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BACKGROUND Since lung transplantation became a viable option for cystic fibrosis (CF) lung disease, adult transplant recipients with CF have superior survival than all the other major diagnostic indications. However, among adults, recipients with CF have a younger age at transplant than other transplant recipients. Over time, the frequency and proportion of lung transplants for CF has increased for adults compared with children. Using a large international transplant registry, we investigated time trends in numbers of transplants, age at transplant, and post-transplant survival and cause of death for recipients with CF. METHODS We conducted a retrospective cohort study of primary lung-alone deceased-donor transplants with a primary diagnostic indication of CF reported to the International Society for Heart and Lung Transplantation Thoracic Transplant Registry from January 2005 through December 2014. We assessed outcomes through December 31, 2015. The study defined the pediatric group as age

INTRODUCTION Survivors of childhood cancers undergo routine pulmonary function testing as they are at an increased lifetime risk for significant lung disease. However, this population also demonstrates growth abnormalities that could influence the interpretation of these tests, as reference equations are based on standing height. We aim to determine the impact of the relative thoracic growth deficiency in childhood cancer survivors on the interpretation of pulmonary function testing. METHODS Standing height and upper segment length (USL) in childhood cancer survivors undergoing pulmonary function testing at a single academic center were compared to age-matched historical standards. Additionally, pulmonary function tests were compared to reference values generated from standing height and doubled USL. RESULTS Data were obtained from 107 cancer survivors. While the subjects demonstrated an overall 6.8% lower standing height vs historical standards, they also demonstrated relative thoracic growth abnormality with a further 9.9% decrement in the ratio USL to standing height. The use of doubled upper segment length as a surrogate measure for standing height in pulmonary function reference equations decreased the number of patients with restrictive lung disease as indicated by spirometry. CONCLUSIONS Childhood cancer survivors have disproportionately worse thoracic growth deficiency vs appendicular growth deficiency. As a result, their USL is disproportionately short for their standing height, which is most commonly used in pulmonary function testing reference equations. This leads to an increased likelihood in these patients meeting pulmonary function test criteria for restrictive lung disease.

Recipient adolescent age for non-lung solid-organ transplantation is associated with higher rates of rejection, graft loss and mortality. Although there have been no studies specifically examining adolescent outcomes after lung transplantation (LTx), limited data from the International Society of Heart and Lung Transplantation (ISHLT) Registry suggest that a similar association may exist. Recently, adolescence has been defined as 10 to 24 years of age, taking into account the biologic and sociologic transitions that occur during this age interval.The ISHLT Registry was used to examine the survival outcomes of LTx recipients 10 to 24 years of age between 2005 and 2013. Given the developmental changes that occur in adolescence, survival outcomes for the tertiles of adolescence (10 to 14, 15 to 19 and 20 to 24 years old) were also examined.Adolescents made up 9% (n = 2,319) of the 24,730 LTxs undertaken during the study period. Kaplan-Meier survival estimates at 3 years showed lower adolescent survival (65%) when compared with younger children (73%, p = 0.006) and adults 25 to 34 (75%, p0.00001) and 35 to 49 (71%, p0.00001) years of age, without a significant survival difference compared with those 50 to 65 years old. Critically, 15- to 19-year-old recipients had the poorest outcomes, with reduced 1-year survival (82%) compared with those 10 to 14 years old (88%, p = 0.02), and reduced 3-year survival (59%) compared with those 10 to 14 (73%, p0.00001) and 20 to 24 (66%, p0.0001) years old.Adolescent LTx recipients have poorer overall survival when compared with younger children and adults, with those 15 to 19 years old having the highest risk of death. This survival disparity among age groups likely reflects the difficult period of adolescence and its biologic and social transitions, which may influence both immunologic function and adherence.

Pediatric lung transplantation has advanced over the years, providing a potential life-prolonging therapy to patients with cystic fibrosis. Despite this, many challenges in lung transplantation remain and result in worse outcomes than other solid organ transplants. As CF lung disease progresses, children and their caregivers are often simultaneously preparing for lung transplantation and end of life. In this article, we will discuss the current barriers to success in pediatric CF lung transplantation as well as approaches to end of life care in this population.

