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Fungal infections create a significant risk to pediatric lung transplant recipients. However, no international consensus guidelines exist for fungal infection prevention strategies. It was the aim to describe the current strategies of antifungal prophylaxis in pediatric lung transplant centers. A self-administered, web-based survey on current practices to prevent fungal infection was circulated to centers within the IPLTC. Twenty-one (88%) IPLTC centers participated, predominantly from Europe and the US. More than 50% of respondents perform adult and pediatric lung transplant operations. Twenty-four percent use universal prophylaxis, 28% give prophylaxis to all patients but stratify the antifungal coverage based on pretransplant risk, and 48% target prophylaxis to only the children with CF or pretransplantation fungal colonization. Commonly, centers aim to target Aspergillus and Candida infection. Monotherapy with either voriconazole or inhaled amphotericin B is used in the majority of centers. Institutions utilize prophylactic therapy for variable time periods (40% 3-6 months; 30% ≥12 months). Alternative drugs were prescribed for lack of tolerance, toxicity, or positive surveillance culture. TDM (itraconazole/voriconazole) was used in 86% of centers. The survey revealed a wide range of antifungal prophylaxis strategies as current international practice in pediatric lung transplant recipients.

s S105 first 3 months from 295 patients transplanted between January 2006 and February 2012. Results: In this cohort with a median follow-up of 4.3 years, there were 28 patients who developed AMR during the observation period. Of these 28 patients, 6 patients (1 male, 5 females) were positive for C4d and C3d in the first posttransplant biopsy. All 6 patients were highly sensitized with PRA > 50% and tested positive for donor-specific antibodies. They were treated for AMR including plasmapheresis. There was no correlation between C4d or C3d capillary endothelial cell positivity with the presence of ischemia in the first 3 months. Ischemic injury, when present, resulted in deposition of complement in the myocyte sarcoplasm and not in the capillaries. Conclusion: Complement deposition in capillary endothelial cells, whether early or late after transplant, is associated with antibody deposition. In contrast, complement deposition secondary to ischemic injury is usually present in the myocyte sarcoplasm. This suggests that activation of complement in ischemic injury occurs through the mannose-binding lectin pathway and not through the classic antibody-mediated pathway. The deposition of complement activation byproducts C4d and C3d, when present in capillary endothelial cells, can safely be interpreted as indicative of AMR as early as the first biopsy posttransplant.

HLT is reserved for children with cardiopulmonary disease not amendable to alternative therapies. Children with CHD with or without ES may be considered for HLT. Outcomes of HLT in this population are not well described. To test the hypothesis that CHD without ES is associated with worse graft survival and identify factors associated with poor outcome, a retrospective analysis of the UNOS database was performed. One hundred and seventy-eight pediatric HLTs were performed between 1987 and 2011. CHD was the diagnosis in 65 patients, of which 34 had CHD without ES. Patients with CHD without ES had decreased patient survival (median 1.31 yr) compared with CHD with ES (4.80 yr, p = 0.05). On multivariable analysis, the following were associated with graft failure: CHD without ES (adjusted HR 1.69, 95% CI 1.09-2.62), younger age (1.04, 1.01-1.08), pretransplant mechanical ventilation (1.75, 1.01-3.06), pretransplant ECMO (3.07, 1.32-7.12), pretransplant PRAs (1.53, 1.06-2.20), and transplant era (1.85, 1.16-2.94). In children with CHD who require HLT, underlying physiology influences outcomes. Those without ES have a worse prognosis. The diagnosis of CHD without ES and preoperative factors may inform decisions in a complex patient population.

Bilateral lung transplantation remains a treatment for end-stage cystic fibrosis (CF) lung disease when there is no further medical or surgical treatment available. The aim of lung transplantation is to improve patient life expectancy. The consensus view that lung transplantation extends life in children has been challenged. However, challengers have faced alternative explanations of their finding and it is largely accepted that lung transplantation in the adolescent patient population is an important treatment modality. The goal of this article is to address these concerns and assist with developing creative approaches to this known challenging subset of patients. The main focus of this article will be to discuss the looming question: what existing evidence or best practice insights could improve bilateral lung transplantation outcomes for adolescent patients with end-stage CF?

