LAM. RESULTS: One hundred twelve surveys were returned (27%). Fifty-one respondents had "ever" been involved in the care of at least one patient with LAM; eight had cared for three or more patients. At the time of the study, 26 respondents were following a total of 46 patients with LAM; 22 of the 51 respirologists (43%) who had ever cared for a patient with LAM reported the death of a patient. Thirty-three patients had been put on wait lists for transplantation; six died while on the wait list. Nineteen patients underwent lung transplantation--six single-lung recipients and 13 bilateral lung recipients. Of the 51 respirologists who had ever cared for a patient with LAM, only 30 (61%) were aware of the LAM Foundation's services. Of the 112 respondents, only 47 (43%) were aware of the LAM Foundation. CONCLUSIONS: This study identified a moderate level of awareness of a significant existing patient support and research service (the LAM Foundation). There were many patients with LAM who were unknown to the LAM Foundation and could benefit from its resources. Results suggest that there may be more patients with LAM in Canada than are reported in the existing literature.