This section of the 19th Official Registry Report of 2016 summarizes data from pediatric lung transplant recipients and their donors for transplants that occurred through June 30, 2015. This report describes donor and recipient characteristics, transplant type and recipient outcomes data. The full Registry slide set available online (www.ishlt.org/ registries) provides more detail, additional analyses and other information not included in this printed report. This year’s report focuses on primary diagnostic indications for transplant. We present data on the distribution of diagnostic categories, demographics of patients with the different lung disorders leading to the need for transplant (Figure 1), associations of the diagnoses with outcomes, and other data of interest related to this topic. Data on heart-lung transplantation in children are not presented in this year’s report, as the number of pediatric heart–lung transplant procedures has remained very low. Only 11 pediatric heart–lung transplant procedures performed in 2014 were reported to the Registry. Data on pediatric heart–lung transplantation were presented in

Background Percutaneous lymphatic intervention (PCL) is a promising new therapy for plastic bronchitis (PB). We characterized bronchoalveolar lavage (BAL) and cast morphology in surgically repaired congenital heart disease (CHD) patients with PB during PCL. We quantified respiratory and bronchoscopic characteristics and correlated them with post-intervention respiratory outcomes. Methods We retrospectively reviewed patients with PB and surgically repaired CHD undergoing PCL and bronchoscopy at our institution. Pre-intervention characteristics, bronchoscopy notes, BAL cell counts, virology, and cultures were collected. A pathologist blinded to clinical data reviewed cast specimens. Respiratory outcomes were evaluated through standardized telephone questionnaire. Results Sixty-two patients were included with a median follow-up of 20 months. No patients experienced airway bleeding, obstruction, or prolonged intubation related to bronchoscopy. Of BAL infectious studies, the positive results were 4 (8%) fungal, 6 (11%) bacterial, and 6 (14%) viral. Median BAL count per 100 cells for neutrophils, lymphocytes, and eosinophils were 13, 10, and 0, respectively. Of 23 bronchial casts analyzed, all contained lymphocytes, and 19 (83%) were proteinaceous, with 14 containing neutrophils and/or eosinophils. Median BAL neutrophil count was greater in patients with proteinaceous neutrophilic or eosinophilic casts compared to casts without neutrophils or lymphocytes (P = 0.030). Post-intervention, there was a significant reduction in respiratory medications and support and casting frequency. Conclusions The predominance of neutrophilic proteinaceous casts and high percentage of positive BAL infectious studies support short-term fibrinolytic and anti-infective therapies in PB in select patients. Flexible bronchoscopy enables safe assessment of cast burden. PCL effectively treats PB and reduces respiratory therapies.

Data are submitted to the ISHLT Registry by national and multinational organ/data exchange organizations and individual centers. Since the Registry’s inception, 418 heart transplant centers, 242 lung transplant centers and 174 heart–lung transplant centers have reported data. The Registry website (www.ishlt.org/registries) provides spread sheets that show data elements collected in the Registry. The online slide set (http://www.ishlt.org/registries/slides.asp? slides=heartLungRegistry) provides POWERPOINT slides of figures and tables that support this study. The site contains additional slides for this report and slide sets from the previous annual reports.

Pulmonary complications are frequently seen in survivors of childhood cancer, and are due to both disease-related and treatment-related causes. While primary lung cancer is extremely rare in the pediatric population, the lung is a common site for metastatic disease. Furthermore, therapies used to treat the pediatric population can often cause pulmonary toxicity. Specifically, chemotherapy, radiation, hematopoietic stem cell transplant, and surgery can all cause long-term damage to the sensitive lung tissue. These pulmonary sequelae can be further subdivided into acute and late effects.