Background The use of induction immunosuppressive agents in pediatric lung transplantation is not universal. The rationale of induction therapy is to use the strongest immunosuppressive drugs at the time when the risk of acute cellular rejection (ACR) is highest. The timing of induction is not universal. We hypothesize that early treatment with antilymphocyte globulin (ATG) prior to reperfusion of the first donor lung will decrease the incidence of ACR. Methods The initial dose of ATG was given during the operative procedure when the recipient was on cardiopulmonary bypass after removal of the recipient lungs and prior to implantation. Patients received additional doses daily for four days. All children were monitored for ACR during the first 6 months posttransplant with transbronchial biopsies at defined intervals (weeks-months) and when clinically indicated. Presence of ACR was defined by International Society for Heart & Lung Transplantation guidelines. Results Recipients from two pediatric centers received ATG based on this protocol. A total of 18 patients were treated with this protocol, and the follow-up period was 6 to 45 months. A total of 63 flexible bronchoscopies with transbronchial biopsies were performed during the first 6 months. A single episode of ACR (≥ grade A2) was identified in this patient population for an incidence of 5.2% ACR grade A2 or above in this patient population. Conclusions Induction therapy with ATG prior to donor lung reperfusion is associated with a low incident of ACR during the first 6 months posttransplant in our patient cohort. Long-term follow-up is needed to ascertain the full effect of this treatment protocol.

To characterize epidemiology and risk factors for respiratory viral infections (RVI) in pediatric lung transplant recipients within the first post‐transplant year, a retrospective multicenter study of pediatric lung transplant recipients from 1988 to 2005 was conducted at 14 centers in the United States and Europe. Data were recorded for 1 year post transplant. Associations between RVI and continuous and categorical risk factors were assessed using Wilcoxon's rank‐sum and χ2 tests, respectively. Associations between time to RVI and risk factors or survival were assessed by multivariable Cox proportional hazards models. Of 576 subjects, 79 subjects (14%) had 101 RVI in the first year post transplant. Subjects with RVI were younger than those without RVI (median ages 9.7, 13; P

Risk factors, morbidity and mortality from pulmonary fungal infections (PFIs) within the first year after pediatric lung transplant have not previously been characterized.A retrospective, multicenter study from 1988 to 2005 was conducted with institutional approval from the 12 participating centers in North America and Europe. Data were recorded for the first post-transplant year. The log-rank test assessed for the association between PFI and survival. Associations between time to PFI and risk factors were assessed by Cox proportional hazards models.Of the 555 subjects transplanted, 58 (10.5%) had 62 proven (Candida, Aspergillus or other) or probable (Aspergillus or other) PFIs within the first year post-transplant. The mean age for PFI subjects was 14.0 years vs 11.4 years for non-PFI subjects (p0.01). Candida and Aspergillus species were recovered equally for proven disease. Comparing subjects with PFI (n = 58) vs those without (n = 404), pre-transplant colonization was associated with PFI (hazard ratio [HR] 2.0; 95% CI 0.95 to 4.3, p = 0.067). Cytomegalovirus (CMV) mismatch, tacrolimus-based regimen and age15 years were associated with PFI (p0.05). PFI was associated with any prior rejection higher than Grade A2 (HR 2.1; 95% CI 1.2 to 3.6). Cystic fibrosis, induction therapy, transplant era and type of transplant were not associated with PFI. PFI was independently associated with decreased 12-month survival (HR 3.9, 95% CI 2.2 to 6.8).Risk factors for PFI include Grade A2 rejection, repeated acute rejection, CMV-positive donor, tacrolimus-based regimen and pre-transplant colonization.