Background Cytomegalovirus (CMV) has been associated with morbidity, including chronic allograft rejection, in transplant recipients. Data from adult centers suggests that CMV hyperimmune globulin (CMVIG) and ganciclovir together are superior in preventing CMV viremia than ganciclovir alone. Methods A retrospective review of pediatric lung transplant recipients at 14 sites in North America and Europe was conducted to evaluate the effect of adding cytomegalovirus immunoglobulin (CMVIG) prophylaxis to at least 3 weeks of intravenous ganciclovir therapy 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. Results Of 599 patients whose records were reviewed, 329 received at least 3 weeks of ganciclovir, with 62 (19%) receiving CMVIG. CMVIG was administered more frequently with CMV donor-positive/recipient-negative serostatus ( p Conclusion The use of CMVIG in addition to antiviral prophylaxis in pediatric lung transplantation requires further evaluation.

Anecdotally, short lung transplant candidates suffer from long waiting times and higher rates of death on the waiting list compared with taller candidates.To examine the relationship between lung transplant candidate height and waiting list outcomes.We conducted a retrospective cohort study of 13,346 adults placed on the lung transplant waiting list in the United States between 2005 and 2011. Multivariable-adjusted competing risk survival models were used to examine associations between candidate height and outcomes of interest. The primary outcome was the time until lung transplantation censored at 1 year.The unadjusted rate of lung transplantation was 94.5 per 100 person-years among candidates of short stature (162 cm) and 202.0 per 100 person-years among candidates of average stature (170-176.5 cm). After controlling for potential confounders, short stature was associated with a 34% (95% confidence interval [CI], 29-39%) lower rate of transplantation compared with average stature. Short stature was also associated with a 62% (95% CI, 24-96%) higher rate of death or removal because of clinical deterioration and a 42% (95% CI, 10-85%) higher rate of respiratory failure while awaiting lung transplantation.Short stature is associated with a lower rate of lung transplantation and higher rates of death and respiratory failure while awaiting transplantation. Efforts to ameliorate this disparity could include earlier referral and listing of shorter candidates, surgical downsizing of substantially oversized allografts for shorter candidates, and/or changes to allocation policy that account for candidate height.

This section of the 32nd official International Society for Heart and Lung Transplantation (ISHLT) Registry Report of 2015 summarizes data from 51,440 adult lung and 3,820 adult heart-lung transplants that occurred through June 30, 2014. This publication reports data for donor and recipient characteristics, transplant events, and recipient treatments and outcomes. This Registry Report focuses on an overall theme of recipient early graft failure. The Registry’s online full slide set provides more detail, additional analyses, and other information not included in this publication.

Dyskeratosis congenita (DKC) is a syndrome characterized by immunodeficiency, bone marrow (BM) failure, somatic abnormalities, and predisposition to malignancy, resulting from mutations in proteins involved in maintenance of telomeres. Pulmonary fibrosis resulting in respiratory failure is a serious complication affecting approximately 20% of DKC patients. Pediatric pulmonologists should consider this diagnosis in patients with lung fibrosis and concurrent immunodeficiency or BM failure.

The LAS was designed to minimize pretransplant mortality while maximizing post-transplant outcome. Recipients12 are not allocated lungs based on LAS. Waitlist mortality has decreased for those12, but not12, suggesting this population may be disadvantaged. To identify predictors of waitlist mortality, a retrospective analysis of the UNOS database was performed since implementation of the LAS. There were 16,973 patients listed for lung transplant in the United States; 12,070 (71.1%) were transplanted, and 2498 (14.7%) patients died or were removed from the wait list. Significantly more pediatric patients died or were removed compared with adults (22.0% vs. 14.4%, p0.01). In multivariate analysis, in addition to higher LAS at time of listing (adj. HR1.058, 1.055-1.060), shorter height (1.008, 1.006-1.010), male gender (1.210, 1.110-1.319), and requiring ECMO (1.613, 1.202-2.163) were associated with pretransplant mortality. Post-transplant survival was not affected by height. The current age cutoff may impose limitations within the current lung allocation system in the United States. Height is an independent predictor of waitlist mortality and may be a valuable factor for the development of a comprehensive lung allocation system.

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.

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.

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.

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