In their provocative paper, "Lung transplantation and survival in children with cystic fibrosis," Liou and colleagues state that "Prolongation of life by means of lung transplantation should not be expected in children with cystic fibrosis. A prospective, randomized trial is needed to clarify whether and when patients derive a survival and quality of life benefit from lung transplantation." Unfortunately, that conclusion is not supportable. Liou's dataset introduced bias against transplantation by using covariates obtained well before the time of transplant (when predicted survival was good) and having a cohort with lower than expected post-transplant survival than reported elsewhere. The calculated hazard ratios are based on factors that may have changed between listing and transplant, and do not reflect true benefit on a patient by patient basis. The findings of the study are contrary to other studies using similar methods. Finally, recent changes in US lung transplant allocation policy may have made the study findings moot. In contrast to Liou's suggestion to perform an ethically and logistically challenging randomized trial to verify the benefit of lung transplantation, a research agenda is recommended for pediatric lung transplantation for cystic fibrosis that focuses on developing strategies to continually reassess and maximize quality of life and survival benefit.

Lung transplant candidates and recipients are at high risk of infections from vaccine-preventable diseases. However, well-established guidelines neither exist for pre- and post-transplant vaccination nor do monitoring guidelines for pediatric lung transplant recipients. To ascertain the current vaccination and monitoring practices of pediatric lung transplant centers, a self-administered questionnaire was distributed to the 18 pediatric lung transplant centers within the International Pediatric Lung Transplant Collaborative in April 2006. Sixteen of 18 centers (89%) surveyed responded. Pretransplant, national vaccination guidelines are followed. Eleven centers reported following standardized vaccination guidelines post-transplant. Vaccines were more commonly provided by the primary-care physician pretransplant (69%) rather than post-transplant (38%). Post-transplant, 50% of the centers recommend live vaccines for household contacts but not for the transplant recipient. Pretransplant monitoring of response to prior vaccination was performed inconsistently except for varicella (88%). Only 44% of the transplant centers measure for response to vaccination post-transplant, mostly hepatitis B. Current vaccination practices of pediatric lung transplant centers are heterogeneous. The lung transplant community would be well served by studies designed to evaluate the efficacy of vaccinations in this population.

PURPOSE OF REVIEW This article reviews current trends in pediatric lung posttransplant management, reveals pitfalls that exist, and introduces additional parameters that may have an impact on long-term survival. RECENT FINDINGS A number of parameters are monitored after transplantation to prevent or identify early complications related to lung transplantation in hope of reducing morbidity and mortality. These include routine laboratory studies, imaging, and monitoring of drug levels and lung function. Drug monitoring allows individualization of a patient's immunosuppressive therapy; however, drug levels alone may not reflect the patient's immune status. ImmuKnow is a general immune-monitoring assay that may help guide therapy. Two major complications are rejection and infection, and bronchoscopy is used to differentiate these two entities. Silent rejection may occur and increase the chance of developing bronchiolitis obliterans; therefore, many centers perform surveillance bronchoscopies. Recently, de-novo anti-histocompatibility locus antigen antibodies and gastroesophageal reflux have been associated with poor outcomes, and many centers are monitoring these entities as part of care following lung transplant. SUMMARY There has been little improvement in long-term outcomes of lung transplantation. Current monitoring methods are utilized to maintain or improve outcomes and recently additional monitoring parameters have been identified which hopefully will improve long-term outcomes.

The members of the cytoplasmic 70-kDa heat shock protein family are involved in appropriate folding and trafficking of newly synthesized proteins in the cell. Hsc70, which is expressed constitutively, and Hsp70, the expression of which is stress- and heat shock-induced, are often considered to have similar cellular functions in this regard, but there are suggestions that the intracellular functions of these homologous but not identical proteins may differ. We tested the hypothesis that Hsc70 and Hsp70 would have differential effects on the expression of the epithelial sodium channel (ENaC). In Xenopus oocytes, overexpression of human Hsc70 decreased the functional (defined as amiloride-sensitive whole-oocyte current) and surface expression of murine ENaC (mENaC) in a concentration-dependent fashion. In contrast, coinjection of a moderate amount of Hsp70 cRNA (10 ng) increased the functional and surface expression of mENaC, whereas a higher amount of coinjected Hsp70 cRNA (30 ng) decreased mENaC functional and surface expression. The increase in mENaC functional expression with coinjection of 10 ng of Hsp70 cRNA was antagonized by the additional coinjection of Hsc70 cRNA in a concentration-dependent fashion. These data are consistent with Hsc70 and Hsp70 having differential and antagonistic effects with regard to the intracellular trafficking of mENaC in oocytes, which may have an impact on our understanding and potential treatment of diseases of aberrant ion channel trafficking.

Purpose Fungal infections pose a significant risk to children following lung transplantation. However, there are at present no internationally agreed upon guidelines for anti-fungal prophylaxis, and current clinical practice varies. The aim of this survey was to ascertain the current strategies of anti-fungal prophylaxis of pediatric lung transplant centers. Methods and Materials In 2012, nominated clinicians at each of the 24 centers within the International Pediatric Lung Transplant Collaborative (IPLTC) were invited to participate in a web-based, self-administered survey on strategies of anti-fungal prophylaxis adopted at their institution. Responders were asked to complete the survey via a combination of multiple choice and free text answers. Results 19 (79%) centers responded to the survey. Centers were predominantly located in the US and Europe, >50% of centers perform pediatric and adult lung transplants. The majority of centers (78%) routinely use pre-emptive/targeted prophylaxis, mainly in patients with pre-transplant fungal colonization. Commonly, institutions aim to target Aspergillus and Candida infection, whilst most choose to use monotherapy, mainly voriconazole or inhaled amphotericine B. Centers employ prophylaxis for variable amounts of time (42% ≤3 months, 42% for ≥12 months). The reasons to change to alternative drugs were intolerability, toxicity or positive surveillance culture. 88% of centers utilize therapeutic drug monitoring. Conclusions This survey has identified a wide range of anti-fungal prophylaxis strategies adopted internationally in the pediatric lung transplant population. There is growing approval for the formation of internationally agreed upon guidelines within the pediatric lung transplant community.

Purpose Lung transplant (LTRX) is a treatment for end-stage cystic fibrosis (CF) lung disease. CF is the leading indication for LTRX in children (6-11) and adolescents (12-17) accounting for 56% and 72% of all transplants, respectively. The half-life of adult recipients was 5.4 years compared with 5.5 years in pediatric recipients. We hypothesize that there is a difference in survival of patients with CF based on age of recipient. Methods and Materials This study was a retrospective analysis of the UNOS Database for all LTRX recipients with CF performed in the United States from October 1999 to June 2011. Patients were grouped on the basis of age into 4 groups [children (age 6-12), adolescents (age 13-18), young adults (age 19-30), and older adults (age 31-50)]. The primary outcome of interest was patient survival. Results There were 3,302 LTRX performed in CF patients ages of 6-50 years; 143 (4%) in children, 461 (14%) in adolescents, 1,568 (48%) in young adults, and 1130 (34%) in older adults with follow-up data available for 99%. Adolescents were more likely to be female, have lower creatinine level, have shorter wait list time and donor ischemic time compared to adults (p Conclusions Adolescents comprise a minority of CF patients that undergo LTRX in the United States and have the lowest overall survival. Older adults have graft survival and patient survival that is over twice as long as adolescents. The decreased survival observed in adolescents is independent of some donor and recipient characteristics. Further study is needed to improve outcomes in this high risk group of patients.

D. Wang, Y. Zhou, D.F. Wax, S. Kaushal, J.G. Gossett. Pediatrics, Children’s Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL; Pediatric Cardiology, C.S. Mott Children’s Hospital, University of Michigan Health System, Ann Arbor, MI; Biostatistics Research Core, Children’s Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL; Surgery, Children’s Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL.

A retrospective review of pediatric lung transplant recipients at fourteen sites in North America and Europe was conducted to evaluate the impact of adding cytomegalovirus immunoglobulin (CMVIG) prophylaxis to at least three weeks of intravenous ganciclovir in pediatric lung transplant recipients. Data were recorded for the first year after transplantation. Associations between time to CMV and risk factors, including CMVIG use, were assessed by multivariable Cox proportional hazards models. Of 599 subjects whose charts were reviewed, 329 received at least three weeks of ganciclovir with 62 (19%) receiving CMVIG. CMVIG was administered more frequently with CMV donor-positive/recipient-negative (D+/R−) serostatus (p